Search

US-12617752-B2 - Rapidly metabolized lipid compound

US12617752B2US 12617752 B2US12617752 B2US 12617752B2US-12617752-B2

Abstract

Provided herein is a class of a rapidly metabolized lipid compound, and particularly relates to compounds represented by formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. Also provided is a nanoparticle pharmaceutical composition comprising said compound, and the application of said compound and its composition in the delivery of nucleic acids.

Inventors

  • Lin Zhang
  • Feng Shi
  • Andong Liu
  • Liu Yang
  • Shaoli Liu
  • Xuhui Wang
  • Moyan Liu
  • Yan Gong
  • Jeffrey Michael WARRINGTON

Assignees

  • BEIJING JITAI LIFE SCIENCES LTD
  • Melis TechBio Co., Ltd.

Dates

Publication Date
20260505
Application Date
20240606
Priority Date
20230616

Claims (20)

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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—.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present application claims the priority of the Chinese Patent Application No. 202310720951.5 filed on Jun. 16, 2023, Chinese Patent Application No. 202310723466.3 filed on Jun. 16, 2023, Chinese Patent Application No. 202410115561.X filed on Jan. 26, 2024, Chinese Patent Application No. 202410437163.X filed on Apr. 11, 2024, Patent Cooperation Treaty Application No. PCT/CN2023/143111 filed on Dec. 29, 2023, and Chinese Patent Application No. 202410239117.9 filed on Mar. 1, 2024. The Patent Applications mentioned above are incorporated herein by reference as part of the disclosure of the present application. TECHNICAL FIELD The present disclosure relates to a novel class of ionizable cationic lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. The present disclosure also relates to lipid nanoparticles and pharmaceutical compositions comprising said compound, and the application of the lipid nanoparticles in the delivery of biologically active substances such as nucleic acids (e.g., mRNA, siRNA, ASO, and DNA). BACKGROUND Gene therapy refers to the introduction of exogenous genes into target cells to correct or compensate for genetic defects or abnormalities within the cell, so as to achieve the purpose of treatment. In the past few decades, research related to the treatment of clinical diseases through gene therapy has received more and more attention. Especially in recent years, siRNA-related drugs and mRNA vaccines have been approved by the FDA for clinical treatment, which has further promoted research and related investment in the field of gene therapy. Nucleic acid substances are easily degraded by nucleases in organisms, and nucleic acid substances themselves are negatively charged, which makes it difficult for them to enter the cell through the cell membrane. As a nucleic acid delivery material, lipid nanoparticles (LNP) are one of the most important nucleic acid delivery systems with the advantages of easy to prepare, good biodegradability, no immunogenicity and good safety. The main components of LNP include cationic lipids, cholesterol, neutral lipids and polyethylene glycol-conjugated lipids. Among them, cationic lipid molecules are the core of LNP delivery system, and their molecular structure plays a decisive role in the delivery efficiency, targeting, and formulation stability, and the like, of the entire liposome nanoparticles. Due to the different requirements of the delivery system for the delivery of different kinds of nucleic acid substances and the specific delivery of different targets, in order to meet the different needs of gene therapy, new lipid molecules need to be further developed. SUMMARY The present disclosure develops a new class of ionizable cationic lipid compounds that can be used to deliver various biologically active substances with high delivery efficiency. The inventor's prior patent CN115850104A discloses that a class of cationic lipid compounds with a pair of geminal dialkyl in each tail has high delivery efficiency. Unexpectedly, after further research, it was found that when the geminal dialkyl structure was applied to cationic lipids containing central nitrogen atoms, the cationic lipids degraded slowly in the liver, making them suitable for applications with slow degradation. For some application scenarios that require accelerating metabolism in vivo, a new class of ionizable lipid compounds is developed. The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof: wherein each group is as defined herein. In another aspect, the present disclosure provides a nanoparticle composition comprising lipid components, and optionally a load, wherein the lipid component comprises the compound of the present disclosure. U.S. Ser. No. 11/246,933B1 discloses that incorporation of a biodegradable group into the tail chain of a lipid compound in a lipid nanoparticle results in faster metabolism and removal of the lipid from the body following delivery of the active agent to a target area. As a result, these lipids which contain the biodegradable groups have lower toxicity than similar lipids without the biodegradable groups. The tail chain of the cationic lipid compound of the present disclosure has biodegradable group(s), thereby has superior toxicity profile to similar lipids without biodegradable groups, such as DLin-MC3-DMA. In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure or a nanoparticle composition of the present disclosure, and optionally pharmaceutically acceptable excipient(s), such as carrier(s), adjuvant(s) or vehicle(s). In another aspect, the present disclosure provides use of the compound of the present disclosure, a nanoparticle composition of the present disclosure, or a pharmaceutical composition