Aztreonam derivatives and uses thereof

1. A compound of Formula (1):

wherein,

each R 1 is independently selected from C 1-6 alkyl, or each R 1 and the geminal carbon atom to which each R 1 is 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, and substituted C 5-6 heteroaryl, 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;

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; and

R 7 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; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein each substituent is independently selected from —OH, —CN, —CF 3 , —OCF 3 , ═O, —NO 2 , C 1-6 alkoxy, C 1-6 alkyl, —COOR, —NR 2 , and —CONR 2 ; wherein each R is independently selected from hydrogen and C 1-6 alkyl.

3. The compound of claim 1 , wherein each of R 5 , R 6 , and R 7 is hydrogen.

4. The compound of claim 1 , wherein,

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

5. The compound of claim 1 , wherein each R 1 is independently C 1-6 alkyl, or each R 1 together with the geminal carbon atom to which each R 1 is bonded form a C 3-6 cycloalkyl ring or a substituted C 3-6 cycloalkyl ring.

6. The compound of claim 1 , wherein R 2 is selected from a single bond, C 1-6 alkyl, C 1-2 alkanediyl, and substituted C 1-2 alkanediyl.

7. The compound of claim 1 , wherein R 3 is selected from —O—C(O)—R 4 , —C(O)—O—R 4 , —S—C(O)—R 4 , —C(O)—S—R 4 , —S—S—R 4 , —NH—R 4 , and —CH(—NH 2 )(—R 4 ); where R 4 is defined as for Formula (1), or each R 4 can be selected from hydrogen and C 1-8 alkyl.

8. The compound of claim 1 , wherein R 3 is —C(O)—O—R 4 , and R 4 is selected from hydrogen and C 1-8 alkyl.

9. The compound of claim 1 , wherein R 3 is —C(O)—O—R 4 ′ wherein R 4 is selected from C 1-8 alkyl, C 1 s heteroalkyl, C 5-7 cycloalkyl, C 5-7 heterocycloalkyl, C 6 aryl, C 7-9 arylalkyl, substituted C 1-8 alkyl, substituted C 1-8 heteroalkyl, substituted C 5-6 cycloalkyl, substituted C 5-6 heterocycloalkyl, substituted C 6 aryl, and C 7-9 arylalkyl.

10. The compound of claim 1 , wherein,

R 2 is a single bond;

R 3 is C 1-3 alkyl;

each R 1 together with the carbon atom to which each R 1 is bonded form a C 4-6 heterocycloalkyl ring or a substituted C 4-6 heterocycloalkyl ring

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

11. The compound of claim 1 , wherein,

each R 1 is methyl;

R 2 is selected from a single bond, methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH 2 CH 3 )—, and 1,2-benzene-diyl;

R 3 is selected from —O—C(O)—R 4 , —C(O)—O—R 4 , —S—C(O)—R 4 , —C(O)—S—R 4 , —S—S—R 4 , —NHR 4 , and —CH(—NH 2 )(—R 4 ), wherein R 4 is selected from C 1 s alkyl, C 1-8 heteroalkyl, C 7-9 arylalkyl, and C 5-7 heterocycloalkyl;

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

12. The compound of claim 1 , wherein,

each R 1 is methyl;

R 2 is selected from a single bond, methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH 2 CH 3 )—, and 1,2-benzene-diyl;

R 3 is selected from —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;

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

13. The compound of claim 1 , wherein,

each R 1 is methyl;

R 2 is selected from a single bond, methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH 2 CH 3 )—, and 1,2-benzene-diyl;

R 3 is selected from —O—C(O)—R 4 , —C(O)—O—R 4 , —S—C(O)—R 4 , —C(O)—S—R 4 , —S—S—R 4 , —NHR 4 , and —CH(—NH 2 )(—R 4 ), wherein R 4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl;

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

14. The compound of claim 1 , wherein,

each R 1 is methyl;

R 2 is selected from a single bond, methanediyl, ethanediyl, —CH(—OH)—, —CH(—O—C(O)—CH 2 CH 3 )—, and 1,2-benzene-diyl;

R 3 is selected from —C(O)—O—R 4 , wherein R 4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl, tert-butyl, 2-methoxyethyl, methylbenzene, oxetane-3-oxy-yl, cyclopentyl, cyclohexyl, and 2-pyrrolidinyl;

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

15. The compound of claim 1 , wherein,

each R 1 is independently C 1-3 alkyl;

each R 2 is a single bond; and

each of R 5 , R 6 , and R 7 is hydrogen.

16. The compound of claim 1 , wherein,

each R 1 is methyl;

R 2 is a single bond;

R 3 is —C(O)—O—R 4 , wherein R 4 is selected from C 1-10 alkyl, C 1-10 heteroalkyl, C 7-10 alkylarene, and C 5-10 heteroalkylcycloalkyl;

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

17. The compound of claim 1 , wherein,

each R 1 can be selected from C 1-6 alkyl;

R 4 can be selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 5-6 cycloalkyl, and C 5-6 heterocycloalkyl;

each of R 5 and R 6 is hydrogen; and

R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, and 4-(yl-methyl)-5-methyl-1,3-dioxol-2-one.

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

2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-methoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid;

2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((3-ethoxy-2,2-dimethyl-3-oxopropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid;

2-((((E)-1-(2-aminothiazol-4-yl)-2-(((2S,3S)-1-((2,2-dimethyl-3-oxo-3-propoxypropoxy)sulfonyl)-2-methyl-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid;

methyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

ethyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

propyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

methyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

ethyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

propyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-ethoxy-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

methyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

ethyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

propyl 3-((((2S,3S)-3-((E)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-methyl-4-oxoazetidin-1-yl)sulfonyl)oxy)-2,2-dimethylpropanoate;

a pharmaceutically acceptable salt of any of the foregoing; and

a combination of any of the foregoing.

19. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.

20. The pharmaceutical composition of claim 19 , wherein the pharmaceutical composition comprises an oral dosage formulation.

21. A method of treating a bacterial infection in a patient having a bacterial infection comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound of claim 1 .

22. The method of claim 19 , wherein administering comprises orally administering.

23. The method of claim 19 , further comprising administering a therapeutically effective amount of a β-lactamase inhibitor to the patient.

24. The method of claim 21 , wherein the bacterial infection is capable of being treated by co-administering a therapeutically effective amount of aztreonam and a β-lactamase inhibitor.

25. A method of treating a bacterial infection in a patient having a bacterial infection comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 19 .

26. The method of claim 25 , wherein administering comprises orally administering.

27. The method of claim 25 , further comprising administering a β-lactamase inhibitor to the patient.