WO2023179497A1 - Lipid compound, lipid carrier based on lipid compound, nucleic acid lipid nanoparticle composition and pharmaceutical formulation - Google Patents

Lipid compound, lipid carrier based on lipid compound, nucleic acid lipid nanoparticle composition and pharmaceutical formulation Download PDF

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WO2023179497A1
WO2023179497A1 PCT/CN2023/082278 CN2023082278W WO2023179497A1 WO 2023179497 A1 WO2023179497 A1 WO 2023179497A1 CN 2023082278 W CN2023082278 W CN 2023082278W WO 2023179497 A1 WO2023179497 A1 WO 2023179497A1
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alkyl
independently
group
heteroalkyl
lipid
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PCT/CN2023/082278
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French (fr)
Chinese (zh)
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黄珂
葛滨溪
高银佳
张楠
董兆芳
孙振华
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苏州科锐迈德生物医药科技有限公司
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Publication of WO2023179497A1 publication Critical patent/WO2023179497A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
    • A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
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    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C327/04—Monothiocarboxylic acids having carbon atoms of thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
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    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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    • C07D295/30—Nitrogen atoms non-acylated

Definitions

  • This invention requires an invention patent application submitted in China on March 21, 2022, titled "A lipid compound and a lipid carrier based on it, a nucleic acid lipid nanoparticle composition and a pharmaceutical preparation", with the application number 202210280492.9 priority, the entire contents of this patent application are incorporated herein by reference.
  • the invention belongs to the field of gene drug delivery, and specifically relates to a lipid compound and a lipid carrier based thereon, a nucleic acid lipid nanoparticle composition and a pharmaceutical preparation.
  • nucleic acid drugs can be used to prevent cancer, bacterial and viral infections, and treat diseases with genetic causes. Since nucleic acid drugs are easy to degrade and difficult to enter cells, they need to be encapsulated and delivered to target cells with the help of carriers. Therefore, the development of safe and efficient delivery carriers has become a prerequisite for the clinical application of gene therapy.
  • Lipid nanoparticles are currently a research hotspot in the field of non-viral gene vectors.
  • LNP is usually composed of four lipid compounds, namely cationic lipids, neutral lipids, sterols and amphipathic lipids. Among them, cationic lipids have the greatest impact on the performance of LNP, such as affecting the encapsulation rate of nucleic acid drugs, nucleic acid Drug delivery efficiency or cytotoxicity in the body, etc.
  • the present invention aims to provide a series of compounds that can be used to prepare lipid carriers alone or together with other lipid compounds to improve the delivery efficiency of nucleic acid drugs in the body and deliver nucleic acid drugs to organs that need to be enriched.
  • the present invention also provides lipid carriers comprising the above compounds.
  • the present invention also provides a nucleic acid lipid nanoparticle composition comprising the above compound or the above lipid carrier.
  • the present invention also provides pharmaceutical preparations comprising the above compound, or the above lipid carrier, or the above nucleic acid lipid nanoparticle composition.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrugs,
  • Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aromatic
  • the radical and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
  • Ra and Ra' are independently or,
  • Ra and Ra’ are connected to each other to form Z;
  • Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group;
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
  • Each R 1 is independently C 1- C 24 alkyl or C 2- C 24 alkenyl
  • Each R 2 is independently hydrogen or C 1- C 24 alkyl
  • Each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group;
  • Each m is independently 0 or 1;
  • the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof Examples of specific compounds.
  • the present invention provides a lipid carrier, which contains the above compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, and non-covalent complex. or prodrugs.
  • the present invention provides a nucleic acid lipid nanoparticle composition, which contains the above compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non- Covalent complexes or prodrugs, or lipid carriers as described above, as well as nucleic acid drugs.
  • the present invention provides a pharmaceutical preparation comprising the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or Prodrugs, or the above-mentioned lipid carrier, or the above-mentioned nucleic acid lipid nanoparticle composition, and pharmaceutically acceptable excipients, carriers and diluents.
  • the invention provides a series of compounds of formula (I) with novel structures.
  • the lipid carrier can be prepared alone or together with other lipid compounds.
  • the particle size is controllable, the distribution is uniform, and it has Monodisperse, with high encapsulation efficiency for negatively charged drugs.
  • it has a tertiary amine structure, it can exhibit different potentials at different pHs, and exhibit positive electricity when loading negatively charged drugs under acidic conditions, so that positively charged lipid carriers and negatively charged drugs attract each other; it can also be used It exhibits electroneutrality or electronegativity under neutral conditions in the body to avoid huge cellular toxicity.
  • Containing multiple degradable functional groups allows lipids to help release more nucleic acids in the body and achieve better expression effects; containing multiple degradable functional groups allows lipid metabolism to be faster.
  • the lipid carrier can also deliver nucleic acid drugs to organs that require enrichment.
  • the compound has a simple synthesis route, cheap and easily available raw materials, and has high market potential.
  • Figure 1 is an imaging diagram of mice injected intramuscularly with LNP@mRNA prepared from Compound 1 of the present invention.
  • Figure 2 is an anatomical imaging diagram of mice injected intramuscularly with LNP@mRNA prepared from Compound 1 of the present invention.
  • Figure 3 is an imaging diagram of mice injected intravenously with LNP@mRNA prepared from Compound 8 of the present invention.
  • Figure 4 is an anatomical imaging diagram of mice injected intravenously with LNP@mRNA prepared from Compound 8 of the present invention.
  • Figure 5 is an imaging diagram of mice injected intravenously with LNP@mRNA prepared from compound 58 of the present invention.
  • Figure 6 is an anatomical imaging diagram of mice injected intravenously with LNP@mRNA prepared from compound 58 of the present invention.
  • Figure 7 shows the metabolism of LNP@mRNA prepared from Compound 1 of the present invention and Dlin-MC3-DMA in mouse liver.
  • Figure 8 shows the metabolism of LNP@mRNA prepared from Compound 1 of the present invention and Dlin-MC3-DMA in mouse spleen.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention that is substantially non-toxic to organisms.
  • Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases. Such salts are also known as acid addition salts or Base addition salt.
  • Common inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • Common organic acids include (but are not limited to) trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, and tartaric acid.
  • Common inorganic bases include (but are not limited to) sodium hydroxide, potassium hydroxide, calcium hydroxide , barium hydroxide, etc.
  • Common organic bases include (but are not limited to) diethylamine, triethylamine, ethambutol, etc.
  • stereoisomer refers to having a vertical asymmetric plane due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), A stable isomer capable of rotating plane-polarized light. Since there are asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomerism, the present invention also includes these stereoisomers and their mixtures. Since the compounds of the present invention and their salts include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomeric and diastereomeric mixtures. Generally, these compounds can be prepared in the form of racemic mixtures.
  • stereoisomers that is, single enantiomers or diastereomers, or single stereoisomer enrichment (purity ⁇ 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%) mixtures.
  • Single stereoisomers of a compound are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparing mixtures of enantiomeric products followed by isolation or resolution, e.g.
  • tautomers refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers include (but are not limited to) interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization chemical, amide-iminoalcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • solvate refers to a substance formed by the combination of a compound of the invention or a pharmaceutically acceptable salt thereof and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates, ethanolates, acetones, etc.
  • chelate refers to a complex with a cyclic structure obtained by the chelation of two or more ligands with the same metal ion to form a chelate ring.
  • non-covalent complex is formed by the interaction of a compound with another molecule without forming a covalent bond between the compound and the molecule. For example, recombination can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • prodrug refers to a derivative compound capable of providing, directly or indirectly, a compound of the invention when administered to a patient.
  • Particularly preferred derivative compounds or prodrugs are compounds that increase the bioavailability of the compounds of the invention when administered to a patient (e.g., compounds that are more readily absorbed into the bloodstream), or that enhance the delivery of the parent compound to the site of action (e.g., the lymphatic system).
  • all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.
  • each independently means that at least two groups (or ring systems) present in the structure with the same or similar value ranges can have the same or different meanings under specific circumstances.
  • the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl.
  • the substituent Y can be either hydrogen, halogen, or hydroxyl, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.
  • alkyl refers to a monovalent straight or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing no unsaturation, and connected to other moieties by a single bond, including (but Not limited to) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, etc.
  • C 1 -C 24 alkyl refers to an alkyl group containing 1 to 24 carbon atoms.
  • branched C 10 -C 15 alkyl refers to branched alkyl groups containing 10 to 15 carbon atoms, including (but not limited to) 1-butylhept-1-yl and 2-butyloctyl. -1-base etc.
  • alkylene refers to a divalent straight-chain or branched aliphatic group, which consists only of carbon atoms and hydrogen atoms, does not contain saturation, and is connected to other fragments through two single bonds, including (But not limited to) methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, etc.
  • C 1 -C 24 alkylene refers to an alkylene group containing 1 to 24 carbon atoms.
  • alkenyl refers to a monovalent linear or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, and connected to other moieties by a single bond, including (but Not limited to) vinyl, propenyl, allyl and other groups.
  • C 2 -C 24 alkenyl refers to an alkenyl group containing 2 to 24 carbon atoms.
  • alkenylene refers to a divalent straight-chain or branched aliphatic group, which consists only of carbon atoms and hydrogen atoms, contains at least one double bond, and is connected to other segments through two single bonds, including but not limited to) wait.
  • C 2 -C 24 alkenylene refers to an alkenylene group containing 2 to 24 carbon atoms.
  • alkynyl refers to a monovalent linear or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond, and connected to other moieties by a single bond, including (but Without limitation) groups such as ethynyl, propynyl, propargyl and 4-pentyn-1-yl.
  • C 2 -C 24 alkynyl refers to an alkynyl group containing 2 to 24 carbon atoms.
  • cycloalkyl refers to a monovalent monocyclic or polycyclic (such as fused, bridged or spirocyclic) aliphatic group consisting only of carbon atoms and hydrogen atoms and bonded to other atoms through a single bond. Fragment linkages include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • C 3 -C 24 alkyl refers to a cycloalkyl group containing 3 to 24 ring atoms.
  • heterocycloalkyl refers to a heterocycloalkyl group containing 3 to 24 ring atoms (or heteroatom groups).
  • aryl refers to a monovalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group consisting only of carbon atoms and hydrogen atoms and connected to other moieties by a single bond , including (but not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, etc.
  • C 6 -C 10 aryl refers to an aryl group containing 6 to 10 ring atoms.
  • arylene refers to a divalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group, which consists only of carbon atoms and hydrogen atoms, and is bonded to other atoms through two single bonds. Fragment connection includes (but is not limited to) 1,4-phenylene, 1,4-naphthylene, 9,10-anthracenylene, 9,10-phenylene, etc.
  • C 6 -C 10 arylene refers to an arylene group containing 6 to 10 ring atoms.
  • pyrazolyl such as 1H -imidazol-1-yl
  • oxazolyl such as oxazol-2-yl
  • thiazolyl such as thiazol-4-yl
  • pyrazolylene such as 1,4-imidazolyl
  • oxazolyl such as 2,4-oxazolyl
  • thiazolyl such as 2,5-thiazolyl
  • hydroxy refers to the -OH group.
  • the invention provides compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof,
  • Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl or ,
  • Ra and Ra' are independently or,
  • Ra and Ra’ are connected to each other to form Z;
  • Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group;
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
  • Each R 1 is independently C 1- C 24 alkyl or C 2- C 24 alkenyl
  • Each R 2 is independently hydrogen or C 1- C 24 alkyl
  • Each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group;
  • Each m is independently 0 or 1;
  • Ra and Ra' in formula (I) are each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 - C 12 heteroalkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from 1 to 3 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 - Group substitution of C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; preferably, Ra and Ra 'Each independently is C 1 -C 6
  • each Z in Formula (I) is independently C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 6 -C 10 arylene, or 5- 10-membered heteroarylene group; preferably, each Z is independently a C 1 -C 6 alkylene group or a C 1 -C 6 heteroalkylene group.
  • W in formula (I) is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cyclic Alkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from 1 to 3 each independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 ring Alkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, W is C 1 -C 12 alkyl or C 1 -C 12 Heteroalkyl, said alkyl and hetero
  • each R 1 in formula (I) is independently C 3- C 24 alkyl or C 3- C 24 alkenyl; preferably, each R 1 is independently branched. C 3- C 24 alkyl or branched C 3- C 24 alkenyl.
  • each R 2 in formula (I) is independently hydrogen or C 1- C 6 alkyl; preferably, each R 2 is independently hydrogen or C 1- C 4 alkyl base.
  • each B 1 , B 2 , B 3 and B 4 in formula (I) is each independently C 1 -C 6 alkylene or C 2 -C 6 alkenylene; preferably , each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 4 alkylene group or a C 2 -C 4 alkenylene group.
  • a compound of Formula (I) has a structure shown in Formula (I-1) or Formula (I-1'):
  • Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, preferably C 1 -C 6 al
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, W is C 1 -C 12 alkyl, preferably C 1 -C 6 alkyl;
  • R 1 is C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
  • B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-2) or Formula (I-2'):
  • Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, C 2 -C 12 alkyn
  • Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
  • Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-3) or Formula (I-3'):
  • Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group; preferably, each Z Each independently is C 1 -C 12 alkylene, preferably C 1 -C 6 alkylene;
  • W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl
  • the base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution;
  • W is C 1 -C 12 alkyl or C 1 -C 12 heteroalkyl, the alkyl and heteroalkyl groups
  • R 1 is C 1- C 24 alkyl or C 2- C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
  • B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-4) or Formula (I-4'):
  • Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl group substituted by a base, a 3-10 membered heterocycloalkyl group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group; preferably, Ra and Ra' are each independently a
  • Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 6 alkylene or C 1 -C 6 heteroalkylene;
  • Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
  • Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • a compound of Formula (I) has a structure shown in Formula (I-5) or Formula (I-5'):
  • Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 8 alkylene or C 1 -C 8 heteroalkylene;
  • Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
  • Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
  • Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
  • each Each is independently selected from the following clips:
  • each Z is independently selected from the following fragments:
  • X is selected from the following fragments:
  • the present invention provides a series of specific compounds falling within the scope of compounds of the general formula, including (but not limited to):
  • the invention provides a lipid carrier, which contains any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or Prodrugs.
  • This type of lipid carrier has high encapsulation efficiency for nucleic acid drugs, which greatly improves the delivery efficiency of nucleic acid drugs in the body.
  • the above-mentioned lipid carrier includes a first lipid compound and a second lipid compound, wherein the first lipid compound includes any of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, Tautomers, solvates, chelates, non-covalent complexes or prodrugs and optionally cationic lipids, the second lipid compound comprising anionic lipids, neutral lipids, sterols and amphiphiles One or a combination of two or more lipids.
  • the above-mentioned first lipid compound is any one of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent compound thereof. Complex or prodrug.
  • the above-mentioned first lipid compound is any one of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-common Valent complexes or combinations of prodrugs and cationic lipids.
  • the second lipid compound is a combination of neutral lipids, sterols, and amphipathic lipids.
  • the second lipid compound is a combination of anionic lipid, neutral lipid, sterol, and amphiphilic lipid.
  • the above-mentioned cationic lipids include (but are not limited to) one of DLinDMA, DODMA, DLin-MC2-MPZ, DLin-KC2-DMA, DOTAP, C12-200, DC-Chol and DOTMA or A combination of two or more is preferred, DLin-KC2-DMA and DOTAP.
  • the above-mentioned anionic lipids include (but are not limited to) phosphatidylserine, phosphatidylinositol, phospholipid One or a combination of two or more of acid, phosphatidylglycerol, DOPG, DOPS and dimyristoylphosphatidylglycerol, preferably DOPG and DOPS.
  • the above-mentioned neutral lipids include (but are not limited to) at least one of DOPE, DSPC, DPPC, DOPC, DPPG, POPC, POPE, DPPE, DMPE, DSPE and SOPE or its anionic or Lipids modified with cationic modifying groups are preferably DSPC.
  • the anionic or cationic modifying group is not limited.
  • the above-mentioned amphiphilic lipids include (but are not limited to) PEG-DMG, PEG-c-DMG, PEG-C14, PEG-c-DMA, PEG-DSPE, PEG-PE, PEG modified of ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, Tween-20, Tween-80, PEG-DPG, PEG-s-DMG, DAA, PEG-c-DOMG and GalNAc-PEG -One or a combination of two or more DSGs, preferably PEG-DMG and Tween-80.
  • the molar ratio of the first lipid compound, anionic lipid, neutral lipid, sterol and amphipathic lipid is (20 ⁇ 65): (0 ⁇ 20 ):(5 ⁇ 25):(25 ⁇ 55):(0.3 ⁇ 15);
  • the molar ratio can be 20:20:5:50:5, 30:5:25:30:10, 20: 5:5:55:15, 65:0:9.7:25:0.3, etc.;
  • any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers is (1 ⁇ 10):(0 ⁇ 10); exemplarily, the molar ratio can be 1: 1, 1:2, 1:5, 1:7.5, 1:10, 2:1, 5:1, 7.5:1, 10:1, etc.
  • the molar ratio of the first lipid compound, anionic lipid, neutral lipid, sterol and amphipathic lipid is (20 ⁇ 55): (0 ⁇ 13): (5 ⁇ 25): (25 ⁇ 51.5): (0.5 ⁇ 15); wherein, in the first lipid compound, any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, The molar ratio of tautomers, solvates, chelates, non-covalent complexes or prodrugs and cationic lipids is (3 ⁇ 4):(0 ⁇ 5).
  • the invention provides a nucleic acid nanoparticle composition, which contains any of the above compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, and non-covalent complexes thereof. drugs or prodrugs or the above-mentioned lipid carriers, as well as nucleic acid drugs.
  • the above-mentioned nucleic acid drugs include (but are not limited to) DNA, siRNA, mRNA, dsRNA, antisense nucleic acid, antisense oligonucleotide, microRNA, antisense microRNA, antagomir, microRNA inhibitor, microRNA One or a combination of two or more RNA activators and immunostimulatory nucleic acids.
  • the above-mentioned nucleic acid drug is combined with any of the above-mentioned compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or
  • the mass ratio of prodrugs is 1:(3 ⁇ 40).
  • the mass ratio of the above-mentioned nucleic acid drug and the above-mentioned lipid carrier is 1: (3-40).
  • the above mass ratio may be 1:3, 1:5, 1:10, 1:15, 1:20, 1:30, etc.
  • the present invention provides a pharmaceutical preparation, which contains any of the above compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or precursor thereof Drug, or the above-mentioned lipid carrier, or the above-mentioned nucleic acid lipid nanoparticle composition, and pharmaceutically acceptable excipients, carriers and diluents.
  • the particle size of the above-mentioned pharmaceutical preparation is 30-500nm; exemplarily, the particle size can be 30nm, 50nm, 100nm, 150nm, 250nm, 350nm, 500nm, etc.
  • the encapsulation rate of nucleic acid drugs in the above-mentioned pharmaceutical preparations is greater than 50%; for example, the encapsulation rate can be 55%, 60%, 65%, 70%, 75%, 79%, 80%, 85%, 89%, 90%, 93%, 95%, etc.
  • the "equivalent (eq)" ratio refers to the molar ratio of solvent or drug.
  • misappropriate amount means that the amount of solvent or drug added has a large adjustable range and has little impact on the synthesis result, and does not need to be specifically limited.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0 eq), stir for 10 minutes, then add 4-hydroxybutylacrylate (1.5eq), and stir at room temperature for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 2 Dissolve intermediate product 2 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.2eq), stir at room temperature for 16h after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), stir at room temperature for 16h after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add intermediate product 2 (1.5eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • Dissolve cystamine dihydrochloride (2.0eq) in an appropriate amount of methylene chloride, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.0eq), after addition, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 3 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.5eq) ), stir at room temperature for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.5eq) ), stir at room temperature for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • intermediate product 2 (1.0eq) in an appropriate amount of ethyl acetate, add 4M hydrochloric acid in ethyl acetate solution (6V), and stir at room temperature for 2 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • intermediate product 3 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
  • intermediate product 3 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of DMF, add intermediate product 2 (2.0eq) and potassium carbonate (3.0eq), and stir at 90°C for 16 hours after addition.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h.
  • TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
  • intermediate product 1 Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours.
  • TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
  • the results showed that the mRNA encapsulation efficiency of LNP@mRNA prepared from the compounds in the table above was greater than 80%, and the particle size of LNP@mRNA prepared by compounds 11, 15, 21, 38, and 59 together with the other three lipids was smaller. In addition, LNPs prepared from these compounds are negatively charged under neutral conditions and have good biological safety. It can be seen that the compound provided by the present invention has a high encapsulation efficiency for nucleic acid drugs, and can be used as a carrier to improve the delivery efficiency of nucleic acid drugs in the body.
  • FIG. 1 is an imaging image of mice injected intramuscularly with LNP@mRNA prepared from Compound 1.
  • Figure 2 is an anatomical image of mice injected intramuscularly with LNP@mRNA prepared from Compound 1. Combining Figures 1 and 2, it can be seen that the main components of mRNA are Expressed in muscle, liver and spleen.
  • Figure 3 is an imaging image of mice injected intravenously with LNP@mRNA prepared from Compound 8.
  • Figure 4 is an anatomical image of mice injected intravenously with LNP@mRNA prepared with Compound 8.
  • Figure 5 is an imaging image of mice injected intravenously with LNP@mRNA prepared from compound 58.
  • Figure 6 is an anatomical image of mice injected intravenously with LNP@mRNA prepared with compound 58. Combining Figures 5 and 6, it can be seen that the main components of mRNA are Expressed in the spleen and a small amount in the liver. Therefore, the above-mentioned lipid compound with a specific structure can be selected as a lipid carrier according to the organ in which the nucleic acid drug needs to be enriched.
  • MC3 cationic lipid DLin-MC3-DMA
  • DSPC disearoylphosphatidylcholine
  • PEG-DMG polyethylene glycol-dimyristate glyceryl ester
  • ethanol dissolve in ethanol (with lipid as the molar ratio of 50:38.5:10:1.5 (wherein, the equivalent of compound 1 or MC3 is 50, the equivalent of cholesterol is 38.5, the equivalent of DSPC is 10, and the equivalent of PEG-DMG is 1.5)
  • concentration is 24.4mg/mL
  • dissolve luciferase mRNA in 10mM citrate buffered saline solution with pH 4.0 drug concentration is 0.276mg/mL
  • the volume ratio of the two solutions is 1:3 ( Among them, the equivalent of the ethanol solution is 1 and the equivalent of the aqueous solution is 3), use microfluidic technology to quickly
  • FIG. 7 shows the metabolism of LNP@mRNA prepared by Compound 1, MC3 and other three lipids in mouse liver. It can be seen that MC3 and LNP@mRNA reached the peak 6 hours after injection, and still maintained a high level after 48 hours. The lipid level of Compound 1 reached a peak at 2 hours after LNP@mRNA injection, and the peak value during the entire 48 hours was much lower than the lipid level of MC3. Therefore, it can be shown that Compound 1 has a higher concentration in the liver than MC3. Fast metabolic rate.
  • Figure 8 shows the metabolism of LNP@mRNA prepared by Compound 1, MC3 and other three lipids in the mouse spleen. It can be seen that MC3 reaches the peak 12 hours after LNP@mRNA injection and still maintains a high level 48 hours later. lipid levels, whereas compound 1 in The peak value was reached 2 hours after LNP@mRNA injection, and the peak value during the entire 48 hours was much lower than the lipid level of compound 1. Therefore, it can be seen that compound 1 has a faster metabolism in the spleen than MC3. Lipids are less concentrated in the liver and spleen, have faster metabolism, higher biosafety and less toxicity than cationic lipids already on the market.
  • Compound 55 was mixed with DOTAP ((2,3-dioleoylpropyl)trimethylammonium chloride), cholesterol, DSPC, and PEG-DMG at a molar ratio of 30:20:38.5:10:1.5 (wherein, compound 55 The equivalent of DOTAP is 30, the equivalent of cholesterol is 38.5, the equivalent of DSPC is 10, and the equivalent of PEG-DMG is 1.5) is dissolved in ethanol (based on the total weight of lipids, the concentration is 24.4 mg/mL) , dissolve luciferase mRNA in 50mM citrate buffered saline solution with pH 4.0 (drug concentration is 0.276mg/mL), the volume ratio of the two solutions is 1:3 (wherein, the equivalent of the ethanol solution is 1, and the equivalent of the aqueous solution is 3), use microfluidic technology to quickly mix the two phases, and use dialysis or tangential flow technology to replace the buffer environment with PBS at pH 7.4 to prepare LNP@
  • Compound 56 was mixed with DOTAP, DOPS (dioleoylphosphatidylserine), cholesterol, DSPC, and PEG-DMG (total 15 mg) at a molar ratio of 20:25:15:25:5:10 (wherein, the equivalent of compound 56 is 20.
  • DOTAP 25
  • DOPS 15
  • cholesterol 25
  • DSPC 5
  • PEG-DMG 5
  • ethanol based on the total weight of lipids, the concentration is 24.4mg /mL
  • luciferase mRNA 5mg
  • 50mM citrate buffered saline solution with pH 4.0 drug concentration is 0.276mg/mL
  • the volume ratio of the two solutions is 1:3 (wherein, the equivalent of the ethanol solution is 1.
  • the equivalent of the aqueous solution is 3).
  • Compound 2 was mixed with DLin-KC2-DMA (CAS number: 1190197-97-7), DOPG (dioleoylphosphatidylglycerol), cholesterol, DSPC, and Tween-80 (total 30 mg) at a ratio of 15:5:3:51.5 :25:0.5 molar ratio (wherein, the equivalent of compound 2 is 15, the equivalent of DLin-KC2-DMA is 5, the equivalent of DOPG is 3, the equivalent of cholesterol is 51.5, the equivalent of DSPC is 25, and the equivalent of Tween-80 Equivalent to 0.5) was dissolved in ethanol (based on the total weight of lipids, the concentration was 24.4mg/mL), and luciferase mRNA (1mg) was dissolved in 50mM citrate buffered saline solution at pH 4.0 (drug concentration was 0.276mg /mL), the volume ratio of the two is 1:3 (where the equivalent of the ethanol solution is 1 and the equivalent of the aque

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Abstract

The present invention belongs to the field of gene drug delivery, and particularly relates to a lipid compound, a lipid carrier based on the lipid compound, a nucleic acid lipid nanoparticle composition and a pharmaceutical formulation. The compound having the structure shown in formula (I) can independently prepare a lipid carrier, or jointly prepare a lipid carrier with other lipid compounds. The lipid carrier shows pH responsiveness, has high encapsulation efficiency on nucleic acid drugs, and is beneficial to improving the in vivo delivery efficiency of nucleic acid drugs. Moreover, the lipid carrier can also deliver a nucleic acid drug to an organ needing enrichment, and has a good application prospect.

Description

一种脂质化合物及基于其的脂质载体、核酸脂质纳米粒组合物和药物制剂A lipid compound and lipid carrier based on it, nucleic acid lipid nanoparticle composition and pharmaceutical preparation
相关申请的交叉引用Cross-references to related applications
本发明要求2022年03月21日在中国提交的，名称为“一种脂质化合物及基于其的脂质载体、核酸脂质纳米粒组合物和药物制剂”，申请号为202210280492.9的发明专利申请的优先权，通过引用的方式将该专利申请的全部内容并入本文。This invention requires an invention patent application submitted in China on March 21, 2022, titled "A lipid compound and a lipid carrier based on it, a nucleic acid lipid nanoparticle composition and a pharmaceutical preparation", with the application number 202210280492.9 priority, the entire contents of this patent application are incorporated herein by reference.
技术领域Technical field
本发明属于基因药物递送领域，具体涉及一种脂质化合物及基于其的脂质载体、核酸脂质纳米粒组合物和药物制剂。The invention belongs to the field of gene drug delivery, and specifically relates to a lipid compound and a lipid carrier based thereon, a nucleic acid lipid nanoparticle composition and a pharmaceutical preparation.
背景技术Background technique
基因治疗技术是现代生物医药领域研究的热点，例如利用核酸药物可预防癌症、细菌和病毒感染及治疗具有遗传病因的疾病等。由于核酸药物具有易降解、难以进入细胞等特点，需要借助载体将其封装起来递送至靶细胞，因此，开发安全高效的递送载体就成为基因治疗在临床应用的前提。Gene therapy technology is a hot research topic in the field of modern biomedicine. For example, nucleic acid drugs can be used to prevent cancer, bacterial and viral infections, and treat diseases with genetic causes. Since nucleic acid drugs are easy to degrade and difficult to enter cells, they need to be encapsulated and delivered to target cells with the help of carriers. Therefore, the development of safe and efficient delivery carriers has become a prerequisite for the clinical application of gene therapy.
脂质纳米颗粒(Lipid nanoparticle，LNP)目前是非病毒基因载体领域的研究热点。2018年，FDA批准了利用LNP递送patisiran(onpattro)来治疗遗传性转甲状腺素蛋白淀粉样变性，自此运用LNP技术递送核酸药物的研究呈现迸发式增长。特别是2020年底，FDA分别批准了Moderna和BioNtech&辉瑞的COVID-19疫苗，此两种疫苗均是利用LNP技术来递送mRNA药物，以实现对COVID-19病毒预防。Lipid nanoparticles (LNP) are currently a research hotspot in the field of non-viral gene vectors. In 2018, the FDA approved the use of LNP to deliver patisiran (onpattro) to treat hereditary transthyretin amyloidosis. Since then, research on the use of LNP technology to deliver nucleic acid drugs has grown explosively. Especially at the end of 2020, the FDA approved the COVID-19 vaccines of Moderna and BioNtech & Pfizer respectively. Both vaccines use LNP technology to deliver mRNA drugs to prevent the COVID-19 virus.
LNP通常由四种脂质化合物组成，即阳离子脂质、中性脂质、甾醇和两亲性脂质，其中，阳离子脂质对LNP性能的影响最大，如影响核酸药物的包封率、核酸药物在体内的递送效率或细胞毒性等。LNP is usually composed of four lipid compounds, namely cationic lipids, neutral lipids, sterols and amphipathic lipids. Among them, cationic lipids have the greatest impact on the performance of LNP, such as affecting the encapsulation rate of nucleic acid drugs, nucleic acid Drug delivery efficiency or cytotoxicity in the body, etc.
因此，需要开发出更多的新型化合物(例如阳离子脂质化合物)，为递送基因药物提供更多的选择。Therefore, more novel compounds (such as cationic lipid compounds) need to be developed to provide more options for delivering gene drugs.
发明内容Contents of the invention
发明要解决的问题Invent the problem to be solved
本发明旨在提供一系列化合物，该化合物可单独制备脂质载体或与其它脂质化合物共同制备脂质载体，提升核酸药物在体内的递送效率，可将核酸药物递送至需要富集的器官。The present invention aims to provide a series of compounds that can be used to prepare lipid carriers alone or together with other lipid compounds to improve the delivery efficiency of nucleic acid drugs in the body and deliver nucleic acid drugs to organs that need to be enriched.
本发明还提供包含上述化合物的脂质载体。The present invention also provides lipid carriers comprising the above compounds.
本发明还提供包含上述化合物或上述脂质载体的核酸脂质纳米粒组合物。The present invention also provides a nucleic acid lipid nanoparticle composition comprising the above compound or the above lipid carrier.
本发明还提供包含上述化合物、或上述脂质载体、或上述核酸脂质纳米粒组合物的药物制剂。The present invention also provides pharmaceutical preparations comprising the above compound, or the above lipid carrier, or the above nucleic acid lipid nanoparticle composition.
用于解决问题的方案solutions to problems
第一方面，本发明提供了如式(I)所示的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，
In a first aspect, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrugs,
其中：in:
X为其中：X is in:
Ra和Ra’各自独立地为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、 3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；或者，Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aromatic The radical and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
Ra和Ra’各自独立地为或者，Ra and Ra' are independently or,
Ra和Ra’相互连接成Z；Ra and Ra’ are connected to each other to form Z;
每一个Z各自独立地为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group;
W为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；或者，W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
W为 W is
每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-、-C(＝O)NR2-、-NR2C(＝O)NR2-、-OC(＝O)NR2-、-NR2C(＝O)O-或-O(C＝O)O-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)-, -C(=O)NR 2 -, -NR 2 C( =O)NR 2 -, -OC(=O)NR 2 -, -NR 2 C(=O)O- or -O(C=O)O-;
每一个R1各自独立地为C1-C24烷基或C2-C24烯基；Each R 1 is independently C 1- C 24 alkyl or C 2- C 24 alkenyl;
每一个R2各自独立地为氢或C1-C24烷基；Each R 2 is independently hydrogen or C 1- C 24 alkyl;
每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；Each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group;
每一个m各自独立地为0或1；Each m is independently 0 or 1;
所述杂烷基、亚杂烷基、杂环烷基、杂芳基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heteroalkylene group, heterocycloalkyl group, heteroaryl group and heteroarylene group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N , NH, O, S, S(=O) or S(=O) 2 .
第二方面，本发明提供了上述式(I)化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物的具体化合物实例。In a second aspect, the present invention provides the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof Examples of specific compounds.
第三方面，本发明提供了一种脂质载体，其包含上述化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物。In a third aspect, the present invention provides a lipid carrier, which contains the above compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, and non-covalent complex. or prodrugs.
第四方面，本发明提供了一种核酸脂质纳米粒组合物，其包含上述化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，或上述脂质载体，以及核酸药物。In the fourth aspect, the present invention provides a nucleic acid lipid nanoparticle composition, which contains the above compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non- Covalent complexes or prodrugs, or lipid carriers as described above, as well as nucleic acid drugs.
第五方面，本发明提供了一种药物制剂，其包含上述化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，或上述脂质载体，或上述核酸脂质纳米粒组合物，以及药学上可接受的赋形剂、载体和稀释剂。In a fifth aspect, the present invention provides a pharmaceutical preparation comprising the above compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or Prodrugs, or the above-mentioned lipid carrier, or the above-mentioned nucleic acid lipid nanoparticle composition, and pharmaceutically acceptable excipients, carriers and diluents.
发明的效果Effect of the invention
本发明提供了一系列结构新颖的式(I)化合物，作为一种新型阳离子脂质，可单独制备脂质载体或与其它脂质化合物共同制备脂质载体，粒径可控，分布均一，具有单分散性，对带有负电的药物具有很高的包封率。并且由于带有叔胺结构，可在不同pH下展现不同电位，在酸性条件下包载负电药物时展现正电，以使带正电的脂质载体与带有负电的药物相互吸引；也可在体内即中性条件下展现电中性或电负性，避免带来巨大的细胞毒性。含有多个可降解的官能团，使得脂质可以帮助核酸在体内更多的释放，表达效果更好；含有多个可降解的官能团，使得脂质代谢速度更快。此外，该脂质载体还可将核酸药物递送至需要富集的器官。The invention provides a series of compounds of formula (I) with novel structures. As a new type of cationic lipid, the lipid carrier can be prepared alone or together with other lipid compounds. The particle size is controllable, the distribution is uniform, and it has Monodisperse, with high encapsulation efficiency for negatively charged drugs. And because it has a tertiary amine structure, it can exhibit different potentials at different pHs, and exhibit positive electricity when loading negatively charged drugs under acidic conditions, so that positively charged lipid carriers and negatively charged drugs attract each other; it can also be used It exhibits electroneutrality or electronegativity under neutral conditions in the body to avoid huge cellular toxicity. Containing multiple degradable functional groups allows lipids to help release more nucleic acids in the body and achieve better expression effects; containing multiple degradable functional groups allows lipid metabolism to be faster. In addition, the lipid carrier can also deliver nucleic acid drugs to organs that require enrichment.
进一步地，该化合物合成路线简单，原料便宜易得，具有很高的市场潜力。Furthermore, the compound has a simple synthesis route, cheap and easily available raw materials, and has high market potential.
附图说明Description of the drawings
图1为由本发明化合物1制备的LNP@mRNA的肌肉注射小鼠成像图。Figure 1 is an imaging diagram of mice injected intramuscularly with LNP@mRNA prepared from Compound 1 of the present invention.
图2为由本发明化合物1制备的LNP@mRNA的肌肉注射小鼠成像解剖图。 Figure 2 is an anatomical imaging diagram of mice injected intramuscularly with LNP@mRNA prepared from Compound 1 of the present invention.
图3为由本发明化合物8制备的LNP@mRNA的静脉注射小鼠成像图。Figure 3 is an imaging diagram of mice injected intravenously with LNP@mRNA prepared from Compound 8 of the present invention.
图4为由本发明化合物8制备的LNP@mRNA的静脉注射小鼠成像解剖图。Figure 4 is an anatomical imaging diagram of mice injected intravenously with LNP@mRNA prepared from Compound 8 of the present invention.
图5为由本发明化合物58制备的LNP@mRNA的静脉注射小鼠成像图。Figure 5 is an imaging diagram of mice injected intravenously with LNP@mRNA prepared from compound 58 of the present invention.
图6为由本发明化合物58制备的LNP@mRNA的静脉注射小鼠成像解剖图。Figure 6 is an anatomical imaging diagram of mice injected intravenously with LNP@mRNA prepared from compound 58 of the present invention.
图7为由本发明化合物1、Dlin-MC3-DMA制备的LNP@mRNA在小鼠肝脏内代谢情况。Figure 7 shows the metabolism of LNP@mRNA prepared from Compound 1 of the present invention and Dlin-MC3-DMA in mouse liver.
图8为由本发明化合物1、Dlin-MC3-DMA制备的LNP@mRNA在小鼠脾脏内代谢情况。Figure 8 shows the metabolism of LNP@mRNA prepared from Compound 1 of the present invention and Dlin-MC3-DMA in mouse spleen.
具体实施方式Detailed ways
在进一步描述本发明之前，应当理解，本发明不限于本文中所述的特定实施方案；还应该理解，本文中所使用的术语仅用于描述而非限定特定实施方案。Before the present invention is further described, it is to be understood that the present invention is not limited to the specific embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing and not limiting the specific embodiments.
[术语定义][Definition of Terms]
除非另有说明，下列术语的含义如下：Unless otherwise stated, the following terms have the following meanings:
术语“药学上可接受的盐”是指对生物体基本上无毒性的本发明的化合物的盐。药学上可接受的盐通常包括(但不限于)本发明的化合物与药学上可接受的无机/有机酸或无机/有机碱反应而形成的盐，此类盐又被称为酸加成盐或碱加成盐。常见的无机酸包括(但不限于)盐酸、氢溴酸、硫酸、磷酸等，常见的有机酸包括(但不限于)三氟乙酸、柠檬酸、马来酸、富马酸、琥珀酸、酒石酸、乳酸、丙酮酸、草酸、甲酸、乙酸、苯甲酸、甲磺酸、苯磺酸、对甲苯磺酸等，常见的无机碱包括(但不限于)氢氧化钠、氢氧化钾、氢氧化钙、氢氧化钡等，常见的有机碱包括(但不限于)二乙胺、三乙胺、乙胺丁醇等。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention that is substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting the compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases. Such salts are also known as acid addition salts or Base addition salt. Common inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. Common organic acids include (but are not limited to) trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, and tartaric acid. , lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Common inorganic bases include (but are not limited to) sodium hydroxide, potassium hydroxide, calcium hydroxide , barium hydroxide, etc. Common organic bases include (but are not limited to) diethylamine, triethylamine, ethambutol, etc.
术语“立体异构体”(或称“旋光异构体”)是指由于具有至少一个手性因素(包括手性中心、手性轴、手性面等)而导致具有垂直的不对称平面，从而能够使平面偏振光旋转的稳定异构体。由于本发明化合物中存在可能导致立体异构的不对称中心以及其它化学结构，因此本发明也包括这些立体异构体及其混合物。由于本发明的化合物及其盐包括不对称碳原子，因而能够以单一立体异构体形式、外消旋物、对映异构体和非对映异构体的混合物形式存在。通常，这些化合物能够以外消旋混合物的形式制备。然而，如果需要的话，可以将这类化合物制备或分离后得到纯的立体异构体，即单一对映异构体或非对映异构体，或者单一立体异构体富集化(纯度≥98％、≥95％、≥93％、≥90％、≥88％、≥85％或≥80％)的混合物。化合物的单一立体异构体是由含有所需手性中心的旋光起始原料合成制备得到的，或者是通过制备得到对映异构体产物的混合物之后再分离或拆分制备得到的，例如转化为非对映异构体的混合物之后再进行分离或重结晶、色谱处理、使用手性拆分试剂，或者在手性色谱柱上将对映异构体进行直接分离。具有特定立体化学的起始化合物既可以商购得到，也可以按照下文中描述的方法制备再通过本领域熟知的方法拆分得到。The term "stereoisomer" (or "optical isomer") refers to having a vertical asymmetric plane due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), A stable isomer capable of rotating plane-polarized light. Since there are asymmetric centers and other chemical structures in the compounds of the present invention that may lead to stereoisomerism, the present invention also includes these stereoisomers and their mixtures. Since the compounds of the present invention and their salts include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, enantiomeric and diastereomeric mixtures. Generally, these compounds can be prepared in the form of racemic mixtures. However, if desired, such compounds can be prepared or isolated to obtain pure stereoisomers, that is, single enantiomers or diastereomers, or single stereoisomer enrichment (purity ≥ 98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%) mixtures. Single stereoisomers of a compound are prepared synthetically from optically active starting materials containing the desired chiral center, or by preparing mixtures of enantiomeric products followed by isolation or resolution, e.g. transformation A mixture of diastereomers is then separated or recrystallized, chromatographed, using chiral resolving reagents, or the enantiomers are separated directly on a chiral chromatography column. Starting compounds with specific stereochemistry are either commercially available or can be prepared as described below and resolved by methods well known in the art.
术语“互变异构体”(或称“互变异构形式”)是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(或称质子转移互变异构体)包括(但不限于)通过质子迁移来进行的互相转化，如酮-烯醇异构化、亚胺-烯胺异构化、酰胺-亚胺醇异构化等。除非另外指出，本发明的化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomers" (or "tautomeric forms") refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions through proton migration, such as keto-enol isomerization, imine-enamine isomerization chemical, amide-iminoalcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
术语“溶剂化物”是指由本发明的化合物或其药学上可接受的盐与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。常见的溶剂化物包括(但不限于)水合物、乙醇合物、丙酮合物等。The term "solvate" refers to a substance formed by the combination of a compound of the invention or a pharmaceutically acceptable salt thereof and at least one solvent molecule through non-covalent intermolecular forces. Common solvates include (but are not limited to) hydrates, ethanolates, acetones, etc.
术语“螯合物”是具有环状结构的配合物，是通过两个或多个配位体与同一金属离子形成螯合环的螯合作用而得到。The term "chelate" refers to a complex with a cyclic structure obtained by the chelation of two or more ligands with the same metal ion to form a chelate ring.
术语“非共价复合物”是通过化合物与另一分子的相互作用而形成的，其中该化合物与该分子之间不形成共价键。例如，可以通过范德华相互作用、氢键键合和静电相互作用(也称作离子键合)来发生复合。The term "non-covalent complex" is formed by the interaction of a compound with another molecule without forming a covalent bond between the compound and the molecule. For example, recombination can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
术语“前体药物”是指在适用于患者后能够直接或间接地提供本发明的化合物的衍生化合物。特别优选的衍生化合物或前药是在施用于患者时可以提高本发明的化合物的生物利用度的化合物(例如， 更易吸收入血)，或者促进母体化合物向作用位点(例如，淋巴系统)递送的化合物。除非另外指出，本发明的化合物的所有前药形式都在本发明的范围之内，且各种前药形式是本领域熟知的。The term "prodrug" refers to a derivative compound capable of providing, directly or indirectly, a compound of the invention when administered to a patient. Particularly preferred derivative compounds or prodrugs are compounds that increase the bioavailability of the compounds of the invention when administered to a patient (e.g., compounds that are more readily absorbed into the bloodstream), or that enhance the delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.
术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或环系)可以在特定情形下具有相同或不同的含义。例如，取代基X和取代基Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基，则当取代基X为氢时，取代基Y既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基；同理，当取代基Y为氢时，取代基X既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基。The term "each independently" means that at least two groups (or ring systems) present in the structure with the same or similar value ranges can have the same or different meanings under specific circumstances. For example, the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl. When the substituent X is hydrogen, the substituent Y can be either hydrogen, halogen, or hydroxyl, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.
术语“任选”或“任选地”是指随后描述的事件或情况可能发生或可能不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the absence of the stated event or circumstance.
术语“包含”和“包括”以其开放、非限制性意义使用。The terms "include" and "include" are used in their open, non-limiting sense.
术语“烷基”是指一价的直链或支链的脂肪族基团，其仅由碳原子和氢原子组成，不含有不饱和度，并且通过一个单键与其它片段连接，包括(但不限于)甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基和叔丁基等。例如，“C1-C24烷基”指包含1至24个碳原子的烷基。具体而言，术语“支链的C10-C15烷基”指包含10至15个碳原子的支链烷基，包括(但不限于)1-丁基庚-1-基和2-丁基辛-1-基等。The term "alkyl" refers to a monovalent straight or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing no unsaturation, and connected to other moieties by a single bond, including (but Not limited to) methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, etc. For example, "C 1 -C 24 alkyl" refers to an alkyl group containing 1 to 24 carbon atoms. Specifically, the term "branched C 10 -C 15 alkyl" refers to branched alkyl groups containing 10 to 15 carbon atoms, including (but not limited to) 1-butylhept-1-yl and 2-butyloctyl. -1-base etc.
术语“亚烷基”是指二价的直链或支链的脂肪族基团，其仅由碳原子和氢原子组成，不含有饱和度，并且通过两个单键分别与其它片段连接，包括(但不限于)亚甲基、1,2-亚乙基、1,3-亚丙基和1,4-亚丁基等。例如，“C1-C24亚烷基”指包含1至24个碳原子的亚烷基。The term "alkylene" refers to a divalent straight-chain or branched aliphatic group, which consists only of carbon atoms and hydrogen atoms, does not contain saturation, and is connected to other fragments through two single bonds, including (But not limited to) methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, etc. For example, "C 1 -C 24 alkylene" refers to an alkylene group containing 1 to 24 carbon atoms.
术语“杂烷基”是指一价的直链或支链的脂肪族基团，其由碳原子、氢原子和1至3个各自独立地为N、NH、O、S、S(＝O)或S(＝O)2的杂原子(或杂原子团)组成，并且通过一个单键与其它片段连接，包括(但不限于)4-氧杂庚-1-基(即3-(丙氧基)丙-1-基)、7-氧杂辛-1-基(即6-(甲氧基)己-1-基)、2-氧杂己-1-基(即(丁氧基)甲基)和4-氮杂-4-甲基戊-1-基(即3-(二甲氨基)丙-1-基)等。例如，“C1-C24杂烷基”指包含1至24个碳原子和1至3个各自独立地为N、NH、O、S、S(＝O)或S(＝O)2的杂原子(或杂原子团)的杂烷基。The term "heteroalkyl" refers to a monovalent linear or branched aliphatic group, which consists of carbon atoms, hydrogen atoms and 1 to 3 independently N, NH, O, S, S (=O ) or S(=O) 2 heteroatoms (or heteroatom groups), and are connected to other fragments through a single bond, including (but not limited to) 4-oxepan-1-yl (i.e. 3-(propoxy base) prop-1-yl), 7-oxa-1-yl (i.e. 6-(methoxy)hex-1-yl), 2-oxa-1-yl (i.e. (butoxy) Methyl) and 4-aza-4-methylpent-1-yl (i.e. 3-(dimethylamino)propan-1-yl), etc. For example, "C 1 -C 24 heteroalkyl" refers to a group containing 1 to 24 carbon atoms and 1 to 3 each independently N, NH, O, S, S(=O), or S(=O) 2 Heteroalkyl groups of heteroatoms (or heteroatom groups).
术语“亚杂烷基”是指二价的直链或支链的脂肪族基团，其由碳原子、氢原子和1至3个各自独立地为N、NH、O、S、S(＝O)或S(＝O)2的杂原子(或杂原子团)组成，并且通过两个单键分别与其它片段连接，包括(但不限于)4-氮杂-4-甲基-1,7-亚庚基和3,4-二硫杂-1,6-亚己基等。例如，“C1-C24亚杂烷基”指包含1至24个碳原子和1至3个各自独立地为N、NH、O、S、S(＝O)或S(＝O)2的杂原子(或杂原子团)的亚杂烷基。The term "heteroalkylene" refers to a divalent straight-chain or branched aliphatic group, which consists of carbon atoms, hydrogen atoms and 1 to 3 independently N, NH, O, S, S (= O) or S(=O) 2 heteroatoms (or heteroatom groups), and are connected to other fragments through two single bonds, including (but not limited to) 4-aza-4-methyl-1,7 -Heptylene and 3,4-dithia-1,6-hexylene, etc. For example, "C 1 -C 24 heteroalkylene" refers to a group containing 1 to 24 carbon atoms and 1 to 3 each independently N, NH, O, S, S(=O), or S(=O) 2 heteroalkylene group of heteroatoms (or heteroatom groups).
术语“烯基”是指一价的直链或支链的脂肪族基团，其仅由碳原子和氢原子组成，含有至少一个双键，并且通过一个单键与其它片段连接，包括(但不限于)乙烯基、丙烯基、烯丙基等基团。例如“C2-C24烯基”指包含2至24个碳原子的烯基。The term "alkenyl" refers to a monovalent linear or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, and connected to other moieties by a single bond, including (but Not limited to) vinyl, propenyl, allyl and other groups. For example, "C 2 -C 24 alkenyl" refers to an alkenyl group containing 2 to 24 carbon atoms.
术语“亚烯基”是指二价的直链或支链的脂肪族基团，其仅由碳原子和氢原子组成，含有至少一个双键，并且通过两个单键分别与其它片段连接，包括(但不限于)等。例如，“C2-C24亚烯基”指包含2至24个碳原子的亚烯基。The term "alkenylene" refers to a divalent straight-chain or branched aliphatic group, which consists only of carbon atoms and hydrogen atoms, contains at least one double bond, and is connected to other segments through two single bonds, including but not limited to) wait. For example, "C 2 -C 24 alkenylene" refers to an alkenylene group containing 2 to 24 carbon atoms.
术语“炔基”是指一价的直链或支链的脂肪族基团，其仅由碳原子和氢原子组成，含有至少一个叁键，并且通过一个单键与其它片段连接，包括(但不限于)乙炔基、丙炔基、炔丙基和4-戊炔-1-基等基团。例如“C2-C24炔基”指包含2至24个碳原子的炔基。The term "alkynyl" refers to a monovalent linear or branched aliphatic group consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond, and connected to other moieties by a single bond, including (but Without limitation) groups such as ethynyl, propynyl, propargyl and 4-pentyn-1-yl. For example, "C 2 -C 24 alkynyl" refers to an alkynyl group containing 2 to 24 carbon atoms.
术语“环烷基”是指一价的单环或多环(例如稠环、桥环或螺环)的脂肪族基团，其仅由碳原子和氢原子组成，并且通过一个单键与其它片段连接，包括(但不限于)环丙基、环丁基、环戊基和环己基等。例如，“C3-C24烷基”指包含3至24个成环原子的环烷基。The term "cycloalkyl" refers to a monovalent monocyclic or polycyclic (such as fused, bridged or spirocyclic) aliphatic group consisting only of carbon atoms and hydrogen atoms and bonded to other atoms through a single bond. Fragment linkages include (but are not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. For example, "C 3 -C 24 alkyl" refers to a cycloalkyl group containing 3 to 24 ring atoms.
术语“杂环烷基”是指一价的单环或多环(例如稠环、桥环或螺环)的脂肪族基团，其由碳原子、氢原子和1至3个各自独立地为N、NH、O、S、S(＝O)或S(＝O)2的杂原子(或杂原子团)组成，并且通过一个单键与其它片段连接，包括(但不限于)吡咯烷-1-基、哌啶-1-基和4-甲基哌嗪-1-基等。例如，“3-24元杂环烷基”指包含3至24个成环原子(或杂原子团)的杂环烷基。 The term "heterocycloalkyl" refers to a monovalent monocyclic or polycyclic (such as fused, bridged or spirocyclic) aliphatic group, which consists of carbon atoms, hydrogen atoms and 1 to 3 independently Composed of heteroatoms (or heteroatom groups) of N, NH, O, S, S(=O) or S(=O) 2 and connected to other fragments through a single bond, including (but not limited to) pyrrolidine-1 -yl, piperidin-1-yl and 4-methylpiperazin-1-yl, etc. For example, "3-24 membered heterocycloalkyl" refers to a heterocycloalkyl group containing 3 to 24 ring atoms (or heteroatom groups).
术语“芳基”是指一价的单环或多环(例如二环、三环或四环)芳香族基团，其仅由碳原子和氢原子组成，并且通过一个单键与其它片段连接，包括(但不限于)苯基、萘基、蒽基和菲基等。例如，“C6-C10芳基”指包含6至10个成环原子的芳基。The term "aryl" refers to a monovalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group consisting only of carbon atoms and hydrogen atoms and connected to other moieties by a single bond , including (but not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, etc. For example, "C 6 -C 10 aryl" refers to an aryl group containing 6 to 10 ring atoms.
术语“亚芳基”是指二价的单环或多环(例如二环、三环或四环)芳香族基团，其仅由碳原子和氢原子组成，并且通过二个单键与其它片段连接，包括(但不限于)1,4-亚苯基、1,4-亚萘基、9,10-亚蒽基和9,10-亚菲基等。例如，“C6-C10亚芳基”指包含6至10个成环原子的亚芳基。The term "arylene" refers to a divalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group, which consists only of carbon atoms and hydrogen atoms, and is bonded to other atoms through two single bonds. Fragment connection includes (but is not limited to) 1,4-phenylene, 1,4-naphthylene, 9,10-anthracenylene, 9,10-phenylene, etc. For example, "C 6 -C 10 arylene" refers to an arylene group containing 6 to 10 ring atoms.
术语“杂芳基”是指一价的单环或多环(例如二环、三环或四环)芳香族基团，其由碳原子、氢原子和1至3个各自独立地为N、NH、O、S、S(＝O)或S(＝O)2的杂原子(或杂原子团)组成，并且通过一个单键与其它片段连接，包括(但不限于)吡唑基(如1H-咪唑-1-基)、噁唑基(如噁唑-2-基)和噻唑基(如噻唑-4-基)等。例如，“5-10元杂芳基”指包含5至10个成环原子(或杂原子团)的杂芳基。The term "heteroaryl" refers to a monovalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group, which consists of carbon atoms, hydrogen atoms and 1 to 3 independently N, Composed of heteroatoms (or heteroatom groups) of NH, O, S, S(=O) or S(=O) 2 , and are connected to other fragments through a single bond, including (but not limited to) pyrazolyl (such as 1H -imidazol-1-yl), oxazolyl (such as oxazol-2-yl) and thiazolyl (such as thiazol-4-yl), etc. For example, "5-10 membered heteroaryl" refers to a heteroaryl group containing 5 to 10 ring atoms (or heteroatom groups).
术语“亚杂芳基”是指二价的单环或多环(例如二环、三环或四环)芳香族基团，其由碳原子、氢原子和1至3个各自独立地为N、NH、O、S、S(＝O)或S(＝O)2的杂原子(或杂原子团)组成，并且通过两个单键与其它片段连接，包括(但不限于)亚吡唑基(如1,4-亚咪唑基)、噁唑基(如2,4-亚噁唑基)和噻唑基(如2,5-亚噻唑基)等。例如，“5-10元亚杂芳基”指包含5至10个成环原子(或杂原子团)的亚杂芳基。The term "heteroarylene" refers to a bivalent monocyclic or polycyclic (such as bicyclic, tricyclic or tetracyclic) aromatic group, which consists of carbon atoms, hydrogen atoms and 1 to 3 independently N , NH, O, S, S (=O) or S (=O) 2 heteroatoms (or heteroatom groups), and are connected to other fragments through two single bonds, including (but not limited to) pyrazolylene (such as 1,4-imidazolyl), oxazolyl (such as 2,4-oxazolyl) and thiazolyl (such as 2,5-thiazolyl), etc. For example, "5-10 membered heteroarylene" refers to a heteroarylene group containing 5 to 10 ring atoms (or heteroatom groups).
术语“羟基”是指-OH基团。The term "hydroxy" refers to the -OH group.
术语“氧代基”是指＝O基团。The term "oxo" refers to an =O group.
[通式化合物][Compound of general formula]
本发明提供了式(I)化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，
The invention provides compounds of formula (I) or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs thereof,
其中：in:
X为其中：X is in:
Ra和Ra’各自独立地为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；或者，Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl or ,
Ra和Ra’各自独立地为或者，Ra and Ra' are independently or,
Ra和Ra’相互连接成Z；Ra and Ra’ are connected to each other to form Z;
每一个Z各自独立地为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group;
W为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；或者， W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
W为 W is
每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-、-C(＝O)NR2-、-NR2C(＝O)NR2-、-OC(＝O)NR2-、-NR2C(＝O)O-或-O(C＝O)O-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)-, -C(=O)NR 2 -, -NR 2 C( =O)NR 2 -, -OC(=O)NR 2 -, -NR 2 C(=O)O- or -O(C=O)O-;
每一个R1各自独立地为C1-C24烷基或C2-C24烯基；Each R 1 is independently C 1- C 24 alkyl or C 2- C 24 alkenyl;
每一个R2各自独立地为氢或C1-C24烷基；Each R 2 is independently hydrogen or C 1- C 24 alkyl;
每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；Each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group;
每一个m各自独立地为0或1；Each m is independently 0 or 1;
所述杂烷基、亚杂烷基、杂环烷基、杂芳基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heteroalkylene group, heterocycloalkyl group, heteroaryl group and heteroarylene group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N , NH, O, S, S(=O) or S(=O) 2 .
在一项实施方案中，式(I)中的Ra和Ra’各自独立地为氢、C1-C12烷基、C2-C12烯基、C2-C12炔基、C1-C12杂烷基、C3-C12环烷基、3-12元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-3个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，Ra和Ra’各自独立地为C1-C6烷基、C2-C6炔基、C1-C10杂烷基或3-10元杂环烷基，所述烷基、炔基、杂烷基和杂环烷基任选地被1-2个各自独立地选自羟基、氧代基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代。In one embodiment, Ra and Ra' in formula (I) are each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 - C 12 heteroalkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl , heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from 1 to 3 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 - Group substitution of C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl; preferably, Ra and Ra 'Each independently is C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 10 heteroalkyl or 3-10 membered heterocycloalkyl, the alkyl, alkynyl, heteroalkyl and heterocycloalkyl optionally substituted by 1-2 groups each independently selected from hydroxyl, oxo, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group replaced.
在一项实施方案中，式(I)中的每一个Z各自独立地为C1-C12亚烷基、C1-C12亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；优选地，每一个Z各自独立地为C1-C6亚烷基或C1-C6亚杂烷基。In one embodiment, each Z in Formula (I) is independently C 1 -C 12 alkylene, C 1 -C 12 heteroalkylene, C 6 -C 10 arylene, or 5- 10-membered heteroarylene group; preferably, each Z is independently a C 1 -C 6 alkylene group or a C 1 -C 6 heteroalkylene group.
在一项实施方案中，式(I)中的W为氢、C1-C12烷基、C2-C12烯基、C2-C12炔基、C1-C12杂烷基、C3-C12环烷基、3-12元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-3个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，W为C1-C12烷基或C1-C12杂烷基，所述烷基和杂烷基任选地被1-2个各自独立地选自3-10元杂环烷基的基团取代。In one embodiment, W in formula (I) is hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cyclic Alkyl, heterocycloalkyl, aryl and heteroaryl are optionally selected from 1 to 3 each independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 ring Alkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, W is C 1 -C 12 alkyl or C 1 -C 12 Heteroalkyl, said alkyl and heteroalkyl are optionally substituted by 1-2 groups each independently selected from 3-10 membered heterocycloalkyl.
在一项实施方案中，式(I)中的每一个R1各自独立地为C3-C24烷基或C3-C24烯基；优选地，每一个R1各自独立地为分支状C3-C24烷基或分支状C3-C24烯基。In one embodiment, each R 1 in formula (I) is independently C 3- C 24 alkyl or C 3- C 24 alkenyl; preferably, each R 1 is independently branched. C 3- C 24 alkyl or branched C 3- C 24 alkenyl.
在一项实施方案中，式(I)中的每一个R2各自独立地为氢或C1-C6烷基；优选地，每一个R2各自独立地为氢或C1-C4烷基。In one embodiment, each R 2 in formula (I) is independently hydrogen or C 1- C 6 alkyl; preferably, each R 2 is independently hydrogen or C 1- C 4 alkyl base.
在一项实施方案中，式(I)中的每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-。In one embodiment, each A 1 , A 2 , A 3 and A 4 in Formula (I) are each independently -O(C=O)-, -(C=O)O-, -C (=O)-, -O-, -S(O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C (=O)NR 2 -; Preferably, each A 1 , A 2 , A 3 and A 4 are independently -O(C=O)-, -(C=O)O-, -O-, -SS-, -NR 2 C(=O)- or -C(=O)NR 2 -.
在一项实施方案中，式(I)中的每一个B1、B2、B3和B4各自独立地为C1-C6亚烷基或C2-C6亚烯基；优选地，每一个B1、B2、B3和B4各自独立地为C1-C4亚烷基或C2-C4亚烯基。In one embodiment, each B 1 , B 2 , B 3 and B 4 in formula (I) is each independently C 1 -C 6 alkylene or C 2 -C 6 alkenylene; preferably , each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 4 alkylene group or a C 2 -C 4 alkenylene group.
在一些实施方案中，式(I)化合物具有如式(I-1)或式(I-1’)所示的结构：

In some embodiments, a compound of Formula (I) has a structure shown in Formula (I-1) or Formula (I-1'):

其中：in:
Ra为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，Ra为C1-C12烷基，优选C1-C6烷基；Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, preferably C 1 -C 6 alkyl;
W为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，W为C1-C12烷基，优选C1-C6烷基；W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, W is C 1 -C 12 alkyl, preferably C 1 -C 6 alkyl;
A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S(O) -, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, A 1 , A 2. A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -SS-, -NR 2 C(＝O)- or -C(＝O)NR 2- ;
R1为C1-C24烷基或C2-C24烯基；优选地，R1为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；R 1 is C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
每一个R2各自独立地为氢或C1-12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
所述杂烷基、杂环烷基和杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heterocycloalkyl group and heteroaryl group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N, NH, O, S, S (= O) or S(=O) 2 .
在一些实施方案中，式(I)化合物具有如式(I-2)或式(I-2’)所示的结构：
In some embodiments, a compound of Formula (I) has a structure shown in Formula (I-2) or Formula (I-2'):
其中：in:
Ra为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，Ra为C1-C12烷基、C2-C12炔基、C1-C12杂烷基、C3-C12环烷基或3-12元杂环烷基，所述烷基、炔基、杂烷基、环烷基和杂环烷基任选地被1-4个各自独立地选自羟基、氧代基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；更优选地，Ra为C1-C6烷基、C2-C6炔基、C1-C6杂烷基、C3-C6环烷基或3-6元杂环烷基， 所述烷基、炔基、杂烷基、环烷基和杂环烷基任选地被1-2个各自独立地选自羟基、氧代基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl or 3-12 membered heterocycloalkyl, the alkyl, alkynyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups are optionally replaced by 1-4 each is independently selected from a hydroxyl group, an oxo group, a C 3 -C 8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group; More preferably, Ra is C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocycloalkyl, The alkyl group, alkynyl group, heteroalkyl group, cycloalkyl group and heterocycloalkyl group are optionally selected from 1 to 2 groups independently selected from hydroxyl, oxo group, C 3 -C 8 cycloalkyl, 3- 8-membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution;
每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, each A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -O-, -SS-, -NR 2 C(＝O)- or -C(=O)NR 2 -;
每一个R1各自独立地为C1-C24烷基或C2-C24烯基；优选地，每一个R1各自独立地为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
每一个R2各自独立地为氢或C1-C12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，每一个B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
所述杂烷基、杂环烷基和杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heterocycloalkyl group and heteroaryl group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N, NH, O, S, S (= O) or S(=O) 2 .
在一些实施方案中，式(I)化合物具有如式(I-3)或式(I-3’)所示的结构：
In some embodiments, a compound of Formula (I) has a structure shown in Formula (I-3) or Formula (I-3'):
其中：in:
每一个Z各自独立地为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；优选地，每一个Z各自独立地为C1-C12亚烷基，优选C1-C6亚烷基；Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group; preferably, each Z Each independently is C 1 -C 12 alkylene, preferably C 1 -C 6 alkylene;
W为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，W为C1-C12烷基或C1-C12杂烷基，所述烷基和杂烷基任选地被1-4个各自独立地选自C3-C8环烷基或3-8元杂环烷基的基团取代；更优选地，W为C1-C8烷基或C1-C8杂烷基，所述烷基和杂烷基任选地被1-2个各自独立地选自C3-C8环烷基或3-8元杂环烷基的基团取代；W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; Preferably, W is C 1 -C 12 alkyl or C 1 -C 12 heteroalkyl, the alkyl and heteroalkyl groups are optional Optionally substituted by 1-4 groups each independently selected from C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl; more preferably, W is C 1 -C 8 alkyl or C 1 -C 8 heteroalkyl, the alkyl and heteroalkyl groups are optionally substituted by 1-2 groups each independently selected from C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl;
A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，A1、A2、A3和A4各自独立地为-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S(O) -, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, A 1 , A 2 , A 3 and A 4 are each independently -SS-, -NR 2 C(=O)- or -C(=O)NR 2 -;
R1为C1-C24烷基或C2-C24烯基；优选地，R1为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；R 1 is C 1- C 24 alkyl or C 2- C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
每一个R2各自独立地为氢或C1-12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
所述杂烷基、亚杂烷基、杂环烷基、杂芳基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heteroalkylene group, heterocycloalkyl group, heteroaryl group and heteroarylene group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N , NH, O, S, S(=O) or S(=O) 2 .
在一些实施方案中，式(I)化合物具有如式(I-4)或式(I-4’)所示的结构：
In some embodiments, a compound of Formula (I) has a structure shown in Formula (I-4) or Formula (I-4'):
其中：in:
Ra和Ra’各自独立地为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，Ra和Ra’各自独立地为C1-C12烷基，所述烷基任选地被1-4个羟基取代；更优选地，Ra和Ra’各自独立地为C1-C6烷基，所述烷基任选地被1-2个羟基取代；Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl group substituted by a base, a 3-10 membered heterocycloalkyl group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group; preferably, Ra and Ra' are each independently a C 1 -C 12 alkyl group, The alkyl group is optionally substituted by 1-4 hydroxyl groups; more preferably, Ra and Ra' are each independently a C 1 -C 6 alkyl group, and the alkyl group is optionally substituted by 1-2 hydroxyl groups;
Z为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；优选地，Z为C1-C12亚烷基或C1-C12亚杂烷基，优选C1-C6亚烷基或C1-C6亚杂烷基；Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 6 alkylene or C 1 -C 6 heteroalkylene;
每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, each A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -SS-, -NR 2 C(＝O)- or -C( ＝O)NR 2 -;
每一个R1各自独立地为C1-C24烷基或C2-C24烯基；优选地，每一个R1各自独立地为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
每一个R2各自独立地为氢或C1-C12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，每一个B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
所述杂烷基、亚杂烷基、杂环烷基、杂芳基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heteroalkylene group, heterocycloalkyl group, heteroaryl group and heteroarylene group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N , NH, O, S, S(=O) or S(=O) 2 .
在一些实施方案中，式(I)化合物具有如式(I-5)或式(I-5’)所示的结构：
In some embodiments, a compound of Formula (I) has a structure shown in Formula (I-5) or Formula (I-5'):
其中：in:
Z为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；优选地，Z为C1-C12亚烷基或C1-C12亚杂烷基，优选C1-C8亚烷基或C1-C8亚杂烷基；Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 8 alkylene or C 1 -C 8 heteroalkylene;
每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、 -C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-、-SS-、 -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, each of A 1 , A 2 , A 3 and A 4 are each independently -O(C=O)-, -(C=O)O-, -O-, -SS-, -NR 2 C(=O)- or -C(=O)NR 2- ;
每一个R1各自独立地为C1-C24烷基或C2-C24烯基；优选地，每一个R1各自独立地为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
每一个R2各自独立地为氢或C1-C12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1- C 12 alkyl; preferably, each R 2 is independently hydrogen;
每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，每一个B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
所述亚杂烷基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkylene and heteroarylene groups each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N, NH, O, S, S (=O) or S(=O) 2 .
在一些具体的实施方案中，每一个各自独立地选自下列片段：
In some specific embodiments, each Each is independently selected from the following clips:
在一些具体的实施方案中，每一个Z各自独立地选自下列片段：
In some specific embodiments, each Z is independently selected from the following fragments:
在一些具体的实施方案中，X选自下列片段：
In some specific embodiments, X is selected from the following fragments:
[具体化合物][Specific compound]
本发明提供了落入通式化合物范围内的一系列具体化合物，包括(但不限于)：








The present invention provides a series of specific compounds falling within the scope of compounds of the general formula, including (but not limited to):








[脂质载体][Lipid carrier]
本发明提供了一种脂质载体，其包含上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物。该类脂质载体对核酸药物的包封效率高，大大提升了核酸药物在体内的递送效率。The invention provides a lipid carrier, which contains any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or Prodrugs. This type of lipid carrier has high encapsulation efficiency for nucleic acid drugs, which greatly improves the delivery efficiency of nucleic acid drugs in the body.
在一些实施方案中，上述脂质载体包含第一脂质化合物和第二脂质化合物，其中，第一脂质化合物包含上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物和任选的阳离子脂质，第二脂质化合物包含阴离子脂质、中性脂质、甾醇和两亲性脂质中的一种或两种以上的组合。In some embodiments, the above-mentioned lipid carrier includes a first lipid compound and a second lipid compound, wherein the first lipid compound includes any of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, Tautomers, solvates, chelates, non-covalent complexes or prodrugs and optionally cationic lipids, the second lipid compound comprising anionic lipids, neutral lipids, sterols and amphiphiles One or a combination of two or more lipids.
在一些具体的实施方案中，上述第一脂质化合物为上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物。In some specific embodiments, the above-mentioned first lipid compound is any one of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent compound thereof. Complex or prodrug.
在另一些具体的实施方案中，上述第一脂质化合物为上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物和阳离子脂质的组合。In other specific embodiments, the above-mentioned first lipid compound is any one of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-common Valent complexes or combinations of prodrugs and cationic lipids.
在一些具体的实施方案中，第二脂质化合物为中性脂质、甾醇和两亲性脂质的组合。In some specific embodiments, the second lipid compound is a combination of neutral lipids, sterols, and amphipathic lipids.
在另一些具体的实施方案中，第二脂质化合物为阴离子脂质、中性脂质、甾醇和两亲性脂质的组合。In other specific embodiments, the second lipid compound is a combination of anionic lipid, neutral lipid, sterol, and amphiphilic lipid.
在一些具体的实施方案中，上述阳离子脂质包括(但不限于)DLinDMA、DODMA、DLin-MC2-MPZ、DLin-KC2-DMA、DOTAP、C12-200、DC-Chol和DOTMA中的一种或两种以上的组合，优选DLin-KC2-DMA和DOTAP。In some specific embodiments, the above-mentioned cationic lipids include (but are not limited to) one of DLinDMA, DODMA, DLin-MC2-MPZ, DLin-KC2-DMA, DOTAP, C12-200, DC-Chol and DOTMA or A combination of two or more is preferred, DLin-KC2-DMA and DOTAP.
在一些具体的实施方案中，上述阴离子脂质包括(但不限于)磷脂酰丝氨酸、磷脂酰肌醇、磷脂 酸、磷脂酰甘油、DOPG、DOPS和二豆蔻酰磷脂酰甘油中的一种或两种以上的组合，优选DOPG和DOPS。In some specific embodiments, the above-mentioned anionic lipids include (but are not limited to) phosphatidylserine, phosphatidylinositol, phospholipid One or a combination of two or more of acid, phosphatidylglycerol, DOPG, DOPS and dimyristoylphosphatidylglycerol, preferably DOPG and DOPS.
在一些具体的实施方案中，上述中性脂质包括(但不限于)DOPE、DSPC、DPPC、DOPC、DPPG、POPC、POPE、DPPE、DMPE、DSPE和SOPE中的至少一种或其经阴离子或阳离子修饰基团修饰的脂质，优选DSPC。阴离子或阳离子修饰基团不作限定。In some specific embodiments, the above-mentioned neutral lipids include (but are not limited to) at least one of DOPE, DSPC, DPPC, DOPC, DPPG, POPC, POPE, DPPE, DMPE, DSPE and SOPE or its anionic or Lipids modified with cationic modifying groups are preferably DSPC. The anionic or cationic modifying group is not limited.
在一些具体的实施方案中，上述两亲性脂质包括(但不限于)PEG-DMG、PEG-c-DMG、PEG-C14、PEG-c-DMA、PEG-DSPE、PEG-PE、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油、吐温-20、吐温-80、PEG-DPG、PEG-s-DMG、DAA、PEG-c-DOMG和GalNAc-PEG-DSG中的一种或两种以上的组合，优选PEG-DMG和吐温-80。In some specific embodiments, the above-mentioned amphiphilic lipids include (but are not limited to) PEG-DMG, PEG-c-DMG, PEG-C14, PEG-c-DMA, PEG-DSPE, PEG-PE, PEG modified of ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, Tween-20, Tween-80, PEG-DPG, PEG-s-DMG, DAA, PEG-c-DOMG and GalNAc-PEG -One or a combination of two or more DSGs, preferably PEG-DMG and Tween-80.
在一些具体的实施方案中，在脂质载体中，第一脂质化合物、阴离子脂质、中性脂质、甾醇和两亲性脂质的摩尔比为(20～65):(0～20):(5～25):(25～55):(0.3～15)；示例性地，摩尔比可以为20:20:5:50:5、30:5:25:30:10、20:5:5:55:15、65:0:9.7:25:0.3等；其中，在第一脂质化合物中，上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物和阳离子脂质的摩尔比为(1～10):(0～10)；示例性地，摩尔比可以为1:1、1:2、1:5、1:7.5、1:10、2:1、5:1、7.5:1、10:1等。In some specific embodiments, in the lipid carrier, the molar ratio of the first lipid compound, anionic lipid, neutral lipid, sterol and amphipathic lipid is (20～65): (0～20 ):(5～25):(25～55):(0.3～15); For example, the molar ratio can be 20:20:5:50:5, 30:5:25:30:10, 20: 5:5:55:15, 65:0:9.7:25:0.3, etc.; wherein, in the first lipid compound, any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers The molar ratio of isomers, solvates, chelates, non-covalent complexes or prodrugs and cationic lipids is (1～10):(0～10); exemplarily, the molar ratio can be 1: 1, 1:2, 1:5, 1:7.5, 1:10, 2:1, 5:1, 7.5:1, 10:1, etc.
在一些更具体的实施方案中，在脂质载体中，第一脂质化合物、阴离子脂质、中性脂质、甾醇和两亲性脂质的摩尔比为(20～55):(0～13):(5～25):(25～51.5):(0.5～15)；其中，在第一脂质化合物中，上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物和阳离子脂质的摩尔比为(3～4):(0～5)。In some more specific embodiments, in the lipid carrier, the molar ratio of the first lipid compound, anionic lipid, neutral lipid, sterol and amphipathic lipid is (20～55): (0～ 13): (5～25): (25～51.5): (0.5～15); wherein, in the first lipid compound, any of the above compounds or their pharmaceutically acceptable salts, stereoisomers, The molar ratio of tautomers, solvates, chelates, non-covalent complexes or prodrugs and cationic lipids is (3~4):(0~5).
[核酸纳米粒组合物][Nucleic acid nanoparticle composition]
本发明提供了一种核酸纳米粒组合物，其包含上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物或上述的脂质载体，以及核酸药物。The invention provides a nucleic acid nanoparticle composition, which contains any of the above compounds or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, and non-covalent complexes thereof. drugs or prodrugs or the above-mentioned lipid carriers, as well as nucleic acid drugs.
在一些实施方案中，上述核酸药物包括(但不限于)DNA、siRNA、mRNA、dsRNA、反义核酸、反义寡核苷酸、微RNA、反义微RNA、antagomir、微RNA抑制剂、微RNA激活剂和免疫刺激性核酸中的一种或两种以上的组合。In some embodiments, the above-mentioned nucleic acid drugs include (but are not limited to) DNA, siRNA, mRNA, dsRNA, antisense nucleic acid, antisense oligonucleotide, microRNA, antisense microRNA, antagomir, microRNA inhibitor, microRNA One or a combination of two or more RNA activators and immunostimulatory nucleic acids.
在一些具体的实施方案中，上述核酸药物与上述任一种化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物的质量比为1:(3～40)。In some specific embodiments, the above-mentioned nucleic acid drug is combined with any of the above-mentioned compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent complexes or The mass ratio of prodrugs is 1:(3~40).
在另一些具体的实施方案中，上述核酸药物与上述脂质载体的质量比为1:(3～40)。In other specific embodiments, the mass ratio of the above-mentioned nucleic acid drug and the above-mentioned lipid carrier is 1: (3-40).
示例性地，上述质量比可以为1:3、1:5、1:10、1:15、1:20、1:30等。For example, the above mass ratio may be 1:3, 1:5, 1:10, 1:15, 1:20, 1:30, etc.
[药物制剂][Pharmaceutical preparations]
本发明提供了一种药物制剂，其包含上述任一化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，或上述脂质载体，或上述核酸脂质纳米粒组合物，以及药学上可接受的赋形剂、载体和稀释剂。The present invention provides a pharmaceutical preparation, which contains any of the above compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or precursor thereof Drug, or the above-mentioned lipid carrier, or the above-mentioned nucleic acid lipid nanoparticle composition, and pharmaceutically acceptable excipients, carriers and diluents.
在一些实施方案中，上述药物制剂的粒径为30～500nm；示例性地，粒径可以为30nm、50nm、100nm、150nm、250nm、350nm、500nm等。In some embodiments, the particle size of the above-mentioned pharmaceutical preparation is 30-500nm; exemplarily, the particle size can be 30nm, 50nm, 100nm, 150nm, 250nm, 350nm, 500nm, etc.
在一些具体的实施方案中，核酸药物在上述药物制剂中的包封率大于50％；示例性地，包封率可以为55％、60％、65％、70％、75％、79％、80％、85％、89％、90％、93％、95％等。In some specific embodiments, the encapsulation rate of nucleic acid drugs in the above-mentioned pharmaceutical preparations is greater than 50%; for example, the encapsulation rate can be 55%, 60%, 65%, 70%, 75%, 79%, 80%, 85%, 89%, 90%, 93%, 95%, etc.
[制备方法][Preparation]
下述实施例中所述实验方法，如无特殊说明，均为常规方法；所述试剂和材料，如无特殊说明，均可从商业途径获得。The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described can be obtained from commercial sources unless otherwise specified.
本发明中，“当量(eq)”比指的是溶剂或药品的摩尔比。In the present invention, the "equivalent (eq)" ratio refers to the molar ratio of solvent or drug.
本发明中，“适量的”指的是所加入溶剂量或药品量可调范围较大，且对合成结果影响较小，可以不作具体限定。In the present invention, "appropriate amount" means that the amount of solvent or drug added has a large adjustable range and has little impact on the synthesis result, and does not need to be specifically limited.
在下述的实施例中，所用溶剂和药品均为分析纯或化学纯；溶剂在使用前均经过重新蒸馏；无水溶剂均按照标准方法或文献方法进行处理。In the following examples, all solvents and drugs used are of analytical or chemical purity; all solvents are redistilled before use; all anhydrous solvents are processed according to standard methods or literature methods.
实施例1：化合物1的合成Example 1: Synthesis of Compound 1
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0 eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0 eq), stir for 10 minutes, then add 4-hydroxybutylacrylate (1.5eq), and stir at room temperature for 16 hours after addition. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物1。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 1.
1H-NMR(400MHz,CDCl3):δ4.17-4.06(m,16h),4.01-3.99(m,8H),2.81-2.78(m,8H),2.48-2.45(m,12H),2.41-2.31(m,18H),2.21(s,3H),1.92-1.83(m,4H),1.77-1.21(m,96H),0.98-0.87(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.17-4.06(m,16h),4.01-3.99(m,8H),2.81-2.78(m,8H),2.48-2.45(m,12H),2.41 -2.31(m,18H),2.21(s,3H),1.92-1.83(m,4H),1.77-1.21(m,96H),0.98-0.87(m,24H).
实施例2：化合物2的合成Example 2: Synthesis of Compound 2
将2-丁基辛酸(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入1,3-丙二醇(3.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve 2-butyloctanoic acid (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 1,3-propanediol ( 3.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入丁二酸(3.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物3。Dissolve intermediate product 2 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.2eq), stir at room temperature for 16h after addition. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
将中间产物3(5.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物2。Dissolve intermediate product 3 (5.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 2.
1H-NMR(400MHz,CDCl3):δ4.23-4.12(m,32H),2.81-2.78(m,8H),2.70-2.64(m,16h),2.55-2.51(m,16h),2.39-2.34(m,4H),2.28(s,3H),2.04-2.00(m,8H),1.80-1.19(m,84H),0.93-0.89(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.23-4.12(m,32H),2.81-2.78(m,8H),2.70-2.64(m,16h),2.55-2.51(m,16h),2.39 -2.34(m,4H),2.28(s,3H),2.04-2.00(m,8H),1.80-1.19(m,84H),0.93-0.89(m,24H).
实施例3：化合物3的合成Example 3: Synthesis of Compound 3
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctylamine (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), stir at room temperature for 16h after addition. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物3。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 3.
1H-NMR(400MHz,CDCl3):δ4.16-4.09(m,16h),3.98-3.89(m,8H),3.42-3.36(m,8H),2.69-2.11(m,35H),1.98-1.91(m,4H),1.78-1.19(m,100H),0.93-0.89(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.16-4.09(m,16h),3.98-3.89(m,8H),3.42-3.36(m,8H),2.69-2.11(m,35H),1.98 -1.91(m,4H),1.78-1.19(m,100H),0.93-0.89(m,24H).
实施例4：化合物4的合成Example 4: Synthesis of Compound 4
将2-丁基辛酸(1.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入3-氨基丙醇(3.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve 2-butyloctanoic acid (1.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 3-aminopropanol ( 3.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入丁二酸(3.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物3。Dissolve intermediate product 2 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.2eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
将中间产物3(5.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物4。Dissolve intermediate product 3 (5.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 4.
1H-NMR(400MHz,CDCl3):δ4.16-4.09(m,24H),3.98-3.89(m,8H),3.21-3.18(m,8H),2.77-2.74(m,16h),2.69-2.11(m,13H),1.78-1.19(m,92H),0.93-0.89(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.16-4.09 (m, 24H), 3.98-3.89 (m, 8H), 3.21-3.18 (m, 8H), 2.77-2.74 (m, 16h), 2.69 -2.11(m,13H),1.78-1.19(m,92H),0.93-0.89(m,24H).
实施例5：化合物5的合成Example 5: Synthesis of Compound 5
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将2-(羟基甲氧基)乙醇(5.0eq)溶解于适量的无水二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.0eq)，搅拌10min再加入三乙胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve 2-(hydroxymethoxy)ethanol (5.0eq) in an appropriate amount of anhydrous dichloromethane, slowly add acryloyl chloride (1.0eq) at 0°C, stir for 10 minutes, and then add triethylamine (1.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入中间产物2(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物3。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add intermediate product 2 (1.5eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
将中间产物3(5.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物5。Dissolve intermediate product 3 (5.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 5.
1H-NMR(400MHz,CDCl3):δ6.18-6.14(m,8H),4.18-4.14(m,16h),3.76-3.63(m,16h),2.49-2.16(m,35H),1.94-1.89(m,4H),1.79-1.17(m,82H),0.93-0.89(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ6.18-6.14(m,8H),4.18-4.14(m,16h),3.76-3.63(m,16h),2.49-2.16(m,35H),1.94 -1.89(m,4H),1.79-1.17(m,82H),0.93-0.89(m,24H).
实施例6：化合物6的合成Example 6: Synthesis of Compound 6
将胱胺二盐酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine dihydrochloride (2.0eq) in an appropriate amount of methylene chloride, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.0eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物6。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 6.
1H-NMR(400MHz,CDCl3):δ3.65-3.51(m,24H),2.83-2.79(m,16h),2.49-2.21(m,23H),1.56-1.17(m,68H),0.93-0.88(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.65-3.51(m,24H),2.83-2.79(m,16h),2.49-2.21(m,23H),1.56-1.17(m,68H),0.93 -0.88(m,24H).
实施例7：化合物10的合成Example 7: Synthesis of Compound 10
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入1-(3-氨基丙基)咪唑(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物10。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add 1-(3-aminopropyl)imidazole (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 10.
1H-NMR(400MHz,CDCl3):δ7.63(s,1H),7.13(s,1H),6.94(s,1H),4.23-4.24(m,2H),3.65-3.52(m,12H),2.83-2.79(m,8H),2.45-2.27(m,10H),1.48-1.17(m,32H),0.93-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ7.63(s,1H),7.13(s,1H),6.94(s,1H),4.23-4.24(m,2H),3.65-3.52(m,12H ),2.83-2.79(m,8H),2.45-2.27(m,10H),1.48-1.17(m,32H),0.93-0.88(m,12H).
实施例8：化合物11的合成Example 8: Synthesis of Compound 11
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入乙醇胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物11。 Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add ethanolamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 11.
1H-NMR(400MHz,CDCl3):δ4.46-4.19(m,12h),3.98-3.89(m,4H),3.42-3.36(m,2H),2.69-2.11(m,16H),1.78-1.19(m,48H),0.93-0.89(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.46-4.19(m,12h),3.98-3.89(m,4H),3.42-3.36(m,2H),2.69-2.11(m,16H),1.78 -1.19(m,48H),0.93-0.89(m,12H).
实施例9：化合物12的合成Example 9: Synthesis of Compound 12
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入乙醇胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物12。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add ethanolamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 12.
1H-NMR(400MHz,CDCl3):δ3.65-3.41(m,14H),2.83-2.80(m,8H),2.61-2.24(m,8H),1.48-1.17(m,32H),0.93-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.65-3.41(m,14H),2.83-2.80(m,8H),2.61-2.24(m,8H),1.48-1.17(m,32H),0.93 -0.88(m,12H).
实施例10：化合物15的合成Example 10: Synthesis of Compound 15
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入4-氨基丁醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物15。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add 4-aminobutanol (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 15.
1H-NMR(400MHz,CDCl3):δ4.46-4.19(m,12h),3.98-3.89(m,4H),3.58-3.49(m,2H),3.02-2.95(m,2H),2.69-2.11(m,14H),1.78-1.19(m,52H),0.93-0.89(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.46-4.19(m,12h),3.98-3.89(m,4H),3.58-3.49(m,2H),3.02-2.95(m,2H),2.69 -2.11(m,14H),1.78-1.19(m,52H),0.93-0.89(m,12H).
实施例11：化合物21的合成Example 11: Synthesis of Compound 21
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入2-(4-甲基哌嗪-1-基)乙胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物21。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add 2-(4-methylpiperazin-1-yl)ethylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain compound 21.
1H-NMR(400MHz,CDCl3):δ4.46-4.19(m,12h),3.98-3.89(m,4H),2.62-2.01(m,29H),1.78-1.19(m,48H),0.93-0.89(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.46-4.19 (m, 12h), 3.98-3.89 (m, 4H), 2.62-2.01 (m, 29H), 1.78-1.19 (m, 48H), 0.93 -0.89(m,12H).
实施例12：化合物22的合成Example 12: Synthesis of Compound 22
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入N,N’-双(2-羟乙基)乙二胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物22。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add N,N'-bis(2-hydroxyethyl)ethylenediamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 22.
1H-NMR(400MHz,CDCl3):δ4.24-4.04(m,12H),3.79-3.78(m,4H),3.04-2.98(m,4H),2.59-2.24 (m,20H),1.94-1.88(m,2H),1.59-1.21(m,48H),0.89-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.24-4.04(m,12H),3.79-3.78(m,4H),3.04-2.98(m,4H),2.59-2.24 (m,20H),1.94-1.88(m,2H),1.59-1.21(m,48H),0.89-0.88(m,12H).
实施例13：化合物26的合成Example 13: Synthesis of Compound 26
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入N-丙基丁胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物26。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add N-propylbutylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 26.
1H-NMR(400MHz,CDCl3):δ3.65-3.41(m,6H),3.04-2.99(m,2H),2.84-2.76(m,4H),2.50-2.44(m,4H),2.24-2.20(m,1H),1.49-1.11(m,22H),0.89-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.65-3.41(m,6H),3.04-2.99(m,2H),2.84-2.76(m,4H),2.50-2.44(m,4H),2.24 -2.20(m,1H),1.49-1.11(m,22H),0.89-0.88(m,12H).
实施例14：化合物28的合成Example 14: Synthesis of Compound 28
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入N,N’-双(2-羟乙基)乙二胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物28。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add N,N'-bis(2-hydroxyethyl)ethylenediamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 28.
1H-NMR(400MHz,CDCl3):δ3.65-3.41(m,16h),2.83-2.80(m,8H),2.61-2.24(m,14H),1.48-1.17(m,32H),0.93-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.65-3.41(m,16h),2.83-2.80(m,8H),2.61-2.24(m,14H),1.48-1.17(m,32H),0.93 -0.88(m,12H).
实施例15：化合物30的合成Example 15: Synthesis of Compound 30
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入N-异丙基-N-(2-(哌嗪-1-基)乙基)丙-2-胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物30。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add N-isopropyl-N-(2-(piperazin-1-yl)ethyl)propan-2-amine (1.0eq), and complete the addition. Stir at room temperature for 16h. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 30.
1H-NMR(400MHz,CDCl3):δ3.65-3.61(m,2H),3.53-3.50(m,4H),2.84-2.69(m,6H),2.53-2.51(m,2H),2.37-2.23(m,13H),1.49-1.14(m,16h),1.01-0.88(m,18H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.65-3.61(m,2H),3.53-3.50(m,4H),2.84-2.69(m,6H),2.53-2.51(m,2H),2.37 -2.23(m,13H),1.49-1.14(m,16h),1.01-0.88(m,18H).
实施例16：化合物32的合成Example 16: Synthesis of Compound 32
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入N-(3-氨基丙基)二甲醇胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物32。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add N-(3-aminopropyl)dimethanolamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 32.
1H-NMR(400MHz,CDCl3):δ4.61-4.58(m,4H),4.24-4.04(m,12H),3.79-3.78(m,4H),2.48-2.24(m,16h),1.94-1.88(m,2H),1.59-1.21(m,50H),0.89-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.61-4.58(m,4H),4.24-4.04(m,12H),3.79-3.78(m,4H),2.48-2.24(m,16h),1.94 -1.88(m,2H),1.59-1.21(m,50H),0.89-0.88(m,12H).
实施例17：化合物36的合成Example 17: Synthesis of Compound 36
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入(4-氨基哌嗪-1-基)甲醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物36。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add (4-aminopiperazin-1-yl)methanol (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 36.
1H-NMR(400MHz,CDCl3):δ4.61-4.58(m,2H),4.24-4.04(m,12H),2.94-2.85(m,4H),2.64-2.24(m,20H),1.94-1.88(m,2H),1.59-1.21(m,48H),0.89-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.61-4.58(m,2H),4.24-4.04(m,12H),2.94-2.85(m,4H),2.64-2.24(m,20H),1.94 -1.88(m,2H),1.59-1.21(m,48H),0.89-0.88(m,12H).
实施例18：化合物38的合成Example 18: Synthesis of Compound 38
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入胱胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物38。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add cystamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 38.
1H-NMR(400MHz,CDCl3):δ4.48-4.14(m,24H),3.79-3.73(m,8H),2.76-2.24(m,32H),1.94-1.88(m,4H),1.59-1.21(m,96H),0.89-0.88(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.48-4.14(m,24H),3.79-3.73(m,8H),2.76-2.24(m,32H),1.94-1.88(m,4H),1.59 -1.21(m,96H),0.89-0.88(m,24H).
实施例19：化合物41的合成Example 19: Synthesis of Compound 41
将己二酸(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve adipic acid (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanol (1.0 eq), after addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.5eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入4-(氨基甲氧基)丁醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物41。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add 4-(aminomethoxy)butanol (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 41.
1H-NMR(400MHz,CDCl3):δ4.48-4.04(m,14H),3.76-3.61(m,6H),3.42-3.33(m,2H),2.51-2.24(m,12H),1.94-1.88(m,2H),1.59-1.21(m,52H),0.89-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.48-4.04(m,14H),3.76-3.61(m,6H),3.42-3.33(m,2H),2.51-2.24(m,12H),1.94 -1.88(m,2H),1.59-1.21(m,52H),0.89-0.88(m,12H).
实施例20：化合物43的合成Example 20: Synthesis of Compound 43
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入N-(3-氨基丙基)二甲醇胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物43。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add N-(3-aminopropyl)dimethanolamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 43.
1H-NMR(400MHz,CDCl3):δ4.63-4.60(m,4H),3.65-3.51(m,12H),2.83-2.79(m,8H),2.49-2.21(m,10H),1.56-1.17(m,34H),0.93-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ4.63-4.60(m,4H),3.65-3.51(m,12H),2.83-2.79(m,8H),2.49-2.21(m,10H),1.56 -1.17(m,34H),0.93-0.88(m,12H).
实施例21：化合物45的合成 Example 21: Synthesis of Compound 45
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入N1,N3-二甲基丙-1,3-二胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物45。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add N 1 , N 3 -dimethylpropane-1,3-diamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 45.
1H-NMR(400MHz,CDCl3):δ3.65-3.51(m,12H),2.83-2.79(m,8H),2.49-2.21(m,16h),1.56-1.17(m,34H),0.93-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.65-3.51(m,12H),2.83-2.79(m,8H),2.49-2.21(m,16h),1.56-1.17(m,34H),0.93 -0.88(m,12H).
实施例22：化合物47的合成Example 22: Synthesis of Compound 47
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入(4-氨基哌嗪)-1-甲醇(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物47。1H-NMR(400MHz,CDCl3):δ4.92-4.89(m,2H),3.54-3.48(m,8H),2.83-2.79(m,12H),2.62-2.55(m,8H),2.34-2.27(m,6H),1.56-1.17(m,32H),0.93-0.88(m,12H)。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add (4-aminopiperazine)-1-methanol (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 47. 1 H-NMR (400MHz, CDCl 3 ): δ4.92-4.89(m,2H),3.54-3.48(m,8H),2.83-2.79(m,12H),2.62-2.55(m,8H),2.34 -2.27(m,6H),1.56-1.17(m,32H),0.93-0.88(m,12H).
实施例23：化合物49的合成Example 23: Synthesis of Compound 49
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(5.0eq)溶解于适量的甲醇中，加入胱胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物49。Dissolve intermediate product 2 (5.0eq) in an appropriate amount of methanol, add cystamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 49.
1H-NMR(400MHz,CDCl3):δ3.65-3.51(m,26H),2.83-2.79(m,16h),2.64-2.48(m,16h),2.64-2.48(m,4H),1.56-1.17(m,64H),0.93-0.88(m,24H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.65-3.51(m,26H),2.83-2.79(m,16h),2.64-2.48(m,16h),2.64-2.48(m,4H),1.56 -1.17(m,64H),0.93-0.88(m,24H).
实施例24：化合物53的合成Example 24: Synthesis of Compound 53
将2-叔丁氧羰基氨基乙硫醇(1.0eq)溶解于适量的二氯甲烷和甲醇(V/V＝1/1)中，边搅拌边缓慢加入2-巯基乙醇(10.0eq)，搅拌4h，再把碘(0.1eq)用甲醇溶解，缓慢加入反应中，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到中间产物1。Dissolve 2-tert-butoxycarbonylaminoethanethiol (1.0eq) in an appropriate amount of dichloromethane and methanol (V/V=1/1), slowly add 2-mercaptoethanol (10.0eq) while stirring, and stir 4h, then dissolve iodine (0.1eq) in methanol, slowly add it to the reaction, and stir at room temperature for 16h after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(1.0eq)溶解于适量的乙酸乙酯中，加入4M盐酸的乙酸乙酯溶液(6V)。室温搅拌2h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物3。Intermediate product 2 (1.0eq) was dissolved in an appropriate amount of ethyl acetate, and 4M hydrochloric acid in ethyl acetate solution (6V) was added. Stir at room temperature for 2h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
将中间产物3(1.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物4。 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.5eq) ), stir at room temperature for 16 hours after addition. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
将中间产物4(6.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物53。Dissolve intermediate product 4 (6.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 53.
1H-NMR(400MHz,CDCl3):δ3.95-3.91(m,8H),3.86-3.83(m,8H),3.55-3.50(m,8H),2.84-2.76(m,16H),2.50-2.44(m,20H),2.15(s,3H),1.49-1.11(m,68H),0.89-0.88(m,24H)。 1 H-NMR (400MHz, CDCl3): δ3.95-3.91(m,8H),3.86-3.83(m,8H),3.55-3.50(m,8H),2.84-2.76(m,16H),2.50- 2.44(m,20H),2.15(s,3H),1.49-1.11(m,68H),0.89-0.88(m,24H).
实施例25：化合物54的合成Example 25: Synthesis of Compound 54
将2-羟乙基二硫化物(5.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve 2-hydroxyethyl disulfide (5.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butanol After adding octanoic acid (1.0eq), stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(6.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物54。Dissolve intermediate product 2 (6.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 54.
1H-NMR(400MHz,CDCl3):δ4.43-4.36(m,8H),3.96-3.89(m,16H),2.84-2.76(m,16H),2.50-2.14(m,23H),1.49-1.11(m,68H),0.89-0.88(m,24H)。 1 H-NMR (400MHz, CDCl3): δ4.43-4.36(m,8H),3.96-3.89(m,16H),2.84-2.76(m,16H),2.50-2.14(m,23H),1.49- 1.11(m,68H),0.89-0.88(m,24H).
实施例26：化合物55的合成Example 26: Synthesis of Compound 55
将2-叔丁氧羰基氨基乙硫醇(1.0eq)溶解于适量的二氯甲烷和甲醇(V/V＝1/1)中，加入2-巯基乙醇(10.0eq)，搅拌10min再缓慢加入2-巯基乙醇(1.1eq)，搅拌4h，再把碘(0.1eq)用甲醇溶解，缓慢加入反应中，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到中间产物1。Dissolve 2-tert-butoxycarbonylaminoethanethiol (1.0eq) in an appropriate amount of dichloromethane and methanol (V/V=1/1), add 2-mercaptoethanol (10.0eq), stir for 10 minutes and then slowly add 2-Mercaptoethanol (1.1eq), stir for 4h, then dissolve iodine (0.1eq) in methanol, add slowly to the reaction, stir at room temperature for 16h after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.5eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid (1.5eq) ), stir at room temperature for 16 hours after addition. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(1.0eq)溶解于适量的乙酸乙酯中，加入4M盐酸的乙酸乙酯溶液(6V)，室温搅拌2h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物3。Dissolve intermediate product 2 (1.0eq) in an appropriate amount of ethyl acetate, add 4M hydrochloric acid in ethyl acetate solution (6V), and stir at room temperature for 2 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
将中间产物3(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物4。Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
将中间产物4(6.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物55。Dissolve intermediate product 4 (6.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 55.
1H-NMR(400MHz,CDCl3):δ4.43-4.36(m,8H),3.67-3.52(m,16H),2.84-2.76(m,16H),2.50-2.14(m,23H),1.49-1.11(m,68H),0.89-0.88(m,24H)。 1 H-NMR (400MHz, CDCl3): δ4.43-4.36(m,8H),3.67-3.52(m,16H),2.84-2.76(m,16H),2.50-2.14(m,23H),1.49- 1.11(m,68H),0.89-0.88(m,24H).
实施例27：化合物56的合成Example 27: Synthesis of Compound 56
将2-巯基乙醇(1.0eq)溶解于适量的四氢呋喃中，加入PPh3(1.5eq)和CBr4(1.5eq)，室温搅拌2h。TLC监控原料反应完全，调节pH＝3-4，用乙酸乙酯萃取，合并的有机层用盐水洗涤，用无水硫酸钠干燥，浓缩，纯化得到中间产物1。Dissolve 2-mercaptoethanol (1.0eq) in an appropriate amount of tetrahydrofuran, add PPh 3 (1.5eq) and CBr 4 (1.5eq), and stir at room temperature for 2 hours. TLC monitors the complete reaction of the raw materials, adjusts the pH to 3-4, extracts with ethyl acetate, washes the combined organic layers with brine, dried over anhydrous sodium sulfate, concentrated, and purified to obtain intermediate product 1.
将2-丁基辛醇(1.0eq)溶解于适量的DMF中，加入中间产物1(2.0eq)和碳酸钾(3.0eq)，加毕90℃搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve 2-butyloctanol (1.0eq) in an appropriate amount of DMF, add intermediate product 1 (2.0eq) and potassium carbonate (3.0eq), and stir at 90°C for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(1.0eq)溶解于适量的二氯甲烷和甲醇(V/V＝1/1)中，加入巯基乙胺(10.0eq)，搅拌4h，再把碘(0.1eq)用甲醇溶解，缓慢加入反应中，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到中间产物3。Dissolve intermediate product 2 (1.0eq) in an appropriate amount of dichloromethane and methanol (V/V=1/1), add mercaptoethylamine (10.0eq), stir for 4 hours, and then dissolve iodine (0.1eq) in methanol , slowly added to the reaction, and stirred at room temperature for 16h after addition. TLC monitored the complete reaction of the raw materials, concentrated and purified to obtain intermediate product 3.
将中间产物3(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物4。 Dissolve intermediate product 3 (1.0eq) in an appropriate amount of dichloromethane, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 4.
将中间产物4(6.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物56。Dissolve intermediate product 4 (6.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 56.
1H-NMR(400MHz,CDCl3):δ3.67-3.62(m,16H),3.51-3.21(m,16H),2.84-2.76(m,16H),2.50-2.14(m,19H),1.68-1.11(m,72H),0.89-0.88(m,24H)。 1 H-NMR (400MHz, CDCl3): δ3.67-3.62(m,16H),3.51-3.21(m,16H),2.84-2.76(m,16H),2.50-2.14(m,19H),1.68- 1.11(m,72H),0.89-0.88(m,24H).
实施例28：化合物57的合成Example 28: Synthesis of Compound 57
将2-羟乙基二硫化物(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve 2-hydroxyethyl disulfide (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and add at room temperature. Stir for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将2-丁基辛醇(1.0eq)溶解于适量的四氢呋喃中，加入PPh3(1.5eq)和CBr4(1.5eq)，室温搅拌2h。TLC监控原料反应完全，调节pH＝3-4，用乙酸乙酯萃取，合并的有机层用盐水洗涤，用无水硫酸钠干燥，浓缩，纯化得到中间产物2。Dissolve 2-butyloctanol (1.0eq) in an appropriate amount of tetrahydrofuran, add PPh 3 (1.5eq) and CBr 4 (1.5eq), and stir at room temperature for 2 hours. TLC monitors the complete reaction of the raw materials, adjusts the pH to 3-4, extracts with ethyl acetate, washes the combined organic layers with brine, dried over anhydrous sodium sulfate, concentrated, and purified to obtain intermediate product 2.
将中间产物1(1.0eq)溶解于适量的DMF中，加入中间产物2(2.0eq)和碳酸钾(3.0eq)，加毕90℃搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物3。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of DMF, add intermediate product 2 (2.0eq) and potassium carbonate (3.0eq), and stir at 90°C for 16 hours after addition. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
将中间产物3(6.0eq)溶解于适量的甲醇中，加入N,N-双(3-氨基丙基)甲胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物57。Dissolve intermediate product 3 (6.0eq) in an appropriate amount of methanol, add N,N-bis(3-aminopropyl)methylamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 57.
1H-NMR(400MHz,CDCl3):δ3.95-3.91(m,8H),3.86-3.83(m,16H),3.55-3.20(m,8H),2.84-2.76(m,16H),2.50-2.44(m,16H),2.15(s,3H),1.49-1.11(m,72H),0.89-0.88(m,24H)。 1 H-NMR (400MHz, CDCl3): δ3.95-3.91(m,8H),3.86-3.83(m,16H),3.55-3.20(m,8H),2.84-2.76(m,16H),2.50- 2.44(m,16H),2.15(s,3H),1.49-1.11(m,72H),0.89-0.88(m,24H).
实施例29：化合物58的合成Example 29: Synthesis of Compound 58
将2-丁基辛酸(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入1,3-丙二醇(3.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve 2-butyloctanoic acid (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 1,3-propanediol ( 3.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入丁二酸(3.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add succinic acid (3.0eq). After addition, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(1.0eq)溶解于适量的二氯甲烷中，加入DMAP(0.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入4-羟基丁基丙烯酸酯(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物3。Dissolve intermediate product 2 (1.0eq) in an appropriate amount of dichloromethane, add DMAP (0.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 4-hydroxybutylacrylate ( 1.2eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 3.
将中间产物3(3.0eq)溶解于适量的甲醇中，加入乙醇胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物58。Dissolve intermediate product 3 (3.0eq) in an appropriate amount of methanol, add ethanolamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the starting material, concentrated and purified to obtain compound 58.
1H-NMR(400MHz,CDCl3):δ4.22-4.16(m,16H),3.89-3.85(m,4H),3.56-3.52(m,2H),2.81-2.78(m,8H),2.57-2.46(m,6H),2.11-1.98(m,6H),1.69-1.19(m,40H),0.93-0.89(m,12H)。 1 H-NMR (400MHz, CDCl3): δ4.22-4.16(m,16H),3.89-3.85(m,4H),3.56-3.52(m,2H),2.81-2.78(m,8H),2.57- 2.46(m,6H),2.11-1.98(m,6H),1.69-1.19(m,40H),0.93-0.89(m,12H).
实施例30：化合物59的合成Example 30: Synthesis of Compound 59
将胱胺二硫酸盐(2.0eq)溶解于适量的二氯甲烷中，加入HOBT(1.5eq)，EDCI(1.5eq)和三乙胺(3.0eq)，搅拌10min再加入2-丁基辛酸(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物1。Dissolve cystamine disulfate (2.0eq) in an appropriate amount of dichloromethane, add HOBT (1.5eq), EDCI (1.5eq) and triethylamine (3.0eq), stir for 10 minutes and then add 2-butyloctanoic acid ( 1.0eq), after adding, stir at room temperature for 16h. TLC monitors the complete reaction of the raw materials, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 1.
将中间产物1(1.0eq)溶解于适量的二氯甲烷中，在0℃下加入缓慢丙烯酰氯(1.2eq)，搅拌10min再加入三乙胺(1.2eq)，加毕室温搅拌16h。TLC监控原料反应完全，用乙酸乙酯萃取两次，收集有机相，然后加入无水硫酸钠干燥，过滤，浓缩，纯化得到中间产物2。Dissolve intermediate product 1 (1.0eq) in an appropriate amount of methylene chloride, slowly add acryloyl chloride (1.2eq) at 0°C, stir for 10 minutes, then add triethylamine (1.2eq), and stir at room temperature for 16 hours. TLC monitors the complete reaction of the raw material, extracts twice with ethyl acetate, collects the organic phase, then adds anhydrous sodium sulfate to dry, filter, concentrate, and purify to obtain intermediate product 2.
将中间产物2(3.0eq)溶解于适量的甲醇中，加入N,N-二异丙基乙二胺(1.0eq)，加毕室温搅拌16h。TLC监控原料反应完全，浓缩，纯化得到化合物59。Dissolve intermediate product 2 (3.0eq) in an appropriate amount of methanol, add N,N-diisopropylethylenediamine (1.0eq), and stir at room temperature for 16 hours after addition. TLC monitored the complete reaction of the raw material, concentrated and purified to obtain compound 59.
1H-NMR(400MHz,CDCl3):δ3.64-3.48(m,12H),2.83-2.22(m,20H),1.56-1.17(m,32H),1.11-0.98(m,12H),0.93-0.88(m,12H)。 1 H-NMR (400MHz, CDCl 3 ): δ3.64-3.48(m,12H),2.83-2.22(m,20H),1.56-1.17(m,32H),1.11-0.98(m,12H),0.93 -0.88(m,12H).
实施例31 Example 31
分别将化合物1、2、6、8、11、15、21、38、54、55、58、59与胆固醇、DSPC(二硬脂酰磷脂酰胆碱)、PEG-DMG(聚乙二醇-二肉豆蔻酸甘油酯)以50:38.5:10:1.5的摩尔比(其中，化合物1、2、6、8、11、15、21、38、54、55、58或59的当量为50，胆固醇的当量为38.5，DSPC的当量为10，PEG-DMG的当量为1.5)溶解于乙醇中(以脂质总重量计，浓度为24.4mg/mL)，将荧光素酶mRNA溶解于pH 4.0的10mM柠檬酸缓冲盐水溶液中(药物浓度为0.276mg/mL)，两种溶液的体积比1:3(其中，乙醇溶液的当量为1，水溶液的当量为3)，使用微流控技术将两相快速混合并使用透析或切向流技术将缓冲环境置换成pH 7.4的PBS，以除去乙醇，制备得到多组LNP@mRNA。Compounds 1, 2, 6, 8, 11, 15, 21, 38, 54, 55, 58, 59 were mixed with cholesterol, DSPC (distearoylphosphatidylcholine), PEG-DMG (polyethylene glycol- Dimyristate) with a molar ratio of 50:38.5:10:1.5 (wherein the equivalent of compound 1, 2, 6, 8, 11, 15, 21, 38, 54, 55, 58 or 59 is 50, The equivalent of cholesterol is 38.5, the equivalent of DSPC is 10, and the equivalent of PEG-DMG is 1.5) is dissolved in ethanol (based on the total weight of lipids, the concentration is 24.4 mg/mL), and the luciferase mRNA is dissolved in pH 4.0 In 10mM citrate buffered saline solution (drug concentration is 0.276mg/mL), the volume ratio of the two solutions is 1:3 (wherein, the equivalent of the ethanol solution is 1 and the equivalent of the aqueous solution is 3). Microfluidic technology is used to combine the two solutions. The phases are quickly mixed and dialysis or tangential flow technology is used to replace the buffer environment with PBS at pH 7.4 to remove ethanol and prepare multiple sets of LNP@mRNA.
测试各LNP@mRNA的粒径、PDI和包封率，其结果如表1所示。The particle size, PDI and encapsulation efficiency of each LNP@mRNA were tested, and the results are shown in Table 1.
表1各LNP@mRNA的粒径、PDI、Zeta、包封率
Table 1 Particle size, PDI, Zeta, and encapsulation efficiency of each LNP@mRNA
结果显示，由上表化合物制备的LNP@mRNA对mRNA包封率均大于80％，且化合物11、15、21、38、59与其它三种脂质共同制备的LNP@mRNA粒径较小。此外，由这几种化合物制备的LNP在中性条件下都呈现负电，生物安全性好。由此可见，本发明提供的化合物对核酸药物的包封率较高，并且，以此作为载体可提升核酸药物在体内的递送效率。The results showed that the mRNA encapsulation efficiency of LNP@mRNA prepared from the compounds in the table above was greater than 80%, and the particle size of LNP@mRNA prepared by compounds 11, 15, 21, 38, and 59 together with the other three lipids was smaller. In addition, LNPs prepared from these compounds are negatively charged under neutral conditions and have good biological safety. It can be seen that the compound provided by the present invention has a high encapsulation efficiency for nucleic acid drugs, and can be used as a carrier to improve the delivery efficiency of nucleic acid drugs in the body.
将制备的各LNP@mRNA通过尾静脉分别注射注入小鼠体内，6小时后测试小鼠体内荧光强度及器官分布情况。图1为由化合物1制备的LNP@mRNA的肌肉注射小鼠成像图，图2为由化合物1制备的LNP@mRNA的肌肉注射小鼠解剖成像图，结合图1和图2可以看到mRNA主要在肌肉、肝脏及脾脏表达。图3为由化合物8制备的LNP@mRNA的静脉注射小鼠成像图，图4为由化合物8制备的LNP@mRNA的静脉注射小鼠解剖成像图，结合图3和图4可以看到mRNA全部在脾脏表达。图5为由化合物58制备的LNP@mRNA的静脉注射小鼠成像图，图6为由化合物58制备的LNP@mRNA的静脉注射小鼠解剖成像图，结合图5和图6可以看到mRNA主要在脾脏表达，少量在肝部表达。因此，可根据核酸药物需要富集的器官而选用特定结构的上述脂质化合物作为脂质载体。Each prepared LNP@mRNA was injected into mice through the tail vein respectively, and the fluorescence intensity and organ distribution in the mice were tested 6 hours later. Figure 1 is an imaging image of mice injected intramuscularly with LNP@mRNA prepared from Compound 1. Figure 2 is an anatomical image of mice injected intramuscularly with LNP@mRNA prepared from Compound 1. Combining Figures 1 and 2, it can be seen that the main components of mRNA are Expressed in muscle, liver and spleen. Figure 3 is an imaging image of mice injected intravenously with LNP@mRNA prepared from Compound 8. Figure 4 is an anatomical image of mice injected intravenously with LNP@mRNA prepared with Compound 8. Combining Figures 3 and 4, you can see all the mRNA Expressed in the spleen. Figure 5 is an imaging image of mice injected intravenously with LNP@mRNA prepared from compound 58. Figure 6 is an anatomical image of mice injected intravenously with LNP@mRNA prepared with compound 58. Combining Figures 5 and 6, it can be seen that the main components of mRNA are Expressed in the spleen and a small amount in the liver. Therefore, the above-mentioned lipid compound with a specific structure can be selected as a lipid carrier according to the organ in which the nucleic acid drug needs to be enriched.
实施例32Example 32
将化合物1和已上市阳离子脂质DLin-MC3-DMA(简写为MC3)与胆固醇、DSPC(二硬脂酰磷脂酰胆碱)、PEG-DMG(聚乙二醇-二肉豆蔻酸甘油酯)以50:38.5:10:1.5的摩尔比(其中，化合物1或MC3的当量为50，胆固醇的当量为38.5，DSPC的当量为10，PEG-DMG的当量为1.5)溶解于乙醇中(以脂质总重量计，浓度为24.4mg/mL)，将荧光素酶mRNA溶解于pH 4.0的10mM柠檬酸缓冲盐水溶液中(药物浓度为0.276mg/mL)，两种溶液的体积比1:3(其中，乙醇溶液的当量为1，水溶液的当量为3)，使用微流控技术将两相快速混合并使用透析或切向流技术将缓冲环境置换成pH 7.4的PBS，以除去乙醇，制备得到两组组LNP@mRNA。Compound 1 and the marketed cationic lipid DLin-MC3-DMA (abbreviated as MC3) were combined with cholesterol, DSPC (distearoylphosphatidylcholine), PEG-DMG (polyethylene glycol-dimyristate glyceryl ester) Dissolve in ethanol (with lipid as the molar ratio of 50:38.5:10:1.5 (wherein, the equivalent of compound 1 or MC3 is 50, the equivalent of cholesterol is 38.5, the equivalent of DSPC is 10, and the equivalent of PEG-DMG is 1.5) Based on the total weight of mass, the concentration is 24.4mg/mL), dissolve luciferase mRNA in 10mM citrate buffered saline solution with pH 4.0 (drug concentration is 0.276mg/mL), the volume ratio of the two solutions is 1:3 ( Among them, the equivalent of the ethanol solution is 1 and the equivalent of the aqueous solution is 3), use microfluidic technology to quickly mix the two phases and use dialysis or tangential flow technology to replace the buffer environment with PBS at pH 7.4 to remove ethanol, and prepare Two groups of LNP@mRNA.
将制备的各组LNP@mRNA通过尾静脉分别注射注入小鼠体内，mRNA均为100μg/只，测试小鼠体内肝脏和脾脏的脂质代谢情况。图7为化合物1、MC3与其它三种脂质共同制备LNP@mRNA在小鼠肝脏内代谢情况，可以看到，MC3与在LNP@mRNA注射6小时达到峰值，48小时后依然保持了较高的脂质水平，而化合物1在LNP@mRNA注射2小时达到峰值，且在整个48小时内峰值远远低于MC3的脂质水平，因此可以说明化合物1相较于MC3与在肝脏内具有更快的代谢速度。图8为化合物1、MC3与其它三种脂质共同制备LNP@mRNA在小鼠脾脏内代谢情况，可以看到，MC3在LNP@mRNA注射12小时达到峰值，48小时后依然保持了较高的脂质水平，而化合物1在 LNP@mRNA注射2小时达到峰值，且在整个48小时内峰值远远低于化合物1的脂质水平，因此可以说明化合物1相较于MC3与在脾脏具有更快的代谢速度。脂质在肝脏、脾脏中富集量更少，相比已上市的阳离子脂质具有更快的代谢速度，生物安全性更高，毒性更小。Each group of prepared LNP@mRNA was injected into mice through the tail vein, and the amount of mRNA was 100 μg/mouse, and the lipid metabolism of the liver and spleen of the mice was tested. Figure 7 shows the metabolism of LNP@mRNA prepared by Compound 1, MC3 and other three lipids in mouse liver. It can be seen that MC3 and LNP@mRNA reached the peak 6 hours after injection, and still maintained a high level after 48 hours. The lipid level of Compound 1 reached a peak at 2 hours after LNP@mRNA injection, and the peak value during the entire 48 hours was much lower than the lipid level of MC3. Therefore, it can be shown that Compound 1 has a higher concentration in the liver than MC3. Fast metabolic rate. Figure 8 shows the metabolism of LNP@mRNA prepared by Compound 1, MC3 and other three lipids in the mouse spleen. It can be seen that MC3 reaches the peak 12 hours after LNP@mRNA injection and still maintains a high level 48 hours later. lipid levels, whereas compound 1 in The peak value was reached 2 hours after LNP@mRNA injection, and the peak value during the entire 48 hours was much lower than the lipid level of compound 1. Therefore, it can be seen that compound 1 has a faster metabolism in the spleen than MC3. Lipids are less concentrated in the liver and spleen, have faster metabolism, higher biosafety and less toxicity than cationic lipids already on the market.
实施例33Example 33
将化合物55与DOTAP((2,3-二油酰基丙基)三甲基氯化铵)、胆固醇、DSPC、PEG-DMG以30:20:38.5:10:1.5的摩尔比(其中，化合物55的当量为30，DOTAP的当量为20，胆固醇的当量为38.5，DSPC的当量为10，PEG-DMG的当量为1.5)溶解于乙醇中(以脂质总重量计，浓度为24.4mg/mL)，将荧光素酶mRNA溶解于pH 4.0的50mM柠檬酸缓冲盐水溶液中(药物浓度为0.276mg/mL)，两种溶液体积比1:3(其中，乙醇溶液的当量为1，水溶液的当量为3)，使用微流控技术将两相快速混合，并使用透析或切向流技术将缓冲环境置换成pH 7.4的PBS，制备得到LNP@mRNA。加入冻存保护剂蔗糖，得到核酸脂质纳米粒药物制剂。Compound 55 was mixed with DOTAP ((2,3-dioleoylpropyl)trimethylammonium chloride), cholesterol, DSPC, and PEG-DMG at a molar ratio of 30:20:38.5:10:1.5 (wherein, compound 55 The equivalent of DOTAP is 30, the equivalent of cholesterol is 38.5, the equivalent of DSPC is 10, and the equivalent of PEG-DMG is 1.5) is dissolved in ethanol (based on the total weight of lipids, the concentration is 24.4 mg/mL) , dissolve luciferase mRNA in 50mM citrate buffered saline solution with pH 4.0 (drug concentration is 0.276mg/mL), the volume ratio of the two solutions is 1:3 (wherein, the equivalent of the ethanol solution is 1, and the equivalent of the aqueous solution is 3), use microfluidic technology to quickly mix the two phases, and use dialysis or tangential flow technology to replace the buffer environment with PBS at pH 7.4 to prepare LNP@mRNA. The cryoprotectant sucrose is added to obtain a nucleic acid lipid nanoparticle drug preparation.
实施例34Example 34
将化合物56与DOTAP、DOPS(二油酰磷脂酰丝氨酸)、胆固醇、DSPC、PEG-DMG(总15mg)以20:25:15:25:5:10的摩尔比(其中，化合物56的当量为20，DOTAP的当量为25，DOPS的当量为15，胆固醇的当量为25，DSPC的当量为5，PEG-DMG的当量为10)溶解于乙醇中(以脂质总重量计，浓度为24.4mg/mL)，将荧光素酶mRNA(5mg)溶解于pH 4.0的50mM柠檬酸缓冲盐水溶液中(药物浓度为0.276mg/mL)，两种溶液体积比1:3(其中，乙醇溶液的当量为1，水溶液的当量为3)，使用微流控技术将两相快速混合，并使用透析或切向流技术将缓冲环境置换成pH 7.4的PBS，制备得到LNP@mRNA。加入冻存保护剂蔗糖，得到核酸脂质纳米粒药物制剂。Compound 56 was mixed with DOTAP, DOPS (dioleoylphosphatidylserine), cholesterol, DSPC, and PEG-DMG (total 15 mg) at a molar ratio of 20:25:15:25:5:10 (wherein, the equivalent of compound 56 is 20. The equivalent of DOTAP is 25, the equivalent of DOPS is 15, the equivalent of cholesterol is 25, the equivalent of DSPC is 5, and the equivalent of PEG-DMG is 10) is dissolved in ethanol (based on the total weight of lipids, the concentration is 24.4mg /mL), dissolve luciferase mRNA (5mg) in 50mM citrate buffered saline solution with pH 4.0 (drug concentration is 0.276mg/mL), the volume ratio of the two solutions is 1:3 (wherein, the equivalent of the ethanol solution is 1. The equivalent of the aqueous solution is 3). Use microfluidic technology to quickly mix the two phases, and use dialysis or tangential flow technology to replace the buffer environment with PBS at pH 7.4 to prepare LNP@mRNA. The cryoprotectant sucrose is added to obtain a nucleic acid lipid nanoparticle drug preparation.
实施例35Example 35
将化合物2与DLin-KC2-DMA(CAS号：1190197-97-7)、DOPG(二油酰磷脂酰甘油)、胆固醇、DSPC、吐温-80(总30mg)以15:5:3:51.5:25:0.5的摩尔比(其中，化合物2的当量为15，DLin-KC2-DMA的当量为5，DOPG的当量为3，胆固醇的当量为51.5，DSPC的当量为25，吐温-80的当量为0.5)溶解于乙醇中(以脂质总重量计，浓度为24.4mg/mL)，将荧光素酶mRNA(1mg)溶解于pH 4.0的50mM柠檬酸缓冲盐水溶液中(药物浓度为0.276mg/mL)，二者体积比1:3(其中，乙醇溶液的当量为1，水溶液的当量为3)，使用微流控技术将两相快速混合，并使用透析或切向流技术将缓冲环境置换成pH 7.4的PBS，制备得到LNP@mRNA。加入冻存保护剂蔗糖，得到核酸脂质纳米粒药物制剂。Compound 2 was mixed with DLin-KC2-DMA (CAS number: 1190197-97-7), DOPG (dioleoylphosphatidylglycerol), cholesterol, DSPC, and Tween-80 (total 30 mg) at a ratio of 15:5:3:51.5 :25:0.5 molar ratio (wherein, the equivalent of compound 2 is 15, the equivalent of DLin-KC2-DMA is 5, the equivalent of DOPG is 3, the equivalent of cholesterol is 51.5, the equivalent of DSPC is 25, and the equivalent of Tween-80 Equivalent to 0.5) was dissolved in ethanol (based on the total weight of lipids, the concentration was 24.4mg/mL), and luciferase mRNA (1mg) was dissolved in 50mM citrate buffered saline solution at pH 4.0 (drug concentration was 0.276mg /mL), the volume ratio of the two is 1:3 (where the equivalent of the ethanol solution is 1 and the equivalent of the aqueous solution is 3), use microfluidic technology to quickly mix the two phases, and use dialysis or tangential flow technology to separate the buffer environment Replace with PBS at pH 7.4 to prepare LNP@mRNA. The cryoprotectant sucrose is added to obtain a nucleic acid lipid nanoparticle drug preparation.
需要说明的是，尽管以具体实例介绍了本发明的技术方案，但本领域技术人员能够理解，本发明应不限于此。以上已经描述了本发明的各实施例，上述说明是示例性的，并非穷尽性的，并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。本文中所用术语的选择，旨在最好地解释各实施例的原理、实际应用或对市场中的技术改进，或者使本技术领域的其它普通技术人员能理解本文披露的各实施例。 It should be noted that although the technical solution of the present invention is introduced with specific examples, those skilled in the art can understand that the present invention should not be limited thereto. The embodiments of the present invention have been described above. The above description is illustrative, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical applications, or technical improvements in the market of the embodiments, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein.

Claims (14)

  1. 式(I)化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，
    A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug thereof,
    其中：in:
    X为其中：X is in:
    Ra和Ra’各自独立地为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；或者，Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl or ,
    Ra和Ra’各自独立地为或者，Ra and Ra' are independently or,
    Ra和Ra’相互连接成Z；Ra and Ra’ are connected to each other to form Z;
    每一个Z各自独立地为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group;
    W为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；或者，W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; or,
    W为 W is
    每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-、-C(＝O)NR2-、-NR2C(＝O)NR2-、-OC(＝O)NR2-、-NR2C(＝O)O-或-O(C＝O)O-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)-, -C(=O)NR 2 -, -NR 2 C( =O)NR 2 -, -OC(=O)NR 2 -, -NR 2 C(=O)O- or -O(C=O)O-;
    每一个R1各自独立地为C1-C24烷基或C2-C24烯基；Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl;
    每一个R2各自独立地为氢或C1-C24烷基；Each R 2 is independently hydrogen or C 1 -C 24 alkyl;
    每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；Each of B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group;
    每一个m各自独立地为0或1；Each m is independently 0 or 1;
    所述杂烷基、亚杂烷基、杂环烷基、杂芳基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heteroalkylene group, heterocycloalkyl group, heteroaryl group and heteroarylene group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N , NH, O, S, S(=O) or S(=O) 2 .
  2. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, characterized in that,
    所述化合物为式(I-1)或式(I-1’)化合物：
    The compound is a compound of formula (I-1) or formula (I-1'):
    其中：in:
    Ra为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，Ra为C1-C12烷基，优选C1-C6烷基；Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, preferably C 1 -C 6 alkyl;
    W为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，W为C1-C12烷基，优选C1-C6烷基；W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 members independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, W is C 1 -C 12 alkyl, preferably C 1 -C 6 alkyl;
    A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S(O) -, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, A 1 , A 2. A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -SS-, -NR 2 C(＝O)- or -C(＝O)NR 2- ;
    R1为C1-C24烷基或C2-C24烯基；优选地，R1为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；R 1 is C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
    每一个R2各自独立地为氢或C1-12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
    B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
    所述杂烷基、杂环烷基和杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heterocycloalkyl group and heteroaryl group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N, NH, O, S, S (= O) or S(=O) 2 .
  3. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, characterized in that,
    所述化合物为式(I-2)或式(I-2’)化合物：

    The compound is a compound of formula (I-2) or formula (I-2'):

    其中：in:
    Ra为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，Ra为C1-C12烷基、C2-C12炔基、C1-C12杂烷基、C3-C12环烷基或3-12元杂环烷基，所述烷基、炔基、杂烷基、环烷基和杂环烷基任选地被1-4个各自独立地选自羟基、氧代基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；更优选地，Ra为C1-C6烷基、C2-C6炔基、C1-C6杂烷基、C3-C6环烷基或3-6元杂环烷基，所述烷基、炔基、杂烷基、环烷基和杂环烷基任选地被1-2个各自独立地选自羟基、氧代基、C3-C8环烷基、3-8元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；Ra is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl The base is optionally composed of 1-4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 yuan Heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl group substitution; preferably, Ra is C 1 -C 12 alkyl, C 2 -C 12 alkynyl, C 1 -C 12 heteroalkyl, C 3 -C 12 cycloalkyl or 3-12 membered heterocycloalkyl, the alkyl, alkynyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups are optionally replaced by 1-4 each is independently selected from a hydroxyl group, an oxo group, a C 3 -C 8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group; More preferably, Ra is C 1 -C 6 alkyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocycloalkyl, so The alkyl, alkynyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups are optionally 1-2 independently selected from hydroxyl, oxo, C 3 -C 8 cycloalkyl, 3-8 Substitution of a 5-membered heterocycloalkyl group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group;
    每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, each A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -O-, -SS-, -NR 2 C(＝O)- or -C(=O)NR 2 -;
    每一个R1各自独立地为C1-C24烷基或C2-C24烯基；优选地，每一个R1各自独立地为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
    每一个R2各自独立地为氢或C1-C12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1 -C 12 alkyl; preferably, each R 2 is independently hydrogen;
    每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，每一个B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
    所述杂烷基、杂环烷基和杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heterocycloalkyl group and heteroaryl group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N, NH, O, S, S (= O) or S(=O) 2 .
  4. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, characterized in that,
    所述化合物为式(I-3)或式(I-3’)化合物：
    The compound is a compound of formula (I-3) or formula (I-3'):
    其中：in:
    每一个Z各自独立地为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；优选地，每一个Z各自独立地为C1-C12亚烷基，优选C1-C6亚烷基；Each Z is independently a C 1 -C 24 alkylene group, a C 1 -C 24 heteroalkylene group, a C 6 -C 10 arylene group or a 5-10 membered heteroarylene group; preferably, each Z Each independently is C 1 -C 12 alkylene, preferably C 1 -C 6 alkylene;
    W为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷 基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，W为C1-C12烷基或C1-C12杂烷基，所述烷基和杂烷基任选地被1-4个各自独立地选自C3-C8环烷基或3-8元杂环烷基的基团取代；更优选地，W为C1-C8烷基或C1-C8杂烷基，所述烷基和杂烷基任选地被1-2个各自独立地选自C3-C8环烷基或3-8元杂环烷基的基团取代；W is hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl, 3-24 yuan Heterocycloalkanes base, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optional Ground cover 1-4 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl, 3-10 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl groups; preferably, W is C 1 -C 12 alkyl or C 1 -C 12 heteroalkyl, the alkyl and heteroalkyl groups are optionally substituted by 1-4 groups each independently selected from C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl are substituted; more preferably, W is C 1 -C 8 alkyl or C 1 -C 8 Heteroalkyl, the alkyl and heteroalkyl are optionally substituted by 1-2 groups each independently selected from C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl;
    A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，A1、A2、A3和A4各自独立地为-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S(O) -, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, A 1 , A 2 , A 3 and A 4 are each independently -SS-, -NR 2 C(=O)- or -C(=O)NR 2 -;
    R1为C1-C24烷基或C2-C24烯基；优选地，R1为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；R 1 is C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, R 1 is C 6 -C 20 alkyl, preferably branched C 6 -C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
    每一个R2各自独立地为氢或C1-12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1-12 alkyl; preferably, each R 2 is independently hydrogen;
    B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；B 1 , B 2 , B 3 and B 4 are each independently C 1 -C 8 alkylene or C 2 -C 8 alkenylene; preferably, B 1 , B 2 , B 3 and B 4 are each independently It is C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
    所述杂烷基、亚杂烷基、杂环烷基、杂芳基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl group, heteroalkylene group, heterocycloalkyl group, heteroaryl group and heteroarylene group each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N , NH, O, S, S(=O) or S(=O) 2 .
  5. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, characterized in that,
    所述化合物为式(I-4)或式(I-4’)化合物：
    The compound is a compound of formula (I-4) or formula (I-4'):
    其中：in:
    Ra和Ra’各自独立地为氢、C1-C24烷基、C2-C24烯基、C2-C24炔基、C1-C24杂烷基、C3-C24环烷基、3-24元杂环烷基、C6-C10芳基或5-10元杂芳基，所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选地被1-4个各自独立地选自羟基、氧代基、C1-C6烷基、C1-C6杂烷基、C3-C10环烷基、3-10元杂环烷基、C6-C10芳基或5-10元杂芳基的基团取代；优选地，Ra和Ra’各自独立地为C1-C12烷基，所述烷基任选地被1-4个羟基取代；更优选地，Ra和Ra’各自独立地为C1-C6烷基，所述烷基任选地被1-2个羟基取代；Ra and Ra' are each independently hydrogen, C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 2 -C 24 alkynyl, C 1 -C 24 heteroalkyl, C 3 -C 24 cycloalkyl base, 3-24 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, the alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl , aryl and heteroaryl are optionally selected from 1 to 4 independently selected from hydroxyl, oxo, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 10 cycloalkyl group substituted by a base, a 3-10 membered heterocycloalkyl group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group; preferably, Ra and Ra' are each independently a C 1 -C 12 alkyl group, The alkyl group is optionally substituted by 1-4 hydroxyl groups; more preferably, Ra and Ra' are each independently a C 1 -C 6 alkyl group, and the alkyl group is optionally substituted by 1-2 hydroxyl groups;
    Z为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；优选地，Z为C1-C12亚烷基或C1-C12亚杂烷基，优选C1-C6亚烷基或C1-C6亚杂烷基；Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 6 alkylene or C 1 -C 6 heteroalkylene;
    每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, each A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -SS-, -NR 2 C(＝O)- or -C( ＝O)NR 2 -;
    每一个R1各自独立地为C1-C24烷基或C2-C24烯基；优选地，每一个R1各自独立地为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
    每一个R2各自独立地为氢或C1-C12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1 -C 12 alkyl; preferably, each R 2 is independently hydrogen;
    每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，每一个B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
    所述杂烷基、亚杂烷基、杂环烷基、杂芳基和亚杂芳基各自独立地具有1至3个杂原子或杂原子 团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkyl, heteroalkylene, heterocycloalkyl, heteroaryl and heteroarylene groups each independently have 1 to 3 heteroatoms or heteroatoms group, the heteroatom or heteroatom group is each independently N, NH, O, S, S(=O) or S(=O) 2 .
  6. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, characterized in that,
    所述化合物为式(I-5)或式(I-5’)化合物：
    The compound is a compound of formula (I-5) or formula (I-5'):
    其中：in:
    Z为C1-C24亚烷基、C1-C24亚杂烷基、C6-C10亚芳基或5-10元亚杂芳基；优选地，Z为C1-C12亚烷基或C1-C12亚杂烷基，优选C1-C8亚烷基或C1-C8亚杂烷基；Z is C 1 -C 24 alkylene, C 1 -C 24 heteroalkylene, C 6 -C 10 arylene or 5-10 membered heteroarylene; preferably, Z is C 1 -C 12 arylene Alkyl or C 1 -C 12 heteroalkylene, preferably C 1 -C 8 alkylene or C 1 -C 8 heteroalkylene;
    每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-C(＝O)-、-O-、-S(O)-、-S-S-、-C(＝O)S-、-SC(＝O)-、-NR2C(＝O)-或-C(＝O)NR2-；优选地，每一个A1、A2、A3和A4各自独立地为-O(C＝O)-、-(C＝O)O-、-O-、-S-S-、-NR2C(＝O)-或-C(＝O)NR2-；Each of A 1 , A 2 , A 3 and A 4 is independently -O(C＝O)-, -(C＝O)O-, -C(＝O)-, -O-, -S( O)-, -SS-, -C(=O)S-, -SC(=O)-, -NR 2 C(=O)- or -C(=O)NR 2 -; preferably, each A 1 , A 2 , A 3 and A 4 are each independently -O(C＝O)-, -(C＝O)O-, -O-, -SS-, -NR 2 C(＝O)- or -C(=O)NR 2 -;
    每一个R1各自独立地为C1-C24烷基或C2-C24烯基；优选地，每一个R1各自独立地为C6-C20烷基，优选支链的C6-C20烷基，更优选支链的C10-C15烷基；Each R 1 is independently C 1 -C 24 alkyl or C 2 -C 24 alkenyl; preferably, each R 1 is independently C 6 -C 20 alkyl, preferably branched C 6 - C 20 alkyl, more preferably branched C 10 -C 15 alkyl;
    每一个R2各自独立地为氢或C1-C12烷基；优选地，每一个R2各自独立地为氢；Each R 2 is independently hydrogen or C 1 -C 12 alkyl; preferably, each R 2 is independently hydrogen;
    每一个B1、B2、B3和B4各自独立地为C1-C8亚烷基或C2-C8亚烯基；优选地，每一个B1、B2、B3和B4各自独立地为C1-C6亚烷基，优选C1-C4亚烷基；Each B 1 , B 2 , B 3 and B 4 is independently a C 1 -C 8 alkylene group or a C 2 -C 8 alkenylene group; preferably, each B 1 , B 2 , B 3 and B 4 is each independently C 1 -C 6 alkylene, preferably C 1 -C 4 alkylene;
    所述亚杂烷基和亚杂芳基各自独立地具有1至3个杂原子或杂原子团，所述杂原子或杂原子团各自独立地为N、NH、O、S、S(＝O)或S(＝O)2。The heteroalkylene and heteroarylene groups each independently have 1 to 3 heteroatoms or heteroatom groups, and the heteroatoms or heteroatom groups are each independently N, NH, O, S, S (=O) or S(=O) 2 .
  7. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, characterized in that,
    每一个各自独立地选自下列片段：
    Every Each is independently selected from the following clips:
  8. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、 螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, Chelate, non-covalent complex or prodrug, characterized by,
    每一个Z各自独立地选自下列片段：
    Each Z is independently selected from the following fragments:
  9. 根据权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，其特征在于，The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex or prodrug, characterized in that,
    X选自下列片段：
    X is selected from the following clips:
  10. 下列化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价化合物或前体药物：









    The following compounds, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, non-covalent compounds or prodrugs thereof:









  11. 一种脂质载体，其包含根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物。A lipid carrier comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non- Covalent complexes or prodrugs.
  12. 根据权利要求11所述的脂质载体，其特征在于，The lipid carrier according to claim 11, characterized in that,
    所述脂质载体包含第一脂质化合物和第二脂质化合物，其中，所述第一脂质化合物包含根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物和任选的阳离子脂质，所述第二脂质化合物包含阴离子脂质、中性脂质、甾醇和两亲性脂质中的一种或两种以上的组合；The lipid carrier includes a first lipid compound and a second lipid compound, wherein the first lipid compound includes the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof , stereoisomers, tautomers, solvates, chelates, non-covalent complexes or prodrugs and optionally a cationic lipid, the second lipid compound comprising an anionic lipid, a neutral lipid One or a combination of two or more lipids, sterols and amphipathic lipids;
    在所述脂质载体中，所述第一脂质化合物、所述阴离子脂质、所述中性脂质、所述甾醇和所述两亲性脂质的摩尔比为(20～65):(0～20):(5～25):(25～55):(0.3～15)；In the lipid carrier, the molar ratio of the first lipid compound, the anionic lipid, the neutral lipid, the sterol and the amphiphilic lipid is (20-65): (0～20):(5～25):(25～55):(0.3～15);
    在所述第一脂质化合物中，根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物和所述阳离子脂质的摩尔比为(1～10):(0～10)；In the first lipid compound, the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate thereof , the molar ratio of the non-covalent complex or prodrug and the cationic lipid is (1 ~ 10): (0 ~ 10);
    优选地，在所述脂质载体中，Preferably, in the lipid carrier,
    所述阳离子脂质包括DLinDMA、DODMA、DLin-MC2-MPZ、DLin-KC2-DMA、DOTAP、C12-200、DC-Chol和DOTMA中的一种或两种以上的组合；The cationic lipid includes one or a combination of two or more of DLinDMA, DODMA, DLin-MC2-MPZ, DLin-KC2-DMA, DOTAP, C12-200, DC-Chol and DOTMA;
    所述阴离子脂质包括磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸、磷脂酰甘油、DPPG、DOPG、DOPS和二豆蔻酰磷脂酰甘油中的一种或两种以上的组合；The anionic lipid includes one or a combination of two or more of phosphatidylserine, phosphatidylinositol, phosphatidic acid, phosphatidylglycerol, DPPG, DOPG, DOPS and dimyristoylphosphatidylglycerol;
    所述中性脂质包括DOPE、DSPC、DPPC、DOPC、POPC、POPE、DPPE、DMPE、DSPE和SOPE中的至少一种或其经阴离子或阳离子修饰基团修饰的脂质；The neutral lipid includes at least one of DOPE, DSPC, DPPC, DOPC, POPC, POPE, DPPE, DMPE, DSPE and SOPE or a lipid modified by an anionic or cationic modification group;
    所述两亲性脂质包括PEG-DMG、PEG-c-DMG、PEG-C14、PEG-c-DMA、PEG-DSPE、PEG-PE、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油、吐温-20、吐温-80、PEG-DPG、PEG-s-DMG、DAA、PEG-c-DOMG和GalNAc-PEG-DSG中的一种或两种以上的组合。The amphipathic lipids include PEG-DMG, PEG-c-DMG, PEG-C14, PEG-c-DMA, PEG-DSPE, PEG-PE, PEG-modified ceramide, PEG-modified dialkylamine, One or a combination of two or more of PEG-modified diacylglycerol, Tween-20, Tween-80, PEG-DPG, PEG-s-DMG, DAA, PEG-c-DOMG and GalNAc-PEG-DSG .
  13. 一种核酸脂质纳米粒组合物，其包含根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，或根据权利要求11或12所述的脂质载体，以及核酸药物；A nucleic acid lipid nanoparticle composition comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate thereof Compounds, non-covalent complexes or prodrugs, or lipid carriers according to claims 11 or 12, and nucleic acid drugs;
    优选地，所述核酸药物包括DNA、siRNA、mRNA、dsRNA、反义核酸、微RNA、反义微RNA、antagomir、微RNA抑制剂、微RNA激活剂和免疫刺激性核酸中的一种或两种以上的组合；Preferably, the nucleic acid drug includes one or both of DNA, siRNA, mRNA, dsRNA, antisense nucleic acid, microRNA, antisense microRNA, antagomir, microRNA inhibitor, microRNA activator and immunostimulatory nucleic acid. A combination of more than one species;
    优选地，所述核酸药物与根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物的质量比为1:(3～40)；或者，所述核酸药物与根据权利要求11或12所述的脂质载体的质量比为1:(3～40)。Preferably, the nucleic acid drug is combined with the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non- The mass ratio of the covalent complex or prodrug is 1:(3-40); or, the mass ratio of the nucleic acid drug and the lipid carrier according to claim 11 or 12 is 1:(3-40) .
  14. 一种药物制剂，其包含根据权利要求1至10中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、溶剂化物、螯合物、非共价复合物或前体药物，或根据权利要求11或12所述的脂质载体，或根据权利要求13所述的核酸脂质纳米粒组合物，以及药学上可接受的赋形剂、载体和稀释剂；A pharmaceutical preparation comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-co- valence complex or prodrug, or the lipid carrier according to claim 11 or 12, or the nucleic acid lipid nanoparticle composition according to claim 13, as well as pharmaceutically acceptable excipients, carriers and diluent;
    优选地，所述药物制剂的粒径为30～500nm。 Preferably, the particle size of the pharmaceutical preparation is 30 to 500 nm.
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CN112979483A (en) * 2021-05-14 2021-06-18 苏州艾博生物科技有限公司 Cationic lipid compound, composition containing same and application
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