ORALLY ADMINISTERED COMBINATIONS OF BETA-LACTAM ANTIBIOTICS AND AVIBACTAM DERIVATIVES FOR TREATING BACTERIAL INFECTIONS

1 . A pharmaceutical composition comprising:

a β-lactam antibiotic or a pharmaceutically acceptable salt thereof; and

an avibactam derivative of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;

R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;

R 3 is selected from C 1-6 alkyl, —O—C(O)—R 4 , —S—C(O)—R 4 , —NH—C(O)—R 4 , —O—C(O)—O—R 4 , —S—C(O)—O—R 4 , —NH—C(O)—O—R 4 , —C(O)—O—R 4 , —C(O)—S—R 4 , —C(O)—NH—R 4 , —O—C(O)—O—R 4 , —O—C(O)—S—R 4 , —O—C(O)—NH—R 4 , —S—S—R 4 , —S—R 4 , —NH—R 4 , —CH(—NH 2 )(—R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 5-6 aryl, substituted C 5-6 heteroaryl, and —CH═C(R 4 ) 2 , wherein,

R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;

R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and

R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl.

2 . The pharmaceutical composition of claim 1 , wherein the β-lactam antibiotic comprises an orally bioavailable β-lactam antibiotic or a pharmaceutically acceptable salt thereof.

3 . The pharmaceutical composition of claim 1 , wherein the β-lactam antibiotic comprises ceftibuten or a pharmaceutically acceptable salt thereof.

4 . The pharmaceutical composition of claim 1 , wherein the avibactam derivative has the structure of Formula (1a):

or a pharmaceutically acceptable salt thereof, wherein,

each R 1 is independently selected from C 1-6 alkyl; and

R 3 is C 1-6 alkyl.

5 . The pharmaceutical composition of claim 1 , wherein the avibactam derivative is selected from:

methyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate;

ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate;

propyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate;

methyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate;

ethyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate;

propyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-ethylbutanoate;

methyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate;

ethyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate;

propyl 2-((((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)methyl)-2-propylpentanoate;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

6 . The pharmaceutical composition of claim 1 , wherein the avibactam derivative is ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate (3), or a pharmaceutically acceptable salt thereof.

7 . The pharmaceutical composition of claim 1 , wherein the avibactam derivative is crystalline ethyl 3-(((((1R,2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl)oxy)sulfonyl)oxy)-2,2-dimethylpropanoate anhydrate characterized by an X-ray powder diffraction (XRPD) pattern having characteristic scattering angles (2θ) at least at 3.16°±0.2°, 6.37°±0.2°, 5.38°±0.2°, and 17.35°±0.2° at a Kα2/Kα1 (0.5) wavelength.

8 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises a weight ratio of avibactam equivalents to β-lactam antibiotic equivalents from 1:1 to 4:1.

9 . The pharmaceutical composition of claim 1 , wherein the bacterial infection is caused by Enterobacteriaceae bacteria.

10 . The pharmaceutical composition of claim 1 , wherein the bacterial infection is caused by bacteria that produce an extended-spectrum β-lactamase enzyme.

11 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises:

from 200 mg to 1,400 mg of the β-lactam antibiotic; and

from 200 mg to 1,400 mg of the avibactam derivative.

12 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises:

from 100 mg to 500 mg of ceftibuten or a pharmaceutically acceptable salt thereof; and

from 300 mg to 1,400 mg of the avibactam derivative or a pharmaceutically acceptable salt thereof.

13 . The pharmaceutical composition of claim 1 , wherein, following oral administration to a patient the composition provides a β-lactam antibiotic plasma concentration greater than 40% fT>MIC for a bacterial strain.

14 . The pharmaceutical composition of claim 1 , wherein, following oral administration to a patient, the composition provides an avibactam plasma concentration greater than 40% fT>C t .

15 . The pharmaceutical composition of claim 1 , wherein, following oral administration to a patient, the composition provides an avibactam plasma concentration characterized by a fAUC:MIC ratio from 10 to 40.

16 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition comprises an oral formulation.

17 . An oral formulation comprising the pharmaceutical composition of claim 1 .

18 . A method of treating a bacterial infection in a patient in need of such treatment comprising orally administering to the patent a therapeutically effective amount of:

a β-lactam antibiotic or a pharmaceutically acceptable salt thereof; and

an avibactam derivative of Formula (1):

or a pharmaceutically acceptable salt thereof, wherein,

each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which they are bonded forms a C 3-6 cycloalkyl ring, a C 3-6 heterocycloalkyl ring, a substituted C 3-6 cycloalkyl ring, or a substituted C 3-6 heterocycloalkyl ring;

R 2 is selected from a single bond, C 1-6 alkanediyl, C 1-6 heteroalkanediyl, C 5-6 cycloalkanediyl, C 5-6 heterocycloalkanediyl, C 6 arenediyl, C 5-6 heteroarenediyl, substituted C 1-6 alkanediyl, substituted C 1-6 heteroalkanediyl, substituted C 5-6 cycloalkanediyl, substituted C 5-6 heterocycloalkanediyl, substituted C 6 arenediyl, and substituted C 5-6 heteroarenediyl;

R 3 is selected from C 1-6 alkyl, —O—C(O)—R 4 , —S—C(O)—R 4 , —NH—C(O)—R 4 , —O—C(O)—O—R 4 , —S—C(O)—O—R 4 , —NH—C(O)—O—R 4 , —C(O)—O—R 4 , —C(O)—S—R 4 , —C(O)—NH—R 4 , —O—C(O)—O—R 4 , —O—C(O)—S—R 4 , —O—C(O)—NH—R 4 , —S—S—R 4 , —S—R 4 , —NH—R 4 , —CH(—NH 2 )(—R 4 ), C 5-6 heterocycloalkyl, C 5-6 heteroaryl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 5-6 aryl, substituted C 5-6 heteroaryl, and —CH═C(R 4 ) 2 , wherein,

R 4 is selected from hydrogen, C 1-8 alkyl, C 1-8 heteroalkyl, C 5-8 cycloalkyl, C 5-8 heterocycloalkyl, C 5-10 cycloalkylalkyl, C 5-10 heterocycloalkylalkyl, C 6-8 aryl, C 5-8 heteroaryl, C 7-10 arylalkyl, C 5-10 heteroarylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-8 cycloalkyl, substituted C 5-8 heterocycloalkyl, substituted C 5-10 cycloalkylalkyl, substituted C 5-10 heterocycloalkylalkyl, substituted C 6-8 aryl, substituted C 5-8 heteroaryl, substituted C 7-10 arylalkyl, and substituted C 5-10 heteroarylalkyl;

R 5 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl; and

R 6 is selected from hydrogen, C 1-6 alkyl, C 5-8 cycloalkyl, C 6-12 cycloalkylalkyl, C 2-6 heteroalkyl, C 5-8 heterocycloalkyl, C 6-12 heterocycloalkylalkyl, substituted C 1-6 alkyl, substituted C 5-8 cycloalkyl, substituted C 6-12 cycloalkylalkyl, substituted C 2-6 heteroalkyl, substituted C 5-8 heterocycloalkyl, and substituted C 6-12 heterocycloalkylalkyl.

19 . The method of claim 18 , wherein the bacterial infection is caused by bacteria that produce a β-lactamase enzyme.

20 . The method of claim 18 , wherein the bacterial infection is caused by an Enterobacteriaceae bacteria.