Rapidly metabolizable ionizable lipid compound

Abstract

Provided in the present invention is an ionizable lipid compound. Specifically, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof. Further provided in the present invention are a nanoparticle pharmaceutical composition containing the compound, and the use of the compound and composition thereof in the delivery of nucleic acids.

Description

Rapidly metabolized ionizable lipid compounds

[0001] This application claims priority to Chinese application 202411433587.5, filed on October 14, 2024, which is incorporated herein by reference in its entirety. Technical Field

[0002] This invention relates to a new class of ionizable cationic lipid compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof. The invention also relates to lipid nanoparticles comprising said compounds and pharmaceutical compositions, and the use of said lipid nanoparticles in the delivery of bioactive substances such as nucleic acids (e.g., mRNA, siRNA, ASO, DNA, etc.). Background Technology

[0003] Gene therapy refers to the introduction of exogenous genes into target cells to correct or compensate for gene defects or abnormalities within the cells, thereby achieving therapeutic goals. Over the past few decades, research into using gene therapy to treat clinical diseases has received increasing attention, especially in recent years with the FDA approval of siRNA-related drugs and mRNA vaccines for clinical treatment, further advancing research and investment in the field of gene therapy.

[0004] Nucleic acids are readily degraded in vivo by nucleases, and their negative charge makes them difficult to pass through cell membranes and enter cells. Lipid nanoparticles (LNPs), as a nucleic acid delivery material, offer advantages such as simple preparation, good biodegradability, non-immunogenicity, and good safety, making them one of the most important nucleic acid delivery systems currently available. The main components of LNPs include cationic lipid molecules, cholesterol, neutral lipids, and polyethylene glycol-conjugated lipids. Among these, cationic lipid molecules are the core of the LNP delivery system, and their molecular structure plays a decisive role in the overall delivery efficiency, targeting, and formulation stability of the liposome nanoparticles.

[0005] Since different types of nucleic acid substances and specific delivery to different targets require different delivery systems, new lipid molecules need to be further developed to meet the different needs of gene therapy. Summary of the Invention

[0006] This invention develops a new class of ionizable cationic lipid compounds that can be used to deliver various bioactive substances with high delivery efficiency.

[0007] The inventors' prior patent CN115850104A discloses a class of cationic lipid compounds with both tail chains having a digethylenedialkyl structure, exhibiting high delivery efficiency. Unexpectedly, further research revealed that when the digethylenedialkyl structure is applied to cationic lipids containing a central nitrogen atom, the cationic lipids degrade more slowly in the liver, making them suitable for applications requiring slow degradation. For applications requiring accelerated in vivo metabolism, the inventors have developed a new class of ionizable cationic lipid compounds.

[0008] This invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, or stereoisomers thereof:

[0009] Wherein, each group is as defined in this invention.

[0010] In another aspect, the present invention provides a nanoparticle composition comprising a lipid component and optionally a loading; wherein the lipid component contains a compound of the present invention.

[0011] In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present invention or the nanoparticle compositions of the present invention, and optionally pharmaceutically acceptable excipients, such as carriers, adjuvants, or mediators.

[0012] In another aspect, the present invention provides the use of the compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention in the preparation of medicaments for treating, diagnosing, or preventing diseases. In one embodiment, the medicament for treating, diagnosing, or preventing diseases is a therapeutic or prophylactic mRNA vaccine.

[0013] In another aspect, the present invention provides the use of the compounds of the present invention, the nanoparticle compositions of the present invention, or the pharmaceutical compositions of the present invention in the preparation of a medicament for delivery of a loading.

[0014] In another aspect, the present invention provides a method for treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0015] In another aspect, the present invention provides compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for the treatment, diagnosis, and / or prevention of diseases.

[0016] In another aspect, the present invention provides a method for delivering a payload to a subject, comprising administering to the subject a compound of the present invention, a nanoparticle composition of the present invention, or a pharmaceutical composition of the present invention.

[0017] In another aspect, the present invention provides compounds, nanoparticle compositions, or pharmaceutical compositions of the present invention for delivering payloads.

[0018] In a specific implementation, the load is selected from one or more of a therapeutic agent, a preventive agent, or a diagnostic agent; preferably, the therapeutic agent, preventive agent, or diagnostic agent is a nucleic acid.

[0019] In a more specific embodiment, the nucleic acid is selected from one or more of ASO, RNA, or DNA.

[0020] In a more specific embodiment, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozymes, preferably mRNA, more preferably modified mRNA.

[0021] definition

[0022] Chemical definition

[0023] The definitions of specific functional groups and chemical terms are described in more detail below.

[0024] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0025] “C 1-20 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. C 1-6Examples of alkyl groups include: methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). The term "C" is used in conjunction with the preceding text. 1-6 "Alkyl" also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3), or i-Bu(-CH2CH(CH3)2). In some embodiments, the alkyl group is preferably a straight-chain alkyl group.

[0026] “C 2-13 "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 13 carbon atoms and at least one carbon-carbon double bond. 2-6 Examples of alkenyl groups include: vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), hexenyl (C6), and so on. The term "C" is used in conjunction with these groups. 2-6 "Alkenyl" also includes heteroalkenyl groups, wherein one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0027] “C 2-13 "Alkyne" refers to a straight-chain or branched hydrocarbon group having 2 to 13 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentyynyl (C5), hexynyl (C6), etc. The term "C" is used in conjunction with other alkynyl groups. 2-6 "Alkyne" also includes heteroyne, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkynyl group may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.

[0028] “C 1-20 "Alkylene" refers to the removal of C 1-20 The alkylene group is a divalent group formed by the other hydrogen atom of an alkyl group, and can be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and so on. Exemplary substituted alkylene groups, for example, those substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH(CH3)-, -C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3) 2- ), substituted propylidenes (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc.

[0029] “C 2-13 "Alkenyl" refers to the group that has been de-carbonied. 2-13 The alkenyl group is a divalent group formed by the other hydrogen atom of the alkenyl group, and can be substituted or unsubstituted. Exemplary unsubstituted alkenyl groups include, but are not limited to, vinylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenyl groups, such as alkenyl groups substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted vinylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propenylene (-C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2-CH=C(CH3)-), etc.

[0030] “C 2-13 "Iso-ynyl" refers to the group that has the C group removed. 2-13 The alkynyl group is a divalent group formed by the other hydrogen atom, and can be substituted or unsubstituted. "C 4-14 "Iso-ynyl" refers to the group that has the C group removed. 4-14The alkynyl group is a divalent group formed by the other hydrogen atom of the alkynyl group, and can be substituted or unsubstituted. Exemplary alkynyl groups include, but are not limited to: ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH2-), etc.

[0031] “C 0-6 "alkylene" refers to chemical bonds and the aforementioned "C" 1-6 Alkylene", "C" 0-4 "alkylene" refers to chemical bonds and the aforementioned "C" 1- 4-alkylene group.

[0032] The term "the total length of variables A and B is x carbon atoms" means that the sum of the number of carbon atoms in the main chain of the group represented by variable A and the number of carbon atoms in the main chain of the group represented by variable B is x.

[0033] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0034] Therefore, "C" 1-10 "Halogenated alkyl" refers to the above "C 1-10 "alkyl" is substituted with one or more halogen groups. In some embodiments, C 1-8 Haloalkyl, C 1-6 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl groups are particularly preferred, and C4 groups are more preferred. 1-2 Halogenated alkyl groups. Exemplary alkyl halogenated groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CHFCH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. The alkyl halogenated group can be substituted at any available connection point, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0035] “C 3-14"Cycloalkyl" or "3- to 14-membered cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms and zero heteroatoms, optionally containing 1, 2, or 3 double or triple bonds. In some embodiments, 3- to 10-membered cycloalkyl, 5- to 10-membered cycloalkyl, 3- to 8-membered cycloalkyl, 3- to 7-membered cycloalkyl, and 3- to 6-membered cycloalkyl are particularly preferred, more preferably 5- to 7-membered cycloalkyl, 4- to 6-membered cycloalkyl, 3- to 5-membered cycloalkyl, 3- to 4-membered cycloalkyl, and 5- to 6-membered cycloalkyl, more preferably 5-membered cycloalkyl, more preferably 6-membered cycloalkyl, and more preferably cyclopropyl. Cycloalkyl also includes a cyclic system in which the aforementioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the bonding point is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate the number of carbons in the cycloalkyl system. Cycloalkyl also includes a cyclic system in which the aforementioned cycloalkyl ring, Substituents on any non-adjacent carbon atoms are linked together to form a bridged ring, forming a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl groups also include the aforementioned cycloalkyl rings, where substituents on the same carbon atom are linked together to form a ring, forming a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), etc. The cycloalkyl group may be optionally substituted with one or more substituents, for example, substituted with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0036] “C 3-14 "Cycloalkylene" refers to the alkylene oxide that has had C removed. 3-14 The cycloalkyl group is a divalent group formed by another hydrogen atom, and can be substituted or unsubstituted. In some embodiments, C 3-10 Cycloalkylene, C 3-7 Cycloalkylene, C 3-6 Cycloalkylene, C 3-5 Cycloalkylene and C 3-4 Cycloalkylene compounds are particularly preferred, especially cyclopropylene compounds.

[0037] "3-14 membered heterocyclic group" or "3 to 14 membered heterocyclic group" refers to a saturated or unsaturated group having a 3 to 14 membered non-aromatic ring system with a ring carbon atom and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, and optionally contains 1, 2, or 3 double or triple bonds. In heterocyclic groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups also include ring systems in which the aforementioned heterocyclic ring is fused with one or more cycloalkyl groups, wherein the linking point is on the heterocyclic ring, or ring systems in which the aforementioned heterocyclic ring is fused with one or more aryl or heteroaryl groups, wherein the linking point is on the heterocyclic ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic ring system. Heterocyclic groups also include the aforementioned heterocyclic ring in which substituents on any non-adjacent carbon or nitrogen atom are linked to form a bridged ring, together forming a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclic groups also include the aforementioned heterocyclic rings, wherein substituents on the same carbon atom are linked together to form a polycyclic heteroalkane sharing a single carbon atom. Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirropropyl, oxacyclopropyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirrobutyl, oxacyclobutyl, and thiorenyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: pyrazolyl, dioxacyclopentyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiohexane, and dioxalyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azirheptanyl, oxaheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc.Exemplary 6-membered heterocyclic groups fused with a C6 aryl ring (also referring herein to 6,6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc. Heterocyclic groups also include those that share one or two atoms with a cycloalkyl, heterocyclic, aryl, or heteroaryl group to form a bridged or spirocyclic ring, wherein the shared atom may be a carbon or nitrogen atom, provided the valence allows. Heterocyclic groups also include those that can be optionally substituted with one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.

[0038] "Hydroxyalkyl" refers to an alkyl group that has been replaced by one or more hydroxyl groups.

[0039] "Alkoxy" refers to the oxyether form of a straight-chain or branched alkyl group, i.e., -O-alkyl. Similarly, "methoxy" refers to -O-CH3.

[0040] "Optionally replaced by..." means that it can be replaced by a specified substituent or not replaced.

[0041] The divalent groups formed by removing one hydrogen atom from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined above are collectively referred to as "subunits". Cyclic groups such as cycloalkyl, heterocyclic, aryl, and heteroaryl are collectively referred to as "cyclogroups".

[0042] The alkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups defined in this article are optional substituted groups.

[0043] "Nucleic acid" refers to single-stranded or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules and their hybrid molecules. Examples of nucleic acid molecules include, but are not limited to, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), self-amplifying RNA (saRNA), and antisense oligonucleotides (ASO). Nucleic acids can be further chemically modified, with modifications selected from one or a combination of pseudouridine, N1-methyl-pseudouridine, 5-methoxyuridine, and 5-methylcytosine. mRNA molecules contain protein-coding regions and may further contain expression regulatory sequences, typical of which include, but are not limited to, a 5' cap, a 5' untranslated region (5'UTR), a 3' untranslated region (3'UTR), a polyadenylated nucleotide sequence (PolyA), and a miRNA binding site.

[0044] "Cationic lipids" refer to lipid molecules that can carry a positive charge under physiological pH conditions. In some embodiments, cationic lipids are amino lipids.

[0045] "Neutral lipids" refer to lipid molecules that are uncharged under specific pH conditions, such as physiological pH conditions. Examples of neutral lipids include, but are not limited to, 1,2-distearyl-sn-glycerol-3-phosphate choline (DSPC), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline (POPC), 1,2-dioleoyl-sn-glycerol-3-phosphate ethanolamine (DOPE), 1,2-dimyristoyl-sn-glycerol-3-phosphate ethanolamine (DMPE), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate ethanolamine (POPE), and 1,2-dipalmitoyl-sn-glycerol-3-phosphate ethanolamine (DPPE).

[0046] "Structural lipids" refer to lipids that enhance the stability of nanoparticles by filling the gaps between lipids, such as steroids. Steroids are compounds with a cyclopentane-polyhydrophenanthrene carbon skeleton. In a preferred embodiment, the steroid is selected from cholesterol, sitosterol, coccosterol, rock saponin, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol, or campesterol.

[0047] "Polymer lipid" refers to a molecule containing both a polymeric moiety and a lipid moiety. In some embodiments, the polymer lipid is a polyethylene glycol (PEG) lipid. Other lipids capable of reducing aggregation, such as products of lipid coupling with compounds having uncharged, hydrophilic, or sterically barrier moieties, may also be used.

[0048] "Lipid nanoparticles" refer to particles containing lipid components and having a nanoscale size.

[0049] "Biodegradable groups" refer to functional groups containing biodegradable bonds, such as esters, disulfide bonds, and amides. Biodegradation can affect the process of clearing compounds from the body. In this invention, the orientation of the biodegradable groups is from the head to the tail of the ionizable lipid molecule.

[0050] Other definitions

[0051] As used herein, the term “treatment” refers to reversing, alleviating, inhibiting, or preventing the progression of an obstacle or condition to which the term applies, or one or more symptoms of such an obstacle or condition. The noun “treatment” as used herein also refers to the action of the verb “to treat,” as defined above.

[0052] As used herein, the term "pharmaceutically acceptable salt" refers to carboxylates and amino acid addition salts of the compounds of the present invention that are suitable for contact with patient tissues within the limits of reliable medical judgment, without producing undue toxicity, irritation, allergic reactions, etc., and are effective for their intended use in proportion to a reasonable benefit / risk ratio, including (where possible) zwitterionic forms of the compounds of the present invention.

[0053] Pharmaceutically acceptable base addition salts are those formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations include sodium, potassium, magnesium, and calcium. Suitable amines include N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucosamine, and procaine.

[0054] The base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with an acid in a conventional manner and then separating the free acid. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salts are equivalent to their respective free acids.

[0055] Salts can be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides prepared from inorganic acids, such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, gluconate, lactobionate, laurylsulfonate, and hydroxyethanesulfonate. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkyl acids, hydroxyalkyl acids, alkyl diacids, aromatic acids, and aliphatic and aromatic sulfonic acids. Representative salts include acetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, naphthates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, and methanesulfonates. Pharmaceutically acceptable salts may include alkali metal and alkaline earth metal-based cations, such as sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine. Salts of amino acids are also included, such as arginine salts, gluconates, and galacturonic acids (see, for example, Berge S. et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19, incorporated herein by reference).

[0056] The term "subject" in the administration includes, but is not limited to: humans (i.e., men or women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0057] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0058] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0059] Generally, the "effective amount" of a pharmaceutical composition refers to a quantity sufficient to elicit a target biological response. As will be understood by those skilled in the art, the effective amount of the pharmaceutical compositions of the present invention can be varied depending on factors such as the biological target, the pharmacokinetics of the pharmaceutical composition, the disease being treated, the administration method, and the age, health status, and symptoms of the subject. Effective amounts include therapeutic effective amounts and prophylactic effective amounts.

[0060] Unless otherwise stated, the “therapeuticly effective amount” of a pharmaceutical composition as used herein is an amount sufficient to provide therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. Therapeuticly effective amount of a pharmaceutical composition refers to the amount of a therapeutic agent, used alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeuticly effective amount” may include amounts that improve overall treatment, reduce or prevent symptoms or causes of a disease or condition, or enhance the therapeutic effects of other therapeutic agents.

[0061] Unless otherwise stated, the “preventive effective amount” of a pharmaceutical composition as used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder, or condition, or an amount sufficient to prevent recurrence of a disease, disorder, or condition. The preventive effective amount of a pharmaceutical composition refers to the amount of the therapeutic agent, used alone or in combination with other agents, that provides preventive benefit in the prevention of a disease, disorder, or condition. The term “preventive effective amount” may include amounts that improve overall prevention or enhance the preventive effect of other preventive agents.

[0062] The term "combination" and related terms refer to the simultaneous or sequential administration of the pharmaceutical composition of the present invention and other therapeutic agents. For example, the pharmaceutical composition of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form. Detailed Implementation Plan

[0063] In this document, “compounds of the present invention” refers to the following compounds, their pharmaceutically acceptable salts, isotopic variants, tautomers or stereoisomers.

[0064] In this document, compounds are named using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomers included in this invention may have carbon-carbon double bonds in the forms of Z and E. Regarding compounds existing in different tautomeric forms, a single compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.

[0065] In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0066] in,

[0067] a = 2, 3, 4, 5 or 6;

[0068] b = 4, 5, 6, 7, 8, 9 or 10;

[0069] c = 1, 2, 3, 4, 5, 6 or 7;

[0070] d = 0, 1, 2, 3 or 4;

[0071] c+d = 3, 4, 5, 6, 7, 8 or 9;

[0072] M1 is selected from -OC(O)O-, -C(O)O-, -OC(O-, -SC(O-) and -C(O)S-;

[0073] M2 is selected from -OC(O)O-, -C(O)NR-, -NRC(O-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-;

[0074] R1 and R2 are independently selected from C 6-14 Alkyl, C 6-14 alkenyl or C 6-14 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups 1s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-;

[0075] R and R' are each independently selected from H and C. 1-20 alkyl;

[0076] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ;

[0077] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0078] R c and R' c Independently selected from H and C 1-14 alkyl;

[0079] R4 and R5 are independently selected from C 1-6 alkyl;

[0080] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene groups;

[0081] The condition is that,

[0082] (1) When M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-;

[0083] (2) When M1 is -OC(O)O- and M2 is -OC(O)O-; and

[0084] (3) The compound is not

[0085] M1 and M2

[0086] In one embodiment, M1 is -OC(O)O-; in another embodiment, M1 is -C(O)O-; in yet another embodiment, M1 is -OC(O)-; in yet another embodiment, M1 is -SC(O)-; in yet another embodiment, M1 is -C(O)S-.

[0087] In one more specific embodiment, M1 is selected from -OC(O)O-, -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in another more specific embodiment, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)-, and -C(O)S-; in another more specific embodiment, M1 is selected from -OC(O)- and -C(O)O-; in another more specific embodiment, M1 is selected from -OC(O)-; in another more specific embodiment, M1 is selected from -C(O)O-; in another more specific embodiment, M1 is selected from -OC(O)O-.

[0088] In one embodiment, M2 is -OC(O)O-; in another embodiment, M2 is -C(O)NR-, for example -C(O)NH-; in another embodiment, M2 is -NRC(O)-, for example -NHC(O)-; in another embodiment, M2 is -OC(O)NR-, for example -OC(O)NH-; in another embodiment, M2 is -NRC(O)O-, for example -NHC(O)O-; in another embodiment, M2 is -NRC(O)NR-, for example -NHC(O)NH-.

[0089] In one more specific embodiment, M2 is selected from -OC(O)O-, -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O-, and -NRC(O)NR-; in another more specific embodiment, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O-, and -NRC(O)NR-; in another more specific embodiment, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, and -NRC(O)NR-; in another more specific embodiment, M2 is selected from -NHC(O)O-, -OC(O)NR-, and -NHC(O)NR-; In another more specific embodiment, M2 is selected from -OC(O)NR- and -NHC(O)NR-; in another more specific embodiment, M2 is selected from -NRC(O)NR-; in another more specific embodiment, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O- and -NHC(O)NH-; in another more specific embodiment, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH- and -NHC(O)NH-; in another more specific embodiment, M2 is selected from -NHC(O)NH-; in another more specific embodiment, M2 is selected from -OC(O)O-.

[0090] R1 and R2

[0091] In one implementation, R1 is C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, preferably C 8-12 Straight-chain alkyl, preferably C 7-11 Straight-chain alkyl, preferably C 8-11Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C 8-9 Straight-chain alkyl, preferably C 11 Straight-chain alkyl, preferably C 10 Straight-chain alkyl, preferably C9 straight-chain alkyl; in another embodiment, R1 is C 6-14 Alkenyl, preferably C 7-12 Alkenyl, preferably C 8-12 Alkenyl; in another embodiment, R1 is C 6-14 Alkyne group, preferably C 7-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R1 is optionally surrounded by one or more R groups. 1s In another embodiment, R1 is optionally replaced by 1, 2, 3 or 4 Rs. 1s Instead, preferably optionally replaced by 1 R 1s In one embodiment, R1 is not replaced; in another embodiment, R1 is optionally replaced by a C. 1-9 Alkyl (preferably C) 6-9 Alkyl, more preferably C 6-7 Alkyl) substitution; in another embodiment, one or more methylene units in R1 are optionally and independently substituted with -NR'-, preferably one methylene unit in R1 is optionally substituted with -NR'-.

[0092] In one embodiment, R1 is -(CH2)5CH3; in another embodiment, R1 is -(CH2)6CH3; in another embodiment, R1 is -(CH2)7CH3; in another embodiment, R1 is -(CH2)8CH3; in another embodiment, R1 is -(CH2)9CH3; in yet another embodiment, R1 is -(CH2) 10 CH3; in another embodiment, R1 is -(CH2). 11CH3; in another embodiment, R1 is -CH2-C≡C-(CH2)5CH3; in another embodiment, R1 is -CH2-C≡C-(CH2)6CH3; in another embodiment, R1 is -(CH2)2-C≡C-(CH2)5CH3; in another embodiment, R1 is -(CH2)4-C≡C-(CH2)3CH3; in another embodiment, R1 is -CH2-CH=CH-(CH2)5CH3; in another embodiment, R1 is -CH2-CH=CH-(CH2)6CH3; in another embodiment, R1 is -(CH2)2-CH=CH-(CH2)5CH3; in another embodiment, R1 is -(CH2)4-CH=CH-(CH2)3CH3; in another embodiment, R1 is -(CH2)5-CH=CH-CH2CH3; in another embodiment, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is In another implementation, R1 is

[0093] In one implementation, R2 is C 6-14 Alkyl, preferably C 7-12 Alkyl, preferably C 8-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl, preferably C 8-9 Alkyl, preferably C9 alkyl, preferably C 8-12 Straight-chain alkyl, preferably C 7-11 Straight-chain alkyl, preferably C 8-11 Straight-chain alkyl, preferably C 9-11 Straight-chain alkyl, preferably C 10-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C 8-9 Straight-chain alkyl, preferably C 11 Straight-chain alkyl, preferably C 10 Straight-chain alkyl, preferably C9 straight-chain alkyl; in another embodiment, R2 is C 6-14 Alkenyl, preferably C 7-12 Alkenyl, preferably C 8-12 Alkenyl; in another embodiment, R2 is C 6-14 Alkyne group, preferably C 7-12 Alkyne group, preferably C 8-12 Alkyne group; in another embodiment, R2 is optionally surrounded by one or more R groups. 1s In another embodiment, R2 is optionally replaced by 1, 2, 3 or 4 Rs. 1s Instead, preferably optionally replaced by 1 R 1s In one embodiment, R2 is not replaced; in another embodiment, R2 is optionally replaced by one C. 1-9 Alkyl (preferably C) 6-9 Alkyl, more preferably C 6-7 Alkyl) substitution; in another embodiment, one or more methylene units in R2 are optionally and independently substituted with -NR'-, preferably one methylene unit in R2 is optionally substituted with -NR'-.

[0094] In one embodiment, R2 is -(CH2)5CH3; in another embodiment, R2 is -(CH2)6CH3; in another embodiment, R2 is -(CH2)7CH3; in another embodiment, R2 is -(CH2)8CH3; in another embodiment, R2 is -(CH2)9CH3; in yet another embodiment, R2 is -(CH2) 10 CH3; in another embodiment, R2 is -(CH2). 11 CH3; in another embodiment, R2 is -CH2-C≡C-(CH2)5CH3; in another embodiment, R2 is -CH2-C≡C-(CH2)6CH3; in another embodiment, R2 is -(CH2)2-C≡C-(CH2)5CH3; in another embodiment, R2 is -(CH2)4-C≡C-(CH2)3CH3; in another embodiment, R2 is -CH2-CH=CH-(CH2)5CH3; in another embodiment, R2 is -CH2-CH=CH-(CH2)6CH3; in another embodiment, R2 is -(CH2)2-CH=CH-(CH2)5CH3; in another embodiment, R2 is -(CH2)4-CH=CH-(CH2)3CH3; in another embodiment, R2 is -(CH2)5-CH=CH-CH2CH3; in another embodiment, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is In another implementation, R2 is

[0095] In a more specific implementation, R1 and R2 are independently selected from C. 6-14 Alkyl, C 6-14 alkenyl and C 6-14 Alkyne group; in another, more specific embodiment, R1 and R2 are independently selected from C 7-12 Alkyl, C 7-12 alkenyl and C 7-12 Alkyne group; in another, more specific embodiment, R1 and R2 are independently selected from C 8-12 Alkyl, C 8-12 alkenyl and C 8-12 Alkyne group; in another, more specific embodiment, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)4-C≡C-(CH2)3CH3, -CH2-CH=CH-( CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0096] R 1s

[0097] In one implementation, R 1s H; in another embodiment, R 1s C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-9Alkyl, preferably C 7-9 Alkyl, preferably C 8-9 Alkyl, preferably C 1-6 Alkyl, preferably C 1-4 Alkyl, preferably C 7-11 Alkyl, preferably C 4-10 Alkyl, preferably C 6-10 Alkyl, preferably C 7-10 Alkyl, preferably C 9-10 Alkyl, preferably C 4-9 Alkyl, preferably C 6-9 Alkyl, preferably C 1-8 Alkyl, preferably C 4-8 Alkyl, preferably C 6-8 Alkyl, preferably C 7-8 Alkyl, preferably C 6-7 Alkyl, preferably C9 alkyl, preferably C8 alkyl, preferably C7 alkyl, preferably C6 alkyl, preferably C5 alkyl; in another embodiment, R 1s -L c -OR c In another implementation, R 1s -L c -SR c In another implementation, R 1s -L c -NR c R' c .

[0098] In a more specific implementation, R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c In another, more specific implementation, R 1s Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R 1s Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R 1s Independently selected from H and C 1- 9-alkyl; in another, more specific embodiment, R 1s Independently selected from H and C 1-6 Alkyl; in another, more specific embodiment, R 1s Independently selected from H and C 1-4 Alkyl; in another, more specific embodiment, R 1s Selected independently from C 5-9Alkyl; in another, more specific embodiment, R 1s Selected independently from C 4-8 Alkyl; in another, more specific embodiment, R 1s Selected independently from C 5-8 Alkyl; in another, more specific embodiment, R 1s Selected independently from C 6-8 Alkyl; in another, more specific embodiment, R 1s Selected independently from C 6-7 Alkyl; in another, more specific embodiment, R 1s Selected independently from C 5-7 alkyl.

[0099] L c R c and R' c

[0100] In one implementation, L c For chemical bonds; in another embodiment, L c C 1-14 Alkylene, preferably C 1-10 Alkylene, preferably C 1-6 Alkylene.

[0101] In a more specific implementation, L c Independently selected from chemical bonds and C 1-14 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-10 Alkylene; in another, more specific embodiment, L c Independently selected from chemical bonds and C 1-6 Alkylene.

[0102] In one implementation, R c H; in another embodiment, R c C 1-14 Alkyl, preferably C 1-10 Alkyl, preferably C 1-6 Alkyl; in another embodiment, R c C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R c It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0103] In one implementation, R' c H; in another embodiment, R' c C 1-14 Alkyl, preferably C 1-10Alkyl, preferably C 1-6 Alkyl; in another embodiment, R' c C 3-14 Cycloalkyl, preferably C 3-10 cycloalkyl; in another embodiment, R' c It is a 3- to 14-membered heterocyclic group, preferably a 3- to 10-membered heterocyclic group.

[0104] In a more specific implementation, R c and R' c Independently selected from H and C 1-14 Alkyl; in another, more specific embodiment, R c and R' c Independently selected from H and C 1-10 Alkyl; in another, more specific embodiment, R c and R' c Independently selected from H and C 1-6 alkyl.

[0105] R4 and R5

[0106] In one implementation, R4 is C 1-6 Alkyl, preferably C 1-3 Alkyl group, preferably methyl group.

[0107] In one implementation, R5 is C 1-6 Alkyl, preferably C 1-3 Alkyl group, preferably methyl group.

[0108] In one implementation, R4, R5, together with the carbon atoms they are attached to, form C. 3-6 Cycloalkylene compounds (e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene), preferably forming C 3-5 Cycloalkylene, preferably forming C 3- 4. Cycloalkylene groups, preferably cyclopropylene groups, and more preferably cyclopentylene groups; in another embodiment, R4, R5 together with the carbon atoms to which they are attached form 3 to 6-membered heterocyclic groups.

[0109] In a more specific embodiment, R4, R5, together with the carbon atoms they are bonded to, form C. 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene groups; in another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); in another, more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form C14. 3-5Cycloalkylene; in another more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form cyclopropylene or cyclopentylene; in another more specific embodiment, R4, R5 together with the carbon atoms to which they are attached form cyclopropylene; in another more specific embodiment, R4, R5 and the carbon atoms to which they are attached do not form a ring.

[0110] a, b, c, and d

[0111] In one implementation, a is 2; in another implementation, a is 3; in another implementation, a is 4; in another implementation, a is 5; in another implementation, a is 6.

[0112] In one more specific embodiment, a = 2, 3, 4, 5 or 6; in another more specific embodiment, a = 2, 3 or 4; in another more specific embodiment, a = 2 or 4; in another more specific embodiment, a = 2 or 3; in another more specific embodiment, a = 3 or 4.

[0113] In one implementation, b is 4; in another implementation, b is 5; in another implementation, b is 6; in another implementation, b is 7; in another implementation, b is 8; in another implementation, b is 9; in another implementation, b is 10.

[0114] In one more specific embodiment, b = 5, 6, 7 or 8; in another more specific embodiment, b = 5, 6 or 7; in another more specific embodiment, b = 5 or 7; in another more specific embodiment, b = 6 or 7.

[0115] In one embodiment, c is 1; in another embodiment, c is 2; in another embodiment, c is 3; in another embodiment, c is 4; in another embodiment, c is 5; in another embodiment, c is 6; in another embodiment, c is 7.

[0116] In a more specific embodiment, c = 1, 2, 3, 4, 5, 6 or 7; in a more specific embodiment, c = 4, 5, 6 or 7; in a more specific embodiment, c = 5 or 6; in a more specific embodiment, c = 3, 4 or 5.

[0117] In one implementation, d is 0; in another implementation, d is 1; in another implementation, d is 2; in another implementation, d is 3; in another implementation, d is 4.

[0118] In one more specific implementation, d = 0, 1, 2, 3, or 4; in another implementation, d = 0, 1, 2, or 3; in yet another implementation, d = 0 or 1.

[0119] In one embodiment, c+d = 3; in another embodiment, c+d = 4; in another embodiment, c+d = 5; in another embodiment, c+d = 6; in another embodiment, c+d = 7; in another embodiment, c+d = 8; in another embodiment, c+d = 9.

[0120] In one more specific embodiment, c+d = 3, 4, 5, 6, 7, 8, or 9; in another embodiment, c+d = 5, 6, or 7; in another embodiment, c+d = 4, 5, or 6; in another embodiment, c+d = 4 or 5; in another embodiment, c+d = 5 or 6; in another embodiment, c+d = 6 or 7.

[0121] Any technical solution or any combination thereof in any of the above specific embodiments can be combined with any technical solution or any combination thereof in other specific embodiments. This invention aims to include combinations of all such technical solutions; however, due to space limitations, they are not listed individually.

[0122] In a more specific embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof.

[0123] in,

[0124] a = 2, 3, 4, 5 or 6;

[0125] b = 4, 5, 6, 7, 8, 9 or 10;

[0126] c = 1, 2, 3, 4, 5, 6 or 7;

[0127] d = 0, 1, 2, 3 or 4;

[0128] c+d = 3, 4, 5, 6, 7, 8 or 9;

[0129] M1 is selected from -OC(O)O-, -C(O)O-, -OC(O-, -SC(O-) and -C(O)S-;

[0130] M2 is selected from -OC(O)O-, -C(O)NR-, -NRC(O-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-;

[0131] R1 and R2 are independently selected from C 6-14Alkyl, C 6-14 alkenyl or C 6-14 Alkyne group, which is optionally surrounded by 1, 2, 3 or 4 R groups 1s Substitution, and one or more methylene units therein are optionally and independently substituted with -NR'-;

[0132] R and R' are each independently selected from H and C. 1-20 alkyl;

[0133] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ;

[0134] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0135] R c and R' c Independently selected from H and C 1-14 alkyl;

[0136] R4 and R5 are independently selected from C 1-6 alkyl;

[0137] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene groups;

[0138] The condition is that,

[0139] (3) When M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-;

[0140] (4) When M1 is -OC(O)O- and M2 is -OC(O)O-; and

[0141] (3) The compound is not

[0142] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein M1 is selected from -OC(O)O-, -C(O)O-, -OC(O)-, -SC(O- and -C(O)S-.

[0143] In a more specific implementation, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, preferably selected from -OC(O)- and -C(O)O-, more preferably selected from -OC(O), and more preferably selected from -C(O)O-.

[0144] In a more specific implementation, M1 is selected from -OC(O)O-.

[0145] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein M2 is selected from -OC(O)O-, -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-.

[0146] In a more specific implementation, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-, preferably selected from -C(O)NR-, -NRC(O)-, -OC(O)NR- and -NRC(O)NR-, and most preferably selected from -NRC(O)NR-.

[0147] In a more specific implementation, M2 is selected from -OC(O)O-.

[0148] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R and R' are each independently selected from H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl groups; preferably selected from H and C. 1-6 Alkyl group; preferably R is H.

[0149] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R1 and R2 are independently selected from C 6-14 Alkyl, preferably C 7-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C 9-10 Straight-chain alkyl, preferably C9 straight-chain alkyl.

[0150] In a more specific implementation, R1 and R2 are optionally represented by 1, 2, 3, or 4 R... 1s Instead, preferably optionally replaced by 1 R 1s replace.

[0151] In a more specific implementation, one of R1 and R2 is replaced by one R 1sOne was replaced, while the other was not replaced.

[0152] In a more specific implementation, R1 and R2 are each independently controlled by one R 1s replace.

[0153] In a more specific embodiment, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, -(CH2)4-C≡C- (CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3,

[0154] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-10 Alkyl groups; preferably selected from H and C. 1-9 Alkyl groups; preferably selected from H and C. 1-6 Alkyl groups, preferably selected from H and C 1-4 Alkyl groups, preferably selected from C10 and C20. 5-9 Alkyl groups, preferably selected from C10 and C20. 6-8 alkyl.

[0155] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein L c Independently selected from chemical bonds and C 1-14 Alkylene; preferably selected from chemical bonds and C 1-10Alkylene; preferably selected from chemical bonds and C 1-6 Alkylene;

[0156] In a more specific implementation plan, R c and R' c Independently selected from H and C 1-14 Alkyl groups; preferably selected from H and C. 1-10 Alkyl groups; preferably selected from H and C. 1-6 alkyl.

[0157] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein R4 and R5 are independently selected from C 1-6 Alkyl; preferably selected from C 1-3 Alkyl; preferably selected from C 1-2 Alkyl; preferably methyl.

[0158] In a more specific implementation, R4, R5, together with the carbon atoms they are bonded to, form C. 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably cyclopropylene.

[0159] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0160] in,

[0161] a = 2, 3, 4, 5 or 6;

[0162] b = 4, 5, 6, 7, 8, 9 or 10;

[0163] c = 1, 2, 3, 4, 5, 6 or 7;

[0164] d = 0, 1, 2, 3 or 4;

[0165] c+d = 3, 4, 5, 6, 7, 8 or 9;

[0166] M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-;

[0167] M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-; preferably, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR- and -NRC(O)NR-; preferably, M2 is selected from -NRC(O)NR-;

[0168] R is independently selected from H and C. 1-3 alkyl;

[0169] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[0170] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ;

[0171] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0172] R c and R' c Independently selected from H and C 1-14 alkyl;

[0173] R4 and R5 are independently selected from C 1-6 alkyl;

[0174] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0175] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0176] in,

[0177] a = 2, 3, or 4;

[0178] b = 5, 6, 7 or 8;

[0179] c = 4, 5, 6 or 7;

[0180] d = 0, 1, 2 or 3;

[0181] c+d = 5, 6 or 7;

[0182] M1 is selected from -OC(O)- and -C(O)O-;

[0183] M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O- and -NHC(O)NH-; preferably, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH- and -NHC(O)NH-; preferably, M2 is selected from -NHC(O)NH-;

[0184] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s Replacement; preferably, one of R1 and R2 is replaced by one R 1s One is replaced, the other is not replaced;

[0185] R 1s Independently selected from H and C 1-14 alkyl;

[0186] R4 and R5 are independently selected from C 1-6 alkyl;

[0187] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0188] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein,

[0189] a = 2, 3, or 4; a = 2 is preferred.

[0190] b = 6 or 7;

[0191] c = 5 or 6;

[0192] d = 0 or 1;

[0193] c+d = 5, 6 or 7; c+d = 6 is preferred.

[0194] M1 is selected from -OC(O)- and -C(O)O-;

[0195] M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O- and -NHC(O)NH-; preferably, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH- and -NHC(O)NH-;

[0196] R1 and R2 are independently selected from C 6-14 Alkyl, preferably C 7-11 Alkyl, preferably C 8-10Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups;

[0197] One of R1 and R2 is controlled by 1 R 1s One is replaced, the other is not replaced;

[0198] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 5-9 Alkyl; preferably selected from C 6-8 alkyl;

[0199] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0200] R c and R' c Independently selected from H and C 1-14 alkyl;

[0201] R4 and R5 are independently selected from C 1-6 Alkyl groups, preferably methyl groups;

[0202] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably forming C 3-4 Cycloalkylene; preferably cyclopropylene;

[0203] Preferably, R1 and R2 are independently selected from -(CH2)8CH3,

[0204] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein,

[0205] a = 2;

[0206] b = 6 or 7;

[0207] c = 5 or 6;

[0208] d = 0 or 1;

[0209] c+d=6;

[0210] M1 is selected from -OC(O)- and -C(O)O-;

[0211] M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O- and -NHC(O)NH-; preferably, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH- and -NHC(O)NH-;

[0212] R1 is selected from C 6-14 Straight-chain alkyl, preferably C 7-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0213] R2 is selected from C 6-14 Alkyl group, preferably R2 is selected from C 7-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace;

[0214] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 5-8 Alkyl; preferably selected from C 6-7 alkyl;

[0215] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0216] R c and R' c Independently selected from H and C 1-14 alkyl;

[0217] R4 and R5 are independently selected from C 1-6 Alkyl groups, preferably methyl groups;

[0218] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably forming C 3-4 Cycloalkylene; preferably cyclopropylene.

[0219] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein,

[0220] a = 2;

[0221] b = 6;

[0222] c = 5 or 6; c = 5 is preferred.

[0223] d = 0 or 1; preferred d = 1;

[0224] c+d = 5, 6 or 7; c+d = 6 is preferred.

[0225] M1 is selected from -OC(O)- and -C(O)O-; preferably, M1 is selected from -OC(O)-;

[0226] M2 is selected from -NHC(O)O-, -OC(O)NH- and -NHC(O)NH-; preferably, M2 is selected from -OC(O)NH- and -NHC(O)NH-; preferably, M2 is selected from -NHC(O)NH-;

[0227] R1 is selected from C 8-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0228] R2 is selected from C 7-12 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace;

[0229] R 1s Independently selected from H and C 1-9 Alkyl; preferably selected from C 5-8 Alkyl; preferably selected from C 6-7 Alkyl group; preferably selected from C7 alkyl groups;

[0230] R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups;

[0231] Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

[0232] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0233] in,

[0234] a = 2, 3, 4, 5 or 6;

[0235] b = 4, 5, 6, 7, 8, 9 or 10;

[0236] c = 1, 2, 3, 4, 5, 6 or 7;

[0237] d = 0, 1, 2, 3 or 4;

[0238] c+d = 3, 4, 5, 6, 7, 8 or 9;

[0239] Both M1 and M2 are selected from -OC(O)O-;

[0240] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[0241] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ;

[0242] L c Independently selected from chemical bonds and C 1-14 Alkylene;

[0243] R c and R' c Independently selected from H and C 1-14 alkyl;

[0244] R4 and R5 are independently selected from C 1-6 Alkyl, preferably C 1-3 alkyl;

[0245] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0246] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof.

[0247] in,

[0248] a = 2, 3, or 4;

[0249] b = 5, 6, or 7;

[0250] c = 3, 4, or 5;

[0251] d = 0 or 1;

[0252] c+d = 4, 5 or 6;

[0253] Both M1 and M2 are selected from -OC(O)O-;

[0254] R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace;

[0255] R 1s Independently selected from H and C 1-14 alkyl;

[0256] R4 and R5 are independently selected from C 1-6 Alkyl, preferably C 1-3 alkyl;

[0257] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

[0258] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein,

[0259] a = 2, 3, or 4; preferably a = 2 or 4.

[0260] b = 6;

[0261] c = 4;

[0262] d = 1;

[0263] M1 and M2 are selected from -OC(O)O-;

[0264] R1 and R2 are independently selected from C 7-11 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups; optionally marked with one R 1s replace;

[0265] Preferably, one of R1 and R2 is controlled by one R 1s One is replaced, the other is not replaced;

[0266] Preferably, R1 and R2 are each independently controlled by one R 1s replace;

[0267] R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C4-8 Alkyl; preferably selected from C 5-7 alkyl;

[0268] L c Independently selected from chemical bonds and C 1-14 Alkylene;

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

[0270] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably C 1-2 Alkyl groups, preferably methyl groups;

[0271] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably forming C 3-4 Cycloalkylene; preferably cyclopropylene;

[0272] Preferably, R 1s The replacement R1 or R2 is selected from

[0273] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein,

[0274] a = 2, 3, or 4; a = 2 is preferred.

[0275] b = 6;

[0276] c = 4;

[0277] d = 1;

[0278] M1 and M2 are selected from -OC(O)O-;

[0279] R1 is selected from C 7-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C9 straight-chain alkyl;

[0280] R2 is selected from C 7-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups; optionally, they are marked with one R. 1s replace;

[0281] R 1s Selected from H and C 1-9 Alkyl; preferably selected from C 6-7 Alkyl group; preferably selected from C6 alkyl groups;

[0282] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably C 1-2 Alkyl groups, preferably methyl groups;

[0283] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably cyclopropylene.

[0284] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein,

[0285] a = 2, 3, or 4; preferably a = 2 or 4.

[0286] b = 6;

[0287] c = 4;

[0288] d = 1;

[0289] M1 and M2 are selected from -OC(O)O-;

[0290] R1 is selected from C 7-11 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups; optionally marked with one R 1s replace;

[0291] R2 is selected from C 7-11 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups; optionally marked with one R 1s replace;

[0292] R 1s Independently selected from H and C 1-9 Alkyl; preferably selected from C 5-7 Alkyl groups; preferably selected from C5 and C7 alkyl groups;

[0293] R4 and R5 are independently selected from C 1-3 Alkyl group, preferably C 1-2 Alkyl groups, preferably methyl groups;

[0294] Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably cyclopropylene.

[0295] In a more specific embodiment, the present invention provides a compound of formula (I) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein the compound is selected from:

[0296] The present invention also provides a method for preparing a compound of formula (I), the method comprising:

[0297] The compound of formula (IA) is reacted with the compound of formula (IB) to obtain the compound of formula (I);

[0298] or,

[0299] The compound of formula (IC) is reacted with the compound of formula (ID) to obtain the compound of formula (I);

[0300] Where X is a halogen, and the other variables are as defined in this paper.

[0301] In a more specific embodiment, the present invention provides a nanoparticle composition comprising a lipid component and optionally a loading; wherein the lipid component contains a compound of the present invention.

[0302] Optionally, the lipid component contains the following components in molar percentage:

[0303] Ionizable cationic lipids 20 mol% - 85 mol%

[0304] Structural lipids: 10 mol% - 75 mol%;

[0305] Neutral lipids: 1.0 mol% - 30 mol%;

[0306] Polymer lipids: 0.25 mol% - 10 mol%;

[0307] Optionally, the lipid component contains the following components in molar percentage:

[0308] 50 mol% of any of the compounds of the present invention mentioned above;

[0309] Neutral lipids 10 mol%;

[0310] Structural lipids 38.5 mol%;

[0311] Polymer lipid 1.5 mol%.

[0312] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the neutral lipid is selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE or DPPE, preferably DSPC and / or DOPE.

[0313] In a more specific embodiment, the present invention provides the above-mentioned nanoparticle composition, wherein the structural lipid is selected from one or more of cholesterol, sitosterol, coccosterol, lycopene, campesterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, alfalfa sterol, ergocalciferol or campesterol, preferably cholesterol and / or β-sitosterol, more preferably cholesterol.

[0314] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the polymer lipid is a polyethylene glycol-modified lipid.

[0315] Optionally, the PEGylated lipid is selected from one or more of the following: PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, and PEG-modified dialkylglycerol.

[0316] Optionally, the PEGylated lipid contains a PEG portion of about 1000 Da to about 20 kDa, preferably a PEG portion of about 1000 Da to about 5000 Da.

[0317] Optionally, the PEGylated lipid is selected from one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000, preferably DMG-PEG2000.

[0318] In a more specific embodiment, the present invention provides the above-described nanoparticle composition, wherein the loading is selected from one or more therapeutic agents, preventive agents, or diagnostic agents;

[0319] Preferably, the therapeutic agent, preventive agent, or diagnostic agent is a nucleic acid;

[0320] Preferably, the nucleic acid is selected from one or more of ASO, RNA, or DNA;

[0321] Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozymes, preferably mRNA, and more preferably modified mRNA.

[0322] The compounds of this invention may include one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures rich in one or more stereoisomers. The isomers can be separated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis.

[0323] The compounds of this invention can exist as tautomers. Tautomers are functional group isomers that arise from the rapid movement of an atom between two positions in a molecule. A tautomer is a special type of functional group isomer; a pair of tautomers can interconvert, but usually the more stable isomer is the dominant form. The most prominent examples are enol and keto tautomers.

[0324] The present invention also includes isotopically labeled compounds (isotopic variants) that are equivalent to those described in formula (IV), but in which one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, for example... 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36Cl. Other isotopes of the present invention containing the aforementioned isotopes and / or other atoms, their prodrugs, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of this invention. Certain isotope-labeled compounds of the present invention, for example, those incorporating radioactive isotopes (e.g.,...) 3 H and 14 Those in category C) can be used for drug and / or substrate tissue distribution determination. Tritium, i.e. 3 H and carbon-14, i.e. 14 Carbon isotopes are particularly preferred because they are easy to prepare and detect. Subsequently, they are replaced by heavier isotopes, such as deuterium, i.e., 2 H, because higher metabolic stability can provide therapeutic benefits, such as prolonged in vivo half-life or reduced dosage requirements, may be preferred in some cases. Isotope-labeled compounds of formula (IV) of the present invention and their prodrugs can generally be prepared by using readily available isotope-labeled reagents instead of non-isotope-labeled reagents when performing the processes and / or the methods disclosed in the examples and preparation examples below.

[0325] This invention also provides pharmaceutical formulations comprising a therapeutically effective amount of a compound of formula (IV) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, or excipient thereof. All such forms are included in this invention.

[0326] Pharmaceutical Compositions and Kits

[0327] In another aspect, the present invention provides a pharmaceutical composition comprising the nanoparticle composition of the present invention and a pharmaceutically acceptable excipient, said nanoparticle composition comprising the compounds of the present invention.

[0328] Pharmaceutically acceptable excipients used in this invention refer to non-toxic carriers, adjuvants, or mediators that do not impair the pharmacological activity of the compounds formulated together. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0329] The present invention also includes a kit (e.g., a pharmaceutical package). The provided kit may include the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other suitable containers) containing the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents. In some embodiments, the provided kit may optionally include a third container containing pharmaceutical excipients for diluting or suspending the nanoparticle composition of the present invention and / or other therapeutic, diagnostic, or preventative agents. In some embodiments, the nanoparticle composition of the present invention and other therapeutic, diagnostic, or preventative agents provided in the first and second containers form a unit dosage form.

[0330] Dosage

[0331] The pharmaceutical compositions provided by this invention can be administered via a variety of routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration, administration via implantation, or other routes of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intramenstrual administration, intralesional administration, and intracranial injection or infusion techniques.

[0332] Typically, an effective amount of the pharmaceutical composition of the present invention is administered. The amount of pharmaceutical composition actually administered may be determined by a physician, depending on relevant circumstances, including the condition being treated or prevented, the chosen route of administration, the actual amount of pharmaceutical composition administered, the individual patient's age, weight and response, the severity of the patient's symptoms, etc.

[0333] When used to prevent the conditions described in this invention, the pharmaceutical composition provided herein is administered to subjects at risk of developing the conditions, typically based on a physician's advice and under physician supervision, at the dosage levels described above. Subjects at risk of developing a specific condition generally include subjects with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to developing the condition.

[0334] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof over a prolonged period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be administered indefinitely, such as for the remainder of the subject's life. In some embodiments, long-term administration is intended to provide a constant level of said compound in the blood over a prolonged period of time, such as within a therapeutic window.

[0335] Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, the pharmaceutical composition can be administered by bolus injection, for instance, to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active component through the body; for example, an intramuscular or subcutaneous bolus dose results in a slow release of the active component, while a bolus dose delivered directly to a vein (e.g., via IV intravenous infusion) allows for a more rapid delivery, causing the concentration of the active component in the blood to rapidly increase to an effective level. In other embodiments, the pharmaceutical composition can be administered in the form of a continuous infusion, for example, via IV intravenous infusion, thereby providing a steady-state concentration of the active component in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition can be administered first, followed by a continuous infusion.

[0336] To provide blood levels similar to or lower than those achieved with an injection dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, more preferably about 0.1 to about 10% by weight, and even more preferably about 0.5 to about 15% by weight.

[0337] From approximately 1 to approximately 120 hours, especially 24 to 96 hours, the injection dose level ranges from approximately 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain adequate steady-state levels, a preload bolus of approximately 0.1 mg / kg to approximately 10 mg / kg or more may also be administered. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0338] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable excipients known in the art. As previously described, in such compositions, the active compound is typically a smaller component, often about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0339] Example

[0340] To make the technical solution of the present invention clearer and more explicit, the present invention will be further described in detail through the following embodiments. The following embodiments are only used to illustrate specific implementation methods of the present invention so that those skilled in the art can understand the present invention, but are not intended to limit the scope of protection of the present invention. In the specific embodiments of the present invention, the technical means or methods, etc., not specifically described, are conventional technical means or methods in the art. Unless otherwise specified, the materials, reagents, etc., used in the embodiments can be obtained commercially.

[0341] Table 1

[0342] Example 1: Synthesis of Compound 1

[0343] In a 20 mL round-bottom flask, 7-bromoheptanoic acid (0.85 g, 4.07 mmol, 1.1 eq.), 2-octyl-decyl alcohol (1.0 g, 3.70 mmol, 1.0 eq.), DMAP (90 mg, 0.739 mmol, 0.2 eq.), and EDCI (1.06 g, 5.546 mmol, 1.5 eq.) were dissolved in 10 mL of dichloromethane and stirred overnight at room temperature. After the reaction was complete, 10 mL of water was added to quench the reaction, and the mixture was extracted with dichloromethane (3 x 15 mL). The organic phase was collected and washed with brine (1 x 10 mL). The organic phase was dried over Na₂SO₄ to remove the solvent, and the crude product was purified by silica gel column chromatography to give 1.5 g of a pale yellow oily compound 1-1.

[0344] In a 1 L three-necked flask, methyl isobutyrate (30 g, 293.74 mmol, 1.0 eq.) and THF (300 mL) were added. The system was cooled to -40 °C, and LDA (2 M, 146.9 mL, 293.74 mmol, 1.0 eq.) was added dropwise. After completion, the system was kept at -40 °C for 1 hour. At this temperature, 1,6-dibromohexane (93.16 g, 381.86 mmol, 1.3 eq.) was added dropwise, followed by DMPU (4.52 g, 35.248 mmol, 0.12 eq.). The system was allowed to warm to room temperature overnight. The system was cooled to 0 °C, and saturated ammonium chloride aqueous solution (200 mL) was added dropwise. The system was extracted with ethyl acetate (3 x 200 mL). The organic phase was collected and washed with saturated brine (1 x 500 mL). The solution was dried over anhydrous Na2SO4, filtered, and concentrated to obtain a yellow oily compound 1-2 (99.1 g, crude), which was directly added to the next step.

[0345] Add 1-2 (97g, crude) and THF (1000mL) to a 2L three-necked flask. Cool to 0℃ under nitrogen protection, then slowly add lithium aluminum hydride (73.2mL, 2.5M), resulting in an exothermic reaction. Stir at 0℃ for 5 minutes, then slowly heat to room temperature. Monitor the reaction for completion using TLC. Slowly add Na2SO4 (100g), filter, wash the filter cake with THF (2 x 200mL), combine the filtrates, concentrate, and purify by silica gel column chromatography to obtain 30.26g of a pale yellow oily compound 1-3.

[0346] In a 100 mL round-bottom flask, nonanoic acid (1.10 g, 6.96 mmol, 1.1 eq.), compound 1-3 (1.5 g, 6.32 mmol, 1.0 eq.), DMAP (0.77 g, 6.32 mmol, 1.0 eq.), and EDCI (1.82 g, 9.49 mmol, 1.5 eq.) were added and dissolved in 15 mL of dichloromethane. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, 50 mL of water was added at room temperature to quench the reaction, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phase was collected and washed with saturated brine (1 x 30 mL). The solution was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by silica gel column chromatography to give 1.95 g of a light colorless oily compound 1-4.

[0347] Compounds 1-4 (500 mg, 1.33 mmol, 1.0 eq.), 3-hydroxypropylamine (1.99 g, 26.50 mmol, 20.0 eq.), and ethanol (5 mL) were added to a 40 mL sealed tube at room temperature. The system was heated to 70 °C and reacted for 3 h. The reaction was monitored by LC-MS until the starting material was almost completely reacted. The system was cooled to room temperature, concentrated under reduced pressure, and redissolved in ethyl acetate (50 mL). The organic phase was washed with water (3 x 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to give 391.2 mg of a pale yellow oily compound 1-5.

[0348] In a 40 mL sealed tube at room temperature, 1-5 (150.00 mg, 0.40 mmol, 1.0 eq.), 1-1 (204.95 mg, 0.44 mmol, 1.1 eq.), potassium carbonate (168.58 mg, 1.20 mmol, 3.0 eq.), and KI (80.41 mg, 0.48 mmol, 1.2 eq.) dissolved in a mixed solvent system of cyclopentyl methyl ether (3 mL) and acetonitrile (1 mL) were added. The mixture was heated to 80 °C and reacted for 18 h. The reaction was monitored by LC-MS until the starting material had largely reacted. After cooling to room temperature, the mixture was filtered. The filter cake was washed with ethyl acetate (2 x 5 mL), and the filtrate was concentrated to obtain the crude product. The crude product was sent to a preparative liquid chromatography system. The preparation conditions were as follows (Column: XSelect CSH Prep C18 OBD Column, 30*150mm, 5μm; Eluent A: H2O / ACN 60 / 40, 10mM NH4HCO3 + 1% NH3·H2O; Eluent B: IPA / ACN 90 / 10; Flow rate: 60mL / min; Gradient program: 70%-88% B in 0-12min), yielding 142.8mg of a yellow oily product 1.

[0349] 1H NMR (300MHz, CDCl3) δ: 3.96 (d, J = 6.0Hz, 2H), 3.82-3.78 (m, 4H), 2.49-2.33 (bs, 5H), 2.30 (d d,J=4.5Hz,7.5Hz,4H),1.78-1.58(m,14H),1.33-1.24(m,49H),0.89-0.88(m,15H); ESI-MS m / z:752.70[M+H] + .

[0350] Example 2: Synthesis of Compound 2

[0351] Compound 2 was prepared according to the method of Example 1, yielding 199.4 mg of an oily product.

[0352] 1 H NMR (400MHz, CDCl3) δ: 3.96 (d, J = 5.6 Hz, 2H), 3.78 (s, 2H), 3.56 (m, 2H), 2.46 (bs, 5H), 2.30 (dd, J = 7.6H z,15.2Hz,4H),1.66-1.61(m,10H),1.59-1.50(m,4H),1.38-1.23(m,51H),0.92-0.88(m,15H); ESI-MS m / z:766.75[M+H] + .

[0353] Example 3: Synthesis of Compound 3

[0354] Compound 3 was prepared according to the method of Example 1, yielding 105.5 mg of an oily product.

[0355] 1 H NMR (300MHz, CD3OD) δ: 3.98 (d, J = 5.4Hz, 2H), 3.80 (s, 2H), 3.61 (t, J = 6.6Hz, 2H), 2.63 (t, J = 6.3Hz, 2H), 2.54-2 .35(m,4H),2.33(dd,J=1.5Hz,7.2Hz,4H),1.72-1.49(m,10H),1.38-1.28(m,56H),0.99-0.92(m,15H); ESI-MS m / z:780.65[M+H] + .

[0356] Example 4: Synthesis of Compound 4

[0357] Compound 4 was prepared according to the method of Example 1, yielding 99.6 mg of an oily product.

[0358] 1 H NMR(300MHz,CD3OD)δ:3.98(d,J=5.7Hz,2H),3.80(s,2H),3.63(t,J=6.0Hz,2H),2.66-2.51(m, 6H), 2.33 (t, J = 7.2Hz, 4H), 1.89-1.49 (m, 12H), 1.38-1.24 (m, 56H), 0.97-0.92 (m, 15H); ESI-MS m / z:794.75[M+H] + .

[0359] Example 5: Synthesis of Compound 5

[0360] Compound 5 was prepared according to the method of Example 1, yielding 163.4 mg of an oily product.

[0361] 1 H NMR (300MHz, CDCl3) δ: 3.95 (d, J = 5.7Hz, 2H), 3.78 (s, 2H), 3.58 (s, 2H), 2.51-2.34 (bs, 6H ),2.32-2.27(m,4H),1.76-1.52(m,14H),1.41-1.26(m,56H),0.89-0.88(m,15H); ESI-MS m / z:808.75[M+H] + .

[0362] Example 6: Synthesis of Compound 6

[0363] Compound 6 was prepared according to the method of Example 1, yielding 137.4 mg of an oily product.

[0364] 1 H NMR (300MHz, CDCl3) δ: 4.08 (t, J = 7.2Hz, 2H), 3.78 (s, 2H), 3.59 (s, 2H), 2.66-2.53 (m, 6H), 2.31 (dd,J=7.5Hz,16.2Hz,4H),1.77-1.49(m,10H),1.41-1.26(m,54H),0.89-0.88(m,15H); ESI-MS m / z:766.70[M+H] + .

[0365] Example 7: Synthesis of Compound 7

[0366] Compound 7 was prepared according to the method of Example 1, yielding 117.8 mg of an oily product.

[0367] 1 H NMR (300MHz, CDCl3) δ: 4.08 (t, J = 7.2Hz, 2H), 3.82-3.78 (m, 4H), 2.75-2.38 (m, 6H), 2.31 (dd ,J=7.5Hz,15.9Hz,4H),1.75-1.53(m,14H),1.44-1.26(m,52H),0.92-0.89(m,15H); ESI-MS m / z:780.70[M+H] + .

[0368] Example 8: Synthesis of Compound 8

[0369] Compound 8 was prepared according to the method of Example 1, yielding 112.0 mg of an oily product.

[0370] 1 H NMR (300MHz, CDCl3) δ: 3.96 (d, J = 5.7Hz, 2H), 3.78 (s, 2H), 3.65-3.60 (m, 2H), 2.66-2.3 4(m,6H),2.29(dd,J=6.0Hz,7.5Hz,4H),1.63-1.23(m,62H),0.89-0.86(m,15H); ESI-MS m / z:752.65[M+H] + .

[0371] Example 9: Synthesis of Compound 9

[0372] Compound 9 was prepared according to the method of Example 1, yielding 184.5 mg of an oily product.

[0373] 1 H NMR (300MHz, CDCl3) δ: 3.96 (d, J = 6.0Hz, 2H), 3.82-3.78 (m, 4H), 2.70-2.34 (m, 6H), 2.29 (d d,J=6.0Hz,7.5Hz,4H),1.72-1.50(m,12H),1.40-1.24(m,52H),0.89-0.88(m,15H); ESI-MS m / z:766.65[M+H] + .

[0374] Example 10: Synthesis of Compound 10

[0375] At room temperature, 5-bromo-1-pentanol (100 g, 598.64 mmol, 1.0 eq.) and imidazole (101.89 g, 1496.60 mmol, 2.5 eq.) were dissolved in DMF (600 mL) in a 1000 mL three-necked flask. Then, TBSCl (99.25 g, 658.50 mmol, 1.1 eq.) was added in portions over 30 min at 0 °C, and the reaction was allowed to proceed overnight at room temperature. The reaction was quenched by adding NaHCO3 aqueous solution (1 L) at 0 °C, extracted with petroleum ether (2 x 500 mL), washed with organic phase brine (2 x 500 mL), dried over anhydrous Na2SO4, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 131 g of a pale yellow oily compound 10⁻¹.

[0376] At room temperature, magnesium powder (12.03 g, 494.81 mmol, 1.6 eq.) and THF (50 mL) were added to a 250 mL three-necked flask, and the temperature was raised to 37 °C. A 10⁻¹ (130.50 g, 463.887 mmol, 1.5 eq.) THF solution (100 mL) was slowly added dropwise. When the system began to exhibit significant exothermic behavior, the M0443-1 THF mixture was diluted to 800 mL, and the temperature was maintained at 50 °C while the addition continued. After the reaction was complete, the reaction mixture was allowed to react at 60 °C for 1 h. The reaction system was then cooled to room temperature, and the Grignard reagent preparation was complete.

[0377] At room temperature, CuBr (4.44 g, 30.93 mmol, 0.1 eq.), LiCl (2.62 g, 61.86 mmol, 0.2 eq.), and THF (350 mL) were added to a 250 mL three-necked flask and stirred at 0 °C for 5 min. TMSCl (50.40 g, 463.89 mmol, 1.5 eq.) was added over 20 min at 0 °C, followed by methyl 3,3-dimethacrylate (35.3 g, 309.26 mmol, 1.0 eq.) over 10 min at 0 °C, and the mixture was stirred at 0 °C for 20 min. The prepared Grignard reagent was then added dropwise, and the reaction was carried out at 0 °C for 2 h.

[0378] After the reaction was completed, the reaction was quenched with saturated NH4Cl solution (1.5 L), extracted with ethyl acetate (3 x 600 mL), washed with organic phase brine (1 x 1500 mL), dried over anhydrous Na2SO4, filtered and evaporated to dryness, yielding 120 g of crude product 10-2, which could be used directly in the next reaction without purification.

[0379] At room temperature, 120 g of compound 10⁻² (crude) was dissolved in 600 mL of THF in a 1 L reaction flask. After cooling to 0 °C, 200 g of TBAF was added in portions, and the reaction was allowed to proceed at room temperature for 2 h. The reaction was quenched with saturated NH₄Cl solution, extracted with ethyl acetate (3 x 400 mL), washed with organic phase brine (1 x 800 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. After purification by silica gel column chromatography, approximately 37 g of compound 10⁻³ was obtained.

[0380] Compound 10⁻³ (37 g, 182.90 mmol, 1.0 eq.) and PPh³ (57.57 g, 219.48 mmol, 1.2 eq.) were dissolved in 150 mL of tetrahydrofuran solution in a 250 mL reaction flask. After cooling to 0 °C, CBr₄ (66.72 g, 201.19 mmol, 1.1 eq.) was added in portions. The reaction was allowed to proceed overnight at room temperature. The reaction was then quenched with 500 mL of ice water at 0 °C and extracted with ethyl acetate (2 x 300 mL). The organic phase was collected, washed with brine (1 x 500 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 42.2 g of the pale yellow compound 10⁻⁴.

[0381] In a 1 L reaction flask, compound 10⁻⁴ (30 g, 113.126 mmol, 1 eq.) was dissolved in 300 mL of tetrahydrofuran. LiAlH₄ (22.63 mL, 2.5 M, 56.56 mmol, 0.5 eq.) was added dropwise over 30 min at 0 °C. After the addition was complete, the reaction was continued at 0 °C for another 10 min. The reaction was quenched by adding Na₂SO₄˙10H₂O (30 g), and the precipitate was dissolved by adding hydrochloric acid. The precipitate was extracted with dichloromethane (2 x 300 mL), and the combined organic phases were washed with saturated brine (1 x 300 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 16 g of a yellow oily compound 10⁻⁵.

[0382] In a 100 mL reaction flask, nonanoic acid (0.95 g, 6.03 mmol, 1.1 eq.), 10⁻⁵ (1.3 g, 5.48 mmol, 1.0 eq.), EDCI (1.26 g, 6.58 mmol, 1.2 eq.), and DMAP (0.67 g, 5.48 mmol, 1.0 eq.) were dissolved in 20 mL of dichloromethane and reacted overnight at room temperature. After the reaction was complete, the reaction was quenched with water (10 mL), extracted with dichloromethane (2 x 15 mL), washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give compound 10⁻⁶.

[0383] Compound 10⁻⁶ (0.5 g, 1.33 mmol, 1.0 eq.), 3-hydroxypropylamine (1.99 g, 26.60 mmol, 20 eq.), and EtOH (5 mL) were added to a 20 mL sealed tube, and the mixture was heated to 80 °C for 1 h. After removing the solvent by vacuum concentration, water (5 mL) was added, and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic phase was washed with saturated brine (6 x 10 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness. The crude product was purified by silica gel column chromatography to give 280 mg of a yellow oily compound 10⁻⁷.

[0384] Compound 10⁻⁷ (280 mg, 0.75 mmol, 1.0 eq.), compound 10⁻¹ (382.56 mg, 0.83 mmol, 1.1 eq.), KI (150.10 mg, 0.90 mmol, 1.2 eq.), K₂CO₃ (312.41 mg, 2.25 mmol, 3.0 eq.), and acetonitrile (3 mL) were added to a 20 mL sealed tube. The mixture was heated to 80 °C and reacted overnight. After the reaction was complete, the reaction system was cooled to room temperature, filtered, and the filter cake was washed with acetonitrile (2 x 3 mL). The filtrate and eluent were combined and evaporated to dryness to obtain the crude product. The crude product was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column 30*150mm, 5μm; Eluent A: H2O / CH3CN 60 / 40, 10mM NH4HCO3+1% NH3H2O; Eluent B: IPA / CH3CN 90 / 10; Flow rate: 60mL / min; Gradient program: 55%-75% B in 0-12min) to obtain 230.9mg of pale yellow compound 10.

[0385] 1 H NMR (300MHz, CDCl3) δ: 4.09 (t, J = 7.5Hz, 2H), 3.95 (d, J = 5.7Hz, 2H), 3.80 (t, J = 5.1Hz, 2H), 2.70-2.34 (m, 6H), 2.29 (dd, J=7.5Hz, 15.0Hz, 4H), 1.74-1.46 (m, 12H), 1.40-1.20 (m, 50H), 0.89-0.86 (m, 15H); ESI-MS m / z:752.65[M+H] + .

[0386] Example 11: Synthesis of Compound 11

[0387] Compound 11 was prepared according to the method of Example 10, yielding 208.3 mg of an oily product.

[0388] 1 H NMR (300MHz, CDCl3) δ: 4.12-4.07 (m, 2H), 3.95 (d, J = 5.7Hz, 2H), 3.80 (t, J = 5.1Hz, 2H), 2.68 (bs, 2 H), 2.45 (bs, 4H), 2.30 (dd, J=7.5Hz, 15.0Hz, 4H), 1.82-1.23 (m, 68H), 0.89-0.86 (m, 15H); ESI-MS m / z:794.80[M+H] + .

[0389] Example 12: Synthesis of Compound 12

[0390] Compound 12 was prepared according to the method of Example 10, yielding 187.5 mg of an oily product.

[0391] 1 H NMR (300MHz, CDCl3) δ: 4.09 (t, J = 7.5Hz, 2H), 3.95 (d, J = 6.0Hz, 2H), 3.58 (bs, 2H), 2.50 (bs, 6H), 2 .30(dd,J=7.5Hz,15.0Hz,4H),1.79-1.42(m,16H),1.40-1.23(m,54H),0.89-0.86(m,15H); ESI-MS m / z:808.75[M+H] + .

[0392] Example 13: Synthesis of Compound 13

[0393] Compound 13 was prepared according to the method of Example 10, yielding 171.7 mg of an oily product.

[0394] 1 H NMR (300MHz, CDCl3) δ: 4.12-4.05 (m, 4H), 3.80 (t, J = 5.4Hz, 2H), 2.68 (bs, 2H), 2 .46(bs,4H),2.31-2.25(m,4H),1.80-1.21(m,66H),0.89-0.86(m,15H); ESI-MS m / z:780.70[M+H] + .

[0395] Example 14: Synthesis of Compound 14

[0396] Compound 14 was prepared according to the method of Example 10, yielding 71.7 mg of an oily product.

[0397] 1 H NMR (300MHz, CDCl3) δ: 4.12-4.07 (m, 2H), 3.96 (d, J = 6.0Hz, 2H), 3.80 (t, J = 5.1Hz, 2H), 2.68 (bs, 2H), 2.45(bs,4H),2.32-2.25(m,4H),1.80-1.51(m,14H),1.38-1.21(m,50H),0.89-0.86(m,15H); ESI-MS m / z:766.70[M+H] + .

[0398] The compounds in the table below were synthesized using the methods described in the above examples, or using similar methods with the corresponding intermediates.

[0399] Table 2

[0400] Example 39: Synthesis of Compound 39

[0401] In a 250 mL round-bottom flask, 9-heptadecyl alcohol (10.0 g, 39.0 mmol, 1.0 eq.) and pyridine (6.17 g, 78.0 mmol, 2.0 eq.) were dissolved in 100 mL of dichloromethane. The reaction system was then cooled to 0 °C. Isobutyryl chloride (10.39 g, 97.5 mmol, 2.5 eq.) was slowly added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water at 0 °C, extracted with dichloromethane, and the organic phases were combined and dried over anhydrous Na₂SO₄. The desiccant was removed by filtration, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography to give a yellow oily compound 39-2 (10.4 g).

[0402] Compound 39-2 (10.0 g, 30.62 mmol, 1.0 eq.) was dissolved in anhydrous THF (100 mL). The reaction system was cooled to -40 °C, and LDA (15.3 mL, 30.6 mmol, 1.0 eq.) was added to the reaction solution under a nitrogen atmosphere. After stirring at -40 °C for 1 hour, 1,6-dibromohexane (14.9 g, 61.2 mmol, 2.0 eq.) and DMPU (471 mg, 3.7 mmol, 0.12 eq.) were added at the same temperature. The reaction system was slowly raised to room temperature and then allowed to react overnight. After the reaction was completed, the reaction solution was added to a saturated NH4Cl solution and extracted with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, filtered to remove the drying agent, and the solvent was removed by rotary evaporation to obtain crude compound 39-3, which could be used directly in the next reaction without purification.

[0403] Compound 39-3 (15 g, 30.6 mmol, 1.0 eq.) and ethanolamine (37.4 g, 612.0 mmol, 20.0 eq.) were dissolved in 80 mL of ethanol. The reaction system was heated to 60 °C and reacted for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, and the ethanol solvent was removed by rotary evaporation. The crude product was dissolved in ethyl acetate, and then a saturated sodium chloride solution was added. After extraction, the organic phases were combined and dried with anhydrous Na₂SO₄. The drying agent was removed by filtration, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography to give a yellow oily compound 39-4 (12.4 g).

[0404] In a 50 mL reaction flask, 6-bromo-1-hexanol (1.5 g, 8.3 mmol, 1.0 eq.) and pyridine (1.31 g, 16.6 mmol, 2.0 eq.) were dissolved in 15 mL of dichloromethane. Nonyl chloroformate (1.88 g, 9.1 mmol, 1.1 eq.) was added dropwise over 15 minutes in an ice bath, and the mixture was left to stand overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, and the organic phases were combined and dried over anhydrous Na₂SO₄. The desiccant was removed by filtration, and the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography to give a yellow oily compound 39-7 (2.5 g).

[0405] Compound 39-7 (200 mg, 0.57 mmol, 1.0 eq.), compound 39-4 (294.2 mg, 0.63 mmol, 1.1 eq.), KI (113.4 mg, 0.68 mmol, 1.2 eq.), K₂CO₃ (236.0 mg, 1.71 mmol, 3.0 eq.), and 5.0 mL of anhydrous acetonitrile were added to an 8 mL sealed tube. The mixture was heated to 80 °C and stirred overnight. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with acetonitrile. The organic phases were combined, and the solvent was removed by rotary evaporation to obtain the crude product. Compound 39 (87.9 mg) was purified by preparative liquid chromatography.

[0406] 1 H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.12 (t, J = 6.6Hz, 4H), 3.61 (m, 2H), 2.62 (m, 6H), 1. 70–1.63(m,4H),1.50(m,8H),1.26(m,49H),1.15(s,6H),0.88(t,J=6.6Hz,9H); ESI-MS m / z:740.55[M+H] + .

[0407] Example 40: Synthesis of Compound 40

[0408] In a 500 mL round-bottom flask, nonanoic acid (15.0 g, 94.8 mmol, 1.0 eq.) and THF (150 mL) were added at room temperature under nitrogen protection. The system was cooled to 0 °C, and NaH (3.64 g, 151.7 mmol, 1.6 eq.) was added in portions, followed by dropwise addition of LDA (85.3 mL, 170.6 mmol, 1.8 eq., 2 M in THF). The mixture was stirred at room temperature for 1 hour, and then 1-iodoheptane (23.6 g, 104.3 mmol, 1.1 eq.) was added to the system at 0 °C. The mixture was stirred overnight at 80 °C. The reaction was monitored by TLC, and a new product spot was observed. The reaction was cooled to room temperature, quenched with ice water, and extracted three times with dichloromethane. The combined organic phases were washed once with saturated NaCl solution, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow oily 2-heptylnonanoic acid (16.36 g).

[0409] In a 250 mL round-bottom flask, 7.0 g (27.3 mmol, 1.0 eq.) of 2-heptylnonanoic acid was dissolved in 70 mL of anhydrous THF at room temperature. The system was cooled to 0 °C, and LiAlH4 (16.38 mL, 2.5 M in THF) was added dropwise over 30 minutes. After the addition was complete, the mixture was brought back to room temperature and stirred for 2 hours. The reaction was monitored by TLC, and the starting material was completely converted. The reaction solution was quenched by pouring it into a saturated sodium chloride solution. The organic phases were extracted with ethyl acetate and combined, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give a pale yellow oily product, 2-heptylnonanol (6.97 g).

[0410] In a 50 mL three-necked round-bottom flask, 2-heptylnonanol (400 mg, 1.65 mmol, 1.0 eq.), pyridine (261.0 mg, 3.30 mmol, 2.0 eq.), DMAP (40.3 mg, 0.33 mmol, 0.2 eq.), p-nitrophenyl chloroformate (399.0 mg, 1.98 mmol, 1.2 eq.), and dichloromethane (4 mL) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Then, 6-bromo-1-hexanol (896.2 mg, 4.95 mmol, 3.0 eq.) and DIEA (639.7 mg, 4.95 mmol, 3.0 eq.) were added. The mixture was stirred overnight at room temperature. The mixture was diluted with dichloromethane (4 mL) and washed once with saturated sodium bicarbonate solution (6 mL). The organic phase was washed once with saturated NaCl (5 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give a pale yellow oily carbonate intermediate compound 40-4 (325 mg).

[0411] Compound 40-4 (250 mg, 0.56 mmol, 1.0 eq.), compound 40-5 (179.0 mg, 0.50 mmol, 0.9 eq.), potassium iodide (110.8 mg, 0.67 mmol, 1.2 eq.), potassium carbonate (230.6 mg, 1.68 mmol, 3.0 eq.), and acetonitrile (2.5 mL) obtained in the previous step were added to an 8 mL sealed tube at room temperature. The mixture was heated to 80 °C and stirred overnight. The reaction was monitored by LC-MS, and the reaction system was cooled to room temperature. The mixture was filtered, concentrated, and purified by Prep-HPLC to give a pale yellow oil product 40 (84.3 mg).

[0412] 1 H NMR (400MHz, CDCl3) δ: 4.14 (t, J = 6.8 Hz, 2H), 4.06 (dd, J = 8.0, 6.0 Hz, 4H), 3.60 (m, 2H), 2.65-2 .53(m,6H),1.73-1.60(m,12H),1.42-1.22(m,46H),1.18(s,6H),0.90(t,J=6.8Hz,9H); ESI-MS m / z:726.50[M+H] + .

[0413] The compounds in the table below were synthesized using the methods described in the above examples, or using similar methods with the corresponding intermediates.

[0414] Table 3

[0415] Example 69: Synthesis of Compound 1a

[0416] At room temperature, 1-nonanol (15 g, 104.0 mmol, 1.0 eq.), 8-bromooctanoic acid (25.5 g, 114.0 mmol, 1.1 eq.), DMAP (2.54 g, 20.8 mmol, 0.2 eq.), DIEA (40.3 g, 312.0 mmol, 3.0 eq.), and EDCI (25.9 g, 135 mmol, 1.3 eq.) were added to a 500 mL three-necked round-bottom flask, followed by 250 mL of DCM. The reaction mixture was stirred at room temperature for 4 hours, and the reaction was monitored by TLC until complete. The reaction mixture was poured into 200 mL of saturated ammonium chloride aqueous solution and extracted with 3 x 100 mL DCM solutions. The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 21 g of a yellow oily compound 1a-2.

[0417] Compound 1a-2 (21 g, 60.1 mmol, 1.0 eq.) and 2-aminoethanol (110 g, 1.80 mol, 30.0 eq.) were added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 100 mL of methanol. The mixture was heated to 60 °C and stirred for 18 hours. The reaction solvent was removed by concentration, and then saturated ammonium chloride aqueous solution and ethyl acetate were added. The mixture was extracted layer by layer, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 14 g of a yellow oily compound 1a-3.

[0418] 9-Heptadecyl alcohol (9.8 g, 38.2 mmol, 1.0 eq.) and triethylamine (15.5 g, 152.8 mmol, 4.0 eq.) were added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and then 2-methylpropionyl chloride (9.8 g, 91.7 mmol, 2.4 eq.) was slowly added. The mixture was allowed to react overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 8.7 g of a yellow oily compound 1a-5.

[0419] Compound 1a-5 (8.7 g, 26.6 mmol, 1.0 eq.) was added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 60 mL THF. The reaction system was cooled to -40 °C, and then LDA (13.1 mL, 26.2 mmol, 0.98 eq.) was slowly added dropwise. The reaction was stirred for 1 hour, and then 1,6-dibromohexane (9.03 g, 37.0 mmol, 1.39 eq.) and DMPU (0.48 g, 3.73 mmol, 0.14 eq.) were added to the reaction system. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 10.1 g of a yellow oily compound 1a-6.

[0420] Compound 1a-6 (1.48 g, 3.04 mmol, 2.0 eq.), compound 1a-3 (500 mg, 1.52 mmol, 1.0 eq.), K₂CO₃ (628.2 mg, 4.55 mmol, 3.0 eq.), KI (302.3 mg, 1.82 mmol, 1.2 eq.), cyclopentyl methyl ether (7.5 mL), and acetonitrile (2.5 mL) were added to a 20 mL round-bottom flask. The mixture was heated to 80 °C and the reaction was allowed to proceed. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to give 96.98 mg of oily compound 1a.

[0421] 1 H NMR(400MHz, CDCl3)δ:4.86-4.80(m,1H),4.04(t,J=7.2Hz,2H),3.57(m,2H),2.62(t,J=7.2Hz,2H),2.49(t,J=7.2Hz,4H ),2.29(t,J=7.2Hz,2H),1.62(m,4H),1.51-1.45(m,10H),1.38-1.23(m,49H),1.15(s,6H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:738.60[M+H] + .

[0422] Example 70: Synthesis of compound 4a

[0423] Compound 4a was prepared according to the method of Example 69, yielding 112.1 mg of an oily product.

[0424] 1H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.05 (t, J = 7.2Hz, 2H), 3.80 (t, J = 5.4Hz, 2H), 2.51-2.73 (m, 6H ),2.29(t,J=7.2Hz,2H),1.65-1.44(m,16H),1.26(m,49H),1.15(s,6H),0.93-0.82(m,9H); ESI-MS m / z:752.70[M+H] + .

[0425] Example 71: Synthesis of compound 56a

[0426] Compound 56a was prepared according to the method of Example 69, yielding 112.2 mg of an oily product.

[0427] 1 H NMR(300MHz, CDCl3)δ:4.87-4.79(m,1H),4.16(t,J=6.6Hz,2H),3.60(m,2H),2.67-2.53(m,6H),2.32-2 .11(m,6H),2.32-2.11(m,6H),1.85-1.76(m,2H),1.66-1.18(m,53H),1.14(s,6H),0.88(m,9H); ESI-MS m / z:734.55[M+H] + .

[0428] Example 72: Synthesis of compound 58a

[0429] Compound 58a was prepared according to the method of Example 69, yielding 104.0 mg of an oily product.

[0430] 1 H NMR (300MHz, CDCl3) δ: 5.53 (s, 1H), 4.87-4.79 (m, 1H), 3.22 (dd, J1 = 6.9Hz, J2 = 13.2Hz, 2H), 2.67- 2.52(m,6H),2.15(t,J=7.2Hz,2H),1.65-1.19(m,63H),1.15(s,6H),0.88(t,J=6.9Hz,9H); ESI-MS m / z:737.60[M+H] + .

[0431] Example 73: Synthesis of Compound 1b

[0432] 9-Heptadecyl 1b-1 (200.0 mg, 0.78 mmol, 1.0 eq.) was dissolved in DCM (2.0 mL). 8-Bromooctanoic acid (226.2 mg, 1.01 mmol, 1.3 eq.), EDCI (179.4 mg, 0.94 mmol, 1.2 eq.), and DMAP (42.9 mg, 1.17 mmol, 1.5 eq.) were added to the solution. The reaction mixture was stirred at room temperature for 3 hours. The solution was then poured into 10 mL of saturated sodium chloride aqueous solution and extracted with 3 x 20 mL DCM solutions. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 300 mg of a yellow oily compound 1b-2.

[0433] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0 °C. Under nitrogen protection, LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction solution. The reaction temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Then, 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.) was added. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 30 g of a yellow oily compound 1b-4.

[0434] Compound 1b-4 (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0 °C. Under nitrogen protection, a borane-tetrahydrofuran solution (1 M, 100.0 mL) was added dropwise to the reaction system. The temperature was raised to 75 °C, and the reaction was stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with a saturated ammonium chloride aqueous solution. The mixture was extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain crude product 1b-5 (13.6 g), which was used directly in the next reaction without further purification.

[0435] Decanoyl chloride (11.0 g, 58.0 mmol, 1.3 eq.) was added to a DCM solution of compound 1b-5 (10.0 g, 44.0 mmol, 1.0 eq.) in 100 mL. Triethylamine (13.5 g, 134.0 mmol, 3.0 eq.) was then added to the reaction mixture, and the mixture was reacted at room temperature for 3 hours. The reaction solution was poured into 100 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 10 g of compound 1b-6.

[0436] Potassium carbonate (1.5 g, 11.1 mmol, 3.0 eq.) and compound 1b-6 (1.4 g, 3.7 mmol, 1.0 eq.) were added to a solution of ethanolamine (2.3 g, 37.2 mmol, 10.0 eq.) in acetonitrile (15.0 mL). The mixture was heated to 70 °C and stirred for 3 hours. The reaction solution was poured into 30 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to give 1.4 g of compound 1b-7. 1 H NMR(300MHz,CD3Cl)δ:0.85-0.89(m,9H),1.20-1.26(m,21H),1.59-1.62(m,4H) ),2.29-2.34(m,2H),2.73-2.76(m,2H),2.87-2.91(m,2H),3.72-3.77(m,3H).

[0437] Compound 1b-2 (300.0 mg, 0.84 mmol, 1.0 eq.) and compound 1b-7 (503.4 mg, 1.09 mmol, 1.3 eq.) were dissolved in DMF (3.0 mL), followed by the addition of potassium carbonate (289.9 mg, 2.1 mmol, 2.5 eq.) and sodium iodide (314.4 mg, 2.1 mmol, 2.5 eq.). The mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was then poured into 20 mL of water and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give compound 1b (158.9 mg).

[0438] 1 H NMR(400MHz, Methanol-d4)δ:0.85-0.95(m,15H),1.17-1.34(m,48H),1.52-1.59(m,8H),1.62-1.64(m,4H),2.27-2 .35(m,4H),2.48-2.53(m,4H),2.63(t,J=6.3Hz,2H),3.61(t,J=6.3Hz,2H),3.80(s,2H),4.84-4.89(m,1H); ESI-MS m / z:738.65[M+H] + .

[0439] Example 74: Synthesis of compound 3b

[0440] Potassium carbonate (549 mg, 4.0 mmol, 3.0 eq.) and compound 1b-6 (500 mg, 1.33 mmol, 1.0 eq.) were added to a DMF (10.0 mL) solution of 4-amino-1-butanol (1.2 g, 13.3 mmol, 10.0 eq.). The mixture was heated to 70 °C and stirred for 3 hours. The reaction solution was poured into 30 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 300 mg of a colorless oily compound 3b-1.

[0441] Compound 1b-2 (462 mg, 1.0 mmol, 1.3 eq.) and compound 3b-1 (297 mg, 0.77 mmol, 1.0 eq.) were dissolved in DMF (5.0 mL), followed by the addition of potassium carbonate (269 mg, 1.9 mmol, 2.5 eq.) and sodium iodide (285 mg, 1.9 mmol, 2.5 eq.). The mixture was heated to 70 °C and stirred for 5 hours. The reaction solution was poured into 20 mL of water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give compound 3b (228 mg).

[0442] 1 H NMR(400MHz, CDCl3)δ:0.80-0.90(m,15H),1.25-1.40(m,48H),1.49-1.66(m,8H),1.74-1.81(m ,8H),2.24-2.37(m,4H),2.47-2.58(m,6H),3.56(s,2H),3.77(s,2H),4.81-4.88(m,1H); ESI-MS m / z:766.85[M+H] + .

[0443] Example 75: Synthesis of Compound 10b

[0444] Compound 10b was prepared according to the method of Example 73, yielding 128 mg of an oily product.

[0445] Example 76: Synthesis of Compound 12b

[0446] Compound 12b was prepared according to the method of Example 73, yielding 105 mg of an oily product.

[0447] 1H NMR(400MHz, CDCl3)δ:0.85-0.95(m,15H),1.19-1.34(m,41H),1.42-1.58(m,4H),1.59-1.63(m,6H),2.23(q,J=7.6H z,4H),2.53(q,J=7.6Hz,4H),2.62(q,J=7.6Hz,2H),3.62(t,J=6.4Hz,2H),3.80(s,2H),4.07(t,J=6.4Hz,2H); ESI-MS m / z:682.60[M+H] + .

[0448] 1 H NMR(300MHz, CDCl3)δ:0.85-0.95(m,15H),1.12-1.36(m,43H),1.40-1.63(m,12H),2.26-2. 31(m,4H),2.42-2.65(m,6H),3.50-3.54(m,2H),3.78(s,2H),4.08(t,J=7.2Hz,2H); ESI-MS m / z:710.80[M+H] + .

[0449] The compounds in Table 4 were synthesized using the methods described in the above examples, or using similar methods with the corresponding intermediates.

[0450] Table 4

[0451] Example 79: Synthesis of Compound 26b

[0452] Methyl isobutyrate (21 g, 205.0 mmol, 1.0 eq.) was dissolved in 200 mL of anhydrous THF and cooled to 0 °C. Under nitrogen protection, LDA (205 mL, 410.0 mmol, 2.0 eq.) was added to the reaction solution. The reaction temperature was raised to room temperature and stirred for 30 minutes, then 1,5-dibromopentane (47 g, 205.0 mmol, 1.0 eq.) was added. The reaction was monitored by TLC until complete. The reaction was quenched with saturated ammonium chloride aqueous solution, extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 30 g of a yellow oily compound, methyl 2,2-dimethyl-7-bromoheptanoate.

[0453] Methyl 2,2-dimethyl-7-bromoheptanol (15.0 g, 40.0 mmol, 1.0 eq.) was dissolved in 30 mL of THF and cooled to 0 °C. Under nitrogen protection, lithium aluminum hydride solution (2 M, 50.0 mL) was added dropwise to the reaction system. The mixture was stirred for 3 hours. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution, extracted with 3 x 300 mL DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain crude 2,2-dimethyl-7-bromoheptanol (13.6 g), which was used directly in the next reaction without further purification.

[0454] 2,2-Dimethyl-7-bromoheptanol (500.0 mg, 2.24 mmol, 1.0 eq.) was dissolved in DCM (10.0 mL). 4-Hexyldecanoic acid (746.2 mg, 2.91 mmol, 1.3 eq.), EDCI (515.7 mg, 2.69 mmol, 1.2 eq.), and DMAP (410.5 mg, 3.36 mmol, 1.5 eq.) were added to the solution. The reaction mixture was stirred at room temperature for 3 hours. The solution was then poured into 10 mL of saturated sodium chloride aqueous solution and extracted with DCM. The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 858 mg of a yellow oily compound 26b-4.

[0455] Compound 26b was prepared according to the method of Example 73, yielding 99.0 mg of an oily product.

[0456] 1 H NMR(300MHz,MeOH-d4)δ:0.86-0.91(m,15H),1.21-1.40(m,50H),1.58-1.71(m,6H),2.32(t,J=7.5Hz,2H),2. 48-2.53(m,4H),2.62(t,J=6.6Hz,2H),3.61(t,J=6.3Hz,2H),3.80(s,2H),4.10(td,J=2.7,6.3Hz,4H); ESI-MS m / z:726.70[M+H] + .

[0457] Example 80: Synthesis of Compound D1

[0458] 1-Nonanol (8.8 g, 61.0 mmol, 1.0 eq.) and triethylamine (24.7 g, 244.0 mmol, 4.0 eq.) were added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 100 mL of DCM. The reaction system was cooled in an ice bath, and then 2-methylpropionyl chloride (15.6 g, 146.4 mmol, 2.4 eq.) was slowly added, and the mixture was allowed to rise to room temperature. The reaction was monitored by TLC until complete. The reaction was quenched by adding saturated ammonium chloride aqueous solution, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 10.8 g of a yellow oily compound D1-2.

[0459] Compound D1-2 (4.8 g, 22.4 mmol, 1.0 eq.) was added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 50 mL THF. The reaction system was cooled to -40 °C, and then LDA (11.0 mL, 21.9 mmol, 0.98 eq.) was slowly added dropwise. The reaction was stirred for 1 hour, and then 1,6-dibromohexane (7.59 g, 31.1 mmol, 1.39 eq.) and DMPU (0.57 g, 4.48 mmol, 0.2 eq.) were added to the reaction system. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 4.6 g of a yellow oily compound D1-3.

[0460] Compound D1-3 (4.6 g, 12.2 mmol, 1.0 eq.) and 2-aminoethanol (14.9 g, 244.0 mmol, 20.0 eq.) were added to a 250 mL three-necked round-bottom flask at room temperature and dissolved in 50 mL of ethanol. The mixture was heated to 60 °C and stirred for 18 hours. The reaction solvent was removed by concentration, and then saturated ammonium chloride aqueous solution and ethyl acetate were added. The mixture was extracted by layer-by-layer extraction, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to dryness to obtain a crude product, which was purified by silica gel column chromatography to give 2.2 g of a yellow oily compound D1-4.

[0461] Compound D1-4 (500 mg, 1.4 mmol, 1.0 eq.), compound 1a-6 (1.37 g, 2.8 mmol, 2.0 eq.), K2CO3 (579 mg, 4.2 mmol, 3.0 eq.), KI (279 mg, 1.68 mmol, 1.2 eq.), cyclopentyl methyl ether (7.5 mL), and acetonitrile (2.5 mL) were added to a 20 mL round-bottom flask. The mixture was heated to 80 °C and the reaction was allowed to proceed. The reaction was monitored by TLC until complete. The reaction was quenched with a saturated ammonium chloride solution at ice water, extracted with DCM, and the organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column chromatography to give 137.9 mg of an oily compound D1.

[0462] 1 H NMR (400MHz, CDCl3) δ: 4.83 (m, 1H), 4.04 (t, J = 7.2Hz, 2H), 3.55 (t, J = 5.6Hz, 2H), 2.60 (t, J = 5.6Hz, 2H), 2.47 (t, J=7.2Hz,4H),1.62(m,2H),1.52-1.40(m,12H),1.36-1.20(m,48H),1.15(m,12H),0.88(t,J=7.2Hz,9H); ESI-MS m / z:766.50[M+H] + .

[0463] Pharmacological experiments

[0464] Experimental Example 1: Preparation of Nanoparticles

[0465] Materials used for assembling lipid nanoparticles include: (1) ionizable lipid compounds: such as the ionizable lipids designed and synthesized in this invention, MC3 or SM102 (purchased from AVT / MCE) as control groups; (2) structural lipids: such as cholesterol (purchased from Sigma-Aldrich); (3) phospholipids: such as DSPC, which is 1,2-distearyl-SN-glycerol-3-phosphocholine (purchased from AVT); (4) polyethylene glycol-modified lipid compounds: such as DMG-PEG2000, which is 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (purchased from AVT); (5) effective components of nucleic acid fragments: such as Luciferase mRNA, siRNA, CRISPR Cas9 mRNA, etc. (self-made). The names and structural formulas of lipid nanoparticle assembly materials are detailed in Table 5.

[0466] Table 5

[0467] Preparation method of lipid nanoparticles: (1) Ionizable lipid compounds, cholesterol, phospholipids and polyethylene glycol-modified lipids were dissolved and mixed in ethanol in the following proportions (molar percentage): 50%, 38.5%, 10% and 1.5%, respectively; (2) mRNA active ingredient was dissolved in 25mM sodium acetate solution (pH=4.5); (3) The organic phase containing the lipid mixture and the aqueous phase containing the mRNA were mixed at a flow rate ratio of 1:1 to 1:4 using an automated high-throughput microfluidic system, with a mixing speed of 10mL / min to 18mL / min; (4) The prepared lipid nanoparticles (N / P ratio of 6) were diluted with phosphate buffer solution and ultrafiltered to the original preparation volume using an ultrafiltration tube with a molecular weight cutoff of 30kDa (purchased from Millipore); (5) The obtained nanoparticles were sterilized by filtration through a 0.2μm sterile filter membrane and then stored at low temperature in a sealed glass bottle.

[0468] Lipid nanoparticles can be prepared using microfluidic mixing systems, but are not limited to this method; other methods include T-type mixers and ethanol injection.

[0469] Experimental Example 2: Characterization of the physical properties of lipid nanoparticles

[0470] The particle size and particle size distribution index (PDI) of the prepared lipid nanoparticles were measured using a Zetasizer Pro (purchased from Malvern Instruments Ltd) and a DynaPro NanoStar (purchased from Wyatt) dynamic light scattering instrument. The degree of RNA encapsulation by the lipid nanoparticles was characterized by the encapsulation efficiency (%), which reflects the degree of binding between the lipid nanoparticles and the RNA fragments. This coefficient was obtained from Quant-it... TM The RiboGreen RNA Assay (purchased from Invitrogen) method was used for measurement. Lipid nanoparticle samples were diluted in TE buffer (10 mM Tris-HCl, 1 mM EDTA, pH 7.5), and a portion of the sample solution was added to 0.5% Triton X-100 and incubated at 37°C for 30 minutes. Immediately after the reaction, the fluorescence values ​​were read using a Varioskan LUX multi-functional microplate reader (purchased from Thermofisher) at an absorption wavelength of 485 nm and an emission wavelength of 528 nm to obtain the encapsulation rate.

[0471] Experiment Example 3: Animal Experiment

[0472] The delivery efficiency and safety of nanoparticles loaded with luciferase mRNA (Trilink, L-7202) in mice were evaluated. SPF-grade female C57BL / 6 mice, 6-8 weeks old and weighing 18-22g, were purchased from Beijing Spefol Biotechnology Co., Ltd. All animals were acclimatized for at least 7 days before the experiment, with free access to food and water, 12 / 12h light / dark cycles, an indoor temperature of 20-26℃, and a humidity of 40-70%. Mice were randomly assigned to groups. The prepared lipid nanoparticles loaded with luciferase mRNA were administered intravenously at a single dose of 0.5 mg / kg mRNA to mice (n=3). Six hours after administration, in vivo bioluminescence detection was performed using a small animal in vivo imaging system (IVIS LUMINA III, purchased from PerkinElmer). The specific operational steps for the detection are as follows: A 15 mg / mL D-fluorescein solution was prepared using physiological saline, and the substrate was administered to each mouse via intraperitoneal injection. Ten minutes after substrate administration, the mice were anesthetized in an anesthesia box using 2.5% isoflurane. The anesthetized mice were then placed in an IVIS (Intraperitoneal Injection System) for fluorescence imaging, and data were collected and analyzed from areas of concentrated fluorescence distribution.

[0473] The in vivo delivery efficiency of the lipid nanoparticle carrier is expressed as the average fluorescence intensity and total photon count of different animals within the same test group, as shown in Table 6. Higher values ​​for fluorescence intensity and total photon count indicate higher in vivo delivery efficiency of the lipid nanoparticles for the mRNA fragment. Lipid nanoparticles containing the cationic lipids of this invention exhibit good in vivo delivery efficiency.

[0474] Table 6

[0475] Experiment Example 4: In vivo clearance rate experiment of ionizable lipids

[0476] 100 μL of empty vector LNP (0.1 mg / mL), composed of ionizable lipids, cholesterol, DSPC, and DMG-PEG 2000 in a ratio of 50:38.5:10:1.5, was injected via the tail vein into 6-8 week old C57 WT female mice (n=3). The animals were euthanized by cervical dislocation at 24 h and 72 h post-administration, and their livers were dissected. Liver samples from untreated animals in the same batch were used as a blank control group. Liver samples were homogenized with water, proteins were precipitated, and calibration standards prepared from the matched blank liver tissue were used. The ionizable lipid content in the samples was quantitatively analyzed using LC-MS / MS.

[0477] The in vivo clearance rate data of ionizable lipids are shown in Table 7.

[0478] Table 7

[0479] The control group compound has the following structure:

[0480] As can be seen from the data in Table 7, the dimethyl compounds in the control group degraded slowly in the liver, with about 90% remaining in the liver 72 hours after administration; while the compounds of the present invention have a faster degradation rate and can be completely degraded in about 72 hours.

[0481] While the invention has been fully described through its embodiments, it is worth noting that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims.

Claims

1. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, in, a = 2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5, 6 or 7; d = 0, 1, 2, 3 or 4; c+d = 3, 4, 5, 6, 7, 8 or 9; M1 is selected from -OC(O)O-, -C(O)O-, -OC(O-, -SC(O-) and -C(O)S-; M2 is selected from -OC(O)O-, -C(O)NR-, -NRC(O-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-; R1and R2are independently selected from C 6-14 alkyl, C 6-14 alkenyl or C 6-14 alkynyl, optionally substituted with 1, 2, 3 or 4 R 1s substituents, and wherein one or more methylene units are optionally and independently replaced with -NR'-; R and R' are each independently selected from H and C 1-20 alkyl; R 1s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; L c independently selected from a chemical bond and C 1-14 alkylene; R c and R' c are independently selected from H and C 1-14 alkyl; R4and R5are independently selected from C 1-6 alkyl; or R4and R5together with the carbon atom to which they are attached form C 3-6 cycloalkylene or 3-6 membered heterocyclylene; The condition is that, (1) When M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-; (2) When M1 is -OC(O)O- and M2 is -OC(O)O-; and (3) The compound is not 2. The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, M1 is selected from -OC(O)O-, -C(O)O-, -OC(O-, -SC(O-) and -C(O)S-; Preferably, M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-, more preferably selected from -OC(O)- and -C(O)O-, more preferably selected from -OC(O), and more preferably selected from -C(O)O-; Preferably, M1 is selected from -OC(O)O-.

3. The compound of formula (I) of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, M2 is selected from -OC(O)O-, -C(O)NR-, -NRC(O-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-; Preferably, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-, and more preferably from -C(O)NR-, -NRC(O)-, -OC(O)NR- and -NRC(O)NR-, and more preferably from -NRC(O)NR-; Preferably, M2 is selected from -OC(O)O-.

4. The compound of formula (I) of any one of claims 1-3, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein R and R' are each independently selected from the group consisting of H and C 1-14 alkyl; preferably selected from the group consisting of H and C 1-9 alkyl; preferably selected from the group consisting of H and C 1-6 alkyl; preferably R is H.

5. The compound of formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R1and R2are independently selected from C 6-14 alkyl, preferably C 7-11 straight-chain alkyl, preferably C 8- 10 straight-chain alkyl, preferably C 9-10 straight-chain alkyl, preferably C9straight-chain alkyl; Preferably, R1and R2are optionally substituted with 1, 2, 3, or 4 R 1s substituents, preferably optionally substituted with 1 R 1s substituents; Preferably, one of R1and R2is substituted with 1 R 1s and the other is unsubstituted; Preferably, R1and R2are each independently substituted with 1 R 1s substituted; Preferably, R1 and R2 are independently selected from the following groups: -(CH2)5CH3, -(CH2)6CH3, -(CH2)7CH3, -(CH2)8CH3, -(CH2)9CH3, -(CH2) 10 CH3, -(CH2) 11 CH3, -CH2-C≡C-(CH2)5CH3, -CH2-C≡C-(CH2)6CH3, -(CH2)2-C≡C-(CH2)5CH3, -(CH2)2-C≡C-(CH2)4CH3, -(CH2)3-C≡C-(CH2)3CH3, -(CH2)4-C≡C- (CH2)3CH3, -CH2-CH=CH-(CH2)5CH3, -CH2-CH=CH-(CH2)6CH3, -(CH2)2-CH=CH-(CH2)5CH3, -(CH2)4-CH=CH-(CH2)3CH3, -(CH2)5-CH=CH-CH2CH3, 6. The compound of formula (I) according to any one of claims 1-5, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R 1s independently selected from H, C 1-14 alkyl, -L c -OR c and -L c -NR c R’ c ; preferably selected from H and C 1-14 alkyl; preferably selected from H and C 1-10 alkyl; preferably selected from H and C 1-9 alkyl; preferably selected from H and C 1-6 alkyl, preferably selected from H and C 1-4 alkyl, preferably selected from C 5-9 alkyl, preferably selected from C 6-8 alkyl.

7. The compound of formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, L c independently selected from a chemical bond and C 1-14 alkylene; preferably selected from a chemical bond and C 1-10 alkylene; preferably selected from a chemical bond and C 1-6 alkylene; Preferably, R c and R' c Independently selected from H and C 1-14 Alkyl groups; preferably selected from H and C. 1-10 Alkyl groups; preferably selected from H and C. 1-6 alkyl.

8. The compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, R4 and R5 are independently selected from C 1-6 Alkyl; preferably selected from C 1-3 Alkyl; preferably selected from C 1-2 Alkyl; preferably methyl; Preferably, R4, R5, together with the carbon atoms they are bonded to, form C. 3-6 Cycloalkylene or 3 to 6-membered heterocyclic alkylene; preferably forming C 3-6 Cycloalkylene groups (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene); preferably forming C 3-5 Cycloalkylene; preferably cyclopropylene or cyclopentylene; preferably cyclopropylene.

9. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof. in, a = 2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5, 6 or 7; d = 0, 1, 2, 3 or 4; c+d = 3, 4, 5, 6, 7, 8 or 9; M1 is selected from -C(O)O-, -OC(O)-, -SC(O)- and -C(O)S-; M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR-, -NRC(O)O- and -NRC(O)NR-; preferably, M2 is selected from -C(O)NR-, -NRC(O)-, -OC(O)NR- and -NRC(O)NR-; preferably, M2 is selected from -NRC(O)NR-; R is independently selected from H and C. 1-3 alkyl; R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace; R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R4 and R5 are independently selected from C 1-6 alkyl; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

10. The compound of formula (I) of claim 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, in, a = 2, 3, or 4; b = 5, 6, 7 or 8; c = 4, 5, 6 or 7; d = 0, 1, 2 or 3; c+d = 5, 6 or 7; M1 is selected from -OC(O)- and -C(O)O-; M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O- and -NHC(O)NH-; preferably, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH- and -NHC(O)NH-; preferably, M2 is selected from -NHC(O)NH-; R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s Replacement; preferably, one of R1 and R2 is replaced by one R 1s One is replaced, the other is not replaced; R 1s Independently selected from H and C 1-14 alkyl; R4 and R5 are independently selected from C 1-6 alkyl; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

11. The compound of formula (I) of claim 9 or 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, a = 2, 3, or 4; a = 2 is preferred. b = 6 or 7; c = 5 or 6; d = 0 or 1; c+d = 5, 6 or 7; c+d = 6 is preferred. M1 is selected from -OC(O)- and -C(O)O-; M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O- and -NHC(O)NH-; preferably, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH- and -NHC(O)NH-; R1 and R2 are independently selected from C 6-14 Alkyl, preferably C 7-11 Alkyl, preferably C 8-10 Alkyl, preferably C 9-10 Alkyl groups, preferably C9 alkyl groups; One of R1 and R2 is controlled by 1 R 1s One is replaced, the other is not replaced; R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 5-9 Alkyl; preferably selected from C 6-8 alkyl; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R4 and R5 are independently selected from C 1-6 Alkyl groups, preferably methyl groups; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably forming C 3-4 Cycloalkylene; preferably cyclopropylene; Preferably, R1 and R2 are independently selected from -(CH2)8CH3, 12. The compound of formula (I) according to any one of claims 9-11, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a＝2； b = 6 or 7; c = 5 or 6; d = 0 or 1; c+d=6; M1 is selected from -OC(O)- and -C(O)O-; M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O- and -NHC(O)NH-; preferably, M2 is selected from -C(O)NH-, -NHC(O)-, -OC(O)NH- and -NHC(O)NH-; R1 is selected from C 6-14 Straight-chain alkyl, preferably C 7-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C9 straight-chain alkyl; R2 is selected from C 6-14 Alkyl group, preferably R2 is selected from C 7-12 Alkyl, preferably C 8-11 Alkyl, preferably C 9-10 Alkyl group, which is optionally marked with one R 1s replace; R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 5-8 Alkyl; preferably selected from C 6-7 alkyl; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R4 and R5 are independently selected from C 1-6 Alkyl groups, preferably methyl groups; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably forming C 3-4 Cycloalkylene; preferably cyclopropylene.

13. The compound of formula (I) of any one of claims 9-12, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a＝2； b＝6； c = 5 or 6; c = 5 is preferred. d = 0 or 1; preferred d = 1; c+d = 5, 6 or 7; c+d = 6 is preferred. M1 is selected from -OC(O)- and -C(O)O-; preferably, M1 is selected from -OC(O)-; M2 is selected from -NHC(O)O-, -OC(O)NH- and -NHC(O)NH-; preferably, M2 is selected from -OC(O)NH- and -NHC(O)NH-; preferably, M2 is selected from -NHC(O)NH-; R1 is selected from C 8-10 Straight-chain alkyl, preferably C9 straight-chain alkyl; R2 is selected from C 7-12 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups, optionally marked with one R 1s replace; R 1s Independently selected from H and C 1-9 Alkyl; preferably selected from C 5-8 Alkyl; preferably selected from C 6-7 Alkyl group; preferably selected from C7 alkyl groups; R4 and R5 are independently selected from C 1-3 Alkyl groups, preferably methyl groups; Or R4 and R5, along with their bonded carbon atoms, form C. 3-4 Cycloalkylene; preferably cyclopropylene.

14. A compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, in, a = 2, 3, 4, 5 or 6; b = 4, 5, 6, 7, 8, 9 or 10; c = 1, 2, 3, 4, 5, 6 or 7; d = 0, 1, 2, 3 or 4; c+d = 3, 4, 5, 6, 7, 8 or 9; Both M1 and M2 are selected from -OC(O)O-; R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace; R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c ; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R4 and R5 are independently selected from C 1-6 Alkyl, preferably C 1-3 alkyl; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

15. The compound of formula (I) of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, in, a = 2, 3, or 4; b = 5, 6, or 7; c = 3, 4, or 5; d = 0 or 1; c+d = 4, 5 or 6; Both M1 and M2 are selected from -OC(O)O-; R1 and R2 are independently selected from C 6-14 Alkyl groups, optionally surrounded by 1, 2, 3 or 4 R groups. 1s replace; R 1s Independently selected from H and C 1-14 alkyl; R4 and R5 are independently selected from C 1-6 Alkyl, preferably C 1-3 alkyl; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkyl or 3-6 membered heterocyclic groups.

16. The compound of formula (I) of claim 14 or 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, wherein, a = 2, 3, or 4; preferably a = 2 or 4. b＝6； c＝4； d＝1； M1 and M2 are selected from -OC(O)O-; R1 and R2 are independently selected from C 7-11 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups; optionally marked with one R 1s replace; Preferably, one of R1 and R2 is controlled by one R 1s One is replaced, the other is not replaced; Preferably, R1 and R2 are each independently controlled by one R 1s replace; R 1s Independently selected from H and C 1-14 Alkyl, -L c -OR c and -L c -NR c R' c Preferred ingredients are H and C. 1-14 Alkyl groups; preferably selected from H and C. 1-9 Alkyl; preferably selected from C 4-8 Alkyl; preferably selected from C 5-7 alkyl; L c Independently selected from chemical bonds and C 1-14 Alkylene; R c and R' c Independently selected from H and C 1-14 alkyl; R4 and R5 are independently selected from C 1-3 Alkyl group, preferably C 1-2 Alkyl groups, preferably methyl groups; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably forming C 3-4 Cycloalkylene; preferably cyclopropylene; Preferably, R 1s The replacement R1 or R2 is selected from 17. The compound of formula (I) of any one of claims 14-16, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a = 2, 3, or 4; a = 2 is preferred. b＝6； c＝4； d＝1； M1 and M2 are selected from -OC(O)O-; R1 is selected from C 7-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl, preferably C9 straight-chain alkyl; R2 is selected from C 7-11 Straight-chain alkyl, preferably C 8-10 Straight-chain alkyl groups, preferably C9 straight-chain alkyl groups; optionally, they are marked with one R. 1s replace; R 1s Selected from H and C 1-9 Alkyl; preferably selected from C 6-7 Alkyl group; preferably selected from C6 alkyl groups; R4 and R5 are independently selected from C 1-3 Alkyl group, preferably C 1-2 Alkyl groups, preferably methyl groups; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably cyclopropylene.

18. The compound of formula (I) of any one of claims 14-16, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, a = 2, 3, or 4; preferably a = 2 or 4. b＝6； c＝4； d＝1； M1 and M2 are selected from -OC(O)O-; R1 is selected from C 7-11 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups; optionally marked with one R 1s replace; R2 is selected from C 7-11 Alkyl, preferably C 8-10 Alkyl groups, preferably C9 alkyl groups; optionally marked with one R 1s replace; R 1s Independently selected from H and C 1-9 Alkyl; preferably selected from C 5-7 Alkyl groups; preferably selected from C5 and C7 alkyl groups; R4 and R5 are independently selected from C 1-3 Alkyl group, preferably C 1-2 Alkyl groups, preferably methyl groups; Or R4 and R5, along with their bonded carbon atoms, form C. 3-6 Cycloalkylene or 3-6 membered heterocyclic alkylene; preferably cyclopropylene.

19. A compound, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, wherein, The compound is selected from:

20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or an isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A nanoparticle composition comprising a lipid component and optionally a loading component; wherein, The lipid component contains a compound of any one of claims 1-19, or an isotopic variant, tautomer, or stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the loading is selected from one or more therapeutic agents, preventative agents, or diagnostic agents.

22. Use of any compound of claims 1-19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or the pharmaceutical composition of claim 20, or the nanoparticle composition of claim 21, in the preparation of a medicament for the treatment, diagnosis or prevention of a disease.

23. Use of a compound of any one of claims 1-19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, or stereoisomer thereof, or the pharmaceutical composition of claim 20, or the nanoparticle composition of claim 21, in the preparation of a medicament for delivery of a load, said load being selected from one or more therapeutic agents, preventative agents, or diagnostic agents.

24. A method of treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 20, or the nanoparticle composition of claim 21.

25. A compound of any one of claims 1-17, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or a pharmaceutical composition of claim 20, or a nanoparticle composition of claim 21, for the treatment, diagnosis or prevention of disease.

26. A method of delivering a payload into a subject, comprising administering to the subject the pharmaceutical composition of claim 20 or the nanoparticle composition of claim 21; in, The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents.

27. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof, or the pharmaceutical composition of claim 20, or the nanoparticle composition of claim 21, for delivery of a payload; in, The load is selected from one or more of therapeutic agents, preventive agents, or diagnostic agents.

28. The nanoparticle composition of claim 21, or the use of claim 22 or 23, or the method of claim 24, wherein, The therapeutic, preventative, or diagnostic agent is a nucleic acid; Preferably, the nucleic acid is selected from one or more of ASO, RNA, or DNA; Preferably, the RNA is selected from one or more of small interfering RNA (siRNA), short hairpin RNA (shRNA), antisense RNA (aRNA), messenger RNA (mRNA), long noncoding RNA (lncRNA), microRNA (miRNA), small activating RNA (saRNA), polymeric coding nucleic acid (MCNA), polymeric coding nucleic acid (PCNA), guide RNA (gRNA), CRISPR RNA (crRNA), or ribozymes, preferably mRNA, and more preferably modified mRNA.

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