Modified aminoglycoside compounds and uses thereof in disabling bacterial ribosome

A compound represented by Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• the dashed line indicates a stereo-configuration of position 6′ being an R configuration or an S configuration;
• X1 is O;
• Rx1, Rx2, Ry1 and Rz are each independently selected from hydrogen, alkyl and cycloalkyl;
• Ry2-Ry9 and Rw1-Rw3 are each independently selected from hydrogen, alkyl, and cycloalkyl;
• R5 and R6 are each independently OR16, wherein R16 is independently selected from hydrogen, a monosaccharide moiety, and a disaccharide moiety;
• R7-R9 are each independently selected from the group consisting of hydrogen and acyl;
• and
• R3 is OR20, wherein R20 is hydrogen, alkyl, or cycloalkyl;
• and wherein either:
• R1 is NR23R24, and each of R23 and R24 is independently hydrogen, alkyl, cycloalkyl or acyl,
• and wherein:
• either:
• R4 is selected from:
• OR20, wherein R20 is a diamine-containing moiety which is:
• -(L1)n-N1-(L2)m-N2
• wherein:
• n and m are each 1;
• L1 and L2 are each independently an alkylene of 2 or 3 carbon atoms in length;
• N1 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms;
• and
• N2 is selected from amine and guanidyl, said amine being —NR′R″ group, wherein R′ and R″ is each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group;
• and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms,
• and a diamine-containing moiety which is:
• —N1-(L2)m-N2-(L3)k-(N3)a-(L4)j(N4)b
• wherein:
• m and k are each 1;
• j is 0 or 1;
• a is 1;
• b is 0 or 1;
• L2, L3 and L4, if present, are each independently an alkylene of 1, 2 or 3 carbon atoms in length;
• N1 is amide;
• N2 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms;
• N3 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms, or, when b and j are each 0, N3 is amine —NR′R″, wherein R′ and R″ are each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group;
• and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms;
• and
• N4, if present, is amine —NR′R″, wherein R′ and R″ is each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group;
• and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms,
• or:
• R4 is OR20 wherein R20 is hydrogen, alkyl, or cycloalkyl, or NR23R24 wherein each of R23 and R24 is independently hydrogen, alkyl, cycloalkyl or acyl;
• and
• R1 is a diamine-containing moiety which is:
• —N1-(L2)m-N2-(L3)k-(N3)a-(L4)j-(N4)b
• wherein:
• m and k are each 1;
• j is 0 or 1;
• a is 1;
• b is 0 or 1;
• L2, L3 and L4, if present, are each independently an alkylene of 1, 2 or 3 carbon atoms in length;
• N1 is amide;
• N2 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms;
• N3 is amine —NR′—, wherein R′ is hydrogen, alkyl, or cycloalkyl, wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms, or, when b and j are each 0, N3 is amine —NR′R″, wherein R′ and R″ are each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group;
• and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms;
• and
• N4, if present, is amine —NR′R″, wherein R′ and R″ is each independently hydrogen, alkyl, or cycloalkyl, or R′ and R″ form together a heterocyclic group;
• and wherein said alkyl group is of 1 carbon atom, 2 carbon atoms, or 3 carbon atoms.