Aryl substituted aminomethyl spectinomycin analogs as antibacterial agents
The invention relates to aryl substituted aminomethyl spectinomycin analogs, derivatives thereof, and related compounds, which are useful as anti-bacterial agents; methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating anti-bacterial infections using the compounds and compositions.
1. A compound having a structure represented by a Formula I:
wherein n is an integer selected from 1, 2, and 3;
wherein R 1 is selected from hydrogen and C1-C4 alkyl;
wherein each occurrence of R 2a and R 2b , when present, is independently selected from hydrogen and C1-C3 alkyl; and
wherein Ar is aryl or heteroaryl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 ,
wherein each occurrence of R 9 , when present, is selected from hydrogen and C1-C3 alkyl;
wherein each occurrence of R 10a and R 10b , when present, is independently selected from hydrogen and C1-C3 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 is selected from hydrogen and methyl.
3. The compound of claim 1 , wherein each occurrence of R 2a and R 2b is hydrogen.
4. The compound of claim 1 , wherein Ar is phenyl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .
5. The compound of claim 4 , wherein Ar is phenyl substituted with 0 to 3 groups independently selected from —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 .
6. The compound of claim 1 , wherein Ar is heteroaryl substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═(C═)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .
7. The compound of claim 6 , wherein Ar is heteroaryl substituted with 0 to 3 groups independently selected from —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 .
8. The compound of claim 1 , wherein Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and 1H-benzo[d]imidazolyl; and wherein Ar is substituted with 0 to 3 groups independently selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .
9. The compound of claim 8 , wherein Ar is selected from phenyl, pyridinyl, pyridazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, oxazolo[4,5-c]pyridinyl, quinolinyl, and 1H-benzo[d]imidazolyl; and wherein Ar is substituted with 0 to 3 groups independently selected from —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 .
10. The compound of claim 1 , having a structure represented by a formula:
wherein each of R 3a , R 3b , R 3c , R 3d , and R 3e are independently selected from hydrogen, halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 , provided that at least two of R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen.
11. The compound of claim 10 , wherein each of R 3a , R 3b , R 3c , R 3d , and R 3e are independently selected from hydrogen, —F, —Cl, —Br, cyano, hydroxyl, —NH 2 , methyl, ethyl, propyl, isopropyl, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CHCl 2 , —CCl 3 , —CH 2 CH 2 F, —CH 2 CHF 2 , —CH 2 CF 3 , —CH 2 CH 2 Cl, —CH 2 CHCl 2 , —CH 2 CCl 3 , —OCH 3 , —OCH 2 CH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 Cl, —OCHCl 2 , —OCCl 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 Cl, —OCH 2 CHCl 2 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 2 CH 3 , —(C═O)OCH 3 , —(C═O)OH, —(C═O)NHCH 2 CH 3 , —(C═O)NHCH 3 , —(C═O)NH 2 , —SO 2 N(CH 3 ) 2 , —SO 2 NHCH 2 CH 3 , —SO 2 NHCH 3 , and —SO 2 NH 2 , provided that at least two of R 3a , R 3b , R 3c , R 3d , and R 3e are hydrogen.
12. The compound of claim 1 , having a structure represented by a formula:
wherein R 3c is selected from halo, cyano, hydroxyl, —NH 2 , C1-C3 alkyl, C1-C3 monoalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 monohaloalkoxy, C1-C3 polyhaloalkoxy, —(C═O)OR 9 , —(C═O)NR 10a R 10b , —SO 2 NR 10a R 10b , —SR 9 , and —SO 2 R 9 .
13. The compound of claim 1 , selected from the group consisting of:
or a subgroup thereof.
14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is a solid dosage form selected from a capsule, a tablet, a pill, a powder, a granule, an effervescing granule, a gel, a paste, a troche, and a pastille.
16. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is a liquid dosage form selected from an emulsion, a solution, a suspension, a syrup, and an elixir.
17. The pharmaceutical composition of claim 14 , further comprising a second active agent.
18. The pharmaceutical composition of claim 17 , wherein the second active agent is an antibacterial agent.
19. A method for the treatment of a bacterial infection in a human subject comprising the step of administering to the human subject a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the compound is formulated as a lotion, a cream, an ointment, a spray, or a soap.
21. The method of claim 19 , wherein the compound is formulated as a solid dosage form.
22. The method of claim 19 , wherein the compound is formulated as a liquid dosage form.
23. The method of claim 22 , wherein the liquid dosage form is formulated for intravenous administration.
24. The method of claim 23 , wherein the bacterial infection is associated with a gram positive bacterial infection.
25. The method of claim 24 , wherein the gram positive bacteria is selected from Bacillus sp. Clostridium sp., Enterococcus sp., Corynebacterium sp., and Staphylococcus sp., Streptococcus sp.
26. The method of claim 19 , wherein the bacterial infection is associated with a gram negative bacterial infection.
27. The method of claim 26 , wherein the gram negative bacteria is selected from Acinetobacter sp., Aeromonas sp., Burkholderia sp., Bordatella sp., Citrobacter sp., Enterobacter sp., Escherichia sp., Francisella sp., Haemophilus sp., Klebsiella sp., Legionella sp., Moraxella sp., Neisseria sp., Proteus sp., Pseudomonas sp., Salmonella sp., Shigella sp., Stenotrophomonas sp., Vibrio sp., and Yersinia sp.
28. The method of claim 19 , further comprising administering to the human subject a therapeutically effective amount of a second active agent.
29. The method of claim 28 , wherein the second active agent comprises at least one antibacterial agent.
30. A method for the treatment of a bacterial infection in a vertebrate animal comprising the step of administering to the vertebrate animal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
31. A method for the treatment in a human subject of a disorder associated with exposure to a biodefense pathogen comprising the step of administering to the human subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.