Ionizable cationic lipids for RNA delivery

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

• wherein:
• R1 and R2 are each independently H or C1-6 alkyl;
• or
• R1 and R2 are joined to form a saturated heterocyclic ring, wherein:
• R1 is a linear C1-4 alkylene;
• and
• R2 is —(CH2)m(X)n—, wherein
• X is O, S, or NR9, wherein R9 is H or C1-6 alkyl;
• m is 1, 2, 3 or 4, and
• n is 0 or 1;
• L1 is a linear C1-6 alkylene optionally substituted with one to three methyl groups;
• Y is selected from the group consisting of:
• wherein:
• each asterisk (*) indicates the atom attached to L2 and L3;
• and
• R10 is H or C1-6 alkyl;
• L2 and L3 are each independently a linear C1-8 alkylene;
• L4, L5, L6, L7, L8 and L9 are each independently absent or —CH2—, provided that:
• at least two of L4, L6 and L8 are —CH2—;
• and
• at least two of L5, L7 and L9 are —CH2—;
• R3 and R4 are each independently H, methyl or ethyl;
• and
• R5, R6, R7 and R8 are each independently selected from the group consisting of:
• (a) linear C1-20 alkyl, wherein each said linear C1-20 alkyl is optionally substituted with one or more substituents selected from the group consisting of:
• (i) C1-6 alkyl, C1-6 alkoxy and —F, wherein each said C1-6 alkyl substituent is optionally substituted with one or more groups selected from the group consisting of C1-3 alkoxy and —F;
• (ii) C3-8 monocycloalkyl, wherein each said C3-8 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and —F;
• (iii) C7-12 bicycloalkyl, wherein each said C7-12 bicycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and —F;
• and
• (iv) C6-10 aryl, wherein each said C6-10 aryl is a monocyclic or bicyclic aromatic hydrocarbon optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and —F;
• (b) C3-8 monocycloalkyl, wherein each said C3-8 monocycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and —F;
• (c) C7-12 bicycloalkyl, wherein each said C7-12 bicycloalkyl is optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and —F;
• and
• (d) C6-10 aryl, wherein each said C6-10 aryl is a monocyclic or bicyclic aromatic hydrocarbon optionally substituted with one or more substituents selected from the group consisting of C1-6 alkyl, C1-6 alkoxy and —F.