CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

• US 20150057276A1
• Filed: 09/20/2012
• Published: 02/26/2015
• Est. Priority Date: 09/21/2011
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Qian, Xiangping, Zhu, Yong-Liang
• Granted Patent: US 9,249,110 B2
• Time in Patent Office: Days
• US Class Current: 514/234.8
• 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

Chemical entities that are kinase inhibitors, 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 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 claim 1, 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 hydrogen.

8. The compound or pharmaceutically acceptable salt of claim 5, wherein R₆ is hydrogen or halo.

9. The compound or pharmaceutically acceptable salt of claim 8, wherein R₆ is halo.

10. The compound or pharmaceutically acceptable salt of claim 9, wherein R₆ is fluoro or chloro.

11. 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.

12. The compound or pharmaceutically acceptable salt of claim 11, wherein R₇ is hydrogen or optionally substituted lower alkyl.

13. The compound or pharmaceutically acceptable salt of claim 12, wherein R₇ is hydrogen.

14. 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.

15. The compound or pharmaceutically acceptable salt of claim 14, wherein R₈ is —

COR₉, —

CONR₉R₁₀, or —

SO₂R₉.

16. The compound or pharmaceutically acceptable salt of claim 14 or 15, 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.

17. The compound or pharmaceutically acceptable salt of claim 14 or 15, wherein R₉ and R₁₀ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

18. 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.

19. 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.

20. The compound or pharmaceutically acceptable salt of claim 19, wherein R₂, R₃, R₄, and R₅ are hydrogen.

21. The compound or pharmaceutically acceptable salt of claim 19 or 20, wherein R₆ is halo.

22. The compound or pharmaceutically acceptable salt of claim 21, wherein R₆ is fluoro.

23. The compound or pharmaceutically acceptable salt of claim 21, wherein R₇ is hydrogen or optionally substituted lower alkyl.

24. The compound or pharmaceutically acceptable salt of claim 23, wherein R₇ is hydrogen.

25. The compound or pharmaceutically acceptable salt of claim 19, Wherein R₈ is —

COR₉, —

CONR₉R₁₀, or —

SO₂R₉.

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

COR₉, —

CONR₉R₁₀, or —

SO₂R₉.

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

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

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

31. A packaged pharmaceutical composition comprising a pharmaceutical composition of claim 29 or 30 and instructions for using the composition to treat a subject suffering from cancer.

32. A method of treating cancer 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.

33. The method of claim 32, wherein the cancer is colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, thyroid cancer, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia);

chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and

polycythemia vera, lymphoma (Hodgkin'"'"'s disease and non-Hodgkin'"'"'s disease), multiple myeloma, Waldenstrom'"'"'s macroglobulinemia, or heavy chain disease.

34. The method of claim 33, wherein the cancer is melanoma.

35. The method of claim 32, wherein the cancer is non-small cell lung cancer.

36. The method of claim 32, wherein the cancer is colon cancer.

37. The method of claim 32, wherein the cancer is thyroid cancer.

38. The method of claim 32, wherein the cancer is ovarian cancer.

39. A method of treating a disorder mediated by Raf in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 1.

40. A method of treating a disorder in a subject in need thereof, comprising:

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

b. if a BRAF mutation is determined to be present in the subject, administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 1.

41. The method of claim 40, wherein the BRAF mutation is in codon 600.

42. The method of claim 40, wherein the BRAF mutation is V600E.

43. The method of claim 40, wherein determining the presence of absence of the BRAF mutation comprises amplifying BRAF nucleic acid from the biological sample and sequencing the amplified nucleic acid.

44. The method of claim 40, wherein determining the presence of absence of the BRAF mutation comprises detecting a mutant BRAF polypeptide in the biological sample using a binding agent to a mutant BRAF polypeptide.

45. The method of claim 44, wherein the binding agent is an antibody.

46. The method of claim 40, wherein the biological sample is isolated from a tumor of the subject.

47. The method of claim 39, wherein the disorder is cancer.

48. The method of claim 47, wherein the cancer is colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, thyroid cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chondroma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing'"'"'s tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms'"'"' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, non-small cell lung cancer, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia);

chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and

polycythemia vera, lymphoma (Hodgkin'"'"'s disease and non-Hodgkin'"'"'s disease), multiple myeloma, Waldenstrom'"'"'s macroglobulinemia, or heavy chain disease.

49. The method of claim 48, wherein the cancer is melanoma.

50. The method of claim 48, wherein the cancer is non-small cell lung cancer.

51. The method of claim 48, wherein the cancer is colon cancer.

52. The method of claim 48, wherein the cancer is thyroid cancer.

53. The method of claim 48, wherein the cancer is ovarian cancer.

54. The method of claim 32, further comprising administering an additional anti-cancer and/or cytotoxic agent.

28. 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-amino ethoxy)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-difluorophenypcyclopropanesulfonamide,

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.