Lipophilic compound, preparation method therefor and use thereof

Abstract

The present invention relates to a lipophilic compound, a preparation method therefor and the use thereof. The lipophilic compound has a structure as shown in formula I: R2-X-R1-OH (formula I); wherein R1 is C2-C26 alkylenecarboxyacyl which contains one carboxyacyl group; R2 is selected from hydrogen, C1-C24 alkylcarboxyacyl / alkenylcarboxyacyl / alkyl / alkenyl, C6-C16 (aryl / heteroaryl / arylalkenyl / aralkyl / polyene)ylcarboxyacyl, C8-C18 aryl / arylalkenyl, dehydroxylated residue of C5-C45terpene alcohol, dehydroxylated residue of C20-C30 lipid-soluble vitamins, dehydroxylated residue of C18-C29 sterols, and carboxyacyl of C19-C26 carboxyl-containing steroids; -OH and the carboxyacyl residue of R1 are covalently linked to form carboxyl; and X is a linking group and covalently links to both R1 and R2. The present invention further relates to the use of the compound in the preparation of a chemically modified drug and in the promotion of transdermal absorption of drug molecules.

Description

A lipophilic compound, preparation method and application thereof Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a lipophilic compound, a preparation method and application thereof. Background Art

[0002] Lipids are important components of human tissues and organs, and different forms of lipid substances exist in the skin, muscles, nerves, bones, and blood. For example, phospholipids are one of the basic substances of life. Cell membranes are mainly composed of phospholipids, glycolipids, and proteins in a certain proportion. Neurophospholipids participate in the formation of brain and peripheral nerve tissues; sterols are important lipid substances for the synthesis of steroid hormones in animals, and triglycerides are mainly used as fat tissue in the body for energy storage. Because lipid substances are highly compatible with the human body, some natural and synthetic lipids or lipophilic substances are widely used in the construction of medical bionic materials and delivery systems for various drugs. Among them, liposomes (liposome) / lipid nanoparticles (LNP) delivery systems are considered to be one of the most successful diagnosis and delivery systems in modern medicine. Its applications include drug carriers, biological diagnostics and signal carriers, vaccine adjuvants, nanomedicine delivery carriers, etc. To date, dozens of liposome drugs have been approved for marketing worldwide, with indications covering tumors, infections, inflammation, and analgesia. In 2018, lipid nanoparticles pioneered RNAi drugs. It set a precedent for successful listing and subsequently shined in the rapid development and market launch of the new crown (COVID-19) vaccine from 2020 to 2021. The application value of lipids and lipophilic substances as a class of drug delivery carriers, especially in the field of nucleic acid drug delivery, has further attracted great attention from the industry.

[0003] Nucleic acid drugs have the advantages of short R&D cycles, high success rates, strong specificity, and the ability to fundamentally regulate pathogenic genes. They mainly include antisense oligonucleotides (ASOs), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), messenger RNA (mRNA), and nucleic acid aptamers (Aptamers). For example, ASOs are short synthetic nucleic acids that use classic Watson-Crick base pairing to hybridize with cellular RNA to regulate gene expression. They can regulate protein synthesis by affecting pre-mRNA processing and splicing, competitively inhibiting mRNA translation, or recruiting nucleases to degrade target mRNA. siRNA is a double-stranded RNA that degrades target mRNA by inducing the formation of an RNA silencing complex (RISC). Nucleic acid aptamers can fold into unique three-dimensional structures and specifically bind to target proteins, small molecules, bacteria, viruses, etc. to exert their effects. However, nucleic acid drugs also have some inherent problems that limit their drugability. For example, they have poor in vivo stability and are easily degraded by nucleases or cleared by the kidneys. They have a large molecular weight and carry a negative charge, making it difficult for them to cross biological barriers such as cell membranes. They lack targeting in the body, and in actual applications, they can cause side effects due to off-target effects. Drugs that enter the circulatory system or cells are subject to nonspecific protein adsorption, immunogenic reactions, or lysosomal hydrolysis, rendering them ineffective. Therefore, in addition to loading through LNP carriers, covalent binding methods such as chemical modification or ligand coupling are effective scientific methods to improve nucleic acid stability, reduce immunogenicity, enhance the ability to cross biological barriers, and improve pharmacokinetic properties.

[0004] Studies have shown that lipids or lipophilic substances covalently bound to oligonucleotides can alter the in vivo distribution of nucleic acids and enhance their delivery efficiency. For example, siRNA covalently bound to cholesterol effectively silences myostatin and induces muscle growth, while siRNA covalently bound to tocopherol reduces ApoB expression in mouse liver. Cholesterol-conjugated RNA can enhance its uptake into specific tissues and cells by preassembling with high-density lipoprotein (HDL) or low-density lipoprotein (LDL). Other studies have found that the in vivo binding efficacy of siRNA-lipid conjugates to different lipoprotein types is influenced by their hydrophilicity. By conjugating to lipids with varying hydrophobicity, the aggregation of RNA drugs to different target tissues can be influenced. Other studies have shown that drug interactions with biological membranes can influence their cellular uptake, retention, distribution, and accumulation, playing a central role in drug bioactivity. The strategy of conjugating drugs to medium-chain fatty acids (MCFAs, generally fatty acids with 6 to 12 carbon atoms) offers important insights for improving the cellular permeability and bioactivity of drugs, primarily small molecules. Alnylam Pharmaceuticals studied siRNA targeting the central nervous system target SOD1 (superoxide dismutase 1). After coupling it to lipophilic alkyl chains of different lengths, it was found that the knockdown activity of siRNA generally increased with the increase of lipid chain length, and the nucleic acid coupled to C16 had the strongest RNAi effect in the rat spinal cord and brain (Nat Biotechnol 2022, 40, 1500-1508). Ionis Pharmaceuticals has coupled ASOs conjugated to various natural lipids, such as cholesterol and hexadecanoic acid (C16). Animal experiments have found that lipids can exponentially enhance the accumulation and knockdown activity of ASOs in tissues (including the heart and quadriceps, etc.) (Nucleic Acids Research 2020, 48, 4382-4395). However, the types of natural lipids or lipophilic alkyl compounds are limited, and some are difficult to obtain. The lipophilic properties limited by the range of their natural structural variations cannot meet the needs of various drugs for the diversity of lipid delivery molecules. Therefore, it is still necessary to develop more types and certain specific structures of lipids or lipophilic substances through synthetic means to support the research on targeted drug delivery and delivery structure-activity relationship for different tissues and organs, and broaden the therapeutic field of macromolecular drugs such as nucleic acids.

[0005] Based on this, the present invention is proposed. Summary of the Invention

[0006] The present invention first relates to a lipophilic compound having a structure as shown in the following formula I:

[0007] R2-X-R1-OH (Formula I),

[0008] in,

[0009] R1 is C2~C 26 an alkylenecarboxylic acid group containing one carboxylic acid group;

[0010] R2 is selected from hydrogen, C1~C 24 Alkylcarboxyl / alkenylcarboxyl / alkyl / alkenyl, C5~C 16 (aromatic / heteroaromatic / aromatic olefin / aromatic alkane / diolefin) carboxyl, C8~C 18 Aromatic / aromatic alkenyl, C5~C 45 Dehydroxylated residues of terpene alcohols, C 20 ~C 30 Dehydroxylated residues of fat-soluble vitamins, C 18 ~C 29 Dehydroxylated residues of sterols, C 19 ~C 26 Carboxyl groups of carboxysteroids;

[0011] -OH is covalently linked to the carboxyl residue of R1 to form a carboxyl group;

[0012] X is a linking group that is covalently linked to both R1 and R2. The linking group X plays a key connecting role in the structure of the compound of the present invention. Different choices of X can affect the chemical stability of the compound. The conversion and connection processes involved are also major steps in the compound preparation method.

[0013] Furthermore, when R1 is When the structure of the compound is as shown in Formula Ia,

[0014] in,

[0015] (1) The connection site on R1 with the X group is located on any carbon of R1 except the 1st acyl carbon to the 3rd hydrocarbon carbon (located on R4), and the carbon chain from the 1st acyl carbon to the carbon connected to the X group in R1 is a linear main carbon chain. The group formed from carbon No. 4 in the linear main carbon chain to the carbon connected to the X group is R4;

[0016] Preferably, the linear main carbon chain is a saturated carbon chain or contains a carbon-carbon double bond;

[0017] Preferably, the attachment site is on a saturated carbon atom;

[0018] Preferably, R4 is selected from: C2 to C 10 Linear alkenyl, C1~C 17 Linear alkylidene; More preferably, R4 is selected from: C6~C9 linear alkenyl, C1~C9 linear alkylidene;

[0019] and,

[0020] (2) The portion other than the linear main carbon chain group on R1 is R3,

[0021] Preferably, R3 is selected from: hydrogen, C2-C8 linear / branched alkene, C1-C 10 Linear / branched alkyl; More preferably, R3 is selected from: hydrogen, C1~C 10 Linear alkyl.

[0022] Further,

[0023] X is selected from:

[0024] Oxygen, sulfur, sulfonyl (ylidene) group, sulfinyl (ylidene) group, imine group, amineoxy subunit, amino / aminooxyformate subunit, dicarboxylic acid diester subunit containing linear / branched / cyclic structure or diol / phenol diether subunit.

[0025] R1 is selected from:

[0026] (1) C4~C 26 A linear alkenecarboxylic acid group, preferably a butylenecarboxylic acid group having a 4-alkane residue, a decenoylenecarboxylic acid group having a 10-alkane residue, or an octadecenoylenecarboxylic acid group having a 12-alkane residue; or

[0027] (2) C2~C 20 Linear alkylenecarboxyl groups, preferably (ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl / nonyl / decyl / undecane / dodecane / tridecane / tetradecane / pentadecane / hexadecane / heptadecane / octadecane) acyl groups having a 2-alkane residue, propionyl groups having a 3-alkane residue, butyryl groups having a 4-alkane residue, valeryl groups having a 5-alkane residue, hexanoyl groups having a 6-alkane residue, heptanoyl groups having a 7-alkane residue, octanoyl groups having an 8-alkane residue, nonyl groups having a 9-alkane residue acyl, decanoyl having a 10-alkane residue, undecanoyl having a 11-alkane residue, dodecanoyl having a 12-alkane residue, octadecanoyl having a 12-alkane residue, tridecanoyl having a 13-alkane residue, tetradecanoyl having a 14-alkane residue, pentadecanoyl having a 15-alkane residue, hexadecanoyl having a 16-alkane residue, heptadecanoyl having a 17-alkane residue, octadecanoyl having an 18-alkane residue; or

[0028] (3) a C4-C8 branched alkylene carboxyl group, preferably an isovaleryl group having a 2-alkane residue, a 3-methylvaleryl group having a 2-alkane residue, a 4-methylvaleryl group having a 2-alkane residue, or a 3,3-dimethylbutanoyl group having a 2-alkane residue; or

[0029] (4) C7~C 10An alkylenecarboxyl group containing a cycloalkyl structure, preferably a cyclohexylideneacetyl group having a 2-alkane residue or a 3-cyclohexylenepropionyl group having a 2-alkane residue; or

[0030] (5) C8~C 16 The aralkylenecarboxylic acid group is preferably a phenylacetylene group having a 2-alkane residue, a phenylpropionylene group having a 2-alkane residue, a phenylbutyrylene group having a 2-alkane residue, a phenylvalerylene group having a 2-alkane residue, a phenylhexanoylene group having a 2-alkane residue, a phenylheptanoylene group having a 2-alkane residue, a p-toluoacetylene group having a 2-alkane residue, a p-toluopropionylene group having a 2-alkane residue, a m-toluopropionylene group having a 2-alkane residue, an o-toluopropionylene group having a 2-alkane residue, a 3-(4-tert-butylphenyl)propionylene group having a 2-alkane residue, a 3-(4-biphenylyl)propionylene group having a 2-alkane residue, a 3-(1-naphthyl)propionylene group having a 2-alkane residue, or a 3-(2-naphthyl)propionylene group having a 2-alkane residue.

[0031] R2 is selected from: hydrogen; or

[0032] (1) C3~C 24 Linear alkenecarboxyl; preferably acryloyl, butenoyl, pentenoyl, pentadienoyl, hexenoyl, hexadienoyl, heptenoyl, octenoyl, nonenoyl, decenoyl, undecenoyl, oleoyl, erucoyl, neuranoyl, linoleoyl, α-linolenoyl, arachidonic acid, eicosapentaenoyl, docosahexaenoyl; or

[0033] (2) C4~C 10 Branched alkenecarboxyl; preferably 2-methacryloyl, 3,3-dimethylacryloyl, 2-methylbutenoyl, 2-methylpentenoyl, 2,2-dimethylpentenoyl, 2-methylhexenoyl, 3,7-dimethyl-6-octenoyl (citronellal (acid) acyl), geranyl (acid) acyl; or

[0034] (3) C6~C 20 An alkenecarboxyl group containing a cyclic structure; preferably a cyclopentenecarboxyl group, a cyclohexenecarboxyl group, a 2-cyclopentenyl-1-acetyl group, a 5-norbornene-2-carboxyl group, a retinoic acid group, an isotretinoic acid group, or a rosincarboxyl group; or

[0035] (4) C1~C2 and C 10 ~C 22 Linear alkanoyl; preferably formyl, acetyl, n-decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, eicosanoyl, behenoyl; or

[0036] (5) C4~C12 branched alkanecarboxyl; preferably iso(butyryl / pentyryl / hexyryl / heptyryl / octyryl / nonyl)acyl, 2-methyl(butyryl / pentyryl / hexyryl / heptyryl / octyryl), 2-ethyl(butyryl / pentyryl / hexyryl / heptyryl / octyryl), 2,2-dimethyl(propyryl / butyryl / hexyryl / heptyryl / octyryl), 3,3-dimethylbutyryl, 4,4-dimethylpentyryl, 5,5-dimethylhexyryl, 6,6-dimethylheptyryl, 7,7-dimethyloctyl, propyryl, 3-methylbutyryl, 3-methylpentyryl, 4-methyl(hexyryl / heptyryl / octyryl); or

[0037] (6) C4~C 16 an alkanecarboxyl group containing a cyclic structure; preferably a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, a cycloheptylcarbonyl group, a cyclopropylacetyl group, a cyclobutylacetyl group, a cyclopentylacetyl group, a cyclohexylacetyl group, a cyclopentylpropionyl group, a cyclohexylpropionyl group, a 4-methylcyclohexylcarbonyl group, a 4-ethylcyclohexylcarbonyl group, a 4-propylcyclohexylcarbonyl group, a 4-isopropylcyclohexylcarbonyl group, a 4-butylcyclohexylcarbonyl group, a 4-pentylcyclohexylcarbonyl group, a 4-hexylcyclohexylcarbonyl group, a 4-ethylbis(cyclohexanecarbonyl group), a 4-pentylbis(cyclohexanecarbonyl group), an adamantanecarbonyl group, an adamantaneacetyl group; or

[0038] (7) C6~C 12 Substituted or unsubstituted aromatic / heteroaromatic carboxylic acid acyl; preferably acetylsalicylic acid acyl, coumaric acid acyl; or

[0039] (8)C9~C 14 Substituted or unsubstituted arylcarboxylic acid acyl; preferably cinnamoyl, 4-phenyl-3-butenoyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl; or

[0040] (9)C8~C 16 Substituted or unsubstituted aralkylcarboxyl; preferably ibuprofenyl, 2-(6-methoxy-2-naphthyl)propionyl; or

[0041] (10)C5~C 16 A heteroatom-containing alkenyl carboxylic acid acyl group; preferably a monoethyl fumarate acyl group, a 3-ethoxyacryloyl group, a 10-hydroxy-2-decenoyl group, a 10-(methyl / ethyl / isopropyl)oxy-2-decenoyl group, a 10-(methyl / ethyl / propyl / butyl)oxy-2-decenoyl group; or

[0042] (11) C8~C 1asubstituted phenyl; preferably 4-(methyl / ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl)phenyl, 4-(methyl / ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl)oxyphenyl, 4-(vinyl / isopropyl / tert-butyl / sec-butyl / tert-pentyl / tert-octyl)phenyl, 4-(2,6-dimethylheptyl)phenyl, 4-methoxyethylphenyl, 4-cyclohexylphenyl, 4-(4-(methyl / ethyl / propyl / butyl)cyclohexyl)phenyl, 4-(1-adamantyl)phenyl, 4-benzylphenyl, 4-(2-phenylprop-2-yl)phenyl, 4-styrylphenyl, pterostilbene 4'-dehydroxylated residue, m-isopropylphenyl, m-tert-butylphenyl, o-sec-butylphenyl, o-ethoxyphenyl, 4-vinyl-2-methoxyphenyl, vanillin 4-dehydroxylated residue, paeonol 2-dehydroxylated residue, 3,5-dimethoxyphenyl; or

[0043] (12)C9~C 12 Substituted or unsubstituted phenylalkenyl; preferably phenylallyl, 4-methoxyphenylallyl, 3,4-dimethoxyphenylallyl, 3,4,5-trimethoxyphenylallyl; or

[0044] (13)C3~C 18 linear alkenyl; preferably allyl, 3-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, 6-hepten-1-yl, 7-octen-1-yl, 8-nonen-1-yl, 9-decen-1-yl, 10-undecen-1-yl, 2-buten-1-yl, 4-hexen-1-yl, 3-hexen-1-yl, 6-nonen-1-yl, 2-penten-1-yl, 2-hexen-1-yl, 2-hepten-1 1-yl, 2-octen-1-yl, 2-nonen-1-yl, 2-decen-1-yl, 2-undecen-1-yl, 2-dodecen-1-yl, 2,4-hexadien-1-yl, 2,4-heptadien-1-yl, 3-octen-1-yl, 2,7-octadien-1-yl, 2,6-nonadien-1-yl, 2,4,6-nonatrien-1-yl, 9-octadecen-1-yl, 2,13-octadecadien-1-yl; or

[0045] (14) C1~C2 and C 10 ~C 22 Linear alkyl; preferably methyl, ethyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, n-docosyl; or

[0046] (15)C3~C 22 branched alkyl; preferably 2-propyl / hexyl / heptyl / octyl, 3-heptyl / octyl / nonyl, 2-ethyl (butyl / pentyl / hexyl), 4-heptyl, 5-nonyl, 3-methyl-1-pentyl, 3,5,5-trimethyl-1-hexyl, 3,7-dimethyl-1-octyl, 2-hexyl-1-decyl, 2-octyl-1-dodecyl; or

[0047] (16)C5~C 17 An alkyl group containing a ring structure; preferably cyclo(pentyl / hexyl / heptyl / octyl)yl, 4-(methyl / ethyl / propyl / butyl / pentyl)cyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl, 4-(4-(methyl / ethyl / propyl / butyl / pentyl)cyclohexyl)cyclohexyl, cyclododecyl, cyclopropylethyl, cyclohexylethyl, cyclo(butyl / pentyl / hexyl)methyl; or

[0048] (17)C5~C 45 The dehydroxylated residue of a branched terpene alcohol; preferably 3-methyl-3-buten-1-yl, a 1-dehydroxylated residue of isopentenol, a 1-dehydroxylated residue of citronellol, a 1-dehydroxylated residue of geraniol, a 1-dehydroxylated residue of nerol, a 2-dehydroxylated residue of myrcenol, a 2-dehydroxylated residue of dihydromyrcenol, a 2-dehydroxylated residue of tetrahydromyrcenol, a 3-dehydroxylated residue of linalool, a 1-dehydroxylated residue of phytol / phytol, a 1-dehydroxylated residue of farnesol / farnesol, a 1-dehydroxylated residue of geranylgeraniol, a 1-dehydroxylated residue of pentyloprenyl alcohol, a 1-dehydroxylated residue of hexaprenyl alcohol, a 1-dehydroxylated residue of heptaprenyl alcohol, a 1-dehydroxylated residue of octaprenyl alcohol, or a 1-dehydroxylated residue of solanesol; or

[0049] (18)C 10 ~C 15 A dehydroxylated residue of a terpene alcohol having a ring structure; preferably a 2-dehydroxylated residue of fenchol, a 1-dehydroxylated residue of menthol, a 1-dehydroxylated residue of isopulegol, a 1-dehydroxylated residue of carveol, a 1-dehydroxylated residue of perillyl alcohol, a dehydroxylated residue of terpineol, a dehydroxylated residue of terpene alcohol, or a dehydroxylated residue of bisabolol; or

[0050] (19)C 20 ~C 29 Dehydroxylated residues of fat-soluble vitamins; preferably, the 1-dehydroxylated residue of vitamin A1, the 1-dehydroxylated residue of vitamin D2 / D3, or the 6-dehydroxylated residue of vitamin E on the benzene ring; or

[0051] (20)C 24 Bile acid acyl; preferably cholic acid acyl, deoxycholic acid acyl, chenodeoxycholic acid acyl, ursodeoxycholic acid acyl, lithocholic acid acyl; or

[0052] (21)C 19 ~C 23 Carboxyl-containing steroidal carboxyl group; preferably 3-oxo-androst-4-ene-17β-carboxyl group; or

[0053] (22)C 18 ~C 29Sterol dehydroxyl residues; preferably 3-dehydroxyl residues of cholesterol / β-sitosterol / stigmasterol / ergosterol, 19-dehydroxyandrost-4-ene-3,17-dione residue, 17-dehydroxyl residue of nandrolone, 17-dehydroxyl residue of methyltestosterone, 3-dehydroxyl residue of pregnenolone, 3-dehydroxyl residue of abiraterone, 21-dehydroxyl residue of prednisone.

[0054] Furthermore,

[0055] The linking group X is specifically selected from the following structures:

[0056] (1)

[0057] (2) in,

[0058] Q1 is hydrogen, C1-C5 hydrocarbon or acyl,

[0059] Q2 is hydrogen or a C1-C4 hydrocarbon group;

[0060] K1 and K2 are linear, branched, cyclic or ring-containing subunits selected from C1 to C 15 Alkylene, C2~C 26 heteroalkylene, C2 alkenylene, C6-C7 substituted / unsubstituted arylene, C4-C5 heteroarylene, C6-C8 aralkylene / heteroaralkylene, K1 may not exist; preferably,

[0061] K1 is selected from:

[0062] K2 is selected from:

[0063] wherein j is 1 to 6, m is 1 to 10, n is 1 to 12, p is 1 to 11, q is 1 to 3, and r is 1 to 2, all of which are integers; and T1 and T2 are each independently a methylene group or do not exist.

[0064] R1 is specifically selected from the following structures:

[0065] (1)

[0066] (2) (n is an integer from 1 to 17); or

[0067] (3) Wherein, M1 is selected from methyl, (n is an integer from 1 to 15), (m is an integer from 1 to 5),

[0068] R2 is specifically selected from the following structures,

[0069] (1) (n is an integer from 1 to 8), (m is 1 or 2), (p is an integer from 1 to 6), (q is an integer from 1 to 5), (r is 7, 11 or 13),

[0070] (2) (n is 1 or 2),

[0071] (3) (n is 1 or 2), (m is 1 or 2),

[0072] (4) Where n is an even number from 8 to 20; or

[0073] (5) wherein n is an integer from 1 to 5, m is an integer from 1 to 4, and r is 1 or 3; or

[0074] (6) (n is an integer from 1 to 5), (m is an integer of 1 to 2, n is an integer of 1 to 4), [M2 is methyl, isopropyl, (p is an integer from 1 to 5), (q is 1 or 4)]; or

[0075] (7)

[0076] (8)

[0077] (9)

[0078] (10) [M3 is selected from hydrogen, methyl, ethyl, isopropyl, (methyl / ethyl / propyl / butyl)acyl]; or

[0079] (11) [M4 is selected from methyl, methoxy, (p is an integer from 1 to 7), (n is an integer from 1 to 7), (m is an integer from 1 to 4)]; or

[0080] (12)

[0081] (13) (n is an integer from 1 to 9), (m is 1 or 3), (p is 1 or 4), (q is an integer from 1 to 8),

[0082] (14) Where n is an even number from 8 to 20; or

[0083] (15) wherein n and m are integers from 3 to 5, and p is an integer from 1 to 3; or

[0084] (16) (M5 is methyl, Isopropyl, tert-butyl, ), wherein n is an integer from 1 to 4, and m is an integer from 1 to 3; or

[0085] (17) (n is an integer from 2 to 8); or

[0086] (18)

[0087] (19)

[0088] (20) wherein R is OH or H; or

[0089] (twenty one)

[0090] (twenty two) (R is H or methyl),

[0091] The present invention also relates to a lipophilic compound, which, based on the structure shown in Formula I, further has the structure of Formula Ia1 or Ia2.

[0092] The present invention also relates to a lipophilic compound, which, based on the structure shown in formula I, further has the structure shown in formula Ib, wherein

[0093] (1) The connection site of R1 to the X group is located on any carbon of R1 except the acyl carbon No. 1; and the linear main carbon chain of the compound from the acyl carbon No. 1 to the carbon connected to the X group in R1 does not contain a carbon-carbon double bond or a triple bond, and the linear carbon chain group formed from the carbon No. 2 to the carbon connected to the X group is R6;

[0094] Preferably, R6 is methine or ethylene; and

[0095] (2) The portion other than the linear main carbon chain group on R1 is R5,

[0096] Preferably, R5 is selected from: hydrogen, C1-C 15 Linear alkyl, C3~C6 branched alkyl, C5~C9 alkyl containing cycloalkyl structure, C6~C 14 Aryl, C7~C 14 Aralkyl;

[0097] The structure of the compound is shown in Formula Ib,

[0098] Furthermore, the lipophilic compound of the present invention has a specific structure as shown in the following table:

[0099] In each specific compound group described in the table, the specific compound having the structure of Formula Ia1 or Ia2 is:

[0100] LM-1101, LM-1102, LM-1103, LM-1104, LM-1105, LM-1106, LM-1107;

[0101] LM-1201, LM-1202, LM-1203, LM-1204, LM-1205, LM-1206, LM-1207, LM-1208, LM-1209, LM-1210, LM-1211, LM-1212, LM-1213, LM-1214;

[0102] LM-1301; LM-1401, LM-1402; LM-1501, LM-1502; LM-1601; LM-1701; LM-1801;

[0103] LM-1901, LM-1902, LM-1903;

[0104] LM-2101, LM-2102, LM-2103, LM-2104, LM-2105, LM-2106;

[0105] LM-2201, LM-2202, LM-2203, LM-2204, LM-2205, LM-2206, LM-2207, LM-2208, LM-2209, LM-2210, LM-2211;

[0106] LM-2301; LM-2401, LM-2402;

[0107] LM-2501, LM-2502, LM-2503, LM-2511;

[0108] LM-2601; LM-2701; LM-2801, LM-2811; LM-2901;

[0109] LM-3101, LM-3102, LM-3103, LM-3104, LM-3105, LM-3106;

[0110] LM-3201; LM-3301; LM-3401;

[0111] LM-4101, LM-4102, LM-4103, LM-4104;

[0112] LM-4201; LM-4301; LM-4401; LM-4501; LM-4601, LM-4602; LM-4701;

[0113] The present invention also relates to derivatives of the lipophilic compound having the structure of formula II,

[0114] in,

[0115] Y1 is a group connecting the lipophilic compound and the branch segment D, selected from O, S,

[0116] q is a positive integer, preferably 2, 3, 4, or 6;

[0117] X and R1 need to be present or absent at the same time. When they are absent, R2 and Y1 are directly connected. In this case, two or more R2 in Formula II may be different from each other, and two or more Y1 may be different from each other;

[0118] Z1 is selected from H,

[0119] D is a branched segment with q+1 linking sites, selected from the following segments and combinations thereof in which residues marked with * and residues not marked with * are directly linked to each other or are linked to each other through additional linking groups; specifically, D is linked to Z1 through a residue marked with * (directly or through a linker-DZ1), and is linked to Y1 through a residue not marked with *;

[0120] Among them, Y2 is or not present (wherein, Y3 is O, S or and the residue marked with ** is the residue not marked with ** in the above D, t is 1 or 2, p is an integer from 1 to 5), T is a methylene group or is absent, M6 is hydrogen or methyl, M7 is hydrogen, methyl or ethyl, Q3 is methyl, ethyl or m is an integer from 1 to 4, and p is an integer from 1 to 5;

[0121] The linker-DZ1 includes but is not limited to O, and combinations thereof, wherein n is an integer from 1 to 5.

[0122] Preferably, the structure of the derivative of the lipophilic compound is as shown in the following table:

[0123] The present invention also relates to a method for preparing the compound of formula I, comprising the steps of:

[0124] (1-1) The main structure is The raw materials are subjected to carboxyl protection reaction to obtain a carboxyl group having a protective group and a main structure of Compounds;

[0125] (1-2) The original group of the hydrocarbon residue of R1 is converted into a sulfonic acid group, a halogen group or other easy-leaving groups, or the conversion is followed by substitution with a nitrogen / sulfur group, or oxidation and subsequent reduction and amination, or activation with a carbonyl donor reagent, or direct use; The raw materials are connected, or oxidized after connection to obtain a compound Optionally, when X is a fragment containing K1 or K2, the step further comprises the step of connecting X, wherein the step of connecting X is: connecting the main structure to The raw material is connected with the raw material whose structural main body is K1 or K2; the connection includes but is not limited to condensation or substitution connection;

[0126] (1-3) removing the carboxyl protecting group to obtain a compound of formula I; or

[0127] (2-1) The main structure is The raw material is kept with the carboxyl group exposed, and the steps of treating the original group of the R1 hydrocarbon residue as described in step (1-2) are performed, or it is used directly;

[0128] (2-2) and the main structure are The raw materials are condensed or substituted, or oxidized after connection, and optionally, the step of connecting X as described in step (1-2) is also added to form a compound of formula I; or,

[0129] (3-1) The structure does not contain carboxyl groups and the main structure is The compound is used as a raw material, and its R1' hydrocarbon residue group is subjected to the steps of treating the original group of the R1 hydrocarbon residue as described in step (1-2), or it is used directly;

[0130] (3-2) and the main structure are The raw materials are condensed or replaced to form a main structure. or oxidation after connection, optionally, adding a step of connecting X as described in step (1-2);

[0131] (3-3) performing a reaction such as carboxyl formation or connection to form a compound of formula I; or

[0132] (4-1) The main structure is The original groups at the residue positions of the raw materials are converted into easy-leaving groups such as sulfonic acid groups and halogen groups, or further substituted into sulfide groups after conversion, or activated with carbonyl donor reagents;

[0133] (4-2) and the main structure are The hydrocarbon residue groups of the raw materials are condensed or substituted, or oxidized after connection. Optionally, the step of connecting X as described in step (1-2) is also added to form a compound of formula I. Optionally, the step as described in step (1-3) or (3-3) needs to be added to form a compound of formula I;

[0134] Optionally, based on the above steps, additional protection, deprotection, connection or functional group conversion steps are added.

[0135] The present invention also relates to a method for preparing the compound of formula II, comprising the following reaction steps:

[0136] (1-1) The main structure is After selective protection and deprotection of the self-reactive groups of the raw materials and modification of the Z1 group, the main structure is obtained. a compound; optionally, Part of the structure is used as the raw material of the main structure to be modified or connected to each other to prepare the main structure in advance. raw materials;

[0137] (1-2) The compound of formula I is modified with or without carboxyl activated ester, and the main structure is The compounds are condensed or substituted to obtain

[0138] (1-3) After deprotection and Z1 group modification steps, the compound of formula II is obtained; or,

[0139] (2-1) the carboxyl group is modified with activated ester or unmodified by the formula I compound and the main structure is The compound of formula II is directly obtained by condensation or substitution reaction.

[0140] Alternatively, the unprotected structure is The compound of formula I can be directly linked to.

[0141] The present invention also relates to a method for preparing compounds of formula Ia1 and Ia2, wherein the raw material containing the R2 group is R2-OH; the raw material containing the R1 group is Characterized in that the method comprises:

[0142] (1) When R2 is hydrogen,

[0143] The raw material containing the R1 group is carboxyl protected or not, the hydroxyl group (referring to alcoholic hydroxyl group) is converted (for example, to a sulfonic acid group, a halogen group or other easy-leaving groups) or not converted, and then substituted with a sulfur-, nitrogen- or nitrogen-oxygen-containing nucleophilic reagent and deprotected when necessary to obtain the compound of formula Ia1 or Ia2 after the hydroxyl group is converted to a thiol group, an amino / amine group or an amino / amineoxy group, that is, Optionally, the alcoholic hydroxyl groups of the above raw materials are oxidized, reduced, and ammoniated / aminated (generally imidized and reduced) to obtain compounds of formula Ia1 and Ia2 after the hydroxyl groups are converted into amino / amine groups; optionally, compounds of formula Ia1 and Ia2 having -NH2 / -ONH2 are used as raw materials and subjected to condensation or substitution reaction with a reagent containing Q1 to obtain compounds of formula Ia1 and Ia2 having -NHQ1 / -ONHQ1; or,

[0144] (2) When R2 is a compound carboxylic acid group,

[0145] The carboxyl group of R2-OH is modified with activated ester or not, and the carboxyl group is protected or not. After ester condensation / esterification and, if necessary, carboxyl deprotection reaction, the structure is obtained. a compound of formula Ia1 / Ia2; or

[0146] The carboxyl group of R2-OH is modified or not modified by activated ester, and the carboxyl group is protected or not protected in step (1) After acid-amine condensation / amidation and, if necessary, carboxyl deprotection reaction, the structure is obtained. a compound of formula Ia1 / Ia2; or

[0147] (3) When R2 is a hydrocarbon residue or a compound dehydroxylated residue,

[0148] raw material With or without carboxyl protection, a dehydration reaction and, if necessary, a carboxyl deprotection reaction are directly carried out with R2-OH to obtain a structure of a compound of formula Ia1 / Ia2; or

[0149] (4) When R2 is a hydrocarbon residue or a compound dehydroxylated residue,

[0150] 1) converting the hydroxyl group of the raw material R2-OH (alcohol or phenolic compound) to obtain a compound having an easily leaving group such as a sulfonic acid group or a halogen, or further replacing the leaving group to obtain R2-SH, R2-NHQ1, or R2-ONHQ1;

[0151] 2) After the hydroxyl group in the raw material compound represented by R2-OH is converted into a sulfonic acid group, a halogen group or other easy-leaving group, it is further reacted with the carboxyl group protected or unprotected in step (1) Interaction, nucleophilic substitution and, if necessary, carboxyl deprotection reaction occur to obtain the structure Compounds of formula Ia1 / Ia2; optionally, the structure is The compound of formula Ia1 / Ia2 is oxidized with or without carboxyl protection to obtain a structure of Compounds of formula Ia1 / Ia2; optionally, compounds of formula Ia1 and Ia2 having -NHR2 / -ONHR2 are used as starting materials and subjected to condensation or substitution reaction with a reagent containing Q1 to obtain compounds of formula Ia1 and Ia2 having -NQ1R2 / -ONQ1R2; or,

[0152] 2') R2-SH, R2-NHQ1 or R2-ONHQ1, further with carboxyl protected or unprotected, hydroxyl converted to sulfonic acid or halogen and other easy leaving groups Nucleophilic substitution reaction and carboxyl deprotection reaction, if necessary, are carried out to obtain the structure a compound of formula Ia1 / Ia2; or

[0153] (5) When R2 is a hydrocarbon residue or a compound dehydroxylated residue,

[0154] After activation of R2-OH by carbonyl donor reagent, it is directly reacted with carboxyl protected or unprotected raw materials Interaction and, if necessary, carboxyl deprotection reaction to obtain the structure a compound of formula Ia1 / Ia2; or

[0155] (6) Dicarboxyl compounds The carboxyl group of the activated ester is modified or not modified, and the raw material containing the R2 group and the raw material containing the R1 group are subjected to condensation reaction and carboxyl deprotection reaction when necessary in a reasonable order to obtain a structure of a compound of formula Ia1 / Ia2; or

[0156] (7) Dihydroxy compounds The above raw materials containing R2 groups and raw materials containing R1 groups are subjected to hydroxyl conversion, nucleophilic substitution or dehydration reaction, and carboxyl deprotection reaction when necessary in a reasonable order to obtain a structure of A compound of formula Ia1 / Ia2.

[0157] The present invention also relates to the use of the compound or derivative in the preparation of chemically modified drugs, wherein the molecular types of the drugs include but are not limited to: small molecule compounds, polypeptides, proteins, polysaccharides, nucleic acids or high molecular polymers;

[0158] The nucleic acid is a natural or artificially synthesized / modified single-stranded nucleic acid or a complementary double-stranded nucleic acid, including but not limited to ASO, Aptamer, siRNA, saRNA, miRNA, mRNA, lncRNA and the like; preferably, the nucleic acid is ASO;

[0159] Preferably, in the compound or derivative, R1 is a C 14 ~C 22 A linear carbon chain group, wherein X is an oxygen, sulfur or imine group attached to a non-terminal carbon atom of R1;

[0160] The method for preparing chemically modified drugs is: covalently linking the compound or derivative to the drug molecule; preferably, the covalent linking method is to activate the compound or derivative and the drug molecule in whole or in part or modify them with chemical groups / fragments before covalently linking them.

[0161] The present invention also relates to a conjugate comprising the compound or derivative and a drug molecule, characterized in that the conjugate is formed by covalently linking a reactive group on the drug molecule to a compound of formula I or a compound of formula II;

[0162] The molecular types of the drug include but are not limited to: small molecule compounds, polypeptides, proteins, polysaccharides, nucleic acids or high molecular polymers;

[0163] The nucleic acid is a natural or artificially synthesized / modified single-stranded nucleic acid or a complementary double-stranded nucleic acid, including but not limited to ASO, Aptamer, siRNA, saRNA, miRNA, mRNA, lncRNA and the like; preferably, the nucleic acid is ASO;

[0164] Preferably, in the compound or derivative, R1 is a C 14 ~C 22 A linear carbon chain group, wherein X is an oxygen, sulfur or imine group attached to a non-terminal carbon atom of R1;

[0165] Preferably, when the drug molecule type is nucleic acid, the conjugate is composed of a reactive group on the sugar ring or base of the nucleic acid molecule and a carboxyl group of the compound of formula I or a reactive group on the compound of formula II. The groups are covalently linked, and a nucleic acid molecule can be covalently linked to one or more compounds of formula I or formula II.

[0166] Furthermore, the conjugate is formed by connecting the compound of formula I with A, and has a structure of formula III; or, the conjugate is formed by connecting the compound of formula II with A, and has a structure of formula IV.

[0167] in,

[0168] A is a nucleic acid residue, e is a positive integer preferably from 1 to 9,

[0169] Z2 is a linking group formed by the participation of Z1 in formula II in the linking reaction,

[0170] Z3 is a linker formed by the reactive group of the nucleic acid participating in the ligation reaction.

[0171] L is a linker between the lipophilic compound or its derivative and the nucleic acid, which may not exist, or may be an atom (group), a structural fragment, and a reasonable combination thereof formed by an additional linking group. Preferably, L is or contains a substituted / unsubstituted chain or ring, including but not limited to an alkylene group, a heteroalkylene group containing an oxyethylene repeating unit, an arylene group, a heteroarylene group, and a chemically reasonable combination thereof.

[0172] Furthermore, L includes but is not limited to the following fragments and optional combinations of the following fragments and additional linkers, wherein m is an integer of 1 to 18, p is an integer of 1 to 6, n is an integer of 1 to 3, and M8 is selected from the group consisting of: methyl, isopropyl,

[0173] Furthermore, e optional compounds of formula I or II can be independently connected to e connectable sites of the nucleic acid through L and / or a linker, and the connection site is located on the sugar ring or base in the middle or at the end of the nucleotide chain. The connection process can occur during or after the synthesis of the nucleic acid.

[0174] Furthermore, Z2, Z3, and the additional linking groups between the atoms (groups) or structural fragments constituting L can be independently selected from: O, S, Wherein, m is an integer of 1 to 6, and Z is selected from H, OH, O - ,SH,S - ;

[0175] Furthermore, the structure of the conjugate is shown in FIG1 ;

[0176] Most preferably, the structure of the conjugate is as follows,

[0177] The present invention also relates to a method for preparing the conjugates of formula III and formula IV, wherein the required raw materials include: an optional compound L1 constituting the L structure in the conjugate, a compound of formula I, a compound of formula II, and a nucleic acid whose main structure is A. The method comprises the following steps:

[0178] (1) performing group protection, deprotection, activation / conversion, or other treatments (hereinafter referred to as "treatment") on the optional raw material L1 to obtain a modified product of L1, or using it directly; performing a ligation reaction on two or more optional L1 and modified products of L1 in a reasonable order to obtain a composition of L1;

[0179] (2) The raw materials, the compound of formula I, the compound of formula II and the nucleic acid whose main structure is A, are subjected to group protection, deprotection or activation / conversion and other treatments respectively to obtain the modified products of formula I, the modified products of formula II and the modified products of A, or are used directly without the above treatments; and are subjected to condensation or substitution and other connection reactions with optional L1, the modified products of L1, and the combination of L1 to obtain the main structure of Compounds;

[0180] (3) After / Untreated, the main structure is The compound of formula I / the modified compound of formula I and the structural main body are connected to the nucleic acid or the modified compound of A to obtain the conjugate of formula III; or After connecting the compounds, the conjugate of formula III is obtained;

[0181] (4) The main structure is The compound of formula II or the modified compound of formula II is connected with the nucleic acid whose main structure is A or the modified compound of A to obtain the conjugate of formula IV; or After connecting the compounds, the conjugate described in formula IV is obtained.

[0182] The present invention also relates to a pharmaceutical composition comprising the conjugate and necessary pharmaceutical excipients; preferably, the drug is a topical drug, and the topical administration includes: transdermal administration, ocular administration, brain administration, pulmonary administration, nasal administration, and oral administration, preferably transdermal administration.

[0183] The present invention also relates to the use of the conjugate in the preparation of a drug. Preferably, the drug is a topical drug. The topical administration includes transdermal administration, ocular administration, brain administration, pulmonary administration, nasal administration, and oral administration, preferably transdermal administration.

[0184]

Term Explanation and Definition

[0185] As used herein, hydrocarbon groups include alkyl, alkenyl, alkynyl, and aryl groups. Alkyl, also known as alkane, is a fully saturated hydrocarbon group. Alkenyl, also known as olefin, may contain one or more unsaturated carbon-carbon double bonds, each of which may independently be in E- or Z-configuration, and the residues may be located on saturated or unsaturated carbon atoms. Unless otherwise specified, hydrocarbon, alkyl, and alkenyl groups herein do not contain heteroatoms other than carbon and hydrogen.

[0186] Residue: In this context, it refers to the part of a compound molecule that remains after a certain atom or group is formally removed, emphasizing the incompleteness of the compound and indicating that a certain structure is an incomplete group, for example, isobutyryl residue It is the isobutyryl group remaining after the hydroxyl group is removed from the isobutyric acid molecule. "Vanillin 4-hydroxyl-free residue" is the group remaining after the hydroxyl group is removed from the 4-position of the benzene ring in the structure of the vanillin compound. In another case, it refers to the residue connection site in the structure, and is intended to indicate the position of the residue connection site of a certain residual group. For example, the description "R1 has 1 carboxyl residue" here "residue" refers to the residue connection site, and it also indicates that the residue connection site in the R1 structure is located on the carboxyl carbon atom. Similarly, "hydrocarbon residue" indicates that the residue connection site of the structure is located on the hydrocarbon carbon atom, and "alkane residue" indicates that the residue connection site is located on the alkyl carbon atom. For another example, the description "X is a linker with 2 residues" means that X has 2 residue connection sites. The description "pentanoyl group with 5-alkane residue" means that the residue site is located on the 5-alkyl carbon atom of the pentanoyl group.

[0187] Subgroup / subresidue: In this article, it refers to an atom (group) or structural fragment that has two monovalent residues by formally eliminating two monovalent atoms or groups (it can also be a divalent residue formed by eliminating one divalent atom / group), for example, It is the remaining 2-decenoyl group after the two hydroxyl groups are removed from the 10-hydroxy-2-decenoic acid molecule;

[0188] A "divalent" radical: as used herein, refers to an atom (group) or structural fragment having three monovalent residues by formally eliminating three monovalent atoms or groups (or a trivalent residue formed by simultaneously eliminating one monovalent and one divalent atom / group). For example, a "divalent alkenyl" is an alkenyl having three alkane residues, or an alkenyl having one alkane residue and one alkene residue.

[0189] Carboxylic acid: In this article, it refers to the acyl group formed by the loss of hydroxyl group from carboxylic acid;

[0190] Alkanoyl: In this article, it refers to the carboxylic acid group remaining after the saturated fatty acid loses the carboxyl hydroxyl group, and usually refers to the carboxylic acid group with more than 10 carbon atoms (preceded by a Chinese number), such as "undecanoyl";

[0191] Alkyl: refers specifically to a hydrocarbon group composed of an alkyl group and an alkenyl group. Its structure may contain one or more unsaturated carbon-carbon double bonds. Except for the double bond carbon atoms, all other carbon atoms are saturated alkyl carbon atoms. Its residue can be located on any carbon atom.

[0192] Alkenylenecarboxylic acid residue: a residue formed by linking an alkenyl group and a carboxylic acid group, which has an acyl residue and an alkene residue in its structure;

[0193] Linear structure: refers to a straight-chain structure without substituents or branches (the residue does not serve as a substituent or branch and can be located at any position in the structure), such as n-heptane, n-pentenyl, and n-decenoylidene;

[0194] Branched structure: a structure with a linear main chain and non-cyclic substituents or branches on the main chain;

[0195] The ring or cyclic structure herein may be saturated or unsaturated, may or may not have substituents, and may or may not contain heteroatoms, but a cycloalkyl group refers to a saturated cyclic alkyl group composed solely of carbon and hydrogen elements, which may have alkyl substituents and contain no heteroatoms;

[0196] Dehydroxylated residue: In this article, it refers to a compound with a hydroxyl group, and the residue structure remaining after removing the hydroxyl group at a certain position;

[0197] Not present: indicates that the entities or residues on the left and right of the atom or group are directly connected by a bond;

[0198] C x ~C y : represents a group or chemical fragment containing an integer number of carbon atoms ranging from x to y, without limiting whether the group or chemical fragment contains other non-carbon atoms;

[0199] Structural body: The main part of the compound structure, generally including the entire carbon skeleton of the compound, with only a few groups or parts of groups at the end of the structure missing. The missing parts are generally heteroatoms, carboxyl groups, and their combinations;

[0200] PG: refers to a protecting group or a group whose main structure is a protecting group;

[0201] In the structures (including groups or chemical fragments) herein, English characters (capital letters with or without superscripts), such as R, X, T1, etc., other than the symbols of chemical elements, are independently present, absent, or selected from the defined ranges unless otherwise specified; except for the symbols of elements, the superscripts of English characters are only numerical numbers and do not indicate the number; in the structures herein, the superscripts outside the brackets can be numbers or lowercase letters defined as numbers, indicating the number of groups / fragments in the brackets or the number of repetitions, and are all integers; unless otherwise specified, English characters that appear repeatedly in the same structure are not independent of each other and refer to the same content, for example, the structure The two T1s must be present, absent, or selected from the same group / fragment.

[0202] In the chemical structure, Indicates a carbon-carbon double bond containing both E / Z configurations; Indicates that the chemical bond is a carbon-carbon single bond or a double bond, and the double bond includes an E / Z configuration; It is a residue symbol and also indicates the site of covalent attachment between groups or chemical fragments.

[0203] C4~C 26 Linear alkenecarboxylic acid group, preferably butylenecarboxylic acid group having a 4-alkane residue, decenoylenecarboxylic acid group having a 10-alkane residue, or octadecenoylenecarboxylic acid group having a 12-alkane residue;

[0204] C2~C 20 The linear alkylenecarboxylic acid group is preferably an (ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl / nonyl / decyl / undecane / dodecane / tridecane / tetradecane / pentadecane / hexadecane / heptadecane / octadecane) acyl group having a 2-alkane residue, a propionyl group having a 3-alkane residue, a butyryl group having a 4-alkane residue, a valeryl group having a 5-alkane residue, a hexanoyl group having a 6-alkane residue, a heptanoyl group having a 7-alkane residue, an octanoyl group having an 8-alkane residue, a 9-alkane residue, a 10-alkane residue, a 11-alkane residue, a 12-alkane residue, a 13-alkane residue, a 14-alkane residue, a 15-alkane residue, a 16-alkane residue, a 17-alkane residue, a 18-alkane residue, a 19-alkane residue, a 20-alkane residue, a 21-alkane residue, a 22-alkane residue, a 23-alkane residue, a 24-alkane residue, a 25-alkane residue, a 26-alkane residue, a 27-alkane residue, a 28-alkane residue, a 29-alkane residue, a 30-alkane residue, a 31-alkane residue, a 32-alkane residue Nonanoyl, decanoyl with a 10-alkane residue, undecanoyl with a 11-alkane residue, dodecanoyl with a 12-alkane residue, octadecanoyl with a 12-alkane residue, tridecanoyl with a 13-alkane residue, tetradecanoyl with a 14-alkane residue, pentadecanoyl with a 15-alkane residue, hexadecanoyl with a 16-alkane residue, heptadecanoyl with a 17-alkane residue, octadecanoyl with an 18-alkane residue;

[0205] C4-C8 branched alkylenecarboxyl group, preferably isovaleryl group having a 2-alkane residue, 3-methylvaleryl group having a 2-alkane residue, 4-methylvaleryl group having a 2-alkane residue, 3,3-dimethylbutanoyl group having a 2-alkane residue;

[0206] C7~C 10 The alkylenecarboxyl group containing a cycloalkyl structure is preferably a cyclohexylideneacetyl group having a 2-alkane residue or a 3-cyclohexylenepropionyl group having a 2-alkane residue;

[0207] C8~C 16 The aralkylenecarboxylic acid group is preferably a phenylacetylene group having a 2-alkane residue, a phenylpropionylene group having a 2-alkane residue, a phenylbutyrylene group having a 2-alkane residue, a phenylvalerylene group having a 2-alkane residue, a phenylhexanoylene group having a 2-alkane residue, a phenylheptanoylene group having a 2-alkane residue, a p-toluoacetylene group having a 2-alkane residue, a p-toluopropionylene group having a 2-alkane residue, a m-toluopropionylene group having a 2-alkane residue, an o-toluopropionylene group having a 2-alkane residue, a 3-(4-tert-butylphenyl)propionylene group having a 2-alkane residue, a 3-(4-biphenylyl)propionylene group having a 2-alkane residue, a 3-(1-naphthyl)propionylene group having a 2-alkane residue, or a 3-(2-naphthyl)propionylene group having a 2-alkane residue.

[0208] C3~C 24 Linear alkenecarboxyl groups; preferably acryloyl, butenoyl, pentenoyl, pentadienoyl, hexenoyl, hexadienoyl, heptenoyl, octenoyl, nonenoyl, decenoyl, undecenoyl, oleoyl, erucoyl, neuranoyl, linoleoyl, α-linolenoyl, arachidonic acid, eicosapentaenoyl, and docosahexaenoyl;

[0209] C4~C 10 Branched alkenecarboxyl groups; preferably 2-methacryloyl, 3,3-dimethylacryloyl, 2-methylbutenoyl, 2-methylpentenoyl, 2,2-dimethylpentenoyl, 2-methylhexenoyl, 3,7-dimethyl-6-octenoyl (citronellyl), geranyl;

[0210] C6~C 20 An alkenecarboxyl group containing a cyclic structure; preferably a cyclopentenecarboxyl group, a cyclohexenecarboxyl group, a 2-cyclopentenyl-1-acetyl group, a 5-norbornene-2-carboxyl group, a retinoic acid acyl group, an isotretinoic acid acyl group, or a rosin (acid) acyl group;

[0211] C1~C2 and C 10 ~C 22 Linear alkanoyl; preferably formyl, acetyl, n-decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, eicosanoyl, behenoyl;

[0212] C4~C 16 Branched alkanecarboxyl; preferably iso(butyryl / pentyryl / hexyryl / heptyryl / octyryl / nonyl)acyl, 2-methyl(butyryl / pentyryl / hexyryl / heptyryl / octyryl), 2-ethyl(butyryl / pentyryl / hexyryl / heptyryl / octyryl), 2,2-dimethyl(propyryl / butyryl / hexyryl / heptyryl / octyryl), 3,3-dimethylbutyryl, 4,4-dimethylpentyryl, 5,5-dimethylhexyryl, 6,6-dimethylheptyryl, 7,7-dimethyloctyl, propyryl, 3-methylbutyryl, 3-methylpentyryl, 4-methyl(hexyryl / heptyryl / octyryl / nonyl), 2-butyl(hexyryl / octyryl), 2-hexyldecanoyl;

[0213] C4~C 16Alkylcarboxyl groups containing a cyclic structure; preferably cyclopropylcarboxyl, cyclobutylcarboxyl, cyclopentylcarboxyl, cyclohexylcarboxyl, cycloheptylcarboxyl, cyclopropylacetyl, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl, cyclopentylpropionyl, cyclohexylpropionyl, 4-methylcyclohexanecarboxyl, 4-ethylcyclohexanecarboxyl, 4-propylcyclohexanecarboxyl, 4-isopropylcyclohexanecarboxyl, 4-butylcyclohexanecarboxyl, 4-pentylcyclohexanecarboxyl, 4-hexylcyclohexanecarboxyl, 4-ethylbiscyclohexanecarboxyl, 4-pentylbiscyclohexanecarboxyl, adamantanecarboxyl, adamantaneacetyl;

[0214] C6~C 12 Substituted or unsubstituted aromatic / heteroaromatic carboxylic acid acyl; preferably acetylsalicylic acid acyl, coumaric acid acyl;

[0215] C9~C 14 Substituted or unsubstituted arylcarboxylic acid acyl; preferably cinnamoyl, 4-phenyl-3-butenoyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl;

[0216] C8~C 16 Substituted or unsubstituted aralkylcarboxyl; preferably ibuprofenyl, 2-(6-methoxy-2-naphthyl)propionyl;

[0217] C5~C 16 Containing heteroatoms, alkenyl carboxylic acid acyl; preferably monoethyl fumarate acyl, 3-ethoxyacryloyl, 10-hydroxy-2-decenoyl, 10-(methyl / ethyl / isopropyl)oxy-2-decenoyl, 10-(methyl / ethyl / propyl / butyl)oxy-2-decenoyl;

[0218] C8~C 18 substituted phenyl; preferably 4-(methyl / ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl)phenyl, 4-(methyl / ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl)oxyphenyl, 4-(vinyl / isopropyl / tert-butyl / sec-butyl / tert-pentyl / tert-octyl)phenyl, 4-(2,6-dimethylheptyl)phenyl, 4-methoxyethylphenyl, 4-cyclohexylphenyl, 4-(4-(methyl / ethyl / propyl / butyl)cyclohexyl)phenyl, 4-(1-adamantyl)phenyl, 4-benzylphenyl, 4-(2-phenylprop-2-yl)phenyl, 4-styrylphenyl, pterostilbene 4'-dehydroxylated residue, m-isopropylphenyl, m-tert-butylphenyl, o-sec-butylphenyl, o-ethoxyphenyl, 4-vinyl-2-methoxyphenyl, vanillin 4-dehydroxylated residue, paeonol 2-dehydroxylated residue, 3,5-dimethoxyphenyl;

[0219] C9~C 12Substituted or unsubstituted phenylalkenyl; preferably phenylallyl, 4-methoxyphenylallyl, 3,4-dimethoxyphenylallyl, 3,4,5-trimethoxyphenylallyl;

[0220] C3~C 18 linear alkenyl; preferably allyl, 3-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, 6-hepten-1-yl, 7-octen-1-yl, 8-nonen-1-yl, 9-decen-1-yl, 10-undecen-1-yl, 2-buten-1-yl, 4-hexen-1-yl, 3-hexen-1-yl, 6-nonen-1-yl, 2-penten-1-yl, 2-hexen-1-yl, 2-hepten-1 -yl, 2-octen-1-yl, 2-nonen-1-yl, 2-decen-1-yl, 2-undecen-1-yl, 2-dodecen-1-yl, 2,4-hexadien-1-yl, 2,4-heptadien-1-yl, 3-octen-1-yl, 2,7-octadien-1-yl, 2,6-nonadien-1-yl, 2,4,6-nonatrien-1-yl, 9-octadecen-1-yl, 2,13-octadecadien-1-yl;

[0221] C1~C2 and C 10 ~C 22 Linear alkyl; preferably methyl, ethyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, n-docosyl;

[0222] C3~C 22 Branched alkyl; preferably 2-propyl / hexyl / heptyl / octyl, 3-heptyl / octyl / nonyl, 2-ethyl (butyl / pentyl / hexyl), 4-heptyl, 5-nonyl, 3-methyl-1-pentyl, 3,5,5-trimethyl-1-hexyl, 3,7-dimethyl-1-octyl, 2-hexyl-1-decyl, 2-octyl-1-dodecyl;

[0223] C5~C 17 Alkyl containing a ring structure; preferably cyclo(pentyl / hexyl / heptyl / octyl)yl, 4-(methyl / ethyl / propyl / butyl / pentyl)cyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl, 4-(4-(methyl / ethyl / propyl / butyl / pentyl)cyclohexyl)cyclohexyl, cyclododecyl, cyclopropylethyl, cyclohexylethyl, cyclo(butyl / pentyl / hexyl)methyl;

[0224] C5~C 45Dehydroxylated residues of branched terpene alcohols; preferably 3-methyl-3-buten-1-yl, 1-dehydroxylated residues of isopentenol, 1-dehydroxylated residues of citronellol, 1-dehydroxylated residues of geraniol, 1-dehydroxylated residues of nerol, 2-dehydroxylated residues of myrcenol, 2-dehydroxylated residues of dihydromyrcenol, 2-dehydroxylated residues of tetrahydromyrcenol, 3-dehydroxylated residues of linalool, 1-dehydroxylated residues of phytol / phytol, 1-dehydroxylated residues of farnesol / farnesol, 1-dehydroxylated residues of geranylgeraniol, 1-dehydroxylated residues of pentyloprenyl alcohol, 1-dehydroxylated residues of hexaprenyl alcohol, 1-dehydroxylated residues of heptaprenyl alcohol, 1-dehydroxylated residues of octaprenyl alcohol, and 1-dehydroxylated residues of solanesol;

[0225] C 10 ~C 15 A dehydroxylated residue of a terpene alcohol having a ring structure; preferably a 2-dehydroxylated residue of fenchol, a 1-dehydroxylated residue of menthol, a 1-dehydroxylated residue of isopulegol, a 1-dehydroxylated residue of carveol, a 1-dehydroxylated residue of perillyl alcohol, a dehydroxylated residue of terpineol, a dehydroxylated residue of terpene alcohol, or a dehydroxylated residue of bisabolol;

[0226] C 20 ~C 29 Dehydroxylated residues of fat-soluble vitamins; preferably, the 1-dehydroxylated residue of vitamin A1, the 1-dehydroxylated residue of vitamin D2 / D3, and the 6-dehydroxylated residue of vitamin E on the benzene ring;

[0227] C 24 Bile acid acyl groups; preferably cholic acid acyl, deoxycholic acid acyl, chenodeoxycholic acid acyl, ursodeoxycholic acid acyl, lithocholic acid acyl;

[0228] C 19 ~C 23 Carboxyl-containing steroidal carboxyl group; preferably 3-oxo-androst-4-ene-17β-carboxyl group;

[0229] C 18 ~C 29 Sterol dehydroxyl residues; preferably 3-dehydroxyl residues of cholesterol / β-sitosterol / stigmasterol / ergosterol, 19-dehydroxyandrost-4-ene-3,17-dione residue, 17-dehydroxyl residue of nandrolone, 17-dehydroxyl residue of methyltestosterone, 3-dehydroxyl residue of pregnenolone, 3-dehydroxyl residue of abiraterone, 21-dehydroxyl residue of prednisone.

[0230] The drugs and drug molecules mentioned in the present invention include drug compound molecules with pharmacological activity, as well as other pharmaceutically applicable forms of drugs, such as prodrugs, drug salts, covalent compounds or combinations of drugs and drug delivery vehicles, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0231] Figure 1 is a schematic diagram of the structure of the conjugate of the lipophilic compound and the nucleic acid drug of the present invention, 1A, coupling through a connecting group with a branched structure; 1B, linear coupling.

[0232] FIG2 is a curve showing the change of drug concentration in the skin of C57BL / 6J mice over time after administration of the CLM-4b* conjugate.

[0233] FIG3 : Curve of drug concentration change over time in the skin of SKH1 hairless mice after administration of CLM-2b* conjugate. DETAILED DESCRIPTION

[0234] Unless otherwise specified, the raw materials, reagents and solvents used in the present invention were of analytical grade.

[0235] Explanation of the abbreviations of main solvents and reagents:

[0236] Boc2O: di-tert-butyl dicarbonate

[0237] DCC: N,N'-dicyclohexylcarbodiimide

[0238] DCM: dichloromethane

[0239] DIAD: diisopropyl azodicarboxylate

[0240] DIC: N,N'-diisopropylcarbodiimide

[0241] DIEA: N,N-diisopropylethylamine

[0242] DMAP: 4-dimethylaminopyridine

[0243] DMT-MM: 4-(4,6-dimethoxytriazin-2-yl)-4-methylmorpholine hydrochloride (a condensation reagent)

[0244] DPPA: diphenylphosphoryl azide

[0245] EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0246] HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (a condensation reagent)

[0247] IBX: 2-iodoacylbenzoic acid

[0248] MSA: Methanesulfonic acid

[0249] NBS: N-bromosuccinimide

[0250] PfpO-TFA: pentafluorophenyl trifluoroacetate

[0251] PPh3: triphenylphosphine

[0252] TBAF: Tetra-n-butylammonium fluoride

[0253] TBDMS-Cl: tert-butyldimethylsilyl chloride

[0254] TEA: triethylamine

[0255] TESH: triethylsilane

[0256] TFA: trifluoroacetic acid

[0257] THF: Tetrahydrofuran

[0258] TsCl: p-Toluenesulfonyl chloride

[0259] Example 1. Synthesis of lipophilic compounds and activated ester derivatives thereof:

[0260] 1. Synthesis of LM-1101

[0261] LM-1101-Z1:

[0262] To a 100 mL single-necked flask equipped with a magnetic stirrer, add trans-2-pentenoic acid (CAS: 13991-37-2, 560 mg, 5.59 mmol, the starting material for the synthesis of the lipophilic compound synthesized by this route, corresponding to the R2 group), DIEA (2.17 g, 16.8 mmol), and DCM (15 mL) in this order and stir rapidly to obtain a clear solution.

[0263] The system temperature was maintained at 20-25°C and stirring was continued (600 r / min). PfpO-TFA (3.13 g, 11.2 mmol) was slowly added dropwise to the flask over 15 min. White smoke was generated during the addition and the solution gradually turned purple.

[0264] After stirring for 30 min, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value is about 0.7), and the reaction solution is purple and homogeneous.

[0265] Stirring was stopped, and the reaction solution was diluted with DCM (20 mL) and transferred to a 100 mL separatory funnel. The solution was washed sequentially with two portions of 5% aqueous sodium bicarbonate solution (15 mL each). The organic phase was separated and dried over anhydrous sodium sulfate. The filtrate was collected after filtration and concentrated under reduced pressure at 40°C to obtain the crude product LM-1101-Z1.

[0266] The crude product was loaded onto 60-100 mesh silica gel (3 g) and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 300 / 1 to 100 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 997 mg of the product as a colorless oily liquid (yield 67%). MS (ESI): m / z [M+Na] + , theoretical value 289.0, measured value 288.9.

[0267] LM-1101:

[0268] To a 50 mL single-necked flask equipped with a magnetic stirrer, ricinoleic acid (SM1, (R, Z)-12-hydroxyoctadec-9-enoic acid, CAS: 141-22-0, 190 mg, 0.637 mmol, the synthetic starting material corresponding to the R1 group in the structure of the lipophilic compound synthesized by this route), DIEA (165 mg, 1.27 mmol) and DMF (8 mL) were added in sequence and rapidly stirred to clarify.

[0269] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). LM-1101-Z1 (186 mg, 0.701 mmol) was added to the flask in three batches within 10 minutes and stirring was continued.

[0270] After 4 h of reaction, the reaction was monitored by LCMS, which showed that most of the raw materials had been converted to form the product.

[0271] Stirring was stopped, and the reaction solution was concentrated under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) with 200-300 mesh silica gel. Elution was performed with a gradient eluent (petroleum ether / ethyl acetate, 15 / 1 to 4 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 99 mg of the product as a light yellow oily liquid (yield 41%. The ester bond at the 12-position of the compound was partially hydrolyzed during silica gel chromatography, resulting in a low yield in this step). MS (ESI): m / z [MH] - , theoretical value 379.3, measured value 379.4.

[0272] LM-1101-Pfp:

[0273] Using LM-1101 as the starting material, the above-mentioned method for synthesizing LM-1101-Z1 was followed, using PfpO-TFA as the activated ester conversion reagent. The reaction process was monitored by TLC and LCMS. The starting material gradually disappeared, and the target product LM-1101-Pfp was not obtained. The reaction process caused most of the ester bond at the 12-position of the main carbon chain of the raw material LM-1101 to break, mainly generating the activated ester byproduct byproduct-A (m / z [M+H] + 465.3), and a small amount of activated ester byproduct-B (m / z [M+Na] + The measured value is 582.6. This indicates that the esters formed between these α,β-unsaturated carboxylic acids (such as trans-2-pentenoic acid corresponding to the R2 group) and the 12-hydroxyl group of ricinoleic acid are relatively unstable and prone to hydrolysis and transesterification (or acyl exchange). To enhance the stability of the ester bond, steric hindrance groups such as alkyl groups can be introduced into the α-position of the carboxylic acid to reduce the occurrence of side reactions.

[0274] 2. Synthesis of LM-1102 and its activated ester

[0275] SM1-Z1:

[0276] 80 g of ricinoleic acid raw material was loaded onto 60-100 mesh silica gel (80 g), and a chromatographic column (filler diameter 11 cm, height 18 cm) was packed with 200-300 mesh silica gel. The column was eluted with a gradient eluent (petroleum ether / ethyl acetate, 100 / 1 to 1 / 5). Fractions containing the product were monitored and collected by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1; color developer: 10% phosphomolybdic acid ethanol solution; product spot R f value of about 0.3), and concentrated under reduced pressure at 40° C. to obtain 21 g of pure colorless oily ricinoleic acid (SM1, (R, Z)-12-hydroxyoctadec-9-enoic acid, CAS: 141-22-0, which is the synthetic starting material corresponding to the R1 group in the structure of the lipophilic compound synthesized by this route).

[0277] Into a 500 mL three-necked flask equipped with a magnetic stirrer, SM1 (20 g, 67.0 mmol), p-toluenesulfonic acid monohydrate (0.2 g, 1.05 mmol), and methanol (200 mL) were added in sequence and stirred rapidly for 5 min to obtain a light yellow homogeneous transparent solution.

[0278] The flask was connected to a nitrogen balloon via a two-way connector and heated in an oil bath at 60°C with constant stirring (400 r / min) for 15 h. The heating was then stopped and the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1). The results showed that the conversion of the raw material was complete and a single product spot (R fvalue of approximately 0.8).

[0279] The reaction solution was concentrated to an oil under reduced pressure and dried under vacuum (50-70 Pa) for 2 h to obtain 21 g of a pale yellow oily liquid, which was the crude product of SM1-Z1 and was used directly in the next step without purification. MS (ESI): m / z [M+Na] + , theoretical value 335.3, measured value 334.9.

[0280] LM-1102-Z1:

[0281] To a 50 mL single-necked flask equipped with a magnetic stirrer, SM1-Z1 (400 mg, 1.28 mmol), trans-2-methyl-2-pentenoic acid (SM2, CAS: 16957-70-3, 291 mg, 2.55 mmol, which is the synthetic starting material corresponding to the R2 group in the structure of the lipophilic compound synthesized by this route), DMAP (312 mg, 2.55 mmol), and DCM (20 mL) were added in sequence and stirred rapidly for 5 min to obtain a colorless transparent solution.

[0282] The system temperature was maintained at 20-25°C and stirring was continued at a constant speed (500 r / min). DIC (322 mg, 2.55 mmol) was added to the flask in three batches within 10-20 min. During this period, a white solid gradually precipitated. Stirring was continued after the addition.

[0283] After 18 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the raw material SM1-Z1 (R f value of about 0.3) was mostly converted to form the main product spot (R f value of approximately 0.7).

[0284] Stirring was stopped and the reaction mixture was filtered. The filter cake was washed with DCM (5-6 mL). The filtrates were combined and added to a 100 mL separatory funnel and washed once with 5% aqueous sodium bicarbonate solution (10 mL). The organic phase was separated and dried over 5 g of anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain 1.3 g of a light yellow oil, which was the crude product of LM-1102-Z1.

[0285] The crude product was loaded onto 60-100 mesh silica gel (2 g) and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 300 / 1 to 100 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 210 mg of the product as a colorless oily liquid (yield 40%). MS (ESI): m / z [M+Na]+ , theoretical value 431.3, measured value 430.9.

[0286] LM-1102:

[0287] LM-1102-Z1 (200 mg, 0.489 mmol) and methanol (10 mL) were added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer, and the mixture was stirred for 2 min to obtain a colorless transparent solution.

[0288] Keep the system temperature at 20-25 ° C and continue stirring (500 r / min), lithium hydroxide monohydrate (61 mg, 1.45 mmol) and purified water (1 mL) are fully mixed to obtain a suspension cooled to below 20 ° C, and added to the above reaction system in 3-4 batches within 5 minutes, during which the system temperature is maintained at 20-25 ° C.

[0289] After stirring for 8 hours, the reaction solution was yellow and transparent. The reaction was detected by TLC (the reaction solution was sampled and the pH was adjusted to 5-6 with 10% hydrochloric acid aqueous solution, the developing solvent was petroleum ether / ethyl acetate, 1 / 1), which showed that the raw material (R f The conversion was completed and a single product spot (R f value of approximately 0.5).

[0290] The reaction solution was concentrated under reduced pressure at 40°C to about 1 / 4 of its original volume, diluted with 20 mL of water, adjusted to pH 5-6 with 10% aqueous hydrochloric acid solution, and the aqueous phase was extracted with two portions of 15 mL of ethyl acetate. The organic phases were combined and washed once with 5% aqueous sodium bicarbonate solution (15 mL). The separated organic phase was dried over 5 g of anhydrous sodium sulfate, and the filtrate was collected by filtration. It was concentrated under reduced pressure at 40°C to an oil and dried in a vacuum environment (50-70 Pa) for 1 h to obtain 144 mg of a yellow oily liquid product (yield 75%).

[0291] MS (ESI): m / z [M+Na] + , theoretical value 417.3, measured value 416.9.

[0292] 1H NMR (400MHz, DMSO-d6) δ11.96 (s, 1H), 6.68-6.59 (m, 1H), 5.48-5.38 (m, 1H), 5.36-5.25 (m, 1H), 4.82 (p, J=6.2Hz, 1H), 2.34-2.20 (m, 2H), 2.2 1-2.09(m, 4H), 2.03-1.93(m, 2H), 1.74(d, J=1.5Hz, 3H), 1.57-1.41(m , 4H), 1.23 (q, J=4.0Hz, 16H), 0.98 (t, J=7.5Hz, 3H), 0.88-0.80 (m, 3H).

[0293] LM-1102-Pfp:

[0294] To a 50 mL single-necked flask equipped with a magnetic stirrer, LM-1102 (135 mg, 0.342 mmol), DIEA (177 mg, 1.37 mmol), and DCM (10 mL) were added in sequence and stirred for 2 min to obtain a light yellow transparent solution.

[0295] The system temperature was maintained at 20-25°C and stirring was continued (600 r / min). PfpO-TFA (192 mg, 0.686 mmol) was slowly added dropwise to the flask over 15 min. White smoke was generated during the addition and the solution gradually turned purple.

[0296] After stirring for 25 min, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value is about 0.7), and the reaction solution is purple and homogeneous.

[0297] Stirring was stopped, and the reaction solution was diluted with DCM (10 mL) and transferred to a 50 mL separatory funnel. The solution was washed sequentially with two portions of 5% aqueous sodium bicarbonate solution (8 mL each). The organic phase was separated and dried over anhydrous sodium sulfate (5 g). The filtrate was collected after filtration and concentrated under reduced pressure at 40° C. to obtain a brown oily liquid, which was the crude product of LM-1102-Pfp.

[0298] The crude product was loaded onto 60-100 mesh silica gel (1 g) and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 300 / 1 to 100 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 140 mg of the product as a colorless oily liquid (yield 73%). MS (ESI): m / z [M+Na] +, theoretical value 583.3, measured value 582.9.

[0299] 1 H NMR (400MHz, DMSO-d6) δ6.63 (t, J=7.5Hz, 1H), 5.49-5.37 (m, 1H), 5.36-5.25 (m, 1H), 4.82 (p, J=6.2Hz, 1H), 2.76 (t, J=7.2Hz, 2H), 2.36-2.21 (m, 2H), 2.15 (p, J=7.5Hz, 2H), 2.04-1.94 (m, 2H), 1.74 (s, 3H), 1.66 (p, J=7.1Hz, 2H), 1.5 8-1.44 (m, 2H), 1.39-1.13 (m, 16H), 0.98 (t, J=7.5Hz, 3H), 0.87-0.78 (m, 3H).

[0300] The activated ester mass spectrometry signal intensity of this lipophilic compound is weak, so a derivatization reaction test was performed: pure LM-1102-Pfp (1 mg) was dissolved in THF (1 mL), and N-Cbz-1,2-diaminoethane (CAS: 72080-83-2, 3 mg) was added to mix thoroughly and allowed to stand for 2-3 minutes. Mass spectrometry analysis of the mixture showed that the activated ester was completely converted to an amide (structure shown below, LM-1102-Y1). MS (ESI): m / z [M+H] + , the theoretical value is 571.4, the measured value is 571.0. This further verifies the structure and reactivity of the activated ester compound.

[0301] The above reaction conversion process shows that the 12-position ester bond of the main carbon chain of compound LM-1102 (and intermediates) can withstand general alkaline hydrolysis and ester exchange reaction conditions, and the introduction of a methyl group at the α-position of the carboxylic acid in its R2 group (replacing trans-2-pentenoic acid with trans-2-methyl-2-pentenoic acid) significantly improves the stability of the ester bond.

[0302] According to the synthetic methods of SM1-Z1 to LM-1102 described in the above examples, the compounds listed in the following table of the present invention were synthesized by replacing appropriate reaction raw materials and / or reagents.

[0303] 3. Synthesis of LM-1103

[0304] LM-1103-Z1:

[0305] Using monoethyl fumarate (CAS: 2459-05-4, 216 mg, 1.5 mmol, as the starting material for the synthesis of the corresponding R2 group) and SM1-Z1 (563 mg, 1.8 mmol) as raw materials, the similar operation steps as those for the synthesis of LM-1102-Z1 were followed to obtain LM-1103-Z1 (550 mg of pale yellow oil, 84% yield; TLC: petroleum ether / ethyl acetate, 10 / 1, R f value of about 0.8). MS (ESI): m / z [M+Na] + , theoretical value 461.3, measured value 460.8.

[0306] Using LM-1103-Z1 as the raw material, the same reaction conditions as those for the synthesis of LM-1102 (LiOH demethylation) were used, and the conversion rate of the target product LM-1103 was less than 5% (the reaction mainly produced the ethyl ester hydrolysis byproduct, m / z [M+Na] + Measured value 432.8). This alkaline hydrolysis condition is not suitable for the synthesis of compound LM-1103.

[0307] LM-1103:

[0308] Using monoethyl fumarate and SM1 (159 mg, 0.533 mmol) as raw materials, LM-1103 (180 mg of colorless oil, 80% yield in this step) was obtained through the similar operation steps as those for the above-mentioned synthesis of LM-1101-Z1 and LM-1101. TLC: petroleum ether / ethyl acetate, 1 / 1, R f value is about 0.7). MS (ESI): m / z [M+Na] + , theoretical value 447.3, measured value 446.8.

[0309] Using LM-1103 as the starting material, and using reaction conditions similar to those used in the synthesis of LM-1102-Pfp (using PfpO-TFA as the activated ester conversion reagent), the desired activated ester product was not obtained. Instead, the reaction primarily produced byproduct-A, an activated ester with the 12-hydroxyl group exposed on the main carbon chain (similar to the reaction results in the synthesis of LM-1101-Pfp).

[0310] 4. Synthesis of LM-1502

[0311] Route 1:

[0312] The raw material SM1-Z1 reacts with succinic anhydride to produce LM-1502-Z1a, which is then dehydrated and condensed with leaf alcohol (CAS: 928-96-1) in the presence of a condensing agent, DCC, to produce the ester product LM-1502-Z2. Finally, the carboxylic acid product LM-1502 is obtained by mild alkaline hydrolysis of the methyl ester and acid treatment.

[0313] Route 2:

[0314] LM-1502-Z1:

[0315] To a 100 mL three-necked flask equipped with a magnetic stirrer, leaf alcohol (CAS: 928-96-1, 830 mg, 8.29 mmol, the starting material for the synthesis of the corresponding R2 group), DIEA (1.61 g, 12.4 mmol), and DCM (18 mL) were added in sequence and stirred rapidly for 2 to 3 min to obtain a colorless transparent solution.

[0316] Maintaining the system temperature at 20-25°C and continuing stirring at 500 rpm, succinic anhydride (996 mg, 9.95 mmol, starting material for the synthesis of the corresponding group X) was added to the flask in three batches over 10 minutes. Stirring was continued for 16 hours. TLC analysis (developing solvent: petroleum ether / ethyl acetate, 3 / 1) indicated near-complete conversion of the starting material, with the formation of a major product spot (R value approximately 0.25).

[0317] The system temperature was maintained at 15-25°C and rapid stirring was continued. A 4N HCl / 1,4-dioxane solution was slowly added thereto until the pH was 3-4. The solvent was then evaporated under reduced pressure at 30-35°C to obtain 3.5 g of a pale yellow solid-liquid mixed crude product of LM-1502-Z1.

[0318] The crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatographic column packed with 200-300 mesh silica gel (packing diameter approximately 2.5 cm, height approximately 12 cm). Elution was performed with a gradient eluent (petroleum ether / ethyl acetate, 4 / 1 to 1 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 1.57 g (95% yield) of the product as a light yellow oil. MS (ESI): m / z [MH] - , theoretical value 199.1, measured value 198.9.

[0319] LM-1502-Z2:

[0320] To a 50 mL single-necked flask equipped with a magnetic stirrer, SM1-Z1 (553 mg, 1.77 mmol), LM-1502-Z1 (425 mg, 2.12 mmol), DMAP (104 mg, 0.848 mmol), and DCM (12 mL) were added in sequence and stirred rapidly for 2 to 3 min to obtain a colorless transparent solution.

[0321] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). DIC (268 mg, 2.12 mmol) was added to the flask in 2-3 batches within 10-15 min, during which a small amount of white solid precipitated.

[0322] After stirring for 18 h, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw material SM1-Z1 was basically complete, and the main product spot (R f value of approximately 0.8).

[0323] The stirring was stopped and the reaction mixture was filtered. The filter cake was washed with DCM (4 mL). The filtrates were combined and the solvent was evaporated under reduced pressure at 40° C. to obtain 1.2 g of crude LM-1502-Z2 as a yellow-white solid-liquid mixture.

[0324] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 200 / 1 to 50 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 779 mg of the product as a colorless oily liquid (yield 89%). MS (ESI): m / z [M+Na] + , theoretical value 517.4, measured value 517.7.

[0325] LM-1502:

[0326] To a 50 mL single-necked flask equipped with a magnetic stirrer, LM-1502-Z2 (720 mg, 1.46 mmol) and 1,4-dioxane (12 mL) were added in sequence and stirred for 2 min to obtain a colorless transparent solution.

[0327] Keep the system temperature at 20-25 ° C and continue stirring (500-550 r / min), fully mix lithium hydroxide monohydrate (183 mg, 4.37 mmol) and purified water (3 mL) to obtain a suspension cooled to below 20 ° C, and added to the above reaction system in 4 batches within 5 minutes, maintaining the system temperature at 20-25 ° C during the period.

[0328] After stirring for 3 hours, the reaction solution was yellow and transparent. The reaction was detected by TLC (the reaction solution was sampled and the pH was adjusted to 5-6 with 10% hydrochloric acid aqueous solution, developing solvent: petroleum ether / ethyl acetate, 1 / 1), which showed that the raw material was completely converted and a single product spot was generated (R f value of approximately 0.5).

[0329] The reaction solution was concentrated under reduced pressure at 40°C to about 1 / 4 of its original volume, diluted with 15 mL of water, and the pH was adjusted to 5-6 with 0.2 M KHSO4 aqueous solution. The aqueous phase was extracted with two 15 mL portions of ethyl acetate, and the combined organic phases were dried over 5 g of anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40°C to obtain an oily crude product.

[0330] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 8 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 10 / 1 to 4 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 239 mg of the product as a colorless oily liquid (yield 34%). MS (ESI): m / z [M+Na] + , theoretical value 503.3, found value 503.6; m / z[MH] - , theoretical value 479.3, measured value 478.9.

[0331] According to the synthetic methods of LM-1502-Z1 to LM-1502 described in the above examples, the compounds listed in the following table of the present invention were synthesized by replacing appropriate reaction raw materials and / or reagents.

[0332] 5. Synthesis of LM-1601

[0333] Route 1:

[0334] The alcohol raw material 3,5,5-trimethyl-1-hexanol (CAS: 3452-97-9) and trans-1,4-cyclohexanedicarboxylic acid monomethyl ester (CAS: 15177-67-0) were sequentially subjected to dehydration condensation, alkaline hydrolysis of the methyl ester and acid treatment to obtain LM-1601-Z2, which was then subjected to mild alkaline hydrolysis and acid treatment to obtain the product LM-1601.

[0335] Route 2:

[0336] LM-1601-Z1:

[0337] Into a 100 mL three-necked flask equipped with a magnetic stirrer, trans-1,4-cyclohexanedicarboxylic acid (CAS: 619-82-9, 1.21 g, 7.0 mmol, starting material for the synthesis of group X), DMAP (171 mg, 1.40 mmol) and DCM (10 mL) were added in sequence and stirred rapidly for 2-3 min to obtain a colorless transparent solution.

[0338] Maintaining the system temperature at 20-25°C and continuing stirring (500 rpm), a solution of DIC (927 mg, 7.35 mmol) in DCM (10 mL) and a solution of 3,5,5-trimethyl-1-hexanol (CAS: 3452-97-9, 1.01 g, 7.0 mmol, the starting material for the synthesis of the corresponding R2 group) in DCM (10 mL) were simultaneously added dropwise to the flask over 10 minutes. A small amount of white solid precipitated during the reaction. Continue stirring the reaction after the additions were complete.

[0339] After 18 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 2 / 1), which showed that the conversion of the raw material alcohol was basically complete and the main product spot (R f value of approximately 0.5).

[0340] Stirring was stopped and the reaction mixture was filtered. The filter cake was washed with DCM (6 mL). The filtrates were combined and the solvent was evaporated under reduced pressure at 40° C. to obtain a crude yellow-white solid.

[0341] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter approximately 4 cm, height approximately 12 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 4 / 1 to 1 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 1.07 g (yield 51%) of the product as a light yellow oil. MS (ESI): m / z [MH] - , theoretical value 297.2, measured value 297.1.

[0342] LM-1601-Z2:

[0343] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM1-Z1 (529 mg, 1.69 mmol), LM-1601-Z1 (460 mg, 1.54 mmol), DMAP (94 mg, 0.77 mmol), and DCM (12 mL) were added in sequence and stirred rapidly for 2 to 3 min to obtain a colorless transparent solution.

[0344] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). DIC (233 mg, 1.85 mmol) was added to the flask in 2-3 batches within 10 minutes, during which a small amount of white solid precipitated.

[0345] After stirring for 18 h, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw material SM1-Z1 was basically complete, and the main product spot (R f value of approximately 0.7).

[0346] Stirring was stopped and the reaction mixture was filtered. The filter cake was washed with DCM (5-6 mL). The filtrates were combined and added to a 100 mL separatory funnel. The mixture was washed once with 5% aqueous sodium bicarbonate solution (10 mL). The organic phase was separated and dried over 5 g of anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain a pale yellow oily crude product.

[0347] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 300 / 1 to 100 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 621 mg of the product as a colorless oily liquid (yield 68%). MS (ESI): m / z [M+Na] + , theoretical value 615.5, measured value 615.1.

[0348] LM-1601:

[0349] To a 50 mL single-necked flask equipped with a magnetic stirrer, LM-1601-Z2 (410 mg, 0.692 mmol) and 1,4-dioxane (8 mL) were added in sequence and stirred for 2 min to obtain a colorless transparent solution.

[0350] Keep the system temperature at 20-25°C and continue stirring (500r / min). Cool the suspension obtained by fully mixing lithium hydroxide monohydrate (87mg, 2.07mmol) and purified water (1.5mL) to below 20°C and add it to the above reaction system in 3-4 batches within 5min, maintaining the system temperature at 20-25°C during the period.

[0351] After stirring for 4 hours, the reaction solution was light yellow and transparent. The reaction was detected by TLC (the reaction solution was sampled and the pH was adjusted to 5-6 with 10% hydrochloric acid aqueous solution, and the developing solvent was petroleum ether / ethyl acetate, 1 / 1). The conversion of the raw material was complete, and a single product spot was generated (R f value of approximately 0.5).

[0352] The reaction solution was concentrated under reduced pressure at 35°C to about 1 / 4 of its original volume, diluted with 15 mL of water, and the pH was adjusted to 5-6 with 0.2 M KHSO4 aqueous solution. The aqueous phase was extracted with two 15 mL portions of ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 40°C to obtain a pale yellow oily crude product.

[0353] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 8 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 10 / 1 to 4 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 184 mg of the product as a colorless oily liquid (yield 46%). MS (ESI): m / z [MH] - , theoretical value 578.5, measured value 578.3.

[0354] 6. Synthesis of LM-1701

[0355] LM-1701-Z2:

[0356] To a 50 mL single-necked flask equipped with a magnetic stirrer, oxalyl chloride (420 mg, 3.3 mmol, a starting material for the synthesis of the corresponding X group) and anhydrous THF (5 mL) were added in sequence, and the mixture was cooled to 0°C.

[0357] Under uniform stirring (400 r / min), a solution of anhydrous DCM (15 mL) containing cyclododecanol (CAS: 1724-39-6, 610 mg, 3.3 mmol, which is the starting material for the synthesis of the R2 group) was added dropwise to the reaction system over 10 minutes, during which the system temperature was maintained at 0-5°C. After the addition, the system temperature was allowed to rise naturally to room temperature (20-25°C) and stirring was continued.

[0358] After reacting for 12 h, the reaction solution was fully concentrated under reduced pressure at 30-35° C. and dried in a vacuum environment (50-70 Pa) for 0.5 h to obtain a pale yellow solid LM-1701-Z1 crude product, which was directly used in subsequent reactions.

[0359] SM1-Z1 (850 mg, 2.72 mmol), pyridine (330 mg, 4.17 mmol) and anhydrous DCM (9 mL) were added to a 50 mL single-necked flask equipped with a magnetic stirrer, stirred at a constant speed (500 r / min) and cooled to 0°C. The crude LM-1701-Z1 was dissolved in anhydrous DCM (15 mL) and added dropwise to the above reaction system within 10 to 15 minutes. After the addition was completed, the temperature was raised to room temperature and stirring was continued.

[0360] After 3 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw material SM1-Z1 was basically complete, and the main product spot (R f value of approximately 0.8).

[0361] Stirring was stopped and the reaction mixture was transferred to a 100 mL separatory funnel and washed once with 5% aqueous sodium bicarbonate solution (10 mL) and saturated aqueous sodium chloride solution (10 mL). The organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain a pale yellow oily crude product of LM-1701-Z2.

[0362] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 15 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 500 / 1 to 100 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 1.24 g of the product as a colorless oily liquid, with a yield of 83%. MS (ESI): m / z [M+Na] + , theoretical value 573.4, measured value 573.6.

[0363] LM-1701:

[0364] To a 50 mL single-necked flask equipped with a magnetic stirrer, LM-1701-Z2 (240 mg, 0.436 mmol) and 1,4-dioxane (8 mL) were added in sequence and stirred for 2 min to obtain a colorless transparent solution.

[0365] Keep the system temperature at 20-25°C and continue stirring (500r / min). Cool the suspension obtained by fully mixing lithium hydroxide monohydrate (55mg, 1.31mmol) and purified water (1mL) to below 20°C and add it to the above reaction system in two batches within 5min, maintaining the system temperature at 20-25°C during the period.

[0366] After stirring for 4 hours, the reaction solution was light yellow and transparent. The reaction was detected by TLC (the reaction solution was sampled and the pH was adjusted to 5-6 with 10% hydrochloric acid aqueous solution, and the developing solvent was petroleum ether / ethyl acetate, 1 / 1). The conversion of the raw material was complete, and a single product spot was generated (R f value of approximately 0.4).

[0367] The reaction solution was concentrated under reduced pressure at 40°C to approximately 1 / 4 of its original volume, diluted with 12 mL of water, and the pH adjusted to 5-6 with 0.2 M KHSO4 aqueous solution. The aqueous phase was extracted with two 12 mL portions of ethyl acetate. The combined organic phases were washed once with 10 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 190 mg of the product as a colorless oily liquid (yield 81%). MS (ESI): m / z [MH] - , theoretical value 535.4, measured value 535.1.

[0368] 7. Synthesis of LM-1204 and its activated ester

[0369] SM1-Z2:

[0370] To a 250 mL single-necked flask equipped with a magnetic stirrer, SM1-Z1 (4.6 g, 14.7 mmol), TEA (4.46 g, 44.1 mmol) and DCM (50 mL) were added in sequence and stirred rapidly for 2-3 min to obtain a transparent homogeneous solution.

[0371] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). A solution of p-toluenesulfonyl chloride (3.08 g, 16.2 mmol) in DCM (50 mL) was added dropwise to the reaction system within 15 min and the reaction was continued with stirring.

[0372] After 16 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 20 / 1), which showed that the conversion of the raw material was basically complete and the product spot (R f value of approximately 0.5).

[0373] The reaction mixture was concentrated to dryness under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatographic column (packing diameter 5 cm, height 15 cm) packed with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 100 / 1 to 50 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to yield 2.91 g of the product as a pale yellow waxy solid, in a 42% yield. MS (ESI): m / z [M+Na] + , theoretical value 489.3, measured value 489.2.

[0374] LM-1204-Z1:

[0375] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM1-Z2 (1.5 g, 3.21 mmol), paeonol (CAS: 552-41-0, 530 mg, 3.19 mmol, the synthetic starting material corresponding to the R2 group), K2CO3 (440 mg, 3.18 mmol) and DMF (20 mL) were added in sequence and stirred rapidly for 2 min to mix evenly.

[0376] The flask was connected to a nitrogen balloon via a two-way connector and heated in an 85°C oil bath with constant stirring (500 r / min) for 24 h. The reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 20 / 1), which showed that most of the raw materials had been converted and a product spot (R fvalue of approximately 0.5).

[0377] Stirring was stopped, and the reaction mixture was diluted with water (80 mL) and transferred to a 250 mL separatory funnel. The aqueous phase was extracted with three 30 mL portions of ethyl acetate. The organic phases were combined and washed once with a saturated aqueous sodium chloride solution (40 mL). The organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain a crude product.

[0378] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 100 / 1 to 50 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 780 mg of the product as a light yellow oily liquid, in a 53% yield. MS (ESI): m / z [M+Na] + , theoretical value 483.3, measured value 483.3.

[0379] LM-1204:

[0380] LM-1204-Z1 (770 mg, 1.67 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102 were followed to obtain LM-1204 (742 mg of a pale yellow oily liquid, 99% yield). MS (ESI): m / z [M+Na] + , theoretical value 469.3, measured value 469.2.

[0381] LM-1204-Pfp:

[0382] LM-1204 (400 mg, 0.896 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102-Pfp were followed to obtain LM-1204-Pfp (305 mg of a pale yellow waxy solid, 56% yield). MS (ESI): m / z [M+Na] + , theoretical value 635.3, measured value 635.2.

[0383] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0384] Synthesis of LM-1206 (Route 2)

[0385] Synthesis method:

[0386] The raw material pterostilbene (CAS: 537-42-8) undergoes a Mitsunobu reaction with SM1-Z1 in the presence of PPh3 and DIAD to produce the etherified product LM-1206-Z1, which is further demethylated by alkaline hydrolysis and acidified to obtain the product LM-1206.

[0387] 8. Synthesis of LM-1202

[0388] SM1-Z3:

[0389] Into a 100 mL single-necked flask equipped with a magnetic stirrer, SM1 (1.1 g, 3.69 mmol) and pyridine (10 mL) were added and stirred rapidly for 2 min to obtain a clear solution.

[0390] The reaction system was cooled to 0-5°C in a cold bath and continued to stir (500 r / min). p-Toluenesulfonyl chloride (773 mg, 4.05 mmol) was added to the reaction system in three batches within 15 min. Stirring was continued while maintaining the temperature after the addition.

[0391] After reacting for 24 h, 5 mL of ice water was added to quench the reaction, and the mixture was concentrated under reduced pressure at 40° C. The resulting residue was mixed with 30 mL of water and stirred evenly.

[0392] The resulting mixture was adjusted to pH 4-5 with 10% aqueous hydrochloric acid and extracted sequentially with two portions of DCM (20 mL each). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to afford 1.2 g of a light yellow oil (72% yield). MS (ESI): m / z [M+Na] + , theoretical value 475.3, measured value 475.4.

[0393] LM-1201:

[0394] To a 100 mL three-necked flask equipped with a magnetic stirrer, add 2-hexen-1-ol (CAS: 928-95-0, 147 mg, 1.46 mmol, the starting material for the synthesis of the corresponding R2 group) and THF (10 mL), and stir rapidly for 2 min to completely dissolve the raw materials.

[0395] The reaction solution was cooled to 0-5°C in an ice-water bath and stirred at a constant speed (500 r / min). KO was added to the flask in three batches within 10 min. t Bu (291 mg, 2.59 mmol) was added, and the system temperature was maintained below 5°C. After the addition, the reaction was continued with stirring for 20 minutes.

[0396] Keeping the system temperature below 5°C, a solution of SM1-Z3 (510 mg, 1.13 mmol) in THF (10 mL) was added dropwise to the reaction system over 15 min. After the addition, the reaction flask was connected to a nitrogen balloon with a two-way connector and heated in a 60°C oil bath with continued stirring (500 r / min) for the reaction.

[0397] After 2 h of reaction, the reaction was detected by TLC (the reaction solution was sampled and the pH was adjusted to 5-6 with 10% hydrochloric acid solution, developing solvent: petroleum ether / ethyl acetate, 3 / 1), which showed that the conversion of the raw material was complete and the product spot (R f value is approximately 0.3).

[0398] Stop stirring, concentrate the reaction solution under reduced pressure to 1 / 4 of the original volume, add 30 mL of water to dilute, adjust the pH to 5-6 with 0.2 M KHSO4 aqueous solution, extract with 3 portions of 20 mL of ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, collect the filtrate, and concentrate under reduced pressure at 40°C to obtain the crude product.

[0399] The crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatographic column (packing diameter 2.5 cm, height 12 cm) packed with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 10 / 1 to 4 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 82 mg of the product as a colorless oily liquid, a yield of 19%. MS (ESI): m / z [MH] - , theoretical value 379.3, measured value 379.7.

[0400] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0401] 9. Synthesis of LM-1202

[0402] LM-1202-Z1:

[0403] To a 50 mL single-necked flask equipped with a magnetic stirrer, citronellol (CAS: 106-22-9, 205 mg, 1.31 mmol, the starting material for the synthesis of the corresponding R2 group) and DMSO (5 mL) were added in sequence and stirred rapidly to obtain a transparent homogeneous solution.

[0404] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). IBX (551 mg, 1.97 mmol) was added to the above reaction system in three batches within 15 min. After the addition, the reaction was continued with stirring.

[0405] After 16 h of reaction, the reaction was detected by LCMS, which showed that the conversion of the raw material was basically complete and the product was generated.

[0406] Stirring was stopped, and the reaction mixture was diluted with water (10 mL). The aqueous phase was extracted with two 10 mL portions of methyl tert-butyl ether. The organic phases were combined and washed once with a saturated aqueous sodium chloride solution (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C. The filtrate was dried under vacuum (50-70 Pa) for 1 h to obtain 236 mg of a light yellow oily liquid, which was used in the next step without purification. No response signal was observed by MS (ESI).

[0407] LM-1202:

[0408] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM1-Z1 (160 mg, 0.512 mmol), LM-1202-Z1 (119 mg, 0.768 mmol) and anhydrous acetonitrile (8 mL) were added in sequence and stirred rapidly for 2 min to mix evenly.

[0409] The flask was connected to a nitrogen balloon via a three-way connector and the internal air was fully replaced. The flask was cooled to below 5°C in an ice-water bath and stirred at a constant speed (500 r / min). Dimethylchlorosilane (73 mg, 0.768 mmol) was added dropwise to the above reaction system via a microsyringe over 5 min. After the addition was completed, the temperature was naturally raised to room temperature (20-25°C) and the reaction was continued with stirring.

[0410] After 12 h of reaction, the reaction was monitored by LCMS, which showed that most of the raw material SM1-Z1 was converted to form an etherified product with the carboxymethyl ester removed.

[0411] The reaction was quenched by adding 1 mL of water. The reaction mixture was concentrated under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatographic column (packing diameter 2.5 cm, height 10 cm) packed with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 10 / 1 to 5 / 1). Fractions containing the product were collected and concentrated under reduced pressure at 40°C. The product was then dried under vacuum (50-70 Pa) for 1 h to afford 101 mg of the product as a pale yellow oily liquid in a 45% yield. MS (ESI): m / z [MH] - , theoretical value 435.4, measured value 435.3.

[0412] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0413] Synthesis of LM-1202 racemate

[0414] Route 1:

[0415] Citronellol (CAS: 106-22-9) reacts with TBDMS-Cl to generate the silicon ether LM-1202-Z1a. Ricinoleic acid SM1 reacts with the oxidant IBX to generate SM1-ZAa containing a keto group. Subsequently, in the presence of TESH and bismuth bromide, LM-1202-Z1a and SM1-ZAa undergo a reductive etherification reaction to obtain the product LM-1202 racemate.

[0416] Route 2:

[0417] Using SM1-Z1 as the starting material, SM1-Z4 was obtained through the similar operation steps as those for the synthesis of LM-1202-Z1. MS (ESI): m / z [M+Na] + Theoretical value: 333.3, measured value: 333.4. Then, using SM1-Z4 and citronellol as raw materials, a similar operation as the above synthesis of LM-1202 using SM1-Z1 and LM-1202-Z1 as raw materials was performed to obtain the racemic compound LM-1202.

[0418] 10. Synthesis of LM-1213

[0419] Route 1:

[0420] Synthesis method:

[0421] 1,4-Cyclohexanediol (CAS: 556-48-9) reacts with TBDMS-Cl to form the monosilyl etherified product LM-1213-Z1a. This product then undergoes a nucleophilic substitution reaction with bromide (CAS: 69620-20-8) in the presence of the strong hydrogen-abstracting reagent NaH to form the etherified product LM-1213-Z2a. Finally, the silyl ether group of LM-1213-Z2a and the keto group of SM1-Z4a undergo reductive etherification in the presence of triethylsilane and bismuth bromide to afford the product LM-1213.

[0422] Route 2:

[0423] LM-1213-Z1:

[0424] LM-1213-Z1 was obtained using 2-octyldodecanol (CAS: 5333-42-6) as the starting material and following similar procedures as for the synthesis of LM-1202-Z1. No MS (ESI) response was observed.

[0425] LM-1213-Z2:

[0426] To a 100 mL three-necked flask equipped with a magnetic stirrer, LM-1213-Z1 (210 mg, 0.703 mmol), 1,4-cyclohexanediol (CAS: 556-48-9, 327 mg, 2.81 mmol) and anhydrous acetonitrile (12 mL) were added in sequence and stirred rapidly for 2 min to obtain a clear solution.

[0427] The flask was connected to a nitrogen balloon via a three-way connector and the internal air was fully replaced. The flask was cooled to below 5°C in an ice-water bath and stirred at a constant speed (500 r / min). Dimethylchlorosilane (100 mg, 1.05 mmol) was added dropwise to the above reaction system via a microsyringe over 15 min. After the addition, the temperature was naturally raised to room temperature (20-25°C) and the reaction was continued with stirring.

[0428] After stirring for 1 h, the reaction flask was transferred to a 40°C oil bath for heating, and the reaction was continued to be stirred at a constant speed (500 r / min).

[0429] After the reaction was continued for 10 h, the reaction was monitored by LCMS, which showed that most of the raw material LM-1213-Z1 was converted to form a monoetherified product.

[0430] The reaction was quenched by adding 1 mL of water. The reaction mixture was concentrated under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatographic column (packing diameter 2.5 cm, height 10 cm) packed with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 10 / 1 to 3 / 1). Fractions containing the product were collected and concentrated under reduced pressure at 40°C. The product was then dried under vacuum (50-70 Pa) for 1 h to afford 106 mg of the product as a colorless oily liquid in a 38% yield. MS (ESI): m / z [M+H] + , theoretical value 397.4, measured value 397.1.

[0431] LM-1213:

[0432] LM-1213-Z2 (80 mg, 0.201 mmol) and SM1-Z4 (75 mg, 0.242 mmol) were used as starting materials and the same steps as those for the synthesis of LM-1202 were followed to obtain LM-1213 (42 mg of a pale yellow oily liquid, 31% yield). MS (ESI): m / z [MH] - , theoretical value 675.6, measured value 675.7.

[0433] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0434] 11. Synthesis of LM-1401

[0435] Route 1:

[0436] The raw material SM1-Z2 undergoes a substitution reaction with potassium phthalimide (CAS: 1074-82-4) to produce SM1-Z5a. The phthaloyl group is then removed with hydrazine hydrate to obtain SM1-Z6 containing an amino group. Subsequently, SM1-Z6 is condensed with 4-methyloctanoic acid (CAS: 54947-74-9) to obtain the amide LM-1401-Z1. Finally, the carboxymethyl ester is removed to obtain the product LM-1401.

[0437] Route 2:

[0438] SM1-Z5:

[0439] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM1-Z1 (1.02 g, 3.26 mmol), triphenylphosphine (1.11 g, 4.24 mmol) and anhydrous DCM (20 mL) were added in sequence and stirred rapidly for 2 to 3 min to obtain a clear solution.

[0440] The system temperature was maintained at -20 to 15°C in a cold bath and stirring was continued (500 r / min). DIAD (857 mg, 4.24 mmol) was slowly added dropwise to the flask over 10 min. Stirring was continued for 15 min after addition.

[0441] While maintaining this temperature, DPPA (1.08 g, 3.91 mmol) was added dropwise to the reaction system within 10 min, and then the temperature was naturally raised to room temperature (20-25° C.) and stirring was continued.

[0442] After 12 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 20 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.4).

[0443] Stirring was stopped, and the reaction solution was concentrated under reduced pressure at 40°C. Methyl tert-butyl ether (15 mL) was added and stirred continuously (400-450 r / min) to obtain a suspension. After standing for 10 min, the suspension was filtered. The filter cake was washed with methyl tert-butyl ether (10 mL). The filtrate was collected and concentrated to dryness under reduced pressure at 40°C to obtain a brown oily crude product.

[0444] The crude product was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter approximately 4 cm, height approximately 12 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 80 / 1 to 20 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 693 mg of the product as a colorless oil (yield 63%). MS (ESI): m / z [M+Na] + , theoretical value 360.3, measured value 360.7.

[0445] SM1-Z6:

[0446] To a 50 mL single-necked flask equipped with a magnetic stirrer, SM1-Z5 (680 mg, 2.01 mmol), triphenylphosphine (634 mg, 2.42 mmol), THF (15 mL) and water (1.5 mL) were added in sequence, and the reaction was stirred (500 r / min) at room temperature (20-25°C).

[0447] After stirring for 16 h, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.5).

[0448] Stirring was stopped, and the reaction solution was concentrated under reduced pressure at 40°C. Methyl tert-butyl ether (6 mL) and ethyl acetate (0.5 mL) were added and stirred continuously (400-450 rpm) to obtain a suspension. The suspension was allowed to stand for 30 minutes and then filtered. The filter cake was washed with methyl tert-butyl ether (5 mL). The filtrate was collected and concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 hour to obtain 657 mg of the product as a colorless oil (yield 105%, containing a small amount of triphenylphosphine by-product). MS (ESI): m / z [M+H] + , theoretical value 312.3, measured value 312.5.

[0449] LM-1401-Z1:

[0450] To a 50 mL single-necked flask equipped with a magnetic stirrer, SM1-Z6 (154 mg, 0.494 mmol), 4-methyloctanoic acid (CAS: 54947-74-9, 82 mg, 0.519 mmol, the starting material for the synthesis of the corresponding R2 group), DIEA (134 mg, 1.04 mmol) and anhydrous DMF (8 mL) were added in sequence and stirred rapidly to mix.

[0451] The system temperature was maintained at 10-15°C in a cold bath and stirring was continued (500 rpm). HATU (CAS: 148893-10-1, 282 mg, 0.741 mmol) was added to the flask in 4-5 batches over 10 min. After the addition, the reaction system was allowed to naturally warm to room temperature (20-25°C) and stirring was continued.

[0452] After 4 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.7).

[0453] The reaction was quenched by adding 5 mL of water, and the reaction mixture was concentrated under reduced pressure at 60°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed with a gradient elution (petroleum ether / ethyl acetate, 200 / 1 to 50 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to afford 125 mg of a light yellow oil (yield 56%). MS (ESI): m / z [M+Na] + , theoretical value 474.4, measured value 474.7.

[0454] LM-1401:

[0455] LM-1401-Z1 (111 mg, 0.246 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102 were followed to obtain LM-1401 (85 mg of a pale yellow oily liquid, 79% yield). MS (ESI): m / z [MH] - , theoretical value 436.4, measured value 436.5.

[0456] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0457] 12. Synthesis of LM-1903

[0458] SM1-Z7:

[0459] To a 100 mL three-necked flask equipped with a magnetic stirrer, pure ricinoleic acid (SM1, 894 mg, 3.0 mmol), 2-(trimethylsilyl)ethanol (CAS: 2916-68-9, 710 mg, 6.0 mmol), DMAP (366 mg, 3.0 mmol) and DCM (30 mL) were added in sequence and stirred rapidly for 3 min to obtain a colorless transparent solution.

[0460] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). DIC (378 mg, 3.0 mmol) was added to the flask in three batches within 10 min, during which a small amount of white solid gradually precipitated.

[0461] After stirring for 16 h, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that most of the raw material SM1 was converted and the main product spot (R f value of approximately 0.5).

[0462] Stirring was stopped and the reaction mixture was filtered. The filter cake was washed with DCM (5-6 mL). The filtrates were combined and added to a 100 mL separatory funnel and washed once with 5% aqueous sodium bicarbonate solution (10 mL). The organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain a crude yellow-white solid-liquid mixture.

[0463] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 30 / 1 to 10 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 860 mg of the product as a colorless oily liquid (yield 72%). MS (ESI): m / z [M+Na] + , theoretical value 421.3, measured value 420.9.

[0464] LM-1903-Z1:

[0465] To a 50 mL single-necked flask equipped with a magnetic stirrer, SM1-Z7 (150 mg, 0.376 mmol), DIEA (97 mg, 0.752 mmol), DMAP (9 mg, 0.0752 mmol) and DCM (6 mL) were added in sequence and stirred rapidly for 2 min to obtain a colorless transparent solution.

[0466] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). A solution of p-nitrophenyl chloroformate (114 mg, 0.564 mmol) in DCM (5 mL) was added dropwise to the flask within 10 min, and stirring was continued for 8 h.

[0467] The system temperature was maintained at 20-25°C and stirring was continued. L-menthol (CAS: 2216-51-5, 118 mg, 0.752 mmol, which is the starting material for the synthesis of the corresponding R2 group) was added to the above reaction solution. The flask was connected to a nitrogen balloon via a two-way connector and heated in a 45°C oil bath with constant stirring (500 r / min).

[0468] After 23 h, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the raw material SM1-Z7 partially remained and the main product spot (R f value of approximately 0.7).

[0469] Stirring was stopped and the solvent was evaporated under reduced pressure at 40°C. The residue was dissolved in ethyl acetate (50 mL) and transferred to a 100 mL separatory funnel. The mixture was washed with 20 mL each of a 5% aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain a crude yellow oil.

[0470] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 200 / 1 to 50 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 76.5 mg of the product as a colorless oily liquid (yield 35%). MS (ESI): m / z [M+Na] + , theoretical value 603.5, measured value 603.6.

[0471] LM-1903:

[0472] LM-1903-Z1 (70 mg, 0.12 mmol) and THF (5 mL) were added sequentially to a 50 mL single-necked flask equipped with a magnetic stirrer, and the mixture was stirred for 2 min to obtain a colorless transparent solution.

[0473] The system temperature was maintained at 20-25° C. and stirring was continued (500 r / min). 1 mol / L TBAF in THF (240 μL, 0.24 mmol) was added to the reaction system.

[0474] After stirring for 6 h, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 5 / 1), which showed that the conversion of the raw materials was complete and the main product spot (R f value is approximately 0.3).

[0475] The stirring was stopped and the reaction solution was concentrated under reduced pressure below 30°C to obtain a pale yellow oily crude product.

[0476] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 8 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 30 / 1 to 10 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 41 mg of the product as a colorless oily liquid (yield 71%). MS (ESI): m / z [MH] - , theoretical value 479.4, measured value 479.8.

[0477] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0478] 13. Synthesis of LM-2101 and its activated ester

[0479] SM3-Z1:

[0480] In a 1 L three-necked flask equipped with a magnetic stirrer, 12-hydroxystearic acid (SM3, CAS: 106-14-9, 200.2 g, 666 mmol, which is the starting material for the synthesis of the lipophilic compound corresponding to the R1 group in the structure of this route), p-toluenesulfonic acid monohydrate (0.59 g, 3.42 mmol), and methanol (500 mL) were added in sequence and stirred rapidly for 5 min to obtain a light yellow transparent homogeneous solution.

[0481] The flask was connected to a nitrogen balloon via a two-way connector and heated in an oil bath at 70°C with constant stirring (300 r / min) for 22 h. The heating was then stopped and the reaction was monitored by TLC (developing solvent: DCM / methanol, 10 / 1). The results showed that the conversion of the starting material was complete and a single product spot (R f value of approximately 0.8).

[0482] The reaction solution was concentrated to dryness under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 2 h to obtain 211.6 g of a yellow-white waxy solid, the crude product of SM1-Z1, which was used directly in the next step without purification. MS (ESI): m / z [M+Na] + , theoretical value 337.3, found value 337.1; m / z[M-OH] + , theoretical value 297.3, measured value 297.2.

[0483] LM-2101-Z1:

[0484] Into a 500 mL three-necked flask equipped with a magnetic stirrer, SM3-Z1 (10 g, 31.8 mmol), trans-2-methyl-2-pentenoic acid (SM2, CAS: 16957-70-3, 5.44 g, 47.7 mmol, the synthetic starting material corresponding to the R2 group), DMAP (1.9 g, 15.6 mmol), and DCM (150 mL) were added in sequence and stirred rapidly for 5 min to obtain a colorless transparent solution.

[0485] The system temperature was maintained at 20-25°C and stirring was continued (450-500 r / min). DIC (4.8 g, 38.0 mmol) was added to the flask in 5 batches within 20 min, during which a white solid gradually precipitated.

[0486] After stirring for 21 h, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the raw material SM3-Z1 (R f value of about 0.3) was mostly converted to form the main product spot (R f value of approximately 0.5).

[0487] Stirring was stopped and the reaction mixture was filtered. The filter cake was washed with DCM (50 mL). The filtrates were combined and added to a 500 mL separatory funnel. The mixture was washed successively with 3 portions of 5% aqueous sodium bicarbonate solution (60 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain a pale yellow oily crude product of LM-2101-Z1.

[0488] The crude product was loaded onto 60-100 mesh silica gel (30 g) and then loaded onto a chromatographic column (packing diameter 8 cm, height 50 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 300 / 1 to 100 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 2 h to obtain 9.24 g (yield 71%) of the product as a colorless oily liquid. MS (ESI): m / z [M+Na] + , theoretical value 433.3, measured value 433.3.

[0489] LM-2101:

[0490] To a 50 mL single-necked flask equipped with a magnetic stirrer, LM-2101-Z1 (9.2 g, 22.4 mmol) and 1,4-dioxane (50 mL) were added in sequence and stirred for 5 min to obtain a colorless transparent solution.

[0491] Maintain the system temperature at 20-25°C and continue stirring (450-500 r / min). Lithium hydroxide monohydrate (2.84 g, 67.6 mmol) and purified water (25 mL) were fully mixed to obtain a suspension cooled to below 20°C and added to the above reaction system in 4-5 batches within 15-20 minutes, maintaining the system temperature at 20-25°C.

[0492] After stirring for 6.5 h, the reaction solution was yellow and transparent. The reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the raw material (R f value of about 0.7) completely converted and disappeared.

[0493] The reaction solution was concentrated under reduced pressure at 30-35°C to about 1 / 4 of its original volume, diluted with 100 mL of water, adjusted to pH 3-4 with 0.2 M KHSO4 aqueous solution, and the aqueous phase was extracted with two portions of 100 mL each of ethyl acetate. The organic phases were combined and dried over 25 g of anhydrous sodium sulfate. The filtrate was collected by filtration, concentrated under reduced pressure at 40°C to an oil, and dried in a vacuum environment (50-70 Pa) for 1 h to obtain a crude yellow oily liquid.

[0494] The crude product was loaded onto 60-100 mesh silica gel (25 g) and then loaded onto a chromatographic column (packing diameter 6 cm, height 40 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 30 / 1 to 10 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 8.1 g of the product as a colorless oily liquid (yield 91%). MS (ESI): m / z [M+Na] + , theoretical value 419.3, measured value 419.2.

[0495] 1 H NMR (400MHz, DMSO-d6) δ11.95 (s, 1H), 6.63 (td, J=7.4, 1.7Hz, 1H), 4.82 (p, J=6.2Hz, 1H), 2.21-2.08 ( m, 4H), 1.75 (s, 3H), 1.55-1.40 (m, 6H), 1.27-1.17 (m, 22H), 0.98 (t, J=7.5Hz, 3H), 0.87-0.80 (m, 3H).

[0496] LM-2101-Pfp:

[0497] To a 250 mL single-necked flask equipped with a magnetic stirrer, LM-2101 (8.1 g, 20.4 mmol), DIEA (3.41 g, 26.4 mmol), and DCM (100 mL) were added in sequence and stirred for 2 min to obtain a light yellow transparent solution.

[0498] The system temperature was maintained at 20-25°C and stirring was continued (550-600 r / min). PfpO-TFA (6.79 g, 24.2 mmol) was slowly added dropwise to the flask over 15 min. A large amount of white smoke was produced during the addition, the solution gradually turned light purple, and the viscosity gradually increased.

[0499] After stirring for 50 min, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value is about 0.7), and the reaction solution is purple and homogeneous.

[0500] Stirring was stopped and the reaction solution was transferred to a 250 mL separatory funnel and washed with two portions of 5% aqueous sodium bicarbonate solution (50 mL each). The organic phase was separated and dried over anhydrous sodium sulfate (20 g). The filtrate was collected after filtration and concentrated under reduced pressure at 40°C to obtain a brown oily liquid, which was the crude product of LM-2101-Pfp.

[0501] The crude product was loaded onto 60-100 mesh silica gel (20 g) and then loaded onto a chromatographic column (packing diameter 6 cm, height 50 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 300 / 1 to 100 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 7.46 g (yield 65%) of the product as a colorless oily liquid. MS (ESI): m / z [M+Na] + , theoretical value 585.3, measured value 585.2.

[0502] 1 H NMR (400MHz, CDCl3) δ6.74-6.69(m, 1H), 4.95-4.88(m, 1H), 2.65(t, J=7.4Hz, 2H), 2.22-2.14(m, 2H), 1.82 (d, J=1.2Hz, 3H), 1.77 (p, J=7.4Hz, 2H), 1.59-1.50 (m, 4H), 1.43-1.37 (m, 2H), 1.27 (br s, 20H), 1.05 (t, J=7.6Hz, 3H), 0.87 (t, J=6.8Hz, 3H).

[0503] The activated ester LM-2101-Pfp (2 mg) was dissolved in THF (1 mL). N,N-dimethylethylenediamine (CAS: 108-00-9, 3 mg) was added, mixed, and allowed to stand for 2-3 minutes. Mass spectrometry analysis of the mixture showed that the activated ester was completely converted to an amide (structure shown below, LM-2101-Y1). MS (ESI): m / z [M+H] + , the theoretical value is 467.4, the measured value is 467.3. This further verifies the structure and reactivity of the activated ester compound.

[0504] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0505] 14. Synthesis of LM-2103

[0506] Using trans-cinnamic acid (CAS: 140-10-3, as the starting material for the synthesis of the corresponding R2 group) and SM3 (462 mg, 1.54 mmol) as raw materials, LM-2103 (190 mg of white solid, 29% yield in this step; TLC: petroleum ether / ethyl acetate, 1 / 1, R f value is about 0.5). MS (ESI): m / z [MH] - , theoretical value 429.3, measured value 429.6.

[0507] Using LM-2103 as the starting material and PfpO-TFA as the activated ester conversion reagent, the target activated ester product, LM-2103-Pfp, was not obtained. The reaction mainly produced an activated ester byproduct, byproduct-C, in which the 12-hydroxyl group of the main carbon chain was trifluoroacetylated (derivatized with ammonia to convert the activated ester into an amide and then analyzed by MS, m / z [M+H] + Measured value 395.9).

[0508] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0509] 15. Synthesis of LM-2101-L1 and its activated ester

[0510] LM-2101-L1-Z1:

[0511] To a 50 mL single-necked flask equipped with a magnetic stirrer, ethanolamine (122 mg, 2.0 mmol) and DCM (5 mL) were added in sequence and stirred rapidly to clarify.

[0512] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). A DCM (5 mL) solution of LM-2101-Pfp (562 mg, 1.0 mmol) was added dropwise to the flask within 5 minutes. Stirring was continued after addition.

[0513] After 1 h of reaction, the reaction was detected by TLC (developing solvent: ethyl acetate), which showed that the conversion of the raw material LM-2101-Pfp was complete and the main product spot (R f value of approximately 0.4).

[0514] Stirring was stopped, and the reaction solution was concentrated under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 1 / 1 to pure ethyl acetate). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 300 mg of the product as a colorless oil (yield 68%). MS (ESI): m / z [M+H] + , theoretical value 440.4, measured value 440.3.

[0515] LM-2101-L1:

[0516] LM-2101-L1-Z1 (158 mg, 0.359 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1502-Z1 were followed to obtain LM-2101-L1 (150 mg of a colorless oil, 77% yield; TLC: DCM / methanol, 20 / 1, R f value is about 0.3). MS (ESI): m / z [M+Na] + , theoretical value 562.4, measured value 562.3.

[0517] LM-2101-L1-Pfp:

[0518] LM-2101-L1 (150 mg, 0.278 mmol) was used as the starting material and the same steps as those for the synthesis of LM-2101-Pfp were followed to obtain LM-2101-L1-Pfp (173 mg of pale yellow oil, 88% yield; TLC: DCM / methanol, 10 / 1, R fThe compound had no mass spectrometry response signal and was derivatized with N,N-dimethylethylenediamine to give LM-2101-L1-Y1. MS (ESI): m / z [M+H] + , theoretical value 610.5, measured value 610.4.

[0519] 16. Synthesis of LM-2101-L2 and its activated ester

[0520] LM-2101-L2-Z1:

[0521] LM-2101-Pfp (500 mg, 0.89 mmol) and 1,3-propylenediamine (132 mg, 1.78 mmol) were used as starting materials and the same procedures as described for the synthesis of LM-2101-L1-Z1 were followed to obtain LM-2101-L2-Z1 (391 mg of a colorless oil, 97% yield). MS (ESI): m / z [M+H] + , theoretical value 453.4, measured value 453.3.

[0522] LM-2101-L2:

[0523] To a 100 mL single-necked flask equipped with a magnetic stirrer, 3,3′-dithiodipropionic acid (CAS: 1119-62-6, 405 mg, 1.93 mmol), DIEA (622 mg, 4.8 mmol) and DCM (13 mL) were added in sequence and stirred for 2 min to obtain a clear solution.

[0524] The system temperature was maintained at 20-25°C and stirring was continued (550-600 r / min). A solution of PfpO-TFA (265 mg, 0.948 mmol) in DCM (2 mL) was slowly added dropwise to the flask over 10 min. Stirring was continued after addition.

[0525] After 1.5 h of reaction, LM-2101-L2-Z1 (390 mg, 0.861 mmol) was dissolved in DCM (3 mL) and added dropwise to the reaction system within 5 min. Stirring was continued after the addition.

[0526] After the reaction was continued for 2 h, the reaction was monitored by TLC (developing solvent: DCM / methanol, 10 / 1), which showed that the starting material (R f The conversion was completed and the main product spot (R f value of approximately 0.7).

[0527] Stirring was stopped, and the reaction solution was diluted with DCM (30 mL) and transferred to a 250 mL separatory funnel. The solution was washed sequentially with three portions of 5% aqueous sodium bicarbonate solution (15 mL each). The organic phase was separated and dried over anhydrous sodium sulfate. The filtrate was collected after filtration and concentrated under reduced pressure at 40°C to give the crude product.

[0528] The crude product was loaded onto 60-100 mesh silica gel (20 g) and then loaded onto a chromatographic column (packing diameter 6 cm, height 50 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (DCM / methanol, 100 / 1 to 25 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 511 mg of the product as a light yellow oily liquid (yield 92%). MS (ESI): m / z [M+H] + , theoretical value 645.4, found value 645.3; m / z[M+Na] + , theoretical value 667.4, measured value 667.3.

[0529] LM-2101-L2-Pfp

[0530] LM-2101-L2 (100 mg, 0.155 mmol) was used as the starting material and the same steps as those for the synthesis of LM-2101-Pfp were followed to obtain LM-2101-L2-Pfp (colorless oil, 48 mg, yield 38%; TLC: DCM / methanol, 10 / 1, R f value of about 0.9). MS (ESI): m / z [M+H] + , theoretical value 811.4, found value 811.2; m / z[M+Na] + , theoretical value 833.4, measured value 833.2.

[0531] 17. Synthesis of LM-2811 and its activated ester

[0532] LM-2811-Z1:

[0533] Citronellol (CAS: 106-22-9, 3.0 g, 19.2 mmol, starting material for the synthesis of the corresponding R2 group) was used as the starting material and the same procedures as described for the synthesis of LM-1502-Z1 were followed to obtain LM-2811-Z1 (4.87 g of a pale yellow oil, 99% yield). MS (ESI): m / z [MH] - , theoretical value 255.2, found value 255.0; m / z [2M+Na-2H] - , theoretical value 533.4, measured value 533.0.

[0534] LM-2811-Z2:

[0535] LM-2811-Z2 (5.04 g, 97% yield) was obtained from SM3-Z1 (2.96 g, 9.42 mmol) and LM-2811-Z1 (2.9 g, 11.3 mmol) using similar procedures as described above for the synthesis of LM-1502-Z2. MS (ESI): m / z [M+Na] + , theoretical value 575.4, measured value 575.5.

[0536] LM-2811:

[0537] LM-2811-Z2 (1.33 g, 2.41 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1502 were followed to obtain LM-2811 (350 mg of a colorless oil, 27% yield). MS (ESI): m / z [M+Na] + , theoretical value 561.4, measured value 561.4.

[0538] LM-2811-Pfp:

[0539] To a 50 mL single-necked flask equipped with a magnetic stirrer, LM-2811 (250 mg, 0.464 mmol), DIEA (120 mg, 0.928 mmol), and DCM (6 mL) were added in sequence and stirred for 2 min to obtain a light yellow transparent solution.

[0540] The system temperature was maintained at 20-25°C and stirring was continued (600 r / min). PfpO-TFA (143 mg, 0.51 mmol) was slowly added dropwise to the flask over 10 min. White smoke was generated during the addition and the solution gradually turned light purple.

[0541] After stirring for 25 min, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 4 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value is about 0.9), and the reaction solution is purple and homogeneous.

[0542] The stirring was stopped and the reaction solution was concentrated under reduced pressure at 30-35°C to obtain a crude brown oily liquid.

[0543] The crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatographic column (packing diameter 2.5 cm, height 10 cm) packed with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 300 / 1 to 100 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 49 mg of the product as a colorless oily liquid (yield 15%). MS (ESI): m / z [M+Na] + , theoretical value 727.4, found value 727.8; m / z[M+K] + , theoretical value 743.4, measured value 743.7.

[0544] 1 H NMR (400MHz, CDCl3) δ5.12-5.04 (m, 1H), 4.88 (p, J=6.2Hz, 1H), 4.19-4.06 (m, 2H), 2.66 (t, J=7.4Hz, 2H), 2.61 (s, 4H), 2.06-1.90 (m, 2H), 1.81-1 .73(m, 2H), 1.68(s, 3H), 1.61-1.57(m, 5H), 1.55-1.48(m, 4H), 1.47-1. 37 (m, 4H), 1.31-1.23 (m, 22H), 0.91 (d, J=6.6Hz, 3H), 0.89-0.86 (m, 3H).

[0545] 18. Synthesis of LM-2801

[0546] LM-2801-Z1:

[0547] LM-2801-Z1 (1.69 g, 46% yield) was obtained using perillyl alcohol (CAS: 536-59-4, 2.1 g, 13.8 mmol, starting material for the synthesis of the corresponding R2 group) and 2,2-dimethylmalonic acid (CAS: 595-46-0, 1.82 g, 13.8 mmol, starting material for the synthesis of the corresponding X group) as starting materials, following similar procedures as described for the synthesis of LM-1601-Z1. MS (ESI): m / z [MH] - , theoretical value 265.2, measured value 265.1.

[0548] LM-2801-Z2:

[0549] LM-2801-Z1 (1.5 g, 5.63 mmol) and SM3-Z1 (1.95 g, 6.2 mmol) were used as starting materials and the same steps as those for the synthesis of LM-1502-Z2 were followed to obtain LM-2801-Z2 (2.15 g, 68% yield, colorless oil). MS (ESI): m / z [M+Na] + , theoretical value 585.4, measured value 585.8.

[0550] LM-2801:

[0551] LM-2801-Z2 (1.1 g, 1.95 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1502 were followed to obtain LM-2801 (792 mg of a colorless oily liquid, 74% yield). MS (ESI): m / z [MH] - , theoretical value 547.4, measured value 547.1.

[0552] According to the synthetic methods of LM-2801-Z1 to LM-2801 described in the above examples, the compounds listed in the following table of the present invention were synthesized by replacing appropriate reaction raw materials and / or reagents.

[0553] 19. Synthesis of LM-2106

[0554] SM3-Z8:

[0555] SM3 (360 mg, 1.2 mmol) was used as the starting material and the same steps as those for the synthesis of SM1-Z7 were followed to obtain SM3-Z8 (398 mg of a colorless oily liquid, 83% yield). MS (ESI): m / z [M+Na] + , theoretical value 423.3, measured value 423.6.

[0556] SM4-Z1:

[0557] To a 25 mL single-necked flask equipped with a magnetic stirrer, (E)-10-hydroxy-2-decenoic acid (SM4, CAS: 14113-05-4, 279 mg, 1.5 mmol, the synthetic starting material corresponding to the R2 group), acetic anhydride (460 mg, 4.5 mmol), pyridine (590 mg, 7.5 mmol) and DCM (5 mL) were added in sequence and stirred rapidly for 5 min to obtain a light yellow transparent homogeneous solution.

[0558] The flask was connected to a nitrogen balloon via a two-way connector and heated in a 40°C oil bath with constant stirring (500 r / min) for 2 h. The heating was then stopped and the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1). The results showed that the conversion of the raw material was complete and a relatively single product spot (R f value of approximately 0.5).

[0559] The reaction solution was concentrated to dryness under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 2 h to obtain 350 mg of a light yellow oil. MS (ESI): m / z [M+Na] + , theoretical value 251.1, measured value 251.1.

[0560] LM-2106-Z1:

[0561] SM3-Z8 (380 mg, 0.948 mmol) and SM4-Z1 (260 mg, 1.14 mmol) were used as starting materials and the same steps as those for the synthesis of LM-2101-Z1 were followed to obtain LM-2106-Z1 (359 mg of a colorless oily liquid, 62% yield). MS (ESI): m / z [M+H] + , theoretical value 611.5, measured value 611.4.

[0562] LM-2106:

[0563] LM-2106-Z1 (301 mg, 0.493 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1903 were followed to obtain LM-2106 (194 mg of a colorless oily liquid, 77% yield). MS (ESI): m / z [MH] - , theoretical value 509.4, measured value 509.0.

[0564] 20. Synthesis of LM-2202 and its activated ester

[0565] LM-2202-Z1:

[0566] Using leaf alcohol (cis-3-hexen-1-ol, CAS: 928-96-1, 3.75 g, 37.4 mmol, the starting material for the synthesis of the corresponding R2 group) as the starting material, LM-2202-Z1 (7.52 g, 79% yield) was obtained as a colorless oily liquid using procedures similar to those described above for SM1-Z2. MS (ESI): m / z [M+Na] + , theoretical value 277.1, measured value 276.8.

[0567] LM-2202:

[0568] Into a 250 mL three-necked flask equipped with a magnetic stirrer, 12-hydroxystearic acid (SM3, 1.65 g, 5.49 mmol) and DMF (30 mL) were added in sequence, and the mixture was rapidly stirred for 2 min to completely dissolve the raw materials.

[0569] The reaction solution was cooled to 0°C in an ice-water bath and stirred at a constant speed (500 r / min). KO was added to the flask in 5 to 6 batches within 30 min. t Bu (1.85 g, 16.5 mmol) was added, and the system temperature was maintained below 10°C. After the addition, the reaction was continued with stirring for 30 minutes.

[0570] Keeping the system temperature below 10°C, a solution of LM-2202-Z1 (4.2 g, 16.5 mmol) in DMF (20 mL) was added dropwise to the reaction system within 15 min. After the addition, the reaction solution was warmed to room temperature. The flask was connected to a nitrogen balloon with a two-way connector and heated in a 60°C oil bath while continuing to stir (500 r / min) for the reaction.

[0571] After 2 h of reaction, the reaction was detected by TLC (the reaction solution was sampled and the pH was adjusted to 5-6 with 10% hydrochloric acid solution, developing solvent: petroleum ether / ethyl acetate, 4 / 1), which showed that the conversion of the raw material was complete and the product spot (R f value is approximately 0.2).

[0572] Stirring was stopped, and the reaction solution was cooled to room temperature. The pH was adjusted to 5-6 with 0.2 M KHSO4 aqueous solution. The reaction mixture was diluted with 150 mL of ethyl acetate and transferred to a 500 mL separatory funnel. The funnel was washed with three portions of 80 mL of saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 60°C to obtain a crude product.

[0573] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 16 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 10 / 1 to 4 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 123 mg of the product as a colorless oily liquid, a 6% yield. MS (ESI): m / z [MH] - , theoretical value 381.3, measured value 381.0.

[0574] LM-2202-Pfp:

[0575] LM-2202 (120 mg, 0.314 mmol) was used as the starting material and the same steps as those for the synthesis of LM-2101-Pfp were followed to obtain LM-2202-Pfp (72 mg of a colorless oily liquid, 42% yield). MS (ESI): m / z [M+H] + , theoretical value 549.3, measured value 549.5.

[0576] Following the derivatization method for LM-2101-Pfp, the activated ester LM-2202-Pfp was derivatized to completely convert it into LM-2202-Y1. MS (ESI): m / z [M+H] + , theoretical value 453.4, measured value 452.9.

[0577] 21. Synthesis of LM-2208

[0578] SM3-Z2:

[0579] SM3-Z1 (3.7 g, 11.8 mmol) was used as the starting material and the same steps as those for the synthesis of SM1-Z2 were followed to obtain SM3-Z2 (3.82 g of pale yellow solid, 69% yield). MS (ESI): m / z [M+Na] + , theoretical value 491.3, measured value 491.1.

[0580] LM-2208-Z1:

[0581] SM3-Z2 (112 mg, 0.239 mmol) and 4-n-butoxyphenol (CAS: 122-94-1, 40 mg, 0.239 mmol, the starting material for the synthesis of the corresponding R2 group) were used as starting materials, and the same procedures as those for the synthesis of LM-1204-Z1 were followed to obtain LM-2208-Z1 (65 mg of a pale yellow oily liquid, 59% yield). MS (ESI): m / z [M+Na] + , theoretical value 485.4, measured value 485.8.

[0582] LM-2208:

[0583] LM-2208-Z1 (60 mg, 0.13 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1204 were followed to obtain LM-2208 (44 mg of a pale yellow solid, 76% yield). MS (ESI): m / z [MH] - , theoretical value 447.4, measured value 447.6.

[0584] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0585] Synthesis of LM-2211 (Route 2)

[0586] Vitamin E (CAS: 2074-53-5) with a phenolic hydroxyl group and SM3-Z1 with an alcoholic hydroxyl group undergo the same reaction steps as those for synthesizing LM-1206 (Route 2) to obtain the product LM-2211.

[0587] 22. Synthesis of LM-2201

[0588] Route 1:

[0589] SM3-Z2 and trans-cinnamyl alcohol (CAS: 4407-36-7) undergo a substitution reaction in the presence of cesium carbonate to obtain the etherified product LM-2201-Z1, and finally the carboxymethyl ester is removed to obtain LM-2201.

[0590] Route 2:

[0591] LM-2201 was obtained using SM3 and trans-cinnamyl alcohol (the starting material for the synthesis of the corresponding R2 group) through similar steps to the aforementioned synthesis of SM1-Z3 and LM-1201. MS (ESI): m / z [MH] - , theoretical value 415.3, measured value 415.5.

[0592] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0593] 23. Synthesis of LM-2205

[0594] LM-2205 was obtained using citronellol (CAS: 106-22-9, the starting material for the synthesis of the corresponding R2 group) and SM3-Z1, following similar procedures as described above for the sequential synthesis of LM-1202-Z1 and LM-1202. MS (ESI): m / z [MH] - , theoretical value 437.4, measured value 437.5.

[0595] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0596] 24. Synthesis of LM-2901

[0597] LM-2901-Z1:

[0598] LM-2901-Z1 was obtained using trans-2-hexenal (CAS: 6728-26-3, the starting material for the synthesis of the corresponding R2 group) and 1,2-cyclohexanediol (CAS: 931-17-9, the starting material for the synthesis of the corresponding X group) as raw materials, following similar procedures as those used to synthesize LM-1213-Z2. MS (ESI): m / z [M+Na] + , theoretical value 221.2, measured value 221.5.

[0599] SM3-Z12:

[0600] SM3-Z12 was obtained by using SM3-Z1 as the starting material and undergoing similar steps as the synthesis of LM-1202-Z1. MS (ESI): m / z [M+Na] + , theoretical value 335.3, measured value 335.5.

[0601] LM-2901:

[0602] LM-2901-Z1 (64 mg, 0.323 mmol) and SM3-Z12 (111 mg, 0.355 mmol) were used as starting materials and the same steps as those for the synthesis of LM-1213 were followed to obtain LM-2901 (28 mg of a pale yellow oily liquid, 18% yield). MS (ESI): m / z [MH] - , theoretical value 479.4, measured value 479.3.

[0603] 25. Synthesis of LM-2301

[0604] LM-2301-Z1:

[0605] To a 250 mL three-necked flask equipped with a magnetic stirrer, citronellol (CAS: 106-22-9, 3.12 g, 20.0 mmol, the starting material for the synthesis of the corresponding R2 group), triphenylphosphine (5.49 g, 21.0 mmol) and DCM (100 mL) were added in sequence and rapidly stirred for 2 min to obtain a colorless transparent solution.

[0606] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). NBS (3.74 g, 21.0 mmol) was added to the flask in 4-5 batches within 15 minutes. After the addition, stirring was continued and the reaction was continued.

[0607] After 12 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 20 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.8).

[0608] Stirring was stopped, and the solvent was evaporated under reduced pressure at 40°C. The resulting pale yellow crude oil was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 4 cm, height 16 cm) with 200-300 mesh silica gel. Elution was performed with a gradient eluent (petroleum ether / ethyl acetate, 200 / 1 to 100 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 1.7 g (yield 39%) of a colorless oily liquid. No response signal was observed by MS (ESI).

[0609] SM3-Z3:

[0610] SM3-Z1 (6.28 g, 20.0 mmol) was used as the starting material and the same steps as those for the synthesis of LM-2301-Z1 were followed to obtain SM3-Z3 (6.7 g of colorless oily liquid, 89% yield). No response signal was observed by MS (ESI).

[0611] SM3-Z4:

[0612] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM3-Z3 (3.76 g, 9.96 mmol) and DMF (30 mL) were added in sequence and stirred for 2 min to obtain a light yellow transparent solution.

[0613] The system temperature was maintained at 20-25° C. and stirring was continued (500 r / min). Potassium thioacetate (2.28 g, 20.0 mmol) was added to the flask in three batches within 5-10 min. After the addition, stirring was continued and the reaction was continued.

[0614] After 16 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.7).

[0615] Stirring was stopped, and the reaction mixture was diluted with 100 mL of ethyl acetate and transferred to a 250 mL separatory funnel. The mixture was washed with two portions of 55 mL of saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40°C to obtain a crude product.

[0616] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 200 / 1 to 100 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 2.88 g of the product as a colorless oily liquid (yield 77%). MS (ESI): m / z [M+Na] + , theoretical value 395.3, measured value 394.8.

[0617] SM3-Z5:

[0618] Into a 250 mL single-necked flask equipped with a magnetic stirrer, SM3-ZA (1.13 g, 3.03 mmol) and methanol (50 mL) were added in sequence and rapidly stirred for 5 min to obtain a colorless, transparent, homogeneous solution.

[0619] Keep the system temperature below 30°C and continue stirring (500 rpm). Add concentrated hydrochloric acid (4 mL) dropwise to the flask over 5 minutes. Connect the flask to a nitrogen balloon with a two-way connector and heat in a 60°C oil bath while continuing stirring.

[0620] After 22 h of reaction, heating was stopped and the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1). The results showed that the conversion of the raw materials was complete and a relatively single product spot was generated (R f value of approximately 0.8).

[0621] The reaction mixture was concentrated to dryness under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. The product was eluted with a gradient eluent (petroleum ether / ethyl acetate, 100 / 1 to 50 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 630 mg of a colorless oil (yield 63%). MS (ESI): m / z [M+Na] + , theoretical value 353.3, measured value 352.8.

[0622] LM-2301-Z2:

[0623] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM3-Z5 (330 mg, 0.998 mmol), LM-2301-Z1 (349 mg, 1.59 mmol), K2CO3 (276 mg, 2.0 mmol) and DMF (10 mL) were added in sequence and stirred rapidly for 2 min to mix evenly.

[0624] The flask was connected to a nitrogen balloon via a two-way connector and heated in an 85°C oil bath with constant stirring (500 r / min) for 2 h. The reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that most of the starting material had been converted, with a relatively single product spot (R f value of approximately 0.5).

[0625] Stirring was stopped, and the reaction mixture was diluted with water (50 mL) and transferred to a 250-mL separatory funnel. The aqueous phase was extracted with two 50-mL portions of DCM. The organic phases were combined and washed once with saturated aqueous sodium chloride solution (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and the solvent was evaporated under reduced pressure at 40° C. to obtain the crude product.

[0626] The crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatography column (packing diameter 4 cm, height 10 cm) packed with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 200 / 1 to 100 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 402 mg of a colorless oil, with a yield of 86%. MS (ESI): m / z [M+H] + , theoretical value 469.4, measured value 468.9.

[0627] LM-2301:

[0628] LM-2301-Z2 (368 mg, 0.785 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102 were followed to obtain LM-2301 (172 mg of a colorless oil, 48% yield). MS (ESI): m / z [M+H] + , theoretical value 455.4, measured value 454.9.

[0629] 1 H NMR (400MHz, CDCl3) δ5.13-5.06 (m, 1H), 2.65 (t, J=7.4Hz, 2H), 2.58-2.39 (m, 3H), 2.04-1.89 (m, 2H), 1.77 (p, J=7 .4Hz, 2H), 1.68(s, 3H), 1.60(s, 3H), 1.59-1.48(m, 5H), 1.45-1.36(m, 5H), 1.32-1.23(m, 22H), 0.90-0.86(m, 6H).

[0630] LM-2301-Pfp:

[0631] LM-2301 (114 mg, 0.25 mmol) was used as the starting material and the same operation steps as those for the synthesis of LM-1102-Pfp were followed to obtain LM-2301-Pfp (120 mg of a colorless oily liquid, 77% yield).

[0632] Following the derivatization method of LM-2101-Pfp, the activated ester LM-2301-Pfp was derivatized to completely convert it into LM-2301-Y1. MS (ESI): m / z [M+H] + , theoretical value 525.5, measured value 524.9.

[0633] 26. Synthesis of LM-2402

[0634] SM3-Z6:

[0635] Into a 250 mL three-necked flask equipped with a magnetic stirrer, SM3-Z1 (2.5 g, 7.95 mmol), triphenylphosphine (3.33 g, 12.7 mmol) and anhydrous DCM (40 mL) were added in sequence and stirred rapidly for 5 min to obtain a clear solution.

[0636] The system temperature was maintained at -20 to 15°C with a cooling bath and stirring was continued (500 r / min). DIAD (2.57 g, 12.7 mmol) was slowly added dropwise to the flask over 15 minutes. Stirring was continued for 15 minutes after addition.

[0637] While maintaining this temperature, N-hydroxyphthalimide (1.56 g, 9.54 mmol) was added to the reaction system in three batches within 10 min, and then the temperature was naturally raised to room temperature (20-25° C.) and stirring was continued.

[0638] After 16 h of reaction, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 5 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.6).

[0639] Stirring was stopped, and the reaction solution was concentrated under reduced pressure at 40°C. Methyl tert-butyl ether (30 mL) and ethyl acetate (7 mL) were added and stirred continuously to obtain a suspension. After standing for 30 min, the suspension was filtered, and the filter cake was washed with methyl tert-butyl ether (10 mL). The filtrate was collected and concentrated to dryness under reduced pressure at 40°C to obtain a brown oily crude product.

[0640] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter approximately 6 cm, height approximately 20 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 50 / 1 to 15 / 1). Fractions containing the product were collected and monitored by TLC. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 1.39 g (yield 38%) of the product as a colorless oil. MS (ESI): m / z [M+Na] + , theoretical value 482.3, measured value 482.6.

[0641] SM3-Z7:

[0642] To a 100 mL single-necked flask equipped with a magnetic stirrer, SM3-Z6 (1.35 g, 2.94 mmol) and methanol (20 mL) were added in sequence and stirred to obtain a clear solution.

[0643] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). 40% hydrazine hydrate (0.5 mL) was added to the reaction system. Subsequently, the flask was connected to a nitrogen balloon with a two-way connector, heated in a 65°C oil bath, and stirred at a constant speed (500 r / min).

[0644] After 2 h of reaction, the reaction was detected by LCMS, which showed that the conversion of the raw materials was complete and the product component was mainly generated.

[0645] The reaction solution was concentrated under reduced pressure at 40°C to about 1 / 5 of its original volume. A large amount of white solid precipitated after cooling.

[0646] DCM (10 mL) and methyl tert-butyl ether (10 mL) were added, stirred for 10 minutes, and then filtered. The filtrate was concentrated under reduced pressure at 40°C. The crude product was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 4 cm, height 12 cm) with 200-300 mesh silica gel. Elution was performed with a gradient eluent (DCM / methanol, 50 / 1 to 15 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 hour to obtain 727 mg of a colorless oil (yield 75%). MS (ESI): m / z [M+H] + , theoretical value 330.3, measured value 330.1.

[0647] LM-2402:

[0648] SM3-Z7 (120 mg, 0.364 mmol) and oleic acid (SM5, CAS: 112-80-1, 113 mg, 0.40 mmol, corresponding to the R2 group) were used as starting materials, and similar procedures were followed for the sequential synthesis of LM-1401-Z1 and LM-1401 to obtain LM-2402 (68 mg of a pale yellow oil, 32% yield over two steps). MS (ESI): m / z [MH] - , theoretical value 578.5, measured value 578.8.

[0649] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0650] 27. Synthesis of LM-1801

[0651] LM-1801 was obtained using SM1-Z1 and adamantanecarboxylic acid (CAS: 828-51-3, the starting material for the synthesis of the corresponding R2 group) through a similar procedure to the aforementioned synthesis of SM3-Z6, SM3-Z7, and LM-2402. MS (ESI): m / z [MH] - , theoretical value 474.4, measured value 474.1.

[0652] 28. Synthesis of LM-2511 and its activated ester

[0653] SM3-Z9:

[0654] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM3-Z3 (3.37 g, 8.93 mmol), potassium phthalimide (CAS: 1074-82-4, 1.82 g, 9.83 mmol) and DMF (30 mL) were added in sequence and stirred for 2 min to obtain a clear solution.

[0655] The flask was connected to a nitrogen balloon via a two-way connector and heated in an 80°C oil bath with constant stirring (500 r / min) for 24 h. The reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 4 / 1), which showed that most of the raw materials had been converted and a product spot (R f value of approximately 0.6).

[0656] Stirring was stopped, and the reaction mixture was diluted with 80 mL of ethyl acetate and transferred to a 250 mL separatory funnel. The mixture was washed with two 50 mL portions of saturated brine, and the organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and the solvent was evaporated at 60°C under reduced pressure to obtain a crude product.

[0657] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 100 / 1 to 10 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 2.6 g of the product as a colorless oily liquid (yield 66%). MS (ESI): m / z [M+H] + , theoretical value 444.3, found value 444.3; m / z[M+Na] + , theoretical value 466.3, measured value 466.2.

[0658] SM3-Z10:

[0659] Into a 100 mL single-necked flask equipped with a magnetic stirrer, SM3-Z9 (2.4 g, 5.41 mmol) and methanol (20 mL) were added in sequence and stirred for 2 min to obtain a colorless transparent solution.

[0660] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). Sodium hydroxide (1.08 g, 27.0 mmol) and purified water (1 mL) were thoroughly mixed to obtain a suspension which was cooled to below 20°C and added to the reaction system in two portions within 5 min.

[0661] After stirring for 2 h, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 4 / 1), indicating that the conversion of the raw materials was complete. LCMS analysis showed that the hydrolysis byproduct SM3-Z10-B of the phthalimide group was approximately 50%.

[0662] The reaction solution was diluted with 100 mL of water and transferred to a 250 mL separatory funnel. The mixture was extracted once with 50 mL of ethyl acetate. The aqueous phase was separated and the pH was adjusted to 3-4 with 10% aqueous hydrochloric acid. The aqueous phase was extracted sequentially with three 50 mL portions of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was collected by filtration, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 1.85 g (80% yield) of a white solid, which was a mixture of the product and a partial hydrolyzate and was used directly in the next step without purification. MS (ESI): SM3-Z10, m / z [M+H] + , theoretical value 430.3, found value 430.2; SM3-Z10-B, m / z [M+H] + , theoretical value 448.3, measured value 448.2.

[0663] SM3-Z11:

[0664] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM3-Z10 (601 mg, 1.4 mmol) and ethanol (10 mL) were added in sequence and stirred evenly.

[0665] The system temperature was maintained at 20-25° C. and stirring was continued (500 r / min). 40% hydrazine hydrate (0.6 mL) was added to the reaction system, and stirring was continued for 2 h.

[0666] Subsequently, the flask was connected to a nitrogen balloon via a two-way connector, heated in an 80°C oil bath, and stirred at a constant speed (500 r / min) for 48 h. The reaction was monitored by TLC (developing solvent: DCM / methanol, 5 / 1), which showed that most of the raw materials had been converted and a product spot (R f value of approximately 0.6).

[0667] The reaction mixture was concentrated under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (DCM / methanol, 20 / 1 to 5 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 398 mg of the product as a white solid (yield 95%). MS (ESI): m / z [M+H] + , theoretical value 300.3, measured value 300.3.

[0668] LM-2511:

[0669] To a 100 mL three-necked flask equipped with a magnetic stirrer, levomenthol (CAS: 2216-51-5, 1.83 g, 11.7 mmol, starting material for the synthesis of the corresponding R2 group), DIEA (1.51 g, 11.7 mmol), DMAP (143 mg, 1.17 mmol) and DCM (20 mL) were added in sequence and stirred rapidly for 3 min to obtain a clear solution.

[0670] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). A solution of p-nitrophenyl chloroformate (2.59 g, 12.8 mmol) in DCM (10 mL) was added dropwise to the flask within 10 min. Stirring was continued after the addition was completed.

[0671] After 16 h of reaction, the reaction solution was concentrated under reduced pressure at 40°C. The residue was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 4 cm, height 12 cm) with 200-300 mesh silica gel. Elution was performed with a gradient eluent (petroleum ether / ethyl acetate, 20 / 1 to 10 / 1). Fractions containing the product were monitored by LCMS and collected. The product was then concentrated under reduced pressure at 40°C to obtain 1.44 g of a menthol carbonate intermediate.

[0672] To a 50 mL single-necked flask equipped with a magnetic stirrer, SM3-Z11 (187 mg, 0.625 mmol), DIEA (161 mg, 1.25 mmol), DCM (5 mL) and DMF (5 mL) were added in sequence and stirred evenly.

[0673] The system temperature was maintained at 20-25°C and stirred at a constant speed (500 r / min). A DCM (3 mL) solution of menthol carbonate intermediate (401 mg, 1.25 mmol) was added dropwise to the flask within 5 min. Stirring was continued after the addition was completed.

[0674] After 16 h of reaction, the solvent was evaporated under reduced pressure at 60°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 30 / 1 to 10 / 1). Fractions containing the product were collected and monitored by LCMS. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to afford 107 mg (yield 36%) of a light yellow oil. MS (ESI): m / z [M+H] + , theoretical value 482.4, found value 482.4; m / z[M+Na] + , theoretical value 504.4, found value 504.4; m / z[MH] - , theoretical value 480.4, measured value 480.1.

[0675] LM-2511-Pfp:

[0676] LM-2511 (107 mg, 0.222 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102-Pfp were followed to obtain LM-2511-Pfp (60 mg of a pale yellow oil, 42% yield). MS (ESI): m / z [M+H] + , theoretical value 648.4, measured value 648.5.

[0677] 1H NMR (400MHz, CDCl3) δ4.62-4.45 (m, 1H), 4.25 (d, J=9.3Hz, 1H), 3.65-3.43 (m, 1H), 2.64 (t, J=7.4Hz, 2H), 2. 07-1.97(m, 1H), 1.96-1.85(m, 1H), 1.80-1.71(m, 2H), 1.70-1.57(m, 4H), 1.48-1.38(m, 4H), 1.34-1.21(br m, 23H), 1.09-0.98 (m, 1H), 0.94-0.84 (m, 10H), 0.78 (d, J=6.9Hz, 3H).

[0678] 29. Synthesis of LM-2503

[0679] Route 1:

[0680] SM3-Z2 undergoes the same reaction steps as the synthesis of SM1-Z6 to obtain the amino compound SM3-Z9, which is then subjected to condensation and deprotection steps similar to the synthesis of LM-1401 with lithocholic acid (CAS: 434-13-9) to obtain the product LM-2503.

[0681] Route 2:

[0682] To a 25 mL single-necked flask equipped with a magnetic stirrer, lithocholic acid (CAS: 434-13-9, 35 mg, 0.0929 mmol, the starting material for the synthesis of the corresponding R2 group), DIEA (18 mg, 0.139 mmol), ethanol (3 mL) and DMF (3 mL) were added in sequence and stirred rapidly to mix.

[0683] The system temperature was maintained at 10-15°C in a cold bath and stirring was continued (550 r / min). DMT-MM (CAS: 3945-69-5, 33 mg, 0.121 mmol) was added to the flask in 2-3 batches within 5 minutes. Stirring was continued for 20 minutes after the addition.

[0684] The mixture was stirred at 10-15°C, and a solution of SM3-Z11 (26 mg, 0.0885 mmol) in DMF (3 mL) was added dropwise to the reaction system within 10 min. The mixture was then naturally warmed to room temperature (20-25°C) and stirred for reaction.

[0685] After 1 h of reaction, the reaction was detected by LCMS, which showed that the conversion of the raw material was basically complete and the target product was mainly generated.

[0686] The reaction was quenched by adding 5 mL of water and concentrated under reduced pressure at 60°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed with a gradient eluent (petroleum ether / ethyl acetate, 20 / 1 to 8 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to yield 26 mg of an off-white solid (yield 45%). MS (ESI): m / z [MH] - , theoretical value 656.6, measured value 656.4.

[0687] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0688] 30. Synthesis of LM-3101 and its activated ester

[0689] SM4-Z2:

[0690] Starting from (E)-10-hydroxy-2-decenoic acid (SM4, CAS: 14113-05-4, 3.0 g, 16.1 mmol, corresponding to the R1 group), SM4-Z2 (colorless oil, 3.55 g) was obtained through similar procedures as described for the synthesis of SM3-Z1. This was used directly in the next step without purification. MS (ESI): m / z [M+H] + , theoretical value 201.1, measured value 201.4.

[0691] LM-3101-Z1:

[0692] SM4-Z2 (100 mg, 0.5 mmol) and retinoic acid (CAS: 302-79-4, 150 mg, 0.5 mmol, corresponding to the starting material for the synthesis of the R2 group) were used as starting materials, and the same procedures as those for the synthesis of LM-2101-Z1 were followed to obtain LM-3101-Z1 (97 mg of a pale yellow oil, 40% yield). MS (ESI): m / z [M+Na] + , theoretical value 505.3, measured value 505.3.

[0693] LM-3101:

[0694] LM-3101-Z1 (97 mg, 0.2 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1502 were followed to obtain LM-3101 (yellow solid 28 mg, yield 30%). MS (ESI): m / z [MH] -, theoretical value 467.3, measured value 467.3.

[0695] LM-3101-Pfp:

[0696] LM-3101 (28 mg, 0.0597 mmol) was used as the starting material and the same operation steps as those for the synthesis of LM-2101-Pfp were followed to obtain LM-3101-Pfp (yellow oil 10 mg, yield 26%).

[0697] Following the derivatization method of LM-2101-Pfp, the activated ester LM-3101-Pfp was derivatized to completely convert it into LM-3101-Y1. MS (ESI): m / z [M+H] + , theoretical value 539.4, measured value 539.4.

[0698] According to the synthetic methods of SM4-Z2 to LM-3101 described in the above examples, appropriate reaction raw materials and / or reagents were replaced to synthesize the compounds listed in the following table of the present invention.

[0699] 31. Synthesis of LM-3103

[0700] SM4-Z2 is contacted with vitamin E (CAS: 2074-53-5) and undergoes the same reaction steps as the synthesis of LM-2211 (Route 2) to obtain the product LM-3103.

[0701] Route 2:

[0702] LM-3103 was obtained using SM4-Z2 and vitamin E (CAS: 2074-53-5, the starting material for the synthesis of the corresponding R2 group) through a similar procedure to the aforementioned synthesis of SM1-Z2, LM-1204-Z1, and LM-1204. MS (ESI): m / z [M+Na] + , theoretical value 621.5, measured value 621.4.

[0703] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0704] 32. Synthesis of LM-3104

[0705] LM-3104 was obtained using oleyl alcohol (CAS: 143-28-2, the starting material for the synthesis of the corresponding R2 group) and SM4-Z2, following similar procedures as described above for the sequential synthesis of LM-1202-Z1 and LM-1202. MS (ESI): m / z [MH] - , theoretical value 435.4, measured value 435.7.

[0706] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0707] 33. Synthesis of LM-3201

[0708] LM-3201 was obtained using SM4-Z2 and hexadecanoic acid (CAS: 57-10-3, the starting material for the synthesis of the corresponding R2 group) through a similar procedure to the aforementioned synthesis of SM3-Z6, SM3-Z7, and LM-2402. MS (ESI): m / z [MH] - , theoretical value 438.4, measured value 438.3.

[0709] 34. Synthesis of LM-4102

[0710] SM6-Z1:

[0711] SM6-Z1 (259 mg, 52% yield) was obtained as a colorless oily liquid using 10-hydroxydecanoic acid (SM6, CAS: 1679-53-4, 325 mg, 1.73 mmol, as the starting material for the synthesis of the corresponding R1 group) through similar procedures as described above for the synthesis of SM1-Z7. MS (ESI): m / z [M+Na] + , theoretical value 311.2, measured value 311.5.

[0712] LM-4102-Z1:

[0713] SM6-Z1 (240 mg, 0.832 mmol) and 1-bromo-2-hexyldecane (CAS: 52997-43-0, 762 mg, 2.5 mmol, corresponding to the starting material for the synthesis of the R2 group) were used as starting materials, and the same procedures as those for the synthesis of LM-2202 were followed to obtain LM-4102-Z1 (111 mg of a colorless oily liquid, 26% yield). MS (ESI): m / z [M+Na] + , theoretical value 535.5, measured value 535.2.

[0714] LM-4102:

[0715] LM-4102-Z1 (105 mg, 0.205 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1903 were followed to obtain LM-4102 (68 mg of a colorless oily liquid, 80% yield). MS (ESI): m / z [MH] - , theoretical value 411.4, measured value 411.6.

[0716] LM-4102 (55 mg, 5% yield) was obtained using SM6 (500 mg, 2.66 mmol) and 1-bromo-2-hexyldecane (CAS: 52997-43-0, 4.06 g, 13.3 mmol) as starting materials and following similar procedures as described for the synthesis of LM-2202. MS (ESI): m / z [MH] - , theoretical value 411.4, measured value 411.1.

[0717] 35. Synthesis of LM-1210

[0718] LM-1210 was obtained using SM1-Z7 and 1-bromo-2-hexyldecane (the starting material for the synthesis of the corresponding R2 group) through similar procedures as described above for the sequential synthesis of LM-4102-Z1 and LM-4102. MS (ESI): m / z [MH] - , theoretical value 521.5, measured value 521.6.

[0719] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0720] 36. Synthesis of LM-4401 and its activated ester

[0721] Route 1:

[0722] In the presence of potassium carbonate, the phenolic hydroxyl group of p-hydroxybenzyl alcohol (CAS: 623-05-2) undergoes nucleophilic substitution with 1-bromo-2-hexyldecane (CAS: 52997-43-0) to form the etherified product LM-4401-Z1. This etherified product then undergoes direct etherification with 10-hydroxydecanoic acid SM6 in the presence of potassium tert-butoxide, a strong hydrogen-abstracting reagent, to yield the product LM-4401.

[0723] Route 2:

[0724] LM-4401-Z1:

[0725] In a 100 mL three-necked flask equipped with a magnetic stirrer, p-hydroxybenzyl alcohol (CAS: 623-05-2, 1.22 g, 9.83 mmol, corresponding to the synthesis starting material of the X group), 1-bromo-2-hexyldecane (CAS: 52997-43-0, 3.0 g, 9.83 mmol, corresponding to the synthesis starting material of the R2 group), K2CO3 (1.63 g, 11.8 mmol) and DMF (30 mL) were added in sequence and stirred rapidly for 2 min to mix evenly.

[0726] The flask was connected to a nitrogen balloon via a two-way connector and heated in an 80°C oil bath with constant stirring (500 r / min) for 16 h. The reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1). The results showed that the starting material p-hydroxybenzyl alcohol (R f The conversion was basically completed, and a relatively single product spot (R f value of approximately 0.8).

[0727] Stirring was stopped, and the reaction mixture was diluted with ethyl acetate (100 mL) and transferred to a 250 mL separatory funnel. The mixture was washed sequentially with three portions of 5% aqueous sodium bicarbonate solution (90 mL each). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was collected and concentrated to dryness under reduced pressure at 40°C. It was then dried under vacuum (50-70 Pa) for 1 hour to obtain 1.35 g of the product as a yellow oil, with a yield of 39%. MS (ESI): m / z [M+H] + , theoretical value 349.3, measured value 349.9.

[0728] LM-4401-Z2:

[0729] Into a 100 mL three-necked flask equipped with a magnetic stirrer, LM-4401-Z1 (1.14 g, 3.27 mmol), triphenylphosphine (0.90 g, 3.43 mmol) and DCM (15 mL) were added in sequence and stirred rapidly for 2 min to obtain a light yellow transparent solution.

[0730] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). NBS (611 mg, 3.43 mmol) was added to the flask in 3-4 batches within 15 min. After the addition, stirring was continued and the reaction was continued.

[0731] After 2 h of reaction, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 10 / 1), which showed that the raw material LM-4401-Z1 (R f The conversion was completed and the main product spot (R f value of approximately 0.8).

[0732] Stirring was stopped, and the solvent was evaporated under reduced pressure at 40°C. The resulting pale yellow crude oil was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 4 cm, height 16 cm) with 200-300 mesh silica gel. Elution was performed with a gradient eluent (petroleum ether / ethyl acetate, 100 / 1 to 20 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 664 mg (yield 49%) of the product as a colorless oily liquid. No response signal was observed by MS (ESI).

[0733] LM-4401:

[0734] LM-4401-Z2 (614 mg, 1.49 mmol) and SM6 (282 mg, 1.5 mmol) were used as starting materials and the same steps as those for the synthesis of LM-2202 were followed to obtain LM-4401 (93 mg of a colorless oily liquid, 12% yield). MS (ESI): m / z [MH] - , theoretical value 517.4, measured value 517.3.

[0735] LM-4401-Pfp:

[0736] LM-4401 (23 mg, 0.0443 mmol) was used as the starting material and the same steps as those for the synthesis of LM-2101-Pfp were followed to obtain LM-4401-Pfp (11 mg of a pale yellow solid, 36% yield). MS (ESI): m / z [M+Na] + , theoretical value 707.4, measured value 707.8.

[0737] 37. Synthesis of LM-4101

[0738] LM-4101 was obtained using SM6 and vitamin E (CAS: 2074-53-5, the starting material for the synthesis of the corresponding R2 group) through a similar procedure to the aforementioned synthesis of SM4-Z5, LM-3103-Z1, and LM-3103. MS (ESI): m / z [MH] - , theoretical value 599.5, measured value 599.7.

[0739] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0740] 38. Synthesis of LM-4602

[0741] Route 1:

[0742] SM6-Z3:

[0743] SM6 was used as the starting material and the same steps as those for the synthesis of SM3-Z1 and SM3-Z3 were followed to obtain SM6-Z3 (a colorless oily liquid). No response signal was observed by MS (ESI).

[0744] SM6-Z4:

[0745] Using SM6-Z3 as the starting material, SM6-Z4 (white solid) was obtained through similar steps to those used in the previous synthesis of SM3-Z9, SM3-Z10, and SM3-Z11. MS (ESI): m / z [M+H] + , theoretical value 188.2, measured value 187.9.

[0746] LM-4602:

[0747] LM-4602 (pale yellow solid 70 mg, yield 23%) was obtained using SM6-Z4 (95 mg, 0.507 mmol) and cholesterol (CAS: 57-88-5, starting material for the synthesis of the corresponding R2 group) as starting materials through procedures similar to those described for the synthesis of LM-2511. MS (ESI): m / z [M+Na] + , theoretical value 622.5, measured value 622.5.

[0748] Route 2:

[0749] SM6-Z2 undergoes the same amination reaction process as the synthesis of SM1-Z6 to obtain SM6-Z4a containing an amino group. Cholesterol (CAS: 57-88-5) reacts with p-nitrophenyl chloroformate to activate the hydroxyl group, which then reacts with SM6-Z4a to generate LM-4602-Z1 containing a carbamate group. After carboxyl demethylation under mild conditions, the product LM-4602 is obtained.

[0750] 39. Synthesis of LM-4103

[0751] LM-4103 was obtained using oleyl alcohol (CAS: 143-28-2, the starting material for the synthesis of the corresponding R2 group) and SM6-Z2, following similar procedures as described above for the sequential synthesis of LM-1202-Z1 and LM-1202. MS (ESI): m / z [M+Na] + , theoretical value 461.4, measured value 461.2.

[0752] 40. Synthesis of LM-4201

[0753] LM-4201-Z1:

[0754] LM-4201-Z1 was obtained using 2-hexyl-1-decanol (CAS: 2425-77-6, the starting material for the synthesis of the corresponding R2 group) through procedures similar to those described for the synthesis of LM-1202-Z1. No MS (ESI) response was observed.

[0755] LM-4201-Z2:

[0756] LM-4201-Z2 was obtained using LM-4201-Z1 and cis-2-butene-1,4-diol (CAS: 6117-80-2, the starting material for the synthesis of the corresponding X group) through similar procedures as those for the synthesis of LM-1213-Z2. MS (ESI): m / z [M+H] + , theoretical value 313.3, measured value 312.9.

[0757] SM6-Z5:

[0758] SM6-Z5 was obtained by using SM6-Z2 as the starting material and undergoing similar steps as the synthesis of SM1-ZA. MS (ESI): m / z [M+Na] + , theoretical value 223.1, measured value 223.2.

[0759] LM-4201:

[0760] LM-4201-Z2 (45 mg, 0.144 mmol) and SM6-Z5 (34 mg, 0.173 mmol) were used as starting materials and the same steps as those for the synthesis of LM-1213 were followed to obtain LM-4201 (20 mg of a pale yellow oily liquid, 29% yield). MS (ESI): m / z [MH] - , theoretical value 481.4, measured value 481.7.

[0761] 41. Synthesis of LM-4301

[0762] LM-4301-Z1:

[0763] In a 100 mL three-necked flask equipped with a magnetic stirrer, resorcinol (CAS: 108-46-3, 550 mg, 5.0 mmol, the starting material for the synthesis of the corresponding X group), K2CO3 (1.45 g, 10.5 mmol) and DMF (25 mL) were added in sequence and stirred rapidly for 2 min to mix evenly.

[0764] The flask was connected to a nitrogen balloon via a two-way connector, heated in an oil bath at 65°C with constant stirring (500 r / min), and a DMF (5 mL) solution of 1-bromo-2-hexyldecane (CAS: 52997-43-0, 1.54 g, 5.05 mmol, corresponding to the synthesis starting material of the R2 group) was slowly added dropwise to the reaction system over 30 min. After completion of the addition, the temperature was raised to 85°C and stirring was continued.

[0765] After 12 h of reaction, stirring was stopped, the reaction solution was diluted with 40 mL of water, the pH was adjusted to 4-5 with 10% aqueous hydrochloric acid solution, and extracted with 3 portions of ethyl acetate (20 mL each) in sequence. The organic phases were combined and washed with saturated brine (40 mL). The separated organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was collected and concentrated under reduced pressure at 60°C to obtain a crude product.

[0766] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 50 / 1 to 8 / 1). Fractions containing the product were collected, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 736 mg (yield 44%) of a light yellow oil. MS (ESI): m / z [M+Na] + , theoretical value 357.3, measured value 357.5.

[0767] LM-4301-Z2:

[0768] LM-4301-Z1 (105 mg, 0.314 mmol) and SM6-Z3 (83 mg, 0.314 mmol) were used as starting materials and the same steps as those for the synthesis of LM-4401-Z1 were followed to obtain LM-4301-Z2 (91 mg of a pale yellow oily liquid, 56% yield). MS (ESI): m / z [M+Na] + , theoretical value 541.4, measured value 541.3.

[0769] LM-4301:

[0770] LM-4301-Z2 (85 mg, 0.164 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102 were followed to obtain LM-4301 (65 mg of a pale yellow oily liquid, 78% yield). MS (ESI): m / z [MH] - , theoretical value 503.4, measured value 503.0.

[0771] 42. Synthesis of LM-4701

[0772] LM-4701 (yellow oil) was obtained using SM6-Z1 and vitamin E (CAS: 2074-53-5, the starting material for the synthesis of the corresponding R2 group) through similar procedures as described above for the sequential synthesis of LM-1903-Z1 and LM-1903. MS (ESI): m / z [M+Na] + , theoretical value 667.5, measured value 667.2.

[0773] 43. Synthesis of LM-5101

[0774] LM-5101-Z1 was obtained using 2-hydroxystearic acid (CAS: 629-22-1, the starting material for the synthesis of the corresponding R1 group) and similar procedures as those for the synthesis of SM3-Z1. MS (ESI): m / z [M+H] + , theoretical value 315.3, measured value 315.5.

[0775] LM-5101-Z1 and SM5 (the starting materials for the synthesis of the corresponding R2 group) were used as raw materials, and the same steps as those for the above-mentioned synthesis of LM-2101-Z1 and LM-2101 were followed to obtain LM-5101 (a pale yellow oil). MS (ESI): m / z [M+Na] + , theoretical value 587.5, measured value 587.4.

[0776] 44. Synthesis of LM-6101

[0777] LM-6101-Z1 was obtained using (R)-2-hydroxy-4-phenylbutyric acid (CAS: 29678-81-7, the starting material for the synthesis of the corresponding R1 group) as the raw material and following similar steps to the synthesis of SM3-Z1.

[0778] LM-6101-Z1 and SM5 (the starting materials for the synthesis of the corresponding R2 group) were used as raw materials and the same steps as those for the above-mentioned synthesis of LM-2101-Z1 and LM-2101 were followed to obtain LM-6101. MS (ESI): m / z [MH] - , theoretical value 443.3, measured value 443.5.

[0779] 45. Synthesis of LM-7101

[0780] LM-7101-Z1 was obtained using hexadecanal (CAS: 629-80-1, the starting material for the synthesis of the corresponding R2 group) and cis-2-butene-1,4-diol (CAS: 6117-80-2, the starting material for the synthesis of the corresponding X group) as raw materials and through similar operation steps as those for the synthesis of LM-4201-Z2.

[0781] LM-7101 was obtained using LM-7101-Z1 and bromoacetic acid (as the starting material for the synthesis of the corresponding R1 group) through similar steps as those for the synthesis of LM-1201. MS (ESI): m / z [MH] - , theoretical value 369.3, measured value 369.4.

[0782] 46. ​​Synthesis of LM-8101

[0783] LM-8101-Z1 was obtained using linoleic acid (CAS: 60-33-3, the starting material for the synthesis of the corresponding R2 group) as the raw material and following similar steps to the synthesis of LM-2101-Pfp.

[0784] LM-8101 was obtained using DL-norleucine (CAS: 616-06-8, the starting material for the synthesis of the corresponding R1 group) and LM-8101-Z1 as raw materials, following similar procedures as described for the synthesis of LB-106. MS (ESI): m / z [M+H] + , theoretical value 394.3, measured value 394.6.

[0785] 47. Synthesis of LM-9201

[0786] 2-Hydroxy-3-methylbutanoic acid (CAS: 4026-18-0, the starting material for the synthesis of the corresponding R1 group) was used as the raw material and the steps similar to those for the aforementioned sequential synthesis of SM3-Z1, SM3-Z6 and SM3-Z7 were followed to obtain LM-9201-Z1.

[0787] LM-9201 was obtained using LM-9201-Z1 and palmitic acid (CAS: 57-10-3, the starting material for the synthesis of the corresponding R2 group) through similar procedures as those for the synthesis of LM-2402. MS (ESI): m / z [MH] - , theoretical value 370.3, measured value 370.0.

[0788] 48. Synthesis of LM-9301

[0789] LM-9301 was obtained using hexadecanal (CAS: 629-80-1, the starting material for the synthesis of the corresponding R2 group) and 2-hydroxylauric acid (CAS: 2984-55-6, the starting material for the synthesis of the corresponding R1 group) as raw materials, following similar procedures as those used to synthesize LM-1213. MS (ESI): m / z [MH] - , theoretical value 439.4, measured value 439.1.

[0790] 49. Synthesis of LB-106

[0791] LB-106-Z1:

[0792] LB-106-Z1 (colorless oily liquid) was obtained using SM3-Z1 and trans-2,3-dimethylacrylic acid (CAS: 80-59-1) as raw materials through similar procedures as described above for the sequential synthesis of LM-2101-Z1, LM-2101, and LM-2101-Pfp. MS (ESI): m / z [M+Na] + , theoretical value 571.3, measured value 571.5.

[0793] SM8-Z1:

[0794] To a 250 mL single-necked flask equipped with a magnetic stirrer, DMF (25 mL), SM8 (CAS: 4767-03-7, 2.5 g, 18.6 mmol) and sodium hydroxide (746 mg, 18.6 mmol) were added in sequence and stirred rapidly until uniform.

[0795] The flask was connected to a nitrogen balloon via a two-way connector and heated in an oil bath at 100°C with constant stirring (500 rpm) until the solution became clear. Benzyl bromide (3.8 g, 22.3 mmol) was then slowly added dropwise to the reaction solution over 20 min while maintaining this temperature. The reaction was continued with stirring.

[0796] After stirring for 15 h, the reaction solution was cooled to room temperature and the reaction was monitored by TLC (developing solvent: dichloromethane / methanol, 10 / 1). The results showed that the conversion of the raw materials was complete and a relatively single product spot was generated (R f value of approximately 0.4).

[0797] The reaction solution was diluted with pure water (50 mL) and extracted with three portions of ethyl acetate (25 mL each). The organic phases were combined and washed once with a saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure at 60°C to obtain a crude product.

[0798] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 4 / 1 to 1 / 5). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 1.5 g of a colorless oily liquid, with a yield of 36%. MS (ESI): m / z [M+Na] + , theoretical value 247.2, measured value 247.3.

[0799] SM8-Z2:

[0800] Into a 100 mL single-necked flask equipped with a magnetic stirrer, SM8-Z1 (1.4 g, 6.24 mmol), N-Boc-3-aminopropyl bromide (CAS: 83948-53-2, 3.12 g, 13.1 mmol), tetrabutylammonium bromide (1.01 g, 3.12 mmol) and DCM (25 mL) were added in sequence and stirred rapidly.

[0801] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). 37% aqueous sodium hydroxide solution (17 mL) was added dropwise to the flask within 10 min. After addition, stirring was continued for 16 h. LCMS showed that the conversion of the raw material was complete.

[0802] The reaction solution was diluted with pure water (40 mL) and extracted with three portions of DCM (15 mL each). The organic phases were combined and washed once with a saturated aqueous sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was collected and concentrated under reduced pressure at 40°C to obtain a crude product.

[0803] The crude product was loaded onto 60-100 mesh silica gel and then applied to a chromatographic column (packing diameter 4 cm, height 12 cm) packed with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 30 / 1 to 10 / 1). Fractions containing the product were collected and concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 1.85 g of a colorless oil, with a yield of 55%. MS (ESI): m / z [M+H] + , theoretical value 539.3, measured value 539.4.

[0804] SM8-Z3:

[0805] To a 100 mL single-necked flask equipped with a magnetic stirrer, SM8-Z2 (1.05 g, 1.95 mmol) and DCM (10 mL) were added in sequence and stirred rapidly until the solution became clear.

[0806] The system temperature was maintained at 20-25°C and stirring was continued (600 r / min). TFA (3 mL) was slowly added dropwise to the flask within 5 min. After addition, stirring was continued for 2 h. LCMS detection showed that the conversion of the raw material was complete.

[0807] The reaction mixture was evaporated under reduced pressure at 40°C to remove the solvent. The residue was dissolved in dichloromethane (20 mL) and washed with 8% aqueous sodium bicarbonate solution (10 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 416 mg of a yellow oil (yield 63%). MS (ESI): m / z [M+H] + , theoretical value 339.2, measured value 339.5.

[0808] SM8-Z4:

[0809] Into a 100 mL single-necked flask equipped with a magnetic stirrer, SM8-Z3 (387 mg, 1.14 mmol), palladium carbon catalyst (40 mg, palladium content 10% wt) and THF (12 mL) were added in sequence and stirred rapidly until uniform.

[0810] The flask was connected to a hydrogen balloon via a three-way connector to replace the internal air. The reaction was stirred at a constant speed (500 r / min) for 2 h. LCMS detection showed that the conversion of the starting material was complete.

[0811] The reaction solution was filtered, and the filtrate was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 hour to obtain 229 mg of a light yellow solid product with a yield of 81%. MS (ESI): m / z [M+Na] + , theoretical value 271.2, measured value 271.2.

[0812] LB-106:

[0813] To a 50 mL single-necked flask equipped with a magnetic stirrer, SM8-Z4 (35 mg, 0.141 mmol), DIEA (55 mg, 0.423 mmol) and DMF (10 mL) were added in sequence and stirred rapidly to clarify.

[0814] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). LB-106-Z1 (170 mg, 0.31 mmol) was added to the flask in three batches within 5 minutes and stirring was continued.

[0815] After 2 h of reaction, the reaction was monitored by TLC (developing solvent: DCM / methanol, 10 / 1), which showed that most of the raw materials had been converted and the main product spot (R f value of approximately 0.8).

[0816] Stirring was stopped, and the reaction mixture was concentrated under reduced pressure at 60°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (DCM / methanol, 50 / 1 to 20 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 73 mg of the product as a light yellow oily liquid (yield 53%). MS (ESI): m / z [MH] - , theoretical value 975.8, measured value 975.4.

[0817] 50. Synthesis of LB-202

[0818] LB-202-S2:

[0819] To a 50 mL single-necked flask equipped with a magnetic stirrer, LB-202-S1 (600 mg, 2.26 mmol) and methanol (10 mL) were added in sequence and stirred rapidly for 2 min to obtain a clear solution.

[0820] The system temperature was maintained at 20-25°C and stirring was continued (500 rpm). 4N HCl / 1,4-dioxane solution (0.5 mL) was added to the reaction system, and stirring was continued for 48 h. LCMS analysis showed that the conversion of the starting material was complete and a single product was generated.

[0821] The reaction solution was concentrated to dryness under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 644 mg of a light yellow solid. MS (ESI): m / z [M+H] + , theoretical value 190.1, measured value 189.9.

[0822] LB-202-Z1:

[0823] LB-202-S2 (96 mg, 0.365 mmol) and LM-1102-Pfp (409 mg, 0.73 mmol) were used as starting materials and the same steps as those for the synthesis of LB-106 were followed to obtain LB-202-Z1 (163 mg of a colorless oil, 47% yield; TLC: petroleum ether / ethyl acetate, 10 / 1, R f value of about 0.7). MS (ESI): m / z [M+H] + , theoretical value 942.7, measured value 942.5.

[0824] LB-202:

[0825] LB-202-Z1 (163 mg, 0.173 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102 were followed to obtain LB-202 (102 mg of colorless oil, 64% yield; TLC: DCM / methanol, 10 / 1, R f value is about 0.6). MS (ESI): m / z [M+H] + , theoretical value 928.7, found value 928.6; m / z[M+Na] + , theoretical value 950.7, measured value 950.5.

[0826] 1 H NMR (400MHz, CDCl3) δ7.67 (t, J=6.0Hz, 1H), 7.39 (d, J=5.3Hz, 1H), 6.72 (td, J=7.4, 1.6Hz, 2H), 6.49 (t, J= 6.5Hz, 1H), 5.50-5.40(m, 2H), 5.39-5.30(m, 2H), 4.98-4.84(m, 2H), 4.38-4.30(m, 1H), 3.79-3.69(m, 1H) , 3.69-3.59 (m, 2H), 3.55-3.42 (m, 1H), 2.93 (t, J=6.4Hz, 2H), 2.37-2.28 (m, 4H), 2.26-2.13 (m, 8H), 2.05- 1.96 (m, 4H), 1.81 (s, 6H), 1.64-1.53 ​​(m, 8H), 1.37-1.21 (m, 32H), 1.04 (t, J=7.5Hz, 6H), 0.92-0.81 (m, 6H).

[0827] LB-202-Pfp:

[0828] LB-202 (98 mg, 0.106 mmol) was used as the starting material and the same operation steps as those for the synthesis of LM-1102 were followed to obtain LB-202-Pfp (75 mg of pale yellow oil, 65% yield; TLC: DCM / methanol, 10 / 1, R f value of about 0.8). MS (ESI): m / z [M+H] + , theoretical value 1094.7, found value 1094.4; m / z[M+Na] + , theoretical value 1116.7, measured value 1116.3.

[0829] 51. Synthesis of LB-201

[0830] SM7-Z1:

[0831] Into a 250 mL single-necked flask equipped with a magnetic stirrer, SM7 (CAS: 111-40-0, 2.5 g, 24.2 mmol) and DMF (25 mL) were added in sequence and stirred rapidly to obtain a clear solution.

[0832] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). A DMF (45 mL) solution of tert-butylphenyl carbonate (CAS: 6627-89-0, 11.8 g, 60.7 mmol) was added dropwise to the reaction system within 30 min. Stirring was continued after addition.

[0833] After 16 hours of reaction, the reaction solution was concentrated to dryness under reduced pressure at 60°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (DCM / methanol, 60 / 1 to 20 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 hour to obtain 4.77 g (yield 65%) of a colorless oil. MS (ESI): m / z [M+H] + , theoretical value 304.2, measured value 304.4.

[0834] SM7-Z2:

[0835] To a 100 mL single-necked flask equipped with a magnetic stirrer, SM7-Z1 (1.21 g, 3.99 mmol) and DCM (30 mL) were added in sequence and stirred rapidly to obtain a clear solution.

[0836] The system temperature was maintained at 20-25° C. and stirring was continued (500 r / min). Succinic anhydride (399 mg, 3.99 mmol) was added to the reaction system in 3-4 batches.

[0837] After stirring for 1 h, the reaction was monitored by TLC (developing solvent: DCM / methanol, 10 / 1), which showed that the starting material SM7-Z1 (R f The conversion was basically completed, and the main product spot (R f value of approximately 0.6).

[0838] The reaction mixture was concentrated to dryness under reduced pressure at 35°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 10 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (DCM / methanol, 30 / 1 to 15 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to yield 1.0 g (yield 62%) of a white foamy solid. MS (ESI): m / z [MH]- , theoretical value 402.2, found value 402.2; m / z[M+Na] + , theoretical value 426.2, measured value 425.8.

[0839] SM7-Z3:

[0840] Into a 100 mL single-necked flask equipped with a magnetic stirrer, SM7-Z2 (1.0 g, 2.48 mmol) and ethyl acetate (10 mL) were added in sequence and stirred rapidly until uniform.

[0841] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). 2N HCl / ethyl acetate (15 mL) solution was added dropwise to the reaction system within 10 min. Stirring was continued after the addition was completed. A white solid gradually precipitated.

[0842] After 2 h of reaction, LCMS detection showed that the raw material was completely converted to form the product.

[0843] The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (7-8 mL) and dried under vacuum (50-70 Pa) for 1 h to obtain 610 mg of a white solid (yield 79%). MS (ESI): m / z [M+H] + , theoretical value 204.1, measured value 203.9.

[0844] LB-201:

[0845] SM7-Z3 (83 mg, 0.266 mmol) and LM-1102-Pfp (328 mg, 0.584 mmol) were used as starting materials and the same operation steps as those for the synthesis of LB-106 were followed to obtain LB-201 (white paste-solid-liquid mixture, 130 mg, yield 51%; TLC: DCM / methanol, 10 / 1, R f value is about 0.5). MS (ESI): m / z [M+H] + , theoretical value 978.7, measured value 978.6.

[0846] 1H NMR (400MHz, CDCl3) δ6.71 (td, J=7.4, 1.6Hz, 2H), 5.49-5.39 (m, 2H), 5.39-5.28 (m, 2H), 4.91 (p, J=6.2Hz, 2H), 3.62-3.21 (m, 8H), 2.63 (br s, 2H), 2.46(br s, 2H), 2.39-2.24 (m, 5H), 2.17 (p, J=7.6Hz, 8H), 2.06-1.95 (m, 4H), 1.81 (s, 6H), 1.62-1.51 (m, 8H), 1.36-1.21 (m, 32H), 1.04 (t, J=7.6Hz, 6H), 0.89-0.83 (m, 6H).

[0847] According to the method described in the above examples and by replacing appropriate reaction raw materials and / or reagents, the compounds listed in the following table of the present invention were synthesized.

[0848] 52. Synthesis of LB-204

[0849] Route 1:

[0850] SM7-ZA:

[0851] Into a 100 mL three-necked flask equipped with a magnetic stirrer, SM7-Z1 (1.5 g, 4.94 mmol), methyl 4-bromobutyrate (CAS: 4897-84-1, 990 mg, 5.47 mmol), TEA (1.0 g, 9.88 mmol) and DMF (18 mL) were added in sequence and stirred rapidly for 2 min to mix evenly.

[0852] The flask was connected to a nitrogen balloon via a two-way connector, heated in an oil bath at 60°C, and stirred at a constant speed (500 r / min) for reaction.

[0853] After 22 h of reaction, the reaction was monitored by TLC (developing solvent: DCM / methanol, 10 / 1), which showed that the starting material SM7-Z1 (R f The conversion was mostly complete, and a relatively single product spot (R f value of approximately 0.6).

[0854] Stirring was stopped, and the reaction mixture was diluted with ethyl acetate (100 mL) and transferred to a 250 mL separatory funnel. The mixture was washed with three portions of saturated aqueous sodium chloride solution (50 mL each). The organic phase was separated and dried over anhydrous sodium sulfate and filtered. The filtrate was collected and concentrated to dryness under reduced pressure at 50°C to obtain a crude product.

[0855] The crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 4 cm, height 12 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (DCM / methanol, 100 / 1 to 50 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 1.76 g of a light yellow oil, with a yield of 88%. MS (ESI): m / z [M+H] + , theoretical value 404.3, measured value 404.3.

[0856] SM7-Z5:

[0857] Into a 100 mL single-necked flask equipped with a magnetic stirrer, SM7-ZA (1.56 g, 3.87 mmol), iodomethane (1.58 g, 11.1 mmol) and DMF (10 mL) were added in sequence and stirred rapidly for 2 min to mix well.

[0858] The flask was connected to a nitrogen balloon via a two-way connector, heated in a 40°C oil bath, and stirred at a constant speed (500 r / min) for reaction.

[0859] After 16 hours of reaction, the reaction was monitored by LCMS, which showed that the conversion of the raw materials was complete and a relatively single target product was generated. TLC (developing solvent: DCM / methanol, 10 / 1), product R f The value is about 0.4.

[0860] Stirring was stopped, and the reaction mixture was diluted with ethyl acetate (50 mL) and transferred to a 250 mL separatory funnel. The mixture was washed sequentially with three portions of saturated aqueous sodium chloride (30 mL each). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was collected and concentrated to dryness under reduced pressure at 60°C. It was then dried under vacuum (50-70 Pa) for 1 hour to obtain 1.19 g of a light yellow oil (56% yield). MS (ESI): m / z [MI] + , theoretical value 418.3, measured value 418.3.

[0861] SM7-Z6:

[0862] SM7-Z5 (1.14 g, 2.09 mmol) was used as the starting material and the same steps as those for the synthesis of SM7-Z3 were followed to obtain SM7-Z6 (924 mg yellow solid). MS (ESI): m / z [M-Cl] + , theoretical value 218.2, measured value 218.4.

[0863] LB-204-Z1:

[0864] SM7-Z6 (924 mg) and SM5 (3.59 g, 12.7 mmol) were used as starting materials and the same steps as those for the synthesis of LM-1401-Z1 were followed to obtain LB-204-Z1 (2.58 g pale yellow oil; TLC: DCM / methanol, 10 / 1, R f value is about 0.5). MS (ESI): m / z [M-Cl] + , theoretical value 746.7, measured value 746.6.

[0865] LB-204:

[0866] LB-204-Z1 (2.58 g, 3.3 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102 were followed to obtain LB-204 (574 mg of a yellow waxy solid, 23% yield). MS (ESI): m / z [M-Cl] + , theoretical value 732.7, measured value 732.6.

[0867] Route 2:

[0868] The raw material SM7-Z1 undergoes a substitution reaction with methyl 4-bromobutyrate (CAS: 4897-84-1) under alkaline conditions to obtain SM7-Z4, which is then deprotected with HCl to obtain SM7-Z5. In the presence of a condensing agent, oleic acid SM5 and SM7-Z5 undergo a condensation reaction to produce LB-106-Z1. This is then subjected to a substitution reaction with iodomethane to obtain the quaternary ammonium salt compound LB-106-Z2. Finally, the carboxyl methyl ester is removed with an alkali to obtain the product LB-106.

[0869] 53. Synthesis of LB-101 and its activated ester

[0870] LB-101-Z1:

[0871] To a 250 mL single-necked flask equipped with a magnetic stirrer, N-Boc-2,3-dihydroxypropylamine (CAS: 137618-48-5, 2.1 g, 11.0 mmol), oleic acid (SM5, 2.82 g, 9.98 mmol), DMAP (1.59 g, 13.0 mmol) and DCM (60 mL) were added in sequence and stirred rapidly for 5 min to obtain a clear solution.

[0872] The system temperature was maintained at 20-25°C and stirring was continued at a constant speed (500 r / min). A solution of DIC (1.64 g, 13.0 mmol) in DCM (40 mL) was added dropwise to the flask over 30 min. During this time, a white solid gradually precipitated. Stirring was continued after the addition.

[0873] After stirring for 1 h, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1), which showed that the starting material SM1-Z1 (R f The conversion was basically completed, and the main product spot (R f value of approximately 0.9).

[0874] Stop stirring and filter the reaction mixture. Wash the filter cake with DCM (7-8 mL). Combine the filtrates and add them to a 250 mL separatory funnel. Wash once with saturated aqueous sodium chloride solution (50 mL). Separate the organic phase, dry it over anhydrous sodium sulfate, filter it, and collect the filtrate, concentrate it under reduced pressure at 40°C to obtain a crude product.

[0875] The crude product was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 6 cm, height 18 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 50 / 1 to 10 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 3.4 g of the product as a colorless oily liquid (yield 75%). MS (ESI): m / z [M+Na] + , theoretical value 478.4, measured value 478.3.

[0876] LB-101-Z2:

[0877] LB-101-Z1 (1.0 g, 2.19 mmol) and dodecanoic acid (CAS: 143-07-7, 528 mg, 2.64 mmol) were used as starting materials, and the same procedures as those for the synthesis of LM-2101-Z1 were followed to obtain LB-101-Z2 (1.08 g, 77% yield, colorless oil). MS (ESI): m / z [M+Na] + , theoretical value 660.5, measured value 660.4.

[0878] LB-101-Z3:

[0879] Using LB-101-Z2 (1.05 g, 1.65 mmol) as the starting material, similar procedures to those for the synthesis of SM8-Z3 were followed to obtain LB-101-Z3 (735 mg of a colorless oil, 83% yield). MS (ESI): m / z [M+H] + , theoretical value 538.5, measured value 538.5.

[0880] LB-101:

[0881] Using LB-101-Z3 (637 mg, 1.12 mmol) as the starting material, similar procedures to those for the synthesis of SM7-Z2 were followed to obtain LB-101 (438 mg of a colorless oil, 58% yield). MS (ESI): m / z [M+Na] + , theoretical value 660.5, measured value 660.4.

[0882] 1 H NMR (400MHz, CDCl3) δ5.92 (t, J=5.9Hz, 1H), 5.40-5.28 (m, 2H), 5.12-5.06 ( m, 1H), 4.25 (dd, J=12.0, 4.3Hz, 1H), 4.13 (dd, J=12.0, 5.7Hz, 1H), 3.57-3.4 2 (m, 2H), 3.08-3.00 (m, 2H), 2.60 (t, J=6.8Hz, 2H), 2.34-2.28 (m, 4H), 2.04 -1.95 (m, 4H), 1.64-1.55 (m, 4H), 1.31-1.24 (m, 36H), 0.88 (t, J=6.8Hz, 6H).

[0883] LB-101-Pfp:

[0884] LB-101 (438 mg, 0.687 mmol) was used as the starting material and the same steps as those for the synthesis of LM-2101-Pfp were followed to obtain LB-101-Pfp (510 mg of a colorless oil, 92% yield). MS (ESI): m / z [M+H] + , theoretical value 804.5, measured value 804.5.

[0885] 54. Synthesis of LB-101-2

[0886] LB-101-Z3 (83 mg, 0.154 mmol) and 9-azido-4,7-dioxanonanoic acid (CAS: 1312309-63-9, 35 mg, 0.17 mmol) were used as starting materials and the same procedures as those for the synthesis of LM-1401-Z1 were followed to obtain LB-101-Z2 (89 mg of a pale yellow oil, 80% yield). MS (ESI): m / z [M+Na] + , theoretical value 745.6, measured value 745.3.

[0887] 55. Synthesis of LT-201 and its activated ester

[0888] LT-201-Z1:

[0889] LT-201-Z1 (530 mg, 64% yield, white solid) was obtained using tromethamine (CAS: 77-86-1, 363 mg, 3.0 mmol) and mono-tert-butyl succinate (CAS: 15026-17-2, 522 mg, 3.0 mmol) as starting materials through procedures similar to those used to synthesize LM-2503. MS (ESI): m / z [M+H] + , theoretical value 278.2, found value 278.1; m / z[M+Na] + , theoretical value 300.2, measured value 300.1.

[0890] LT-201-Z2:

[0891] To a 100 mL single-necked flask equipped with a magnetic stirrer, LT-201-Z1 (340 mg, 1.22 mmol), LM-2101 (1.95 g, 4.9 mmol), DMAP (298 mg, 2.44 mmol), DCM (10 mL) and acetonitrile (10 mL) were added in sequence and stirred rapidly for 5 min to obtain a clear solution.

[0892] The system temperature was maintained at 20-25°C and stirring was continued at a constant speed (500 r / min). EDCI (941 mg, 4.9 mmol) was added to the flask in 5 batches within 15 minutes. Stirring was continued after the addition.

[0893] After 16 h of reaction, the reaction was monitored by TLC (developing solvent: petroleum ether / ethyl acetate, 4 / 1), which showed that the raw material LT-201-Z1 (R f value <0.1) is basically converted to form the main product spot (R f value of approximately 0.7).

[0894] Stirring was stopped, and the reaction solution was concentrated under reduced pressure at 40°C. The crude product was loaded onto 60-100 mesh silica gel and loaded onto a chromatographic column (packing diameter 4 cm, height 15 cm) filled with 200-300 mesh silica gel. Elution was performed with a gradient eluent (petroleum ether / ethyl acetate, 30 / 1 to 10 / 1). Fractions containing the product were collected by TLC monitoring, concentrated under reduced pressure at 40°C, and dried under vacuum (50-70 Pa) for 1 h to obtain 1.2 g (yield 71%) of the product as a colorless oily liquid. No response signal was observed by MS (ESI).

[0895] LT-201:

[0896] LT-201-Z2 (780 mg, 0.552 mmol) and 1,4-dioxane (5 mL) were added sequentially to a 100 mL single-necked flask equipped with a magnetic stirrer, and the mixture was stirred for 2 min to obtain a colorless transparent solution.

[0897] The system temperature was maintained at 20-25° C. and stirring was continued (500 rpm). 4N HCl / 1,4-dioxane solution (5 mL) was added to the reaction system.

[0898] After stirring for 2.5 h, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.8).

[0899] Stirring was stopped, and the reaction mixture was concentrated under reduced pressure below 30°C. The crude product was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 2.5 cm, height 8 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 4 / 1 to 1 / 1). Fractions containing the product were monitored by TLC and collected. The mixture was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 547 mg of the product as a light yellow oily liquid (yield 73%). MS (ESI): m / z [1 / 2M-H] - , theoretical value 677.0, measured value 676.8.

[0900] LT-201-Pfp:

[0901] LT-201 (350 mg, 0.258 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102-Pfp were followed to obtain LT-201-Pfp (161 mg of a colorless oil, 41% yield). No response signal was observed by MS (ESI).

[0902] Mixing LT-201-Pfp with dilute ammonia water can produce the activated ester converted to an amide derivative LT-201-Y1. MS (ESI): m / z [1 / 2M+H] + , theoretical value 678.5, measured value 678.2.

[0903] 56. Synthesis of LB-107 and its activated ester

[0904] LB-107-Z1:

[0905] Starting from 3-methylamino-1,2-propanediol (CAS: 40137-22-2, 1.94 g, 18.5 mmol) and tert-butyl bromoacetate (3.0 g, 15.4 mmol), a similar procedure to that described for the synthesis of SM7-ZA was used to obtain LB-107-Z1 (crude product, 4.45 g of a pale yellow solid, used directly in the next step). MS (ESI): m / z [M+H] +, theoretical value 220.1, found value 220.2; m / z[M+Na] + , theoretical value 242.1, measured value 242.1.

[0906] LB-107-Z2:

[0907] LB-107-Z1 (657 mg, theoretical amount 2.27 mmol) and palmitic acid (CAS: 57-10-3, 1.75 g, 6.82 mmol) were used as raw materials and the same operation steps as those for the synthesis of LM-1102-Z1 were performed to obtain LB-107-Z2 (colorless oil, 682 mg, yield 43%; TLC: petroleum ether / ethyl acetate, 10 / 1, R f The value was about 0.6). No response signal was found by MS (ESI).

[0908] LB-107:

[0909] To a 50 mL single-necked flask equipped with a magnetic stirrer, LB-107-Z2 (682 mg, 0.98 mmol) and DCM (5 mL) were added in sequence and stirred rapidly until the solution became clear.

[0910] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). TFA (10 mL) was slowly added dropwise to the flask within 5 minutes. After the addition, stirring was continued for 6 hours. LCMS detection showed that the raw material was completely converted to generate the product.

[0911] The reaction mixture was evaporated under reduced pressure at 40°C to remove the solvent. The residue was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 2.5 cm, height 10 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (DCM / methanol, 50 / 1 to 10 / 1). Fractions containing the product were collected and monitored by LCMS. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 796 mg of a white solid (yield 127%), as a TFA salt. MS (ESI): m / z [M+H] + , theoretical value 640.5, measured value 640.6.

[0912] 1H NMR (400MHz, CDCl3) δ5.23-5.18 (m, 1H), 4.36 (dd, J=11.9, 3.4Hz, 1H), 4.13 (dd, J=11.9, 6.2Hz, 1H), 3.73 (dd, J=17.9, 2.9H z, 2H), 2.82 (d, J=6.3Hz, 2H), 2.54 (s, 3H), 2.33-2.28 (m, 4H), 1.65-1.54 (m, 4H), 1.34-1.22 (m, 48H), 0.88 (t, J=7.0Hz, 6H).

[0913] LB-107-Pfp:

[0914] LB-107 (100 mg, theoretical amount 0.123 mmol) was used as the starting material and the same operation steps as those for the synthesis of LM-2101-Pfp were performed to obtain LB-107-Pfp (white waxy solid 47 mg, yield 47%; TLC: petroleum ether / ethyl acetate, 10 / 1, R f value of about 0.8). MS (ESI): m / z [M+H] + , theoretical value 806.5, measured value 806.5.

[0915] 57. Synthesis of LB-108 and its activated ester

[0916] LB-108-Z1:

[0917] Using (E,E)-farnesol (CAS: 106-28-5, 2.5 g, 11.2 mmol) and N-Boc-iminodiacetic acid (CAS: 56074-20-5, 1.31 g, 5.62 mmol) as starting materials, LB-108-Z1 (colorless oil, 3.52 g, yield 98%) was obtained through similar operation steps as those for the synthesis of LM-1102-Z1. TLC: petroleum ether / ethyl acetate, 4 / 1, R f value is about 0.7). MS (ESI): m / z [M+Na] + , theoretical value 664.5, measured value 664.4.

[0918] LB-108-Z2:

[0919] To a 100 mL single-necked flask equipped with a magnetic stirrer, LB-108-Z1 (3.3 g, 5.14 mmol) and 1,4-dioxane (10 mL) were added in sequence and stirred for 2 min to obtain a clear solution.

[0920] The reaction system was cooled to 0-5°C in an ice-water bath and stirred at a constant speed (500 r / min). 4N HCl / 1,4-dioxane solution (10 mL) was slowly added dropwise to the reaction system over 10 min. After the addition was completed, the temperature was naturally raised to room temperature and stirring was continued.

[0921] After stirring for 2 h, the reaction was monitored by LCMS, which showed that most of the starting material had been converted to form the product.

[0922] Stirring was stopped, and the reaction solution was concentrated under reduced pressure below 30°C and dried in a vacuum environment (50-70 Pa) for 1 hour to obtain 3.01 g of a light yellow oily product, which was used directly in the next step. MS (ESI): m / z [M+Na] + , theoretical value 564.4, measured value 564.3.

[0923] LB-108:

[0924] Starting from LB-108-Z2 (1.0 g, theoretical amount 1.71 mmol) and bromoacetic acid (286 mg, 2.1 mmol), a procedure similar to that described for the synthesis of SM7-ZA was used to obtain LB-108 (silica gel column chromatography: DCM / methanol, 100 / 1 to 20 / 1; colorless waxy solid-liquid mixture, 254 mg, yield 25%). MS (ESI): m / z [MH] - , theoretical value 598.4, found value 598.4; m / z[M+Na] + , theoretical value 622.4, measured value 622.4.

[0925] LB-108-Pfp:

[0926] LB-108 (45 mg, 0.075 mmol) was used as the starting material and the same steps as those for the synthesis of LM-2101-Pfp were followed to obtain LB-108-Pfp (32 mg of pale yellow oil, 55% yield). This compound had no mass spectrometry response signal.

[0927] 1 H NMR (400MHz, CDCl3) δ5.38-5.27(m, 2H), 5.16-5.03(m, 4H), 4.71-4.58(m, 4H), 3.81-3.4 8(m, 6H), 2.15-1.93(m, 12H), 1.77-1.64(m, 11H), 1.63-1.57(m, 8H), 1.44-1.38(m, 9H).

[0928] After derivatization with ammonia, LB-108-Y1 was obtained. MS (ESI): m / z [M+Na] +, theoretical value 621.4, found value 621.4; after derivatization with N,N-dimethylethylenediamine, LB-108-Y2 was obtained, MS (ESI): m / z [M+H] + , theoretical value 670.5, measured value 670.4.

[0929] 58. Synthesis of LT-303-Pfp

[0930] SM9-Z1:

[0931] Using eleostearic acid (SM9, CAS: 533-87-9, 4.75 g, 15.6 mmol) as the starting material, a similar procedure to that described for the synthesis of SM3-Z1 was used to obtain SM9-Z1 (4.84 g pale yellow solid, 97% yield). MS (ESI): m / z [M+H] + , theoretical value 319.2, found value 319.3; m / z[M+Na] + , theoretical value 341.2, measured value 341.2.

[0932] SM9-Z2:

[0933] To a 250 mL single-necked flask equipped with a magnetic stirrer, SM9-Z1 (4.84 g, 15.2 mmol), TEA (3.07 g, 30.4 mmol) and DCM (30 mL) were added in sequence and stirred rapidly for 2-3 min to obtain a transparent homogeneous solution.

[0934] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). A solution of p-toluenesulfonyl chloride (3.19 g, 16.7 mmol) in DCM (30 mL) was added dropwise to the reaction system within 15 min, and the reaction was continued with stirring.

[0935] After 18 h, the reaction was detected by TLC (developing solvent: petroleum ether / ethyl acetate, 1 / 1), which showed that the conversion of the raw material was complete and a relatively single product spot was generated (R f value of approximately 0.6).

[0936] The reaction mixture was concentrated to dryness under reduced pressure at 40°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then loaded onto a chromatographic column (packing diameter 6 cm, height 18 cm) filled with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 8 / 1 to 2 / 1). Fractions containing the product were monitored by TLC and collected. The product was then concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 3.09 g of the product as a colorless oil, with a yield of 43%. MS (ESI): m / z [M+H] +, theoretical value 473.2, found value 473.2; m / z[M+Na] + , theoretical value 495.2, measured value 495.2.

[0937] SM9-Z3:

[0938] SM9-Z2 (2.80 g, 6.26 mmol) was used as the starting material and the same steps as those for the synthesis of SM3-Z9 were followed to obtain SM9-Z3 (white waxy solid 2.58 g, yield 92%). MS (ESI): m / z [M+H] + , theoretical value 448.3, found value 448.2; m / z[M+Na] + , theoretical value 470.2, measured value 470.2.

[0939] SM9-Z4:

[0940] SM9-Z3 (2.78 g, 6.21 mmol) was used as the starting material and the same steps as those for the synthesis of SM3-Z7 were followed to obtain SM9-ZA (yellow-white solid 714 mg, yield 36%). MS (ESI): m / z [M+H] + , theoretical value 318.3, measured value 318.3.

[0941] LT-303-Z1:

[0942] SM9-Z4 (614 mg, 1.93 mmol) and SM5 (546 mg, 1.93 mmol) were used as starting materials and the same steps as those for the synthesis of LM-1401-Z1 were followed to obtain LT-303-Z1 (white solid 784 mg, yield 69%). MS (ESI): m / z [M+H] + , theoretical value 582.5, found value 582.5; m / z[M+Na] + , theoretical value 604.5, measured value 604.5.

[0943] LT-303:

[0944] LT-303-Z1 (576 mg, 0.991 mmol) was used as the starting material and the same steps as those for the synthesis of LM-1102 were followed to obtain LT-303 (white solid 240 mg, yield 43%). MS (ESI): m / z [M+H] + , theoretical value 568.5, found value 568.5; m / z[M+Na] + , theoretical value 590.5, found value 590.4; m / z[MH] - , theoretical value 566.5, measured value 566.5.

[0945] 1 H NMR (400MHz, CDCl3) δ5.52 (t, J=5.8Hz, 1H), 5.39-5.29 (m, 2H), 3.46-3.36 (m, 2H), 3.29-3.18 (m, 2H), 2.34 (t, J=7.3Hz, 2H), 2.29-2.20 (m, 1H), 2.16 (t, J=7.7Hz, 2H), 2.00 (q, J=6.6Hz, 4H), 1.68-1.56 (m, 4H), 1.53-1.41 (m, 8H), 1.37-1.23 (m, 34H), 0.88 (t, J=6.8Hz, 3H).

[0946] LT-303-Pfp:

[0947] To a 50 mL single-necked flask equipped with a magnetic stirrer, LT-303-Z1 (100 mg, 0.176 mmol), pentafluorophenol (32 mg, 0.174 mmol) and DCM (5 mL) were added in sequence and stirred rapidly for 2 min to obtain a colorless transparent solution.

[0948] The system temperature was maintained at 20-25°C and stirring was continued (500 r / min). DIC (67 mg, 0.528 mmol) was added to the flask in three batches within 30 min. After the addition, the reaction was continued with stirring.

[0949] After 1.5 h of reaction, the reaction was detected by TLC (developing solvent: DCM / methanol, 10 / 1), which showed that the conversion of the raw materials was basically complete and the main product spot (R f value of approximately 0.7).

[0950] Stirring was stopped and the reaction mixture was concentrated under reduced pressure at 35°C. The resulting crude product was loaded onto 60-100 mesh silica gel and then packed onto a chromatographic column (packing diameter 2.5 cm, height 8 cm) with 200-300 mesh silica gel. Elution was performed using a gradient eluent (petroleum ether / ethyl acetate, 10 / 1 to 2 / 1). Fractions containing the product were monitored by TLC and collected. The product was concentrated under reduced pressure at 40°C and dried under vacuum (50-70 Pa) for 1 h to obtain 60 mg of a white solid (yield 46%). MS (ESI): m / z [M+H] + , theoretical value 734.5, found value 734.4; m / z[M+Na] + , theoretical value 756.5, measured value 756.4.

[0951] After mixing LT-303-Pfp with dilute ammonia, the activated ester is completely converted into the amide derivative LT-303-Y1. MS (ESI): m / z [M+H] +, theoretical value 567.5, measured value 567.5.

[0952] Example 2: Testing of transmembrane delivery ability of lipophilic compounds and their derivatives on ASOs:

[0953] The lipophilic compound and its derivatives (hereinafter collectively referred to as "compound") of the present invention are covalently linked to an ASO having the ability to inhibit androgen receptor (AR) mRNA expression to obtain an ASO conjugate. The conjugate is tested for mRNA expression inhibition efficiency at the cellular level to evaluate the transmembrane delivery ability of the compound to the ASO.

[0954] For example,

[0955] The optional ASO is an antisense oligonucleotide sequence 5'-AAGTTGTAGTAGTCGC-3' (from the document Human Molecular Genetics, 2015, Vol. 24, No. 21, 5985-5994) that has a knockdown effect on AR mRNA, which serves as the ASO portion of the conjugate (AR-ASO), and the ASO is chemically modified. The chemical modification scheme is that the 5' and 3' ends of the sequence are each 4 consecutive ribose 2'-position methoxyethyl-substituted nucleotides, and the remaining nucleotides of the sequence are all ribose 2'-position deoxynucleotides, and all phosphodiester bonds of the sequence are thio-modified (phosphorothioate diester bonds), and its 3' or 5' end is modified with a chemical linker such as an amino group.

[0956] The optional lipophilic compounds are oleic acid (corresponding to the ASO-containing conjugate structure of CLM-1), LM-1102 (corresponding to the ASO-containing conjugate structure of CLM-2a, 2b, 2c), LM-1204 (corresponding to the ASO-containing conjugate structure of CLM-3), LM-2101 (corresponding to the ASO-containing conjugate structure of CLM-4a, 4b, 4c), LM-2301 (corresponding to the ASO-containing conjugate structure of CLM-5), ricinoleic acid (corresponding to the ASO-containing conjugate structure of CLM-6), LM-2202 (corresponding to the ASO-containing conjugate structure of CLM-14), LM-4102 (corresponding to the ASO-containing conjugate structure of CLM-15), LM-4401 (corresponding to the ASO-containing conjugate structure of CLM-16), LM-2101-L1 (corresponding to the ASO-containing conjugate structure of CLM-2 The corresponding conjugate structures are CLM-17), LM-2101-L2 (the corresponding conjugate structure containing ASO is CLM-18), LM-2511 (the corresponding conjugate structures containing ASO are CLM-19a and 19b), palmitic acid (the corresponding conjugate structure containing ASO is CLM-20), LM-2811 (the corresponding conjugate structure containing ASO is CLM-21), LB-205 (the corresponding conjugate structure containing ASO is CLD-1), LB-101 (the corresponding conjugate structure containing ASO is CLD-3), LB-202 (the corresponding conjugate structure containing ASO is CLD-5), LB-107 (the corresponding conjugate structure containing ASO is CLD-8), LB-108 (the corresponding conjugate structure containing ASO is CLD-9), and LT-303 (the corresponding conjugate structure containing ASO is CLD-10). After the compound is further converted into an activated ester, it can be directly conjugated with an ASO having an amino linker.

[0957] The steps for linking the lipophilic compound to the ASO are generally known to those skilled in the art, for example:

[0958] The activated ester of the lipophilic compound (Pfp ester) was dissolved in DMSO to a 10 mM compound solution. The amino-modified ASO was dissolved in a saturated sodium borate solution at a 5 mM ASO concentration. Equal volumes of the two solutions were mixed and diluted with DMSO to a final oil-water ratio (DMSO to water by volume) of 3:1 to 6:1 to complete the reaction mixture. The resulting solution was shaken at 25-37°C for 2-6 hours to complete the coupling reaction, and the reaction results were monitored by LCMS. The crude product was ethanol precipitated and purified by HPLC to obtain the conjugate of the lipophilic compound and ASO.

[0959] The following is the experimental effect of some conjugates on the in vitro expression inhibition of target mRNA in human immortalized epidermal cells (HaCaT).

[0960] Experimental process:

[0961] (1) Incubation reagent preparation: Prepare DMEM medium containing 1% FBS and 1% insulin-transferrin-selenium-aminoethanol (GIBCO, 51500056). Dissolve the ASO conjugate powder in sterile water to a concentration of 1 mM. Dilute the 1 mM ASO conjugate stock solution with the prepared medium to prepare incubation complexes at predetermined concentrations (10 μM, 3 μM, and 1 μM). Mix by pipetting 10 times.

[0962] (2) Cell treatment: Cells were plated one day before transfection at a concentration of 6 × 10 cells per well. 3 The cells were plated in a 96-well plate and 100 μL of DMEM medium containing 10% FBS was added to each well. Before transfection, the cell line confluence should be >70% under microscope observation. The old medium was discarded and 100 μL of the incubation reagent prepared in step (1) was added to each well. The cells were cultured in a 5% CO2 incubator at 37°C.

[0963] (3) After 24 hours of incubation, total RNA was extracted from the cells, and the expression of AR mRNA in the cells was detected by quantitative real-time PCR. The PCR primers and probes used to amplify the internal reference gene Actin and the target gene AR are shown in the following table:

[0964] PCR primer and probe sequences

[0965] Relative gene expression was calculated using the 2^-ΔΔCT method (Livak method), and the inhibition rate of antisense oligonucleotide mRNA expression level was calculated according to the following equation:

[0966] Inhibition rate = (1-2^-ΔΔCT) × 100%.

[0967] The experimental groups are:

[0968] Each test group, blank control group (Blank, cells not treated with any ASO), each negative control group (NC-1: cells treated with non-targeting ASO without conjugated compound and random sequence; NC-2: cells treated with non-targeting ASO conjugated with the same compound as CLM-1 and random sequence), C-0 control group (cells treated with AR-ASO without conjugated compound).

[0969] The inhibition efficiency of some ASO conjugates on AR mRNA expression in HaCaT cells is shown in Tables 1 and 2.

[0970] The test results show that at a concentration of 10 μM, ASOs not conjugated with compounds have a weak inhibitory effect on AR mRNA expression (40%), while ASOs conjugated with compounds mostly have a significant inhibitory effect on AR mRNA expression (67-97%).

[0971] Furthermore, at a concentration of 3 μM, most ASOs conjugated with the compounds also had moderate or good AR mRNA expression inhibitory effects (47-91%).

[0972] Table 1 Inhibitory effect of ASO conjugates (10 μM) on AR mRNA expression in HaCaT cells

[0973] Table 2 Inhibitory efficiency of ASO conjugates (3 μM and 1 μM) on AR mRNA expression in HaCaT cells

[0974] In contrast, when a compound-siRNA conjugate targeting the same target region was tested, its inhibitory effect on AR mRNA expression was weaker than that of the compound-ASO conjugate.

[0975] As described in the aforementioned summary of the invention, the structures of the conjugates (containing AR-ASO) in each test group are specifically as follows:

[0976] The structure of CLM-1(AR) is:

[0977] The structure of CLM-2a(AR) is:

[0978] The structure of CLM-2b(AR) is:

[0979] The structure of CLM-3(AR) is:

[0980] The structure of CLM-4a(AR) is:

[0981] The structure of CLM-4b(AR) is:

[0982] The structure of CLM-5(AR) is:

[0983] The structure of CLM-6(AR) is:

[0984] The structure of CLM-14(AR) is:

[0985] The structure of CLM-15(AR) is:

[0986] The structure of CLM-16(AR) is:

[0987] The structure of CLM-17(AR) is:

[0988] The structure of CLM-18(AR) is:

[0989] The structure of CLM-19a(AR) is:

[0990] The structure of CLM-19b(AR) is:

[0991] The structure of CLM-20(AR) is:

[0992] The structure of CLM-21(AR) is:

[0993] The structure of CLD-1(AR) is:

[0994] The structure of CLD-3(AR) is:

[0995] The structure of CLD-5(AR) is:

[0996] The structure of CLD-8(AR) is:

[0997] The structure of CLD-9(AR) is:

[0998] The structure of CLD-10(AR) is:

[0999] Example 3, PK test of skin application of compound and ASO conjugate:

[1000] The compounds LM-1102 and LM-2101 of the present invention were covalently linked to multiple ASOs with AR mRNA expression inhibitory effects, respectively, to obtain multiple ASO conjugates, each named CLM-2b* (LM-1102 conjugated to the 3' end of the ASO molecule) and CLM-4b* (LM-2101 conjugated to the 3' end of the ASO molecule). Tissue distribution tests were performed after application to animal skin to evaluate the effects of the lipophilic compounds of the present invention on the PK characteristics of the ASOs.

[1001] (1) Tissue distribution experiment of a single topical application on the skin of C57BL / 6J mice

[1002] 6-8 week old male C57BL / 6J mice were selected, with 5 animals in each group. CLM-4b* was applied once to the back skin at a concentration of 10 mg / mL and a volume of 15 μL / cm 2 The smear area was 3 cm × 3 cm. Before sampling, the skin surface was cleaned of residual drug, and after removing the stratum corneum, liquid chromatography-fluorescence detection (LC-FLD) (with a lower limit of quantification (LLOQ) of 5 ng / mL in plasma and 50 ng / g in other tissues) was used to measure drug levels in plasma, skin, liver, and kidney 5 minutes, 1 hour, 4 hours, 24 hours, 48 ​​hours, and 168 hours after sampling. The results are as follows:

[1003] BQL means below the quantitative limit

[1004] (2) Tissue distribution experiment of a single topical application on the skin of SKH1 mice

[1005] Male SKH1 hairless mice aged 6 to 8 weeks were selected, with 3 animals per group. A single application of 10 mg / mL of unconjugated ASO or CLM-2b* was performed on the back skin at a volume of 10 μL / cm 2 The smear area was 4 cm × 4 cm. The samples were cleaned to remove the drug and the stratum corneum was removed. Liquid chromatography-fluorescence detection (LC-FLD, with a lower limit of quantification (LLOQ) of 5 ng / mL in plasma and 50 ng / g in other tissues) was used to measure the drug content in plasma, skin, liver, and kidney 5 minutes, 1 hour, 4 hours, 6 hours, 24 hours, and 48 hours after the test. The results are as follows:

[1006] BQL means below the quantitative limit

[1007] The results of the conjugate PK test show that

[1008] (1) After a single application, the CLM-4b* conjugate rapidly enters the skin and reaches a peak concentration approximately 4 hours later. The concentration then decreases rapidly, but significant drug accumulation is still observed after 24 hours. There is also a certain degree of drug exposure in the blood and liver and kidney tissues.

[1009] (2) The CLM-2b* conjugate enters the skin slowly, gradually being absorbed and reaching its peak in about 6 to 24 hours, and then accumulating for a certain period of time. It is basically undetectable in the blood and liver and kidney tissues;

[1010] (3) The tissue and organ distribution of non-conjugated ASO molecules after administration is significantly different from that of conjugated ASO molecules, and their elimination rate in the skin is significantly higher than that of conjugated ASO molecules.

[1011] In summary, both compounds (LM-1102 and LM-2101) have the effect of promoting drug transdermal absorption.

[1012] Finally, it should be noted that the above embodiments are only used to help those skilled in the art understand the essential content of the present invention and are not used to limit the scope of protection of the present invention.

Claims

1. A lipophilic compound, characterized in that The compound has the structure shown in the following formula I, R2-X-R1-OH (Formula I), in, R1 is C2~C 26 an alkylenecarboxylic acid group containing one carboxylic acid group; R2 is selected from hydrogen, C1~C 24 Alkylcarboxyl / alkenylcarboxyl / alkyl / alkenyl, C5~C 16 (aromatic / heteroaromatic / aromatic olefin / aromatic alkane / diolefin) carboxyl, C8~C 18 Aromatic / aromatic alkenyl, C5~C 45 Dehydroxylated residues of terpene alcohols, C 20 ~C 30 Dehydroxylated residues of fat-soluble vitamins, C 18 ~C 29 Dehydroxylated residues of sterols, C 19 ~C 26 Carboxyl groups of carboxysteroids; -OH is covalently linked to the carboxyl residue of R1 to form a carboxyl group; X is a linking group that is covalently linked to both R1 and R2.

2. The compound according to claim 1, characterized in that When R1 is When the structure of the compound is as shown in Formula Ia, in, (1) The connection site of R1 to the X group is located on any carbon of R1 except the acyl carbon No. 1 to the hydrocarbon carbon No. 3, and the carbon chain from the acyl carbon No. 1 to the carbon connected to the X group in R1 is a linear main carbon chain, and the group formed from the carbon No. 4 to the carbon connected to the X group in the linear main carbon chain is R4; Preferably, the linear main carbon chain is a saturated carbon chain or contains a carbon-carbon double bond; Preferably, the attachment site is on a saturated carbon atom; Preferably, R4 is selected from: C2 to C 10 Linear alkenyl, C1~C 17 Linear alkylidene; More preferably, R4 is selected from: C6~C9 linear alkenyl, C1~C9 linear alkylidene; and, (2) The portion other than the linear main carbon chain group on R1 is R3, Preferably, R3 is selected from: hydrogen, C2-C8 linear / branched alkene, C1-C 10 Linear / branched alkyl; More preferably, R3 is selected from: hydrogen, C1~C 10 Linear alkyl.

3. The compound according to claim 1 or 2, characterized in that X is selected from oxygen, sulfur, sulfonyl (ylidene) group, sulfinyl (ylidene) group, imine group, amineoxy subunit, amino / aminooxyformate subunit, dicarboxylic acid diester subunit containing linear / branched / cyclic structure or diol / phenol diether subunit.

4. The compound according to claim 1 or 2, characterized in that R1 is selected from: (1) C4~C 26 A linear alkenecarboxylic acid group, preferably a butylenecarboxylic acid group having a 4-alkane residue, a decenoylenecarboxylic acid group having a 10-alkane residue, or an octadecenoylenecarboxylic acid group having a 12-alkane residue; or (2) C2~C 20 Linear alkylenecarboxyl groups, preferably (ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl / nonyl / decyl / undecane / dodecane / tridecane / tetradecane / pentadecane / hexadecane / heptadecane / octadecane) acyl groups having a 2-alkane residue, propionyl groups having a 3-alkane residue, butyryl groups having a 4-alkane residue, valeryl groups having a 5-alkane residue, hexanoyl groups having a 6-alkane residue, heptanoyl groups having a 7-alkane residue, octanoyl groups having an 8-alkane residue, nonyl groups having a 9-alkane residue acyl, decanoyl having a 10-alkane residue, undecanoyl having a 11-alkane residue, dodecanoyl having a 12-alkane residue, octadecanoyl having a 12-alkane residue, tridecanoyl having a 13-alkane residue, tetradecanoyl having a 14-alkane residue, pentadecanoyl having a 15-alkane residue, hexadecanoyl having a 16-alkane residue, heptadecanoyl having a 17-alkane residue, octadecanoyl having an 18-alkane residue; or (3) a C4-C8 branched alkylene carboxyl group, preferably an isovaleryl group having a 2-alkane residue, a 3-methylvaleryl group having a 2-alkane residue, a 4-methylvaleryl group having a 2-alkane residue, or a 3,3-dimethylbutyryl group having a 2-alkane residue; or (4) C7~C 10 An alkylenecarboxyl group containing a cycloalkyl structure, preferably a cyclohexylideneacetyl group having a 2-alkane residue or a 3-cyclohexylenepropionyl group having a 2-alkane residue; or (5) C8~C 16 The aralkylenecarboxylic acid group is preferably a phenylacetylene group having a 2-alkane residue, a phenylpropionylene group having a 2-alkane residue, a phenylbutyrylene group having a 2-alkane residue, a phenylvalerylene group having a 2-alkane residue, a phenylhexanoylene group having a 2-alkane residue, a phenylheptanoylene group having a 2-alkane residue, a p-toluoacetylene group having a 2-alkane residue, a p-toluopropionylene group having a 2-alkane residue, a m-toluopropionylene group having a 2-alkane residue, an o-toluopropionylene group having a 2-alkane residue, a 3-(4-tert-butylphenyl)propionylene group having a 2-alkane residue, a 3-(4-biphenylyl)propionylene group having a 2-alkane residue, a 3-(1-naphthyl)propionylene group having a 2-alkane residue, or a 3-(2-naphthyl)propionylene group having a 2-alkane residue.

5. The compound according to claim 1 or 2, characterized in that R2 is selected from: hydrogen; or (1) C3~C 24 Linear alkenecarboxyl; preferably acryloyl, butenoyl, pentenoyl, pentadienoyl, hexenoyl, hexadienoyl, heptenoyl, octenoyl, nonenoyl, decenoyl, undecenoyl, oleoyl, erucoyl, neuranoyl, linoleoyl, α-linolenoyl, arachidonic acid, eicosapentaenoyl, docosahexaenoyl; or (2) C4~C 10 Branched alkenecarboxyl; preferably 2-methacryloyl, 3,3-dimethylacryloyl, 2-methylbutenoyl, 2-methylpentenoyl, 2,2-dimethylpentenoyl, 2-methylhexenoyl, 3,7-dimethyl-6-octenoyl (citronellyl), geranyl; or (3) C6~C 20 An alkenecarboxyl group containing a cyclic structure; preferably a cyclopentenecarboxyl group, a cyclohexenecarboxyl group, a 2-cyclopentenyl-1-acetyl group, a 5-norbornene-2-carboxyl group, a retinoic acid group, an isotretinoic acid group, or a rosincarboxyl group; or (4) C1~C2 and C 10 ~C 22 Linear alkanoyl; preferably formyl, acetyl, n-decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, eicosanoyl, behenoyl; or (5) C4~C 12 branched alkanoyl; preferably iso(butyryl / pentyryl / hexyryl / heptyryl / octyryl / nonyl)acyl, 2-methyl(butyryl / pentyryl / hexyryl / heptyryl / octyryl), 2-ethyl(butyryl / pentyryl / hexyryl / heptyryl / octyryl), 2,2-dimethyl(propyryl / butyryl / hexyryl / heptyryl / octyryl), 3,3-dimethylbutyryl, 4,4-dimethylpentyryl, 5,5-dimethylhexyryl, 6,6-dimethylheptyryl, 7,7-dimethyloctyl, propyryl, 3-methylbutyryl, 3-methylpentyryl, 4-methyl(hexyryl / heptyryl / octyryl); or (6) C4~C 16 an alkanecarboxyl group containing a cyclic structure; preferably a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, a cycloheptylcarbonyl group, a cyclopropylacetyl group, a cyclobutylacetyl group, a cyclopentylacetyl group, a cyclohexylacetyl group, a cyclopentylpropionyl group, a cyclohexylpropionyl group, a 4-methylcyclohexylcarbonyl group, a 4-ethylcyclohexylcarbonyl group, a 4-propylcyclohexylcarbonyl group, a 4-isopropylcyclohexylcarbonyl group, a 4-butylcyclohexylcarbonyl group, a 4-pentylcyclohexylcarbonyl group, a 4-hexylcyclohexylcarbonyl group, a 4-ethylbis(cyclohexanecarbonyl group), a 4-pentylbis(cyclohexanecarbonyl group), an adamantanecarbonyl group, an adamantaneacetyl group; or (7) C6~C 12 Substituted or unsubstituted aromatic / heteroaromatic carboxylic acid acyl; preferably acetylsalicylic acid acyl, coumaric acid acyl; or (8)C9~C 14 Substituted or unsubstituted arylcarboxylic acid group; preferably cinnamoyl, 4-phenyl-3-butenoyl, 4-methoxycinnamoyl, 3,4-dimethoxycinnamoyl; or (9)C8~C 16 Substituted or unsubstituted aralkylcarboxyl; preferably ibuprofenyl, 2-(6-methoxy-2-naphthyl)propionyl; or (10)C5~C 16 A heteroatom-containing alkenyl carboxylic acid acyl group; preferably a monoethyl fumarate acyl group, a 3-ethoxyacryloyl group, a 10-hydroxy-2-decenoyl group, a 10-(methyl / ethyl / isopropyl)oxy-2-decenoyl group, a 10-(methyl / ethyl / propyl / butyl)oxy-2-decenoyl group; or (11) C8~C 18 substituted phenyl; preferably 4-(methyl / ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl)phenyl, 4-(methyl / ethyl / propyl / butyl / pentyl / hexyl / heptyl / octyl)oxyphenyl, 4-(vinyl / isopropyl / tert-butyl / sec-butyl / tert-pentyl / tert-octyl)phenyl, 4-(2,6-dimethylheptyl)phenyl, 4-methoxyethylphenyl, 4-cyclohexylphenyl, 4-(4-(methyl / ethyl / propyl / butyl)cyclohexyl)phenyl, 4-(1-adamantyl)phenyl, 4-benzylphenyl, 4-(2-phenylprop-2-yl)phenyl, 4-styrylphenyl, pterostilbene 4'-dehydroxylated residue, m-isopropylphenyl, m-tert-butylphenyl, o-sec-butylphenyl, o-ethoxyphenyl, 4-vinyl-2-methoxyphenyl, vanillin 4-dehydroxylated residue, paeonol 2-dehydroxylated residue, 3,5-dimethoxyphenyl; or (12)C9~C 12 Substituted or unsubstituted phenylalkenyl; preferably phenylallyl, 4-methoxyphenylallyl, 3,4-dimethoxyphenylallyl, 3,4,5-trimethoxyphenylallyl; or (13)C3~C 18 linear alkenyl; preferably allyl, 3-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, 6-hepten-1-yl, 7-octen-1-yl, 8-nonen-1-yl, 9-decen-1-yl, 10-undecen-1-yl, 2-buten-1-yl, 4-hexen-1-yl, 3-hexen-1-yl, 6-nonen-1-yl, 2-penten-1-yl, 2-hexen-1-yl, 2-hepten-1 1-yl, 2-octen-1-yl, 2-nonen-1-yl, 2-decen-1-yl, 2-undecen-1-yl, 2-dodecen-1-yl, 2,4-hexadien-1-yl, 2,4-heptadien-1-yl, 3-octen-1-yl, 2,7-octadien-1-yl, 2,6-nonadien-1-yl, 2,4,6-nonatrien-1-yl, 9-octadecen-1-yl, 2,13-octadecadien-1-yl; or (14) C1~C2 and C 10 ~C 22 Linear alkyl; preferably methyl, ethyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, n-docosyl; or (15)C3~C 22 Branched alkyl; preferably 2-propyl / hexyl / heptyl / octyl, 3-heptyl / octyl / nonyl, 2-ethyl (butyl / pentyl / hexyl), 4-heptyl, 5-nonyl, 3-methyl-1-pentyl, 3,5,5-trimethyl-1-hexyl, 3,7-dimethyl-1-octyl, 2-hexyl-1-decyl, 2-octyl-1-dodecyl; or (16)C5~C 17 An alkyl group containing a ring structure; preferably cyclo(pentyl / hexyl / heptyl / octyl)yl, 4-(methyl / ethyl / propyl / butyl / pentyl)cyclohexyl, 4-isopropylcyclohexyl, 4-tert-butylcyclohexyl, 4-(4-(methyl / ethyl / propyl / butyl / pentyl)cyclohexyl)cyclohexyl, cyclododecyl, cyclopropylethyl, cyclohexylethyl, cyclo(butyl / pentyl / hexyl)methyl; or (17)C5~C 45 The dehydroxylated residue of a branched terpene alcohol; preferably 3-methyl-3-buten-1-yl, a 1-dehydroxylated residue of isopentenol, a 1-dehydroxylated residue of citronellol, a 1-dehydroxylated residue of geraniol, a 1-dehydroxylated residue of nerol, a 2-dehydroxylated residue of myrcenol, a 2-dehydroxylated residue of dihydromyrcenol, a 2-dehydroxylated residue of tetrahydromyrcenol, a 3-dehydroxylated residue of linalool, a 1-dehydroxylated residue of phytol / phytol, a 1-dehydroxylated residue of farnesol / farnesol, a 1-dehydroxylated residue of geranylgeraniol, a 1-dehydroxylated residue of pentyloprenyl alcohol, a 1-dehydroxylated residue of hexaprenyl alcohol, a 1-dehydroxylated residue of heptaprenyl alcohol, a 1-dehydroxylated residue of octaprenyl alcohol, or a 1-dehydroxylated residue of solanesol; or (18)C 10 ~C 15 A dehydroxylated residue of a terpene alcohol having a ring structure; preferably a 2-dehydroxylated residue of fenchol, a 1-dehydroxylated residue of menthol, a 1-dehydroxylated residue of isopulegol, a 1-dehydroxylated residue of carveol, a 1-dehydroxylated residue of perillyl alcohol, a dehydroxylated residue of terpineol, a dehydroxylated residue of terpene alcohol, or a dehydroxylated residue of bisabolol; or (19)C 20 ~C 29 Dehydroxylated residues of fat-soluble vitamins; preferably, the 1-dehydroxylated residue of vitamin A1, the 1-dehydroxylated residue of vitamin D2 / D3, or the 6-dehydroxylated residue of vitamin E on the benzene ring; or (20)C 24 Bile acid acyl; preferably cholic acid acyl, deoxycholic acid acyl, chenodeoxycholic acid acyl, ursodeoxycholic acid acyl, lithocholic acid acyl; or (21)C 19 ~C 23 Carboxyl-containing steroidal carboxyl group; preferably 3-oxo-androst-4-ene-17β-carboxyl group; or (22)C 18 ~C 29 Sterol dehydroxyl residues; preferably 3-dehydroxyl residues of cholesterol / β-sitosterol / stigmasterol / ergosterol, 19-dehydroxyandrost-4-ene-3,17-dione residue, 17-dehydroxyl residue of nandrolone, 17-dehydroxyl residue of methyltestosterone, 3-dehydroxyl residue of pregnenolone, 3-dehydroxyl residue of abiraterone, 21-dehydroxyl residue of prednisone.

6. The compound according to claim 3, characterized in that X is selected from: (1) or (2) in, Q1 is hydrogen, C1-C5 hydrocarbon or acyl, Q2 is hydrogen or a C1-C4 hydrocarbon group; K1 and K2 are linear, branched, cyclic or ring-containing subunits selected from C1 to C 15 Alkylene, C2~C 26 heteroalkylene, C2 alkenylene, C6-C7 substituted / unsubstituted arylene, C4-C5 heteroarylene, C6-C8 aralkylene / heteroaralkylene, K1 may not exist; preferably, K1 is selected from: K2 is selected from: wherein j is 1 to 6, m is 1 to 10, n is 1 to 12, p is 1 to 11, q is 1 to 3, and r is 1 to 2, all of which are integers; and T1 and T2 are each independently a methylene group or do not exist.

7. The compound according to claim 4, characterized in that R1 is selected from: (1) or (2) (n is an integer from 1 to 17); or (3) Wherein, M1 is selected from methyl, (n is an integer from 1 to 15), (m is an integer from 1 to 5), 8. The compound according to claim 5, characterized in that R2 is selected from (1) (n is an integer from 1 to 8), (m is 1 or 2), (p is an integer from 1 to 6), (q is an integer from 1 to 5), (r is 7, 11 or 13), or (2) (n is 1 or 2), or (3) (n is 1 or 2), (m is 1 or 2), or (4) Where n is an even number from 8 to 20; or (5) wherein n is an integer from 1 to 5, m is an integer from 1 to 4, and r is 1 or 3; or (6) (n is an integer from 1 to 5), (m is an integer of 1 to 2, n is an integer of 1 to 4), [M2 is methyl, isopropyl, (p is an integer from 1 to 5), (q is 1 or 4)]; or (7) or (8) or (9) or (10) [M3 is selected from hydrogen, methyl, ethyl, isopropyl, (methyl / ethyl / propyl / butyl)acyl]; or (11) [M4 is selected from methyl, methoxy, (p is an integer from 1 to 7), (n is an integer from 1 to 7), (m is an integer from 1 to 4)]; or (12) or (13) (n is an integer from 1 to 9), (m is 1 or 3), (p is 1 or 4), (q is an integer from 1 to 8), or (14) Where n is an even number from 8 to 20; or (15) wherein n and m are integers from 3 to 5, and p is an integer from 1 to 3; or (16) (M5 is methyl, Isopropyl, tert-butyl, )、 wherein n is an integer from 1 to 4, and m is an integer from 1 to 3; or (17) (n is an integer from 2 to 8); or (18) or (19) or (20) wherein R is OH or H; or (21) or (22) (R is H or methyl), 9. The compound according to any one of claims 1-3, 5, 6, and 8, characterized in that The compound further has the structure of Formula I a1, I a2, 10. The compound according to any one of claims 1, 3, 5, 6, and 8, characterized in that (1) The connection site of R1 to the X group is located on any carbon of R1 except the acyl carbon No. 1; and the linear main carbon chain of the compound from the acyl carbon No. 1 to the carbon connected to the X group in R1 does not contain a carbon-carbon double bond or a triple bond, and the linear carbon chain group formed from the carbon No. 2 to the carbon connected to the X group is R6; Preferably, R6 is methine or ethylene; and (2) The portion other than the linear main carbon chain group on R1 is R5, Preferably, R5 is selected from: hydrogen, C1-C 15 Linear alkyl, C3~C6 branched alkyl, C5~C9 alkyl containing cycloalkyl structure, C6~C 14 Aryl, C7~C 14 Aralkyl.

11. The compound according to claim 1, characterized in that The structure of the compound is as follows, 12. A derivative of the lipophilic compound according to claim 1, characterized in that Having the structure of formula II, in, Y1 is a group connecting the lipophilic compound according to claim 1 to claim 3 and the branched fragment D, selected from O, S, q is a positive integer, preferably 2, 3, 4, or 6; X and R1 need to be present or absent at the same time. When they are absent, R2 and Y1 are directly connected. In this case, two or more R2 in Formula II may be different from each other, and two or more Y1 may be different from each other; Z1 is selected from H, D is a branched segment with q+1 linking sites, selected from the following segments and combinations thereof in which residues marked with * and residues not marked with * are directly linked to each other or are linked to each other through additional linking groups; specifically, D is linked to Z1 through a residue marked with * (directly or through a linker-DZ1), and is linked to Y1 through a residue not marked with *; Among them, Y2 is or not present (wherein, Y3 is O, S or The residue marked with ** is the residue not marked with * in the above D, t is 1 or 2, p is an integer from 1 to 5), T is a methylene group or is absent, M6 is hydrogen or methyl, M7 is hydrogen, methyl or ethyl, Q3 is methyl, ethyl or m is an integer from 1 to 4, and p is an integer from 1 to 5; The linker-DZ1 includes but is not limited to O, and combinations thereof, wherein n is an integer from 1 to 5.

13. A conjugate, characterized in that The conjugate comprises the compound according to any one of claims 1 to 11 or the derivative according to claim 12, and a drug molecule, wherein the conjugate is formed by covalently linking a reactive group on the drug molecule to a compound of formula I or a compound of formula II; The molecular types of the drug include but are not limited to: small molecule compounds, polypeptides, proteins, polysaccharides, nucleic acids or high molecular polymers; The nucleic acid is a natural or artificially synthesized / modified single-stranded nucleic acid or a complementary double-stranded nucleic acid, including but not limited to ASO, Aptamer, siRNA, saRNA, miRNA, mRNA, lncRNA and the like; preferably, the nucleic acid is ASO; Preferably, in the compound according to any one of claims 1 to 11 or the derivative according to claim 12, R1 is a C 14 ~C 22 A linear carbon chain group, wherein X is an oxygen, sulfur or imine group attached to a non-terminal carbon atom of R1; Preferably, when the drug molecule type is nucleic acid, the conjugate is composed of a reactive group on the sugar ring or base of the nucleic acid molecule and a carboxyl group of the compound of formula I or a reactive group on the compound of formula II. The groups are covalently linked, and a nucleic acid molecule can be covalently linked to one or more compounds of formula I or formula II.

14. A pharmaceutical composition comprising the conjugate according to claim 13 and necessary pharmaceutical excipients; preferably, the drug is a topical drug, and the topical administration comprises: The administration may be transdermal administration, ocular administration, brain administration, pulmonary administration, nasal administration, or oral administration, with transdermal administration being preferred.

15. A method for preparing a compound of formula I, characterized in that: The steps include: (1-1) The main structure is The raw materials are subjected to carboxyl protection reaction to obtain a carboxyl group having a protective group and a main structure of Compounds; (1-2) The original group of the hydrocarbon residue of R1 is converted into a sulfonic acid group, a halogen group or other easy-leaving groups, or the conversion is followed by substitution with a nitrogen / sulfur group, or oxidation and subsequent reduction and amination, or activation with a carbonyl donor reagent, or direct use; The raw materials are connected, or oxidized after connection to obtain compound R2-X-R1-PG. Optionally, when X is a fragment containing K1 or K2, the step further comprises the step of connecting X, wherein the step of connecting X is: connecting the main structure to The raw material is connected with the raw material whose structural main body is K1 or K2; the connection includes but is not limited to condensation or substitution connection; (1-3) removing the carboxyl protecting group to obtain a compound of formula I; or (2-1) The main structure is The raw material is kept with the carboxyl group exposed, and the steps of treating the original group of the R1 hydrocarbon residue as described in step (1-2) are performed, or it is used directly; (2-2) and the main structure are The raw materials are condensed or substituted, or oxidized after connection, and optionally, the step of connecting X as described in step (1-2) is also added to form a compound of formula I; or, (3-1) The structure does not contain carboxyl groups and the main structure is The compound is used as a raw material, and its R1' hydrocarbon residue group is subjected to the steps of treating the original group of the R1 hydrocarbon residue as described in step (1-2), or it is used directly; (3-2) and the main structure are The raw materials are condensed or replaced to form a main structure. or oxidation after connection, optionally, adding a step of connecting X as described in step (1-2); (3-3) performing a reaction such as carboxyl formation or connection to form a compound of formula I; or (4-1) The main structure is The original groups at the residue positions of the raw materials are converted into easy-leaving groups such as sulfonic acid groups and halogen groups, or further substituted into sulfide groups after conversion, or activated with carbonyl donor reagents; (4-2) and the main structure are The hydrocarbon residue groups of the raw materials are condensed or substituted, or oxidized after connection. Optionally, the step of connecting X as described in step (1-2) is also added to form a compound of formula I. Optionally, the step as described in step (1-3) or (3-3) needs to be added to form a compound of formula I; Optionally, based on the above steps, additional protection, deprotection, connection or functional group conversion steps are added.

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