Janus kinase inhibitors and uses thereof

• US 10,017,477 B2
• Filed: 04/23/2015
• Issued: 07/10/2018
• Est. Priority Date: 04/23/2014
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Gray, Nathanael S., Tan, Li
• Primary Examiner(s): Pagano, Alexander R
• Assistant Examiner(s): SACKEY, EBENEZER O
• Application Number:
  US15/305,801
• Publication Number:
  US 20170044111A1
• Time in Patent Office: 1,174 Days
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• 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 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention provides kinase inhibitors, such as compounds of Formula (I) and Formula (II). The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). Also provided are pharmaceutical compositions, kits, methods, and uses that involve the compounds for reducing the activity of a kinase and/or treating and/or preventing a condition associated with aberrant activity of a kinase (e.g., a proliferative disease, inflammatory disorder, autoimmune disorder, painful condition, and/or viral infection). (I) (II)

Claims

1. A compound of Formula (I):

3. The compound of claim 1, wherein the group

4. The compound of claim 1, wherein the group

5. The compound of claim 1, wherein the ring system:

6. The compound of claim 1, wherein the ring system:

7. The compound of claim 1, wherein the ring system:

8. The compound of claim 1 of the Formula:

9. The compound of claim 1 of the Formula:

10. The compound of claim 1 selected from the group consisting of:

14. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

15. A method of reducing the activity of a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the activity of the Janus kinase (JAK).

16. A method of treating a condition associated with aberrant activity of a Janus kinase in a subject in need thereof, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the condition, wherein the condition is a hematological malignancy.

17. A kit comprising:

a compound of claim 1, or a pharmaceutically acceptable salt thereof; and

instructions for using the kit.

24. The method of claim 16, wherein the hematological malignancy is leukemia or lymphoma.

25. The method of claim 16, wherein the Janus kinase is Janus kinase 3 (JAK3).

2. A compound of Formula (II):

11. The compound of claim 2 of the Formula:

12. The compound of claim 2 of the Formula:

13. The compound of claim 2 selected from the group consisting of:

20. A pharmaceutical composition comprising a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A kit comprising:

a compound of claim 2, or a pharmaceutically acceptable salt thereof; and

instructions for using the kit.

22. A method of reducing the activity of a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject a compound of claim 2, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the activity of the Janus kinase (JAK).

23. A method of treating a condition associated with aberrant activity of a Janus kinase in a subject in need thereof, the method comprising administering to the subject a compound of claim 2, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the condition, wherein the condition is a hematological malignancy.

26. The method of claim 23, wherein the hematological malignancy is leukemia or lymphoma.

27. The method of claim 23, wherein the Janus kinase is Janus kinase 3 (JAK3).

18. A labeled compound of Formula (I) or (II):

19. The labeled compound of claim 18: