Ionizable lipid compound and composition thereof

Abstract

The invention provides a compound which is a compound as shown in a formula (I) or a stereoisomer, a tautomer, a solvate and a pharmaceutically acceptable salt of the compound as shown in the formula (I), wherein A is O or S; r1 is H, C1-C10 straight chain or branched chain alkyl; n is any integer from 0 to 2; l1 and L2 are respectively and independently selected from substituted or non-substituted C1-C10 alkylene groups; g1 and G2 are respectively and independently selected from-C (= O)-,-OC (= O)-,-C (= O) O-,-C (= O) N (H)-,-(H) NC (= O)-,-OC (= O) O-,-(H) NC (= O) N (H)-,-O-,-S-,-NH-and-S-S-; z1 and Z2 are respectively and independently selected from vitamins and C1-C20 branched-chain-containing alkyl groups, and Z1 and Z2 are not C1-C20 branched-chain-containing alkyl groups at the same time; the compound provided by the invention is applied to delivery of mRNA, and has higher delivery efficiency and lower toxicity.

Description

Technical Field

[0001] This invention belongs to the field of biochemistry technology, specifically, it relates to an ionizable lipid compound and its composition. Background Technology

[0002] The working principle of mRNA vaccines is to introduce mRNA encoding specific antigen proteins into somatic cells. The host cell's expression system synthesizes the antigen protein, inducing the host's immune system to produce various effects, including B and T cell-specific immune responses to the antigen, thereby exerting therapeutic and preventative effects. For mRNA to exert its therapeutic effect, it needs to reach specific cells and express a sufficient amount of protein. Due to the negative charge and macromolecular properties of mRNA, naked mRNA is difficult to reach target organs and cells through blood circulation. Therefore, a safe and efficient delivery system is needed to help protect mRNA from nuclease degradation and increase cellular uptake and endosome escape.

[0003] Various mRNA delivery vectors have been developed, including lipid nanoparticles (LNPs), polymer nanoparticles, inorganic nanoparticles, and protein-based virus-like nanoparticles. Among them, LNPs are currently the most important mRNA delivery vector. LNPs are typically composed of ionizable lipids, helper phospholipids, polyethylene glycol (PEG) lipids, and cholesterol. As the core component, ionizable lipids play key roles in LNPs, including compressing mRNA, influencing transfection efficiency, and affecting immunogenicity. Ionizable lipids and mRNA form a complex through electrostatic interactions. Under normal physiological pH, ionizable lipids are uncharged. Once the LNP enters the endosome, the ionizable cationic lipids are protonated, thereby disrupting the stability of the endosome membrane and promoting the escape of mRNA molecules.

[0004] Currently, the application of LNPs in existing technologies is limited by factors such as delivery efficiency and safety. Safety is particularly a concern, as LNPs can trigger severe inflammatory responses, limiting their use, especially in patients with pre-existing inflammatory diseases. Ionizable lipids are the main component of LNPs that triggers high inflammatory activity, characterized by extensive neutrophil infiltration, activation of multiple inflammatory pathways, and the secretion of various inflammatory cytokines and chemokines. The inflammatory properties of ionizable lipids may be the cause of both the induction of adaptive immune responses and side effects in mRNA-LNPs. Moderna's marketed vaccine, based on LNPs prepared from SM-102, significantly activates the interleukin-1 (IL-1) inflammatory pathway, triggering a broad spectrum of pro-inflammatory cytokines (including IL-6). The activation of these inflammatory pathways is a key reason for adverse reactions after vaccination.

[0005] Therefore, there is a need to develop ionizable lipids that offer higher delivery efficiency and greater safety. Summary of the Invention

[0006] This invention aims to at least partially address one of the technical problems existing in the delivery of lipid compounds in LNPs in the prior art. To this end, this invention provides an ionizable lipid compound that features high delivery efficiency and good safety.

[0007] The first aspect of this invention provides a compound of formula (I), including its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, or deuterated compounds:

[0008]

[0009] in,

[0010] A represents O and S;

[0011] R1 is H, C1-C 10 Straight-chain or branched alkyl groups;

[0012] n is any integer from 0 to 2;

[0013] L1 and L2 are each independently selected from substituted or unsubstituted C1-C. 10 Alkylene;

[0014] G1 and G2 are each independently selected from -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)N(H)-, -(H)NC(=O)-, -OC(=O)O-, -(H)NC(=O)N(H)-, -O-, -S-, -NH-, -SS-, ;

[0015] Z1 and Z2 are each independently selected from vitamins C1-C. 20 Contains branched alkyl groups, Z1 and Z2 are not both C1-C 20 Contains branched alkyl groups;

[0016] In this invention, the straight-chain or branched alkyl group is unsubstituted or substituted by one or more groups;

[0017] In this invention, when straight-chain or branched alkyl groups are substituted, the substituted groups are each independently selected from one or more halogens, -OH, -SH, -NH2, -NO2, cyano, oxo, C1-C3 alkyl, C2-C8 alkenyl, C2-C 10 alkynyl group;

[0018] In this invention, the vitamins include fat-soluble vitamins and water-soluble vitamins;

[0019] In a specific embodiment of the present invention, the vitamins are vitamin A, vitamin D, vitamin E, and vitamin K;

[0020] The compound of formula (I) provided by this invention, or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein the vitamin is vitamin E;

[0021] The present invention provides a compound of formula (I) or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein A is O;

[0022] The present invention provides a compound of formula (I) or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein R1 is H;

[0023] The compound of formula (I) provided by the present invention or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein L1 and L2 are each independently selected from substituted or unsubstituted C5-C6 alkylene groups;

[0024] The compound of formula (I) provided by the present invention or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein G1 and G2 are each independently selected from -OC(=O)- and -C(=O)O-;

[0025] The compound of formula (I) provided by the present invention or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein G1 and G2 are each independently selected from -C(=O)N(H)- and -(H)NC(=O)-;

[0026] The compound of formula (I) provided by the present invention or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein G1 and G2 are each independently selected from -OC(=O)O- and -(H)NC(=O)N(H)-;

[0027] The compound of formula (I) provided by the present invention or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein G1 and G2 are each independently selected from -O-, -S-, -NH-, -SS-;

[0028] The compound of formula (I) provided by this invention, or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, or deuterated compounds, wherein Z1 and Z2 are different, wherein Z1 is a vitamin and Z2 is C. 10 -C 20 Contains branched alkyl groups; or Z2 is vitamin and Z1 is C. 10 -C 20 Contains branched alkyl groups;

[0029] The compound of formula (I) provided by the present invention or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein Z1 and Z2 are the same, and Z1 and Z2 are vitamins;

[0030] The present invention provides a compound of formula (I) or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, wherein n is 1;

[0031] The present invention provides a compound of formula (I) or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, or deuterated compounds, wherein the C1-C 20 Contains branched alkyl groups and has at least one of the following structures:

[0032]

[0033]

[0034] In a specific embodiment of the present invention, in the compound of formula (I), A is O, R1 is H, n is 1, and Z1 is vitamin E;

[0035] In a specific embodiment of the present invention, in the compound of formula (I), A is O, R1 is H, n is 2, Z1 is vitamin E, and Z2 is vitamin E;

[0036] The compounds, stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, or deuterated compounds provided by this invention have the following structures:

[0037]

[0038]

[0039]

[0040]

[0041]

[0042] On the other hand, the present invention provides the use of the above-mentioned compounds or their stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds in the preparation of liposomes, lipid nanoparticles, drug carriers or complexes.

[0043] On the other hand, the present invention provides a composition characterized in that it comprises the above-mentioned compound or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, pharmaceutically active molecules, and pharmaceutically acceptable excipients.

[0044] The composition provided by the present invention comprises at least one excipient selected from neutral phospholipids, steroids and polyethylene glycol lipids.

[0045] In another aspect, this invention proposes the use of the aforementioned compounds in the preparation of liposomes, lipid nanoparticles, drug carriers, or complexes. According to embodiments of the invention, the aforementioned compounds have ionizable properties and can be used to prepare liposomes or lipid nanoparticles. The prepared liposomes or lipid nanoparticles can serve as drug carriers, forming nucleic acid drug-liposome complexes.

[0046] In some embodiments, the above-mentioned compounds can be used to prepare liposomes in polymer form; the above-mentioned compounds can be covalently linked with other substances to prepare liposomes; the above-mentioned compounds can undergo chemical reactions with other substances to prepare liposomes. According to embodiments of the present invention, the specific method of preparing liposomes using the above-mentioned compounds is not limited; the use of the above-mentioned compounds to prepare liposomes, where the liposomes contain all or part of the structure of the above-mentioned compounds, is considered an application of the present invention.

[0047] For application purposes, the compounds of the present invention (typically in the form of liposomes combined with a bioactive ingredient) can be applied as crude chemicals or formulated as pharmaceutical compositions. The pharmaceutical compositions of the present invention comprise a compound of structure (I) and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compound of structure (I) is present in the composition in an amount that effectively forms liposomes and delivers the bioactive ingredient, for example, for treating a specific disease or condition. Appropriate concentrations and dosages can be readily determined by those skilled in the art.

[0048] In another aspect, the present invention proposes liposomes or lipid nanoparticles comprising the aforementioned compounds. According to embodiments of the present invention, the liposomes or lipid nanoparticles can be effectively delivered to organs such as the liver and spleen, effectively activating the body's immunity and increasing the level of specific antibodies in the animal's body.

[0049] In another aspect, the present invention provides a drug carrier. According to embodiments of the present invention, the drug carrier comprises the aforementioned compound or the aforementioned liposomes or lipid nanoparticles. According to embodiments of the present invention, the aforementioned compound is an ionizable lipid, the drug carrier is an ionizable carrier, and the aforementioned compound, liposomes, or lipid nanoparticles can be used to load drugs and deliver drugs into cells.

[0050] In another aspect, the present invention provides a complex. According to embodiments of the present invention, the complex comprises the aforementioned compound, or comprises the aforementioned liposomes, lipid nanoparticles, or drug carriers; and a bioactive ingredient. As mentioned above, the aforementioned compound is an ionizable lipid, and the drug carrier is an ionizable carrier. Thus, drugs can be loaded using the aforementioned compound, liposomes, or lipid nanoparticles, and a complex containing a bioactive ingredient can be prepared, which can deliver the bioactive ingredient into the body's cells for the treatment of diseases.

[0051] In another aspect, the present invention provides a pharmaceutical composition. According to embodiments of the present invention, the pharmaceutical composition comprises the aforementioned compound, or comprises the aforementioned liposomes or lipid nanoparticles, or the aforementioned drug carrier, or the aforementioned complex. As described above, the aforementioned compounds, liposomes or lipid nanoparticles, drug carriers, and complexes have advantages such as strong delivery capability and good immune activation effect. Loading bioactive components onto the aforementioned compounds, liposomes or lipid nanoparticles, or drug carriers can deliver the bioactive components or drug active molecules into the body, which is beneficial for the loaded bioactive components to exert their therapeutic effects and for the treatment of diseases.

[0052] In some embodiments, the pharmaceutical composition further includes pharmaceutically acceptable excipients or carriers.

[0053] The pharmaceutical composition provided by the present invention comprises a bioactive component or a pharmaceutically active molecule selected from DNA, ASO, siRNA, miRNA, mRNA, ribozymes, nucleic acid aptamers or combinations thereof; preferably mRNA.

[0054] In this invention, the pharmaceutical composition is prepared as lipid nanoparticles.

[0055] In a specific embodiment, the pharmaceutically acceptable carrier includes a buffer solution;

[0056] In another aspect, the present invention provides a pharmaceutical use. According to embodiments of the present invention, the present invention provides the use of the aforementioned compounds, or liposomes or lipid nanoparticles, or drug carriers, or complexes, or pharmaceutical compositions comprising the aforementioned compounds in the preparation of a medicament. As described above, the aforementioned compounds, liposomes or lipid nanoparticles, drug carriers, and complexes have advantages such as strong delivery capability and good safety. Loading bioactive components onto the aforementioned compounds, liposomes, or drug carriers can deliver the bioactive components into the body, which is beneficial for the loaded bioactive components to exert their therapeutic effects and for the treatment of diseases.

[0057] In a final aspect, the present invention provides a method for preparing a compound. According to embodiments of the present invention, the method for preparing the aforementioned compound is provided.

[0058] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

[0059] In a specific embodiment of the present invention, the mRNA contains at least one chemical modification;

[0060] Further, the chemical modification is selected from the following: pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4'-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deazo-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, dihydropseudouridine, 5-methyluridine, 5-methyluridine, 5-methoxyuridine, and 2'-O-methyluridine.

[0061] Furthermore, the mRNA comprises a subset selected from pseudouridine or a pseudouridine analogue;

[0062] Furthermore, the mRNA is modified with N1-methylpseuuridine;

[0063] In this invention, the lipid nanoparticles comprise one or more of ionizable lipids, phospholipids, sterols, and PEG-modified lipids.

[0064] In a specific embodiment of the present invention, the lipid nanoparticles contain ionizable lipids in a molar ratio of 20% to 50%.

[0065] In a specific embodiment of the present invention, the lipid nanoparticles contain phospholipids in a molar ratio of 5% to 20%.

[0066] In a specific embodiment of the present invention, the lipid nanoparticles contain 30% to 60% sterols in a molar ratio.

[0067] In a specific embodiment of the present invention, the lipid nanoparticles contain PEG-modified lipids in a molar ratio of 0% to 5%;

[0068] In this invention, the pharmaceutical composition further includes an adjuvant;

[0069] In a specific embodiment of the present invention, the excipients include one or more selected from injectable buffer media, lyophilized or cryoprotectant;

[0070] The adjuvant is one or more of Freund's incomplete adjuvant, Freund's complete adjuvant, aluminum hydroxide adjuvant, aluminum phosphate adjuvant, emulsion adjuvant, liposome adjuvant, and microbial adjuvant;

[0071] In a specific embodiment of the present invention, the pharmaceutical composition is formulated for intramuscular or intravenous injection.

[0072] The pharmaceutical composition is prepared into lipid nanoparticles, and the mRNA is encapsulated in the lipid nanoparticles.

[0073] In a specific embodiment of the present invention, the mRNA is encapsulated in lipid nanoparticles using a microfluidic device;

[0074] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0075] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0076] Figure 1 This is an image of in vivo bioluminescence expression in mice in Experiment Example 4;

[0077] Figure 2 This is a bar chart showing the in vivo luminescence intensity in mice in Experiment Example 4;

[0078] Figure 3 Bioluminescent images of anatomical tissues and organs from mouse experiment 4;

[0079] Figure 4 This is a bar chart showing the statistical intensity of liver luminescence after dissection of the mouse in Experiment 4;

[0080] Figure 5 This is a bar chart showing the statistical intensity of the spleen luminescence after dissection of the mouse in Experiment 4;

[0081] Figure 6 The graph shows the hEPO expression levels in mice in Experiment 5.

[0082] Figure 7 The graph shows the results of biochemical index detection in the blood samples of mice in Experiment 6. Detailed Implementation

[0083] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0084] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0085] It should be noted that the structural and chemical formula descriptions in the embodiments or implementations of this invention are intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of this invention. Those skilled in the art should recognize that many similar or equivalent methods and materials can be used to practice this invention. This invention is by no means limited to the methods and materials described herein. In the event that one or more of the linked documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, terminology application, described techniques, etc.), this invention shall prevail.

[0086] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments or implementations, but may also be provided in combination in a single embodiment or implementation. Conversely, various features of the invention, for brevity, have been described in a single embodiment or implementation, but may also be provided individually or in any suitable sub-combination.

[0087] It should be noted that the technical solutions disclosed in the embodiments or implementation schemes of this invention are intended to cover all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of this invention. Those skilled in the art should recognize that many similar or equivalent methods and materials can be used to practice this invention. This invention is by no means limited to the methods and materials described herein. In the event that one or more of the cited documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, terminology application, described techniques, etc.), this invention shall prevail.

[0088] It should be further appreciated that certain features of the invention, for clarity, have been described in multiple independent embodiments or implementations, but may also be provided in combination in a single embodiment or implementation. Conversely, various features of the invention, for brevity, have been described in a single embodiment or implementation, but may also be provided individually or in any suitable sub-combination.

[0089] Definitions and explanations:

[0090] Unless otherwise indicated, the technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains, and unless otherwise indicated, all patent publications cited in the entirety of this disclosure are incorporated herein by reference.

[0091] In this document, the terms “comprising” or “including” are open-ended expressions, meaning that they include the contents specified in this invention, but do not exclude other aspects.

[0092] This document also includes isotopically labeled compounds of the present invention that are identical to those compounds described herein except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally occurring common atoms. Exemplary isotopes that may also be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C 14 C 15 N、 16 O、 17 O、 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0093] Compounds of the present invention comprising other isotopes of the aforementioned isotopes and / or other atoms, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotope-labeled compounds of the present invention, such as radioactive isotopes, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds... 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. In addition, heavier isotopes, such as deuterium, are used. 2 H substitution can offer therapeutic advantages stemming from greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some cases.

[0094] The stereochemical definitions and conventions used in this invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds,” John Wiley & Sons, Inc., New York, 1994. The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, are also included within the scope of this invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral centers (or multiple chiral centers) in the molecule. The prefixes d and l, or (+) and (-), are symbols used to specify the plane-polarized rotation caused by a compound, where (-) or l indicates that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are generally called mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or method.

[0095] Depending on the choice of raw materials and methods, the compounds of this invention can exist as one or a mixture of possible isomers, for example, as pure optical isomers, or as mixtures of isomers, such as as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R)- or (S)- isomers can be prepared using chiral synthons or chiral formulations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may be cis or trans (cis- or trans-) configuration.

[0096] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0097] Unless otherwise stated, the structures described in this invention also represent all isomers (e.g., enantiomers, diastereomeric atropisomers, and geometric (or conformational) forms) including this structure; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers of the compounds of this invention, as well as mixtures of enantiomers, diastereomeric mixtures, and mixtures of geometric isomers (or conformational isomers), are all within the scope of this invention.

[0098] Any asymmetric atom (e.g., carbon, etc.) in the compounds of the present invention may exist in a racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom has at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% enantiomeric excess in the (R)- or (S)- configuration. If possible, substituents on atoms having unsaturated double bonds may be present in cis-(Z)- or trans-(E)- form.

[0099] Therefore, as described in this invention, unless otherwise specified, the compounds of this invention may exist in one or a mixture of possible isomers (including cis and trans isomers, optical isomers (e.g., R and S corresponding isomers), diastereomers, geometric isomers, rotational isomers, and shunting isomers), for example, in essentially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0100] In this article, solid lines can be used. solid wedge Or virtual wedge Describe the carbon-carbon bonds of the compounds of this application. Solid lines are used to depict bonds to asymmetric carbon atoms, indicating all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or imaginary wedges are used to depict stereoisomers indicated by the presence of bonds to asymmetric carbon atoms. When present in racemic mixtures, solid and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry.

[0101] Any mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example by chromatography and / or stepwise crystallization, based on the physicochemical differences of the components.

[0102] Racemic mixtures of any resulting end product or intermediate can be separated into optical enantiomers using known methods, such as by separating their diastereomeric salts. Racemic products can also be separated by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents. In particular, enantiomers can be prepared by asymmetric synthesis (e.g., Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012); Eliel, ELStereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0103] In this paper, the term "tautomer" or "tautomer form" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerization is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons. A specific example of a keto-enol tautomer is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. A specific example of a phenol-keto tautomer is the interconversion between pyridine-4-ol and pyridine-4(1H)-keto. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0104] In this document, the term "solvent" refers to an association formed by one or more solvent molecules with the compounds of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0105] In this document, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated.

[0106] In this document, the term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts (such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates) and organic acid salts (such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates) formed by reactions with amino groups, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbic acid salts, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, transbutenedioates, glucono-p-gluconate, glyceryl phosphates, gluconates, hemisulfates, heptanates, hexanoates, hydroiodates, 2-hydroxy-ethanesulfonates, lacturonates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pyruvates, pectates, persulfates, 3-phenylpropionates, picrates, pentanoates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + Salts of (C1-C4 alkyl)4. This invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts, including sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts, and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-C8 sulfonates, and aromatic sulfonates.

[0107] In this document, the terms “optionally,” “optionally,” or “optionally” generally refer to an event or condition that may, but may not, occur, and the description includes both cases in which the event or condition occurs and cases in which the event or condition does not occur.

[0108] In this document, the terms "optionally substituted" and "substituted or unsubstituted" are used interchangeably. Generally, the term "optionally," whether preceding or following the term "substituted," indicates that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents mentioned may be, but are not limited to, F, Cl, Br, CN, OH, NH2, NO2, etc.

[0109] In this document, the term "one or more" (e.g., in the definition of substituents in compounds of the general formula of the present invention) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, and even more especially one or two".

[0110] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive terms “each…independently is”, “…each independently is”, and “…independently is” used in this invention are interchangeable and should be interpreted broadly. They can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0111] In this article, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0112] In this paper, the minimum and maximum carbon atom content in hydrocarbon groups are indicated by prefixes, for example, prefix C. a -C b This refers to a carbon atom containing "a" to "b". For example, "C1-C..." n "C1-C" refers to a saturated / unsaturated carbon chain, either straight or branched, containing 1, 2, 3, 4, 5, ..., or n carbon atoms; further understanding, "C1-C" refers to a saturated / unsaturated carbon chain, either straight or branched. n "Should be interpreted as including any subranges, such as C1-C" 40 C2-C 40 C1-C 18 C3-C 24 C1-C 16 C4-C 10 C4-C8, C1-C3.

[0113] In this article, the term "C1-C" 40 "Alkyl" refers to a saturated monovalent hydrocarbon group with a straight or branched chain having 1, 2, 3, 4, 5, ... or 40 carbon atoms, such as C2-C. 40Alkyl, C2-C 24 Alkyl, C3-C 24 Alkyl, C3-C 11 Alkyl, C4-C 10 Alkyl, C4-C8 alkyl. This includes, but is not limited to, methyl, ethyl, n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), and n-pentyl (-CH2CH2CH2CH2C). H3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2C) H2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH2CH(CH3)2), 3 -Methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc., wherein the alkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0114] In this article, the term "C2-C" 40 "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2, 3, 4, 5, ... or 40 carbon atoms, wherein at least one C-C position is in an sp2 double bond unsaturated state. The alkenyl group can be independently unsubstituted or substituted by one or more substituents described in this invention, including groups with "cis," "trans," or "Z" or "E" orientations. Specific examples include, but are not limited to, allyl (-CH=CH2), allyl (-CH2CH=CH2), etc. For example, C2-C... 40 alkenyl, C2-C18 alkenyl, C3-C 24 alkenyl, C3-C 11 alkenyl, C4-C 10 Alkenyl, C4-C8 alkenyl.

[0115] In this article, the term "C2-C" 40 "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group having 2, 3, 4, 5, ... or 40 carbon atoms, wherein at least one C-C position is sp triple unsaturated. The alkynyl group may be independently unsubstituted or substituted by one or more substituents described in this invention. Specific examples include, but are not limited to, ethyl alkynyl (-C≡CH2), propynyl alkynyl (-CH2C≡CH), 1-propynyl (-C≡C-CH3), etc. For example, C2-C... 40 alkynyl group, C2-C 18 alkynyl group, C3-C 24 alkynyl group, C3-C 11 alkynyl group, C4-C 10 Alkynyl, C4-C8 alkynyl.

[0116] In the description of the functional groups of this invention It is used to describe the position of the substituent group.

[0117] In the description of the functional groups of this invention This is used to describe compounds; the carbon-carbon bond here can be a single bond. It can also be a double bond.

[0118] In this document, the term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated.

[0119] In this document, the term "one or more" (e.g., in the definition of substituents in compounds of the general formula of the present invention) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, and even more especially one or two".

[0120] In this article, "ionizable lipids" includes cationic lipids, ionizable lipids, and their derivatives.

[0121] In this article, "liposomes" or "liposome nanoparticles (LNPs)" refers to a drug delivery system that uses biocompatible lipid materials as carriers to dissolve or encapsulate drugs or other bioactive substances in the lipid core or adsorb and attach them to the surface of nanoparticles.

[0122] In this document, the term "pharmaceuticalally acceptable excipient" includes any solvent, dispersion medium, coating material, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, colorant, or combination thereof, all of which are known to those skilled in the art (as described in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in cases where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is covered.

[0123] In this document, the term "prevention" refers to the use of a drug or measure to achieve a preventive pharmacological and / or physiological effect in healthy or high-risk individuals, preventing the onset or worsening of a disease. In this document, the term "treatment" refers to the use of a drug or measure to achieve a desired pharmacological and / or physiological effect. The effect may be preventive in terms of complete or partial prevention of the disease or its symptoms, and / or therapeutic in terms of partial or complete cure of the disease and / or adverse effects caused by the disease.

[0124] In this document, the term "treatment" refers to the administration of a drug or compound to an individual to achieve a desired pharmacological and / or physiological effect. This effect may be preventative in terms of complete or partial prevention of a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. As used herein, "treatment" encompasses diseases in mammals, particularly humans, including: (a) prevention of disease or the onset of a condition in an individual who is susceptible but has not yet been diagnosed with the disease; (b) inhibition of disease, such as blocking disease progression; or (c) relief of disease, such as reducing symptoms associated with the disease. As used herein, "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, relieve, improve, reduce, or inhibit the individual's disease, including but not limited to administration of a drug containing a compound described herein to an individual in need.

[0125] The effective amount of the complex or pharmaceutical composition described in this invention can vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the bioactive ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0126] The effective amount of the complex or pharmaceutical composition described in this invention can vary depending on the administration method and the severity of the disease to be treated. A preferred effective amount can be determined by those skilled in the art based on various factors (e.g., through clinical trials). These factors include, but are not limited to: pharmacokinetic parameters of the bioactive ingredient, such as bioavailability, metabolism, and half-life; the severity of the disease to be treated, the patient's weight, the patient's immune status, and the route of administration. For example, due to the urgency of the treatment condition, several separate doses may be administered daily, or the dose may be reduced proportionally.

[0127] The complexes or pharmaceutical compositions of the present invention can be incorporated into drugs suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms, such as liquids, semi-solids, and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions) or lyophilized powders. Typical drugs are injection solutions. The aforementioned complexes or pharmaceutical compositions can be administered by intravenous infusion, injection, intramuscular injection, or subcutaneous injection.

[0128] According to embodiments of the present invention, the administration route of the method is intramuscular injection or intravenous injection.

[0129] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0130] The complexes or pharmaceutical compositions of the present invention can be incorporated into drugs suitable for parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). These drugs can be prepared in various forms, such as liquids, semi-solids, and solid dosage forms, including but not limited to liquid solutions (e.g., injection solutions and infusion solutions) or lyophilized powders. Typical drugs are injection solutions. The aforementioned complexes or pharmaceutical compositions can be administered by intravenous infusion, injection, intramuscular injection, subcutaneous injection, or intratumoral injection.

[0131] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0132] Example 1: Preparation of Compound 1

[0133]

[0134] The specific steps are as follows:

[0135] (1) In the organic solvent dichloromethane, haloacid (SM-1, 1eq) and vitamin E (SM-2, 1.1eq) were esterified in the presence of DMAP (1.5eq) and EDC hydrochloride (1.5eq). The reaction temperature was room temperature and the reaction time was 12h. After the reaction was completed, the intermediate compound 1-1 was obtained by washing, drying, concentration under reduced pressure and column chromatography purification.

[0136] (2) 2-Aminoethanol (SM-3, 3eq) and haloester (SM-4, 1eq) were heated and refluxed in ethanol for 12 hours. After the reaction was completed, the intermediates 1-2 were obtained by post-treatment.

[0137] (3) In the organic solvent acetonitrile, intermediate 1-1 (1eq) and intermediate 1-2 (1.1eq) react in the presence of potassium carbonate and potassium iodide at a reaction temperature of 75-85℃; the reaction solution is post-treated and purified to obtain target compound 1.

[0138] Tests confirmed that compound 1 has the correct structure.

[0139] Other compounds of the present invention (compounds 2 to 19) can be prepared using different starting materials via a similar route to that described in Example 1. The structures of compounds 2 to 19 were confirmed to be correct.

[0140] The NMR detection data of compounds 1–19 are shown in Table 1:

[0141] Table 1

[0142]

[0143]

[0144]

[0145] Example 2: Preparation of LUC-mRNA lipid nanoparticles (LUC-mRNA-LNP)

[0146] Compound 1, obtained in Example 1, was an ionizable lipid that was loaded with luciferase (Luc)-encoded mRNA to prepare compound 1-LNPs@LUC-mRNA.

[0147] The specific steps are as follows:

[0148] (1) Solution preparation: Dissolve ionizable lipid compound 1, DOPE (or DSPC), cholesterol (Chol), and DMG-PEG2000 in anhydrous ethanol to prepare an ionizable lipid solution; the concentration of compound 1 in the ionizable lipid solution is 10 mg / mL, and the molar ratio of compound 1, DSPC, cholesterol (Chol), and DMG-PEG2000 is 50:10:38.5:1.5;

[0149] LUC-mRNA was diluted to the appropriate concentration with 10mM pH 6.0 PBS buffer (prepared with RNase-free water) and then used.

[0150] (2) LNP preparation: The ionizable lipid solution obtained in step (1) was mixed with the LUC-mRNA solution in a microfluidic manner to prepare compound 1-LNPs@LUC-mRNA; the mass ratio of ionizable lipid to mRNA was controlled to be 8:1; the microfluidic mixing process parameters were: the volume ratio of ethanol phase to water phase was 1:4, and the flow rate was 9 mL / min.

[0151] Using a similar procedure as described above, compound 1 obtained in Example 1 was used as an ionizable lipid to load and encapsulate hEPO-encoded mRNA, thus preparing compound 1-LNPs@hEPO-mRNA.

[0152] Comparative Example 3

[0153] Using a similar procedure to Example 2, commercially available SM102 was used as a control ionizable lipid instead of compound 1 in Example 2. Luciferase (Luc)-encoded mRNA and hEPO-encoded mRNA were respectively loaded and encapsulated to prepare SM102-LNPs@LUC-mRNA and SM102-LNPs@hEPO-mRNA.

[0154] Using a similar procedure to Example 2, commercially available ALC0315 and MC3 were used as control ionizable lipids instead of compound 1 in Example 2. hEPO-encoded mRNA was loaded and encapsulated to prepare ALC0315-LNPs@hEPO-mRNA and MC3-LNPs@hEPO-mRNA.

[0155] Experiment 4: LNP mRNA delivery efficiency test

[0156] Balb / C mice were randomly divided into three groups and injected via tail vein with PBS, SM102-LNP loaded with LUC-mRNA (SM102-LNPs@LUC-mRNA), and compound 1-LNP loaded with LUC-mRNA (compound 1-LNPs@LUC-mRNA), respectively, at a dose of 1 mg / kg. Six hours after the intravenous injection, D-fluorescein sodium working solution was injected into the Balb / C mice intraperitoneally. The bioluminescence of the mice was then observed and photographed using a small animal in vivo imaging system.

[0157] After in vivo imaging, the mice in each group were euthanized, and the main organs (including heart, liver, spleen, lungs, and kidneys) were dissected and removed. They were quickly washed with physiological saline, and excess water was absorbed with filter paper. Under the same conditions, in vivo imaging was performed in the bioluminescence channel using an in vivo imaging system, and the bioluminescence intensity of the isolated organs was counted.

[0158] result:

[0159] like Figure 1 The in vivo imaging image of the mouse is shown below:

[0160] from Figure 1 and Figure 2 It is known that, compared with the LNP prepared by SM102, the LNP prepared by the ionizable lipid compound 1 of this application has a 1.5 times higher in vivo bioluminescence intensity in mice;

[0161] from Figures 3-5 It is known that the distribution of effects in isolated organs is similar to that in living organisms; after modification with vitamin E, the lipid compound 1 in this application can be ionized, and its LUC expression in mouse liver and spleen is 1.5 to 2 times that of the control SM102;

[0162] In the figure, 1 represents the Control group; 2 represents the SM-102 group; and 3 represents compound 1 (W3).

[0163] This indicates that the vitamin E-modified compound (I) of this application, as an ionizable lipid, can significantly enhance the delivery efficiency of LNP to mRNA, and its expression in the liver and spleen is significantly higher than that of LNP prepared by SM102 as an ionizable lipid.

[0164] Experiment 5: LNP mRNA delivery efficiency test

[0165] Balb / C mice were randomly divided into three groups and injected via tail vein with hEPO-mRNA-loaded SM102-LNP, hEPO-mRNA-loaded ALC0315-LNP, hEPO-mRNA-loaded MC3-LNP, and hEPO-mRNA-loaded compound 1-LNP (as described in this application), at a dose of 1 mg / kg. Blood samples were collected from the retro-orbital venous plexus of the mice at 0, 3, 6, 9, and 20 h, and serum was obtained by centrifugation. The hEPO expression in each group was measured using an ELISA kit.

[0166] result:

[0167] like Figure 6 As shown, LNPs loaded with hEPO-mRNA were prepared using vitamin E-modified ionizable lipid compound 1. The expression levels of LNPs in mice were higher than those of the control group products SM-102, ALC-0315, and MC3 at any quality control point from 0 to 20 h.

[0168] This indicates that the ionizable lipid modified with vitamin E in this application has a stronger mRNA delivery capability compared to existing lipid compounds (SM-102, ALC-0315, and MC3), significantly enhancing the mRNA delivery efficiency of LNP and achieving unexpected results and safety.

[0169] Test Example 6, Safety Test

[0170] Healthy Balb / C mice were randomly divided into four groups and administered intravenous injections every two days: PBS (Control group), ALC-0315-LNP loaded with hEPO-mRNA (ALC-0315 group), SM102-LNP loaded with hEPO-mRNA (SM-102 group), and compound 1-LNP loaded with hEPO-mRNA (W3 group). The dosage was 1.5 mg / kg, and the injections were administered four times. After administration, mice in each group were sacrificed, and serum samples were collected by centrifugation (3000 rpm, 10 min) for analysis of cardiac, hepatic, and renal function. Key indicators included ALB2, ALTL, AMYL2, and ASTL. The effects of repeated administration on mouse blood were analyzed using a complete blood count and blood biochemistry analyzer.

[0171] Blood sample biochemical test results as follows Figure 7As shown, compared with the control group, the ALC-0315 group (ALC-0315-LNP loaded with hEPO-mRNA), and the SM-102 group (SM102-LNP loaded with hEPO-mRNA), there were no significant differences in the values ​​of various blood sample indicators of the vitamin E-modified ionizable lipid group (W3) of this application, indicating that it has good safety while improving delivery efficiency during the dosing cycle.

[0172] Using similar procedures as in Examples 2-5 above, compounds 2-19 of this application were prepared as LNPs of ionizable lipids. After delivery efficiency and safety tests, they showed similar beneficial effects to compound 1 as an LNP of ionizable lipids.

[0173] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0174] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound that is a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or deuterated compound of formula (I): in, A represents O and S; R1 is H, C1-C 10 Straight-chain or branched alkyl groups; n is any integer from 0 to 2; L1 and L2 are each independently selected from substituted or unsubstituted C1-C. 10 Alkylene; G1 and G2 are each independently selected from -C(=O)-, -OC(=O)-, -C(=O)O-, -C(=O)N(H)-, -(H)NC(=O)-, -OC(=O)O-, -(H)NC(=O)N(H)-, -O-, -S-, -NH-, -SS-, ; Z1 and Z2 are each independently selected from vitamins C1-C. 20 Contains branched alkyl groups, Z1 and Z2 are not both C1-C 20 Contains branched alkyl groups.

2. The compound according to claim 1, characterized in that, The vitamins include fat-soluble vitamins and water-soluble vitamins.

3. The compound according to claim 2, characterized in that, The vitamin mentioned is vitamin E.

4. The compound according to claim 1, characterized in that, A is O.

5. The compound according to claim 1, characterized in that, R1 is H.

6. The compound according to claim 1, characterized in that, L1 and L2 are each independently selected from substituted or unsubstituted C5-C6 alkylene groups.

7. The compound according to claim 1, characterized in that, G1 and G2 are each independently selected from -OC(=O)- and -C(=O)O-.

8. The compound according to claim 1, characterized in that, Z1 and Z2 are not the same, where Z1 is vitamin C and Z2 is vitamin C. 10 -C 20 Contains branched alkyl groups; or Z2 is vitamin and Z1 is C. 10 -C 20 Contains branched alkyl groups.

9. The compound according to claim 1, characterized in that, Z1 and Z2 are the same, and Z1 and Z2 are vitamins.

10. The compound according to claim 1, characterized in that, The value of n is 1.

11. The compound according to claim 1, characterized in that, The C1-C 20 Contains branched alkyl groups and has at least one of the following structures:

12. The compound according to claim 1, characterized in that, A represents O, R1 represents H, n represents 1, and Z1 represents Vitamin E.

13. The compound according to claim 1, characterized in that, A represents O, R1 represents H, n represents 2, Z1 represents Vitamin E, and Z2 represents Vitamin E.

14. The compound according to claim 1, characterized in that, The compound includes:

15. A lipid nanoparticle comprising the compounds of claims 1 to 14, characterized in that, The lipid nanoparticles deliver bioactive ingredients to the liver or spleen.

16. A composition comprising the compounds of claims 1 to 14, characterized in that, The composition also includes pharmaceutically active molecules and pharmaceutically acceptable excipients.

17. A pharmaceutical composition comprising the compound of any one of claims 1 to 14 or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts or deuterated compounds, and a pharmaceutically acceptable carrier, excipient, or adjuvant; characterized in that, Pharmaceutically acceptable carriers include buffer solutions.

18. A drug carrier comprising the compound according to any one of claims 1 to 14, or the lipid nanoparticle according to claim 15, characterized in that, The drug carrier is an ionizable carrier that can load drugs and deliver them into cells.

19. A complex comprising the compound according to any one of claims 1 to 14, or the lipid nanoparticle according to claim 15, or the drug carrier according to claim 18, characterized in that, The complex contains bioactive components.

20. The use of the compound of claims 1-14, or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, or deuterated compounds, in the preparation of liposomes, lipid nanoparticles, drug carriers, or complexes; characterized in that, The compound, or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, or deuterated compounds, are ionizable lipids that can be used to prepare liposomes and lipid nanoparticles. The prepared liposomes or lipid nanoparticles can serve as drug carriers to form nucleic acid drug-liposome complexes.

21. The compound of claims 1 to 14, or its stereoisomers, tautomers, solvates, pharmaceutically acceptable salts, or deuterated compounds.

22. The lipid nanoparticles of claim 15, characterized in that, The bioactive ingredient is selected from DNA, ASO, siRNA, miRNA, mRNA, ribozymes, nucleic acid aptamers or combinations thereof; preferably mRNA.

23. The lipid nanoparticles of claim 22, characterized in that, The mRNA contains at least one chemical modification.

24. The lipid nanoparticles of claim 15, characterized in that, The lipid nanoparticles comprise one or more of ionizable lipids, phospholipids, sterols, and PEG-modified lipids.

Images