Beta-lactamase inhibitors

1. A compound of Formula (A):

wherein p is 1 or 2;

R 1 and R 2 are independently selected from H and C 1 -C 4 alkyl optionally substituted with up to three groups selected from halo, CN, —OR, oxo, and —NRR′;

Z is NR 3 or N—OR 3 ;

R 3 is independently selected at each occurrence from H, Cy, and C 1 -C 4 alkyl optionally substituted with up to three groups selected from Cy, halo, CN, —OR, and —NRR′;

Cy is a C 3 -C 6 cycloalkyl ring or 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S as ring members, and Cy is optionally substituted with up to three groups selected from oxo, halo, C 1 -C 2 alkyl, CN, —OR, and —NRR′; and

R and R′ are independently selected from H and C 1 -C 4 alkyl optionally substituted with one or two groups selected from halo, —OH, —CN, —O—(C 1 -C 4 alkyl), oxo, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 ,

or R and R′ taken together with the nitrogen atom to which both are attached can form a ring selected from piperidine, morpholine, pyrrolidine, and azetidine, wherein the ring is optionally substituted with one or two groups selected from halo, C 1 -C 2 alkyl, —OH, —CN, —O—(C 1 -C 4 alkyl), oxo, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 ;

or a salt or zwitterionic form thereof.

2. The compound of claim 1 , which a compound of one of the following formulas:

or

or a salt or zwitterionic form thereof.

3. The compound of claim 1 , which is a compound of Formula (I):

wherein:

R 1 and R 2 are independently selected from H and C 1 -C 4 alkyl optionally substituted with up to three groups selected from halo, CN, —OR, oxo, and —NRR′;

Z is NR 3 or N—OR 3 ;

R 3 is independently selected at each occurrence from H, Cy, and C 1 -C 4 alkyl optionally substituted with up to three groups selected from Cy, halo, CN, —OR, and —NRR′;

Cy is a C 3 -C 6 cycloalkyl ring, or 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S as ring members, and Cy is optionally substituted with up to three groups selected from oxo, halo, C 1 -C 2 alkyl, CN, —OR, and —NRR′; and

R and R′ are independently selected from H and C 1 -C 4 alkyl optionally substituted with one or two groups selected from halo, —OH, —CN, —O—(C 1 -C 4 alkyl), oxo, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 ,

or R and R′ taken together with the nitrogen atom to which both are attached can form a ring selected from piperidine, morpholine, pyrrolidine, and azetidine, wherein the ring is optionally substituted with one or two groups selected from halo, C 1 -C 2 alkyl, —OH, —CN, —O—(C 1 -C 4 alkyl), oxo, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 ;

Y is a cationic group;

n is 0 or 1; and

when n is 0 the compound of Formula I is in a zwitterionic form.

4. The compound of claim 1 , wherein Z is NR 3 ,

and R 3 is H or C 1 -C 4 alkyl optionally substituted with —OR or —NRR′, or a salt or zwitterionic form thereof.

5. The compound of claim 4 , wherein R 3 is C 1 -C 2 alkyl optionally substituted with —OR or —NRR′, or a salt or zwitterionic form thereof.

6. The compound of claim 4 , wherein R 3 is H, or a salt or zwitterionic form thereof.

7. The compound of claim 1 , wherein R 1 and R 2 are both H, or a salt or zwitterionic form thereof.

8. The compound of claim 1 , which has the structure:

wherein X is —OR or —NRR′;

as a salt or zwitterionic form thereof.

9. The compound of claim 1 , which is selected from:

and the salt or zwitterionic forms thereof.

10. A compound of Formula (VI):

wherein:

R 1 and R 2 are independently selected from H and C 1 -C 4 alkyl optionally substituted with up to three groups selected from halo, CN, —OR, oxo, and —NRR′;

Z is NR 3 or N—OR 3 ;

R 3 is independently selected at each occurrence from H, Cy, and C 1 -C 4 alkyl optionally substituted with up to three groups selected from Cy, halo, CN, —OR, and —NRR′;

Cy is a C 3 -C 6 cycloalkyl ring or 4-6 membered heterocyclic ring containing one or two heteroatoms selected from N, O and S as ring members, and Cy is optionally substituted with up to three groups selected from oxo, halo, C 1 -C 2 alkyl, CN, —OR, and —NRR′; and

R and R′ are independently selected from H and C 1 -C 4 alkyl optionally substituted with one or two groups selected from halo, C 1 -C 2 alkyl, —OH, —CN, —O—(C 1 -C 4 alkyl), oxo, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 ,

or R and R′ taken together with the nitrogen atom to which both are attached can form a ring selected from piperidine, morpholine, pyrrolidine, and azetidine, wherein the ring is optionally substituted with one or two groups selected from halo, C 1 -C 2 alkyl, —OH, —CN, —O—(C 1 -C 4 alkyl), oxo, —NH 2 , —NH(C 1 -C 4 alkyl), and —N(C 1 -C 4 alkyl) 2 ;

A is H or —CH 2 -Ph, where Ph represents phenyl optionally substituted with one or two groups selected from halo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy;

or a salt thereof.

11. The compound of claim 1 having the formula (VII):

12. The compound of claim 11 in crystalline form.

13. The compound of claim 12 , which exhibits an endotherm on differential scanning calorimetry between 283° C. and 350° C.

14. The compound of claim 12 , characterized by XRPD peaks at diffraction angles (2Theta) of 8.3 and 16.6 degrees.

15. A process to make a compound of Formula (I),

according to claim 3 ;

wherein the process comprises contacting a compound of Formula (III)

wherein Z, R 1 and R 2 and R 3 are as defined in claim 3 ,

with a sulfonylating agent in the presence of a base.

16. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.

17. A pharmaceutical combination, comprising a compound according to claim 1 and a beta-lactam antibiotic.

18. A method to treat a subject having a Gram-negative bacterial infection, which comprises administering to the subject an effective amount of a beta-lactam antibiotic and a compound of Formula (A) according to claim 1 .