Protein kinase inhibitors (variants), use thereof in treating oncological diseases and a pharmaceutical composition based thereon

• US 9,522,910 B2
• Filed: 04/01/2014
• Issued: 12/20/2016
• Est. Priority Date: 06/16/2011
• Status: Active Grant

• Current Assignee: Obshchestvo S Ogranichennoy Otvetstvennostyou "Fusion Pharma"
• Original Assignee: Obshchestvo S Ogranichennoy Otvetstvennostyou "Fusion Pharma"
• Inventors: Chilov, Germes G., Titov, Ilya Y.
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US14/242,241
• Publication Number:
  US 20140213592A1
• Time in Patent Office: 994 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates to the treatment of oncological, chronic inflammatory and similar diseases with the aid of new families of chemical compounds having improved efficiency with regard to the inhibition of Abl kinase and mutant forms thereof, as well as other therapeutically significant kinases. It describes protein kinase inhibitors in the form of compounds of general formula (I) and compounds of general formula (II), or a tautomer, an individual isomer, a mixture of isomers, a pharmaceutically acceptable salt, a solvate or a hydrate thereof.

Claims

1. A compound selected from compounds of the following structures, or a pharmaceutically acceptable salt thereof:

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

3. The compound of claim 2, wherein the compound inhibits Abl kinase with an IC₅₀ of less than 20 nM, inhibits Abl (T315I) kinase with an IC₅₀ of less than 20 nM and inhibits proliferation of K562 cells with an IC₅₀ of less than 100 nM.

4. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

5. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

6. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

7. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

8. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

9. The compound of pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

10. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

11. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound has the following structure:

12. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1, and a pharmaceutically acceptable carrier, solvent or filler.

13. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 2, and a pharmaceutically acceptable carrier, solvent or filler.

14. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

15. A method of treating a disease, wherein the disease is acute myelogenous leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, non-small cell lung cancer or a gastrointestinal stromal tumor, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

16. A method of treating cancer, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 2.

17. A method of treating a disease, wherein the disease is acute myelogenous leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, non-small cell lung cancer or a gastrointestinal stromal tumor, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 2.

18. A method of treating leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

19. The method of claim 18, wherein the leukemia is resistant to treatment with imatinib, or another kinase inhibitor.

20. A method of treating leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 2.

21. The method of claim 20, wherein the leukemia is resistant to treatment with imatinib, or another kinase inhibitor.

22. A method of treating chronic myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

23. The method of claim 22, wherein the leukemia is resistant to treatment with imatinib, dasatinib, or nilotinib, or another kinase inhibitor.

24. A method of treating chronic myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 2.

25. The method of claim 24, wherein the leukemia is resistant to treatment with imatinib, dasatinib, or nilotinib, or another kinase inhibitor.

26. A method of treating chronic myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 3.

27. The method of claim 26, wherein the leukemia is resistant to treatment with imatinib, dasatinib, or nilotinib, or another kinase inhibitor.

28. A method of treating acute myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

29. The method of claim 28, wherein the leukemia is resistant to treatment with imatinib, dasatinib, or nilotinib, or another kinase inhibitor.

30. A method of treating acute myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 2.

31. The method of claim 30, wherein the leukemia is resistant to treatment with imatinib, dasatinib, or nilotinib, or another kinase inhibitor.

32. A method of treating acute myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 3.

33. The method of claim 32, wherein the leukemia is resistant to treatment with imatinib, dasatinib, or nilotinib, or another kinase inhibitor.

34. A method of treating Philadelphia chromosome-positive acute lymphoblastic leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, non-small cell lung cancer or a gastrointestinal stromal tumor, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

35. A method of treating Philadelphia chromosome-positive acute lymphoblastic leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, non-small cell lung cancer or a gastrointestinal stromal tumor, comprising administering to a subject in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 2.

36. A method of treating Philadelphia chromosome-positive acute lymphoblastic leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, non-small cell lung cancer or a gastrointestinal stromal tumor, comprising administering to a subject in need of such treatment an effective amount of a compound according to claim 3.

37. A pharmaceutically acceptable salt of the compound according to claim 2, wherein the compound inhibits Abl kinase with an IC₅₀ of less than 20 nM, inhibits Abl (T315I) kinase with an IC₅₀ of less than 20 nM and inhibits proliferation of K562 cells with an IC₅₀ of less than 100 nM.

38. A method of treating chronic myelogenous leukemia, comprising administering to a subject in need of such treatment a pharmaceutically acceptable salt according to claim 37.

39. A method of treating acute myelogenous leukemia, comprising administering to a subject in need of such treatment an effective amount of a pharmaceutically acceptable salt according to claim 37.

40. A method of treating Philadelphia chromosome-positive acute lymphoblastic leukemia, chronic myelogenous leukemia, hepatocellular carcinoma, non-small cell lung cancer or a gastrointestinal stromal tumor, comprising administering to a subject in need of such treatment an effective amount of a pharmaceutically acceptable salt according to claim 37.

41. The method of claim 14, wherein the cancer is a cancer wherein the inhibition of kinases is therapeutically beneficial.

42. The method of claim 16, wherein the cancer is a cancer wherein the inhibition of kinases is therapeutically beneficial.

43. The method of claim 14, wherein the cancer is a cancer wherein the inhibition of Abl or Abl (T3151) is therapeutically beneficial.

44. The method of claim 16, wherein the cancer is a cancer wherein the inhibition of Abl or Abl (T3151) is therapeutically beneficial.

45. The method of claim 14, wherein the cancer is a cancer that expresses Abl or Abl (T3151).

46. The method of claim 16, wherein the cancer is a cancer that expresses Abl or Abl (T3151).

47. The method of claim 14, wherein the cancer is a cancer wherein the inhibition of ABL2/ARG, DDR2, FMS, FRK, LCK, LYN, PDGFRA, RET, BLK, EPHA2, EPHA8, EPHB1, EPHB2, FGR, FLT4, FYN, HCK, KDR, or PDGFRb is therapeutically beneficial.

48. The method of claim 16, wherein the cancer is a cancer wherein the inhibition of ABL2/ARG, DDR2, FMS, FRK, LCK, LYN, PDGFRA, RET, BLK, EPHA2, EPHA8, EPHB1, EPHB2, FGR, FLT4, FYN, HCK, KDR, or PDGFRb is therapeutically beneficial.

49. The method of claim 14, wherein the cancer is a cancer that expresses ABL2/ARG, DDR2, FMS, FRK, LCK, LYN, PDGFRA, RET, BLK, EPHA2, EPHA8, EPHB1, EPHB2, FGR, FLT4, FYN, HCK, KDR, or PDGFRb.

50. The method of claim 16, wherein the cancer is a cancer that expresses ABL2/ARG, DDR2, FMS, FRK, LCK, LYN, PDGFRA, RET, BLK, EPHA2, EPHA8, EPHB1, EPHB2, FGR, FLT4, FYN, HCK, KDR, or PDGFRb.