Tricyclic urea compounds as JAK2 V617F inhibitors

Patent metadata

Field	Value
Publication number	US-12187725-B2
Application number	US-202318237535-A
Country	US
Kind code	B2
Filing date	Aug 24, 2023
Priority date	Jul 2, 2020
Publication date	Jan 7, 2025
Grant date	Jan 7, 2025

Abstract

The present application provides tricyclic urea compounds that modulate the activity of the V617F variant of JAK2, which are useful in the treatment of various diseases, including cancer.

First claim

What is claimed is:

1. A method of treating a myeloproliferative disorder selected from polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post polycythemia vera myelofibrosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound, which is 7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the myeloproliferative disorder is polycythemia vera.

3. The method of claim 1 , wherein the myeloproliferative disorder is essential thrombocythemia.

4. The method of claim 1 , wherein the myeloproliferative disorder is myelofibrosis with myeloid metaplasia.

5. The method of claim 1 , wherein the myeloproliferative disorder is primary myelofibrosis.

6. The method of claim 1 , wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis.

7. The method of claim 1 , wherein the myeloproliferative disorder is post polycythemia vera myelofibrosis.

8. A method of treating a myeloproliferative disorder selected from polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post polycythemia vera myelofibrosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound, which is 2-((1S,4S)-4-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl) acetonitrile, or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the myeloproliferative disorder is polycythemia vera.

10. The method of claim 8 , wherein the myeloproliferative disorder is essential thrombocythemia.

11. The method of claim 8 , wherein the myeloproliferative disorder is myelofibrosis with myeloid metaplasia.

12. The method of claim 8 , wherein the myeloproliferative disorder is primary myelofibrosis.

13. The method of claim 8 , wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis.

14. The method of claim 8 , wherein the myeloproliferative disorder is post polycythemia vera myelofibrosis.

15. A method of treating a myeloproliferative disorder selected from polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post polycythemia vera myelofibrosis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound, which is 1-(4-(3-methyl-7-(4-((4-(methylsulfonyl) piperidin-1-yl) methyl) phenyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)phenyl)cyclopropane-1-carbonitrile, or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein the myeloproliferative disorder is polycythemia vera.

17. The method of claim 15 , wherein the myeloproliferative disorder is essential thrombocythemia.

18. The method of claim 15 , wherein the myeloproliferative disorder is myelofibrosis with myeloid metaplasia.

19. The method of claim 15 , wherein the myeloproliferative disorder is primary myelofibrosis.

20. The method of claim 15 , wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis.

21. The method of claim 15 , wherein the myeloproliferative disorder is post polycythemia vera myelofibrosis.

22. The method of claim 1 , wherein the compound is 7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-indazol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2 (1H)-one.

23. The method of claim 22 , wherein the myeloproliferative disorder is polycythemia vera.

24. The method of claim 22 , wherein the myeloproliferative disorder is essential thrombocythemia.

25. The method of claim 22 , wherein the myeloproliferative disorder is myelofibrosis with myeloid metaplasia.

26. The method of claim 22 , wherein the myeloproliferative disorder is primary myelofibrosis.

27. The method of claim 22 , wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis.

28. The method of claim 22 , wherein the myeloproliferative disorder is post polycythemia vera myelofibrosis.

29. The method of claim 8 , wherein the compound is 2-((15,4S)-4-(7-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-3-methyl-8-(1-methyl-1H-indazol-5-yl)-2-oxo-3,6-dihydroimidazo [4,5-d]pyrrolo [2,3-b]pyridin-1 (2H)-yl)cyclohexyl) acetonitrile.

30. The method of claim 29 , wherein the myeloproliferative disorder is polycythemia vera.

31. The method of claim 29 , wherein the myeloproliferative disorder is essential thrombocythemia.

32. The method of claim 29 , wherein the myeloproliferative disorder is myelofibrosis with myeloid metaplasia.

33. The method of claim 29 , wherein the myeloproliferative disorder is primary myelofibrosis.

34. The method of claim 29 , wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis.

35. The method of claim 29 , wherein the myeloproliferative disorder is post polycythemia vera myelofibrosis.

36. The method of claim 15 , wherein the compound is 1-(4-(3-methyl-7-(4-((4-(methylsulfonyl)piperidin-1-yl)methyl)phenyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2,3,6-tetrahydroimidazo [4,5-d] pyrrolo [2,3-b]pyridin-8-yl)phenyl) cyclopropane-1-carbonitrile.

37. The method of claim 36 , wherein the myeloproliferative disorder is polycythemia vera.

38. The method of claim 36 , wherein the myeloproliferative disorder is essential thrombocythemia.

39. The method of claim 36 , wherein the myeloproliferative disorder is myelofibrosis with myeloid metaplasia.

40. The method of claim 36 , wherein the myeloproliferative disorder is primary myelofibrosis.

41. The method of claim 36 , wherein the myeloproliferative disorder is post-essential thrombocythemia myelofibrosis.

42. The method of claim 36 , wherein the myeloproliferative disorder is post polycythemia vera myelofibrosis.

Assignees

• Incyte Corp

Inventors

• Ai Yanran
• Bai Yu
• Barbosa Joseph
• Feng Hao
• Konkol Leah C
• Liu Xun
• Pan Jun
• Wang Haisheng
• Wu Liangxing
• Yao Wenqing
• Yue Eddy W

Classifications

• C07D471/14 Primary

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61P37/00 Primary

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title