Ionizable lipid molecules, their preparation methods, and their use

Abstract

The present invention relates to ionizable lipid molecules, methods for preparing them, and their uses. Specifically, the present invention provides compounds represented by the following formula (I), or their stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates, the definitions of each group in the formula as described in the specification. The present invention further provides lipid nanoparticles containing the ionizable lipid compound represented by formula (I). Compositions and related uses are further provided. The formula I compound of the present invention can be used to prepare lipid nanoparticles for the in vivo and in vitro delivery of nucleic acid therapeutic agents or activators. [Formula 1] JPEG2026508928000388.jpg70133 (I)

Description

[Technical Field]

[0001] This invention relates to ionizable lipid molecules, as well as a method for preparing and using them. [Background technology]

[0002] Nucleic acid drugs primarily include antisense nucleic acids, small interfering nucleic acids, microRNAs, messenger nucleic acids, and the CRISPR system. These nucleic acid drugs can effectively modulate and control the function of human genes in various ways, thereby exerting therapeutic effects. However, compared to conventional small molecules, nucleic acid drugs generally have large molecular weights and carry strong negative charges, making it difficult for them to penetrate cell membranes and enter cells to exert their effects. Furthermore, nucleic acids are susceptible to degradation by various nucleases, resulting in loss of function.

[0003] The successful application of ionizable lipid molecules has rapidly accelerated the clinical application of nucleic acid drugs. Onpattro, the first siRNA drug, delivers DLin-MC3-DMA to hepatocytes as an ionizable liposome and is used to treat neurological disorders caused by transthyretin amyloidosis (hATTR, familial amyloid polyneuropathy). Modena and BioNTech / Pfizer developed two COVID-19 vaccines using SM-102 and ALC-0315, respectively, effectively addressing the 2019 COVID-19 pandemic. Generally, nucleic acid drugs need to consist of four components: ionizable lipids, phospholipids, cholesterol, and PEG. Of these, ionizable lipids play the most crucial role in the process of delivering nucleic acid molecules into cells and releasing them to function within the cytoplasm. Various ionizable lipid molecules have been developed to date, and diverse delivery functions have been achieved through structural modification and formulation optimization. However, further improvements to ionizable lipid molecules for nucleic acid delivery remain necessary. [Overview of the project] [Problems that the invention aims to solve]

[0004] This invention provides a delivery vector that can be used to deliver genes to cells, as well as a method for preparing and using the same, in order to overcome the shortcomings of the prior art. [Means for solving the problem]

[0005] A first aspect of the present invention provides an ionizable lipid molecule, which is a compound represented by chemical formula (I), a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, or a solvate thereof. [ka] (I)

[0006] (In equation (I),

[0007] L1, L2, and L3 are each independently selected from an arbitrarily substituted alkylene group, an arbitrarily substituted alkenylene group, and an arbitrarily substituted alkynylene group.

[0008] M1, M2, and M3 are each independently selected from -C(O)O- and -OC(O)-.

[0009] R1, R2, and R3 are each independently selected from an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted alkynyl group.

[0010] L4 is selected from an optionally substituted alkylene group, an optionally substituted alkenylene group, and an optionally substituted alkynylene group.

[0011] R4 is -OR5, and R5 is selected from H, an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted alkynyl group.

[0012] m is an integer between 3 and 6.

[0013] A second aspect of the present invention provides lipid nanoparticles, the lipid nanoparticles containing an ionizable lipid compound represented by formula (I).

[0014] A third aspect of the present invention provides a composition comprising an ionizable lipid compound represented by formula (I), or the lipid nanoparticles.

[0015] A fourth aspect of the present invention provides a method for treating or preventing a target disease or disorder, the method comprising administering lipid nanoparticles containing a therapeutic agent or activator described in any embodiment of the present invention and a pharmaceutical composition described in any embodiment of this specification.

[0016] A fifth aspect of the present invention provides the use of a compound of formula (I) described in any embodiment of the present invention in the preparation of lipid nanoparticles or pharmaceutical compositions. [Effects of the Invention]

[0017] The ionizable lipid molecules of the present invention can effectively deliver various forms of nucleic acid drugs, such as ASO, siRNA, miRNA, mRNA, saRNA, and sgRNA, enabling various nucleic acid molecules to enter cells and function to achieve therapeutic effects. [Brief explanation of the drawing]

[0018] [Figure 1] Figure 1 shows the molecular structure of positive control 1.

[0019] [Figure 2] Figure 2 shows a photograph of the fluorescence intensity of mice 6 hours after intramuscular injection.

[0020] [Figure 3] Figure 3 shows a photograph of the fluorescence intensity of mice 6 hours after intravenous injection.

[0021] [Figure 4] Figure 4 shows a photograph of the fluorescence intensity of mice 24 hours after intramuscular injection.

[0022] [Figure 5] Figure 5 shows a photograph of the fluorescence intensity of mice 24 hours after intravenous injection.

[0023] [Figure 6] Figure 6 is a graph showing the whole-body fluorescence intensity values ​​of mice 6 hours and 24 hours after intravenous injection.

[0024] [Figure 7] Figure 7 is a graph showing the whole-body fluorescence intensity values ​​of mice 6 hours and 24 hours after intramuscular injection.

[0025] [Figure 8] Figure 8 is a graph showing the fluorescence intensity values ​​of the injection site in mice 6 hours and 24 hours after intramuscular injection.

[0026] [Figure 9] Figure 9 is a graph showing the fluorescence intensity values ​​of the liver and abdomen of mice 6 hours and 24 hours after intramuscular injection.

[0027] [Figure 10] Figure 10 shows a photograph of the fluorescence intensity of mice 6 hours after intramuscular injection.

[0028] [Figure 11] Figure 11 shows a photograph of the fluorescence intensity of mice 24 hours after intramuscular injection.

[0029] [Figure 12] Figure 12 is a graph showing the whole-body fluorescence intensity values ​​of mice 6 hours and 24 hours after intramuscular injection.

[0030] [Figure 13]Figure 13 is a graph showing the fluorescence intensity values ​​of the injection site in mice 6 hours and 24 hours after intramuscular injection.

[0031] [Figure 14] Figure 14 shows a photograph of the fluorescence intensity of mice 6 hours after intramuscular injection.

[0032] [Figure 15] Figure 15 shows a photograph of the fluorescence intensity of mice 24 hours after intramuscular injection.

[0033] [Figure 16] Figure 16 is a graph showing the whole-body fluorescence intensity values ​​of mice 6 hours and 24 hours after intramuscular injection.

[0034] [Figure 17] Figure 17 is a graph showing the fluorescence intensity values ​​at the injection site of mice 6 hours and 24 hours after intramuscular injection. [Modes for carrying out the invention]

[0035] Within the scope of the present invention, it should be understood that preferred technical solutions can be formed by combining the above-mentioned technical features of the present invention with the technical features specifically described below (for example, in the examples).

[0036] I. Terminology

[0037] Unless otherwise specified, the following terms used herein have the following meanings:

[0038] As used herein, "includes," "includes," etc., should be interpreted in an open and comprehensive sense, and throughout this specification and the claims, unless otherwise required by context, they shall mean "includes, but not limited to."

[0039] In the present invention, the reference to “one embodiment” means that certain features, structures, or properties described with reference to that embodiment are included in at least one embodiment of the present invention. Therefore, the phrase “in one or more embodiments” appearing in various places in this specification does not necessarily refer to the same embodiment. Furthermore, certain features, structures, or properties can be combined in any suitable manner in one or more embodiments.

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. The singular forms “one,” “the,” and “the said” as used herein and in the claims include multiple subjects unless the context clearly indicates otherwise.

[0041] An "effective dose" or "therapeutic effective dose" of an activator or therapeutic agent, such as a therapeutic nucleic acid, is the amount sufficient to produce the desired effect (e.g., an increase or inhibition of the expression of a target sequence compared to the normal expression level detected in the absence of the nucleic acid).

[0042] As used herein, “nucleic acid” refers to a polymer comprising at least two deoxyribonucleotides or ribonucleotides in single-stranded or double-stranded form, and includes DNA, RNA, and hybrids thereof. DNA can take the form of an antisense molecule, plasmid DNA, cDNA, PCR product, or vector. RNA can take the form of small hairpin RNA (shRNA), messenger RNA (mRNA), antisense RNA, small interfering RNA (siRNA), microRNA (miRNA), self-replicating RNA (saRNA), small guide RNA (sgRNA), multivalent RNA, dicer substrate RNA, or viral RNA (vRNA), and combinations thereof.

[0043] As used herein, “gene” means a nucleic acid (e.g., DNA or RNA) sequence containing a partial or full-length coding sequence necessary to produce a polypeptide or precursor polypeptide.

[0044] As used herein, "lipids" refers to a group of organic compounds that include, but are not limited to, fatty acid esters, and are generally poorly soluble in water but soluble in many organic solvents. Lipids are usually classified into at least three categories: (1) "simple lipids" including fats, oils, and waxes; (2) "complex lipids" including phospholipids and glycolipids; and (3) "derived lipids" such as steroids.

[0045] A "steroid" is a compound containing the following carbon skeleton: [ka]

[0046] Non-specific examples of steroids include cholesterol, among others.

[0047] The "cholesterol derivative" may be a cholesterol derivative known in the art used in the preparation of lipid nanoparticles. An example of a cholesterol derivative is commonly used cholesterol (CAS: 57-88-5).

[0048] As used herein, the term "polymer-conjugated lipid" refers to a molecule containing a lipid moiety and a polymer moiety. An example of a polymer-conjugated lipid is a polyethylene glycol (PEG)-ylated lipid. The term "PEG-ylated lipid" refers to a molecule containing a lipid moiety and a polyethylene glycol moiety. Polyethylene glycol-ylated lipids are known in the art and include 1-(monomethoxy-polyethylene glycol)-2,3-dimyristoyl glycerol (PEG-DMG), PEG-DAG (diacyl glycerol), PEG-PE (phosphatidylethanolamine), PEG-S-DAG, PEG-DSPE (-distearoyl phosphatidylethanolamine), PEG-cer (ceramide), and PEG dialkoxypropyl carbamate, among others. In a preferred embodiment of the present invention, the polymer-conjugated lipid is PEG2000-DMG.

[0049] As used herein, the term "neutral lipid" refers to a lipid substance that exists in the form of a zwitterion that is uncharged or neutral at a selected pH. At physiological pH, such lipids include, but are not limited to, phosphatidylcholine, such as 1,2-distearoyl-sn-glycerol-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycerol-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC), phosphatidylethanolamine, such as 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine (DOPE), sphingomyelin (SM), and ceramide. Neutral lipids may be synthetically derived or naturally derived.

[0050] As used herein, “lipid nanoparticles” refers to particles having dimensions of at least 1 nanometer scale (e.g., 1 to 1000 nm). Lipid nanoparticles can be included in formulations for delivering activators or therapeutic agents (e.g., nucleic acids) to target sites (e.g., cells, tissues (e.g., diseased tissue such as tumor tissue), organs). In some embodiments, the lipid nanoparticles of the present invention include nucleic acids. Such lipid nanoparticles typically include one or more compounds of formula (I) of the present invention, one or more helper lipid molecules, one or more cholesterol or cholesterol derivatives, and / or one or more polymers. It contains bound lipid molecules. The helper lipid molecules may be one or more types of neutral lipid molecules. The activator or therapeutic agent may be encapsulated in the lipid portion of the lipid nanoparticles, or in an aqueous space surrounded by some or all of the lipid portions of the lipid nanoparticles, to protect it from enzymatic degradation or other undesirable effects induced by host organism or cellular mechanisms, such as harmful immune responses.

[0051] As is well known in the art, the average diameter of the lipid nanoparticles may be about 30 nm to about 200 nm, 30 nm to about 150 nm, about 40 nm to about 150 nm, about 50 nm to about 150 nm, about 60 nm to about 130 nm, about 70 nm to about 110 nm, about 70 nm to about 100 nm, about 80 nm to about 100 nm, about 90 nm to about 100 nm, about 70 nm to about 90 nm, about 80 nm to about 90 nm, about 70 nm to about 80 nm, or about 30 nm, about 35 nm, about 40 nm, about 45 nm, about 50 nm, about 55 nm, about 60 nm, about 65 nm, about 70 nm, about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 105 nm, about 110 nm, about 115 nm, about 120 nm, about 125 nm, about 130 nm, about 135 nm, about 140 nm, about 145 nm, or about 150 nm, and the lipid nanoparticles are substantially non-toxic. In certain embodiments, the nucleic acid is resistant to degradation by nucleases in aqueous solution when present in the lipid nanoparticles. Lipid nanoparticles containing nucleic acids and methods for their manufacture are known in the prior art, and reference may be made, for example, to CN102712935A or related patents, the disclosures of which are hereby incorporated by reference in their entirety for all purposes.

[0052] The form of the lipid nanoparticles of the present invention is not particularly limited, but examples of the form in which the ionizable lipid of the present invention is dispersed in an aqueous solvent include unilamellar liposomes, multilamellar liposomes, or unspecified lamellar structures.

[0053] As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0054] "Hydroxy group" refers to -OH.

[0055] "Oxo group" refers to -C(=O).

[0056] "Carboxyl group" refers to -COOH.

[0057] "Nitro group" refers to -NO2.

[0058] The "cyano group" refers to -CN.

[0059] The term "amino group" refers to -NH2.

[0060] An "alkyl group" refers to a linear or branched saturated aliphatic hydrocarbon group containing, for example, 1 to 24, 1 to 18, 1 to 15, 1 to 12, 3 to 10, or 1 to 8 carbon atoms. Examples include methyl, ethyl, propyl, butyl, pentyl, heptyl, undecyl, tridecyl, pentadecyl, heptadecyl, heneicosyl, triacontanyl, methylpentadecyl, and hexylnonyl groups. Alkyl groups are linked to the rest of the molecule by single bonds.

[0061] An "alkylene group" is a compound having 1 to 24, 1 to 18, 1 to 15, 1 to 12, 3 to 10, or 1 to 8 carbon atoms, and is formed by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH(CH3)CH2-. A saturated, branched, or linear hydrocarbon group having two monovalent centers obtained by [the process].

[0062] An "alkoxy group" refers to an alkyl-O- group, where the alkyl group is as defined herein. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy groups. An alkylene oxy group refers to an alkylene group with an oxygen atom attached to one end. The alkylene group is as defined herein. An example of an alkylene oxy group is -CH2CH2-O-.

[0063] An "alkoxyoxo group" refers to a group in which an oxo group is linked to the oxygen of an alkoxy group, such as CH3OC(=O)- or CH3CH2OC(=O)-.

[0064] "Alkyl sulfinyl group" refers to an alkyl-S(=O)- group.

[0065] An "alkenyl group" refers to a linear or branched aliphatic hydrocarbon group containing 2-24, 2-18, 2-15, 2-12, 3-10, or 2-8 carbon atoms, and includes one or more unsaturated carbon-carbon double bonds, such as vinyl, propenyl, tridecene, tetradecadienyl, and octadecatrienyl groups, which are linked to the rest of the molecule by single bonds.

[0066] An "alkenylene group" refers to a divalent, linear or branched alkenyl group, typically containing 2-24, 2-18, 2-15, 2-12, 3-10, or 2-8 carbon atoms, and including one or more unsaturated carbon-carbon double bonds, linked to the rest of the molecule by two single bonds. An example of an alkenylene group is -CHCH=CHCH-.

[0067] A "cycloalkenyl group" refers to an unsaturated cyclic alkenyl group containing 3 to 10 ring carbon atoms.

[0068] An "alkynyl group" refers to a straight or branched aliphatic hydrocarbon group containing 2-24, 2-18, 2-15, 2-12, 3-10, or 2-8 carbon atoms, and includes one or more unsaturated carbon-carbon triple bonds, such as an ethynyl group or a propynyl group, which are linked to the rest of the molecule by single bonds.

[0069] A "cycloalkynyl group" refers to an unsaturated cyclic alkynyl group containing 3 to 10 ring carbon atoms.

[0070] An "alkynylene group" refers to a divalent linear or branched alkynyl group, typically containing 3-24, 3-18, 3-15, 3-12, 3-10, or 3-8 carbon atoms, and including one or more unsaturated carbon-carbon triple bonds, which are linked to the rest of the molecule by two single bonds. An example of an alkenylene group is -CHC≡CCH-.

[0071] "Acyl group" refers to an alkyl-C(O)-group such as an acetyl group or a propionyl group.

[0072] "Aryl group" refers to a carbocyclic ring system group containing hydrogen, 6 to 18 carbon atoms (preferably 6 to 14 carbon atoms), and at least one aromatic ring. The aryl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and may include a fused ring system or a bridged ring system. Aryl groups include, but are not limited to, aryl groups derived from acentriylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenacene, phenanthrene, heptene, pyrene, and triphenylene.

[0073] "Aryloxy group" refers to -OR, where R is an aryl group.

[0074] "Carbocyclyl group" refers to a stable saturated or unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, and the number of ring carbon atoms can be 3 to 18. The carbocyclyl group may include a fused ring or a bridged ring system having 3 to 18 carbon atoms, is saturated, and is linked to the rest of the molecule by a single bond. In some embodiments, the carbocyclyl group is cycloalkyl, and representative cycloalkyl groups include 3 to 15 carbon atoms (C3-C 15 cycloalkyl group), 3 to 10 carbon atoms (C3-C 10This includes, but is not limited to, cycloalkyl groups with 3 to 8 carbon atoms (C3-C8 cycloalkyl groups), 3 to 6 carbon atoms (C3-C6 cycloalkyl groups), 3 to 5 carbon atoms (C3-C5 cycloalkyl groups), or 3 to 4 carbon atoms (C3-C4 cycloalkyl groups). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Examples of polycyclic cycloalkyl groups include adamantyl, norbornyl, dekalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cisdecalin, transdecalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. In preferred embodiments, the cycloalkyl group is a 3- to 8-membered ring cycloalkyl group such as a cyclopropyl, cyclopentyl, and cyclohexyl group.

[0075] A "heterocyclyl group" refers to a stable 3-20 member non-aromatic cyclic group consisting of 2-14 carbon atoms and 1-6 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. A heterocyclyl group may be monocyclic, bicyclic, tricyclic, or more cyclic, and may include fused, bridging, or spirocyclic systems. A heterocyclyl group may be partially or completely saturated. A heterocyclyl group may be linked to other parts of the compound by single bonds via carbon atoms or heteroatoms. Preferred heterocyclyl groups are stable 4-11 member non-aromatic monocyclic, bicyclic, bridging, or spirocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably stable 4-8 member non-aromatic monocyclic, bicyclic, bridging, or spirocyclic groups containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heterocyclyl groups include pyrrolidinyl group, morpholinyl group, piperazinyl group, homopiperazinyl group, piperidinyl group, thiomorpholinyl group, 2,7-diazaspiro[3.5]nonane-7-yl group, 2-oxa-6-azaspiro[3.3]heptan-6-yl group, 2,5-diazabicyclo[2.2.1]heptan-2-yl group, azetidinyl group, pyranyl group, tetrahydropyranyl group, thiopyranyl group, and tetrahydro This includes, but is not limited to, groups such as furanyl group, oxazinyl group, dioxolyl group, tetrahydroisoquinolinyl group, decahydroisoquinolinyl group, imidazolinyl group, imidazolidinyl group, quinadinyl group, thiazolidinyl group, isothiazolidinyl group, isoxazolidinyl group, indolinyl group, octahydroindolyl group, octahydroisoindolyl group, pyrrolidinyl group, pyrazolidinyl group, and phthalimide group.

[0076] A "heteroaryl group" refers to a 5-16 member conjugated ring system having 1-15 carbon atoms (preferably 1-10 carbon atoms) and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur within the ring. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, or otherwise. The above ring systems are also acceptable. The heteroaryl group is preferably a stable 5-12 membered aromatic group containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a stable 5-10 membered aromatic group containing 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, or a stable 5-6 membered aromatic group containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include thienyl group, imidazolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, oxadiazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridadinyl group, benzimidazolyl group, benzopyrazolyl group, indolyl group, furaryl group, pyrrolyl group, triazolyl group, tetrazolyl group, triazinyl group, indolidinyl group, isoindyl group, indazolyl group, isoindazolyl group, prinyl group, quinolyl group, isoquinolyl group, diazinyl group, naphthylidinyl group, quinoxalinyl group, pteridinyl group, carbazolyl group, carbolinyl group, phenanthrolinyl group, phenanthrolinyl group, acridinyl group, phenadinyl group, isothiazolyl group This includes, but is not limited to, lyl groups, benzothiazolyl groups, benzothienyl groups, oxatriazolyl groups, synnolinyl groups, quinazolinyl groups, phenylthio groups, indolidinyl groups, o-phenantrenyl groups, isoxazolyl groups, phenoxadinyl groups, phenothiazinyl groups, 4,5,6,7-tetrahydrobenzo[b]thienyl groups, naphthopyridinyl groups, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, and imidazo[1,2-a]pyrazine.

[0077] In this specification, when a group is "optionally substituted," it may be optionally substituted with 1 to 5 substituents, the substituents of which may be selected from alkyl groups, alkenyl groups, alkynyl groups, halogens, haloalkyl groups, haloalkenyl groups, haloalkynyl groups, cyano groups, nitro groups, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted cycloalkyl groups, and optionally substituted heterocyclyl groups. These substituents, aryl groups, heteroaryl groups, cycloalkyl groups, and heterocyclyl groups, may each be optionally substituted with groups such as alkyl groups, alkenyl groups, alkynyl groups, halogens, haloalkyl groups, haloalkenyl groups, haloalkynyl groups, cyano groups, nitro groups, aryl groups, heteroaryl groups, cycloalkyl groups, and heterocyclyl groups. It should be understood that the number of substituents is influenced by the molecular structure of the compound. For example, when the substituent is an aryl group, heteroaryl group, cycloalkyl group, or heterocyclyl group, the number of substituents is usually one, and when the substituent is a halogen, the number of halogen atoms may be 2 to 5, depending on the chain length of the substituent or the number of ring carbon atoms.

[0078] In this specification, “ionizable lipid compound” means a lipid compound that exists in a charged form at a specific pH value or pH range, and includes positively charged or negatively charged lipid compounds, preferably positively charged lipid compounds (i.e., cationic lipid compounds). The specific pH value or pH range means the pH value or pH range of the environment in which the lipid compound is stored or intended to be used, and includes, but is not limited to, physiological pH.

[0079] In this specification, “pharmaceutically acceptable salts” include acid addition salts and base addition salts.

[0080] "Pharmacologically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the biological efficacy and properties of a free base. The inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. The organic acids include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, and ammonium compounds. Capric acid, 4-acetylaminobenzoic acid, camphor acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonate, cinnamic acid, citric acid, cyclamic acid, lauryl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauryl acid This includes phosphoric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid, among others.

[0081] A "pharmaceutically acceptable base addition salt" refers to a salt that retains the biological efficacy and properties of a free acid. These salts are prepared by adding an inorganic or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary amines, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and salts of basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine (TEA), tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, pheniramine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0082] In this specification, “pharmaceutical composition” means a formulation comprising a pharmaceutically active ingredient and a compound of formula (I) of the present invention. A pharmaceutical composition typically contains a therapeutically effective amount of a therapeutic agent or activator, i.e., a therapeutic agent or activator. “Therapeutically effective amount” means an amount sufficient to produce a therapeutic effect in a mammal, preferably a human, when administered to the mammal. The amount of therapeutic agent or activator constituting the “therapeuticly effective amount” varies depending on the therapeutic agent or activator used, the symptoms and their severity, the method of administration, and the age of the mammal being treated, but can be routinely determined by those skilled in the art based on their knowledge and this disclosure.

[0083] The “pharmaceutically acceptable carriers or excipients” as described herein include, but are not limited to, adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the FDA or NMPA as permissible for use in humans or livestock.

[0084] As used herein, “treatment” encompasses the treatment of a target disease or condition in a mammal, preferably a human, suffering from the target disease or condition, and includes the following:

[0085] (1) In mammals, those that are particularly susceptible to the disease or condition, but are not yet in that state Preventing the onset of a disease or condition when the condition has not been diagnosed.

[0086] (2) To suppress the progression of the disease or condition, that is, to prevent its progression.

[0087] (3) To alleviate the disease or condition, that is, to reduce the disease or condition,

[0088] (4) Relieving symptoms caused by the disease or condition, that is, reducing pain without addressing the underlying disease or condition.

[0089] As used herein, “disease” and “condition” may be used interchangeably, or they may be distinguished because certain diseases or conditions are not yet recognized as diseases because the pathogen is unknown (i.e., the cause has not yet been identified), and are considered merely undesirable conditions or syndromes for which clinicians have identified a more or less specific set of symptoms.

[0090] In this specification, “mammals” include humans, livestock such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits, etc.), and non-livestock (e.g., wild animals).

[0091] Compounds of formula (I) or their pharmaceutically acceptable salts may have one or more chiral centers, thus potentially giving rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R)-, (S)-, (D)-, or (L)- (in the case of amino acids) based on absolute stereochemistry. The present invention includes all such isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or separated using conventional techniques such as chromatography or fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemics (or racemics of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). If a compound described herein contains an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compound shall include both E and Z geometric isomers. Similarly, all tautomers shall also be included.

[0092] A "stereoisomer" refers to a compound that is composed of the same atoms bonded together by the same bonds, but has different three-dimensional structures that cannot be converted into each other. This invention encompasses various stereoisomers and mixtures thereof, and also includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and cannot be superimposed (nonsuperimposeable).

[0093] "Tautomerism" refers to the transfer of a proton from one atom in a molecule to another atom in the same molecule. The present invention includes any tautomer of the aforementioned compounds.

[0094] II. Ionizable Lipid Molecules

[0095] The ionizable lipid molecules described herein have the structural formula shown in the following formula (I). [ka] (I)

[0096] (In the formula, L1, L2, and L3 are each independently selected from an optionally substituted alkylene group, an optionally substituted alkenylene group, and an optionally substituted alkynylene group; M1, M2, and M3 are each independently selected from -C(O)O- and -OC(O)-; R1, R2, and R3 are each independently selected from an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted alkynyl group; L4 is selected from an optionally substituted alkylene group, an optionally substituted alkenylene group, and an optionally substituted alkynylene group; R4 is -OR5; R5 is selected from H, an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted alkynyl group; and m is an integer between 3 and 6.)

[0097] This specification also includes stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, and solvates of the compound represented by chemical formula (I).

[0098] In formula (I), if a group is "optionally substituted", the substituent may be selected from a hydroxyl group, an alkoxy group, a halogen, an alkyl group, a haloalkyl group, an alkyl group substituted with a hydroxyl group, an alkenyl group, a haloalkenyl group, an alkenyl group substituted with a hydroxyl group, -NR'R'', an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted heterocyclyl group. The number of substituents may be 1 to 6. R' and R'' are independently H and C, respectively. 1~4It is selected from an alkyl group. The alkyl group in the alkyl group, alkoxy group, haloalkyl group, and alkyl group substituted by a hydroxy group is C 1~6 alkyl group or C 1~4 alkyl group may be, and the alkenyl group in the alkenyl group, haloalkenyl group and alkenyl group substituted by a hydroxy group is C 2~6 alkenyl group or C 2~4 alkenyl group may be. The cycloalkyl group is optionally substituted by 1 to 4 substituents selected from halogen, C 1~4 alkyl group, hydroxy group, and -NR’R’’, and is C 3~8 cy cloalkyl group may be. The aryl group may be a 6- to 14-membered aryl group, for example, a phenyl group and a naphthyl group, and the aryl group may be optionally substituted by 1 to 4 substituents selected from halogen, C 1~4 alkyl group, hydroxy group, and -NR’R’’. The heteroaryl group may be a 5- to 10-membered heteroaryl group, for example, a 5- to 10-membered nitrogen-containing and / or oxygen-containing heteroaryl group, such as a pyridyl group, a pyrazolyl group, and an imidazolyl group, etc., and the heteroaryl group may be optionally substituted by 1 to 4 substituents selected from halogen, C 1~4 alkyl group, hydroxy group, and -NR’R’’. The heterocyclyl group may be a 4- to 10-membered heterocyclyl group, preferably a 4- to 10-membered nitrogen-containing and / or oxygen-containing heterocyclyl group, such as a morpholinyl group, a piperidinyl group, a piperazinyl group, and a pyrrolidinyl group, etc., and the heterocyclyl group may be optionally substituted by 1 to 4 substituents selected from halogen, C 1~4 alkyl group, hydroxy group, and -NR’R’’.

[0099] In a preferred embodiment, in formula (I), L1, L2, L3 are each independently an optionally substituted C 1~24 alkylene group, an optionally substituted C 2~24Alkenylene group, and optionally substituted C 2~24 Selected from alkynylene groups. Preferably, L1, L2, and L3 are each independently -(CH2) n - is selected from and n is an integer between 1 and 24, preferably between 2 and 24, more preferably between 3 and 15, and even more preferably between 3 and 11. In some embodiments, n in L1, L2, and L3 are independently integers between 3 and 8. In some embodiments, L1, L2, and L3 are the same base.

[0100] In a preferred embodiment, in formula (I), R1, R2, and R3 are each independently substituted with any C 1~24 Alkyl alkyl groups, optionally substituted C 2~24 Alkenyl group, and optionally substituted C 2~24 Selected from alkynyl groups. Preferably, R1, R2, and R3 are each independently of any one or more C 1~24 C substituted with alkyl group 1~24 Alkyl alkyl group, optionally one or more C 1~24 C substituted with alkyl group 2~24 Selected from alkenyl groups. In one or more embodiments, the C 2~24 The alkenyl group contains 1 to 4 carbon-carbon double bonds. The carbon-carbon double bonds may be in a Z and / or E configuration, but are preferably in a Z configuration.

[0101] In a preferred embodiment, in formula (I), R1, R2, and R3 are each independently selected from the following: [ka]

[0102] (Here, a is an integer from 1 to 24, preferably an integer from 2 to 20, more preferably an integer from 3 to 15, R 1a and R 2a Each time it appears, it is independently H or C 1~24 It is an alkyl group, or each R 1aH or C 1~24 It is an alkyl group and has at least one R 2a It is adjacent to the R carbon atom it is linked to. 2a and together with the carbon atom it is linked to, it forms a carbon-carbon double bond, R 3a teeth, (It is either an H group or a methyl group.)

[0103] In some embodiments, a, R 1a , R 2a , R 3a Each of the following is selected such that R1, R2, and R3 each independently contain 1 to 40, preferably 1 to 30, more preferably 1 to 24, and even more preferably 3 to 24 carbon atoms.

[0104] In some embodiments, at least one R 1a H is H, and for example, all R 1a H is H and at least one R 2a H is H, and for example, all R 2a is H. In some other embodiments, at least one R 1a H is H, and for example, all R 1a is H and at least one R 2a C 1~24 Alkyl alkyl group, preferably C 3~20 Alkyl alkyl groups, more C 3~15 It is an alkyl group.

[0105] In some embodiments, R1, R2, and R3 are each independently selected from the following: [ka]

[0106] (Here, p is an integer from 0 to 2, p' is an integer from 1 to 24, p'' is an integer from 0 to 24, and b, c, d, and e are each independent integers from 1 to 22, R 1b and R2b Each time it appears, it is independently H or C 1~12 It is an alkyl group, or each R 1b H or C 1~12 It is an alkyl group and has at least one R 2b It is adjacent to the R carbon atom it is linked to. 2b and together with the carbon atom it is linked to, it forms a carbon-carbon double bond, R 1c and R 2c Each time it appears, it is independently H or C 1~12 It is an alkyl group, or each R 1c H or C 1~12 It is an alkyl group and has at least one R 2c It is adjacent to the R carbon atom it is linked to. 2c and together with the carbon atom it is linked to, it forms a carbon-carbon double bond, R 1d and R 2d Each time it appears, it is independently H or C 1~12 It is an alkyl group, or each R 1d H or C 1~12 It is an alkyl group and has at least one R 2d It is adjacent to the R carbon atom it is linked to. 2d and together with the carbon atom it is linked to, it forms a carbon-carbon double bond, R 1e and R 2e Each time it appears, it is independently H or C 1~12 It is an alkyl group, or each R 1e H or C 1~12 It is an alkyl group and has at least one R 2e It is adjacent to the R carbon atom it is linked to. 2e and together with the carbon atom it is linked to, it forms a carbon-carbon double bond, R 3a (This is either an H or a methyl group.)

[0107] In some embodiments, p’ and p’’ are each selected such that R1, R2, and R3 each independently contain from 1 to 40, preferably from 1 to 30, more preferably from 1 to 24, and still more preferably from 3 to 24 carbon atoms.

[0108] In some embodiments, p’ and p’’ are the same integer.

[0109] In some embodiments, b, c, d, e, R 1b , R 2b , R 1c , R 2c , R 1d , R 2d , R 1e , R 2e are each selected such that R1, R, R2, and R3 each independently contain from 1 to 40, preferably from 1 to 30, more preferably from 1 to 24, and still more preferably from 3 to 24 carbon atoms.

[0110] In some embodiments, at least one R 1b is H, for example all R 1b are H, at least one R 2b is H, for example all R 2b are H, at least one R 1c is H, for example all R 1c are H, at least one R 2c is H, for example R 2c is H, at least one R 1d is H, for example all R 1d are H, at least one R 2d is H, for example all R 2d are H, at least one R 1e is H, for example all R 1e are H, at least one R 2e is H, for example all R 2e is H.

[0111] In some embodiments, b, c, d, and e are each an integer between 1 and 10, independently of each other.

[0112] In some embodiments,

[0113] [ka] Examples include,

[0114] -(CH2) p× CH3(p× is an integer between 1 and 23, preferably between 3 and 14). [ka] This includes, but is not limited to, these.

[0115] In some embodiments,

[0116] [ka] Examples include, [ka] This includes, but is not limited to, these.

[0117] In some embodiments,

[0118] [ka] Examples include, [ka] This includes, but is not limited to, these.

[0119] In some embodiments, R1, R2, and R3 are each independently of C 2~24Selected alkenyl groups, with 1 to 4 carbon atoms. 1~6 The group may be substituted with an alkyl group, preferably a methyl group, and the number of carbon-carbon double bonds may be 1 to 4, but preferably 1 to 2, and the carbon-carbon double bonds may be in an E configuration. Examples of the alkenyl group include: [ka] This includes, but is not limited to, these.

[0120] In one or more embodiments, R1, R2, and R3 are the same group.

[0121] In a preferred embodiment, in formula (I), L4 is optionally replaced by C. 1~8 Alkylene group, optionally substituted C 2~6 Alkenylene group, and optionally substituted C 2~6 Selected from alkynylene groups, preferably L4 is -(CH2) o - is selected from, where o is an integer from 1 to 8. In some embodiments, L4 is optionally replaced with C 1~6 Alkylene group, optionally substituted C 2~6 Alkenylene group, and optionally substituted C 2~6 Selected from alkynylene groups, preferably L4 is -(CH2) o - is selected from, where o is an integer from 1 to 6, preferably an integer from 2 to 5, more preferably 2, 3 or 4.

[0122] In a preferred embodiment, in formula (I), R5 is H, optionally substituted with C. 1~6 Alkyl alkyl groups, optionally substituted C 2~6 Alkenyl group, and optionally substituted C 2~6 Selected from alkynyl groups, preferably R5 is H, C 1~6 Selected from alkyl groups.

[0123] In a preferred embodiment, the compound of formula (I) has the following structure. [ka] or [ka]

[0124] (Here, f, g, h, i, j, k, g1, g2, i1, i2, k1, k2, r, s, t, u, v, w, x, y, z are all independent integers between 1 and 24.)

[0125] In some embodiments, f, h, and j are each independently integers between 2 and 24, preferably between 3 and 15, and more preferably between 3 and 11.

[0126] In some embodiments, g, g1, g2, i, i1, i2, k, k1, k2 are each independently integers from 1 to 15, preferably from 3 to 15.

[0127] In some embodiments, r, s, t, u, v, w, x, y, and z are each independent integers from 1 to 15, preferably from 1 to 10.

[0128] In some embodiments, q is an integer from 1 to 6, preferably an integer from 2 to 5, and more preferably an integer from 2 to 4.

[0129] In some embodiments, f, h, and j are the same integer; g, i, and k are the same integer; g1, g2, i1, i2, k1, and k2 are the same integer; r, t, and v are the same integer; s, u, and w are the same integer; and x, y, and z are the same integer.

[0130] In equations (I), (Ia), (Ib), (Ic), and (Id), m is an integer between 3 and 6, for example, 3, 4, 5, or 6.

[0131] In some embodiments, the compound of formula (I) of the present invention is the compound represented by formula (Ia), where i and k are each independently integers from 1 to 15, preferably independently integers from 3 to 15, preferably i and k are the same integer; h and j are each independently integers from 2 to 11, preferably independently integers from 3 to 7, preferably h and j are the same integer; m is 3, 4, 5 or 6, preferably 3 or 4; f is an integer from 3 to 11, preferably an integer from 3 to 6; g is an integer from 3 to 15, preferably an integer from 6 to 12; and q is an integer from 2 to 5.

[0132] In some embodiments, the compound of formula (I) of the present invention is the compound represented by formula (Ia), where i, k, and g are each an integer from 1 to 15, preferably each an integer from 3 to 15, and more preferably each an integer from 8 to 12. Preferably, i, k, and g are the same integer, f, h, and j are each independently integers from 2 to 11, preferably independently integers from 3 to 7, preferably f, h, and j are the same integer, m is 3, 4, 5, or 6, preferably 3 or 4, and q is an integer from 2 to 5, preferably 2 or 3.

[0133] In some embodiments, the compound of formula (I) of the present invention is the compound represented by formula (Id), where h and j are each independently integers from 2 to 11, preferably independently integers from 3 to 8, preferably h and j are the same integer; m is 3, 4, 5 or 6, preferably 3 or 4; t and v are each independently integers from 1 to 10, preferably independently integers from 5 to 10, preferably t and v are the same integer; y and z are each independently integers from 1 to 10, preferably independently integers from 3 to 8, preferably y and z are the same integer; f is an integer from 3 to 11, preferably an integer from 3 to 8; r is an integer from 1 to 10, preferably an integer from 5 to 10; x is an integer from 1 to 10, preferably an integer from 3 to 8; and q is an integer from 2 to 5.

[0134] In some embodiments, the compound of formula (I) of the present invention is the compound represented by formula (Id), where f, h, and j are each independently integers from 2 to 11, preferably independently integers from 3 to 7, preferably f, h, and j are the same integer; m is 3, 4, 5, or 6, preferably 3 or 4; t, r, and v are each independently integers from 1 to 10, preferably independently integers from 6 to 10, preferably t, r, and v are the same integer; x, y, and z are each independently integers from 1 to 10, preferably independently integers from 3 to 7, preferably x, y, and z are the same integer; and q is an integer from 2 to 5.

[0135] III. Lipid Nanoparticles

[0136] The compound of formula (I) of the present invention can be used to prepare lipid nanoparticles for delivering nucleic acid therapeutic agents or activators in vivo and in vitro.

[0137] In addition to the compound of formula (I) of the present invention, the lipid nanoparticles of the present invention may further contain one or more helper lipid molecules, one or more cholesterol or cholesterol derivatives, and / or one or more polymer-bound lipid molecules.

[0138] Preferably, the helper lipid molecule is a neutral lipid molecule, preferably selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE, and SM. In a preferred embodiment, the lipid nanoparticles contain DOPE.

[0139] Preferably, the cholesterol derivative is cholesterol (abbreviated as chol, CAS: 57-88-5).

[0140] Preferably, in the polymer-bound lipid molecule, the polymer is polyethylene glycol. In preferred embodiments, the polymer-bound lipid molecule is selected from PEG-DAG, PEG-PE, PEG-S-DAG, PEG-DSPE, PEG-cer, and PEG-dialkoxypropyl carbamate. Preferably, the lipid nanoparticles contain PEG2000-DSPE.

[0141] In preferred embodiments, if present in the lipid nanoparticles, the molar ratio of compound (I), its stereoisomer, racemate, or pharmaceutically acceptable salt to helper lipid molecules, cholesterol or cholesterol derivatives, or polymer-bound lipid molecules is 60 to 5:60. ~5:50~5:10~1, preferably 60~30:30~10:50~30:5~1.

[0142] The average particle size of the lipid nanoparticles of the present invention is typically 50 nm to 200 nm, preferably 80 nm to 120 nm.

[0143] The lipid nanoparticles of the present invention can be used to express proteins encoded by mRNA, wherein the protein is a protein that can treat, prevent or improve the physiological function of an organism, and includes antigens, antibodies, and proteins having biological functions known in the field. Alternatively, they can be used to upregulate endogenous protein expression by delivering a miRNA inhibitor targeting a specific miRNA, or a set of miRNAs that modulate one or more target mRNAs. Alternatively, they can be used to downregulate (e.g., silencing) the protein and / or mRNA levels of a target gene. Alternatively, they can be used to deliver mRNA and plasmids to express transgenes. Alternatively, they can be used to induce pharmacological effects resulting from protein expression, such as delivering appropriate erythropoietin mRNA to increase red blood cell production, or delivering mRNA encoding a desired antigen or antibody to defend against infection.

[0144] In preferred embodiments, the lipid nanoparticles of the present invention comprise a therapeutic agent or activator, preferably the therapeutic agent or activator being a nucleic acid therapeutic agent or activator. More preferably, the nucleic acid therapeutic agent or activator is selected from messenger RNA (mRNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), self-replicating RNA (saRNA), small guide RNA (sgRNA), ribozymes, and aptamers.

[0145] The lipid nanoparticles of the present invention can be prepared using conventional methods in the art. For example, compound I is mixed with helper lipid molecules, cholesterol, and polymer-bound lipid molecules in a specific molar ratio and dissolved in ethanol to obtain an ethanol-lipid solution. mRNA is dissolved in citrate buffer to obtain an aqueous mRNA solution. The ethanol-lipid solution and the aqueous mRNA solution are mixed in a constant volume ratio using a microfluidic device. After replacing the liquid by ultrafiltration, the ethanol is removed and the solution is diluted to a fixed volume with Dulbecco's phosphoric acid-saturated saline (DPBS). Finally, the lipid nanoparticles are filtered through a 0.2 μm sterile filter to obtain an LNP formulation using ionizable lipids.

[0146] IV. Composition

[0147] The present invention also provides compositions containing a compound represented by formula (I) of the present invention. In some embodiments, the composition is a pharmaceutical composition containing a compound represented by formula (I) of the present invention, a therapeutic agent or an activator, and one or more helper lipid molecules, one or more cholesterol or cholesterol derivatives and / or one or more polymer-bound lipid molecules.

[0148] Preferably, the helper lipid molecule is a neutral lipid molecule, preferably selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE, and SM. In a preferred embodiment, the lipid nanoparticles contain DOPE or DSPC.

[0149] Preferably, the cholesterol derivative is cholesterol.

[0150] Preferably, in the polymer-bound lipid molecule, the polymer is polyethyleneglycinate. This is a call. In preferred embodiments, the polymer-bound lipid molecule is selected from PEG-DMG, PEG-DAG, PEG-PE, PEG-S-DAG, PEG-DSPE, PEG-cer, and PEG-dialkoxypropyl carbamate. Preferably, the lipid nanoparticles contain PEG2000-DMG.

[0151] Preferably, the therapeutic agent or activator is a nucleic acid therapeutic agent or activator. More preferably, the nucleic acid therapeutic agent or activator is selected from messenger RNA (mRNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), self-replicating RNA (saRNA), small guide RNA (sgRNA), ribozyme, and aptamer.

[0152] Preferably, the pharmaceutical composition contains a therapeutic or preventive amount of lipid nanoparticles according to any embodiment of the present invention and a pharmaceutically acceptable carrier or excipient. In particular, the compound of formula (I) of the present invention is present in the composition in a therapeutic or preventive amount of the therapeutic or activating agent to effectively form lipid nanoparticles and deliver an effective amount for the treatment of a specific target disease or condition. Appropriate concentrations and doses can be easily determined by those skilled in the art.

[0153] The pharmaceutical compositions of the present invention can be formulated in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, intraperitoneal, sublingual, oral cavity, rectal, vaginal, and nasal cavity. As used herein, the term "intraperitoneal" includes subcutaneous, intravenous, intramuscular, intradermal, intrasternal, or infusion techniques.

[0154] Depending on the specific dosage form and route of administration, appropriate pharmaceutically acceptable carriers and excipients can be selected. For example, as a solid composition for oral administration, the pharmaceutical composition can be formulated in the form of powders, granules, compressed tablets, pills, capsules, chewing gum, flakes, etc. Such solid compositions typically contain one or more inert diluents or edible carriers. Furthermore, binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginic acid, sodium alginate, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotex; flow enhancers such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavorings such as peppermint, methyl salicylate, or orange flavor; and one or more colorants may be present.

[0155] If the pharmaceutical composition is in the form of a capsule, for example a gelatin capsule, in addition to the above-mentioned types of materials, it may also contain a liquid carrier such as polyethylene glycol or oil.

[0156] The pharmaceutical compositions of the present invention can be prepared by methods well known in the pharmaceutical field. For example, a pharmaceutical composition intended for injection can be prepared by mixing the lipid nanoparticles of the present invention with sterile distilled water or other carriers to form a solution.

[0157] The pharmaceutical composition of the present invention is administered in a therapeutically effective dose, the dose of which varies depending on several factors, including the activity of the particular therapeutic agent used, the metabolic stability and duration of action of the therapeutic agent, the patient's age, weight, overall health status, sex and diet, route and timing of administration, excretion rate, drug combination, severity of a particular disorder or condition, and the target population.

[0158] V. Treatment methods and use

[0159] The lipid nanoparticles and pharmaceutical compositions of the present invention may be used to treat or prevent a target disease or disorder by delivering therapeutic agents or activators, such as nucleic acids, in vivo and in vitro.

[0160] Accordingly, the present invention provides the use of a compound of formula (I) described in any embodiment of the present invention in the production of lipid nanoparticles or pharmaceutical compositions for treating or preventing a target disease or disorder, the use of lipid nanoparticles described in any embodiment of the present invention in the production of a drug for treating or preventing a target disease or disorder, and a compound of formula (I), lipid nanoparticles or pharmaceutical compositions described in any embodiment of the present invention for treating or preventing a target disease or disorder.

[0161] The present invention also provides a method for treating or preventing a target disease or disorder, the method comprising administering a therapeutically effective or preventively effective amount of a therapeutic agent or activator, such as a nucleic acid, to a subject in need, wherein the therapeutic agent or activator is encapsulated within lipid nanoparticles containing a compound of formula (I) as described in any of the embodiments herein. Alternatively, the method comprises administering a therapeutically effective or preventively effective amount of a pharmaceutical composition as described in any of the embodiments herein to a subject in need.

[0162] The diseases and disorders described herein may be any of the various diseases and disorders known in the art that are suitable for treatment and prevention with the therapeutic agents or activators (e.g., nucleic acids) described herein and depend on the specific biological function of the therapeutic agents or activators (e.g., nucleic acids) delivered by lipid nanoparticles. In some embodiments, the pharmaceutical composition is a vaccine, and the method comprises immunizing an individual to make the individual immunized to the corresponding disease or disorder. In some embodiments, the disease or disorder includes, but is not limited to, infections such as infections caused by viruses and / or bacteria. Exemplary diseases or disorders include influenza, hepatitis B, hepatitis C, and infections caused by COVID-19. In some embodiments, the disease or disorder also includes tumors, including solid tumors and hematological malignancies, as well as various inflammations.

[0163] In this specification, suitable routes and methods of administration are well known in the art and include, but are not limited to, oral, topical, transdermal, inhalation, intraperitoneal, sublingual, oral cavity, rectal, vaginal, and nasal cavity, as described above. In some embodiments, the intraperitoneal route of administration includes subcutaneous injection, intravenous, intramuscular, intradermal, intrasternal injection, or infusion techniques.

[0164] The present invention also includes the use of the compound of formula (I) in delivering therapeutic agents or activators, such as nucleic acids, or in the manufacture of reagents for delivering therapeutic agents or activators, such as nucleic acids. The present invention further provides a method for delivering therapeutic agents or activators, such as nucleic acids, in vivo or in vitro, the method comprising encapsulating the therapeutic agent or activator in lipid nanoparticles prepared using the compound of formula (I), and delivering the therapeutic agent or activator via the lipid nanoparticles or a composition comprising the lipid nanoparticles. The nucleic acid may be as described in any of the embodiments herein. In some embodiments, the therapeutic agent or activator (e.g., nucleic acid) is delivered to a target site (e.g., a cell, a tissue (e.g., a diseased tissue such as tumor tissue), or an organ) via the lipid nanoparticles or a composition comprising the lipid nanoparticles. In some embodiments, the cell is an immune cell and includes, but is not limited to, T cells, dendritic cells (DC cells), or tumor-infiltrating lymphocytes (TILs).

[0165] VI. Method for preparing the compound of formula (I)

[0166] The compound of formula (I) of the present invention can be prepared using the following conventional synthesis scheme 1 or 2.

[0167] Scheme 1: [ka]

[0168] Scheme 2: [ka]

[0169] Herein, R1, R2, R3, R4, L1, L2, L3, L4, M1, M2, M3, and m are as defined in any of the embodiments herein. X may be a halogen, such as Br or Cl. First, compound 1 and compound 2 are reacted to produce compound 3a, which may be carried out under conditions suitable for condensation. Conditions suitable for condensation are, for example, one selected from the following: (1) H2SO4; (2) EDC·HCl and DMAP; (3) Oxalyl chloride. 3b and 3c can be synthesized in the same manner as 3a. Then, 3a, 3b, 3c, and 4 are reacted under conditions suitable for nucleophilic substitution (e.g., alkaline) to produce the compound of formula (I). Alternatively, 3a, 3b, 3c, and 5 are reacted under conditions suitable for a nucleophilic substitution reaction (e.g., alkaline conditions) to produce compound 6, and then compound 6 and compound 7 are reacted under conditions suitable for a nucleophilic substitution reaction (e.g., alkaline conditions) to produce compound (I).

[0170] The present invention will be further described below based on specific examples. It should be understood that these examples are merely illustrative and do not limit the scope of the present invention. Unless otherwise specified, the methods and reagents used in the examples are conventional methods and reagents in the art.

[0171] Examples

[0172] First example: Synthesis of ionizable lipid molecules

[0173] Example 1

[0174] Diundecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(undecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0175] Step 1: Synthesis of undecyl 8-bromooctanoate [ka]

[0176] Undecanol (1.0 g, 5.8 mmol) and 8-bromooctanoic acid (1.6 g, 7.5 mmol) were mixed, the mixture was heated to 60°C, concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 3 hours. After confirming that the starting materials had been completely consumed by thin-layer chromatography (TLC), the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 1.8 g of a colorless oily product (yield: 82.2%).

[0177] 1 H-NMR (400 MHz, CDCl3)δ 4.06 (t, J = 6.7 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.90 - 1.80 (m, 2H), 1.67 - 1.58 (m, 4H), 1.48 - 1.39 (m, 2H), 1.37 - 1.31 (m, 7H), 1.30 - 1.27 (m, 4H), 1.26 (s, 9H), 0.88 (t, J = 6.7 Hz, 3H).

[0178] Step 2: Synthesis of diundecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(undecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0179] 2-((3-aminopropyl)amino)ethane-1-ol (135 mg, 1.1 mmol) was dissolved in acetonitrile (16 mL), and undecyl 8-bromooctanoate (1.4 g, 3.8 mmol), K2CO3 (0.7 g, 5.1 mmol), and KI (13 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (50 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 50:1 to obtain 0.5 g of a colorless oily product (yield: 43.5%).

[0180] ESI-MS m / z:cald for C 62 H 123 N2O7[M+H] + : 1007.9, found 1007.9.

[0181] 1 H-NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.7 Hz, 6H), 3.57 - 3.50 (m, 2H), 2.58 - 2.42 (m, 5H), 2.42 - 2.35 (m, 6H), 2.28 (t, J = 7.5 Hz, 6H), 1.65 - 1.52 (m, 13H), 1.49 - 1.41 (m, 5H), 1.40 - 1.33 (m, 5H), 1.33 - 1.23 (m, 64H), 0.88 (t, J = 6.8 Hz, 9H).

[0182] Example 2

[0183] Di(heptadecan-9-yl)8,8'-((3-((8-(heptadecan-9-oxy)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0184] Step 1: Synthesis of heptadecane-9-yl-8-bromooctanoate [ka]

[0185] Heptadecane-9-ol (9.0 g, 35.1 mmol) and 8-bromooctanoic acid (8.6 g, 38.6 mmol) were dissolved in dichloromethane (DCM) (100 mL). EDC·HCl (13.5 g, 70.2 mmol), DMAP (8.6 g, 70.2 mmol), and triethylamine (14.2 g, 140.4 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, an appropriate amount of water was added, followed by extraction with DCM (100 mL x 3). The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography at PE:EA = 20:1 to obtain 5.6 g of a pale yellow oily product (yield: 34.3%).

[0186] 1 H-NMR (400 MHz, CDCl3)δ 4.92 - 4.80 (m, 1H), 3.40 (t, J = 6.8 Hz, 2H), 2.28 (t, J = 7.4 Hz, 2H), 1.91 - 1.72 (m, 2H), 1.68 - 1.59 (m, 2H), 1.54 - 1.47 (m, 4H), 1.46 - 1.42 (m, 1H), 1.42 - 1.27 (m, 12H), 1.26 (s, 17H), 0.88 (t, J = 6.7 Hz, 6H).

[0187] Step 2: Di(heptadecan-9-yl)8,8'-((3-((8-(heptadecan-9-oxy)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0188] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (6 mL), and heptadecan-9-yl 8-bromooctanoate (1.4 g, 3.0 mmol), K2CO3 (0.4 g, 3.0 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (50 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography at DCM:MeOH = 40:1 to obtain 73 mg of a colorless oily product (yield: 11.6%).

[0189] ESI-MS m / z:cald for C 80 H 159 N2O7[M+H] + : 1260.1, found 1260.1.

[0190] 1 H-NMR (400 MHz, CDCl3)δ 4.91 - 4.80 (m , 3H), 3.54 (t, J = 5.2 Hz, 2H), 2.57 - 2.35 (m, 14H), 2.27 (t, J = 7.5 Hz, 8H), 1.67 - 1.55 (m, 10H), 1.50 (d, J = 6.1 Hz, 14H), 1.45 - 1.36 (m, 11H), 1.31 - 1.25 (m, 78H), 0.87 (t, J = 6.7 Hz, 18H).

[0191] Example 3

[0192] Di((E)-3,7-dimethylocta-2,6-dien-1-yl)8,8'-((3-((8-(((E)-3,7-dimethyloctan-2,6-dien-1-yl)oxo)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanejyl)dioctanoate [ka]

[0193] Step 1: Synthesis of (E)-3,7-dimethyloctane-2,6-dien-1-yl-8-bromooctanoate [ka]

[0194] Under nitrogen protection, 8-bromooctanoic acid (5 g, 22.41 mmol) was dissolved in 100 mL of anhydrous DCM, and oxalyl chloride (3.41 g, 28.89 mmol, 1.2 eq) was added to the solution under an ice bath. Subsequently, the mixture was reacted at 40°C for 1 hour, and then concentrated under reduced pressure. It was redissolved in 100 mL of anhydrous DCM. (E)-3,7-dimethyloctan-2,6-dien-1-ol (2.77 g, 7.93 mmol, 0.8 eq) was dissolved in 20 mL of Et3N, and this mixture was added dropwise to the reaction solution and stirred at room temperature for 1 hour. After the reaction was complete, the solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.3 g of the target product (yield 28.6%).

[0195] Step 2: Synthesis of di((E)-3,7-dimethyloctane-2,6-dien-1-yl)8,8'-((3-((8-(((E)-3,7-dimethyloctane-2,6-dien-1-yl)oxo)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanejyl)dioctanoate [ka]

[0196] Dissolve 2-((3-aminopropyl)amino)ethane-1-ol (0.1g, 0.846 mmol) in 20 mL of anhydrous acetonitrile to make (E)-3,7-dimethyloctan-2,6-dien-1-yl 8-bromooctanoate (1.06g, 2.96 mmol). Add K2CO3 (0.584g, 4.23 mmol, 5 eq) and KI (14mg, 0.084 mmol, 0.1 eq), heat to 85°C, and leave overnight. After the reaction is complete, DCM 20 mL was added and filtered to remove insoluble matter. The solution was washed with 20 mL of saturated saline solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Finally, 0.54 g of the target product (67% yield) was obtained.

[0197] ESI-MS m / z:cald for C 59 H 105 N2O7[M+H] + :953.8, found 953.8.

[0198] 1 H NMR (400 MHz, CDCl3)δ 5.40 - 5.32 (m, 3H), 5.15 - 5.07 (m, 3H), 4.61 (d, J = 7.1 Hz, 6H), 3.77 - 3.64 (m, 4H), 2.91 - 2.87 (m, 1H), 2.83 - 2.75 (m, 4H), 2.73 - 2.64 (m, 4H), 2.59 - 2.53 (m, 2H), 2.37 - 2.28 (m, 7H), 2.17 - 2.03 (m, 12H), 1.92 - 1.85 (m, 2H), 1.72 (d, J = 8.0 Hz, 17H), 1.68 - 1.61 (m, 17H), 1.51 (d, J = 8.5 Hz, 2H), 1.35 (d, J = 8.5 Hz, 16H), 1.31 - 1.24 (m, 4H).

[0199] Example 4

[0200] Diheptyl 8,8'-((3-((8-(heptyloxy)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegyl)dioctanoate [ka]

[0201] Step 1: Synthesis of heptyl 8-bromooctanoate [ka]

[0202] Under nitrogen protection, 8-bromooctanoic acid (5 g, 22.41 mmol) was dissolved in anhydrous DCM (100 mL), and oxalyl chloride (3.41 g, 28.89 mmol, 1.2 eq) was added to the solution under an ice bath. Subsequently, the reaction was carried out at 40°C for 1 hour, and then concentrated under reduced pressure. The solution was redissolved in 100 mL of anhydrous DCM. n-heptanol (2.08 g, 17.93 mmol, 0.8 eq) was dissolved in 20 mL of Et3N and added dropwise to the reaction mixture, and stirred at room temperature for 1 hour. After the reaction was complete, the solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. 1.39 g of the target product (yield 19.3%) was obtained.

[0203] Step 2: Synthesis of diheptyl 8,8'-((3-((8-(heptyloxy)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegyl)dioctanoate: [ka]

[0204] 2-((3-aminopropyl)amino)ethane-1-ol (0.1 g, 0.846 mmol) was dissolved in 20 mL of anhydrous acetonitrile. Heptyl 8-bromooctanoate (0.95 g, 2.96 mmol, 3.5 eq), K2CO3 (0.584 g, 4.23 mmol, 5 eq), and KI (14 mg, 0.084 mmol, 0.1 eq) were added, and the mixture was heated to 85°C and left overnight. After the reaction was complete, 20 mL of DCM was added and the mixture was filtered to remove insoluble matter. The solution was washed with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Finally, 0.21 g of the target product (yield 29.6%) was obtained.

[0205] ESI-MS m / z:cald for C 50 H 99 N2O7[M+H] + :839.7, found 839.7.

[0206] 1 H NMR (400 MHz, CDCl3)δ 4.08 (t, J = 6.8 Hz, 6H), 3.80 - 3.69 (m, 4H), 2.93 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 8.2 Hz, 4H), 2.75 - 2.65 (m, 4H), 2.61 - 2.53 (m, 2H), 2.37 - 2.30 (m, 5H), 1.64 (t, J = 6.9 Hz, 16H), 1.40 - 1.25 (m, 42H), 0.95 - 0.87 (m, 9H).

[0207] Example 5

[0208] Dipentyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(pentyloxy)octyl)amino)propyl)azanejyl)dioctanoate [ka]

[0209] Step 1: Synthesis of pentyl 8-bromooctanoate [ka]

[0210] Under nitrogen protection, bromooctanoic acid (5 g, 22.41 mmol) was dissolved in 100 mL of anhydrous DCM, and oxalyl chloride (3.41 g, 28.89 mmol, 1.2 eq) was added to the solution under an ice bath. Subsequently, the mixture was reacted at 40°C for 1 hour, and then concentrated under reduced pressure. Anhydrous DCM The solution was redissolved in 100 mL. Amyl alcohol (1.58 g, 17.93 mmol, 0.8 eq) was dissolved in 20 mL of Et3N and added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. 1.39 g of the target product (yield 19.3%) was obtained.

[0211] Step 2: Synthesis of dipentyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(pentyloxy)octyl)amino)propyl)azanejyl)dioctanoate: [ka]

[0212] 2-((3-aminopropyl)amino)ethane-1-ol (0.1 g, 0.846 mmol) was dissolved in 20 mL of anhydrous acetonitrile. Pentyl 8-bromooctanoate (0.95 g, 2.96 mmol, 3.5 eq), K2CO3 (0.584 g, 4.23 mmol, 5 eq), and KI (14 mg, 0.084 mmol, 0.1 eq) were added, and the mixture was heated to 85°C and left overnight. After the reaction was complete, 20 mL of DCM was added and the mixture was filtered to remove insoluble matter. The solution was washed with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Finally, 0.21 g of the target product (yield 29.6%) was obtained.

[0213] ESI-MS m / z:cald for C 44 H 87 N2O7[M+H] + :755.6, found 755.6.

[0214] 1 H NMR (400 MHz, CDCl3)δ 4.12 - 4.02 (m, 6H), 3.64 - 3.57 (m, 2H), 2.70 (s, 1H), 2.66 - 2.52 (m, 8H), 2.52 - 2.45 (m, 2H), 2.33 - 2.25 (m, 6H), 1.82 - 1.72 (m, 2H), 1.67 - 1.50 (m, 16H), 1.50 - 1.40 (m, 2H), 1.39 - 1.30 (m, 27H), 1.30 - 1.22 (m, 4H), 0.96 - 0.87 (m, 9H).

[0215] Example 6

[0216] Di((Z)-non-2-en-1-yl)8,8'-((3-((2-hydroxyethyl)(8-(((Z)-non-2-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanediyl)dioctanoate [ka]

[0217] Step 1: Synthesis of (Z)-non-2-en-1-yl-8-bromooctanoate [ka]

[0218] 1.0 g, 7.0 mmol of cis-2-nonen-1-ol and 1.9 g, 8.4 mmol of 8-bromooctanoic acid were mixed. The mixture was heated to 60°C, then concentrated sulfuric acid (0.1 mL) was added. The mixture was stirred at this temperature for 5 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 50:1 to obtain 2.2 g of a colorless oily product (yield: 91.7%).

[0219] 1H-NMR (400 MHz, CDCl3)δ 5.70 - 5.59 (m, 1H), 5.58 - 5.46 (m, 1H), 3.43 - 3.36 (m, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 2.15 - 2.05 (m, 2H), 1.90 - 1.80 (m, 2H), 1.68 - 1.59 (m, 2H), 1.47 - 1.39 (m, 2H), 1.38 - 1.25 (m, 12H), 0.92 - 0.84 (m, 3H).

[0220] Step 2: Synthesis of di((Z)-non-2-en-1-yl)8,8'-((3-((2-hydroxyethyl)(8-(((Z)-non-2-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0221] N-(2-hydroxyethyl)-1,3-propylenediamine (60 mg, 0.5 mmol) was dissolved in acetonitrile (6 mL), and (Z)-non-2-en-1-yl 8-bromooctanoate (0.6 g, 1.7 mmol), K2CO3 (0.3 g, 2.3 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (50 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography at DCM:MeOH = 40:1 to obtain 180 mg of a colorless oily product (yield: 38.5%).

[0222] ESI-MS m / z:cald for C 56 H 105 N2O7[M+H] + : 917.5, found 917.5.

[0223] 1H-NMR (400 MHz, CDCl3)δ 5.68 - 5.58 (m, 3H), 5.56 - 5.46 (m, 3H), 4.61 (d, J = 6.8 Hz, 6H), 3.53 (t, J = 5.2 Hz, 2H), 2.57 - 2.36 (m, 10H), 2.35 (d, J = 5.1 Hz, 2H), 2.29 (t, J = 7.5 Hz, 6H), 2.14 - 2.04 (m, 6H), 1.66 - 1.50 (m, 8H), 1.44 - 1.24 (m, 48H), 0.91 - 0.83 (m, 9H).

[0224] Example 7

[0225] Di((4Z,7Z)-deca-4,7-dien-1-yl)8,8'-((3-((8-(((4Z,7Z)-deca-4,7-dien-1-yl)oxo)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanediyl)dioctanoate [ka]

[0226] Step 1: Synthesis of (4Z,7Z)-deca-4,7-diene-1-yl-8-bromooctanoate [ka]

[0227] (4Z,7Z)-decadienol (0.9 g, 5.8 mmol) and 8-bromooctanoic acid (1.6 g, 7.0 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 4 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 30:1 to obtain 1.3 g of a colorless oily product (yield: 61.9%).

[0228] 1H-NMR (400 MHz, CDCl3)δ 5.47 - 5.23 (m, 4H), 4.07 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.6 Hz, 2H), 2.30 (t, J = 7.5 Hz, 2H), 2.19 - 2.01 (m, 4H), 1.90 - 1.80 (m, 2H), 1.74 - 1.58 (m, 4H), 1.48 - 1.39 (m, 2H), 1.39 - 1.23 (m, 4H), 0.97 (t, J = 7.5 Hz, 3H).

[0229] Step 2: Synthesis of di((4Z,7Z)-deca-4,7-dien-1-yl)8,8'-((3-((8-(((4Z,7Z)-deca-4,7-dien-1-yl)oxo)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0230] N-(2-hydroxyethyl)-1,3-propylenediamine (120 mg, 1.0 mg) (mol) was dissolved in acetonitrile (8 mL), and (4Z,7Z)-deca-4,7-dien-1-yl 8-bromooctanoate (1.3 g, 3.6 mmol), K2CO3 (0.6 g, 4.6 mmol), and KI (10 mg) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (50 mL x 3) was added for extraction. After drying the combined organic phase, it was concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 340 mg of a colorless oily product (yield: 35.0%).

[0231] ESI-MS m / z:cald for C59H105N2O7 [M+H] + : 953.5, found 953.5.

[0232] 1 H-NMR (400 MHz, CDCl3)δ 5.48 - 5.18 (m, 12H), 4.07 (t, J = 6.6 Hz, 6H), 3.57 - 3.50 (m, 2H), 2.77 (t, J = 6.6 Hz, 6H), 2.57 - 2.25 (m, 19H), 2.17 - 1.97 (m, 13H), 1.73 - 1.65 (m, 7H), 1.63 - 1.53 (m, 4H), 1.41 (s, 5H), 1.35 - 1.23 (m, 21H), 0.97 (t, J = 7.5 Hz, 9H).

[0233] Example 8

[0234] Di((Z)-non-6-en-1-yl)8,8'-((3-((2-hydroxyethyl)(8-(((Z)-non-6-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanediyl)dioctanoate [ka]

[0235] Step 1: Synthesis of (Z)-non-6-en-1-yl-8-bromooctanoate [ka]

[0236] Under nitrogen protection, bromooctanoic acid (5 g, 22.41 mmol) was dissolved in 100 mL of anhydrous DCM, and oxalyl chloride (3.41 g, 28.89 mmol, 1.2 eq) was added to the solution under an ice bath. Subsequently, the mixture was reacted at 40°C for 1 hour, then concentrated under reduced pressure and purified by column chromatography. The solution was redissolved in 100 mL of anhydrous DCM. (Z)-non-6-en-1-ol(2 Dissolve 0.55g (17.93 mmol, 0.8 eq) in 20 mL of Et3N and proceed as described above. The solution was added dropwise and stirred at room temperature for 1 hour. After the reaction was complete, the liquid-liquid was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.78 g of the target product (yield 35.7%).

[0237] Step 2: Synthesis of di((Z)-non-6-en-1-yl)8,8'-((3-((2-hydroxyethyl)(8-(((Z)-non-6-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanegiyl)dioctanoate: [ka]

[0238] 2-((3-aminopropyl)amino)ethane-1-ol (0.15 g, 1.27 mmol) was dissolved in 20 mL of anhydrous acetonitrile. (Z)-non-6-en-1-yl 8-bromooctanoate (1.54 g, 4.44 mmol, 3.5 eq), K2CO3 (0.877 g, 6.35 mmol, 5 eq), and KI (0.21 g, 0.127 mmol, 0.1 eq) were added, and the mixture was heated to 85°C and left overnight. After the reaction was complete, 20 mL of DCM was added and the mixture was filtered to remove insoluble matter. The solution was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Finally, 0.32 g of the target product (yield 27.6%) was obtained.

[0239] ESI-MS m / z:cald for C 56 H 105 N2O7[M+H] + :917.8, founded 917.8.

[0240] 1H NMR (400 MHz, CDCl3)δ 5.46 - 5.29 (m, 6H), 4.09 (t, J = 6.7 Hz, 6H), 3.81 - 3.71 (m, 1H), 3.59 (t, J = 5.2 Hz, 2H), 2.64 - 2.54 (m, 4H), 2.54 - 2.43 (m, 8H), 2.32 (t, J = 7.5 Hz, 6H), 2.13 - 1.99 (m, 13H), 1.69 - 1.59 (m, 13H), 1.50 - 1.47 (m, 3H), 1.45 - 1.38 (m, 12H), 1.36 - 1.25 (m, 21H), 0.99 (t, J = 7.5 Hz, 9H).

[0241] Example 9

[0242] Dinonyl 8,8'-((3-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)aminopropyl)azanegyl)dioctanoate [ka]

[0243] Step 1: Synthesis of nonyl-8-bromooctanoate [ka]

[0244] 8-bromooctanoic acid (7.23 g, 32.4 mmol) was dissolved in 100 mL of DCM, and oxalyl chloride (4.94 g, 38.89 mmol) was slowly added. The resulting mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain 8 g of crude product. Half of this was taken and dissolved in DCM (150 mL) and TEA (3.28 g, 32.4 mmol). Then 1-nonyl alcohol (2.34 g, 16.2 mmol) was added, and the mixture was stirred at 40°C for 4 hours. Once it was confirmed that the starting materials had been completely consumed by TLC, the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 4.5 g of a colorless oily product (yield: 79.5%).

[0245] Step 2: Synthesis of dinonyl 8,8'-((3-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)propyl)azanejyl)dioctanoate [ka]

[0246] 2-((3-aminopropyl)amino)ethane-1-ol (59.1 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (DMF) (5 mL), and nonyl 8-bromooctanoate (611.36 mg, 1.75 mmol), K2CO3 (345.53 mg, 2.5 mmol), and KI (13 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (50 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.3 g of a colorless oily product (yield: 65%).

[0247] ESI-MS m / z:cald for C 56 H 111 N2O7[M+H] + :923.7, found 923.7.

[0248] 1H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6 .8 Hz, 6H), 3.67 (t, J = 5.1 Hz, 2H), 3.00-2.84 (m, 3H), 2.84-2.74 (m, 4H), 2.73-2.63 (m, 4H), 2.56 (t, J = 7.8 Hz, 2H), 2.29 (t, J = 7.5 Hz, 6H), 2.02-1.88 (m, 2H), 1.71-1.56 (m, 16H), 1.54-1.45 (m, 2H), 1.42 - 1.13 (m, 54H), 0.88 (t, J = 6.7 Hz, 9H).

[0249] Example 10

[0250] Di((Z)-pento-2-en-1-yl)8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(((Z)-pento-2-en-1-yl)oxo)octyl)amino)propyl)azanejyl)dioctanoate [ka]

[0251] Step 1: Synthesis of (Z)-pento-2-en-1-yl-8-bromooctanoate [ka]

[0252] 8-bromooctanoic acid (7.23 g, 32.4 mmol) was dissolved in 100 mL of DCM, and oxalyl chloride (4.94 g, 38.89 mmol) was slowly added. The resulting mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain 8 g of crude product. Half of this was taken and dissolved in DCM (150 mL) and TEA (3.28 g, 32.4 mmol). (Z)-pento-2-en-1-ol (1.395 g, 16.2 mmol) was added, and the mixture was stirred at 40°C for 4 hours. Once it was confirmed that the starting materials had been completely consumed by TLC, the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 4.0 g of a colorless oily product (yield: 84.78%).

[0253] Step 2: Synthesis of di((Z)-pento-2-en-1-yl)8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(((Z)-pento-2-en-1-yl)oxo)octyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0254] 2-((3-aminopropyl)amino)ethane-1-ol (59.1 mg, 0.5 mmol) was dissolved in DMF (5 mL), and (Z)pento-2-en-1-yl 8-bromooctanoate (509.65 mg, 1.75 mmol), K2CO3 (345.53 mg, 2.5 mmol), and KI (13 mg) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (50 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.1 g of a colorless oily product (yield: 26.7%).

[0255] ESI-MS m / z:cald for C 44 H 81 N2O7[M+H] + :949.4, founded 949.4.

[0256] 1 H NMR (400 MHz, CDCl3)δ 5.71 - 5.59 (m, 3H), 5.55 - 5.43 (m, 3H), 4.62 (dd, J = 6.9, 1.3 Hz, 6H), 3.67 (t, J = 5.0 Hz, 2H), 2.99-2.90 (m, 1H), 2.87-2.78 (m, 4H), 2.74 - 2.65 (m, 4H), 2.61 - 2.51 (m, 2H), 2.31 (t, J = 7.5 Hz, 6H), 2.17-2.07 (m, 6H), 2.02-1.88 (m, 2H), 1.70-1.56 (m, 10H), 1.54-1.44 (m, 2H), 1.39-1.24 (m, 20H), 1.00 (t, J = 7.5 Hz, 9H).

[0257] Example 11

[0258] Diundecyl 6,6'-((3-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0259] Step 1: Synthesis of undecyl 6-bromohexanoate [ka]

[0260] Undecanol (2.0 g, 11.6 mmol) and 6-bromohexanoic acid (2.7 g, 13.9 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 20:1 to obtain 3.5 g of a colorless oily product (yield: 86.4%).

[0261] 1H-NMR (400 MHz, CDCl3)δ 4.06 (t, J = 6.7 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.95 - 1.80 (m, 2H), 1.70 - 1.59 (m, 4H), 1.54 - 1.40 (m, 2H), 1.27 (d, J = 7.7 Hz, 16H), 0.88 (t, J = 6.7 Hz, 3H).

[0262] Step 2: Synthesis of Diundecyl 6,6'-((3-((2-Hydroxyethyl)(6-Oxo-6-(Undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0263] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (6 mL), and undecyl 6-bromohexanoate (0.6 g, 1.8 mmol), K2CO3 (0.3 g, 2.3 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 40:1 to obtain 160 mg of a colorless oily product (yield: 34.0%).

[0264] ESI-MS m / z:cald for C56 H 111 N2O7[M+H] + : 923.5, found 923.5.

[0265] 1H-NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.53 (t, J = 5.2 Hz, 2H), 2.56 - 2.34 (m, 12H), 2.29 (t, J = 7.5 Hz, 6H), 1.68 - 1.57 (m, 12H), 1.49 - 1.39 (m, 6H), 1.28 (d, J = 17.3 Hz, 57H), 0.88 (t, J = 6.8 Hz, 9H).

[0266] Example 12

[0267] Diundecyl 4,4'-((3-((2-hydroxyethyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0268] Step 1: Synthesis of undecyl 4-bromobutanoate [ka]

[0269] 1-Undecanol (2.0 g, 11.6 mmol) and 4-bromo-n-butyric acid (2.3 g, 13.9 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 20:1 to obtain 3.3 g of a colorless oily product (yield: 88.5%).

[0270] 1H-NMR (400 MHz, CDCl3)δ 4.07 (t, J = 6.7 Hz, 2H), 3.46 (t, J = 6.4 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.22 - 2.11 (m, 2H), 1.66 - 1.60 (m, 2H), 1.35 - 1.23 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H).

[0271] Step 2: Synthesis of diundecyl 4,4'-((3-((2-hydroxyethyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0272] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (8 mL), and undecyl 4-bromobutanoate (0.6 g, 1.8 mmol), K2CO3 (0.3 g, 2.3 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 180 mg of a colorless oily product (yield: 42.0%).

[0273] ESI-MS m / z:cald for C 50 H 99 N2O7[M+H] + : 839.3, found 839.3.

[0274] 1H-NMR (400 MHz, CDCl3)δ 4.09 - 4.01 (m, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.57 (t, J = 5.2 Hz, 2H), 2.48 (t, J = 7.2 Hz, 4H), 2.41 (t, J = 7.2 Hz, 6H), 2.35 - 2.26 (m, 6H), 2.02 (s, 1H), 1.82 - 1.68 (m, 6H), 1.66 - 1.49 (m, 8H), 1.27 (d, J = 8.8 Hz, 48H), 0.88 (t, J = 6.7 Hz, 9H).

[0275] Example 13

[0276] Ditridecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(tridecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0277] Step 1: Synthesis of tridecyl 8-bromooctanoate [ka]

[0278] Under nitrogen protection, bromooctanoic acid (5 g, 22.41 mmol) was dissolved in 100 mL of anhydrous DCM, and oxalyl chloride (3.41 g, 28.89 mmol, 1.2 eq) was added to the solution under an ice bath. Subsequently, the mixture was reacted at 40°C for 1 hour, and then concentrated under reduced pressure. Anhydrous DCM The solution was redissolved in 100 mL. Tridecanol (2.55 g, 17.93 mmol, 0.8 eq) was dissolved in 20 mL of Et3N and added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. 2.44 g of the target product (yield 26.8%) was obtained.

[0279] Step 2: Synthesis of ditridecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(tridecyloxy)octyl)amino)propyl)azanegyl)dioctanoate: [ka]

[0280] 2-((3-aminopropyl)amino)ethane-1-ol (0.1 g, 0.846 mmol) was dissolved in 20 mL of anhydrous acetonitrile. Tridecyl 8-bromooctanoate (1.2 g, 2.96 mmol, 3.5 eq), K2CO3 (0.584 g, 6.35 mmol, 5 eq), and KI (0.21 g, 0.127 mmol, 0.1 eq) were added, and the mixture was heated to 85°C and left overnight. After the reaction was complete, 20 mL of DCM was added and the mixture was filtered to remove insoluble matter. The solution was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Finally, 0.34 g of the target product (yield 36.8%) was obtained.

[0281] ESI-MS m / z:cald for C 68 H 135 N2O7[M+H] + : 1092.0, found 1092.0.

[0282] 1 H NMR (400 MHz, CDCl3)δ 4.09 (t, J = 6.8 Hz, 6H), 3.79 - 3.72 (m, 1H), 2.76 - 2.57 (m, 8H), 2.52 (t, J = 7.6 Hz, 2H), 2.32 (t, J = 7.5 Hz, 6H), 1.71 - 1.55 (m, 16H), 1.45 - 1.20 (m, 85H), 0.92 (t, J (= 6.8 Hz, 9H).

[0283] Example 14

[0284] Diundecyl 10,10'-((3-((2-hydroxyethyl)(10-oxo-10-(undecyloxy)decyl)amino)propyl)azanegyl)dicapate [ka]

[0285] Step 1: Synthesis of Undecyl 10-Bromoca Plate [ka]

[0286] Under nitrogen protection, bromodecanoic acid (5 g, 19.9 mmol) was dissolved in 100 mL of anhydrous DCM, and oxalyl chloride (3.03 g, 23.89 mmol, 1.2 eq) was added to the solution under an ice bath. Subsequently, the reaction was carried out at 40°C for 1 hour, and then concentrated under reduced pressure. The solution was redissolved in 100 mL of anhydrous DCM. 1-Undecanol (2.74 g, 15.93 mmol, 0.8 eq) was dissolved in 20 mL of Et3N and added dropwise to the reaction mixture, and stirred at room temperature for 1 hour. After the reaction was complete, the solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. 1.96 g of the target product (yield 24.3%) was obtained.

[0287] Step 2: Synthesis of Diundecyl 10,10'-((3-((2-hydroxyethyl)(10-oxo-10-(undecyloxy)decyl)amino)propyl)azanegyl) dika plate: [ka]

[0288] 2-((3-aminopropyl)amino)ethane-1-ol (0.1 g, 0.846 mmol) was dissolved in 20 mL of anhydrous acetonitrile. Undecyl 10-bromoca plate (1.2 g, 2.96 mmol, 3.5 eq), K2CO3 (0.584 g, 6.35 mmol, 5 eq), and KI (0.21 g, 0.127 mmol, 0.1 eq) were added, and the mixture was heated to 85°C and left overnight. After the reaction was complete, 20 mL of DCM was added and the mixture was filtered to remove insoluble matter. The solution was washed with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Finally, 0.34 g of the target product (yield 36.8%) was obtained.

[0289] ESI-MS m / z:cald for C 68 H 135 N2O7[M+H] + :1092.0, found 1092.0.

[0290] 1 H NMR (400 MHz, CDCl3)δ 4.09 (t, J = 6.8 Hz, 6H), 3.83 - 3.76 (m, 1H), 3.24 - 3.17 (m, 1H), 3.09 (t, J = 8.5 Hz, 3H), 2.88 - 2.77 (m, 2H), 2.65 (d, J = 9.1 Hz, 1H), 2.33 (t, J = 7.5 Hz, 7H), 2.12 - 1.98 (m, 2H), 1.80 - 1.54 (m, 16H), 1.46 - 1.16 (m, 85H), 1.01 - 0.83 (m, 10H).

[0291] Example 15

[0292] Di((Z)-non-2-en-1-yl)10,10'-((3-((2-hydroxyethyl)(10-(((Z)-non-2-en-1-yl)oxo)-10-oxodecyl)amino)propyl)azanediyl)dicapate [ka]

[0293] Step 1: Synthesis of (Z)-non-2-en-1-yl10-bromoca plate [ka]

[0294] Under nitrogen protection, 10-bromodecanoic acid (5g, 19.9 mmol) was dissolved in anhydrous DCM 100. Dissolve in mL and add oxalyl chloride (3.03 g, 23.89 mmol, 1.2 eq) to the solution under an ice bath. Then, react at 40°C for 1 hour, followed by concentration under reduced pressure. Anhydrous DCM The solution was redissolved in 100 mL. (Z)-non-2-en-1-ol (2.74 g, 15.93 mmol, 0.8 eq) was dissolved in 20 mL of Et3N and added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. 3.93 g of the target product (yield 52.6%) was obtained.

[0295] Step 2: Synthesis of di((Z)-non-2-en-1-yl)10,10'-((3-((2-hydroxyethyl)(10-(((Z)-non-2-en-1-yl)oxo)-10-oxodecyl)amino)propyl)azanegyl) dicaplate: [ka]

[0296] 2-((3-aminopropyl)amino)ethane-1-ol (0.1 g, 0.846 mmol) was dissolved in 20 mL of anhydrous acetonitrile. (Z)-non-2-en-1-yl-10-bromocaprate (1.11 g, 2.96 mmol, 3.5 eq), K2CO3 (0.584 g, 4.23 mmol, 5 eq), and KI (0.014 g, 0.084 mmol, 0.1 eq) were added, and the mixture was heated to 85°C and left overnight. After the reaction was complete, 20 mL of DCM was added and the mixture was filtered to remove insoluble matter. The solution was washed with 20 mL of saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Finally, 0.319 g of the target product (yield 22.4%) was obtained.

[0297] ESI-MS m / z:cald for C 62 H 117 N2O7[M+H] + :1001.9, found 1001.9.

[0298] 1 H NMR (400 MHz, CDCl3)δ 5.73 - 5.62 (m, 2H), 5.61 - 5.50 (m, 2H), 4.73 - 4.62 (m, 6H), 4.21 - 4.12 (m, 1H), 3.69 - 3.61 (m, 1H), 2.83 - 2.63 (m, 6H), 2.53 - 2.48 (m, 2H), 2.34 (t, J = 7.6 Hz, 6H), 2.18 - 2.06 (m, 8H), 1.88 - 1.75 (m, 2H), 1.69 - 1.62 (m, 6H), 1.45 - 1.21 (m, 64H), 0.97 - 0.88 (m, 9H).

[0299] Example 16

[0300] Di((Z)-non-2-en-1-yl)4,4'-((3-((2-hydroxyethyl)(4-(((Z)-non-2-en-1-yl)oxo)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[0301] Step 1: Synthesis of (Z)-non-2-en-1-yl-4-bromobutanoate [ka]

[0302] (Z)-non-2-en-1-ol (1.0 g, 7.0 mmol) and 4-bromo-butyric acid (1.4 g, 8.4 mmol) were mixed, and the mixture was heated to 60°C. Then concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 20:1 to obtain 1.9 g of a colorless oily product (yield: 95.0%).

[0303] 1 H-NMR (400 MHz, CDCl3)δ 5.70 - 5.60 (m, 1H), 5.57 - 5.46 (m, 1H), 4.67 - 4.60 (m, 2H), 3.46 (t, J = 6.5 Hz, 2H), 2.51 (t, J = 7.2 Hz, 2H), 2.23 - 2.04 (m, 4H), 1.38 - 1.22 (m, 8H), 0.92 - 0.84 (m, 3H).

[0304] Step 2: Synthesis of di((Z)-non-2-en-1-yl)4,4'-((3-((2-hydroxyethyl)(4-(((Z)-non-2-en-1-yl)oxo)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[0305] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (8 mL), and (Z)-non-2-en-1-yl 4-bromobutanoate (0.6 g, 2.0 mmol), K2CO3 (0.4 g, 2.6 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 58 mg of a colorless oily product (yield: 15.2%).

[0306] ESI-MS m / z:cald for C 44 H 81 N2O7[M+H] + :749.1, found 749.1.

[0307] 1H-NMR (400 MHz, CDCl3)δ 5.69 - 5.57 (m, 3H), 5.56 - 5.46 (m, 3H), 4.65 - 4.58 (m, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.56 (t, J = 5.2 Hz, 2H), 2.48 (t, J = 7.2 Hz, 4H), 2.41 (t, J = 7.2 Hz, 6H), 2.36 - 2.27 (m, 6H), 2.14 - 2.04 (m, 6H), 1.82 - 1.68 (m, 6H), 1.61 - 1.49 (m, 2H), 1.38 - 1.25 (m, 25H), 0.92 - 0.84 (m, 9H).

[0308] Example 17

[0309] Di((Z)-hexyl-2-en-1-yl)8,8'-((3-((8-(((Z)-hexyl-2-en-1-yl)oxo)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0310] Step 1: Synthesis of (Z)-Hexa-2-En-1-yl-8-bromooctanoate [ka]

[0311] 8-bromooctanoic acid (10.1 g, 45.27 mmol) was dissolved in 150 mL of DCM, and oxalyl chloride (6.9 g, 54.33 mmol) was slowly added. The resulting mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain 10 g of crude product. 5 g was taken, dissolved in DCM (200 ml) and TEA (4.09 g, 40.4 mmol), and cis(Z)-hexyl-2-en-1-ol (2.02 g, 20.19 mmol) was added. The mixture was stirred at 40°C for 4 hours. Once it was confirmed that the starting materials had been completely consumed by TLC, the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 4.0 g of a colorless oily product (yield: 64.9%).

[0312] Step 2: Di((Z)-hexyl-2-en-1-yl)8,8'-((3-((8-(((Z)-hexane-2-en-2-yl)oxy)-8-oxyoctyl)(2-hydroxyethyl)amino)propyl)azadiyl)dioctanoic acid [ka]

[0313] N-(2-hydroxyethyl)-1,3-propylenediamine (108.6 mg, 0.92 mmol) was dissolved in DMF (5 mL), and (Z)hexyl-2-en-1-yl 8-bromooctanoate (981.8 mg, 3.22 mmol), K2CO3 (762.8 mg, 5.52 mmol), and KI (30 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (80 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.1 g of a colorless oily product (yield: 13.74%).

[0314] ESI-MS m / z:cald for C 47 H 87 N2O7[M+H] + : 791.7, found 791.7.

[0315] 1 H NMR (400 MHz, CDCl3)δ 5.74-5.62 (m, 3H), 5.62 - 5.52 (m, 3H), 4.66 (d, J = 6.8 Hz, 6H), 3.59 (t, J = 5.2 Hz, 2H), 2.60 (t, J = 5.2 Hz, 2H), 2.56-2.42 (m, 9H), 2.34 (t, J = 7.5 Hz, 6H), 2.17 - 2.07 (m, 6H), 1.71-1.58 (m, 8H), 1.54-1.37 (m, 13H), 1.37-1.24 (m, 19H), 0.94 (t, J = 7.4 Hz, 9H).

[0316] Example 18

[0317] Diundecyl 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(undecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0318] Step 1: Synthesis of undecyl 8-bromooctanoate [ka]

[0319] 8-Bromooctanoic acid (9 g, 40.34 mmol) and 1-Undecanol (5 g, 29 mmol) were dissolved after stirring at 60°C for 0.5 hours, and 3 drops of concentrated sulfuric acid were added. The mixture was reacted at 60°C for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and eluted by column chromatography at PE:EA = 15:1 to obtain 8.2 g of a colorless oily product (yield: 74.9%).

[0320] Step 2: Synthesis of diundecyl 8,8'-((3-((8-oxo-8-(undecyloxy)octyl)aminopropyl)azanegyl)dioctanoate [ka]

[0321] Propane-1,3-diamine (80 mg, 1.08 mmol) was dissolved in DMF (5 mL), and undecyl 8-bromooctanoate (1.22 g, 3.24 mmol), K2CO3 (895.54 mg, 6.48 mmol), and KI (30 mg) were added, respectively. The mixture was stirred at 60°C for 6 hours. An appropriate amount of water was added, and then EA (80 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.32 g of a colorless oily product (yield: 30.75%).

[0322] Step 3: Synthesis of diundecyl 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(undecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0323] Diundecyl 8,8'-((3-((8-oxo-8-(undecyloxy)octyl)amino)propyl)azanegyl)dioctanoate (320 mg, 0.332 mmol) was dissolved in DMF (5 mL), and 3-chloro-1-propanol (62.77 mg, 0.664 mmol), K2CO3 (138.2 mg, 1 mmol), and KI (30 mg) were added, respectively. The mixture was stirred at 90°C for 16 hours. Next, EA (80 mL × 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.13 g of a colorless oily product (yield: 38.33%).

[0324] ESI-MS m / z:cald for C 63 H 125 N2O7[M+H] + : 1021.9, found 1021.9.

[0325] 1 H NMR (400 MHz, CDCl3)δ 4.09 (t, J = 6.8 Hz, 6H), 3.81 (t, J = 5.2 Hz, 2H), 3.02-2.94 (m, 2H), 2.93-2.81 (m, 5H), 2.79 - 2.58 (m, 4H), 2.33 (t, J = 7.5 Hz, 6H), 2.13-2.01 (m, 2H), 1.85 - 1.77 (m, 2H), 1.77-1.68 (m, 4H), 1.68-1.60 (m, 12H), 1.59-1.51 (m, 2H), 1.43 - 1.23 (m, 68H), 0.92 (t, J = 6.7 Hz, 9H).

[0326] Example 19

[0327] Di((Z)-non-2-en-1-yl)8,8'-((3-((3-hydroxypropyl)(8-(((Z)-non-2-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanediyl)dioctanoate [ka]

[0328] Step 1: Synthesis of (Z)-non-2-en-1-yl-8-bromooctanoate [ka]

[0329] 8-bromooctanoic acid (5 g, 22.41 mmol) and (Z)-non-2-en-1-ol (3.188 g, 22.41 mmol) were stirred at 60°C for 0.5 hours, then dissolved. Three drops of concentrated sulfuric acid were added, and the mixture was reacted at 60°C for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 6 g of a colorless oily product (yield: 77%).

[0330] Step 2: Synthesis of di((Z)-non-2-en-1-yl)8,8'-((3-((8-(((Z)-non-2-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0331] Propane-1,3-diamine (128 mg, 1.73 mmol) was dissolved in DMF (5 mL), and (Z)-non-2-en-1-yl 8-bromooctanoate (1.8 g, 5.18 mmol), K2CO3 (956.34 mg, 6.92 mmol), and KI (30 mg) were added, respectively. The mixture was stirred at 60°C for 6 hours. An appropriate amount of water was added, and then EA (80 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.67 g of a colorless oily product (yield: 44.34%).

[0332] Step 3: Synthesis of di((Z)-non-2-en-1-yl)8,8'-((3-((3-hydroxypropyl)(8-(((Z)-non-2-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0333] Di((Z)-non-2-en-1-yl)8,8'-((3-((8-(((Z)-non-2-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanejyl)dioctanoate (420 mg, 0.48 mmol) was dissolved in DMF (5 mL), and 3-chloro-1-propanol (90.76 mg, 0.96 mmol), K2CO3 (276.4 mg, 2 mmol), and KI (30 mg) were added, respectively, and the mixture was stirred at 90°C for 16 hours. Next, EA (80 mL × 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.1 g of a colorless oily product (yield: 22.36%).

[0334] ESI-MS m / z:cald for C 57 H 107 N2O7[M+H] + : 931.6, found 931.6.

[0335] 1 H NMR (400 MHz, CDCl3)δ 5.75 - 5.64 (m, 3H), 5.61 - 5.48 (m, 3H), 4.66 (dd, J = 6.8, 1.3 Hz, 6H), 3.81 (t, J = 5.2 Hz, 2H), 3.07-2.71 (m, 9H), 2.68 - 2.48 (m, 5H), 2.34 (t, J = 7.5 Hz, 6H), 2.19 - 2.10 (m, 6H), 2.05-1.91 (m, 2H), 1.84 - 1.60 (m, 12H), 1.58-1.48 (m, 2H), 1.48 - 1.27 (m, 42H), 0.96 - 0.88 (m, 9H).

[0336] Example 20

[0337] Diundecyl 8,8'-((3-((4-hydroxybutyl)(8-oxo-8-(undecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0338] Step 1: Synthesis of diundecyl 8,8'-((3-((4-hydroxybutyl)(8-oxo-8-(undecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0339] Di((Z)-non-2-en-1-yl)8,8'-((3-((8-(((Z)-non-2-en-1-yl)oxo)-8-oxooctyl)amino)propyl)azanejyl)dioctanoate (660 mg, 0.685 mmol) was dissolved in DMF (5 mL), and 4-chloro-1-butanol (148.74 mg, 1.37 mmol), K2CO3 (207.3 mg, 1.5 mmol), and KI (30 mg) were added, respectively, and the mixture was stirred at 90°C for 16 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.07 g of a colorless oily product (yield: 9.87%).

[0340] ESI-MS m / z:cald for C 64 H 127 N2O7[M+H] + : 1036.0, found 1036.0.

[0341] 1 H NMR (400 MHz, CDCl3)δ 4.08 (t, J = 6.8 Hz, 6H), 3.65 (t, J = 5.3 Hz, 2H), 3.52-3.46 (m, 1H), 3.01 - 2.62 (m, 13H), 2.32 (t, J = 7.5 Hz, 6H), 2.2-2.05 (m, 2H), 1.82-1.54 (m, 21H), 1.44 - 1.18 (m, 66H), 0.91 (t, J = 6.7 Hz, 9H).

[0342] Example 21

[0343] Tetra((Z)-non-2-en-1-yl)8,8',8'',8'''-(propane-1,3-diyldi(azanthriyl))tetraoctanoate [ka]

[0344] Step 1: Synthesis of tetra((Z)-non-2-en-1-yl)8,8',8'',8'''-(propane-1,3-diyldi(axantryyl))tetraoctanoate [ka]

[0345] Propane-1,3-diamine (154 mg, 2.077 mmol) was dissolved in DMF (5 mL), and (Z)-non-2-en-1-yl 8-bromooctanoate (2.17 g, 6.25 mmol), K2CO3 (1 g, 7.25 mmol), and KI (30 mg) were added, respectively. The mixture was stirred at 60°C for 6 hours. An appropriate amount of water was added, and then EA (80 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.6 g of a colorless oily product (yield: 25.34%).

[0346] ESI-MS m / z:cald for C 71 H 131 N2O8[M+H] + : 1140.0, found 1140.0.

[0347] 1 H NMR (400 MHz, CDCl3)δ 5.80 - 5.62 (m, 4H), 5.61 - 5.49 (m, 4H), 4.66 (dd, J = 6.8, 1.3 Hz, 8H), 2.72-2.40 (m, 10H), 2.34 (t, J = 7.5 Hz, 8H), 2.21 - 2.03 (m, 8H), 1.70-1.59 (m, 10H), 1.59-1.45 (m, 7H), 1.44 - 1.24 (m, 59H), 0.96 - 0.81 (m, 12H).

[0348] Example 22

[0349] Dipentadecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(pentadecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0350] Step 1: Synthesis of pentadecyl 8-bromooctanoate [ka]

[0351] 1-Pentadecanol (1.0 g, 4.4 mmol) and 8-bromooctanoic acid (1.2 g, 5.3 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 5 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 10:1 to obtain 1.8 g of a colorless oily product (yield: 94.7%).

[0352] 1 H-NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.7 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.90 - 1.79 (m, 2H), 1.66 - 1.58 (m, 4H), 1.43 (t, J = 6 .8 Hz, 2H), 1.36 - 1.24 (m, 28H), 0.88 (t, J = 6.8 Hz, 3H).

[0353] Step 2: Synthesis of dipentadecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(pentadecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0354] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (8 mL), and pentadecyl 8-bromooctanoate (0.9 g, 2.0 mmol), K2CO3 (0.4 g, 2.6 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 120 mg of a colorless oily product (yield: 20.0%).

[0355] ESI-MS m / z:cald for C 74 H 147 N2O7[M+H] + : 1176.0, found 1176.0.

[0356] 1 H-NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.57 - 2.33 (m, 11H), 2.28 (t, J = 7.5 Hz, 6H), 1.66 - 1.58 (m, 12H), 1.46 - 1.38 (m, 6H), 1.33 - 1.23 (m, 94H), 0.88 (t, J = 6.8 Hz, 9H).

[0357] Example 23

[0358] Diundecyl 12,12'-((3-((2-hydroxyethyl)(12-oxo-12-(undecyloxy)dodecyl)amino)propyl)azanegyl)dodecanoate [ka]

[0359] Step 1: Synthesis of undecyl-12-bromododecanoate [ka]

[0360] 1-Undecanol (1.0 g, 5.8 mmol) and 12-bromododecanoic acid (1.9 g, 7.0 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 5 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 30:1 to obtain 2.2 g of a colorless oily product (yield: 88.0%).

[0361] 1 H-NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.7 Hz, 2H), 3.40 (t, J = 6.9 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.90 - 1.79 (m, 2H), 1.66 - 1.57 (m, 4H), 1.46 - 1.38 (m, 2H), 1.34 - 1.24 (m, 28H), 0.88 (t, J = 6.8 Hz, 3H).

[0362] Step 2: Synthesis of Diundecyl 12,12'-((3-((2-hydroxyethyl)(12-oxo-12-(undecyloxy)dodecyl)amino)propyl)azanegyl)dodecanoate [ka]

[0363] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), and undecyl 12-bromododecanoate (0.9 g, 2.0 mmol), K2CO3 (0.4 g, 2.6 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 25:1 to obtain 220 mg of a colorless oily product (yield: 36.7%).

[0364] ESI-MS m / z:cald for C 74 H 147 N2O7[M+H] + : 1176.0, found 1176.0.

[0365] 1H-NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.7 Hz, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.59 - 2.34 (m, 12H), 2.28 (t, J = 7.5 Hz, 6H), 1.61 (t, J = 7.2 Hz, 12H), 1.45 - 1.39 (m, 6H), 1.27 (d, J = 9.1 Hz, 92H), 0.88 (t, J = 6.8 Hz, 9H).

[0366] Example 24

[0367] Ji((9Z,12Z)-Octadeca-9,12-Dien-1-Il)8,8'-((3 -((2-hydroxyethyl)(8-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-8-oxooctyl)amino)propyl)azanejyl)dioctanoate [ka]

[0368] Step 1: Synthesis of (9Z,12Z)-octadeca-9,12-diene-1-yl-8-bromooctanoate [ka]

[0369] (9Z,12Z)-octadeca-9,12-dien-1-ol (1.0 g, 3.6 mmol) and 8-bromooctanoic acid (1.0 g, 4.5 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 30:1 to obtain 1.6 g of a colorless oily product (yield: 92.1%).

[0370] 1 H-NMR (400 MHz, CDCl3)δ5.43 - 5.27 (m, 4H), 4.05 (t, J = 6.7 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 2.09 - 1.99 (m, 4H), 1.90 - 1.79 (m, 2H), 1.67 - 1.58 (m, 4H), 1.48 - 1.39 (m, 2H), 1.37 - 1.26 (m, 20H), 0.89 (t, J = 6.8 Hz, 3H).

[0371] Step 2: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)8,8'-((3-((2-hydroxyethyl)(8-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-8-oxooctyl)amino)propyl)azanegiyl)dioctanoate [ka]

[0372] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), and (9Z,12Z)-octadeca-9,12-dien-1-yl 8-bromooctanoic acid (1.0 g, 2.0 mmol), K2CO3 (0.4 g, 2.6 mmol), and KI (10 mg) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction, and the mixture was combined. The organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with a DCM:MeOH ratio of 30:1 to obtain 220 mg of a colorless oily product (yield: 33.5%).

[0373] ESI-MS m / z:cald for C 83 H 153 N2O7[M+H] + : 1290.1, found 1290.1.

[0374] 1 H-NMR (400 MHz, CDCl3)δ 5.43 - 5.27 (m, 12H), 4.05 (t, J = 6.8 Hz, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 6.4 Hz, 6H), 2.57 - 2.34 (m, 11H), 2.28 (t, J = 7.6 Hz, 6H), 2.08 - 2.01 (m, 12H), 1.61 (t, J = 7.1 Hz, 12H), 1.47 - 1.39 (m, 6H), 1.36 - 1.24 (m, 70H), 0.89 (t, J = 6.8 Hz, 9H).

[0375] Example 25

[0376] Di((Z)-non-2-en-1-yl)6,6'-((3-((2-hydroxyethyl)(6-(((Z)-non-2-en-1-yl)oxo)-6-oxohexyl)amino)propyl)azanegiyl)dihexanoate [ka]

[0377] Step 1: Synthesis of (Z)-non-2-en-1-yl-6-bromohexanoate [ka]

[0378] 1.0 g, 7.0 mmol of cis-2-nonen-1-ol and 1.6 g, 8.4 mmol of 6-bromohexanoic acid were mixed. The mixture was heated to 60°C, then concentrated sulfuric acid (0.1 mL) was added. The mixture was stirred at this temperature for 5 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 2.1 g of a colorless oily product (yield: 95.5%).

[0379] 1 H-NMR (400 MHz, CDCl3)δ 5.70 - 5.59 (m, 1H), 5.57 - 5.46 (m, 1H), 4.66 - 4.59 (m, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 2.14 - 2.04 (m, 2H), 1.93 - 1.81 (m, 2H), 1.71 - 1.61 (m, 2H), 1.53 - 1.41 (m, 2H), 1.39 - 1.22 (m, 8H), 0.92 - 0.84 (m, 3H).

[0380] Step 2: Synthesis of di((Z)-non-2-en-1-yl)6,6'-((3-((2-hydroxyethyl)(6-(((Z)-non-2-en-1-yl)oxo)-6-oxohexyl)amino)propyl)azanegiyl)dihexanoate [ka]

[0381] 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol) was dissolved in acetonitrile (8 mL), and (Z)-non-2-en-1-yl 6-bromohexanoate (0.6 g, 2.0 mmol), K2CO3 (0.4 g, 2.6 mmol), and KI (10 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 150 mg of a colorless oily product (yield: 35.5%).

[0382] ESI-MS m / z:cald for C 50 H 93 N2O7[M+H] + : 833.3, found 833.3.

[0383] 1H-NMR (400 MHz, CDCl3)δ 5.69 - 5.58 (m, 3H), 5.57 - 5.46 (m, 3H), 4.65 - 4.58 (m, 6H), 3.53 (t, J = 5.2 Hz, 2H), 2.58 - 2.34 (m, 11H), 2.31 (t, J = 7.5 Hz, 6H), 2.15 - 2.04 (m, 6H), 1.69 - 1.59 (m, 7H), 1.50 - 1.40 (m, 6H), 1.39 - 1.23 (m, 32H), 0.92 - 0.84 (m, 9H).

[0384] Example 26

[0385] Ditridecyl 6,6'-((3-((2-hydroxyethyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0386] Step 1: Synthesis of tridecyl 6-bromohexanoate [ka]

[0387] Tridecyl 6-bromohexanoate was obtained using trideca-1-ol and 6-bromohexanoic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain 16.5 g of the target molecule (yield: 94.8%).

[0388] 1 H NMR (400 MHz, CDCl3)δ 4.06 (t, J = 6.8 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.92 - 1.83 (m, 2H), 1.70 - 1.59 (m, 4H), 1.53 - 1.42 (m, 2H), 1.26 (d, J = 4.3 Hz, 20H), 0.88 (t, J = 6.8 Hz, 3H).

[0389] Step 2: Synthesis of ditridecyl 6,6'-((3-((2-hydroxyethyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0390] Using tridecyl 6-bromohexanoate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, ditridecyl 6,6'-((3-((2-hydroxyethyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azanejyl)dihexanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain 252 mg of the target molecule (yield: 49.0%).

[0391] ESI-MS m / z:cald for C 62 H 123 N2O7[M+H] + : 1008.0, found 1008.0.

[0392] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.53 (t, J = 5.2 Hz, 2H), 2.54 (t, J = 5.2 Hz, 2H), 2.50 - 2.34 (m, 10H), 2.29 (t, J = 7.5 Hz, 6H), 1.67 - 1.56 (m, 13H), 1.47 - 1.39 (m, 6H), 1.34 - 1.24 (m, 68H), 0.87 (t, J = 6.8 Hz, 9H).

[0393] Example 27

[0394] Diundecyl 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0395] Step 1: Synthesis of undecyl 6-bromohexanoate [ka]

[0396] Using undeca-1-ol and 6-bromohexanoic acid as starting materials, undecyl 6-bromohexanoate was obtained by referring to step 1 of Example 19. The crude product was purified by column chromatography to obtain 11.6 g of the target molecule (yield: 86.6%).

[0397] 1 H NMR (400 MHz, CDCl3)δ 4.06 (t, J = 6.7 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.93 - 1.81 (m, 2H), 1.69 - 1.59 (m, 4H), 1.55 - 1.40 (m, 2H), 1.33 - 1.22 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H).

[0398] Step 2: Synthesis of 6,6'-(3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)azahexyl)diundecyldihexanoate [ka]

[0399] Using undecyl 6-bromohexanoate and 1,3-propanediamine as starting materials, 6,6'-(3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)azahexyl)diundecyldihexanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain 1.1 g of the target molecule (yield: 26.2%).

[0400] ESI-MS m / z:cald for C 54 H 107 N2O6[M+H] + : 880.0, Found 880.0.

[0401] 1H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 6H), 2.66 - 2.55 (m, 4H), 2.44 (t, J = 7.1 Hz, 2H), 2.40 - 2.34 (m, 4H), 2.32 - 2.25 (m, 6H), 1.68 - 1.58 (m, 14H), 1.54 - 1.39 (m, 6H), 1.35 - 1.23 (m, 55H), 0.90 - 0.85 (m, 9H).

[0402] Step 3: Synthesis of Diundecyl 6,6'-((3-((3-Hydroxypropyl)(6-Oxo-6-(Undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0403] Using 6,6'-(3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)azahexyl)diundecyldihexanoate and 3-chloro-1-propanol as starting materials, diundecyl 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain 320 mg of the target molecule (yield: 27.4%).

[0404] ESI-MS m / z:cald for C 57 H 113 N2O7[M+H] + : 938.0, found 938.0.

[0405] 1H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 6H), 3.77 (t, J = 5.1 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.52 - 2.34 (m, 10H), 2.32 - 2.25 (m, 6H), 1.66 - 1.57 (m, 13H), 1.52 - 1.39 (m, 6H), 1.36 - 1.20 (m, 58H), 1.00 - 0.78 (m, 9H).

[0406] Example 28

[0407] Diundecyl 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0408] Step 1: Synthesis of Diundecyl 6,6'-((3-((4-Hydroxybutyl)(6-Oxo-6-(Undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0409] Using 6,6'-(3-((6-oxo-6-(undecyloxy)hexyl)amino)propyl)azahexyl)diundecyldihexanoate and 4-chloro-1-butanol as starting materials, diundecyl 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(undecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain 104 mg of the target molecule (yield: 12.4%).

[0410] ESI-MS m / z:cald for C 58 H115 N2O7[M+H] + : 952.0, found 952.0.

[0411] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.54 (t, J = 4.6 Hz, 2H), 2.48 - 2.34 (m, 11H), 2.33 - 2.25 (m, 6H), 1.66 - 1.55 (m, 17H), 1.51 - 1.39 (m, 6H), 1.35 - 1.24 (m, 57H), 0.88 (t, J = 6.7 Hz, 9H).

[0412] Example 29

[0413] 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(tridecyloxy)octyl)amino)propyl)azahexyl)distearate [ka]

[0414] Step 1: Synthesis of tridecyl 8-bromooctanoate [ka]

[0415] Tridecyl 8-bromohexyl octanoate was obtained using trideca-1-ol and 8-bromooctanoic acid as starting materials, following step 1 of Example 19. The crude product was purified by column chromatography to obtain 7.2 g of the target molecule (yield: 79.23%).

[0416] Step 2: Synthesis of 8,8'-((3-((8-oxo-8-(tridecyloxy)octyl)amino)propyl)azahexyl)distearate [ka]

[0417] Using tridecyl 8-bromooctanoate and 1,3-propanediamine as starting materials, 8,8'-((3-((8-oxo-8-(tridecyloxy)octyl)amino)propyl)azahexyl)distearate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain 1.2 g of the target molecule (yield: 46.65%).

[0418] ESI-MS m / z:cald for C 66 H 131 N2O6[M+H] + : 1048.0, found 1048.0.

[0419] Step 3: Synthesis of 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(tridecyloxy)octyl)amino)propyl)azahexyl)distearate [ka]

[0420] Using 8,8'-((3-((8-oxo-8-(tridecyloxy)octyl)amino)propyl)azahexyl)distearate and 3-chloro-1-propanol as starting materials, 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(tridecyloxy)octyl)amino)propyl)azahexyl)distearate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain 0.15 g of the target molecule (yield: 23.67%).

[0421] ESI-MS m / z:cald for C 69 H 137 N2O7[M+H] + : 1106.0, found 1106.0.

[0422] 1H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 6H), 3.72-3.81 (m, 2H), 2.97 - 2.68 (m, 8H), 2.67-2.47 (m, 5H),2.28 (t, J = 7.5 Hz, 6H), 2.07-1.90 (m, 2H), 1.84 - 1.71 (m, 2H), 1.70 - 1.55 (m, 16H), 1.53 - 1.43 (m, 2H), 1.46 - 1.09 (m, 78H), 0.87 (t, J = 6.9 Hz, 9H).

[0423] Example 30

[0424] 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azadiyl)ditridecyldihexanoate [ka]

[0425] Step 1: Synthesis of tridecyl 6-bromohexanoate [ka]

[0426] Tridecyl 6-bromohexanoate was obtained using trideca-1-ol and 6-bromohexanoic acid as starting materials, following step 1 of Example 19. The crude product was purified by column chromatography to obtain 7 g of the target molecule (yield: 72.37%).

[0427] Step 2: Synthesis of 6,6'-((3-((6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azahexyl)ditridecyldihexanoate [ka]

[0428] Using tridecyl 6-bromohexanoate and 1,3-propanediamine as starting materials, 6,6'-((3-((6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azahexyl)ditridecyldihexanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain 1.5 g of the target molecule (yield: 35.38%).

[0429] ESI-MS m / z:cald for C 60 H 119 N2O6[M+H] + : 964.0, found 964.0.

[0430] Step 3: Synthesis of 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azadiyl)ditridecyldihexanoate [ka]

[0431] Using 6,6'-((3-((6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azahexyl)ditridecyldihexanoate and 3-chloro-1-propanol as starting materials, 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azadiyl)ditridecyldihexanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0432] ESI-MS m / z:cald for C 63 H 125 N2O7[M+H] + : 1022.0, found 1022.0.

[0433] 1H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 6H), 3.76 (t, J = 5.3 Hz, 2H), 2.94 - 2.76 (m, 8H), 2.75 - 2.55 (m, 5H), 2.36-2.24 (m, 6H), 2.09-1.95 (m, 2H), 1.88 - 1.74 (m, 2H), 1.74-1.51 (m, 18H), 1.44-1.12 (m, 66H), 0.87 (t, J = 6.7 Hz, 9H).

[0434] Example 31

[0435] 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azadiyl)ditridecyldihexanoate [ka]

[0436] Step 1: Synthesis of 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azadiyl)ditridecyldihexanoate [ka]

[0437] Using 6,6'-((3-((6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azahexyl)ditridecyldihexanoate and 4-chloro-1-butanol as starting materials, the process was carried out according to step 3 of Example 19 to obtain 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(tridecyloxy)hexyl)amino)propyl)azadiyl)ditridecyldihexanoate. The crude product was purified by column chromatography to obtain 0.09 g of the target molecule (yield: 9.3%).

[0438] ESI-MS m / z:cald for C 64 H127 N2O7[M+H] + : 1036.0, found 1036.0.

[0439] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.64 (t, J = 5.4 Hz, 2H), 3.02-2.59 (m, 12H), 2.31 (m, 6H), 2.15-1.96 (m, 2H), 1.86-1.50 (m, 22H), 1.45-1.16 (m, 66H), 0.88 (t, J = 6.8 Hz, 9H).

[0440] Example 32

[0441] 7,7'-(3-((2-hydroxyethyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0442] Step 1: Synthesis of undecyl 7-bromoheptanoate [ka]

[0443] Using undeca-1-ol and 7-bromoheptanoic acid as starting materials, undecyl 7-bromoheptanoate was obtained by referring to step 1 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0444] Step 2: Synthesis of 7,7'-(3-((2-hydroxyethyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0445] Using undecyl 7-bromoheptanoate and 2-((3-aminopropyl)amino)ethane-1-ol as raw materials, refer to step 2 of Example 3, 7,7'-(3-(( 2-hydroxyethyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0446] ESI-MS m / z:cald for C 59 H 117 N2O7[M+H] + : 966.0, found 966.0.

[0447] Example 33

[0448] 7,7'-(3-((2-hydroxyethyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0449] Step 1: Synthesis of tridecyl 7-bromoheptanoate [ka]

[0450] Tridecyl 7-bromoheptanoate was obtained using trideca-1-ol and 7-bromoheptanoic acid as starting materials, following step 1 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0451] Step 2: 7,7'-(3-((2-hydroxyethyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0452] Using tridecyl 7-bromoheptanoate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, 7,7'-(3-((2-hydroxyethyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate was obtained by referring to step 2 of Example 3. The crude product was subjected to column chromatography. The target molecule was obtained by further purification.

[0453] ESI-MS m / z:cald for C 65 H 129 N2O7[M+H] + : 1050.0, found 1050.0.

[0454] Example 34

[0455] 7,7'-(3-((3-hydroxypropyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0456] Step 1: Synthesis of 7,7'-((3-((7-oxo-7-(tridecyloxy)heptyl)aminopropyl)azahexyl)diheptanoate [ka]

[0457] Using tridecyl 7-bromoheptanoate and 1,3-propanediamine as starting materials, 7,7'-((3-((7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azahexyl)diheptanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0458] ESI-MS m / z:cald for C 63 H 125 N2O6[M+H] + : 1006.0, found 1006.0.

[0459] Step 2: Synthesis of 7,7'-(3-((3-hydroxypropyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0460] Using 7,7'-((3-((7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azahexyl)diheptanoate and 3-chloro-1-propanol as starting materials, 7,7'-(3-((3-hydroxypropyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0461] ESI-MS m / z:cald for C 66 H 131 N2O7[M+H] + : 1064.0, found 1064.0.

[0462] Example 35

[0463] 7,7'-(3-((4-hydroxybutyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0464] Step 1: Synthesis of 7,7'-(3-((4-hydroxybutyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0465] Using 7,7'-((3-((7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azahexyl)diheptanoate and 4-chloro-1-butanol as starting materials, 7,7'-(3-((4-hydroxybutyl)(7-oxo-7-(tridecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0466] ESI-MS m / z:cald for C 67 H 133 N2O7[M+H] + : 1078.0, found 1078.0.

[0467] Example 36

[0468] 7,7'-(3-((3-hydroxypropyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0469] Step 1: Synthesis of 7,7'-(3-((7-oxo-7-(undecyloxy)heptyl)aminopropyl)azahexyl)diheptanoate [ka]

[0470] Using undecyl 7-bromoheptanoate and 1,3-propanediamine as starting materials, 7,7'-(3-((7-oxo-7-(undecyloxy)heptyl)amino)propyl)azahexyl)diheptanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0471] ESI-MS m / z:cald for C 57 H 113 N2O6[M+H] + : 922.0, found 922.0.

[0472] Step 3: Synthesis of 7,7'-(3-((3-hydroxypropyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0473] Using 7,7'-(3-((7-oxo-7-(undecyloxy)heptyl)amino)propyl)azahexyl)diheptanoate and 3-chloro-1-propanol as raw materials, refer to step 2 of Example 3, and 7,7'-(3-((3-hydroxypropyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)dih Butanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0474] ESI-MS m / z:cald for C 60 H 119 N2O7[M+H] + : 980.0, found 980.0.

[0475] Example 37

[0476] 7,7'-(3-((4-hydroxybutyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0477] Step 1: Synthesis of 7,7'-(3-((4-hydroxybutyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate [ka]

[0478] Using 7,7'-(3-((7-oxo-7-(undecyloxy)heptyl)amino)propyl)azahexyl)diheptanoate and 4-chloro-1-butanol as starting materials, 7,7'-(3-((4-hydroxybutyl)(7-oxo-7-(undecyloxy)heptyl)amino)propyl)azadiyl)diheptanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0479] ESI-MS m / z:cald for C 61 H 121 N2O7[M+H] + : 994.0, found 994.0.

[0480] Example 38

[0481] Diundecyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(undecyloxy)pentyl)aminopropyl)azadiyl)dipentanoate [ka]

[0482] Step 1: Synthesis of undecyl 5-bromopentanoate [ka]

[0483] Using undeca-1-ol and 5-bromovaleric acid as starting materials, undecyl 5-bromopentanoate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0484] Step 2: Synthesis of diundecyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate [ka]

[0485] Using undecyl 5-bromopentanoate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, diundecyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0486] ESI-MS m / z:cald for C 53 H 105 N2O7[M+H] + : 882.0, found 882.0.

[0487] Example 39

[0488] Ditridecyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(tridecyloxy)pentyl)aminopropyl)azadiyl)dipentanoate [ka]

[0489] Step 1: Synthesis of tridecyl 5-bromopentanoate [ka]

[0490] Tridecyl 5-bromopentanoate was obtained using trideca-1-ol and 5-bromovaleric acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0491] Step 2: Synthesis of ditridecyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate [ka]

[0492] Using tridecyl 5-bromopentanoate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, ditridecyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0493] ESI-MS m / z:cald for C 59 H 117 N2O7[M+H] + : 966.0, found 966.0.

[0494] Example 40

[0495] 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)ditridecyldipentanoate [ka]

[0496] Step 1: Synthesis of 5,5'-((3-((5-oxo-5-(tridecyloxy)pentyl)aminopropyl)azadiyl)ditridecyldipentanoate [ka]

[0497] Using tridecyl 5-bromopentanoate and 1,3-propanediamine as starting materials, the reaction was carried out according to step 2 of Example 19 to obtain 5,5'-((3-((5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)ditridecidopentanoate. The crude product was purified by column chromatography to obtain the target molecule.

[0498] ESI-MS m / z:cald for C 57 H 113 N2O6[M+H] + : 922.0, found 922.0.

[0499] Step 2: Synthesis of 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)ditridecyldipentanoate [ka]

[0500] Using 5,5'-((3-((5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)ditridecyldipentanoate and 3-chloro-1-propanol as starting materials, 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)ditridecyldipentanoate was obtained by referring to step 3 of Example 19. The crude product was subjected to column chromatography. Further purification yielded the target molecule.

[0501] ESI-MS m / z:cald for C 60 H119 N2O7[M+H] + : 980.0, found 980.0.

[0502] Example 41

[0503] Ditridecyl 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(tridecyloxy)pentyl)aminopropyl)azadiyl)dipentanoate [ka]

[0504] Step 1: Synthesis of ditridecyl 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate [ka]

[0505] Ditridecyl 5,5'-((3-((5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate and 4-chloro-1-butanol were used as starting materials, and following step 3 of Example 19, ditridecyl 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(tridecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0506] ESI-MS m / z:cald for C 61 H 121 N2O7[M+H] + : 994.0, found 994.0.

[0507] Example 42

[0508] Diundecyl 5,5'-((3-((3-hydroxypropyl)(5-oxo-5-(undecyloxy)pentyl)aminopropyl)azadiyl)dipentanoate [ka]

[0509] Step 1: Synthesis of diundecyl 5,5'-((3-((5-oxo-5-(undecyloxy)pentyl)aminopropyl)azahexyl)dipentanoate [ka]

[0510] Using undecyl 5-bromopentanoate and 1,3-propanediamine as starting materials, diundecyl 5,5'-((3-((5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)dipentanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0511] ESI-MS m / z:cald for C 51 H 101 N2O6[M+H] + : 838.0, found 838.0.

[0512] Step 2: Synthesis of diundecyl 5,5'-((3-((3-hydroxypropyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate [ka]

[0513] Diundecyl 5,5'-((3-((5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)dipentanoate and 3-chloro-1-propanol were used as raw materials, and the process was carried out according to step 3 of Example 19 to obtain diundecyl 5,5'-((3-((3-hydroxypropyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azadiyl)dipentanoate. The crude product was purified by column chromatography to obtain 130 mg of the target molecule (yield: 52.0%).

[0514] ESI-MS m / z:cald for C 54 H 107 N2O7[M+H] + : 896.0, found 896.0.

[0515] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.77 (t, J = 5.1 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.47 - 2.36 (m, 10H), 2.34 - 2.28 (m, 6H), 1.63 (tt, J = 13.8, 6.1 Hz, 18H), 1.54 - 1.39 (m, 7H), 1.28 (d, J = 17.4 Hz, 46H), 0.88 (t, J (= 6.7 Hz, 9H).

[0516] Example 43

[0517] Diundecyl 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)dipentanoate [ka]

[0518] Step 1: Synthesis of diundecyl 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)dipentanoate [ka]

[0519] Diundecyl 5,5'-((3-((5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)dipentanoate and 4-chloro-1-butanol were used as starting materials, and following step 3 of Example 19, diundecyl 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)dipentanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0520] ESI-MS m / z:cald for C 55 H 109 N2O7[M+H] + : 910.0, found 910.0.

[0521] Example 44

[0522] Didodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)(2-hydroxyethyl)amino)propyl)azahexyl)dihexanoate [ka]

[0523] Step 1: Synthesis of dodecyl 6-bromohexanoate [ka]

[0524] Using dodeca-1-ol and 6-bromohexanoic acid as starting materials, dodecyl 6-bromohexanoate was obtained by referring to step 1 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0525] Step 2: Synthesis of Didodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)(2-hydroxyethyl)amino)propyl)azahexyl)dihexanoate [ka]

[0526] Using dodecyl 6-bromohexanoate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, didodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)(2-hydroxyethyl)amino)propyl)azahexyl)dihexanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0527] ESI-MS m / z:cald for C 59 H 117 N2O7[M+H] + : 966.0, found 966.0.

[0528] Example 45

[0529] Zidodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)(3- Hydroxypropyl aminopropyl azahexyl dihexanoate [ka]

[0530] Step 1: Synthesis of didodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)aminopropyl)azahexyl)dihexanoate [ka]

[0531] Using dodecyl 6-bromohexanoate and 1,3-propanediamine as starting materials, didodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)amino)propyl)azahexyl)dihexanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0532] ESI-MS m / z:cald for C 57 H 113 N2O6[M+H] + : 922.0, found 922.0.

[0533] Step 3: Synthesis of 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)diundecyldipentanoate [ka]

[0534] Using didodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)amino)propyl)azahexyl)dihexanoate and 3-chloro-1-propanol as starting materials, 5,5'-((3-((4-hydroxybutyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azahexyl)diundecyldipentanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain the target molecule.

[0535] ESI-MS m / z:cald for C 60 H 119 N2O7[M+H] + : 980.0, found 980.0.

[0536] Example 46

[0537] Didodecyl 6,6'-((3-((6-(dodecyloxy)-6-oxohexyl)(4-hydroxybutyl)amino)propyl)azanegyl)dihexanoate [ka]

[0538] Step 1: Synthesis of dodecyl 6-bromohexanoate [ka]

[0539] Using dodeca-1-ol and 6-bromohexanoic acid as starting materials, dodecyl 6-bromohexanoate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0540] Step 2: Synthesis of Didodecyl 6,6'-((3-((6-(dodecoxy)-6-oxohexyl)aminopropyl)azanegyl)dihexanoate [ka]

[0541] Using dodecyl 6-bromohexanoate and 1,3-propanediamine as starting materials, didodecyl 6,6'-((3-((6-(dodecyloxy)-6-oxohexyl)amino)propyl)azanejyl)dihexanoate was obtained by referring to step 2 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0542] ESI-MS m / z:cald for C 57 H 113 N2O6[M+H] + : 922.5, found 922.5.

[0543] Step 3: Synthesis of Didodecyl 6,6'-((3-((6-(dodecyloxy)-6-oxohexyl)(4-hydroxybutyl)amino)propyl)azanegyl)dihexanoate [ka]

[0544] Using didodecyl 6,6'-((3-((6-(dodecyloxy)-6-oxohexyl)amino)propyl)azanegyl)dihexanoate as a starting material, we followed step 3 of Example 18 to obtain didodecyl 6,6'-((3-((6-(dodecyloxy)-6-oxohexyl)(4-hydroxybutyl)amino)propyl)azanegyl)dihexanoate. The crude product was purified by column chromatography to obtain the target molecule.

[0545] ESI-MS m / z:cald for C 61 H 121 N2O7[M+H] + : 922.5, found 922.5.

[0546] Example 47

[0547] Didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(2-hydroxyethyl)amino)propyl)azanegyl)diheptanoate [ka]

[0548] Step 1: Synthesis of dodecyl 7-bromoheptanoate [ka]

[0549] Using dodeca-1-ol and 7-bromoheptanoic acid as starting materials, dodecyl 7-bromoheptanoate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0550] Step 2: Synthesis of Didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(2-hydroxyethyl)amino)propyl)azanegyl)diheptanoate [ka]

[0551] Using dodecyl 7-bromoheptanoate as a starting material, we followed step 2 of Example 3 to obtain didodecyl 7,7'-((3-((7-(dodecoxy)-7-oxoheptyl)(2-hydroxyethyl)amino)propyl)azanejyl)diheptanoate. The crude product was purified by column chromatography to obtain the target molecule.

[0552] ESI-MS m / z:cald for C 62 H 123 N2O7[M+H] + : 1008.7, found 1008.7.

[0553] Example 48

[0554] Didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(3-hydroxypropyl)amino)propyl)azanegyl)diheptanoate [ka]

[0555] Step 1: Synthesis of didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)aminopropyl)azanegyl)diheptanoate [ka]

[0556] Using dodecyl 7-bromoheptanoate and 1,3-propanediamine as starting materials, didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)amino)propyl)azanejyl)diheptanoate was obtained by referring to step 2 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0557] ESI-MS m / z:cald for C 60 H 119 N2O6[M+H] + : 964.6, found 964.6.

[0558] Step 3: Synthesis of didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(3-hydroxypropyl)amino)propyl)azanegyl)diheptanoate [ka]

[0559] Using didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)amino)propyl)azanegyl)diheptanoate and 3-chloro-1-propanol as starting materials, we followed step 3 of Example 18 to obtain didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(3-hydroxypropyl)amino)propyl)azanegyl)diheptanoate. The crude product was purified by column chromatography to obtain the target molecule.

[0560] ESI-MS m / z:cald for C 63 H 125 N2O7[M+H] + : 1022.7, found 1022.7.

[0561] Example 49

[0562] Didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(4-hydroxybutyl)amino)propyl)azanegyl)diheptanoate [ka]

[0563] Step 1: Synthesis of didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(4-hydroxybutyl)amino)propyl)azanegyl)diheptanoate [ka]

[0564] Using didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)amino)propyl)azanegyl)diheptanoate and 4-chloro-1-butanol as starting materials, we followed step 3 of Example 18 to obtain didodecyl 7,7'-((3-((7-(dodecyloxy)-7-oxoheptyl)(4-hydroxybutyl)amino)propyl)azanegyl)diheptanoate. The crude product was purified by column chromatography to obtain the target molecule.

[0565] ESI-MS m / z:cald for C 64 H 127 N2O7[M+H] + : 1036.7, found 1036.7.

[0566] Example 50

[0567] Didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegyl)dioctanoate [ka]

[0568] Step 1: Synthesis of dodecyl 8-bromooctanoate [ka]

[0569] Using dodeca-1-ol and 8-bromooctanoic acid as starting materials, dodecyl 8-bromooctanoate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0570] Step 2: Synthesis of didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanegyl)dioctanoate [ka]

[0571] Using dodecyl 8-bromooctanoate as a starting material, didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(2-hydroxyethyl)amino)propyl)azanejyl)dioctanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0572] ESI-MS m / z:cald for C 65 H 129 N2O7[M+H] + : 1050.7, found 1050.7.

[0573] Example 51

[0574] Didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(3-hydroxypropyl)amino)propyl)azanegyl)dioctanoate [ka]

[0575] Step 1: Synthesis of didodecyl 8,8'-((3-((8-(dodecoxy)-8-oxooctyl)aminopropyl)azanegyl)dioctanoate [ka]

[0576] Using dodecyl 8-bromooctanoate and 1,3-propanediamine as starting materials, we followed step 2 of Example 18 to obtain didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)aminopropyl)azanegyl)dioctanoate. The crude product was purified by column chromatography to obtain the target molecule.

[0577] ESI-MS m / z:cald for C 63 H 125 N2O6[M+H] + : 1006.7, found 1006.7.

[0578] Step 3: Synthesis of didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(3-hydroxypropyl)amino)propyl)azanegyl)dioctanoate [ka]

[0579] Using didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)amino)propyl)azanejyl)dioctanoate and 3-chloro-1-propanol as starting materials, didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(3-hydroxypropyl)amino)propyl)azanejyl)dioctanoate was obtained by referring to step 3 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0580] ESI-MS m / z:cald for C 66 H 131N2O7[M+H] + : 1064.8, found 1064.8.

[0581] Example 52

[0582] Didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(4-hydroxybutyl)amino)propyl)azanegyl)dioctanoate [ka]

[0583] Step 1: Synthesis of didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(4-hydroxybutyl)amino)propyl)azanegyl)dioctanoate [ka]

[0584] The raw materials are didodecyl 8,8'-((3-((8-(dodecoxy)-8-oxooctyl)aminopropyl)azanegyl)dioctanoate and 4-chloro-1-butanol. Referring to step 3 of Example 18, didodecyl 8,8'-((3-((8-(dodecyloxy)-8-oxooctyl)(4-hydroxybutyl)amino)propyl)azanejyl)dioctanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0585] ESI-MS m / z:cald for C 67 H 133 N2O7[M+H] + : 1078.8, found 1078.8.

[0586] Example 53

[0587] Ditetradecyl 6,6'-((3-((2-hydroxyethyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0588] Step 1: Synthesis of tetradecyl 6-bromohexanoate [ka]

[0589] Tetradecyl-6-bromohexanoate was obtained using tetradeca-1-ol and 6-bromohexanoic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0590] Step 2: Synthesis of ditetradecyl 6,6'-((3-((2-hydroxyethyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0591] Using tetradecyl 6-bromohexanoate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, ditetradecyl 6,6'-((3-((2-hydroxyethyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanejyl)dihexanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0592] ESI-MS m / z:cald for C 65 H 129 N2O7[M+H] + : 1050.8, found 1050.8.

[0593] Example 54

[0594] Ditetradecyl 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0595] Step 1: Synthesis of ditetradecyl 6,6'-((3-((6-oxo-6-(tetradecyloxy)hexyl)aminopropyl)azanegyl)dihexanoate [ka]

[0596] Using tetradecyl 6-bromohexanoate and 1,3-propanediamine as starting materials, ditetradecyl 6,6'-((3-((6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanejyl)dihexanoate was obtained by referring to step 2 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0597] ESI-MS m / z:cald for C 63 H 125 N2O6[M+H] + : 1006.7, found 1006.7.

[0598] Step 3: Synthesis of ditetradecyl 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0599] Ditetradecyl 6,6'-((3-((6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanejyl)dihexanoate and 3-chloro-1-propanol were used as raw materials, and following step 3 of Example 18, ditetradecyl 6,6'-((3-((3-hydroxypropyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanejyl)dihexanoate was obtained. The crude product was subjected to column chromatography. The target molecule was obtained by purification using tography.

[0600] ESI-MS m / z:cald for C 66 H 131 N2O7[M+H] + : 1064.8, found 1064.8.

[0601] Example 55

[0602] Ditetradecyl 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0603] Step 1: Synthesis of ditetradecyl 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate [ka]

[0604] Using ditetradecyl 6,6'-((3-((6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate and 4-chloro-1-butanol as starting materials, ditetradecyl 6,6'-((3-((4-hydroxybutyl)(6-oxo-6-(tetradecyloxy)hexyl)amino)propyl)azanegyl)dihexanoate was obtained by referring to step 3 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0605] ESI-MS m / z:cald for C 67 H 133 N2O7[M+H] + : 1078.8, found 1078.8.

[0606] Example 56

[0607] Ditetradecyl 7,7'-((3-((2-hydroxyethyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegyl)diheptanoate [ka]

[0608] Step 1: Synthesis of tetradecyl 7-bromoheptanoate [ka]

[0609] Tetradecyl 7-bromoheptanoate was obtained using tetradeca-1-ol and 7-bromoheptanoic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0610] Step 2: Synthesis of ditetradecyl 7,7'-((3-((2-hydroxyethyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegyl)diheptanoate [ka]

[0611] Using tetradecyl 7-bromoheptanoate as a starting material, ditetradecyl 7,7'-((3-((2-hydroxyethyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegyl)diheptanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0612] ESI-MS m / z:cald for C 68 H 135 N2O7[M+H] + : 1092.8, found 1092.8.

[0613] Example 57

[0614] Ditetradecyl 7,7'-((3-((3-hydroxypropyl)(7-oxo-7-(tetradecyloxy)heptyl)aminopropyl)azanegyl)diheptanoate [ka]

[0615] Step 1: Synthesis of ditetradecyl 7,7'-((3-((7-oxo-7-(tetradecyloxy)heptyl)aminopropyl)azanegyl)diheptanoate [ka]

[0616] Using dodecyl 7-bromoheptanoate and 1,3-propanediamine as starting materials, ditetradecyl 7,7'-((3-((7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanejyl)diheptanoate was obtained by referring to step 2 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0617] ESI-MS m / z:cald for C 66 H 131 N2O6[M+H] + : 1048.8, found 1048.8.

[0618] Step 2: Synthesis of ditetradecyl 7,7'-((3-((3-hydroxypropyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegiyl)diheptanoate [ka]

[0619] Using ditetradecyl 7,7'-((3-((7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanejyl)diheptanoate and 3-chloro-1-propanol as starting materials, ditetradecyl 7,7'-((3-((3-hydroxypropyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanejyl)diheptanoate was obtained by referring to step 3 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0620] ESI-MS m / z:cald for C 69 H 137 N2O7[M+H] + : 1106.9, found 1106.9.

[0621] Example 58

[0622] Ditetradecyl 7,7'-((3-((4-hydroxybutyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegyl)diheptanoate [ka]

[0623] Step 1: Synthesis of ditetradecyl 7,7'-((3-((4-hydroxybutyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegiyl)diheptanoate [ka]

[0624] Ditetradecyl 7,7'-((3-((7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegyl)diheptanoate and 4-chloro-1-butanol were used as starting materials, and following step 3 of Example 18, ditetradecyl 7,7'-((3-((4-hydroxybutyl)(7-oxo-7-(tetradecyloxy)heptyl)amino)propyl)azanegyl)diheptanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0625] ESI-MS m / z:cald for C 70 H 139 N2O7[M+H] + : 1120.9, found 1120.9.

[0626] Example 59

[0627] Ditetradecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0628] Step 1: Synthesis of tetradecyl 8-bromooctanoate [ka]

[0629] Tetradecyl-8-bromooctanoate was obtained using tetradeca-1-ol and 8-bromooctanoic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0630] Step 2: Synthesis of ditetradecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0631] Using tetradecyl 8-bromooctanoate as a starting material, ditetradecyl 8,8'-((3-((2-hydroxyethyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanejyl)dioctanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0632] ESI-MS m / z:cald for C 71 H 141 N2O7[M+H] + : 1134.9, found 1134.9.

[0633] Example 60

[0634] Ditetradecyl 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0635] Step 1: Synthesis of ditetradecyl 8,8'-((3-((8-oxo-8-(tetradecyloxy)octyl)aminopropyl)azanegyl)dioctanoate [ka]

[0636] Using tetradecyl 8-bromooctanoate and 1,3-propanediamine as starting materials, ditetradecyl 8,8'-((3-((8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanejyl)dioctanoate was obtained by referring to step 2 of Example 18. The crude product was purified by column chromatography to obtain the target molecule.

[0637] ESI-MS m / z:cald for C 69 H 137 N2O6[M+H] + : 1090.9, found 1090.9.

[0638] Step 3: Synthesis of ditetradecyl 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0639] Ditetradecyl 8,8'-((3-((8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanejyl)dioctanoate and 3-chloro-1-propanol were used as raw materials, and following step 3 of Example 18, ditetradecyl 8,8'-((3-((3-hydroxypropyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanejyl)dioctanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0640] ESI-MS m / z:cald for C 72 H 143 N2O7[M+H] + : 1148.9, found 1148.9.

[0641] Example 61

[0642] Ditetradecyl 8,8'-((3-((4-hydroxybutyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0643] Step 1: Synthesis of ditetradecyl 8,8'-((3-((4-hydroxybutyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanegyl)dioctanoate [ka]

[0644] Ditetradecyl 8,8'-((3-((8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanejyl)dioctanoate and 4-chloro-1-butanol were used as starting materials, and following step 3 of Example 18, ditetradecyl 8,8'-((3-((4-hydroxybutyl)(8-oxo-8-(tetradecyloxy)octyl)amino)propyl)azanejyl)dioctanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0645] ESI-MS m / z:cald for C 73 H 145 N2O7[M+H] + : 1163.0, found 1163.0.

[0646] Example 62

[0647] Ditridecyl 4,4'-((3-((2-hydroxyethyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0648] Step 1: Synthesis of tridecyl 4-bromobutanoate [ka]

[0649] Tridecyl 4-bromobutanoate was obtained using trideca-1-ol and 4-bromobutyric acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain 8.3 g of the target molecule (yield: 95.4%).

[0650] 1 H NMR (400 MHz, CDCl3)δ 4.07 (t, J = 6.8 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.22 - 2.12 (m, 2H), 1.67 - 1.57 (m, 2H), 1.33 - 1.22 (m, 20H), 0.88 (t, J = 6.7 Hz, 3H).

[0651] Step 2: Synthesis of ditridecyl 4,4'-((3-((2-hydroxyethyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0652] Using tridecyl 4-bromobutanoate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, ditridecyl 4,4'-((3-((2-hydroxyethyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanejyl)dibutanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain 110 mg of the target molecule (yield: 23.4%).

[0653] ESI-MS m / z:cald for C 56 H 111 N2O7[M+H] + : 923.8, found 923.8.

[0654] 1 H NMR (400 MHz, CDCl3)δ4.11 - 4.01 (m, 6H), 3.55 (t, J = 5.2 Hz, 2H), 2.57 (t, J = 5.2 Hz, 2H), 2.52 - 2.38 (m, 10H), 2.35 - 2.27 (m, 6H), 1.81 - 1.69 (m, 6H), 1.61 (m, 8H), 1.32 - 1.23 (m, 61H), 0.88 (t, J = 6.7Hz, 9H).

[0655] Example 63

[0656] Ditridecyl 4,4'-((3-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0657] Step 1: Synthesis of tridecyl 4-bromobutanoate [ka]

[0658] Tridecyl 4-bromobutanoate was obtained using trideca-1-ol and 4-bromobutyric acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0659] Step 2: Ditridecyl 4,4'-((3-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0660] Using tridecyl 4-bromobutanoate and 3-((3-aminopropyl)amino)propan-1-ol as starting materials, ditridecyl 4,4'-((3-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanejyl)dibutanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain 106 mg of the target molecule (yield: 16.6%).

[0661] ESI-MS m / z:cald for C 57 H 113 N2O7[M+H] + : 937.8, found 937.8.

[0662] 1 H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.67 - 2.60 (m, 2H), 2.50 - 2.36 (m, 14H), 2.34 - 2.28 (m, 8H), 1.74 - 1.58 (m, 21H), 1.26 (m, 50H), 0.88 (s, 9H).

[0663] Example 64

[0664] Diundecyl 4,4'-((3-((3-hydroxypropyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0665] Step 1: Synthesis of undecyl 4-bromobutanoate [ka]

[0666] Using undeca-1-ol and 4-bromobutyric acid as starting materials, undecyl 4-bromobutanoate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0667] Step 2: Synthesis of diundecyl 4,4'-((3-((3-hydroxypropyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0668] Using undecyl 4-bromobutanoate and 3-((3-aminopropyl)amino)propan-1-ol as starting materials, diundecyl 4,4'-((3-((3-hydroxypropyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanejyl)dibutanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain 93 mg of the target molecule (yield: 13.9%).

[0669] ESI-MS m / z:cald for C 51 H 101 N2O7[M+H] + : 853.7, found 853.7.

[0670] 1H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.64 (t, J = 5.6 Hz, 2H), 2.50 - 2.36 (m, 10H), 2.31 (t, J = 7.5 Hz, 6H), 1.78 - 1.57 (m, 16H), 1.33 - 1.22 (m, 49H), 0.88 (t, J = 6.8 Hz, 9H).

[0671] Example 65

[0672] Ditridecyl 4,4'-((3-((4-hydroxybutyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0673] Step 1: Synthesis of tridecyl 4-bromobutanoate [ka]

[0674] Tridecyl 4-bromobutanoate was obtained using trideca-1-ol and 4-bromobutyric acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0675] Step 2: Synthesis of ditridecyl 4,4'-((3-((4-hydroxybutyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0676] Using tridecyl 4-bromobutanoate and 4-((3-aminopropyl)amino)butan-1-ol as starting materials, ditridecyl 4,4'-((3-((4-hydroxybutyl)(4-oxo-4-(tridecyloxy)butyl)amino)propyl)azanejyl)dibutanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0677] ESI-MS m / z:cald for C 58 H 115 N2O7[M+H] + :951.8, found 951.8.

[0678] Example 66

[0679] Diundecyl 4,4'-((3-((4-hydroxybutyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0680] Step 1: Synthesis of undecyl 4-bromobutanoate [ka]

[0681] Using undeca-1-ol and 4-bromobutyric acid as starting materials, undecyl 4-bromobutanoate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0682] Step 2: Diundecyl 4,4'-((3-((4-hydroxybutyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanegyl)dibutanoate [ka]

[0683] Using undecyl 4-bromobutanoate and 4-((3-aminopropyl)amino)butan-1-ol as starting materials, diundecyl 4,4'-((3-((4-hydroxybutyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)azanejyl)dibutanoate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0684] ESI-MS m / z:cald for C 52 H 103 N2O7[M+H] + :868.4, found 869.4.

[0685] Example 67

[0686] Diundecyl 3,3'-((3-((2-hydroxyethyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0687] Step 1: Synthesis of undecyl 3-bromopropionate [ka]

[0688] Using undeca-1-ol and 3-bromopropionic acid as starting materials, undecyl 3-bromopropionate was obtained by referring to Step 1 of Example 3. The crude product was purified by column chromatography to obtain 4 g of the target molecule (yield: 44.89%).

[0689] Step 2: Synthesis of diundecyl 3,3'-((3-((2-hydroxyethyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0690] Using undecyl 3-bromopropionate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, diundecyl 3,3'-((3-((2-hydroxyethyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanejyl)dipropionate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain 0.15 g of the target molecule (yield: 14.7%).

[0691] ESI-MS m / z:cald for C 47 H 93 N2O7[M+H] + :797.7, found 797.7.

[0692] 1 H NMR (400 MHz, CDCl3)δ 4.06 (m, 6H), 3.56 (t, J = 5.1 Hz, 2H), 2.85-2.69 (m, 6H), 2.61-2.54 (m, 2H), 2.54-2.35 (m, 10 H), 1.72-1.52 (m, 8H), 1.41 - 1.18 (m, 49H), 0.88 (t, J = 6.8 Hz, 9H).

[0693] Example 68

[0694] Diundecyl 3,3'-((3-((3-hydroxypropyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0695] Step 1: Synthesis of undecyl 3-bromopropionate [ka]

[0696] Using undeca-1-ol and 3-bromopropionic acid as starting materials, undecyl 3-bromopropionate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0697] Step 2: Synthesis of diundecyl 3,3'-((3-((3-hydroxypropyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0698] Using undecyl 3-bromopropionate and 3-((3-aminopropyl)amino)propan-1-ol as raw materials, diundecyl 3,3'-((3-((3-hydroxypropyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0699] ESI-MS m / z:cald for C 48 H 95 N2O7[M+H] + :811.7, found 811.7.

[0700] Example 69

[0701] Diundecyl 3,3'-((3-((4-hydroxybutyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0702] Step 1: Synthesis of undecyl 3-bromopropionate [ka]

[0703] Using undeca-1-ol and 3-bromopropionic acid as starting materials, undecyl 3-bromopropionate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0704] Step 4: Synthesis of diundecyl 3,3'-((3-((4-hydroxybutyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0705] Using undecyl 3-bromopropionate and 4-((3-aminopropyl)amino)butan-1-ol as raw materials, diundecyl 3,3'-((3-((4-hydroxybutyl)(3-oxo-3-(undecyloxy)propyl)amino)propyl)azanegyl)dipropionate was obtained by referring to step 2 of Example 3. The crude product was subjected to column chromatography. The target molecule was obtained by purification using tography.

[0706] ESI-MS m / z:cald for C 49 H 97 N2O7[M+H] + :825.7, found 825.7.

[0707] Example 70

[0708] Ditridecyl 3,3'-((3-((2-hydroxyethyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0709] Step 1: Synthesis of tridecyl 3-bromopropionate [ka]

[0710] Tridecyl 3-bromopropionate was obtained using trideca-1-ol and 3-bromopropionic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain 1.8 g of the target molecule (yield: 41.35%).

[0711] Step 2: Ditridecyl 3,3'-((3-((2-hydroxyethyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0712] Using tridecyl 3-bromopropionate and 2-((3-aminopropyl)amino)ethane-1-ol as raw materials, refer to step 2 of Example 3, ditridecyl 3,3'-((3-((2-hydroxyethyl)(3-oxo-3-(tridecyloxy)propionate (Aminopropyl)azanegyl)dipropionate was obtained. The crude product was purified by column chromatography to obtain 0.18 g of the target molecule (yield: 20.42%).

[0713] ESI-MS m / z:cald for C 53 H 105 N2O7[M+H] + :881.8, found 881.8.

[0714] 1H NMR (400 MHz, CDCl3)δ 4.06 (m, 6H), 3.56 (t, J = 5.0 Hz, 2H), 2.90-2.69 (m, 6H), 2.65 - 2.53 (m, 2H), 2.52 - 2.35 (m, 10H), 1.73-1.50 (m, 8H), 1.45 - 1.16 (m, 61H), 0.88 (t, J = 6.8 Hz, 9H).

[0715] Example 71

[0716] Ditridecyl 3,3'-((3-((3-hydroxypropyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0717] Step 1: Synthesis of tridecyl 3-bromopropionate [ka]

[0718] Tridecyl 3-bromopropionate was obtained using trideca-1-ol and 3-bromopropionic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0719] Step 3: Synthesis of ditridecyl 3,3'-((3-((3-hydroxypropyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0720] Using tridecyl 3-bromopropionate and 3-((3-aminopropyl)amino)propan-1-ol as raw materials, ditridecyl 3,3'-((3-((3-hydroxypropyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanejyl)dipropionate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0721] ESI-MS m / z:cald for C 54 H 107 N2O7[M+H] + :895.8, found 895.8.

[0722] Example 72

[0723] Ditridecyl 3,3'-((3-((4-hydroxybutyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanegyl)dipropionate [ka]

[0724] Step 1: Synthesis of tridecyl 3-bromopropionate [ka]

[0725] Tridecyl 3-bromopropionate was obtained using trideca-1-ol and 3-bromopropionic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0726] Step 3: Ditridecyl 3,3'-((3-((4-hydroxybutyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanegyl)dipropio Synthesis of nates [ka]

[0727] Using tridecyl 3-bromopropionate and 4-((3-aminopropyl)amino)butan-1-ol as starting materials, ditridecyl 3,3'-((3-((4-hydroxybutyl)(3-oxo-3-(tridecyloxy)propyl)amino)propyl)azanegyl)dipropionate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0728] ESI-MS m / z:cald for C 55 H 109 N2O7[M+H] + :909.8, found 909.8.

[0729] Example 73

[0730] Diundecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0731] Step 1: Synthesis of undecyl 2-bromoacetate [ka]

[0732] Using undeca-1-ol and 3-bromoacetic acid as starting materials, undecyl 2-bromoacetate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0733] Step 2: Synthesis of Diundecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0734] Using undecyl 2-bromoacetate and 2-((3-aminopropyl)amino)ethane-1-ol as raw materials, diundecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanegyl)diacetate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0735] ESI-MS m / z:cald for C 44 H 87 N2O7[M+H] + :755.6, found 755.6.

[0736] Example 74

[0737] Diundecyl 2,2'-((3-((3-hydroxypropyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0738] Step 1: Synthesis of undecyl 2-bromoacetate [ka]

[0739] Using undeca-1-ol and 3-bromoacetic acid as starting materials, undecyl 2-bromoacetate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0740] Step 2: Synthesis of Diundecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0741] Using undecyl 2-bromoacetate and 3-((3-aminopropyl)amino)propan-1-ol as raw materials, diundecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanejyl)diacetate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0742] ESI-MS m / z:cald for C 45 H 89 N2O7[M+H] + :769.6, found 769.6.

[0743] Example 75

[0744] Diundecyl 2,2'-((3-((4-hydroxybutyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0745] Step 1: Synthesis of undecyl 2-bromoacetate [ka]

[0746] Using undeca-1-ol and 3-bromoacetic acid as starting materials, undecyl 2-bromoacetate was obtained by referring to step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0747] Step 2: Synthesis of Diundecyl 2,2'-((3-((4-Hydroxybutyl)(2-Oxo-2-(Undecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0748] Undecyl 2-bromoacetate and 4-((3-aminopropyl)amino)butane Using -1-ol as a starting material, diundecyl 2,2'-((3-((4-hydroxybutyl)(2-oxo-2-(undecyloxy)ethyl)amino)propyl)azanegyl)diacetate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0749] ESI-MS m / z:cald for C 46 H 91 N2O7[M+H] + :783.6, found 783.6.

[0750] Example 76

[0751] Ditridecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0752] Step 1: Synthesis of tridecyl 2-bromoacetate [ka]

[0753] Tridecyl 2-bromoacetate was obtained using trideca-1-ol and 2-bromoacetic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0754] Step 2: Ditridecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0755] Using tridecyl 2-bromoacetate and 2-((3-aminopropyl)amino)ethane-1-ol as starting materials, ditridecyl 2,2'-((3-((2-hydroxyethyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanejyl)diacetate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0756] ESI-MS m / z:cald for C 50 H 99 N2O7[M+H] + : 834.7, found 834.7.

[0757] Example 77

[0758] Ditridecyl 2,2'-((3-((3-hydroxypropyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0759] Step 1: Synthesis of tridecyl 2-bromoacetate [ka]

[0760] Tridecyl 2-bromoacetate was obtained using trideca-1-ol and 2-bromoacetic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0761] Step 2: Synthesis of ditridecyl 2,2'-((3-((3-hydroxypropyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanegyl) diacetate [ka]

[0762] Using tridecyl 2-bromoacetate and 3-((3-aminopropyl)amino)propan-1-ol as starting materials, ditridecyl 2,2'-((3-((3-hydroxypropyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanejyl)diacetate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0763] ESI-MS m / z:cald for C 51 H 101 N2O7[M+H] + :853.7, found 853.7.

[0764] Example 78

[0765] Ditridecyl 2,2'-((3-((4-hydroxybutyl)(2-oxo-2-(to Lidecyl(oxy)ethyl)amino)propyl)azanegyl)diacetate [ka]

[0766] Step 1: Synthesis of tridecyl 2-bromoacetate [ka]

[0767] Tridecyl 2-bromoacetate was obtained using trideca-1-ol and 2-bromoacetic acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0768] Step 2: Synthesis of ditridecyl 2,2'-((3-((4-hydroxybutyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanegyl) diacetate [ka]

[0769] Using tridecyl 2-bromoacetate and 4-((3-aminopropyl)amino)butan-1-ol as starting materials, ditridecyl 2,2'-((3-((4-hydroxybutyl)(2-oxo-2-(tridecyloxy)ethyl)amino)propyl)azanejyl)diacetate was obtained by referring to step 2 of Example 3. The crude product was purified by column chromatography to obtain the target molecule.

[0770] ESI-MS m / z:cald for C 52 H 103 N2O7[M+H] + :867.7, found 867.7.

[0771] Example 79

[0772] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)8,8'-((3-(2-hydroxyethyl)(8-((9Z,12Z)-tetradeca-9,13-dien-1-)oxy)-8-oxyoctyl)amino)propyl)azadiyl)dioctanoic acid [ka]

[0773] Step 1: Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl-8-bromooctanoic acid [ka]

[0774] (9Z,12Z)-octadeca-9,12-dien-1-ol (1.0 g, 3.6 mmol) and 8-bromooctanoic acid (1.0 g, 4.5 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 30:1 to obtain 1.6 g of a colorless oily product (yield: 92.1%).

[0775] ESI-MS m / z:cald for C 26 H 47 BrO2[M+H] + :471.6, found 471.6.

[0776] 1 H-NMR (400 MHz, CDCl3)δ5.43 - 5.27 (m, 4H), 4.05 (t, J = 6.7 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 2.09 - 1.99 (m, 4H), 1.90 - 1.79 (m, 2H), 1.67 - 1.58 (m, 4H), 1.48 - 1.39 (m, 2H), 1.37 - 1.26 (m, 20H), 0.89 (t, J = 6.8 Hz, 3H).

[0777] Step 2: Di((9Z,12Z)-octadeca-9,12-dien-1-yl)8,8'-((3-(2-hydroxyethyl)(8-((9Z,12Z)-tetradeca-9,13-dien-1-)oxy)-8-oxooctyl)amino)propyl)azadiylazanegiyl)dioctanoic acid [ka]

[0778] N-(2-hydroxyethyl)-1,3-propylenediamine (60 mg, 0.5 mmol) was dissolved in acetonitrile (10 mL), and (9Z,12Z)-octadeca-9,12-dien-1-yl 8-bromooctanoic acid (1.0 g, 2.0 mmol), K2CO3 (0.4 g, 2.6 mmol), and KI (10 mg) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with a DCM:MeOH ratio of 30:1 to obtain 220 mg of a colorless oily product (yield: 33.5%).

[0779] ESI-MS m / z:cald for C 83 H 152 N2O7[M+H] + : 1290.1, found 1290.1.

[0780] 1H-NMR (400 MHz, CDCl3) δ 5.43 - 5.27 (m, 12H), 4.05 (t, J = 6.8 Hz, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 6.4 Hz, 6H), 2.57 - 2.34 (m, 11H), 2.28 (t, J = 7.6 Hz, 6H), 2.08 - 2.01 (m, 12H), 1.61 (t, J = 7.1 Hz, 12H), 1.47 - 1.39 (m, 6H), 1.36 - 1.24 (m, 70H), 0.89 (t, J = 6.8 Hz, 9H).

[0781] Example 80

[0782] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((2-hydroxyethyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[0783] Step 1: Synthesis of (10Z,13Z)-octadeca-10,13-diene-1-yl-4-bromobutanoate [ka]

[0784] (10Z,13Z)-octadeca-10,13-dien-1-ol and 4-bromobutyric acid were used as starting materials, and (10Z,13Z)-octadeca-10,13-dien-1-yl 4-bromobutanoate was obtained by referring to Step 1 of Example 3. The crude product was purified by column chromatography to obtain 4.2 g of the target molecule (yield: 88.7%).

[0785] 1H NMR (400 MHz, CDCl3)δ 5.44 - 5.28 (m, 4H), 4.07 (t, J = 6.7 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 6.5 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.25 - 2.11 (m, 2H), 2.10 - 1.98 (m, 4H), 1.67 - 1.58 (m, 2H), 1.37 - 1.27 (m, 16H), 0.89 (t, J = 6.8 Hz, 3H).

[0786] Step 2: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((2-hydroxyethyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[0787] Using (10Z,13Z)-octadeca-10,13-dien-1-yl 4-bromobutanoate as a starting material, the procedure was followed according to Step 2 of Example 3 to obtain di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((2-hydroxyethyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanejyl)dibutanoate. The crude product was purified by column chromatography to obtain 82 mg of the target molecule (yield: 14.3%).

[0788] ESI-MS m / z:cald for C 71 H 128 N2O7[M+H] + : 1121.8, found 1121.9.

[0789] 1H NMR (400 MHz, CDCl3)δ 5.45 - 5.22 (m, 12H), 4.09 - 3.98 (m, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 6.5 Hz, 6H), 2.56 (t, J = 5.2 Hz, 2H), 2.47 (t, J = 7.2 Hz, 4H), 2.41 (t, J = 7.2 Hz, 6H), 2.35 - 2.25 (m, 6H), 2.18 - 1.92 (m, 12H), 1.80 - 1.69 (m, 6H), 1.65 - 1.54 (m, 8H), 1.35 - 1.26 (m, 49H), 0.89 (t, J = 6.7 Hz, 9H).

[0790] Example 81

[0791] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[0792] Step 1: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[0793] (10Z,13Z)-octadeca-10,13-dien-1-yl 4-bromobutanoate and 1,3-propanamine were used as starting materials, and following step 2 of Example 18, di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanejyl)dibutanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0794] ESI-MS m / z:cald for C 69 H 124 N2O6[M+H] + : 1077.8, found 1077.9.

[0795] Step 3: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[0796] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanejyl)dibutanoate and 3-chloro-1-propanol were used as raw materials, and following step 3 of Example 18, di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-((3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxo)-4-oxobutyl)amino)propyl)azanejyl)dibutanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0797] ESI-MS m / z:cald for C 72 H 130 N2O7[M+H] + : 1135.8, found 1135.9.

[0798] 1 H NMR (400 MHz, CDCl3)δ 5.46 - 5.25 (m, 12H), 4.12 - 3.99 (m, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 6.5 Hz, 6H), 2.64 (t, J = 5.7 Hz, 2H), 2.53 - 2.35 (m, 10H), 2.31 (t, J = 7.4 Hz, 6H), 2.05 (q, J = 6.8 Hz, 12H), 1.86 - 1.66 (m, 11H), 1.64 - 1.59 (m, 6H), 1.42 - 1.23 (m, 48H), 0.89 (t, J = 6.8 Hz, 9H).

[0799] Example 82

[0800] Diundecyl 4,4'-((4-((3-hydroxypropyl)(4-oxo-4-(undecyloxy)butyl)amino)butyl)azanegyl)dibutanoate [ka]

[0801] Step 1: Synthesis of undecyl 4-bromobutanoate [ka]

[0802] 4-bromobutyric acid (4.6 g, 27.8 mmol) and undecanol (4.0 g, 23.2 mmol) were stirred at 60°C for 0.5 hours, then dissolved, and 2 drops of concentrated sulfuric acid were added. The mixture was reacted at 60°C for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 20:1 to obtain 6.7 g of a colorless oily product (yield: 89.3%).

[0803] Step 2: Synthesis of diundecyl 4,4'-((4-((4-oxo-4-(undecyloxy)butyl)amino)butyl)azanegyl)dibutanoate [ka]

[0804] Butane-1,4-diamine (274 mg, 3.1 mmol) was dissolved in ACN (40 mL), and undecyl 4-bromobutanoate (3.0 g, 9.3 mmol), K2CO3 (2.1 g, 15.6 mmol), and KI (50 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (80 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 10:1 to obtain 390 mg of a colorless oily product (yield: 15.6%).

[0805] ESI-MS m / z:cald for C 49 H 96 N2O6[M+H] + : 809.3, found 809.3.

[0806] 1H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 2.85 - 2.65 (m, 4H), 2.52 - 2.44 (m, 5H), 2.43 - 2.37 (m, 3H), 2.32 (t, J = 7.2 Hz, 4H), 1.90 - 1.85 (m, 2H), 1.80 - 1.68 (m, 5H), 1.64 - 1.55 (m, 6 H), 1.56 - 1.48 (m, 2H), 1.32 - 1.21 (m, 50H), 0.88 (t, J = 6.8 Hz, 9H).

[0807] Step 3: Diundecyl 4,4'-((4-((3-hydroxypropyl)(4-oxo-4-(undecyloxy)butyl)amino)butyl)azanegyl)dibutanoate [ka]

[0808] Diundecyl 4,4'-((4-((4-oxo-4-(undecyloxy)butyl)amino)butyl)azanegyl)dibutanoate (390 mg, 0.5 mmol) was dissolved in DMF (8 mL), and 3-chloro-1-propanol (137 mg, 1.4 mmol), K2CO3 (333 mg, 2.4 mmol), and KI (20 mg) were added, respectively. The mixture was stirred at 90°C for 16 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 10:1 to obtain 82 mg of a colorless oily product (yield: 19.3%).

[0809] ESI-MS m / z:cald for C 52 H 102 N2O7[M+H] + : 867.4, found 867.9.

[0810] 1H NMR (400 MHz, CDCl3)δ 4.06 (td, J = 6.8, 2.5 Hz, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.67 (s, 2H), 2.45 (s, 9H), 2.32 (t, J = 7.3 Hz, 6H), 1.87 - 1.66 (m, 10H), 1.61 (t, J = 7.1 Hz, 6H), 1.43 (d, J = 6.0 Hz, 4H), 1.28 (d, J = 16.9 Hz, 48H), 0.88 (t, J = 6.7 Hz, 9H).

[0811] Example 83

[0812] Dinonyl 4,4'-(5-((3-hydroxypropyl)(4-oxo-4-(undecyloxy)butyl)aminopentyl)azahexyl)dibutanoate [ka]

[0813] Step 1: Synthesis of undecyl 4-bromobutanoate [ka]

[0814] 4-bromobutyric acid (10 g, 59.88 mmol) and undecanol (10.32 g, 59.88 mmol) were stirred at 60°C for 0.5 hours, then dissolved, and 2 drops of concentrated sulfuric acid were added. The mixture was reacted at 60°C for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 20:1 to obtain 15 g of a colorless oily product (yield: 78%).

[0815] Step 2: Synthesis of dinonyl 4,4'-(5-((4-oxo-4-(undecyloxy)butyl)amino)pentyl)azahexyl)dibutanoate [ka]

[0816] 1,5-Diaminopentane (787.2 mg, 7.7 mmol) was dissolved in DMF (50 mL), and undecyl 4-bromobutanoate (7.426 g, 23.11 mmol), K2CO3 (4.79 g, 34.66 mmol), and KI (50 mg) were added, respectively. The mixture was stirred at 60°C for 6 hours. An appropriate amount of water was added, and then EA (120 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 10:1 to obtain 650 mg of a colorless oily product (yield: 10.25%).

[0817] ESI-MS m / z:cald for C 50 H 98 N2O6[M+H] + : 824.3, found 824.3.

[0818] Step 3: Dinonyl 4,4'-(5-((3-hydroxypropyl)(4-oxo-4-(undecyloxy)butyl)amino)pentyl)azahexyl)dibutanoate [ka]

[0819] Dinonyl 4,4'-(5-((4-oxo-4-(undecyloxy)butyl)amino)pentyl)azahexyl)dibutanoate (650 mg, 0.789 mmol) was dissolved in DMF (10 mL), and 3-chloro-1-propanol (147 mg, 1.5 mmol), K2CO3 (414.6 mg, 3 mmol), and KI (20 mg) were added, respectively. The mixture was stirred at 90°C for 16 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 10:1 to obtain 120 mg of a colorless oily product (yield: 17.25%).

[0820] ESI-MS m / z:cald for C 53 H 104 N2O7[M+H] + : 882.4, found 882.4.

[0821] 1 H NMR (400 MHz, CDCl3)δ 4.10 (m, 6H), 3.83 (t, J = 5.2 Hz, 2H), 2.69 (t, J = 5.6 Hz, 2H), 2.54 - 2.27 (m, 15H), 1.91 - 1.58 (m, 20H), 1.43-1.22 (m, 50H), 0.92 (t, J = 6.7 Hz, 9H).

[0822] Example 84

[0823] Azetidinyl 4,4'-(4-((4-(dodecyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)dibutanoate

[0824] [ka]

[0825] Step 1: Didodecyl 4,4'-(4-((4-(dodecyloxy)-4-oxobutyl)amino)butyl)azetidinyl)dibutanoate [ka]

[0826] Using dodecyl 4-bromobutanoate and 1,4-butanediamine as starting materials, didodecyl 4,4'-(4-((4-(dodecyloxy)-4-oxobutyl)amino)butyl)azetidinyl)dibutanoate was obtained by referring to step 2 of Example 82. The crude product was purified by column chromatography to obtain the target molecule.

[0827] ESI-MS m / z:cald for C 52 H 103 N2O6[M+H] + : 852.4, found 852.6.

[0828] Step 2: Synthesis of azetidinyl 4,4'-(4-((4-(dodecyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)dibutanoate [ka]

[0829] Using didodecyl 4,4'-(4-((4-(dodecyloxy)-4-oxobutyl)amino)butyl)azetidinyl)dibutanoate and 3-chloro-1-propanol as starting materials, azetidinyl 4,4'-(4-((4-(dodecyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)dibutanoate was obtained by referring to step 3 of Example 82. The crude product was purified by column chromatography to obtain the target molecule.

[0830] ESI-MS m / z:cald for C 55 H 109 N2O7[M+H] + : 909.5, found 909.7.

[0831] Example 85

[0832] 4,4'-((4-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate diester [ka]

[0833] Step 1: 4,4'-(4-(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate diester [ka]

[0834] Using tridecyl 4-bromobutanoate and 1,4-butanediamine as starting materials, the 4,4'-(4-(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoic acid diester was obtained by referring to step 2 of Example 82. The crude product was purified by column chromatography to obtain the target molecule.

[0835] ESI-MS m / z:cald for C 55 H 109 N2O6[M+H] + : 893.5, found 893.7.

[0836] Step 2: Synthesis of 4,4'-((4-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl) dibutanoate diester [ka]

[0837] Using 4,4'-(4-(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoic acid diester and 3-chloro-1-propanol as starting materials, 4,4'-((4-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoic acid diester was obtained by referring to step 3 of Example 82. The crude product was purified by column chromatography to obtain the target molecule.

[0838] ESI-MS m / z:cald for C 58 H 115 N2O7[M+H] + : 951.6, found 951.8.

[0839] Example 86

[0840] Didecyl 4,4'-((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azadiyl)dibutanoate [ka]

[0841] Step 1: Didecyl 4,4'-(4-((4-(decyloxy)-4-oxobutyl)aminobutyl)azadiyl)dibutanoate [ka]

[0842] Using decyl 4-bromobutanoate and 1,4-butanediamine as starting materials, following step 2 of Example 82, didecyl 4,4'-(4-((4-(decyloxy)-4-o Xobutyl)amino)butyl)azadiyl)dibutanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0843] ESI-MS m / z:cald for C 46 H 91 N2O6[M+H] + : 767.2, found 767.4.

[0844] Step 2: Synthesis of didecyl 4,4'-((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azadiyl)dibutanoate [ka]

[0845] Using didecyl 4,4'-(4-((4-(decyloxy)-4-oxobutyl)amino)butyl)azadiyl)dibutanoate and 3-chloro-1-propanol as starting materials, 4,4'-((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azadiyl)didecyldibutanoate was obtained by referring to step 3 of Example 82. The crude product was purified by column chromatography to obtain the target molecule.

[0846] ESI-MS m / z:cald for C 49 H 97 N2O7[M+H] + : 825.3, found 825.5.

[0847] Example 87

[0848] Dinonyl 4,4'-((4-((2-hydroxyethyl)(4-oxo-4-(undecyloxy)butyl)amino)butyl)azadiylazanejyl)dibutanoate [ka]

[0849] Step 1: Synthesis of undecyl 4-bromobutanoate [ka]

[0850] Using undeca-1-ol and 4-bromobutyric acid as raw materials, step 1 of Example 19 By referencing the results, undecyl 6-bromohexanoate was obtained. The crude product was purified by column chromatography to obtain 3.3 g of the target molecule (yield: 88.5%).

[0851] 1H NMR (400 MHz, CDCl3)δ 4.07 (t, J = 6.7 Hz, 2H), 3.46 (t, J = 6.4 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.22 - 2.11 (m, 2H), 1.66 - 1.59 (m, 2H), 1.35 - 1.23 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H).

[0852] Step 2: Synthesis of dinonyl 4,4'-(3-((4-oxo-4-(undecyloxy)butyl)amino)propyl)azetidinyl)dibutanoate [ka]

[0853] Using undecyl 4-bromobutanoate and 1,4-butanediamine as starting materials, dinonyl 4,4'-(3-((4-oxo-4-(undecyloxy)butyl)amino)propyl)azetidinyl)dibutanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain 390 mg of the target molecule (yield: 16.0%).

[0854] ESI-MS m / z:cald for C 49 H 97 N2O6[M+H] + : 809.7, found 809.2.

[0855] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 2.85 -2.65 (m, 4H), 2.52 - 2.44 (m, 5H), 2.40 (m, 3H), 2.32 (m, 4H), 2.04 - 1.88 (m, 2H), 1.80 - 1.68 (m, 5H), 1.64 - 1.57 (m, 6H), 1.55 - 1.47 (m, 2H), 1.32 - 1.21 (m, 50H), 0.88 (t, J = 6.8 Hz, 9H).

[0856] Step 3: Synthesis of dinonyl 4,4'-((4-((2-hydroxyethyl)(4-oxo-4-(undecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate [ka]

[0857] Using dinonyl 4,4'-(3-((4-oxo-4-(undecyloxy)butyl)amino)propyl)azetidinyl)dibutanoate and bromoethanol as raw materials, refer to step 3 of Example 19, and 4,4'-((4-((2-hydroxyethyl (4-oxo-4-(undecyloxy)butyl)amino)butyl)azetidinyl)dinonyl dibutanoate was obtained. The crude product was purified by column chromatography to obtain 63 mg of the target molecule (yield: 17.1%).

[0858] ESI-MS m / z:cald for C 51 H 101 N2O7[M+H] + : 853.7, found 853.2.

[0859] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.54 (t, J = 5.4 Hz, 2H), 2.59 (m, 2H), 2.52 - 2.37 (m, 11H), 2.31 (m, 7H), 1.83 - 1.67 (m, 7H), 1.61 (m, 7H), 1.40 (m, 4H), 1.27 (m, 45H), 0.88 (t, J = 6.8 Hz, 9H).

[0860] Example 88

[0861] Dinonyl 5,5'-((4-((3-hydroxypropyl)(5-oxo-5-(undecyloxy)pentyl)amino)butyl)dipentanoate [ka]

[0862] Step 1: Synthesis of undecyl 5-bromopentanoate [ka]

[0863] Using undeca-1-ol and 5-bromovaleric acid as starting materials, undecyl 5-bromopentanoate was obtained by referring to Step 1 of Example 19. The crude product was purified by column chromatography to obtain 1.8 g of the target molecule (yield: 92.8%).

[0864] 1 H NMR (400 MHz, CDCl3)δ 4.06 (t, J = 6.7 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H), 2.34 (t, J = 7.3 Hz, 2H), 1.95 - 1.85 (m, 2H), 1.84 - 1.73 (m, 2H), 1.62 (t, J = 7.1 Hz, 2H), 1.33 - 1.23 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H).

[0865] Step 2: Synthesis of (4-((3-((t-butyldimethylsilyl)oxy)propyl)amino)butyl)t-butylcarbamate [ka]

[0866] (3-bromopropoxy)(t-butyl)dimethylsilane (2.0 g, 7.9 mmol) was dissolved in acetonitrile (40 mL), and (4-aminobutyl)t-butylcarbamate (1.8 g, 9.5 mmol), K2CO3 (3.3 g, 23.7 mmol), and KI (130 mg, 0.8 mmol) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (50 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 20:1 to obtain 1.5 g of a colorless oily product (yield: 54.1%).

[0867] ESI-MS m / z:cald for C 18 H 41 N2O3Si [M+H] + : 361.6, found 361.8.

[0868] 1 H NMR (400 MHz, CDCl3)δ 3.68 (t, J = 6.1 Hz, 2H), 3.11 (m, 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.64 - 2.58 (m, 2H), 1.79 - 1.64 (m, 4H), 1.54 - 1.48 (m, 4H), 1.43 (s, 9H), 0.88 (d, J = 1.1 Hz, 9H), 0.04 (d, J = 1.1 Hz, 6H).

[0869] Step 3: Synthesis of undecyl 5-((4-(t-butoxyoxo)amino)butyl)(3-((t-butyldimethylsilyl)oxy)propyl)amino)pentanoate [ka]

[0870] (4-((3-((t-butyldimethylsilyl)oxy)propyl)amino)butyl)t-butylcarbamate (300 mg, 0.8 mmol) was dissolved in acetonitrile (10 mL), and undecyl 5-bromopentanoate (279 mg, 0.8 mmol), potassium carbonate (345 mg, 2.5 mmol), and KI (13.8 mg, 0.08 mmol) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (20 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 0.5 g of a colorless oily product (yield: 97.7%).

[0871] ESI-MS m / z:cald for C 34 H 71 N2O5Si [M+H] + : 616.0, found 616.1.

[0872] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 2H), 3.62 (t, J = 6.3 Hz, 2H), 3. 16 - 3.04 (m, 2H), 2.43 (d, J = 29.8 Hz, 5H), 2.30 (t, J = 7.4 Hz, 2H), 1.62 (m, 8H), 1.45 (m, 14H), 1.28 (m, 17H), 0.88 (s, 12H), 0.04 (s, 6H).

[0873] Step 4: Synthesis of undecyl 5-((4-aminobutyl)(3-hydroxypropyl)amino)pentanoate [ka]

[0874] Undecyl 5-((4-(t-butoxyoxo)amino)butyl)(3-((t-butyldimethylsilyl)oxy)propyl)amino)pentanoate (500 mg, 0.8 mmol) was dissolved in DCM (20 mL), TMSOTf (368 mg, 1.6 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After neutralization by dropwise addition to saturated sodium bicarbonate solution under an ice bath, an appropriate amount of water was added, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried together and evaporated to dryness. The mixture was then passed through a column and eluted at DCM:MeOH(NH3) = 10:1 to obtain 256 mg of a colorless oily product (yield: 78.6%).

[0875] ESI-MS m / z:cald for C 23 H 49 N2O3[M+H] + : 401.6, found401.8.

[0876] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 2H), 3.83 - 3.74 (m, 2H), 2.71 (t, J = 6.7 Hz, 2H), 2.63 (t, J = 5.6 Hz, 2H), 2.47 - 2.38 (m, 5H), 2.32 (t, J = 7.2 Hz, 2H), 1.70 - 1.65 (m, 2H), 1.64 - 1.57 (m, 4H), 1.54 - 1.41 (m, 6H), 1.35 - 1.23 (m, 18H), 0.87 (t, J = 6.8 Hz, 3H).

[0877] Step 5: Synthesis of dinonyl 5,5'-((4-((3-hydroxypropyl)(5-oxo-5-(undecyloxy)pentyl)amino)butyl)azetidinyl)dipentanoate [ka]

[0878] Undecyl 5-((4-aminobutyl)(3-hydroxypropyl)amino)pentano Eth (256 mg, 0.6 mmol) was dissolved in acetonitrile (10 mL), and undecyl 5-bromopentanoate (536 mg, 1.9 mmol), potassium carbonate (265 mg, 1.9 mmol), and KI (10.6 mg, 0.06 mmol) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (20 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 210 mg of a colorless oily product (yield: 36.1%).

[0879] ESI-MS m / z:cald for C 55 H 109 N2O7[M+H] + : 909.8, found 909.8.

[0880] 1 H NMR (400 MHz, CDCl3)δ 4.10 - 4.00 (m, 6H), 3.78 (t, J = 5.1 Hz, 2H), 2.63 (t, J = 5.6 Hz, 2H), 2.46 - 2.35 (m, 10H), 2.34 - 2.28 (m, 6H), 1.68 - 1.57 (m, 17H), 1.52 - 1.37 (m, 10H), 1.27 (d, J = 8.3 Hz, 46H), 0.88 (t, J = 6.8 Hz, 9H).

[0881] Example 89

[0882] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-(4-(3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azanediyl)dibutanoate [ka]

[0883] Step 1: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-(4-(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azanejyl)dibutanoate [ka]

[0884] (10Z,13Z)-octadeca-10,13-dien-1-yl 4-bromobutanoate and 1,4-butanediamine were used as starting materials, and following step 2 of Example 82, di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-(4-(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azanejyl)dibutanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0885] ESI-MS m / z:cald for C 70 H 127 N2O6[M+H] + : 1091.8, found 1091.6.

[0886] Step 2: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-(4-(3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azanegiyl)dibutanoate [ka]

[0887] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-(4-(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azanejyl)dibutanoate and 3-chloro-1-propanol were used as raw materials, and following step 3 of Example 82, di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-(4-(3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azanejyl)dibutanoate was obtained. The crude product was purified by column chromatography to obtain the target molecule.

[0888] ESI-MS m / z:cald for C 73 H 133 N2O7[M+H] + : 1150.9, found 1150.7.

[0889] 1 H NMR (400 MHz, CDCl3)δ 5.41 - 5.29 (m, 12H), 4.07 - 4.03 (m, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.76 (t, J = 6.5 Hz, 6H), 2.64 (t, J = 5.8 Hz, 2H), 2.52 - 2.36 (m, 10H), 2.32 (t, J = 7.4 Hz, 6H), 2.15-2.0 (m, 13H), 1.86 - 1.5 (m, 20H), 1.31-1.25 (m, 46H), 0.86 (t, J = 6.8 Hz, 9H).

[0890] Example 90

[0891] Tridecyl 8-(29-hydroxy-15-oxo-23-(8-oxo-8-(tridecyloxy)octyl)-23,27-diaza-14-oxanonacosan-27-yl)octanoate [ka]

[0892] Step 1: Synthesis of tridecyl 8-bromooctanoate [ka]

[0893] 8-bromooctanoic acid (5 g, 22.41 mmol) was dissolved in 100 mL of DCM, and oxalyl chloride (8.53 g, 67.23 mmol) was slowly added. The resulting mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain 12 g of crude product. 150 mL of DCM and TEA (3.28 g, 32.4 mmol) were added and dissolved. Then 1-tridecyl alcohol (4.49 g, 22.41 mmol) was added, and the mixture was stirred at 40°C for 4 hours. Once it was confirmed that the starting materials had been completely consumed by TLC, the mixture was directly mixed with the sample and purified by column chromatography at PE:EA = 10:1 to obtain 2.44 g of a colorless oily product (yield: 26.8%).

[0894] Step 2: Synthesis of tridecyl 8-(29-hydroxy-15-oxo-23-(8-oxo-8-(tridecyloxy)octyl)-23,27-diaza-14-oxanonacosan-27-yl)octanoate [ka]

[0895] 2-((3-aminopropyl)amino)ethane-1-ol (0.1g, 846.17 Dissolve umol) in 20 mL of MeCN, add tridecyl 8-bromooctanoate (1.2 g, 2.96 mmol), potassium carbonate (0.82 g, 5.92 mmol), and KI (10 mg), stir at 85°C, and leave overnight. Add 50 mL of water and 50 mL of EA, separate the liquids, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography. Purification by column chromatography using DCM (containing 5% EA):MeOH = 50:1~5:1 yielded 340 mg of a pale yellow oily product (yield: 36.8%).

[0896] ESI-MS m / z:cald for C 68 H 135 N2O7[M+H] + :1092.0, found 1092.1.

[0897] Example 91

[0898] Undecyl 10-(29-hydroxy-13-oxo-23-(10-oxo-10-(undecyl)oxydecyl)-23,27-diaza-12-oxanonacosan-27-yl)capate [ka]

[0899] Step 1: Synthesis of Undecyl 10-Bromoca Plate [ka]

[0900] 10-Bromodecanoic acid (5 g, 19.91 mmol) was dissolved in 100 mL of DCM, and oxalyl chloride (7.58 g, 59.723 mmol) was slowly added. The resulting mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain 12.3 g of crude product. 150 mL of DCM and 5 g of TEA were added and dissolved. 1-Undecanol (3.43 g, 19.91 mmol) was added, and the mixture was stirred at 40°C for 4 hours. Once it was confirmed that the starting materials had been completely consumed by TLC, the mixture was directly mixed and purified by column chromatography with PE:EA = 10:1 to obtain 1.96 g of a colorless oily product (yield: 24.3%).

[0901] Step 2: Synthesis of undecyl 10-(29-hydroxy-13-oxo-23-(10-oxo-10-(undecyloxy)decyl)-23,27-diaza-12-oxanonacosan-27-yl)capate [ka]

[0902] 2-((3-aminopropyl)amino)ethane-1-ol (0.1 g, 846.17 ml) was dissolved in 20 mL of MeCN, and undecyl 10-bromoca plate (1.2 g, 2.96 mmol), potassium carbonate (0.82 g, 5.92 mmol), and KI (10 mg) were added. The mixture was stirred at 85°C and left overnight. 50 mL of water and 50 mL of EA were added, and after liquid-liquid extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Column chromatography was performed using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 310 mg of a pale yellow oily product (yield: 33.6%).

[0903] ESI-MS m / z:cald for C 68 H 135 N2O7[M+H] + :1092.0, found 1092.1.

[0904] Example 92

[0905] 10-((7Z)-27-hydroxy-21-(10-(((2Z)-non-2-enyl)oxy)-10-oxodecyl)-11-oxo-21,25-diaza-10-oxaheptacosan-7-en-25-yl)decanoic acid-(2Z)-non-2-en-1-yl ester [ka]

[0906] Step 1: Synthesis of (2Z)-non-2-en-1-yl10-bromoca plate [ka]

[0907] 10-Bromodecanoic acid (5 g, 19.91 mmol) was dissolved in 100 mL of DCM, and oxalyl chloride (7.58 g, 59.723 mmol) was slowly added. The resulting mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain 12.3 g of crude product. 150 mL of DCM and 5 g of TEA were added and dissolved. (2Z)-non-2-en-1-ol (2.83 g, 19.91 mmol) was added, and the mixture was stirred at 40°C for 4 hours. Once it was confirmed that the starting materials had been completely consumed by TLC, the mixture was directly mixed and purified by column chromatography at PE:EA = 10:1 to obtain 3.3 g of a colorless oily product (yield: 52.6%).

[0908] Step 2: Synthesis of 10-((7Z)-27-hydroxy-21-(10-(((2Z)-non-2-enyl)oxy)-10-oxodecyl)-11-oxo-21,25-diaza-10-oxaheptacosan-7-en-25-yl)decanoic acid-(2Z)-non-2-en-1-yl ester [ka]

[0909] Dissolve 2-((3-aminopropyl)amino)ethane-1-ol (0.1g, 846.17umol) in 20mL of MeCN, and add (2Z)-non-2-en-1-yl 10-bromocap plate (1.11g, 2.96 mmol), potassium carbonate (0.82g, 5.92 mmol) and KI (10 mg) were added, and the mixture was stirred at 85°C and left overnight. 50 mL of water and 50 mL of EA were added, and after liquid-liquid extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Column chromatography was performed using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 190 mg of a pale yellow oily product (yield: 22.4%).

[0910] ESI-MS m / z:cald for C 62 H 117 N2O7[M+H] + :1001.9, found 1001.9.

[0911] Example 93

[0912] Decyl 4-(20-(2-hydroxyethyl)-12,24-dioxo-16,20-diaza-11,25-dioxapentatriacontan-16-yl)butanoate [ka]

[0913] Step 1: Synthesis of Decyl 4-Bromobutanoate [ka]

[0914] Decane-1-ol (10 g, 63.18 mmol) and 4-bromobutyric acid (11.61 g, 69.49 mmol) were mixed and heated to 65°C. Once the reaction mixture was completely melted, 3 drops of concentrated sulfuric acid were added and the mixture was stirred overnight at 65°C. After the reaction was complete, heating was stopped and EA was added. The mixture was washed with 100 mL of aqueous solution and 100 mL of saturated NaHCO3 solution. The aqueous phase was removed, and the organic phase was washed with saturated brine. The mixture was then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Purification by column chromatography at PE:EA = 10:1 yielded 15.2 g of a colorless oily product (yield 78.3%).

[0915] Step 2: Synthesis of Decyl 4-(20-(2-hydroxyethyl)-12,24-dioxo-16,20-diaza-11,25-dioxapentatriacontan-16-yl)butanoate [ka]

[0916] 2-((3-aminopropyl)amino)ethane-1-ol (1 g, 8.46 mmol) was dissolved in 50 mL of MeCN, and decyl 4-bromobutanoate (9.10 g, 29.62 mmol), potassium carbonate (7.02 g, 50.77 mmol), and KI (20 mg) were added. The mixture was stirred at 85°C and left overnight. 100 mL of water and 100 mL of EA were added, and after liquid-liquid extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 yielded 302.4 mg of a pale yellow oily product (yield: 4.44%).

[0917] ESI-MS m / z :cald for C 47 H 93 N2O7[M+H] + :797.7, found 798.45.

[0918] Example 94

[0919] Dodecyl 4-(22-(2-hydroxyethyl)-14,26-dioxo-18,22-diaza-13,27-dioxanatriacontan-18-yl)butanoate [ka]

[0920] Step 1: Synthesis of dodecyl-4-bromobutanoate [ka]

[0921] Dodecane-1-ol (12.0 mL, 53.67 mmol) and 4-bromobutyric acid (9.86 g, 59.03 mmol) were mixed and heated to 65°C. Once the reaction mixture was completely melted, 3 drops of concentrated sulfuric acid were added, and stirring was continued overnight at 65°C. After the reaction was complete, heating was stopped, and the mixture was washed with 100 mL of EA and 100 mL of saturated NaHCO3 solution. The aqueous phase was removed, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Purification by column chromatography at PE:EA = 10:1 yielded 17.8 g of a colorless oily product (yield 98.9%).

[0922] Step 2: Dodecyl 4-(22-(2-hydroxyethyl)-14,26-dioxo-18,22-diaza-13,27-dioxanatriacontan-18-yl)butanoate [ka]

[0923] 2-((3-aminopropyl)amino)ethane-1-ol (1 g, 8.46 mmol) was dissolved in 50 mL of MeCN, and dodecyl 4-bromobutanoate (9.93 g, 29.62 mmol), potassium carbonate (7.02 g, 50.77 mmol), and KI (20 mg) were added. The mixture was stirred at 85°C and left overnight. 100 mL of water and 100 mL of EA were added, and after liquid-liquid extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Column chromatography was performed using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 3.64 g of a pale yellow oily product (yield: 48.45%).

[0924] ESI-MS m / z:cald for C 53 H 105 N2O7[M+H] + :881.8, founded 881.8.

[0925] Example 95

[0926] 8-((6Z,10Z,50Z,53Z)-32-(3-hydroxypropyl)-20,40-dioxo-28,32-diaza-19,41-dioxanonepentacontan-6,9,50,53-tetraen-28-yl)(10Z,12Z)-octadeca-9,12-dien-1-yloctanoate [ka]

[0927] Step 1: Synthesis of (10Z,12Z)-octadeca-9,12-diene-1-yl-8-bromooctanoate [ka]

[0928] (10Z,12Z)-octadeca-9,12-dien-1-ol (2 g, 7.51 mmol) and 8-bromooctanoic acid (1.67 g, 8.26 mmol) were mixed and heated to 65°C. Once the reaction mixture was completely melted, 3 drops of concentrated sulfuric acid were added, and stirring was continued overnight at 65°C. After the reaction was complete, heating was stopped, and the mixture was washed with 100 mL of EA and 100 mL of saturated NaHCO3 solution. The aqueous phase was removed, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Purification by column chromatography at PE:EA = 10:1 yielded 1.98 g of a colorless oily product (yield 55.9%).

[0929] Step 2: Synthesis of 8-((30Z,33Z)-8-(8-(((10Z,12Z)-octadeca-9,12-dienyl)oxy)-8-oxooctyl)-2,2,3,3-tetramethyl-20-oxo-8,12-diaza-4,21-dioxa-3-cyrannotriacontan-30,33-dien-12-yl)-(10Z,12Z)-octadeca-9,12-dien-1-yloctanoate [ka]

[0930] 3-((2,2,3,3-tetramethyl-4-oxa-3-silahept-7-yl)amino)propan-1-amine (200 mg, 0.81 mmol) was dissolved in 20 mL of MeCN, and (10Z,12Z)-octadeca-9,12-dien-1-yl8-bromooctanoate (1.3 g, 2.84 mmol), potassium carbonate (672.5 mg, 4.87 mmol), and KI (10 mg) were added. The mixture was stirred at 85°C and left overnight. 50 mL of water and 50 mL of EA were added, and after liquid-liquid extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Column chromatography was performed using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 759.2 mg of a pale yellow oily product (yield: 66%).

[0931] Step 3: Synthesis of 8-((6Z,10Z,50Z,53Z)-32-(3-hydroxypropyl)-20,40-dioxo-28,32-diaza-19,41-dioxanonapentacontan-6,9,50,53-tetraen-28-yl)-(10Z,12Z)-octadeca-9,12-dien-1-yloctanoate [ka]

[0932] 8-((30Z,33Z)-8-(8-((10Z,12Z)-octadeca-9,12-dienyl)oxy}-8-oxooctyl)-2,2,3,3-tetramethyl-20-oxo-8,12-diaza-4,21-dioxa-3-cyrannotriacontan-30,33-dien-12-yl)-(10Z,12Z)-octadeca-9,12-dien-1-yloctanoate (759.2 mg, 0.54 mmol) was dissolved in 10 mL of THF, TBAF (198.42 mg, 0.76 mmol) was added, and the mixture was stirred overnight at room temperature. The mixture was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 566 mg of a pale yellow oily product (yield: 80.9%).

[0933] ESI-MS m / z:cald for C 84 H 155 N2O7[M+H] + :1304.2, found 1304.65.

[0934] Example 96

[0935] 8-((6Z,10Z,46Z,49Z)-30-(3-hydroxypropyl)-20,36-dioxo-26,30-diaza-19,37-dioxapentatriacontane-6,9,46,49-tetraen-26-yl)(7Z,10Z)-hexadeca-7,10-dien-1-yloctanoate [ka]

[0936] Step 1: Synthesis of (10Z,12Z)-octadeca-9,12-dien-1-yl-6-bromohexanoate [ka]

[0937] (10Z,12Z)-octadeca-9,12-dien-1-ol (2 g, 7.51 mmol) and 6-bromohexanoic acid (1.61 g, 8.26 mmol) were mixed and heated to 65°C. Once the reaction mixture was completely melted, 3 drops of concentrated sulfuric acid were added, and stirring was continued overnight at 65°C. After the reaction was complete, heating was stopped, and the mixture was washed with 100 mL of EA and 100 mL of saturated NaHCO3 solution. The aqueous phase was removed, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Purification by column chromatography at PE:EA = 10:1 yielded 1.67 g of a colorless oily product (yield 51%).

[0938] Step 2: Synthesis of 8-((28Z,31Z)-8-(6-(((10Z,12Z)-octadeca-9,12-dienyl)oxy)-6-oxohexyl)-2,2,3,3-tetramethyl-18-oxo-8,12-diaza-4,19-dioxa-3-silaheptatriacontan-28,31-dien-12-yl)(7Z,10Z)-hexadeca-7,10-dien-1-yloctanoate [ka]

[0939] 3-((2,2,3,3-tetramethyl-4-oxa-3-silahept-7-yl)amino)propan-1-amine (200 mg, 0.81 mmol) was dissolved in 20 mL of MeCN, and (10Z,12Z)-octadeca-9,12-dien-1-yl-6-bromohexanoate (1.3 g, 2.84 mmol), potassium carbonate (672.5 mg, 4.87 mmol), and KI (10 mg) were added. The mixture was stirred at 85°C and left overnight. 50 mL of water and 50 mL of EA were added, and after liquid-liquid extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. Column chromatography was performed using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 675 mg of a pale yellow oily product (yield: 62.5%).

[0940] Step 3: Synthesis of 8-(6Z,10Z,46Z,49Z)-30-(3-hydroxypropyl)-20,36-dioxo-26,30-diaza-19,37-dioxapentatriacontan-6,9,46,49-tetraen-26-yl)(7Z,10Z)-hexadeca-7,10-dien-1-yloctanoate [ka]

[0941] Dissolve 8-(((28Z,31Z)-8-(6-((10Z,12Z)-octadeca-9,12-dienyl)oxy)-6-oxohexyl)-2,2,3,3-tetramethyl-18-oxo-8,12-diaza-4,19-dioxa-3-silaheptatriacontan-28,31-dien-12-yl)(7Z,10Z)-hexadeca-7,10-dien-1-yloctanoate (675 mg, 0.51 mmol) in 10 mL of THF, TBAF (198 mg, 0.76 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 457 mg of a pale yellow oily product (yield: 73.8%).

[0942] ESI-MS m / z:cald for C 78 H 143 N2O7[M+H] + :1220.1, found 1220.75.

[0943] Example 97

[0944] 8,8'-(3-((2-hydroxyethyl)(8-oxo-8-((Z)-pento-2-ene-1-oxy)oxy)octyl)amino)propyl)azadiyl)dioctanoate [ka]

[0945] Step 1: Synthesis of (Z)pento-2-en-1-yl-8-bromooctanoate [ka]

[0946] 8-bromooctanoic acid (7.23 g, 32.4 mmol) was dissolved in 100 mL of DCM, and oxalyl chloride (4.94 g, 38.89 mmol) was slowly added. The resulting mixture was refluxed for 4 hours, then concentrated under reduced pressure to obtain the crude product. Half of this was taken, and DCM (150 ml) and TEA (3.28 g, 32.4 mmol) were added and dissolved. Then cis-2-penten-1-ol (1.40 g, 16.2 mmol) was added, and the mixture was stirred at 40°C for 4 hours. Once it was confirmed that the starting materials had been completely consumed by TLC, the mixture was directly mixed. The target molecule was then purified by column chromatography at a ratio of PE:EA = 15:1 to obtain 4.0 g (yield: 84.78%).

[0947] Step 2: Synthesis of 8,8'-(3-((2-hydroxyethyl)(8-oxo-8-((Z)-pento-2-ene-1-oxy)oxy)octyl)amino)propyl)azadiyl)dioctanoate [ka]

[0948] N-(2-hydroxyethyl)-1,3-propanediamine (59.1 mg, 0.5 mmol) was dissolved in DMF (5 mL), and (Z)pento-2-en-1-yl 8-bromooctanoate (509 mg, 1.75 mmol), potassium carbonate (345 mg, 2.5 mmol), and KI (13 mg) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (50 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.1 g of the target molecule (yield: 26.7%).

[0949] ESI-MS m / z:cald for C 44 H 81 N2O7[M+H] + : 749.6, found 749.45

[0950] 1 H NMR (400 MHz, CDCl3)δ 5.71 - 5.59 (m, 3H), 5.55 - 5.43 (m, 3H), 4.62 (m, 6H), 3.67 (t, J = 5.0 Hz, 2H), 2.99-2.90 (m, 1H), 2.87-2.78 (m, 4H), 2.74 - 2.65 (m, 4H), 2.61 - 2.51 (m, 2H), 2.31 (t, J = 7.5 Hz, 6H), 2.17-2.07 (m, 6H), 2.02-1.88 (m, 2H), 1.70-1.56 (m, 10H), 1.54-1.44 (m, 2H), 1.39-1.24 (m, 20H), 1.00 (t, J = 7.5 Hz, 9H).

[0951] Example 98

[0952] Tetraundecyl 8,8',8'',8''-(((3-hydroxypropyl)azanegyl)di(propane-3,1-diyl))di(azantriyl)tetraoctanoate [ka]

[0953] Step 1: Synthesis of 8,8',8'',8''-((azanejyldi(propane-3,1-diyl))di(azantriyl))tetraundecyltetraoctanoate [ka]

[0954] Di(3-aminopropyl)amine (191.32 mg, 1.46 mmol) was dissolved in DMF (5 mL), and undecyl 8-bromooctanoate (2.2 g, 5.83 mmol), potassium carbonate (1 g, 7.29 mmol), and KI (50 mg) were added, respectively. The mixture was stirred at 60°C for 6 hours. An appropriate amount of water was added, and then EA (100 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.62 g of a colorless oily product (yield: 32.28%).

[0955] ESI-MS m / z:cald for C 82 H 162 N3O8[M+H] + : 1317.2, found 1317.2

[0956] Step 2: Synthesis of tetraundecyl 8,8',8'',8''-(((3-hydroxypropyl)azanegyl)di(propane-3,1-diyl))di(azantriyl)tetraoctanoate [ka]

[0957] 8,8',8'',8''-((azadiyldi(propane-3,1-diyl))di(azantriyl))tetraundecyltetraoctanoate (620 mg, 0.47 mmol) was dissolved in DMF (5 mL), and 3-chloro-1-propanol (88.87 mg, 0.94 mmol), potassium carbonate (276.4 mg, 2 mmol), and KI (50 mg) were added, respectively, and the mixture was stirred at 90°C for 16 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1. 0.14 g of the target molecule (yield: 21.66%) was obtained.

[0958] ESI-MS m / z:cald for C85 H 168 N3O9[M+H] + : 1375.3, found 1375.15

[0959] 1 H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 8H), 3.80-3.65 (m, 3H), 2.83 - 2.67 (m, 9H), 2.83 - 2.37 (m, 12H), 2.28 (t, J = 7.5 Hz, 8H), 1.91-1.71 (m, 5H), 1.67-1.52 (m, 20H), 1.50 - 1.40 (m, 3H), 1.44 - 1.17 (m, 87H), 0.87 (t, J = 6.7 Hz, 12H).

[0960] Example 99

[0961] Tetratridecyl 8,8',8'',8''-(((3-hydroxypropyl)azanegyl)di(propane-3,1-diyl))di(azantriyl)tetraoctanoate [ka]

[0962] Step 1: Synthesis of tetratridecyl 8,8',8'',8''-((azanejyldi(propane-3,1-diyl))di(azantriyl))tetraoctanoate [ka]

[0963] Di(3-aminopropyl)amine (243 mg, 1.85 mmol) was dissolved in DMF (8 mL), and tridecyl 8-bromooctanoate (3 g, 7.4 mmol), potassium carbonate (1.28 g, 9.25 mmol), and KI (50 mg) were added, respectively. The mixture was stirred at 60°C for 6 hours. An appropriate amount of water was added, and then EA (100 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.76 g of the target molecule (yield: 28.74%).

[0964] ESI-MS m / z:cald for C 90 H 178 N3O8[M+H] + : 1429.4, found 1429.4

[0965] Step 2: Tetratridecyl 8,8',8'',8''-(((3-hydroxypro Synthesis of (Pyr)azanejyl)di(propane-3,1-diyl)di(azantriyl)tetraoctanoate [ka]

[0966] Tetratridecyl 8,8',8'',8''-((azanejyldi(propane-3,1-diyl))di(azantriyl))tetraoctanoate (760 mg, 0.53 mmol) was dissolved in DMF (5 mL), and 3-chloro-1-propanol (100.2 mg, 1.06 mmol), potassium carbonate (276.4 mg, 2 mmol), and KI (50 mg) were added, respectively. The mixture was stirred at 90°C for 16 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.16 g of the target molecule (yield: 20.29%).

[0967] ESI-MS m / z:cald for C93 H 184 N3O9[M+H] + : 1487.4, found 1488.4

[0968] 1 H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 8H), 3.77 (t, J = 5.1 Hz, 2H), 2.62 (t, J = 5.5 Hz, 3H), 2.50-2.32 (m, 16H), 2.28 (t, J = 7.5 Hz, 8H), 1.74-1.52 (m, 22H), 1.51-1.35 (m, 10H), 1.34-1.20 (m, 102H),0.87 (t, J = 6.7 Hz, 12H).

[0969] Example 100

[0970] 4,4'-Ditridecyl((5-((3-Hydroxypropyl)(4-Oxo-4-(Tridecyloxy)butyl)aminopentyl)azetidinyl)dibutanoate [ka]

[0971] Step 1: Synthesis of tridecyl 4-bromobutanoate [ka]

[0972] Tridecyl 4-bromobutanoate was obtained using trideca-1-ol and 4-bromobutyric acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain 14 g of the target molecule (yield: 66.9%).

[0973] Step 2: Synthesis of 4,4'-Ditridecyl((5-(4-Oxo-4-(tridecyloxy)butyl)aminopentyl)azetidinyl)dibutanoate [ka]

[0974] 1,5-Pentanediamine (633.7 mg, 6.2 mmol) was dissolved in DMF (35 mL), and tridecyl 4-bromobutanoate (6.5 g, 18.6 mmol), potassium carbonate (3.73 g, 26.96 mmol), and KI (50 mg) were added separately. The mixture was stirred at 60°C for 6 hours. An appropriate amount of water was added, and then EA (100 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 565 mg of the target product (yield: 10.04%).

[0975] ESI-MS m / z:cald for C 56 H 111 N2O6[M+H] + : 907.8, found 907.8

[0976] Step 3: Synthesis of 4,4'-Ditridecyl((5-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)aminopentyl)azetidinyl)dibutanoate [ka]

[0977] 4,4'-Ditridecyl((5-(4-oxo-4-(tridecyloxy)butyl)aminopentyl)azetidinyl)dibutanoate (565 mg, 0.62 mmol) was dissolved in DMF (5 mL), and 3-chloro-1-propanol (118 mg, 1.25 mmol), potassium carbonate (258 mg, 1.87 mmol), and KI (50 mg) were added, respectively. The mixture was stirred at 90°C for 16 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 0.06 g of the target product (yield: 9.97%).

[0978] ESI-MS m / z:cald for C 59 H 117 N2O7[M+H] + : 965.9, found 965.8

[0979] 1 H NMR (400 MHz, CDCl3)δ 4.11- 4.00 (m, 6H), 3.82-3.64 (m, 2H), 2.68-2.62 (m, 1H), 2.52-2.32 (m, 10H), 2.31-2.20 (m, 6H), 2.10-1.87 (m, 2H), 1.85-1.66 (m, 9H), 1.65-1.55 (m, 6H), 1.38-1.16 (m, 65H), 0.88 (t, J = 6.7 Hz, 9H).

[0980] Example 101

[0981] 4,4'-Ditridecyl((4-((3-Hydroxypropyl)(4-Oxo-4-(Tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate [ka]

[0982] Step 1: Synthesis of 4,4'-Ditridecyl((4-(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate [ka]

[0983] Using tridecyl 4-bromobutanoate and 1,4-butanediamine as starting materials, 4,4'-ditridecyl((4-(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain 1 g of the target molecule (yield: 14.84%).

[0984] ESI-MS m / z:cald for C 55 H 109 N2O6[M+H] + : 893.8, found 893.8

[0985] Step 2: Synthesis of 4,4'-Ditridecyl((4-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate [ka]

[0986] Using 4,4'-ditridecyl((4-(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate and 3-chloro-1-propanol as starting materials, 4,4'-ditridecyl((4-((3-hydroxypropyl)(4-oxo-4-(tridecyloxy)butyl)amino)butyl)azetidinyl)dibutanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain 0.06 g of the target molecule (yield: 6.3%).

[0987] ESI-MS m / z:cald for C 58 H 115 N2O7[M+H] + : 951.9, found 951.8

[0988] 1H NMR (400 MHz, CDCl3)δ 4.12-3.94 (m, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.73 - 2.59 (m, 2H), 2.51-2.36 (m, 9H), 2.31 (t, J = 7.4 Hz, 6H), 1.89 - 1.78 (m, 2H), 1.77 - 1.65 (m, 6H), 1.64 - 1.54 (m, 6H), 1.50 - 1.35 (m, 6H), 1.35 - 1.17 (m, 60H), 0.88 (t, J = 6.7 Hz, 9H).

[0989] Example 102

[0990] 4,4'-Didecyl((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azetidinyl)dibutanoate [ka]

[0991] Step 1: Synthesis of Decyl 4-Bromobutanoate [ka]

[0992] Decyl 4-bromobutanoate was obtained using decane-1-ol and 4-bromobutyric acid as starting materials, following step 1 of Example 3. The crude product was purified by column chromatography to obtain 0.06 g of the target molecule (yield: 6.3%).

[0993] Step 2: Synthesis of 4,4'-Ditridecyl((5-(4-Oxo-4-(tridecyloxy)butyl)aminopentyl)azetidinyl)dibutanoate [ka]

[0994] Using decyl 4-bromobutanoate and 1,4-butanediamine as starting materials, 4,4'-ditridecyl((5-(4-oxo-4-(tridecyloxy)butyl)amino)pentyl)azetidinyl)dibutanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain 700 mg of the target molecule (yield: 9.35%).

[0995] ESI-MS m / z:cald for C 46 H 91 N2O6[M+H] + : 767.7, found 767.7

[0996] Step 3: Synthesis of 4,4'-didecyl((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azetidinyl)dibutanoate [ka]

[0997] Using 4,4'-ditridecyl((5-(4-oxo-4-(tridecyloxy)butyl)amino)pentyl)azetidinyl)dibutanoate and 3-chloro-1-propanol as starting materials, 4,4'-didecyl((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azetidinyl)dibutanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain 0.1 g of the target molecule (yield: 13.29%).

[0998] ESI-MS m / z:cald for C 58 H 115 N2O7[M+H] + : 951.9, found 951.9

[0999] 1 H NMR (400 MHz, CDCl3)δ 4.05 (m, 2.7 H z, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.71 - 2.62 (m, 2H), 2.52 - 2.36 (m, 10H), 2.31 (t, J = 7.3 Hz, 6H), 1.85 - 1.78 (m, 2H), 1.78 - 1.66 (m, 6H), 1.66 - 1.56 (m, 6H), 1.49 - 1.39 (m, 4H), 1.39 - 1.18 (m, 61H), 0.88 (t, J = 6.7 Hz, 9H).

[1000] Example 103

[1001] 4,4'-Didodecyl((4-(dodecoxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azetidinyl)dibutanoate [ka]

[1002] Step 1: Synthesis of dodecyl-4-bromobutanoate [ka]

[1003] Using dodecane-1-ol and 4-bromobutyric acid as starting materials, dodecyl 4-bromobutanoate was obtained by referring to Step 1 of Example 3. The crude product was purified by column chromatography to obtain 10.25 g of the target molecule (yield: 91.87%).

[1004] Step 2: Synthesis of 4,4'-didodecyl((4-(dodecoxy)-4-oxobutyl)aminobutyl)azetidinyl)dibutanoate [ka]

[1005] Using dodecyl 4-bromobutanoate and 1,4-butanediamine as starting materials, 4,4'-didodecyl((4-(dodecyloxy)-4-oxobutyl)amino)butyl)azetidinyl)dibutanoate was obtained by referring to step 2 of Example 19. The crude product was purified by column chromatography to obtain 900 mg of the target molecule (yield: 10.37%).

[1006] ESI-MS m / z:cald for C 52 H 103 N2O6[M+H] + : 851.8, found 851.8

[1007] Step 3: Synthesis of 4,4'-didodecyl((4-(dodecoxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azetidinyl)dibutanoate [ka]

[1008] Using 4,4'-didodecyl((4-(dodecoxy)-4-oxobutyl)amino)butyl)azetidinyl)dibutanoate and 3-chloro-1-propanol as starting materials, 4,4'-didodecyl((4-(dodecoxy)-4-oxobutyl)(3-hydroxypropyl)amino)butyl)azetidinyl)dibutanoate was obtained by referring to step 3 of Example 19. The crude product was purified by column chromatography to obtain 85 mg of the target molecule (yield: 8.84%).

[1009] ESI-MS m / z:cald for C 55 H 109 N2O7[M+H] + : 909.8, found 909.8

[1010] 1H NMR (400 MHz, CDCl3)δ 4.12-3.93 (m, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.73 - 2.62 (m, 2H), 2.56 - 2.37 (m, 9H), 2.35 - 2.27 (m, 7H), 1.89 - 1.65 (m, 8H), 1.66 - 1.54 (m, 6H), 1.51-1.36 (m, 4H), 1.37 - 1.17 (m, 55H), 0.88 (t, J = 6.8 Hz, 9H).

[1011] Example 104

[1012] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((4-(3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azetidinyl)dibutanoate [ka]

[1013] Step 1: Synthesis of (9Z,12Z)-octadeca-9,12-diene-1-yl-4-bromobutanoate [ka]

[1014] 4-bromobutyric acid (12.5 g, 74.85 mmol) and (9Z,12Z)-octadeca-9,12-dien-1-ol (19.95 g, 74.85 mmol) were stirred at 60°C for 0.5 hours, then dissolved, and 3 drops of concentrated sulfuric acid were added. The mixture was reacted at 60°C for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 23 g of the desired product (yield: 76.55%).

[1015] Step 2: Synthesis of (4-((3-((t-butyldimethylsilyl)oxy)propyl)amino)butyl)t-butylcarbamate [ka]

[1016] 2-Methylpropai-2-yl[(4-aminobutyl)amino]methylformate (4.13 g, 21.96 mmol) was dissolved in DMF (100 mL), and 7-bromo-2,2,3,3-tetramethyl-4-oxo-3-silaheptane (5.56 g, 21.96 mmol), potassium carbonate (6.07 g, 43.91 mmol), and KI (0.36 g, 2.20 mmol) were added, respectively, and the mixture was stirred at 80°C for 18 hours. 500 mL of water was added, and then EA (100 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 2.74 g of the target product (yield: 34.6%).

[1017] ESI-MS m / z:cald for C 18 H 41 N2O3Si [M+H] + : 361.3, found 361.3

[1018] Step 3: Synthesis of (4-((3-((t-butyldimethylsilyl)oxy)propyl)amino)butyl)t-butylcarbamate [ka]

[1019] (4-((3-((t-butyldimethylsilyl)oxy)propyl)amino)butyl)t-butylcarbamate (5.33 g, 14.78 mmol) was dissolved in DMF (70 mL), and (9Z,12Z)-octadeca-9,12-dien-1-yl 4-bromobutanoate (6.14 g, 14.78 mmol), potassium carbonate (4.09 g, 29.56 mmol), and KI (250 mg, 1.478 mmol) were added, respectively. The mixture was stirred at 85°C for 16 hours. After cooling to room temperature, the mixture was diluted with 200 mL of water, and then extracted with EA (100 mL x 3). The combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 7.81 g of a colorless oily product (yield: 76.0%).

[1020] ESI-MS m / z:cald for C 40 H 79 N2O5Si [M+H] + : 695.6, found 695.6

[1021] Step 4: Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl-4-((4-aminobutyl)(3-hydroxypropyl)amino)butanoate [ka]

[1022] (9Z,12Z)-Octadeca-9,12-dien-1-yl-4-((4-((t-butoxyoxo)amino)butyl)(3-(((t-butyldimethylsilyl)oxy)propyl)amino)butanoate (7.81 g, 11.23 mmol) was dissolved in DCM (50 mL), and then trimethylsilyltrifluoromethanesulfonate (4.99 g, 22.46 mmol) was added. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with 50 mL of DCM, then washed twice with saturated sodium bicarbonate aqueous solution, the organic phase was dried, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 2.58 g of the target product (yield: 47.8%).

[1023] ESI-MS m / z:cald for C 29 H 57 N2O3[M+H] + : 481.4, Found 481.4

[1024] Step 5: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((4-(3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)butyl)azetidinyl)dibutanoate [ka]

[1025] (9Z,12Z)-octadeca-9,12-dien-1-yl-4-((4-aminobutyl)(3-hydroxypropyl)amino)butanoate (2.58 g, 5.366 mmol) and (9Z,12Z)-octadeca-9,12-dien-1-yl-4-bromobutanoate (5.57 g, 13.4 mmol) were added to a 100 mL single-necked flask. Then, 30 mL of DMF, potassium carbonate (2.22 g, 16.1 mmol), and potassium iodide (50 mg) were added. The mixture was stirred at 85°C for 16 hours. After cooling to room temperature, the mixture was diluted with 100 mL of water. Then, it was extracted three times with EA (100 mL x 3). The organic phases were combined and washed twice with saturated sodium bicarbonate aqueous solution. After drying the organic phases, the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 2.5 g of the target product (yield: 40.5%).

[1026] ESI-MS m / z:cald for C 73 H 133 N2O7[M+H] + : 1150.0, found 1150.0

[1027] 1 H NMR (400 MHz, CDCl3)δ 5.56 - 5.16 (m, 12H), 4.17 - 3.95 (m, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 6.5 Hz, 6H), 2.64 (t, J = 5.7 Hz, 2H), 2.53-2.36 (m, 10H), 2.31 (t, J = 7.4 Hz, 6H), 2.05 (q, J = 6.9 Hz, 12H), 1.84-1.64 (m, 10H), 1.64 - 1.56 (m, 6H), 1.52-1.19 (m, 51H), 0.89 (t, J = 6.7 Hz, 9H).

[1028] Example 105

[1029] 4,4'-(3-(((2-hydroxyethyl)((E)-4-oxo-4-(undecyloxy)buto-2-en-1-yl)amino)propyl)azadiyl)(2E,2'E)-di(buto-2enoic acid) [ka]

[1030] Step 1: Synthesis of undecyl(E)-4-bromobut-2-enoic acid [ka]

[1031] 4-bromocrotonic acid (4.79 g, 29 mmol) and undecanol (5 g, 29 mmol) were stirred at 60°C for 0.5 hours, then dissolved, and 3 drops of concentrated sulfuric acid were added. The mixture was reacted at 60°C for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 15:1 to obtain 7.7 g of a colorless oily product (yield: 83.11%).

[1032] Step 2: Synthesis of di(2-hexyldecyl)4,4'-((3-(di(2-hydroxyethyl)amino)propyl)azadiyl)dibutanoate [ka]

[1033] Undecyl(E)-4-bromobut-2-enoic acid (4.225 g, 13.327 mmol) was dissolved in DMF (15 mL), and 2-(3-aminopropyl)amino)ethane-1-ol (350 mg, 2.96 mmol), potassium carbonate (2.05 g, 14.8 mmol), and KI (50 mg) were added, respectively. The mixture was stirred at 85°C for 5 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was subjected to column chromatography and gradient elution to 50% with PE:EA to obtain 0.185 g of a pale yellow oily product (yield: 7.5%).

[1034] ESI-MS m / z:cald for C 50 H 93 N2O7[M+H] + : 833.7, found 833.7.

[1035] 1 H NMR (400 MHz, CDCl3)δ 6.90 (m, 2H), 5.98 (m, 2H), 4.17 - 3.98 (m, 6H), 3.98 - 3.89 (m, 1H), 3.87 - 3.76 (m, 1H), 3.70 - 3.55 (m, 1H), 3.21 (m, 3H), 2.84-2.71 (m, 1H), 2.70 - 2.57 (m, 1H), 2.57 - 2.43 (m, 2H), 2.42 - 2.38 (m, 1H), 2.38 - 2.20 (m, 2H), 2.17 - 2.00 (m, 1H), 1.90 - 1.78 (m, 1H), 1.78 - 1.68 (m, 3H), 1.67 - 1.46 (m, 8H), 1.45 - 1.05 (m, 50H), 0.87 (t, J = 6.8 Hz, 9H).

[1036] Example 106

[1037] 4,4'-(3-((3-hydroxypropyl)((E)-4-oxo-4-(undecyloxy)buto-2-en-1-yl)amino)propyl)azanegyl)(2E,2'E)-di(buto-2-enoic acid) [ka]

[1038] Step 1: Synthesis of undecyl(E)-2,2,3,3-tetramethyl-8,12-di((E)-4-oxo-4-(undecyloxy)buto-2-en-1-yl)-4-oxo-8,12-diaza-3-silane-hexadectetradecanoate [ka]

[1039] Undecyl(E)-4-bromobut-2-enoic acid (3.5 g, 10.96 mmol) was dissolved in DMF (45 mL), and N1-(3-((t-butyldimethylsilyl)oxy)propyl)propane-1,3-diamine (600 mg, 2.43 mmol), potassium carbonate (1.68 g, 12.17 mmol), and KI (40 mg) were added, respectively. The mixture was stirred at 85°C for 5 hours. Next, EA (80 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was subjected to column chromatography and gradient elution to 40% with PE:EA to obtain 1.4 g of the target product (yield: 59.82%).

[1040] ESI-MS m / z:cald for C 57 H 109 N2O7Si [M+H] + : 961.8, found 961.8.

[1041] 1 H NMR (400 MHz, CDCl3)δ 6.99-6.77 (m, 3H), 5.98 (d, J = 15.9 Hz, 3H), 4.34 - 4.00 (m, 6H), 3.62 (t, J = 6.2 Hz, 2H), 3.28 - 3.15 (m, 6H), 2.58-2.23 (m, 6H), 1.72 - 1.61 (m, 9H), 1.42-1.17 (m, 49H), 0.97 - 0.80 (m, 18H), 0.04 (s, 6H).

[1042] Step 3: Synthesis of 4,4'-(3-((3-hydroxypropyl)((E)-4-oxo-4-(undecyloxy)buto-2-en-1-yl)amino)propyl)azanegyl)(2E,2'E)-di(buto-2enoic acid) [ka]

[1043] Undecyl(E)-2,2,3,3-tetramethyl-8,12-di((E)-4-oxo-4-(undecyloxy)buto-2-en-1-yl)-4-oxo-8,12-diaza-3-silane-hexadectetradecanoate was dissolved in DCM (25 mL), then TMSOTf (416 mg, 1.87 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM, then washed with saturated sodium bicarbonate, the organic phase was dried, and the mixture was concentrated under reduced pressure. The crude product was subjected to column chromatography and gradient elution to 60% with PE:EA to obtain 0.72 g of a pale yellow oily product (yield: 90.79%).

[1044] ESI-MS m / z:cald for C 51 H 95 N2O7[M+H] + : 847.7, found 847.7.

[1045] 1 H NMR (400 MHz, CDCl3)δ 6.91 (m, 3H), 6.32-5.68 (m, 3H), 4.12 (t, J = 6.8 Hz, 6H), 3.75 (t, J = 5.3 Hz, 2H), 3.7 - 3.3 (m, 6H), 2.64 (t, J = 5.9 Hz, 2H), 2.47 (m, 4H), 1.85-1.44 (m, 13H), 1.43 - 1.13 (m, 46H), 0.87 (t, J = 6.7 Hz, 9H).

[1046] Example 107

[1047] Dinonyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(undecyloxy)pentyl)aminopropyl)azanegyl)dipentanoate [ka]

[1048] Step 1: Synthesis of undecyl 5-bromopentanoate [ka]

[1049] 5-bromovareic acid (1.3 g, 7.0 mmol) and 1-undecanol (1.0 g, 5.8 mmol) were dissolved by stirring at 60°C, then one drop of concentrated sulfuric acid was added, and the mixture was reacted at 60°C for 6 hours. Once it was confirmed by TLC that the starting materials had been completely consumed, the mixture was directly mixed and purified by column chromatography at PE:EA = 30:1 to obtain 1.8 g of a colorless oily product (yield: 92.8%).

[1050] 1 H NMR (400 MHz, CDCl3)δ 4.06 (t, J = 6.7 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H), 2.34 (t, J = 7.3 Hz, 2H), 1.95 - 1.85 (m, 2H), 1.84 - 1.73 (m, 2H), 1.62 (m, 2H), 1.33 - 1.23 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H).

[1051] Step 2: Synthesis of dinonyl 5,5'-((3-((2-hydroxyethyl)(5-oxo-5-(undecyloxy)pentyl)amino)propyl)azanegyl)dipentanoate [ka]

[1052] Undecyl 5-bromopentanoate (684 mg, 2.0 mmol) is administered to MeCN (1 Dissolve in 0 mL of 2-((3-aminopropyl)amino)ethane-1-ol (60 mg, 0.5 mmol), potassium carbonate (352 mg, 2.6 mmol), and KI (8.3 mg, 0.05 mmol), respectively, and stir at 85°C for 16 hours. Next, extract with DCM (30 mL x 3), dry the combined organic phase, and concentrate under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 114 mg of a colorless oily product (yield: 25.3%).

[1053] ESI-MS m / z:cald for C 53 H 105 N2O7[M+H] + : 881.8, found 881.6.

[1054] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8 Hz, 6H), 3.54 (t, J = 5.2 Hz, 2H), 2.55 (t, J = 5.2 Hz, 2H), 2.51 - 2.35 (m, 10H), 2.31 (t, J = 7.6 Hz, 6H), 1.65 - 1.55 (m, 14H), 1.50 - 1.41 (m, 6H), 1.33 - 1.23 (m, 49H), 1.06 - 0.71 (m, 9H).

[1055] Example 108 Di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-(3-(3-hydroxypropyl)(4-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)amino)propyl)azanediyl)dibutanoate [ka]

[1056] Step 1: Synthesis of (9Z,12Z)-octadeca-9,12-diene-1-yl-4-bromobutanoate: [ka]

[1057] (9Z,12Z)-octadeca-9,12-dien-1-ol (10.0 g, 37.5 mmol) and 4-bromobutyric acid (7.5 g, 45.0 mmol) were mixed, and the mixture was heated to 60°C. Concentrated sulfuric acid (0.1 mL) was added, and the mixture was stirred at this temperature for 16 hours. When it was confirmed by TLC that the starting materials had been almost completely consumed, an appropriate amount of water was added, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, the solvent was evaporated, and the mixture was directly mixed and passed through a column to elute at PE:EA = 30:1 to obtain 7.9 g of a colorless oily product (yield: 50.7%).

[1058] 1 H NMR (400 MHz, CDCl3)δ 5.46 - 5.27 (m, 4H), 4.08 (t, J = 6.7 Hz, 2H), 3.47 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.24 - 2. 11 (m, 2H), 2.09 - 2.00 (m, 4H), 1.67 - 1.58 (m, 2H), 1.41 - 1.24 (m, 16H), 0.89 (t, J = 6.7 Hz, 3H).

[1059] Step 2: Synthesis of N1-(3-((t-butyldimethylsilyl)oxy)propyl)propane-1,3-diamine: [ka]

[1060] Propane-1,3-diamine (2.9 g, 39.5 mmol) was dissolved in methanol (30 mL), and while stirring, (3-bromopropoxy)(t-butyl)dimethylsilane (2.0 g, 7.9 mL) dissolved in methanol (20 mL) was added dropwise. The mixture was stirred at room temperature for 18 hours, and after the solvent evaporated, the mixture was directly mixed and eluted through a column at a DCM:MeOH(NH3) ratio of 10:1 to obtain 1.0 g of a colorless oily product (yield 50.4%).

[1061] ESI-MS m / z:cald for C 12 H 31 N2OSi [M+H] + :247.2, found 247.4.

[1062] 1 H NMR (400 MHz, CDCl3)3.68 (t, J = 6.1 Hz, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.72 - 2.62 (m, 4H), 1.74 - 1.59 (m, 4H), 1.53 (s, 3H), 0.88 (s, 9H), 0.04 (s, 6H).

[1063] Step 3: Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl2,2,3,3-tetramethyl-8-(4-(((6Z,9Z)-heptadeca-6,9-dien-1-yl)oxy)-4-oxobutyl)-12-(4-((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)-4-oxo-8,12-diaza-3-silahexadecane-16-acid ester [ka]

[1064] N1-(3-((t-butyldimethylsilyl)oxy)propyl)propan-1,3-diamine (0.5g, 1.9mmol) is dissolved in MeCN (27mL), and (9Z,12Z)-octadeca-9,12-dien-1-yl 4-bromobutanoate (2.7g, 6.5mmol), potassium carbonate (1.6g, 11.2mmol), and KI (31mg, 0.2 mmol) was added to each and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, then EA (20 mL x 3) was added and extracted. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with A:B = 30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 1.5 g of a colorless oily product (yield: 64.3%).

[1065] ESI-MS m / z:cald for C 78 H 145 N2O7Si[M+H] + : 1250.1, found 1250.3.

[1066] 1 H NMR (400 MHz, CDCl3)δ 5.45 - 5.26 (m, 12H), 4.04 (t, J = 6.8 Hz, 6H), 3.62 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.5 Hz, 6H), 2.54 - 2.36 (m, 11H), 2.33 - 2.27 (m, 6H), 2.08 - 2.01 (m, 12H), 1.78 - 1.67 (m, 7H), 1.64 - 1.57 (m, 8H), 1.37 - 1.26 (m, 50H), 0.96 - 0.82 (m, 18H), 0.04 (s, 6H).

[1067] Step 4: Synthesis of di((9Z,12Z)-octadeca-9,12-dien-1-yl)4,4'-((3-(3-hydroxypropyl)(4-(((6Z,9Z)-heptadeca-6,9-dien-1-yloxy)-4-oxobutyl)amino)propyl)azanegiyl)dibutanoate [ka]

[1068] (9Z,12Z)-Octadeca-9,12-dien-1-yl2,2,3,3-tetramethyl-8-(4-(((6Z,9Z)-heptadeca-6,9-dien-1-yl)oxy)-4-oxobutyl)-12-(4-((9Z,12Z)-Octadeca-9,12-dien-1-yl)oxy)-4-oxobutyl)-4-oxo-8,12-diaza-3-silahexadecane-16-acid ester (3.0g, 2.4 mmol) was dissolved in THF (20mL), and then 1.0 M Add TBAF tetrahydrofuran solution (4.8 mL, 4.8 mmol), stir at room temperature for 3 hours, add an appropriate amount of water, extract with EA (20 mL x 3), combine with the organic phase, dry, evaporate to dryness, the mixture is mixed, and eluted through a column with A:B = 10%~30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 0.8 g of a colorless oily product (yield: 27.9%).

[1069] ESI-MS m / z:cald for C 72 H 131 N2O7[M+H] + : 1136.0, found 1136.2.

[1070] 1 H NMR (400 MHz, CDCl3)δ 5.46 - 5.25 (m, 12H), 4.12 - 3.99 (m, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 6.5 Hz, 6H), 2.64 (m, 2H), 2.53 - 2.35 (m, 10H), 2.31 (t, J = 7.4 Hz, 6H), 2.11 - 1.98 (m, 12H), 1.86 - 1.66 (m, 11H), 1.64 - 1.59 (m, 6H), 1.42 - 1.23 (m, 48H), 0.89 (t, J (= 6.8 Hz, 9H).

[1071] Example 109

[1072] 4-(3-((2-hydroxyethyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)(4-oxide-4-(undecyloxy)butyl)amino)-4-oxobutanoate [ka]

[1073] Step 1: Synthesis of 4-oxo-4-(undecyloxy)butyric acid [ka]

[1074] Dihydrofuran-2,5-dione (1.0 g, 10.0 mmol) and 1-undecanol (1.7 g, 10.0 mmol) were dissolved in DMF (10 mL), then DMAP (1.2 g, 10.0 mmol) was added and the mixture was stirred at room temperature for 16 hours. An appropriate amount of 1N hydrochloric acid was then added, followed by extraction with DCM (30 mL x 3). The combined organic phase was dried and then concentrated under reduced pressure. A crude product of 2.7 g (yield: 99.2%) was obtained.

[1075] 1H NMR (400 MHz, CDCl3)δ 4.08 (t, J = 6.7 Hz, 2H), 2.70 - 2.64 (m, 2H), 2.57 - 2.63 (m, 2H), 1.67 - 1.55 (m, 2H), 1.33 - 1.22 (m, 16H), 0.87 (t, J = 6.8 Hz, 3H).

[1076] Step 2: Synthesis of (3-((2-((t-butyldimethylsilyl)oxy)ethyl)amino)propyl)t-butylcarbamate [ka]

[1077] (2-bromoethoxy)(t-butyl)dimethylsilane (4.8 g, 20.1 mmol) was dissolved in acetonitrile (100 mL), and (3-aminopropyl)t-butylcarbamate (3.5 g, 20.1 mmol) and potassium carbonate (5.5 g, 40.2 mmol) were added, respectively. The mixture was stirred at 80°C for 18 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 20:1 to obtain 2.8 g of a colorless oily product (yield: 41.9%).

[1078] ESI-MS m / z:cald for C 16 H 37 N2O3Si [M+H] + : 333.3, found 333.1.

[1079] 1 H NMR (400 MHz, CDCl3)δ 5.18 (br.s, 1H), 3.75 (t, J = 5.3 Hz, 2H), 3.22 (d, J = 6.5 Hz, 2H), 2.77 - 2.69 (m, 4H), 1.75 - 1.67 (m, 2H), 1.44 (s, 9H), 0.90 (s, 9H), 0.07 (s, 6H).

[1080] Step 4: Synthesis of Undecyl 4-((3-((t-butoxyoxo)amino)propyl)(2-((t-butyldimethylsilyl)oxy)ethyl)amino)butanoate [ka]

[1081] (3-((2-((t-butyldimethylsilyl)oxy)ethyl)amino)propyl)t-butylcarbamate (1.5 g, 4.5 mmol) was dissolved in acetonitrile (60 mL), and undecyl 4-bromobutanoate (2.2 g, 6.8 mmol), potassium carbonate (1.2 g, 9.0 mmol), and KI (83 mg, 0.5 mmol) were added, respectively, and the mixture was stirred at 85 °C for 16 hours. An appropriate amount of water was added, and then DCM (20 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 2.1 g of a colorless oily product (yield: 81.3%).

[1082] ESI-MS m / z:cald for C 31 H 65 N2O5Si [M+H] + : 573.5, found 573.7.

[1083] 1H NMR (400 MHz, CDCl3)δ 4.09 - 4.02 (m, 2H), 3.65 (t, J = 6.5 Hz, 2H), 3.17 (d, J = 6.3 Hz, 2H), 2.58 - 2.40 (m, 6H), 2.32 (t, J = 7.4 Hz, 2H), 1.81 - 1.69 (m, 2H), 1.68 - 1.54 (m, 6H), 1.43 (s, 9H), 1.26 (s, 15H), 0.92 - 0.86 (m, 12H), 0.05 (s, 6H).

[1084] Step 4: Synthesis of Undecyl 4-(3-aminopropyl)(2-((t-butyldimethylsilyl)oxy)ethyl)amino)butanoate [ka]

[1085] Undecyl 4-((3-((t-butoxyoxo)amino)propyl)(2-((t-butyldimethylsilyl)oxy)ethyl)amino)butanoate (1.5 g, 2.6 mmol) was dissolved in DCM (50 mL), TMSOTf (0.6 g, 2.6 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. After neutralization by dropwise addition to saturated sodium bicarbonate solution under an ice bath, an appropriate amount of water was added, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried together and evaporated to dryness. The mixture was mixed and eluted through a column at DCM:MeOH(NH3) = 20:1 to obtain 1.1 g of a colorless oily product (yield: 88.9%).

[1086] ESI-MS m / z:cald for C 26 H 57 N2O3Si[M+H] + : 473.4, found473.6.

[1087] 1H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 2H), 3.64 (m, 2H), 2.73 (t, J = 6.7 Hz, 1H), 2.60 - 2.43 (m, 6H), 2.31 (t, J = 7.4 Hz, 2H), 1.95 (m, 2H), 1.79 - 1.69 (m, 2H), 1.66 - 1.52 (m, 4H), 1.38 - 1.16 (m, 17H), 0.90 - 0.84 (m, 12H), 0.05 (s, 6H).

[1088] Step 5: Synthesis of 2,2,3,3-tetramethyl-7-(4-oxo-4-(undecyloxy)butyl)-4-oxo-7,11-diaza-3-silapentriacontane-15-undecylester [ka]

[1089] Undecyl 4-(3-aminopropyl)(2-((t-butyldimethylsilyl)oxy)ethyl)amino)butanoate (1.1 g, 2.3 mmol) was dissolved in acetonitrile (50 mL), and undecyl 4-bromobutanoate (0.8 g, 2.3 mmol), potassium carbonate (0.6 g, 4.6 mmol), and KI (10.6 mg, 0.06 mmol) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 800 mg of a colorless oily product (yield: 48.2%).

[1090] ESI-MS m / z:cald for C 41 H 85 N2O5Si[M+H] + : 713.6, found 713.4.

[1091] 1H NMR (400 MHz, CDCl3)δ 4.07 - 4.01 (m , 4H), 3.69 - 3.60 (m, 2H), 2.72 - 2.63 (m, 3H), 2.61 - 2.44 (m, 6H), 2.39 - 2.27 (m, 4H), 1.88 - 1.71 (m, 3H), 1.69 - 1.53 (m, 6H), 1.41 - 1.18 (m, 35H), 0.90 - 0.85 (m, 15H), 0.05 (s, 6H).

[1092] Step 6: Synthesis of 2,2,3,3-tetramethyl-12-oxo-7,11-di(4-oxo-4-(undecyloxy)butyl)-4-oxo-7,11-diaza-3-silapentriacontane-15-acid undecyl ester [ka]

[1093] 2,2,3,3-tetramethyl-7-(4-oxo-4-(undecyloxy)butyl)-4-oxo-7,11-diaza-3-silapentriacontane-15-undecylester (300 mg, 0.4 mmol) was dissolved in DMF (20 mL), and 4-oxo-4-(undecyloxy)butyric acid (120 mg, 0.4 mmol), DIEA (163 mg, 1.3 mmol), and HATU (176 mg, 0.5 mmol) were added separately. The mixture was stirred at room temperature for 2 hours. An appropriate amount of water was added, and then DCM (30 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with DCM:MeOH = 30:1 to obtain 250 mg of a colorless oily product (yield: 61.4%).

[1094] ESI-MS m / z:cald for C 56 H 111 N2O8Si [M+H] + : 967.8, found 967.6.

[1095] 1 H NMR (400 MHz, CDCl3)δ 4.10 - 3.99 (m, 6H), 3.67 - 3.59 (m, 2H), 3.38 - 3.25 (m, 4H), 2.69 - 2.52 (m, 6H), 2.51 - 2.40 (m, 4H), 2.36 - 2.24 (m, 4H), 1.95 - 1.78 (m, 2H), 1.77 - 1.67 (m, 3H), 1.65 - 1.57 (m, 8H), 1.31 - 1.23 (m, 47H), 0.90 - 0.85 (m, 18H), 0.04 (s, 6H).

[1096] Step 7: Synthesis of 4-(3-((2-hydroxyethyl)(4-oxo-4-(undecyloxy)butyl)amino)propyl)(4-oxide-4-(undecyloxy)butyl)amino)-4-oxobutanoate [ka]

[1097] 2,2,3,3-Tetramethyl-12-oxo-7,11-di(4-oxo-4-(undecyloxy)butyl)-4-oxo-7,11-diaza-3-silapentriacone Undecyl tan-15 acid (240 mg, 0.3 mmol) was dissolved in THF (5 mL), TBAF (97 mg, 0.4 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After neutralization by dropwise addition to saturated sodium bicarbonate solution under an ice bath, an appropriate amount of water was added, and the mixture was extracted with DCM (20 mL x 3). The organic phase was dried together and evaporated to dryness. The mixture was mixed and eluted through a column with DCM:MeOH(NH3) = 25:1 to obtain 150 mg of a colorless oily product (yield: 70.9%).

[1098] ESI-MS m / z:cald for C 50 H 97 N2O8[M+H] + : 853.7, found 853.5.

[1099] 1 H NMR (400 MHz, CDCl3)δ 4.13 - 3.98 (m, 6H), 3.60 - 3.49 (m, 2H), 3.40 - 3.28 (m, 4H), 2.72 - 2.52 (m, 6H), 2.52 - 2.41 (m, 4H), 2.39 - 2.25 (m, 4H), 2.01 - 1.91 (m, 1H), 1.91 - 1.85 (m, 1H), 1.85 - 1.76 (m, 3H), 1.75 - 1.58 (m, 8H), 1.32 - 1.24 (m, 48H), 0.88 (t, J = 6.7 Hz, 9H).

[1100] Example 110

[1101] Azetidinyl 4,4'-(4-((4-hydroxybutyl)(4-oxo-4-(undecyloxy)butyl)amino)butyl)dibutanoate [ka]

[1102] Step 1: Synthesis of azetidinyl 4,4'-(4-((4-hydroxybutyl)(4-oxo-4-(undecyloxy)butyl)amino)butyl)dibutanoate [ka]

[1103] Dinonyl 4,4'-(3-((4-oxo-4-(undecyloxy)butyl)amino)propyl)azetidinyl)dibutanoate (350 mg, 0.4 mmol) was dissolved in DMF (8 mL), and 1-chloro-4-butanol (98 mg, 0.9 mmol), potassium carbonate (179 mg, 1.3 mmol), and KI (21.6 mg, 0.1 mmol) were added, respectively, and the mixture was stirred at 85°C for 16 hours. Next, DCM (50 mL x 3) was added for extraction, and the combined organic phase was dried and concentrated under reduced pressure. The crude product was purified by column chromatography using DCM (containing 5% EA):MeOH = 50:1 to 5:1 to obtain 142 mg of a colorless oily product (yield: 40.3%).

[1104] ESI-MS m / z:cald for C 53 H 105 N2O7[M+H]+ : 881.8, found 881.6.

[1105] 1 H NMR (400 MHz, CDCl3)δ 4.12 - 3.98 (m, 6H), 3.55 (t, J = 4.8 Hz, 2H), 2.49 - 2.36 (m, 12H), 2.31 (t, J = 7.4 Hz, 6H), 1.88 - 1.80 (m, 2H), 1.80 - 1.72 (m, 5H), 1.72 - 1.57 (m, 12H), 1.54 - 1.45 (m, 2H), 1.45 - 1.23 (m, 47H), 0.88 (t, J = 6.7 Hz, 9H).

[1106] Example 111 Di((9Z,12Z)-octadeca-9,12-dien-1-yl)5,5'-((3-((3-hydroxypropyl)(5-((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-5-oxopentyl)amino)propyl)azanegiyl)dipentanoate [ka]

[1107] Step 1: Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl-5-bromopentanoate: [ka]

[1108] (9Z,12Z)-octadeca-9,12-dien-1-ol (5.0 g, 18.8 mmol) and 5-bromovareic acid (3.7 g, 20.6 mmol) were mixed. The mixture was heated to 60°C, then two drops of concentrated sulfuric acid were added. The mixture was stirred at this temperature for 16 hours. When it was confirmed by TLC that the starting materials had been almost completely consumed, an appropriate amount of water was added, and the mixture was extracted with EA (30 mL x 3). The organic phase was combined and evaporated to dryness. The mixture was then mixed and eluted through a column at PE:EA = 30:1 to obtain 7.2 g of a colorless oily product (yield: 89.3%).

[1109] 1 H NMR (400 MHz, CDCl3)δ 5.43 - 5.28 (m, 4H), 4.06 (t, J = 6.7 Hz, 2H), 3.41 (t, J = 6.6 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.34 (t, J = 7.2 Hz, 2H), 2.10 - 1.99 (m, 4H), 1.95 - 1.85 (m, 2H), 1.84 - 1.73 (m, 2H), 1.67 - 1.58 (m, 2H), 1.37 - 1.26 (m, 16H), 0.89 (t, J = 6.7 Hz, 3H).

[1110] Step 2: Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl2,2,3,3-tetramethyl-8-(5-(((6Z,9Z)-octa-6,9-dien-1-yl)oxy)-5-oxopentyl)-12-(5-((((9Z,12Z)-heptadeca-9,12-dien-1-yl(oxy))-5-oxypentyl)-4-oxo-8,12-diaza-3-silaheptadecane-17-acid ester: [ka]

[1111] N1-(3-((t-butyldimethylsilyl)oxy)propyl)propane-1,3-diamine (100 mg, 0.4 mmol) was dissolved in MeCN (15 mL), and (9Z,12Z)-octadeca-9,12-dien-1-yl 5-bromopentanoate (575 mg, 1.3 mmol), potassium carbonate (280 mg, 2.0 mmol), and KI (10 mg, 0.04 mmol) were added, respectively, and the mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (20 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with A:B = 30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 400 mg of a colorless oily product (yield: 76.3%).

[1112] ESI-MS m / z:cald for C 81 H 151 N2O7Si[M+H] + : 1292.1, found 1292.3.

[1113] 1 H NMR (400 MHz, CDCl3)δ 5.48 - 5.23 (m, 12H), 4.05 (t, J = 6.8 Hz, 6H), 3.62 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 6.5 Hz, 6H), 2.50 - 2.34 (m, 11H), 2.30 (t, J = 7.5 Hz, 6H), 2.10 - 1.98 (m, 12H), 1.70 - 1.53 (m, 18H), 1.49 - 1.40 (m, 6H), 1.37 - 1.26 (m, 47H), 0.93 - 0.83 (m, 18H), 0.04 (s, 6H).

[1114] Step 3: Di((9Z,12Z)-octadeca-9,12-dien-1-yl)5,5'-((3-((3-hydroxypropyl)(5-((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-5-oxopentyl)amino)propyl) Synthesis of (Nezyl)dipentanoate [ka]

[1115] (9Z,12Z)-Octadeca-9,12-dien-1-yl2,2,3,3-tetramethyl-8-(5-(((6Z,9Z)-Octadeca-6,9-dien-1-yl)oxy)-5-oxopentyl)-12-(5-((((9Z,12Z)-Heptadeca-9,12-dien-1-yl(oxy))-5-oxypentyl)-4-Oxo-8,12-diaza-3-silahe Dissolve butadecane-17-acid ester (400 mg, 0.3 mmol) in THF (10 mL), then add TBAF (196 mg, 0.6 mmol), stir at room temperature for 2 hours, add an appropriate amount of water, extract with EA (20 mL x 3), combine with the organic phase, dry, evaporate to dryness, the mixture is mixed, and eluted through a column with A:B = 10%~30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1).

[1116] ESI-MS m / z:cald for C 75 H 137 N2O7[M+H] + : 1178.0, found 1178.2.

[1117] 1 H NMR (400 MHz, CDCl3)δ 5.45 - 5.26 (m, 12H), 4.05 (t, J = 6.8 Hz, 6H), 3.77 (t, J = 5.2 Hz, 2H), 2.77 (t, J = 6.5 Hz, 6H), 2.63 (t, J = 5.7 Hz, 2H), 2.50 - 2.35 (m, 10H), 2.34 - 2.28 (m, 6H), 2.10 - 1.99 (m, 13H), 1.75 - 1.69 (m, 2H), 1.69 - 1.59 (m, 16H), 1.59 - 1.44 (m, 7H), 1.37 - 1.29 (m, 45H), 0.89 (t, J = 6.7 Hz, 9H).

[1118] Example 112

[1119] 4,4'-Didodecyl((3-((4-(dodecoxy)-4-oxobutyl)(3-hydroxypropyl)amino)propyl)azetidinyl)dibutanoate [ka]

[1120] Step 1: Synthesis of 2,2,3,3-tetramethyl-8,12-di(5-oxo-5-(undecyloxy)pentyl)-4-oxo-8,12-diaza-3-silaheptadecane-17-undecyl ester [ka]

[1121] N1-(3-((t-butyldimethylsilyl)oxy)propyl)propane-1,3-diamine (100 mg, 0.4 mmol) was dissolved in MeCN (15 mL), and dodecyl 4-bromobutanoate (449 mg, 1.3 mmol), potassium carbonate (280 mg, 2.0 mmol), and KI (10 mg, 0.04 mmol) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (20 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with A:B = 30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 300 mg of a colorless oily product (yield: 73.2%).

[1122] ESI-MS m / z:cald for C 60 H 121 N2O7Si[M+H] + : 1009.9, found 1009.7.

[1123] 1 H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 6H), 3.62 (t, J = 6.3 Hz, 2H), 2.54 - 2.47 (m, 2H), 2.47 - 2.35 (m, 10H), 2.34 - 2.25 (m, 6H), 1.80 - 1.67 (m, 10H), 1.70 - 1.60 (m, 9H), 1.60 - 1.51 (m, 2H), 1.30 - 1.24 (m, 49H), 0.89 - 0.85 (m, 18H), 0.04 (s, 6H).

[1124] Step 2: Synthesis of 4,4'-didodecyl((3-((4-(dodecoxy)-4-oxobutyl)(3-hydroxypropyl)amino)propyl)azetidinyl)dibutanoate [ka]

[1125] 2,2,3,3-tetramethyl-8,12-di(5-oxo-5-(undecyloxy)pentyl)-4-oxo-8,12-diaza-3-silaheptadecane-17-undecylester (300 mg, 0.3 mmol) was dissolved in THF (10 mL), then TBAF (155 mg, 0.6 mmol) was added, the mixture was stirred at room temperature for 2 hours, an appropriate amount of water was added, and the mixture was extracted with EA (20 mL x 3). The organic phases were combined and dried, and evaporated to dryness. The mixture was mixed and eluted through a column with A:B = 10%~30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 210 mg of a colorless oily product (yield: 78.9%).

[1126] ESI-MS m / z:cald for C 54 H 107 N2O7[M+H] + : 895.8, found 895.6.

[1127] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8, Hz, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.64 (t, J = 5.7 Hz, 2H), 2.50 - 2.36 (m, 10H), 2.34 - 2.27 (m, 6H), 1.88 - 1.80 (m, 2H), 1.80 - 1.69 (m, 8H), 1.69 - 1.56 (m, 9H), 1.32 - 1.24 (m, 52H), 0.88 (t, J = 6.7 Hz, 9H).

[1128] Example 113 Didecyl 4,4'-((3-((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)propyl)azetidinyl)dibutanoate [ka]

[1129] Step 1: Synthesis of 1,12-di(4-(decyloxy)-4-oxobutyl)-2,2,3,3-tetramethyl-4-oxo-8,12-diaza-3-silahexadecane-16-caprete [ka]

[1130] N1-(3-((t-butyldimethylsilyl)oxy)propyl)propane-1,3-diamine (100 mg, 0.4 mmol) was dissolved in MeCN (15 mL), and dodecyl 4-bromobutanoate (374 mg, 1.2 mmol), potassium carbonate (280 mg, 2.0 mmol), and KI (10 mg, 0.04 mmol) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (20 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with A:B = 30% (A: PE / EA = 5 / 1, B: DCM / MeOH(NH3) = 10 / 1) to obtain 295 mg of a colorless oily product (yield: 78.6%).

[1131] ESI-MS m / z:cald for C 54 H 109 N2O7Si[M+H] + : 925.8, found 925.6.

[1132] 1 H NMR (400 MHz, CDCl3)δ 4.04 (t, J = 6.8 Hz, 6H), 3.62 (t, J = 6.3 Hz, 2H), 2.56 - 2.48 (m, 2H), 2.48 - 2.34 (m, 10H), 2.33 - 2.26 (m, 6H), 1.85 - 1.70 (m, 9H), 1.70 - 1.60 (m, 9H), 1.60 - 1.50 (m, 2H), 1.33 - 1.25 (m, 38H), 1.05 - 0.68 (m, 18H), 0.04 (s, 6H).

[1133] Step 2: Synthesis of didecyl 4,4'-((3-((4-(decyloxy)-4-oxobutyl)(3-hydroxypropyl)amino)propyl)azetidinyl)dibutanoate [ka]

[1134] 8,12-di(4-(decyloxy)-4-oxobutyl)-2,2,3,3-tetramethyl-4-oxo-8,12-diaza-3-silahexadecane-16-caprete (295 mg, 0.3 mmol) was dissolved in THF (10 mL), then TBAF (167 mg, 0.6 mmol) was added, the mixture was stirred at room temperature for 2 hours, an appropriate amount of water was added, and the mixture was extracted with EA (20 mL x 3). The organic phases were combined and dried, and evaporated to dryness. The mixture was mixed and eluted through a column with A:B = 10%~30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 190 mg of a colorless oily product (yield: 73.5%).

[1135] ESI-MS m / z:cald for C 48 H 95 N2O7[M+H] + : 811.7, found 811.5.

[1136] 1 H NMR (400 MHz, CDCl3)δ 4.05 (t, J = 6.8, Hz, 6H), 3.78 (t, J = 5.2 Hz, 2H), 2.64 (t, J = 5.7 Hz, 2H), 2.53 - 2.36 (m, 10H), 2.35 - 2.26 (m, 6H), 1.84 - 1.67 (m, 9H), 1.64 - 1.56 (m, 8H), 1.33 - 1.24 (m, 42H), 0.90 - 0.84 (m, 9H).

[1137] Example 114

[1138] Di((9Z,12Z)-octadeca-9,12-dien-1-yl)7,7'-((3-(3-hydroxypropyl)(7-(((9Z,12Z)-octadeca-9,12-dien-1-yl)oxy)-7-oxoheptyl)amino)propyl)azepane)diheptanoate [ka]

[1139] Step 1: Synthesis of (9Z,12Z)-octadeca-9,12-diene-1-yl7-bromoheptanoate: [ka]

[1140] (9Z,12Z)-octadeca-9,12-dien-1-ol (2.0 g, 7.5 mmol) and 7-bromoheptanoic acid (1.7 g, 8.3 mmol) were mixed. The mixture was heated to 60°C, then two drops of concentrated sulfuric acid were added. The mixture was stirred at this temperature for 16 hours. When it was confirmed by TLC that the starting materials had been almost completely consumed, an appropriate amount of water was added, and the mixture was extracted with EA (30 mL x 3). The organic phase was combined and evaporated to dryness. The mixture was then mixed and eluted through a column at PE:EA = 30:1 to obtain 3.2 g of a colorless oily product (yield: 93.2%).

[1141] 1 H NMR (400 MHz, CDCl3)δ 5.45 - 5.27 (m, 4H), 4.06 (t, J = 6.8 Hz, 2H), 3.40 (t, J = 6.8 Hz, 2H), 2.77 (t, J = 6.6 Hz, 2H), 2.30 (t, J = 7.5 Hz, 2H), 2.10 - 1.99 (m, 4H), 1.91 - 1.80 (m, 2H), 1.69 - 1.58 (m, 4H), 1.50 - 1.41 (m, 2H), 1.38 - 1.28 (m, 18H), 0.89 (t, J = 6.8 Hz, 3H).

[1142] Step 2: Synthesis of (9Z,12Z)-octadeca-9,12-dien-1-yl2,2,3,3-tetramethyl-8,12-di(7-(((9Z,12Z)octa-9,112-dien-1-yl)oxy)-7-oxoheptyl)-4-oxo-8,12-aza-3-silanone-19-acid ester [ka]

[1143] N1-(3-((t-butyldimethylsilyl)oxy)propyl)propane-1,3-diamine (100 mg, 0.4 mmol) was dissolved in MeCN (30 mL), and (9Z,12Z)-octadeca-9,12-dien-1-yl7-bromoheptanoate (650 mg, 1.4 mmol), potassium carbonate (280 mg, 2.0 mmol), and KI (10 mg, 0.04 mmol) were added, respectively. The mixture was stirred at 85°C for 16 hours. An appropriate amount of water was added, and then EA (20 mL x 3) was added for extraction. The combined organic phase was dried and then concentrated under reduced pressure. The crude product was purified by column chromatography with A:B = 30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 300 mg of a colorless oily product (yield: 53.7%).

[1144] ESI-MS m / z:cald for C 87 H 163 N2O7Si[M+H] + : 1376.2, found 1376.4.

[1145] 1 H NMR (400 MHz, CDCl3)δ 5.46 - 5.32 (m, 12H), 4.08 (t, J = 6.8 Hz, 6H), 3.66 (t, J = 6.3 Hz, 2H), 2.81 (t, J = 6.5 Hz, 6H), 2.51 (m, 2H), 2.41 (m, 9H), 2.32 (t, J = 7.5 Hz, 6H), 2.18 - 1.98 (m, 12H), 1.73 - 1.55 (m, 21H), 1.52 - 1.31 (m, 62H), 1.03 - 0.77 (m, 18H), 0.08 (s, 6H).

[1146] Step 3: Di((9Z,12Z)-octadeca-9,12-dien-1-yl)7,7'-((3-(3-hydroxypropyl)(7-(((9Z,12Z)-octadeca- Synthesis of 9,12-dien-1-yl)oxy)-7-oxoheptyl)amino)propyl)azepan)diheptanoate [ka]

[1147] (9Z,12Z)-Octadeca-9,12-dien-1-yl2,2,3,3-tetramethyl-8,12-di(7-(((9Z,12Z)Octadeca-9,112-dien-1-yl)oxy)-7-oxoheptyl)-4-oxo-8,12-aza-3-silanone-19-acid ester (300 mg, 0.2 mmol) is dissolved in THF (10 mL), and then TBAF ( 114 mg (0.4 mmol) was added, stirred at room temperature for 3 hours, an appropriate amount of water was added, and extraction was performed with EA (20 mL x 3). The organic phase was combined and dried, and evaporated to dryness. The mixture was mixed and eluted through a column with A:B = 10%~30% (A:PE / EA = 5 / 1, B:DCM / MeOH(NH3) = 10 / 1) to obtain 132 mg of a colorless oily product (yield: 48.0%).

[1148] ESI-MS m / z:cald for C 81 H 149 N2O7[M+H] + : 1262.1, found 1262.3.

[1149] 1H NMR (400 MHz, CDCl3)δ 5.48 - 5.23 (m, 12H), 4.05 (t, J = 6.8 Hz, 6H), 3.78 (t, J = 5.1 Hz, 2H), 2.77 (t, i = 6.5 Hz, 6H), 2.63 (t, J = 5.5 Hz, 2H), 2.48 - 2.34 (m, 10H), 2.29 (t, J = 7.5 Hz, 7H), 2.13 - 1.97 (m, 14H), 1.72 - 1.54 (m, 20H), 1.50 - 1.40 (m, 6H), 1.34 - 1.27 (m, 54H), 0.89 (t, J = 6.7 Hz, 9H).

[1150] Example 2: Preparation and detection of lipid nanoparticles (LNP formulations)

[1151] An ethanol-lipid solution was prepared by dissolving the ionizable lipid compound from Example 1 and positive control 1 in ethanol with DOPE, cholesterol, and DMG-PEG2000 (all purchased from iWeiTuo (Shanghai) Pharmaceutical Technology Co., Ltd.) in a molar ratio of 50:10:48.25:1.25. Green fluorescent protein (eGFP) mRNA was diluted in 20 mM citrate buffer (pH=6.1) to obtain an aqueous mRNA solution. Lipid nanoparticles were prepared with a total lipid to mRNA N / P ratio of 12 by mixing the ethanol-lipid solution and the aqueous mRNA solution in a volume ratio of 1:3 using a microfluidic device (MaiDingNa (Shanghai) Instrument Technology Co., Ltd., Model: INano® L). The liquid was replaced by ultrafiltration to remove ethanol, and the solution was brought to volume with DPBS. Finally, the lipid nanoparticles were filtered through a 0.2 μm sterile filter to obtain LNP formulations in which eGFP mRNA was encapsulated using ionizable lipid / DOPE / cholesterol / DMG-PEG2000 (50 / 10 / 48.25 / 1.25 mol%). The mRNA content ranged from 0.002 mg / ml to 0.5 mg / ml.

[1152] The size and polydispersity index (PDI) of lipid nanoparticles were measured using dynamic light scattering with a 173° backscatter detection mode on a Malvern Zetasizer Nano ZS (Malvern UK). Encapsulation efficiency was measured using the Ribogreen assay. The test results are shown in Table 1.

[1153] Third example: In vitro transfection experiment of lipid nanoparticles (LNP formulation)

[1154] In this example, mouse bone marrow-derived dendritic cells DC2.4 (purchased from Millipore) were used as the validation cell line for the lipid nanoparticle transfection experiment. DC2.4 cells were attached and grown. All cell culture steps were carried out strictly according to the prescribed procedures, using sterile reagents and performing aseptic techniques on a sterile workbench. The main steps were as follows:

[1155] 1) Cell resuscitation: The stored cell cryopreservation solution was removed from the -80°C freezer and immediately placed in a 37°C water bath. Thawing was completed within 1 minute by rapid, continuous shaking. Fresh culture medium was pre-added to 15 mL centrifuge tubes, and the cell solution was added to the centrifuge tubes in a biosafety cabinet. Centrifuge tubes of the same mass were placed symmetrically in a centrifuge and centrifuged at a low speed of 1200 rpm for 5 minutes. After centrifugation, the supernatant was removed, and an appropriate amount of culture medium was slowly added along the wall of the tube. The cells were gently pipetted to uniformly disperse them, and the cell suspension was pipetted and added to a pre-prepared culture flask. The initial state and distribution of the resuscitation cells were observed under a microscope. The culture flasks were placed in a 5% CO2 incubator and incubated at 37°C, and the resuscitation time was recorded.

[1156] 2) Cell Passaging: Under a microscope, when the cell density in the field of view reached 80%-90%, the cells were passaged. Adherent cells need to be digested with trypsin. To prevent residual serum in the medium from reducing trypsin activity, the original culture medium was removed and then washed once with DPBS solution. After aspirating and removing the DPBS solution, trypsin was added to break down proteins at the intercellular junctions, separating the cells and facilitating further culturing. After gently shaking to homogenize, the cells were placed in an incubator and digested for 2-3 minutes. Immediately after digestion was complete, an appropriate amount of medium was added to the original culture dish to stop digestion. Finally, the cells were carefully pipetted using a pipette to uniformly disperse them. They were inoculated in a fixed proportion according to the requirements of the experiment and then passaged. The cells were cultured. In the case of suspension cells, the trypsin digestion step is not necessary.

[1157] Transfection of DC2.4 cells

[1158] 1) Resuscitation of DC2.4 cells: DC2.4 cells stored frozen were removed from a -80°C freezer and immediately thawed rapidly in a 37°C water bath. After thawing, they were added to pre-warmed culture medium, centrifuged at 1200 rpm for 5 minutes, the supernatant was discarded, and an appropriate amount of the resuscitated DC2.4 cells were resuspended in DMEM medium containing 10% FBS. The cells were then activated and cultured in a 37°C, 5% CO2 incubator.

[1159] 2) If necessary for the experiment, DC2.4 cells were seeded in 24-well plates the day before transfection. Cell count and viability were recorded by cell counting. 2 × 10⁶ cells per well 5 Cell suspensions were prepared. A predetermined volume of DMEM medium containing 10% FBS was added and mixed uniformly. For subsequent transfection, 1 mL was added per well.

[1160] 3) After 24 hours, the culture medium was gently aspirated and removed using a pipette 30 minutes prior to the end of the interval. Each well was then washed with 1 mL of DPBS and aspirated again. Subsequently, 300 μL of serum-free Opti-MEM medium was added to each well for further transfection.

[1161] 4) The LNP preparation prepared in Example 2 was diluted in Opti-MEM medium to an mRNA concentration of 1 μg / ml.

[1162] 5) 200 μl of the diluted mixture (containing 200 ng of mRNA per well) was evenly dropped onto the top of each well. The wells were then activated and incubated in a 37°C, 5% CO2 incubator.

[1163] 6) After 24 hours, cell viability (%), eGFP positivity (%), and mean fluorescence intensity data were obtained by cell fluorescence imaging and flow cytometry.

[1164] Experimental results

[1165] Tables 1-1 to 1-3 show the characteristics of the lipid nanoparticles prepared in Example 2 and the eGFP-mRNA expression levels on DC2.4 after 24 hours, normalized based on Example 11. [Table 1-1] [Table 1-2] [Table 1-3]

[1166] Example 4: In vivo transfection experiment of lipid nanoparticles (LNP formulations)

[1167] Lipid nanoparticles (LNPs) of Fluc-mRNA (FLuc mRNA from Yoshiryo Co., Ltd., 1 mg / mL), SM-102 (CAS number: 2089251-47-6, iWeiTuo (Shanghai) Pharmaceutical Technology Co., Ltd.), and positive control 1 (US10195156B2, prepared according to the method described in the above example, the main difference being the substitution of 2-((3-aminopropyl)amino)ethane-1-ol with 2-((2-aminoethyl)amino)ethane-1-ol; see Figure 1 for structure) were prepared according to the method described in Example 2. Specific parameters are shown in Table 2. Cholesterol (Chol), DSPC, DOPE, and DMG-PEG2000 were purchased from iWeiTuo (Shanghai) Pharmaceutical Technology Co., Ltd. Mice were randomly selected and injected intravenously and intramuscularly with the lipid nanoparticles at a dose of 0.5 mg / kg (4 mice per group). Mice directly injected with Tris and Fluc-mRNA were used as controls. Six hours later, 200 μl of 10 mg / ml D-luciferin potassium salt was injected into each mouse via the tail vein. Ten minutes later, the mice were placed under an in vivo imaging system, and the total fluorescence intensity of each mouse was observed and recorded. Twenty-four hours later, the mice were placed under an in vivo imaging system, and the total fluorescence intensity of each mouse was observed and recorded. [Table 2]

[1168] In intramuscular injection, some lipid nanoparticles remained at the injection site, while the remainder remained mainly in the liver. In intravenous injection, the lipid nanoparticles completely migrated to the chest and abdomen. As shown in Figures 2-9, the fluorescence intensity of the samples from Examples 11, 12, and 21 was stronger than that of positive control 1 and comparable to that of SM-102. In particular, in the case of intramuscular administration, Examples 11, 12, and 21 maintained high fluorescence intensity, and the expression of 12 and 21 in the chest and abdomen was much lower than that of SM-102.

[1169] LNP lipid nanoparticles of Fluc-mRNA were prepared according to the method of Example 2. Specific parameters are shown in Table 3. Mice were randomly selected and intramuscularly injected with the lipid nanoparticles at a dose of 0.5 mg / kg (2 mice per group). Mice directly injected with Tris were used as controls. After 6 hours, 200 μl of 10 mg / ml D-luciferin potassium salt was injected into the tail vein of each mouse. After 10 minutes, the mice were placed under an in vivo imaging system, and the total fluorescence intensity of each mouse was observed and photographs were taken for recording. After 24 hours, the mice were placed under an in vivo imaging system, and the total fluorescence intensity of each mouse was observed and photographs were taken for recording. [Table 3]

[1170] In intramuscular injection, some lipid nanoparticles remained at the injection site, while the remainder remained mainly in the liver. As shown in Figures 10-13, systemic expression in the above examples was superior to positive control 1, and examples 1, 12, and 81 were superior to SM-102. In terms of injection site, these examples were superior to positive control 1 and SM-102. Therefore, the above examples are superior by using DSPC instead of DOPE, and process-related explorations such as TFF can also be performed.

[1171] Fluc-mRNA LNP lipid nanoparticles were prepared according to the method of Example 2. Specific parameters are shown in Table 4. Mice were randomly selected and intramuscularly injected with lipid nanoparticles at a dose of 0.5 mg / kg (3 mice per group). Mice directly injected with Tris were used as controls. After 6 hours, 200 μl of 10 mg / ml D-luciferin potassium salt was injected into the tail vein of each mouse. After 10 minutes, the mice were placed under an in vivo imaging system, and the total fluorescence intensity of each mouse was observed and photographs were taken for recording. After 24 hours, the mice were placed under an in vivo imaging system, and the total fluorescence intensity of each mouse was observed and photographs were taken for recording. [Table 4]

[1172] In intramuscular injection, some of the lipid nanoparticles remained at the injection site, while the remainder remained mainly in the liver. As shown in Figures 14-17, Example 89 was superior to positive controls 1 and SM-102 in terms of systemic expression and injection site.

Claims

1. The compound represented by the following formula (I), or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates. 【Chemistry 1】 (I) In the above formula (I), L １ , L ２ , L ３ Each of these is independently selected from an arbitrarily substituted alkylene group, an arbitrarily substituted alkenylene group, and an arbitrarily substituted alkynylene group. M １ M ２ M ３ These are independently selected from -C(O)O- and -OC(O)-, R １ 、 R ２ 、 R ３ are each independently selected from an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted alkynyl group, L ４ This is selected from an optionally substituted alkylene group, an optionally substituted alkenylene group, and an optionally substituted alkynylene group. R ４ is, -OR ５ And R ５ is selected from H, an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted alkynyl group. m is an integer between 3 and 6.

2. L １ , L ２ , L ３ Each of these is an arbitrarily substituted C, independently of the others. １～２４ Alkylene group, optionally substituted C ２～２４ Alkenylene group and optionally substituted C ２～２４ Selected from the alkynylene group, R １ , R ２ , R ３ Each of these is an arbitrarily substituted C, independently of the others. １～２４ Alkyl alkyl groups, optionally substituted C ２～２４ Alkenyl group, and optionally substituted C ２～２４ Selected from alkynyl groups, L ４ is an arbitrarily substituted C １～６ Alkylene group, optionally substituted C ２～６ Alkenylene group and optionally substituted C ２～６ Selected from the alkynylene group, R ５ H, and C as arbitrarily substituted. １～６ Alkyl alkyl groups, optionally substituted C ２～６ Alkenyl group, and optionally substituted C ２～６ A compound according to claim 1, selected from an alkynyl group, or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, or solvate.

3. L １ , L ２ , L ３ Each is independent of the other, -(CH ２ ) ｎ - is selected from, where n is an integer from 1 to 24, preferably an integer from 2 to 24, more preferably an integer from 3 to 15. L ４ is, -(CH ２ ) ｏ - is selected from, where o is an integer from 1 to 6, preferably an integer from 2 to 5, more preferably an integer from 2 to 4. R ５ H and C １～６ A compound according to claim 1 or 2, selected from alkyl groups, or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates.

4. R １ , R ２ , R ３ Each of these is independently one or more C １～２４ C optionally substituted with alkyl groups １～２４ Alkyl alkyl group, one or more C １～２４ C optionally substituted with alkyl groups ２～２４ A compound according to any one of claims 1 to 3, wherein the compound is a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug or solvate thereof, selected from alkenyl groups, preferably the alkenyl group containing 1 to 4 carbon-carbon double bonds.

5. R １ , R ２ , R ３ Each of these is independently selected from the following formulas, and is characterized by being a compound according to any one of claims 1 to 4 or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug or solvate. 【Chemistry 2】 (Here, a is an integer from 1 to 24, R １ａ and R ２ａ Each time it appears, it is independently either H or C １～２４ It is an alkyl group, or each R １ａ H or C １～２４ It is an alkyl group, R ２ａ This is the adjacent R along with the carbon atom it is linked to. ２ａ and together with the carbon atom it is linked to, it forms a carbon-carbon double bond, R ３ａ (This is either an H or a methyl group.)

6. R １ , R ２ , R ３ Each of these is independently selected from the following formulas to be a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, or solvate of the compound or tautomer described in any one of claims 1 to 5 or therein. 【Transformation 3】 【Chemistry 4】 or 【Transformation 5】 (Here, p is an integer from 0 to 2, p' is an integer from 1 to 24, and p'' is an integer from 0 to 24.) b, c, d, and e are each independent integers between 1 and 22. R １ｂ and R ２ｂ Each time it appears, it is independently either H or C １～１２ It is an alkyl group, or each R １ｂ H or C １～１２ It is an alkyl group and has at least one R ２ｂ This is the adjacent R along with the carbon atom it is linked to. ２ｂ and together with the carbon atom it is linked to, it forms a carbon-carbon double bond. R １ｃ and R ２ｃ Each time it appears, it is independently either H or C １～１２ It is an alkyl group, or each R １ｃ H or C １～１２ It is an alkyl group and has at least one R ２ｃ This is the adjacent R along with the carbon atom it is linked to. ２ｃ and together with the carbon atom it is linked to, it forms a carbon-carbon double bond. R １ｄ and R ２ｄ Each time it appears, it is independently either H or C １～１２ It is an alkyl group, or each R １ｄ H or C １～１２ It is an alkyl group and has at least one R ２ｄ This is the adjacent R along with the carbon atom it is linked to. ２ｄ and together with the carbon atom it is linked to, it forms a carbon-carbon double bond. R １ｅ and R ２ｅ each independently, every time it appears, is H or C １～１２ alkyl group, or each R １ｅ is independently H or C １～１２ alkyl group, and at least one R ２ｅ together with the carbon atom to which it is attached and the adjacent R ２ｅ form a carbon-carbon double bond together with the carbon atom to which it is attached. )

7. The compound of formula (I) is a compound according to any one of claims 1 to 6, having a structure represented by the following formulas (Ia), (Ib), (Ic), or (Id), or a stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, or solvate thereof. 【Transformation 6】 or 【Transformation 7】 (Here, f, g, h, i, j, k, g1, g2, i1, i2, k1, k2, r, s, t, u, v, w, x, y, z are all independent integers between 1 and 24, and q is an integer between 1 and 6.)

8. f, h, and j are each independent integers between 2 and 24, preferably between 3 and 15. g, g1, g2, i, i1, i2, k, k1, k2 are each independent integers from 3 to 24, preferably from 3 to 15. r, s, t, u, v, w, x, y, z are each independent integers from 1 to 15, preferably from 1 to 10. q is an integer between 2 and 5, preferably between 2 and 4. Preferably, in formula (Ia), i and k are each an independent integer from 1 to 15, preferably an independent integer from 3 to 15, preferably i and k are the same integer; h and j are each an independent integer from 2 to 11, preferably an independent integer from 3 to 7, preferably h and j are the same integer; m is 3, 4, 5 or 6, preferably 3 or 4; f is an integer from 3 to 11, preferably an integer from 3 to 6; g is an integer from 3 to 15, preferably an integer from 6 to 12; and q is an integer from 2 to 5. More preferably, in formula (Ia), i, k, and g are each an independent integer from 1 to 15, preferably an independent integer from 3 to 15, more preferably an independent integer from 8 to 12, preferably i, k, and g are the same integer, f, h, and j are each an independent integer from 2 to 11, preferably an independent integer from 3 to 7, preferably f, h, and j are the same integer, m is 3, 4, 5, or 6, preferably 3 or 4, and q is an integer from 2 to 5, preferably 2 or 3. Preferably, in formula (Id), h and j are each independent integers from 2 to 11, preferably independently integers from 3 to 8, preferably h and j are the same integer; m is 3, 4, 5 or 6, preferably 3 or 4; t and v are each independent integers from 1 to 10, preferably independently integers from 5 to 10, preferably t and v are the same integer; y and z are each independent integers from 1 to 10, preferably independently integers from 3 to 8, preferably y and z are the same integer; f is an integer from 3 to 11, preferably an integer from 3 to 8; r is an integer from 1 to 10, preferably an integer from 5 to 10; x is an integer from 1 to 10, preferably an integer from 3 to 8; and q is an integer from 2 to 5. More preferably, in formula (Id), f, h, and j are each an independent integer from 2 to 11, preferably each an independent integer from 3 to 7, preferably f, h, and j are the same integer, m is 3, 4, 5, or 6, preferably 3 or 4, t, r, and v are each an independent integer from 1 to 10, preferably each an independent integer from 6 to 10, preferably t, r, and v are the same integer, x, y, and z are each an independent integer from 1 to 10, preferably each an independent integer from 3 to 7, preferably x, y, and z are the same integer, and q is an integer from 2 to 5, the compound according to claim 7 or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, or solvates.

9. Lipid nanoparticles comprising a compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug or solvate according to any one of claims 1 to 8, preferably the lipid nanoparticles further comprising one or more helper lipid molecules, one or more cholesterol or cholesterol derivatives and / or one or more polymer-bound lipid molecules.

10. The helper lipid molecule is a neutral lipid molecule, preferably selected from DSPC, DPPC, DMPC, DOPC, POPPC, DOPE, and SM, more preferably DOPE or DSPC, and / or The lipid nanoparticle according to claim 9, wherein the polymer of the polymer-bound lipid molecule is polyethylene glycol, and preferably the polymer-bound lipid molecule is selected from PEG-DMG, PEG-DAG, PEG-PE, PEG-S-DAG, PEG-DSPE, PEG-Cer, and PEG dialkoxypropyl carbamate, and preferably PEG2000-DMG.

11. Lipid nanoparticles according to any one of claims 9 to 10, wherein the lipid nanoparticles are such that the compound or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs or solvates are to a helper lipid molecule, cholesterol or cholesterol derivative, or polymer-bound lipid molecule, and the molar ratio is 60 to 5:60 to 5:50 to 5:10 to 1, preferably 60 to 30:30 to 10:50 to 30:5 to 1.

12. The lipid nanoparticles further contain a therapeutic agent or activator, preferably the therapeutic agent or activator is a nucleic acid therapeutic agent or activator, and more preferably the nucleic acid therapeutic agent or activator is selected from messenger RNA (mRNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), self-replicating RNA (saRNA), small guide RNA (sgRNA), ribozyme, and aptamer, according to any one of claims 9 to 11.

13. A composition comprising a compound according to any one of claims 1 to 8 or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug, or solvate, Preferably, the composition is a pharmaceutical composition comprising a compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug or solvate, therapeutic agent or activator described in any one of claims 1 to 8, and one or more helper lipid molecules, one or more cholesterol or cholesterol derivatives and / or one or more polymer-bound lipid molecules.

14. The helper lipid molecule is a neutral lipid molecule, preferably selected from DSPC, DPPC, DMPC, DOPC, POPPC, DOPE, and SM, more preferably DOPE or DSPC, and / or The polymer in the polymer-bound lipid molecule is polyethylene glycol, and preferably the polymer-bound lipid molecule is selected from PEG-DMG, PEG-DAG, PEG-PE, PEG-S-DAG, PEG-DSPE, PEG-Cer, and PEG dialkoxypropyl carbamate, preferably PEG2000-DMG, and / or The composition according to claim 13, wherein the therapeutic agent or activator is a nucleic acid therapeutic agent or activator, preferably selected from messenger RNA (mRNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), self-replicating RNA (saRNA), small guide RNA (sgRNA), ribozyme, and aptamer.

15. (1) Use of a compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug or solvate according to any one of claims 1 to 8 in the preparation of lipid nanoparticles or pharmaceutical compositions for treating or preventing a target disease or disorder, (2) Use of a compound or its stereoisomer, tautomer, pharmaceutically acceptable salt, prodrug or solvate according to any one of claims 1 to 8 in the preparation of a therapeutic agent or activator, for example, a reagent for delivering nucleic acids, or (3) Use of lipid nanoparticles according to any one of claims 9 to 12 in the preparation of a drug for treating or preventing a target disease or disorder, (4) A use selected from the use of the composition according to claim 13 or 14 in the preparation of a drug for treating or preventing a target disease or disorder.

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