Ionizable lipids for nucleic acid delivery

A method for modifying a cell, the method comprising:

• contacting the cell with a pharmaceutical composition comprising a nucleic acid payload encapsulated in a lipid mix composition comprising a compound, or pharmaceutically acceptable salt thereof, of Formula I:
• wherein:
• L1 is a direct bond or C1-C5 alkylene;
• E1 is —O—, —OC(O)O—, —OC(O)-δ1, —OC(O)N(Q)-δ1, —OC(O)S-δ1, —N(Q)C(O)-δ1, —N(Q)C(O)O-δ1, —C(O)O-δ1, or —C(O)N(Q)-δ1;
• Q is H or C1-C5 alkyl;
• δ1 designates the bond linked to R1;
• R1 is selected from:
• and wherein:
• R4 and R5 are each independently C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• alternatively R4 and R5 may join to form 4-6 membered heterocyclic ring containing oxygen (O) or up to 2 nitrogen (N),
• optionally substituted with 1 or 2 substituents that are each independently C1-C6 alkyl, cyclopropyl, OH, or C1-C3 alkoxy;
• R6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl or 2-hydroxyethyl;
• R7 is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
• a and c′ are each independently 1, 2, 3, 4, or 5;
• b, c and e are each independently 0, 1, or 2;
• d is 1 or 2;
• R2 is H, C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, or
• L2 is a direct bond or δ2-(CR8R8′)k-δ3 wherein R8 and R8′ are each independently H, C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl;
• δ2 designates the bond linked to E2, and δ3 designates the bond linked to cyclopentyl scaffold described in formula (I);
• k is 1, 2, 3, 4, or 5;
• E2 is —O—, —OC(O)O—, —OC(O)-δ4, —OC(O)N(Q)-δ4, —N(Q)C(O)-δ4, —N(Q)C(O)O-δ4, —C(O)N(Q)-δ4 or —C(O)O-δ4;
• Q is H or C1-C5 alkyl;
• where δ4 designates the bond linked to R3;
• R3 is C8-C20 alkyl, C8-C20 alkenyl, C8-C20 alkynyl,
• wherein:
• f is 0 or 1;
• g is 1 or 2;
• g′ is 1, 2, 3, 4, or 5;
• h is 0, 1, 2, 3 or 4;
• R9 is a C6-C20 chain having the formula —(CH2)i-[L4-(CH2)]j—R12, wherein:
• L4 is selected from
• i is an integer in the range 6-20;
• j is 0, 1, 2, or 3;
• R12 is H or C4-C8 alkyl;
• R9′ is H, C4-C10 alkyl, C4-C10 alkenyl, or C4-C10 alkynyl;
• R10 and R10′ are each independently C4-C10 alkyl, C4-C10 alkenyl, or C4-C10 alkynyl;
• L3 is —OC(O)-δ5, —O-δ5, or a direct bond;
• δ5 designates the bond linked to R10 and R10′;
• and
• R11=R9, or has the formula:
• and
• transfecting the nucleic acid payload into the cell.