Ionizable cationic lipid for RNA delivery

1. A compound of formula 2

wherein

R 1 is branched alkyl of the structure (CH 3 (CH 2 ) m ) 2 CH—, wherein m is 2 or 3;

R 2 is a linear alkyl of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons, a branched alkyl of 3, 4, 5, 6, 7, 8, or 9 carbons, or an alkenyl or alkynyl of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbons;

R 3 is —(CH 2 ) p —, wherein p is 2, 3, 4, 5 or 6;

R 4 and R 5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons;

L 1 and L 2 are the same or different, of the structure —(CH 2 ) n —, wherein n is 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18;

L 3 is a bond;

X 1 is —CO—O— whereby -L 2 -CO—O—R 2 is formed;

X 2 is S or O; and

X 3 is —CO—O— whereby -L 1 -CO—O—R 1 is formed; and

wherein m+n+p is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein m is 3.

3. The compound of claim 1 , wherein m+n+p is 13, 14, or 15.

4. The compound of claim 1 , wherein R 4 and R 5 are independently methyl or ethyl.

5. The compound of claim 1 , wherein X 2 is S.

6. The compound of claim 1 , wherein R 2 is (CH 3 (CH 2 ) m ) 2 CH— and m is 2 or 3.

7. The compound of claim 1 , wherein R 2 is an alkenyl of 9, 10, or 11 carbons.

8. The compound of claim 1 , wherein L 1 and L 2 are the same.

9. The compound of claim 1 , wherein m is 3 and n is 7, 8 or 9.

10. The compound of claim 1 , wherein its pKa is 8-11.

11. A compound of formula 2

wherein

R 1 is branched alkyl of the structure (CH 3 (CH 2 ) m ) 2 CH—, wherein m is 2 or 3;

R 2 is a linear alkyl of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons, a branched alkyl of 3, 4, 5, 6, 7, 8, or 9 carbons, or an alkenyl or alkynyl of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbons;

R 3 is —(CH 2 ) p —, wherein p is 2, 3, 4, 5 or 6;

R 4 and R 5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons;

L 1 and L 2 are the same or different, of the structure —(CH 2 ) n —, wherein n is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18;

L 3 is of the structure —(CH 2 ) q —, wherein q is 1, 2, 3, 4, 5 or 6;

X 1 is —CO—O—, whereby -L 2 -CO—O—R 2 is formed;

X 2 is S or O; and

X 3 is —CO—O—, whereby -L 1 -CO—O—R 1 is formed; and

wherein m+n+p+q is 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 11 , wherein m is 3.

13. The compound of claim 11 , wherein m+n+p+q is 13, 14, 15, or 16.

14. The compound of claim 11 , wherein R 4 and R 5 are independently methyl or ethyl.

15. The compound of claim 11 , wherein X 2 is S.

16. The compound of claim 11 , wherein R 2 is (CH 3 (CH 2 ) m ) 2 CH— and m is 2 or 3.

17. The compound of claim 11 , wherein its pKa is 8-11.

18. A compound of formula 2

wherein

R 1 is branched alkyl of the structure (CH 3 (CH 2 ) m ) 2 CH—, wherein m is 1, 2, or 3;

R 2 is a linear alkyl of 1, 2, 3, 4, 5, 6, 7, 8, or 9 carbons, a branched alkyl of 3, 4, 5, 6, 7, 8, or 9 carbons, or an alkenyl or alkynyl of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbons;

R 3 is —(CH 2 ) p —, wherein p is 2, 3, 4, 5 or 6;

R 4 and R 5 are the same or different, each a hydrogen, or a linear or branched alkyl of 1, 2, 3, 4, 5 or 6 carbons;

L 1 and L 2 are the same or different, of the structure —(CH 2 ) n —CH═CH—(CH 2 ) r —,

wherein n and r each is independently selected from 1 to 15, wherein n+r is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16;

L 3 is a bond;

X 1 is —CO—O— whereby -L 2 -CO—O—R 2 is formed;

X 2 is S or O; and

X 3 is —CO—O— whereby -L 1 -CO—O—R 1 is formed; and

m+n+p+r is 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27;

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 18 , wherein X 2 is S.

20. The compound of claim 18 , wherein m+n+p+r is 12, 13, 14, or 15.