Substituted quinoxalines as B-raf kinase inhibitors

• US 9,249,110 B2
• Filed: 09/20/2012
• Issued: 02/02/2016
• Est. Priority Date: 09/21/2011
• 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:
  US14/346,692
• Publication Number:
  US 20150057276A1
• Time in Patent Office: 1,230 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 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: A61P 35/00 Antineoplastic agents
• 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: 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 2600/156 Polymorphic or mutational markers
• CPC Class Codes: G01N 2333/912 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/5748 involving oncogenic proteins

Abstract

Described herein are kinase inhibitors represented by Formula I:

and pharmaceutical compositions thereof for use in the treatment of cancer.

Claims

1. A compound of Formula I:

2. The compound or pharmaceutically acceptable salt of claim 1, 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, and R₂, R₃, R₄, and R₅ are independently hydrogen or halo.

3. The compound or pharmaceutically acceptable salt of claim 2, wherein R₂, R₃, R₄, and R₅ are hydrogen.

4. The compound or pharmaceutically acceptable salt of claim 2 or 3, wherein R₆ is halo.

5. The compound or pharmaceutically acceptable salt of claim 4, wherein R₆ is fluoro.

6. The compound or pharmaceutically acceptable salt of claim 4, wherein R₇ is hydrogen or optionally substituted lower alkyl.

7. The compound or pharmaceutically acceptable salt of claim 6, wherein R₇ is hydrogen.

8. The compound or pharmaceutically acceptable salt of claim 2, wherein R₈ is —

COR₉, —

CONR₉R₁₀, or —

SO₂R₉.

9. The compound or pharmaceutically acceptable salt of claim 1, wherein R₂, R₃, R₄, and R₅ are independently hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl.

10. The compound or pharmaceutically acceptable salt of claim 9, wherein R₂, R₃, R₄, and R₅ are independently hydrogen or halo.

11. The compound or pharmaceutically acceptable salt of claim 10, wherein R₂, R₃, R₄, and R₅ are independently hydrogen.

12. The compound or pharmaceutically acceptable salt of claim 9, wherein R₆ is hydrogen or halo.

13. The compound or pharmaceutically acceptable salt of claim 12, wherein R₆ is halo.

14. The compound or pharmaceutically acceptable salt of claim 13, wherein R₆ is fluoro or chloro.

15. The compound or pharmaceutically acceptable salt of claim 1, wherein R₇ is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

16. The compound or pharmaceutically acceptable salt of claim 15, wherein R₇ is hydrogen or optionally substituted lower alkyl.

17. The compound or pharmaceutically acceptable salt of claim 16, wherein R₇ is hydrogen.

18. The compound or pharmaceutically acceptable salt of claim 1, wherein R₈ is —

COR₉, —

CO₂R₉, —

CONR₉R₁₀, —

C(NR₁₁)NR₉R₁₀, —

C(NCN)NR₉R₁₀, —

SO₂R₉, or —

SO₂NR₉R₁₀, and wherein R₉ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

R₁₀ and R₁₁ are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

19. The compound or pharmaceutically acceptable salt of claim 18, wherein R₈ is —

COR₉, —

CONR₉R₁₀, or —

SO₂R₉.

20. The compound or pharmaceutically acceptable salt of claim 18 or 19, wherein, whenever present, R₉ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl;

and R₁₀ and R₁₁ are independently hydrogen or optionally substituted alkyl.

21. The compound or pharmaceutically acceptable salt of claim 18 or 19, wherein R₉ and R₁₀ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

22. 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.

23. The compound or pharmaceutically acceptable salt of claim 22, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

24. The compound or pharmaceutically acceptable salt of claim 23, 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.

25. The compound or pharmaceutically acceptable salt of claim 1, wherein R₆ is hydrogen or halo and R₈ is —

COR₉, —

CONR₉R₁₀, or —

SO₂R₉.

26. The compound or pharmaceutically acceptable salt of claim 25, 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.

27. The compound or pharmaceutically acceptable salt of claim 1, wherein R₇ and R₈ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

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

29. The pharmaceutical composition of claim 28, wherein the composition is formulated in a form chosen from the group consisting of tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols.

30. A packaged pharmaceutical composition comprising the pharmaceutical composition of claim 28 or 29 and instructions for using the composition.

31. 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.

32. The method of claim 31, 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.

33. The method of claim 32, wherein the binding agent is an antibody.

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

35. The method of claim 31, wherein the B-raf mutation is V600E.

36. The method of claim 31, 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.

37. The method of claim 31, wherein the biological sample is isolated from a tumor of the subject.

38. 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 a compound or pharmaceutically acceptable salt of claim 1.

39. The method of claim 38, further comprising administering an additional anti-cancer and/or cytotoxic agent.

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

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

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

N-(4-chloro-2-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)cyclopropanesulfonamide,

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

N-(4-chloro-2-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)cyclopropanesulfonamide,

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

N-(4-chloro-2-fluoro-3-(3-(pyrrolidin-1-yl)quinoxaline-6-carbonyl)phenyl)cyclopropanesulfonamide,

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

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

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

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

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

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

N-(4-chloro-2-fluoro-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)-4-chloro-2-fluorophenyl)propane-1-sulfonamide,

N-(3-(3-(1H-pyrazol-4-yl)quinoxaline-6-carbonyl)-4-chloro-2-fluorophenyl)cyclopropanesulfonamide,

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

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

N-(4-chloro-2-fluoro-3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)cyclopropanesulfonamide,

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

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

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

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

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

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

N-(2-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)cyclopropanesulfonamide,

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

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

N-(2-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)cyclopropanesulfonamide,

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

N-(2-fluoro-3-(3-(pyrrolidin-1-yl)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

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

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

N-(3-(3-(2-aminoethoxy)quinoxaline-6-carbonyl)-2-fluorophenyl)propane-1-sulfonamide,

N-(2-fluoro-3-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide,

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

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

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

N-(2-fluoro-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-fluorophenyl)cyclopropanesulfonamide,

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

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

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

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

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

N-(2-fluoro-3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)cyclopropanesulfonamide,

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

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

N-(4-chloro-2-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(4-chloro-2-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(4-chloro-2-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(4-chloro-2-fluoro-3-(3-(pyrrolidin-1-yl)quinoxaline-6-carbonyl)phenyl)-3-fluorobenzenesulfonamide,

N-(4-chloro-2-fluoro-3-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(4-chloro-2-fluoro-3-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

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

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

N-(3-(3-cyanoquinoxaline-6-carbonyl)-2-fluorophenyl)-3-fluorobenzenesulfonamide,

3-fluoro-N-(2-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(2-fluoro-3-(3-morpholinoquinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

3-fluoro-N-(2-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(2-fluoro-3-(3-(piperazin-1-yl)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

3-fluoro-N-(2-fluoro-3-(3-(pyrrolidin-1-yl)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(2-fluoro-3-(3-(2-hydroxyethoxy)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

N-(2-fluoro-3-(3-((2-hydroxyethyl)amino)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

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

3-fluoro-N-(2-fluoro-3-(3-(pyridin-3-yl)quinoxaline-6-carbonyl)phenyl)benzenesulfonamide,

and pharmaceutically acceptable salts thereof.