Hydrophobically tagged janus kinase inhibitors and uses thereof

• US 9,862,688 B2
• Filed: 04/23/2015
• Issued: 01/09/2018
• 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:
  US15/305,845
• Publication Number:
  US 20170044112A1
• Time in Patent Office: 992 Days
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• 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 487/04 Ortho-condensed systems

Abstract

The present invention provides Janus kinase inhibitors, such as compounds of Formula (I) and Formula (II) wherein R^Y1 and R^Y2 comprise a tagged hydrophobic moiety R^H. The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). The hydrophobic moiety R^H may signal to the intracellular protein homeostasis machinery to induce degradation of the targeted kinase. 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).

Claims

1. A compound of Formula (I):

3. The compound of claim 1, wherein both R^J1 and R^J2 are hydrogen.

4. The compound of claim 1, wherein a is 1 or 2 and at least one instance of R^C is halogen.

5. The compound of claim 1, wherein each of R^D1, R^D2, and R^D3 is hydrogen.

6. The compound of claim 1, wherein the group

7. The compound of claim 1, wherein the group

8. The compound of claim 1, wherein L¹ is

9. The compound of claim 1, wherein -L¹-R^H represents a group of the formula:

10. The compound of claim 1, wherein R^H is:

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

12. The compound of claim 1 of the formula:

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

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

17. A method of reducing the activity of a Janus kinase (JAK) or a receptor tyrosine kinase (RTK) 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) or the receptor tyrosine kinase (RTK).

18. A method of treating a condition associated with aberrant activity of a Janus kinase (JAK) or a receptor tyrosine kinase (RTK) 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.

19. A kit comprising:

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

instructions for using the kit.

20. The compound of claim 1, wherein G₁ is NR^G1a.

21. The compound of claim 1, wherein G₁ is CHR^G1a.

22. The compound of claim 1, wherein G₂ is N(R^G2a)-L¹-R^H.

23. The compound of claim 1, wherein G₂ is O-L¹-R^H.

24. The compound of claim 1, wherein R^G1a and one instance of R^G2a are joined to form the group —

C(R^B)₂—

C(R^B)₂—

.

25. The compound of claim 1, wherein represents a single bond or double bond.

26. The compound of claim 1, wherein R^G2a is hydrogen or substituted or unsubstituted C_1-6 alkyl.

27. The compound of claim 1, wherein L³ is a bond or unsubstituted C_1-3alkylene.

28. The compound of claim 1, wherein at least one instance of R^A is substituted or unsubstituted C_1-6 alkyl.

29. The compound of claim 1, wherein R^G is hydrogen or —

CH₃.

30. The compound of claim 1, wherein R^X is hydrogen, —

F, —

Br, —

Cl, —

CN, or —

OR^X1.

31. The compound of claim 1, wherein G⁵ is NR^E;

and R^E is hydrogen or —

CH₃.

32. The compound of claim 1, wherein a is 0, 1, or 2.

33. The compound of claim 1, wherein R^D3 is —

CH₂N(R^D1a)₂ or —

CH₂OR^D1a.

34. The compound of claim 1, wherein R^D4 is hydrogen.

35. The compound of claim 10, wherein q is 0.

36. The method of claim 17, wherein the Janus kinase is JAK3.

37. The method of claim 18, wherein the Janus kinase is JAK3.

38. The method of claim 17, wherein the receptor tyrosine kinase is an epidermal growth factor receptor (EGFR) tyrosine kinase.

39. The method of claim 18, wherein the receptor tyrosine kinase is an epidermal growth factor receptor (EGFR) tyrosine kinase.

40. The method of claim 18, wherein the hematological malignancy is leukemia or lymphoma.

2. A compound of Formula (II):

14. The compound of claim 2 of the formula:

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