Granted Patent B2

US 12,617,752 · App. 18/736,389 · Granted May 5, 2026

Inventors: Lin Zhang (Beijing, CN); Feng Shi (Beijing, CN); Andong Liu (Beijing, CN); Liu Yang (Beijing, CN); Shaoli Liu (Beijing, CN); Xuhui Wang (Beijing, CN); Moyan Liu (Beijing, CN); Yan Gong (Beijing, CN); Jeffrey Michael Warrington (Cambridge, MA)

Assignees: Beijing Jitai Life Sciences Ltd; Metis TechBio Co., Ltd.

C07C229/24A61K9/5123C07C69/675

Abstract

Claims (528)

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

wherein,

G 1 and G 2 are independently selected from a chemical bond, C 1-13 linear alkylene, C 2-13 linear alkenylene, and C 2-3 linear alkynylene, each of which is optionally substituted with one or more R G1 ;

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

R G1 is independently H, C 1-14 alkyl, —L a -OR a , L a -SR a , or -L a -NR a R′ a ;

G 3 is C 4-14 linear alkylene, C 4-14 linear alkenylene, or C 4-14 linear alkynylene, each of which is optionally substituted with one or more R 3 ;

R G3 is independently —H, -L a -OR a , -L a -SR a , or -L a -NR a R′ a ;

L a is independently a chemical bond or C 1-4 alkylene;

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

G 4 is a chemical bond, C 1-6 alkylene, C 2-6 alkenylene, or C 2-6 alkynylene, each of which is optionally substituted with one or more R G4 ;

R G4 is independently H, C 1-6 alkyl, -L b -OR b , -L b -SR b , or -L b -NR b R′ b ;

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

R b and R′ b are independently selected from H, and C 1-6 alkyl;

or, two R G4 attached to the same carbon atom are taken together with the carbon atom to which they are attached to form C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, each of which is optionally substituted with one or more R 4g ;

R 4g is independently H, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, -L e -OR e , -L e -SR e , or -L e -NR e R′ e ;

L e is independently a chemical bond or C 1-8 alkylene;

R e and R′ e are independently selected from H, C 1-8 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclyl;

M 1 and M 2 are independently selected from —C(O)O—, —OC(O)—, —O—, —SC(O)O—, —OC(O)NR—, —NRC(O)NR—, —OC(O)S—, —OC(O)O—, —NRC(O)O—, —SC(O)—, —C(O)S—, —NR—, —C(O)NR—, —NRC(O)—, —NRC(O)S—, —SC(O)NR—, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR—, —NRC(S)O—, —S—S—, and —S(O) 0-2 —; Q is selected from a chemical bond, —C(O)O—, —O—, —SC(O)O—, —OC(O)NR f —, —NR f C(O)NR f —, —OC(O)S—, —OC(O)O—, —NR f C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —NR f —, —C(O)NR f —, —NR f C(O)—, —NRC(O)S—, —SC(O)NR f —, —C(O)—, —OC(S)—, —C(S)O—, —OC(S)NR f —, —NR f C(S)O—, —S—S—, —S(O) 0-2 —, phenylene, and pyridinylene;

R 1s independently selected from H, and C 1-10 alkyl;

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

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

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

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

R c and R′ c are independently selected from H, C 1-20 alkyl, C 3-14 cycloalkyl, and 3- to 14-membered heterocyclyl;

R 3 is selected from CN, —OR g , —C(O)R g , —OC(O)R g , —NR″C(O)R g , —NR g R′ g , —NR″C(O)NR g R′ g , —NR″C(O)R g , —NR″S(O) 2 R g , —OC(O)NR g R′ g , —NR″C(O)OR g , —N(OR g )C(O)R g , —N(OR g )S(O) 2 R g , —N(OR g )C(O)OR g , —N(OR g )C(O)R g R′ g , 3- to 14-membered heterocyclyl, and 5- to 14-membered heteroaryl;

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

R″ is independently H or C 1-6 alkyl;

R 4 and R 5 are independently C 1 alkyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3 a cycloalkylene or 3- to 6-membered heterocyclylene.

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

wherein,

a=1, 2, 3, 4, 5, or 6;

b=4, 5, 6, 7, 8, 9, or 10;

c=1, 2, 3, 4, 5, or 6;

d===0, 1, 2, 3, or 4;

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

the other groups are as defined in claim 1 .

3 . The compound of fornnula (II) or formula (III) of claim 2 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof,

wherein,

the substitution site of R 1s on R 1 or R 2 is separated from M 1 or M 2 by 0-10 carbon atoms,

alternatively 0-6 carbon atoms, alternatively 0-4 carbon atoms, alternatively 0-2 carbon atoms,

alternatively 0 carbon atoms;

alternatively, the substitution site of R 1s on R 1 or R 2 is separated from M 1 or M 2 by 1-10 carbon atoms, alternatively 1-6 carbon atoms, alternatively 1-4 carbon atoms, alternatively 1-2 carbon atoms; alternatively 2-10 carbon atoms, alternatively 2-6 carbon atoms, alternatively 2-4 carbon atoms;

alternatively, R 1 is not substituted with R 1s and the substitution site of R 1s on R 2 is separated from M 2 by 0-10 carbon atoms, alternatively 1-10 carbon atoms, alternatively 1-6 carbon atoms,

alternatively 1-4 carbon atoms, alternatively 1-2 carbon atoms; alternatively 2-10 carbon atoms,

alternatively 2-6 carbon atoms, alternatively 2-4 carbon atoms;

alternatively, R 1 is substituted with R 1s , and R 2 is not substituted with R 1s ;

alternatively, R 4 and R 5 are not taken together with the carbon atom to which they are attached to form a ring;

alternatively, d is not 0.

4 . The compound of formula (II) of claim 2 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof,

wherein

a=2, 3, 4, 5, or 6;

b=4, 5, 6, 7, 8, 9, or 10;

c=1, 2, 3, 4, 5, or 6;

d=0, 1, 2, 3, or 4;

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

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

M 1 and M 2 are independently selected from —C(O)O— and —C(O)S—; alternatively, one of M 1 and M 2 is —C(O)O— or —C(O)S—, and the other is —OC(O)— or —SCO)—;

R 1 and R 2 are independently C 6-14 alkyl, which is optionally substituted with 1, 2, 3, or 4 R 1s ;

R 1s is independently H, C 1-14 alkyl, -L c -OR c , or -L c -NR c R′ c , alternatively H or C 1-4 alkyl;

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

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

R 4 and R 5 are independently C 1-3 alkyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene or 3-to 6-membered heterocyclylene;

alternatively,

a=2, 3, or 4;

b=4, 5, 6, 7, 8, or 9; alternatively b=5, 6, 7, or 8; alternatively b=5, 6, or 7;

c=2, 3, 4, 5, or 6;

d=0, 1, 2, 3, or 4;

c+d=5 or 6;

M 1 and M 2 are independently —C(O)O— or —OC(O)—; alternatively, M 1 and M 2 are —C(O)O—;

alternatively, one of M 1 and M 2 is —C(O)O—, and the other is —OC(O)—;

R 1 and R 2 are independently C 7-12 alkyl, alternatively C 8-12 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently H or C 1-10 alkyl, alternatively H or C 1-9 alkyl;

R 4 and R 5 are independently C 1-3 alkyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene, alternatively C 3-5 cycloalkylene;

alternatively,

a=2, 3, or 4;

b=4, 5, 6, 7, 8, or 9; alternatively b=5, 6, 7, or 8; alternatively b=5 or 7;

c=2, 3, 4, 5, or 6;

d=0, 1, 2, 3, or 4; alternatively d=0, 1, 2, or 4;

c+d=5 or 6; alternatively c+d=6;

M 1 and M 2 are —C(O)O—;

or, one of M 1 and M 2 is —C(O)O—, and the other is —OC(O)—;

R 1 and R 2 are independently selected from: —(CH 2 ) 6 CH 3 , —(CH 2 ) 7 CH 3 , —(CH 2 ) 8 CH 3 , —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH 3 , —(CH 2 ) 11 CH 3 ,

alternatively —(CH 2 ) 7 CH 3 , —(CH 2 ) 8 CH 3 , —(CH 2 ) 9 CH 3 , (CH 2 ) 10 CH 3 , —(CH 2 ) 11 CH 3 ,

alternatively —(CH 2 ) 8 CH 3 , —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH—(CH 2 ) 11 CH 3 ,

R 4 and R 5 are methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, alternatively cyclopropylene or cyclopentylene, alternatively cyclopropylene;

alternatively, only one of R 1 and R 2 is substituted.

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

a=2;

b=5;

c=2, 3, 4, 5, or 6; alternatively c=6;

d=0, 1, 2, 3, or 4; alternatively d 0;

c+d=5 or 6, alternatively 6:

M 1 and M 2 are —C(O)O—;

R 1 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 8-9 alkyl, or alternatively C 9 alkyl, which is optionally substituted with 1 R 1 ;

R 1s is independently H or C 1-10 alkyl, alternatively H or C 1-9 alkyl, alternatively C 6-8 alkyl, alternatively C 7-8 alkyl;

R 2 is C 7-11 linear alkyl, alternatively C 10-11 linear alkyl, alternatively C 11 linear alkyl, which is optionally substituted with 1 C 1-3 alkyl, alternatively optionally substituted with 1 methyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

alternatively R 1 is

alternatively

alternatively, R 2 is —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH 3 , or

alternatively,

a=2, 3, or 4; alternatively a=2;

b=7;

c=2, 3, 4, 5, or 6; alternatively c=2, 3, or 4; alternatively c=2;

d=0, 1, 2, 3, or 4; alternatively d=2, 3, or 4; alternatively d=4;

c+d=5 or 6, alternatively 6;

M 1 and M 2 are —C(O)O—;

R 1 is C 8-11 linear alkyl, alternatively C 9-10 linear alkyl, alternatively C 9 linear alkyl;

R 2 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 9-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently H or C 1-10 alkyl, alternatively H or C 1-9 alkyl, alternatively C 6-9 alkyl, alternatively C 7-8 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

alternatively, R 2 is

alternatively

alternatively,

a=2;

b=7;

c=3 or 4; alternatively c=4;

d=2;

M j and M 2 are —C(O)O—;

R 1 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 8-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently H or C 1-10 alkyl, alternatively H or C 1-9 alkyl;

R 2 is C 7-11 linear alkyl, alternatively C 9 linear alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

alternatively,

a=2, 3, or 4; alternatively a=2 or 4;

b=6 or 7; alternatively b=7;

c=2, 3, 4, 5, or 6; alternatively c=5 or 6;

d=0, 1, 2, 3, or 4; alternatively d=0 or 1;

c+d=5 or 6, alternatively 6;

M 1 is —OC(O)—; and M 2 is —C(O)O—;

R 1 is C 7-11 linear alkyl, alternatively C 9-10 linear alkyl;

R 2 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 9-10 linear alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 7-9 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

alternatively, when a=4, R 4 and R 5 are not taken together with the carbon atom to which they are attached to form a ring; alternatively, R 1s is independently C 8-9 alkyl;

alternatively, R 2 is

6 . The compound of formula (II) of claim 2 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof,

wherein

a=2, 3, 4, 5, or 6;

b=4, 5, 6, 7, 8, 9, or 10;

c=1, 2, 3, 4, 5, or 6;

d=0, 1, 2, 3, or 4;

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

M 1 and M 2 are independently selected from —C(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, —N—HC(O)—, and —C(O)NH—, alternatively —C(O)O—, —OC(O)—, —SC(O)—, and —C(O)S—; alternatively, one of M 1 and M 2 is —C(O)O— or —C(O)S—, and the other is —C(O)O—, —C(O)S—, —C(O)NH—, —OC(O)— or —SC(O)— alternatively —C(O)O—, —C(O)S—, —OC(O)— or —SC(O)—;

R 1 and R 2 are independently C 6-14 alkyl, C 6-14 alkenyl, or C 6-14 alkynyl, each of which is optionally substituted with 1, 2, 3, or 4 R 1s ;

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

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

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

R 4 and R 5 are independently C13 alkyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene or 3- to 6-membered heterocyclylene;

alternatively,

a=2, 3, or 4;

b=4, 5, 6, 7, 8, or 9, alternatively b=5, 6, 7, or 8, alternatively b=5, 6, or 7;

c=2, 3, 4, 5, or 6;

d=0, 1, 2, 3, or 4;

c+d=5, 6, or 7;

M 1 and M 2 are independently —C(O)O—, —OC(O)—, —C(O)S— or —C(O)NH—, alternatively —C(O)O—, —OC(O)—, or —C(O)S—; alternatively, one of M 1 and M 2 is —C(O)O—, and the other is —C(O)O—, —(C(O)S—, —C(O)NH—, or —OC(O)—, alternatively —C(O)O—, —C(O)S—, or —OC(O)—;

R 1 and R 2 are independently C 7-12 alkyl, C 7-12 alkenyl, or C 7-12 alkynyl, alternatively C 8-12 alkyl, C 8-12 alkenyl, or C 8-12 alkynyl, each of which is optionally substituted with 1 R 1s ;

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

R 4 and R 5 are independently C 1-3 alkyl;

or, R 1 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene, alternatively C 3-5 cycloalkylene;

alternatively,

a=2, 3, or 4;

b=4, 5, 6, 7, 8, or 9; alternatively b=5, 6, 7, or 8; alternatively b=5 or 7;

c=2, 3, 4, 5, or 6;

d=01, 2, 3, or 4;

c+d=5, 6, or 7; alternatively c+d==6;

one of M 1 and M 2 is —C(O)O—, and the other is —C(O)O—, —C(O)S—, —C(O)NH—, or —OC(O)—, alternatively —C(O)O—, —C(O)S—, or —OC(O)—;

R 1 and R 2 are independently selected from: —(CH 2 ) 6 CH 3 , —(CH 2 ) 7 CH 3 , —(CH 2 ) 5 CH 3 , —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH 3 , —(CH 2 ) 11 CH 3 , —CH 2 —CH═CH—CH—(CH 2 ) 5 CH 3 , —CH 2 —C≡C—(CH 2 ) 5 CH 3 , —(CH 2 ) 2 —C≡C—(CH 2 ) 10 CH 3 , —(CH 2 ) 3 —C≡C—(CH 2 ) 3 CH 3 ,

alternatively: —(CH 2 ) 7 CH 3 , —(CH 2 —) 8 CH 3 , —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH 3 , —(CH 2 ) 11 CH 3 , —CH 2 —CH═CH—(CH 2 )CH 5 , —CH 2 —C≡C—(C 2 )CH 3 , —(CH 2 ) 2 —C≡C—(CH 2 ) 4 CH 3 , —(CH 2 ) 3 —C≡C—(C 2 ) 3 CH 3 ,

alternatively: —(CH 2 ) 8 CH 3 —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH 3 , —(CH 2 ) 11 CH 3 , —CH 2 —CH═C—(CH 2 ) 5 CH 3 , —CH 2 —C≡C—(CH 2 ) 5 CH 3 , —(CH 2 ) 2 —C≡C—(CH 2 ) 4 CH 3 , —(CH 2 ) 3 —C≡C—(CH 2 ) 3 CH 3 ,

R 4 and R 5 are methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene, alternatively cyclopropylene or cyclopentylene, alternatively cyclopropylene;

alternatively, only one of R 1 and R 2 is substituted.

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

a=2;

b=5;

c=5 or 6; alternatively c=6;

d=0 or 1; alternatively d=0,

c+d=5 or 6, alternatively 6;

M 1 is —C(O)O—, and M 2 is —C(O)O— or —C(O)S—; alternatively M 1 and M 2 are —C(O)O—;

R 1 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 8-9 alkyl, or alternatively C 9 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently H or C 1-10 alkyl, alternatively H or C 1-9 alkyl, alternatively C 6-8 alkyl,

alternatively C 7-8 alkyl;

R 2 is C 7-11 linear alkyl, alternatively C 10-11 linear alkyl, alternatively C 11 linear alkyl, which is optionally substituted with 1 C 1-3 alkyl, alternatively optionally substituted with 1 methyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

alternatively, R 1 is

alternatively

alternatively, R 2 is —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH, or

alternatively,

a=2, 3, or 4; alternatively a=2;

b=5, 6, or 7: alternatively b=7;

c=2, 3, 4, 5, or 6; alternatively c=2, 3, or 4; alternatively c=2;

d=0, 1, 2, 3, or 4; alternatively d=2, 3, or 4; alternatively d=4;

c+d=5 or 6, alternatively 6;

M 1 and M 2 are —C(O)O—;

R 1 and R 2 are independently C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 9-11 alkyl, alternatively C 9-10 alkyl, which is optionally substituted with 1 R 1s ; and only one of R 1 and R 2 is substituted;

R 1s is independently H or C 1-10 alkyl, alternatively C 6-10 alkyl, alternatively C 7-9 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene, alternatively not to form a ring;

alternatively,

R 1 is C 8-12 linear alkyl, alternatively C 9-11 linear alkyl, alternatively C 9-10 linear alkyl;

R 1 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 9-11 alkyl, alternatively C 9-10 alkyl, which is optionally substituted with 1 R 1s ; when R 2 is C 10 linear alkyl, R 1s is C 9-10 alkyl, alternatively C 9 alkyl;

alternatively, R 2 is

alternatively

alternatively,

a=2, 3, or 4;

b=6;

c=4, 5, or 6; alternatively c=5 or 6; alternatively c=5;

d=1 or 2; alternatively d=1;

c+d=6, 7, or 8; alternatively 6 or 7; alternatively 6;

M 1 is —OC(O)—; M 2 is —C(O)O—;

R 1 is C 7-12 linear alkyl, alternatively C 8-11 linear alkyl, alternatively C 9-11 linear alkyl;

R 2 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 9-12 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 7-11 alkyl, alternatively C 7-10 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

provided that, when c=4, a=2 or 3;

alternatively, R 2 is

alternatively,

a=2 or 4; b=6; c=5 or 6, alternatively c=5; d=1;

R 1 is C 8-9 linear alkyl, alternatively C 9 linear alkyl;

R 2 is C 9-10 alkyl, alternatively C 10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 7-8 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

alternatively,

a=2, 3 or 4, alternatively 2 or 4; b==6; c=5; d=2;

R 1 is C 9-10 linear alkyl, alternatively C 9 linear alkyl;

R 2 is C 9-11 alkyl, which is optionally substituted with 1 Rai;

R 1s is independently C 7-9 alkyl,

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

alternatively,

a=2, 3 or 4; alternatively a=2 or 4;

b=7;

c=5 or 6; alternatively c=5;

d=0 or 1; alternatively d::=1;

c+d=5 or 6, alternatively 6;

M 1 is —OC(O)—; M 2 is —C(O)O—;

R 1 is C 8-11 linear alkyl, alternatively C 9-10 linear alkyl, which is optionally substituted with 1 C 1-9 alkyl (alternatively C 6-9 alkyl, alternatively C 6-7 alkyl);

R 2 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively (C 9-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 7-9 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

alternatively, R 1 is —(CH 2 ) 8 CH 3 , —(CH 2 ) 9 CH 3 ,

R 2 is

alternatively, when a=4,

R 1 is C 9-10 linear alkyl;

R 2 is C 9-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is C 8-9 alkyl;

R 4 and R 5 are not taken together with the carbon atom to which they are attached to form a ring;

alternatively, when a=2,

R 1 is C 10 linear alkyl;

alternatively R 1s is C 8-9 alkyl, alternatively C 9 alkyl;

alternatively,

a=2, 3, or 4; alternatively a=2 or 4;

b=7;

c=4;

d=2;

M 1 is —OC(O)—; M 2 is —C(O)O—;

R 1 is C 8-11 linear alkyl, alternatively C 9-10 linear alkyl;

R 2 is C 8-11 alkyl, alternatively C 9-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 7-9 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene, alternatively not to form a ring;

alternatively, R 2 is

alternatively,

a=2, 3, or 4; alternatively a=2;

b=8;

c=5;

d=1;

M 1 is —OC(O)—; M 2 is —C(O)O—;

R 1 is C 8-12 linear alkyl, alternatively C 9-11 linear alkyl, alternatively C 10-11 linear alkyl;

R 2 is C 8-11 alkyl, alternatively C 9-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 7-9 alkyl, alternatively C 7-8 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene, alternatively not to form a ring;

alternatively, R 2 is

alternatively,

a=2;

b=6, 7, or 8, alternatively b=7;

c=5;

d=1;

M 1 is —OC(O)—; M 2 is —C(O)O—;

R 1 is C 8-11 linear alkyl, alternatively C 9-10 linear alkyl, alternatively C 9 linear alkyl;

R 2 is C 8-11 alkyl, alternatively C 9-10 alkyl, alternatively C 9 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 7 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

alternatively, R 2 is

alternatively,

a=2 or 3, alternatively a=2;

b=7;

c=3;

d=3;

M 1 is —OC(O)—; M 2 is —C(O)O—;

R 1 is C 8-11 linear alkyl, alternatively C 9-10 linear alkyl, alternatively C 9 linear alkyl;

R 2 is C 8-11 alkyl, alternatively C 9-10 alkyl, alternatively C 9 alkyl, which is optionally substituted with 1 R 1 ,

R 1s is independently C 6-7 alkyl, alternatively C 7 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

alternatively, R 2 is

8 . The compound of formula (I) of claim 2 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof,

wherein,

a=2, 3, 4, 5, or 6;

b=4, 5, 6, 7, 8, 9 or 10;

c=1, 2, 3, 4, 5, or 6;

d=0, 1, 2, 3, or 4,

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

one of M 1 and M 2 is —OC(O)O—, and the other is —C(O)O—, —OC(O)—, —SC(O)—, or —C(O)S—;

R 1 and R 2 are independently C 6-14 alkyl, which is optionally substituted with 1, 2, 3, or 4 R 1s ;

R 1s is independently H, C 1-14 alkyl, -L c -OR c , or -L e -NR c R′ c alternatively H or C 1-14 alkyl;

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

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

R 4 and R 5 are independently C 1-3 alkyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene or 3- to 6-membered heterocyclylene;

alternatively,

a=2, 3, or 4;

b=4, 5, 6, or 7, alternatively b=5 or 6, alternatively b=6;

c=2, 3, 4, 5, or 6; alternatively c=2, 4, 5, or 6;

d=0, 1, 2, 3, or 4; alternatively d=0, 1, 2, or 4;

c+d=5 or 6, alternatively c+d=6;

one of M 1 and M 2 is —OC(O)O—, and the other is —C(O)O— or —OC(O)—;

R 1 and R 2 are independently C 7-12 alkyl, alternatively C 9-11 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently H or C 1-10 alkyl; alternatively H or C 4-10 alkyl;

R 4 and R 5 are independently C 1-3 alkyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene, alternatively C 3-4 cycloalkylene;

alternatively,

a=2, 3, or 4;

b=4, 5, 6, or 7, alternatively b=5 or 6, alternatively b=6;

c=2, 3, 4, 5, or 6; alternatively c=2, 4, 5, or 6;

d=0, 1, 2, 3, or 4; alternatively d=0, 1, 2, or 4;

c+d=5 or 6, alternatively c+d=6;

one of M 1 and M 2 is —OC(O)O—, and the other is —C(O)O— or —OC(O)—;

R 1 and R 2 are independently selected from —(CH 2 ) 8 CH 3 , —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH 3 ,

R 4 and R 5 are methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form cyclopropylene;

alternatively, only one of R 1 and R 2 is substituted;

alternatively, M 1 is —C(O)O— or —OC(O)—, alternatively —C(O)O—, and M 2 is —OC(O)O—;

alternatively, M 1 is —OC(O)O—, and M 2 is —OC(O)—.

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

a=2;

b=5 or 6, alternatively b=6;

c=4, 5, or 6; alternatively c=4 or 6; alternatively c=6;

d=0, 1, or 2; alternatively d=0 or 2;

c+d=6;

M 1 is —C(O)O—, and M 2 is —OC(O)O—;

R 1 is C 8-11 alkyl, alternatively C 9-10 , alkyl, alternatively C 9 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is C 7-9 alkyl, alternatively C 7 alkyl;

R 2 is C 8-11 linear alkyl, alternatively C 9-10 linear alkyl, alternatively C 9 linear alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively not to form a ring;

alternatively, R 1 is

alternatively

alternatively,

a=2;

b=6;

c=4, 5, or 6; alternatively c=5 or 6; alternatively c=6;

d=0, 1, or 2; alternatively d=0 or 1;

c+d=6;

M 1 is —C(O)O—, and M 2 is —OC(O)O—;

R 1 is C 8-10 linear alkyl, alternatively C 9-10 linear alkyl, alternatively C 9 linear alkyl;

R 2 is C 8-10 alkyl, alternatively C 9-10 alkyl, alternatively C 9 alkyl, which is optionally substituted with 1 R 1s ,

R 1s is C 6-7 alkyl, alternatively C 7 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively not to form a ring;

alternatively, R 2 is

alternatively

alternatively,

a=2;

b=5 or 6; alternatively b=6;

c=5;

d=1;

M 1 is —OC(O)—, and M 2 is —OC(O)O—;

R 1 is C 8-10 alkyl, alternatively C 9-10 alkyl, alternatively C 9 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is C 6-8 alkyl, alternatively C 6-7 alkyl;

R 2 is C 8-12 linear alkyl, alternatively C 10-11 linear alkyl;

R 4 and R 5 are independently C1-alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively not to form a ring;

alternatively, R 1 is

alternatively

alternatively,

a=−2, 3 or 4; alternatively a=2;

b=5, 6, 7, or 8; alternatively b=6 or 7; alternatively b=7;

c=4, 5, or 6; alternatively c=4;

d=0, 1, or 2; alternatively d=1;

c+d=5 or 6; alternatively c+d=5;

M 1 is —OC(O)O—, M 2 is —OC(O)—;

R 1 is C 8-12 alkyl, alternatively C 8-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is C 6-10 alkyl, alternatively C 6-8 alkyl;

R 2 is C 8-12 linear alkyl, alternatively C 8-10 linear alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively not to form a ring;

alternatively, R 1 is

10 . The compound of formula (III) of claim 2 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof,

wherein,

Q is —SC(O)— or —OC(O)—;

R g and R′ g are independently C 1-6 alkyl;

a=2, 3, 4, 5, or 6; alternatively a=2, 3, or 4;

b=4, 5, 6, 7, 8, or 9; alternatively b=5, 6, or 7;

c=2, 3, 4, 5, or 6;

d=0, 1, 2, 3, or 4;

c+d=5 or 6;

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

R 1 and R 2 are independently C 6-14 alkyl, which is optionally substituted with 1, 2, 3, or 4 R 1s ;

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

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

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

R 4 and R 5 are independently C 1-3 alkyl,

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene or 3- to 6-membered heterocyclylene;

alternatively,

Q is —SC(O)— or —OC(O)—;

R g and R′ g are independently C 1-3 alkyl;

a=3 or 4;

b=6 or 7;

c=2, 3, 4, or 5; alternatively 2 or 5;

d=1, 2, 3, or 4; alternatively 1 or 4;

c+d=5 or 6;

M y and M 2 are independently selected from —C(O)O—, —OC(O)—, and —OC(O)O—; alternatively, M 1 and M 2 are not simultaneously —OC(O)O—;

R 1 and R 2 are independently C 7-12 alkyl, alternatively C 8-10 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently H or C 1-10 alkyl; alternatively H or C 1-9 alkyl;

R 4 and R 5 are independently C 1-3 alkyl,

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 6 cycloalkylene;

alternatively,

Q is —SC(O)—;

R g and R′ g are methyl;

a=3 or 4;

b=6 or 7;

c=2, 4, or 5; alternatively 2 or 5;

d=1, 2, or 4; alternatively 1 or 4;

c+d=6;

M 1 and M 2 are independently selected from —C(O)O—, —OC(O)—, and —OC(O)O—; alternatively, M 1 and M 2 are not simultaneously —OC(O)O—;

R 1 and R 2 are independently —(CH 2 ) 7 CH 3 , —(CH 2 ) 8 CH—, —(CH 2 ) 9 CH 3 ,

R 4 and R 5 are methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form cyclopropylene, alternatively not to form a ring;

alternatively, only one of R 1 and R 2 is substituted; alternatively, R 1 is unsubstituted, and R 2 is substituted.

11 . The compound of formula (II) of claim 2 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof,

wherein, M, and M 2 are independently —C(O)O— or —C(O)S—, alternatively —C(O)O—;

the other groups are as defined in claim 2 .

12 . The compound of formula (I) of claim 2 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof,

wherein, one of M 1 and M 2 is —C(O)O— or —C(O)S—, alternatively —C(O)O—, and the other is —OC(O)— or —SC(O)—, alternatively —OC(O)—;

the other groups are as defined in claim 2 ;

alternatively, R 1s is independently H or C 1-6 alkyl; alternatively H or C 1-4 alkyl;

alternatively, R 1s is independently C 1-8 alkyl, alternatively C 4-8 alkyl, alternatively C 6-8 alkyl,

alternatively C 7-8 alkyl, alternatively C 8 alkyl;

alternatively M 1 is —OC(O)— or —SC(O)—, alternatively —OC(O)—; and M 2 is —C(O)O—Or —C(O)S—,

alternatively —C(O)O—.

13 . A compound of formula (II) or formula (III), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof:

wherein

Q is a chemical bond, —SC(O)— or —OC(O)—;

R g and R′ g are independently C 1-6 alkyl;

a=2, 3, 4, 5, or 6;

b=6 or 7;

c=5 or 6;

d=0 or 1;

c+d=5 or 6;

M 1 is —OC(O)— or —SC(O)—; and M 2 is —C(O)O— or —C(O)S—;

R 1 and R 2 are independently C 7-12 alkyl, alternatively C 8-12 alkyl, which is optionally substituted with 1 R 1s ;

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

R 4 and R 5 are independently C 1-3 alkyl,

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-6 cycloalkylene;

alternatively, only one of R 1 and R 2 is substituted; alternatively, R 1 is unsubstituted, and R 2 is substituted;

alternatively,

Q is —SC(O)— or —OC(O)—, alternatively —SC(O)—;

R g and R′ g are independently C 1-3 alkyl, alternatively methyl;

a=2, 3, or 4; alternatively a=2 or 4; alternatively a=4;

b=6 or 7; alternatively b=7;

c=5 or 6; alternatively c=5;

d=0 or 1; alternatively d=1;

c+d=5 or 6; alternatively c+d=6;

M 1 is —OC(O)—; M 2 is —C(O)O—;

R 1 is C 7-11 linear alkyl, alternatively C 9-10 linear alkyl, alternatively C 9 linear alkyl;

R 2 is C 7-12 alkyl, alternatively C 8-12 alkyl, alternatively C 9-10 alkyl, alternatively C 9 alkyl, which is optionally substituted with 1 R 1s ;

R 1s is independently C 1-9 alkyl, alternatively C 1-8 alkyl, alternatively C 4-9 alkyl, alternatively C 4-8 alkyl;

R 4 and R 5 are independently C 1-3 alkyl, alternatively methyl;

or, R 4 and R 5 are taken together with the carbon atom to which they are attached to form C 3-4 cycloalkylene, alternatively cyclopropylene;

alternatively, the substitution site of R 1s on R 1 or R 2 is separated from M 1 or M 2 by 0-10 carbon atoms, alternatively 0-6 carbon atoms, alternatively 0-4 carbon atoms, alternatively 0-2 carbon atoms, alternatively 0 carbon atom;

alternatively, R 1 is not substituted with R 1s , and the substitution site of R 1s on R 2 is separated from M 2 by 0-10 carbon atoms, alternatively 1-10 carbon atoms, alternatively 1-6 carbon atoms,

alternatively 1-4 carbon atoms, alternatively 1-2 carbon atoms; alternatively 2-10 carbon atoms,

alternatively 2-6 carbon atoms, alternatively 2-4 carbon atoms;

alternatively, R 2 is

alternatively

alternatively

alternatively

alternatively, R 4 and R 5 are not taken together with the carbon atom to which they are attached to form a ring.

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

15 . A nanoparticle composition, comprising a lipid component, and optionally a load, wherein the lipid component comprises the compound of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, and the load is selected from one or more of therapeutic, prophylactic, and diagnostic agents.

16 . The nanoparticle composition of claim 15 , wherein the therapeutic, prophylactic, or diagnostic agents is a nucleic acid;

alternatively, the nucleic acid is selected from one or more of ASO, RNA, and DNA; alternatively, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), multimeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA) guide RNA (gRNA), CRISPRRNA (crRNA), and nucleases, alternatively mRNA, more alternatively modified mRNA.

17 . A method for delivering a load in a subject, comprising administering to the subject the nanoparticle composition of claim 15 ;

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

18 . A method for preparing a compound of formula (II), comprising:

reacting a compound of formula (IIA) with a compound of formula (IIB) to give the compound of formula (II),

wherein X is halogen, and the other variables are as defined in claim 2 ;

or,

reacting a compound of formula (TIC) with a compound of formula (IID), to give the compound of formula (II),

wherein X is halogen, and the other variables are as defined in claim 2 .

19 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, G 1 is C 2-6 linear alkylene.

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

21 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, R 4 and R 5 are taken together with the carbon atom to which they are attached to form cyclopropylene.

22 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, Q is selected from a chemical bond, —SC(O)— and —OC(O)—.

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

24 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

25 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

26 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

27 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

28 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

29 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

30 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

31 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

32 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

33 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

34 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant tautomer, or stereoisomer thereof, wherein, the compound is

35 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant tautomer, or stereoisomer thereof, wherein, the compound is

36 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

37 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

38 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

39 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof wherein, the compound is

40 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

41 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, the compound is

42 . The compound of formula (I) 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.

Assignments (5)

Priority Claims (6)

Continuity (1)

References Cited (49)