Antibacterial aminoglycoside analogs

1. A compound having the following structure (I):

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

Q 1 is hydrogen,

Q 2 is hydrogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 4 R 5 , —(CR 10 R 11 ) p R 12 ,

Q 3 is hydrogen, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(═NH)NR 4 R 5 , —(CR 10 R 11 ) p R 12 ,

each R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 10 is, independently, hydrogen or C 1 -C 6 alkyl, or R 1 and R 2 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R 2 and R 3 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms, or R 1 and R 3 together with the atoms to which they are attached can form a carbocyclic ring having from 4 to 6 ring atoms, or R 4 and R 5 together with the atom to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms;

each R 6 and R 7 is, independently, hydrogen, hydroxyl, amino or C 1 -C 6 alkyl, or R 6 and R 7 together with the atoms to which they are attached can form a heterocyclic ring having from 4 to 6 ring atoms;

each R 9 is, independently, hydrogen or methyl;

each R 11 is, independently, hydrogen, hydroxyl, amino or C 1 -C 6 alkyl;

each R 12 is, independently, hydroxyl or amino;

each n is, independently, an integer from 0 to 4;

each m is, independently, an integer from 0 to 4; and

each p is, independently, an integer from 1 to 5, and

wherein (i) at least two of Q 1 , Q 2 and Q 3 are other than hydrogen, and (ii) if Q 1 is hydrogen, then at least one of Q 2 and Q 3 is —C(═NH)NR 4 R 5 .

2. A compound of claim 1 wherein R 8 is hydrogen.

3. A compound of claim 1 wherein each R 9 is methyl.

4. A compound of claim 1 wherein Q 1 and Q 2 are other than hydrogen.

5. A compound of claim 4 wherein Q 3 is hydrogen.

6. A compound of claim 4 wherein Q 1 is:

wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

each R 3 is hydrogen.

7. A compound of claim 6 wherein Q 1 is:

8. A compound claim 4 wherein Q 2 is —(CR 10 R 11 ) p R 12 .

9. A compound of claim 8 wherein each R 10 is hydrogen.

10. A compound of claim 9 wherein each R 11 is hydrogen.

11. A compound of claim 4 wherein the compound is:

6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin;

6′-(2-Hydroxy-ethyl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin;

6′-(2-Hydroxy-propanol)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin;

6′-(Methyl-piperidin-4-yl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin;

6′-(Methyl-cyclopropyl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin;

6′-(3-Amino-propyl)-1-(4-amino-2(R)-hydroxy-butyryl) -sisomicin;

6′-Methyl-cyclopropyl-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin;

6′-Methyl-piperidinyl-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin;

6′-(2-Hydroxy-ethyl)-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin;

6′-(2-Hydroxy-propanol)-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin;

6′-(3-Amino-propyl)-1-(3-amino-2(R)-hydroxy-propionyl) -sisomicin;

6′-(Methyl-piperidin-4-yl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin;

6′-(Methyl-cyclopropyl)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin;

6′-(2-Hydroxy-propanol)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin;

6′-(Methyl-piperidin-4-yl)-1-(3-amino-2(S)-hydroxy -propionyl)-sisomicin;

6′-(2-Hydroxy-ethyl)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin;

6′-(3-Amino-propyl)-1-(3-amino-2(S)-hydroxy-propionyl) -sisomicin;

6′-(Methyl-cyclopropyl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin;

6′-(2-Hydroxy-propanol)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin;

6′-(3-Amino-2-hydroxy-propyl)-1-(3-amino-2(S)-hydroxy -propionyl)-sisomicin;

6′-(2-Hydroxy-ethyl)-1-(2-hydroxy-acetyl)-sisomicin;

6′-(3-Amino-propyl)-1-(2-amino-ethylsulfonamide)-sisomicin;

6′-(2-Hydroxy-propanol)-1-(2-amino-ethylsulfonamide)-sisomicin;

6′-(2(S)-Hydroxy-propanol)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin;

6′-(2-Hydroxy-ethyl)-1-(2-amino-ethylsulfonamide)-sisomicin;

6′-(Methyl-trans-3-amino-cyclobutyl)-1-(4-amino-2(S) -hydroxy-butyryl)-sisomicin;

6′-(2-Hydroxy-ethyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl) -sisomicin;

6′-(2-Hydroxy-4-amino-butyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomicin;

6′-(Methyl-cyclopropyl)-1-(3-hydroxy-azetidin-3-yl-acetyl) -sisomicin;

6′-(2-Hydroxy-ethyl)-1-(3-hydroxy-azetidin-3-yl-acetyl) -sisomicin;

6′-(Methyl-(1-hydroxy-3-methylamino-cyclobutyl)-1-(4-amino -2(S)-hydroxy-butyryl) -sisomicin;

6′-(3-Amino-propyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl) -sisomicin;

6′-(Methyl-cyclopropyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl) -sisomicin;

6′-(2-Hydroxy-3-amino-propyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomicin;

6′-(3-Amino-propyl)-1-(4-amino-2(S)-hydroxy-butyryl) -sisomicin;

6′-(Methyl-pyrrolidin-2-yl)-1-(4-amino-2(S)-hydroxy -butyryl)-sisomicin;

6′-(3-Amino-propyl)-1-(3-hydroxy-azetidin-3-yl-acetyl) -sisomicin;

6′-(3-Amino-propyl)-1-(1-hydroxy-3-amino-cyclobutyl-acetyl) -sisomicin;

6′-(Methyl-trans-3-amino-cyclobutyl)-1-(3-amino-2(S) -hydroxy-propionyl)-sisomicin;

6′-(Methyl-trans-3-amino-cyclobutyl)-1-(1-hydroxy-3-amino -cyclobutyl-acetyl)-sisomicin;

6′-(2-Hydroxy-ethyl)-1-(1-hydroxy-3-amino -cyclobutyl -acetyl)-sisomicin;

6′-Methylcyclopropyl-1-(2-(azetidin-3-yl)-2-hydroxy-acetyl) -sisomicin;

6′-(Methyl-trans-3-amino-cyclobutyl)-1-(2-(azetidin-3-yl)-2-hydroxy-acetyl)-sisomicin;

6′-(2-Hydroxy-ethyl)-1-(2-(azetidin-3-yl)-2-hydroxy -acetyl)-sisomicin;

6′-(3-Amino-propyl)-1-(2-(azetidin-3-yl)-2-hydroxy -acetyl)-sisomicin;

6′-(Methyl-trans-3-amino-cyclobutyl)-1-(3-hydroxy-pyrrolidin-3-yl-acetyl)-sisomicin;

6′-(2-Hydroxy-3-amino-propyl)-1-(2-(azetidin-3-yl)-2-hydroxy-acetyl)-sisomicin; or 6′-(Methyl-3-amino-1-hydroxy-cyclobutyl)-1-(2-(azetidin-3-yl)-2-hydroxy-acetyl)-sisomicin.

12. A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

13. A method of treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 1 or a composition of claim 12 .

14. A compound of claim 4 wherein the compound is 6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin.

15. A compound of claim 2 , wherein each R 9 is methyl.

16. A compound of claim 15 , wherein Q 3 is hydrogen.

17. A compound of claim 16 , wherein Q 1 is:

wherein:

R 1 is hydrogen;

R 2 is hydrogen; and

each R 3 is hydrogen.

18. A compound of claim 17 , wherein Q 1 is:

19. A compound of claim 18 , wherein Q 1 is:

20. A compound of claim 19 , wherein Q 2 is —(CR 10 R 11 ) p R 12 .

21. A compound of claim 20 , wherein each R 10 is hydrogen.

22. A compound of claim 21 , wherein each R 11 is hydrogen.

23. A compound of claim 22 , wherein p is 2.

24. A compound of claim 23 , wherein R 12 is hydroxyl.

25. A pharmaceutical composition comprising a compound of claim 24 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

26. A method for treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 24 or a composition of claim 25 .

27. A pharmaceutical composition comprising 6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

28. A method for treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a composition of claim 27 .

29. A compound of claim 1 , wherein

Q 1 is

 and

Q 2 is —(CR 10 R 11 ) p R 12 .

30. A compound of claim 29 wherein R 8 is hydrogen.

31. A compound of claim 29 wherein each R 9 is methyl.

32. A compound of claim 29 wherein Q 3 is hydrogen.

33. A compound of claim 29 wherein R 1 is hydrogen, R 2 is hydrogen and each R 3 is hydrogen.

34. A compound of claim 29 , wherein n is 1 or 2.

35. A compound of claim 33 , wherein n is 1 or 2.

36. A compound of claim 29 , wherein each R 10 is hydrogen, each R 11 is hydrogen and R 12 is hydroxyl.

37. A compound of claim 29 , wherein p is 2.

38. A compound of claim 36 , wherein p is 2.

39. A compound of claim 29 , wherein R 1 is hydrogen, R 2 is hydrogen, each R 3 is hydrogen, each R 10 is hydrogen, each R 11 is hydrogen and R 12 is hydroxyl.

40. A compound of claim 29 , wherein n is 1 or 2, and p is 2.

41. A compound of claim 39 , wherein n is 1 or 2, and p is 2.

42. A compound of claim 29 , wherein Q 1 is:

43. A pharmaceutical composition comprising a compound of claim 29 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

44. A method for treating a bacterial infection in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 29 or a composition of claim 43 .