Degradable lipid for active molecule delivery and lipid nanoparticle thereof

1 . A lipid compound of formula (I),

wherein

R 2a and R 3a are each independently selected from the group consisting of hydrogen, a monovalent aliphatic group, a monovalent heteroaliphatic group, a monovalent aromatic group, a monovalent heteroaromatic group, and Ht;

t and s are each independently 0 or 1, and when t or s is zero, it means that the part is directly a single bond, provided that t and s are not both 0;

A 1 , A 2 , and A 3 are each independently selected from the group consisting of a single bond, a divalent aliphatic group, a divalent heteroaliphatic group, a divalent aromatic group, and a divalent heteroaromatic group;

each Ht is independently at each occurrence —R 1 —X—R 2 —Y—R 3 —Z—R 4 ,

wherein

each R 1 is independently at each occurrence selected from the group consisting of a divalent aliphatic group, a divalent heteroaliphatic group, a divalent aromatic group, and a divalent heteroaromatic group;

each X is independently at each occurrence

wherein

m is 1-6;

W is selected from the group consisting of O, S, and NR c ;

L 1 is directly connected to R 1 and is selected from the group consisting of a single bond, O, S, and NR d ;

L 2 is selected from the group consisting of a bond, O, S, and NR e ;

wherein R c , R d , and R e are each independently selected from the group consisting of hydrogen, hydroxy, an oxyaliphatic group, a monovalent aliphatic group, a monovalent heteroaliphatic group, a monovalent aromatic group, and a monovalent heteroaromatic group;

Y and Z are both S;

each R 2 is independently at each occurrence selected from the group consisting of a single bond, a divalent aliphatic group, a divalent heteroaliphatic group, a divalent aromatic group, and a divalent heteroaromatic group;

R 3 is independently at each occurrence

each R 4 is independently at each occurrence a hydrophobic group selected from the group consisting of —(CH 2 CH 2 O) y —C 3-8 alkyl, —(CH 2 CH 2 O) y —C 3-8 alkenyl and —(CH 2 CH 2 O) y —C 3-8 alkynyl, wherein y is 0 or 1 or 2.

2 . The lipid compound of claim 1 , wherein t is 0 and s is 1; or t is 1 and s is 0.

3 . The lipid compound of claim 1 , wherein R 1 is selected from the group consisting of a C 1-6 divalent aliphatic group and a C 1-6 divalent heteroaliphatic group.

4 . The lipid compound of claim 1 , wherein L 1 is selected from the group consisting of a single bond, O, S, and NH.

5 . The lipid compound of claim 1 , wherein X is

wherein R d and R e are as defined for formula (I) in claim 1 .

6 . The lipid compound of claim 5 , wherein R d and R e are each independently selected from the group consisting of H and a C 1-4 monovalent aliphatic group.

7 . The lipid compound of claim 1 , wherein each R 2 is independently at each occurrence selected from the group consisting of a single bond and a C 1-6 divalent aliphatic group.

8 . The lipid compound of claim 7 , wherein each R 2 is independently at each occurrence C 1-4 divalent aliphatic group.

9 . The lipid compound of claim 1 , wherein

each R 4 is independently at each occurrence selected from the group consisting of C 3-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, (CH 2 CH 2 O)—C 3-8 alkyl, (CH 2 CH 2 O)—C 3-8 alkenyl, (CH 2 CH 2 O)—C 3-8 alkynyl, (CH 2 CH 2 O) 2 —C 3-8 alkyl, (CH 2 CH 2 O) 2 —C 3-8 alkenyl and (CH 2 CH 2 O) 2 —C 3-8 alkynyl; or

each R 4 is independently at each occurrence selected from the group consisting of C 4-8 alkyl, C 4-8 alkenyl, C 4-8 alkynyl, (CH 2 CH 2 O)—C 4-8 alkyl, (CH 2 CH 2 O)—C 4-8 alkenyl, (CH 2 CH 2 O) 2 —C 4-8 alkynyl, (CH 2 CH 2 O) 2 —C 4-8 alkyl, (CH 2 CH 2 O) 2 —C 4-8 alkenyl and (CH 2 CH 2 O) 2 —C 4-8 alkynyl.

10 . The lipid compound of claim 9 , wherein the alkyl in the C 4-8 alkyl, (CH 2 CH 2 O)—C 4-8 alkyl or (CH 2 CH 2 O) 2 —C 4-8 alkyl is a linear alkyl; the alkenyl in the C 4-8 alkenyl, (CH 2 CH 2 O)—C 4-8 alkenyl or (CH 2 CH 2 O) 2 —C 4-8 alkenyl is a linear alkenyl; and the alkynyl in the C4-8 alkynyl, (CH 2 CH 2 O)—C 4-8 alkynyl or (CH 2 CH 2 O) 2 —C 4-8 alkynyl is a linear alkynyl.

11 . The lipid compound of claim 9 , wherein each R 4 is independently at each occurrence selected from the group consisting of —(CH 2 CH 2 O)—(CH 2 ) 3 CH 3 , —(CH 2 CH 2 O) 2 —(CH 2 ) 3 CH 3 , —(CH 2 CH 2 O)—(CH 2 ) 4 CH 3 , —(CH 2 CH 2 O) 2 —(CH 2 ) 4 CH 3 , —(CH 2 CH 2 O)—(CH 2 ) 5 CH 3 , —(CH 2 CH 2 O) 2 —(CH 2 ) 5 CH 3 , —(CH 2 CH 2 O)—(CH 2 ) 6 CH 3 , —(CH 2 CH 2 O) 2 —(CH 2 ) 6 CH 3 , —(CH 2 CH 2 O)—(CH 2 ) 7 CH 3 and —(CH 2 CH 2 O) 2 —(CH 2 ) 7 CH 3 .

12 . The lipid compound of claim 1 , wherein each Ht is independently at each occurrence

wherein Y and Z are both S; or Y is S and Z is O; or Y is O and Z is S; or Y and Z are both O; each R 3 is independently at each occurrence

and R 44 is C 4-8 alkyl, C 4-8 alkenyl or C 4-8 alkynyl.

13 . The lipid compound of claim 12 , wherein each R 44 is independently at each occurrence selected from the group consisting of —(CH 2 ) 3 CH 3 , —(CH 2 ) 4 CH 3 , —(CH 2 ) 5 CH 3 , —(CH 2 ) 6 CH 3 and —(CH 2 ) 7 CH 3 .

14 . The lipid compound of claim 1 , wherein

t is 1, s is 0, A 2 is a single bond, and A 1 and A 3 are each independently selected from the group consisting of a divalent aliphatic group and a divalent heteroaliphatic group; or

t is 1, s is 0, A 2 is a single bond, and A 1 and A 3 are each independently a C 1-6 divalent aliphatic group; or

t is 1, s is 0, A 2 is a single bond, A 1 and A 3 are each independently selected from the group consisting of —CH 2 CH 2 — and —CH 2 CH 2 CH 2 —, and

R 2a is selected from the group consisting of hydrogen and a monovalent aliphatic group.

15 . The lipid compound of claim 1 , wherein

t is 1, s is 1, and A 1 , A 2 and A 3 are each independently selected from the group consisting of a divalent aliphatic group and a divalent heteroaliphatic group; or

t is 1, s is 1, and A 1 , A 2 and A 3 are each independently a C 1-6 divalent aliphatic group; or

t is 1, s is 1, and A 1 , A 2 and A 3 are each independently selected from the group consisting of —CH 2 CH 2 — and —CH 2 CH 2 CH 2 —, and

R 2a and R 3a are each independently selected from the group consisting of hydrogen and a monovalent aliphatic group.

16 . The lipid compound of claim 1 , wherein

wherein R 2a and R 3a are each independently selected from the group consisting of hydrogen and a monovalent aliphatic group.

17 . A lipid compound selected from the group consisting of

YX17

YX31

YX27

YX28

YX35

YX29

and

YX33

18 . A pharmaceutical composition comprising a pharmaceutical carrier and a lipid nanoparticle, wherein the lipid nanoparticle comprises the lipid compound of claim 1 and a pharmaceutically active molecule.

19 . A method for regulating gene expression comprising delivering a nucleic acid to a cell, the method comprising: contacting the cell with the pharmaceutical composition of claim 18 under conditions sufficient to cause uptake of the nucleic acid into the cell.