Ionizable lipid compounds

1. A compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof:

wherein,

M 1 and M 2 are independently selected from —(O)O—, —OC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —C(O)NR a —, and —NR a C(O)—;

Q is —C(O)O—;

G 5 is a chemical bond;

G 6a and G 6b are independently a chemical bond or C 1-7 alkylene;

G 6a and G 6b have a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms;

R 9 and R 10 are independently H or C 1-8 alkyl;

G 1 , G 2 , G 3 and G 4 are independently a chemical bond, C 1-13 alkylene, C 2-13 alkenylene or C 2-13 alkynylene, which is optionally substituted with one or more R s ;

G 1 and G 2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

G 3 and G 4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

R 3 and R 4 are independently H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C 6-10 aryl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*:

or, R 3 and R 4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl, which is optionally substituted with one or more R*;

or, R 4 and Ro are taken together with the atoms to which they are attached to form 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*;

R* is independently H, halogen, cyano, C 1-10 alkyl, C 1-10 haloalkyl, -L b -OR b , -L b -SR b or -L b -NR b R′ b ;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

R 1 and R 2 are independently C 4-20 alkyl, C 4-20 alkenyl or C 4-20 alkynyl, which is optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with —NR″—;

R s is independently H, C 1-14 alkyl, -L d -OR d , -L d -SR d or -L d -NR d R′ d ;

R is independently H, C 1-20 alkyl, -L a -OR a , -L a -SR a or -L a -NR a R′ a ;

R″ is independently H or C 1-20 alkyl;

L a and L e are independently a chemical bond or C 1-20 alkylene;

L b and L f are independently a chemical bond or C 1-10 alkylene;

L d is independently a chemical bond or C 1-14 alkylene;

R a and R′ a are independently H, C 1-20 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C 1-20 alkyl, -L e -OR e , -L e -SR e and -L e -NR e R′ e ;

R b and R′ b are independently selected from H, C 1-10 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl, which are optionally substituted with one or more of the following substituents: H, C 1-10 alkyl, -L f -OR f , -L f -SR f and -L f -NR f R′ f ,

R d and R′ d are independently H or C 1-14 alkyl;

R e and R′ e are independently H or C 1-20 alkyl;

R f and R′ f are independently H or C 1-10 alkyl.

2. The compound of formula (IV) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has the structure of formula (V):

wherein,

Q is —C(O)O—;

G 6a and G 6b are independently a chemical bond or C 1-5 alkylene;

G 6a and G 6b have a total length of 0, 1, 2, 3, 4 or 5 carbon atoms;

R 9 is selected from H and C 1-6 alkyl;

one of L 3 and L 5 , or one of L 4 and L 6 is —(CR s R s ′) 2 —, —CH═CH—, or —C═C—, and the other is a chemical bond;

G 1a , G 1b , G 2a , G 2b , G 3a , G 3b , G 4a and G 4b are independently a chemical bond or C 1-7 alkylene, which is optionally substituted with 1, 2, 3, 4 or 5 R s ;

G 1a , G 1b , G 2a and G 2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms;

G 3a , G 3b , G 4a and G 4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms;

R 3 and R 4 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 10-membered cycloalkyl and 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

or, R 3 and R 4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

or, R 4 and R 5 are taken together with the atoms to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

R* is independently H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L b -OR b or -L b -NR b R′ b ;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O, S or NR a ;

L 1 and L 2 are independently —(CRR′) 2 —, —CH═CH—, —C≡C— or —NR″—;

G 7 , G 8 , G 9 and G 10 are independently a chemical bond or C 1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R;

G 7 and G 8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms;

G 9 and G 10 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms;

R s and R s ′ are independently H, C 1-10 alkyl, -L d -OR d or -L d -NR d R′ d ;

R and R′ are independently H, C 1-14 alkyl, -L a -OR a or -L a -NR a R′ a ;

R″ is independently H or C 1-14 alkyl;

L a is independently a chemical bond or C 1-14 alkylene;

L b is independently a chemical bond or C 1-6 alkylene;

L d is independently a chemical bond or C 1-10 alkylene;

R a and R′ a are independently H, C 1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl;

R b and R′ b are independently H, C 1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl;

R a and R′ a are independently H or C 1-10 alkyl.

3. The compound of formula (IV) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, which has the structure of formula (VI) or formula (VII):

wherein,

a, a′, b and g are independently 0, 1, 2, 3, 4 or 5, a′ and b are not 0 at the same time;

a′+g=0, 1, 2, 3, 4 or 5;

c and e are independently 3, 4, 5, 6, 7, 8 or 9;

d and f are independently 0, 1, 2, 3 or 4;

c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9;

methylenes in

 are optionally and independently substituted with 1, 2, 3, 4 or 5 C 1-6 alkyl;

R 3 and R 4 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

or, R 3 and R 4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;

R* is independently H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L b -OR b or -L b -NR b R′ b ;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O, S or NR a ;

L 1 and L 2 are independently —(CRR′) 2 —, —CH═CH—, —C≡C— or —NR″—;

G 7 , G 8 , G 9 and G 10 are independently a chemical bond or C 1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R;

G 7 and G 8 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms;

G 9 and G 10 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms;

R and R′ are independently H, C 1-14 alkyl, -L a -OR a or -L a -NR a R′ a ;

L a is independently a chemical bond or C 1-14 alkylene;

L b is independently a chemical bond or C 1-6 alkylene;

R a and R′ a are independently H, C 1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl;

R b and R′ b are independently H, C 1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl;

R″ is independently H or C 1-14 alkyl.

4. The compound of formula (VI) or formula (VII) of claim 3 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 0, 1, 2, 3 or 4;

a′ and b are independently 0, 1, 2, 3 or 4;

g is 0, 1 or 2;

a′+g=0, 1, 2, 3, 4 or 5;

c and e are independently 3, 4, 5 or 6;

d and f are independently 0, 1 or 2;

c+d=4, 5 or 6, e+f=4, 5 or 6;

methylenes in

 are optionally and independently substituted with 1, 2, 3, 4 or 5 C 1-6 alkyl;

methylenes in

 are optionally and independently substituted with 1 or 2 C 1-6 alkyl;

R 3 and R 4 are independently C 1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*;

R* is independently H, C 1-6 alkyl, C 1-6 haloalkyl or —OR b ;

or, R 3 and R 4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O, S or NR a ;

L 1 and L 2 are independently —(CHR) 2 —, —CH═CH—, —C≡C— or —NR″—;

G 7 and G 9 are independently a chemical bond or C 1-6 alkylene;

G 9 and G 10 are independently C 1-10 alkylene;

G 7 and G 8 have a total length of 6, 7, 8, 9 or 10 carbon atoms;

G 9 and G 10 have a total length of 6, 7, 8, 9 or 10 carbon atoms;

1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;

R is independently H or C 1-8 alkyl;

R″ is independently H or C 1-10 alkyl;

R a is independently H or C 1-10 alkyl;

R b is independently H or C 1-6 alkyl.

5. The compound of formula (VI) of claim 4 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 0, 1, 2, 3 or 4;

c and e are independently 3, 4, 5 or 6;

d and f are independently 0, 1 or 2;

c+d=4, 5 or 6, e+f=4, 5 or 6;

R 3 and R 4 are independently C 1-6 alkyl;

or, R 3 and R 4 are taken together with the N atom to which they are attached to form 4- to 6-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*;

R* is independently H, C 1-6 alkyl or C 1-6 haloalkyl;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O, S or NR a ;

L 1 and L 2 are independently —(CHR) 2 —, —CH═CH—, —C≡C— or —NR″—;

G 7 and G 9 are independently a chemical bond or C 1-5 alkylene;

G 9 and G 10 are independently C 1-8 alkylene;

G 7 and G 8 have a total length of 6, 7, 8, 9 or 10 carbon atoms;

G 9 and G 10 have a total length of 6, 7, 8, 9 or 10 carbon atoms;

1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;

R is independently H or C 1-8 alkyl;

R″ is independently H or C 7-9 alkyl;

R a is independently H or C 8-10 alkyl.

6. The compound of formula (VI) of claim 5 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 2, 3 or 4;

c and e are independently 3, 4, 5 or 6;

d and f are independently 0, 1 or 2;

c+d=4, 5 or 6, e+f=4, 5 or 6;

R 3 and R 4 are independently C 1-6 alkyl;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O or S;

L 1 and L 2 are independently —(CHR) 2 —, —CH═CH— or —C≡C—;

G 7 and G 9 are independently C 1-4 alkylene;

G 9 and G 10 are independently C 2-7 alkylene;

G 7 and G 8 have a total length of 6, 7 or 8 carbon atoms;

G 9 and G 10 have a total length of 6, 7 or 8 carbon atoms;

1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;

R is independently H or C 1-7 alkyl;

provided that, when Li is —C≡C—, then G 7 is C 1-2 alkylene, or when L 2 is —C≡C—, then G 9 is C 1-2 alkylene.

7. The compound of formula (VI) of claim 5 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 2, 3 or 4;

c and e are independently 4, 5 or 6;

d and f are 0;

R 3 and R 4 are independently C 1-6 alkyl;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are O;

L 1 and L 2 are independently —(CHR) 2 — or —CH═CH—;

G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;

G 8 and G 10 are independently —(CH 2 ) 6 — or —(CH 2 ) 7 —;

G 7 and G 8 have a total length of 7 or 8 carbon atoms;

G 9 and G 10 have a total length of 7 or 8 carbon atoms;

1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;

R is independently H or C 4-6 alkyl.

8. The compound of formula (VI) of claim 5 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 2;

c and e are independently 4, 5 or 6;

d and f are 0;

R 3 and R 4 are independently C 1-6 alkyl;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O or S;

one of L 1 and L 2 is —C≡C—, the other is —(CHR) 2 —, or both of L 1 and L 2 are —C≡C—;

G 7 and G 9 are —CH 2 —;

G 9 and G 10 are independently —(CH 2 ) 6 — or —(CH 2 ) 7 —;

1 methylene in G 8 or G 10 is optionally and independently substituted with 1 R;

R is independently H or C 4-6 alkyl;

provided that, only one of the -G 7 -L 1 -G 8 -H and -G 9 -L 2 -G 10 -H is substituted with one non-hydrogen R substituent and the other is unsubstituted.

9. The compound of formula (VI) of claim 5 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 2;

c and e are independently 4, 5 or 6;

d and f are 0;

R 3 and R 4 are independently C 1-3 alkyl;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O or S;

both of L 1 and L 2 are —C≡C—;

G 7 and G 9 are —CH 2 —;

G 8 and G 10 are independently —(CH 2 ) 6 — or —(CH 2 ) 7 —.

10. The compound of formula (VI) of claim 5 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 2;

c and e are 3;

d and f are 2;

R 3 and R 4 are independently C 1-3 alkyl;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O or S;

L 1 and L 2 are —(CHR) 2 —;

G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;

G 9 and G 10 are independently —(CH 2 ) 5 —, —(CH 2 ) 6 — or —(CH 2 ) 7 —;

G 7 and G 8 have a total length of 6, 7 or 8 carbon atoms;

G 9 and G 10 have a total length of 6, 7 or 8 carbon atoms;

1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;

R is independently H or C 1-7 alkyl.

11. The compound of formula (VI) of claim 5 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein,

a is 2;

c and e are 4, 5, or 6;

d and f are 0;

R 3 and R 4 are independently C 1-6 alkyl;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are S;

L 1 and L 2 are —(CHR) 2 —;

G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;

G 9 and G 10 are independently —(CH 2 ) 5 —, —(CH 2 ) 6 — or —(CH 2 ) 7 —;

G 7 and G 8 have a total length of 7 or 8 carbon atoms;

G 9 and G 10 have a total length of 7 or 8 carbon atoms;

1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;

R is independently H or C 4-6 alkyl.

12. The compound of formula (VII) of claim 4 , or a pharmaceutically acceptable salt isotopic variant, tautomer or stereoisomer thereof, wherein,

a′ and b are 2;

g is 0 or 1;

c and e are 5;

d and f are 0;

R 3 is C 1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*;

R* is independently H, C 1-6 alkyl, C 1-6 haloalkyl or —OR b ;

R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;

Y 1 and Y 2 are independently O or S;

L 1 and L 2 are —(CHR) 2 —;

G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;

G 9 and G 10 are independently —(CH 2 ) 5 —, —(CH 2 ) 6 — or —(CH 2 ) 7 —;

G 7 and G 8 have a total length of 6, 7 or 8 carbon atoms;

G 9 and G 10 have a total length of 6, 7 or 8 carbon atoms;

1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;

R is independently H or C 4-6 alkyl;

R b is independently H or C 1-6 alkyl.

13. The compound of formula (IV) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, the compound is selected from the following:

or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

14. A pharmaceutical composition, comprising the compound of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, and pharmaceutically acceptable excipient(s).

15. A method of delivering a load in a subject, comprising administering to the subject the pharmaceutical composition of claim 14 ;

wherein, the load is one or more of therapeutic, prophylactic or diagnostic agents.

16. A method for preparing the compound of general formula (II), comprising:

reacting the compound of general formula (IIb) with the compound of general formula (IIc), to give the compound of general formula (II);

wherein,

R 1 , R 2 , G 1 , G 2 , G 3 or G 4 is as defined in claim 1 ;

G 6 is C 1-8 alkyl;

M 1 or M 2 is as defined in claim 1 ;

R 3 or R 4 is as defined in claim 1 ;

R 5 , R 6 , R 7 or R 8 is as defined in claim 1 .

17. The compound of formula (IV) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein M 1 and M 2 are independently selected from —(O)O—, —OC(O)—, —SC(O)—, and —C(O)S—.

18. The compound of formula (IV) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein M 1 and M 2 are independently selected from —(O)O-and-OC(O)—.

19. The compound of formula (VI) of claim 7 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a is 2, or 3.

20. The compound of formula (VI) of claim 7 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, -G 7 -L 1 -G 8 -H and -G 9 -L 2 -G 10 -H are not-(CH 2 ) 9 CH 3 at the same time.

21. The compound of formula (VI) of claim 8 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, one of L 1 and L 2 is —C≡C—, the other is —(CHR) 2 —.

22. The compound of formula (VI) of claim 10 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R is independently H or C 1-6 alkyl.

23. The compound of formula (VI) of claim 10 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R is Me.

24. The compound of formula (VI) of claim 11 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, G 7 and G 8 have a total length of 8 carbon atoms.

25. The compound of formula (VI) of claim 11 , or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, G 9 and G 10 have a total length of 8 carbon atoms.