IP Library › Granted Patent US 9,771,382
Granted Patent B2
US 9,771,382 · App. 15/194,433 · Granted Sep 26, 2017

Beta-lactamase inhibitors

Inventors: Christopher J. Burns (Malvern, PA); Denis Daigle (Street, MD); Bin Liu (Plainsboro, 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 9,771,382
App. No.
15/194,433
Granted
Sep 26, 2017
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 (92)

1. A compound of Formula (I) or Formula (Ia), a pharmaceutically acceptable salt, polymorph, solvate, prodrug, 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 1, 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 thiophene, furan, pyridine, thiazole, naphthalene, pyrazole, or isoxazole, each independently 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 —CN, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heteroaryl, —OH, —OR 10 , —SR 10 , —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 , —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)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 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, optionally substituted C 1 -C 6 alkyl, or a pharmaceutically acceptable prodrug;

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;

R 3 is hydrogen;

X 1 and X 2 are —OH;

R d is hydrogen;

Z is >C═O; and

each R 1 and R 2 are independently selected from the group consisting of 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.

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

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

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

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

7. The compound of claim 1 wherein:

each R 4 and R 5 is hydrogen;

each R 6 and R 7 is hydrogen; and

v is 1.

8. 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.

9. The pharmaceutical composition of claim 8 , further comprising a beta-lactam antibiotic selected from a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or a combination thereof.

10. A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 8 , optionally in combination with a beta-lactam antibiotic.

11. A compound of Formula (I) or Formula (Ia), a pharmaceutically acceptable salt, polymorph, solvate, prodrug, 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 1, 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 thiophene, furan, naphthalene, pyrazole, or isoxazole, each independently 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 —CN, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycle, 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 , —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 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, optionally substituted C 1 -C 6 alkyl, or a pharmaceutically acceptable prodrug;

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.

12. The compound of claim 11 , wherein:

R a , R b , and R c are hydrogen;

R 3 is hydrogen;

X 1 and X 2 are —OH;

R d is hydrogen;

Z is >C═O; and

each R 1 and R 2 are independently selected from the group consisting of 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.

13. The compound of claim 11 , 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 , —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 , —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 , —(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 , —(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 , —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 , —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 , -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, and —O(CR 6 R 7 ) v O-Heterocyclyl.

14. The compound of claim 11 , 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 5 )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.

15. The compound of claim 11 , wherein p is 2 or 3.

16. The compound of claim 11 wherein:

each R 4 and R 5 is hydrogen;

each R 6 and R 7 is hydrogen; and

v is 1.

17. A pharmaceutical composition comprising a compound of claim 11 or a pharmaceutically acceptable salt, polymorph, solvate, prodrug, N-oxide, or isomer thereof, and a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17 , further comprising a beta-lactam antibiotic selected from a penicillin, cephalosporin, carbapenem, monobactam, bridged monobactam, or a combination thereof.

19. A method of treating a bacterial infection in a subject, comprising administering to the subject a pharmaceutical composition of claim 17 , optionally in combination with a beta-lactam antibiotic.

Assignments (3)
CONFIRMATORY LICENSE Recorded Dec 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 062120/0949 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 18, 2016
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 039389/0314 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 5, 2016
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 039258/0157 →
Continuity (4)
Continuation 14759853
Provisional Application 61783261 · Mar 14, 2013
Provisional Application 61751161 · Jan 10, 2013
Related Publication 20160304539A1 · Oct 20, 2016