Boronic acid derivatives and therapeutic uses thereof

• US 10,294,249 B2
• Filed: 06/28/2017
• Issued: 05/21/2019
• Est. Priority Date: 06/30/2016
• Status: Active Grant

• Current Assignee: Qpex Biopharma, Inc.
• Original Assignee: Qpex Biopharma, Inc.
• Inventors: Hecker, Scott J., Reddy, Raja K., Glinka, Tomasz, Rodny, Olga
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US15/636,424
• Publication Number:
  US 20180002351A1
• Time in Patent Office: 692 Days
• Field of Search: 558286, 558288, 514 64, 568286
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/05 Cyclic compounds having at least one ring containing boron but no carbon in the ring
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs).

Claims

1. A compound having the structure of the Formula Ic or IIc, or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein R is selected from the group consisting of H, C_1-9 alkyl, —

CR¹⁰R¹¹OC(O)C_1-9alkyl, —

CR¹⁰R¹¹OC(O)OC_1-9alkyl, —

CR¹⁰R¹¹OC(O)C_6-10aryl, —

CR¹⁰R¹¹OC(O)OC_6-10aryl and

3. The compound of claim 1, wherein R is —

CR¹⁰R¹¹OC(O)C_1-9alkyl, —

CR¹⁰R¹¹OC(O)C_3-7carbocyclyl, —

CR¹⁰R¹¹OC(O)(3 to 7 membered heterocyclyl), or —

CR¹⁰R¹¹OC(O)C_2-8alkoxyalkyl.

4. The compound of claim 3, wherein the 3 to 7 membered heterocyclyl of R is

5. The compound of claim 1, wherein R is —

CR¹⁰R¹¹OC(O)OC_1-9alkyl, —

CR¹⁰R¹¹OC(O)OC_3-7carbocyclyl, —

CR¹⁰R¹¹OC(O)O(3 to 7 membered heterocyclyl), or —

CR¹⁰R¹¹OC(O)OC_2-8alkoxyalkyl.

6. The compound of claim 5, wherein the 3 to 7 membered heterocyclyl of R is

7. The compound of claim 1, wherein R is —

CR¹⁰R¹¹C(O)NR¹³R¹⁴.

8. The compound of claim 1, wherein R is —

CR¹⁰R¹¹OC(O)O(CH₂)_1-3C(O)NR¹¹R¹⁴, —

CR¹⁰R¹¹OC(O)O(CH₂)_2-3OC(O)C_1-4 alkyl, —

CR¹⁰R¹¹OC(O)(CH₂)_1-3OC(O)C_1-4 alkyl, or —

CR¹⁰OR¹¹OC(O)O(CH₂)_1-3C(O)OC_1-4 alkyl.

9. The compound of claim 1, wherein each J, L and M is CR¹².

10. The compound of claim 9, wherein each R¹² is independently hydrogen, halogen, C_1-6 alkoxy, or C_1-6 haloalkoxy.

11. The compound of claim 1, wherein at least one of J, L and M is N.

12. The compound of claim 1, wherein M is N.

13. The compound of claim 1, wherein R² and R³ together with the atoms to which they are attached form C_3-7 cycloalkyl optionally substituted with one or more R⁵.

14. The compound of claim 13, having the structure of Formula Id or IId, or a pharmaceutically acceptable salt thereof:

15. The compound of claim 14, having the structure of Formula Id-1, Id-2, IId-1 or IId-2, or a pharmaceutically acceptable salt thereof:

16. The compound of claim 1, wherein R¹ is hydrogen or C_1-6 hydroxyalkyl.

17. The compound of claim 1, wherein R⁴ is hydrogen.

18. The compound of claim 1, wherein R⁶ is —

C(O)OR.

19. The compound of claim 18, wherein R is H.

20. The compound of claim 1, wherein R⁷ is —

OH.

21. The compound of claim 1, wherein Y² is —

O—

.

22. The compound of claim 1, wherein Y³ is —

OH.

23. The compound of claim 1, wherein Y⁴ is —

OH.

24. The compound of claim 1, wherein t is 0, and R⁵ is selected from the group consisting of amino, halogen, cyano, hydroxy, optionally substituted C_1-6 alkoxy, acyl, C-carboxy, C-amido, N-amido, N-sulfonamido, —

SR^c, —

C(O)(CH₂)_0-3SR^c, —

C(O)(CH₂)_1-3R^d, —

NR^fC(O)NR^fR^g, —

NR^fS(O)₂NR^fR^g, —

C(═

NR^e)R^c, —

C(═

NR^e)NR^fR^g, —

NR^fCR^c(═

NR^e), —

NR^fC(═

NR^e)NR^fR^g, —

S(O)(CH₂)_1-3R^c, and —

NR^fS(O)₂NR^fOR^d.

25. The compound of claim 1, selected from the group consisting of

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable excipient.

27. The pharmaceutical composition of claim 26, further comprising an additional medicament.

28. A method of treating a bacterial infection caused by β

-lactam antibacterial agent-resistant enterobacteriaceae, comprising administering a compound of claim 1, or a pharmaceutically acceptable salt thereof to a subject in need thereof.

29. The method of claim 28, further comprising administering to the subject an additional medicament selected from β

-lactam antibacterial agents.

30. The compound of claim 15, wherein each J, L and M is CR¹².

31. The compound of claim 30, wherein each R¹² is independently hydrogen, halogen, C_1-6 alkoxy, or C_1-6 haloalkoxy.

32. The compound of claim 31, wherein R⁶ is —

C(O)OR.

33. The compound of claim 25, wherein the pharmaceutically acceptable salt is a sodium salt.

38. The method of claim 28, wherein the pharmaceutically acceptable salt is a sodium salt.

34. A compound selected from the group consisting of

35. The compound of claim 34, wherein the pharmaceutically acceptable salt is a sodium salt.

36. A compound selected from the group consisting

37. The compound of claim 36, wherein the pharmaceutically acceptable salt is a sodium salt.