Beta-lactamase inhibitors

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

wherein:

L is a bond, —CR 1 R 2 -, >C═O, or ═CR 1 -;

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 0, 1, 2, 3, or 4;

provided that

when n is 0, then L is —CR 1 R 2 — or ═CR 1 —;

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

Z is >C═O, >C═S, or >SO 2 ;

CycA is an optionally substituted 3-10 membered non-aromatic carbocycle, wherein an optional olefin functionality of the non-aromatic carbocycle is not directly attached to an oxygen, sulfur, or nitrogen substituent;

each Y is selected from the group consisting of fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, ═O, —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) 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 NR 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) v C(═NR 5 )NR 4 R 5 , —O(CR 6 R) 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) 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 , 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 Y taken together with the carbon atom to which it is attached forms an optionally substituted spiro-carbocycle or optionally substituted spiro-heterocycle;

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.

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 claim 1 , wherein R d is hydrogen or C 1 -C 4 -alkyl.

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

7. The compound of claim 1 , wherein:

L is a bond, —CR 1 R 2 —, or ═CR 1 —;

M is a bond or —O—;

m is 0; and

n is 1 or 2.

8. The compound of claim 1 , wherein:

L is a bond or >C═O;

M is a bond or —N(R 4 )—; and

m and n are 0.

9. The compound of claim 1 , wherein:

L is a bond;

M is a bond; and

m or n are 1.

10. The compound of claim 1 , wherein:

L is —CR 1 R 2 — or ═CR 1 —;

M is a bond; and

m and n are 0.

11. The compound of claim 1 , wherein CycA is cyclobutane, cyclopentane, cyclohexane, or cyclohexene, wherein the olefin functionality of the cyclohexene is not directly attached to an oxygen, sulfur, or nitrogen substituent.

12. The compound of claim 11 , wherein CycA is cyclohexane.

13. The compound of claim 1 , wherein at least one

Y is selected from the group consisting of —NR 4 R 5 , —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 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 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 C(═NR 5 )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 ), Heteroaryl, and —O(CR 6 R 7 ) v NR 4 R 5 .

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

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

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

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

or a pharmaceutically acceptable salt, solvate, polymorph, stereoisomer, tautomer, metabolite, 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, solvate, polymorph, stereoisomer, tautomer, metabolite, 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.