Aminoglycoside Antibiotics with Reduced Ototoxicity

A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

• wherein
• the bond is a single bond or double bond;
• each of R11 and R12 independently is H, C(O)Ra, C(O)ORa, C(O)NHRa, C(O)NRaRb, or S(O)nRa, in which n is 1, or 2, and each of Ra and Rb, independently is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5 to 14-membered heteroaryl;
• or Ra and Rb, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom;
• and each of Ra, Rb, and the 4 to 12-membered heterocycloalkyl ring formed by Ra and Rb, is optionally substituted;
• each of R21, R22, R23, and R24, independently, is H or optionally substituted C1-C6 alkyl;
• each of R31 and R32, independently, is H or OH;
• R41 is H or CH2OH;
• and
• each of R51 and R52, independently, is OH, NH2, unsubstituted mono-C1-C6 alkylamino, or unsubstituted di-C1-C6 alkylamino,
• provided that at least one of R11 and R12 is not H;
• further when R12 is C(O)Ra or S(O)2Ra, then (i) Ra is not alkyl substituted with NH2 or (ii) Ra is unsubstituted alkyl or alkyl substituted with one or more -Q-T, wherein Q is a bond or C1-C3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T is H, halo, cyano, —ORc, —C(O)Rc, —C(O)ORc, —C(O)NRcRd, —NRdC(O)Rc, —NRdC(O)ORc, —S(O)2Rc, —S(O)2NRcRd, RS1, —NHRS1, or —N(RS1)2, in which each of Rc and Rd, independently is H or RS2, each of RS1 and RS2, independently, is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl;
• or Rc and Rd, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom or 5 to 14-membered heteroaryl.