BETA-LACTAMASE INHIBITORS

• US 20140194386A1
• Filed: 01/10/2014
• Published: 07/10/2014
• Est. Priority Date: 01/10/2013
• Status: Active Grant

• Current Assignee: Venatorx Pharmaceuticals, Inc.
• Original Assignee: Venatorx Pharmaceuticals, Inc.
• Inventors: BURNS, Christopher J., DAIGLE, Denis, LIU, Bin, McGARRY, Daniel, PEVEAR, Daniel C., TROUT, Robert E. Lee, JACKSON, Randy W.
• Granted Patent: US 9,040,504 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/546 containing further heterocyclic rings, e.g. cephalothin
• 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 31/04 Antibacterial agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• 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

Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.

Claims

1. A compound of Formula (I) or Formula (Ia), a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof:

4. The compound of claim 1, wherein R^a, R^b, and R^c are hydrogen.

6. The compound of claim 1, wherein R³ is hydrogen.

7. The compound of claim 1, wherein X¹ and X² are —

OH.

8. The compound of claim 1, wherein R^d is hydrogen or C₁-C₄-alkyl.

10. The compound of claim 1, wherein Z is >

C═

O.

11. The compound of claim 1, wherein:

M is —

O—

, —

S—

, —

SO₂—

, or —

N(R⁴)—

;

m is 0 or 1; and

n is 1 or 2.

13. The compound of claim 1, wherein:

M is a bond; and

m and n are 0.

14. The compound of claim 1, wherein:

M is a bond; and

m or n are 1.

16. The compound of claim 1, wherein ArA is selected from the group consisting of benzene, pyridine, pyrimidine, thiophene, thiazole, triazole, indole, benzimidazole, azaindole, thienopyrazole, quinoline, quinazoline, and quinoxaline.

19. The compound of claim 1, wherein at least one Y is selected from the group consisting of —

NR⁴R⁵, —

NR⁴C(═

NR⁵)NR⁴R⁵, —

C(═

NR⁴)NR⁴R⁵, —

N(R⁴)C(═

NR⁵)R⁶, —

(CR⁶R⁷)_vNR⁴R⁵, —

(CR⁶R⁷)_vN(R⁴)C(═

NR⁵)NR⁴R⁵, —

NR⁴(CR⁶R⁷)_vNR⁴R⁵, —

NR⁴(CR⁶R⁷)_vOR¹⁰, —

(CR⁶R⁷)_vNR⁴(CR⁶R⁷)_vNR⁴R⁵, NR⁵C(═

NR⁵)NR⁴(CR⁶R⁷)_vNR⁴R⁵, —

NR⁴(CR⁶R⁷)_vN(R⁴)C(═

NR⁵)NR⁴R⁵, —

NR⁵C(O)CR⁶(NR⁴R⁵)(CR⁶R⁷)_vNR⁴R⁵, —

(CR⁶R⁷)_vC(═

NR⁵)NR⁴R⁵, —

(CR⁶R⁷)_vN(R⁴)C(O)(CR⁶R⁷)_vNR⁴R⁵, —

C(═

NR⁴)NR⁴C(O)R⁶, —

NR⁴(CR⁶R⁷)_vHeteroaryl, and —

O(CR⁶R⁷)_vNR⁴R⁵.

22. The compound of claim 1, wherein two Y groups taken together with the carbon atoms to which they are attached form an optionally substituted carbocycle or an optionally substituted heterocycle.

24. The compound of claim 22, wherein two Y groups, together with the atoms to which they are attached form a pyrrolidine ring.

25. The compound of claim 1, wherein p is 1 or 2.

27. The compound of claim 1, wherein R⁴ and R⁵ are independently hydrogen or optionally substituted C₁-C₆ alkyl.

29. The compound of claim 1, wherein R⁶ and R⁷ are independently hydrogen, fluoro, or optionally substituted C₁-C₆ alkyl.

30. The compound of claim 1, wherein the compound is selected from the group represented by the following structures:

31. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof, and a pharmaceutically acceptable excipient.

32. The pharmaceutical composition of claim 31, further comprising a beta-lactam antibiotic.

34. A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 31, optionally in combination with a beta-lactam antibiotic.

2. (canceled)

3. (canceled)

5. (canceled)

9. (canceled)

12. (canceled)

15. (canceled)

17. (canceled)

18. (canceled)

20. (canceled)

21. (canceled)

23. (canceled)

26. (canceled)

28. (canceled)

33. (canceled)