Derivatives of relebactam and uses thereof

1. A compound 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; and

R 6 is selected from a moiety of Formula (2), a moiety of Formula (3), a moiety of Formula (4), and a moiety of Formula (5):

wherein,

each R 7 is independently selected from hydrogen, C 1-8 alkyl, or each R 7 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;

n is an integer from 1 to 4;

X is selected from O and NH;

R 8 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 9 is selected from hydrogen and C 1-6 alkyl;

R 10 is selected from 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 11 is selected from hydrogen and C 1-6 alkyl; and

R 12 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.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

each R 1 is independently C 1-6 alkyl;

R 2 is a single bond; and

R 3 is —C(O)—O—R 4 , wherein R 4 is selected from C 1-8 alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, and C 5-7 heterocycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is a moiety of Formula (2):

wherein,

each R 1 is independently C 1-6 alkyl;

R 2 is a single bond;

R 3 is —C(O)—O—R 4 ;

R 4 is C 1-6 alkyl;

n is 1;

each R 7 is independently selected from hydrogen and C 1-6 alkyl; and

R 8 is selected from C 1-6 alkyl and —CH(—R 13 )—NH 2 , wherein R 13 is selected from C 1-6 alkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is a moiety of Formula (3):

wherein,

each R 1 is independently C 1-6 alkyl;

R 2 is a single bond;

R 3 is —C(O)—O—R 4 ; and

R 4 is C 1-6 alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is a moiety of Formula (4):

wherein,

each R 1 is independently C 1-6 alkyl;

R 2 is a single bond;

R 3 is —C(O)—O—R 4 ;

R 4 is C 1-6 alkyl;

R 9 is selected from hydrogen, methyl, ethyl, and isopropyl; and

R 10 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is a moiety of Formula (5):

wherein,

each R 1 is independently C 1-6 alkyl;

R 2 is a single bond;

R 3 is —C(O)—O—R 4 ;

R 4 is C 1-6 alkyl;

R 11 is selected from hydrogen, methyl, ethyl, and isopropyl; and

R 12 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl.

7. The compound of claim 1 , wherein the compound is selected from:

tert-butyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

acetoxymethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

1-(isobutyryloxy)ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

(pivaloyloxy)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

(isobutyryloxy)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

1-acetoxyethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

1-(pivaloyloxy)ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate,

or a pharmaceutically acceptable salt of any of the foregoing.

8. The compound of claim 1 , wherein the compound has the structure of Formula (13):

or a pharmaceutically acceptable salt thereof, wherein,

each R 1 is independently C 1-3 alkyl;

R 2 is a single bond;

R 3 is —C(O)—O—R 4 , wherein R 4 is C 1-4 alkyl;

R 7 is selected from hydrogen and C 1-4 alkyl; and

R 8 is C 1-4 alkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein

each R 1 is independently selected from methyl, ethyl, n-propyl, and iso-propyl;

R 4 is selected from methyl, ethyl, n-propyl, and iso-propyl;

R 7 is selected from hydrogen, methyl, ethyl, n-propyl, and iso-propyl; and

R 8 is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, and tert-butyl.

10. The compound of claim 8 , selected from:

acetoxymethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxoprop oxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

1-(isobutyryloxy)ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

(pivaloyloxy)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

(isobutyryloxy)methyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

1-acetoxyethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

1-(pivaloyloxy)ethyl 4-((2S,5R)-6-(((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)oxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-1-carboxylate;

or a pharmaceutically acceptable salt of any of the foregoing.

11. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable vehicle.

12. A method of inhibiting a β-lactamase enzyme in a patient comprising administering to the patient an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the β-lactamase enzyme is a Class A β-lactamase enzyme or a Class C β-lactamase enzyme.

13. The method of claim 12 , wherein administering comprises orally administering.

14. The method of claim 12 , wherein administering comprises administering an oral dosage form.