IP Library › Granted Patent US 9,403,850
Granted Patent B2
US 9,403,850 · App. 14/759,853 · Granted Aug 2, 2016

Beta-lactamase inhibitors

Inventors: Christopher J. Burns (Malvern, PA); Denis Daigle (Street, MD); Bin Liu (Dayton, NJ); Daniel McGarry (Malvern, PA); Daniel C. Pevear (Downingtown, PA); Robert E. Lee Trout (Collegeville, PA); Randy W. Jackson (Livingston, MT)
Assignee: VENATORX PHARMACEUTICALS, INC.
C07F5/025A61K31/407A61K31/496A61K31/546A61K31/69A61K45/06
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Quick Facts
Patent No.
US 9,403,850
App. No.
14/759,853
Granted
Aug 2, 2016
Kind
B2
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 (54)

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

wherein:

M is a bond, —O—, —S—, —S(O)—, SO 2 —, or —N(R 4 )—;

m is 0, 1, or 2;

n is 0, 1, 2, or 3;

provided that

when n is 0, then M is a bond;

p is 2, 3, 4, or 5;

X 1 and X 2 are independently selected from —OH, —OR 8 , or F;

Z is >C═O, >C═S, or >SO 2 ;

ArA is an aromatic or heteroaromatic ring system optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 10 , and —SR 10 ;

each Y is selected from the group consisting of

—NR 4 R 5 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —O(CR 6 R 7 ) v NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v OR 10 , —NR 4 (CR 6 R 7 ) v S(O) 0,1,2 R 10 , —C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —S(O) 0,1,2 NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —OC(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —S(O) 0,1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —S(O) 0,1,2 —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 C(O)R 6 , —NR 4 SO 2 R 6 , —NR 4 C(O)R 6 , —NR 4 C(═O)OR 6 , —C(O)NR 4 R 5 , —(CR 6 R 7 ) v C(O)NR 4 R 5 , —SO 2 NR 4 R 5 , -Heteroaryl-NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , -Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , -Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —N(R 4 )-Heteroaryl-NR 4 R 5 , —N(R 4 )—Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl, —(CR 6 R 7 ) v Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl, —NR 4 (CR 6 R 7 ) v Heteroaryl, —NR 4 (CR 6 R 7 ) v Heterocyclyl, —O(CR 6 R 7 ) v Heteroaryl, —O(CR 6 R 7 ) v Heterocyclyl, —NR 4 (CR 6 R 7 ) v NR 5 -Heteroaryl, —NR 4 (CR 6 R 7 ) v NR 5 -Heterocyclyl, —O(CR 6 R 7 ) v NR 5 -Heteroaryl, —O(CR 6 R 7 ) v NR 5 -Heterocyclyl, —O(CR 6 R 7 ) v O-Heterocyclyl, —NR 4 R 5 R 9+ Q − , —(CR 6 R 7 ) v NR 4 R 5 R 9+ Q − , —NR 4 (CR 6 R 7 ) v NR 4 R 5 R 9+ Q − , —NR 4 R 9+ (CR 6 R 7 ) v NR 4 R 5 R 9+ Q − 2 , —(CR 6 R 7 ) v (T) + Q − , and —O(CR 6 R 7 ) v NR 4 R 5 R 9+ Q − ;

wherein:

T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;

Q is a pharmaceutically acceptable counterion; and

v is 1-4;

or two Ys taken together with the carbon atoms to which they are attached to ArA form an optionally substituted carbocycle or an optionally substituted heterocycle;

R a , R b , and R c are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 10 , —NR 4 R 5 , and —SR 10 ;

R 1 and R 2 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , and —NR 4 R 5 ,

or R 1 and R 2 taken together form an oxo, oxime, or an optionally substituted carbocycle or optionally substituted heterocycle with the carbon to which they are attached;

R 3 is hydrogen or optionally substituted C 1 -C 6 alkyl;

R d , R 4 and R 5 are independently selected from the group consisting of hydrogen, —OH, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an optionally substituted saccharide;

or R 4 and R 5 taken together form an optionally substituted heterocycle with the nitrogen to which they are attached;

R 6 and R 7 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , —NR 4 R 5 , —NR 4 C(O)R 5 , —C(O)NR 4 R 5 , —NR 4 SO 2 R 5 , optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

or R 6 and R 7 taken together form an oxo, oxime, or an optionally substituted carbocycle or an optionally substituted heterocycle with the carbon to which they are attached;

R 8 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, or a pharmaceutically acceptable boronate ester group;

R 9 is optionally substituted C 1 -C 6 alkyl;

R 10 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl.

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

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

4. The compound of claim 1 , wherein X 1 and X 2 are —OH.

5. The compound of claim 1 , wherein R d is hydrogen.

6. The compound of claim 1 , wherein Z is >C═O.

7. The compound of claim 1 , wherein:

M is a bond; and

m and n are 0.

8. The compound of claim 1 , wherein:

M is a bond; and

m or n are 1.

9. 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.

10. The compound of claim 1 , wherein at least one Y is selected from the group consisting of —NR 4 R 5 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —O(CR 6 R 7 ) v NR 4 R 5 , —C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 C(O)R 6 , —NR 4 C(O)R 6 , —(CR 6 R 7 ) v C(O)NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , -Heterocyclyl-N(R 4 )C(═NR 4 )NR 4 R 5 , —N(R 4 )—Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl, and —NR 4 (CR 6 R 7 ) v Heterocyclyl.

11. 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.

12. The compound of claim 11 , wherein the carbocycle or heterocycle is optionally substituted with one to three substituents selected from the group consisting of fluoro, chloro, bromo, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 10 , —SR 10 , —NR 4 R 5 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —O(CR 6 R 7 ) v NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , -Heteroaryl-NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl, and —(CR 6 R 7 ) v Heterocyclyl.

13. The compound of claim 1 , wherein p is 2 or 3.

14. The compound of claim 1 , wherein R 4 and R 5 are independently hydrogen or optionally substituted C 1 -C 6 alkyl.

15. The compound of claim 1 , wherein each R 6 and R 7 are independently hydrogen, fluoro, or optionally substituted C 1 -C 6 alkyl.

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

or a pharmaceutically acceptable salt, solvate, polymorph, N-oxide, or isomer thereof, wherein the compound is present in a closed, cyclic form according to Formula I and as shown in the structures above, an open, acyclic form according to Formula Ia, or mixtures thereof.

17. A compound selected from the group represented by the following structures:

or a pharmaceutically acceptable salt, solvate, polymorph, N-oxide, or isomer thereof, wherein the compound is present in a closed, cyclic form according to Formula I and as shown in the structures above, an open, acyclic form according to Formula Ia, or mixtures thereof.

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

19. The pharmaceutical composition of claim 18 , further comprising a beta-lactam antibiotic.

20. A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 18 , optionally in combination with a beta-lactam antibiotic.

Assignments (2)
CONFIRMATORY LICENSE Recorded Nov 14, 2022
From: VENATORX PHARMACEUTICALS INC
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 061933/0845 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 11, 2015
From: BURNS, CHRISTOPHER J.; DAIGLE, DENIS; LIU, BIN; MCGARRY, DANIEL; PEVEAR, DANIEL C.; TROUT, ROBERT E. LEE; JACKSON, RANDY W.
To: VENATORX PHARMACEUTICALS, INC.
Reel/Frame 036298/0521 →
Continuity (3)
Provisional Application 61751161 · Jan 10, 2013
Provisional Application 61783861 · Mar 14, 2013
Related Publication 20160016978A1 · Jan 21, 2016