Bis-ester and amide cationic lipids

A cationic lipid having a structure according to Formula (II):

• or a pharmaceutically acceptable salt thereof,
• wherein R3 is selected from hydrogen, or optionally substituted (C1-C6)alkyl;
• R4 is selected from hydrogen, —OH, —NH2, optionally substituted (C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C3)alkylene-optionally substituted aryl, or optionally substituted (C1-C3)alkylene-optionally substituted heteroaryl;
• e and g are integers that are each independently selected from 0, 1, 2, 3, or 4;
• f and h are integers that are each independently selected from 1, 2, 3, 4, 5 or 6;
• each Y2 is independently selected from hydrogen or —OH;
• R5A, R5B, R5C, and R5D are each independently selected from optionally substituted (C5-C25)alkyl, optionally substituted (C5-C25)alkenyl, or —W1—X1;
• each W1 is independently selected from a covalent bond, optionally substituted (C1-C10)alkylene or optionally substituted (C2-C10)alkenylene;
• and
• each X1 is independently selected from —(*C═O)—O-optionally substituted (C3-C25)alkyl, —(*C═O)—O-optionally substituted (C3-C25)alkenyl, —*O—(C═O)-optionally substituted (C3-C25)alkyl, or —*O—(C═O)-optionally substituted (C3-C25)alkenyl, wherein the atom marked with a * is connected to W1 or —CH(Y2)—when W1 is a covalent bond.

A cationic lipid having a structure according to Formula (III):

• or a pharmaceutically acceptable salt thereof,
• wherein R9 is selected from hydrogen, or optionally substituted (C1-C6)alkyl;
• R10 is selected from hydrogen, —OH, —NH2, optionally substituted (C1-C6)alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (C1-C3)alkylene-optionally substituted aryl, or optionally substituted (C1-C3)alkylene-optionally substituted heteroaryl;
• i and k are integers that are each independently selected from 0, 1, 2, 3, or 4;
• j and l are integers that are each independently selected from 1, 2, 3, 4, 5 or 6;
• each Y3 is independently selected from hydrogen or —OH;
• each R12 is independently selected from hydrogen or optionally substituted (C1-C6)alkyl;
• R11A, R11B, R11C, and R11D are each independently selected from optionally substituted (C5-C25)alkyl, optionally substituted (C5-C25)alkenyl, or —W1—X1;
• each W1 is independently selected from a covalent bond, optionally substituted (C1-C10)alkylene or optionally substituted (C2-C10)alkenylene;
• and
• each X1 is independently selected from —(*C═O)—O-optionally substituted (C3-C25)alkyl, —(*C═O)—O-optionally substituted (C3-C25)alkenyl, —*O—(C═O)-optionally substituted (C3-C25)alkyl, or —*O—(C═O)-optionally substituted (C3-C25)alkenyl, wherein the atom marked with a * is connected to W1 or —CH(Y3)—when W1 is a covalent bond.

A cationic lipid having a structure according to Formula (IV):

• or a pharmaceutically acceptable salt thereof,
• wherein
• m and n are integers that are each independently selected from 1, 2, 3, 4, 5 or 6;
• Z3 is an aromatic amino acid residue, wherein the α-carbon carboxyl group (—C(O)O—) of the aromatic amino acid residue is bound to the —(CH2)m and the α-carbon aminyl group (—NH—) of the aromatic amino acid residue is bound to the Z4;
• Z4 is selected from
• or wherein the right hand side of each depicted structure is bound to the —(CH2)n—;
• each Y4 is independently selected from hydrogen or —OH;
• R13A, R13B, R13C, and R13D are each independently selected from optionally substituted (C5-C25)alkyl, optionally substituted (C5-C25)alkenyl, or —W1—X1;
• each W1 is independently selected from a covalent bond, optionally substituted (C1-C10)alkylene or optionally substituted (C2-C10)alkenylene;
• and
• each X1 is independently selected from —(*C═O)—O-optionally substituted (C3-C25)alkyl, —(*C═O)—O-optionally substituted (C3-C25)alkenyl, —*O—(C═O)-optionally substituted (C3-C25)alkyl, or —*O—(C═O)-optionally substituted (C3-C25)alkenyl, wherein the atom marked with a * is connected to W1 or —CH(Y4)—when W1 is a covalent bond.