Sulfur-Containing Ionizable Lipids for the Delivery of Therapeutic Agents

A lipid having a structure of Formula A:

• or a pharmaceutically acceptable salt thereof;
• wherein
• m is 4 to 8;
• and
• n is 4 to 8;
• R2 and R3 are independently linear or branched optionally substituted C3 to C20 alkyl and optionally comprising 0-2 carbon-carbon double bonds, or are independently unsubstituted, saturated C6 alkyl;
• R1 and R4 are independently linear or branched optionally substituted C3 to C20 alkyl and optionally comprising 0-2 carbon-carbon double bonds;
• A is either C or N, and
• if A is C, then W1 and Y are either bonded to each other or not bonded to each other, and
• if W1 and Y are bonded to each other, then
• W1 is O or S;
• W2 is O or S;
• X is CH;
• Y is (CH2)q, wherein q is 1 or 2;
• Z is selected from one of structures a-c below, wherein the wavy line represents the bond to X:
• a.
• type 2 ionizable head group, wherein the n of the type 2 ionizable head group is 1 to 5;
• b.
• type 3 ionizable head group, wherein the m and n of the type 3 ionizable head group are independently 1 to 5;
• c.
• type 4 ionizable head group, wherein the m and n of the type 4 ionizable head group are independently 2 to 5 and wherein R=C1-C6 alkyl or cycloalkyl;
• if W1 and Y are not bonded to each other, then
• W1 is H;
• W2 is O, S, NH or NR2a, wherein R2a is a C1 to C4 alkyl optionally substituted with an OH group;
• and the moiety
• of Formula A is a group selected from structures d-h below, wherein the wavy line represents the bond to W2:
• d.
• type 1 ionizable head group, wherein the n of the type 1 ionizable head group is 1 to 5;
• e.
• type 5 ionizable head group, wherein the m and n of the type 5 ionizable head group are independently 1 to 5;
• f.
• type 6 ionizable head group, wherein the m of the type 6 ionizable head group is 1 to 5 and the n is independently 2 to 5 and wherein the R=C1-C6 alkyl or cycloalkyl;
• g. (CH2)n—OH type 7 ionizable head group, wherein the n of the type 7 ionizable head group is 1 to 5;
• h.
• type 8 ionizable head group, wherein the n of the type 7 ionizable head group is 1 to 5;
• i.
• type 9 ionizable head group, wherein m and n of the type 9 ionizable head group are independently 1 to 5;
• if A is N, then
• W1 and Y are absent;
• W2 and X together form a group of structure (CRaRb)p, wherein Ra and Rb are independently H or C1-C8alkyl or cycloalkyl, and wherein p is 2 to 6;
• and
• Z is OH or NR′R″, wherein R′ and R″ are independently optionally substituted C1-C8alkyl or cycloalkyl, or wherein R′ and R″ together with the N atom of NR′R″, form an optionally substituted heterocyclic ring that incorporates the N atom to which the R′ and R″ are each bound.