BORONIC ACID DERIVATIVES AND THERAPEUTIC USES THEREOF

• US 20180002351A1
• Filed: 06/28/2017
• Published: 01/04/2018
• Est. Priority Date: 06/30/2016
• Status: Active Grant

• Current Assignee: Qpex Biopharma, Inc.
• Original Assignee: Rempex Pharmaceuticals, Inc (Melinta Therapeutics, Inc.)
• Inventors: Hecker, Scott J., Reddy, Raja K., Glinka, Tomasz, Rodny, Olga
• Granted Patent: US 10,294,249 B2
• Time in Patent Office: Days
• 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 I or II, or pharmaceutically acceptable salts 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)NR¹³R¹⁴, —

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

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

CR¹⁰R¹¹OC(O)O(CH₂)_1-3C(O)OC_1-4 alkyl.

10. The compound of claim 1, having the structure of Formula Ia or IIa, or pharmaceutically acceptable salts thereof:

11. The compound of claim 10, having the structure of Formula Ib or IIb, or pharmaceutically acceptable salts thereof:

12. The compound of claim 11, having the structure of Formula Ic or IIc, or pharmaceutically acceptable salts thereof:

13. The compound of claim 11, wherein each J, L and M is CR¹².

14. The compound of claim 13, wherein R¹² is hydrogen, halogen, C_1-6 alkoxy, or C_1-6 haloalkoxy.

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

16. The compound of claim 15, wherein M is N.

17. The compound of claim 1, wherein R² and R³ together with the atoms to which they are attached form a ring or ring system selected from the group consisting of C_3-7 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl, and 5-10 membered heteroaryl, each optionally substituted with one or more R⁵.

18. The compound of claim 17, wherein R² and R³ together with the atoms to which they are attached form C_3-7 carbocyclyl optionally substituted with one or more R⁵.

20. The compound of claim 18, having the structure of Formula Id or IId, or pharmaceutically acceptable salts thereof:

21. The compound of claim 20, having the structure of Formula Id-1, Id-2, IId-1 or IId-2, or pharmaceutically acceptable salts thereof:

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

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

25. The compound of claim 1, wherein R³ and R⁴ together with the atoms to which they are attached form C_3-7carbocyclyl, optionally substituted with one or more R⁵.

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

C(O)OR.

30. The compound of claim 29, wherein R is H.

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

OH.

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

O—

.

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

OH.

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

OH.

35. The compound of claim 1, wherein Y⁵ is absent and 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^e, and —

NR^fS(O)₂NR^fOR^d.

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

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

78. The pharmaceutical composition of claim 77, further comprising an additional medicament.

84. A method of treating a bacterial infection, comprising administering a compound of claim 1 to a subject in need thereof.

85. The method of claim 84, further comprising administering to the subject an additional medicament.

9. (canceled)

19. (canceled)

24. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

37. A compound having the structure of the Formula III or IV, or pharmaceutically acceptable salts thereof:

38-51. -51. (canceled)

52. A compound having the structure of Formula V, or pharmaceutically acceptable salts thereof:

53-65. -65. (canceled)

66. A compound having the structure of Formula VI, or pharmaceutically acceptable salts thereof:

67-76. -76. (canceled)

79-83. -83. (canceled)

86-94. -94. (canceled)