Lipid nanoparticle targeting muscle

Abstract

The present invention relates to a lipid nanoparticle, comprising an ionizable lipid, a structural lipid, a phospholipid, and a polymer conjugated lipid. The lipid nanoparticle can achieve the enrichment and delivery of drugs in muscles. The present invention further provides a preparation method for the lipid nanoparticle, a pharmaceutical composition of the lipid nanoparticle, and use of the lipid nanoparticle and the pharmaceutical composition in delivery of nucleic acids.

Description

Muscle-targeted lipid nanoparticles

[0001] This application claims the rights of Chinese application No. 202410239117.9 filed on March 1, 2024, Chinese application No. 202410773562.3 filed on June 14, 2024, PCT application No. PCT / CN2024 / 099393 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,

[0002] The disclosures herein claim priority from Chinese application No. 202510206974.3 filed on February 24, 2025, and Chinese application No. 202510208194.2 filed on February 24, 2025, which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to the field of biomedicine, and in particular to a muscle-targeted lipid nanoparticle delivery system. Background Art

[0004] 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 (LNPs) 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.

[0005] Muscular disorders generally refer to skeletal muscle disorders. Skeletal muscle is the primary organ for movement and energy metabolism. Muscle diseases include myosarcomas, myovascular tumors, neuromuscular diseases, and rare conditions such as acid maltase deficiency (Pompe), Duchenne muscular dystrophy (DMD), and congenital progressive muscular dystrophy (CMD). Neuromuscular diseases are a general term for common conditions, including muscular dystrophies, neurogenic diseases, inflammatory diseases, congenital diseases, toxic diseases, metabolic diseases, and endocrine diseases. These neuromuscular diseases can directly affect skeletal muscle, motor neurons, peripheral nerves, and the neuromuscular junction. Treatment of muscle diseases is challenging due to the large number and complexity of skeletal muscle and the large size of pathogenic genes. While new nucleic acid therapies are being developed, and lipid nanoparticles (LNPs) offer significant promise for expanding the potential of nucleic acid-based therapies, nucleic acid therapies also present challenges, such as safety, efficacy, and low muscle targeting efficiency.

[0006] The most common routes of administration for lipid nanoparticles are intravenous and intramuscular injection. Intravenously administered LNPs are primarily distributed in the liver and spleen, but also in the lungs. Currently, there are no reports of intravenously administered LNPs targeting muscle. The present invention aims to provide muscle-targeted lipid nanoparticles that, through systemic administration, can deliver more prophylactic and / or therapeutic agents to the muscle and less to the liver. Summary of the Invention

[0007] The present invention provides a muscle-targeted lipid nanoparticle, which can be used to deliver various bioactive substances and has a better muscle-targeted delivery effect through systemic administration.

[0008] After administration, the lipid nanoparticles of the present invention can have a distribution ratio of muscle to isolated liver of greater than 1, preferably greater than 2, more preferably greater than 5, and even more preferably greater than 10.

[0009] To achieve the above object of the invention, one aspect of the present invention provides a lipid nanoparticle, wherein the lipid nanoparticle comprises the following lipid components in molar percentage:

[0010] Ionizable lipids 25 mol%-80 mol%:

[0011] Structural lipids 3 mol%-60 mol%;

[0012] Phospholipids 0.5 mol%-60 mol%;

[0013] Polymer conjugated lipids: 0.25 mol%-10 mol%.

[0014] In some specific embodiments, the ionizable lipid is a compound represented by formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0015] in,

[0016] 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*;

[0017] 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*;

[0018] 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*;

[0019] 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 ;

[0020] 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;

[0021] 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 ;

[0022] k is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0023] j is selected from 0 or 1;

[0024] The dotted line connecting Q and W does not exist or is a chemical bond;

[0025] W is selected from C, CH or N;

[0026] 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**;

[0027] 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;

[0028] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0029] The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0030] 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 ;

[0031] R5, R6, R7 and R8 are independently selected from H or C 1-8 alkyl, optionally substituted with one or more R*;

[0032] 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*;

[0033] 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*;

[0034] 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;

[0035] 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**;

[0036] 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-;

[0037] R0 is independently -(CRR')-;

[0038] 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;

[0039] or R and R' together with the carbon atom to which they are attached form a 3-8 membered cycloalkylene group;

[0040] No more than three R0 or R0' in each chain attached to W are cycloalkylene;

[0041] Q3 and Q4 are independently H, -(CRR')-, C 6-10 an aryl or steroid group, preferably H or -(CRR')-;

[0042] A1, A2, A3, and A4 are independently -(CR 18 R 18 -CR 18 =CR 18 )-or-(CR 18 R 18 -C≡C)-;

[0043] R 18 are independently H or C 1-20 alkyl;

[0044] N1 and N2 are independently biodegradable groups;

[0045] Z does not exist, C 1-10 Alkylene or -OP(O)(OH)-O-;

[0046] 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;

[0047] 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;

[0048] o, p, w, and x are each independently selected from 0, 1, or 2;

[0049] s and t are independently selected from 0 or 1;

[0050] 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;

[0051] L a and L e Independently selected from chemical bonds or C 1-20 alkylene;

[0052] L b and L fIndependently selected from chemical bonds or C 1-10 alkylene;

[0053] L c Independently selected from chemical bonds or C 1-8 alkylene;

[0054] L d Independently selected from chemical bonds or C 1-14 alkylene;

[0055] 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 ;

[0056] 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 ;

[0057] R c and R' c Independently selected from H or C 1-8 alkyl;

[0058] R d and R' d Independently selected from H or C 1-14 alkyl;

[0059] R e and R' e Independently selected from H or C 1-20 alkyl;

[0060] R f and R' f Independently selected from H or C 1-10 alkyl;

[0061] The condition is that when W is N, j = 0, and the dotted line connecting Q and W does not exist;

[0062] or for

[0063] 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;

[0064] 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 ;

[0065] 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;

[0066] 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 ;

[0067] 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*.

[0068] In some specific embodiments, the ionizable lipid is a compound represented by formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0069] in,

[0070] 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, or 3 to 14-membered heterocyclyl, optionally substituted with one or more R*;

[0071] 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*;

[0072] or R4 and the nitrogen atom to which it 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*;

[0073] 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 ;

[0074] 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;

[0075] R** is independently selected from H, C 1-8 Alkyl, -L c -OR c 、-L c -SR c 、-L c-NR c R' c ;

[0076] k is selected from 0, 1, 2, 3, 4, 5 or 6;

[0077] j is selected from 0 or 1;

[0078] The dotted line connecting Q and W does not exist or is a chemical bond;

[0079] W is selected from C, CH or N;

[0080] 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**;

[0081] 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;

[0082] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0083] The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0084] 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 ;

[0085] R5, R6, R7 and R8 are independently selected from H or C 1-8 alkyl, optionally substituted with one or more R*;

[0086] 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-、-NRb 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-, or -S(O) 0-2 -;

[0087] 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**;

[0088] 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-;

[0089] R0 is independently -(CRR')-;

[0090] 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;

[0091] or R and R' together with the carbon atom to which they are attached form a 3-8 membered cycloalkylene group;

[0092] No more than three R0 or R0' in each chain attached to W are cycloalkylene;

[0093] Q3 and Q4 are independently H, -(CRR')-, C 6-10 an aryl or steroid group, preferably H or -(CRR')-;

[0094] A1, A2, A3, and A4 are independently -(CR 18 R 18 -CR 18 =CR 18 )-or-(CR 18 R 18 -C≡C)-;

[0095] R 18 are independently H or C 1-20 alkyl;

[0096] N1 and N2 are independently biodegradable groups;

[0097] Z does not exist, C 1-10 Alkylene or -OP(O)(OH)-O-;

[0098] 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;

[0099] 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;

[0100] o, p, w, and x are each independently selected from 0, 1, or 2;

[0101] s and t are independently selected from 0 or 1;

[0102] 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;

[0103] L a and L e Independently selected from chemical bonds or C 1-20 alkylene;

[0104] L b and L f Independently selected from chemical bonds or C 1-10 alkylene;

[0105] L c Independently selected from chemical bonds or C 1-8 alkylene;

[0106] L dIndependently selected from chemical bonds or C 1-14 alkylene;

[0107] 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 ;

[0108] 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 ;

[0109] R c and R' c Independently selected from H or C 1-8 alkyl;

[0110] R d and R' d Independently selected from H or C 1-14 alkyl;

[0111] R e and R' e Independently selected from H or C 1-20 alkyl;

[0112] R f and R' f Independently selected from H or C 1-10 alkyl;

[0113] The condition is that when W is N, j=0, and the dotted line connecting Q and W does not exist.

[0114] In some specific embodiments, the polymer-conjugated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol;

[0115] Preferably, the polymer-conjugated lipid comprises a PEG moiety of 400 Da to 20 kDa, preferably a PEG moiety of about 1000 Da to about 10000 Da, preferably a PEG moiety of about 1000 Da to about 5000 Da;

[0116] Preferably, the polymer-conjugated lipid is a compound represented by formula (IIP-A1) or (IIIP-A1), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0117] Among them, R 11 is H, optionally substituted alkyl or an oxygen protecting group;

[0118] R 21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, optionally substituted with one or more Rv;

[0119] n1 is an integer from 1 to 250;

[0120] Rv is independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -L c1 -OR c1 、-L c -SR c1 and -L c1 -NR c R' c1 ;

[0121] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0122] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0123] In another aspect, the present invention provides a lipid nanoparticle composition comprising the lipid nanoparticle of the present invention and optionally comprising a cargo.

[0124] In another aspect, the present invention provides a method for preparing the lipid nanoparticle composition, comprising: mixing the components in the lipid component, and then mixing with a load to obtain.

[0125] In another aspect, the present invention provides a pharmaceutical composition comprising the lipid nanoparticle composition of the present invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

[0126] In another aspect, the present invention provides use of the lipid nanoparticles of the present invention, the lipid nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention in the preparation of a medicament for treating, diagnosing, or preventing a disease.

[0127] In another aspect, the present invention provides use of the lipid nanoparticles of the present invention, the lipid nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention in the preparation of drugs for gene editing, protein replacement and / or supplementation, or gene interference.

[0128] Preferably, the lipid nanoparticles, lipid nanoparticle composition or pharmaceutical composition is administered systemically, preferably by systemic injection, preferably by intravenous injection, arterial injection or intraperitoneal injection, more preferably by intraperitoneal injection or intravenous injection.

[0129] In another aspect, the present invention provides use of the lipid nanoparticles of the present invention, the lipid nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention in the preparation of a drug for delivering a load.

[0130] In another aspect, the present invention provides a method for treating, diagnosing or preventing a disease in a subject, comprising administering to the subject a lipid nanoparticle of the present invention, a lipid nanoparticle composition of the present invention or a pharmaceutical composition of the present invention.

[0131] In another aspect, the present invention provides the lipid nanoparticles of the present invention, the lipid nanoparticle composition of the present invention or the pharmaceutical composition of the present invention for use in treating, diagnosing and / or preventing a disease.

[0132] In another aspect, the present invention provides a method of delivering a cargo in a subject, comprising administering to the subject a lipid nanoparticle of the present invention, a lipid nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0133] In another aspect, the present invention provides a use of the lipid nanoparticle of the present invention, the lipid nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention for delivering a load.

[0134] In certain embodiments, the cargo is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent;

[0135] Preferably, the therapeutic agent, preventive agent or diagnostic agent is selected from one or more of small molecule compounds, polypeptides, proteins and nucleic acids;

[0136] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASOs), RNA or DNA;

[0137] 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 mRNA, siRNA, gRNA, more preferably modified mRNA;

[0138] Preferably, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

[0139] In another aspect, the present invention provides 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 the present invention, the lipid nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention to the subject by systemic administration;

[0140] The systemic administration is preferably systemic injection, preferably intravenous injection, arterial injection or intraperitoneal injection, more preferably intraperitoneal injection or intravenous injection. BRIEF DESCRIPTION OF THE DRAWINGS

[0141] Figures 1 and 2 show the distribution of Cy7-labeled luciferase-mRNA-loaded lipid nanoparticles LNP1-1 and LNP1-2 in C57 mice 6 hours after tail vein administration and whole-body bioluminescence imaging results in Example 5 of the present invention;

[0142] Figures 3 to 5 are the whole-body bioluminescence imaging results of lipid nanoparticles in C57 mice 6 hours after tail vein administration of luciferase-mRNA-encapsulated lipid nanoparticles LNP1, LNP2 and a control group (SM102-LNP; same as LNP1-2) in Example 6 of the present invention;

[0143] FIG6 shows the bioluminescence imaging results of lipid nanoparticles LNP1 loaded with luciferase-mRNA in Example 6 of the present invention in the whole body muscles and in vitro liver of C57 mice 6 hours after tail vein administration;

[0144] FIG7 shows the whole-body fluorescence imaging results of Ai9 mice 5 days after intravenous administration (2 mpk) of Cre-mRNA-loaded lipid nanoparticles LNP1 and intramuscular administration (0.1 mpk) of the control group (SM102-LNP) in Example 7 of the present invention;

[0145] Figures 8 to 10 are the results of fluorescence microscopy imaging of Ai9 mouse leg muscle sections stained 5 days after administration of Cre-mRNA encapsulated lipid nanoparticles LNP1 and SM102-LNP in Example 7 of the present invention;

[0146] FIG11 shows the results of fluorescence microscopy imaging of diaphragm sections of Ai9 mice stained with Cre-mRNA encapsulated by lipid nanoparticles LNP1 and SM102-LNP in Example 7 of the present invention 5 days after administration;

[0147] FIG12 is the whole-body fluorescence imaging results of mTmG mice 7 days after administration of Cre-mRNA encapsulated by lipid nanoparticles LNP1 in Example 8 of the present invention;

[0148] Figures 13 to 15 are the results of fluorescence microscopy imaging of leg muscle, heart and diaphragm sections of mTmG mice stained 7 days after administration of Cre-mRNA encapsulated by lipid nanoparticles LNP1 in Example 8 of the present invention;

[0149] Figure 16 shows the whole-body bioluminescence imaging results of lipid nanoparticles LNP Index4 and LNP Index9 (classic formula) loaded with luciferase-mRNA in Example 10 of the present invention in C57 mice 6 hours after tail vein administration (0.5 mpk);

[0150] FIG17 shows the whole-body bioluminescence imaging results of marmosets (face up) 5 hours after administration of lipid nanoparticles encapsulating luciferase-mRNA in Example 13 of the present invention;

[0151] Figure 18 is a mass spectrum of compound 5P;

[0152] FIG19 is a mass spectrum of compound 6P.

[0153] definition

[0154] Unless otherwise defined, all technical terms, symbols, and other scientific terms or expressions used herein are intended to have the meanings commonly understood by those skilled in the art to which this disclosure belongs. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ease of reference, and such definitions included herein should not necessarily be construed to represent a substantial difference from what is generally understood in the art.

[0155] Chemical definition

[0156] Definitions of specific functional groups and chemical terms are described in more detail below.

[0157] 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 、C 1-3 、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.

[0158] “C 1-20 "C5-30 alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. "C5-30 alkyl" refers to a straight chain or branched 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 7-11Alkyl, 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, C 1-6 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).

[0159] “C 2-13 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 13 carbon atoms and at least one carbon-carbon double bond. 4-20"Alkenyl" refers to a straight or branched chain hydrocarbon group having 4 to 20 carbon atoms and at least one carbon-carbon double bond. 2-26 "Alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 26 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 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 19-26 Alkenyl is preferred. In some embodiments, C 4-14 Alkenyl, C 6-14 Alkenyl, C 4-10 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.

[0160] “C 2-13 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 13 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 4-20 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 4 to 20 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 2-26 "Alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 26 carbon atoms and at least one carbon-carbon double bond. 2-30"Alkynyl" 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 "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 10-30 Alkynyl, 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 4-18 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.

[0161] “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 6-9Alkylene, 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, C 1-13 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.

[0162] “C 2-13 "Alkenylene" refers to the removal of C 2-13 A divalent group is formed by adding another hydrogen atom of the alkenyl group and may be substituted or unsubstituted. 4-14 "Alkenylene" refers to the removal of C 4-14 In some embodiments, C 6-14Alkenylene, C 4-10 Alkenylene, C 2-10 Alkenylene, C 2-9 Alkenylene, C 2-6 Alkenylene and C 2-4 Alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like.

[0163] “C 2-13 "Alkynylidene" refers to the removal of C 2-13 The other hydrogen of the alkynyl group forms a divalent group, which may be substituted or unsubstituted. 4-14 "Alkynylidene" refers to the removal of C 4-14 In some embodiments, C 6-14 Alkynylidene, C 4-10 Alkynylidene, C 2-10 Alkynylidene, C 2-9 Alkynylidene, C 2-6 Alkynylidene and C 2-4 Alkyne is particularly preferred. Exemplary alkynyl includes, but is not limited to, ethynyl (-C≡C-), substituted or unsubstituted propynyl (-C≡CCH2-), and the like.

[0164] “C 0-6 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-6 Alkylene", "C 0-4 "Alkylene" refers to the chemical bond and the above-mentioned "C 1-4 "Alkylene".

[0165] The term "the total length of variable A and variable B is x carbon atoms" or "variable A + variable B = x carbon atoms" means that the sum of the number of carbon atoms in the main chain of the group represented by variable A and the number of carbon atoms in the main chain of the group represented by variable B is x.

[0166] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0167] 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, C 1-3 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 can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0168] “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.

[0169] “C 3-14 "Cycloalkylene" refers to the removal of C3-14 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.

[0170] "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.

[0171] “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.

[0172] "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.

[0173] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups.

[0174] "Alkoxy" refers to the oxygen ether form of a straight or branched chain alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0175] "Optionally substituted..." means that the group may be substituted with a designated substituent or may be unsubstituted.

[0176] The divalent groups formed by removing another hydrogen from the above-defined alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "subunits". The ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl groups are collectively referred to as "cyclyls".

[0177] Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like are defined herein as optionally substituted groups.

[0178] 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(=NRbb )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;

[0179] 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;

[0180] 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;

[0181] 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;

[0182] 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;

[0183] R dd Each 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)2R ee 、-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;

[0184] 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;

[0185] 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;

[0186] R gg Each of the independently: halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1- 6 alkyl) 2, -N(C1-6 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 1-6 alkyl), -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, -SO2C1-6 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.

[0187] 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.

[0188] "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.

[0189] "Oxygen protecting group" refers to a substituent present on an oxygen atom. Oxygen protecting groups include but are not limited to -R aa 、-N(R bb )2, -C(=O)SR aa 、-C(=O)R aa 、-CO2 R 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 、-SO2 R 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).

[0190] 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).

[0191] "Biodegradable groups" refer to chemical groups that can be broken down in vivo through the action of enzymes or microbial metabolism. These groups typically contain specific chemical structures that can be recognized and acted upon by enzymes within the body, allowing the polymeric materials or drugs attached to these groups to be broken down into smaller molecules over a period of time, ultimately converting them into substances that are environmentally friendly or bioavailable. Examples of biodegradable groups include, but are not limited to: ester bonds, commonly found in polyesters and degraded by esterases; peptide bonds, present in proteins and polypeptides and degraded by peptidases; aliphatic ether bonds, found in certain polyethers and also degraded by specific enzymes; and carboxyl and hydroxyl groups, which, due to their strong hydrophilicity, facilitate the hydrolysis of polymeric materials. US Patent No. 11246933 B1 discloses that incorporating biodegradable groups into the tail chain of lipid compounds within lipid nanoparticles can accelerate metabolism and facilitate clearance of the lipid from the body after delivery of the active agent to the target area, thereby making the lipids containing biodegradable groups less toxic than similar lipids without biodegradable groups. The cationic lipid compound of the present invention has a biodegradable group in its tail chain, so its toxicity is better than similar lipids without biodegradable groups, such as DLin-MC3-DMA. The direction of the biodegradable group of the present invention is from the head to the tail of the ionizable lipid molecule.

[0192] As used herein, "lipid nanoparticles" or "nanoparticles" refer to particles containing lipid components and having nanometer-scale dimensions.

[0193] In this article, Indicates chemical bond connections.

[0194] In this article, 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 (IIP-A1) also naturally include

[0195] In the general structure of the present application, for example, in formula (IIP-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; 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.

[0196] Other definitions

[0197] 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.

[0198] As used herein, the term "pharmaceutically acceptable salt" refers to those carboxylate salts, amino acid addition salts of the compounds of the present invention 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 invention.

[0199] 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.

[0200] 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 invention, the salts are equivalent to their respective free acids.

[0201] 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).

[0202] "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.

[0203] "Disease," "disorder," and "condition" are used interchangeably herein.

[0204] 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").

[0205] 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 invention can 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 encompasses both a therapeutically effective amount and a prophylactically effective amount.

[0206] 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.

[0207] 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.

[0208] "Combination" and related terms refer to the simultaneous or sequential administration of a pharmaceutical composition of the present invention and other therapeutic agents. For example, a pharmaceutical composition of the present invention can be administered simultaneously or sequentially with the other therapeutic agents in separate unit dosage forms, or can be administered simultaneously with the other therapeutic agents in a single unit dosage form. Specific implementation plan

[0209] As used herein, the "compound of the present invention" refers to the following compounds of formula (I), formula (II), formula (II'), formula (II"), formula (III), formula (III'), (III"), formula (IP'), formula (IP), formula (IIP), formula (IIIP), formula (IVP), formula (VP), etc., and pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers thereof.

[0210] Herein, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood that (unless otherwise specified) all optical isomers and mixtures thereof are encompassed. In addition, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur 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.

[0211] In one embodiment, the present invention provides a muscle-targeted lipid nanoparticle that can be used to deliver various bioactive substances, and has a better muscle-targeted delivery effect through systemic administration.

[0212] Preferably, the ratio of the lipid nanoparticles distributed to muscle / to isolated liver after administration is greater than 1, preferably greater than 2, more preferably greater than 5, and more preferably greater than 10.

[0213] Preferably, the ratio of the lipid nanoparticles distributed to muscle / to isolated liver after administration is above 1, preferably above 2, above 5, above 10, above 20, above 30, above 50, or above 100.

[0214] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the lipid nanoparticles contain the following molar percentages of lipid components: ionizable lipids 25 mol%-80 mol%; structural lipids 3 mol%-60 mol%; phospholipids 0.5 mol%-60 mol%; polymer-conjugated lipids 0.25 mol%-10 mol%.

[0215] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the lipid nanoparticles contain the following molar percentages of lipid components: ionizable lipids 30 mol%-70 mol%; structural lipids 3 mol%-50 mol%; phospholipids 0.5 mol%-50 mol%; polymer-conjugated lipids 0.25 mol%-5 mol%.

[0216] Preferably, the lipid nanoparticles contain the following components in molar percentages: 35 mol%-65 mol% of ionizable lipids; 3 mol%-45 mol% of structural lipids; 5 mol%-40 mol% of phospholipids; and 0.25 mol%-5 mol% of polymer-conjugated lipids.

[0217] Preferably, the lipid nanoparticles contain the following components in molar percentages: 40 mol%-60 mol% of ionizable lipids; 5 mol%-40 mol% of structural lipids; 5 mol%-35 mol% of phospholipids; and 0.25 mol%-4.5 mol% of polymer-conjugated lipids.

[0218] Preferably, the lipid nanoparticles contain the following components in molar percentages: 40 mol%-60 mol% of ionizable lipids; 15 mol%-40 mol% of structural lipids; 5 mol%-35 mol% of phospholipids; 0.25 mol%-4.5 mol% of polymer-conjugated lipids;

[0219] Preferably, the lipid nanoparticles contain the following components in molar percentages: 40 mol%-60 mol% of ionizable lipids; 15 mol%-40 mol% of structural lipids; 5 mol%-30 mol% of phospholipids; 0.25 mol%-3 mol% of polymer-conjugated lipids;

[0220] Preferably, the lipid nanoparticles contain the following components in molar percentages: 45 mol%-60 mol% of ionizable lipids; 15 mol%-40 mol% of structural lipids; 5 mol%-30 mol% of phospholipids; 0.25 mol%-3 mol% of polymer-conjugated lipids;

[0221] Preferably, the lipid nanoparticles contain the following components in molar percentages: 45 mol%-60 mol% of ionizable lipids; 25 mol%-40 mol% of structural lipids; 5 mol%-25 mol% of phospholipids; and 0.25 mol%-3 mol% of polymer-conjugated lipids.

[0222] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipid is selected from the compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0223] in,

[0224] R3 and R4 are independently selected from C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10Alkynyl, 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*;

[0225] 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*;

[0226] 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*;

[0227] 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 ;

[0228] 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;

[0229] 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 ;

[0230] k is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0231] j is selected from 0 or 1;

[0232] The dotted line connecting Q and W does not exist or is a chemical bond;

[0233] W is selected from C, CH or N;

[0234] 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 1-8Alkylene, optionally substituted with one or more R**;

[0235] 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;

[0236] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0237] The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0238] 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 ;

[0239] R5, R6, R7 and R8 are independently selected from H or C 1-8 alkyl, optionally substituted with one or more R*;

[0240] 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*;

[0241] 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*;

[0242] 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 bC(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;

[0243] 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**;

[0244] 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-;

[0245] R0 is independently -(CRR')-;

[0246] 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;

[0247] or R and R' together with the carbon atom to which they are attached form a 3-8 membered cycloalkylene group;

[0248] No more than three R0 or R0' in each chain attached to W are cycloalkylene;

[0249] Q3 and Q4 are independently H, -(CRR')-, C 6-10an aryl or steroid group, preferably H or -(CRR')-;

[0250] A1, A2, A3, and A4 are independently -(CR 18 R 18 -CR 18 =CR 18 )-or-(CR 18 R 18 -C≡C)-;

[0251] R 18 are independently H or C 1-20 alkyl;

[0252] N1 and N2 are independently biodegradable groups;

[0253] Z does not exist, C 1-10 Alkylene or -OP(O)(OH)-O-;

[0254] 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;

[0255] 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;

[0256] o, p, w, and x are each independently selected from 0, 1, or 2;

[0257] s and t are independently selected from 0 or 1;

[0258] 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;

[0259] L a and L e Independently selected from chemical bonds or C 1-20 alkylene;

[0260] L b and L f Independently selected from chemical bonds or C 1-10 alkylene;

[0261] L c Independently selected from chemical bonds or C 1-8 alkylene;

[0262] L d Independently selected from chemical bonds or C 1-14 alkylene;

[0263] R a and R' a Independently selected from H, C1-20 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 ;

[0264] 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 ;

[0265] R c and R' c Independently selected from H or C 1-8 alkyl;

[0266] R d and R' d Independently selected from H or C 1-14 alkyl;

[0267] R e and R' e Independently selected from H or C 1-20 alkyl;

[0268] R f and R' f Independently selected from H or C 1-10 alkyl;

[0269] The condition is that when W is N, j = 0, and the dotted line connecting Q and W does not exist;

[0270] or for

[0271] 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;

[0272] RG7 Independently selected from H, C 1-6 Alkyl, -L b -OR b 、-L b -SR b and -L b -NR b R' b ;

[0273] 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;

[0274] 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 ;

[0275] 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*.

[0276] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipid is selected from the compound of formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0277] in,

[0278] 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, or 3 to 14-membered heterocyclyl, optionally substituted with one or more R*;

[0279] 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*;

[0280] or R4 and the nitrogen atom to which it 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*;

[0281] 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 ;

[0282] 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;

[0283] R** is independently selected from H, C 1-8 Alkyl, -L c -OR c 、-L c -SR c 、-L c -NR c R' c ;

[0284] k is selected from 0, 1, 2, 3, 4, 5 or 6;

[0285] j is selected from 0 or 1;

[0286] The dotted line connecting Q and W does not exist or is a chemical bond;

[0287] W is selected from C, CH or N;

[0288] G5 is selected from chemical bonds or C1-24 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**;

[0289] 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;

[0290] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0291] The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0292] 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 ;

[0293] R5, R6, R7 and R8 are independently selected from H or C 1-8 alkyl, optionally substituted with one or more R*;

[0294] 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 bC(S)O-, -SS-, or -S(O) 0-2 -;

[0295] 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**;

[0296] 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-;

[0297] R0 is independently -(CRR')-;

[0298] 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;

[0299] or R and R' together with the carbon atom to which they are attached form a 3-8 membered cycloalkylene group;

[0300] No more than three R0 or R0' in each chain attached to W are cycloalkylene;

[0301] Q3 and Q4 are independently H, -(CRR')-, C 6-10 an aryl or steroid group, preferably H or -(CRR')-;

[0302] A1, A2, A3, and A4 are independently -(CR 18 R 18 -CR 18 =CR18 )-or-(CR 18 R 18 -C≡C)-;

[0303] R 18 are independently H or C 1-20 alkyl;

[0304] N1 and N2 are independently biodegradable groups;

[0305] Z does not exist, C 1-10 Alkylene or -OP(O)(OH)-O-;

[0306] 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;

[0307] 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;

[0308] o, p, w, and x are each independently selected from 0, 1, or 2;

[0309] s and t are independently selected from 0 or 1;

[0310] 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;

[0311] L a and L e Independently selected from chemical bonds or C 1-20 alkylene;

[0312] L b and L f Independently selected from chemical bonds or C 1-10 alkylene;

[0313] L c Independently selected from chemical bonds or C 1-8 alkylene;

[0314] L d Independently selected from chemical bonds or C 1-14 alkylene;

[0315] 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 -SRe or -L e -NR e R' e ;

[0316] 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 ;

[0317] R c and R' c Independently selected from H or C 1-8 alkyl;

[0318] R d and R' d Independently selected from H or C 1-14 alkyl;

[0319] R e and R' e Independently selected from H or C 1-20 alkyl;

[0320] R f and R' f Independently selected from H or C 1-10 alkyl;

[0321] The condition is that when W is N, j=0, and the dotted line connecting Q and W does not exist.

[0322] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipid is selected from the compound of formula (II), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0323] in,

[0324] M1 and M2 are independently 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 aC(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 -;

[0325] Q is selected from a chemical bond, -C(O)O-, -O-, -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 pyridinylene, wherein the phenylene or pyridinylene is optionally substituted with one or more R*;

[0326] G5 is selected from chemical bonds or C 1-8 Alkylene, optionally substituted with one or more R**;

[0327] G 6a and G 6b Independently selected from chemical bonds or C 1-7 Alkylene, optionally substituted with one or more R**;

[0328] And G 6a and G 6b has a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms;

[0329] R9, R 10 and R** are independently selected from H, C 1-8 Alkyl, -L c -OR c、-L c -SR c or -L c -NR c R' c ;

[0330] 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;

[0331] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0332] The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0333] R3 and R4 are independently selected from H, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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*:

[0334] or R3, 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*;

[0335] or R4, R9 together with the atoms to which they are attached form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*;

[0336] 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 ;

[0337] R5, R6, R7 and R8 are independently selected from C 1-8 alkyl, optionally substituted with one or more R*;

[0338] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl or C 4-20Alkynyl, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with -NR"-;

[0339] 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 ;

[0340] R is independently selected from H, C 1-20 Alkyl, -L a -OR a 、-L a -SR a or -L a -NR a R' a ;

[0341] R" is independently selected from H or C 1-20 alkyl;

[0342] L a and L e Independently selected from chemical bonds or C 1-20 alkylene;

[0343] L b and L f Independently selected from chemical bonds or C 1-10 alkylene;

[0344] L c Independently selected from chemical bonds or C 1-8 alkylene;

[0345] L d Independently selected from chemical bonds or C 1-14 alkylene;

[0346] 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 ;

[0347] 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 ;

[0348] R c and R' c Independently selected from H or C 1-8 alkyl;

[0349] R d and R' d Independently selected from H or C 1-14 alkyl;

[0350] R e and R' e Independently selected from H or C 1-20 alkyl;

[0351] R f and R' f Independently selected from H or C 1-10 alkyl.

[0352] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipid is selected from the compound of formula (II'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0353] in,

[0354] M1 and M2 are independently selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NRa-, -NRaC(O)NRa-, -OC(O)S-, -OC(O)O-, -NRaC(O)O-, -OC(O)-, -SC(O)-, -C(O) S-, -NRa-, -C(O)NRa-, -NRaC(O)-, -NRaC(O)S-, -SC(O)NRa-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NRa-, -NRaC(S)O-, -SS-, or -S(O) 0-2 -;

[0355] a, b and g are independently selected from 0, 1, 2, 3, 4 or 5, and a and b are not 0 at the same time;

[0356] a+g=0, 1, 2, 3, 4, or 5;

[0357] G1 and G3 are independently selected from 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

[0358] G2 and G4 are independently 0, 1, 2, 3 or 4 carbon atoms;

[0359] G1+G2=3, 4, 5, 6, 7, 8 or 9 carbon atoms, G3+G4=3, 4, 5, 6, 7, 8 or 9 carbon atoms;

[0360] The methylene group in the 1-6 Alkyl substitution;

[0361] R3 is selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, or 5 R*;

[0362] or R3 together with the N atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R*;

[0363] R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L b -OR b or -L b -NR b R' b ;

[0364] R5, R6, R7 and R8 are independently H or C 1-6 Alkyl, optionally substituted with 1, 2, 3, 4 or 5 R*;

[0365] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl or C 4-20 Alkynyl, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with -NR"-;

[0366] R and R' are independently selected from H, C 1-14 Alkyl, -L a -OR a or -L a -NR a R'a ;

[0367] L a Independently selected from chemical bonds or C 1-14 alkylene;

[0368] L b Independently selected from chemical bonds or C 1-6 alkylene;

[0369] R a and R' a Independently selected from H, C 1-14 an alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 10-membered heterocyclyl group;

[0370] R b and R' b Independently selected from H, C 1-6 an alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 10-membered heterocyclyl group;

[0371] R" is independently selected from H or C 1-14 alkyl.

[0372] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipid is selected from the compound of formula (II'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0373] in,

[0374] M1 and M2 are independently selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NRa-, -NRaC(O)NRa-, -OC(O)S-, -OC(O)O-, -NRaC(O)O-, -OC(O)-, -SC(O)-, -C(O) S-, -NRa-, -C(O)NRa-, -NRaC(O)-, -NRaC(O)S-, -SC(O)NRa-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NRa-, -NRaC(S)O-, -SS-, or -S(O) 0-2 -; Preferably -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -OC(O)O-, -C(O)NR a -and-NR a C(O)-; preferably -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -OC(O-;

[0375] a, b and g are independently selected from 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3; a and b are not 0 at the same time;

[0376] a+g=0, 1, 2, 3, 4, or 5;

[0377] G1 and G3 are independently selected from 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms; preferably 2, 3, 4, 5 or 6 carbon atoms;

[0378] G2 and G4 are independently 0, 1, 2, 3 or 4 carbon atoms; preferably 0, 1 or 2 carbon atoms;

[0379] G1+G2=3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably 4, 5, 6, 7, 8 carbon atoms;

[0380] G3+G4=3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably 4, 5, 6, 7, 8 carbon atoms;

[0381] The methylene group in the 1-6 Alkyl substitution;

[0382] R3 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclic group, preferably C 1-6 Alkyl and C 1-6 haloalkyl, optionally substituted with 1, 2, 3, 4 or 5 R*;

[0383] or R3 together with the N atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R*;

[0384] R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L b -OR b or -L b -NR b R' b ; preferably H, C 1-6 Alkyl, C 1-6 Haloalkyl or -L b -OR b ; R5, R6, R7 and R8 are independently H or C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably methyl, optionally substituted with 1, 2, 3, 4 or 5 R*;

[0385] R1 and R2 are independently selected from C4-20 Alkyl, C 4-20 Alkenyl or C 4-20 Alkynyl, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with -NR";

[0386] R and R' are independently selected from H, C 1-14 Alkyl, -L a -OR a or -L a -NR a R' a ;

[0387] L a Independently selected from chemical bonds or C 1-14 alkylene;

[0388] L b Independently selected from chemical bonds or C 1-6 Alkylene, preferably a chemical bond;

[0389] R a and R' a Independently selected from H, C 1-14 Alkyl, 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclic group, preferably H or C 1- 14 alkyl;

[0390] R b and R' b Independently selected from H, C 1-6 Alkyl, 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclic group, preferably H or C 1-6 Alkyl, preferably H;

[0391] R" is independently selected from H or C 1-14 alkyl.

[0392] In a preferred embodiment, R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl or C 4-20 Alkynyl, which is optionally substituted with one or more R, said R being selected from C 1-6 Alkyl, preferably C 1-3 alkyl.

[0393] Preferably, R1 and R2 are independently selected from

[0394] Preferably, a and b are 2; g is 0 or 1, preferably 1.

[0395] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipid is selected from the compound of formula (III), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0396] in,

[0397] G1 and G2 are independently selected from chemical bonds, C 1-13 Straight chain alkylene, C 2-13 Straight chain alkenylene and C 2-13 Straight chain alkynylene, which is optionally substituted by one or more R G1 replace;

[0398] The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;

[0399] R G1 Independently selected from H, C 1-14 Alkyl, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0400] G3 is selected from C 4-14 Straight chain alkylene, C 4-14 Straight chain alkenylene and C 4-14 Straight chain alkynylene, which is optionally substituted by one or more R G3 replace;

[0401] R G3 Independently selected from H, -L a -OR a 、-L a -SR a and -L a -NR a R' a ;

[0402] L a independently selected from chemical bonds and C 1-14 alkylene;

[0403] R a and R' a Independently selected from H, C 1-14 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0404] G7 is selected from chemical bonds, C 1-6 Alkylene, C2-6 Alkenylene and C 2-6 Alkyne group, which is optionally substituted by one or more R G7 replace;

[0405] 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 ;

[0406] L b independently selected from chemical bonds and C 1-6 alkylene;

[0407] R b and R' b Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0408] 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;

[0409] 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 ;

[0410] L e independently selected from chemical bonds and C 1-8 alkylene;

[0411] R e and R' e Independently selected from H, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0412] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O )S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -; preferably selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; preferably -C(O)O-, -OC(O)-, -SC(O)O-, -OC(O)S- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -OC(O-; preferably -OC(O)O-;

[0413] 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 pyridinyl, wherein the phenylene or pyridinyl is optionally substituted with one or more R*; preferably 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 -、-NRf 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-, and -S(O) 0-2 -; preferably chemical bonds, -OC(O)- and -SC(O)-;

[0414] R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L f -OR f 、-L f -SR f and -L f -NR f R' f ;

[0415] L f independently selected from chemical bonds and C 1-8 alkylene;

[0416] R f and R' f Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably H and C 1-10 alkyl;

[0417] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted by one or more R 1s substituted, and wherein one or more methylene units are optionally and independently replaced by -NR'-;

[0418] R 1s Independently selected from H, C 1-20 Alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0419] R and R' are each independently selected from H and C 1-20 alkyl;

[0420] L c independently selected from chemical bonds and C 1-20alkylene;

[0421] R c and R' c Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0422] R'3 is selected from CN, -OR g 、-C(O)R g 、-OC(O)R g 、-NR”C(O)R g 、-NR g R' g 、-NR”C(O)NR g R' g 、-NR”C(O)R g 、-NR”S(O)2R g 、-OC(O)NR g R' g 、-NR”C(O)OR g 、-N(OR g )C(O)R g 、-N(OR g )S(O)2R g 、-N(OR g )C(O)OR g 、-N(OR g )C(O)R g R' g , 3 to 14 membered heterocyclic and 5 to 14 membered heteroaryl; preferably CN, -OR g and -NR g R' g ; preferably selected from -OR g and -NR g R' g ; preferably -OR g ; preferably OH;

[0423] R g and R' g Independently selected from H, C 1-10 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl;

[0424] R" is independently selected from H and C 1-6 alkyl;

[0425] R5 and R6 are independently selected from C 1-8 Alkyl, preferably C 1-3 Alkyl, more preferably methyl, optionally replaced by one or more R 4s replace;

[0426] Or R5, R6 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4s replace;

[0427] R 4s are independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -OR d 、-L d -SR d and -L d -NR d R' d ;

[0428] L d independently selected from chemical bonds and C 1-8 alkylene;

[0429] R d and R' d Independently selected from H, C 1-8 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0430] In some preferred embodiments, the compound of formula (III), or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt,

[0431] in,

[0432] Q1 is selected from -C(O)O-, -SC(O)O-, -OC(O)S-, -OC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -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-, and -S(O) 0-2 -; preferably chemical bonds, -OC(O)- and -SC(O)-;

[0433] M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)O-, -OC(O)S- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -OC(O)-; preferably -OC(O)O-;

[0434] The remaining groups are as defined in the compound of formula (III) herein;

[0435] In some preferred embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the compound of formula (III), or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, is of formula (III'):

[0436] in,

[0437] a = 1, 2, 3, 4, 5, or 6;

[0438] b = 4, 5, 6, 7, 8, 9, or 10;

[0439] c = 1, 2, 3, 4, 5, or 6;

[0440] d = 0, 1, 2, 3, or 4;

[0441] c+d=3, 4, 5, 6, 7, 8, or 9;

[0442] The remaining groups are as defined herein for the compound of formula (III).

[0443] In a preferred embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-.

[0444] In a preferred embodiment, R5 and R6 are independently selected from C 1-6 Alkyl; preferably selected from C 1-3 Alkyl; preferably methyl;

[0445] Preferably, R5 and R6 are optionally replaced by 1, 2 or 3 R 4s replace.

[0446] Preferably, a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5; preferably a=2, 3 or 4.

[0447] Preferably, b=4, 5, 6, 7, 8 or 9; preferably b=5, 6, 7 or 8; preferably b=6, 7 or 8.

[0448] Preferably, c=2, 3, 4, 5 or 6; preferably c=2, 3, 4 or 5.

[0449] Preferably, d=0, 1, 2 or 3.

[0450] Preferably, c+d=4, 5, 6, 7 or 8; preferably c+d=5, 6 or 7.

[0451] In a preferred embodiment, R5 and R6 together with the carbon atom to which they are attached form C3-10 Cycloalkylene or 3 to 10 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene; preferably forming C 3-6 Cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably forms cyclopropylene or cyclopentylene; preferably forms cyclopropylene;

[0452] Preferably, R5 and R 65 The ring formed with the carbon atom to which they are attached is optionally substituted with 1, 2 or 3 R 4s replace.

[0453] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the compound of formula (III), or its isotopic variant, tautomer or stereoisomer, or a pharmaceutically acceptable salt thereof, is a structure of formula (III"):

[0454] in,

[0455] a = 1, 2, 3, 4, 5, or 6;

[0456] b = 4, 5, 6, 7, 8, 9, or 10;

[0457] c = 1, 2, 3, 4, 5, or 6;

[0458] d = 0, 1, 2, 3, or 4;

[0459] c+d=3, 4, 5, 6, 7, 8, or 9;

[0460] The remaining groups are as defined herein for the compound of formula (III).

[0461] In a preferred embodiment, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-.

[0462] In a preferred embodiment, R5 and R6 are independently selected from C 1-6 Alkyl, preferably selected from C 1-3 Alkyl, more preferably methyl;

[0463] Preferably, R5 and R6 are optionally replaced by 1, 2 or 3 R 4s replace.

[0464] In a preferred embodiment, said R5 and R6 together with the carbon atom to which they are attached form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene, preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene, preferably forming C3-6 Cycloalkylene, preferably forming C 3-5 Cycloalkylene, preferably forming cyclopropylene or cyclopentylene, preferably forming cyclopropylene;

[0465] Preferably, the ring formed by R5 and R6 and the carbon atom to which they are attached is optionally substituted by 1, 2 or 3 R 4s replace.

[0466] Preferably, a=2, 3, 4 or 5; preferably a=3 or 4.

[0467] Preferably, b=5, 6, 7 or 8; preferably b=6 or 7.

[0468] Preferably, c=2, 3, 4 or 5; preferably c=2, 4 or 5.

[0469] Preferably, d=1, 2, 3 or 4; preferably d=1, 2 or 4.

[0470] Preferably, c+d=4, 5, 6, 7 or 8; preferably c+d=5, 6 or 7; preferably c+d=6.

[0471] Preferably, the present invention provides the above-mentioned lipid nanoparticles, wherein the compound of formula (I) is selected from one or more of:

[0472] In a preferred embodiment, the present invention provides the above-mentioned lipid nanoparticles, wherein the compound of formula (I) is selected from the above-mentioned compound 133, compound 134, compound 135, compound 136, compound 137, compound 138, compound 139 or compound 140.

[0473] In a preferred embodiment, the present invention provides the above-mentioned lipid nanoparticles, wherein the compound of formula (I) is selected from one or more of the following compounds:

[0474] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipids are selected from one or more of the following: 1,2-dioleoyloxy-3-dimethylaminopropane (DODAP), 1,2-dioleyloxy-3-dimethylaminopropane (DODMA), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), 2,2-dilinoleoyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), 4-(N,N-dimethylamino)butanoic acid (dilinoleyl) ) methyl ester (DLin-MC3-DMA), 8-[(2-hydroxyethyl)(6-oxo-6-decyloxyhexyl)amino]octanoic acid (heptadecan-9-yl) ester (SM-102) and [(4-hydroxybutyl) azadiyl] bis(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315); preferably selected from 4-(N,N-dimethylamino) butyric acid (dilinoleyl) methyl ester (DLin-MC3-DMA) and / or [(4-hydroxybutyl) azadiyl] bis(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315).

[0475] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the amount of the ionizable lipid is 25-80 mol% of the total lipid present in the lipid nanoparticles.

[0476] Preferably, the amount of the ionizable lipid is 30-70 mol%, preferably 35-65 mol%, preferably 40-60 mol%, more preferably 45-60 mol% of the total lipid present in the lipid nanoparticles.

[0477] Preferably, the amount of ionizable lipid is 25 mol% to 80 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of ionizable lipid is 30 mol% to 70 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of ionizable lipid is 35 mol% to 65 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of ionizable lipid is 40 mol% to 60 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of ionizable lipid is 45 mol% to 60 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of ionizable lipid is 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol%, 60 mol%, 65 mol%, 70 mol%, 75 mol% or 80 mol% of the total lipid present in the lipid nanoparticle.

[0478] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the structural lipid is selected from one or more of the following: cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campesterol, preferably selected from cholesterol and / or β-sitosterol, more preferably cholesterol.

[0479] Preferably, the amount of structural lipid is 3 mol% to 60 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of structural lipid is 3 mol% to 50 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of structural lipid is 3 mol% to 45 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of structural lipid is 5 mol% to 40 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of structural lipid is 15 mol% to 40 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of structural lipid is 25 mol% to 40 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of structural lipid is 3 mol%, 5 mol%, 7.5 mol%, 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol%, 50 mol%, 55 mol% or 60 mol% of the total lipid present in the lipid nanoparticle.

[0480] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the phospholipid is selected from the following one or more: distearoylphosphatidylcholine (DSPC), glycol phosphatidylethanolamine (DOPE), dimercaptoglycerol phosphate (DMPC), 1,2-diacetyl-sn-glycero-3-phosphocholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dimercapto-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-cosanoyl-sn-glycero-3-phosphoethanolamine (DPPE), dipalmitoylphosphatidylcholine (DPPC), hexadecanoyl-2-(9Z octadecenoyl)-sn-glycero-3-phosphoethanolamine (POPE).

[0481] Preferably, the amount of phospholipids is between 0.5 mol% and 60 mol% of the total lipids present in the lipid nanoparticles. Preferably, the amount of phospholipids is between 0.5 mol% and 50 mol% of the total lipids present in the lipid nanoparticles. Preferably, the amount of phospholipids is between 5 mol% and 40 mol% of the total lipids present in the lipid nanoparticles. Preferably, the amount of phospholipids is between 5 mol% and 35 mol% of the total lipids present in the lipid nanoparticles. Preferably, the amount of phospholipids is between 5 mol% and 30 mol% of the total lipids present in the lipid nanoparticles. Preferably, the amount of phospholipids is between 5 mol% and 25 mol% of the total lipids present in the lipid nanoparticles. Preferably, the amount of phospholipids is 0.5%, 2.5%, 5 mol%, 7.5 mol%, 10 mol%, 15 mol%, 20 mol%, 25 mol%, 30 mol%, 35 mol%, 40 mol%, 45 mol% or 50 mol% of the total lipids present in the lipid nanoparticles.

[0482] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol and PEG-modified dialkylglycerol.

[0483] Preferably, the polymer-conjugated lipid comprises a PEG moiety of 400 Da to 20 kDa, preferably a PEG moiety of about 1000 Da to about 10000 Da, and preferably a PEG moiety of about 1000 Da to about 5000 Da.

[0484] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is selected from a compound of formula (IIP-A1) or formula (IIIP-A1), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0485] Among them, R 11 is H, optionally substituted alkyl or an oxygen protecting group;

[0486] R 21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, optionally substituted with one or more Rv;

[0487] n1 is an integer from 1 to 250;

[0488] R VIndependently 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 ;

[0489] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0490] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0491] In some preferred embodiments,

[0492] 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;

[0493] Preferably, R 21 、R 31 、R 41 Independently selected from C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl; preferably C 11-26 alkyl;

[0494] Preferably, R 21 、R 31 、R 41 Independently selected from C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl; preferably C 12-26 alkyl;

[0495] Preferably, R 21 、R 31 、R 41 Independently selected from C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl; preferably C 13-26 alkyl;

[0496] Preferably, R 21 、R 31 、R 41 Independently selected from C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl; preferably C 14-26 alkyl;

[0497] Preferably, R 21 、R 31 、R 41 Independently selected from C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl; preferably C 15-26 alkyl;

[0498] Preferably, R 21 、R 31 、R 41 Independently selected from C 16-26 Alkyl, C 16-26 Alkenyl, C 16-26 Alkynyl; preferably C 16-26 alkyl;

[0499] Preferably, R 21 、R 31 、R 41 Independently selected from C 17-26 Alkyl, C 17-26 Alkenyl, C 17-26 Alkynyl; preferably C 17-26 alkyl;

[0500] Preferably, R 21 、R 31 、R 41 Independently selected from C 18-26 Alkyl, C 18-26 Alkenyl, C 18-26 Alkynyl; preferably C 18-26 alkyl;

[0501] Preferably, it is optionally substituted with one or more (preferably 1) Rv;

[0502] Preferably, Rv is independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ; preferably H, C 1-26 Alkyl, C2-26 Alkenyl and C 2-26 Alkynyl; preferably H and C 1-26 alkyl;

[0503] Preferably, L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0504] Preferably, 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.

[0505] In some preferred embodiments, n1 is an integer from 10 to 120; preferably, n1 is an integer from 30 to 80.

[0506] In some specific embodiments, n1 is 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.

[0507] In some specific embodiments, n1 is 10, 15, 20, 25, 30, 35, 40, 44, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110 or 120; preferably, n1 is in the range such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 400 g / mol to about 6000 g / mol, for example, 2000 g / mol, 2500 g / mol, 3000 g / mol, 3500 g / mol, 4000 g / mol, 4500 g / mol or 5000 g / mol.

[0508] In some embodiments, n1 is about 44 and the PEG moiety has an average molecular weight of about 2000 g / mol; in other embodiments, n1 is about 80 and the PEG moiety has an average molecular weight of about 3500 g / mol; in other embodiments, n1 is about 114 and the PEG moiety has an average molecular weight of about 5000 g / mol.

[0509] In some specific embodiments, n1 is in a range such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 1500 g / mol to about 2500 g / mol; more preferably, has an average molecular weight of 2000 g / mol.

[0510] In some preferred embodiments, R1 is C 1-3 Alkyl; preferably -CH3.

[0511] Preferably, the polymer conjugated lipid of formula (IIP-A1) or formula (IIIP-A1) is a compound of formula (IVP-A1) or formula (VP-A1), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof

[0512] in,

[0513] o', p', q' are each optionally 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;

[0514] The remaining variables are as defined in the present invention;

[0515] Preferably, R 21 、R 31 and R 41 Not R V replace;

[0516] Preferably, in formula (IVP-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;

[0517] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0518] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably C1-20 alkyl;

[0519] Preferably, in formula (VP-A1), R V For H.

[0520] In some specific embodiments, the polymer-conjugated lipid is selected from one or more of the following compounds:

[0521] wherein n1 is each independently an integer of 10-120; preferably an integer of 30-80; 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, 144 or 120, more preferably 44, 80 or 114;

[0522] Preferably, n1 ranges from 400 g / mol to about 6000 g / mol of the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1), for example, 2000 g / mol, 2500 g / mol, 3000 g / mol, 3500 g / mol, 4000 g / mol, 4500 g / mol, or 5000 g / mol; more preferably, from 1500 g / mol to about 2500 g / mol; and even more preferably, from 2000 g / mol.

[0523] In a specific embodiment, the polymer lipid is DSPE-PEG-2000, DSPE-PEG-3500 or DSPE-PEG-5000.

[0524] In some embodiments, the polymer-conjugated lipid is selected from one or more of the following compounds:

[0525] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is a compound of formula (IP'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0526] in,

[0527] L is absent or a divalent linking group;

[0528] L2 is absent or CH2;

[0529] R 11 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, or an oxygen protecting group;

[0530] n1 is an integer from 1 to 250;

[0531] R w Select H or

[0532] Q 11 independently selected from -C(O)O-, -OC(O)- or -OC(O)O-;

[0533] 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;

[0534] 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 ;

[0535] 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;

[0536] 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;

[0537] Preferably, R w is H; preferably, R w for

[0538] Preferably, Q 11 Independently selected from -C(O)O- or -OC(O)-; preferably -C(O)O-; preferably -OC(O)-; preferably -OC(O)O-.

[0539] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is a compound of formula (IP), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0540] in,

[0541] L is absent or a divalent linking group;

[0542] L2 is absent or CH2;

[0543] R 11 is H, alkyl or cycloalkyl;

[0544] n1 is an integer from 1 to 250;

[0545] R w Select H or

[0546] 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;

[0547] 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 ;

[0548] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0549] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0550] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is a compound of formula (IIP), formula (IIP-A1), formula (IIP-A2) or formula (IIP-A3), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0551] in,

[0552] L is absent or a divalent linking group;

[0553] R 11 is H, alkyl or cycloalkyl;

[0554] n1 is an integer from 1 to 250;

[0555] 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;

[0556] 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 ;

[0557] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0558] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0559] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is a compound of formula (IVP), formula (IVP-B), formula (IVP-C), formula (IVP-A1), formula (IVP-A2) or formula (IVP-A3), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0560] in,

[0561] 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;

[0562] The remaining variables are defined as in Formula (IP') or Formula (IP);

[0563] 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;

[0564] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0565] R c1 and R' c1 Independently selected from C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0566] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is a compound of Formula (IIIP), Formula (IIIP-A1), Formula (IIIP-A2) or Formula (IIIP-A3), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0567] L is absent or a divalent linking group;

[0568] R 11 is H, alkyl or cycloalkyl;

[0569] n1 is an integer from 1 to 250;

[0570] 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 RV replace;

[0571] 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 ;

[0572] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0573] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0574] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is a compound of formula (VP), formula (VP-A1), formula (VP-A2) or formula (VP-A3), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0575] 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;

[0576] Each variable is individually defined as in Formula (IP'), Formula (IP), or Formula (IVP).

[0577] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein,

[0578] 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;

[0579] Preferably, L is selected from -NHC(O)-, -OC(O)-, -C(O)-, -OC(O)O- or absent; preferably or not present; preferably or not present; preferably or does not exist;

[0580] Preferably, L is selected from -NHC(O)-, -OC(O)-, -C(O)-, or absent;

[0581] Preferably, L is selected from or does not exist;

[0582] Preferably, L is selected from Or does not exist.

[0583] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, 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) RV replace;

[0584] 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;

[0585] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0586] 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 alkyl;

[0587] Preferably,

[0588] 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;

[0589] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0590] R c1and 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;

[0591] Preferably, R V is H;

[0592] Preferably, in Formula (IVP), Formula (IVP-B), Formula (IVP-C), Formula (IVP-A1), Formula (IVP-A2), Formula (IVP-A3), Formula (VP), Formula (VP-A1), Formula (VP-A2), and Formula (VP-A3), R 21 、R 31 and R 41 Not R V replace.

[0593] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, 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;

[0594] 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.

[0595] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, 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;

[0596] 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.

[0597] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein o', p', q' are each independently an integer of 0-15, 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 of 0-10, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; preferably, o', p', q' are each independently an integer of 0-5, for example, 0, 1, 2, 3, 4, 5; preferably, o', p', q' are each independently an integer of 0-3, for example, 0, 1, 2, 3; preferably, o', p', q' are each independently 0.

[0598] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is selected from the following compounds:

[0599] 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;

[0600] 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.

[0601] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer-conjugated lipid is selected from the following compounds:

[0602] Preferably, the polymer-conjugated lipid is selected from the following compounds:

[0603] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the polymer conjugated lipid is selected from one or more of the following: DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000, DSPE-PEG2000-Mannose, DSPE-PEG2000. amine, DSPE-PEG3350, DSPE-PEG3500, DSPE-PEG4000, DPPE-PEG3500, Ceramide-PEG5000, DSPE-PEG5000 and ALC-0159, preferably DSPE-PEG2000, DSPE-PEG3350, DSPE-PEG3500, DSPE-PEG4000 and / or DSPE-PEG5000.

[0604] In some embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the amount of the polymer-conjugated lipid is 0.25 mol% to 10 mol% of the total lipid present in the lipid nanoparticle. Preferably, the amount of the polymer-conjugated lipid is 0.25 mol% to 5 mol% of the total lipid present in the lipid nanoparticle.

[0605] Preferably, the amount of polymer-conjugated lipid is between 0.25 mol% and 4.5 mol% of the total lipid present in the lipid nanoparticle.

[0606] Preferably, the amount of polymer-conjugated lipid is between 0.5 mol% and 2 mol% of the total lipid present in the lipid nanoparticle.

[0607] Preferably, the amount of polymer-conjugated lipid is between 0.25 mol% and 2 mol% of the total lipid present in the lipid nanoparticle.

[0608] Preferably, the amount of polymer-conjugated lipid is between 0.25 mol% and 3 mol% of the total lipid present in the lipid nanoparticle.

[0609] Preferably, the amount of polymer-conjugated lipid is between 2 mol% and 4.5 mol% of the total lipid present in the lipid nanoparticle.

[0610] Preferably, the amount of polymer-conjugated lipid is 0.25 mol%, 0.5 mol%, 0.8 mol%, 0.9 mol%, 1 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, 1.6 mol%, 1.7 mol%, 1.8 mol%, 1.9 mol%, 2 mol%, 2.25 mol%, 2.5 mol%, 2.75 mol%, 3 mol%, 3.25 mol%, 3.5 mol%, 3.75 mol%, 4 mol%, 4.25 mol%, 4.5 mol%, 4.75 mol%, 5 mol%, 5.5 mol%, 6 mol%, 6.5 mol%, 7 mol%, 7.5 mol%, 8 mol%, 8.5 mol%, 9 mol%, 9.5 mol% or 10 mol% of the total lipid present in the lipid nanoparticles.

[0611] In some specific embodiments, the molecular weight of the polymer lipid is 2000 g / mol-3000 g / mol, preferably 2000 g / mol, and its molar percentage in the lipid nanoparticle is 1.0 mol%-2.0 mol%, preferably 1.5 mol%.

[0612] In some specific embodiments, the polymer lipid has a molecular weight of 3000 g / mol-4000 g / mol, preferably 3500 g / mol, and its molar percentage in the lipid nanoparticles is 0.7 mol%-1 mol%, preferably 0.86 mol%.

[0613] In some specific embodiments, the molecular weight of the polymer lipid is 4500 g / mol-5500 g / mol, preferably 5000 g / mol, and its molar percentage in the lipid nanoparticle is 0.5 mol%-0.7 mol%, preferably 0.6 mol%.

[0614] In another aspect, the present invention provides a lipid nanoparticle composition comprising the aforementioned lipid nanoparticle and an optional load.

[0615] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the lipid nanoparticles contain the following components in molar percentages: 25 mol%-80 mol% of ionizable lipids; 3 mol%-60 mol% of structural lipids; 0.5 mol%-60 mol% of phospholipids; 0.25 mol%-10 mol% of polymer-conjugated lipids.

[0616] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the ionizable lipid is selected from any one or more of Compound 133, Compound 134, Compound 135, Compound 136, Compound 137, Compound 138, Compound 139, or Compound 140:

[0617] Preferably, the ionizable lipids are selected from one or more of the following:

[0618] In some specific embodiments, the present invention provides the above-mentioned lipid nanoparticles, wherein the lipid nanoparticles contain the following components in molar percentages: 30 mol%-70 mol% of ionizable lipids; 3 mol%-50 mol% of structural lipids; 0.5 mol%-50 mol% of phospholipids; 0.25 mol%-5 mol% of polymer-conjugated lipids.

[0619] In a specific embodiment, the lipid nanoparticles contain the following components in molar percentages: 35 mol%-65 mol% of ionizable lipids; 3 mol%-45 mol% of structural lipids; 5 mol%-40 mol% of phospholipids; and 0.25 mol%-5 mol% of polymer-conjugated lipids.

[0620] In a specific embodiment, the lipid nanoparticles contain the following components in molar percentages: 40 mol%-60 mol% of ionizable lipids; 5 mol%-40 mol% of structural lipids; 5 mol%-35 mol% of phospholipids; and 0.25 mol%-4.5 mol% of polymer-conjugated lipids.

[0621] Preferably, the lipid nanoparticles contain the following components in molar percentages: 40 mol%-60 mol% of ionizable lipids; 15 mol%-40 mol% of structural lipids; 5 mol%-35 mol% of phospholipids; 0.25 mol%-4.5 mol% of polymer-conjugated lipids;

[0622] Preferably, the lipid nanoparticles contain the following components in molar percentages: 40 mol%-60 mol% of ionizable lipids; 15 mol%-40 mol% of structural lipids; 5 mol%-30 mol% of phospholipids; 0.25 mol%-3 mol% of polymer-conjugated lipids;

[0623] Preferably, the lipid nanoparticles contain the following components in molar percentages: 45 mol%-60 mol% of ionizable lipids; 15 mol%-40 mol% of structural lipids; 5 mol%-30 mol% of phospholipids; 0.25 mol%-3 mol% of polymer-conjugated lipids;

[0624] Preferably, the lipid nanoparticles contain the following components in molar percentages: 45 mol%-60 mol% of ionizable lipids; 25 mol%-40 mol% of structural lipids; 5 mol%-25 mol% of phospholipids; and 0.25 mol%-3 mol% of polymer-conjugated lipids.

[0625] In a specific embodiment, the lipid nanoparticles contain the following molar percentages of components:

[0626] Any one or more of Compound 133, Compound 134, Compound 135, Compound 136, Compound 137, Compound 138, Compound 139, or Compound 140: 25 mol%-80 mol%;

[0627] Cholesterol: 3 mol%-60 mol%;

[0628] Distearoylphosphatidylcholine (DSPC): 0.5 mol%-60 mol%;

[0629] DMG-PEG2000 or DSPE-PEG2000: 0.25 mol%-10 mol%.

[0630] In a specific embodiment, the lipid nanoparticles contain the following molar percentages of components:

[0631] Any one or more of Compound 133, Compound 134, Compound 135, Compound 136, Compound 137, Compound 138, Compound 139, or Compound 140: 50 mol%;

[0632] Cholesterol: 38.5 mol% or 10 mol%;

[0633] Distearoylphosphatidylcholine (DSPC): 38.5 mol% or 10 mol%;

[0634] DSPE-PEG2000: 1.5 mol%.

[0635] In a specific embodiment, the lipid nanoparticles contain the following molar percentages of components:

[0636] Any one or more of Compound 133, Compound 134, Compound 135, Compound 136, Compound 137, Compound 138, Compound 139, or Compound 140: 50 mol%;

[0637] Cholesterol: 30 mol%-35 mol%;

[0638] Distearoylphosphatidylcholine (DSPC): 15 mol%-16 mol%;

[0639] DSPE-PEG2000: 0.25mol%-3mol%.

[0640] In another aspect, the present invention provides a lipid nanoparticle composition comprising the lipid nanoparticle and an optional load.

[0641] In some specific embodiments, the cargo is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent.

[0642] Preferably, the therapeutic agent, preventive agent or diagnostic agent is selected from one or more of small molecule compounds, polypeptides, proteins and nucleic acids;

[0643] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASOs), RNA or DNA;

[0644] 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 mRNA, siRNA, gRNA, more preferably modified mRNA;

[0645] Preferably, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

[0646] The present invention provides the above-mentioned nanoparticle composition, wherein the N:P molar ratio of the N atoms in the ionizable lipid to the P atoms in the load molecule is (1-15):1, preferably (2-12):1, and preferably (2-9):1.

[0647] In some specific embodiments, the N:P molar ratio of N atoms in the ionizable lipid to P atoms in the charge molecule is (2-15):1, preferably (2-10):1, and more preferably (2-6):1.

[0648] In some specific embodiments, the N:P molar ratio of N atoms in the ionizable lipid to P atoms in the charge molecule is (2-12):1, preferably (2-8):1, and more preferably (2-6):1.

[0649] In some specific embodiments, the N:P molar ratio of N atoms in the ionizable lipid to P atoms in the charge molecule is (1-12):1, preferably (4-11):1, preferably (4-10):1, and more preferably (4-9):1.

[0650] In some specific embodiments, the N:P molar ratio of N atoms in the ionizable lipid to P atoms in the charge molecule is 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, or 12.

[0651] In some embodiments, the present invention provides the above-mentioned nanoparticle composition, wherein the particle size of the particles is 40-200 nm, preferably 40-160 nm, preferably 40-150 nm, more preferably 40-120 nm, and more preferably 40-100 nm.

[0652] In some embodiments, the present invention provides the above-mentioned nanoparticle composition, wherein the particle size of the particles is 40-500 nm, preferably 50-250 nm, preferably 50-200 nm, and more preferably 50-150 nm.

[0653] In some specific embodiments, the particle size is 50-300 nm, preferably 50-180 nm, and more preferably 50-120 nm.

[0654] In some specific embodiments, the particle size is 50-200 nm, preferably 50-160 nm, preferably 70-150 nm, and more preferably 70-120 nm.

[0655] In some specific embodiments, the particles have a particle size of 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 170 nm, 180 nm, 190 nm, or 200 nm.

[0656] In another aspect, the present invention provides a method for preparing the lipid nanoparticle composition, comprising: mixing the lipid components in the lipid nanoparticles, and then mixing with a load to obtain the composition.

[0657] In another aspect, the present invention provides a pharmaceutical composition comprising the lipid nanoparticle composition of the present invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

[0658] In another aspect, the present invention provides use of the lipid nanoparticle composition of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating, diagnosing or preventing a disease;

[0659] Preferably, the disease is selected from muscle diseases or muscle-related diseases.

[0660] In another aspect, the present invention provides use of the lipid nanoparticle composition of the present invention or the pharmaceutical composition of the present invention in the preparation of drugs for gene editing, protein replacement and / or supplementation, or gene interference.

[0661] Preferably, the lipid nanoparticle composition or pharmaceutical composition is administered systemically, preferably by systemic injection, preferably by intravenous injection, arterial injection or intraperitoneal injection, more preferably by intraperitoneal injection or intravenous injection.

[0662] In another aspect, the present invention provides use of the lipid nanoparticle composition of the present invention or the pharmaceutical composition of the present invention in preparing a drug for delivering a load, preferably use thereof in preparing a drug for delivering a load to muscle.

[0663] In another aspect, the present invention provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a lipid nanoparticle composition of the present invention or a pharmaceutical composition of the present invention;

[0664] Preferably, the disease is a muscle disease or a muscle-related disease.

[0665] In another aspect, the present invention provides a lipid nanoparticle composition of the present invention or a pharmaceutical composition of the present invention for use in treating, diagnosing and / or preventing a disease; preferably, the disease is selected from a muscle disease or a muscle-related disease.

[0666] In another aspect, the present invention provides a method of delivering a cargo in a subject, comprising administering to the subject a lipid nanoparticle composition of the present invention or a pharmaceutical composition of the present invention.

[0667] In another aspect, the present invention provides a nanoparticle composition of the present invention or a pharmaceutical composition of the present invention for use in delivering a load;

[0668] Preferably, it is used to deliver load to muscle.

[0669] In some embodiments, the cargo is selected from one or more of a therapeutic agent, a prophylactic agent, or a diagnostic agent;

[0670] Preferably, the therapeutic agent, preventive agent or diagnostic agent is selected from one or more of small molecule compounds, polypeptides, proteins and nucleic acids;

[0671] Preferably, the nucleic acid is selected from one or more of antisense oligonucleotides (ASOs), RNA or DNA;

[0672] 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 mRNA, siRNA, gRNA, more preferably modified mRNA;

[0673] Preferably, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

[0674] In another aspect, the present invention provides a method for treating or preventing a muscle disease in a subject suffering from a muscle disease or a muscle-related disease, comprising administering a therapeutically effective amount of the lipid nanoparticles of the present invention, the lipid nanoparticle composition of the present invention, or the pharmaceutical composition of the present invention to the subject by systemic administration.

[0675] The systemic administration is preferably systemic injection, preferably intravenous injection, arterial injection or intraperitoneal injection, more preferably intraperitoneal injection or intravenous injection.

[0676] In another aspect, the present invention provides an ionizable lipid compound having the structure of formula (II'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0677] in,

[0678] M1 and M2 are independently selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NRa-, -NRaC(O)NRa-, -OC(O)S-, -OC(O)O-, -NRaC(O)O-, -OC(O)-, -SC(O)-, -C(O) S-, -NRa-, -C(O)NRa-, -NRaC(O)-, -NRaC(O)S-, -SC(O)NRa-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NRa-, -NRaC(S)O-, -SS-, or -S(O) 0-2 -;

[0679] a, b and g are independently selected from 0, 1, 2, 3, 4 or 5, and a and b are not 0 at the same time;

[0680] a+g=0, 1, 2, 3, 4, or 5;

[0681] G1 and G3 are independently selected from 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;

[0682] G2 and G4 are independently 0, 1, 2, 3 or 4 carbon atoms;

[0683] G1+G2=3, 4, 5, 6, 7, 8 or 9 carbon atoms, G3+G4=3, 4, 5, 6, 7, 8 or 9 carbon atoms;

[0684] The methylene group in the 1-6 Alkyl substitution;

[0685] R3 is selected from H, C 1-6 Alkyl, C 1-6 haloalkyl, 3- to 10-membered cycloalkyl, or 3- to 10-membered heterocyclyl, optionally substituted with 1, 2, 3, 4, or 5 R*;

[0686] or R3 together with the N atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R*;

[0687] R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L b -OR b or -L b -NR b R' b ;

[0688] R5, R6, R7 and R8 are independently H or C 1-6 Alkyl, optionally substituted with 1, 2, 3, 4 or 5 R*;

[0689] R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl or C 4-20 Alkynyl, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with -NR"-;

[0690] R and R' are independently selected from H, C 1-14 Alkyl, -L a -OR a or -L a -NR a R' a ;

[0691] L a Independently selected from chemical bonds or C 1-14 alkylene;

[0692] L b Independently selected from chemical bonds or C 1-6 alkylene;

[0693] R a and R' aIndependently selected from H, C 1-14 an alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 10-membered heterocyclyl group;

[0694] R b and R' b Independently selected from H, C 1-6 an alkyl group, a 3- to 10-membered cycloalkyl group, or a 3- to 10-membered heterocyclyl group;

[0695] R" is independently selected from H or C 1-14 alkyl.

[0696] In a preferred embodiment, R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl or C 4-20 Alkynyl, which is optionally substituted with one or more R, said R being selected from C 1-6 Alkyl, preferably C 1-3 alkyl;

[0697] In a preferred embodiment, R1 and R2 are independently selected from

[0698] Preferably, the ionizable lipid compound of formula (II') is selected from one or more of the following:

[0699] In another aspect, the present invention provides a use of a polymer-conjugated lipid or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of muscle-targeted lipid nanoparticles or drugs, wherein the polymer-conjugated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol and PEG-modified dialkylglycerol.

[0700] Preferably, the polymer-conjugated lipid comprises a PEG moiety of 400 Da to 20 kDa, preferably a PEG moiety of about 1000 Da to about 10000 Da, and preferably a PEG moiety of about 1000 Da to about 5000 Da.

[0701] In some specific embodiments, the polymer-conjugated lipid has a structure of Formula (IIP-A1) or Formula (IIIP-A1), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0702] Among them, R 11 is H, optionally substituted alkyl or an oxygen protecting group;

[0703] 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;

[0704] n1 is an integer from 1 to 250;

[0705] 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 ;

[0706] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0707] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl;

[0708] Preferably, 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 C15-26 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;

[0709] 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; preferably H and C 1-26 alkyl;

[0710] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0711] 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.

[0712] Among them, R 11 is H, optionally substituted alkyl or an oxygen protecting group;

[0713] R 21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, optionally substituted with one or more Rv;

[0714] n1 is an integer from 1 to 250;

[0715] 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 ;

[0716] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0717] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0718] In some preferred embodiments,

[0719] R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl;

[0720] Preferably, R 21 、R 31 、R 41 Independently selected from C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl;

[0721] Preferably, R 21 、R 31 、R 41 Independently selected from C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl;

[0722] Preferably, R 21 、R 31 、R 41 Independently selected from C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl;

[0723] Preferably, R 21 、R 31 、R 41 Independently selected from C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl;

[0724] Preferably, R 21 、R 31 、R 41 Independently selected from C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl;

[0725] Preferably, R 21 、R 31 、R 41 Independently selected from C 16-26 Alkyl, C 16-26 Alkenyl, C 16-26 Alkynyl;

[0726] Preferably, R 21 、R 31 、R 41 Independently selected from C 17-26 Alkyl, C 17-26 Alkenyl, C 17-26 Alkynyl;

[0727] Preferably, R 21 、R 31 、R 41 Independently selected from C 18-26 Alkyl, C 18-26 Alkenyl, C 18-26 Alkynyl;

[0728] Preferably, it is optionally substituted with one or more Rv;

[0729] Preferably, Rv is independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0730] Preferably, L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0731] Preferably, R c1 and R' c1Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0732] In some preferred embodiments, n1 is an integer from 10 to 120; preferably, n1 is an integer from 30 to 80.

[0733] In some specific embodiments, n1 is 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.

[0734] In some specific embodiments, n1 is 10, 15, 20, 25, 30, 35, 40, 44, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110 or 120; preferably, n1 is in the range such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 400 g / mol to about 6000 g / mol, for example, 2000 g / mol, 2500 g / mol, 3000 g / mol, 3500 g / mol, 4000 g / mol, 4500 g / mol or 5000 g / mol.

[0735] In some specific embodiments, n1 is in a range such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 1000 g / mol to about 5000 g / mol.

[0736] In some preferred embodiments, R1 is C 1-3 Alkyl; preferably -CH3.

[0737] Preferably, the polymer-conjugated lipid of formula (IIP-A1) or formula (IIIP-A1) is a compound of formula (IVP-A1) or formula (VP-A1),

[0738] or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0739] in,

[0740] o', p', q' are each optionally 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.

[0741] In some specific embodiments, the polymer-conjugated lipid of formula (IIP-A1) is

[0742] Among them, R 21 、R 31 Independently selected from C 18-26 Alkyl, C 18-26 Alkenyl, C 18-26 alkynyl, which is optionally substituted with one or more Rv;

[0743] Preferably, R 21 、R 31 Independently selected from linear C 18-26 Alkyl, straight chain C 18-26 Alkenyl and straight chain C 18-26 Alkynyl.

[0744] In some specific embodiments, the polymer-conjugated lipid is selected from one or more of the following compounds:

[0745] wherein n1 is each independently an integer of 10-120; preferably an integer of 30-80; 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, 144 or 120, more preferably 44, 80 or 114;

[0746] Preferably, n1 is in the range such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 400 g / mol to about 6000 g / mol; for example, it can be 2000 g / mol, 2500 g / mol, 3000 g / mol, 3500 g / mol, 4000 g / mol, 4500 g / mol or 5000 g / mol;

[0747] In some specific embodiments, the polymer conjugated lipid is selected from one or more of the following: DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000, DSPE-PEG2000-Mannose, DSPE-PEG2000 amine, DSPE-PEG3350, DSPE-PEG3500, DSPE-PEG4000, DPPE-PEG3500, Ceramide-PEG5000, DSPE-PEG5000 and ALC-0159, preferably DSPE-PEG2000, DSPE-PEG3350, DSPE-PEG3500, DSPE-PEG4000 and / or DSPE-PEG5000.

[0748] In some preferred embodiments, the use of the polymer-conjugated lipid or its isotopic variant, tautomer or stereoisomer, or pharmaceutically acceptable salt thereof in preparing muscle-targeted lipid nanoparticles or drugs is achieved by systemic administration. In a more preferred embodiment, the systemic administration is systemic injection, preferably intravenous injection, arterial injection or intraperitoneal injection, preferably intraperitoneal injection or intravenous injection.

[0749] In another aspect, the present invention provides a polymer-conjugated lipid compound having a structure of Formula (IIP-A1) or Formula (IIIP-A1) or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0750] Among them, R 11 is H, optionally substituted alkyl or an oxygen protecting group;

[0751] R 21 、R 31 、R 41 Independently selected from C 5-30 Alkyl, C 5-30 Alkenyl, C 5-30 Alkynyl, optionally substituted with one or more Rv;

[0752] n is an integer from 1 to 250;

[0753] Rv is independently selected from H, C 1-30 Alkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, -Lc1 -OR c1 、-L c1 -SR c1 and -L c1 -NR c1 R' c1 ;

[0754] L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0755] R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0756] In some preferred embodiments,

[0757] R 21 、R 31 、R 41 Independently selected from C 10-26 Alkyl, C 10-26 Alkenyl, C 10-26 Alkynyl;

[0758] Preferably, R 21 、R 31 、R 41 Independently selected from C 11-26 Alkyl, C 11-26 Alkenyl, C 11-26 Alkynyl;

[0759] Preferably, R 21 、R 31 、R 41 Independently selected from C 12-26 Alkyl, C 12-26 Alkenyl, C 12-26 Alkynyl;

[0760] Preferably, R 21 、R 31 、R 41 Independently selected from C 13-26 Alkyl, C 13-26 Alkenyl, C 13-26 Alkynyl;

[0761] Preferably, R 21 、R 31 、R 41 Independently selected from C 14-26 Alkyl, C 14-26 Alkenyl, C 14-26 Alkynyl;

[0762] Preferably, R21 、R 31 、R 41 Independently selected from C 15-26 Alkyl, C 15-26 Alkenyl, C 15-26 Alkynyl;

[0763] Preferably, R 21 、R 31 、R 41 Independently selected from C 16-26 Alkyl, C 16-26 Alkenyl, C 16-26 Alkynyl;

[0764] Preferably, R 21 、R 31 、R 41 Independently selected from C 17-26 Alkyl, C 17-26 Alkenyl, C 17-26 Alkynyl;

[0765] Preferably, R 21 、R 31 、R 41 Independently selected from C 18-26 Alkyl, C 18-26 Alkenyl, C 18-26 Alkynyl;

[0766] Preferably, it is optionally substituted with one or more Rv;

[0767] Preferably, Rv is independently selected from H, C 1-26 Alkyl, C 2-26 Alkenyl, C 2-26 Alkynyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ;

[0768] Preferably, L c1 independently selected from chemical bonds and C 1-20 alkylene;

[0769] Preferably, R c1 and R' c1 Independently selected from H, C 1-20 Alkyl, C 3-14 cycloalkyl and 3- to 14-membered heterocyclic groups.

[0770] In some preferred embodiments, n1 is an integer from 10 to 120; preferably, n is an integer from 30 to 80.

[0771] In some specific embodiments, n1 is 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.

[0772] In some specific embodiments, n1 is 10, 15, 20, 25, 30, 35, 40, 44, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110 or 120; preferably, n is in the range such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 400 g / mol to about 6000 g / mol, for example, 2000 g / mol, 2500 g / mol, 3000 g / mol, 3500 g / mol, 4000 g / mol, 4500 g / mol or 5000 g / mol.

[0773] In some specific embodiments, n1 is in a range such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 1500 g / mol to about 2500 g / mol; more preferably, has an average molecular weight of 2000 g / mol.

[0774] In some preferred embodiments, R1 is C 1-3 Alkyl, preferably -CH3.

[0775] In some preferred embodiments, R2, R3, and R4 are independently selected from

[0776] In some preferred embodiments, the polymer-conjugated lipid of formula (IIP-A1) or formula (IIIP-A1) is a compound of formula (IVP-A1) or formula (VP-A1),

[0777] or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0778] in,

[0779] o', p', q' are each optionally 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.

[0780] In some specific embodiments, the polymer-conjugated lipid of formula (IV) is

[0781] Among them, R 21 、R 31 Independently selected from C 18-26 Alkyl, C 18-26 Alkenyl, C 18-26 alkynyl, which is optionally substituted with one or more Rv;

[0782] Preferably, R 21 、R 31 Independently selected from linear C 18-26 Alkyl, straight chain C 18-26 Alkenyl and straight chain C 18-26 Alkynyl.

[0783] In some specific embodiments, the polymer-conjugated lipid is selected from one or more of the following compounds:

[0784] wherein n1 is each independently an integer of 10-120; preferably an integer of 30-80; 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, 144 or 120, more preferably 44, 80 or 114;

[0785] Preferably, n1 ranges from 400 g / mol to about 6000 g / mol of the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1); for example, 2000 g / mol, 2500 g / mol, 3000 g / mol, 3500 g / mol, 4000 g / mol, 4500 g / mol, or 5000 g / mol; more preferably, from 1500 g / mol to about 2500 g / mol; and even more preferably, from 2000 g / mol.

[0786] In some specific embodiments, the polymer-conjugated lipid compound of formula (IV) or formula (V) is:

[0787] In another aspect, the present invention provides a lipid nanoparticle comprising the polymer-conjugated lipid of the present invention.

[0788] In some embodiments, the lipid nanoparticles contain the following lipid components in molar percentages: 25 mol%-80 mol% of ionizable lipids; 3 mol%-60 mol% of structural lipids; 0.5 mol%-60 mol% of phospholipids;

[0789] The polymer conjugated lipid represented by formula (IV) or formula (V) is 0.25 mol% to 10 mol%.

[0790] The ionizable lipids, structural lipids, and phospholipids are defined as above. The content of each component in the lipid nanoparticles is consistent with that of the lipid nanoparticles described above.

[0791] In another aspect, the present invention provides a use of the polymer-conjugated lipid compound or the lipid nanoparticle of the present invention in any of the following fields:

[0792] i. Preparation of drugs for targeting muscles;

[0793] ii. Preparation of drug delivery payload

[0794] iii. Preparation of a medicament for treating muscle diseases or muscle-related diseases;

[0795] iv. Use in the preparation of a medicament for delivering a gene product to the muscle of a subject, wherein the gene product is a medicament for gene editing, protein replacement and / or supplementation, or gene interference.

[0796] In another aspect, the present invention provides a compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

[0797] In the present application, in the polymer-conjugated lipid compound, each variable may be defined as follows.

[0798] L

[0799] 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)-.

[0800] 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-.

[0801] 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-.

[0802] 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.

[0803] 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 -NHC(O)-, -OC(O)-, -C(O)-, -OC(O)O- 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 absent; in another more specific embodiment, L is selected from Or does not exist.

[0804] 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.

[0805] L2

[0806] In one embodiment, L2 is absent or CH2; in one embodiment, L2 is absent; in another embodiment, L2 is CH2.

[0807] Q 11

[0808] 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-.

[0809] 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)-.

[0810] R w

[0811] In one embodiment, R w is H; in another embodiment, R w for

[0812] R 11

[0813] 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.

[0814] 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 11C 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.

[0815] 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.

[0816] In a specific embodiment, R 11 H, C 1-30 Alkyl or C 3-14 Cycloalkyl; in another specific embodiment, R 11 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.

[0817] n1

[0818] 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.

[0819] 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.

[0820] 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.

[0821] 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.

[0822] R w

[0823] 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

[0824] Q 11

[0825] 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-.

[0826] 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)-.

[0827] R 21 、R 31 、R 41

[0828] 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 Not replaced.

[0829] In one embodiment, R 31 C5-30 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 20-26 alkenyl; 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 C5-26 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 Not replaced.

[0830] 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 C 17-26 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 C13 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 C 18-26 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 VSubstituted; in another embodiment, R 41 Optionally replaced by 1 R V Substituted; in another embodiment, R 41 Not replaced.

[0831] 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 C 14-26 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 、R41 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.

[0832] 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.

[0833] 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 31By 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.

[0834] In one embodiment, R 21 、R 31 and R 41 Not R V replace.

[0835] Rv

[0836] 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 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 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 C10-26 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 .

[0837] 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, 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 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, RV Independently C 10-26 alkyl.

[0838] L c1 、R c1 and R' c1

[0839] 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;

[0840] 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.

[0841] 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 It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0842] 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 C1-6 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;

[0843] 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.

[0844] 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.

[0845] o', p', and q'

[0846] 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.

[0847] 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.

[0848] 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.

[0849] 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.

[0850] 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.

[0851] In a more specific embodiment, q' is independently an integer from 0 to 10, for example, 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, for example, 0, 1, 2, 3, 4, 5; in another more specific embodiment, q' is independently an integer from 0 to 3, for example, 0, 1, 2, 3.

[0852] Beneficial effects of the present invention:

[0853] The present invention provides a lipid nanoparticle. By combining polymer-conjugated lipids with ionizable lipids, structural lipids and phospholipids, the lipid nanoparticles are distributed to muscles / to isolated liver at a ratio of greater than 1, greater than 2, greater than 5, greater than 10, greater than 20, greater than 30, greater than 50 or greater than 100 after systemic administration, especially systemic injection administration, thereby achieving targeted delivery to muscles.

[0854] Example

[0855] In order to make the technical solution of the present invention clearer and more specific, the present invention is further described in detail by the following examples. The following examples are only used to illustrate the specific embodiments of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, the technical means or methods not specifically described are conventional technical means or methods in the art. The materials, reagents, etc. used in the examples, unless otherwise specified, can be obtained from commercial sources.

[0856] abbreviation:

[0857] Example 1: Synthesis of compounds

[0858] Preparation Example 1: Synthesis of Compound 136

[0859] In a 100 mL sealed tube, add 4-dimethylamino-1-butanol (3.0 g, 25.5 mmol, 1.0 eq.) and thiourea (8.4 g, 110.0 mmol, 4.3 eq.) and then add an aqueous solution of HBr (48%, 60 mL). Heat to 120°C and stir overnight. The mixture was directly used in the next step without purification.

[0860] The system was cooled to 0°C, and NaOH (10.2 g, 255.0 mmol, 10.0 eq.) was added portionwise. The mixture was heated to 120°C and reacted for 2 hours. The mixture was cooled to room temperature and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The solvent was removed to obtain 2.45 g of compound 136-3 as a colorless oil.

[0861] In a 100 mL three-necked flask, compound 136-4 (1.26 g, 5.0 mmol, 1.0 eq.), 1-nonanol (0.72 g, 5.0 mmol, 1.0 eq.), EDCI (1.44 g, 7.5 mmol, 1.5 eq.), and DMAP (0.31 g, 2.5 mmol, 0.5 eq.) were added and dissolved in 20 mL of dichloromethane. The mixture was stirred at room temperature overnight, extracted with dichloromethane, and washed with water (3 x 20 mL). The combined organic phases were evaporated under reduced pressure and directly mixed. Purification on a silica gel column gave 1.6 g of compound 136-5.

[0862] In a 100 mL three-necked flask, compound 136-6 (1.5 g, 5.8 mmol, 1.0 eq.), 2-heptyl-1-nonanol (1.40 g, 5.8 mmol, 1.0 eq.), EDCI (1.66 g, 8.7 mmol, 1.5 eq.), and DMAP (0.35 g, 2.9 mmol, 0.5 eq.) were dissolved in 20 mL of dichloromethane and stirred at room temperature overnight. The mixture was washed with water (3 x 15 mL). The organic phase was then rotary evaporated under reduced pressure and directly mixed. Purification by silica gel column chromatography afforded 3.3 g of compound 136-7.

[0863] Compound 136-7 (2.8 g, 5.8 mmol, 1.0 eq.) was dissolved in 20 mL of dichloromethane in a 100 mL three-necked flask. HCl / dioxane (4 M, 14 mL) was added and stirred at room temperature overnight. The organic solvent was removed by rotary evaporation, and the reaction solution was adjusted to neutral with saturated sodium bicarbonate solution. The reaction solution was extracted with DCM (3 x 20 mL). The organic phase was collected, dried over anhydrous Na2SO4, and purified on a silica gel column to obtain 1.95 g of compound 136-8.

[0864] In a 40 mL sealed tube, compound 136-8 (680 mg, 1.8 mmol, 1.0 eq.), KI (365 mg, 2.2 mmol, 1.2 eq.), KCO (745 mg, 5.4 mmol, 3.0 eq.), and compound 136-5 (668.9 mg, 1.8 mmol, 1.0 eq.) were dissolved in 10 mL of acetonitrile and heated to 80°C with stirring overnight. After the reaction, the mixture was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (2 x 5 mL). The filtrate was collected, dried, and purified by column chromatography to obtain 580 mg of compound 136-9 as a yellow oil.

[0865] Compound 136-9 (200 mg, 0.29 mmol, 1.0 eq.) was dissolved in 5 mL of The reaction system was cooled to 5°C and TEA (59.5 mg, 0.59 mmol, 2.0 eq.) and BTC (87.3 mg, 0.29 mmol, 1.0 eq.) were added dropwise. The reaction mixture was stirred at 5°C for 1 hour. After concentration to remove DCM, 5 mL of tetrahydrofuran was added. In another 20 mL sealed tube, compound 136-3 (101.9 mg, 0.76 mmol, 2.6 eq.) was dissolved in 5 mL of tetrahydrofuran and cooled to 0°C. NaH (60%, 58.0 mg, 1.45 mmol, 5.0 eq.) was added. After stirring at 0°C for 1 hour, the THF mixed solution prepared above was added dropwise. The reaction was continued for 1 hour. The reaction solution was poured into 10 mL of ice water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to remove the desiccant. The solvent was removed to obtain the crude product, which was purified by Prep-HPLC (Column: XSelect C18 (30×150 mm, 5 μm); Eluent A: H2O / ACN 60 / 40, 10 mM NH4HCO3 + 1% NH3·H2O; Eluent B: IPA / ACN 90 / 10; Flow rate: 60 mL / min; Gradient program: 65%-85% B in 0-12 min) to give 126.9 mg of compound 136 as a light yellow oil.

[0866] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J = 6.6 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.36-3.15 (m, 4H), 2.90 (t, J=6.9Hz,2H),2.41(s,2H),2.31-2.24(m,10H),1.64-1.16(m,61H),0.93-0.77(m,15H); ESI-MS m / z:839.65[M+H] + .

[0867] Preparation Example 2: Synthesis of Compound M2

[0868] Compound M2 was prepared by referring to the method of Preparation Example 1 to obtain 157.3 mg of an oily product.

[0869] 1H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 4.06 (t, J = 6.9Hz, 2H), 3.37-3.17 (m, 4H), 2 .90(t,J=6.9Hz,2H),2.39-2.25(m,12H),1.79-1.18(m,70H),0.93-0.83(m,15H); ESI-MS m / z:895.80[M+H] + .

[0870] Preparation Example 3: Synthesis of Compound M3

[0871] Compound M3 was prepared by referring to the method of Preparation Example 1 to obtain 184.0 mg of an oily product.

[0872] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J=6.9Hz, 2H), 3.96 (d, J=5.7Hz, 2H), 3.35-3.18 (m, 4H), 2.91 (t, J= 7.2Hz,2H),2.43-2.27(m,12H),1.87-1.77(m,2H),1.61-1.18(m,57H),0.93-0.84(m,15H); ESI-MS m / z:825.55[M+H] + .

[0873] Preparation Example 4: Synthesis of Compound M4

[0874] Compound M4 was prepared by referring to the method of Preparation Example 1 to obtain 103.2 mg of an oily product.

[0875] 1 H NMR (300MHz, CDCl3) δ: 4.07 (q, J=6.9Hz, 4H), 3.26 (m, 4H), 2.90 (t, J=6.9Hz, 2H), 2.54-2.42 (m, 5H), 2.30 (q, J = 7.8Hz, 5H), 1.74-1.52 (m, 16H), 1.42-1.22 (m, 45H), 0.93-0.83 (m, 15H); ESI-MS m / z:825.65[M+H] + .

[0876] Preparation Example 5: Synthesis of Compound M5

[0877] Compound M5 was prepared by referring to the method of Preparation Example 1 to obtain 82.3 mg of an oily product.

[0878] 1 H NMR (300MHz, CDCl3) δ: 4.05 (td, J=6.9, 5.4Hz, 4H), 3.26 (m, 4H), 2.97 -2.85(m,2H),2.40-2.30(m,10H),1.60(m,14H),1.34-1.21(m,45H),0.94-0.83(m,15H); ESI-MS m / z:811.70[M+H] + .

[0879] Preparation Example 6: Synthesis of Compound M6

[0880] Compound M6 was prepared by referring to the method of Preparation Example 1 to obtain 42.7 mg of an oily product.

[0881] 1 H NMR (300MHz, CDCl3) δ: 4.06 (t, J = 6.9 Hz, 4H), 3.26 (m, 4H), 2.90 (t, J = 7.2 Hz, 2H), 2.62 (m, 6H), 2.30 (q, J=7.0Hz, 4H), 1.59 (m, 14H), 1.42-1.15 (m, 43H), 0.94-0.84 (m, 15H); ESI-MS m / z:797.65[M+H] + .

[0882] Preparation Example 7: Synthesis of Compound M7

[0883] Compound M7 was prepared by referring to the method of Preparation Example 1 to obtain 145.3 mg of an oily product.

[0884] 1 H NMR (300MHz, CDCl3) δ: 4.05 (q, J = 6.6Hz, 4H), 3.26 (m, 4H), 2.95-2.85 (m, 2H), 2.42 -2.26(m,10H),1.64-1.59(m,14H),1.33-1.10(m,51H),0.93-0.83(m,15H); ESI-MS m / z:853.70[M+H] + .

[0885] Preparation Example 8: Synthesis of Compound M8

[0886] Compound M8 was prepared by referring to the method of Preparation Example 1 to obtain 125.4 mg of an oily product.

[0887] 1H NMR (300MHz, CDCl3) δ: 4.06 (t, J = 6.6 Hz, 4H), 3.26 (m, 4H), 2.90 (t, J = 6.6 Hz, 2H), 2.4 7-2.27(m,10H),1.68-1.60(m,16H),1.39-1.27(m,47H),0.94-0.83(m,15H); ESI-MS m / z:840.10[M+H] + .

[0888] Preparation Example 9: Synthesis of Compound M9

[0889] Compound M9 was prepared by referring to the method of Preparation Example 1 to obtain 120.4 mg of an oily product.

[0890] 1 H NMR (300MHz, CD3OD) δ: 4.06 (td, J=6.6, 3.6Hz, 4H), 3.31 (p, J=1.5Hz, 2H), 2.96-2.85 (m, 2H ),2.45-2.18(m,12H),1.65-1.58(m,14H),1.34-1.17(m,47H),0.95-0.85(m,15H); ESI-MS m / z:825.70[M+H] + .

[0891] Preparation Example 10: Synthesis of Compound 139

[0892] Compound 139 was prepared by referring to the method of Preparation Example 1 to obtain 228 mg of an oily product.

[0893] 1 H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 3.78 (s, 2H), 3.33-3.18 (m, 4H), 2.90 (t, J = 6.6Hz ,2H),2.38-2.25(m,12H),1.69-1.44(m,16H),1.34-1.17(m,48H),0.90-0.85(m,15H); ESI-MS m / z:853.65[M+H] + .

[0894] Preparation Example 11: Synthesis of Compound M11

[0895] Compound M11 was prepared by referring to the method of Preparation Example 1 to obtain 117.9 mg of an oily product.

[0896] 1H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 3.78 (s, 2H), 3.36-3.17 (m, 4H), 2.92 (t, J = 7.2Hz, 2H), 2.46 (t, J = 7.2 Hz,2H),2.34-2.22(m,10H),1.90-1.80(m,3H),1.62-1.49(m,14H),1.34-1.17(m,51H),0.93-0.86(m,15H); ESI-MS m / z:881.65[M+H] + .

[0897] Preparation Example 12: Synthesis of Compound M12

[0898] Compound M12 was prepared by referring to the method of Preparation Example 1 to obtain 75.3 mg of an oily product.

[0899] 1 H NMR (300MHz, CDCl3) δ: 4.86 (p, J = 6.3Hz, 1H), 3.78 (s, 2H), 3.36-3.17 (m, 4H), 2.91 (t, J = 6.6Hz ,2H),2.48-2.28(m,12H),1.89-1.60(m,10H),1.51-1.16(m,60H),0.93-0.87(m,15H); ESI-MS m / z:895.70[M+H] + .

[0900] Preparation Example 13: Synthesis of Compound M13

[0901] Compound M13 was prepared by referring to the method of Preparation Example 1 to obtain 95.1 mg of an oily product.

[0902] 1 H NMR (400MHz, CDCl3) δ: 4.86 (p, J = 6.4Hz, 1H), 4.09 (t, J = 7.6Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 7 .6Hz,2H),2.40-2.26(m,12H),1.63-1.50(m,21H),1.32-1.16(m,49H),0.90-0.86(m,15H); ESI-MS m / z:895.80[M+H] + .

[0903] Preparation Example 14: Synthesis of Compound M14

[0904] Compound M14 was prepared by referring to the method of Preparation Example 1 to obtain 63.6 mg of an oily product.

[0905] 1 H NMR (400MHz, CDCl3) δ: 4.09 (p, J = 7.6Hz, 2H), 3.96 (d, J = 6.0Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 7 .2Hz,2H),2.57-2.26(m,12H),1.67-1.43(m,20H),1.32-1.16(m,41H),0.90-0.86(m,15H); ESI-MS m / z:839.70[M+H] + .

[0906] Preparation Example 15: Synthesis of Compound M15

[0907] Compound M15 was prepared by referring to the method of Preparation Example 1 to obtain 70.5 mg of an oily product.

[0908] 1 H NMR(300MHz,CD3OD)δ:4.12(t,J=7.2Hz,2H),4.05(t,J=6.6Hz,2H),3.35(s,2H),2.90(t,J=6.6 Hz,2H),2.40-2.26(m,12H),1.62-1.56(m,16H),1.39-1.21(m,43H),0.98-0.84(m,15H); ESI-MS m / z:811.80[M+H] + .

[0909] Preparation Example 16: Synthesis of Compound M16

[0910] Compound M16 was prepared by referring to the method of Preparation Example 1 to obtain 46.4 mg of an oily product.

[0911] 1 H NMR(400MHz,CD3OD)δ:4.12(t,J=7.2Hz,2H),4.07(t,J=6.4Hz,2H),3.35(m,2H),2.92-2.83(m ,2H),2.39-2.26(m,12H),1.64-1.51(m,16H),1.44-1.21(m,41H),0.95-0.86(m,15H); ESI-MS m / z:797.65[M+H] + .

[0912] Preparation Example 17: Synthesis of Compound M17

[0913] Compound M17 was prepared by referring to the method of Preparation Example 1 to obtain 34.8 mg of an oily product.

[0914] 1 H NMR(300MHz, CDCl3)δ:4.12-4.03(m,4H),3.31(m,4H),3.06-2.78(m,10H),2.32-2.25(m,4 H),2.00-1.95(m,2H),1.62-1.56(m,14H),1.44-1.21(m,37H),0.94-0.85(m,15H); ESI-MS m / z:783.60[M+H] + .

[0915] Preparation Example 18: Synthesis of Compound M18

[0916] 18-1 (5.0 g, 22.40 mmol, 1.0 eq.) and decanoic acid (5.0 g, 29.12 mmol, 1.3 eq.) were added to a DMF (50 mL) solution. Potassium carbonate (9.3 g, 67.21 mmol, 3.0 eq.) was added under nitrogen protection and stirring was continued at 70°C for 2 hours. After the reaction was completed, it was cooled to room temperature and diluted with 100 mL of water. It was then extracted with dichloromethane (3 x 300 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 300 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was removed by rotary evaporation to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain compound 18-2 (7.7 g) as a yellow oil.

[0917] 18-2 (7.7 g, 24.48 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (80 mL), and triphenylphosphine (25.6 g, 97.93 mmol, 4.0 eq.) and carbon tetrabromide (32.4 g, 97.93 mmol, 4.0 eq.) were added under nitrogen protection. The mixture was stirred at room temperature for 5 hours, filtered, and the filtrate was diluted with 100 ml of water, then extracted with ethyl acetate (3×300 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (3×300 mL), dried over anhydrous sodium sulfate, and filtered to collect the organic phase. The organic solvent was removed by rotary evaporation to obtain a crude product, which was purified by silica gel column to obtain compound 18-3 (8.9 g) as a light yellow oil.

[0918] 18-3 (4.0 g, 10.59 mmol, 1.0 eq.) was dissolved in 40 mL of acetonitrile, and benzylamine (2.2 g, 21.19 mmol, 2.0 eq.) was added under ice-cooling conditions. The reaction was incubated at 50°C under nitrogen for 16 h. After completion of the reaction, the mixture was cooled to room temperature and diluted with 50 mL of water. The mixture was then extracted with dichloromethane (3 x 100 mL). The combined organic phases were washed with saturated sodium chloride aqueous solution (3 x 100 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to obtain the crude product. The crude product was purified on a silica gel column to obtain compound 18-4 (3.1 g) as a colorless oil.

[0919] 18-4 (1.0 g, 2.47 mmol, 1.0 eq.) was dissolved in 10.0 mL of DMF. Under nitrogen protection, 18-5 (1.2 g, 2.97 mmol, 1.2 eq.), potassium carbonate (1.0 g, 7.43 mmol, 3.0 eq.), and sodium iodide (0.9 g, 6.19 mmol, 2.5 eq.) were added in sequence. The mixture was stirred at 70°C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with 10 mL of water, and then extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered to collect the organic phase. The organic solvent was removed by rotary evaporation to obtain the crude product. The yellow oily compound 18-6 (1.5 g) was obtained by purification on a silica gel column.

[0920] 18-6 (1.5 g, 2.06 mmol, 1.0 eq.) was dissolved in 15 mL of ethanol, and palladium carbon (700.0 mg) was added at room temperature under hydrogen protection. The reaction was allowed to proceed overnight at room temperature under hydrogen atmosphere. The palladium carbon was removed by filtration, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain a crude product, which was used directly in the next step without purification to obtain a colorless oily compound 18-7 (1.1 g);

[0921] 18-7 (260 mg, 0.39 mmol, 1.0 eq.) was dissolved in 2 mL of dichloromethane, and triphosgene (81.07 mg, 0.27 mmol, 0.7 eq.) and triethylamine (118.49 mg, 1.17 mmol, 3.0 eq.) were added under ice-bath conditions. The mixture was stirred at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure. The above concentrate and 4-dimethylamino-1-butanethiol (259.4 mg, 1.93 mmol, 5.0 eq.) were dissolved in 5 mL of tetrahydrofuran, and sodium hydroxide (124.89 mg, 1.93 mmol, 5.0 eq.) was added in sequence under ice-bath conditions. , 3.12 mmol, 8.0 eq.), pyridine (92.62 mg, 1.17 mmol, 3.0 eq.) and 4-dimethylaminopyridine (95.37 mg, 0.78 mmol, 2.0 eq.) were added and stirred at room temperature for 3 hours. After the reaction was completed, 10 mL of water was added to dilute the mixture, followed by extraction with ethyl acetate (3×50 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (3×50 mL), and dried over anhydrous sodium sulfate. The organic phases were collected by filtration, and the organic solvent was removed by rotary evaporation to obtain the crude product. The crude product was purified by HPLC (column: YMC-Actus Triart C820X150 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 M18 (71.4 mg) as a yellow oil.

[0922] 1 H NMR(400MHz,CD3OD)δ:0.86-0.95(m,15H),1.26-1.43(m,45H),1.59-1.61(m,14H),2.26(s, 6H),2.29-2.39(m,6H),2.90(t,J=6.8Hz,2H),3.29-3.32(m,4H),4.07-4.12(m,4H); ESI-MS m / z:825.70[M+H] + .

[0923] Preparation Example 19: Synthesis of Compound M19

[0924] Compound M19 was prepared by referring to the method of Preparation Example 18 to obtain 72.0 mg of an oily product.

[0925] 1H NMR(300MHz,CD3OD)δ:0.90-0.92(m,15H),1.28-1.34(m,41H),1.43-1.61(m,16H),2.25(s, 6H),2.29-2.39(m,6H),2.90(t,J=6.6Hz,2H),3.29-3.31(m,4H),4.03-4.11(m,4H); ESI-MS m / z:811.90[M+H] + .

[0926] Preparation Example 20: Synthesis of Compound M20

[0927] Compound M20 was prepared by referring to the method of Preparation Example 18 to obtain 74.5 mg of an oily product.

[0928] 1 H NMR(400MHz,CD3OD)δ:0.88-0.92(m,15H),1.21-1.35(m,40H),1.45-1.62(m,15H),2.27(s,6 H),2.29-2.40(m,6H),2.90(t,J=6.4Hz,2H),3.29-3.31(m,4H),4.08(q,J=6.8Hz,4H); ESI-MS m / z:797.70[M+H] + .

[0929] Preparation Example 21: Synthesis of Compound M21

[0930] Compound M21 was prepared by referring to the method of Preparation Example 18 to obtain 77.1 mg of an oily product.

[0931] 1 H NMR(300MHz, CDCl3)δ:0.82-0.95(m,15H),1.14-1.40(m,41H),1.45-1.85(m,18H),2. 26-2.69(m,12H),2.90(t,J=6.9Hz,2H),3.19-3.37(m,4H),4.03-4.09(m,4H); ESI-MS m / z:825.95[M+H] + .

[0932] Preparation Example 22: Synthesis of Compound M22

[0933] Compound M22 was prepared by referring to the method of Preparation Example 18 to obtain 98.9 mg of an oily product.

[0934] 1 H NMR(300MHz,CD3OD)δ:0.85-0.92(m,15H),1.21-1.62(m,61H),2.25(s,6H),2.29-2.38( m,6H),2.90(t,J=6.9Hz,2H),3.29-3.32(m,4H),4.07(dd,J=6.3Hz,11.7Hz,4H); ESI-MS m / z:839.95[M+H] + .

[0935] Preparation Example 23: Synthesis of Compound M23

[0936] Compound M23 was prepared by referring to the method of Preparation Example 18 to obtain 130.5 mg of an oily product.

[0937] 1 H NMR (300MHz, CDCl3) δ: 3.96 (d, J = 6.0Hz, 2H), 3.89 (s, 2H), 3.35-3.18 (m, 4H), 2.91 (t, J = 7.2Hz, 2H), 2.44-2.28 ( m,12H),1.87-1.79(m,2H),1.77-1.60(m,10H),1.34-1.17(m,47H),0.90-0.85(m,9H),0.52-0.32(m,4H); ESI-MS m / z:823.60[M+H] + .

[0938] Preparation Example 24: Synthesis of Compound M24

[0939] Compound M24 was prepared by referring to the method of Preparation Example 18 to obtain 79.4 mg of an oily product.

[0940] 1 H NMR (300MHz, CDCl3) δ: 3.95 (d, J = 5.7Hz, 2H), 3.90 (s, 2H), 3.35-3.19 (m, 4H), 2.90 (t, J = 7.2Hz, 2H), 2.67 (s, 4H),2.34-2.27(m,4H),1.72-1.51(m,16H),1.29-1.21(m,49H),0.90-0.83(m,9H),0.46-0.36(m,4H); ESI-MS m / z:837.75[M+H] + .

[0941] Preparation Example 25: Synthesis of Compound M25

[0942] Compound M25 was prepared by referring to the method of Preparation Example 18 to obtain 67.0 mg of an oily product.

[0943] 1 H NMR (300MHz, CD3OD) δ: 4.05 (t, J = 6.9 Hz, 2H), 3.92 (s, 2H), 3.32 (s, 2H), 2.92-2.88 (m, 2H), 2.41-2.25 (m,12H),1.71-1.48(m,14H),1.34-1.25(m,45H),0.98-0.83(m,9H),0.47(m,2H),0.39(m,2H); ESI-MS m / z:809.75[M+H] + .

[0944] Preparation Example 26: Synthesis of Compound M26

[0945] Compound M26 was prepared by referring to the method of Preparation Example 18 to obtain 33.5 mg of an oily product.

[0946] 1 H NMR(400MHz,CD3OD)δ:4.07(t,J=6.4Hz,2H),3.92(s,2H),3.34(s,2H),2.90(t,J=6.8Hz,2H),2.40-2.32(m,6H) ,2.27(s,6H),1.60(m,16H),1.40-1.18(m,41H),0.93-0.88(m,9H),0.48-0.46(m,2H),0.43-0.39(m,2H); ESI-MS m / z:795.70[M+H] + .

[0947] Preparation Example 27: Synthesis of Compound M27

[0948] Compound M27 was prepared by referring to the method of Preparation Example 18 to obtain 32.0 mg of an oily product.

[0949] 1H NMR (300MHz, CDCl3) δ: 4.05 (t, J = 6.6 Hz, 2H), 3.90 (s, 2H), 3.24 (s, 4H), 2.96-2.75 (m, 8H), 2.30 (q, J = 7 .2Hz,4H),1.74-1.62(m,18H),1.32-1.18(s,37H),0.93-0.82(m,9H),0.46(m,2H),0.36(m,2H); ESI-MS m / z:781.65[M+H] + .

[0950] Preparation Example 28: Synthesis of Compound M28

[0951] Compound M28 was prepared by referring to the method of Preparation Example 18 to obtain 41 mg of an oily product.

[0952] 1 H NMR (400MHz, CDCl3) δ: 4.13 (s, 2H), 3.96 (d, J = 6.0Hz, 2H), 3.31-3.24 (m, 4H), 2.90 (t, J = 6.8Hz, 2H), 2. 54-2.26(m,10H),1.67-1.45(m,18H),1.29-1.21(m,45H),0.90-0.82(m,9H),0.32-0.29(m,4H); ESI-MS m / z:837.70[M+H] + .

[0953] Preparation Example 29: Synthesis of Compound M29

[0954] Compound M29 was prepared by referring to the method of Preparation Example 18 to obtain 68.8 mg of an oily product.

[0955] 1 H NMR(300MHz,CD3OD)δ:0.26(m,4H),0.86-0.96(m,9H),1.24-1.41(m,41H),1.61-1.74(m,16H),2. 27(s,6H),2.29-2.41(m,6H),2.90(t,J=6.6Hz,2H),3.32-3.41(m,4H),4.03-4.09(m,4H); ESI-MS m / z:809.65[M+H] + .

[0956] Preparation Example 30: Synthesis of Compound M30

[0957] Compound M30 was prepared by referring to the method of Preparation Example 18 to obtain 86.5 mg of an oily product.

[0958] 1 H NMR(300MHz,CD3OD)δ:0.21-0.28(m,4H),0.86-0.95(m,9H),1.21-1.45(m,39H),1.61-1.74(m,16H) ,2.22(s,6H),2.25-2.39(m,6H),2.90(t,J=6.6Hz,2H),3.30-3.35(m,4H),4.04-4.11(m,4H); ESI-MS m / z:795.70[M+H] + .

[0959] Preparation Example 31: Synthesis of Compound M31

[0960] Compound M31 was prepared by referring to the method of Preparation Example 18 to obtain 86.5 mg of an oily product.

[0961] 1 H NMR(300MHz,CD3OD)δ:0.27(m,4H),0.81-0.96(m,9H),1.27-1.34(m,37H),1.59-1.74(m,16H),2.2 5(s,6H),2.28-2.38(m,6H),2.90(t,J=6.6Hz,2H),3.31-3.35(m,4H),4.06(t,J=6.6Hz,4H); ESI-MS m / z:781.85[M+H] + .

[0962] Preparation Example 32: Synthesis of Compound M32

[0963] Under nitrogen protection, compound 32-1 (1.0 g, 4.60 mmol, 1.0 eq.), pyridine (0.74 mL, 9.2 mmol, 2.0 eq.), DMAP (112.4 mg, 0.92 mmol, 0.2 eq.), and p-nitrophenyl chloroformate (1.11 g, 5.52 mmol, 1.2 eq.) were dissolved in 20 mL of dichloromethane in a 100 mL three-necked round-bottom flask at room temperature. After stirring the reaction system at room temperature for 1 hour, 2-nonyl-1-decanol (3.93 g, 13.8 mmol, 3.0 eq.) and DIEA (2.40 mL, 13.8 mmol, 3.0 eq.) were added to the reaction system. The reaction system was stirred at room temperature overnight. TLC monitoring of the reaction revealed a new product. DCM (20 mL) was added for dilution and the mixture was washed once with saturated sodium bicarbonate solution (10 mL). The organic phase was washed twice with saturated NaCl solution (40 mL), dried over anhydrous NaSO, filtered, and concentrated. The crude product was purified on a silica gel column to afford compound 32-2 (1.68 g) as a light yellow oil.

[0964] Compound M32 was prepared by referring to the method of Preparation Example 1 to obtain 78.5 mg of an oily product.

[0965] 1 H NMR (300MHz, CDCl3) δ: 4.68 (p, J = 6.0Hz, 1H), 4.11 (t, J = 6.6Hz, 2H), 3.78 (s, 2H), 3.36-3.22 (m, 4H), 2.90 (t,J=6.9Hz,2H),2.47-2.29(m,10H),1.70-1.56(m,18H),1.29-1.21(m,50H),0.90-0.86(m,15H); ESI-MS m / z:897.70[M+H] + .

[0966] Preparation Example 33: Synthesis of Compound M33

[0967] Compound M33 was prepared by referring to the method of Preparation Example 32 to obtain 189.8 mg of an oily product.

[0968] 1H NMR (400MHz, CDCl3) δ: 4.12 (t, J = 6.4Hz, 2H), 4.02 (d, J = 5.6Hz, 2H), 3.78 (s, 2H), 3.32-3.24 (m, 4H), 2.92 (t, J = 7.2 Hz,2H),2.47-2.30(m,10H),1.85-1.84(m,2H),1.66-1.40(m,7H),1.26-1.18(m,48H),0.93-0.88(m,15H); ESI-MS m / z:827.55[M+H] + .

[0969] Preparation Example 34: Synthesis of Compound M34

[0970] Compound M34 was prepared by referring to the method of Preparation Example 32 to obtain 129.4 mg of an oily product.

[0971] 1 H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.6 Hz, 2H), 4.02 (d, J = 5.7 Hz, 2H), 3.78 (s, 2H), 3.36-3.21 (m, 4H), 2.90 (t,J=6.9Hz,2H),2.36-2.26(m,10H),1.63-1.41(m,13H),1.26-1.18(m,46H),0.89-0.86(m,15H); ESI-MS m / z:841.65[M+H] + .

[0972] Preparation Example 35: Synthesis of Compound M35

[0973] Compound M35 was prepared by referring to the method of Preparation Example 32 to obtain 135.6 mg of an oily product.

[0974] 1 H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.3Hz, 2H), 4.02 (d, J = 5.7Hz, 2H), 3.89 (s, 2H), 3.31-3.22 (m, 4H), 2.90 (t, J = 6.9 Hz,2H),2.34-2.26(m,10H),1.65-1.48(m,13H),1.27-1.19(m,46H),0.90-0.86(m,9H),0.45-0.35(m,4H); ESI-MS m / z:839.50[M+H] + .

[0975] Preparation Example 36: Synthesis of Compound M36

[0976] Compound M36 was prepared by referring to the method of Preparation Example 32 to obtain 123.1 mg of an oily product.

[0977] 1 H NMR (300MHz, CDCl3) δ: 4.12 (t, J = 6.6 Hz, 2H), 4.02 (t, J = 6.6 Hz, 2H), 3.84 (s, 2H), 3.34-3.19 (m, 4H), 2.90 (t, J = 6 .6Hz,2H),2.46-2.20(m,10H),1.84(m,2H),1.65-1.44(m,13H),1.27-1.19(m,46H),0.92-0.86(m,15H); ESI-MS m / z:855.60[M+H] + .

[0978] Preparation Example 37: Synthesis of Compound 133

[0979] 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.

[0980] 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.

[0981] 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.

[0982] 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.

[0983] 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 x 50 mL). The organic phases were combined, washed with saturated aqueous sodium chloride solution (3 x 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 column 19 x 250 mm, 5 μmn; 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 give 82 mg of yellow oily compound 133.

[0984] 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] + .

[0985] Preparation Example 38: Synthesis of Compound M38

[0986] Referring to the method of Preparation Example 37, 138.0 mg of compound M38 was prepared as an oily product.

[0987] 1 H NMR (300MHz, CD3OD) δ: 0.86-0.94 (m, 15H), 1.18-1.42 (m, 45H), 1.49-1.74 (m, 13H), 2.33 (q, J = 7.5Hz, 4H), 2. 47(t,J=7.5Hz,4H),2.61(t,J=7.5Hz,2H),3.62(t,J=6.0Hz,2H),3.80(s,2H),4.10(t,J=6.6Hz,2H); ESI-MS m / z:724.75[M+H] + .

[0988] Preparation Example 39: Synthesis of Compound M39

[0989] Referring to the method of Preparation Example 37, 113.5 mg of compound M39 was prepared as an oily product.

[0990] 1 H NMR(300MHz,CD3OD)δ:0.88-0.97(m,15H),1.12-1.41(m,52H),1.50-1.63(m,14H),2.30-2.3 5(m,4H),2.48-2.53(m,6H),3.55(t,J=6.0Hz,2H),3.80(s,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:780.80[M+H] + .

[0991] Preparation Example 40: Synthesis of Compound M40

[0992] Referring to the method of Preparation Example 37, 90 mg of compound M40 was prepared as an oily product.

[0993] 1 H NMR(300MHz,CD3OD)δ:0.89-0.98(m,15H),1.22-1.34(m,40H),1.48-1.63(m,10H),2.32(q,J=7.5Hz,4H),2. 50(q,J=7.5Hz,4H),2.62(t,J=6.6Hz,2H),3.62(t,J=6.6Hz,2H),3.80(s,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:668.70[M+H] + .

[0994] Preparation Example 41: Synthesis of Compound 134

[0995] By referring to the method of Preparation Example 37, 174 mg of compound 134 was prepared as an oily product.

[0996] 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] + .

[0997] Preparation Example 42: Synthesis of Compound M42

[0998] Referring to the method of Preparation Example 37, 93.6 mg of compound M42 was prepared as an oily product.

[0999] 1 H NMR(300MHz, CDCl3)δ:0.88-0.94(m,15H),1.18-1.43(m,42H),1.51-1.65(m,14 H),2.28-2.32(m,4H),2.56-2.69(m,6H),3.62(m,2H),4.02-4.12(m,4H); ESI-MS m / z:710.70[M+H] + .

[1000] Preparation Example 43: Synthesis of Compound M43

[1001] Referring to the method of Preparation Example 37, 185.7 mg of compound M43 was prepared as an oily product.

[1002] 1 H NMR(300MHz,CD3OD)δ:0.89-0.96(m,15H),1.24-1.43(m,46H),1.57-1.61(m,14H),2.26-2.32(m ,4H),2.48-2.53(m,4H),2.62(t,J=6.3Hz,2H),3.61(t,J=6.6Hz,2H),4.08-4.14(m,4H); ESI-MS m / z:738.75[M+H] + .

[1003] Preparation Example 44: Synthesis of Compound M44

[1004] Referring to the method of Preparation Example 37, 177.7 mg of compound M44 was prepared as an oily product.

[1005] 1 H NMR (300MHz, CD3OD) δ: 0.89-0.95 (m, 15H), 1.23-1.73 (m, 62H), 2.30 (dt, J = 4.2Hz, 7.5Hz, 4H ),2.43-2.56(m,4H),2.61(t,J=6.9Hz,2H),3.62(t,J=6.0Hz,2H),4.08-4.14(m,4H); ESI-MS m / z:752.70[M+H] + .

[1006] Preparation Example 45: Synthesis of Compound M45

[1007] Dimethyl carbonate (10.7 g, 118.86 mmol, 3.0 eq.) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. Under nitrogen, sodium hydride (2.8 g, 118.86 mmol, 3.0 eq.) was added and stirred at 0°C for 1 hour. 4,4-Dimethylcyclohexanone (5.0 g, 39.62 mmol, 1.0 eq.) was then added and stirred at reflux for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and diluted with 100 mL of water. The mixture was then extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride (3 x 100 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was then removed by rotary evaporation to yield the crude product. Purification by silica gel column chromatography afforded compound 45-1 (5.0 g) as a yellow oil.

[1008] 45-1 (5.0 g, 27.139 mmol, 1.0 eq.) was dissolved in methanol (50 mL) and sodium methoxide (4.4 g, 81.417 mmol, 3.0 eq.) was added under nitrogen. The reaction was stirred at reflux for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with dichloromethane (3 x 200 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 100 mL), dried over anhydrous sodium sulfate, and filtered to collect the organic phase. The organic solvent was removed using a rotary evaporator to obtain compound 45-2 (5.0 g) as a yellow oil.

[1009] 45-2 (5.0 g, 23.12 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (50 mL) and, under nitrogen, borane tetrahydrofuran solution (50.0 mL) was added. The mixture was stirred at 75°C for 3 hours. After the reaction was completed, the mixture was cooled to 0°C and methanol (10 mL) was added to quench the reaction. The organic solvent was removed by rotary evaporation to obtain a crude product, which was then purified by silica gel column chromatography to obtain compound 45-3 (2.5 g) as a yellow oil.

[1010] 45-3 (1.5 g, 9.36 mmol, 1.0 eq.) was dissolved in dichloromethane (15 mL) and, under nitrogen, decanoic acid (1.8 g, 10.29 mmol, 1.1 eq.), EDCI (2.7 g, 14.04 mmol, 1.5 eq.) and N,N-dimethylaminopyridine (1.7 g, 14.04 mmol, 1.5 eq.) were added in sequence. The mixture was stirred at room temperature for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction solution 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 a crude product, which was purified by silica gel column to obtain a yellow oily compound 45-4 (1.5 g).

[1011] Compound 45-4 (1.5 g, 4.77 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (15 mL). Triphenylphosphine (3.7 g, 14.31 mmol, 3.0 eq.) and carbon tetrabromide (4.7 g, 14.31 mmol, 3.0 eq.) were added under nitrogen and stirred at room temperature for 5 hours. After completion, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was removed by rotary evaporation to obtain a crude product, which was then purified on a silica gel column to obtain compound 45-5 (1.5 g) as a yellow oil.

[1012] Referring to the method of Preparation Example 37, 95 mg of compound M45 was prepared as an oily product.

[1013] 1 H NMR(300MHz,DMSO-d6)δ:0.89-0.98(m,15H),1.18-1.55(m,46H),1.57-1.61(m,8H),2 .28-2.33(m,4H),2.45-2.64(m,6H),3.59(t,J=6.6Hz,2H),4.02-4.12(m,4H); ESI-MS m / z:696.65[M+H] + .

[1014] Preparation Example 46: Synthesis of Compound M46

[1015] Referring to the method of Preparation Example 45, 99.3 mg of compound M46 was prepared as an oily product.

[1016] 1 H NMR(400MHz,CD3OD)δ:0.89-0.96(m,15H),1.22-1.41(m,40H),1.46-1.63(m,12H),2.30(t,J=7.5 Hz,4H),2.44-2.52(m,4H),2.61(t,J=6.6Hz,2H),3.61(t,J=6.6Hz,2H),4.02-4.07(m,4H); ESI-MS m / z:682.65[M+H] + .

[1017] Preparation Example 47: Synthesis of Compound M47

[1018] Referring to the method of Preparation Example 45, 92.2 mg of compound M47 was prepared as an oily product.

[1019] 1 H NMR (400MHz, CD3OD) δ: 0.91-0.99 (m, 15H), 1.17-1.70 (m, 56H), 2.30-2.34 (m, 4H), 2.42-2.63 (m, 6H), 3.63 (t, J = 6.6Hz, 2H), 4.03-4.13 (m, 4H); ESI-MS m / z:710.65[M+H] + .

[1020] Preparation Example 48: Synthesis of Compound M48

[1021] Referring to the method of Preparation Example 45, 94 mg of compound M48 was prepared as an oily product.

[1022] 1 H NMR (400MHz, CD3OD) δ: 0.93-0.99 (m, 15H), 1.19-1.64 (m, 56H), 2.29-2.34 (m, 4H), 2.42-2.51 (m, 6H), 3.55 (t, J = 5.7Hz, 2H), 4.02-4.08 (m, 4H); ESI-MS m / z:710.75[M+H] + .

[1023] Preparation Example 49: Synthesis of Compound M49

[1024] Isopropylidene diethyl malonate (10.0 g, 49.94 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (50 mL) and cuprous chloride (500 mg, 5.0 mmol, 0.1 eq.) and 3-butenyl magnesium bromide (76.0 mL, 74.92 mmol, 1.5 eq.) were added at -30 ° C under nitrogen protection. The reaction was stirred at room temperature for 12 hours. After the reaction was completed, ammonium chloride (100 mL) was added to the reaction solution for dilution, and dichloromethane (3 x 100 mL) was extracted. 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 by silica gel column to obtain yellow oily compound 49-2 (8.0 g);

[1025] Compound 49-2 (8.0 g, 31.21 mmol, 1.0 eq.) was dissolved in a mixture of dimethyl sulfoxide (100 mL) and water (1 mL). Lithium chloride (130.0 mg, 3.12 mmol, 0.1 eq.) was added under nitrogen and stirred at 180°C for 8 hours. After completion of the reaction, the mixture was cooled to room temperature and diluted with water (100 mL). 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), dried over anhydrous sodium sulfate, and filtered. The organic phase was removed by rotary evaporation to obtain a crude product, which was then purified on a silica gel column to obtain compound 49-3 (4.2 g) as a yellow oil.

[1026] Compound 49-3 (3.9 g, 21.16 mmol, 1.0 eq.) was dissolved in n-heptane (40 mL) and added with hydrobromic acid and acetic acid solution (10.3 g, 42.33 mmol, 2.0 eq.) at 0°C under nitrogen. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 100 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was removed by rotary evaporation to obtain a crude product, which was then purified on a silica gel column to obtain compound 49-4 (3.1 g) as a yellow oil.

[1027] Dissolve 49-4 (3.0 g, 11.31 mmol, 1.0 eq.) in tetrahydrofuran (10 mL). Under nitrogen, add borane tetrahydrofuran solution (30.0 mL) at 0°C. Heat to 75°C and stir for 5 hours. After completion, cool to 0°C and quench with methanol (30 mL). Remove the organic solvent using a rotary evaporator to obtain compound 49-5 (2.0 g) as a yellow oil.

[1028] Compound 49-5 (2.0 g, 8.96 mmol, 1.0 equiv.) was dissolved in DMF (20.0 mL). Potassium carbonate (3.7 g, 26.88 mmol, 3.0 eq.) and undecanoic acid (1.83 g, 9.85 mmol, 1.1 eq.) were added under nitrogen and stirred at 70°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with 50 mL of water, and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The organic phases were then removed by rotary evaporation to afford the crude product. The crude product was purified by silica gel column chromatography to afford compound 49-6 (2.4 g) as a yellow oil.

[1029] Referring to the method of Preparation Example 45, 91 mg of compound M49 was prepared as an oily product.

[1030] 1 H NMR (300MHz, CD3OD) δ: 0.88-0.94 (m, 15H), 1.22-1.74 (m, 64H), 2.30 (t, J = 7.2Hz, 4H), 2. 49-2.52(m,4H),2.60(t,J=7.2Hz,2H),3.62(t,J=6.0Hz,2H),4.06-4.12(m,4H); ESI-MS m / z:766.70[M+H] + .

[1031] Preparation Example 50: Synthesis of Compound M50

[1032] Referring to the method of Preparation Example 49, 77 mg of compound M50 was prepared as an oily product.

[1033] 1 H NMR (300MHz, CD3OD) δ: 0.87-0.93 (m, 15H), 1.21-1.63 (m, 52H), 2.28-2.34 (m, 4H), 2.50-2.66 (m, 6H), 3.62 (t, J = 6.3Hz, 2H), 4.04-4.10 (m, 4H); ESI-MS m / z:682.70[M+H] + .

[1034] Preparation Example 51: Synthesis of Compound M51

[1035] Referring to the method of Preparation Example 49, 90 mg of compound M51 was prepared as an oily product.

[1036] 1 H NMR (400MHz, CD3OD) δ: 0.90-0.96 (m, 15H), 1.22-1.63 (m, 56H), 2.29-2.33 (m, 4H), 2.46-2.52 (m, 6H), 3.55 (t, J = 6.0Hz, 2H), 4.04-4.10 (m, 4H); ESI-MS m / z:710.90[M+H] + .

[1037] Preparation Example 52: Synthesis of Compound M52

[1038] Referring to the method of Preparation Example 49, 95.1 mg of compound M52 was prepared as an oily product.

[1039] 1 H NMR(400MHz,CD3OD)δ:0.90-0.94(m,15H),1.25-1.36(m,47H),1.40-1.73(m,19H),2.30-2.35(m,4H),2.48-2 .54(m,4H),2.63(t,J=7.2Hz,2H),3.64(t,J=6.0Hz,2H),4.00(d,J=5.6Hz,2H),4.10(t,J=6.4Hz,2H); ESI-MS m / z:780.95[M+H] + .

[1040] Preparation Example 53: Synthesis of Compound M53

[1041] Referring to the method of Preparation Example 49, 76 mg of compound M53 was prepared as an oily product.

[1042] 1 H NMR (300MHz, CD3OD) δ: 0.88-0.93 (m, 15H), 1.21-1.63 (m, 66H), 2.30 (t, J = 7.5Hz, 4H), 2. 46-2.53(m,6H),3.55(t,J=6.0Hz,2H),4.00(d,J=5.6Hz,2H),4.06-4.12(m,4H); ESI-MS m / z:780.80[M+H] + .

[1043] Preparation Example 54: Synthesis of Compound M54

[1044] Referring to the method of Preparation Example 49, 90.5 mg of compound M54 was prepared as an oily product.

[1045] 1 H NMR(300MHz,CD3OD)δ:0.88-0.93(m,15H),1.21-1.63(m,66H),2.28-2.33(m,4H) ,2.50-2.66(m,6H),3.63(t,J=6.3Hz,2H),4.10(dd,J=6.6Hz,12.6Hz,4H); ESI-MS m / z:780.75[M+H] + .

[1046] Preparation Example 55: Synthesis of Compound M55

[1047] Referring to the method of Preparation Example 49, 75.7 mg of compound M55 was prepared as an oily product.

[1048] 1 H NMR(300MHz,CD3OD)δ:0.89-0.97(m,15H),1.23-1.63(m,70H),2.28-2.33(m,4H) ,2.46-2.53(m,6H),3.55(t,J=5.7Hz,2H),4.10(dd,J=6.3Hz,12.6Hz,4H); ESI-MS m / z:808.75[M+H] + .

[1049] Preparation Example 56: Synthesis of Compound M56

[1050] Referring to the method of Preparation Example 49, 94.1 mg of compound M56 was prepared as an oily product.

[1051] 1 H NMR(400MHz,CD3OD)δ:0.88-0.92(m,15H),1.23-1.69(m,62H),2.29-2.33(m,4H),2.46-2.52 (m,4H),2.61(t,J=7.2Hz,2H),3.62(t,J=6.0Hz,2H),4.07(dd,J=6.4Hz,12.0Hz,4H); ESI-MS m / z:752.90[M+H] + .

[1052] Preparation Example 57: Synthesis of Compound M57

[1053] 1,1-Cyclopropane dimethanol (6.0 g, 58.75 mmol, 1.0 eq.) was dissolved in dichloromethane (60 mL) and Dess-Martin reagent (74.8 g, 176.24 mmol, 3.0 eq.) was added at 0°C under nitrogen protection. The mixture was stirred at room temperature for 5 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and the pH was adjusted to 7 with saturated sodium bicarbonate. 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 compound 57-1 (3.5 g) as a yellow oil.

[1054] A solution of sodium hydride (2.6 g, 61.2 mmol, 3.0 eq.) in tetrahydrofuran (30 mL) was cooled to 0°C. Under nitrogen, triethyl phosphinoacetate (13.7 g, 61.2 mmol, 3.0 eq.) was slowly added and stirred at room temperature for 1 hour. The reaction system was then cooled to 0°C and 57-1 (2.0 g, 20.4 mmol, 1.0 eq.) was added to the reaction solution. The reaction was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was diluted with water (100 mL) 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 the crude product, which was purified on a silica gel column to obtain compound 57-2 (2.4 g) as a yellow oil.

[1055] Compound 57-2 (2.4 g, 10.08 mmol, 1.0 eq.) was dissolved in ethanol (20 mL). Cobalt chloride hexahydrate (476.4 mg, 2.01 mmol, 0.2 eq.) and sodium borohydride (1.5 g, 40.34 mmol, 4.0 eq.) were added under nitrogen at 0°C and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 50 mL), dried over anhydrous sodium sulfate, and filtered. The organic phase was removed by rotary evaporation to obtain a crude product, which was then purified on a silica gel column to obtain compound 57-3 (1.8 g) as a yellow oil.

[1056] Dissolve 57-3 (1.8 g, 7.43 mmol, 1 eq.) in tetrahydrofuran (10 mL) and add borane tetrahydrofuran solution (18.0 mL) at 0°C under nitrogen protection. Stir and react at 75°C for 3 hours. After completion of the reaction, cool to room temperature and quench the reaction with methanol (10 mL). Remove the organic solvent using a rotary evaporator to obtain compound 57-4 (1.0 g, 85%) as a yellow oil.

[1057] Compound 57-4 (500.0 mg, 3.16 mmol, 1.0 eq.) was dissolved in dichloromethane (5 mL). Under nitrogen, decanoic acid (653.2 mg, 3.79 mmol, 1.2 eq.), EDCI (908.6 mg, 4.74 mmol, 1.5 eq.), and DMPA (579.0 mg, 4.74 mmol, 1.5 eq.) were added sequentially. The reaction was stirred at room temperature for 5 hours. After completion, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, washed with saturated sodium chloride solution (3 x 50 mL), and dried over anhydrous sodium sulfate. The organic phases were 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 57-5 (500 mg) as a yellow oil.

[1058] Referring to the method of Preparation Example 45, 77.7 mg of compound M57 was prepared as an oily product.

[1059] 1H NMR(400MHz,CD3OD)δ:0.16(m,4H),0.79-0.82(m,9H),1.13-1.38(m,46H),1.40-1.64(m,12H),2.18-2.24(m,4H),2 .37-2.52(m,4H),2.51(t,J=6.4Hz,2H),3.51(t,J=6.4Hz,2H),3.89(d,J=5.6Hz,2H),4.00(t,J=6.4Hz,2H); ESI-MS m / z:722.45[M+H] + .

[1060] Preparation Example 58: Synthesis of Compound M58

[1061] Referring to the method of Preparation Example 57, 85 mg of compound M58 was prepared as an oily product.

[1062] 1 H NMR(300MHz,CD3OD)δ:0.24-0.26(m,4H),0.91-0.97(m,9H),1.24-1.75(m,60H),2.27-2.34(m,4H),2.43-2. 50(m,4H),2.60(t,J=7.5Hz,2H),3.62(t,J=6.0Hz,2H),3.98(d,J=5.4Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:736.65[M+H] + .

[1063] Preparation Example 59: Synthesis of Compound M59

[1064] Referring to the method of Preparation Example 57, 90.2 mg of compound M59 was prepared as an oily product.

[1065] 1 H NMR(300MHz,CD3OD)δ:0.22(m,4H),0.89-0.96(m,9H),1.22-1.75(m,62H),2.28-2.34(m,4H), 2.43-2.50(m,6H),3.55(t,J=6.3Hz,2H),3.98(d,J=5.7Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:750.55[M+H] + .

[1066] Preparation Example 60: Synthesis of Compound M60

[1067] Referring to the method of Preparation Example 57, 80 mg of compound M60 was prepared as an oily product.

[1068] 1 H NMR (300MHz, CD3OD) δ: 0.26-0.28 (m, 4H), 0.91-0.97 (m, 9H), 1.22-1.75 (m, 64H), 2.32 (dt, J = 5.1Hz, 7.8Hz, 4H), 2. 47-2.53(m,4H),2.62(t,J=6.6Hz,2H),3.61(t,J=6.6Hz,2H),3.98(d,J=5.7Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:764.75[M+H] + .

[1069] Preparation Example 61: Synthesis of Compound M61

[1070] Referring to the method of Preparation Example 57, 85 mg of compound M61 was prepared as an oily product.

[1071] 1 H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.91-0.94(m,9H),1.26-1.37(m,52H),1.50-1.74(m,14H),2.31-2.36(m,4H) ),2.47-2.51(m,4H),2.63(t,J=7.0Hz,2H),3.65(t,J=6.5Hz,2H),4.01(d,J=5.5Hz,2H),4.10(t,J=6.5Hz,2H); ESI-MS m / z:778.70[M+H] + .

[1072] Preparation Example 62: Synthesis of Compound M62

[1073] Referring to the method of Preparation Example 57, 90 mg of compound M62 was prepared as an oily product.

[1074] 1H NMR(300MHz,CD3OD)δ:0.24-0.26(m,4H),0.88-0.92(m,9H),1.25-1.41(m,52H),1.52-1.73(m,16H),2.28- 2.34(m,4H),2.48-2.54(m,6H),3.55(t,J=6.0Hz,2H),4.00(d,J=5.7Hz,2H),4.07(t,J=6.6Hz,2H); ESI-MS m / z:792.65[M+H] + .

[1075] Preparation Example 63: Synthesis of Compound M63

[1076] Referring to the method of Preparation Example 57, 89.6 mg of compound M63 was prepared as an oily product.

[1077] 1 H NMR(400MHz,CD3OD)δ:0.25-0.26(m,4H),0.88-0.92(m,9H),1.23-1.34(m,41H),1.40-1.72(m,15H),2.30( t,J=7.6Hz,4H),2.47-2.52(m,4H),2.61(t,J=6.4Hz,2H),3.61(t,J=6.4Hz,2H),4.05-4.11(m,4H); ESI-MS m / z:708.75[M+H] + .

[1078] Preparation Example 64: Synthesis of Compound M64

[1079] Referring to the method of Preparation Example 57, 79.7 mg of compound M64 was prepared as an oily product.

[1080] 1 H NMR(400MHz, CD3OD)δ:0.25-0.26(m,4H),0.88-0.92(m,9H),1.23-1.72(m,58H),2.28-2.32(dt,J=1.6H z,7.6Hz,4H),2.44-2.49(m,4H),2.60(t,J=7.2Hz,2H),3.62(t,J=6.0Hz,2H),4.05-4.12(m,4H); ESI-MS m / z:722.70[M+H] + .

[1081] Preparation Example 65: Synthesis of Compound M65

[1082] Referring to the method of Preparation Example 57, 101.4 mg of compound M65 was prepared as an oily product.

[1083] 1 H NMR(300MHz,CD3OD)δ:0.25-0.26(m,4H),0.88-0.92(m,9H),1.23-1.75(m,60H),2.30 (t,J=7.2Hz,4H),2.44-2.50(m,6H),3.55(t,J=6.0Hz,2H),4.04-4.12(m,4H); ESI-MS m / z:736.85[M+H] + .

[1084] Preparation Example 66: Synthesis of Compound M66

[1085] Referring to the method of Preparation Example 57, 106.4 mg of compound M66 was prepared as an oily product.

[1086] 1 H NMR(300MHz,CD3OD)δ:0.28-0.29(m,4H),0.89-0.93(m,9H),1.26-1.75(m,62H),2.30(t,J=7.5Hz,4H),2.48- 2.54(m,4H),2.63(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),4.08(t,J=6.6Hz,2H),4.10(t,J=6.6Hz,2H); ESI-MS m / z:750.70[M+H] + .

[1087] Preparation Example 67: Synthesis of Compound M67

[1088] Referring to the method of Preparation Example 57, 85 mg of compound M67 was prepared as an oily product.

[1089] 1 H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.91-0.94(m,9H),1.26-1.74(m,64H),2.32(dt,J=2.5Hz,7.5Hz,4H),2. 48-2.52(m,4H),2.64(t,J=7.5Hz,2H),3.65(t,J=7.0Hz,2H),4.09(t,J=6.5Hz,2H),4.12(t,J=6.5Hz,2H); ESI-MS m / z:764.65[M+H] + .

[1090] Preparation Example 68: Synthesis of Compound M68

[1091] Referring to the method of Preparation Example 57, 86.8 mg of compound M68 was prepared as an oily product.

[1092] 1 H NMR(400MHz,CD3OD)δ:0.25-0.26(m,4H),0.91-0.94(m,9H),1.24-1.74(m,66H),2.30(dt ,J=1.6Hz,7.6Hz,4H),2.45-2.50(m,6H),3.55(t,J=5.6Hz,2H),4.05-4.12(m,4H); ESI-MS m / z:778.80[M+H] + .

[1093] Preparation Example 69: Synthesis of Compound M69

[1094] Referring to the method of Preparation Example 57, 80 mg of compound M69 was prepared as an oily product.

[1095] 1 H NMR(300MHz,CD3OD)δ:0.25-0.26(m,4H),0.89-0.94(m,9H),1.26-1.73(m,68H),2.30(t,J=7.5H z,4H),2.47-2.54(m,4H),2.62(t,J=6.6Hz,2H),3.61(t,J=6.3Hz,2H),4.04-4.12(m,4H); ESI-MS m / z:792.80[M+H] + .

[1096] Preparation Example 70: Synthesis of Compound M70

[1097] Referring to the method of Preparation Example 57, 87 mg of compound M70 was prepared as an oily product.

[1098] 1 H NMR(300MHz,CD3OD)δ:0.26-0.27(m,4H),0.88-0.92(m,9H),1.26-1.73(m,70H),2.30(t,J=7.5H z,4H),2.43-2.49(m,4H),2.59(t,J=7.5Hz,2H),3.62(t,J=6.0Hz,2H),4.04-4.12(m,4H); ESI-MS m / z:806.80[M+H]+ .

[1099] Preparation Example 71: Synthesis of Compound M71

[1100] Referring to the method of Preparation Example 57, 97 mg of compound M71 was prepared as an oily product.

[1101] 1 H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.94-0.98(m,9H),1.29-1.75(m,60H),2.33(dt,J=5.5Hz,7. 5Hz,4H),2.50-2.54(m,4H),2.64(t,J=6.5Hz,2H),3.63(t,J=6.5Hz,2H),4.07(q,J=6.5Hz,4H); ESI-MS m / z:736.70[M+H] + .

[1102] Preparation Example 72: Synthesis of Compound M72

[1103] Referring to the method of Preparation Example 57, 83.3 mg of compound M72 was prepared as an oily product.

[1104] 1 H NMR(500MHz,CD3OD)δ:0.28-0.29(m,4H),0.91-0.94(m,9H),1.26-1.38(m,47H),1.50-1.73(m,15H),2.31- 2.35(m,4H),2.46-2.50(m,4H),2.62(t,J=7.0Hz,2H),3.65(t,J=6.0Hz,2H),4.08(q,J=7.0Hz,4H); ESI-MS m / z:750.65[M+H] + .

[1105] Preparation Example 73: Synthesis of Compound M73

[1106] Referring to the method of Preparation Example 57, 99 mg of compound M73 was prepared as an oily product.

[1107] 1H NMR(400MHz,CD3OD)δ:0.26-0.27(m,4H),0.88-0.92(m,9H),1.16-1.40(m,46H),1.45-1.74(m, 18H),2.28-2.33(m,4H),2.44-2.49(m,6H),3.55(t,J=5.6Hz,2H),4.06(q,J=6.4Hz,4H); ESI-MS m / z:765.00[M+H] + .

[1108] Preparation Example 74: Synthesis of Compound M74

[1109] Referring to the method of Preparation Example 57, 80 mg of compound M74 was prepared as an oily product.

[1110] 1 H NMR(300MHz,CD3OD)δ:0.26-0.28(m,4H),0.91-0.97(m,9H),1.23-1.75(m,62H),2.31(dt,J=4.2Hz,7.2Hz,4H),2. 47-2.53(m,4H),2.62(t,J=6.3Hz,2H),3.61(t,J=6.6Hz,2H),4.00(d,J=6.0Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:750.75[M+H] + .

[1111] Preparation Example 75: Synthesis of Compound M75

[1112] Referring to the method of Preparation Example 57, 83 mg of compound M75 was prepared as an oily product.

[1113] 1 H NMR(300MHz,CD3OD)δ:0.26-0.27(m,4H),0.91-0.94(m,9H),1.22-1.40(m,50H),1.45-1.75(m,14H),2.27-2.34(m,4H) ),2.45-2.51(m,4H),2.61(t,J=6.9Hz,2H),3.63(t,J=6.0Hz,2H),3.98(d,J=5.4Hz,2H),4.06(t,J=6.6Hz,2H); ESI-MS m / z:764.70[M+H] + .

[1114] Preparation Example 76: Synthesis of Compound M76

[1115] Referring to the method of Preparation Example 57, 100.4 mg of compound M76 was prepared as an oily product.

[1116] 1 H NMR(400MHz,CD3OD)δ:0.28-0.29(m,4H),0.93-0.97(m,9H),1.25-1.42(m,50H),1.47-1.74(m,16H),2.28- 2.33(m,4H),2.49-2.52(m,6H),3.55(t,J=6.0Hz,2H),3.98(d,J=5.6Hz,2H),4.06(t,J=6.8Hz,2H); ESI-MS m / z:778.80[M+H] + .

[1117] Preparation Example 77: Synthesis of Compound M77

[1118] In a 250 mL round-bottom flask, 9-heptadecanol (10.0 g, 39.0 mmol, 1.0 eq.) and pyridine (6.17 g, 78.0 mmol, 2.0 eq.) were dissolved in 100 mL of dichloromethane. The reaction system was then cooled to 0°C and isobutyryl chloride (10.39 g, 97.5 mmol, 2.5 eq.) was slowly added to the reaction solution. The mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding water at 0°C and extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na2SO4. The desiccant was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column to obtain compound 77-2 (10.4 g) as a yellow oil.

[1119] Compound 77-2 (10.0 g, 30.62 mmol, 1.0 eq.) was dissolved in anhydrous THF (100 mL), and the reaction system was cooled to -40°C. LDA (15.3 mL, 30.6 mmol, 1.0 eq.) was added to the reaction solution under a nitrogen atmosphere and stirred at -40°C for 1 hour. 1,6-dibromohexane (14.9 g, 61.2 mmol, 2.0 eq.) and DMPU (471 mg, 3.7 mmol, 0.12 eq.) were then added at the same temperature. The reaction system was slowly warmed to room temperature and allowed to react overnight. After the reaction was completed, the reaction solution was added to a saturated NH4Cl solution and extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na2SO4. The desiccant was removed by filtration and the solvent was removed by rotary evaporation to obtain crude compound 77-3, which was used directly in the next step without purification.

[1120] Compound 77-3 (15 g, 30.6 mmol, 1.0 eq.) and 3-hydroxypropylamine (45.0 g, 612.0 mmol, 20.0 equiv) were dissolved in 80 ml of ethanol. The reaction system was heated to 60° C. for 2 hours. After the reaction, the reaction system was cooled to room temperature and the ethanol solvent was removed by rotary evaporation. The crude product was dissolved in ethyl acetate and then added with saturated sodium chloride solution. After extraction, the organic phases were combined and dried over anhydrous Na2SO4. The desiccant was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column to obtain compound 77-4 (12.6 g) as a yellow oil.

[1121] In a 50 mL reaction flask, 6-bromo-1-hexanol (77-5) (1.5 g, 8.3 mmol, 1.0 eq.) and pyridine (1.31 g, 16.6 mmol, 2.0 eq.) were dissolved in 15 mL of dichloromethane. Nonyl chloroformate (77-6, 1.88 g, 9.1 mmol, 1.1 equiv) was added dropwise over 15 minutes under an ice bath. The mixture was allowed to stand at room temperature overnight. The reaction was quenched by adding saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic phases were combined and dried over anhydrous Na2SO4. The desiccant was removed by filtration and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column to obtain compound 77-7 (2.5 g) as a yellow oil.

[1122] In an 8 mL sealed tube, compound 77-7 (200 mg, 0.57 mmol, 1.0 eq.), compound 77-4 (304.8 mg, 0.63 mmol, 1.1 eq.), KI (113.4 mg, 0.68 mmol, 1.2 eq.), K2CO3 (236.0 mg, 1.71 mmol, 3.0 eq.) and 5.0 ml of anhydrous acetonitrile were added, heated to 80 ° C and stirred overnight to react, cooled to room temperature, filtered, and the filter cake was washed with acetonitrile and the organic phases were combined. The solvent was removed by rotary evaporation to obtain the reaction crude product, which was purified by preparative liquid chromatography to give M77 (93.9 mg).

[1123] 1 H NMR (300MHz, CDCl3) δ: 4.85 (p, J = 6.6 Hz, 1H), 4.12 (t, J = 6.6 Hz, 4H), 3.79 (t, J = 5.1 Hz, 2H), 2.65 (m, 2H), 2.42 (m, 4 H),1.77-1.64(m,6H),1.51(t,J=6.0Hz,10H),1.28(d,J=4.5Hz,47H),1.17(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:754.60[M+H] + .

[1124] The compounds in the following table were synthesized by the methods of the above preparation examples, or by similar methods using the corresponding intermediates.

[1125] Preparation Example 78 Synthesis of Compound 1

[1126] A solution of compound 1-1 (100 g, 979 mmol) in tetrahydrofuran (800 mL) was cooled to -40°C. LDA (2 M, 490 mL) was slowly added dropwise to the solution. Stirring was continued for 1 hour. A solution of compound 1-2 (315 g, 1.37 mol) in tetrahydrofuran (100 mL) was added dropwise to the reaction system at the same temperature. The reaction system was stirred overnight. The reaction system was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 1-3 (115 g). 1 H NMR (400MHz, CDCl3): δppm 1.06-1.11(m,6H),1.13-1.22(m,2H),1.29-1.39(m,2H),1.42-1.49(m,2H),1.73-1.82(m,2H),3.28-3.40(m,2H),3.55-3.66(m,3H);

[1127] A solution of compound 1-3 (100 g, 398 mmol), TsCH2CN (38.9 g, 199 mmol) and TBAI (14.7 g, 39.8 mmol) in dimethyl sulfoxide (800 mL) was cooled to 0°C and sodium hydride (20.7 g, 517 mmol) was slowly added in batches. The reaction was allowed to react overnight at room temperature. The reaction system was quenched with saturated sodium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain 115 g of crude compound 1-4, which was used directly in the next step without separation and purification.

[1128] To a solution of crude compound 1-4 (110 g, 205 mmol) in dichloromethane (880 mL) was added 330 mL of concentrated hydrochloric acid and allowed to react at room temperature for 2 hours. TLC confirmed the complete reaction. The reaction system was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, and 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 then purified by silica gel column chromatography to obtain compound 1-5 (30.0 g, 80.9 mmol, 39.4% yield).

[1129] TMSOK (11.0 g, 86.4 mmol) was added to a solution of compound 1-5 (8.0 g, 21.6 mmol) in tetrahydrofuran (35.0 mL) at room temperature, and the reaction system was heated to 70°C with stirring. TLC monitored the complete consumption of the reaction starting materials. The reaction solution was cooled to room temperature, and the organic solvent was removed by rotary evaporation. 20 mL of water was added to the crude product and extracted with dichloromethane. The aqueous layer was collected, and the pH value of the solution was adjusted to less than 5 with 1 M hydrochloric acid. The solution was extracted with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was collected by filtration and concentrated to obtain compound 1-6 (7.0 g). 1 H NMR (400MHz, CDCl3): δppm 1.03 (s, 12H), 1.08-1.17 (m, 8H), 1.34-1.45 (m, 8H), 2.21 (t, J = 7.2Hz, 4H);

[1130] Potassium carbonate (482 mg, 3.48 mmol) was added to a DMF solution of compound 1-6 (294 mg, 0.87 mmol) and 1-7 (771 mg, 3.48 mmol). The reaction temperature was then raised to 60°C for 6 hours. The complete disappearance of the reactant 1-6 was monitored. The reaction system was cooled to room temperature and quenched with saturated sodium chloride aqueous solution. The organic phases were extracted with ethyl acetate and combined, and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified on a silica gel column to obtain compound 1-8 (325 mg).

[1131] Compound 1-8 (325 mg) was dissolved in 4.0 mL of methanol, and sodium borohydride (30 mg, 0.84 mmol) was added to the reaction system. The reaction was allowed to proceed at room temperature. TLC monitoring showed that the reactant completely disappeared. The reaction system was quenched with a saturated aqueous sodium chloride solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product of compound 1-9 (260 mg), which was used directly in the next step without purification.

[1132] The crude product of compound 1-9 (260 mg, 0.42 mmol), 1-10 (73.1 mg, 0.63 mmol), EDCI (238 mg, 1.26 mmol), triethylamine (0.17 mL, 1.26 mmol) and DMAP (51 mg, 0.42 mmol) were dissolved in 5.0 mL of dichloromethane, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was quenched with saturated aqueous sodium chloride solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered to collect the organic phase. The organic solvent was removed by rotary evaporator to obtain a crude product, which was purified by preparative high performance liquid chromatography to obtain compound 1 (130 mg).

[1133] 1H NMR (400MHz, CDCl3): δppm 0.89(t,J=7.2Hz,6H),1.15(s,12H),1.27(m,40H),1.49(m,8H),1.61(m,4H),2.26(s,6H),2 .44-2.52(t,J=7.2Hz,2H),2.63(t,J=7.2Hz,2H),4.04(t,J=6.8Hz,4H),4.86(m,1H); ESI-MS m / z:724.7[M+H] + .

[1134] Preparation Example 79: Synthesis of Compound 104

[1135] Compound 1-6 (448 mg, 1.3 mmol) was dissolved in 5.0 mL of dichloromethane. The reaction system was cooled to 0°C in an ice bath. DMF (10 μL, 0.13 mmol) was added, and oxalyl chloride (0.44 mL, 5.2 mmol) was then added dropwise to the reaction solution. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by rotary evaporation to obtain a crude oily acyl chloride (330 mg), which was used directly in the next step.

[1136] 1-Decanethiol 33-1 (455 mg, 2.61 mmol) was added to a solution of crude acyl chloride (330 mg, 0.87 mmol) in DCE (3.0 mL). The reaction was heated to 70°C overnight. The reaction solution was cooled to room temperature and the solvent was removed by rotary evaporation to obtain a crude product. The crude product was purified by silica gel column to obtain compound 33-2 (400 mg). 1 H NMR (400MHz, CDCl3): δppm 0.84-0.87(m,6H),1.14-1.18(m,12H),1.20-1.28(m,36H),1.48-1.55(m,12H),2.33(t,J=7.2Hz,4H),2.79(t,J=7.2Hz,4H).

[1137] Compound 33-2 (300 mg, 0.46 mmol) was dissolved in 3.0 mL of methanol, and NaBH4 (52.5 mg, 1.38 mmol) was added in portions. The reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. TLC monitoring showed that the reaction starting material completely disappeared. The reaction solution was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was collected by filtration and concentrated to obtain 300 mg of crude compound 33-3, which was used directly in the next reaction without further purification.

[1138] The crude compound 33-3 (300 mg, 0.46 mmol), 1-11 (98.8 mg, 0.69 mmol), EDCI (264.5 mg, 1.38 mmol), triethylamine (0.19 mL, 1.38 mmol) and DMAP (56.2 mg, 0.46 mmol) were dissolved in 8.0 mL of dichloromethane. The reaction solution was stirred at room temperature until the reaction raw material 33-3 was completely consumed. The reaction solution was quenched with saturated sodium chloride aqueous solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to collect the organic phase. The organic solvent was removed by rotary evaporation. The crude product was purified by preparative high performance liquid chromatography to obtain compound 104 (67.3 mg).

[1139] 1 H NMR (400MHz, CDCl3): δppm 0.81(t,J=6.8Hz,6H),1.08(s,12H),1.09-1.31(m,42H),1.35-1.51(m,14H),1.61-2.25(m,8H),2.73(t,J=7.2Hz,4H),4.77(m,1H); m / z:782.7[M+H] + .

[1140] Preparation Example 80: Synthesis of Compound 110

[1141] Compound 110 was prepared by referring to the synthetic method of compound 104 to obtain 34.4 mg of an oily product.

[1142] 1 H NMR (400MHz, CDCl3): δppm 0.81(t,J=7.2Hz,6H),1.12(s,12H),1.14-1.27(m,34H),1.44-1.48(m,12H),1.66-1.77(m,7H),2.05-2.24(m ,4H),2.53(m,2H),2.75(t,J=7.2Hz,4H),2.90-2.92(m,2H),3.57(t,J=5.2Hz,2H),4.74-4.80(m,1H); ESI-MS m / z:798.6[M+H] + .

[1143] Preparation Example 81: Synthesis of Compound 113

[1144] Compound 113 was prepared by referring to the synthetic method of compound 110 to obtain 31.1 mg of an oily product.

[1145] 1H NMR (400MHz, CDCl3): δppm 0.81(t,J=7.2Hz,6H),1.08(s,12H),1.10-1.24(m,36H),1.36-1.43(m,8H),1.48-1.54(m,6H),1.64-1.72(m,6H),2.05(t,J=6.8Hz,1H) ,2.15(d,J=6.8Hz,2H),2.47(t,J=5.6Hz,2H),2.82-2.89(m,2H),3.54(t,J=5.6Hz,2H),3.97(t,J=6.8Hz,4H),4.73-4.79(m,1H); ESI-MS m / z:766.6[M+H] + .

[1146] Preparation Example 82: Synthesis of Compound 114

[1147] Compound 114 was prepared by referring to the synthetic method of compound 110 to obtain 32.7 mg of an oily product.

[1148] 1 H NMR (400MHz, CDCl3): δppm 0.85-0.88(m,9H),1.07(s,12H),1.09-1.35(m,46H),1.41-1.58(m,13H),1.97-2.25(m,3H),2.32(d,J=5.6Hz,2H),2.83-2.86(m,2H) ,3.17-3.19(m,2H),3.78-3.81(d,J=7.2Hz,2H),3.92(d,J=5.6Hz,2H),4.01(t,J=6.4Hz,2H),4.10(m,1H),4.81-4.86(m,1H); ESI-MS m / z:836.7[M+H] + .

[1149] Preparation Example 83 Synthesis of Compound 137

[1150] In a 1 L four-necked round-bottom flask, THF (40 mL) and 137-1 (20 g, 172.3 mmol, 1.00 eq) were added at room temperature. The system was cooled to -40°C and LDA (86.2 mL, 172.3 mmol, 1.00 eq) was added dropwise over 1 h. The mixture was stirred at -40°C for 1 h. Dibromobutane (51.2 g, 239.5 mmol, 1.39 eq) was then added dropwise at -40°C over 30 min. Finally, DMPU (3.3 g, 25.8 mmol, 0.15 eq) was added dropwise at -40°C over 1 h. The mixture was kept at -40°C for 1 h. The mixture was allowed to warm to room temperature and stirred for 18 h. The reaction was monitored by TLC. After the starting material was consumed, the reaction was quenched with saturated NH4Cl (50 mL) at 0°C, and the system was diluted with water (40 mL) and ethyl acetate (40 mL). Extraction and separation were performed, and the aqueous phase was back-extracted once with ethyl acetate (50 mL). The organic phases were combined and washed twice with saturated NaCl (75 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was passed through a silica gel column (PE:EA=10:1) to obtain a light yellow oil 137-2 (20.8 g, 48.28%).

[1151] In a 500 mL three-necked round-bottom flask, THF (208 mL) and 137-2 (98 g, 83.2 mmol, 1.00 eq) were added at room temperature. The system was cooled to -10°C and LiAlH4 (33.3 mL, 66.5 mmol, 0.8 eq, 2 M in THF) was added dropwise over 20 minutes. The system was stirred at -10°C for 5 minutes and the reaction was monitored by TLC. The conversion of the starting material was complete. The reaction was quenched with 2M HCl (aq.) (30 mL) at -10°C and the system was diluted with water (200 mL) and ethyl acetate (1 L). Extraction and separation were performed. The aqueous phase was back-extracted once with ethyl acetate (200 mL). The combined organic phases were washed twice with saturated NaCl (500 mL). The organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude light yellow product 137-3 (19.5 g).

[1152] In a 500 mL three-necked flask, THF (40 mL) and NaH (7.50 g, 187.5 mmol, 4.00 eq) were added at room temperature. TosMIC (9.15 g, 48.9 mmol, 1.00 eq) was added portionwise under nitrogen at 25 °C, followed by TBAI (1.73 g, 4.69 mmol, 0.10 eq). The system was stirred at 25 °C for 20 min. Finally, 137-3 (19.5 g, 93.7 mmol, 2.00 eq) was dissolved in THF (155 mL) and added dropwise to the above system at 25 °C. The system was stirred at 25 °C for an additional 1 h. The reaction was monitored by TLC, and the conversion of the starting material was complete. The reaction was quenched with ice water (400 mL) at 20°C, and the system was extracted with MTBE (2*500 mL). The organic phases were combined and washed once with saturated NaCl (500 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product 137-4 (22 g), which was directly used in the next step.

[1153] Crude product 137-4 (22 g), CH3OH (220 mL) and 12N HCl (12.2 mL) were added to a 500 mL three-necked flask at room temperature. The system was reacted at 80°C for 3 h. The reaction was monitored by LCMS. The conversion of the starting material was complete. The system was cooled to room temperature and the pH was adjusted to 7 with saturated sodium carbonate. The methanol was removed by concentration under reduced pressure. The system was dissolved and diluted with water (200 mL) and ethyl acetate (200 mL). Extraction and separation were performed. The aqueous phase was back-extracted once with ethyl acetate (200 mL). The organic phases were combined and washed once with saturated NaCl (200 mL). The organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was passed through a silica gel column (PE:EA=4:1) to obtain a light yellow oil 135-5 (13.2 g, three-step yield: 55.44%).

[1154] In a 500 mL three-necked flask, isodecyl alcohol (32 g, 202.2 mmol, 1.00 eq), PPh3 (106.05 g, 404.3 mmol, 2.0 eq) and THF (320 mL) were added at room temperature. CBr4 (73.75 g, 222.4 mmol, 1.1 eq) was added portionwise at 0°C under nitrogen protection. The system was allowed to warm up freely and stirred at 25°C for 3 h. The reaction was monitored by TLC. The conversion of the starting material was complete. The system was concentrated under reduced pressure to remove THF, and the mixture was redissolved in PE (500 mL). The mixture was slurried and filtered. The filtrate was concentrated and the crude product was passed through a silica gel column (PE:EA=50:1) to give 137-6 (35 g, 78.27%) as a yellow oil.

[1155] In a 1 L three-necked round-bottom flask, 137-6 (35 g, 158.2 mmol, 1.00 eq), NaCN (15.51 g, 316.5 mmol, 2.00 eq), and DMF (700 mL) were added at room temperature. The system was reacted at 70°C for 12 h. The reaction was monitored by TLC and LCMS, and the product signal was observed. The reaction mixture was cooled to room temperature and poured into ice water (1000 mL). The system was extracted with MTBE (2 x 1000 mL). The layers were separated, and the aqueous phase was back-extracted once with MTBE (1000 mL). The combined organic phases were washed once with saturated NaCl (1000 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column (PE:EA = 10:1) to obtain 137-7 (23.5 g, 88.77%) as a yellow oil.

[1156] In a 250 mL three-necked round-bottom flask, 137-7 (23.5 g, 140.5 mmol, 1.00 eq) and EtOH (82.25 mL) were added at room temperature. KOH (70.93 g, 1264.2 mmol, 9.00 eq) was dissolved in H2O (82.25 mL) and added to the system. The reaction was carried out at 110°C for 12 h. The reaction was monitored by TLC and LCMS. The starting material was completely reacted. The reaction was cooled to room temperature and the pH was adjusted to 2 with 2N HCl. The system was diluted with water (200 mL) and ethyl acetate (500 L). Extraction and separation were performed. The aqueous phase was back-extracted once with ethyl acetate (200 mL). The organic phases were combined and washed twice with saturated NaCl (500 mL). The organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and the crude product was passed through a silica gel column (PE:EA=10:1) to obtain 137-8 (26.1 g, 99.74%) as a yellow oil.

[1157] In a 250 mL three-necked flask, 137-5 (4 g, 13.9 mmol, 1.00 eq), 137-8 (5.72 g, 30.7 mmol, 2.20 eq), EDCI (6.69 g, 34.9 mmol, 2.50 eq), DMAP (1.71 g, 14.0 mmol, 1.00 eq), and DCM (40 mL) were added at room temperature. The reaction was allowed to react at 20°C for 2 h. The reaction was monitored by TLC and LCMS. When the product signal appeared, the reaction system was concentrated under reduced pressure to remove DCM. The system was then diluted with saturated NH4Cl solution (500 mL) and ethyl acetate (500 mL), extracted, and separated. The aqueous phase was back-extracted once with ethyl acetate (200 mL), and the organic phases were combined and washed once with saturated NaCl (500 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was passed through a silica gel column (PE:EA=50:1) to give 137-9 (8.49 g, 97.59%) as a yellow oil.

[1158] In a 250 mL three-necked flask, 137-9 (8.49 g, 13.6 mmol, 1.00 eq), methanol (51 mL), and THF (17 mL) were added at room temperature. NaBH4 (515.52 mg, 13.6 mmol, 1.00 eq) was added at 0°C and the mixture was allowed to react at 25°C for 2 h. The reaction was monitored by TLC, and the reaction was complete. The reaction system was quenched with water (1000 mL), diluted with ethyl acetate (200 mL), extracted, and separated. The aqueous phase was back-extracted once with ethyl acetate (200 mL). The organic phases were combined and washed once with saturated NaCl (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product of 137-10 (8.43 g) was obtained.

[1159] In a 250 mL three-necked round-bottom flask, 137-10 (8.43 g, 13.5 mmol, 1.00 eq), acid (4.88 g, 16.2 mmol, 1.20 eq), EDCI (3.88 g, 20.2 mmol, 1.50 eq), DMAP (1.65 g, 13.5 mmol, 1.00 eq), and DCM (84.3 mL) were added at room temperature. The system was reacted at 25°C for 2 h. The reaction was monitored by TLC. The conversion of the starting material was complete. The reaction system was concentrated under reduced pressure to remove DCM. The system was diluted with saturated NH4Cl solution (500 mL) and ethyl acetate (500 mL). Extraction and separation were performed. The aqueous phase was back-extracted once with ethyl acetate (200 mL). The combined organic phases were washed once with saturated NaCl (500 mL). The organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to obtain crude product 137-11 (12.4 g).

[1160] In a 250 mL three-necked round-bottom flask, 137-11 (12.4 g, 13.6 mmol, 1.00 eq) and THF (62 mL) were added at room temperature. TBAF (16.4 mL, 16.4 mmol, 1.20 eq, 1 M in THF) was added dropwise at 0°C. The system was reacted at 25°C for 2 h. TLC confirmed complete conversion of the starting material. The reaction system was concentrated under reduced pressure to remove THF. The system was then diluted with H2O (500 mL) and ethyl acetate (500 mL), extracted, and separated. The aqueous phase was back-extracted once with ethyl acetate (200 mL). The combined organic phases were washed once with saturated NaCl (500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was passed through a silica gel column (DCM:MeOH = 50:1) to afford 137 (6.2208 g, 54.46% yield for three steps) as a yellow oil.

[1161] 1H NMR (300MHz, Chloroform-d, ppm) δ4.86 (p, J = 6.3Hz, 1H), 3.77 (s, 4H), 3.65 (t, J = 5.3Hz, 2H), 2.99 (d, J = 11. 5Hz,2H),2.60(t,J=5.3Hz,2H),2.39–2.12(m,8H),1.93–0.98(m,42H),0.92–0.70(m,30H); m / z(ES+),[M+H] + :795.75.

[1162] Preparation Example 84 Synthesis of Compound 138

[1163] THF (1400 mL) and CH3OH (100 mL) were added to a 5L four-necked round-bottom flask. The system was cooled to 0°C and NaBH4 (107 g, 2.82 mol, 2.0 eq) was added portionwise. Glutaric anhydride (200 g, 1.41 mol, 1.0 eq) was dissolved in THF (600 mL) and added dropwise to the system at 0°C using a constant pressure dropping funnel. After the addition was complete, the system was warmed to 25°C and reacted for 3 hours. The reaction was monitored by TLC to confirm complete conversion of the starting material. The system was cooled to 0°C and quenched with 1N HCl (2000 mL). MTBE (1500 mL) was then added to the system and stirred for 10 min. The layers were separated and the aqueous phase was extracted with MTBE (500 mL*3). The combined organic phases were washed once with saturated NaHCO3 (1000 mL) and once with saturated NaCl (1000 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (PE / EA=3 / 1) to obtain 138-2 (153.2 g, 85.1%) as a light yellow oil.

[1164] To a 5 L four-necked round-bottom flask, 138-2 (153.2 g, 1.2 mol, 1.0 eq) and DCM (1532 mL) were added. The system was cooled to -78°C and DIBAL-H (1800 mL, 1.8 mol, 1.5 eq, 1 M in DCM) was added dropwise at -78°C using a constant pressure dropping funnel. After the addition was complete, the temperature was maintained at -78°C for 2 h. The reaction was monitored by TLC. Conversion of the starting material was complete. The system was warmed to 0°C and slowly quenched with sodium potassium tartrate solution (1000 mL) at 0°C. The layers were separated, and the aqueous phase was back-extracted once with DCM (500 mL). The combined organic phases were washed once with saturated NaCl (1000 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (PE / EA = 3 / 1) to afford 138-3 (105.7 g, 67.9%) as a pale yellow oil.

[1165] In a 3 L four-necked round-bottom flask, 138-3 (105.7 g, 812.5 mmol, 1.0 eq), ACN (1057 mL) and witting reagent (407.2 g, 1218.7 mmol, 1.5 eq) were added. The temperature was raised to 80°C for 24 h. The reaction was monitored by TLC. The conversion of the starting material was complete. The system was cooled to room temperature and concentrated under reduced pressure to remove acetonitrile. MTBE (1000 mL) was added and the mixture was slurried for 30 min. The mixture was filtered and the filter cake was rinsed with MTBE (200 mL*2). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was passed through a silica gel column (PE / EA=10 / 1) to obtain 138-4 (79.2 g, 52.4%) as a light yellow oil.

[1166] 138-4 (79.2 g), CH3OH (792 mL) and Pd / C (7.92 g) were added to a 2 L single-necked round-bottom flask. The gas was replaced with hydrogen three times and hydrogenated at 25°C for 12 h. The reaction was monitored by TLC. The conversion of the starting material was complete. The system was filtered, the filter cake was rinsed with DCM (100 mL*2), and the filtrate was concentrated under reduced pressure to give 138-5 (63.5 g) as a light yellow oil.

[1167] In a 2 L three-necked round-bottom flask, 138-5 (63.5 g, 337.6 mmol, 1.0 eq), DCM (635 mL) and PPh3 (106.2 g, 405.1 mmol, 1.2 eq) were added, and CBr4 (121.7 g, 371.3 mmol, 1.1 eq) was added in batches. The reaction was incubated at 25 ° C for 1 h. The reaction was monitored by TLC. The conversion of the starting material was complete. The system was concentrated under reduced pressure to remove DCM, and PE / MTBE = 5 / 1 (500 mL) was added to slurry for 30 min. The mixture was filtered and the filter cake was rinsed with PE / MTBE = 5 / 1 (100 mL * 2). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was passed through a silica gel column (PE / EA = 50 / 1) to obtain a light yellow oil 138-6 (60 g, 71.1%).

[1168] To a 500 mL three-necked flask, DMSO (60 mL) and NaH (1.36 g, 34 mmol, 2.0 eq) were added at room temperature. TosMIC (3.31 g, 17 mmol, 1.00 eq) was added portionwise at 25°C under nitrogen, followed by TBAI (627 mg, 1.7 mmol, 0.1 eq). The system was stirred at 25°C for 30 min. Finally, 138-6 (8.5 g, 34 mmol, 2 eq) was dissolved in DMSO (25 mL) and added dropwise at 25°C. After the addition was complete, the mixture was allowed to react at 25°C for 1 h. TLC confirmed complete conversion of the starting material. The reaction was quenched with ice water (400 mL) at 20°C and extracted with MTBE (2 x 200 mL). The combined organic phases were washed once with saturated NaCl (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 138-7 (53.7 g), a brownish-red oil, which was used directly in the next step.

[1169] To a 2L three-necked round-bottom flask, add 138-7 (53.7 g, crude), CH3OH (1057 mL), and 12N HCl (25 mL). Heat to 70°C and react for 1 h. Monitor the reaction by TLC to ensure complete conversion of the starting material. Cool the system to room temperature, adjust the pH to 7 with saturated Na2CO3, and concentrate under reduced pressure to remove CH3OH. The crude product is redissolved in EA (500 mL) and H2O (500 mL). Extract and separate the layers. The organic phase is washed once with saturated NaCl (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to yield 138-8 (45.4 g), a brownish-red oil, which is used directly in the next step.

[1170] 138-8 (45.4 g) and EtOH (450 mL) were added to a 2 L three-necked round-bottom flask. NaOH (19.6 g) was dissolved in H2O (275 mL) and then added to the above system. The system was stirred at 20°C for 2 h. The reaction was monitored by TLC. The conversion of the starting material was complete. The system was adjusted to pH 2-3 with 1N HCl and concentrated under reduced pressure to remove ethanol. EA (500 mL*2) was used for extraction, and the organic phases were separated. The combined organic phases were washed once with saturated NaCl (500 mL). The organic phases were dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was passed through a silica gel column (PE / EA = 1 / 1) to obtain a light yellow solid 138-9 (10.1 g, three-step yield: 24.6%).

[1171] In a 500 mL single-necked round-bottom flask, 138-9 (5.0 g, 14.6 mmol, 1.0 eq), DCM (50 mL), and DMF (1 drop) were added. The system was cooled to 0°C, and (COCl)2 (7.4 g, 58.4 mmol, 4.0 eq) was added dropwise. After the addition was complete, the reaction was incubated at 25°C for 1 h. The DCM and excess oxalyl chloride were removed by pressure concentration, and the crude product was set aside.

[1172] In a 500 mL three-necked round-bottom flask, isodecanol (5.08 g, 32.1 mmol, 2.2 eq), DCM (40 mL) and Et3N (8.87 g, 87.6 mmol, 6.0 eq) were added. The system was cooled to 0°C and the prepared acyl chloride was dissolved in DCM (10 mL) and added dropwise to the system. After the addition was complete, the reaction was stirred at 25°C for 2 h. The reaction was monitored by TLC. The conversion of the starting material was complete. The system was quenched by adding H2O (50 mL). The mixture was extracted and separated. The organic phase was washed once with saturated NaCl (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column (PE / EA = 10 / 1) to obtain a light yellow oil 138-10 (4.52 g, 49.5%).

[1173] In a 250 mL three-necked flask, 138-10 (4.52 g, 7.260 mmol, 1.00 eq), methanol (27 mL), and THF (9 mL) were added at room temperature. NaBH4 (276.12 mg, 7.260 mmol, 1.00 eq) was added at 0°C and reacted at 25°C for 1 h. The reaction was monitored by TLC. The starting material reacted completely and the reaction was quenched with water (50 mL) at 0°C. The mixture was diluted with ethyl acetate (50 mL), extracted, and separated. The aqueous phase was back-extracted once with ethyl acetate (50 mL). The combined organic phases were washed once with saturated NaCl (100 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain 138-12 (4.49 g) as a yellow oil.

[1174] In a 250 mL three-necked round-bottom flask, 138-12 (4.49 g, 7.189 mmol, 1 eq), acid (2.6 g, 8.627 mmol, 1.2 eq), EDCI (2.1 g, 10.783 mmol, 1.5 eq), DMAP (878.3 mg, 7.189 mmol, 1 eq), and DCM (45 mL) were added at room temperature. The system was reacted at 25°C for 1 h. The reaction was monitored by TLC, and the starting material conversion was complete. The reaction system was concentrated under reduced pressure to remove DCM. The system was dissolved and diluted with saturated NH4Cl solution (50 mL) and ethyl acetate (50 mL), extracted, and separated. The aqueous phase was back-extracted once with ethyl acetate (50 mL). The combined organic phases were washed once with saturated NaCl (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. 138-13 (6.7 g) was obtained as a yellow oil.

[1175] To a 250 mL three-necked round-bottom flask, 138-13 (6.7 g) and DCM (67 mL) were added at room temperature. HCl in 1,4-dioxane (67 mL, 4 M in 1,4-dioxane) was added dropwise at 0°C. The system was reacted at 25°C for 1 h. The reaction was monitored by TLC, indicating complete conversion of the starting material. The reaction system was concentrated under reduced pressure, and the crude product was passed through a silica gel column (DCM / MeOH = 50 / 1) to obtain a crude product. The product was dissolved and diluted with saturated NaHCO₃ solution (50 mL) and ethyl acetate (50 mL), extracted, and separated. The aqueous phase was back-extracted once with ethyl acetate (50 mL). The combined organic phases were washed once with saturated NaCl (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a yellow oil (2.6435 g, three-step yield: 45.83%).

[1176] 1 H NMR(300MHz, Methanol-d4)δ4.76(q,J=5.9Hz,1H),4.18–4.01(m,4H),3.68(t,J=6.1Hz,2H),2.99(d,J=11.6Hz,2H),2 .55(t,J=6.1Hz,2H),2.36–2.03(m,8H),1.86–1.45(m,16H),1.43–1.01(m,25H),0.98–0.73(m,31H); m / z(ES+),[M+H] + :794.65.

[1177] Other ionizable lipid compounds can be prepared by referring to the above compounds and the preparation methods described in Chinese published patent application CN 115850104 A. Polymer conjugated lipids can be prepared by referring to the preparation methods in the prior art or can be commercially obtained.

[1178] Preparation Example 85 Synthesis of Compound 1P:

[1179] 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 1P-1 (11 g).

[1180] 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 1P-3 (6 g) as a yellow oil, which was used directly in the next reaction without purification.

[1181] Compound 1P-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 1P-5 (7 g).

[1182] Compound 1P-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 1P-6 (3.0 g) as a white solid.

[1183] Compound 1P-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, the reaction was diluted with 50 mL of water and 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 1P-7 (4 g) as a colorless oil.

[1184] Compound 1P-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, the reaction was diluted with 30 mL of water and 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 1P-8 (1.2 g) as a colorless oil.

[1185] Polyethylene glycol methyl ether (PEG 2000) compound 1P-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 sequentially. The reaction was allowed to react at room temperature for 5 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 1P-11 (1.5 g) as a white solid.

[1186] Compound 1P-8 (1.0 g, 0.78 mmol, 1.0 eq.) was dissolved in 10 mL of dichloromethane. Under nitrogen, 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 sequentially. The reaction was allowed to react at room temperature for 4 hours. After completion, the reaction was diluted with 30 mL of water and 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 the crude product, which was purified on a silica gel column to obtain compound 1P-12 (1.4 g) as a white solid.

[1187] Compound 1P-12 (1.2 g, 0.37 mmol, 1.0 eq.) was dissolved in 12 mL of ethyl acetate. Under nitrogen, palladium / carbon (600 mg) was added. The atmosphere was replaced with hydrogen three times. The reaction system was allowed to react at room temperature under a hydrogen atmosphere for 5 hours. After completion, the reaction was filtered, and the filter cake was washed with ethyl acetate (3 x 50 mL). The combined filtrates were then removed from the organic solvent using a rotary evaporator to yield 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 over 9 min) to yield 520.8 mg of compound 1P as a white solid.

[1188] 1H 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] + .

[1189] Preparation Example 86 Synthesis of Compound 2P:

[1190] Compound 2P was prepared by referring to the method of Preparation Example 86 to obtain 412.1 mg of an oily product.

[1191] 1 H 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] + .

[1192] Preparation Example 87 Synthesis of Compound 3P:

[1193] Compound 3P was prepared by referring to the method of Preparation Example 85 to obtain 394.1 mg of an oily product.

[1194] 1H 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 PNMR(300MHz,CD3OD)δ0.25;MS m / z(MALDI-TOF):4677.73[M+H] + .

[1195] Preparation Example 88 Synthesis of Compound 4P:

[1196] Compound 4P was prepared by referring to the method of Preparation Example 85 to obtain 515.5 mg of an oily product.

[1197] 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] + .

[1198] Preparation Example 89 Synthesis of Compound 5P:

[1199] Compound 5P was prepared by referring to the method of Preparation Example 85 to obtain 504.3 mg of an oily product. The mass spectrum is shown in Figure 18.

[1200] 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] + .

[1201] Preparation Example 90 Synthesis of Compound 6P:

[1202] Polyethylene glycol methyl ether (PEG 2000) compound 1P-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 6P-1 (1 g) as a yellow solid.

[1203] Under nitrogen protection, compound 6P-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, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phases were combined, washed with saturated sodium chloride aqueous solution (3 x 10 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. 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 6P-2 (800 mg).

[1204] Compound 6P-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, 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 (HPLC column: YMC-Actus Triart C820×150 mm, 5 μm; phase A: acetonitrile / water (10 mmol / L ammonium bicarbonate + 0.05% ammonia), phase B: isopropanol / acetonitrile; flow rate: 20 mL / min; gradient: 75% B to 95% B, 9 min) to obtain compound 6P (191.0 mg) as a yellow oil. The mass spectrum is shown in Figure 19 .

[1205] 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] + .

[1206] Preparation Example 91 Synthesis of Compound 7P:

[1207] Compound 7P was prepared by referring to the method of Preparation Example 90 to obtain 115.8 mg of an oily product.

[1208] 1 H 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....

Claims

1. A lipid nanoparticle comprising the following lipid components in molar percentages: Ionizable lipids 25 mol%-80 mol%: Structural lipids 3 mol%-60 mol%; Phospholipids 0.5 mol%-60 mol%; Polymer conjugated lipid 0.25mol%-10mol%; in, The ionizable lipid is a compound represented by formula (I), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, 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*; 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*; 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*; 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 ; 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; 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 ; k is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; j is selected from 0 or 1; The dotted line connecting Q and W does not exist or is a chemical bond; W is selected from C, CH or N; 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**; 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; The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; 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 ; R5, R6, R7 and R8 are independently selected from H or C 1-8 alkyl, optionally substituted with one or more R*; 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*; 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*; 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; 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**; 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-; R0 is independently -(CRR')-; 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; or R and R' together with the carbon atom to which they are attached form a 3-8 membered cycloalkylene group; No more than three R0 or R0' in each chain attached to W are cycloalkylene; Q3 and Q4 are independently H, -(CRR')-, C 6-10 an aryl or steroid group, preferably H or -(CRR')-; A1, A2, A3, and A4 are independently -(CR 18 R 18 -CR 18 =CR 18 )-or-(CR 18 R 18 -C≡C)-; R 18 are independently H or C 1-20 alkyl; N1 and N2 are independently biodegradable groups; Z does not exist, C 1-10 Alkylene or -OP(O)(OH)-O-; 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; 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; o, p, w, and x are each independently selected from 0, 1, or 2; s and t are independently selected from 0 or 1; 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; L a and L e Independently selected from chemical bonds or C 1-20 alkylene; L b and L f Independently selected from chemical bonds or C 1-10 alkylene; L c Independently selected from chemical bonds or C 1-8 alkylene; L d Independently selected from chemical bonds or C 1-14 alkylene; 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 ; 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 ; R c and R' c Independently selected from H or C 1-8 alkyl; R d and R' d Independently selected from H or C 1-14 alkyl; R e and R' e Independently selected from H or C 1-20 alkyl; R f and R' f Independently selected from H or C 1-10 alkyl; The condition is that when W is N, j = 0, and the dotted line connecting Q and W does not exist; or for 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; 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 ; 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; 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 ; 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*.

2. The lipid nanoparticle of claim 1, comprising the following molar percentages of lipid components: Ionizable lipids 30 mol%-70 mol%; Structural lipids 3 mol%-50 mol%; Phospholipids 0.5 mol%-50 mol%; Polymer-conjugated lipid 0.25 mol%-5 mol%; Preferably, the lipid nanoparticles contain the following components in molar percentages: Ionizable lipids 35 mol%-65 mol%; Structural lipids 3 mol%-45 mol%; Phospholipids 5mol%-40mol%; Polymer-conjugated lipid 0.25 mol%-5 mol%; Preferably, the lipid nanoparticles contain the following components in molar percentages: Ionizable lipids 40 mol%-60 mol%; Structural lipids 5mol%-40mol%; Phospholipids 5mol%-35mol%; Polymer conjugated lipid 0.25mol%-4.5mol%.

3. The lipid nanoparticle of claim 1 or 2, wherein the ionizable lipid is selected from a compound of formula (II), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, M1 and M2 are independently 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-, -S-S- or -S(O) 0-2 -; Q is selected from a chemical bond, -C(O)O-, -O-, -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 pyridinylene, wherein the phenylene or pyridinylene is optionally substituted with one or more R*; G5 is selected from chemical bonds or C 1-8 Alkylene, optionally substituted with one or more R**; G 6a and G 6b Independently selected from chemical bonds or C 1-7 Alkylene, optionally substituted with one or more R**; And G 6a and G 6b has a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms; R9, R 10 and R** are independently selected from H, C 1-8 Alkyl, -L c -OR c 、-L c -SR c or -L c -NR c R' c ; 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; The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; The total length of G3 and G4 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R3 and R4 are independently selected from H, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, 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*: or R3, 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*; or R4, R9 together with the atoms to which they are attached form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*; 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 ; R5, R6, R7 and R8 are independently selected from C 1-8 alkyl, optionally substituted with one or more R*; R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl or C 4-20 Alkynyl, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with -NR"-; 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 ; R is independently selected from H, C 1-20 Alkyl, -L a -OR a 、-L a -SR a or -L a -NR a R' a ; R" is independently selected from H or C 1-20 alkyl; L a and L e Independently selected from chemical bonds or C 1-20 alkylene; L b and L f Independently selected from chemical bonds or C 1-10 alkylene; L c Independently selected from chemical bonds or C 1-8 alkylene; L d Independently selected from chemical bonds or C 1-14 alkylene; 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 ; 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 ; R c and R' c Independently selected from H or C 1-8 alkyl; R d and R' d Independently selected from H or C 1-14 alkyl; R e and R' e Independently selected from H or C 1-20 alkyl; R f and R' f Independently selected from H or C 1-10 alkyl.

4. The lipid nanoparticle of claim 3, wherein the ionizable lipid is selected from a compound of formula (II'), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, M1 and M2 are independently selected from -C(O)O-, -O-, -SC(O)O-, -OC(O)NRa-, -NRaC(O)NRa-, -OC(O)S-, -OC(O)O-, -NRaC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -NRa-, -C(O)NRa-, -NRaC(O)-, -NRaC(O)S-, -SC(O)NRa-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NRa-, -NRaC(S)O-, -S-S- or -S(O) 0-2 -; preferably -C(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -OC(O)O-, -C(O)NR a - and -NR a C(O)-; preferably -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -OC(O)-; a, b and g are independently selected from 0, 1, 2, 3, 4 or 5, preferably 0, 1, 2 or 3; a and b are not 0 at the same time; a+g=0, 1, 2, 3, 4, or 5; G1 and G3 are independently selected from 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms; preferably 2, 3, 4, 5 or 6 carbon atoms; G2 and G4 are independently 0, 1, 2, 3 or 4 carbon atoms; preferably 0, 1 or 2 carbon atoms; G1+G2=3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably 4, 5, 6, 7, 8 carbon atoms; G3+G4=3, 4, 5, 6, 7, 8 or 9 carbon atoms, preferably 4, 5, 6, 7, 8 carbon atoms; The methylene group in the 1-6 Alkyl substitution; R3 is selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 3 to 10-membered cycloalkyl or 3 to 10-membered heterocyclic group, preferably C 1-6 Alkyl and C 1-6 haloalkyl, optionally substituted with 1, 2, 3, 4 or 5 R*; or R3 together with the N atom to which they are attached form a 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R*; R* is independently selected from H, halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -L b -OR b or -L b -NR b R' b ; preferably H, C 1-6 Alkyl, C 1-6 Haloalkyl or -L b -OR b ; R5, R6, R7 and R8 are independently H or C 1-6 Alkyl, preferably C 1-3 Alkyl, preferably methyl, optionally substituted with 1, 2, 3, 4 or 5 R*; R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl or C 4-20 Alkynyl, optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with -NR"; R and R' are independently selected from H, C 1-14 Alkyl, -L a -OR a or -L a -NR a R' a ; L a Independently selected from chemical bonds or C 1-14 alkylene; L b Independently selected from chemical bonds or C 1-6 Alkylene, preferably a chemical bond; R a and R' a Independently selected from H, C 1-14 Alkyl, 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclic group, preferably H or C 1- 14 alkyl; R b and R' b Independently selected from H, C 1-6 Alkyl, 3 to 10 membered cycloalkyl or 3 to 10 membered heterocyclic group, preferably H or C 1-6 Alkyl, preferably H; R" is independently selected from H or C 1-14 alkyl; Preferably, the R is selected from C 1-6 Alkyl, preferably C 1-3 alkyl; Preferably, said R1 and R2 are independently selected from Preferably, a and b are 2; g is 0 or 1, preferably 1.

5. The lipid nanoparticle of claim 1 or 2, wherein the ionizable lipid is selected from a compound of formula (III), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, G1 and G2 are independently selected from chemical bonds, C 1-13 Straight chain alkylene, C 2-13 Straight chain alkenylene and C 2-13 Straight chain alkynylene, which is optionally substituted by one or more R G1 replace; The total length of G1 and G2 is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms; R G1 Independently selected from H, C 1-14 Alkyl, -L a -OR a 、-L a -SR a and -L a -NR a R' a ; G3 is selected from C 4-14 Straight chain alkylene, C 4-14 Straight chain alkenylene and C 4-14 Straight chain alkynylene, which is optionally substituted by one or more R G3 replace; R G3 Independently selected from H, -L a -OR a 、-L a -SR a and -L a -NR a R' a ; L a Independently selected from chemical bonds and C 1-14 alkylene; R a and R' a Independently selected from H, C 1-14 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; 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; 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 ; L b Independently selected from chemical bonds and C 1-6 alkylene; R b and R' b Independently selected from H, C 1-6 Alkyl, C 3-10 cycloalkyl and 3- to 10-membered heterocyclyl; 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; 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 ; L e Independently selected from chemical bonds and C 1-8 alkylene; R e and R' e Independently selected from H, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -O-, -SC(O)O-, -OC(O)NR-, -NRC(O)NR-, -OC(O)S-, -OC(O)O-, -NRC(O)O-, -SC(O)-, -C(O )S-, -NR-, -C(O)NR-, -NRC(O)-, -NRC(O)S-, -SC(O)NR-, -C(O)-, -OC(S)-, -C(S)O-, -OC(S)NR-, -NRC(S)O-, -SS-, and -S(O) 0-2 -; preferably selected from -C(O)O-, -OC(O)-, -OC(O)O-, -SC(O)-, -C(O)S-, -C(O)NR- and -NRC(O)-; preferably -C(O)O-, -OC(O)-, -SC(O)O-, -OC(O)S- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -OC(O-; preferably -OC(O)O-; 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 pyridylene, wherein the phenylene or pyridylene is optionally substituted by one or more R*; preferably 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-, and -S(O) 0-2 -; preferably chemical bonds, -OC(O)- and -SC(O)-; R* is independently selected from H, halogen, cyano, C 1-10 Alkyl, C 1-10 Halogenated alkyl, -L f -OR f 、-L f -SR f and -L f -NR f R' f ; L f Independently selected from chemical bonds and C 1-8 alkylene; R f and R' f Independently selected from H, C 1-10 Alkyl, C 3-14 Cycloalkyl and 3 to 14 membered heterocyclic groups; preferably H and C 1-10 alkyl; R1 and R2 are independently selected from C 4-20 Alkyl, C 4-20 Alkenyl and C 4-20 Alkynyl, which is optionally substituted by one or more R 1s substituted, and wherein one or more methylene units are optionally and independently replaced by -NR'-; R 1s Independently selected from H, C 1-20 Alkyl, -L c -OR c 、-L c -SR c and -L c -NR c R' c ; R and R' are each independently selected from H and C 1-20 alkyl; L c Independently selected from chemical bonds and C 1-20 alkylene; R c and R' c Independently selected from H, C 1-20 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; R'3 is selected from CN, -OR g 、-C(O)R g 、-OC(O)R g 、-NR”C(O)R g 、-NR g R' g 、-NR”C(O)NR g R' g 、-NR”C(O)R g 、-NR”S(O)2R g 、-OC(O)NR g R' g 、-NR”C(O)OR g 、-N(OR g )C(O)R g 、-N(OR g )S(O)2R g 、-N(OR g )C(O)OR g 、-N(OR g )C(O)R g R' g , 3 to 14 membered heterocyclic and 5 to 14 membered heteroaryl; preferably CN, -OR g and -NR g R' g ; preferably selected from -OR g and -NR g R' g ; preferably -OR g ; preferably OH; R g and R' g Independently selected from H, C 1-10 Alkyl, C 3-10 Cycloalkyl and 3 to 10 membered heterocyclic groups; preferably H and C 1-10 alkyl; R" is independently selected from H and C 1-6 alkyl; R5 and R6 are independently selected from C 1-8 Alkyl, preferably C 1-3 Alkyl, more preferably methyl, optionally replaced by one or more R 4s replace; Or R5, R6 together with the carbon atom to which they are attached form C 3-14 Cycloalkylene or 3 to 14 membered heterocyclylene, which is optionally substituted by one or more R 4s replace; R 4s are independently selected from H, halogen, cyano, C 1-8 Alkyl, C 1-8 Halogenated alkyl, -L d -OR d 、-L d -SR d and -L d -NR d R' d ; L d Independently selected from chemical bonds and C 1-8 alkylene; R d and R' d Independently selected from H, C 1-8 Alkyl, C 3-14 Cycloalkyl and 3- to 14-membered heterocyclyl; Preferably, in the compound of formula (III), or its isotopic variant, tautomer or stereoisomer, or its pharmaceutically acceptable salt, Q1 is selected from -C(O)O-, -SC(O)O-, -OC(O)S-, -OC(O)O-, -OC(O)-, -SC(O)-, -C(O)S-, -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-, and -S(O) 0- 2-; preferably chemical bonds, -OC(O)- and -SC(O)-; M1 and M2 are independently selected from -C(O)O-, -OC(O)-, -SC(O)O-, -OC(O)S- and -OC(O)O-; preferably -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; preferably -C(O)O- and -OC(O)-; preferably -OC(O)O-.

6. The lipid nanoparticle of claim 5, wherein the compound of formula (III), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, has a structure of formula (III'): in, a = 1, 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=3, 4, 5, 6, 7, 8, or 9; M1, M2, R1, R2, R5, and R6 are each defined in claim 5; Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; Preferably, R5 and R6 are independently selected from C 1-6 Alkyl, preferably selected from C 1-3 Alkyl, more preferably methyl; Preferably, R5 and R6 are optionally replaced by 1, 2 or 3 R 4s replace; Preferably, a=2, 3, 4, 5 or 6; preferably a=2, 3, 4 or 5; preferably a=2, 3 or 4; Preferably, b=4, 5, 6, 7, 8 or 9; preferably b=5, 6, 7 or 8; preferably b=6, 7 or 8; Preferably, c = 2, 3, 4, 5 or 6; preferably c = 2, 3, 4 or 5; Preferably, d=0, 1, 2 or 3; Preferably, c+d=4, 5, 6, 7 or 8; preferably c+d=5, 6 or 7.

7. The lipid nanoparticle of claim 5 or 6, wherein the R5, R6 together with the carbon atom to which they are attached form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene, preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene, preferably forming C 3-6 Cycloalkylene, preferably forming C 3-5 Cycloalkylene, preferably forming cyclopropylene or cyclopentylene, preferably forming cyclopropylene; Preferably, the ring formed by R4, R5 and the carbon atom to which they are attached is optionally substituted by 1, 2 or 3 R 4s replace.

8. The lipid nanoparticle of claim 5, wherein the compound of formula (III) is a structure represented by formula (III"): in, a = 1, 2, 3, 4, 5, or 6; b = 4, 5, 6, 7, 8, 9, or 10; c = 1, 2, 3, 4, 5, or 6; d = 0, 1, 2, 3, or 4; c+d=3, 4, 5, 6, 7, 8, or 9; M1, M2, R1, R2, R5, and R6 are each defined in claim 5; Preferably, M1 and M2 are independently selected from -C(O)O-, -OC(O)- and -OC(O)O-; Preferably, R5 and R6 are independently selected from C 1-6 Alkyl, preferably selected from C 1-3 Alkyl, more preferably methyl; Preferably, R5 and R6 are optionally replaced by 1, 2 or 3 R 4s replace; Preferably, the R5, R6 together with the carbon atom to which they are attached form C 3-10 Cycloalkylene or 3 to 10 membered heterocyclylene, preferably forming C 3-6 Cycloalkylene or 3 to 6 membered heterocyclylene, preferably forming C 3-6 Cycloalkylene, preferably forming C 3-5 Cycloalkylene, preferably forming cyclopropylene or cyclopentylene, preferably forming cyclopropylene; Preferably, the ring formed by R5 and R6 and the carbon atom to which they are attached is optionally substituted by 1, 2 or 3 R 4s replace; Preferably, a=2, 3, 4 or 5; preferably a=3 or 4; Preferably, b=5, 6, 7 or 8; preferably b=6 or 7; Preferably, c = 2, 3, 4 or 5; preferably c = 2, 4 or 5; Preferably, d = 1, 2, 3 or 4; preferably d = 1, 2 or 4; Preferably, c+d=4, 5, 6, 7 or 8; preferably c+d=5, 6 or 7; preferably c+d=6.

9. The lipid nanoparticle of claim 1, 2 or 5, wherein the compound of formula (I) is selected from any one or more of the following:

10. The lipid nanoparticle of any one of claims 1 to 9, wherein the ionizable lipid is selected from one or more of the following: 1,2-dioleoyloxy-3-dimethylaminopropane (DODAP), 1,2-dioleyloxy-3-dimethylaminopropane (DODMA), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), 2,2-dilinoleoyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), 4-(N,N-dimethylamino)- 4-(N,N-dimethylamino)butyric acid (dilinoleyl) methyl ester (DLin-MC3-DMA), 8-[(2-hydroxyethyl)(6-oxo-6-decyloxyhexyl)amino]octanoate (heptadecan-9-yl) ester (SM-102) and [(4-hydroxybutyl)azadiyl]bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315); preferably selected from 4-(N,N-dimethylamino)butyric acid (dilinoleyl) methyl ester and / or [(4-hydroxybutyl)azadiyl]bis(hexane-6,1-diyl)bis(2-hexyldecanoate).

11. The lipid nanoparticle of any one of claims 1 to 10, wherein the polymer-conjugated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol; Preferably, the polymer-conjugated lipid comprises a PEG moiety of 400 Da to 20 kDa, more preferably a PEG moiety of about 1000 Da to about 5000 Da.

12. The lipid nanoparticle of claim 11, wherein the polymer-conjugated lipid is selected from a compound of formula (IIP-A1) or formula (V), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in, R 11 is H, optionally substituted alkyl or an oxygen protecting group; 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; 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 heterocyclic groups.

13. The lipid nanoparticle of claim 12, 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 (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 H, C 1-26 Alkyl, C 2-26 Alkenyl and C 2-26 Alkynyl; preferably H and C 1-26 alkyl; 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.

14. The lipid nanoparticle of claim 12 or 13, 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 (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 400 g / mol to about 6000 g / mol; more preferably, has an average molecular weight of 1500 g / mol to about 5000 g / mol; more preferably, has an average molecular weight of 2000 g / mol, 3500 g / mol, or 5000 g / mol.

15. The lipid nanoparticle of any one of claims 12 to 14, wherein R 11 C 1-3 Alkyl, preferably -CH3.

16. The lipid nanoparticle of claim 12, wherein the polymer-conjugated lipid of formula (IIP-A1) or formula (IIIP-A1) is a compound of formula (IVP-A1) or formula (VP-A1), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 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; The remaining variables are as defined in any one of claims 12-15; Preferably, R 21 、R 31 and R 41 Not R V replace; Preferably, in formula (IVP-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 (VP-A1), R V For H.

17. The lipid nanoparticle of any one of claims 12-16, wherein the polymer-conjugated lipid is selected from one or more of the following compounds: 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, 44, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 144 or 120, more preferably 44, 80 or 114; Preferably, n1 ranges such that the PEG moiety of Formula (IIP-A1) or Formula (IIIP-A1) has an average molecular weight of 400 g / mol to about 6000 g / mol; more preferably, has an average molecular weight of 1500 g / mol to about 5000 g / mol; more preferably, has an average molecular weight of 2000 g / mol, 3500 g / mol, or 5000 g / mol.

18. The lipid nanoparticle of any one of claims 1 to 10, wherein the polymer-conjugated lipid is a compound of formula (IP'), 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-.

19. The lipid nanoparticle of claim 18, wherein the polymer-conjugated lipid is a compound of formula (IP), 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, 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 heterocyclic groups.

20. The lipid nanoparticle of claim 19, wherein the polymer-conjugated lipid is a compound of formula (IIP), formula (IIP-A1), formula (IIP-A2) or formula (IIP-A3), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 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 heterocyclic groups.

21. The lipid nanoparticle of claim 20, wherein the polymer-conjugated lipid is a compound of Formula (IVP), Formula (IVP-B), Formula (IVP-C), Formula (IVP-A1), Formula (IVP-A2), or Formula (IVP-A3), or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 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 (IP') or Formula (IP); 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.

22. The lipid nanoparticle of claim 19, wherein the polymer-conjugated lipid is a compound of Formula (IIIP), Formula (IIIP-A1), Formula (IIIP-A2) or Formula (IIIP-A3), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 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 、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.

23. The lipid nanoparticle of claim 22, wherein the polymer-conjugated lipid is a compound of formula (VP), formula (VP-A1), formula (VP-A2) or formula (VP-A3), or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 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 individually defined as in Formula (IP'), Formula (IP) or Formula (IVP).

24. The lipid nanoparticle according to any one of claims 18 to 23, 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 -NHC(O)-, -OC(O)-, -C(O)-, -OC(O)O- or absent; 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.

25. The lipid nanoparticle according to any one of claims 18 to 24, 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 heterocyclic groups; preferably H and C 1-20 alkyl; Preferably, 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, R V is H; Preferably, in Formula (IVP), Formula (IVP-B), Formula (IVP-C), Formula (IVP-A1), Formula (IVP-A2), Formula (IVP-A3), Formula (VP), Formula (VP-A1), Formula (VP-A2), and Formula (VP-A3), R 21 、R 31 and R 41 Not R V replace.

26. The lipid nanoparticle according to any one of claims 18 to 25, wherein n1 is an integer of 10 to 120; preferably an integer of 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, 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 6, 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.

27. The lipid nanoparticle according to any one of claims 18 to 26, 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.

28. The lipid nanoparticle according to any one of claims 18 to 27, 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.

29. The lipid nanoparticle according to any one of claims 18 to 28, wherein The polymer conjugated lipid is selected from the following compounds: 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; 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.

30. The lipid nanoparticle according to any one of claims 18 to 29, wherein The polymer conjugated lipid is selected from the following compounds: Preferably, the polymer-conjugated lipid is selected from the following compounds:

31. The lipid nanoparticle of any one of claims 1 to 10, wherein the polymer conjugated lipid is selected from one or more of the following: DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000, DSPE-PEG2000-Mannose, DSPE-PEG2000 amine, DSPE-PEG3350, DSPE-PEG3500, DSPE-PEG4000, DPPE-PEG3500, Ceramide-PEG5000, DSPE-PEG5000 and ALC-0159, preferably DSPE-PEG2000, DSPE-PEG3350, DSPE-PEG3500, DSPE-PEG4000 and / or DSPE-PEG5000.

32. The lipid nanoparticle of any one of claims 1-31, wherein the structured lipid is selected from one or more of the following: cholesterol, sitosterol, coprosterol, saposterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campesterol, preferably selected from cholesterol and / or β-sitosterol, more preferably cholesterol.

33. The lipid nanoparticle of any one of claims 1-32, wherein the phospholipid is selected from one or more of the following: distearoylphosphatidylcholine (DSPC), glycolylphosphatidylethanolamine (DOPE), dimercaptoglycerol phosphate (DMPC), 1,2-diacetyl-sn-glycero-3-phosphocholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dimercapto-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-cosanoyl-sn-glycero-3-phosphoethanolamine (DPPE), dipalmitoylphosphatidylcholine (DPPC), and hexadecanoyl-2-(9Z octadecenoyl)-sn-glycero-3-phosphoethanolamine (POPE).

34. A lipid nanoparticle composition comprising the lipid nanoparticle of any one of claims 1-33 and an optional load.

35. The lipid nanoparticle composition of claim 34, 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 mRNA, siRNA, gRNA, more preferably modified mRNA; Preferably, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

36. The lipid nanoparticle composition of claim 34 or 35, wherein The N:P molar ratio of the N atoms in the ionizable lipid to the P atoms in the charge molecule is (1-15):1, preferably (2-12):1, preferably (2-9):1; Preferably, the N:P molar ratio of the N atoms in the ionizable lipid to the P atoms in the load molecule is (2-15):1, preferably (2-12):1, more preferably (2-10):1, more preferably (2-8):1, more preferably (2-6):1; preferably, the N:P molar ratio of the N atoms in the ionizable lipid to the P atoms in the load molecule is (1-12):1, preferably (4-11):1, more preferably (4-10):1, more preferably (4-9):1; Preferably, the N:P molar ratio of the N atoms in the ionizable lipid to the P atoms in the charge molecule is 6, 7.5, 9, or 10.

5.

37. The lipid nanoparticle composition of any one of claims 34 to 36, wherein the particle size is 40-500 nm, preferably 50-250 nm, preferably 50-200 nm, more preferably 50-150 nm; Preferably, the particle size is 40-200 nm, preferably 40-160 nm, preferably 40-150 nm, more preferably 40-120 nm, more preferably 40-100 nm; Preferably, the particle size is 50-300 nm, preferably 50-180 nm, more preferably 50-120 nm; Preferably, the particle size is 50-200 nm, preferably 50-160 nm, preferably 70-150 nm, more preferably 70-120 nm.

38. A method for preparing the lipid nanoparticle composition according to any one of claims 34 to 37, comprising: The lipid components in the lipid nanoparticles are mixed, and then mixed with the load to obtain the product.

39. A pharmaceutical composition comprising the lipid nanoparticle composition according to any one of claims 34 to 37, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.

40. Use of the lipid nanoparticle composition according to any one of claims 34 to 37 or the pharmaceutical composition according to claim 39 in the preparation of a medicament for treating, diagnosing or preventing a disease; Preferably, the disease is selected from muscle diseases or muscle-related diseases.

41. Use of the lipid nanoparticles according to any one of claims 1 to 33, the lipid nanoparticle composition according to any one of claims 34 to 37, or the pharmaceutical composition according to claim 39 in the preparation of drugs for gene editing, protein replacement and / or supplementation, or gene interference.

42. Use of the lipid nanoparticle according to any one of claims 1 to 33, the lipid nanoparticle composition according to any one of claims 34 to 37, or the pharmaceutical composition according to claim 39 in the preparation of a drug for delivering a load, preferably in the preparation of a drug for delivering a load to muscle.

43. A method for treating, diagnosing, or preventing a disease in a subject using the lipid nanoparticle of any one of claims 1 to 33, the lipid nanoparticle composition of any one of claims 34 to 37, or the pharmaceutical composition of claim 39, comprising administering the lipid nanoparticle composition or the pharmaceutical composition to the subject; Preferably, the disease is a muscle disease or a muscle-related disease.

44. The method of claim 43, wherein the lipid nanoparticle composition or pharmaceutical composition is administered via a nanoparticle system, preferably systemically, preferably intravenously, intraarterially or intraperitoneally, more preferably intraperitoneally or intravenously.

45. The lipid nanoparticle of any one of claims 1-33, the lipid nanoparticle composition of any one of claims 34-37, or the pharmaceutical composition of claim 39, for use in delivering a load; Preferably, it is used to deliver load to muscle.

46. ​​The use of claim 42 or the lipid nanoparticle or lipid nanoparticle composition or pharmaceutical composition of claim 45, 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 mRNA, siRNA, gRNA, more preferably modified mRNA; Preferably, the DNA is selected from one or more of plasmid DNA (pDNA), single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), preferably one or more of minicircle DNA (mcDNA), complementary DNA (cDNA), chloroplast DNA (cpDNA), multicopy single-stranded DNA (msDNA), mitochondrial DNA (mtDNA) or ribosomal DNA (rDNA).

47. A method for treating or preventing a muscle disease or a muscle-related disease in a subject suffering from the disease, comprising administering to the subject by systemic administration a therapeutically effective amount of the lipid nanoparticle according to any one of claims 1 to 33, the lipid nanoparticle composition according to claims 34-37, or the pharmaceutical composition according to claim 39; The systemic administration is preferably systemic injection, preferably intravenous injection, arterial injection or intraperitoneal injection, more preferably intraperitoneal injection or intravenous injection.

48. Use of the polymer-conjugated lipid compound according to any one of claims 12 to 30 or lipid nanoparticles containing the polymer-conjugated lipid compound according to any one of claims 12 to 30 in any of the following fields: i. Preparation of drugs for targeting muscles; ii. Preparation of a medicament for treating muscle diseases or muscle-related diseases; iii. Use in the preparation of a medicament for delivering a gene product to the muscle of a subject, wherein the gene product is a medicament for gene editing, protein replacement and / or supplementation, or gene interference.

49. A compound, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the following:

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