Pegylated lipid compound, lipid nanoparticles thereof, composition thereof, and use thereof

Abstract

The present application relates to the technical field of biomedicines, and in particular to a pegylated lipid compound, lipid nanoparticles thereof, a composition thereof, and a use thereof. The present application has the following advantages: the lipid nanoparticles of the pegylated lipid compound of the present application have good in vivo delivery efficiency for loads, and the lipid nanoparticles of the pegylated lipid compound of the present application have good systemic overall muscular delivery efficiency.

Description

PEGylated lipid compound, lipid nanoparticles thereof, composition thereof and use thereof

[0001] This application claims priority to Chinese application No. 202410239117.9 filed on March 1, 2024, Chinese application No. 202410773562.3 filed on June 14, 2024, Chinese application No. 202411856239.9 filed on December 16, 2024, Chinese application No. 202411858267.4 filed on December 16, 2024, Chinese application No. 202510206974.3 filed on February 24, 2025, and Chinese application No. 202510208194.2 filed on February 24, 2025, all of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present application belongs to the field of biomedicine technology, and specifically relates to PEGylated lipid compounds, lipid nanoparticles thereof, compositions thereof, and uses thereof. Background Art

[0003] As a new treatment method, nucleic acid drug gene therapy has achieved breakthrough progress in many fields such as infectious diseases and tumor treatment in a short period of time. Lipid nanoparticles (LNP) are one of the most advanced carriers for safely and efficiently delivering nucleic acid drugs (mRNA, siRNA, etc.) to specific target organs and protecting them from degradation. They have many advantages such as high encapsulation rate, good cell transfection efficiency, strong tissue penetration, low cytotoxicity and immunogenicity, and have been successfully used in multiple commercial products. Taking FDA-approved drugs as an example, the mRNA COVID-19 vaccine developed by Moderna and Pfizer-BioNTech, and the siRNA drug Onpattro developed by Alnylam, both use lipid nanoparticle drug delivery systems.

[0004] Since the development of nucleic acid drugs, delivery systems have always been the main bottleneck restricting their development, and the advancement of lipid nanoparticle (LNP) technology has greatly promoted the development of nucleic acid drugs. Lipid nanoparticles are currently the most thoroughly studied mRNA delivery system. Lipid nanoparticles are generally composed of four components: ionizable lipids / phospholipids / cholesterol / PEGylated lipids (PEG lipids). The physical and chemical stability of the lipid components affects particle size, charge, membrane fluidity and formulation stability, and is crucial for effective drug delivery. PEGylated lipid compounds are conjugates of polyethylene glycol and lipids. PEGylated lipid compounds have the advantages of increasing the stability of LNPs, extending their blood circulation half-life, improving their tumor targeting efficiency and enhancing drug efficacy. Since the discovery of the advantages of PEGylated lipid compounds, PEGylated lipid compounds have been widely used in lipid nanoparticles.

[0005] Therefore, there is an urgent need to develop a novel PEGylated lipid compound, lipid nanoparticles thereof, compositions thereof and uses thereof. Summary of the Invention

[0006] The present application provides a novel PEGylated lipid compound, lipid nanoparticles thereof, compositions thereof, and uses thereof. The lipid nanoparticles of the PEGylated lipid compound of the present application have good in vivo delivery efficiency for nucleic acids. The lipid nanoparticles of the PEGylated lipid compound of the present application have good systemic delivery efficiency to whole-body muscle.

[0007] In order to achieve the above technical objectives, the technical solutions adopted in this application are:

[0008] In one aspect, the present application provides a PEGylated lipid compound having a structure of formula (I'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0009] Wherein, each variable is as defined in this application.

[0010] In one aspect, the present application provides a PEGylated lipid compound having a structure of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0011] in,

[0012] L is absent or a divalent linking group;

[0013] L2 is absent or CH2;

[0014] R 11 is H, alkyl or cycloalkyl;

[0015] n1 is an integer from 1 to 250;

[0016] R w Select H or

[0017] R 21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace;

[0018] R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0019] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0020] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0021] In some embodiments of the present disclosure, R 11 is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

[0022] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, is of formula (II) or formula (III):

[0023] in,

[0024] L is absent or a divalent linking group;

[0025] R 11 is H, alkyl or cycloalkyl;

[0026] n1 is an integer from 1 to 250;

[0027] R21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace;

[0028] R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0029] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0030] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0031] In some embodiments of the present disclosure, R 11 is H, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl.

[0032] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, is of formula (IV) or formula (V):

[0033] in,

[0034] o', p', q' are each independently an integer from 0 to 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20;

[0035] The remaining variables are defined the same as in formula (I).

[0036] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein,

[0037] L is selected from -NHC(O)-, -OC(O)-, -C(O)-, or absent;

[0038] Preferably, L is selected from Or does not exist.

[0039] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, is of formula (II-A1), (II-A2), (II-A3), (III-A1), (III-A2) or (III-A3):

[0040] Wherein, each variable is defined in the same manner as in formula (I), formula (II) or formula (III).

[0041] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, is (IV-A1), (IV-A2)), (IV-A3)), (V-A1), (V-A2) or (V-A3) structure:

[0042] Wherein, each variable is defined in the same manner as in formula (I), formula (IV) or formula (V).

[0043] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl, preferably C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl, preferably C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl, preferably C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl, preferably C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl, preferably C15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl, more preferably C 10-20 Alkyl, C 10-20 Alkenyl or C 10- 20 Alkynyl, which is optionally substituted by one or more R V replace;

[0044] R V Independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably, R V Independently selected from H, C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl;

[0045] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0046] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0047] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein n1 is an integer of 10-120; preferably an integer of 30-80; preferably 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 41, 42, 43, 44, 45, 46 , 47, 48, 49, 50, 55, 60, 65, 70, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 or 120; more preferably 44, 45, 78, 80, 111 or 114;

[0048] Preferably, n1 is in the range such that the PEG portion of the PEGylated lipid compound as described above has an average molecular weight of about 400 g / mol to about 6000 g / mol; more preferably, it has an average molecular weight of about 1500 g / mol to about 5000 g / mol; more preferably, it has an average molecular weight of about 2000 g / mol, about 3350 g / mol, about 3500 g / mol or about 5000 g / mol.

[0049] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 11 H, C 1-30 Alkyl or C 3-14 Cycloalkyl; preferably, R 11 H, C 1-20 Alkyl or C 3-10 Cycloalkyl; preferably, R 11 H, C 1-10 Alkyl or C 3-10 Cycloalkyl; preferably, R 11 H, C 1-6 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 H, C 1-3 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 It is H, -CH3.

[0050] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein o', p', q' are each independently an integer from 0 to 15, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; preferably, o', p', q' are each independently an integer from 0 to 10, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; preferably, o', p', q' are each independently an integer from 0 to 5, for example, 0, 1, 2, 3, 4, 5; preferably, o', p', q' are each independently an integer from 0 to 3, for example, 0, 1, 2, 3; preferably, o', p', q' are each independently 0.

[0051] On the other hand, the present application provides a PEGylated lipid compound having a structure of formula (I'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0052] in,

[0053] L is absent or a divalent linking group;

[0054] L2 is absent or CH2;

[0055] R 11 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or an oxygen protecting group;

[0056] n1 is an integer from 1 to 250;

[0057] R w Select H or

[0058] Q 11 independently selected from -C(O)O-, -OC(O)- or -OC(O)O-;

[0059] R 21 、R 31 、R 41 Each independently selected from C 3-50 Alkyl, C 3-50 Alkenyl, C 3-50 Alkynyl, which is optionally substituted by one or more R V replace;

[0060] R V Independently selected from H, C 3-50 Alkyl, C 3-50 Alkenyl, C 3-50 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0061] L c1 independently selected from chemical bonds and C 1-50 Alkylene, C 3-50 Alkenyl, C 3-50 Alkynyl and C 3-10 saturated or partially unsaturated cycloalkyl;

[0062] R c1 and R' c1 Independently selected from H, C 3-50 Alkyl, C 3-30 Cycloalkyl, C 3-50 Alkenyl and C 3-50 Alkynyl;

[0063] Preferably, R w is H; preferably, R w for

[0064] Preferably, Q 11 Independently selected from -C(O)O- or -OC(O)-; preferably -C(O)O-; preferably -OC(O)-; preferably -OC(O)O-.

[0065] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, is of formula (I):

[0066] in,

[0067] L is absent or a divalent linking group;

[0068] L2 is absent or CH2;

[0069] R 11 is H, alkyl or cycloalkyl;

[0070] n1 is an integer from 1 to 250;

[0071] R w Select H or

[0072] R 21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace;

[0073] R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0074] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0075] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14Cycloalkyl and 3- to 14-membered heterocyclyl;

[0076] Preferably, in formula (I') or formula (I), when R w When H is

[0077] R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, and

[0078] 1) R 21 By one or more R V substituted, preferably by one R V replace;

[0079] R 31 Not R V Replace; or

[0080] 2) R 21 Not R V replace;

[0081] R 31 By one or more R V substituted, preferably by one R V Replace; or

[0082] 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace;

[0083] R V Independently selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl;

[0084] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0085] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0086] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, has a structure of Formula (II), Formula (II-A1), Formula (II-A2) or Formula (II-A3):

[0087] in,

[0088] L is absent or a divalent linking group;

[0089] R 11 is H, alkyl or cycloalkyl;

[0090] n1 is an integer from 1 to 250;

[0091] R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace;

[0092] R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0093] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0094] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0095] Preferably,

[0096] L is absent or a divalent linking group;

[0097] R 11 is H, alkyl or cycloalkyl;

[0098] n1 is an integer from 1 to 250;

[0099] R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, and

[0100] 1) R 21 By one or more R V substituted, preferably by one R V replace;

[0101] R 31 Not R V Replace; or

[0102] 2) R 21 Not R V replace;

[0103] R 31 By one or more R V substituted, preferably by one R V Replace; or

[0104] 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace;

[0105] R V Independently selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl;

[0106] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0107] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0108] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, has a structure of formula (IV), formula (IV-B), formula (IV-C), formula (IV-A1), formula (IV-A2) or formula (IV-A3):

[0109] in,

[0110] o' and p' are each independently an integer from 0 to 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20;

[0111] The remaining variables are defined as in formula (I') or formula (I);

[0112] Preferably, R V Independently selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl;

[0113] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0114] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0115] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, has a structure of formula (III), (III-A1), (III-A2) or (III-A3):

[0116] wherein each variable is as defined in Formula (I'), Formula (I) or Formula (II);

[0117] Preferably,

[0118] L is absent or a divalent linking group;

[0119] R 11 is H, alkyl or cycloalkyl;

[0120] n1 is an integer from 1 to 250;

[0121] R 21 、R 31 and R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace;

[0122] R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0123] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0124] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0125] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, has a structure of Formula (V), Formula (V-A1), Formula (V-A2) or Formula (V-A3):

[0126] wherein o', p', and q' are each independently an integer from 0 to 20, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20;

[0127] Each variable is independently defined as in Formula (I'), Formula (I) or Formula (IV).

[0128] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein,

[0129] L is -L3-(CH2)n2-L4-, wherein L3 and L4 are independently selected from absent, -NHC(O)-, -C(O)NH-, -C(O)O-, -OC(O)-, -C(O)-, -OC(O)O-, -P(O)3-, and n2 is an integer from 1 to 5, for example, 1, 2, 3, 4 or 5;

[0130] Preferably, L is selected from or not present; preferably or not present; preferably or not present; preferably or does not exist;

[0131] Preferably, L is selected from -NHC(O)-, -OC(O)-, -C(O)-, or absent;

[0132] Preferably, L is selected from or does not exist;

[0133] Preferably, L is selected from Or does not exist.

[0134] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl (preferably C 10-26 Alkyl), preferably C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl (preferably C 11-26 Alkyl), preferably C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl (preferably C 12-26 Alkyl), preferably C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl (preferably C 13-26 Alkyl), preferably C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl (preferably C14-26 Alkyl), preferably C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl (preferably C 15-26 Alkyl), more preferably C 10- 20 Alkyl, C 10-20 Alkenyl or C 10-20 Alkynyl (preferably C 10-20 Alkyl, preferably C 10-20 Straight chain alkyl, preferably C 12-20 Straight chain alkyl, preferably C 15-20 linear alkyl), which is optionally replaced by one or more (preferably 1) R V replace;

[0135] R V Independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably, R V Independently selected from H, C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl;

[0136] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0137] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0138] Preferably, in formula (II), formula (II-A1), formula (II-A2) or formula (II-A3),

[0139] 1) R 21 By one or more R V substituted, preferably by one R V replace;

[0140] R 31 Not R V Replace; or

[0141] 2) R 21 Not R Vreplace;

[0142] R 31 By one or more R V substituted, preferably by one R V Replace; or

[0143] 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace;

[0144] R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10-26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl;

[0145] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0146] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl;

[0147] Preferably, in formula (IV), formula (IV-A1), formula (IV-A2) or formula (IV-A3),

[0148] R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NRc1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10-26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl;

[0149] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0150] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl;

[0151] Preferably, in Formula (IV), Formula (IV-A1), Formula (IV-A2), Formula (IV-A3), Formula (V), Formula (V-A1), Formula (V-A2) or Formula (V-A3), R 21 、R 31 and R 41 Not R V replace;

[0152] Preferably, in Formula (V), Formula (V-A1), Formula (V-A2) or Formula (V-A3), R V For H.

[0153] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein n1 is an integer of 10-120; preferably an integer of 30-80; preferably 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 0, 55, 60, 65, 70, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 or 120; preferably 40-50, 75-85, 105-115; more preferably 44, 45, 78, 80, 111 or 114;

[0154] Preferably, n1 is in the range such that the PEG portion of the PEGylated lipid compound of any one of claims 1 to 8 has an average molecular weight of about 400 g / mol to about 6000 g / mol; more preferably, an average molecular weight of about 1500 g / mol to about 5000 g / mol; more preferably, an average molecular weight of about 2000 g / mol, about 3350 g / mol, about 3500 g / mol or about 5000 g / mol.

[0155] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 11 H, C 1-30 Alkyl or C 3-14 Cycloalkyl; preferably, R 11 H, C 1-20 Alkyl or C 3-10 Cycloalkyl; preferably, R 11 H, C 1-10 Alkyl or C 3-10 Cycloalkyl; preferably, R 11 H, C 1-6 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 H, C 1-3 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 For H, -CH3;

[0156] Preferably, R 11 C 1-30 Alkyl, preferably C 1-20 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably -CH3.

[0157] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein o', p', q' are each independently an integer from 0 to 15, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; preferably, o', p', q' are each independently an integer from 0 to 10, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; preferably, o', p', q' are each independently an integer from 0 to 5, for example, 0, 1, 2, 3, 4, 5; preferably, o', p', q' are each independently an integer from 0 to 3, for example, 0, 1, 2, 3; preferably, o', p', q' are each independently 0.

[0158] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, has a structure of formula (II-A1) or formula (IV-A1),

[0159] in,

[0160] R 11 is H, optionally substituted alkyl or an oxygen protecting group;

[0161] R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace;

[0162] n1 is an integer from 1 to 250;

[0163] R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0164] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0165] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0166] o' and p' are each independently an integer of 0-20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0167] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, has a structure of formula (III-A1) or formula (V-A1),

[0168] in,

[0169] R 11 is H, optionally substituted alkyl or an oxygen protecting group;

[0170] R 21 、R 31 and R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace;

[0171] n1 is an integer from 1 to 250;

[0172] R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0173] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0174] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0175] o', p', q' are each independently an integer from 0 to 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

[0176] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl (preferably C 10-26 Alkyl), preferably C 11-26Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl (preferably C 11-26 Alkyl), preferably C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl (preferably C 12-26 Alkyl), preferably C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl (preferably C 13-26 Alkyl), preferably C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl (preferably C 14-26 Alkyl), preferably C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl (preferably C 15-26 Alkyl), preferably C 16-26 Alkyl, C 16-26 Alkenyl, C 16-26 Alkynyl (preferably C 16-26 Alkyl), preferably C 17-26 Alkyl, C 17-26 Alkenyl, C 17-26 Alkynyl (preferably C 17-26 Alkyl), preferably C 18-26 Alkyl, C 18-26 Alkenyl, C 18-26 Alkynyl (preferably C 18-26 alkyl), which is optionally replaced by one or more R V replace;

[0177] R V Independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; preferably H, C 1-26 Alkyl, C 2-26 Alkenyl and C 2-26 Alkynyl;

[0178] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0179] R c1 and R' c1 Independently selected from H, C1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably H and C 1-20 Alkylene.

[0180] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, in Formula (IV-A1) or Formula (V-A1), R 21 、R 31 and R 41 Not R V replace;

[0181] Preferably, in formula (IV-A1), R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10- 26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl;

[0182] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0183] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl;

[0184] Preferably, in formula (V-A1), R V is H;

[0185] Preferably, in formula (II-A1),

[0186] 1) R 21 By one or more R V substituted, preferably by one RV replace;

[0187] R 31 Not R V Replace; or

[0188] 2) R 21 Not R V replace;

[0189] R 31 By one or more R V substituted, preferably by one R V Replace; or

[0190] 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace;

[0191] R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10-26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl;

[0192] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0193] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl.

[0194] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein n1 is an integer from 10 to 120; preferably an integer from 30 to 80; preferably 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 44, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 114 or 120;

[0195] Preferably, n1 ranges such that the PEG moiety of formula (IV) or formula (V) has an average molecular weight of 400 g / mol to about 6000 g / mol; more preferably, it has an average molecular weight of 1500 g / mol to about 5000 g / mol; more preferably, it has an average molecular weight of 2000 g / mol, 3500 g / mol or 5000 g / mol.

[0196] In some preferred embodiments of the present disclosure, the PEGylated lipid compound according to the present disclosure or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R 11 C 1-3 Alkyl, preferably -CH3.

[0197] On the other hand, the present application provides a PEGylated lipid compound or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

[0198] wherein n1 is each independently an integer from 10 to 120; preferably an integer from 30 to 80; preferably 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 or 120, more preferably 44, 45, 78, 80, 111 or 114.

[0199] In some preferred embodiments of the present disclosure, n1 ranges such that the PEG portion of the PEGylated lipid compound has an average molecular weight of about 400 g / mol to about 6000 g / mol; more preferably, an average molecular weight of about 1500 g / mol to about 5000 g / mol; more preferably, an average molecular weight of about 2000 g / mol, about 3350 g / mol, about 3500 g / mol, or about 5000 g / mol.

[0200] On the other hand, the present application provides a PEGylated lipid compound or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound is selected from the following compounds:

[0201] Preferably, the PEGylated lipid compound is selected from the following compounds:

[0202] On the other hand, the present application provides lipid nanoparticles comprising the aforementioned PEGylated lipid compound or its isotopic variant, isomer or solvate, or a pharmaceutically acceptable salt thereof.

[0203] On the other hand, the present application provides a lipid nanoparticle composition, which comprises a lipid component and, optionally, a load; wherein the lipid component contains a PEGylated lipid compound as described above or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0204] In some preferred embodiments of the present disclosure, the molar percentage of the PEGylated lipid compound in the lipid component is 0.25 mol% to 10 mol%.

[0205] In some preferred embodiments of the present disclosure, the lipid component comprises the following components in molar percentages:

[0206] Ionizable lipids 25 mol%-80 mol%:

[0207] Structural lipids 3 mol%-60 mol%;

[0208] Neutral lipids 0.5 mol%-60 mol%;

[0209] 0.25 mol% - 10 mol% of the PEGylated lipid compound as described above.

[0210] In some preferred embodiments of the present disclosure, the lipid component comprises the following components in molar percentages:

[0211] Ionizable lipids 50 mol%;

[0212] neutral lipids 15.2 mol%;

[0213] structural lipids 33.3 mol%;

[0214] 1.5 mol% of the PEGylated lipid compound as described above.

[0215] In some preferred embodiments of the present disclosure, the lipid component comprises the following components in molar percentages:

[0216] Ionizable lipids 50 mol%;

[0217] neutral lipids 15.2 mol%;

[0218] structural lipids 33.94 mol%;

[0219] 0.86 mol% of the PEGylated lipid compound as described above.

[0220] In some preferred embodiments of the present disclosure, the lipid component comprises the following components in molar percentages:

[0221] Ionizable lipids 50 mol%;

[0222] neutral lipids 15.2 mol%;

[0223] structural lipids 34.2 mol%;

[0224] 0.6 mol% of the PEGylated lipid compound as described above.

[0225] In a more specific embodiment, the present application provides the above-mentioned nanoparticle composition, wherein the ionizable lipid is a compound represented by formula (X), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0226] in,

[0227] R3 and R4 are independently selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 3 to 14-membered cycloalkyl, -C 1-10 Alkylene-3 to 14-membered cycloalkyl, 3 to 14-membered heterocyclic group, C 6-10 aryl or 5- to 14-membered heteroaryl, optionally substituted with one or more R*;

[0228] or R3 and R4 together with the nitrogen atom to which they are attached form a 3- to 14-membered heterocyclic group, which is optionally substituted with one or more R*;

[0229] or the nitrogen atom to which R4 is connected, (R0') k One R0' and the atoms between them together form a 4-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring, which is optionally substituted with one or more R*;

[0230] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L b -OR b 、-L b -SR b or -L b -NR b R' b ;

[0231] R0' is independently a methylene group optionally substituted by one or two R**, or the two substituents on R0' together with the C atom to which they are attached form a 3-8 membered cycloalkylene group;

[0232] R** is independently selected from H, C 1-8 Alkyl, -L c -OR c 、-L c -SR c or -L c -NR c R' c ;

[0233] k is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0234] j is selected from 0 or 1;

[0235] The dotted line connecting Q and W does not exist or is a chemical bond;

[0236] W is selected from C, CH or N;

[0237] G5 is selected from chemical bonds or C 1-24 Alkylene, C 2-24 Alkenylene, 3-8 membered cycloalkylene, C 3-8 Cycloalkenylene, preferably a chemical bond or C 1-8 Alkylene, optionally substituted with one or more R**;

[0238] G1, G2, G3 and G4 are independently selected from chemical bonds, C 1-13 Alkylene, C 2-13 Alkenylene or C 2-13 Alkyne group, which is optionally substituted by one or more R s replace;

[0239] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0240] The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0241] R s Independently selected from H, C 1-14 Alkyl, -L d -OR d 、-L d -SR d or -L d -NR d R' d ;

[0242] R5, R6, R7 and R8 are independently selected from H or C 1-8 alkyl, optionally substituted with one or more R*;

[0243] Or R5, R6 together with the carbon atom to which they are attached form C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, optionally substituted with one or more R*;

[0244] Or R7, R8 together with the carbon atom to which they are attached form C 3-14 cycloalkylene or 3- to 14-membered heterocyclylene, optionally substituted with one or more R*;

[0245] When the dashed line connecting Q and W is absent, Q is absent or selected from: -C(O)O-, -O-, -NH-, -SC(O)O-, -OC(O)NR b -、-NR b C(O)NR b -、-OC(O)S-、-OC(O)O-、-NR b C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR b -、-C(O)NR b -、-NR b C(O)-、-NR b C(O)S-、-SC(O)NR b -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR b -、-NR b C(S)O-, -SS-, -S(O) 0-2 -, phenylene or pyridylene;

[0246] When the dotted line connecting Q and W is a chemical bond, G5 is absent, and Q and W form a 5-10 membered monocyclic or bicyclic ring, which is optionally substituted with one or more R**;

[0247] M1 and M2 are independently absent or selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NR a -、-NR a C(O)NR a -、-OC(O)S-、-OC(O)O-、-NR a C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NR a -、-C(O)NR a -、-NR a C(O)-、-NR a C(O)S-、-SC(O)NR a -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR a -、-NR a C(S)O-, -SS-, or -S(O) 0- 2-;

[0248] R0 is independently -(CRR')-;

[0249] R and R' are independently selected from H, C 1-20 Alkyl, -L a -OR a 、-L a -SR a or -L a -NR a R' a , preferably R' is H;

[0250] or R and R' together with the carbon atom to which they are attached form a 3-8 membered cycloalkylene group;

[0251] No more than three R0 or R0' in each chain attached to W are cycloalkylene;

[0252] Q3 and Q4 are independently H, -(CRR')-, C 6-10 an aryl or steroid group, preferably H or -(CRR')-;

[0253] A1, A2, A3, and A4 are independently -(CR 18 R 18 -CR 18 =CR 18 )-or-(CR 18 R 18 -C≡C)-;

[0254] R 18 are independently H or C 1-20 alkyl;

[0255] N1 and N2 are independently biodegradable groups;

[0256] Z does not exist, C 1-10 Alkylene or -OP(O)(OH)-O-;

[0257] The dotted line connected to Z does not exist or is a chemical bond. When Z does not exist, Q3 and Q4 are not directly connected;

[0258] m, n, q, r, u, v, y, z are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0259] o, p, w, and x are each independently selected from 0, 1, or 2;

[0260] s and t are each independently selected from 0 or 1;

[0261] The total length of the segments from G1 to Q3 or the total length of the segments from G3 to Q4 is 8 to 30 atoms, preferably 10 to 25 atoms;

[0262] L a and L e Independently selected from chemical bonds or C 1-20 alkylene;

[0263] L b and L f Independently selected from chemical bonds or C 1-10 alkylene;

[0264] L c Independently selected from chemical bonds or C 1-8 alkylene;

[0265] L d Independently selected from chemical bonds or C 1-14 alkylene;

[0266] R a and R' a Independently selected from H, C 1-20 alkyl, 3 to 14 membered cycloalkyl, 3 to 14 membered heterocyclyl, which is optionally substituted with one or more of the following substituents: H, C 1-20 Alkyl, -L e -OR e 、-L e -SR e or -L e -NR e R' e;

[0267] R b and R' b Independently selected from H, C 1-10 alkyl, 3 to 14 membered cycloalkyl, 3 to 14 membered heterocyclyl, which is optionally substituted with one or more of the following substituents: H, C 1-10 Alkyl, -L f -OR f 、-L f -SR f or -L f -NR f R' f ;

[0268] R c and R' c Independently selected from H or C 1-8 alkyl;

[0269] R d and R' d Independently selected from H or C 1-14 alkyl;

[0270] R e and R' e Independently selected from H or C 1-20 alkyl;

[0271] R f and R' f Independently selected from H or C 1-10 alkyl;

[0272] The condition is that when W is N, j = 0, and the dotted line connecting Q and W does not exist;

[0273] or for

[0274] G7 is selected from chemical bonds, C 1-6 Alkylene, C 2-6 Alkenylene and C 2-6 Alkyne group, which is optionally substituted by one or more R G7 replace;

[0275] R G7 Independently selected from H, C 1-6 Alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0276] or two R attached to the same carbon atom G7 Together with the carbon atoms to which they are attached, they form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4g replace;

[0277] R 4g are independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L e -OR e 、-L e -SR e and -L e -NR e R' e ;

[0278] Q1 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)-、-NR f C(O)S-、-SC(O)NR f -, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR f -、-NR f C(S)O-, -SS-, -S(O) 0-2 -, phenylene and pyridinylene, wherein the phenylene or pyridinylene is optionally substituted with one or more R*.

[0279] In a more specific embodiment, the ionizable lipid is selected from the group consisting of:

[0280] In a more specific embodiment, the present application provides the above-mentioned nanoparticle composition, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE, preferably DSPC and / or DOPE.

[0281] In a more specific embodiment, the present application provides the above-mentioned nanoparticle composition, wherein the structured lipid is selected from one or more of cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol.

[0282] In some preferred embodiments of the present disclosure, according to the lipid nanoparticle composition of the present disclosure, the payload is selected from one or more of a therapeutic agent, a prophylactic agent or a diagnostic agent.

[0283] In some preferred embodiments of the present disclosure, the therapeutic agent, preventive agent or diagnostic agent is selected from one or more of small molecule compounds, polypeptides, proteins and nucleic acids.

[0284] In some preferred embodiments of the present disclosure, the nucleic acid is selected from one or more of antisense oligonucleotides (ASOs), RNA or DNA.

[0285] In some preferred embodiments of the present disclosure, the RNA is selected from one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polyencoding nucleic acid (MCNA), polymeric encoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA) or ribozyme, preferably one or more of modified mRNA, mRNA, siRNA, gRNA.

[0286] In some preferred embodiments of the present disclosure, the DNA is selected from one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

[0287] In some preferred embodiments of the present disclosure, according to the lipid nanoparticle composition of the present disclosure, the particle size of the particles is 40-500 nm, preferably 40-250 nm, preferably 40-200 nm, more preferably 40-150 nm;

[0288] Preferably, the particle size is 40-200 nm, preferably 40-160 nm, preferably 40-150 nm, more preferably 40-120 nm.

[0289] On the other hand, the present application provides a method for preparing the lipid nanoparticle composition as described above, comprising: mixing the lipid components in the lipid nanoparticles, and then mixing with a load to obtain.

[0290] On the other hand, the present application provides a pharmaceutical composition comprising a PEGylated lipid compound as described above or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, a lipid nanoparticle as described above or a lipid nanoparticle composition as described above, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

[0291] On the other hand, the present application provides the use of the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the aforementioned lipid nanoparticle, the aforementioned lipid nanoparticle composition, or the aforementioned pharmaceutical composition in the preparation of a medicament for treating, diagnosing or preventing a disease;

[0292] Preferably, the disease is a muscle or muscle-related disease.

[0293] On the other hand, the present application provides the use of the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the aforementioned lipid nanoparticle, the aforementioned lipid nanoparticle composition, and the aforementioned pharmaceutical composition in the preparation of drugs for gene editing, protein replacement and / or supplementation, and gene interference.

[0294] On the other hand, the present application provides the use of the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the aforementioned lipid nanoparticle, the aforementioned lipid nanoparticle composition, and the aforementioned pharmaceutical composition in the preparation of a drug for delivering a load.

[0295] On the other hand, the present application provides a method for treating, diagnosing or preventing a disease in a subject by using the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the aforementioned lipid nanoparticle, the aforementioned lipid nanoparticle composition, or the aforementioned pharmaceutical composition, comprising administering the lipid nanoparticle composition or the pharmaceutical composition described herein to the subject;

[0296] Preferably, the disease is a muscle or muscle-related disease.

[0297] On the other hand, the present application uses the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the aforementioned lipid nanoparticle, the aforementioned lipid nanoparticle composition, or the aforementioned pharmaceutical composition for delivering a load;

[0298] Preferably, for delivering load to muscle.

[0299] In another aspect, the present application provides a method for delivering a load in a subject, comprising administering the pharmaceutical composition or the nanoparticle composition of the present application to the subject.

[0300] On the other hand, the present application provides for the use of the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the aforementioned lipid nanoparticle, the aforementioned lipid nanoparticle composition, or the aforementioned pharmaceutical composition for delivering nucleic acids.

[0301] In some preferred embodiments of the present disclosure, the nucleic acid is selected from one or more of antisense oligonucleotides (ASOs), RNA or DNA.

[0302] In some preferred embodiments of the present disclosure, the RNA is selected from one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polyencoding nucleic acid (MCNA), polymeric encoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA) or ribozyme, preferably one or more of modified mRNA, mRNA, siRNA, gRNA.

[0303] In some preferred embodiments of the present disclosure, the DNA is selected from one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

[0304] In some preferred embodiments of the present disclosure, the nucleic acid is selected from one or more of ASO, mRNA, modified mRNA, siRNA, gRNA, mcDNA, and pDNA.

[0305] On the other hand, the present application provides a method for treating or preventing a muscle disease or a muscle-related disease in a subject, comprising administering a therapeutically effective amount of the lipid nanoparticles as described above, the lipid nanoparticle composition as described above, or the pharmaceutical composition as described above to the subject by systemic administration;

[0306] Preferably, the systemic administration is systemic injection, more preferably intravenous injection, arterial injection or intraperitoneal injection.

[0307] On the other hand, the present application provides a method for preparing the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (IV-A1) comprises:

[0308] wherein PG is independently an oxygen protecting group, preferably Bn;

[0309] The remaining variables are defined the same as in formula (I), formula (IV) or formula (V).

[0310] On the other hand, the present application provides a method for preparing the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (IV-A2) comprises:

[0311] Wherein, each variable is defined in the same manner as in formula (I), formula (IV) or formula (V).

[0312] On the other hand, the present application provides a method for preparing the aforementioned PEGylated lipid compound or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (V-A3) comprises:

[0313] Wherein, each variable is defined in the same manner as in formula (I), formula (IV) or formula (V).

[0314] On the other hand, the present application provides a method for preparing the aforementioned PEGylated lipid compound, or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (IV-A1) comprises:

[0315] reacting a compound of formula (A1) with a compound of formula (E1) to obtain a compound of formula (A2);

[0316] Deprotecting the compound of formula (A2) to obtain a compound of formula (IV-A1);

[0317] wherein PG is independently an oxygen protecting group, preferably Bn;

[0318] The remaining variables are as defined in the present application, preferably as defined in formula (I'), formula (I), formula (IV) or formula (V) of the present application.

[0319] On the other hand, the present application provides a method for preparing the aforementioned PEGylated lipid compound, or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (IV-A2) comprises:

[0320] reacting a compound of formula (B1) with a compound of formula (E2) to obtain a compound of formula (B2);

[0321] reacting the compound of formula (B2) to obtain the compound of formula (B3); preferably reacting under alkaline conditions;

[0322] reacting a compound of formula (B3) with a compound of formula (E3) and / or formula (E4) to obtain a compound of formula (IV-A2);

[0323] Wherein, each variable is as defined in the present application, preferably as defined in formula (I'), formula (I), formula (IV) or formula (V) in the present application.

[0324] On the other hand, the present application provides a method for preparing the aforementioned PEGylated lipid compound, or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (V-A3) comprises:

[0325] reacting a compound of formula (C1) with a compound of formula (E5) to obtain a compound of formula (C2);

[0326] reacting a compound of formula (C2) with a compound of formula (E6) to obtain a compound of formula (V-A3);

[0327] Wherein, each variable is defined as in any one of the present application, preferably as defined in formula (I'), formula (I), formula (IV) or formula (V) in the present application.

[0328] This application has the following advantages:

[0329] (1) This application provides a novel PEGylated lipid compound, which provides more options for the subsequent preparation of lipid nanoparticles and nucleic acid delivery.

[0330] (2) The lipid nanoparticles prepared from the PEGylated lipid compounds of the present application have good in vivo delivery efficiency for nucleic acids.

[0331] (3) The lipid nanoparticles prepared from the PEGylated lipid compounds of the present application have good systemic whole-body muscle delivery efficiency.

[0332] (4) The lipid nanoparticles prepared by the PEGylated lipid compound of the present application can deliver less load to the liver.

[0333] (5) The PEGylated lipid compounds of this application are expected to provide a new strategy for nucleic acid delivery. BRIEF DESCRIPTION OF THE DRAWINGS

[0334] In order to more clearly illustrate the specific embodiments of the present disclosure or the technical solutions in the prior art, the following will briefly introduce the drawings required for the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present disclosure. For those skilled in the art, other drawings can be obtained based on these drawings without inventive work. The drawings herein are incorporated into and constitute a part of the specification, illustrate embodiments consistent with the specification, and together with the specification, are used to explain the principles of the specification.

[0335] FIG1 shows a mass spectrum of compound 5;

[0336] FIG2 shows the mass spectrum of compound 6.

[0337] Definition and Description

[0338] In order to make it easier to understand the application, certain technical and scientific terms are specifically defined below. In the application, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. In addition, cell and tissue culture, microbiology-related terms and laboratory operation steps used herein are all terms and routine steps widely used in the corresponding fields. At the same time, in order to better understand the application, the definitions and explanations of related terms are provided below. It should be understood that the application is not limited to specific methods, reagents, compounds, compositions or biological systems, and of course the above can be changed. It should also be understood that the terms used in the application are only for the purpose of describing specific embodiments and are not intended to be limiting.

[0339] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0340] As used herein, the terms "comprise," "comprises," and "having," and any variations thereof, are intended to cover non-exclusive inclusions. For example, a process, method, apparatus, product, or device comprising a series of steps is not limited to the listed steps or modules but may optionally include steps not listed, or other steps inherent to such process, method, product, or device.

[0341] In the description herein, references to “some embodiments,” “some implementation schemes,” or “some implementation plans” describe a subset of all possible embodiments, but it will be understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0342] The term "alkyl" refers to a chain (straight or branched) saturated aliphatic hydrocarbon group. The alkyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more groups described in this application.

[0343] The term "alkylene" refers to a divalent group formed by removing another hydrogen from an alkyl group, which may be substituted or unsubstituted.

[0344] The term "cycloalkyl" can be considered as a cycloalkane molecule with one or more hydrogen atoms missing. Cycloalkyl groups can be substituted or unsubstituted.

[0345] The terms "heterocycle" and "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon radical, wherein one or more (preferably 1 to 4 or 1 to 3 or 1 to 2) ring atoms are selected from nitrogen, oxygen or S(O) t3 (wherein t3 is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. The term "heterocyclyl" is preferably a 3- to 6-membered heterocycloalkyl group; wherein one or more (preferably 1 to 4) ring atoms are selected from nitrogen, oxygen or S(O) t3 wherein t3 is an integer from 0 to 2, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, R is hydrogen or any substituent defined herein). The ring carbon atoms of the heterocyclic group may optionally be substituted with 1, 2 or 3 oxo groups to form a cyclic ketone, cyclic lactone or cyclic lactam structure.

[0346] When a numerical range is listed, it is intended to include every value and sub-range within the stated range. For example, "C 1-6 "Alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0347] “C 1-20 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 20 carbon atoms. 1-30 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 30 carbon atoms. 5-30 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 5 to 30 carbon atoms. In some embodiments, C 10-30 Alkyl, C 10-26 Alkyl, C 13-26 Alkyl, C 14-26 Alkyl, C 15-26 Alkyl, C 16-26 Alkyl, C 17-26 Alkyl, C 18-26 Alkyl and C 19-26 Alkyl is preferred. In some embodiments, C 4-20 Alkyl, C 6- 14 Alkyl, C 7-12 Alkyl, C 8-12 Alkyl, C 4-10 Alkyl, C 7-11 Alkyl, C 8-11 Alkyl, C 8-10 Alkyl, C 9-10 Alkyl, C 8-9 Alkyl, C 4-9 Alkyl, C 6-9 Alkyl, C 7-9 Alkyl, C9 alkyl, C 2-8 Alkyl, C 5-8 Alkyl, C 7-8 Alkyl, C 4-6 Alkyl, C 1- 20 Alkyl, C 1-14 Alkyl, C 2-14 Alkyl, C 1-13 Alkyl, C 1-12 Alkyl, C 1-10 Alkyl, C 1-9 Alkyl, C 1-8 Alkyl, C 1-7 Alkyl, C 2-7 Alkyl, C1-6 Alkyl, C 2-6 Alkyl, C 1-5 Alkyl, C5 alkyl, C 1-4 Alkyl, C 2-4 Alkyl, C 1-3 Alkyl, C 2-3 Alkyl, C 1-2 Alkyl and Me are preferred. 1-6 Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term “C 1-6 "Alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2).

[0348] “C 2-30 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 30 carbon atoms and at least one carbon-carbon double bond. 2-30 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 30 carbon atoms and at least one carbon-carbon double bond. 5-30 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 5 to 30 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-26 Alkenyl, C 2-24 Alkenyl, C 2-20 Alkenyl, C 2-18 Alkenyl, C 2-16 Alkenyl is preferred. In some embodiments, C 10-30 Alkenyl, C 5-26 Alkenyl, C 10-26 Alkenyl, C 11-26 Alkenyl, C 12-26 Alkenyl, C 13-26 Alkenyl, C 14-26 Alkenyl, C 15-26 Alkenyl, C 16-26 Alkenyl, C 17-26 Alkenyl, C 18-26 Alkenyl and C 19-26Alkenyl is preferred. In some embodiments, C 4-26 Alkenyl, C 4-20 Alkenyl, C 4-18 Alkenyl, C 4-16 Alkenyl, C 4-14 Alkenyl, C 6-14 Alkenyl, C 4-10 Alkenyl, C 2-13 Alkenyl, C 2-10 Alkenyl, C 2-9 Alkenyl, C 2- 6 alkenyl and C 2-4 Alkenyl is preferred. 2-6 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. The term "C 2-6 "Alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). An alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0349] “C 2-30 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 30 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 5-30 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 5 to 30 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-30 Alkynyl, C 2-26 Alkynyl, C 2-20 Alkynyl, C 2-18 Alkynyl, C 2-16 Alkynyl, C 2-14 Alkynyl is preferred. In some embodiments, C 5-26 Alkynyl, C 10-26 Alkynyl, C 11-26 Alkynyl, C 12-26 Alkynyl, C 13-26 Alkynyl, C 14-26 Alkynyl, C 15-26 Alkynyl, C 16-26 Alkynyl, C 17-26 Alkynyl, C 18-26 Alkynyl and C 19-26 Alkynyl is preferred. In some embodiments, C 10-30 Alkynyl, C 5-26 Alkynyl, C 10-26 Alkynyl, C 11-26 Alkynyl, C12-26 Alkynyl, C 13-26 Alkynyl, C 14-26 Alkynyl, C 15-26 Alkynyl, C 16-26 Alkynyl, C 17-26 Alkynyl, C 18-26 Alkynyl and C 19-26 Alkynyl is preferred. In some embodiments, C 4-20 Alkynyl, C 4-18 Alkynyl, C 4-16 Alkynyl, C 4-14 Alkynyl, C 6-14 Alkynyl, C 4-10 Alkynyl, C 2-10 Alkynyl, C 2-9 Alkynyl, C 2-6 Alkynyl and C 2-4 Alkynyl is preferred. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), hexynyl (C6), and the like. The term "C 2-6 "Alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups can be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0350] “C 1-20 "Alkylene" refers to the removal of C 1-20 In some embodiments, C 4-20 Alkylene, C 6-14 Alkylene, C 7-12 Alkylene, C 8-12 Alkylene, C 4-10 Alkylene, C 7-11 Alkylene, C 8-11 Alkylene, C 8-10 Alkylene, C 9-10 Alkylene, C 8-9 Alkylene, C 4-9 Alkylene, C 6-9 Alkylene, C 7-9 Alkylene, C9 alkylene, C 2-8 Alkylene, C 5-8 Alkylene, C 7-8 Alkylene, C 4-6 Alkylene, C 1-20 Alkylene, C 1-14 Alkylene, C 2-14 Alkylene, C1-13 Alkylene, C 1-12 Alkylene, C 1-10 Alkylene, C 1-9 Alkyl, C 1-8 Alkylene, C 1-7 Alkylene, C 2-7 Alkylene, C 1-6 Alkylene, C 2-6 Alkylene, C 1-5 Alkylene, C5 alkylene, C 1-4 Alkylene, C 2- 4 alkylene, C 1-3 Alkylene, C 2-3 Alkylene, C 1-2 Alkylene and methylene are preferred. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylenes, for example, alkylenes substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0351] “C 0-6 "Alkylene" refers to a chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to a chemical bond and the above-mentioned "C 1-4 "Alkylene".

[0352] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0353] Therefore, “C 1-10 "Haloalkyl" refers to the above-mentioned "C 1-10 Alkyl", which is substituted by one or more halogen groups. In some embodiments, C 1-8 Halogenated alkyl, C 1-6 Halogenated alkyl, C 1-4 Halogenated alkyl, C1-3 Halogenated alkyl is particularly preferred, more preferably C 1- 2 haloalkyl. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. "C 3-14 "Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2 or 3 double bonds or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl and 3- to 6-membered cycloalkyl are particularly preferred, more preferably 5- to 7-membered cycloalkyl, 4- to 6-membered cycloalkyl, 3- to 5-membered cycloalkyl, 3- to 4-membered cycloalkyl and 5- to 6-membered cycloalkyl, more preferably 5-membered cycloalkyl, more preferably 6-membered cycloalkyl, more preferably cyclopropyl. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to refer to the number of carbons in the cycloalkyl system. Cycloalkyl also includes rings in which the above-mentioned cycloalkyl ring, Wherein the substituents on any non-adjacent carbon atoms are connected to form a bridged ring, together forming a polycycloalkane sharing two or more carbon atoms. Cycloalkyl also includes the above-mentioned cycloalkyl ring, wherein the substituents on the same carbon atom are connected to form a ring, together forming a polycycloalkane sharing one carbon atom. Exemplary cycloalkyls include but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), and the like. The cycloalkyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0354] “C 3-14 "Cycloalkylene" refers to the removal of C 3-14 In some embodiments, C 3-10 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene is particularly preferred, and cyclopropylene is especially preferred.

[0355] "3-14 membered heterocyclyl" or "3- to 14-membered heterocyclic group" refers to a saturated or unsaturated radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally containing 1, 2, or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valence permits. In some embodiments, 3 to 10-membered heterocyclyl is preferably a 3 to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5 to 10-membered heterocyclyl is preferably a 5 to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3 to 8-membered heterocyclyl is preferably a 3 to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; in some embodiments, 3 to 7-membered heterocyclyl is preferably a 3 to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; 5 to 7-membered heterocyclyl is preferably a A 5- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 3- to 6-membered heterocyclyl, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 4- to 6-membered heterocyclyl, which is a 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 5-membered heterocyclyl, which is a 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably a 6-membered heterocyclyl, which is a 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Heterocyclyl also includes a ring system in which the above-mentioned heterocyclyl ring is fused to one or more cycloalkyl groups, wherein the point of attachment is on the heterocyclyl ring, or a ring system in which the above-mentioned heterocyclyl ring is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes a heterocyclyl ring in which any substituents on non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes a heterocyclyl ring in which the substituents on the same carbon atom are connected to form a ring, together forming a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyls containing one heteroatom include, but are not limited to, aziridine, oxirane, and thiorenyl. Exemplary 4-membered heterocyclyls containing one heteroatom include, but are not limited to, azetidinyl, oxirane, and thiidine. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, pyrazolidinyl, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thienyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl groups) include, but are not limited to, dihydroindolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Heterocyclyl groups also include those in which the above-mentioned heterocyclyl groups share one or two atoms with a cycloalkyl, heterocyclyl, aryl, or heteroaryl group to form a bridged or spirocyclic ring. The shared atoms may be carbon or nitrogen atoms, as valence permits. Heterocyclyl groups also include those in which the above-mentioned heterocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0356] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 Aryl also includes ring systems in which an aryl ring as described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Aryl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0357] "5-14 membered heteroaryl" or "5 to 14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom as long as the valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above-mentioned heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-10 membered heteroaryl is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryls are particularly preferred and are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryls containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryls containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryls containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryls containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryls containing one heteroatom include, but are not limited to, pyridinyl or pyridonyl. Exemplary 6-membered heteroaryls containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxepinyl, and thieptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. A heteroaryl group can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0358] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups.

[0359] "Alkoxy" refers to the oxygen ether form of a straight or branched alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3. As used herein, the term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, which may include variants of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" or "optionally substituted" means that it may be substituted or not, and unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievable.

[0360] When any variable (e.g., Rv) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rv, the group may optionally be substituted with up to two Rv, and each occurrence of Rv is an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0361] In any embodiment, any or all hydrogens present in the compound, or hydrogens in a specific group or moiety within the compound, may be replaced by deuterium or tritium. From one to the maximum number of hydrogens present in the compound may be replaced by deuterium. From one to the maximum number of hydrogens present in any group in the general compound or in the specific compound may be deuterated. For example, when describing a group as ethyl, the ethyl group may be C2H5 or C2H5 in which x (1 to 5) hydrogens are replaced by deuterium, such as C2D x H 5-x When describing a group as a deuterated ethyl group, the deuterated ethyl group may be C2H5 in which x (1 to 5) hydrogen atoms are replaced by deuterium, for example, C2D x H 5-x The stable deuterated derivatives described herein are preferably stable deuterated isotope derivatives obtained by replacing any deuterated hydrogen atom in each formula with 1 to a maximum number (e.g., 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, etc.) of deuterium atoms.

[0362] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and other groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl are collectively referred to as "cyclyls".

[0363] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, etc., as defined herein, are optionally substituted groups.

[0364] Exemplary substituents on carbon atoms include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2, -C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2, -SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa)3、-OSi(R aa )3、-C(=S)N(R bb )2, -C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NR bb )2、-P(R cc )2、-P(R cc )3、-OP(R cc )2、-OP(R cc )3、-B(R aa )2、-B(OR cc )2, -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0365] Or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replace;

[0366] R aa Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0367] R bb Each of the following is independently selected from: hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0368] R cc Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc The groups are combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0369] R ddEach of the is independently selected from: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee 、-ON(R ff )2、-N(R ff )2,、-N(R ff )3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O)R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、-C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R ee 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=NR ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2, -SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3、-OSi(R ee )3、-C(=S)N(R ff )2, -C(=O)SR ee 、-C(=S)SR ee 、-SC(=S)SR ee 、-P(=O)2Ree 、-P(=O)(R ee )2、-OP(=O)(R ee )2、-OP(=O)(OR ee )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0370] R ee Each of R is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0371] R ff Each of R is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0372] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1- 6 alkyl) 2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3 + X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3, -C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1- 6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6-alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 Aryl, 3-7 membered heterocyclic group, 5-10 membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; wherein X - For the counter ion.

[0373] Exemplary substituents on nitrogen atoms include, but are not limited to, hydrogen, -OH, -OR aa 、-N(R cc )2, -CN, -C(=O)R aa 、-C(=O)N(R cc )2, -CO2R aa 、-SO2R aa 、-C(=NR bb )R aa 、-C(=NR cc )OR aa 、-C(=NR cc )N(R cc )2、-SO2N(R cc )2, -SO2R cc 、-SO2OR cc 、-SOR aa 、-C(=S)N(R cc )2, -C(=O)SR cc 、-C(=S)SR cc 、-P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)2N(R cc )2、-P(=O)(NR cc )2, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R attached to the nitrogen atom cc The groups are combined to form a heterocyclic or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and R dd As mentioned above.

[0374] "Oxygen protecting group" refers to a substituent present on an oxygen atom. Oxygen protecting groups include but are not limited to -R aa 、-N(Rbb )2, -C(=O)SR aa 、-C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-S(=O)R aa 、-SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3 + X - 、-P(OR cc )2、-P(ORcc)3 + X - 、-P(=O)(R aa )2、-P(=O)(OR cc )2 and -P(=O)(N(R bb )2)2, where X - 、R aa 、R bb and R cc As defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd ed., John Wiley & Sons, 1999 (which is incorporated herein by reference).

[0375] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP ), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1- Benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenyloxyseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-pyridylmethyl, 4-pyridylmethyl, 3-methyl-2-pyridylmethyl N-oxido, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenyl methyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromobenzoyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4',4"-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxide anion group, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyl tert-hexylsilyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, Methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid acetal), pivalate, adamantanoate (adamantoate), crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)carbonate 1-(4-(2-(phenylphosphonium)ethyl)carbonate (Psec), 2-(triphenylphosphonium)ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, tert-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxy) esters, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, N,N,N',N'-tetramethylphosphorodiamidate alkyl ester, N-phenylcarbamic acid alkyl ester, borate, dimethylphosphinoyl, 2,4-dinitrophenylsulfenic acid alkyl ester, sulfate, mesylate, benzylsulfonate and tosylate (Ts).

[0376] In this application, a "group" contains at least one atom and refers to a free radical formed by the loss of one or more atoms from a compound. Relative to a compound, a group formed by the loss of some groups is also called a residue. The valence of a group is not particularly limited, and for example, it can be divided into monovalent groups, divalent groups, trivalent groups, tetravalent groups, ..., and centrivalent groups. Among them, groups with a valence of 2 or greater are collectively referred to as linking groups. Linking groups can also contain only one atom, such as oxy groups and thiol groups.

[0377] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and hybrid molecules thereof. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASOs). The nucleic acid may be further chemically modified, and the chemical modification is selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. The mRNA molecule contains a protein coding region and may further contain an expression regulatory sequence. Typical expression regulatory sequences include, but are not limited to, a 5' cap (5' cap), a 5' untranslated region (5' UTR), a 3' untranslated region (3' UTR), a polyadenylic acid sequence (PolyA), and a miRNA binding site.

[0378] Some compounds and salts according to the present application may exist in different crystalline forms (polymorphs), which are within the scope of the present application.

[0379] In this application, and Indicates the absolute configuration of a stereocenter. in Refers to the chemical bond connection.

[0380] When the ring appears When the connection position is uncertain, it means that the connection site is located at Any atom in the monocyclic ring, as long as the valence permits.

[0381] References to "compounds" herein include "solvates" thereof. "Solvates" refer to complexes formed between the compounds of the present invention and a solvent. These complexes are either reacted in the solvent or precipitated or crystallized from the solvent. For example, a complex formed with water is referred to as a "hydrate." Solvates of the compounds represented by Formula (I) herein are within the scope of this application.

[0382] In this application, It indicates the existing form of the conjugated lipid compound when forming lipid nanoparticles, which can be It is understood that when referring to such structures herein, the compounds include Compounds of the form, for example, the compound of formula (IV-A1) also naturally includes

[0383] In the general structure of the present application, for example, in formula (IV-A1), n1 represents the number of ethylene glycol repeating units. When n1 is 44 or 45, or an integer between 40 and 50, it indicates that the PEG portion has an average molecular weight of about 2000 g / mol; when n1 is an integer between 75 and 80, it indicates that the PEG portion has an average molecular weight of about 3500 g / mol; and when n1 is 111 or 114, or an integer between 110 and 120, it indicates that the PEG portion has an average molecular weight of about 5000 g / mol. Those skilled in the art will appreciate that n1 represents an average value.

[0384] The present application includes prodrugs of the above-mentioned compounds. Prodrugs include known amino protecting groups and carboxyl protecting groups, which are hydrolyzed under physiological conditions or released via enzymatic reactions to yield the parent compound. Specific prodrug preparation methods can be found in (Saulnier, MG; Frennesson, DB; Deshpande, MS; Hansel, SB and Vysa, DM Bioorg. Med. Chem Lett. 1994, 4, 1985-1990; and Greenwald, RB; Choe, YH; Conover, CD; Shum, K.; Wu, D.; Royzen, MJ Med. Chem. 2000, 43, 475.).

[0385] The "compound" of the present application includes its precursor compound or synthetic intermediate compound, and the precursor compound or synthetic intermediate compound can be obtained by simple treatment to obtain the compound described in the present application, for example, the compound of the present application has an amino protecting group, an oxygen protecting group, a phosphate protecting group or a carboxylic acid protecting group.

[0386] As used herein, the term "hydroxy" refers to -OH.

[0387] As used herein, the term "oxo" refers to =0.

[0388] As used herein, the term "carboxyl" refers to -C(=O)OH.

[0389] As used herein, the term "acetyl (Ac)" refers to -COCH3.

[0390] "Ionizable lipids" means that the lipids are ionizable such that they can exist in either a positively charged or neutral form depending on the pH. In some embodiments, the ionizable lipid is an amino lipid.

[0391] "Neutral lipids" refer to lipid molecules that are uncharged under specific pH conditions, such as physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE).

[0392] "Structured lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentanylphenyl carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol, or campesterol.

[0393] "Polymer lipid" refers to a molecule containing a polymer portion and a lipid portion. In some cases, it is also referred to as a "polymer-conjugated lipid" or "polymer-conjugated lipid." In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid or a PEGylated lipid.

[0394] "Lipid nanoparticles" refer to particles containing lipid components and having nanometer dimensions.

[0395] Numerical values ​​in this application generally refer to a range of ±10%, which may be expanded to ±15% or ±20% in some cases, but not exceeding ±25%. These values ​​are based on the pre-set values. For example, if the molar percentage of ionizable lipids to total lipids is approximately 50 mol%, this generally includes a molar percentage of ionizable lipids of 40 mol% to 60 mol%, preferably 45 mol% to 55 mol%. The PEG moiety has a number average molecular weight of approximately 2000 g / mol, which generally includes a number average molecular weight of 1500 to 2500 g / mol.

[0396] The average molecular weight refers to the average molecular weight of a polymer. There are many ways to calculate the average molecular weight, including number average molecular weight, weight average molecular weight, etc.

[0397] Number average molecular weight (Mn): The number average molecular weight is the average of the masses of the individual molecules in a polymer. The number average molecular weight is calculated by dissolving a polymer sample, diluting it appropriately, and then analyzing it using an appropriate instrument, such as a gel permeation chromatograph. By measuring the concentration of the polymer sample at different molecular weights, the number average molecular weight of the polymer can be determined.

[0398] Weight-average molecular weight (Mw): The weight-average molecular weight is the weighted average of the masses of the individual molecules in a polymer. It is calculated by measuring the concentration of a polymer sample at different molecular weights, then summing the weights of the polymers weighted by their molecular weights, and dividing the sum by the total mass of the polymers. The weight-average molecular weight is closer to the actual molecular weight of the polymer than the number-average molecular weight.

[0399] Other definitions

[0400] The term "treat" as used herein relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The noun "treat" as used herein relates to the action of the verb treat, which is as just defined.

[0401] Herein, muscle includes cardiac muscle, skeletal muscle (including diaphragm), smooth muscle, etc., and muscle-related diseases include skeletal muscle-related diseases and cardiac-related diseases.

[0402] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts and amino acid addition salts of the compounds of the present application that are suitable for use in contact with patient tissues within the scope of sound medical judgment, do not produce undue toxicity, irritation, allergic response, etc., are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the present application.

[0403] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine.

[0404] Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this application, the salts are equivalent to their respective free acids.

[0405] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides prepared from inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate, and isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginate, gluconate, galacturonate, and the like are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, incorporated herein by reference).

[0406] "Subjects" to be administered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys, marmosets), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0407] "Disease," "disorder," and "condition" are used interchangeably herein.

[0408] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduces the severity of, or delays or slows the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject develops a particular disease, disorder, or condition ("prophylactic treatment").

[0409] Generally, an "effective amount" of a pharmaceutical composition refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those skilled in the art, the effective amount of the pharmaceutical composition of the present application may vary depending on factors such as the biological target, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the mode of administration, and the age, health, and symptoms of the subject. An effective amount includes both a therapeutically effective amount and a prophylactically effective amount.

[0410] As used herein, unless otherwise specified, a "therapeutically effective amount" of a pharmaceutical composition is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a pharmaceutical composition refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic effect of other therapeutic agents.

[0411] Unless otherwise specified, a "prophylactically effective amount" of a pharmaceutical composition as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount to prevent the recurrence of a disease, disorder, or condition. A prophylactically effective amount of a pharmaceutical composition refers to an amount of a therapeutic agent, when used alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" can include an amount that improves overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.

[0412] "Combination" and related terms refer to the simultaneous or sequential administration of the pharmaceutical composition of the present application and other therapeutic agents. For example, the pharmaceutical composition of the present application can be administered simultaneously or sequentially with the other therapeutic agent in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agent in a single unit dosage form. Specific implementation plan

[0413] Herein, the "compound of the present application" refers to the following compound, or a pharmaceutically acceptable salt thereof, an isotopic variant, a tautomer or a stereoisomer thereof.

[0414] Herein, compounds are named using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise indicated) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed herein may appear in both Z and E forms with carbon-carbon double bonds. Compounds that exist in different tautomeric forms are not limited to any particular tautomer, but are intended to encompass all tautomeric forms.

[0415] In the compounds of the present application, each variable may be defined as follows.

[0416] L

[0417] In one embodiment, L is absent; in another embodiment, L is a divalent linking group, such as -L3-(CH2)n2-L4-; in another embodiment, L is a chemical bond; in another embodiment, L is Preferred In another embodiment, L is Preferred In another embodiment, L is Preferred In another embodiment, L is Preferred In another embodiment, L is -NHC(O)-; in another embodiment, L is -OC(O)-; in another embodiment, L is -C(O)-.

[0418] In one embodiment, L3 is absent; in another embodiment, L3 is -NHC(O)-; in another embodiment, L3 is -C(O)NH-; in another embodiment, L3 is -C(O)O-; in another embodiment, L3 is -OC(O)-; in another embodiment, L3 is -C(O)-; in another embodiment, L3 is -OC(O)O-; in another embodiment, L3 is -P(O)3-.

[0419] In one embodiment, L4 is absent; in another embodiment, L4 is -NHC(O)-; in another embodiment, L4 is -C(O)NH-; in another embodiment, L4 is -C(O)O-; in another embodiment, L4 is -OC(O)-; in another embodiment, L4 is -C(O)-; in another embodiment, L4 is -OC(O)O-; in another embodiment, L4 is -P(O)3-.

[0420] In one embodiment, n2 is 1; in another embodiment, n2 is 2; in another embodiment, n2 is 3; in another embodiment, n2 is 4; in another embodiment, n2 is 5.

[0421] In a more specific embodiment, L is -L3-(CH2)n2-L4-, wherein L3 and L4 are independently selected from absent, -NHC(O)-, -C(O)NH-, -C(O)O-, -OC(O)-, -C(O)-, -OC(O)O-, -P(O)3-, and n2 is an integer from 1 to 5, such as 1, 2, 3, 4 or 5; in another more specific embodiment, L is selected from or absent; in another more specific embodiment, L is selected from or absent; in another more specific embodiment, L is selected from or absent; in another more specific embodiment, L is selected from Or does not exist.

[0422] In a more specific embodiment, L is -NHC(O)-, -OC(O)-, -C(O)- or absent; in another more specific embodiment, L is Or absent; in another more specific embodiment, L is Or does not exist.

[0423] L2

[0424] In one embodiment, L2 is absent or CH2; in one embodiment, L2 is absent; in another embodiment, L2 is CH2.

[0425] Q 11

[0426] In one embodiment, Q 11 is -C(O)O-; in another embodiment, Q 11 is -OC(O)-; in another embodiment, Q 11 is -OC(O)O-.

[0427] In a more specific embodiment, Q 11 are independently selected from -C(O)O-, -OC(O)- or -OC(O)O-; in another more specific embodiment, Q 11 Independently selected from -C(O)O- or -OC(O)-.

[0428] Rw

[0429] In one embodiment, R w is H; in another embodiment, R w for

[0430] R 11

[0431] In one embodiment, R 11 is H; in another embodiment, R 11 is an alkyl group, preferably C 1-30 Alkyl, preferably C 1-20 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably -CH3; in another embodiment, R 11 It is a cycloalkyl group.

[0432] In one embodiment, R 11 C 1-30 Alkyl; in another embodiment, R 11 C 1-20 Alkyl; in another embodiment, R 11 C 1-10 Alkyl; in another embodiment, R 11 C 1-6 Alkyl; in another embodiment, R 11 C 1-3 Alkyl; in another embodiment, R 11 is -(CH2)2CH3, -CH2CH3 or -CH3; in another embodiment, R 11 is -CH3; preferably, the alkyl group is optionally substituted or unsubstituted.

[0433] In one embodiment, R 11 C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-6 Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), preferably C 3-5 Cycloalkyl, preferably C 3-4 Cycloalkyl, preferably cyclopropyl, preferably cyclopentyl; preferably, the cycloalkyl is optionally substituted or unsubstituted.

[0434] In a specific embodiment, R 11 H, C 1-30 Alkyl or C 3-14 Cycloalkyl; in another specific embodiment, R11 H, C 1-20 Alkyl or C 3-10 Cycloalkyl; in another specific embodiment, R 11 H, C 1-10 Alkyl or C 3-10 Cycloalkyl; in another specific embodiment, R 11 H, C 1-6 Alkyl or C 3-6 Cycloalkyl; in another specific embodiment, R 11 H, C 1-3 Alkyl or C 3-6 Cycloalkyl In another specific embodiment, R 11 It is H, -CH3.

[0435] n1

[0436] In one embodiment, n1 is an integer from 1 to 250; in another embodiment, n1 is an integer from 10 to 120; in another embodiment, n1 is an integer from 30 to 80.

[0437] In one embodiment, n1 is 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, or 110-120; in another embodiment, n1 is 10-30, 20-40, 30-50, 40-60, 50-80, 60-90, or 90-120; in another embodiment, n1 is 15-35, 25-45, 35-55, 45-65, 55-75, 65-85, 75-95, 85-105, 95-105, or 105-120; in another embodiment, n1 is 30-55; in another embodiment, n1 is 40-50; In another embodiment, n1 is 70-90; in another embodiment, n1 is 100-120; in another embodiment, n1 is 40-45; in another embodiment, n1 is 45-50; in another embodiment, n1 is 50-55; in another embodiment, n1 is 65-70; in another embodiment, n1 is 70-75; in another embodiment, n1 is 75-80; in another embodiment, n1 is 75-85; in another embodiment, n1 is 100-105; in another embodiment, n1 is 105-110; in another embodiment, n1 is 105-115; in another embodiment, n1 is 110-115.

[0438] In one embodiment, n1 is 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 44, 45, 46, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 114 or 120. In another embodiment, n1 is 5, 10, 15, 20, 25, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 4, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120. In another embodiment, n1 is 30, 35, 40, 44, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 114 or 120; in another embodiment, n1 is 44, 45 or 46; in another embodiment, n1 is 75, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85; in another embodiment, n1 is 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 or 120. In another embodiment, n1 is 44; in another embodiment, n1 is 45; in another embodiment, n1 is 46; in another embodiment, n1 is 77; in another embodiment, n1 is 78; in another embodiment, n1 is 79; in another embodiment, n1 is 80; in another embodiment, n1 is 110; in another embodiment, n1 is 111; in another embodiment, n1 is 112; in another embodiment, n1 is 113; in another embodiment, n1 is 114; in another embodiment, n1 is 115.

[0439] In one embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 400 g / mol to about 6000 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 1500 g / mol to about 5000 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound has an average molecular weight of about 1500-about 2500 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound has an average molecular weight of about 3000-about 4000 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound has an average molecular weight of about 4500-about 5500 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound has an average molecular weight of about 1800-about 2200 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound has an average molecular weight of about 1500-about 2500 g / mol. In another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound has an average molecular weight of about 3200 to about 3800 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 4800 to about 5200 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 2000 g / mol, about 3000 g / mol, about 3350 g / mol or about 5000 g / mol; in another embodiment, the range of n1 is such that the polyethylene glycol of the present application has an average molecular weight of about 1000 g / mol, about 2000 g / mol, about 3350 g / mol or about 5000 g / mol. In another embodiment, the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 2000 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 3000 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 3350 g / mol; in another embodiment, the range of n1 is such that the PEG portion of the PEGylated lipid compound of the present application has an average molecular weight of about 5000 g / mol.

[0440] R w

[0441] In one embodiment, R w Select H or Preferably H or In another embodiment, R w is H; in another embodiment, R w for Preferred

[0442] Q 11

[0443] In one embodiment, Q 11 is -C(O)O-; in another embodiment, Q 11 is -OC(O)-; in another embodiment, Q 11 is -OC(O)O-.

[0444] In a more specific embodiment, Q 11 are independently selected from -C(O)O-, -OC(O)- or -OC(O)O-; in another more specific embodiment, Q 11 Independently selected from -C(O)O- or -OC(O)-.

[0445] R 21 、R 31 、R 41

[0446] In one embodiment, R 21 C 5-30 Alkyl, preferably C 5-26 Alkyl, preferably C 10-26 Alkyl, preferably C 11-26 Alkyl, preferably C 12-26 Alkyl, preferably C 13-26 Alkyl, preferably C 14-26 Alkyl, preferably C 15-26 Alkyl, preferably C 16-26 Alkyl, preferably C 17-26 Alkyl, preferably C 18-26 Alkyl, preferably C 19-26 Alkyl, preferably C 20-26 Alkyl; in another embodiment, R 21 C 10-25 Alkyl; in another embodiment, R 21 C 10-20 Alkyl; in another embodiment, R 21 C 10-20 Straight chain alkyl, preferably C 10 Straight chain alkyl, preferably C 11 Straight chain alkyl, preferably C 12 Straight chain alkyl, preferably C 13 Straight chain alkyl, preferably C 14 Straight chain alkyl, preferably C 15 Straight chain alkyl, preferably C 16 Straight chain alkyl, preferably C 17 Straight chain alkyl, preferably C 18 Straight chain alkyl, preferably C19 Straight chain alkyl, preferably C 20 Straight chain alkyl; in another embodiment, R 21 C 5-30 Alkenyl, preferably C 5-26 Alkenyl, preferably C 10-26 Alkenyl, preferably C 11-26 Alkenyl, preferably C 12-26 Alkenyl, preferably C 13-26 Alkenyl, preferably C 14-26 Alkenyl, preferably C 15-26 Alkenyl, preferably C 16-26 Alkenyl, preferably C 17-26 Alkenyl, preferably C 18-26 Alkenyl, preferably C 19-26 Alkenyl, preferably C 20-26 alkenyl; in another embodiment, R 21 C 10-25 alkenyl; in another embodiment, R 21 C 10-20 alkenyl; in another embodiment, R 21 C 5-30 Alkynyl, preferably C 5-26 Alkynyl, preferably C 10-26 Alkynyl, preferably C 11-26 Alkynyl, preferably C 12-26 Alkynyl, preferably C 13-26 Alkynyl, preferably C 14-26 Alkynyl, preferably C 15-26 Alkynyl, preferably C 16-26 Alkynyl, preferably C 17-26 Alkynyl, preferably C 18-26 Alkynyl, preferably C 19-26 Alkynyl, preferably C 20-26 Alkynyl; in another embodiment, R 21 C 10-25 Alkynyl; in another embodiment, R 21 C 10-20 Alkynyl; in another embodiment, R 21 Optionally, one or more R V Substituted; in another embodiment, R 21 Optionally 1, 2, 3 or 4 R V Substituted; in another embodiment, R 21 Optionally replaced by 1 R V Substituted; in another embodiment, R 21 By 1 R V Replace and R 21 and R V Same; in another embodiment, R 21 By 1 RV Replace and R 21 and R V Different; in another embodiment, R 21 Not replaced.

[0447] In one embodiment, R 31 C 5-30 Alkyl, preferably C 5-26 Alkyl, preferably C 10-26 Alkyl, preferably C 11-26 Alkyl, preferably C 12-26 Alkyl, preferably C 13-26 Alkyl, preferably C 14-26 Alkyl, preferably C 15-26 Alkyl, preferably C 16-26 Alkyl, preferably C 17-26 Alkyl, preferably C 18-26 Alkyl, preferably C 19-26 Alkyl, preferably C 20-26 Alkyl; in another embodiment, R 31 C 10-25 Alkyl; in another embodiment, R 31 C 10-20 Alkyl; in another embodiment, R 31 C 10-20 Straight chain alkyl, preferably C 10 Straight chain alkyl, preferably C 11 Straight chain alkyl, preferably C 12 Straight chain alkyl, preferably C 13 Straight chain alkyl, preferably C 14 Straight chain alkyl, preferably C 15 Straight chain alkyl, preferably C 16 Straight chain alkyl, preferably C 17 Straight chain alkyl, preferably C 18 Straight chain alkyl, preferably C 19 Straight chain alkyl, preferably C 20 Straight chain alkyl; in another embodiment, R 31 C 5-30 Alkenyl, preferably C 5-26 Alkenyl, preferably C 10-26 Alkenyl, preferably C 11-26 Alkenyl, preferably C 12-26 Alkenyl, preferably C 13-26 Alkenyl, preferably C 14-26 Alkenyl, preferably C 15-26 Alkenyl, preferably C 16-26 Alkenyl, preferably C 17-26 Alkenyl, preferably C 18-26 Alkenyl, preferably C 19-26 Alkenyl, preferably C 20-26alkenyl; in another embodiment, R 31 C 10-25 alkenyl; in another embodiment, R 31 C 10-20 alkenyl; in another embodiment, R 31 C 5-30 Alkynyl, preferably C 5-26 Alkynyl, preferably C 10-26 Alkynyl, preferably C 11-26 Alkynyl, preferably C 12-26 Alkynyl, preferably C 13-26 Alkynyl, preferably C 14-26 Alkynyl, preferably C 15-26 Alkynyl, preferably C 16-26 Alkynyl, preferably C 17-26 Alkynyl, preferably C 18-26 Alkynyl, preferably C 19-26 Alkynyl, preferably C 20-26 Alkynyl; in another embodiment, R 31 C 10-25 Alkynyl; in another embodiment, R 31 C 10-20 Alkynyl; in another embodiment, R 31 Optionally, one or more R V Substituted; in another embodiment, R 31 Optionally 1, 2, 3 or 4 R V Substituted; in another embodiment, R 31 Optionally replaced by 1 R V Substituted; in another embodiment, R 31 By 1 R V Replace and R 31 and R V Same; in another embodiment, R 31 By 1 R V Replace and R 31 and R V Different; in another embodiment, R 31 Not replaced.

[0448] In one embodiment, R 41 C 5-30 Alkyl, preferably C 5-26 Alkyl, preferably C 10-26 Alkyl, preferably C 11-26 Alkyl, preferably C 12-26 Alkyl, preferably C 13-26 Alkyl, preferably C 14-26 Alkyl, preferably C 15-26 Alkyl, preferably C 16-26 Alkyl, preferably C17-26 Alkyl, preferably C 18-26 Alkyl, preferably C 19-26 Alkyl, preferably C 20-26 Alkyl; in another embodiment, R 41 C 10-25 Alkyl; in another embodiment, R 41 C 10-20 Alkyl; in another embodiment, R 41 C 10-20 Straight chain alkyl, preferably C 10 Straight chain alkyl, preferably C 11 Straight chain alkyl, preferably C 12 Straight chain alkyl, preferably C 13 Straight chain alkyl, preferably C 14 Straight chain alkyl, preferably C 15 Straight chain alkyl, preferably C 16 Straight chain alkyl, preferably C 17 Straight chain alkyl, preferably C 18 Straight chain alkyl, preferably C 19 Straight chain alkyl, preferably C 20 Straight chain alkyl; in another embodiment, R 41 C 5-30 Alkenyl, preferably C 5-26 Alkenyl, preferably C 10-26 Alkenyl, preferably C 11-26 Alkenyl, preferably C 12-26 Alkenyl, preferably C 13-26 Alkenyl, preferably C 14-26 Alkenyl, preferably C 15-26 Alkenyl, preferably C 16-26 Alkenyl, preferably C 17-26 Alkenyl, preferably C 18-26 Alkenyl, preferably C 19-26 Alkenyl, preferably C 20-26 alkenyl; in another embodiment, R 41 C 10-25 alkenyl; in another embodiment, R 41 C 10-20 alkenyl; in another embodiment, R 41 C 5-30 Alkynyl, preferably C 5-26 Alkynyl, preferably C 10-26 Alkynyl, preferably C 11-26 Alkynyl, preferably C 12-26 Alkynyl, preferably C 13-26 Alkynyl, preferably C 14-26 Alkynyl, preferably C 15-26 Alkynyl, preferably C 16-26 Alkynyl, preferably C 17-26 Alkynyl, preferably C18-26 Alkynyl, preferably C 19-26 Alkynyl, preferably C 20-26 Alkynyl; in another embodiment, R 41 C 10-25 Alkynyl; in another embodiment, R 41 C 10-20 Alkynyl; in another embodiment, R 41 Optionally, one or more R V Substituted; in another embodiment, R 31 Optionally 1, 2, 3 or 4 R V Substituted; in another embodiment, R 41 Optionally replaced by 1 R V Substituted; in another embodiment, R 41 By 1 R V Replace and R 41 and R V Same; in another embodiment, R 41 By 1 R V Replace and R 41 and R V Different; in another embodiment, R 41 Not replaced.

[0449] In one embodiment, R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl; in another embodiment, R 21 、R 31 、R 41 Independently selected from C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl; in another embodiment, R 21 、R 31 、R 41 Independently selected from C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl; in another embodiment, R 21 、R 31 、R 41 Independently selected from C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl; in another embodiment, R 21 、R 31 、R 41 Independently selected from, preferably C14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl; in another embodiment, R 21 、R 31 、R 41 Independently selected from C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl; in another embodiment, R 21 、R 31 、R 41 Independently selected from C 10-20 Alkyl, C 10-20 Alkenyl or C 10-20 Alkynyl; in another embodiment, R 21 、R 31 、R 41 Optionally, one or more R V Substituted; in another embodiment, R 21 、R 31 、R 41 Optionally 1, 2, 3 or 4 R V Substituted; in another embodiment, R 21 、R 31 、R 41 Optionally replaced by 1 R V Substituted; in another embodiment, R 21 、R 31 、R 41 Not replaced.

[0450] In one embodiment, R 21 、R 31 、R 41 Independently selected from -(CH2) 10 CH3, -(CH2) 11 CH3, -(CH2) 12 CH3, -(CH2) 14 CH3, -(CH2) 14 CH3, -(CH2) 15 CH3, -(CH2) 16 CH3, -(CH2) 17 CH3, -(CH2) 18 CH3 and -(CH2) 19 CH3, in another embodiment, R 21 、R 31 、R 41 Independently selected from -(CH2) 11 CH3; In another embodiment, R 21 、R 31、R 41 Independently selected from -(CH2) 10 CH3; In another embodiment, R 21 、R 31 、R 41 Independently selected from -(CH2) 10 CH3, which is optionally replaced by one or more R V Substitution is preferably by 1, 2, 3 or 4 R V substituted, preferably by 1 R V replace.

[0451] In one embodiment, R 21 By one or more R V substituted, preferably by one R V Replacement, R 31 Not R V Substituted; in another embodiment, R 21 Not R V Replacement, R 31 By one or more R V substituted, preferably by one R V Substituted; in another embodiment, R 21 and R 31 By one or more R V substituted, preferably by one R V replace.

[0452] In one embodiment, R 21 、R 31 and R 41 Not R V replace.

[0453] Rv

[0454] In one embodiment, R V is H; in another embodiment, R V C 1-30 Alkyl, preferably C 4-30 Alkyl, preferably C 4-26 Alkyl, preferably C 6-26 Alkyl, preferably C 10-26 Alkyl, preferably C 10-20 Alkyl; in another embodiment, R V C 10-20 Straight chain alkyl, preferably C 10 Straight chain alkyl, preferably C 11 Straight chain alkyl, preferably C 12 Straight chain alkyl, preferably C 13 Straight chain alkyl, preferably C 14 Straight chain alkyl, preferably C 15Straight chain alkyl, preferably C 16 Straight chain alkyl, preferably C 17 Straight chain alkyl, preferably C 18 Straight chain alkyl, preferably C 19 Straight chain alkyl, preferably C 20 Straight chain alkyl; in another embodiment, R V C 2-30 Alkenyl, preferably C 4-30 Alkenyl, preferably C 4-26 Alkenyl, preferably C 6-26 Alkenyl, preferably C 10-26 Alkenyl, preferably C 10-20 Alkenyl, preferably C 10-20 Straight chain alkenyl; in another embodiment, R V C 2-30 Alkynyl, preferably C 4-30 Alkynyl, preferably C 4-26 Alkynyl, preferably C 6- 26 Alkynyl, preferably C 10-26 Alkynyl, preferably C 10-20 Alkynyl, preferably C 10-20 Straight chain alkynyl; in another embodiment, R V -L c1 -OR c1 In another embodiment, R V -L c1 -SR c1 In another embodiment, R V -L c1 -NR c1 R' c1 .

[0455] In a specific embodiment, R V Independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 In another embodiment, R V Independently selected from H, C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl; In another embodiment, R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 In another embodiment, R V Independently selected from C 1-26 Alkyl, C 2- 26 Alkenyl, C 2-26 Alkynyl; In another embodiment, R V Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl and C 10-26 Alkynyl; In another embodiment, R V Independently selected from C 10-26 Alkyl and C 10-26 alkenyl; in another embodiment, R V Independently C 10-26 Alkyl; in another embodiment, R V Independently C 10-20 alkyl.

[0456] L c1 、R c1 and R' c1

[0457] In one embodiment, L c1 is a chemical bond; in another embodiment, L c1 C 1-20 Alkylene, preferably C 1-18 Alkylene, preferably C 1-16 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 alkylene;

[0458] In a more specific embodiment, L c1 independently selected from chemical bonds and C 1-16 Alkylene; in another more specific embodiment, L c1 independently selected from chemical bonds and C 1-10 Alkylene; in another more specific embodiment, L c1 independently selected from chemical bonds and C 1-6 Alkylene.

[0459] In one embodiment, R c1 is H; in another embodiment, R c1 C1-20 Alkyl, preferably C 1-18 Alkylene, preferably C 1-16 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene; in another embodiment, R c1 C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-6 Cycloalkyl; in another embodiment, R c1 It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0460] In one embodiment, R' c1 is H; in another embodiment, R' c1 C 1-20 Alkyl, preferably C 1-18 Alkylene, preferably C 1-16 Alkylene, preferably C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene; in another embodiment, R' c1 C 3-14 Cycloalkyl, preferably C 3-10 Cycloalkyl, preferably C 3-6 Cycloalkyl; in another embodiment, R' c1 is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group;

[0461] In a more specific embodiment, R c1 and R' c1 Independently selected from H and C 1-14 Alkyl; in another more specific embodiment, R c1 and R' c1 Independently selected from H and C 1-10 Alkyl; in another more specific embodiment, R c1 and R' c1 Independently selected from H and C 1-6 alkyl.

[0462] In a more specific embodiment, R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 cycloalkyl and 3 to 14 membered heterocyclyl; in another more specific embodiment, R c1 and R' c1 Independently C 1-20 alkyl.

[0463] o', p', and q'

[0464] In one embodiment, o' is 1; in another embodiment, o' is 2; in another embodiment, o' is 3; in another embodiment, o' is 4; in another embodiment, o' is 5; in another embodiment, o' is 6; in another embodiment, o' is 7; in another embodiment, o' is 8; in another embodiment, o' is 9; in another embodiment, o' is 10; in another embodiment, o' is 11; in another embodiment, o' is 12; in another embodiment, o' is 13; in another embodiment, o' is 14; and in another embodiment, o' is 15.

[0465] In one embodiment, p' is 1; in another embodiment, p' is 2; in another embodiment, p' is 3; in another embodiment, p' is 4; in another embodiment, p' is 5; in another embodiment, p' is 6; in another embodiment, p' is 7; in another embodiment, p' is 8; in another embodiment, p' is 9; in another embodiment, p' is 10; in another embodiment, p' is 11; in another embodiment, p' is 12; in another embodiment, p' is 13; in another embodiment, p' is 14; and in another embodiment, p' is 15.

[0466] In one embodiment, q' is 1; in another embodiment, q' is 2; in another embodiment, q' is 3; in another embodiment, q' is 4; in another embodiment, q' is 5; in another embodiment, q' is 6; in another embodiment, q' is 7; in another embodiment, q' is 8; in another embodiment, q' is 9; in another embodiment, q' is 10; in another embodiment, q' is 11; in another embodiment, q' is 12; in another embodiment, q' is 13; in another embodiment, q' is 14; and in another embodiment, q' is 15.

[0467] In a more specific embodiment, o' is independently an integer from 0 to 10, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; in another more specific embodiment, o' is independently an integer from 0 to 5, such as 0, 1, 2, 3, 4, 5; in another more specific embodiment, o' is independently an integer from 0 to 3, such as 0, 1, 2, 3.

[0468] In a more specific embodiment, p' is independently an integer from 0 to 10, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; in another more specific embodiment, p' is independently an integer from 0 to 5, such as 0, 1, 2, 3, 4, 5; in another more specific embodiment, p' is independently an integer from 0 to 3, such as 0, 1, 2, 3.

[0469] In a more specific embodiment, q' is independently an integer from 0 to 10, such as 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; in another more specific embodiment, q' is independently an integer from 0 to 5, such as 0, 1, 2, 3, 4, 5; in another more specific embodiment, q' is independently an integer from 0 to 3, such as 0, 1, 2, 3. The compounds of the present application may include one or more asymmetric centers, and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereoisomeric forms. For example, the compounds of the present application may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis.

[0470] The compounds of the present application may exist as tautomers. Tautomers are functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Tautomers are a special type of functional group isomer. A pair of tautomers can convert between each other, but the more stable isomer usually predominates. The most prominent examples are enol and keto tautomers.

[0471] The present application also includes isotopically labeled compounds (isotopic variants), which are identical to those described in formula (I) and formula (II), but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, for example 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, their prodrugs and pharmaceutically acceptable salts of the compounds or prodrugs are all within the scope of the present application. Certain isotope-labeled compounds of the present invention, such as those that introduce radioactive isotopes (e.g. 3 H and 14 C) can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. 2 H, because greater metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically labeled compounds of Formula (IV) and prodrugs thereof can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents when performing the processes disclosed in the following schemes and / or Examples and Preparations.

[0472] The present application also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms belong to the present application.

[0473] Pharmaceutical compositions and kits

[0474] In another aspect, the present application provides a pharmaceutical composition comprising the nanoparticle composition of the present application and a pharmaceutically acceptable excipient, wherein the nanoparticle composition comprises the compound of the present application.

[0475] The pharmaceutically acceptable excipient used in the present application refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present application include (but are not limited to) ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[0476] The present application also includes a kit (e.g., a pharmaceutical package). The kit provided may include the nanoparticle composition of the present application and other therapeutic agents, diagnostic agents, or prophylactic agents, as well as a first and second container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispersible package or other suitable container) containing the nanoparticle composition of the present application and other therapeutic agents, diagnostic agents, or prophylactic agents. In some embodiments, the kit provided may also optionally include a third container containing a pharmaceutical excipient for diluting or suspending the nanoparticle composition of the present application and / or other therapeutic agents, diagnostic agents, or prophylactic agents. In some embodiments, the nanoparticle composition of the present application and other therapeutic agents, diagnostic agents, or prophylactic agents provided in the first container and the second container are combined to form a unit dosage form.

[0477] Drug administration

[0478] The pharmaceutical composition provided herein can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration by implant or other modes of administration. For example, parenteral administration used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration, intrathecal administration, intralesional administration, and intracranial injection or infusion techniques.

[0479] Typically, an effective amount of the pharmaceutical composition of the present application is administered. The amount of the pharmaceutical composition actually administered can be determined by a physician based on the relevant circumstances, including the condition to be treated or prevented, the selected route of administration, the actual pharmaceutical composition administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.

[0480] When used to prevent the conditions described herein, the pharmaceutical compositions provided herein are administered to a subject at risk of developing the condition, typically based on the advice and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition typically include those with a family history of the condition, or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0481] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration can continue indefinitely, e.g., for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood over an extended period of time, e.g., within the therapeutic window.

[0482] Various methods of administration can be used to further deliver the pharmaceutical composition of the present application. For example, in some embodiments, the pharmaceutical composition can be administered by injection, for example, in order to increase the concentration of the compound in the blood to an effective level. The injection dose depends on the target systemic level of the active component by the body, for example, the intramuscular or subcutaneous injection dose slowly releases the active component, and the injection (for example, by IV intravenous drip) directly delivered to the vein can be delivered more quickly so that the concentration of the active component in the blood is rapidly increased to an effective level. In other embodiments, the pharmaceutical composition can be given in a continuous infusion form, for example, by IV intravenous drip, so as to provide the active component of a steady-state concentration in the subject's body. In addition, in other embodiments, the pharmaceutical composition of the injection dose can be first given, and then continuous infusion.

[0483] To provide blood levels similar to, or lower than, those obtained with an injectable dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.

[0484] From about 1 to about 120 hours, and particularly from 24 to 96 hours, the injected dose level is in the range of about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To achieve adequate steady-state levels, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered. For a 40 to 80 kg human patient, the maximum total dose may not exceed about 2 g / day.

[0485] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.

[0486] Example

[0487] To make the purpose, technical solutions, and advantages of the embodiments of the present application more clear, the technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the chemical reaction formulas in the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, not all of the embodiments. The following is merely a further description of the present application, and the scope of protection of the present application is not limited thereto.

[0488] In the specific embodiments of this application, any technical means or methods not otherwise specified are conventional in the art. Materials, reagents, etc. used in the examples are commercially available unless otherwise specified. Table 1 below lists the abbreviations of common chemical substances used in the examples and comparative examples of this application.

[0489] Table 1. Abbreviations of common chemical substances

[0490] Example 1

[0491] Synthesis of compound 1:

[0492] Stearic acid (25 g, 87.88 mmol, 1.0 eq.) was dissolved in 250 mL of tetrahydrofuran. Under nitrogen, sodium hydride (5.62 g, 60%, 140.61 mmol, 1.6 eq.) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Lithium diisopropylamide (79 mL, 2.0 M in THF) was then added to the reaction system, and stirring continued at 0°C for 30 minutes. 1-Iodohexadecane (46.45 g, 131.82 mmol, 1.5 eq.) was then added to the reaction system. The mixture was heated to 80°C and stirred for 12 hours. After completion, the reaction was cooled to room temperature, diluted with water (200 mL), and the pH was adjusted to 5 with 1N hydrochloric acid. The mixture was extracted with dichloromethane (3 x 250 mL). The organic phases were combined, washed with saturated sodium chloride (3 x 250 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporator to obtain a crude product, which was purified by silica gel column to obtain white solid compound 1-1 (11 g).

[0493] Phosphorus oxychloride (6.4 g, 41.62 mmol, 1.1 eq.) was dissolved in 100 mL of dichloromethane and cooled to 0°C. Under nitrogen, triethylamine (7.7 g, 75.67 mmol, 2.0 eq.) and 2,2-dimethyl-1,3-dioxolane-4-methanol (5.0 g, 37.88 mmol, 1.0 eq.) were added. The reaction was stirred at room temperature for 2 hours. After completion, the reaction was diluted with 100 mL of water and extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain compound 1-3 (6 g) as a yellow oil, which was used directly in the next step without purification.

[0494] Compound 1-3 (6.0 g, 24.09 mmol, 1.0 eq.) was dissolved in 60 mL of dichloromethane and cooled to 0°C. Under nitrogen, triethylamine (4.9 g, 48.19 mmol, 2.0 eq.) and compound 1-4 (6.8 g, 24.09 mmol, 1.0 eq.) were added. The reaction was stirred at room temperature for 1 hour. Triethylamine (4.9 g, 48.19 mmol, 2.0 eq.) and benzyl alcohol (2.6 g, 24.09 mmol, 1.0 eq.) were then added to the reaction system at 0°C. The reaction was continued at room temperature for 5 hours. After completion of the reaction, the mixture was diluted with 100 mL of water and extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporator to obtain a crude product, which was purified by silica gel column to obtain white solid compound 1-5 (7 g).

[0495] Compound 1-5 (6.0 g, 10.58 mmol, 1.0 eq.) was dissolved in 60 mL of methanol and p-toluenesulfonic acid (2.8 g, 15.88 mmol, 1.5 eq.) was added at 0°C under nitrogen. The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, the pH was adjusted to 7 with saturated sodium bicarbonate and the mixture was extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain a crude product, which was purified on a silica gel column to obtain compound 1-6 (3.0 g) as a white solid.

[0496] Compound 1-6 (3.0 g, 5.68 mmol, 1.0 eq.) was dissolved in 30 mL of dichloromethane. Under nitrogen, compound 1-1 (4.3 g, 8.52 mmol, 3.0 eq.), EDCI (3.6 g, 2.28 mmol, 4.0 eq.), and DMAP (694.8 mg, 5.68 mmol, 1.0 eq.) were added sequentially. The reaction was allowed to react at room temperature for 12 hours. After completion of the reaction, 50 mL of water was added for dilution, and the mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 50 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation to obtain the crude product, which was purified on a silica gel column to obtain compound 1-7 (4 g) as a colorless oil.

[0497] Compound 1-7 (2.0 g, 1.32 mmol, 1.0 eq.) was dissolved in 20 mL of dichloromethane and piperidine (1.1 g, 13.26 mmol, 10.0 eq.) was added under nitrogen. The reaction was allowed to react at room temperature for 2 hours. After completion of the reaction, 30 mL of water was added for dilution, and the mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 30 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain a crude product. The crude product was purified on a silica gel column to obtain compound 1-8 (1.2 g) as a colorless oil.

[0498] Polyethylene glycol methyl ether (PEG 2000) compound 1-9 (2.0 g, 1.00 mmol, 1.0 eq.) was dissolved in 20 mL of dichloromethane. Under nitrogen protection, triethylamine (564.2 mg, 4.00 mmol, 4.0 eq.) and di(p-nitrobenzene) carbonate (912.0 mg, 3.00 mmol, 3.0 eq.) were added in sequence. The reaction was allowed to react at room temperature for 5 hours. After the reaction was completed, 30 mL of water was added for dilution, and the mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 30 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column to obtain compound 1-11 (1.5 g) as a white solid.

[0499] Compound 1-8 (1.0 g, 0.78 mmol, 1.0 eq.) was dissolved in 10 mL of dichloromethane. Under nitrogen protection, compound 1-11 (1.6 g, 0.78 mmol, 1.0 eq.), DIEA (301.2 mg, 2.32 mmol, 3.0 eq.), and DMAP (283.4 mg, 2.32 mmol, 1.0 eq.) were added in sequence. The reaction was allowed to react at room temperature for 4 hours. After completion of the reaction, 30 mL of water was added for dilution, and the mixture was extracted with dichloromethane (3 x 30 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 30 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column to obtain compound 1-12 (1.4 g) as a white solid.

[0500] Compound 1-12 (1.2 g, 0.37 mmol, 1.0 eq.) was dissolved in 12 mL of ethyl acetate and palladium / carbon (600 mg) was added under nitrogen. The atmosphere was replaced with hydrogen three times. The reaction system was allowed to react at room temperature for 5 hours under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered, the filter cake was washed with ethyl acetate (3 x 50 mL), the filtrates were combined, and the organic solvent was removed using a rotary evaporator to obtain the crude product. The product was purified by HPLC (column: YMC-Actus Triart C820 x 150 mm, 5 μm; phase A: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water), phase B: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain 520.8 mg of compound 1 as a white solid.

[0501] 1 H NMR (300MHz, CD3OD): δ0.88-0.91(m,12H),1.14-1.38(m,112H),1.40-1.50(m, 4H),1.52-1.71(m,4H),2.33-2.36(m,2H),3.32-3.34(m,2H),3.36-3.39(m,4H ),3.53-3.61(m,2H),3.62-3.65(m,172H),3.86-3.90(m,2H),3.90-4.02(m,2H ),4.08-4.21(m,2H),4.21-4.32(m,1H),4.59-4.62(m,1H),5.17-5.28(m,1H); 31 P NMR (300MHz, CD3OD) δ0.25; MS m / z (MALDI-TOF): 3147.78[M+H] + .

[0502] Example 2:

[0503] Synthesis of compound 2:

[0504] Compound 2 was prepared by the method of Example 1 to obtain 412.1 mg of an oily product.

[0505] 1H NMR (300MHz, CD3OD): δ0.83-0.96(m,12H),1.05-1.75(m,120H),2.28-2.42(m,2H),3.29-3.30(m,1H),3.31(s,3H),3.33-3.41(m,2H), 3.51-3.55(m,3H),3.55-3.85(m,305H),3.86-3.97(m,4H),3.97-4.06(m,2H),4.06-4.17(m,3H),4.58-4.62(m,1H),5.21-5.23(m,1H); 31 P NMR (300MHz, CD3OD) δ0.11; MS m / z (MALDI-TOF): 4735.58[M+H] + .

[0506] Example 3:

[0507] Synthesis of compound 3:

[0508] Compound 3 was prepared by the method of Example 1 to obtain 394.1 mg of an oily product.

[0509] 1 H NMR (300MHz, CD3OD): δ0.88-0.90(m,12H),1.17-1.38(m,103H),1.40-1.52(m,5H),1.52-1.7 0(m,4H),2.33-2.36(m,2H),3.31-3.33(m,2H),3.33-3.36(m,3H),3.50-3.53(m,2H),3.54-3 .62(m,2H),3.63-3.78(m,312H),3.79-3.87(m,2H),3.89-3.94(m,2H),3.95-4.02(m,2H),4. 05-4.16(m,1H),4.16-4.21(m,2H),4.21-4.30(m,1H),4.59-4.62(m,1H),5.17-5.22(m,1H); 31 P NMR (300MHz, CD3OD) δ0.25; MS m / z (MALDI-TOF): 4677.73[M+H] + .

[0510] Example 4:

[0511] Synthesis of compound 4:

[0512] Compound 4 was prepared by the method of Example 1 to obtain 515.5 mg of an oily product.

[0513] 1 H NMR (400MHz, CD3OD): δ0.83-0.97(m,12H),1.14-1.67(m,104H),2.30-2.4 1(m,2H),3.32-3.35(m,2H),3.35-3.38(m,3H),3.43-3.49(m,2H),3.53-3 .56(m,2H),3.56-3.79(m,309H),3.80-3.85(m,4H),3.85-3.93(m,2H),4. 06-4.14(m,1H),4.15-4.25(m,2H),4.46-4.65(m,2H),5.17-5.26(m,1H); 31 P NMR (400MHz, CD3OD) δ0.25; MS m / z (MALDI-TOF): 4620.73[M+H] + .

[0514] Example 5:

[0515] Synthesis of compound 5:

[0516] Compound 5 was prepared by the method of Example 1 to obtain 504.3 mg of an oily product. The mass spectrum is shown in Figure 1.

[0517] 1 H NMR (500MHz, CD3OD): δ0.88-0.91(m,12H),1.29-1.33(m,103H),1.40-1.46(m,4H),1.51 -1.60(m,4H),2.33-2.36(m,2H),3.32-3.35(m,2H),3.35-3.40(m,3H),3.48-3.59(m,4H),3.59-3.75(m,318H),3.86-3.88 (m,2H),3.88-3.90(m,2H),3.90-3.97(m,2H),4.10-4.15(m,1H),4.15-4.17(m,2H),4.59-4.65(m,2H),5.21-5.25(m,1H); 31 P NMR (500MHz, CD3OD) δ0.24; MS m / z (MALDI-TOF): 4768.88[M+Na] + .

[0518] Example 6:

[0519] Synthesis of compound 6:

[0520] Polyethylene glycol methyl ether (PEG 2000) compound 1-9 (1.0 g, 0.48 mmol, 1.0 eq.) was dissolved in a mixture of 20 mL of tetrahydrofuran and 0.1 mL of water. Under nitrogen, sodium hydroxide (155.4 mg, 3.89 mmol, 8.0 eq.) and epichlorohydrin (898.9 mg, 9.72 mmol, 20.0 eq.) were added sequentially. The reaction was stirred at 70°C for 18 hours. Then, sodium hydroxide (77.7 mg, 1.94 mmol, 4.0 eq.) and epichlorohydrin (449.5 mg, 4.86 mmol, 10.0 eq.) were added sequentially under nitrogen. The reaction was continued at 70°C for 18 hours. After completion of the reaction, the mixture was cooled to room temperature and filtered through celite. A pH = 7 phosphate buffer solution (5 mL) was added to the filtrate, which was then concentrated to remove tetrahydrofuran. After concentration, water (10 mL) was added and the mixture was extracted with ethyl acetate (2 x 5 mL), followed by extraction with dichloromethane (2 x 10 mL). The combined organic phases were dried over anhydrous sodium sulfate, collected by filtration, and the organic solvent removed by rotary evaporation to obtain a crude product. The crude product was recrystallized by adding isopropanol, filtered, and the filter cake was dried under reduced pressure to obtain Compound 6-1 (1 g) as a yellow solid.

[0521] Under nitrogen protection, compound 6-1 (1.0 g, 0.48 mmol, 1.0 eq.) was dissolved in 2.0 M potassium hydroxide aqueous solution and stirred at room temperature for 12 hours. After the reaction was completed, saturated sodium chloride aqueous solution (20 mL) was added to the reaction solution for dilution, extracted with dichloromethane (3 x 20 mL), and the organic phases were combined and washed with saturated sodium chloride aqueous solution (3 x 10 mL). The organic phase was dried over anhydrous sodium sulfate. The organic phase was collected by filtration and the organic solvent was removed by rotary evaporation to obtain a crude product. Recrystallization was performed with methyl tert-butyl ether, suction filtration, and the filter cake was dried under reduced pressure to obtain a yellow solid compound 6-2 (800 mg).

[0522] Compound 6-2 (800.0 mg, 0.37 mmol, 1.0 eq.) was dissolved in 10 mL of dichloromethane. Under nitrogen, compound 1-1 (572.7 mg, 1.11 mmol, 3.0 eq.), DCC (232.2 mg, 1.11 mmol, 3.0 eq.), and DMAP (45.8 mg, 0.37 mmol, 1.0 eq.) were added sequentially. The mixture was allowed to react at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with water (30 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined and washed with saturated sodium chloride aqueous solution (3 x 50 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and the organic phase was removed by rotary evaporation to obtain a crude product. The product was purified by HPLC (column: YMC-Actus Triart C820×150 mm, 5 μm; phase A: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% aqueous ammonia), phase B: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain compound 6 (191.0 mg) as a yellow oil. The mass spectrum is shown in Figure 2 .

[0523] 1 H NMR (300MHz, DMSO-d6): δ0.84-0.86(m,12H),1.02-1.48(m,115H),1.48-1.70(m,5H),2.15-2.34(m,2H),3.2 9(s,3H),3.41-3.70(m,178H),3.78-3.90(m,1H),3.90-4.15(m,1H),4.32-4.59(m,1H),5.05-5.27(m,1H);MS m / z(MALDI-TOF):3135.36[M+Na] + .

[0524] Example 7:

[0525] Synthesis of compound 7:

[0526] Compound 7 was prepared by the method of Example 6 to obtain 115.8 mg of an oily product.

[0527] 1H NMR (400MHz, DMSO-d6): δ0.88-0.96(m,12H),1.18-1.56(m,88H),2.25-2.34(m,2H),3.30-3.32(m,3H),3.41-3. 48(m,18H),3.48-3.75(m,162H),3.83-3.87(m,1H),3.91-4.11(m,1H),4.37-4.45(m,1H),5.00-5.22(m,1H); MS m / z(MALDI-TOF):2778.45[M+Na] + .

[0528] Example 8:

[0529] Synthesis of compound 8:

[0530] Compound 8 was prepared by the method of Example 6 to obtain 137.3 mg of an oily product.

[0531] 1 H NMR (400MHz, CD3OD): δ0.90-0.95(m,12H),1.09-1.91(m,120H),2.28-2.42(m,2H),3.32-3.40(m,3H),3.52-3.54(m,2H) ,3.54-3.56(m,2H),3.58-3.75(m,269H),3.77-3.83(m,2H),4.06-4.12(m,1H),4.44-4.62(m,1H),5.19-5.30(m,1H); m / z(MALDI-TOF):4588.90[M+Na] + .

[0532] Example 9:

[0533] Synthesis of compound 9:

[0534] Compound 9-1 (10.0 g, 73.45 mmol, 1.0 eq.) and imidazole (15.0 g, 220.35 mmol, 3.0 eq.) were dissolved in DMF. TBDPSCl (20.2 g, 73.45 mmol, 1.0 eq.) was added dropwise to the reaction mixture at room temperature under a nitrogen atmosphere. The mixture was allowed to react overnight at room temperature. After completion, the reaction system was poured into saturated aqueous sodium bicarbonate solution to quench the reaction. The mixture was extracted with ethyl acetate (3 x 200 mL). The organic phases were combined and washed with saturated brine (3 x 300 mL). The organic phases were dried over anhydrous sodium sulfate and filtered. The organic solvent was removed using a rotary evaporator to obtain a crude product. The crude product was purified on a silica gel column to obtain compound 9-2 (20.2 g).

[0535] Compound 9-2 (10.0 g, 26.70 mmol, 1.0 eq.) was dissolved in 300 mL of dichloromethane. Under nitrogen, stearic acid (45.57 g, 160.20 mmol, 6.0 eq.), EDCI (30.7 g, 160.20 mmol, 6.0 eq.), and DMAP (9.79 g, 80.1 mmol, 3.0 eq.) were added sequentially. The reaction was allowed to react at room temperature for 12 hours. After completion, the reaction was diluted with 500 mL of water. The organic phase was separated and separated, and the aqueous phase was extracted with dichloromethane (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride aqueous solution (3 x 300 mL), and dried over anhydrous sodium sulfate. The organic phase was filtered and the organic solvent was removed using a rotary evaporator to obtain the crude product, which was purified on a silica gel column to obtain compound 9-3 (18 g) as a colorless oil.

[0536] Compound 9-3 (5.0 g, 4.26 mmol, 1.0 eq.) and triethylamine (1.78 mL, 12.78 mmol, 3.0 eq.) were dissolved in 50 mL of tetrahydrofuran. Triethylamine trihydrofluoride (2.08 mL, 12.78 mmol, 3.0 eq.) was added to the reaction system. The reaction was allowed to react at room temperature. After completion, 100 mL of saturated sodium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 100 mL), and dried over anhydrous sodium sulfate. The filtrate was collected by filtration, and the organic solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified on a silica gel column to obtain compound 9-4 (2.5 g) as a colorless oil.

[0537] Compound 9-4 (1.0 g, 1.07 mmol, 1.0 eq.) was dissolved in 10 mL of acetonitrile. Under nitrogen, triethylamine (216 mg, 2.14 mmol, 2.0 eq.), 4-dimethylaminopyridine (131 mg, 1.07 mmol, 1.0 eq.), and succinic anhydride (214 mg, 2.14 mmol, 2.0 eq.) were added sequentially in an ice bath. The reaction system was stirred at 60°C for 2 hours. After completion, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x 15 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 20 mL), and dried over anhydrous sodium sulfate. The filtrate was collected by filtration, and the organic solvent was removed by rotary evaporation to obtain the crude product, which was purified on a silica gel column to obtain compound 9-5 (900 mg) as a white solid.

[0538] Compound 9-5 (300 mg, 0.29 mmol, 1.0 equiv.) was dissolved in 5 mL of dichloromethane. Polyethylene glycol 3500 compound 9-6 (1.02 g, 0.29 mmol, 1.0 eq.), EDCI (67 mg, 0.44 mmol, 1.5 eq.), and DMAP (35 mg, 0.29 mmol, 1.0 eq.) were added sequentially at room temperature under nitrogen. The mixture was allowed to react at room temperature for 12 hours. After completion, the reaction mixture was quenched with water (5 mL) and extracted with dichloromethane (3 x 5 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 5 mL), and dried over anhydrous sodium sulfate. The organic phase was collected by filtration, and the organic solvent was removed using a rotary evaporator to obtain the crude product. The product was purified by HPLC (HPLC column: XBridge Shield RP18OBD Column 19 x 250 mm, 5 μm; phase A: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water), phase B: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain compound 9 (214.6 mg) as a yellow oil.

[0539] 1 H NMR (400MHz, CD3OD): δ0.80-0.98(m,9H),1.10-1.82(m,90H),2.27-2.44(m,6H),2.57-2.72(m,4H), 3.35-3.38(m,3H),3.42-4.07(m,311H),4.10-4.16(m,5H),4.16-4.20(m,2H),4.20-4.25(m,2H);MS m / z(MALDI-TOF):4549.72[M+Na] + .

[0540] Example 10:

[0541] Synthesis of compound 10:

[0542] Compound 10 was prepared by the method of Example 9 to obtain 215.7 mg of an oily product.

[0543] 1 H NMR (400MHz, CD3OD): δ0.87-0.94(m,9H),1.18-1.38(m,84H),1.56-1.66(m,6H),2.29-2.40(m,6H),2.62-2.68(m,4H),3.34-3.37(m,3H), MS m / z(MALDI-TOF):5782.94[M+Na] + .

[0544] Example 11:

[0545] Synthesis of compound 133

[0546] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0°C. LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction mixture under nitrogen. The reaction temperature was raised to room temperature and stirred for 30 minutes before the addition of 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.). The reaction was monitored by TLC until completion. The reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM (3 x 300 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 30 g of compound 133-1 as a yellow oil.

[0547] Compound 133-1 (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0°C. Borane-tetrahydrofuran solution (1 M, 100.0 mL) was added dropwise to the reaction system under nitrogen. The temperature was raised to 75°C and stirred for 3 hours. After the reaction, the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The mixture was extracted with DCM (3 x 300 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain crude product 133-2 (13.6 g), which was used directly in the next step without purification.

[0548] Decanoyl chloride (11.0 g, 58.0 mmol, 1.3 eq.) was added to a solution of compound 133-2 (10.0 g, 44.0 mmol, 1.0 eq.) in DCM (100 mL). Triethylamine (13.5 g, 134.0 mmol, 3.0 eq.) was then added to the reaction system and allowed to react at room temperature for 3 hours. The reaction solution was poured into 100 mL of water and extracted with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product, which was then purified on a silica gel column to obtain 10 g of compound 133-3.

[0549] Potassium carbonate (1.5 g, 11.1 mmol, 3.0 eq.) and compound 133-3 (1.4 g, 3.7 mmol, 1.0 eq.) were added to a solution of ethanolamine (2.3 g, 37.2 mmol, 10.0 eq.) in acetonitrile (15.0 mL). The mixture was heated to 70°C and stirred for 3 hours. The reaction solution was poured into 30 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product, which was purified on a silica gel column to obtain 1.4 g of compound 133-4.

[0550] 133-5 (211.0 mg, 0.50 mmol, 1.2 eq.) and 133-4 (150.0 mg, 0.42 mmol, 1.0 eq.) were added to a solution of N,N-dimethylformamide (2 mL). Under nitrogen, potassium carbonate (173.9 mg, 1.26 mmol, 3.0 eq.) and sodium iodide (157.5 mg, 1.05 mmol, 2.5 eq.) were added. The mixture was stirred at 70°C for 6 h. After completion of the reaction, the mixture was cooled to room temperature, diluted with 10 mL, and then extracted with dichloromethane (3×50 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (3×50 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was removed by rotary evaporation to obtain the crude product, which was purified by HPLC (column: Xselect CSH F-Phenyl OBD 82 mg of yellow oily compound 133 was purified using a column (19x250 mm, 5 μm; phase A: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% ammonia water), phase B: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min).

[0551] 1H NMR(300MHz, CDCl3)δ:0.83-0.94(m,15H),1.18-1.42(m,43H),1.48-1.67(m,10H),2.28-2.35(m,4H),2. 46-2.52(m,4H),2.61(t,J=6.6Hz,2H),3.61(t,J=6.6Hz,2H),3.80(s,2H),4.05(t,J=6.6Hz,2H); ESI-MS m / z:696.60[M+H] + .

[0552] Example 12:

[0553] Synthesis of compound 134

[0554] According to the method of Example 11, 174 mg of compound 134 was prepared as an oily product.

[0555] 1 H NMR(400MHz,CD3OD)δ:0.85-0.95(m,15H),1.20-1.40(m,43H),1.50-1.60(m,4H),1.61-1.70(m,7H) ),2.28-2.33(m,4H),2.48-2.64(m,5H),3.51-3.63(m,2H),3.80(s,2H),4.04-4.08(m,2H); ESI-MS m / z:696.60[M+H] + .

[0556] Other compounds of the present application can be prepared by referring to the above examples and prior art.

[0557] Pharmacological experiments

[0558] Experimental Example 1: Preparation of lipid nanoparticles

[0559] The materials used for lipid nanoparticle assembly are: (1) ionizable lipid compounds: such as the ionizable lipids designed and synthesized in this application or SM102 (purchased from AVT) as a control group; (2) structural lipids: such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids: such as DSPC, which is 1,2-distearoyl-SN-glycero-3-phosphocholine (distearoylphosphatidylcholine, purchased from AVT); (4) polyethylene glycol lipid compounds: such as the polyethylene glycol lipids designed and synthesized in this application or DMG-PEG2000 as a control, which is dimyristoylglycerol-polyethylene glycol 2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, purchased from AVT); (5) nucleic acid fragment active ingredients: such as Luciferase mRNA, CRISPR Cas 9 mRNA (purchased from Trilink or homemade), gRNA (purchased from GenScript), etc. The names and structural formulas of lipid nanoparticle assembly materials are detailed in Table 2-1 and Table 2-2.

[0560] Table 2-1. Names and structural formulas of lipid nanoparticle assembly materials

[0561] Table 2-2. PEGylated lipid compounds used for lipid nanoparticle assembly

[0562] Preparation method of lipid nanoparticles: (1) ionizable lipid compound, structural lipid (cholesterol), phospholipid and polymer conjugated lipid are dissolved and mixed in ethanol in molar percentage; (2) nucleic acid (such as mRNA) active ingredient is dissolved in 25mM citric acid buffer solution (pH=4.0); (3) using an automated high-throughput microfluidic system, the organic phase containing the lipid mixture and the aqueous phase containing the nucleic acid (such as mRNA) component are mixed at a flow rate ratio of 1:3, and the mixing speed is between 5mL / min and 20mL / min; (4) the prepared lipid nanoparticles (N / P ratio of 6) are diluted with phosphate buffered saline solution, and the nanoparticle solution is ultrafiltered to the original preparation volume using an ultrafiltration tube with a molecular weight cutoff of 30kDa (purchased from Millipore); (5) the obtained nanoparticles are sterilized by filtration through a 0.2μm sterile filter membrane and stored at low temperature in a sealed glass bottle.

[0563] Methods for preparing lipid nanoparticles include, but are not limited to, microfluidic mixing systems and also include T-type mixers and ethanol injection methods.

[0564] Experimental Example 2: Characterization of physical properties of lipid nanoparticles

[0565] The particle size and particle size dispersion index (PDI) of the prepared lipid nanoparticles were measured using Zetasizer Pro (purchased from Malvern Instruments Ltd) and DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instruments. The degree of RNA encapsulation by lipid nanoparticles is characterized by the encapsulation efficiency (Encapsulation Efficiency%), which reflects the degree of binding between lipid nanoparticles and RNA fragments. This coefficient is measured by the method of Quant-itTM RiboGreen RNA Assay (purchased from Invitrogen). The lipid nanoparticle sample was diluted in TE buffer (10mM Tris-HCl, 1mM EDTA, pH=7.5), and a portion of the sample solution was taken out and 0.5% Triton (Triton X-100) was added and allowed to stand at 37°C for 30 minutes. Add Immediately after the reaction, the fluorescence value was read on a Varioskan LUX multifunctional microplate reader (purchased from Thermofisher) at an absorption wavelength of 485 nm and an emission wavelength of 528 nm to obtain the encapsulation efficiency value.

[0566] Experimental Example 3: Animal Experiment

[0567] Evaluation of the delivery effect, distribution and safety of nanoparticles loaded with luciferase mRNA (Trilink, L-7202) in mice. The experimental mice were SPF-grade C57BL / 6 female mice, 6-8 weeks old, weighing 18-22g, purchased from Beijing Sibeifu Biotechnology Co., Ltd. All animals were adaptively raised for more than 7 days before the experiment. During the experiment, they had free access to food and water, and the light was alternating between light and dark for 12 / 12h. The indoor temperature was 20-26°C and the humidity was 40-70%. The mice were randomly divided into groups. The lipid nanoparticles loaded with luciferase mRNA prepared above were injected into the mice by intravenous administration at a single dose of 2 mg / kg mRNA. Six hours after administration, the mice were subjected to in vivo bioluminescence detection using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer). Before imaging, the hind limbs and dorsal sides of the mice were shaved. The assay procedure is as follows: a 20 mg / mL D-luciferin solution is prepared in normal saline and administered intraperitoneally to each mouse. Ten minutes after administration, the mouse is anesthetized with 2.5% isoflurane in an anesthesia chamber. The anesthetized mouse is placed in an IVIS system for in vivo fluorescence imaging, with data acquisition and analysis performed on areas of concentrated fluorescence. Following in vivo imaging, the mice are sacrificed by cervical dislocation, and the liver is harvested from each mouse for ex vivo imaging to obtain the ex vivo liver signal.

[0568] Lipid nanoparticles were prepared with reference to Experimental Example 1. The materials used for lipid nanoparticle assembly were as follows: (1) ionizable lipid: Compound 134; (2) structural lipid: cholesterol (purchased from Sigma-Aldrich); (3) phospholipid: DSPC is 1,2-distearoylphosphatidylcholine (purchased from AVT); (4) PEGylated lipid compound: PEGylated lipid designed and synthesized in the present application or DMG-PEG2000 (dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, purchased from AVT) as a control; (5) nucleic acid fragment active ingredient: such as Luciferase mRNA. The specific formula of lipid nanoparticles (LNPs) is shown in Table 3. Luciferase mRNA (Trilink, L-7202) is encapsulated, and N / P=6.

[0569] The in vivo delivery efficiency of lipid nanoparticle delivery vehicles is expressed as the average fluorescence intensity (p / s / cm2 / sr) across animals within the same test group. Unless otherwise noted, the bioluminescence scale is 2E07-2E08. Regions of interest (ROIs) were delineated using IVIS software, and the average value was calculated. Higher average photon counts indicate higher in vivo delivery efficiency of the lipid nanoparticles for the mRNA fragment. The average fluorescence expression (Avg Radiance [p / s / cm2 / sr]) in in vivo muscle and isolated liver, as well as the ratio of the two, are shown in Table 4.

[0570] It can be seen from Table 4 that compared with the lipid nanoparticles of DMG-PEG2000, the lipid nanoparticles of PEGylated lipid compounds 4, 5, 6, 7 and 9 have higher delivery efficiency in muscle; and the ratio of the average photon number of living muscle to the average photon number of isolated liver of the lipid nanoparticles of PEGylated lipid compounds 4, 5, 6, 7 and 9 is significantly higher than that of the control group, indicating that the lipid nanoparticles of the PEGylated lipid compounds of the present application have good in vivo delivery efficiency for nucleic acids.

[0571] The lipid nanoparticles of the PEGylated lipid compound of the present application are more widely distributed throughout the mouse body, and the lipid nanoparticles of the PEGylated lipid compound of the present application have good systemic whole-body muscle delivery efficiency.

[0572] Table 3. LNP formulation

[0573] Table 4. Delivery efficiency related data

[0574] Experimental Example 4: Delivery effect of lipid nanoparticles prepared by PEGylated lipids of the present invention

[0575] Lipid nanoparticles were prepared according to Experimental Example 1, and the physical properties of lipid nanoparticles were characterized according to Experimental Example 2. Lipid nanoparticle assembly materials: (1) ionizable lipid: Compound 134; (2) structural lipid: cholesterol (purchased from Sigma-Aldrich); (3) phospholipid: DSPC is 1,2-distearoyl-SN-glycero-3-phosphocholine (distearoylphosphatidylcholine, purchased from AVT); (4) PEGylated lipid compound: PEGylated lipid designed and synthesized as described in this application; the molar percentages of each component are shown in Table 5, and Luciferase mRNA (commercially available) was encapsulated, with N / P=6. The experimental mice were SPF-grade C57BL / 6 female mice, 6-8 weeks old, weighing 18-22 g. The mice were injected with the tail vein. 6 hours after the tail vein injection of 0.5 mpk, the results of the components and molar percentages of lipid nanoparticles in the C57 mouse LNP and the average fluorescence expression (Avg Radiance [p / s / cm2 / sr]) in the muscles in vivo and in vitro liver are shown in Table 6:

[0576] Table 5

[0577] Table 6

[0578] The foregoing descriptions of specific exemplary embodiments of the present application are for purposes of illustration and description. These descriptions are not intended to limit the present application to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments are selected and described for the purpose of explaining the specific principles of the present application and their practical application, thereby enabling those skilled in the art to realize and utilize the various exemplary embodiments of the present application and various options and modifications. The scope of the present application is intended to be defined by the claims and their equivalents.

Claims

1. A PEGylated lipid compound having the structure of formula (I'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, L is absent or a divalent linking group; L2 is absent or CH2; R 11 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or an oxygen protecting group; n1 is an integer from 1 to 250; R w Select H or Q 11 independently selected from -C(O)O-, -OC(O)- or -OC(O)O-; R 21 、R 31 、R 41 Each independently selected from C 3-50 Alkyl, C 3-50 Alkenyl, C 3-50 Alkynyl, which is optionally substituted by one or more R V replace; R V Independently selected from H, C 3-50 Alkyl, C 3-50 Alkenyl, C 3-50 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; L c1 independently selected from chemical bonds and C 1-50 Alkylene, C 3-50 Alkenyl, C 3-50 Alkynyl and C 3-10 saturated or partially unsaturated cycloalkyl; R c1 and R' c1 Independently selected from H, C 3-50 Alkyl, C 3-30 Cycloalkyl, C 3-50 Alkenyl and C 3-50 Alkynyl; Preferably, R w is H; preferably, R w for Preferably, Q 11 Independently selected from -C(O)O- or -OC(O)-; preferably -C(O)O-; preferably -OC(O)-; preferably -OC(O)O-.

2. The PEGylated lipid compound according to claim 1 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound has a structure of formula (I): in, L is absent or a divalent linking group; L2 is absent or CH2; R 11 is H, alkyl or cycloalkyl; n1 is an integer from 1 to 250; R w Select H or R 21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace; R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; Preferably, in formula (I') or formula (I), when R w When H is R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, and 1) R 21 By one or more R V substituted, preferably by one R V replace; R 31 Not R V Replace; or 2) R 21 Not R V replace; R 31 By one or more R V substituted, preferably by one R V Replace; or 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace; R V Independently selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

3. The PEGylated lipid compound according to claim 1 or 2, or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound has a structure of formula (II), formula (II-A1), formula (II-A2) or formula (II-A3): in, L is absent or a divalent linking group; R 11 is H, alkyl or cycloalkyl; n1 is an integer from 1 to 250; R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace; R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; Preferably, L is absent or a divalent linking group; R 11 is H, alkyl or cycloalkyl; n1 is an integer from 1 to 250; R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, and 1) R 21 By one or more R V substituted, preferably by one R V replace; R 31 Not R V Replace; or 2) R 21 Not R V replace; R 31 By one or more R V substituted, preferably by one R V Replace; or 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace; R V Independently selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

4. The PEGylated lipid compound according to any one of claims 1 to 3, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound has a structure of formula (IV), formula (IV-B), formula (IV-C), formula (IV-A1), formula (IV-A2) or formula (IV-A3): in, o' and p' are each independently an integer from 0 to 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20; The remaining variables are defined as in formula (I') or formula (I); Preferably, R V Independently selected from C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

5. The PEGylated lipid compound according to claim 1 or 2, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound is of formula (III), (III-A1), (III-A2) or (III-A3): in, Each variable is defined as in Formula (I'), Formula (I) or Formula (II); Preferably, L is absent or a divalent linking group; R 11 is H, alkyl or cycloalkyl; n1 is an integer from 1 to 250; R 21 、R 31 and R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace; R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

6. The PEGylated lipid compound according to claim 5 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound is of formula (V), formula (V-A1), formula (V-A2) or formula (V-A3): in, o', p', q' are each independently an integer from 0 to 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20; Each variable is independently defined as in Formula (I'), Formula (I) or Formula (IV).

7. The PEGylated lipid compound according to any one of claims 1 to 6, or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein: L is -L3-(CH2)n2-L4-, wherein L3 and L4 are independently selected from absent, -NHC(O)-, -C(O)NH-, -C(O)O-, -OC(O)-, -C(O)-, -OC(O)O-, -P(O)3-, and n2 is an integer from 1 to 5, for example, 1, 2, 3, 4 or 5; Preferably, L is selected from or not present; preferably or not present; preferably or not present; preferably or does not exist; Preferably, L is selected from -NHC(O)-, -OC(O)-, -C(O)-, or absent; Preferably, L is selected from or does not exist; Preferably, L is selected from Or does not exist.

8. The PEGylated lipid compound according to any one of claims 1 to 7, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl (preferably C 10-26 Alkyl), preferably C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl (preferably C 11-26 Alkyl), preferably C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl (preferably C 12-26 Alkyl), preferably C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl (preferably C 13-26 Alkyl), preferably C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl (preferably C 14-26 Alkyl), preferably C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl (preferably C 15-26 Alkyl), more preferably C 10-20 Alkyl, C 10-20 Alkenyl or C 10-20 Alkynyl (preferably C 10-20 Alkyl, preferably C 10-20 Straight chain alkyl, preferably C 12-20 Straight chain alkyl, preferably C 15-20 linear alkyl), which is optionally replaced by one or more (preferably 1) R V replace; R V Independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably, R V Independently selected from H, C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; Preferably, in formula (II), formula (II-A1), formula (II-A2) or formula (II-A3), 1) R 21 By one or more R V substituted, preferably by one R V replace; R 31 Not R V Replace; or 2) R 21 Not R V replace; R 31 By one or more R V substituted, preferably by one R V Replace; or 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace; R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10-26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl; Preferably, in formula (IV), formula (IV-A1), formula (IV-A2) or formula (IV-A3), R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10-26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl; Preferably, in Formula (IV), Formula (IV-A1), Formula (IV-A2), Formula (IV-A3), Formula (V), Formula (V-A1), Formula (V-A2) or Formula (V-A3), R 21 、R 31 and R 41 Not R V replace; Preferably, in Formula (V), Formula (V-A1), Formula (V-A2) or Formula (V-A3), R V For H.

9. The PEGylated lipid compound according to any one of claims 1 to 8, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n1 is an integer of 10-120; preferably an integer of 30-80; preferably 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 or 120; preferably 40-50, 75-85, 105-115; more preferably 44, 45, 78, 80, 111 or 114; Preferably, n1 is in the range such that the PEG portion of the PEGylated lipid compound of any one of claims 1 to 8 has an average molecular weight of about 400 g / mol to about 6000 g / mol; more preferably, an average molecular weight of about 1500 g / mol to about 5000 g / mol; more preferably, an average molecular weight of about 2000 g / mol, about 3350 g / mol, about 3500 g / mol or about 5000 g / mol.

10. The PEGylated lipid compound according to any one of claims 1 to 9, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 11 H, C 1-30 Alkyl or C 3-14 Cycloalkyl; preferably, R 11 H, C 1-20 Alkyl or C 3-10 Cycloalkyl; preferably, R 11 H, C 1-10 Alkyl or C 3-10 Cycloalkyl; preferably, R 11 H, C 1-6 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 H, C 1-3 Alkyl or C 3-6 Cycloalkyl; preferably, R 11 For H, -CH3; Preferably, R 11 C 1-30 Alkyl, preferably C 1-20 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably -CH3.

11. The PEGylated lipid compound according to any one of claims 4, 6 to 10, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: o', p', q' are each independently an integer from 0 to 15, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15; preferably, o', p', q' are each independently an integer from 0 to 10, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; preferably, o', p', q' are each independently an integer from 0 to 5, for example, 0, 1, 2, 3, 4, 5; preferably, o', p', q' are each independently an integer from 0 to 3, for example, 0, 1, 2, 3; preferably, o', p', q' are each independently 0.

12. The PEGylated lipid compound according to claim 1 or 2, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound is of formula (II-A1) or formula (IV-A1), in, R 11 is H, optionally substituted alkyl or an oxygen protecting group; R 21 and R 31 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace; n1 is an integer from 1 to 250; R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; o' and p' are each independently an integer of 0-20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

13. The PEGylated lipid compound according to claim 1 or 2, or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the PEGylated lipid compound has a structure of formula (III-A1) or formula (V-A1), in, R 11 is H, optionally substituted alkyl or an oxygen protecting group; R 21 、R 31 and R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, which is optionally substituted by one or more R V replace; n1 is an integer from 1 to 250; R V Independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; o', p', q' are each independently an integer from 0 to 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20.

14. The PEGylated lipid compound according to claim 12 or 13, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl (preferably C 10-26 Alkyl), preferably C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl (preferably C 11-26 Alkyl), preferably C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl (preferably C 12-26 Alkyl), preferably C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl (preferably C 13-26 Alkyl), preferably C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl (preferably C 14-26 Alkyl), preferably C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl (preferably C 15-26 Alkyl), preferably C 16-26 Alkyl, C 16-26 Alkenyl, C 16-26 Alkynyl (preferably C 16-26 Alkyl), preferably C 17-26 Alkyl, C 17-26 Alkenyl, C 17-26 Alkynyl (preferably C 17-26 Alkyl), preferably C 18-26 Alkyl, C 18-26 Alkenyl, C 18-26 Alkynyl (preferably C 18-26 alkyl), which is optionally replaced by one or more R V replace; R V Independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ; preferably H, C 1-26 Alkyl, C 2-26 Alkenyl and C 2-26 Alkynyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably H and C 1-20 Alkylene.

15. The PEGylated lipid compound according to any one of claims 12 to 14, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: In formula (IV-A1) or formula (V-A1), R 21 、R 31 and R 41 Not R V replace; Preferably, in formula (IV-A1), R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10- 26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl; Preferably, in formula (V-A1), R V is H; Preferably, in formula (II-A1), 1) R 21 By one or more R V substituted, preferably by one R V replace; R 31 Not R V Replace; or 2) R 21 Not R V replace; R 31 By one or more R V substituted, preferably by one R V Replace; or 3) R 21 and R 31 By one or more R V substituted, preferably by one R V replace; R V Independently selected from C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 , preferably C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, preferably C 10-26 Alkyl, C 10-26 Alkenyl and C 10-26 Alkynyl, preferably C 10-26 Alkyl and C 10-26 Alkenyl, preferably C 10-26 alkyl; L c1 independently selected from chemical bonds and C 1-20 alkylene; R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C 1-20 alkyl.

16. The PEGylated lipid compound according to any one of claims 12 to 15, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n1 is an integer from 10 to 120; preferably an integer from 30 to 80; preferably 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 44, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 114 or 120; Preferably, n1 ranges such that the PEG moiety of formula (IV) or formula (V) has an average molecular weight of 400 g / mol to about 6000 g / mol; more preferably, it has an average molecular weight of 1500 g / mol to about 5000 g / mol; more preferably, it has an average molecular weight of 2000 g / mol, 3500 g / mol or 5000 g / mol.

17. The PEGylated lipid compound according to any one of claims 12 to 16, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 11 C 1-3 Alkyl, preferably -CH3.

18. A PEGylated lipid compound or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: in, n1 is each independently an integer from 10 to 120; preferably an integer from 30 to 80; preferably 10, 13, 15, 16, 17, 20, 25, 30, 35, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 90, 95, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 or 120, more preferably 44, 45, 78, 80, 111 or 114; Preferably, n1 ranges from about 400 g / mol to about 6000 g / mol of the PEG portion of the PEGylated lipid compound; more preferably, from about 1500 g / mol to about 5000 g / mol; and more preferably, from about 2000 g / mol, about 3350 g / mol, about 3500 g / mol, or about 5000 g / mol.

19. A PEGylated lipid compound or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The PEGylated lipid compound is selected from the following compounds: Preferably, the PEGylated lipid compound is selected from the following compounds:

20. A lipid nanoparticle comprising the PEGylated lipid compound according to any one of claims 1 to 19 or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

21. A lipid nanoparticle composition comprising a lipid component and optionally a cargo; wherein The lipid component contains the PEGylated lipid compound according to any one of claims 1 to 19 or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof; Preferably, the molar percentage of the PEGylated lipid compound in the lipid component is 0.25 mol% to 10 mol%; Preferably, the lipid component comprises the following components in molar percentages: Ionizable lipids 25 mol%-80 mol%: Structural lipids 3 mol%-60 mol%; Neutral lipids 0.5 mol%-60 mol%; 0.25 mol% to 10 mol% of the PEGylated lipid compound according to any one of claims 1 to 19; Preferably, the lipid component comprises the following components in molar percentages: Ionizable lipids 50 mol%; neutral lipids 15.2 mol%; structural lipids 33.3 mol%; 1.5 mol% of the PEGylated lipid compound according to any one of claims 1 to 19; Preferably, the lipid component comprises the following components in molar percentages: Ionizable lipids 50 mol%; neutral lipids 15.2 mol%; structural lipids 33.94 mol%; 0.86 mol% of the PEGylated lipid compound according to any one of claims 1 to 19; Preferably, the lipid component comprises the following components in molar percentages: Ionizable lipids 50 mol%; neutral lipids 15.2 mol%; structural lipids 34.2 mol%; 0.6 mol% of the PEGylated lipid compound according to any one of claims 1 to 19.

22. The lipid nanoparticle composition of claim 21, wherein the cargo is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent; Preferably, the therapeutic agent, preventive agent or diagnostic agent is selected from one or more of small molecule compounds, polypeptides, proteins and nucleic acids; Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASOs), RNA or DNA; Preferably, the RNA is selected from one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polyencoding nucleic acid (MCNA), polyencoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA) or ribozyme, preferably one or more of modified mRNA, mRNA, siRNA, gRNA; Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

23. The lipid nanoparticle composition of claim 21 or 22, wherein the particle size is 40-500 nm, preferably 40-250 nm, preferably 40-200 nm, more preferably 40-150 nm; Preferably, the particle size is 40-200 nm, preferably 40-160 nm, preferably 40-150 nm, more preferably 40-120 nm.

24. A method for preparing the lipid nanoparticle composition according to any one of claims 21 to 23, comprising: The lipid components in the lipid nanoparticles are mixed, and then mixed with the load to obtain the product.

25. A pharmaceutical composition comprising the PEGylated lipid compound according to any one of claims 1 to 19 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the lipid nanoparticle according to claim 20 or the lipid nanoparticle composition according to any one of claims 21 to 24, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

26. Use of the PEGylated lipid compound according to any one of claims 1 to 19 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the lipid nanoparticle according to claim 20, the lipid nanoparticle composition according to any one of claims 21 to 24, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for treating, diagnosing or preventing a disease; Preferably, the disease is a muscle or muscle-related disease.

27. Use of the PEGylated lipid compound according to any one of claims 1-19 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the lipid nanoparticle according to claim 20, the lipid nanoparticle composition according to any one of claims 21-24, and the pharmaceutical composition according to claim 25 in the preparation of drugs for gene editing, protein replacement and / or supplementation, or gene interference.

28. Use of the PEGylated lipid compound according to any one of claims 1 to 19 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the lipid nanoparticle according to claim 20, the lipid nanoparticle composition according to any one of claims 21 to 24, or the pharmaceutical composition according to claim 25 in the preparation of a drug for delivering a load.

29. A method for treating, diagnosing or preventing a disease in a subject, comprising administering to the subject the lipid nanoparticle of claim 20, the lipid nanoparticle composition of any one of claims 21 to 24, or the pharmaceutical composition of claim 25; Preferably, the disease is a muscle or muscle-related disease.

30. The PEGylated lipid compound according to any one of claims 1 to 19 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the lipid nanoparticle according to claim 20, the lipid nanoparticle composition according to any one of claims 21 to 24, or the pharmaceutical composition according to claim 25, for use in delivering a load; Preferably, for delivering load to muscle.

31. Use of the PEGylated lipid compound according to any one of claims 1 to 19 or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, the lipid nanoparticle according to claim 20, the lipid nanoparticle composition according to any one of claims 21 to 24, or the pharmaceutical composition according to claim 25 for delivering nucleic acids; Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASOs), RNA or DNA; Preferably, the RNA is selected from one or more of interfering RNA (RNAi), small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), modified messenger RNA (mmRNA), long non-coding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polyencoding nucleic acid (MCNA), polyencoding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), circular RNA (circRNA), self-replicating RNA (SrRNA) or ribozyme, preferably one or more of modified mRNA, mRNA, siRNA, gRNA; Preferably, the DNA is selected from one or more of single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of plasmid DNA (pDNA), minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA); More preferably, the nucleic acid is selected from one or more of ASO, mRNA, modified mRNA, siRNA, gRNA, mcDNA, and pDNA.

32. A method for treating or preventing a muscle disease or a muscle-related disease in a subject suffering from the disease, comprising administering a therapeutically effective amount of the lipid nanoparticle of claim 20, the lipid nanoparticle composition of any one of claims 21 to 24, or the pharmaceutical composition of claim 25 to the subject by systemic administration; Preferably, the systemic administration is systemic injection, more preferably intravenous injection, arterial injection or intraperitoneal injection.

33. A method for preparing the PEGylated lipid compound according to claim 4, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (IV-A1) comprises: reacting a compound of formula (A1) with a compound of formula (E1) to obtain a compound of formula (A2); Deprotecting the compound of formula (A2) to obtain a compound of formula (IV-A1); wherein PG is independently an oxygen protecting group, preferably Bn; The remaining variables are as defined in any one of claims 1 to 11, preferably as defined in formula (I'), formula (I), formula (IV) or formula (V) in any one of claims 1 to 11.

34. A method for preparing the PEGylated lipid compound according to claim 4, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (IV-A2) comprises: reacting a compound of formula (B1) with a compound of formula (E2) to obtain a compound of formula (B2); reacting the compound of formula (B2) to obtain the compound of formula (B3); preferably reacting under alkaline conditions; reacting a compound of formula (B3) with a compound of formula (E3) and / or formula (E4) to obtain a compound of formula (IV-A2); Wherein, each variable is defined as in any one of claims 1 to 11, preferably as defined in formula (I'), formula (I), formula (IV) or formula (V) of any one of claims 1 to 11.

35. A method for preparing the PEGylated lipid compound according to claim 4, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the method for preparing the compound of formula (V-A3) comprises: reacting a compound of formula (C1) with a compound of formula (E5) to obtain a compound of formula (C2); reacting a compound of formula (C2) with a compound of formula (E6) to obtain a compound of formula (V-A3); Wherein, each variable is defined as in any one of claims 1 to 11, preferably as defined in formula (I'), formula (I), formula (IV) or formula (V) of any one of claims 1 to 11.

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