Substituted quinoxalines as B-RAF kinase inhibitors

• US 9,249,111 B2
• Filed: 09/28/2012
• Issued: 02/02/2016
• Est. Priority Date: 09/30/2011
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Qian, Xiangping, Zhu, Yong-Liang
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US14/346,696
• Publication Number:
  US 20140343068A1
• Time in Patent Office: 1,222 Days
• Field of Search: 514/249, 544/116, 544/353, 544/359, 546/268.1, 548/335.1, 548/373.1, 548/518
• 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. Specifically quinoxaline derivatives of Formula I:

and their use in modulating the activity of B-raf and/or mutant B-raf kinase to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism are disclosed. Also disclosed are methods of treating cancer associated with B-raf and/or mutant B-raf kinase activity in a subject, comprising administering the compounds of Formula I.

Claims

1. A compound of Formula I:

2. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁ is hydrogen, cyano, optionally substituted-alkoxy, optionally substituted-aryloxy, optionally substituted amino, optionally substituted-alkyl, optionally substituted heterocycloalkyl, optionally substituted-aryl, or optionally substituted-heteroaryl.

3. The compound or pharmaceutically acceptable salt of claim 2, 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 pyrrolidinyl, optionally substituted-piperidinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted pyridyl.

5. The compound or pharmaceutically acceptable salt of any one of claims 1 to 4, wherein R₂, R₃, R₄, and R₅ are independently hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl.

6. The compound or pharmaceutically acceptable salt of claim 5, wherein R₂, R₃, R₄, and R₅ are independently hydrogen or halo.

7. The compound or pharmaceutically acceptable salt of claim 6, wherein R₂, R₃, R₄, and R₅ are independently hydrogen.

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

9. The compound or pharmaceutically acceptable salt of claim 8, wherein R₉ is hydrogen or optionally substituted lower alkyl.

10. The compound or pharmaceutically acceptable salt of claim 9, wherein R₉ is hydrogen.

11. The compound or pharmaceutically acceptable salt of claim 9, wherein R₉ is optionally substituted benzyl.

12. The compound or pharmaceutically acceptable salt of claim 11, wherein R₉ is benzyl.

13. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁₀ is hydrogen, halo or methyl.

14. The compound or pharmaceutically acceptable salt of claim 13, wherein R₁₀ is fluoro.

15. The compound or pharmaceutically acceptable salt of claim 13, wherein R₁₀ is chloro.

16. The compound or pharmaceutically acceptable salt of claim 1, wherein R₆ is fluoro.

17. The compound or pharmaceutically acceptable salt of claim 1, wherein R₆ is chloro.

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

19. The compound or pharmaceutically acceptable salt of claim 1, wherein R₇ is fluoro.

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

21. The compound or pharmaceutically acceptable salt of claim 1, wherein each of R₆ and R₇ is fluoro.

22. The compound or pharmaceutically acceptable salt of claim 1, wherein R₈ is hydrogen.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of claim 1 or 23.

25. The pharmaceutical composition of claim 24, wherein the composition is formulated in a form chosen from the group consisting of tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols.

26. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 24 and instructions for using the pharmaceutical composition.

27. A method of inhibiting B-raf kinase activity in a subject which comprises administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 1 or 23.

28. 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 1 or 23.

29. The method of claim 28, wherein determining the presence of absence of the B-raf mutation comprises detecting a mutant B-raf polypeptide in the biological sample using a binding agent to a mutant B-raf polypeptide.

30. The method of claim 29, wherein the binding agent is an antibody.

31. The method of claim 28, wherein the B-raf mutation is in codon 600.

32. The method of claim 28, wherein the B-raf mutation is V600E.

33. The method of claim 28, wherein determining the presence of absence of the B-raf mutation comprises amplifying B-raf nucleic acid from the biological sample and sequencing the amplified nucleic acid.

34. The method of claim 28, wherein the biological sample is isolated from a tumor of the subject.

35. The method of claim 27 or 28, further comprising administering an additional anti-cancer and/or cytotoxic agent.

23. A compound or pharmaceutically acceptable salt chosen from the group consisting of:

(2-chloro-5-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2-fluoro-5-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2,6-dichloro-3-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-((3-fluorobenzyl)oxy)-6-methylphenyl)(quinoxalin-6-yl)methanone,

(2-fluoro-3-((3-fluorobenzyl)oxy)-6-methylphenyl)(quinoxalin-6-yl)methanone,

(6-fluoro-3-((3-fluorobenzyl)oxy)-2-methylphenyl)(quinoxalin-6-yl)methanone,

(6-chloro-3-((3-fluorobenzyl)oxy)-2-methylphenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-((3-fluorobenzyl)oxy)phenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-chloro-3-((3-fluorobenzyl)oxy)phenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-fluoro-5-((3-fluorobenzyl)oxy)phenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-chloro-5-((3-fluorobenzyl)oxy)phenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(5-((3-fluorobenzyl)oxy)-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-((3-fluorobenzyl)oxy)-2,6-dimethylphenyl)(quinoxalin-6-yl)methanone,

(3-((3-fluorobenzyl)oxy)-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-((3-fluorobenzyl)oxy)-2-methylphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-((3-chlorobenzyl)oxy)-6-fluorophenyl)(quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-3-((trifluoromethyl)benzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-((4-chloro-3-(trifluoromethyl)benzyl)oxy)-6-fluorophenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-6-fluorophenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-((3-chlorobenzyl)oxy)-6-fluorophenyl)(3-methylquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-methylquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

7-(2-chloro-3-((3-chlorobenzyl)oxy)-6-fluorobenzoyl)quinoxaline-2-carbonitrile,

7-(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)benzoyl)quinoxaline-2-carbonitrile,

(2-chloro-3-((3-chlorobenzyl)oxy)-6-fluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-chloro-3-((3-chlorobenzyl)oxy)-6-fluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-chloro-3-((4-chloro-3-(trifluoromethyl)benzyl)oxy)-6-fluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-chloro-3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-6-fluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2-chloro-3-((3-chlorobenzyl)oxy)-6-fluorophenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(5-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(quinoxalin-6-yl)methanone,

(3-((3-chlorobenzyl)oxy)-2,6-difluorophenyl)(quinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(3-((4-chloro-3-(trifluoromethyl)benzyl)oxy)-2,6-difluorophenyl)(quinoxalin-6-yl)methanone,

(3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-2,6-difluorophenyl)(quinoxalin-6-yl)methanone,

(3-((3-chlorobenzyl)oxy)-2,6-difluorophenyl)(3-methylquinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-methylquinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

7-(3-((3-chlorobenzyl)oxy)-2,6-difluorobenzoyl)quinoxaline-2-carbonitrile,

7-(2,6-difluoro-3-((3-fluorobenzyl)oxy)benzoyl)quinoxaline-2-carbonitrile,

(3-((3-chlorobenzyl)oxy)-2,6-difluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-((3-chlorobenzyl)oxy)-2,6-difluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-(trifluoromethyl)benzyl)oxy)phenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-((4-chloro-3-(trifluoromethyl)benzyl)oxy)-2,6-difluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-((3-chloro-4-(trifluoromethyl)benzyl)oxy)-2,6-difluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-((3-chlorobenzyl)oxy)-2,6-difluorophenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(3-(5-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-(pyridin-3-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-((3-fluorobenzyl)oxy)phenyl)methanone,

quinoxalin-6-yl(2,3,6-trifluoro-5-((3-fluorobenzyl)oxy)phenyl)methanone,

(2,3-difluoro-5-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(2,5-difluoro-3-((3-fluorobenzyl)oxy)phenyl)(quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2-chlorophenyl)(quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2-fluorophenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-fluorophenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-dichlorophenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-methylphenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-fluoro-6-methylphenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-6-fluoro-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-6-chloro-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chlorophenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chlorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-fluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chlorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-fluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2-fluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(5-(benzyloxy)-2-chlorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(3-(benzyloxy)-6-chloro-2-fluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(5-(benzyloxy)-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-dimethylphenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-methylphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5-difluorophenyl)(quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-methylquinoxalin-6-yl)methanone,

7-(3-(benzyloxy)-2,5,6-trifluorobenzoyl)quinoxaline-2-carbonitrile,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(pyrrolidin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(3-(benzyloxy)-2,5,6-trifluorophenyl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

7-(3-(benzyloxy)-2,5,6-trifluorobenzoyl)quinoxaline-2-carbonitrile,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-pyrazol-4-yl)quinoxalin-6-yl)(3-(benzyloxy)-2,5,6-trifluorophenyl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(3-(benzyloxy)-2,5,6-trifluorophenyl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,5,6-trifluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-methylquinoxalin-6-yl)methanone,

7-(3-(benzyloxy)-2-chloro-6-fluorobenzoyl)quinoxaline-2-carbonitrile,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-(pyrrolidin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(3-(benzyloxy)-2-chloro-6-fluorophenyl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

7-(3-(benzyloxy)-2-chloro-6-fluorobenzoyl)quinoxaline-2-carbonitrile,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-pyrazol-4-yl)quinoxalin-6-yl)(3-(benzyloxy)-2-chloro-6-fluorophenyl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(3-(benzyloxy)-2-chloro-6-fluorophenyl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2-chloro-6-fluorophenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-methylquinoxalin-6-yl)methanone,

7-(5-(benzyloxy)-2,3-difluorobenzoyl)quinoxaline-2-carbonitrile,

(5-(benzyloxy)-2,3-difluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-(pyrrolidin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(5-(benzyloxy)-2,3-difluorophenyl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

7-(5-(benzyloxy)-2,3-difluorobenzoyl)quinoxaline-2-carbonitrile,

(5-(benzyloxy)-2,3-difluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-pyrazol-4-yl)quinoxalin-6-yl)(5-(benzyloxy)-2,3-difluorophenyl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(5-(benzyloxy)-2,3-difluorophenyl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(5-(benzyloxy)-2,3-difluorophenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-methylquinoxalin-6-yl)methanone,

7-(3-(benzyloxy)-2,6-difluorobenzoyl)quinoxaline-2-carbonitrile,

(3-(benzyloxy)-2,6-difluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-(pyrrolidin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(3-(benzyloxy)-2,6-difluorophenyl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

7-(3-(benzyloxy)-2,6-difluorobenzoyl)quinoxaline-2-carbonitrile,

(3-(benzyloxy)-2,6-difluorophenyl)(3-methoxyquinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-pyrazol-4-yl)quinoxalin-6-yl)(3-(benzyloxy)-2,6-difluorophenyl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(3-(benzyloxy)-2,6-difluorophenyl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(3-(benzyloxy)-2,6-difluorophenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(quinoxalin-6-yl)methanone,

(2,6-difluoro-3-methoxyphenyl)(quinoxalin-6-yl)methanone,

(3-chloroquinoxalin-6-yl)(2,6-difluoro-3-hydroxyphenyl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-phenylquinoxalin-6-yl)methanone,

7-(2,6-difluoro-3-hydroxybenzoyl)quinoxaline-2-carbonitrile,

(2,6-difluoro-3-hydroxyphenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2-chloro-5-hydroxyphenyl)(quinoxalin-6-yl)methanone,

(2-fluoro-5-hydroxyphenyl)(quinoxalin-6-yl)methanone,

(2-fluoro-3-hydroxyphenyl)(quinoxalin-6-yl)methanone,

(2,6-dichloro-3-hydroxyphenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-hydroxy-6-methylphenyl)(quinoxalin-6-yl)methanone,

(2-fluoro-3-hydroxy-6-methylphenyl)(quinoxalin-6-yl)methanone,

(6-fluoro-3-hydroxy-2-methylphenyl)(quinoxalin-6-yl)methanone,

(6-chloro-3-hydroxy-2-methylphenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-hydroxyphenyl)(quinoxalin-6-yl)methanone,

(2-chloro-3-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-fluoro-3-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-chloro-3-hydroxyphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-fluoro-3-hydroxyphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2-fluoro-5-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-chloro-5-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(6-chloro-2-fluoro-3-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(5-hydroxy-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-hydroxy-2,6-dimethylphenyl)(quinoxalin-6-yl)methanone,

(3-hydroxy-2-methylphenyl)(quinoxalin-6-yl)methanone,

(3-hydroxy-2-methylphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(2,5-difluoro-3-hydroxyphenyl)(quinoxalin-6-yl)methanone,

(3-methylquinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

7-(2,3,6-trifluoro-5-hydroxybenzoyl)quinoxaline-2-carbonitrile,

(3-methoxyquinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-morpholinoquinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(piperazin-1-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(pyrrolidin-1-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(2-hydroxyethoxy)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(2-methoxyethoxy)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

7-(2,3,6-trifluoro-5-hydroxybenzoyl)quinoxaline-2-carbonitrile,

(3-methoxyquinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(pyridin-3-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(1 H-pyrazol-4-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(3-(pyridin-3-yl)quinoxalin-6-yl)(2,3,6-trifluoro-5-hydroxyphenyl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-methylquinoxalin-6-yl)methanone,

7-(2-chloro-6-fluoro-3-hydroxybenzoyl)quinoxaline-2-carbonitrile,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-(pyrrolidin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(2-chloro-6-fluoro-3-hydroxyphenyl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone, 7-(2-chloro-6-fluoro-3-hydroxybenzoyl)quinoxaline-2-carbonitrile,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-pyrazol-4-yl)quinoxalin-6-yl)(2-chloro-6-fluoro-3-hydroxyphenyl)methanone,

(3-(1 H-imidazol-1-yl)quinoxalin-6-yl)(2-chloro-6-fluoro-3-hydroxyphenyl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin -6-yl)methanone,

(2-chloro-6-fluoro-3-hydroxyphenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin -6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-methylquinoxalin-6-yl)methanone,

7-(2,3-difluoro-5-hydroxybenzoyl)quinoxaline-2-carbonitrile,

(2,3-difluoro-5-hydroxyphenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-(pyrrolidin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(2,3-difluoro-5-hydroxyphenyl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

7-(2,3-difluoro-5-hydroxybenzoyl)quinoxaline-2-carbonitrile,

(2,3-difluoro-5-hydroxyphenyl)(3-methoxyquinoxalin-6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-(pyridin-3-yl)quinoxalin-6-yl)methanone,

(3-(1H-pyrazol-4-yl)quinoxalin-6-yl)(2,3-difluoro-5-hydroxyphenyl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(2,3-difluoro-5-hydroxyphenyl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2,3-difluoro-5-hydroxyphenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-methylquinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-morpholinoquinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-(piperazin-1-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-(pyrrolidin-1-yl)quinoxalin-6-yl)methanone,

(3-(2-aminoethoxy)quinoxalin-6-yl)(2,6-difluoro-3-hydroxyphenyl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-((2-hydroxyethyl)amino)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-(2-hydroxyethoxy)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-(2-methoxyethoxy)quinoxalin-6-yl)methanone,

(3-(1H-pyrazol-4-yl)quinoxalin-6-yl)(2,6-difluoro-3-hydroxyphenyl)methanone,

(3-(1H-imidazol-1-yl)quinoxalin-6-yl)(2,6-difluoro-3-hydroxyphenyl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-(2-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone,

(2,6-difluoro-3-hydroxyphenyl)(3-(4-methyl-1H-imidazol-1-yl)quinoxalin-6-yl)methanone, ps and pharmaceutically acceptable salts thereof.