WO2024078614A1 - 用于递送生物活性成分的氨基脂质化合物和脂质纳米颗粒 - Google Patents
用于递送生物活性成分的氨基脂质化合物和脂质纳米颗粒 Download PDFInfo
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- WO2024078614A1 WO2024078614A1 PCT/CN2023/124497 CN2023124497W WO2024078614A1 WO 2024078614 A1 WO2024078614 A1 WO 2024078614A1 CN 2023124497 W CN2023124497 W CN 2023124497W WO 2024078614 A1 WO2024078614 A1 WO 2024078614A1
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- Prior art keywords
- stereoisomer
- pharmaceutically acceptable
- acceptable salt
- lipid compound
- amino lipid
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Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C219/16—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 at least one of the hydroxy groups esterified by an inorganic acid or a derivative thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
Definitions
- the present disclosure relates to an amino lipid compound that can be used to prepare lipid nanoparticles for delivering active ingredients and a preparation method thereof.
- the present disclosure also relates to lipid nanoparticles and pharmaceutical compositions containing the amino lipid compound, and uses thereof.
- nucleic acid drugs include mRNA, antisense oligonucleotides (ASOs), microRNA (miRNA), small interfering RNA (siRNA) and aptamers, etc., which are gradually being developed into a new treatment method with great therapeutic potential in the fields of cancer treatment, infectious disease prevention and genetic disease treatment.
- ASOs antisense oligonucleotides
- miRNA microRNA
- siRNA small interfering RNA
- aptamers etc.
- nucleic acid drugs via lipid nanoparticles
- the targeting, safety and delivery efficiency of nucleic acid drug delivery still need to be improved.
- Different nucleic acid drugs, cells (or tissues, organs) and application scenarios all require lipid nanoparticles with different properties to match. Therefore, in order to meet the delivery needs of different application scenarios of nucleic acid drugs, there is a huge demand for the development of different lipid nanoparticles, especially amino lipid compounds used to configure lipid nanoparticles.
- One aspect of the present disclosure provides an amino lipid compound represented by formula (I):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, X, R1 and R2 are each as defined below.
- Another aspect of the present disclosure provides a method for preparing the amino lipid compound.
- Another aspect of the present disclosure provides use of the amino lipid compound for preparing a delivery vehicle for an active ingredient.
- Another aspect of the present disclosure provides lipid nanoparticles containing the amino lipid compound.
- Another aspect of the present disclosure provides a pharmaceutical composition containing the lipid nanoparticles.
- Another aspect of the present disclosure provides a method for delivering a biologically active ingredient to a cell, a tissue or an organ via the lipid nanoparticle or the pharmaceutical composition.
- Another aspect of the present disclosure provides a method for producing a polypeptide and/or protein of interest in mammalian cells by the lipid nanoparticle or pharmaceutical composition.
- Another aspect of the present disclosure provides use of the amino lipid compound, lipid nanoparticle or pharmaceutical composition in preparing a drug.
- Another aspect of the present disclosure provides a method for preventing and/or treating a disease or disorder in a mammal in need thereof by using the lipid nanoparticle or pharmaceutical composition.
- Another aspect of the present disclosure provides use of the amino lipid compound, lipid nanoparticle or pharmaceutical composition in the preparation of a drug for nucleic acid transfer.
- hydrocarbyl as used herein means the group remaining after an aliphatic hydrocarbon loses one hydrogen atom, including straight-chain or branched, saturated or unsaturated hydrocarbyl groups.
- Hydrocarbyl groups include, but are not limited to, alkyl, alkenyl and alkynyl groups.
- the hydrocarbyl group has 1 to 24 carbon atoms (C 1 -C 24 hydrocarbyl), for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms (C 1 , C 2 , C 3 , ... C 21 , C 22 , C 23 or C 24 hydrocarbyl).
- hydrocarbon groups include, but are not limited to, C1 - C24 hydrocarbon groups, C1 - C22 hydrocarbon groups, C1 - C20 hydrocarbon groups, C1 - C18 hydrocarbon groups, C1 - C16 hydrocarbon groups, C1 - C12 hydrocarbon groups, C1 - C10 hydrocarbon groups, C1 - C8 hydrocarbon groups, C1 - C7 hydrocarbon groups, C1 - C6 hydrocarbon groups, C1 - C4 hydrocarbon groups, C1 - C3 hydrocarbon groups, C1 - C2 hydrocarbon groups, C2 - C8 hydrocarbon groups , C2- C4 hydrocarbon groups, C4 - C8 hydrocarbon groups, C4 - C9 hydrocarbon groups, C5 - C8 hydrocarbon groups, C1- C4 hydrocarbon groups, C2 - C8 hydrocarbon groups, C3 hydrocarbon groups, C4 hydrocarbon groups, C5 hydrocarbon groups, C6 hydrocarbon groups, C7 hydrocarbon groups , and C8 hydrocarbon groups.
- the hydrocarbon group is optionally substituted, and the substituents are defined below in relation to "optionally substituted".
- the hydrocarbon group has zero branches (ie, a straight chain), one branch, two branches, or more branches.
- alkylene as used herein means a divalent group remaining after the above-mentioned alkyl group further loses one hydrogen atom. Unless otherwise clearly stated in the specification, the alkylene group may also be optionally substituted.
- alkyl as used herein is a linear or branched saturated monovalent hydrocarbon radical.
- the alkyl group has 1 to 24 carbon atoms (C 1 -C 24 alkyl), for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms (C 1 , C 2 , C 3 , ... C 21 , C 22 , C 23 or C 24 alkyl).
- alkyl groups include, but are not limited to, C 1 -C 24 alkyl, C 1 -C 22 alkyl, C 1 -C 20 alkyl, C 1 -C 18 alkyl, C 1 -C 16 alkyl, C 1 -C 12 alkyl, C 1 -C 10 alkyl, C 1 -C 8 alkyl, C 1 -C 7 alkyl, C 1 -C 6 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl, C 1 -C 2 alkyl, C 2 -C 8 alkyl, C 2 -C 4 alkyl, C 4 -C 8 alkyl, C 4 -C 9 alkyl, C 5 -C 8 alkyl, C 1 -C 4 alkyl, C 2 -C 8 -alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl
- alkylene as used herein means a divalent group remaining after the above-mentioned alkyl group further loses one hydrogen atom. Unless otherwise specifically stated in the specification, the alkylene group may also be optionally substituted.
- the alkenyl group has 2 to 24 carbon atoms ( C2 - C24 alkenyl), for example, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms ( C2 , C3, C4 , ... C21 , C22 , C23 or C24 alkenyl), and has 1, 2, 3, 4 or more double bonds.
- Alkenyl groups include, but are not limited to, C2 - C24 alkenyl, C2 - C22 alkenyl, C2- C20 alkenyl, C2- C18 alkenyl, C2- C16 alkenyl, C2 - C12 alkenyl , C2 - C10 alkenyl, C2- C8 alkenyl , C2-C7 alkenyl, C2-C6 alkenyl, C2-C4 alkenyl, C2-C3 alkenyl , C4 - C8 alkenyl , C4 - C9 alkenyl, C5 - C8 alkenyl, which have 1, 2, 3, 4 or more double bonds.
- alkenyl has 1 double bond. Unless otherwise clearly stated in this specification, alkenyl is optionally substituted.
- alkenylene used herein means a divalent group remaining after the above alkenyl further loses one hydrogen atom. Unless otherwise specifically stated in the specification, the alkenylene group may also be optionally substituted.
- alkynyl as used herein is a linear or branched monovalent hydrocarbon radical comprising one or more triple bonds (C ⁇ C).
- the alkynyl group has 2 to 24 carbon atoms ( C2 - C24 alkynyl), for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 carbon atoms (C2, C3, C4, ... C21, C22 , C23 or C24 alkynyl ) , and has 1, 2, 3, 4 or more triple bonds.
- Alkynyl groups include, but are not limited to, C2 - C24 alkynyl, C2 - C22 alkynyl , C2 - C20 alkynyl, C2- C18 alkynyl , C2- C16 alkynyl, C2 -C12 alkynyl, C2 - C10 alkynyl, C2 - C8 alkynyl, C2 -C7 alkynyl, C2- C6 alkynyl, C2 - C4 alkynyl, C2 - C3 alkynyl, C4 - C8 alkynyl, C4 -C9 alkynyl , C5 - C8 alkynyl having 1, 2 , 3, 4 or more triple bonds.
- alkynyl has 1 triple bond. Unless otherwise clearly stated in this specification, alkynyl is optionally substituted.
- alkynylene refers to a divalent group remaining after the above alkynyl group further loses one hydrogen atom. Unless otherwise specifically stated in the specification, the alkynylene group may also be optionally substituted.
- cycloalkyl refers to saturated (i.e., “cycloalkyl” and “cycloalkylene”) or unsaturated (i.e., having one or more double bonds (cycloalkenyl) and/or triple bonds (cycloalkynyl) in the ring) monocyclic or polycyclic hydrocarbon rings having ring carbon atoms.
- “cycloalkyl”, “cycloalkylene” and “hydrocarbon ring” have, for example, 3-10, suitably 3-8, more suitably 3-6, such as 5-6 or 5-7, ring carbon atoms.
- Cycloalkyl “cycloalkylene” and “hydrocarbon ring” include, but are not limited to (ethylene) cyclopropyl (ring), (ethylene) cyclobutyl (ring), (ethylene) cyclopentyl (ring), (ethylene) cyclohexyl (ring), (ethylene) cycloheptyl (ring), (ethylene) cyclooctyl (ring), (ethylene) cyclononyl (ring), (ethylene) cyclohexenyl (ring) and the like. Unless otherwise expressly stated in the specification, cycloalkyl, cycloalkylene and hydrocarbon ring are optionally substituted.
- cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused or bridged systems, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.).
- cycloalkyl has, for example, 3 to 10, for example, 3-7, 5-6 or 5-7 carbon atoms. Unless otherwise expressly stated in the specification, cycloalkyl is optionally substituted.
- heteroalkyl or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) used herein refers to a stable straight-chain, branched or cyclic hydrocarbon radical or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom. Heteroatoms refer to atoms other than carbon and hydrogen. In certain embodiments, heteroalkyl contains one, two, or more heteroatoms. In certain embodiments, heteroalkyl contains one or more identical or different heteroatoms. Preferably, the heteroatoms are selected from O, N and S.
- heteroalkylene or its subordinate concepts (such as heteroalkylene, heteroalkenylene, heteroalkynylene, heteroarylene, etc.) used herein refers to the divalent group remaining after the heteroalkyl defined above further loses one hydrogen atom. Unless otherwise clearly stated in this specification, heteroalkylene or its subordinate concepts (such as heteroalkylene, heteroalkenylene, heteroalkynylene, heteroarylene, etc.) are also optionally substituted.
- heterocycle means a cyclic group having a cyclic structure and containing one or more heteroatoms in the ring-forming atoms. In certain embodiments, one or more heteroatoms contained in the ring-forming atoms are the same or different. In certain embodiments, one or more heteroatoms contained in the ring-forming atoms are selected from N, O and S.
- Heterocycle “heterocyclyl” or “heterocyclylene” disclosed herein are saturated or unsaturated. In certain embodiments, “heterocycle”, “heterocyclyl” or “heterocyclylene” contain monocycle, bicycle, or polycycle.
- heterocycle is a 4 to 10-membered heterocycle, such as a 4 to 7-membered heterocycle, a 5 to 7-membered heterocycle.
- the heterocycle is a 4 to 10-membered heterocycle that may be optionally substituted, wherein the ring-forming atoms contain 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O and S.
- the heterocycle is an optionally substituted 4- to 7-membered saturated heterocycle, wherein the ring atoms contain 1, 2, 3 or 4 heteroatoms selected from N, O and S; more preferably, the heterocycle is It has a 5 to 7 yuan (e.g., 5 to 6 yuan) saturated heterocycle which may be optionally substituted, wherein the ring atoms include 1, 2 or 3 heteroatoms selected from N, O and S.
- heterocycles include, but are not limited to, azetidine, oxetanyl, tetrahydrofuran, pyrrolidine, imidazolidine, pyrazolidine, tetrahydropyran, piperidine, morpholine, thiomorpholine, piperazine, preferably pyrrolidine, piperidine, piperazine and morpholine.
- the heterocycle may be optionally substituted with one or more substituents, and the substituents are defined as "optionally substituted” below. Unless otherwise expressly stated in this specification, heterocycle, heterocyclyl or heterocyclylene may be optionally substituted.
- aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
- C 6-14 aryl means an aromatic group containing 6 to 14 (e.g., 6 to 12) carbon atoms, such as phenyl or naphthyl. Unless otherwise specifically stated in this specification, aryl is optionally substituted.
- heteroaryl refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic group having a conjugated ⁇ electron system, whose ring atoms are composed of carbon atoms and at least one heteroatom, for example, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms, wherein there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and 1, 2, 3, 4 or 5 identical or different heteroatoms independently selected from N, O, S and S(O) 2 .
- One or more ring carbon atoms in the heteroaryl may be replaced by C(O).
- the heteroaryl may be benzo-fused. Unless otherwise explicitly stated in this specification, the heteroaryl is optionally substituted.
- the term "optionally substituted” means that one or more hydrogen atoms attached to an atom or group are independently unsubstituted or independently substituted with one or more (eg, 1, 2, 3 or 4) substituents.
- the substituents are independently selected from, but not limited to, deuterium (D), tritium (T), halogen, -OH, mercapto, cyano, -CD3 , C1 - C6 alkyl (preferably C1 - C3 alkyl), C2 - C6 alkenyl, C2 - C6 alkynyl, cycloalkyl (preferably C3 - C8 cycloalkyl), aryl, heterocyclyl (preferably 3-8 membered heterocyclyl), heteroaryl , aryl C1 -C6 alkyl, heteroaryl C1- C6 alkyl, C1 -C6 haloalkyl , -OC1- C6 alkyl (preferably -OC1 - -
- Riii is hydrogen, or alkyl, or alkenyl, or alkynyl, or heteroalkyl, or heteroalkenyl, or heteroalkynyl as defined herein. In some embodiments, Riii is hydrogen, or C 1 -C 12 alkyl, or C 2 -C 12 alkenyl, or C 2 -C 12 alkynyl, or C 2 -C 12 heteroalkyl, or C 3 -C 12 heteroalkenyl, or C 3 -C 12 heteroalkynyl, as defined herein.
- substituents themselves may be further substituted, for example, with one or more substituents as defined herein.
- C 1 -C 6 alkyl as a substituent may be further substituted with one or more substituents as described herein.
- halo or halogen group is defined to include F, Cl, Br, or I.
- pharmaceutically acceptable salts refer to acid addition salts or base addition salts of the disclosed compounds that retain the biological effectiveness and properties of the disclosed compounds and that are generally not biologically or otherwise undesirable.
- the compounds of the present invention are capable of forming acid and/or base salts due to the presence of amino and/or carboxyl groups or groups similar thereto.
- Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and/or organic acids with the compounds of the present disclosure, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and the like; such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactose disulfonic acid
- Acid gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid
- Pharmaceutically acceptable base addition salts can be formed with inorganic bases and/or organic bases and the compounds of the present disclosure, and salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts and aluminum salts, etc.
- Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, denanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins, etc.
- the numerical ranges described herein should be understood to include the boundary values and any and all subranges contained therein.
- the range “1 to 10” should be understood to include not only the explicitly stated values of 1 and 10, but also any single value (e.g., 2, 3, 4, 5, 6, 7, 8, and 9) and subranges (e.g., 1 to 2, 1.5 to 2.5, 1 to 3, 1.5 to 3.5, 2.5 to 4, 3 to 4.5, etc.) within the range of 1 to 10.
- This principle also applies to ranges with only one value as the minimum or maximum value.
- the term “isomer” means different compounds with the same molecular formula.
- “Stereoisomers” are isomers that differ only in the arrangement of their atoms in space.
- “Atropisomers” are stereoisomers resulting from hindered rotation about a single bond.
- “Isomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A mixture of a pair of enantiomers in any ratio may be called a “racemic” mixture.
- “Diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.
- “Tautomers” refer to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is found, and may vary depending on, for example, whether the compound is a solid or in an organic or aqueous solution.
- stereoisomers may also include E and Z isomers or mixtures thereof, as well as cis and trans isomers or mixtures thereof.
- Nucleic acids and/or polynucleotides useful in the present disclosure include a coding region encoding a polypeptide of interest, a 5′-UTR located at the 5′-end of the coding region, and a 3′-UTR located at the 3′-end of the coding region.
- the nucleic acid or polynucleotide also includes at least one of a polyadenylic acid region and a Kozak sequence.
- the nucleic acid or polynucleotide (e.g., mRNA) may also include a 5′ cap structure.
- nucleic acid may include one or more alternative nucleosides, such as 5-substituted uridines (e.g., 5-methoxyuridine), 1-substituted pseudouridines (e.g., 1-methyl-pseudouridine or 1-ethyl-pseudouridine), and/or 5-substituted cytidines (e.g., 5-methyl-cytidine).
- 5-substituted uridines e.g., 5-methoxyuridine
- 1-substituted pseudouridines e.g., 1-methyl-pseudouridine or 1-ethyl-pseudouridine
- cytidines e.g., 5-methyl-cytidine
- 5'-UTR or "5' untranslated region” may be an RNA sequence in mRNA that is located upstream of a coding sequence and is not translated into a protein.
- the 5'-UTR in a gene usually starts at the transcription start site and ends at the nucleotide upstream of the translation start codon of the coding sequence.
- the 5'-UTR may contain elements that control gene expression, such as a ribosome binding site, a 5'-terminal oligopyrimidine tract, and a translation start signal such as a Kozak sequence.
- mRNA may be post-transcriptionally modified by the addition of a 5' cap.
- the 5'-UTR in a mature mRNA may also refer to an RNA sequence between the 5' cap and the start codon.
- the term "3' untranslated region" or "3'-UTR” may be an mRNA that is located downstream of a coding sequence and is not translated into a protein.
- the 3'-UTR in an mRNA is located between the stop codon and the poly(A) sequence of the coding sequence, for example, starting from the nucleotide downstream of the stop codon and ending at the nucleotide upstream of the poly(A) sequence.
- the sequence of the 5'-UTR and/or 3'-UTR may be homologous or heterologous to the sequence of the coding region.
- the 3′-UTR may include a 3′-UTR derived from at least one gene of an albumin gene, an ⁇ -globin gene, a ⁇ -globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen ⁇ gene.
- poly(A) region is used interchangeably with “poly(A) sequence” and "poly(A) tail", and naturally occurring poly(A) sequences are generally composed of adenine ribonucleotides.
- the "poly(A) region” refers to a poly(A) sequence comprising nucleotides or nucleotide segments other than adenine ribonucleotides.
- the poly(A) sequence is generally located at the 3' end of the mRNA, such as the 3' end (downstream) of the 3'-UTR.
- the poly-A region may have different lengths.
- the length of the poly-A region of the nucleic acid molecules of the present disclosure is at least 30 nucleotides; in some embodiments, the length of the poly-A region of the nucleic acid molecules of the present disclosure is at least 80 nucleotides; in some embodiments, the length of the poly-A region of the nucleic acid molecules of the present disclosure is at least 100 nucleotides.
- the term "5' cap structure” the 5' cap structure is generally located at the 5' end of the mature mRNA. In some embodiments, the 5' cap structure is connected to the 5' end of the mRNA via a 5'-5'-triphosphate bond.
- the 5' cap structure is generally formed by modified (e.g., methylated) ribonucleotides (especially by guanine nucleotide derivatives).
- m7GpppN (cap 0 or "cap0”, is a cap structure formed by the 5' phosphate group of hnRNA reacting with the 5'-phosphate group of m7GTP under the action of guanylyl transferase to form a 5', 5'-phosphodiester bond), wherein N is the terminal 5' nucleotide of the nucleic acid carrying the 5' cap structure.
- the 5′ cap structure includes but is not limited to cap 0, cap 1 (a cap structure formed by further methylating the 2'-OH of the first nucleotide sugar group of hnRNA on the basis of cap 0, or "cap1”), cap 2 (a cap structure formed by further methylating the 2'-OH of the second nucleotide sugar group of hnRNA on the basis of cap 1, or "cap2”), cap 4, cap 0 analogs, cap 1 analogs, cap 2 analogs, or cap 4 analogs.
- cap 1 a cap structure formed by further methylating the 2'-OH of the first nucleotide sugar group of hnRNA on the basis of cap 0, or "cap1”
- cap 2 a cap structure formed by further methylating the 2'-OH of the second nucleotide sugar group of hnRNA on the basis of cap 1, or "cap2”
- cap 4 cap 0 analogs, cap 1 analogs, cap 2 analogs, or cap 4 analogs.
- the present disclosure provides an amino lipid compound represented by the following formula (I):
- A1 , A2 and A3 are one of the following:
- A1 is C1 - C5 alkyl or C1 - C5 heteroalkyl
- A2 is C1- C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene or a bond
- A1 is C1 - C3 alkylene or C1 - C3 heteroalkylene
- A2 is C1 - C3 alkylene or C1 - C3 heteroalkylene
- A3 is C1 - C5 alkylene or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a four-membered ring, a five-membered ring or a six-membered ring;
- A1 is C1 - C3 alkylene or C1 - C3 heteroalkylene
- A2 is C1-C5 alkyl or C1-C5 heteroalkyl
- A3 is C1 - C5 alkylene
- A1 and A3 together with the nitrogen atom to which they are commonly connected form a four-membered ring, a five-membered ring, or a six-membered ring;
- a 4 is a C 1 ⁇ C 5 alkylene group or a bond
- A5 is a C1 - C16 alkylene group or a bond
- a 6 is a C 1 -C 16 alkylene group or a bond
- A7 is a C1 - C18 alkylene group or a bond
- A8 is a C1 - C18 alkylene group or a bond
- R3 is H or C1-C8 alkylene
- R 4 is H or C 1 ⁇ C 3 alkylene
- Z 3 is -O-, -N(R 6 )-, -S- or a bond
- Z 4 is -O-, -N(R 7 )-, -S- or a bond
- Z 5 is -O- or -S-;
- a 9 is a C 1 ⁇ C 3 alkylene group or a bond
- a 10 is a C 1 -C 8 hydrocarbon group
- a 11 is a C 1 -C 3 hydrocarbon group
- R 6 is H, C 1 -C 8 hydrocarbon group
- R7 is H, C1 - C8 hydrocarbon group
- X is C or N
- R 1 is H or a C 1 -C 18 hydrocarbon group, Z 6 R 8 or -CH(OR 9 ) 2 ;
- R8 is H, C1 - C18 hydrocarbon group, C1 - C18 heterohydrocarbon group containing O or S;
- R 9 is a C 1 ⁇ C 18 hydrocarbon group, or a C 1 ⁇ C 18 heterohydrocarbon group containing O or S;
- R 2 is H or a C 1 -C 18 hydrocarbon group, Z 7 R 10 or -CH(OR 11 ) 2 ;
- R 10 is H, C 1 ⁇ C 18 hydrocarbon group, or C 1 ⁇ C 18 heterohydrocarbon group containing O or S;
- R 11 is a C 1 ⁇ C 18 hydrocarbon group, or a C 1 ⁇ C 18 heterohydrocarbon group containing O or S;
- the hydrocarbon group is an alkyl group, an alkenyl group or an alkynyl group;
- the alkylene group is an alkylene group, an alkenylene group or an alkynylene group;
- the heteroalkyl group is a heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group.
- the present disclosure provides an amino lipid compound of formula (I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 is Z 6 R 8 or -CH(OR 9 ) 2 , and R 2 is Z 7 R 10 or -CH(OR 11 ) 2 .
- A1 is a C1 - C5 hydrocarbon group or a C1 - C5 heteroalkyl group
- A2 is a C1 - C5 hydrocarbon group or a C1 - C5 heteroalkyl group
- A3 is a C1 - C5 alkylene group or a bond, that is, it has the structure shown in formula (Ia):
- a 4 , A 5 , A 6 , A 7 , A 8 , Z 1 , Z 2 , Y, X, R 1 and R 2 are as defined in formula (I).
- A1 is C1 - C3 alkylene or C1 - C3 heteroalkylene
- A2 is C1 - C3 alkylene or C1 - C3 heteroalkylene
- A3 is C1-C5 alkylene or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly connected form a four-membered ring, a five-membered ring or a six-membered ring, that is, having the structure shown in formula (Ib):
- a 4 , A 5 , A 6 , A 7 , A 8 , Z 1 , Z 2 , Y, X, R 1 and R 2 are as defined in formula (I).
- A1 is C1 - C3 alkylene or C1 - C3 heteroalkylene
- A2 is C1 - C5 alkyl or C1 -C5 heteroalkyl
- A3 is C1 - C5 alkylene
- A1 and A3 together with the nitrogen atom to which they are commonly connected form a four-membered ring, a five -membered ring or a six-membered ring, that is, having the structure shown in formula (Ic):
- a 4 , A 5 , A 6 , A 7 , A 8 , Z 1 , Z 2 , Y, X, R 1 and R 2 are as defined in formula (I).
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, R1 and R2 are as defined in formula (I).
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, R1 and R2 are as defined in formula (I).
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, X, R2 and R9 are as defined in formula (I).
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, R2 and R9 are as defined in formula (I).
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, R2 and R9 are as defined in formula (I).
- R 1 is -CH(OR 9 ) 2 ;
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, X, R9 and R11 are as defined in formula (I).
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, R9 and R11 are as defined in formula (I).
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y, R9 and R11 are as defined in formula (I).
- Z 3 is -O-
- Z 4 is -O-
- X is C
- R 1 is -CH(OR 9 ) 2 and R 2 is -CH(OR 11 ) 2 ,
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , R9 and R11 are as defined in formula (I).
- Z 3 is -O-
- Z 4 is -O-
- X is C
- R 1 is -CH(OR 9 ) 2 and R 2 is -CH(OR 11 ) 2 ,
- a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , R 9 and R 11 are as defined in formula (I).
- the present disclosure provides formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 is C1 , C2 , C3 , C4 , or C5 hydrocarbon group, C1 , C2 , C3 , C4 , or C5 heterohydrocarbon group, C1 , C2 , or C3 hydrocarbonylene group, or C1 , C2 , or C3 heterohydrocarbonylene group.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A2 is C1 , C2 , C3 , C4 , C5 hydrocarbon group, C1 , C2 , C3 , C4 , C5 heterohydrocarbon group, C1 , C2 , C3 hydrocarbon group, or C1 , C2 , C3 heterohydrocarbon group.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is C 1 , C 2 , C 3 , C 4 , C 5 alkylene or a bond.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 4 is C 1 , C 2 , C 3 alkylene or a bond.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A5 is C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 or C16 alkylene.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A6 is C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 or C16 alkylene.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A7 is C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 or C18 alkylene.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A8 is C1 , C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 or C18 alkylene.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 9 is C 1 , C 2 , or C 3 alkylene.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A10 is C1 , C2 , C3 , C4 , C5 , C6 , C7 or C8 alkylene.
- the present disclosure provides formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), The amino lipid compound of (IIa), (IIb), (III), (IIIa) or (IIIb), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 11 is a C 1 , C 2 , or C 3 alkylene group.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R6 is H or C1 , C2 , C3 , C4 , C5 , C6 , C7 or C8 hydrocarbon group.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R7 is H or C1 , C2 , C3 , C4 , C5 , C6 , C7 or C8 hydrocarbon group.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb) or (IV) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R3 is H or C1 , C2 , C3 , C4 , C5 , C6 , C7 or C8 alkylene.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb) or (IV) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 4 is H or C 1 , C 2 , or C 3 alkylene.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb) or (IV) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 4 is an optionally substituted C 1 -C 3 alkylene group
- R 4 is a C1-C3 alkylene group optionally substituted by a hydroxyl group, an ester group, an alkoxy group, an alkyl group, a halogen, an oxygen group, a sulfur group, an amino group, or an amide group.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib) (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 is H or C1 , C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 or C18 hydrocarbon group.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib) (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 is H, a C1 - C18 straight-chain alkyl group, a C2 - C18 straight-chain alkenyl group, or a C2 - C18 straight-chain alkynyl group.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib) (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 is a C1 , C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 straight-chain alkyl group, or a C2 , C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 straight-chain alkenyl group, or a C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11, C12, C13, C14, C15 , C16, C17, C18 straight-chain alkenyl group.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib) (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 1 is H, C 3 -C 18 branched alkyl, C 3 -C 18 branched alkenyl, or C 4 -C 18 branched alkynyl.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib) (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 is a branched alkane of C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , or C18 C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 branched alkenyl, or C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 branched alkynyl.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 is C1, C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 hydrocarbon group, or C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 heterohydrocarbon group containing O or S.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 is a C1 - C18 straight-chain alkyl group, or a C2 - C18 straight-chain alkenyl group, or a C2 - C18 straight-chain alkynyl group, or a C1 - C18 straight-chain heteroalkyl group containing O or S, or a C2 - C18 straight-chain heteroalkenyl group containing O or S, or a straight-chain heteroalkynyl group containing O or S.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 is a C1 , C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 straight-chain alkyl group, or a C2 , C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 straight-chain alkenyl group, or a C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11, C12, C13, C14, C15 , C16, C17, C18 straight-chain alkenyl group C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 is a C3 - C18 branched alkyl group, or a C3 - C18 branched alkenyl group, or a C4 - C18 branched alkynyl group, or a C3 - C18 branched heteroalkyl group containing O or S, or a C3 - C18 branched heteroalkenyl group containing O or S, or a C4 - C18 branched heteroalkynyl group containing O or S.
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 is a branched -chain alkyl group of C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11, C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched-chain alkenyl group of C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched-chain alkenyl group of C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 C 15 , C 16 , C 17 , C 18 branched alkynyl, or C 3 , C 4 , C 5 , C 6 , C 7
- the present disclosure provides an amino lipid compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 is C1, C2 , C3 , C4 , C5 , C6 , C7, C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 hydrocarbon group, or C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 heterohydrocarbon group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 is a C1 - C18 straight-chain alkyl group, or a C2 - C18 straight-chain alkenyl group, or a C2 - C18 straight-chain alkynyl group, or a C1 - C18 straight-chain heteroalkyl group containing O or S, or a C2 - C18 straight-chain heteroalkenyl group containing O or S, or a C2 - C18 straight-chain heteroalkynyl group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 is a C1 , C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15, C16 , C17 , C18 straight-chain alkyl group, or a C2 , C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 straight-chain alkenyl group, or a C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11, C12, C13, C14, C15 , C16, C17, C18 straight-chain alkenyl group .
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 is a C3 - C18 branched alkyl group, or a C3 - C18 branched alkenyl group, or a C4 - C18 branched alkynyl group, or a C3 - C18 branched heteroalkyl group containing O or S, or a C3 - C18 branched heteroalkenyl group containing O or S, or a C4 - C18 branched heteroalkynyl group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 is a branched- chain alkyl group of C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11, C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched-chain alkenyl group of C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched-chain alkenyl group of C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 C 15 , C 16 , C 17 , C 18 branched alkynyl, or C 3 , C 4 , C 5 , C 6 , C 7 ,
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R2 is H or C1 , C2 , C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , or C18 hydrocarbon group.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R2 is H, a C1 - C18 straight-chain alkyl group, a C2 - C18 straight-chain alkenyl group, or a C2 - C18 straight-chain alkynyl group.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R2 is a straight-chain alkyl group of C1 , C2 , C3 , C4 , C5, C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a straight-chain alkenyl group of C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 straight chain alkynyl.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 2 is H, C 3 -C 18 branched alkyl, C 3 -C 18 branched alkenyl, or C 4 -C 18 branched alkynyl.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R2 is a branched alkyl group of C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched alkenyl group of C3 , C4 , C5 , C6 , C7 , C8 , C9, C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched alkenyl group of C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 C 15 , C 16 , C 17 , C 18 branched alkynyl.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 10 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 hydrocarbon group, or C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 heterohydrocarbon group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R10 is a C1 - C18 straight-chain alkyl group, a C2 - C18 straight-chain alkenyl group, a C2 - C18 straight-chain alkynyl group, or a C1 - C18 straight-chain alkyl group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R10 is a straight-chain alkyl group of C1 , C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a straight-chain alkenyl group of C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 straight-chain alkynyl, or C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 10 is a C 3 -C 18 branched alkyl group, or a C 3 -C 18 branched alkenyl group, or a C 4 -C 18 branched alkynyl group, or a C 3 -C 18 branched heteroalkyl group containing O or S, or a C 3 -C 18 branched heteroalkenyl group containing O or S, or a C 4 -C 18 branched heteroalkynyl group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R10 is a branched -chain alkyl group of C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11, C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched-chain alkenyl group of C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , or a branched-chain alkenyl group of C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 C 15 , C 16 , C 17 , C 18 branched alkynyl, or C 3 , C 4 , C 5 , C 6 , C 7
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa) or (IIb) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 11 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 hydrocarbon group, or C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 heterohydrocarbon group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or A pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 11 is a C 1 -C 18 straight-chain alkyl group, or a C 2 -C 18 straight-chain alkenyl group, or a C 2 -C 18 straight-chain alkynyl group, or a C 1 -C 18 straight-chain heteroalkyl group containing O or S, or a C 2 -C 18 straight-chain heteroalkenyl group containing O or S, or a C 2 -C 18 straight-chain heteroalkynyl group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 11 is a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7, C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 straight-chain alkyl group, or a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 straight-chain alkenyl group, or a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 straight-chain alkynyl, or C 1 , C 2 , C 3 , C 4 , C 5
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 11 is a C 3 -C 18 branched alkyl group, or a C 3 -C 18 branched alkenyl group, or a C 4 -C 18 branched alkynyl group, or a C 3 -C 18 branched heteroalkyl group containing O or S, or a C 3 -C 18 branched heteroalkenyl group containing O or S, or a C 4 -C 18 branched heteroalkynyl group containing O or S.
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 11 is a branched alkyl group of C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , or a branched alkenyl group of C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , or C 15 , C 16 , C 17 , C 18 branched alkynyl, or C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12, C 13 , C 14 , C 15 , C 16 , C 17 , C 18 branched heteroalkyl containing O or S, or C 3
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (Va), (Vb), (Vc) or (Vd) as described above, or A pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- hydrocarbyl, hydrocarbylene, alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene and heterohydrocarbyl groups are optionally substituted;
- hydrocarbyl, hydrocarbylene, alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene and heterohydrocarbyl groups are optionally substituted with hydroxy, ester, hydrocarbyloxy, hydrocarbyl, halogen, oxygen, sulfur, amino, amido groups.
- the present disclosure provides an amino lipid compound represented by the following formula (II-I):
- A1 , A2 and A3 are one of the following:
- A1 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene or a bond
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a nitrogen-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene
- A1 and A3 together with the nitrogen atom to which they are commonly attached form a N-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1- C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene
- A1 , A2 and A3 together with the nitrogen atom to which they are commonly attached form a spiro heterocycle, fused heterocycle or bridged heterocycle containing N;
- a 4 is a C 1 ⁇ C 5 alkylene group or a bond
- a 5 , A 6 , A 7 , A 8 and A 12 are each independently a C 1 -C 18 alkylene group or a bond;
- X is C or N
- R 1 is H, C 1 -C 24 hydrocarbon group, C 1 -C 24 heterohydrocarbon group, Z 6 R 8 or -CH(OR 9 ) 2 ;
- R 2 is H, C 1 -C 24 hydrocarbon group, C 1 -C 24 heterohydrocarbon group, Z 7 R 10 or -CH(OR 11 ) 2 ;
- Z 3 and Z 4 are each independently -O-, -N(R 6 )-, -S- or a bond;
- Z 5 is -O- or -S-;
- R 6 are each independently H or C 1 -C 8 hydrocarbon group
- R8 and R10 are each independently H, C1 - C24 hydrocarbon group or C1 - C24 heterohydrocarbon group containing O or S;
- R9 and R11 are each independently a C1 - C24 hydrocarbon group or a C1 - C24 heterohydrocarbon group containing O or S;
- a 9 is a C 1 ⁇ C 8 alkylene group or a bond
- a 10 and A 11 are each independently a C 1 -C 8 hydrocarbon group
- the hydrocarbon group is an alkyl group, an alkenyl group or an alkynyl group;
- the alkylene group is an alkylene group, an alkenylene group or an alkynylene group;
- the heteroalkyl group is a heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group;
- the heteroalkylene group is a heteroalkylene group, a heteroalkenylene group or a heteroalkynylene group.
- the present disclosure provides an amino lipid compound represented by the following formula (II-I):
- A1 , A2 and A3 are one of the following:
- A1 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene or a bond
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a N-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene
- A1 and A3 together with the nitrogen atom to which they are commonly attached form a N-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1- C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene
- A1 , A2 and A3 together with the nitrogen atom to which they are commonly attached form a spiro heterocycle, fused heterocycle or bridged heterocycle containing N;
- a 4 is a C 1 ⁇ C 5 alkylene group or a bond
- a 5 , A 6 , A 7 , A 8 and A 12 are each independently C 1 -C 18 alkylene, C 1 -C 18 heteroalkylene or a bond;
- X is C or N
- R1 is H, C1 - C24 hydrocarbon group, C1 - C24 heterohydrocarbon group, Z6R8 , -C ( R6 ) ( OA13Z8R9 ) 2 , -C ( R6 )( SA13Z8R9 ) 2 , or -C( R6 )( SA13Z8R9 )( OA13Z8R9 ) ;
- R 2 is H, C 1 -C 24 hydrocarbon group, C 1 -C 24 heterohydrocarbon group, Z 7 R 10 , -C(R 6 )(OA 14 Z 9 R 11 ) 2 , -C(R 6 )(SA 14 Z 9 R 11 ) 2 , or -C(R 6 )(SA 14 Z 9 R 11 )(OA 14 Z 9 R 11 );
- Z 3 and Z 4 are each independently -O-, -N(R 6 )-, -S- or a bond;
- Z 5 is -O- or -S-;
- R 6 are each independently H or C 1 -C 8 hydrocarbon group
- R8 and R10 are each independently H, C1 - C24 hydrocarbon group or C1 - C24 heterohydrocarbon group containing O or S;
- R9 and R11 are each independently a C1 - C24 hydrocarbon group or a C1 - C24 heterohydrocarbon group containing O or S;
- a 9 is a C 1 ⁇ C 8 alkylene group or a bond
- a 10 and A 11 are each independently a C 1 -C 8 hydrocarbon group
- a 13 and A 14 are each independently C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene or a bond;
- the hydrocarbon group is an alkyl group, an alkenyl group or an alkynyl group;
- the alkylene group is an alkylene group, an alkenylene group or an alkynylene group;
- the heteroalkyl group is a heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group;
- the heteroalkylene group is a heteroalkylene group, a heteroalkenylene group or a heteroalkynylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, when applicable, comprising one or more of the following features.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 is H and A2 is H; or A1 is H and A2 is not H; or A1 is not H and A2 is H.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable or a stereoisomer thereof, wherein:
- A1 and A2 are each independently C1 , C2 , C3 , C4 , C5 hydrocarbon group, or C1 , C2 , C3 , C4 , C5 heterohydrocarbon group, or C1, C2 , C3 , C4 , C5 hydrocarbon group, or C1 , C2 , C3 , C4 , C5 heterohydrocarbon group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 are each independently C1 - C5 alkyl, or C2 - C5 alkenyl having 1 or 2 double bonds, or C2 - C5 alkynyl having 1 or 2 triple bonds, or C1 - C5 heteroalkyl containing S or O, or C2 - C5 heteroalkenyl containing S or O having 1 or 2 double bonds, or C2 - C5 heteroalkynyl containing S or O having 1 or 2 triple bonds, or C1 - C5 alkylene, or C2 - C5 alkenylene having 1 or 2 double bonds, or C2 - C5 alkynylene having 1 or 2 triple bonds, or C1 - C5 heteroalkylene containing S or O, or C2 - C5 heteroalkenylene containing S or O having 1 or 2 double bonds, or C2 - C5 heteroalkynylene containing S or O having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and/or A2 is an unsubstituted C1 - C5 hydrocarbon group, or an unsubstituted C1 - C5 heterohydrocarbon group, or an unsubstituted C1 - C5 hydrocarbonylene group, or an unsubstituted C1 - C5 heterohydrocarbonylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and/or A2 is/are substituted C1 - C5 hydrocarbon group, or substituted C1 - C5 heterohydrocarbon group, or substituted C1 - C5 hydrocarbonylene group, or substituted C1- C5 heterohydrocarbonylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and/or A2 is/are substituted C1 - C5 alkyl, or substituted C2- C5 alkenyl, or substituted C3 - C5 alkynyl, or substituted C1 - C5 alkylene, or substituted C2 - C5 alkenylene, or substituted C3 - C5 alkynylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 12 is each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, and C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and/or A2 is
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and/or A2 can also be
- a is 1, 2, 3, 4 or 5;
- a is 1, 2 or 3.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a key.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is C 1 , C 2 , C 3 , C 4 , or C 5 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a C 1 -C 5 alkylene group, or a C 2 -C 5 alkenylene group having 1 or 2 double bonds, or a C 2 -C 5 alkynylene group having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable or a stereoisomer thereof, wherein:
- a 3 is unsubstituted C 1 -C 5 alkylene, or unsubstituted C 2 -C 5 alkenylene, or unsubstituted C 3 -C 5 alkynylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a substituted C 1 -C 5 alkylene group, a substituted C 2 -C 5 alkenylene group, or a substituted C 3 -C 5 alkynylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 When the dashed line connecting A1 and A2 is a bond and the dashed line connecting A1 and A3 is absent, A1 and A2 together with the nitrogen atom to which they are commonly attached form a three-membered, four-membered, five-membered, six-membered, seven-membered or eight-membered heterocyclic ring containing N.
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a N-containing four-membered, five-membered, or six-membered heterocyclic ring.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A3 When the dashed line connecting A1 and A3 is a bond and the dashed line connecting A1 and A2 is absent, A1 and A3 together with the nitrogen atom to which they are commonly attached form a three-membered, four-membered, five-membered, six-membered, seven-membered or eight-membered heterocyclic ring containing N.
- A1 and A3 together with the nitrogen atom to which they are commonly attached form a N-containing three-membered, four-membered, five-membered, or six-membered heterocyclic ring.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- c is 1, 2, 3, 4 or 5;
- c is 2, 3 or 4;
- c is 2 or 3.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 4 is a key.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 4 is C 1 , C 2 , C 3 , C 4 , or C 5 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 4 is a C 1 -C 5 alkylene group, or a C 2 -C 5 alkenylene group having 1 or 2 double bonds, or a C 2 -C 5 alkynylene group having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 4 is unsubstituted C 1 -C 5 alkylene, or unsubstituted C 2 -C 5 alkenylene, or unsubstituted C 3 -C 5 alkynylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 4 is a substituted C 1 -C 5 alkylene group, or a substituted C 2 -C 5 alkenylene group, or a substituted C 3 -C 5 alkynylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 5 , A 6 , A 7 , A 8 and A 12 are each independently a C 1 -C 18 alkylene group or a bond.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A5 , A6 , A7 , A8 and A12 are each independently C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 alkylene group or a bond.
- a 5 , A 6 , A 7 , A 8 , and A 12 are each independently a bond.
- A5 , A6 , A7 , A8 and A12 are each independently C1 , C2 , C3, C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 alkylene .
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 5 , A 6 , A 7 , A 8 and A 12 are each independently a C 1 -C 18 alkylene group, or a C 2 -C 18 alkenylene group having 1, 2, 3 or more double bonds, or a C 2 -C 18 alkynylene group having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A12 is C2 , C3 , C4 , C5 , C6 , C7, C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 or C18 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A12 is a bond, and A5 and A6 are not C1 alkylene groups at the same time.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A7 and A8 are each independently C1 , C2 , C3 , C4 , C5 , C6 , C7 alkylene or a bond.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A12 is a C1 alkylene group
- A5 is a C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13, C14 , C15 , C16 , C17 , or C18 alkylene group
- A6 is a C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , or C18 alkylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A5 and/or A6 are unsubstituted C1 - C12 alkylene, or unsubstituted C2 - C12 alkenylene, or unsubstituted C3 - C12 alkynylene.
- A5 and/or A6 are unsubstituted C1 - C12 alkylene, or unsubstituted C3 - C9 alkylene, or unsubstituted C4 - C9 alkylene, or unsubstituted C5 - C8 alkylene, or unsubstituted C8 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A5 and/or A6 are substituted C1- C12 alkylene, or substituted C2 - C12 alkenylene, or substituted C3 - C12 alkynylene.
- A5 and/or A6 are substituted C1 - C12 alkylene, or substituted C3 - C9 alkylene, or substituted C4 - C9 alkylene, or substituted C5 - C8 alkylene, or substituted C8 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A7 and/or A8 are unsubstituted C1 - C12 alkylene, or unsubstituted C2 - C12 alkenylene, or unsubstituted C3 - C12 alkynylene.
- A7 and/or A8 are unsubstituted C1 - C5 alkylene, or unsubstituted C2 - C4 alkylene, or unsubstituted C3 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A7 and/or A8 are substituted C1 - C12 alkylene, or substituted C2 - C12 alkenylene, or substituted C3 - C12 alkynylene.
- A7 and/or A8 are substituted C1 - C5 alkylene, or substituted C2 - C4 alkylene, or substituted C3 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 12 is an unsubstituted C 1 -C 12 alkylene group, or an unsubstituted C 2 -C 12 alkenylene group, or an unsubstituted C 3 -C 12 alkynylene group.
- a 12 is an unsubstituted C 1 -C 5 alkylene group, or an unsubstituted C 1 -C 3 alkylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 12 is a substituted C 1 -C 12 alkylene group, or a substituted C 2 -C 12 alkenylene group, or a substituted C 3 -C 12 alkynylene group.
- a 12 is a substituted C 1 -C 5 alkylene group, or a substituted C 1 -C 3 alkylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 9 is a key.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A9 is C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 alkylene, or C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 heteroalkylene. base.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 9 is a C 1 -C 8 alkylene group, or a C 2 -C 8 alkenylene group having 1, 2 or more double bonds, or a C 2 -C 8 alkynylene group having 1, 2 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each A 9 is each independently an unsubstituted C 1 -C 8 alkylene group, or an unsubstituted C 2 -C 8 alkenylene group, or an unsubstituted C 3 -C 8 alkynylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- At least one of A 9 is a substituted C 1 -C 8 alkylene group, a substituted C 2 -C 8 alkenylene group, or a substituted C 3 -C 8 alkynylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A10 and A11 are each independently a C1 , C2 , C3 , C4, C5 , C6 , C7 , or C8 hydrocarbon group, or a C1 , C2 , C3 , C4 , C5 , C6 , C7 , or C8 heterohydrocarbon group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each A 10 and each A 11 are each independently a C 1 -C 8 alkyl group, or a C 2 -C 8 alkenyl group having 1, 2 or more double bonds, or a C 2 -C 8 alkenyl group having 1, 2 or more double bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each A 10 and/or each A 11 is an unsubstituted C 1 -C 8 alkyl group, or an unsubstituted C 2 -C 8 alkenyl group, or an unsubstituted C 3 -C 8 alkynyl group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- each A 10 and/or each A 11 is a substituted C 1 -C 8 alkyl group, or a substituted C 2 -C 8 alkenyl group, or a substituted C 3 -C 8 alkynyl group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R13 and/or R14 may be connected to the C atom of the substituted A10 or A11 to form a three-membered ring, a four - membered ring, a five-membered ring or a six -membered ring.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 5 is an unsubstituted C 1 -C 8 alkyl, or an unsubstituted C 2 -C 8 alkenyl, or an unsubstituted C 2 -C 8 alkynyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 5 is a substituted C 1 -C 8 alkyl, or a substituted C 2 -C 8 alkenyl, or a substituted C 2 -C 8 alkynyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and R2 are each independently C1 , C2 , C3 , C4 , C5, C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13, C14 , C15 , C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23 , C24 hydrocarbon groups, or C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13, C14, C15 , C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23, C24 hydrocarbon groups . , C 20 , C 21 , C 22 , C 23 , C 24 heteroalkyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and/or R2 are C1 - C24 alkyl groups (e.g., C5 - C16 alkyl groups, C6 - C14 alkyl groups, C6 - C12 alkyl groups), C2 - C24 alkenyl groups (e.g., C5 - C16 alkenyl groups, C6 - C14 alkenyl groups, C6 - C12 alkenyl groups), or C2 - C24 alkynyl groups (e.g., C5 - C16 alkynyl groups, C6 - C14 alkynyl groups, C6 - C12 alkynyl groups).
- C1 - C24 alkyl groups e.g., C5 - C16 alkyl groups, C6 - C14 alkyl groups, C6 - C12 alkyl groups
- C2 - C24 alkenyl groups e.g., C5 - C16 alkenyl groups, C6 - C
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and/or R2 are unsubstituted C1 - C24 alkyl (e.g., unsubstituted C5-C16 alkyl, unsubstituted C6-C14 alkyl, unsubstituted C6-C12 alkyl), unsubstituted C2-C24 alkenyl (e.g.
- unsubstituted C5 -C16 alkenyl unsubstituted C6-C14 alkenyl , unsubstituted C6 - C12 alkenyl
- unsubstituted C2 - C24 alkynyl e.g., unsubstituted C5 - C16 alkynyl, unsubstituted C6 - C14 alkynyl, unsubstituted C6 - C12 alkynyl ).
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable or a stereoisomer thereof, wherein:
- R1 and/or R2 are substituted C1 - C24 alkyl (e.g., substituted C5-C16 alkyl, substituted C6-C14 alkyl, substituted C6-C12 alkyl), substituted C2-C24 alkenyl (e.g. , substituted C5 - C16 alkenyl , substituted C6 - C14 alkenyl, substituted C6 - C12 alkenyl), substituted C2 - C24 alkynyl (e.g., substituted C5 - C16 alkynyl, substituted C6 - C14 alkynyl, substituted C6 -C12 alkynyl , substituted C10 alkynyl).
- C1 - C24 alkyl e.g., substituted C5-C16 alkyl, substituted C6-C14 alkyl, substituted C6-C12 alkyl
- substituted C2-C24 alkenyl e.g.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and R2 are each independently a C1 - C24 straight-chain alkyl group, or a C2 - C24 straight-chain alkenyl group having 1, 2, 3, 4 or more double bonds, or a C2 - C24 straight-chain alkynyl group having 1, 2, 3, 4 or more triple bonds, or a C1 - C24 straight-chain heteroalkyl group containing O or S, or a C2 - C24 straight-chain heteroalkenyl group containing O or S having 1, 2, 3, 4 or more double bonds, or a C2 - C24 straight-chain heteroalkynyl group containing O or S having 1, 2, 3, 4 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and R2 are each independently C1 , C2 , C3 , C4 , C5, C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23 , C24 straight chain alkyl, or C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9, C10 , C11 , C12 , C13, C14, C15 , C16 , C17 , C18 , C19, C20 , C21 , C22 , C23 , C24 straight chain alkyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and R2 are each independently a C3 - C24 branched alkyl, or a C3 - C24 branched alkenyl having 1, 2, 3, 4 or more double bonds, or a C4 - C24 branched alkynyl having 1, 2, 3, 4 or more triple bonds, or a C3 - C24 branched heteroalkyl containing O or S, or a C3 - C24 branched heteroalkenyl containing O or S having 1, 2, 3, 4 or more double bonds, or a C4 - C24 branched heteroalkynyl containing O or S having 1, 2, 3, 4 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and R2 are each independently C3 , C4 , C5 , C6 , C7, C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19, C20 , C21 , C22 , C23 , C24 branched alkyl, or C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16, C17, C18 , C19 , C20 , C21 , C22 , C23 , C24 branched alkyl .
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable or a stereoisomer thereof, wherein:
- R8 and R10 are each independently C1 , C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23 , C24 hydrocarbon groups, or C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13, C14, C15 , C16 , C17 , C18 , C19 , C20 , C21, C22 , C23, C24 hydrocarbon groups.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and/or R10 are C1 - C20 alkyl groups (e.g., C2 - C10 alkyl, C2 - C8 alkyl, C7 - C18 alkyl), or C1 - C16 alkenyl groups (e.g. , C5-C12 alkenyl, C5-C8 alkenyl , C5 alkenyl , C6 alkenyl), or C5 - C16 alkynyl groups (e.g., C5 - C12 alkynyl, C10 alkynyl).
- C1 - C20 alkyl groups e.g., C2 - C10 alkyl, C2 - C8 alkyl, C7 - C18 alkyl
- C1 - C16 alkenyl groups e.g. , C5-C12 alkenyl, C5-C8 alkenyl , C5 alkenyl , C6 alkenyl
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and/or R10 are unsubstituted C1 - C20 alkyl (e.g. unsubstituted C2 - C10 alkyl, unsubstituted C2 - C8 alkyl, unsubstituted C7- C18 alkyl), or unsubstituted C1 - C16 alkenyl (e.g. unsubstituted C5 - C12 alkenyl, unsubstituted C5 - C8 alkenyl, unsubstituted C5 alkenyl, unsubstituted C6 alkenyl), or unsubstituted C5-C16 alkynyl ( e.g. unsubstituted C5 - C12 alkynyl, unsubstituted C10 alkynyl).
- C1 - C20 alkyl e.g. unsubstituted C2 - C10 alkyl, unsubstituted C2 -
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and/or R10 is a substituted C1 - C20 alkyl group (e.g., a substituted C2 - C10 alkyl group, a substituted C2 - C8 alkyl group, a substituted C7 - C18 alkyl group), or a substituted C1 - C16 alkenyl group (e.g., a substituted C5 - C12 alkenyl group, a substituted C5 - C8 alkenyl group, a substituted C5 alkenyl group, a substituted C6 alkenyl group), or a substituted C5 - C16 alkynyl group (e.g., a substituted C5 - C12 alkynyl group, a substituted C10 alkynyl group).
- a substituted C1 - C20 alkyl group e.g., a substituted C2 - C10 alkyl group, a substituted C2 - C8 alkyl
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and R10 are each independently a C1 - C24 straight-chain alkyl group, or a C2 - C24 straight-chain alkenyl group having 1, 2, 3, 4 or more double bonds, or a C2 - C24 straight-chain alkynyl group having 1, 2, 3, 4 or more triple bonds, or a C1 - C24 straight-chain heteroalkyl group containing O or S, or a C2 - C24 straight-chain heteroalkenyl group containing O or S having 1, 2, 3, 4 or more double bonds, or a C2 - C24 straight-chain heteroalkynyl group containing O or S having 1, 2, 3, 4 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and R10 are each independently C1 , C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23 , C24 straight chain alkyl, or C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10, C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19 C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13, C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 ,
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and R10 are each independently a C3 - C24 branched alkyl, or a C3 - C24 branched alkenyl having 1, 2, 3, 4 or more double bonds, or a C4 - C24 branched alkynyl having 1, 2, 3, 4 or more triple bonds, or a C3 - C24 branched heteroalkyl containing O or S, or a C3 - C24 branched heteroalkenyl containing O or S having 1, 2, 3, 4 or more double bonds, or a C4 - C24 branched heteroalkynyl containing O or S having 1, 2, 3, 4 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and R10 are each independently C3 , C4 , C5 , C6, C7 , C8, C9 , C10 , C11 , C12 , C13 , C14 , C15, C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23 , C24 branched alkyl, or C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16, C17, C18 , C19 , C20 , C21 , C22 , C23 , C24 branched alkyl .
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 8 and/or R 10 are each independently substituted aryl.
- R 8 or R 10 is a phenyl substituted by an alkyl group, for example:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R8 and R10 are each independently
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 6 is each independently C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 hydrocarbon group, or C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 heterohydrocarbon group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable or a stereoisomer thereof, wherein:
- R 6 is each independently a C 1 -C 8 alkyl group, or a C 2 -C 8 alkenyl group having 1, 2 or more double bonds, or a C 2 -C 8 alkynyl group having 1, 2 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 6 is each independently C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 or C 8 alkyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each R 6 is independently an unsubstituted C 1 -C 8 alkyl, or an unsubstituted C 2 -C 8 alkenyl, or an unsubstituted C 2 -C 8 alkynyl, or an unsubstituted C 1 -C 8 heteroalkyl, or an unsubstituted C 2 -C 8 heteroalkenyl, or an unsubstituted C 2 -C 8 heteroalkynyl.
- R 6 is independently an unsubstituted C 1 -C 5 alkyl, an unsubstituted C 1 -C 3 alkyl, or an unsubstituted C 1 alkyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- each R 6 is a substituted C 1 -C 8 alkyl, or a substituted C 2 -C 8 alkenyl, or a substituted C 2 -C 8 alkynyl.
- one of each R 6 is a substituted C 1 -C 5 alkyl, a substituted C 1 -C 3 alkyl, or a substituted C 3 alkyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 13 and A 14 are each independently C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 alkylene, or C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 heteroalkylene, or a bond.
- a 13 and A 14 are each independently a bond.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 13 and A 14 are each independently a C 1 -C 8 alkylene group, or a C 2 -C 8 alkenylene group having 1, 2 or more double bonds, or a C 2 -C 8 alkynylene group having 1, 2 or more triple bonds, or a bond.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each A 13 and each A 14 are each independently a C 1 -C 8 alkylene group, a C 2 -C 8 alkenylene group or a C 2 -C 8 alkynylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each A 13 and/or each A 14 is an unsubstituted C 1 -C 8 alkylene group, or an unsubstituted C 2 -C 8 alkenylene group, or an unsubstituted C 2 -C 8 alkynylene group.
- a 13 and A 14 are each independently an unsubstituted C 2 -C 5 alkylene group or an unsubstituted C 3 -C 4 alkylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- each A 13 and/or each A 14 is a substituted C 1 -C 8 alkylene group, or a substituted C 2 -C 8 alkenylene group, or a substituted C 2 -C 8 alkynylene group.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 and R11 are each independently C1 , C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23 , C24 hydrocarbon groups, or C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8, C9 , C10 , C11 , C12 , C13, C14, C15 , C16 , C17 , C18 , C19 , C20 , C21, C22 , C23, C24 hydrocarbon groups.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each R 9 is independently C 1 -C 12 alkyl (e.g., C 3 -C 9 alkyl, C 5 -C 8 alkyl, C 6 alkyl, C 7 alkyl), C 5 -C 16 alkenyl (e.g., C 5 -C 12 alkenyl, C 5 -C 8 alkenyl, C 6 alkenyl), C 5 -C 16 alkynyl (e.g., C 9 -C 11 alkynyl, C 10 alkynyl).
- C 5 -C 12 alkyl e.g., C 3 -C 9 alkyl, C 5 -C 8 alkyl, C 6 alkyl, C 7 alkyl
- C 5 -C 16 alkenyl e.g., C 5 -C 12 alkenyl, C 5 -C 8 alkenyl, C 6 alkenyl
- C 5 -C 16 alkynyl e.g., C 9 -C 11 al
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each R9 is an unsubstituted C1 - C12 alkyl group (e.g., an unsubstituted C3 - C9 alkyl group, an unsubstituted C5 - C8 alkyl group, an unsubstituted C6 alkyl group, an unsubstituted C7 alkyl group), an unsubstituted C5 - C16 alkenyl group (e.g., an unsubstituted C5 - C12 alkenyl group, an unsubstituted C5 - C8 alkenyl group, an unsubstituted C6 alkenyl group), an unsubstituted C5 - C16 alkynyl group (e.g., an unsubstituted C9 - C11 alkynyl group, an unsubstituted C10 alkynyl group).
- an unsubstituted C1 - C12 alkyl group e.g.,
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- each R 9 is a substituted C 1 -C 12 alkyl group (for example, a substituted C 3 -C 9 alkyl group, a substituted C 5 -C 8 alkyl group, a substituted C 6 alkyl group, a substituted C 7 alkyl group), a substituted C 5 -C 16 alkenyl group (for example, a substituted C 5 -C 12 alkenyl group, a substituted C 5 -C 8 alkenyl group, a substituted C 6 alkenyl group), or a substituted C 5 -C 16 alkynyl group (for example, a substituted C 9 -C 11 alkynyl group, a substituted C 10 alkynyl group).
- a substituted C 1 -C 12 alkyl group for example, a substituted C 3 -C 9 alkyl group, a substituted C 5 -C 8 alkyl group, a substituted C 6 alkyl group, a substituted C 7
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each R 11 is independently C 1 -C 12 alkyl (e.g., C 3 -C 9 alkyl, C 5 -C 8 alkyl, C 6 alkyl, C 7 alkyl), C 5 -C 16 alkenyl (e.g., C 5 -C 12 alkenyl, C 5 -C 8 alkenyl, C 6 alkenyl), C 5 -C 16 alkynyl (e.g., C 9 -C 11 alkynyl, C 10 alkynyl).
- C 5 -C 12 alkyl e.g., C 3 -C 9 alkyl, C 5 -C 8 alkyl, C 6 alkyl, C 7 alkyl
- C 5 -C 16 alkenyl e.g., C 5 -C 12 alkenyl, C 5 -C 8 alkenyl, C 6 alkenyl
- C 5 -C 16 alkynyl e.g., C 9 -C 11 al
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Each R 11 is an unsubstituted C 1 -C 12 alkyl group (e.g., an unsubstituted C 3 -C 9 alkyl group, an unsubstituted C 5 -C 8 alkyl group, an unsubstituted C 6 alkyl group, an unsubstituted C 7 alkyl group), an unsubstituted C 5 -C 16 alkenyl group (e.g., an unsubstituted C 5 -C 12 alkenyl group, an unsubstituted C 5 -C 8 alkenyl group, an unsubstituted C 6 alkenyl group), an unsubstituted C 5 -C 16 alkynyl group (e.g., an unsubstituted C 9 -C 11 alkynyl group, an unsubstituted C 10 alkynyl group).
- an unsubstituted C 1 -C 12 alkyl group e.g.,
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- each R 11 is a substituted C 1 -C 12 alkyl group (for example, a substituted C 3 -C 9 alkyl group, a substituted C 5 -C 8 alkyl group, a substituted C 6 alkyl group, a substituted C 7 alkyl group), a substituted C 5 -C 16 alkenyl group (for example, a substituted C 5 -C 12 alkenyl group, a substituted C 5 -C 8 alkenyl group, a substituted C 6 alkenyl group), or a substituted C 5 -C 16 alkynyl group (for example, a substituted C 9 -C 11 alkynyl group, a substituted C 10 alkynyl group).
- a substituted C 1 -C 12 alkyl group for example, a substituted C 3 -C 9 alkyl group, a substituted C 5 -C 8 alkyl group, a substituted C 6 alkyl group, a substituted C 7
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 and R11 are each independently a C1 - C24 straight-chain alkyl group, or a C2 - C24 straight-chain alkenyl group having 1, 2, 3, 4 or more double bonds, or a C2 - C24 straight-chain alkynyl group having 1, 2, 3, 4 or more triple bonds, or a C1 - C24 straight-chain heteroalkyl group containing O or S, or a C2 - C24 straight-chain heteroalkenyl group containing O or S having 1, 2, 3, 4 or more double bonds, or a C2 - C24 straight-chain heteroalkynyl group containing O or S having 1, 2, 3, 4 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 and R11 are each independently C1 , C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19 , C20 , C21 , C22 , C23 , C24 straight chain alkyl, or C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10, C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 , C19 C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13, C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 ,
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 and R11 are each independently a C3 - C24 branched alkyl, or a C3 - C24 branched alkenyl having 1, 2, 3, 4 or more double bonds, or a C4 - C24 branched alkynyl having 1, 2, 3, 4 or more triple bonds, or a C3 - C24 branched heteroalkyl containing O or S, or a C3 - C24 branched heteroalkenyl containing O or S having 1, 2, 3, 4 or more double bonds, or a C4 - C24 branched heteroalkynyl containing O or S having 1, 2, 3, 4 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 and R11 are each independently C3 , C4 , C5 , C6, C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15, C16 , C17 , C18 , C19, C20 , C21 , C22 , C23 , C24 branched alkyl, or C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16, C17, C18 , C19 , C20 , C21 , C22 , C23 , C24 branched alkyl .
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 and/or R11 is C1 - C12 alkyl ( C3 -C9 alkyl , C5 - C8 alkyl , C6 alkyl , C7 alkyl ) , C5-C16 alkenyl (e.g.
- R 13 and/or R 14 can be connected to the C atom on the substituted R 9 or R 11 to form a three-membered ring, a four-membered ring, a five-membered ring or a six-membered ring.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein at least one of each R 9 and/or each R 11 is independently a substituted aryl group.
- R 9 and R 11 are phenyl groups substituted with an alkyl group, for example:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R9 and R11 are each independently
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Z 8 are each independently a bond.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- Z 9 are each independently a bond.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 1 is H, a C 1 -C 24 hydrocarbon group, a C 1 -C 24 heterohydrocarbon group, Z 6 R 8 or -CH(OR 9 ) 2 .
- R 1 is -CH(OR 9 ) 2 .
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 2 is H, a C 1 -C 24 hydrocarbon group, a C 1 -C 24 heterohydrocarbon group, Z 7 R 10 or -CH(OR 11 ) 2 .
- R 2 is -CH(OR 11 ) 2 .
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 13 is each independently C 1 -C 12 alkylene, C 2 -C 12 alkenylene having 1, 2, 3 or more double bonds, C 2 -C 12 alkynylene having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkylene containing S or O, C 2 -C 12 heteroalkenylene containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynylene containing S or O having 1, 2, 3 or more triple bonds;
- R 14 is each independently H, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a C 2 -C 24 alkynyl e.g., a C 5 -C 16 alkynyl, a C 6 -C 14 alkynyl, a C 6 -C 12 alkynyl, a C 10 alkynyl
- R 13 and/or R 14 may be connected to the C atom
- R 14 can also be independently substituted aryl, substituted cycloalkyl or substituted heterocyclic.
- R 14 is aryl substituted by alkyl.
- R 14 is phenyl substituted by alkyl, for example:
- R 14 is unsubstituted cycloalkyl, such as cyclobutyl, cyclopentyl, or cyclohexyl.
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 1 and R 2 are each independently a C 5 -C 16 alkyl substituted by a hydroxyl group, for example, a C 6 -C 14 alkyl substituted by a hydroxyl group, a C 6 -C 12 alkyl substituted by a hydroxyl group, or a C 10 alkyl substituted by a hydroxyl group.
- R 1 and R 2 are each independently a C 10 alkyl group, for example:
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R1 and R2 are each independently
- the present disclosure provides an amino lipid compound of formula (II-I) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein R 1 is Z 6 R 8 or -CH(OR 9 ) 2 , and R 2 is Z 7 R 10 or -CH(OR 11 ) 2 .
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-Ia):
- A1 is H, C1 - C5 hydrocarbon group or C1 - C5 heterohydrocarbon group;
- A2 is H, C1 - C5 hydrocarbon group or C1 - C5 heterohydrocarbon group;
- a 3 is a C 1 ⁇ C 5 alkylene group or a bond
- A4 , A5 , A6 , A7, A8 , Z1 , Z2 , Y1 , X, R1 , R2 and A12 are as defined in formula (II-I).
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, when applicable, comprising one or more of the following features.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 are each independently H.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 are each independently C1 , C2 , C3 , C4 , or C5 hydrocarbon groups, or C1 , C2 , C3 , C4 , or C5 heterohydrocarbon groups.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 are each independently a C1 - C5 alkyl, or a C2 - C5 alkenyl having 1 or 2 double bonds, or a C2 - C5 alkynyl having 1 or 2 triple bonds, or a C1 - C5 heteroalkyl containing S or O, or a C2 - C5 heteroalkenyl containing S or O having 1 or 2 double bonds, or a C2 - C5 heteroalkynyl containing S or O having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 12 is each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 are each independently
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 can also be independently
- a is 1, 2, 3, 4 or 5;
- a is 1, 2 or 3.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a key.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is C 1 , C 2 , C 3 , C 4 , or C 5 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a C 1 -C 5 alkylene group, or a C 2 -C 5 alkenylene group having 1 or 2 double bonds, or a C 2 -C 5 alkynylene group having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ia) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- c is 1, 2, 3, 4 or 5;
- c is 2, 3 or 4;
- c is 2 or 3.
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-Ib):
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- a 3 is a C 1 ⁇ C 5 alkylene group or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a N-containing heterocyclic ring;
- A4 , A5 , A6 , A7, A8 , Z1 , Z2 , Y1 , X, R1 , R2 and A12 are as defined in formula (II-I).
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, when applicable, comprising one or more of the following features.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 are each independently C1 , C2 , C3 , C4 , or C5 alkylene, or C1 , C2 , C3 , C4 , or C5 heteroalkylene.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 are each independently a C1 - C5 alkylene group, or a C2 - C5 alkenylene group having 1 or 2 double bonds, or a C2 - C5 alkynylene group having 1 or 2 triple bonds, or a C1 - C5 heteroalkylene group containing S or O, or a C2 - C5 heteroalkenylene group containing S or O having 1 or 2 double bonds, or a C2 - C5 heteroalkynylene group containing S or O having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 12 is each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a key.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is C 1 , C 2 , C 3 , C 4 , or C 5 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a C 1 -C 5 alkylene group, or a C 2 -C 5 alkenylene group having 1 or 2 double bonds, or a C 2 -C 5 alkynylene group having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a nitrogen-containing three-membered, four-membered, five-membered, six-membered, seven-membered or eight-membered heterocyclic ring.
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a four-membered, five-membered, or six-membered heteroaryl group containing N. ring.
- the present disclosure provides an amino lipid compound of formula (II-Ib) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- c is 1, 2, 3, 4 or 5;
- c is 2, 3 or 4;
- c is 2 or 3.
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-Ic):
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is H, C1 - C5 hydrocarbon group or C1 - C5 heterohydrocarbon group;
- a 3 is a C 1 -C 5 alkylene group
- A1 and A3 together with the nitrogen atom to which they are attached together form a N-containing heterocyclic ring;
- A4 , A5 , A6 , A7, A8 , Z1 , Z2 , Y1 , X, R1 , R2 and A12 are as defined in formula (II-I).
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, when applicable, comprising one or more of the following features.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A2 is H.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 1 is C 1 , C 2 , C 3 , C 4 , or C 5 alkylene, or C 1 , C 2 , C 3 , C 4 , or C 5 heteroalkylene.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 is C1 - C5 alkylene, or C2 - C5 alkenylene having 1 or 2 double bonds, or C2 - C5 alkynylene having 1 or 2 triple bonds, or C1 - C5 heteroalkylene containing S or O, or C2 - C5 heteroalkenylene containing S or O having 1 or 2 double bonds, or C2 - C5 heteroalkynylene containing S or O having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A2 is C1 , C2 , C3 , C4 , or C5 hydrocarbon group, or C1 , C2 , C3 , C4 , or C5 heterohydrocarbon group.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A2 is C1 - C5 alkyl, or C2 - C5 alkenyl having 1 or 2 double bonds, or C2 - C5 alkynyl having 1 or 2 triple bonds, or C1 -C5 heteroalkyl containing S or O, or C2 - C5 heteroalkenyl containing S or O having 1 or 2 double bonds, or C2 - C5 heteroalkynyl containing S or O having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- R 12 is each independently hydrogen, C 1 -C 12 alkyl, C 2 -C 12 alkenyl having 1, 2, 3 or more double bonds, C 2 -C 12 alkynyl having 1, 2, 3 or more triple bonds, C 1 -C 12 heteroalkyl containing S or O, C 2 -C 12 heteroalkenyl containing S or O having 1, 2, 3 or more double bonds, or C 2 -C 12 heteroalkynyl containing S or O having 1, 2, 3 or more triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 2 can also be
- a is 1, 2, 3, 4 or 5;
- a is 1, 2 or 3.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is C 1 , C 2 , C 3 , C 4 , or C 5 alkylene.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- a 3 is a C 1 -C 5 alkylene group, or a C 2 -C 5 alkenylene group having 1 or 2 double bonds, or a C 2 -C 5 alkynylene group having 1 or 2 triple bonds.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- A1 and A3 together with the nitrogen atom to which they are commonly attached form a nitrogen-containing three-membered, four-membered, five-membered, six-membered, seven-membered or eight-membered heterocyclic ring.
- A1 and A3 together with the nitrogen atom to which they are commonly attached form a N-containing three-membered, four-membered, five-membered, or six-membered heterocyclic ring.
- the present disclosure provides an amino lipid compound of formula (II-Ic) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
- c is 1, 2, 3, 4 or 5;
- c is 2, 3 or 4;
- c is 2 or 3.
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-Id):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R1 , R2 and A12 are as defined in formula (II-I).
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-Ie):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R1 , R2 and A12 are as defined in formula (II-I).
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-II):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , X, R2 , R9 and A12 are defined as in Formula (II-
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-IIa):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R2 , R9 and A12 are as defined in formula (II-I).
- the present disclosure provides an amino lipid compound of formula (II-IIa) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, when applicable, comprising one or more of the following features.
- a 12 is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , or C 18 alkylene.
- A12 is C2 , C3 , C4 , C5, C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , or C18 alkylene.
- a 12 is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , or C 18 alkenylene.
- A12 is C2 , C3 , C4 , C5, C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , or C18 alkynylene.
- A5 and A6 are not methylene at the same time.
- A5 and A6 are each independently C1 , C2 , C3 , C4 , C5 , C6 alkylene or a bond.
- A5 and A6 are each independently C1 , C2 , C3 , C4 , C5 , C6 alkylene or a bond.
- a 5 and A 6 are each independently C 2 , C 3 , C 4 , C 5 , C 6 alkenylene or a bond.
- a 5 and A 6 are each independently C 2 , C 3 , C 4 , C 5 , C 6 alkynylene or a bond.
- a 5 and A 6 are each independently C 1 , C 2 alkylene or a bond.
- a 5 and A 6 are each independently C 1 , C 2 alkylene or a bond.
- a 5 and A 6 are each independently C 2 alkenylene or a bond.
- a 5 and A 6 are each independently C 2 alkynylene or a bond.
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-IIb):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R2 , R9 and A12 are as defined in formula (II-I).
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-III):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , X, R9 , R11 and A12 are defined as in Formula (II- I).
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-IIIa):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R9 , R11 and A12 are as defined in formula (II-I).
- the present disclosure provides an amino lipid compound of formula (II-IIIa) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, when applicable, comprising one or more of the following features.
- a 12 is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , or C 18 alkylene.
- A12 is C2 , C3 , C4 , C5, C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , or C18 alkylene.
- a 12 is C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , or C 18 alkenylene.
- A12 is C2 , C3 , C4 , C5, C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , or C18 alkynylene.
- A5 and A6 are not methylene at the same time.
- A5 and A6 are each independently C1 , C2 , C3 , C4 , C5 , C6 alkylene or a bond.
- A5 and A6 are each independently C1 , C2 , C3 , C4 , C5 , C6 alkylene or a bond.
- a 5 and A 6 are each independently C 2 , C 3 , C 4 , C 5 , C 6 alkenylene or a bond.
- a 5 and A 6 are each independently C 2 , C 3 , C 4 , C 5 , C 6 alkynylene or a bond.
- a 5 and A 6 are each independently C 1 , C 2 alkylene or a bond.
- a 5 and A 6 are each independently C 1 , C 2 alkylene or a bond.
- a 5 and A 6 are each independently C 2 alkenylene or a bond.
- a 5 and A 6 are each independently C 2 alkynylene or a bond.
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-IIIb):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R9 , R11 and A12 are as defined in formula (II-I).
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-IVa) or (II-IVb):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , R9 , R11 and A12 are as defined in formula (II-I).
- the present disclosure provides an amino lipid compound of formula (II-IVa) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- A1 , A2 and A3 are one of the following:
- A1 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene or a bond
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a nitrogen-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene
- A1 and A3 together with the nitrogen atom to which they are commonly attached, form a N-containing heterocyclic ring
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1- C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene
- A1 , A2 and A3 together with the nitrogen atom to which they are commonly attached form a spiro heterocycle, fused heterocycle or bridged heterocycle containing N;
- a 4 is a C 1 ⁇ C 5 alkylene group or a bond
- a 5 , A 6 , A 7 , A 8 and A 12 are each independently C 1 -C 18 alkylene, C 1 -C 18 heteroalkylene or a bond;
- R 6 are each independently H or C 1 -C 8 hydrocarbon group
- Each R 9 and each R 11 are independently a C 1 -C 24 hydrocarbon group or a C 1 -C 24 heterohydrocarbon group containing O or S;
- Each A 9 is a C 1 -C 8 alkylene group or a bond
- Each A 10 and each A 11 are independently a C 1 -C 8 hydrocarbon group
- the hydrocarbon group is an alkyl group, an alkenyl group or an alkynyl group;
- the alkylene group is an alkylene group, an alkenylene group or an alkynylene group;
- the heteroalkyl group is a heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group;
- the heteroalkylene group is a heteroalkylene group, a heteroalkenylene group or a heteroalkynylene group.
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-Va), (II-Vb), (II-Vc), (II-Vd), (II-Ve), (II-Vf), (II-Vg) or (II-Vh):
- a 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , R 9 , R 11 and A 12 are as defined in formula (II-I).
- the amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-VIa):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R1 and R2 are as defined in formula (II-I).
- the present disclosure provides an amino lipid compound of formula (II-VIa) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- A1 , A2 and A3 are one of the following:
- A1 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene or a bond
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a nitrogen-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene
- A1 and A3 together with the nitrogen atom to which they are commonly attached, form a N-containing heterocyclic ring
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1- C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene
- A1 , A2 and A3 together with the nitrogen atom to which they are commonly attached form a spiro heterocycle, fused heterocycle or bridged heterocycle containing N;
- a 4 is a C 1 ⁇ C 5 alkylene group or a bond
- a 5 , A 6 , A 7 and A 8 are each independently C 1 -C 18 alkylene, C 1 -C 18 heteroalkylene or a bond;
- X is C or N
- R1 is H, C1 - C24 hydrocarbon group, C1 - C24 heterohydrocarbon group, Z6R8 , -C ( R6 ) ( OA13Z8R9 ) 2 , -C ( R6 )( SA13Z8R9 ) 2 , or -C( R6 )( SA13Z8R9 )( OA13Z8R9 ) ;
- R 2 is H, C 1 -C 24 hydrocarbon group, C 1 -C 24 heterohydrocarbon group, Z 7 R 10 , -C(R 6 )(OA 14 Z 9 R 11 ) 2 , -C(R 6 )(SA 14 Z 9 R 11 ) 2 , or -C(R 6 )(SA 14 Z 9 R 11 )(OA 14 Z 9 R 11 );
- Z 3 and Z 4 are each independently -O-, -N(R 6 )-, -S- or a bond;
- Z 5 is -O- or -S-;
- R 6 are each independently H or C 1 -C 8 hydrocarbon group
- R8 and R10 are each independently H, C1 - C24 hydrocarbon group or C1 - C24 heterohydrocarbon group containing O or S;
- Each R 9 and each R 11 are independently a C 1 -C 24 hydrocarbon group or a C 1 -C 24 heterohydrocarbon group containing O or S;
- Each A 9 is a C 1 -C 8 alkylene group or a bond
- Each A 10 and each A 11 are independently a C 1 -C 8 hydrocarbon group
- Each A 13 and each A 14 are each independently C 1 -C 8 alkylene, C 1 -C 8 heteroalkylene or a bond;
- the hydrocarbon group is an alkyl group, an alkenyl group or an alkynyl group;
- the alkylene group is an alkylene group, an alkenylene group or an alkynylene group;
- the heteroalkyl group is a heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group;
- the heteroalkylene group is a heteroalkylene group, a heteroalkenylene group or a heteroalkynylene group.
- A5 and A6 are each independently C1 , C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 alkylene or a bond, and are not methylene at the same time.
- a 5 and A 6 are each independently C 1 , C 2 alkylene or a bond, and are not methylene at the same time.
- a 5 and A 6 are each independently C 3 , C 4 , C 5 or C 6 alkylene.
- a 5 and A 6 are each independently C 7 , C 8 , C 9 or C 10 alkylene.
- a 5 and A 6 are each independently C 11 , C 12 , C 13 , or C 14 alkylene.
- a 5 and A 6 are each independently C 15 , C 16 , C 17 , or C 18 alkylene.
- A5 and A6 are each independently C1 , C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11 , C12 , C13 , C14 , C15 , C16 , C17 , C18 alkylene or a bond, and are not methylene at the same time.
- a 5 and A 6 are each independently C 1 , C 2 alkylene or a bond, and are not methylene at the same time.
- a 5 and A 6 are each independently C 3 , C 4 , C 5 or C 6 alkylene.
- a 5 and A 6 are each independently C 7 , C 8 , C 9 or C 10 alkylene.
- a 5 and A 6 are each independently C 11 , C 12 , C 13 or C 14 alkylene.
- a 5 and A 6 are each independently C 15 , C 16 , C 17 , or C 18 alkylene.
- A5 and A6 are each independently C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11, C12, C13, C14, C15, C16 , C17 , C18 alkenylene or a bond .
- a 5 and A 6 are each independently C 2 alkenylene or a bond.
- a 5 and A 6 are each independently C 3 , C 4 , C 5 , or C 6 alkenylene.
- a 5 and A 6 are each independently C 7 , C 8 , C 9 or C 10 alkenylene.
- a 5 and A 6 are each independently C 11 , C 12 , C 13 , or C 14 alkenylene.
- a 5 and A 6 are each independently C 15 , C 16 , C 17 , or C 18 alkenylene.
- A5 and A6 are each independently C2 , C3 , C4, C5 , C6 , C7 , C8 , C9 , C10 , C11, C12, C13, C14, C15, C16 , C17 , C18 alkynylene , or a bond.
- a 5 and A 6 are each independently C 2 alkynylene or a bond.
- a 5 and A 6 are each independently C 3 , C 4 , C 5 , or C 6 alkynylene.
- a 5 and A 6 are each independently C 7 , C 8 , C 9 , or C 10 alkynylene.
- a 5 and A 6 are each independently C 11 , C 12 , C 13 , or C 14 alkynylene.
- a 5 and A 6 are each independently C 15 , C 16 , C 17 , or C 18 alkynylene.
- A1 and A2 are each independently C1 - C5 alkyl, preferably C1 - C3 alkyl, such as methyl, ethyl, n-propyl or isopropyl;
- A3 is C1 - C5 alkylene, preferably C2 - C4 alkylene, such as -( CH2 ) 2- , -( CH2 ) 3- , -( CH2 ) 4- ;
- A7 and A8 are each independently a bond;
- R1 and R2 are each independently C1 - C24 hydrocarbon, preferably C1 - C24 alkyl, more preferably C
- the amino lipid compound represented by formula (II-VIa), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-VIa-a):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R9 and R2 are as defined in formula (II-VIa).
- the amino lipid compound represented by formula (II-VIa), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-VIa-b):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , Y1 , R9 and R11 are as defined in formula (II-VIa).
- the amino lipid compound represented by formula (II-VIa), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has a structure represented by formula (II-VIa-c):
- A1 , A2 , A3 , A4 , A5 , A6 , A7 , A8 , Z1 , Z2 , R9 and R11 are as defined in formula (II-VIa).
- the present disclosure provides an amino lipid compound of formula (II-VIa-c) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- A1 , A2 and A3 are one of the following:
- A1 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene or a bond
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene or a bond
- A1 and A2 together with the nitrogen atom to which they are commonly attached form a nitrogen-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is H, C1 - C5 alkyl or C1 - C5 heteroalkyl
- A3 is C1 - C5 alkylene
- A1 and A3 together with the nitrogen atom to which they are commonly attached form a N-containing heterocycle
- A1 is C1 - C5 alkylene or C1 - C5 heteroalkylene
- A2 is C1- C5 alkylene or C1 - C5 heteroalkylene
- A3 is C1 - C5 alkylene
- A1 , A2 and A3 together with the nitrogen atom to which they are commonly attached form a spiro heterocycle, fused heterocycle or bridged heterocycle containing N;
- a 4 is a C 1 ⁇ C 5 alkylene group or a bond
- a 5 , A 6 , A 7 and A 8 are each independently C 1 -C 18 alkylene, C 1 -C 18 heteroalkylene or a bond;
- R 6 are each independently H or C 1 -C 8 hydrocarbon group
- Each R 9 and each R 11 are independently a C 1 -C 24 hydrocarbon group or a C 1 -C 24 heterohydrocarbon group containing O or S;
- Each A 9 is a C 1 -C 8 alkylene group or a bond
- Each A 10 and each A 11 are independently a C 1 -C 8 hydrocarbon group
- the hydrocarbon group is an alkyl group, an alkenyl group or an alkynyl group;
- the alkylene group is an alkylene group, an alkenylene group or an alkynylene group;
- the heteroalkyl group is a heteroalkyl group, a heteroalkenyl group or a heteroalkynyl group;
- the heteroalkylene group is a heteroalkylene group, a heteroalkenylene group or a heteroalkynylene group.
- the amino lipid compound represented by formula (II-IVa), (II-VIa) or (II-VIa-c), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, includes one or more of the following features when applicable.
- a 4 is a bond
- Y 1 is -N(R 6 )C( ⁇ O)O-, -OC( ⁇ O)N(R 6 )-, or -OC( ⁇ O)O-.
- Y 1 is -N(R 6 )C( ⁇ O)O- or -OC( ⁇ O)N(R 6 )-.
- each R 6 is independently H, or C 1 -C 8 alkyl substituted with —OC( ⁇ O)R 14 , —C( ⁇ O)OR 14 , or —OR 14 .
- Y 1 is -N(R 6 )C( ⁇ O)O- or -OC( ⁇ O)N(R 6 )-, wherein each R 6 is independently a C 1 -C 8 alkyl group (eg, C 1 -C 5 alkyl group, C 1 -C 3 alkyl group) substituted with -OC( ⁇ O)R 14 , -C( ⁇ O)OR 14 , or -OR 14 .
- each R 6 is independently a C 1 -C 8 alkyl group (eg, C 1 -C 5 alkyl group, C 1 -C 3 alkyl group) substituted with -OC( ⁇ O)R 14 , -C( ⁇ O)OR 14 , or -OR 14 .
- Y 1 is -N(R 5 )-.
- Z 1 is -OC( ⁇ O)N(H)-.
- a 4 is a bond
- Z 1 and Z 2 are C( ⁇ O)O—.
- A4 is a bond
- A4 is a bond
- A4 is a bond
- A4 is a bond
- a 4 is a bond
- a 12 is C 1 -C 3 alkylene, for example C 2 -C 3 alkylene.
- a 12 is C 1 -C 3 alkylene (eg, C 1 alkylene), and A 5 and A 6 are each independently C 3 -C 9 alkylene (eg, C 4 -C 9 alkylene, C 5 -C 9 alkylene, C 6 alkylene, C 7 alkylene, C 8 alkylene).
- R 1 is -C(R 6 )(OR 9 ) 2 .
- R 1 is -C(H)(OR 9 ) 2 .
- R 2 is -C(R 6 )(OR 11 ) 2 .
- R 2 is -C(H)(OR 11 ) 2 .
- R 2 is Z 7 R 10 .
- R 2 is -OR 10 .
- R 2 is a substituted C 1 -C 24 alkyl, such as a substituted C 5 -C 16 alkyl, a substituted C 6 -C 14 alkyl, or a substituted C 6 -C 12 alkyl.
- R 2 is a C 1 -C 24 alkyl substituted with a hydroxyl group, such as a C 5 -C 16 alkyl substituted with a hydroxyl group, such as a C 6 -C 14 alkyl substituted with a hydroxyl group, a C 6 -C 12 alkyl substituted with a hydroxyl group, or a C 10 alkyl substituted with a hydroxyl group.
- R 1 is -C(R 6 )(OR 9 ) 2 and R 2 is -C(R 6 )(OR 11 ) 2 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -C(H)(OR 11 ) 2 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -C( ⁇ O)OR 10 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -OR 10 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is C 1 -C 24 alkyl substituted by hydroxy (eg, R 2 is C 5 -C 16 alkyl substituted by hydroxy, C 6 -C 14 alkyl substituted by hydroxy, C 6 -C 12 alkyl substituted by hydroxy, or C 10 alkyl substituted by hydroxy).
- R 1 is -C(H)(OR 9 ) 2
- R 1 is -C(H)(OR 9 ) 2
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -OR 10 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is substituted C 1 -C 24 alkyl (eg, R 2 is substituted C 5 -C 16 alkyl, substituted C 6 -C 14 alkyl, substituted C 6 -C 12 alkyl, or substituted C 10 alkyl).
- R 1 is -C(H)(OR 9 ) 2
- R 2 is C 1 -C 24 alkyl substituted by hydroxy (for example, R 2 is C 5 -C 16 alkyl substituted by hydroxy, C 6 -C 14 alkyl substituted by hydroxy, C 6 -C 12 alkyl substituted by hydroxy, or C 10 alkyl substituted by hydroxy).
- R1 is -C(H)( OR9 ) 2
- R2 is C1 - C24 alkyl substituted by hydroxy (for example, R2 is C5 - C16 alkyl substituted by hydroxy, C6 - C14 alkyl substituted by hydroxy, C6 - C12 alkyl substituted by hydroxy, or C10 alkyl substituted by hydroxy)
- A5 and A6 are each independently C2 - C10 alkylene (for example, C5 - C9 alkylene, C8 alkylene).
- a 7 and A 8 are unsubstituted C 1 -C 5 alkylene (eg, unsubstituted C 2 -C 4 alkylene)
- R 1 is -C(H)(OR 9 ) 2
- a 7 and A 8 are unsubstituted C 1 -C 5 alkylene (eg, unsubstituted C 2 -C 4 alkylene)
- R 1 is -C(H)(OR 9 ) 2
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -C(H)(OR 11 ) 2 .
- Y 1 is -OC( ⁇ O)N(H)-
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -C(H)(OR 11 ) 2 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -C(H)(OR 11 ) 2 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is -C(H)(OR 11 ) 2 .
- R 1 is -C(H)(OR 9 ) 2
- R 2 is C 1 -C 24 alkyl substituted by hydroxy (for example, R 2 is C 5 -C 16 alkyl substituted by hydroxy, C 6 -C 14 alkyl substituted by hydroxy, C 6 -C 12 alkyl substituted by hydroxy, or C 10 alkyl substituted by hydroxy).
- a 9 is C 1 -C 8 alkylene.
- a 9 is C 1 -C 5 alkylene.
- a 9 is C 1 -C 3 alkylene.
- a 10 is C 1 -C 8 alkyl, such as C 1 , C 2 , C 3 , C 5 , C 8 alkyl.
- R 10 is C 1 -C 24 alkyl, C 2 -C 24 alkenyl, or C 2 -C 24 alkynyl.
- R 10 is a linear C 2 -C 10 alkyl group.
- R 10 is a linear C 2 -C 8 alkyl group.
- R 10 is a branched C 7 -C 18 alkyl group, for example:
- R 10 is C 5 _C 16 alkenyl.
- R 10 is C 5 _C 12 alkenyl.
- R 10 is C 5 -C 8 alkenyl, such as C 5 , C 6 alkenyl.
- R 10 is C 5 -C 16 alkynyl.
- R 10 is C 5 -C 12 alkynyl, for example C 10 alkynyl.
- R 9 is C 9 -C 11 alkynyl, for example C 10 alkynyl.
- R 14 is C 1 -C 12 alkyl.
- R 14 is C 1 -C 5 alkyl.
- R 14 is C 2 -C 12 alkenyl having 1, 2, 3, or more double bonds.
- R 14 is C 4 -C 8 alkenyl having 1 double bond, for example, C 6 alkenyl having 1 double bond.
- a 5 and A 6 are each independently C 1 -C 11 alkylene.
- a 5 and A 6 are each independently C 3 -C 10 alkylene.
- a 5 and A 6 are each independently C 4 -C 9 alkylene.
- a 5 and A 6 are each independently C 5 -C 9 alkylene, such as C 6 , C 7 , C 8 alkylene.
- a 7 and A 8 are each independently C 1 -C 12 alkylene.
- a 7 and A 8 are each independently C 5 -C 10 alkylene.
- a 7 and A 8 are each independently C 1 -C 5 alkylene.
- a 7 and A 8 are each independently C 2 -C 4 alkylene.
- A7 and A8 are C3 alkylene.
- a 7 or A 8 is a bond.
- a 7 is a bond
- a 8 is a bond
- each R 9 is each independently C 1 -C 12 alkyl, C 5 -C 16 alkenyl, or C 5 -C 16 alkynyl.
- each R 9 is independently C 3 -C 9 alkyl.
- each R 9 is independently C 5 -C 8 alkyl, such as C 6 , C 7 , C 8 alkyl.
- each R 9 is independently C 5 -C 12 alkenyl.
- each R 9 is independently C 5 -C 8 alkenyl, such as C 6 alkenyl.
- each R 9 is independently C 9 -C 11 alkynyl, such as C 10 alkynyl.
- each R 11 is independently C 1 -C 12 alkyl.
- each R 11 is independently C 3 -C 9 alkyl.
- each R 11 is independently C 5 -C 8 alkyl, such as C 6 , C 7 , C 8 alkyl.
- each R 11 is independently C 5 -C 12 alkenyl.
- each R 11 is independently C 5 -C 8 alkenyl, such as C 6 alkenyl.
- each R 11 is independently C 9 -C 11 alkynyl, for example C 10 alkynyl.
- the dashed line connecting A1 and A2 and the dashed line connecting A1 and A3 are absent.
- the dashed line connecting A 1 and A 2 is a bond and the dashed line connecting A 1 and A 3 is not present.
- the dashed line connecting A 1 and A 3 is a bond and the dashed line connecting A 1 and A 2 is not present.
- a 1 and A 2 are each independently C 1 -C 5 alkyl, or C 1 -C 5 alkylene.
- a 1 and A 2 are each independently C 1 -C 3 alkyl.
- a 1 and A 2 are each independently C 1 -C 2 alkyl.
- A2 is C1 - C3 alkyl, for example C1 - C2 alkyl.
- a 3 is C 1 -C 5 alkylene.
- a 3 is C 2 -C 4 alkylene, for example C 3 alkylene.
- the dashed line connecting A 1 and A 2 and the dashed line connecting A 1 and A 3 are absent, and A 1 and A 2 are each independently C 1 -C 3 alkyl, for example C 1 -C 2 alkyl.
- the dashed line connecting A1 and A2 and the dashed line connecting A1 and A3 are absent, and A1 and/or A2 are unsubstituted C1 - C5 alkyl, such as unsubstituted C1 - C4 alkyl, unsubstituted C1 - C3 alkyl, unsubstituted C1 - C2 alkyl.
- the dashed line connecting A1 and A2 and the dashed line connecting A1 and A3 are absent, and A1 and A2 are each independently unsubstituted C1 - C5 alkyl, such as unsubstituted C1 - C4 alkyl, unsubstituted C1 - C3 alkyl, unsubstituted C1 - C2 alkyl.
- the dashed line connecting A1 and A2 and the dashed line connecting A1 and A3 are absent, and A1 and/or A2 are substituted C1 - C5 alkyl, such as substituted C1 - C4 alkyl, substituted C1 - C3 alkyl, substituted C1 - C2 alkyl.
- a 1 and/or A 2 is C 1 -C 5 alkylene.
- A1 and A2 when the dashed line connecting A1 and A2 is a bond and the dashed line connecting A1 and A3 is absent, A1 and A2 together with the nitrogen atom to which they are commonly attached form a four-membered, five-membered, or six-membered heterocyclic ring containing N.
- a 1 and/or A 2 when the dashed line connecting A 1 and A 2 is a bond and the dashed line connecting A 1 and A 3 is absent, A 1 and/or A 2 is unsubstituted C 1 -C 5 alkylene.
- a 1 and A 2 are each independently unsubstituted C 1 -C 5 alkylene.
- a 1 and/or A 2 is a substituted C 1 -C 5 alkylene.
- A2 is C1 - C3 alkyl
- A1 and/or A3 is C1 - C5 alkylene
- A1 and A3 when the dashed line connecting A1 and A3 is a bond and the dashed line connecting A1 and A2 is absent, A1 and A3 together with the nitrogen atom to which they are commonly attached form a four-membered, five-membered, or six-membered heterocyclic ring containing N.
- A1 is unsubstituted C1 - C5 alkylene
- A2 is unsubstituted C1 - C5 alkyl (e.g., unsubstituted C1 - C4 alkyl, unsubstituted C1 - C3 alkyl, unsubstituted C1 - C2 alkyl).
- A1 when the dashed line connecting A1 and A3 is a bond and the dashed line connecting A1 and A2 is absent, A1 is unsubstituted C1 - C5 alkylene, and A2 is substituted C1 - C5 alkyl (e.g., substituted C1 - C4 alkyl, substituted C1 - C3 alkyl, substituted C1 - C2 alkyl).
- A1 when the dashed line connecting A1 and A3 is a bond and the dashed line connecting A1 and A2 is absent, A1 is substituted C1 - C5 alkylene, and A2 is unsubstituted C1 - C5 alkyl (e.g., unsubstituted C1 - C4 alkyl, unsubstituted C1 - C3 alkyl, unsubstituted C1 - C2 alkyl).
- A1 when the dashed line connecting A1 and A3 is a bond and the dashed line connecting A1 and A2 is absent, A1 is substituted C1 - C5 alkylene, and A2 is unsubstituted C1 - C5 alkyl (e.g., unsubstituted C1 - C4 alkyl, unsubstituted C1 - C3 alkyl, unsubstituted C1 - C2 alkyl).
- A1 is substituted C1 - C5 alkylene
- A2 is substituted C1 - C5 alkyl (e.g., substituted C1 - C4 alkyl, substituted C1 - C3 alkyl, substituted C1 - C2 alkyl).
- A1 or A2 is
- A1 and A2 are each independently C1 - C5 alkyl, C1 - C2 alkyl, or C1 - C5 alkylene substituted with C1 - C3 alkyl, for example: In some embodiments, A 3 is unsubstituted C 1 -C 5 alkylene.
- a 3 is unsubstituted C 2 -C 4 alkylene.
- a 3 is unsubstituted C 3 alkylene.
- a 3 is substituted C 1 -C 5 alkylene, such as substituted C 2 -C 4 alkylene, substituted C 3 alkylene.
- a 3 is C 3 alkylene substituted by one or two R 14 , wherein R 14 is C 1 -C 12 alkyl (eg, C 1 -C 5 alkyl, C 1 -C 3 alkyl, C 1 alkyl).
- a 3 is a C 3 alkylene group substituted by two -R 14 groups, wherein R 14 is a C 1 -C 12 alkyl group (e.g., C 1 -C 5 alkyl group, C 1 -C 3 alkyl group, C 1 alkyl group).
- c is 1, 2, 3, 4 or 5.
- the present disclosure provides an amino lipid compound of formula (II-VIa-c) as described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein
- A4 is a bond
- A5 and A6 are each independently C3 - C10 alkylene
- A7 and A8 are each independently C2 - C4 alkylene
- each R9 is each independently C3 - C9 alkyl
- each R11 is each independently C3 - C9 alkyl
- the dotted line connecting A1 and A2 and the dotted line connecting A1 and A3 do not exist
- A1 and A2 are each independently C1 - C3 alkyl
- A3 is C2 - C4 alkylene.
- A4 is a bond
- A5 and A6 are each independently C3
- a 4 is a bond
- a 5 and A 6 are each independently C 3
- amino lipid compound represented by formula (II-I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof has formula (II-VIb):
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Abstract
提供用于制备递送活性成分的脂质纳米颗粒的氨基脂质化合物及其制备方法,含有所述氨基脂质化合物的脂质纳米颗粒和药物组合物,及其用途。
Description
本公开涉及可以用于制备递送活性成分的脂质纳米颗粒的氨基脂质化合物及其制备方法。本公开还涉及含有所述氨基脂质化合物的脂质纳米颗粒和药物组合物,及其用途。
将生物活性成分(如核酸、蛋白质和小分子药物等)安全有效靶向递送至细胞、组织和/或器官是药物递送领域一直以来的技术难题,尤其是核酸药物,其在血浆中易于被核酸酶降解。核酸类药物包括mRNA、反义寡核苷酸(Antisense oligonucleotides,ASOs)、微小RNA(MicroRNA,miRNA)、小干扰RNA(Small interfering RNA,siRNA)和核酸适体(Aptamers)等,正在逐渐被开发成为一种新型的治疗方式,在癌症治疗、传染性疾病预防和遗传疾病治疗等领域有着巨大治疗潜力。
通过脂质纳米颗粒递送核酸药物已经被广泛使用,然而,核酸药物递送的靶向性、安全性和递送效率仍有待改进,不同的核酸药物、细胞(或组织、器官)以及应用场景,都需要不同性质的脂质纳米颗粒进行匹配。因此,为适应核酸药物不同应用场景的递送需要,开发不同的脂质纳米颗粒,尤其是用于配置脂质纳米颗粒的氨基脂质化合物,存在巨大的需求。
发明内容
本公开的一个方面提供由式(I)表示的氨基脂质化合物:
其中A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、X、R1和R2各自如下文所定义。
本公开的另一方面提供制备所述氨基脂质化合物的方法。
本公开的另一方面提供所述氨基脂质化合物用于制备活性成分的递送载体的用途。
本公开的另一方面提供脂质纳米颗粒,所述脂质纳米颗粒含有所述氨基脂质化合物。
本公开的另一方面提供药物组合物,所述药物组合物含有所述脂质纳米颗粒。
本公开的另一方面提供一种通过所述脂质纳米颗粒或药物组合物将生物活性成分递送至细胞、组织或器官中的方法。
本公开的另一方面提供一种通过所述脂质纳米颗粒或药物组合物在哺乳动物细胞中产生感兴趣多肽和/或蛋白质的方法。
本公开的另一方面提供所述氨基脂质化合物、脂质纳米颗粒或药物组合物在制备药物中的用途。
本公开的另一方面提供一种通过所述脂质纳米颗粒或药物组合物预防和/或治疗有需要的哺乳动物的疾病或病症的方法。
本公开的另一方面提供所述氨基脂质化合物、脂质纳米颗粒或药物组合物在制备用于核酸转移的药物中的用途。
定义
除非在下文中另有定义,本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意指在本领域中通常所理解的技术,包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解,但仍然阐述以下定义以更好地解释本发明。
本文所用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的,且不排除其它未列举的元素或方法步骤。
本文所用的术语“烃基”意指脂肪烃失去1个氢原子后剩余的基团,包括直链的或支化的、饱和的或不饱和的烃基。烃基包括但不限于烷基、烯基和炔基。优选地,烃基具有1至24个碳原子(C1-C24烃基),例如具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个碳原子(C1、C2、C3、……C21、C22、C23或C24烃基)。烃基的实例包括但不限于C1-C24烃基、C1-C22烃基、C1-C20烃基、C1-C18烃基、C1-C16烃基、C1-C12烃基、C1-C10烃基、C1-C8烃基、C1-C7烃基、C1-C6烃基、C1-C4烃基、C1-C3烃基、C1-C2烃基、C2-C8烃基、C2-C4烃基、C4-C8烃基、C4-C9烃基、C5-C8烃基、C1-C4烃基、C2-C8烃基、C3烃基、C4烃基、C5烃基、C6烃基、C7烃基和C8烃基。除非在本说明书中另外明确说明,烃基是可任选取代的,取代基参见下文有关“任选取代的”的定义。在某些实施例中,烃基具有零个支链(即为直链)、一个支链、两个支链、或多个支链。
本文所用的术语“亚烃基”意指上述烃基进一步失去1个氢原子后剩余的二价基团。除非在本说明书中另外明确说明,亚烃基也是可任选取代的。
本文所用的术语“烷基”是直链或支化的饱和一价烃基。优选地,烷基具有1至24个碳原子(C1-C24烷基),例如具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个碳原子(C1、C2、C3、……C21、C22、C23或C24烷基)。烷基的实例包括但不限于C1-C24烷基、C1-C22烷基、C1-C20烷基、C1-C18烷基、C1-C16烷基、C1-C12烷基、C1-C10烷基、C1-C8烷基、C1-C7烷基、C1-C6烷基、C1-C4烷基、C1-C3烷基、C1-C2烷基、C2-C8烷基、C2-C4烷基、C4-C8烷基、C4-C9烷基、C5-C8烷基、C1-C4烷基、C2-C8烷基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、正己基、正庚基、正辛基、正壬基、正癸基、正十一烷基、正十二烷基、正十三烷基和十三烷-7-基。除非在本说明书中另外明确说明,烷基是可任选取代的。
本文所用的术语“亚烷基”意指上述烷基进一步失去1个氢原子后剩余的二价基团。除非在本说明书中另外明确说明,亚烷基也是可任选取代的。
本文所用的术语“烯基”是直链或支化的一价烃基,其包含1个或更多个双键(C=C)。优选地,烯基具有2至24个碳原子(C2-C24烯基),例如具有2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个碳原子(C2、C3、C4、……C21、C22、C23或C24烯基),并且具有1、2、3、4或更多个双键。烯基包括但不限于C2-C24烯基、C2-C22烯基、C2-C20烯基、C2-C18烯基、C2-C16烯基、C2-C12烯基、C2-C10烯基、C2-C8烯基、C2-C7烯基、C2-C6烯基、C2-C4烯基、C2-C3烯基、C4-C8烯基、C4-C9烯基、C5-C8烯基,其具有1、2、3、4或更多个双键。一些更具体的实例包括但不限于乙烯基、丙烯基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-2-烯基、己-1-烯基、己-2-烯基、己-3-烯基、庚-1-烯基、庚-2-烯基、庚-3-烯基、辛-1-烯基、辛-2-烯基、辛-3-烯基、壬-1-烯基、壬-2-烯基和壬-3-烯基。在一些实施方案中,所述烯基具有1个双键。除非在本说明书中另外明确说明,烯基是可任选取代的。
本文所用的术语“亚烯基”意指上述烯基进一步失去1个氢原子后剩余的二价基团。除非在本说明书中另外明确说明,亚烯基也是可任选取代的。
本文所用的术语“炔基”是直链或支化的一价烃基,其包含1个或更多个叁键(C≡C)。优选地,炔基具有2至24个碳原子(C2-C24炔基),例如具有2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24个碳原子(C2、C3、C4、……C21、C22、C23或C24炔基),并且具有1、2、3、4或更多个叁键。炔基包括但不限于C2-C24炔基、C2-C22炔基、C2-C20炔基、C2-C18炔基、C2-C16炔基、C2-C12炔基、C2-C10炔基、C2-C8炔基、C2-C7炔基、C2-C6炔基、C2-C4炔基、C2-C3炔基、C4-C8炔基、C4-C9炔基、C5-C8炔基,其具有1、2、3、4或更多个叁键。一些更具体的实例包括但不限于乙炔基、丙炔基、丁-1-炔基、丁-2-炔基、戊-1-炔基、戊-2-炔基、己-1-炔基、己-2-炔基、己-3-炔基、庚-1-炔基、庚-2-炔基、庚-3-炔基、辛-1-炔基、辛-2-炔基、辛-3-炔基、壬-1-炔基、壬-2-炔基和壬-3-炔基。在一些实施方案中,所述炔基具有1个叁键。除非在本说明书中另外明确说明,炔基是可任选取代的。
本文所用的术语“亚炔基”意指上述炔基进一步失去1个氢原子后剩余的二价基团。除非在本说明书中另外明确说明,亚炔基也是可任选取代的。
本文所用的术语“环烃基”、“亚环烃基”和“烃环”是指具有环碳原子的饱和(即,“环烷基”和“亚环烷基”)或不饱和的(即在环内具有一个或多个双键(环烯基)和/或三键(环炔基))单环或多环烃环。在某些实施例中,“环烃基”、“亚环烃基”和“烃环”具有例如3-10个,适合地具有3-8个,更适合地具有3-6个,例如5-6或5-7个,环碳原子。“环烃基”、“亚环烃基”和“烃环”包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。除非在本说明书中另外明确说明,环烃基、亚环烃基和烃环是可任选取代的。
本文所用的术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环,诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基,或双环,包括螺环、稠合或桥连系统,诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)。在某些实施例中,环烷基具有例如3至10个,例如3-7、5-6或5-7个碳原子。除非在本说明书中另外明确说明,环烷基是可任选取代的。
本文所用的术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等)指稳定的直链的、支链的或环状的烃原子团或其组合,由一定数目的碳原子和至少一个杂原子组成。杂原子指除了碳和氢以外的其他原子。在某些实施例中,杂烃基含有一个,两个,或多个杂原子。在某些实施例中,杂烃基含有的一个或多个相同或不同的杂原子。优选地,所述杂原子选自O、N和S。杂烃基实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-CH2-O-CH2-CH3、-CH2-(CH2)3-O-(CH2)5-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-CH=CH-O-CH3、-CH2-CH=N-OCH3、–CH=CH-N(CH3)-CH3和-CH2-NH-OCH3。除非在本说明书中另外明确说明,杂烃基是可任选取代的。
本文所用的术语“亚杂烃基”或者其下位概念(比如亚杂烷基、亚杂烯基、亚杂炔基、亚杂芳基等)意指如上文所定义的杂烃基进一步失去1个氢原子后剩余的二价基团。除非在本说明书中另外明确说明,亚杂烃基或者其下位概念(比如亚杂烷基、亚杂烯基、亚杂炔基、亚杂芳基等)也是可任选取代的。
本文所用的术语“杂环”、“杂环基”或“亚杂环基”意指具有环状结构,且成环原子中包含一个或多个杂原子的环状基团。在某些实施例中,成环原子中包含的一个或多个相同或不同的杂原子。在某些实施例中,成环原子中包含的一个或多个杂原子选自N、O和S。本文中公开的“杂环”、“杂环基”或“亚杂环基”是饱和的或不饱和的。在某些实施例中,“杂环”、“杂环基”或“亚杂环基”包含单环,双环,或多环。在某些实施例中,“杂环”、“杂环基”或“亚杂环基”为4至10元杂环,例如4至7元杂环,5至7元杂环。优选地,在某些实施例中,杂环为可被任选取代的4至10元杂环,其中成环原子中包含1、2、3、4、5或6个选自N、O、和S的杂原子。更优选的,杂环为可被任选取代的4至7元饱和杂环,其中成环原子包含1、2、3或4个选自N、O和S的杂原子;更优选的,杂环为
具有可被任选取代的5至7元(例如5至6元)饱和杂环,其中成环原子包含1、2或3个选自N、O和S的杂原子。杂环的实例包括但不限于:氮杂环丁烷、氧杂环丁基、四氢呋喃、吡咯烷、咪唑烷、吡唑烷、四氢吡喃、哌啶、吗啉、硫吗啉、哌嗪,优选吡咯烷、哌啶、哌嗪和吗啉。所述杂环可以任选被一个或多个取代基取代,取代基参见下文有关“任选取代的”的定义。除非在本说明书中另外明确说明,杂环、杂环基或亚杂环基是可任选取代的。
如本文中所使用,术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如,如本文中所使用,术语“C6-14芳基”意指含有6至14个(例如6至12个)碳原子的芳族基团,诸如苯基或萘基。除非在本说明书中另外明确说明,芳基是可任选取代的。
如本文中所使用,术语“杂芳基”指具有共轭π电子系统的单环或多环(例如双环或三环)芳族基团,其环原子由碳原子以及至少一个杂原子构成,例如具有5至14(例如5、6、7、8、9、10、11、12、13或14)个环原子,其中具有1、2、3、4、5、6、7、8、9、10、11、12或13个碳原子和独立地选自N、O、S和S(O)2的1、2、3、4或5个相同或不同的杂原子。杂芳基中的1或多个环碳原子可以被C(O)替代。杂芳基可以是苯并稠合的。除非在本说明书中另外明确说明,杂芳基是可任选取代的。
本文所用的术语“任选取代的”意指与原子或基团连接的1个或多个氢原子独立地未被取代,或独立地被1个或多个(例如1、2、3或4个)取代基取代。所述取代基独立地选自,但不限于:氘(D)、氚(T)、卤素、-OH、巯基、氰基、-CD3、C1-C6烷基(优选C1-C3烷基)、C2-C6烯基、C2-C6炔基、环烷基(优选C3-C8环烷基)、芳基、杂环基(优选3-8元杂环基)、杂芳基、芳基C1-C6烷基、杂芳基C1-C6烷基、C1-C6卤代烷基、-OC1-C6烷基(优选-OC1-C3烷基)、-OC2-C6烯基、OC1-C6烷基苯基、C1-C6烷基-OH(优选C1-C4烷基-OH)、C1-C6烷基-SH、C1-C6烷基-O-C1-C6烷基、OC1-C6卤代烷基、-NH2、C1-C6烷基-NH2(优选C1-C3烷基-NH2)、-N(C1-C6烷基)2(优选-N(C1-C3烷基)2)、-NH(C1-C6烷基)(优选-NH(C1-C3烷基))、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、硝基、-C(O)-OH、-C(O)OC1-C6烷基(优选-C(O)OC1-C3烷基)、-CONRiRii(其中Ri和/或Rii是H、D和C1-C6烷基,优选C1-C3烷基)、-NHC(O)(C1-C6烷基)、-NHC(O)(苯基)、-N(C1-C6烷基)C(O)(C1-C6烷基)、-N(C1-C6烷基)C(O)(苯基)、-C(O)C1-C6烷基、-C(O)杂芳基(优选-C(O)-5-7元杂芳基)、-C(O)C1-C6烷基苯基、-C(O)C1-C6卤代烷基、-OC(O)C1-C6烷基(优选-OC(O)C1-C3烷基)、-S(O)2-C1-C6烷基、-S(O)-C1-C6烷基、-S(O)2-苯基、-S(O)2-C1-C6卤代烷基、-S(O)2NH2、-S(O)2NH(C1-C6烷基)、-S(O)2NH(苯基)、-NHS(O)2(C1-C6烷基)、-NHS(O)2(苯基)和-NHS(O)2(C1-C6卤代烷基),其中所述的烷基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选地被选自以下中的一个或多个取代基进一步取代,但不限于:卤素、-OH、-NH2、环烷基、3-8元杂环基、C1-C4烷基、C1-C4卤代烷基-、-OC1-C4烷基、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基)2、-CONH(C1-C6烷基)、-CONH2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2(苯基)、-SO2(C1-C6卤代烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(苯基)、-NHSO2(C1-C6烷基)、-NHSO2(苯基)和-NHSO2(C1-C6卤代烷基)。当一个原子或基团被多个取代基取代时,所述多个取代基可以相同或不同。
在某些实施方案中,所述取代基可以独立地选自,但不限于:卤素(例如氯、溴、氟或碘)、羧酸(例如-C(=O)OH)、氧(例如=O)、硫(例如=S)、羟基(例如-OH)、酯基(例如-C(=O)ORiii或-OC(=O)Riii)、醛基(例如-C(=O)H)、羰基(例如-C(=O)Riii,或由C=O表示)、酰卤基(例如-C(=O)X,其中X是选自溴、氟、氯或碘)、碳酸酯基(例如-OC(=O)ORiii)、烷氧基(例如-ORiii)、缩醛(例如-C(ORiii)2Riii,其中各ORiii是相同或不同的烷氧基)、磷酸根(例如P(=O)4
3-)、巯基(例如-SH)、亚砜(例如-S(=O)Riii)、亚磺酸(例如-S(=O)OH)、磺酸(例如-S(=O)2OH)、硫醛(例如-C(=S)H)、硫酸根(例如S(=O)4
2-)、磺酰基(例如-S(=O)2Riii)、亚磺酰基(例如-S(=O)Riii)、酰胺(例如-C(=O)N(Riii)2或-N(Riii)C(=O)Riii)、叠氮基(例如-N3)、硝基(例如-NO2)、氰基(例如-CN)、异氰基(例如-NC)、酰氧基
(例如-OC(=O)Riii)、氨基(例如-N(Riii)2、-N(Riii)H或-NH2)、氨甲酰基(例如-OC(=O)N(Riii)2、-OC(=O)N(Riii)H或-OC(=O)NH2)、磺酰胺(例如-S(=O)2N(Riii)2、-S(=O)2N(Riii)H、-S(=O)2NH2、-N(Riii)S(=O)2Riii、-N(H)S(=O)2Riii、-N(Riii)S(=O)2H或-N(H)S(=O)2H)、烷基、烯基、炔基、环烃基(例如环烷基、环烯基或环炔基基)、杂环烃基(例如含有一个或多个选自S、N和O杂原子的杂环烷基,或含有一个或多个选自S、N和O杂原子的杂环烯基)、芳基(例如苯基、或稠环基)、杂芳基(例如包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基)、-C(=O)SRiii、-C(=N-CN)N(Riii)2、-C(=N-O-CH3)N(Riii)2、-C(=N-SO2-NH2)N(Riii)2、-C(=CH-NO2)N(Riii)2,-OC(=O)N(Riii)2、-CHN(Riii)N(Riii)2、-C(=O)N(Riii)ORiii、-N(Riii)2C(=O)ORiii、-OP(=O)(ORiii)2,-P(=O)(ORiii)2、-N(ORiii)C(=O)Riii、-N(ORiii)S(=O)2Riii、-N(ORiii)C(=O)ORiii、-N(ORiii)C(=O)N(Riii)2、-N(ORiii)C(=S)N(Riii)2、-N(ORiii)C(NRiii)N(Riii)2、-N(ORiii)C(CHRiii)N(Riii)2。在前述任一种中,Riii是如本文所定义的氢,或烷基,或烯基,或炔基,或杂烷基,或杂烯基,或杂炔基。在一些实施方案中,Riii是如本文所定义的氢,或C1‐C12烷基,或C2‐C12烯基,或C2‐C12炔基,或C2‐C12杂烷基,或C3‐C12杂烯基,或C3‐C12杂炔基。
在某些实施方案中,取代基本身可以进一步被例如一个或多个如本文所定义的取代基取代。例如,作为取代基的C1-C6烷基可以进一步被一个或多个如本文所述的取代基取代。
如本文中所使用,术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用,“药学上可接受的盐”指本公开化合物的酸加成盐或碱加成盐,所述盐保留本公开化合物的生物有效性和特性,并且通常不是生物学上或其他方面不合需要的盐。在许多情况下,由于氨基和/或羧基基团或与其类似的基团的存在,本发明的化合物能够形成酸盐和/或碱盐。
药学可接受的酸加成盐可以用无机酸和/或有机酸与本公开的化合物形成,所述无机酸例如,但不限于盐酸、氢溴酸、硫酸、硝酸和磷酸等;所述有机酸例如,但不限于乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸和十一碳烯酸等。
药学可接受的碱加成盐可以用无机碱和/或有机碱与本公开的化合物形成,来源于无机碱的盐包括,但不限于,钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐和铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐和镁盐。来源于有机碱的盐包括,但不限于,下列伯胺、仲胺、叔胺、取代的胺(包括天然存在的取代的胺)、环状胺和碱性离子交换树脂的盐:例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、丹醇、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明(hydrabamine)、胆碱、甜菜碱、苯乙苄胺(benethamine)、苄星青霉素(benzathine)、乙二胺、葡糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶和聚胺树脂等。特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱和咖啡因。
本文中所述的数值范围应理解为涵盖边界值和其中包含的任何和所有子范围。例如,范围“1至10”应理解为不仅包括明确记载的1和10的值,而且还包括1至10范围内的任何单个值(例如2、3、4、5、6、7、8和9)和子范围(例如1至2、1.5至2.5、1至3、1.5至3.5、2.5至4、3至4.5等等)。该原则亦适用于仅用一个数值作为最小值或最大值的范围。
如本文中所使用,术语“异构体”意指具有相同分子式的不同化合物。“立体异构体”是仅原子在空间中的排列方式不同的异构体。“阻转异构体”是由绕单键的受阻旋转得到的立体异构体。“对映
异构体”是一对互为不可重叠的镜像的立体异构体。一对对映异构体的任何比例的混合物可称为“外消旋”混合物。“非对映异构体”是具有至少两个不对称原子但不互为镜像的立体异构体。“互变异构体”是指化合物的彼此平衡的异构形式。异构形式的浓度将取决于发现化合物的环境,并且可取决于例如化合物是固体还是在有机溶液或水溶液中而有所不同。
在某些实施方案中,“立体异构体”还可包括E和Z异构体或其混合物,以及顺式和反式异构体或其混合物。
可用于本公开中的核酸和/或多核苷酸包括编码所关注多肽的编码区、位于编码区的5′-末端的5′-UTR、位于编码区的3′-末端的3′-UTR)。在一些实施方案中,核酸或多核苷酸还包括聚腺苷酸区域和Kozak序列中的至少一种。在一些实施方案中,核酸或多核苷酸(例如mRNA)还可以包括5’帽结构。核酸的任一个区域都可以包括一种或多种替代性核苷,例如5-取代的尿苷(例如5-甲氧基尿苷)、1-取代的假尿苷(例如1-甲基-假尿苷或1-乙基-假尿苷)和/或5-取代的胞苷(例如5-甲基-胞苷)。
术语“5′-UTR”或“5′非翻译区”可以是mRNA中位于编码序列上游,且不被翻译为蛋白质的RNA序列。基因中的5′-UTR通常从转录起始位点开始,且在编码序列的翻译起始密码子上游的核苷酸结束。5′-UTR可以包含控制基因表达的元件,如核糖体结合位点、5′-末端寡嘧啶束和翻译起始信号如Kozak序列。mRNA可以通过添加5′帽进行转录后修饰。因此,成熟mRNA中的5′-UTR也可以指5′帽和起始密码子之间的RNA序列。如本文所用,术语“3′非翻译区”或“3′-UTR”可以是mRNA中位于编码序列下游,且不被翻译为蛋白质的。mRNA中的3′-UTR位于编码序列的终止密码子和poly(A)序列之间,例如从终止密码子下游的核苷酸开始到poly(A)序列上游的核苷酸结束。5′-UTR和/或3′-UTR的序列可与编码区的序列是同源的或异源的。3′-UTR可以包含源自白蛋白基因、α-珠蛋白基因、β-珠蛋白基因、酪氨酸羟化酶基因、脂加氧酶基因和胶原蛋白α基因中至少一种基因的3′-UTR。
如本文所用,术语“聚腺苷酸区域”与“poly(A)序列”和“poly(A)尾”可互换使用,天然存在的poly(A)序列通常由腺嘌呤核糖核苷酸组成。优选地,“聚腺苷酸区域”是指包含除腺嘌呤核糖核苷酸之外的核苷酸或核苷酸区段的poly(A)序列。poly(A)序列通常位于mRNA的3′端,例如3′-UTR的3′端(下游)。poly-A区可具有不同长度。具体地说,在一些实施方案中,本公开的核酸分子的poly-A区的长度为至少30个核苷酸;在一些实施方案中,本公开的核酸分子的poly-A区的长度为至少80个核苷酸;在一些实施方案中,本公开的核酸分子的poly-A区的长度为至少100个核苷酸。
如本文所用,术语“5′帽子结构”:5′帽子结构通常位于成熟mRNA的5′末端。在一些实施方案中,5′帽子结构通过5′-5′-三磷酸酯键与mRNA的5′-末端连接。5′帽子结构通常是由修饰的(例如甲基化的)核糖核苷酸(尤其是由鸟嘌呤核苷酸衍生物)形成。例如m7GpppN(帽0或称“cap0”,是hnRNA的5'磷酸基团在鸟苷酸转移酶的作用下与m7GTP的5'-磷酸基团作用形成5',5'-磷酸二酯键而形成的帽结构),其中N是携带5′帽子结构的核酸的末端5′核苷酸。在一些实施例中,5′帽子结构包括但不限于帽0、帽1(在帽0的基础上对hnRNA第一个核苷酸糖基2'-OH进一步发生甲基化而形成的帽结构,或称“cap1”)、帽2(在帽1的基础上对hnRNA第二位核苷酸糖基2'-OH进一步甲基化而形成的帽结构,或称“cap2”)、帽4、帽0类似物、帽1类似物、帽2类似物,或帽4类似物。
氨基脂质化合物
一个方面,本公开提供由以下式(I)表示的氨基脂质化合物:
或其药学上可接受的盐,或其立体异构体,
其中,
A1、A2和A3为以下情形之一:
(1)当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为C1‐C5烃基或C1‐C5杂烃基,A2为C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键;
(2)当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C3亚烃基或C1‐C3亚杂烃基,A2为C1‐C3亚烃基或C1‐C3亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成四元环、五元环或六元环;或
(3)当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C3亚烃基或C1‐C3亚杂烃基,A2为C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成四元环、五元环或六元环;
A4为C1‐C5亚烃基或键;
A5为C1‐C16亚烃基或键;
A6为C1‐C16亚烃基或键;
A7为C1‐C18亚烃基或键;
A8为C1‐C18亚烃基或键;
Z1为‐C(=O)O‐、‐OC(=O)‐、-O-、‐C(=O)‐、‐S‐、-C(=O)S-、-SC(=O)-、-C(=O)NR3‐或-NR3C(=O)‐;
R3为H或C1‐C8亚烃基;
Z2为‐C(=O)O‐、‐OC(=O)‐、-O-、‐C(=O)‐、‐S‐、-C(=O)S-、-SC(=O)-、-C(=O)NR4‐或-NR4C(=O)‐;
R4为H或C1‐C3亚烃基;
Y为-Z3C(=O)Z4-、-N(R5)-;
Z3为-O-、-N(R6)-、‐S‐或键;
Z4为-O-、-N(R7)-、‐S‐或键;
R5为-C(=O)A9Z5A10或-C(=O)A11;
Z5为-O-或‐S‐;
A9为C1‐C3亚烃基或键;
A10为C1‐C8烃基;
A11为C1‐C3烃基;
R6为H、C1‐C8的烃基;
R7为H、C1‐C8的烃基;
X为C或N;
R1为H或C1‐C18的烃基、Z6R8或-CH(OR9)2;
Z6为‐C(=O)O‐、‐OC(=O)‐或-O-;
R8为H、C1‐C18烃基、含有O或者S的C1‐C18杂烃基;
R9为C1‐C18烃基、含有O或者S的C1‐C18杂烃基;
R2为H或C1‐C18的烃基、Z7R10或-CH(OR11)2;
Z7为‐C(=O)O‐、‐OC(=O)‐或-O-;
R10为H、C1‐C18烃基、含有O或者S的C1‐C18杂烃基;
R11为C1‐C18烃基、含有O或者S的C1‐C18杂烃基;
优选地,所述烃基为烷基、烯基或炔基;
优选地,所述亚烃基为亚烷基、亚烯基或亚炔基;
优选地,所述杂烃基为杂烷基、杂烯基或杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中R1为Z6R8或-CH(OR9)2,R2为Z7R10或-CH(OR11)2。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为C1‐C5烃基或C1‐C5杂烃基,A2为C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键,即具有式(Ia)所示的结构:
其中,A4、A5、A6、A7、A8、Z1、Z2、Y、X、R1和R2的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C3亚烃基或C1‐C3亚杂烃基,A2为C1‐C3亚烃基或C1‐C3亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成四元环、五元环或六元环,即具有式(Ib)所示的结构:
其中,A4、A5、A6、A7、A8、Z1、Z2、Y、X、R1和R2的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C3亚烃基或C1‐C3亚杂烃基,A2为C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成四元环、五元环或六元环,即具有式(Ic)所示的结构:
其中,A4、A5、A6、A7、A8、Z1、Z2、Y、X、R1和R2的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当X为C时,即具有式(Id)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、R1和R2的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当X为N时,即具有式(Ie)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、R1和R2的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当R1为-CH(OR9)2时,即具有式(II)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、X、R2和R9的定义如式(I)中所定义。
在一些实施方案中,式(II)表示的氨基脂质化合物中,当X为C时,即具有式(IIa)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、R2和R9的定义如式(I)中所定义。
在一些实施方案中,式(II)表示的氨基脂质化合物中,当X为N时,即具有式(IIb)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、R2和R9的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当
R1为-CH(OR9)2;
R2为-CH(OR11)2时,
即具有式(III)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、X、R9和R11的定义如式(I)中所定义。
在一些实施方案中,式(III)表示的氨基脂质化合物中,当X为C时,即具有式(IIIa)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、R9和R11的定义如式(I)中所定义。
在一些实施方案中,式(III)表示的氨基脂质化合物中,当X为N时,即具有式(IIIb)所示
的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y、R9和R11的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当
Y为-Z3C(=O)Z4-;
Z3为-O-;
Z4为-O-;
X为C;
R1为-CH(OR9)2和R2为-CH(OR11)2时,
即具有式(IV)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、R9和R11的定义如式(I)中所定义。
在一些实施方案中,式(I)表示的氨基脂质化合物中,当
Y为-Z3C(=O)Z4-;
Z3为-O-;
Z4为-O-;
X为C;
Z1为‐C(=O)O‐、‐OC(=O)‐;
Z2为‐C(=O)O‐、‐OC(=O)‐;
R1为-CH(OR9)2和R2为-CH(OR11)2时,
即具有式(Va)、(Vb)、(Vc)或(Vd)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、R9和R11的定义如式(I)中所定义。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、
(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1为C1、C2、C3、C4、C5烃基,C1、C2、C3、C4、C5杂烃基,C1、C2、C3亚烃基,或者C1、C2、C3亚杂烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A2为C1、C2、C3、C4、C5烃基,C1、C2、C3、C4、C5杂烃基,C1、C2、C3亚烃基,或者C1、C2、C3亚杂烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1、C2、C3、C4、C5亚烃基或键。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A4为C1、C2、C3亚烃基或键。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A5为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A6为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A7为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A8为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)或(IIIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A9为C1、C2、C3亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)或(IIIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A10为C1、C2、C3、C4、C5、C6、C7、C8亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、
(IIa)、(IIb)、(III)、(IIIa)或(IIIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A11为C1、C2、C3亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)或(IIIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R6为H或C1、C2、C3、C4、C5、C6、C7、C8烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)或(IIIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R7为H或C1、C2、C3、C4、C5、C6、C7、C8烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)或(IV)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R3为H或C1、C2、C3、C4、C5、C6、C7、C8亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)或(IV)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R4为H或C1、C2、C3亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)或(IV)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R4为任选取代的C1‐C3亚烃基;
优选地,R4为被羟基、酯基、烃氧基、烃基、卤素、氧、硫、氨基、酰胺基任选取代的C1‐C3亚烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1为H或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1为H、C1‐C18的直链烷基、C2‐C18的直链烯基、或C2‐C18的直链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1为H、C3‐C18的支链烷基、C3‐C18的支链烯基、或C4‐C18的支链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烷
基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18烃基,或者含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18杂烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8为C1‐C18直链烷基、或C2‐C18的直链烯基、或C2‐C18的直链炔基、或含有O或者S的C1‐C18直链杂烷基、或含有O或者S的C2‐C18的直链杂烯基、或含有O或者S的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链炔基,或含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烷基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烯基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8为C3‐C18的支链烷基、或C3‐C18的支链烯基、或C4‐C18的支链炔基、或含有O或者S的C3‐C18的支链杂烷基、或含有O或者S的C3‐C18的支链杂烯基、或含有O或者S的C4‐C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链炔基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂烷基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂烯基,或含有O或者S的C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)或(Ie)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8为
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18烃基,或者含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18杂烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9为C1‐C18直链烷基、或C2‐C18的直链烯基、或C2‐C18的直链炔基、或含有O或者S的C1‐C18直链杂烷基、或含有O或者S的C2‐C18的直链杂烯基、或含有O或者S的C2‐C18的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链炔基,或含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烷基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烯基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9为C3‐C18的支链烷基、或C3‐C18的支链烯基、或C4‐C18的支链炔基、或含有O或者S的C3‐C18的支链杂烷基、或含有O或者S的C3‐C18的支链杂烯基、或含有O或者S的C4‐C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链炔基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂烷基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、
C18的支链杂烯基,或含有O或者S的C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9为
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R2为H或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R2为H、C1‐C18的直链烷基、C2‐C18的直链烯基、或C2‐C18的直链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R2为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R2为H、C3‐C18的支链烷基、C3‐C18的支链烯基、或C4‐C18的支链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R2为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R10为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18烃基,或含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18杂烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R10为C1‐C18直链烷基、或C2‐C18的直链烯基、或C2‐C18的直链炔基、或含有O或者S的C1‐C18
直链杂烷基、或含有O或者S的C2‐C18的直链杂烯基、或含有O或者S的C2‐C18的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R10为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链炔基,或含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烷基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烯基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R10为C3‐C18的支链烷基、或C3‐C18的支链烯基、或C4‐C18的支链炔基、或含有O或者S的C3‐C18的支链杂烷基、或含有O或者S的C3‐C18的支链杂烯基、或含有O或者S的C4‐C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R10为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链炔基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂烷基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂烯基,或含有O或者S的C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)或(IIb)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R10为
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R11为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18烃基,或含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18杂烃基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或
其药学上可接受的盐,或其立体异构体,其中:
R11为C1‐C18直链烷基、或C2‐C18的直链烯基、或C2‐C18的直链炔基、或含有O或者S的C1‐C18直链杂烷基、或含有O或者S的C2‐C18的直链杂烯基、或含有O或者S的C2‐C18的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R11为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链炔基,或含有O或者S的C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烷基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂烯基,或含有O或者S的C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R11为C3‐C18的支链烷基、或C3‐C18的支链烯基、或C4‐C18的支链炔基、或含有O或者S的C3‐C18的支链杂烷基、或含有O或者S的C3‐C18的支链杂烯基、或含有O或者S的C4‐C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R11为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链炔基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂烷基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂烯基,或含有O或者S的C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18的支链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R11为
在一些实施方案中,本公开提供如上文所述的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(II)、(IIa)、(IIb)、(III)、(IIIa)、(IIIb)、(IV)、(Va)、(Vb)、(Vc)或(Vd)的氨基脂质化合物,或
其药学上可接受的盐,或其立体异构体,其中:
所述烃基、亚烃基、烷基、亚烷基、烯基、亚烯基、炔基、亚炔基和杂烃基是任选取代的;
任选地,所述烃基、亚烃基、烷基、亚烷基、烯基、亚烯基、炔基、亚炔基和杂烃基任选地被羟基、酯基、烃氧基、烃基、卤素、氧、硫、氨基、酰胺基取代。
再一个方面,本公开提供由以下式(II-I)表示的氨基脂质化合物:
或其药学上可接受的盐,或其立体异构体,
其中,
A1、A2和A3为以下情形之一:
(1)当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为H、C1‐C5烃基或C1‐C5杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键;
(2)当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成含N的杂环;或
(3)当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成含N的杂环;
(4)当连接A1和A2的虚线以及连接A1和A3的虚线为键时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基,A1、A2和A3连同它们共同连接的氮原子一起形成含N的螺环杂环、稠合杂环或桥环杂环;
A4为C1‐C5亚烃基或键;
A5、A6、A7、A8和A12各自独立地为C1‐C18亚烃基或键;
Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
Y1为-Z3C(=O)Z4-、-N(R5)-、-Z3C(=S)Z4-、-OS(=O)2O-、-OS(=O)O-、-OS(=O)2NH-、-NHS(=O)2NH-、-NHS(=O)2-、-S(=O)2NH-、-S(=O)2O-、-OS(=O)2-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-O-、-S-、-NHS(=O)2O-、-NHP(=O)O-、-OP(=O)NH-、-NHP(=O)(OH)O-、-OP(=O)(OH)NH-、-OC(=O)S-或-SC(=O)O-;
X为C或N;
R1为H、C1‐C24的烃基、C1‐C24的杂烃基、Z6R8或-CH(OR9)2;
R2为H、C1‐C24的烃基、C1‐C24的杂烃基、Z7R10或-CH(OR11)2;
Z3和Z4各自独立地为-O-、-N(R6)-、‐S‐或键;
Z6和Z7各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
R5为-C(=O)A9Z5A10、-C(=O)A11、H或C1‐C8烃基;
Z5为-O-或‐S‐;
R6各自独立地为H或C1‐C8烃基;
R8和R10各自独立地为H、C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
R9和R11各自独立地为C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
A9为C1‐C8亚烃基或键;
A10和A11各自独立地为C1‐C8烃基;
优选地,所述烃基为烷基、烯基或炔基;
优选地,所述亚烃基为亚烷基、亚烯基或亚炔基;
优选地,所述杂烃基为杂烷基、杂烯基或杂炔基;
优选地,所述亚杂烃基为亚杂烷基、亚杂烯基或亚杂炔基。
再另一个方面,本公开提供由以下式(II-I)表示的氨基脂质化合物:
或其药学上可接受的盐,或其立体异构体,
其中,
A1、A2和A3为以下情形之一:
(1)当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为H、C1‐C5烃基或C1‐C5杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键;
(2)当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成含N的杂环;
(3)当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成含N的杂环;
(4)当连接A1和A2的虚线以及连接A1和A3的虚线为键时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基,A1、A2和A3连同它们共同连接的氮原子一起形成含N的螺环杂环、稠合杂环或桥环杂环;
A4为C1‐C5亚烃基或键;
A5、A6、A7、A8和A12各自独立地为C1‐C18亚烃基、C1‐C18亚杂烃基或键;
Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-
C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
Y1为-Z3C(=O)Z4-、-N(R5)-、-Z3C(=S)Z4-、-OS(=O)2O-、-OS(=O)O-、-OS(=O)2NH-、-NHS(=O)2NH-、-NHS(=O)2-、-S(=O)2NH-、-S(=O)2O-、-OS(=O)2-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-O-、-S-、-NHS(=O)2O-、-NHP(=O)O-、-OP(=O)NH-、-NHP(=O)(OH)O-、-OP(=O)(OH)NH-、-OC(=O)S-或-SC(=O)O-;
X为C或N;
R1为H、C1‐C24的烃基、C1‐C24的杂烃基、Z6R8、-C(R6)(OA13Z8R9)2、-C(R6)(SA13Z8R9)2或-C(R6)(SA13Z8R9)(OA13Z8R9);
R2为H、C1‐C24的烃基、C1‐C24的杂烃基、Z7R10、-C(R6)(OA14Z9R11)2、-C(R6)(SA14Z9R11)2或-C(R6)(SA14Z9R11)(OA14Z9R11);
Z3和Z4各自独立地为-O-、-N(R6)-、‐S‐或键;
Z6和Z7各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
R5为-C(=O)A9Z5A10、-C(=O)A11、H或C1‐C8烃基;
Z5为-O-或‐S‐;
Z8和Z9各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-、-NHS(=O)2O-或键;
R6各自独立地为H或C1‐C8烃基;
R8和R10各自独立地为H、C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
R9和R11各自独立地为C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
A9为C1‐C8亚烃基或键;
A10和A11各自独立地为C1‐C8烃基;
A13和A14各自独立地为C1‐C8亚烃基、C1‐C8亚杂烃基或键;
优选地,所述烃基为烷基、烯基或炔基;
优选地,所述亚烃基为亚烷基、亚烯基或亚炔基;
优选地,所述杂烃基为杂烷基、杂烯基或杂炔基;
优选地,所述亚杂烃基为亚杂烷基、亚杂烯基或亚杂炔基。
本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,当适用时包括一个或多个以下特征。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1为H,A2为H;或A1为H,A2不为H;或A1不为H,A2为H。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接
受的盐,或其立体异构体,其中:
A1和A2各自独立地为C1、C2、C3、C4、C5烃基,或C1、C2、C3、C4、C5杂烃基,或C1、C2、C3、C4、C5亚烃基,或C1、C2、C3、C4、C5亚杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地为C1-C5烷基,或具有1或2个双键的C2-C5烯基,或具有1或2个三键的C2-C5炔基,或含有S或O的C1-C5杂烷基,或具有1或2个双键的含有S或O的C2-C5杂烯基,或具有1或2个三键的含有S或O的C2-C5杂炔基,或C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基,或含有S或O的C1-C5亚杂烷基,或具有1或2个双键的含有S或O的C2-C5亚杂烯基,或具有1或2个三键的含有S或O的C2-C5亚杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和/或A2为未被取代的C1-C5烃基,或未被取代的C1-C5杂烃基,或未被取代的C1-C5亚烃基,或未被取代的C1-C5亚杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和/或A2为被取代的C1-C5烃基,或被取代的C1-C5杂烃基,或被取代的C1-C5亚烃基,或被取代的C1-C5亚杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和/或A2为被取代的C1-C5烷基,或被取代的C2-C5烯基,或被取代的C3-C5炔基,或被取代的C1-C5亚烷基,或被取代的C2-C5亚烯基,或被取代的C3-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和/或A2为被羟基,氰基,苯基,C3‐C7环烃基,包含1-3个独立地选自氮、氧或硫的杂原子的C3‐C7环烃基,5至6元单环基,包含1-4个独立地选自氮、氧和硫的杂原子的杂芳基,包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基,-OR12,-C(=O)R12,-C(=O)SR12,-OC(=O)R12,-OC(=O)OR12,-N(R12)2,-C(=O)N(R12)2,-C(=S)N(R12)2,-S(=O)2R12,-S(=O)2N(R12)2,-OC(=O)N(R12)2,-CH(NR12)N(R12)2,-C(NR12)2R12,-C(=O)N(R12)OR12,-CH(R12)N(R12)2C(=O)OR12,-C(R12)3,-N(R12)C(=O)R12,-N(R12)C(=O)OR12,-N(R12)S(=O)2R12,-N(R12)C(=O)N(R12)2,-N(R12)C(=S)N(R12)2,-N(R12)C(NR12)N(R12)2,-N(R12)C(CHR12)N(R12)2,-N(OR12)C(=O)R12,-N(OR12)S(=O)2R12,-N(OR12)C(=O)OR12,-N(OR12)C(=O)N(R12)2,-N(OR12)C(=S)N(R12)2,-N(OR12)C(NR12)N(R12)2,-N(OR12)C(CHR12)N(R12)2,-OP(=O)(OR12)2,-P(=O)(OR12)2,或包含1-3个独立地选自氮、氧、硫的杂原子的3至7元脂环族和3至7元杂环基的环,-C(=N-CN)N(R12)2,-C(=N-O-CH3)N(R12)2,-C(=N-SO2-NH2)N(R12)2,-C(=CH-NO2)N(R12)2或-C(=O)OR12取代的C1-C5烷基、C2-C5烯基、C3-C5炔基、C1-C5亚烷基、C2-C5亚烯基、C3-C5亚炔基,
其中,R12各自独立地为氢,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和/或A2为被C1-C5烷基、=O、-C0-C5亚烷基-羟基、-C(=O)N(R15)2取代的含有1-3个独立地选自氮、氧或硫的杂原子的C3‐C7环烃基,任选地被C1-C5烷基、羟基取代的包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基,
或者取代的C1-C5烷基、C2-C5烯基、C3-C5炔基、C1-C5亚烷基、C2-C5亚烯基、C3-C5亚炔基,其中R15各自独立地为H或者C1-C3的烷基,d为0、1、2、3、4或5。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和/或A2为
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和/或A2还可以为
其中,a为1、2、3、4或5;
优选地,所述a为1、2或3。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1、C2、C3、C4、C5亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接
受的盐,或其立体异构体,其中:
A3为未被取代的C1-C5亚烷基,或未被取代的C2-C5亚烯基,或未被取代的C3-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为被取代的C1-C5亚烷基,或被取代的C2-C5亚烯基,或被取代的C3-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C5亚烷基、C2-C5亚烯基、C3-C5亚炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当A3为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C5亚烷基、C2-C5亚烯基、C3-C5亚炔基时,R13和/或R14可以与A3上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1和A2连同它们共同连接的氮原子一起形成含N的三元、四元、五元、六元、七元或八元杂环。
在一些实施方案中,A1和A2连同它们共同连接的氮原子一起形成含N的三元、四元、五元或六元杂环。
在一些实施方案中,A1和A2连同它们共同连接的氮原子一起形成含N的四元、五元或六元杂环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1和A3连同它们共同连接的氮原子一起形成含N的三元、四元、五元、六元、七元或八元杂环。
在一些实施方案中,A1和A3连同它们共同连接的氮原子一起形成含N的三元、四元、五元或六元杂环。
在一些实施方案中,A1和A3连同它们共同连接的氮原子一起形成含N的四元、五元或六元杂环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
为
其中,c为1、2、3、4或5;
优选地,所述c为2、3或4;
优选地,所述c为2或3。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A4为键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A4为C1、C2、C3、C4、C5亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A4为C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A4为未被取代的C1-C5亚烷基,或未被取代的C2-C5亚烯基,或未被取代的的C3-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A4为被取代的C1-C5亚烷基,或被取代的C2-C5亚烯基,或被取代的C3-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A4为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C5亚烷基、C2-C5亚烯基、C3-C5亚炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当A4为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C5亚烷基、C2-C5亚烯基、C3-C5亚炔基时,R13和/或R14可以与A4上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A5、A6、A7、A8和A12各自独立地为C1‐C18亚烃基或键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A5、A6、A7、A8和A12各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、
C13、C14、C15、C16、C17、C18亚烃基或键。
在一些实施方案中,A5、A6、A7、A8和A12各自独立地为键。
在另一些实施方案中,A5、A6、A7、A8和A12各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A5、A6、A7、A8和A12各自独立地为C1-C18亚烷基,或具有1、2、3或更多个双键的C2-C18亚烯基,或具有1、2、3或更多个三键的C2-C18亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A12为键,且A5和A6不同时为C1亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A7和A8各自独立地为C1、C2、C3、C4、C5、C6、C7亚烃基或键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A12为C1亚烃基,A5为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烃基;或A12为C1亚烃基,A6为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A5和/或A6为未被取代的C1-C12亚烷基,或未被取代的C2-C12亚烯基,或未被取代的C3-C12亚炔基。例如,A5和/或A6为未被取代的C1-C12亚烷基、或未被取代的C3-C9亚烷基、或未被取代的C4-C9亚烷基、或未被取代的C5-C8亚烷基、或未被取代的C8亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A5和/或A6为被取代的C1-C12亚烷基,或被取代的C2-C12亚烯基,或被取代的C3-C12亚炔基。例如,A5和/或A6为被取代的C1-C12亚烷基、或被取代的C3-C9亚烷基、或被取代的C4-C9亚烷基、或被取代的C5-C8亚烷基、或被取代的C8亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A7和/或A8为未被取代的C1-C12亚烷基,或未被取代的C2-C12亚烯基,或未被取代的C3-C12亚炔基。例如,A7和/或A8为未被取代的C1-C5亚烷基、或未被取代的C2-C4亚烷基、或未被取代的
C3亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A7和/或A8为被取代的C1-C12亚烷基,或被取代的C2-C12亚烯基,或被取代的C3-C12亚炔基。例如,A7和/或A8为被取代的C1-C5亚烷基、或被取代的C2-C4亚烷基、或被取代的C3亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A12为未被取代的C1-C12亚烷基,或未被取代的C2-C12亚烯基,或未被取代的C3-C12亚炔基。例如,A12为未被取代的C1-C5亚烷基、或未被取代的C1-C3亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A12为被取代的C1-C12亚烷基,或被取代的C2-C12亚烯基,或被取代的C3-C12亚炔基。例如,A12为被取代的C1-C5亚烷基、或被取代的C1-C3亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A5、A6、A7、A8和A12中的至少一个为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C12亚烷基、C2-C12亚烯基、C3-C12亚炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当A5、A6、A7、A8和A12中的至少一个为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C12亚烷基、C2-C12亚烯基、C3-C12亚炔基时,R13和/或R14可以与被取代的A5、A6、A7、A8或A12上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A9为键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A9为C1、C2、C3、C4、C5、C6、C7、C8亚烃基,或C1、C2、C3、C4、C5、C6、C7、C8亚杂烃
基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A9为C1-C8亚烷基,或具有1、2或更多个双键的C2-C8亚烯基,或具有1、2或更多个三键的C2-C8亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A9各自独立地为未被取代的C1-C8亚烷基,或未被取代的C2-C8亚烯基,或未被取代的C3-C8亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A9中至少一个为被取代的C1-C8亚烷基,或被取代的C2-C8亚烯基,或被取代的C3-C8亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A9中至少一个为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代C1-C8亚烷基、C2-C8亚烯基、C3-C8亚炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当A9为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C8亚烷基、C2-C8亚烯基、C3-C8亚炔基时,R13和/或R14可以与被取代的A9上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A10和A11各自独立地为C1、C2、C3、C4、C5、C6、C7、C8烃基,或C1、C2、C3、C4、C5、C6、C7、C8杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A10和各A11各自独立地为C1-C8烷基,或具有1、2或更多个双键的C2-C8烯基,或具有1、
2或更多个三键的C2-C8炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A10和/或各A11为未被取代的C1-C8烷基,或未被取代的C2-C8烯基,或未被取代的C3-C8炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A10和/或各A11中的至少一个为被取代的C1-C8烷基,或被取代的C2-C8烯基,或被取代的C3-C8炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A10和/或各A11中至少一个为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C8烷基、C2-C8烯基、C3-C8炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当A10和/或A11为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C8烷基、C2-C8烯基、C3-C8炔基时,R13和/或R14可以与被取代的A10或A11上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中R5为未被取代的C1‐C8烷基,或未被取代的C2‐C8烯基,或未被取代的C2‐C8炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中R5为被取代的C1‐C8烷基,或被取代的C2‐C8烯基,或被取代的C2‐C8炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R5为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1‐C8烷基、C2‐C8烯基或C2‐C8炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当R5为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1‐C8烷基、C2‐C8烯基或C2‐C8炔基时,R13和/或R14可以与R5上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
Y1为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-C(=S)O-、-OC(=S)-、‐C(=S)‐、-C(=S)S-、-SC(=S)-、-C(=S)N(R6)-、-N(R6)C(=S)-、-OC(=S)O-、-OC(=S)S-、-SC(=S)O-、-SC(=S)S-、-N(R6)C(=S)O-、-OC(=S)N(R6)-、-N(R6)C(=S)N(R6)-、-SC(=S)N(R6)-、-N(R6)C(=S)S-、-N(C(=S)A9OA10)-、-OS(=O)2O-、-OS(=O)O-、-OS(=O)2NH-、-NHS(=O)2NH-、-NHS(=O)2-、-S(=O)2NH-、-S(=O)2O-、-OS(=O)2--OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-NHS(=O)2O-、-NHP(=O)O-、-OP(=O)NH-、-NHP(=O)(OH)O-、-OP(=O)(OH)NH-、-OC(=O)S-或-SC(=O)O-。
在一些实施方案中,Y1为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A11)、-OS(=O)2O-、-OS(=O)O-、-OS(=O)2NH-、-NHS(=O)2NH-、-NHS(=O)2-、-S(=O)2NH-、-S(=O)2O-、-OS(=O)2-、-OS(=O)2O-、-OS(=O)O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-NHS(=O)2O-、-NHP(=O)O-、-OP(=O)NH-、-NHP(=O)(OH)O-、-OP(=O)(OH)NH-、-OC(=O)S-或-SC(=O)O-。
在一些实施方案中,Y1为-N(H)C(=O)N(H)-、-S-、-OC(=O)O-、-N(H)C(=O)O-、-OC(=O)N(H)-、-C(=O)O-、-OC(=O)-、--N((CH2)3C(=O)OC5H11)C(=O)O-、-OC(=O)N((CH2)3C(=O)OC5H11)-、-N(H)C(=O)-、-C(=O)N(H)-、-N(C(=O)(CH2)3OC8H17)、-N(C(=O)CH2OCH3)、-N(C(=O)CH3)、-N(C(=O)C3H7)、-N(C3H7)C(=O)O-、-OC(=O)N(C6H13)-、-C(=O)N(C4H9)-、-N(CH(CH3)2)C(=O)-、-N((CH2)3C(=O)OC2H5)C(=O)O-、-N((CH2)3C(=O)OCH2CH=CHC3H7)C(=O)O-、-N(C4H9)C(=O)-、-O-、-S(=O)2O-、-OS(=O)2-、-OS(=O)2O-、-OS(=O)O-、-S(=O)2NH-、-NHS(=O)2-、-OS(=O)2NH-、-NHS(=O)2NH-、-OP(=O)(H)O-、-OP(=O)(OH)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)N(H)-、-N(H)C(=O)S-、-C(=O)S-或-SC(=O)-。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
Y1为-C(=O)O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-
OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-C(=S)O-、-OC(=S)-、‐C(=S)‐、-C(=S)S-、-SC(=S)-、-C(=S)N(R6)-、-N(R6)C(=S)-、-OC(=S)O-、-OC(=S)S-、-SC(=S)O-、-SC(=S)S-、-N(R6)C(=S)O-、-OC(=S)N(R6)-、-N(R6)C(=S)N(R6)-、-SC(=S)N(R6)-、-N(R6)C(=S)S-、-N(C(=S)A9OA10)-、-OS(=O)2O-、-OS(=O)O-、-OS(=O)NH-、-NHS(=O)2NH-、-NHS(=O)2-、-S(=O)2NH-、-S(=O)2O-、-OS(=O)2-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-NHS(=O)2O-、-NHP(=O)O-、-OP(=O)NH-、-NHP(=O)(OH)O-、-OP(=O)(OH)NH-、-OC(=O)S-或-SC(=O)O-。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
Z1为-C(=O)O-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
Z2为-C(=O)O-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和R2各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24烃基,或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和/或R2为C1‐C24的烷基(例如C5‐C16烷基、C6‐C14烷基、C6‐C12烷基)、C2‐C24的烯基(例如C5‐C16烯基、C6‐C14烯基、C6‐C12烯基)、C2‐C24的炔基(例如C5‐C16炔基、C6‐C14炔基、C6‐C12炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和/或R2为未被取代的C1‐C24的烷基(例如未被取代的C5‐C16烷基、未被取代的C6‐C14烷基、未被取代的C6‐C12烷基)、未被取代的C2‐C24的烯基(例如未被取代的C5‐C16烯基、未被取代的C6‐C14烯基、未被取代的C6‐C12烯基)、未被取代的C2‐C24的炔基(例如未被取代的C5‐C16炔基、未被取代的C6‐C14炔基、未被取代的C6‐C12炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接
受的盐,或其立体异构体,其中:
R1和/或R2为被取代的C1‐C24的烷基(例如被取代的C5‐C16烷基、被取代的C6‐C14烷基、被取代的C6‐C12烷基)、被取代的C2‐C24的烯基(例如被取代的C5‐C16烯基、被取代的C6‐C14烯基、被取代的C6‐C12烯基)、被取代的C2‐C24的炔基(例如被取代的C5‐C16炔基、被取代的C6‐C14炔基、被取代的C6‐C12炔基、被取代的C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和R2各自独立地为C1‐C24的直链烷基,或具有1、2、3、4或更多个双键的C2‐C24的直链烯基,或具有1、2、3、4或更多个三键的C2‐C24的直链炔基,或含有O或者S的C1‐C24的直链杂烷基,或含有O或者S的具有1、2、3、4或更多个双键的C2‐C24的直链杂烯基,或含有O或者S的具有1、2、3、4或更多个三键的C2‐C24的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和R2各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链炔基,或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和R2各自独立地为C3‐C24支化的烷基,或具有1、2、3、4或更多个双键的C3‐C24支化的烯基,或具有1、2、3、4或更多个三键的C4‐C24支化的炔基,或含有O或者S的C3‐C24支化的杂烷基,或含有O或者S的具有1、2、3、4或更多个双键的C3‐C24支化的杂烯基,或含有O或者S的具有1、2、3、4或更多个三键的C4‐C24支化的杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和R2各自独立地为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的炔基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂烷基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂烯基,或含有O或者S的C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接
受的盐,或其立体异构体,其中:
R8和R10各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24烃基,或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和/或R10为C1-C20的烷基(例如C2‐C10烷基、C2‐C8烷基、C7‐C18烷基),或C1-C16的烯基(例如C5‐C12烯基、C5‐C8烯基、C5烯基、C6烯基),或C5‐C16炔基(例如C5‐C12炔基、C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和/或R10为未被取代的C1-C20的烷基(例如未被取代的C2‐C10烷基、未被取代的C2‐C8烷基、未被取代的C7‐C18烷基),或未被取代的C1-C16的烯基(例如未被取代的C5‐C12烯基、未被取代的C5‐C8烯基、未被取代的C5烯基、未被取代的C6烯基),或未被取代的C5‐C16炔基(例如未被取代的C5‐C12炔基、未被取代的C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和/或R10为被取代的C1-C20的烷基(例如被取代的C2‐C10烷基、被取代的C2‐C8烷基、被取代的C7‐C18烷基),或被取代的C1-C16的烯基(例如被取代的C5‐C12烯基、被取代的C5‐C8烯基、被取代的C5烯基、被取代的C6烯基),或被取代的C5‐C16炔基(例如被取代的C5‐C12炔基、被取代的C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和R10各自独立地为C1‐C24的直链烷基,或具有1、2、3、4或更多个双键的C2‐C24的直链烯基,或具有1、2、3、4或更多个三键的C2‐C24的直链炔基,或含有O或者S的C1‐C24的直链杂烷基,或含有O或者S的具有1、2、3、4或更多个双键的C2‐C24的直链杂烯基,或含有O或者S的具有1、2、3、4或更多个三键的C2‐C24的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和R10各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链炔基;或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和R10各自独立地为C3‐C24支化的烷基,或具有1、2、3、4或更多个双键的C3‐C24支化的烯基,或具有1、2、3、4或更多个三键的C4‐C24支化的炔基,或含有O或者S的C3‐C24支化的杂烷基,或含有O或者S的具有1、2、3、4或更多个双键的C3‐C24支化的杂烯基,或含有O或者S的具有1、2、3、4或更多个三键的C4‐C24支化的杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和R10各自独立地为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的炔基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂烷基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂烯基,或含有O或者S的C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和/或R10为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C20的烷基(例如被取代的C2‐C10烷基、被取代的C2‐C8烷基、被取代的C7‐C18烷基)、C1-C16的烯基(例如被取代的C5‐C12烯基、被取代的C5‐C8烯基、被取代的C5烯基、被取代的C6烯基)、C5‐C16炔基(例如被取代的C5‐C12炔基、被取代的C10炔基),
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当R8和/或R10各自独立地被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代时,R13和/或R14可以与被取代的R8或R10上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中R8和/或R10各自独立地为被取代的芳基。在一些实施方案中,R8或R10为被烷基取代的苯基,例如:
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R8和R10各自独立地为
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R6各自独立地为C1、C2、C3、C4、C5、C6、C7、C8烃基,或C1、C2、C3、C4、C5、C6、C7、C8杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接
受的盐,或其立体异构体,其中:
R6各自独立地为C1-C8烷基,或具有1、2或更多个双键的C2-C8烯基,或具有1、2或更多个三键的C2-C8炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R6各自独立地为C1、C2、C3、C4、C5、C6、C7或C8烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R6各自独立地为未被取代的C1-C8烷基,或未被取代的C2-C8烯基,或未被取代的C2-C8炔基,或未被取代的C1-C8杂烷基,或未被取代的C2-C8杂烯基,或未被取代的C2-C8杂炔基。例如,R6各自独立地为未被取代的C1‐C5烷基、未被取代的C1‐C3烷基、未被取代的C1烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R6中至少一个为被取代的C1-C8烷基,或被取代的C2-C8烯基,或被取代的C2-C8炔基,例如,各R6中的一个为被取代的C1‐C5烷基、被取代的C1‐C3烷基、被取代的C3烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R6中至少一个为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C8烷基、C2-C8烯基、C2-C8炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当R6为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C8烷基、C2-C8烯基、C2-C8炔基时,R13和/或R14可以与被取代的R6上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A13和A14各自独立地为C1、C2、C3、C4、C5、C6、C7、C8亚烃基,或C1、C2、C3、C4、C5、C6、C7、C8亚杂烃基,或键。
在一些实施方案中,A13和A14各自独立地为键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A13和A14各自独立地为C1-C8亚烷基,或具有1、2或更多个双键的C2-C8亚烯基,或具有1、2或更多个三键的C2-C8亚炔基,或键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A13和各A14各自独立地为C1-C8亚烷基、C2-C8亚烯基、C2-C8亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A13和/或各A14为未被取代的C1-C8亚烷基,或未被取代的C2-C8亚烯基,或未被取代的C2-C8亚炔基。例如,A13和A14各自独立地为未被取代的C2-C5亚烷基、未被取代的C3-C4亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A13和/或各A14中至少一个为被取代的C1-C8亚烷基,或被取代的C2-C8亚烯基,或被取代的C2-C8亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各A13和/或各A14中至少一个为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C8亚烷基、C2-C8亚烯基、C2-C8亚炔基,
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:当A13和/或A14为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C8亚烷基、C2-C8亚烯基、C2-C8亚炔基时,R13和/或R14可以与被取代的A13或A14上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9和R11各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24烃基,或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R9各自独立地为C1-C12烷基(例如C3-C9烷基、C5-C8烷基、C6烷基、C7烷基)、C5‐C16烯基(例如C5‐C12烯基、C5‐C8烯基、C6烯基)、C5‐C16炔基(例如C9‐C11炔基、C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R9为未被取代的C1-C12烷基(例如未被取代的C3-C9烷基、未被取代的C5-C8烷基、未被取代的C6烷基、未被取代的C7烷基)、未被取代的C5‐C16烯基(例如未被取代的C5‐C12烯基、未被取代的C5‐C8烯基、未被取代的C6烯基)、未被取代的C5‐C16炔基(例如未被取代的C9‐C11炔基、未被取代的C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R9中至少有一个为被取代的C1-C12烷基(例如被取代的C3-C9烷基、被取代的C5-C8烷基、被取代的C6烷基、被取代的C7烷基)、被取代的C5‐C16烯基(例如被取代的C5‐C12烯基、被取代的C5‐C8烯基、被取代的C6烯基)、被取代的C5‐C16炔基(例如被取代的C9‐C11炔基、被取代的C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R11各自独立地为C1-C12烷基(例如C3-C9烷基、C5-C8烷基、C6烷基、C7烷基)、C5‐C16烯基(例如C5‐C12烯基、C5‐C8烯基、C6烯基)、C5‐C16炔基(例如C9‐C11炔基、C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R11为未被取代的C1-C12烷基(例如未被取代的C3-C9烷基、未被取代的C5-C8烷基、未被取代的C6烷基、未被取代的C7烷基)、未被取代的C5‐C16烯基(例如未被取代的C5‐C12烯基、未被取代的C5‐C8烯基、未被取代的C6烯基)、未被取代的C5‐C16炔基(例如未被取代的C9‐C11炔基、未被取代的C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R11中至少有一个为被取代的C1-C12烷基(例如被取代的C3-C9烷基、被取代的C5-C8烷基、被取代的C6烷基、被取代的C7烷基)、被取代的C5‐C16烯基(例如被取代的C5‐C12烯基、被取代的C5‐C8烯基、被取代的C6烯基)、被取代的C5‐C16炔基(例如被取代的C9‐C11炔基、被取代的C10炔基)。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9和R11各自独立地为C1‐C24的直链烷基,或具有1、2、3、4或更多个双键的C2‐C24的直链烯基,或具有1、2、3、4或更多个三键的C2‐C24的直链炔基,或含有O或者S的C1‐C24的直链杂烷基,或含有O或者S的具有1、2、3、4或更多个双键的C2‐C24的直链杂烯基,或含有O或者S的具有1、2、3、4或更多个三键的C2‐C24的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9和R11各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链炔基;或C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂烷基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂烯基,或C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24的直链杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9和R11各自独立地为C3‐C24支化的烷基,或具有1、2、3、4或更多个双键的C3‐C24支化的烯基,或具有1、2、3、4或更多个三键的C4‐C24支化的炔基,或含有O或者S的C3‐C24支化的杂烷基,或含有O或者S的具有1、2、3、4或更多个双键的C3‐C24支化的杂烯基,或含有O或者S的具有1、2、3、4或更多个三键的C4‐C24支化的杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9和R11各自独立地为C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的烷基,或C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的烯基,或C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的炔基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂烷基,或含有O或者S的C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂烯基,或含有O或者S的C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18、C19、C20、C21、C22、C23、C24支化的杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
各R9和/或各R11中的至少一个为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C12烷基(C3-C9烷基、C5-C8烷基、C6烷基、C7烷基)、C5‐C16烯基(例如C5‐C12烯基、C5‐C8烯基C6烯基)、被取代的C5‐C16炔基(例如的C9‐C11炔基、C10炔基),
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当R9和/或R11为被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1-C12烷基(C3-C9烷基、C5-C8烷基、C6烷基、C7烷基)、C5‐C16烯基(例如C5‐C12烯基、C5‐C8烯基C6烯基)、被取代的C5‐C16炔基(例如的C9‐C11炔基、C10炔基)时,R13和/或R14可以与被取代的R9或R11上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中各R9和/或各R11中的至少一个各自独立地为被取代的芳基。在一些实施方案中,R9和R11为被烷基取代的苯基,例如:
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R9和R11各自独立地为
优选为
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
Z8各自独立地为键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
Z9各自独立地为键。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1为H、C1‐C24的烃基、C1‐C24的杂烃基、Z6R8或-CH(OR9)2。
在一些实施方案中,R1为-CH(OR9)2。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R2为H、C1‐C24的烃基、C1‐C24的杂烃基、Z7R10或-CH(OR11)2。
在一些实施方案中,R2为-CH(OR11)2。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和/或R2为被羟基、卤素、=O、=S、氰基、环烃基、芳基、杂环、-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1‐C24的烷基(例如C5‐C16烷基、C6‐C14烷基、C6‐C12
烷基)、C2‐C24的烯基(例如C5‐C16烯基、C6‐C14烯基、C6‐C12烯基)、C2‐C24的炔基(例如C5‐C16炔基、C6‐C14炔基、C6‐C12炔基、C10炔基),
其中,
R13各自独立地为C1‐C12亚烷基,具有1、2、3或更多个双键的C2‐C12亚烯基,具有1、2、3或更多个三键的C2‐C12亚炔基,含有S或者O的C1‐C12亚杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12亚杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12亚杂炔基;
R14各自独立地为H,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
当R1和/或R2各自独立地被-R14、-R13OR14、-R13SR14、‐R13OC(=O)OR14、‐R13OC(=O)SR14、‐R13C(=O)N(R14)2、-R13OC(=O)R14、‐R13SC(=O)OR14、‐R13N(R14)C(=O)R14或-R13C(=O)OR14取代的C1‐C24的烷基(例如C5‐C16烷基、C6‐C14烷基、C6‐C12烷基)、C2‐C24的烯基(例如C5‐C16烯基、C6‐C14烯基、C6‐C12烯基)、C2‐C24的炔基(例如C5‐C16炔基、C6‐C14炔基、C6‐C12炔基、C10炔基)时,R13和/或R14可以与被取代的R1或R2上的C原子连接形成三元环、四元环、五元环或者六元环。
在一些实施方案中,R14还可以各自独立地为被取代的芳基、被取代的环烃基或被取代的杂环基。在一些实施方案中,R14为被烷基取代的芳基。在一些实施方案中,R14为被烷基取代的苯基,例如:
在一些实施方案中,R14为未被取代的环烷基,例如环丁基、环戊基或环己基。
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和R2各自独立地为被羟基取代的C5‐C16烷基,例如,被羟基取代的C6‐C14烷基、被羟基取代的C6‐C12烷基、被羟基取代的C10烷基。在一些实施方案中,R1和R2各自独立地为C10烷基,例如:
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
R1和R2各自独立地为
优选为:
在一些实施方案中,本公开提供如上文所述的式(II-I)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中R1为Z6R8或-CH(OR9)2,R2为Z7R10或-CH(OR11)2。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-Ia)所示的结构:
其中,
A1为H、C1‐C5烃基或C1‐C5杂烃基;
A2为H、C1‐C5烃基或C1‐C5杂烃基;
A3为C1‐C5亚烃基或键;
A4、A5、A6、A7、A8、Z1、Z2、Y1、X、R1、R2和A12的定义如式(II-I)中所定义。
本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,当适用时包括一个或多个以下特征。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地为H。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地为C1、C2、C3、C4、C5烃基,或C1、C2、C3、C4、C5杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地为C1-C5烷基,或具有1或2个双键的C2-C5烯基,或具有1或2个三键的C2-C5炔基,或含有S或O的C1-C5杂烷基,或具有1或2个双键的含有S或O的C2-C5杂烯基,或具有1或2个三键的含有S或O的C2-C5杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地任选地被羟基,氰基,苯基,C3‐C7环烃基,包含1-3个独立地选自氮、氧或硫的杂原子的C3‐C7环烃基,5至6元单环基,包含1-4个独立地选自氮、氧和硫的杂原子的杂芳基,包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基,-OR12,-C(=O)R12,-C(=O)SR12,-OC(=O)R12,-OC(=O)OR12,-N(R12)2,-C(=O)N(R12)2,-C(=S)N(R12)2,-S(=O)2R12,-S(=O)2N(R12)2,-OC(=O)N(R12)2,-CH(NR12)N(R12)2,-C(NR12)2R12,-C(=O)N(R12)OR12,-CH(R12)N(R12)2C(=O)OR12,-C(R12)3,-N(R12)C(=O)R12,-N(R12)C(=O)OR12,-N(R12)S(=O)2R12,-N(R12)C(=O)N(R12)2,-N(R12)C(=S)N(R12)2,-N(R12)C(NR12)N(R12)2,-N(R12)C(CHR12)N(R12)2,-N(OR12)C(=O)R12,-N(OR12)S(=O)2R12,-N(OR12)C(=O)OR12,-N(OR12)C(=O)N(R12)2,-N(OR12)C(=S)N(R12)2,-N(OR12)C(NR12)N(R12)2,-N(OR12)C(CHR12)N(R12)2,-OP(=O)(OR12)2,-P(=O)(OR12)2,或包含1-3个独立地选自氮、氧、硫的杂原子的3至7元脂环族和3至7元杂环基的环,-C(=N-CN)N(R12)2,-C(=N-O-CH3)N(R12)2,-C(=N-SO2-NH2)N(R12)2,-C(=CH-NO2)N(R12)2或-C(=O)OR12取代;
其中,R12各自独立地为氢,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地任选地被任选地被C1-C5烷基、=O、-C0-C5亚烷基-羟基、-C(=O)N(R15)2取代的含有1-3个独立地选自氮、氧或硫的杂原子的C3‐C7环烃基,任选地被C1-C5烷基、羟基取代的包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基,
或者取代,其中R15各自独立地为H或者C1-C3的烷基,d为0、1、2、3、4或5。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地为
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2还可以各自独立地为
其中,a为1、2、3、4或5;
优选地,所述a为1、2或3。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为键。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1、C2、C3、C4、C5亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ia)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
为
其中,c为1、2、3、4或5;
优选地,所述c为2、3或4;
优选地,所述c为2或3。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-Ib)所示的结构:
其中,
A1为C1‐C5亚烃基或C1‐C5亚杂烃基;
A2为C1‐C5亚烃基或C1‐C5亚杂烃基;
A3为C1‐C5亚烃基或键;
A1和A2连同它们共同连接的氮原子一起形成含N的杂环;
A4、A5、A6、A7、A8、Z1、Z2、Y1、X、R1、R2和A12的定义如式(II-I)中所定义。
本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,当适用时包括一个或多个以下特征。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地为C1、C2、C3、C4、C5亚烃基,或C1、C2、C3、C4、C5亚杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地为C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基,或含有S或O的C1-C5亚杂烷基,或具有1或2个双键的含有S或O的C2-C5亚杂烯基,或具有1或2个三键的含有S或O的C2-C5亚杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地任选地被羟基,氰基,苯基,C3‐C7环烃基,包含1-3个独立地选自氮、氧或硫的杂原子的C3‐C7环烃基,5至6元单环基,包含1-4个独立地选自氮、氧和硫的杂原子的杂芳基,包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基,-OR12,-C(=O)R12,-C(=O)SR12,-OC(=O)R12,-OC(=O)OR12,-N(R12)2,-C(=O)N(R12)2,-C(=S)N(R12)2,-S(=O)2R12,-S(=O)2N(R12)2,-OC(=O)N(R12)2,-CH(NR12)N(R12)2,-C(NR12)2R12,-C(=O)N(R12)OR12,-CH(R12)N(R12)2C(=O)OR12,-C(R12)3,-N(R12)C(=O)R12,-N(R12)C(=O)OR12,-N(R12)S(=O)2R12,-N(R12)C(=O)N(R12)2,-N(R12)C(=S)N(R12)2,-N(R12)C(NR12)N(R12)2,-N(R12)C(CHR12)N(R12)2,-N(OR12)C(=O)R12,-N(OR12)S(=O)2R12,-N(OR12)C(=O)OR12,-N(OR12)C(=O)N(R12)2,-N(OR12)C(=S)N(R12)2,-N(OR12)C(NR12)N(R12)2,-N(OR12)C(CHR12)N(R12)2,-OP(=O)(OR12)2,-P(=O)(OR12)2,或包含1-3个独立地选自氮、氧、硫的杂原子的3至7元脂环族和3至7元杂环基的环,-C(=N-CN)N(R12)2,-C(=N-O-CH3)N(R12)2,-C(=N-SO2-NH2)N(R12)2,-C(=CH-NO2)N(R12)2或-C(=O)OR12取代;
其中,R12各自独立地为氢,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为键。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1、C2、C3、C4、C5亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2连同它们共同连接的氮原子一起形成含N的三元、四元、五元、六元、七元或八元杂环。
在一些实施方案中,A1和A2连同它们共同连接的氮原子一起形成含N的三元、四元、五元或六元杂环。
在一些实施方案中,A1和A2连同它们共同连接的氮原子一起形成含N的四元、五元或六元杂
环。
在一些实施方案中,本公开提供如上文所述的式(II-Ib)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
为
其中,c为1、2、3、4或5;
优选地,所述c为2、3或4;
优选地,所述c为2或3。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-Ic)所示的结构:
其中,
A1为C1‐C5亚烃基或C1‐C5亚杂烃基;
A2为H、C1‐C5烃基或C1‐C5杂烃基;
A3为C1‐C5亚烃基;
A1和A3连同它们共同连接的氮原子一起形成含N的杂环;
A4、A5、A6、A7、A8、Z1、Z2、Y1、X、R1、R2和A12的定义如式(II-I)中所定义。
本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,当适用时包括一个或多个以下特征。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A2为H。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1为C1、C2、C3、C4、C5亚烃基,或C1、C2、C3、C4、C5亚杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1为C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基,或含有S或O的C1-C5亚杂烷基,或具有1或2个双键的含有S或O的C2-C5亚杂烯基,或具有1或2个三键的含有S或O的C2-C5亚杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A2为C1、C2、C3、C4、C5烃基,或C1、C2、C3、C4、C5杂烃基。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A2为C1-C5烷基,或具有1或2个双键的C2-C5烯基,或具有1或2个三键的C2-C5炔基,或含有S或O的C1-C5杂烷基,或具有1或2个双键的含有S或O的C2-C5杂烯基,或具有1或2个三键的含有S或O的C2-C5杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地任选地被羟基,氰基,苯基,C3‐C7环烃基,包含1-3个独立地选自氮、氧或硫的杂原子的C3‐C7环烃基,5至6元单环基,包含1-4个独立地选自氮、氧和硫的杂原子的杂芳基,包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基,-OR12,-C(=O)R12,-C(=O)SR12,-OC(=O)R12,-OC(=O)OR12,-N(R12)2,-C(=O)N(R12)2,-C(=S)N(R12)2,-S(=O)2R12,-S(=O)2N(R12)2,-OC(=O)N(R12)2,-CH(NR12)N(R12)2,-C(NR12)2R12,-C(=O)N(R12)OR12,-CH(R12)N(R12)2C(=O)OR12,-C(R12)3,-N(R12)C(=O)R12,-N(R12)C(=O)OR12,-N(R12)S(=O)2R12,-N(R12)C(=O)N(R12)2,-N(R12)C(=S)N(R12)2,-N(R12)C(NR12)N(R12)2,-N(R12)C(CHR12)N(R12)2,-N(OR12)C(=O)R12,-N(OR12)S(=O)2R12,-N(OR12)C(=O)OR12,-N(OR12)C(=O)N(R12)2,-N(OR12)C(=S)N(R12)2,-N(OR12)C(NR12)N(R12)2,-N(OR12)C(CHR12)N(R12)2,-OP(=O)(OR12)2,-P(=O)(OR12)2,或包含1-3个独立地选自氮、氧、硫的杂原子的3至7元脂环族和3至7元杂环基的环,-C(=N-CN)N(R12)2,-C(=N-O-CH3)N(R12)2,-C(=N-SO2-NH2)N(R12)2,-C(=CH-NO2)N(R12)2或-C(=O)OR12取代;
其中,R12各自独立地为氢,C1‐C12烷基,具有1、2、3或更多个双键的C2‐C12烯基,具有1、2、3或更多个三键的C2‐C12炔基,含有S或者O的C1‐C12杂烷基,具有1、2、3或更多个双键的含有S或者O的C2‐C12杂烯基,或者具有1、2、3或更多个三键的含有S或者O的C2‐C12杂炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A2各自独立地任选地被任选地被C1-C5烷基、=O、-C0-C5亚烷基-羟基、-C(=O)N(R15)2取代的含有1-3个独立地选自氮、氧或硫的杂原子的C3‐C7环烃基,任选地被C1-C5烷基、羟基取代的包含1-4个独立地选自氮、氧或硫的杂原子的8至10元双环杂芳基,
或者取代,其中R15各自独立地为H或者C1-C3的烷基,d为0、1、2、3、4或5。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A2为
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A2还可以为
其中,a为1、2、3、4或5;
优选地,所述a为1、2或3。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1、C2、C3、C4、C5亚烃基。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A3为C1-C5亚烷基,或具有1或2个双键的C2-C5亚烯基,或具有1或2个三键的C2-C5亚炔基。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
A1和A3连同它们共同连接的氮原子一起形成含N的三元、四元、五元、六元、七元或八元杂环。
在一些实施方案中,A1和A3连同它们共同连接的氮原子一起形成含N的三元、四元、五元或六元杂环。
在一些实施方案中,A1和A3连同它们共同连接的氮原子一起形成含N的四元、五元或六元杂环。
在一些实施方案中,本公开提供如上文所述的式(II-Ic)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:
为
其中,c为1、2、3、4或5;
优选地,所述c为2、3或4;
优选地,所述c为2或3。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-Id)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R1、R2和A12的定义如式(II-I)中所定义。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-Ie)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R1、R2和A12的定义如式(II-I)中所定义。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-II)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、X、R2、R9和A12的定义如式(II-
I)中所定义。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-IIa)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R2、R9和A12的定义如式(II-I)中所定义。
本公开提供如上文所述的式(II-IIa)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,当适用时包括一个或多个以下特征。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚烃基。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚烷基。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚烯基。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚炔基。
在一些实施方案中,A5和A6不同时为亚甲基。
在一些实施方案中,Z1为-C(=O)O-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-。
在一些实施方案中,Z2为-C(=O)O-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-。
在一些实施方案中,A5和A6各自独自地为C1、C2、C3、C4、C5、C6亚烃基或键。
在一些实施方案中,A5和A6各自独自地为C1、C2、C3、C4、C5、C6亚烷基或键。
在一些实施方案中,A5和A6各自独自地为C2、C3、C4、C5、C6亚烯基或键。
在一些实施方案中,A5和A6各自独自地为C2、C3、C4、C5、C6亚炔基或键。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烃基或键。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烷基或键。
在一些实施方案中,A5和A6各自独自地为C2亚烯基或键。
在一些实施方案中,A5和A6各自独自地为C2亚炔基或键。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-IIb)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R2、R9和A12的定义如式(II-I)中所定义。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-III)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、X、R9、R11和A12的定义如式(II-
I)中所定义。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-IIIa)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R9、R11和A12的定义如式(II-I)中所定义。
本公开提供如上文所述的式(II-IIIa)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,当适用时包括一个或多个以下特征。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚烃基。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚烷基。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚烯基。
在一些实施方案中,A12为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17或C18亚炔基。
在一些实施方案中,A5和A6不同时为亚甲基。
在一些实施方案中,Z1为-C(=O)O-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-。
在一些实施方案中,Z2为-C(=O)O-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-。
在一些实施方案中,A5和A6各自独自地为C1、C2、C3、C4、C5、C6亚烃基或键。
在一些实施方案中,A5和A6各自独自地为C1、C2、C3、C4、C5、C6亚烷基或键。
在一些实施方案中,A5和A6各自独自地为C2、C3、C4、C5、C6亚烯基或键。
在一些实施方案中,A5和A6各自独自地为C2、C3、C4、C5、C6亚炔基或键。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烃基或键。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烷基或键。
在一些实施方案中,A5和A6各自独自地为C2亚烯基或键。
在一些实施方案中,A5和A6各自独自地为C2亚炔基或键。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-IIIb)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R9、R11和A12的定义如式(II-I)中所定义。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-IVa)或(II-IVb)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、R9、R11和A12的定义如式(II-I)中所定义。
在一些实施方案中,本公开提供如上文所述的式(II-IVa)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中
A1、A2和A3为以下情形之一:
(1)当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为H、C1‐C5烃基或C1‐C5杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键;
(2)当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成含N的杂环;或
(3)当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成含N的杂环;
(4)当连接A1和A2的虚线以及连接A1和A3的虚线为键时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基,A1、A2和A3连同它们共同连接的氮原子一起形成含N的螺环杂环、稠合杂环或桥环杂环;
A4为C1‐C5亚烃基或键;
A5、A6、A7、A8和A12各自独立地为C1‐C18亚烃基、C1‐C18亚杂烃基或键;
Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
R6各自独立地为H或C1‐C8烃基;
各R9和各R11各自独立地为C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
各A9为C1‐C8亚烃基或键;
各A10和各A11各自独立地为C1‐C8烃基;
优选地,所述烃基为烷基、烯基或炔基;
优选地,所述亚烃基为亚烷基、亚烯基或亚炔基;
优选地,所述杂烃基为杂烷基、杂烯基或杂炔基;
优选地,所述亚杂烃基为亚杂烷基、亚杂烯基或亚杂炔基。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-Va)、(II-Vb)、(II-Vc)、(II-Vd)、(II-Ve)、(II-Vf)、(II-Vg)或(II-Vh)所示的结构:
其中,A1、A2、A3、A4、A5、A6、A7、A8、R9、R11和A12的定义如式(II-I)中所定义。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-VIa)所示的结构:
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R1和R2的定义如式(II-I)中所定义。
在一些实施方案中,本公开提供如上文所述的式(II-VIa)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中
A1、A2和A3为以下情形之一:
(1)当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为H、C1‐C5烃基或C1‐C5杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键;
(2)当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成含N的杂环;或
(3)当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成含N的杂环;
(4)当连接A1和A2的虚线以及连接A1和A3的虚线为键时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基,A1、A2和A3连同它们共同连接的氮原子一起形成含N的螺环杂环、稠合杂环或桥环杂环;
A4为C1‐C5亚烃基或键;
A5、A6、A7和A8各自独立地为C1‐C18亚烃基、C1‐C18亚杂烃基或键;
Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
Y1为-Z3C(=O)Z4-、-N(R5)-、-Z3C(=S)Z4-、-OS(=O)2O-、-OS(=O)O-、-OS(=O)2NH-、-NHS(=O)2NH-、-NHS(=O)2-、-S(=O)2NH-、-S(=O)2O-、-OS(=O)2-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-O-、-S-、-NHS(=O)2O-、-NHP(=O)O-、-OP(=O)NH-、-NHP(=O)(OH)O-、-OP(=O)(OH)NH-、-OC(=O)S-或-SC(=O)O-;
X为C或N;
R1为H、C1‐C24的烃基、C1‐C24的杂烃基、Z6R8、-C(R6)(OA13Z8R9)2、-C(R6)(SA13Z8R9)2或-C(R6)(SA13Z8R9)(OA13Z8R9);
R2为H、C1‐C24的烃基、C1‐C24的杂烃基、Z7R10、-C(R6)(OA14Z9R11)2、-C(R6)(SA14Z9R11)2或-C(R6)(SA14Z9R11)(OA14Z9R11);
Z3和Z4各自独立地为-O-、-N(R6)-、‐S‐或键;
Z6和Z7各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
R5为-C(=O)A9Z5A10、-C(=O)A11、H或C1‐C8烃基;
Z5为-O-或‐S‐;
Z8和Z9各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、
-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-、-NHS(=O)2O-或键;
R6各自独立地为H或C1‐C8烃基;
R8和R10各自独立地为H、C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
各R9和各R11各自独立地为C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
各A9为C1‐C8亚烃基或键;
各A10和各A11各自独立地为C1‐C8烃基;
各A13和各A14各自独立地为C1‐C8亚烃基、C1‐C8亚杂烃基或键;
优选地,所述烃基为烷基、烯基或炔基;
优选地,所述亚烃基为亚烷基、亚烯基或亚炔基;
优选地,所述杂烃基为杂烷基、杂烯基或杂炔基;
优选地,所述亚杂烃基为亚杂烷基、亚杂烯基或亚杂炔基。
在一些实施方案中,A5和A6各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烃基或键,且不同时为亚甲基。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烃基或键,且不同时为亚甲基。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚烃基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚烃基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚烃基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚烃基。
在一些实施方案中,A5和A6各自独立地为C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烷基或键,且不同时为亚甲基。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烷基或键,且不同时为亚甲基。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚烷基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚烷基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚烷基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚烷基。
在一些实施方案中,A5和A6各自独立地为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚烯基或键。
在一些实施方案中,A5和A6各自独自地为C2亚烯基或键。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚烯基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚烯基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚烯基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚烯基。
在一些实施方案中,A5和A6各自独立地为C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、C12、C13、C14、C15、C16、C17、C18亚炔基或键。
在一些实施方案中,A5和A6各自独自地为C2亚炔基或键。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚炔基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚炔基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚炔基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚炔基。
在一些实施方案中,A1和A2各自独自地为C1-C5烷基,优选为C1-C3烷基,例如甲基、乙基、正丙基或异丙基;A3为C1-C5亚烷基,优选为C2-C4亚烷基,例如-(CH2)2-、-(CH2)3-、-(CH2)4-;Y1为-Z3C(=O)Z4-,优选为-N(R6)C(=O)N(R6)-,更优选为-N(H)C(=O)N(H)-;Z1和Z2各自独立地为-C(=O)O-或-OC(=O)-;A7和A8各自独立地为键;R1和R2各自独立地为C1‐C24的烃基,优选为C1‐C24的烷基,更优选为C3‐C12的直链烷基或C7‐C21的支化的烷基,例如-C4H9、-C5H11、-C6H13、-
C7H15、-C8H17、-C9H19、-CH(C4H9)2、-CH(C5H11)2、-CH(C6H13)2、-CH(C7H15)2、-CH(C8H17)2、-CH(C9H19)2、-CH2CH(C6H13)(C4H9)。
在一些实施方案中,式(II-VIa)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-VIa-a)所示的结构:
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R9和R2的定义如式(II-VIa)中所定义。
在一些实施方案中,式(II-VIa)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-VIa-b)所示的结构:
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R9和R11的定义如式(II-VIa)中所定义。
在一些实施方案中,式(II-VIa)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-VIa-c)所示的结构:
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、R9和R11的定义如式(II-VIa)中所定义。
在一些实施方案中,本公开提供如上文所述的式(II-VIa-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中
A1、A2和A3为以下情形之一:
(1)当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为H、C1‐C5烃基或C1‐C5杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键;
(2)当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成含N的杂环;或
(3)当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成含N的杂环;
(4)当连接A1和A2的虚线以及连接A1和A3的虚线为键时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基,A1、A2和A3连同它们共同连接的氮原子一起形成含N的螺环杂环、稠合杂环或桥环杂环;
A4为C1‐C5亚烃基或键;
A5、A6、A7和A8各自独立地为C1‐C18亚烃基、C1‐C18亚杂烃基或键;
Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;
R6各自独立地为H或C1‐C8烃基;
各R9和各R11各自独立地为C1‐C24烃基或含有O或者S的C1‐C24杂烃基;
各A9为C1‐C8亚烃基或键;
各A10和各A11各自独立地为C1‐C8烃基;
优选地,所述烃基为烷基、烯基或炔基;
优选地,所述亚烃基为亚烷基、亚烯基或亚炔基;
优选地,所述杂烃基为杂烷基、杂烯基或杂炔基;
优选地,所述亚杂烃基为亚杂烷基、亚杂烯基或亚杂炔基。
式(II-IVa)、(II-VIa)或(II-VIa-c)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,当适用时包括一个或多个以下特征。
在一些实施方案中,A4为键。
在一些实施方案中,Y1为-Z3C(=O)Z4-或-N(R5)-。
在一些实施方案中,Y1为-N(R6)C(=O)O-、-OC(=O)N(R6)-或-OC(=O)O-。
在一些实施方案中,Y1为-OC(=O)O-。
在一些实施方案中,Y1为-N(R6)C(=O)O-或-OC(=O)N(R6)-。
在一些实施方案中,R6各自独立地为H,或者被-OC(=O)R14、-C(=O)OR14、-OR14取代的C1-C8烷基。
在一些实施方案中,Y1为-N(R6)C(=O)O-或-OC(=O)N(R6)-,其中,R6各自独立地为被-OC(=O)R14、-C(=O)OR14、-OR14取代的C1-C8烷基(例如C1‐C5烷基、C1‐C3烷基)。
在一些实施方案中,Y1为-N(H)C(=O)O-。
在一些实施方案中,Y1为-OC(=O)N(H)-。
在一些实施方案中,Y1为-N(R5)-。
在一些实施方案中,Y1为-N(C(=O)A9OA10)-。
在一些实施方案中,Y1为-N(C(=O)A10)-。
在一些实施方案中,Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-C(=O)N(R6)-、-N(R6)C(=O)-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-C(=O)S-、-SC(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-或-OP(=O)(H)O-。
在一些实施方案中,Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-OC(=O)O-、-N(H)C(=O)O-或-OC(=O)N(H)-。
在一些实施方案中,Z1和Z2各自独立地为-C(=O)O-或-OC(=O)-。
在一些实施方案中,Z1为-C(=O)O-。
在一些实施方案中,Z1为-OC(=O)-。
在一些实施方案中,Z1为-OC(=O)O-。
在一些实施方案中,Z1为-N(H)C(=O)O-。
在一些实施方案中,Z1为-OC(=O)N(H)-。
在一些实施方案中,Z2为-C(=O)O-。
在一些实施方案中,Z2为-OC(=O)-。
在一些实施方案中,Z2为-OC(=O)O-。
在一些实施方案中,Z2为-N(H)C(=O)O-。
在一些实施方案中,Z2为-OC(=O)N(H)-。
在一些实施方案中,Z1和Z2为-C(=O)O-。
在一些实施方案中,Z1和Z2为-OC(=O)-。
在一些实施方案中,Z1和Z2为-OC(=O)O-。
在一些实施方案中,Z1和Z2为-N(H)C(=O)O-。
在一些实施方案中,Z1和Z2为-OC(=O)N(H)-。
在一些实施方案中,Z1为-C(=O)O-,Z2为-OC(=O)-。
在一些实施方案中,A4为健,Z1和Z2为C(=O)O-。
在一些实施方案中,A4为健,Z1和Z2为-OC(=O)-。
在一些实施方案中,A4为健,Z1和Z2为-OC(=O)O-。
在一些实施方案中,A4为健,Z1和Z2为-N(H)C(=O)O-。
在一些实施方案中,A4为健,Z1和Z2为-OC(=O)N(H)-。
在一些实施方案中,A4为健,Z1为-C(=O)O-,Z2为-OC(=O)-。
在一些实施方案中,A12为C1-C3亚烷基,例如C2-C3亚烷基。
在一些实施方案中,A12为C1-C3亚烷基(例如C1亚烷基),A5和A6各自独立地为C3-C9亚烷基(例如C4-C9亚烷基、C5-C9亚烷基、C6亚烷基、C7亚烷基、C8亚烷基)。
在一些实施方案中,R1为-C(R6)(OR9)2。
在一些实施方案中,R1为-C(H)(OR9)2。
在一些实施方案中,R2为-C(R6)(OR11)2。
在一些实施方案中,R2为-C(H)(OR11)2。
在一些实施方案中,R2为Z7R10。
在一些实施方案中,R2为-C(=O)OR10。
在一些实施方案中,R2为-OC(=O)R10。
在一些实施方案中,R2为-OR10。
在一些实施方案中,R2为-N(H)C(=O)R10。
在一些实施方案中,R2为-C(=O)N(R6)R10。
在一些实施方案中,R2为被取代的C1‐C24烷基,例如被取代的C5‐C16烷基,被取代的C6‐C14烷基,被取代的C6‐C12烷基。在一些实施方案中,R2为被羟基取代的C1‐C24烷基,例如被羟基取代的C5‐C16烷基,例如被羟基取代的C6‐C14烷基,被羟基取代的C6‐C12烷基,被羟基取代的C10烷基。
在一些实施方案中,R1为-C(R6)(OR9)2,R2为-C(R6)(OR11)2。
在一些实施方案中,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
在一些实施方案中,R1为-C(H)(OR9)2,R2为-C(=O)OR10。
在一些实施方案中,R1为-C(H)(OR9)2,R2为-OC(=O)R10。
在一些实施方案中,R1为-C(H)(OR9)2,R2为-OR10。
在一些实施方案中,R1为-C(H)(OR9)2,R2为被羟基取代的C1‐C24烷基(例如R2为被羟基取代的C5‐C16烷基、被羟基取代的C6‐C14烷基、被羟基取代的C6‐C12烷基或被羟基取代的C10烷基)。
在一些实施方案中,Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为-C(=O)OR10。
在一些实施方案中,Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为-OC(=O)R10。
在一些实施方案中,Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为-OR10。
在一些实施方案中,Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为被取代的C1‐C24烷基(例如R2为被取代的C5‐C16烷基、被取代的C6‐C14烷基、被取代的C6‐C12烷基或被取代的C10烷基)。
在一些实施方案中,Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为被羟基取代的C1‐C24烷基(例如R2为被羟基取代的C5‐C16烷基、被羟基取代的C6‐C14烷基、被羟基取代的C6‐C12烷基或被羟基取代的C10烷基)。
在一些实施方案中,Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为被羟基取代的C1‐C24烷基(例如R2为被羟基取代的C5‐C16烷基、被羟基取代的C6‐C14烷基、被羟基取代的C6‐C12烷基或被羟基取代的C10烷基),A5和A6各自独立地为C2-C10亚烷基(例如,C5-C9亚烷基,C8亚烷基)。
在一些实施方案中,Y1为-OC(=O)O-,A7和A8为未被取代的C1-C5亚烷基(例如,未被取代的C2-C4亚烷基),R1为-C(H)(OR9)2,R2为-C(=O)OR10。
在一些实施方案中,Y1为-OC(=O)O-,A7和A8为未被取代的C1-C5亚烷基(例如,未被取代的C2-C4亚烷基),R1为-C(H)(OR9)2,R2为-OC(=O)R10。
在一些实施方案中,Y1为-N(H)C(=O)O-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
在一些实施方案中,Y1为-OC(=O)N(H)-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
在一些实施方案中,Y1为-N(C(=O)A9OA10)-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
在一些实施方案中,Y1为-N(C(=O)A10)-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
在一些实施方案中,Y1为-N(C(=O)A10)-,R1为-C(H)(OR9)2,R2为被羟基取代的C1‐C24烷基(例如R2为被羟基取代的C5‐C16烷基、被羟基取代的C6‐C14烷基、被羟基取代的C6‐C12烷基或被羟基取代的C10烷基)。
在一些实施方案中,A9为C1‐C8亚烷基。
在一些实施方案中,A9为C1‐C5亚烷基。
在一些实施方案中,A9为C1‐C3亚烷基。
在一些实施方案中,A10为C1‐C8烷基,例如C1、C2、C3、C5、C8烷基。
在一些实施方案中,R10为C1‐C24烷基、C2‐C24烯基或C2‐C24炔基。
在一些实施方案中,R10为直链的C2‐C10烷基。
在一些实施方案中,R10为直链的C2‐C8烷基。
在一些实施方案中,R10为支化的C7‐C18烷基,例如:
在一些实施方案中,R10为C5‐C16烯基。
在一些实施方案中,R10为C5‐C12烯基。
在一些实施方案中,R10为C5‐C8烯基,例如C5、C6烯基。
在一些实施方案中,R10为C5‐C16炔基。
在一些实施方案中,R10为C5‐C12炔基,例如C10炔基。
在一些实施方案中,R9为C9‐C11炔基,例如C10炔基。
在一些实施方案中,R14为C1‐C12烷基。
在一些实施方案中,R14为C1‐C5烷基。
在一些实施方案中,R14为具有1、2、3或更多个双键的C2‐C12烯基。
在一些实施方案中,R14为具有1个双键的C4‐C8烯基,例如具有1个双键的C6烯基。
在一些实施方案中,A5和A6各自独立地为C1-C11亚烷基。
在一些实施方案中,A5和A6各自独立地为C3-C10亚烷基。
在一些实施方案中,A5和A6各自独立地为C4-C9亚烷基。
在一些实施方案中,A5和A6各自独立地为C5-C9亚烷基,例如C6、C7、C8亚烷基。
在一些实施方案中,A7和A8各自独立地为C1-C12亚烷基。
在一些实施方案中,A7和A8各自独立地为C5-C10亚烷基。
在一些实施方案中,A7和A8各自独立地为C1-C5亚烷基。
在一些实施方案中,A7和A8各自独立地为C2-C4亚烷基。
在一些实施方案中,A7和A8为C3亚烷基。
在一些实施方案中,A7或者A8为键。
在一些实施方案中,A7为键。
在一些实施方案中,A8为键。
在一些实施方案中,各R9各自独立地为C1-C12烷基、C5-C16烯基或C5-C16炔基。
在一些实施方案中,各R9各自独立地为C3-C9烷基。
在一些实施方案中,各R9各自独立地为C5-C8烷基,例如C6、C7、C8烷基。
在一些实施方案中,各R9各自独立地为C5‐C12烯基。
在一些实施方案中,各R9各自独立地为C5‐C8烯基,例如C6烯基。
在一些实施方案中,各R9各自独立地为C9‐C11炔基,例如C10炔基。
在一些实施方案中,各R11各自独立地为C1-C12烷基。
在一些实施方案中,各R11各自独立地为C3-C9烷基。
在一些实施方案中,各R11各自独立地为C5-C8烷基,例如C6、C7、C8烷基。
在一些实施方案中,各R11各自独立地为C5‐C12烯基。
在一些实施方案中,各R11各自独立地为C5‐C8烯基,例如C6烯基。
在一些实施方案中,各R11各自独立地为C9‐C11炔基,例如C10炔基。
在一些实施方案中,连接A1和A2的虚线以及连接A1和A3的虚线为不存在。
在一些实施方案中,连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在。
在一些实施方案中,连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在。
在一些实施方案中,A1和A2各自独立地为C1-C5烷基,或C1-C5亚烷基。
在一些实施方案中,A1和A2各自独立地为C1-C3烷基。
在一些实施方案中,A1和A2各自独立地为C1-C2烷基。
在一些实施方案中,A2为C1-C3烷基,例如C1-C2烷基。
在一些实施方案中,A3为C1-C5亚烷基。
在一些实施方案中,A3为C2-C4亚烷基,例如C3亚烷基。
在一些实施方案中,连接A1和A2的虚线以及连接A1和A3的虚线为不存在,A1和A2各自独立地为C1-C3烷基,例如C1-C2烷基。
在一些实施方案中,连接A1和A2的虚线以及连接A1和A3的虚线为不存在,A1和/或A2为未被取代的C1-C5烷基,例如未被取代的C1-C4烷基、未被取代的C1-C3烷基、未被取代的C1-C2烷基。
在一些实施方案中,连接A1和A2的虚线以及连接A1和A3的虚线为不存在,A1和A2各自独立地为未被取代的C1-C5烷基,例如未被取代的C1-C4烷基、未被取代的C1-C3烷基、未被取代的C1-C2烷基。
在一些实施方案中,连接A1和A2的虚线以及连接A1和A3的虚线为不存在,A1和/或A2为被取代的C1-C5烷基,例如被取代的C1-C4烷基、被取代的C1-C3烷基、被取代的C1-C2烷基。
在一些实施方案中,当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1和/或A2为C1-C5亚烷基。
在一些实施方案中,当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1和A2连同它们共同连接的氮原子一起形成含N的四元、五元或六元的杂环。
在一些实施方案中,当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1和/或A2为未被取代的C1-C5亚烷基。
在一些实施方案中,当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1和A2各自独立地为未被取代的C1-C5亚烷基。
在一些实施方案中,当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1和/或A2为被取代的C1-C5亚烷基。
在一些实施方案中,当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A2为C1-C3烷基,A1和/或A3为C1-C5亚烷基。
在一些实施方案中,当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1和A3连同它们共同连接的氮原子一起形成含N的四元、五元或六元的杂环。
在一些实施方案中,当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为未被取代的C1-C5亚烷基,A2为未被取代的C1-C5烷基(例如,未被取代的C1-C4烷基、未被取代的C1-C3烷基、未被取代的C1-C2烷基)。
在一些实施方案中,当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为未被取代的C1-C5亚烷基,A2为被取代的C1-C5烷基(例如,被取代的C1-C4烷基、被取代的C1-C3烷基、被取代的C1-C2烷基)。
在一些实施方案中,当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为被取代的C1-C5亚烷基,A2为未被取代的C1-C5烷基(例如,未被取代的C1-C4烷基、未被取代的C1-C3烷基、未被取代的C1-C2烷基)。
在一些实施方案中,当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为被取代的C1-C5亚烷基,A2为被取代的C1-C5烷基(例如,被取代的C1-C4烷基、被取代的C1-C3烷基、被取代的C1-C2烷基)。
在一些实施方案中,A1或A2为被羟基、-OR12、-C(=O)OR12、-OC(=O)R12或C1-C5烷基取代的C1-C5烷基、C1-C2烷基或C1-C5亚烷基,其中,R12各自独立地为C1‐C12烷基,例如,A1或A2为
在一些实施方案中,A1和A2各自独立地为被C1-C3烷基取代的C1-C5烷基、C1-C2烷基或C1-C5亚烷基,例如:在一些实施方案中,A3为未被取代的C1-C5亚烷基。
在一些实施方案中,A3为未被取代的C2-C4亚烷基。
在一些实施方案中,A3为未被取代的C3亚烷基。
在一些实施方案中,A3为被取代的C1-C5亚烷基,例如被取代的C2-C4亚烷基、被取代的C3亚烷基。
在一些实施方案中,A3为被一个或两个R14取代的C3亚烷基,其中,R14为C1‐C12烷基(例如C1‐C5烷基、C1‐C3烷基、C1烷基)。
在一些实施方案中,A3为被两个-R14取代的C3的亚烷基,其中,R14为C1‐C12烷基(例如C1‐C5烷基、C1‐C3烷基、C1烷基)。例如A3为
在一些实施方案中,具有如下结构之一:
其中,c为1、2、3、4或5。
在一些实施方案中,各R9和/或各R11为被-R13OC(=O)R14、-R13C(=O)OR14或-R13OR14取代的C1-C12烷基(例如:C3-C9烷基、C5-C8烷基、C6烷基),其中,R14为C1‐C12烷基(例如C1‐C5烷基、C1‐C3烷基、C1烷基)。
在一些实施方案中,R9和R11为被-R13OC(=O)R14、-R13C(=O)OR14或-R13OR14取代的C2‐C5烷基(例如C3‐C4烷基),其中,R14为C1‐C12烷基(例如C1‐C5烷基、C1‐C3烷基、C1烷基)。例如:R9和R11为
在一些实施方案中,本公开提供如上文所述的式(II-VIa-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中
Z1和Z2各自独立地为-C(=O)O-和-OC(=O)-,A4为键,A5和A6各自独立地为C3-C10亚烷基,A7和A8各自独立地为C2-C4亚烷基,各R9各自独立地为C3-C9烷基,各R11各自独立地为C3-C9烷基,连接A1和A2的虚线以及连接A1和A3的虚线为不存在,A1和A2各自独立地为C1-C3烷基,A3为C2-C4亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-VIa-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中Z1和Z2为-C(=O)O-,A4为键,A5和A6各自独立地为C3-C10亚烷基,A7和A8各自独立地为C2-C4亚烷基,各R9各自独立地为C3-C9烷基,各R11各自独立地为C3-C9烷基,连接A1和A2的虚线以及连接A1和A3的虚线为不存在,A1和A2各自独立地为C1-C3烷基,A3为C2-C4亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-VIa-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中Z1和Z2各自独立地为-C(=O)O-和-OC(=O)-,A4为键,A5和A6各自独立地为C3-C10亚烷基,A7和A8各自独立地为C2-C4亚烷基,各R9各自独立地为C3-C9烷基,各R11各自独立地为C3-C9烷基,连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在,A1和A2各自独立地为C1-C5亚烷基,A3为C2-C4亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-VIa-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中Z1和Z2各自独立地为-C(=O)O-和-OC(=O)-,A4为键,A5和A6各自独立地为C3-C10亚烷基,A7和A8各自独立地为C2-C4亚烷基,各R9各自独立地为C3-C9烷基,各R11各自独立地为C3-C9烷基,连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在,A1和A2连同它们共同连接的氮原子一起形成含N的四元、五元或六元的杂环,A3为C2-C4亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-VIa-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中Z1和Z2各自独立地为-C(=O)O-和-OC(=O)-,A4为键,A5和A6各自独立地为C3-C10亚烷基,A7和A8各自独立地为C2-C4亚烷基,各R9各自独立地为C3-C9烷基,各R11各自独立地为C3-C9烷基,连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在,A2为C1-C3烷基,A1和A3各自独立地为C1-C5亚烷基。
在一些实施方案中,本公开提供如上文所述的式(II-VIa-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中Z1和Z2各自独立地为-C(=O)O-和-OC(=O)-,A4为键,A5和A6各自独立地为C3-C10亚烷基,A7和A8各自独立地为C2-C4亚烷基,各R9各自独立地为C3-C9烷基,各R11各自独立地为C3-C9烷基,连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在,A2为C1-C3烷基,A1和A3连同它们共同连接的氮原子一起形成含N的四元、五元或六元的杂环。
在一些实施方案中,式(II-I)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-VIb):
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R1和R2的定义如式(II-I)中所定义。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烃基或键。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚烃基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚烃基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚烃基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚烃基。
在一些实施方案中,A5和A6各自独自地为C1、C2亚烷基或键。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚烷基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚烷基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚烷基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚烷基。
在一些实施方案中,A5和A6各自独自地为C2亚烯基或键。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚烯基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚烯基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚烯基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚烯基。
在一些实施方案中,A5和A6各自独自地为C2亚炔基或键。
在一些实施方案中,A5和A6各自独自地为C3、C4、C5或C6亚炔基。
在一些实施方案中,A5和A6各自独自地为C7、C8、C9或C10亚炔基。
在一些实施方案中,A5和A6各自独自地为C11、C12、C13或C14亚炔基。
在一些实施方案中,A5和A6各自独自地为C15、C16、C17或C18亚炔基。
在一些实施方案中,式(II-VIb)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体
异构体中,具有式(II-VIb-a)所示的结构:
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R9和R2的定义如式(II-VIb)中所定义。
在一些实施方案中,式(II-VIb)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-VIb-b)所示的结构:
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、Y1、R9和R11的定义如式(II-VIb)中所定义。
在一些实施方案中,式(II-VIb)表示的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体中,具有式(II-VIb-c)所示的结构:
其中,
A1、A2、A3、A4、A5、A6、A7、A8、Z1、Z2、R9和R11的定义如式(II-VIb)中所定义。
在一些实施方案中,本公开提供如上文所述的式(II-I)、(II-Ia)、(II-Ib)、(II-Ic)、(II-Id)、(II-Ie)、(II-II)、(II-IIa)、(II-IIb)、(II-III)、(II-IIIa)、(II-IIIb)、(II-IVa)、(II-IVb)、(II-Va)、
(II-Vb)、(II-Vc)、(II-Vd)、(II-Ve)、(II-Vf)、(II-Vg)、(II-Vh)、(II-VIa)、(II-VIa-a)、(II-VIa-b)、(II-VIa-c)(II-VIb)、(II-VIb-a)、(II-VIb-b)或(II-VIb-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中所述烃基、亚烃基、烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、杂烃基或亚杂烃基任选地被羟基、酯基、烃氧基、烃基、卤素、氧、硫、氨基、酰胺基取代。
在一些实施方案中,本公开提供如上文所述的式(II-I)、(II-Ia)、(II-Ib)、(II-Ic)、(II-Id)、(II-Ie)、(II-II)、(II-IIa)、(II-IIb)、(II-III)、(II-IIIa)、(II-IIIb)、(II-IVa)、(II-IVb)、(II-Va)、(II-Vb)、(II-Vc)、(II-Vd)、(II-Ve)、(II-Vf)、(II-Vg)、(II-Vh)、(II-VIa)、(II-VIa-a)、(II-VIa-b)、(II-VIa-c)(II-VIb)、(II-VIb-a)、(II-VIb-b)或(II-VIb-c)的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中所述氨基脂质化合物具有以下表1中所示的结构之一。
表1
本公开的氨基脂质化合物由于含有长的非极性残基,全部具有疏水性特征,并且由于氨基同时又具有亲水性特征。由于这种两亲性特征,本公开的氨基脂质化合物可以用于形成脂质纳米颗粒,例如脂质双层、胶束、脂质体等。在本公开的范围内,术语“脂质纳米颗粒”意指将氨基脂质化合物放入水溶液中制得的纳米大小的物质。这些颗粒特别地是脂质纳米粒、脂质双层泡囊(脂质体)、多层泡囊或胶束。
在一些实施方案中,所述脂质纳米颗粒是含有本公开的氨基脂质化合物的脂质体。在本公开的范围内,脂质体是由包裹含水隔室的脂质两亲性分子的双层组成的微泡囊。
脂质体形成不是一个自发的过程。当脂质放入水中时首先形成脂质泡囊,因此形成一个双层或一系列双层,每个通过水分子分开。可以通过在水中用超声波处理脂质泡囊来形成脂质体。
在本公开的范围内,术语“脂质双层”意指由两层脂质分子形成的薄膜。术语“胶束”意指分散在液体胶体中的表面活性剂分子的聚集物。水溶液中的典型胶束接触水时与亲水性头部区域形成聚集物,螯合胶束中心的疏水性单尾区。
在一个方面,本公开提供本公开的氨基脂质化合物用于制备活性成分的递送载体的用途。在一些实施方案中,所述递送载体为脂质纳米颗粒的形式,例如脂质双层、胶束、脂质体。
脂质纳米颗粒(LNP)
在另一方面,本公开提供脂质纳米颗粒,所述脂质纳米颗粒含有本公开的氨基脂质化合物。
在一些实施方案中,所述脂质纳米颗粒还含有辅助脂质、结构脂质和PEG-脂质(聚乙二醇-脂质)中的一种或多种。
在一些进一步的实施方案中,所述脂质纳米颗粒还含有所述辅助脂质、所述结构脂质和所述PEG-脂质。
在一些实施方案中,以所述氨基脂质化合物、所述辅助脂质、所述结构脂质和所述PEG-脂质的总量计,所述脂质纳米颗粒包含以下量(摩尔百分比)的所述氨基脂质化合物:约25.0%-75.0%,例如约25.0%-28.0%、28.0%-32.0%、32.0%-35.0%、35.0%-40.0%、40.0%-42.0%、42.0%-45.0%、45.0%-46.3%、46.3%-48.0%、48.0%-49.5%、49.5%-50.0%、50.0%-55.0%、55.0%-60.0%、60.0%-65.0%、或65.0%-75.0%。
在一些实施方案中,以所述氨基脂质化合物、所述辅助脂质、所述结构脂质和所述PEG-脂质的总量计,所述脂质纳米颗粒包含以下量(摩尔百分比)的所述辅助脂质:约5.0%-45.0%,例如约5.0%-9.0%、9.0%-9.4%、9.4%-10.0%、10.0%-10.5%、10.5%-11.0%、11.0%-15.0%、15.0%-16.0%、16.0%-18.0%、18.0%-20.0%、20.0%-25.0%、25.0%-33.5%、33.5%-37.0%、37.0%-40.0%、40.0%-42.0%、或42.0%-45.0%。
在一些实施方案中,以所述氨基脂质化合物、所述辅助脂质、所述结构脂质和所述PEG-脂质的总量计,所述脂质纳米颗粒包含以下量(摩尔百分比)的所述结构脂质:约0.0%-50.0%,例如约0.0%-10.0%、10.0%-15.5%、15.5%-18.5%、18.5%-22.5%、22.5%-23.5%、23.5%-28.5%、28.5%-33.5%、33.5%-35.0%、35.0%-36.5%、36.5%-38.0%、38.0%-38.5%、38.5%-39.0%、39.0%-39.5%、39.5%-40.5%、40.5%-41.5%、41.5%-42.5%、42.5%-42.7%、42.7%-43.0%、43.0%-43.5%、43.5%-45.0%、45.0%-46.5%、46.5%-48.5%、或46.5%-50.0%。
在一些实施方案中,以所述氨基脂质化合物、所述辅助脂质、所述结构脂质和所述PEG-脂质的总量计,所述脂质纳米颗粒包含以下量(摩尔百分比)的所述PEG-脂质:约0.5%-5.0%,例如约0.5%-1.0%、1.0%-1.5%、1.5%-1.6%、1.6%-2.0%、2.0%-2.5%、2.5%-3.0%、3.0%-3.5%、3.5%-4.0%、4.0%-4.5%、或4.5%-5.0%。
在一些如上文所述的实施方案中,所述辅助脂质为磷脂类物质。所述磷脂类物质通常是半合成的,也可以是天然来源的或被化学修饰的。所述磷脂类物质包括但不限于DSPC(二硬脂酰磷脂酰胆碱)、DOPE(二油酰磷脂酰乙醇胺)、DOPC(二油酰基卵磷脂)、DOPS(二油酰磷脂酰丝氨酸)、DSPG(1,2-二十八烷酰基-sn-甘油-3-磷酸-(1’-rac-甘油))、DPPG(二棕榈酰磷脂酰甘油)、DPPC(二棕榈酰磷脂酰胆碱)、DGTS(1,2-二棕榈酰-sn-甘油-3-O-4'-(N,N,N-三甲基)高丝氨酸)、溶血磷脂等。优选地,所述辅助脂质是选自DSPC、DOPE、DOPC和DOPS中的一种或多种。在一些实施方案中,所述辅助脂质是DSPC和/或DOPE。
在一些实施方案中,所述结构脂质为甾醇类物质,包括但不限于胆固醇、胆固醇酯、固醇类激素、固醇类维生素、胆汁酸、胆甾醇、麦角甾醇、β-谷甾醇和氧化胆固醇衍生物等。优选地,所述结构脂质是选自胆固醇、胆固醇酯、固醇类激素、固醇类维生素和胆汁酸中的至少一种。在一些实施方案中,所述结构脂质是胆固醇,优选高纯度胆固醇,特别是注射级高纯度胆固醇,例如CHO-HP(由AVT生产)。
如本文所用的,术语PEG-脂质(聚乙二醇-脂质)为聚乙二醇和脂类结构的缀合物。优选地,所述PEG-脂质选自PEG-DMG和PEG-二硬脂酰磷脂酰乙醇胺(PEG-DSPE),优选为PEG-DMG。优选地,所述PEG-DMG是1,2-二肉豆蔻酸甘油酯的聚乙二醇(PEG)衍生物。优选地,所述PEG的平均分子量为约2000至5000,优选约2000。
在一些如上文所述的实施方案中,在所述脂质纳米颗粒中,本公开的氨基脂质化合物:辅助脂质:结构脂质:PEG-脂质的摩尔比为约45:10:42.5:2.5、或45:11:41.5:2.5、或42.0:10.5:45.0:2.5、或42.0:16.0:39.5:2.5、或40.0:16.0:41.5:2.5、或40.0:18.0:39.5:2.5、或35.0:16.0:46.5:2.5、或35.0:25.0:36.5:3.5、或28.0:33.5:35.0:3.5、或32.0:37.0:40.5:0.5、或35.0:40.0:22.5:2.5、或40.0:42.0:15.5:2.5、或40.0:20.0:38.5:1.5、或45.0:15.0:38.5:1.5、或55.0:5.0:38.5:1.5、或60.0:5.0:33.5:1.5、或45.0:20.0:33.5:1.5、或50.0:20.0:28.5:1.5、或55.0:20.0:23.5:1.5、或60.0:20.0:18.5:1.5、或40.0:15.0:43.5:1.5、或50.0:15.0:33.5:1.5、或55.0:15.0:28.5:1.5、或60.0:15.0:23.5:1.5、或40.0:10.0:48.5:1.5、或45.0:10.0:43.5:1.5、或55.0:10.0:33.5:1.5、或40.0:5.0:53.5:1.5、或45.0:5.0:48.5:1.5、或50.0:5.0:43.5:1.5。在一些此类实施方案中,所述辅助脂质为DOPE,所述结构脂质为CHO-HP。
在另一些如上文所述的实施方案中,在所述脂质纳米颗粒中,本公开的氨基脂质化合物:辅助脂质:结构脂质:PEG-脂质的摩尔比为约50.0:10.0:38.5:1.5、或50.0:9.0:38.0:3.0、或49.5:10.0:39.0:1.5、或48.0:10.0:40.5:1.5、或46.3:9.4:42.7:1.6、或45.0:9.0:43.0:3.0、或45.0:11.0:41.5:2.5、或42.0:10.5:45.0:2.5、或42.0:16.0:39.5:2.5、或40.0:16.0:41.5:2.5、或40.0:18.0:39.5:2.5、或35.0:40.0:22.5:2.5、或40.0:20.0:38.5:1.5、或45.0:15.0:38.5:1.5、或55.0:5.0:38.5:1.5、或60.0:5.0:33.5:1.5、或45.0:20.0:33.5:1.5、或50.0:20.0:28.5:1.5、或55.0:20.0:23.5:1.5、或60.0:20.0:18.5:1.5、或40.0:15.0:43.5:1.5、或50.0:15.0:33.5:1.5、或55.0:15.0:28.5:1.5、或60.0:15.0:23.5:1.5、或40.0:10.0:
48.5:1.5、或45.0:10.0:43.5:1.5、或55.0:10.0:33.5:1.5、或40.0:5.0:53.5:1.5、或45.0:5.0:48.5:1.5、或50.0:5.0:43.5:1.5。在一些此类实施方案中,所述辅助脂质为DSPC,所述结构脂质为CHO-HP。
在一些实施方案中,所述脂质纳米颗粒具有如下表2中No.1-24所示摩尔百分比(%)的本公开的氨基脂质化合物、辅助脂质、结构脂质和PEG-脂质,以所述氨基脂质化合物、所述辅助脂质、所述结构脂质和所述PEG-脂质的总量计:
表2
在一些实施方案中,所述脂质纳米颗粒具有如下表3中No.25-42所示摩尔百分比(%)的本公开的氨基脂质化合物、辅助脂质、结构脂质和PEG-脂质,以所述氨基脂质化合物、所述辅助脂质、所述结构脂质和所述PEG-脂质的总量计:
表3
如上文所述,本公开的脂质纳米颗粒可以用作活性成分的递送载体。
在一些实施方案中,所述活性成分包括治疗剂和/预防剂。
术语“治疗剂”或“预防剂”是指当施用给受试者时具有治疗、诊断和/或预防作用和/或引起所希望的生物和/或药理学作用的任何试剂。
“有效量”或“治疗有效量”指当对哺乳动物(优选为人)施用时,足以在哺乳动物(优选为人)中实现治疗的本发明化合物,或包含所述本发明化合物的脂质纳米颗粒的量。构成“治疗有效量”的本发明脂质纳米颗粒的量将取决于化合物、病况及其严重性、施用方式以及待治疗哺乳动物的年龄,但可以由本领域的普通技术人员依据其自身的知识和本公开内容来常规确定。
优选地,所述药物活性成分是生物活性成分,生物活性成分是在引入细胞或宿主中时具有生物作用的物质,例如,通过刺激免疫应答或炎性应答、通过发挥酶活性或通过补充突变等来起作用。生物活性成分包括但不限于核酸、蛋白、肽、抗体、小分子,及其混合物。
优选地,所述生物活性成分是核酸。
在一些实施方案中,生物活性成分是抗肿瘤剂、抗生素、免疫调节剂、抗炎剂、作用于中枢神经系统的药剂,多肽、多肽类(polypeptoid)或其混合物。
当脂质纳米颗粒将活性成分包裹在其内部含水空间中时,其可以称为“脂质纳米颗粒药物”。
在本公开的范围内,术语“细胞”是一般术语,并且包括单个细胞、组织、器官、昆虫细胞、禽类细胞、鱼细胞、两栖类细胞、哺乳动物细胞、初级细胞、连续细胞系、干细胞和/或遗传工程化细胞(如表达异源多肽或蛋白的重组细胞)的培养。重组细胞包括,例如,表达异源多肽或蛋白(如生长因子或血液因子)的细胞。
在一些如上文所述的实施方案中,本公开的脂质纳米颗粒还含有核酸。
在一些实施方案中,在所述脂质纳米颗粒中,本公开的氨基脂质化合物和所述核酸的质量比为约(5-30):1,例如约(5-10):1、(10-15):1、(15-20):1、(20-25):1或(25-30):1,优选约10:1。
在一些实施方案中,所述核酸选自RNA、反义寡核苷酸、DNA。
在一些实施方案中,所述RNA选自信使RNA(mRNA)、核糖体RNA(rRNA)、微RNA(miRNA)、转移RNA(tRNA)、小的抑制RNA(siRNA)、小的核RNA(snRNA)、小发夹RNA(shRNA)、单链向导RNA(sgRNA)、cas9mRNA或其混合物。
在一些实施方案中,所述信使RNA(mRNA)编码感兴趣多肽和/或蛋白质。包括任何天然或非天然存在或以其它方式修饰的多肽。在一些实施方案中,由mRNA编码的多肽和/或蛋白质在细胞中表达时可以具有治疗和/或预防作用。
在一些实施方案中,所述RNA是siRNA,所述siRNA能够选择性降低感兴趣基因的表达或下调该基因的表达。例如,siRNA的选择可以使得在将包括该siRNA的脂质纳米颗粒施用给有需要受试者后使与特定疾病、病症或病况有关的基因沉默。siRNA可以包含与编码所关注基因或蛋白质的mRNA序列互补的序列。在一些实施方案中,siRNA可以是免疫调节性siRNA。
在某些实施方案中,所述RNA是sgRNA和/或cas9mRNA。sgRNA和/或cas9mRNA可以用作基因编辑工具。例如,sgRNA-cas9复合物可以影响细胞基因的mRNA翻译。
在一些实施方案中,所述RNA是shRNA或者其编码载体或质粒。shRNA可以在将适当构建体递送至核中后在目标细胞内部产生。与shRNA相关的构建体和机制是相关领域中众所周知的。
在一些实施方案中,所述DNA为质粒。
在一些实施方案中,所述脂质纳米颗粒用于转移核酸。在一些实施方案中,所述脂质纳米颗粒可以用于例如基因治疗、基因疫苗接种、蛋白替代疗法、反义治疗或通过干扰RNA进行的治疗。
药物组合物
在另一方面,本发明提供药物组合物,所述药物组合物含有如上文所述的脂质纳米颗粒以及药学上可接受的载体、稀释剂或赋形剂。
在一些实施方案中,所述药物组合物还含有缓冲液。在一些此类实施方案中,所述缓冲液选自磷酸盐缓冲液和Tris缓冲液,优选磷酸盐缓冲液。在一些实施方案中,所述缓冲液的浓度为约5mmol/L-30mmol/L,优选为约10mmol/L。在一些实施方案中,所述缓冲液的pH为约6-8,优选为约7-8,更优选为约7-7.5。
在一些实施方案中,所述药物组合物还含有冷冻保护剂。在一些此类实施方案中,所述冷冻保护剂选自蔗糖和海藻糖,优选为蔗糖。在一些实施方案中,所述冷冻保护剂的浓度为约50mg/ml-100mg/ml。
在一些如上文所述的实施方案中,所述药物组合物还含有冷冻保护剂。在一些此类实施方案中,所述冷冻保护剂选自蔗糖和海藻糖,优选为蔗糖。在一些实施方案中,所述冷冻保护剂的浓度为约50mg/ml-100mg/ml。
用途
本公开的脂质纳米颗粒具有优良的包封生物活性成分的性能。包含生物活性成分的脂质纳米颗粒可以用于将多种治疗剂中的任何一种递送至细胞中。本公开包括如上所述的脂质纳米颗粒将生物活性成分递送至细胞中的用途。本发明还提供将生物活性成分递送至细胞、组织或器官中的方法,所述方法包括使包含所述生物活性成分的本公开的脂质纳米颗粒与所述细胞、组织或器官接触。这给个体提供了新的治疗处理的可能性。
在一些实施方案中,所述组织或器官选自由以下组成的组:脾、肝、肾、肺、股骨、眼组织、血管中的血管内皮、淋巴,以及肿瘤组织。
优选地,所述细胞是哺乳动物细胞;进一步优选,所述哺乳动物细胞是在哺乳动物体内。如本文所用的,个体可以是任何哺乳动物,优选选自小鼠、大鼠、猪、猫、狗、马、山羊、牛和猴子等。在一些优选的实施方案中,个体是人。
本公开提供一种在哺乳动物细胞中产生感兴趣多肽和/或蛋白质的方法,所述方法包括使细胞与包括编码感兴趣多肽和/或蛋白质的mRNA的脂质纳米颗粒接触,在细胞与脂质纳米颗粒接触后,mRNA可以被吸收至细胞中并翻译产生感兴趣多肽和/或蛋白质。
再一方面,本公开提供本公开的氨基脂质化合物、脂质纳米颗粒或药物组合物在制备药物中的用途。优选地,所述药物为核酸药物。优选地,所述药物组合物用于疾病的治疗和/或预防。
在一些实施方案中,所述疾病选自由以下组成的组:罕见病、感染性疾病、癌症、遗传性疾病、自体免疫性疾病、糖尿病、神经退化性疾病、心血管、肾血管疾病,以及代谢性疾病。
所述药物用于例如基因治疗、蛋白质替代疗法、反义治疗或通过干扰RNA进行的治疗以及基因疫苗接种。
在一些实施方案中,所述癌症选自肺癌、胃癌、肝癌、食管癌、结肠癌、胰腺癌、脑癌、淋巴癌、血癌或前列腺癌中的一种或多种。在一些实施方案中,所述遗传疾病选自血友病,地中海贫血、高雪氏病中的一种或多种。
在一些实施方案中,所述基因疫苗接种优选用于治疗和/或预防癌症、过敏、毒性和病原体感染。在一些实施方案中,所述病原体选自病毒、细菌或真菌中的一种或多种。
本公开提供一种治疗有需要的哺乳动物的疾病或病症的方法,所述方法包括向所述哺乳动物施用治疗有效量的根据前述的脂质纳米颗粒。
优选地,所述疾病或病症选自由以下组成的组:罕见病、感染性疾病、癌症、遗传性疾病、自体免疫性疾病、糖尿病、神经退化性疾病、心血管、肾血管疾病,以及代谢性疾病。
又一方面,本公开提供本公开的氨基脂质化合物、脂质纳米颗粒或药物组合物在制备用于核酸转移的药物中的用途。在一些实施方案中,所述核酸选自RNA、反义寡核苷酸、DNA。在一些实施方案中,所述RNA选自信使RNA(mRNA)、核糖体RNA(rRNA)、微RNA(miRNA)、转移RNA(tRNA)、小的抑制RNA(siRNA)、小的核RNA(snRNA)、小发夹RNA(shRNA)、单链向导RNA(sgRNA)、cas9mRNA或其混合物。在一些实施方案中,所述DNA为质粒。
制备方法
再一方面,本公开还提供制备本公开的式(Id)或(Ie)的氨基脂质化合物的一般合成方法,如下所示:
又一方面,本公开还提供制备本公开的式(II-I)的氨基脂质化合物的一般合成方法,如下所示:
(1)当X为C,Y1为-Z3C(=O)Z4-,且Z3、Z4均不为键,A12为键时,
或
(2)当X为C,Y1为-N(R5)时,
或
(3)当X为C,Y1为-Z3C(=O)Z4,且Z3为键,Z4不为键时,
或
(4)当X为C,Y1为-Z3C(=O)Z4,且Z3不为键,Z4为键时,
或
(5)X为N,Y1为-Z3C(=O)Z4-,且Z4为键,A12为键时,
或
(6)X为N,Y1为-Z3C(=O)Z4-,且Z4为键,A12不为键时,
再一方面,本公开的脂质纳米颗粒或药物组合物可以按照本领域已知的方法制备。例如,所述方法可以包括如下步骤:
(1)配料:配制适合的水相;以及配制包含本公开的氨基脂质化合物和任选存在的辅助脂质、结构脂质和/或PEG-脂质的有机相;
(2)包封:将合适量的所述水相与所述有机相混合;
(3)透析:任选地对步骤(2)的混合物进行透析;
(4)除菌:任选地对步骤(3)的产物进行除菌,例如通过除菌过滤器,例如0.22μm的微孔滤膜。
在一些实施方案中,本公开的含有核酸、特别是mRNA的脂质纳米颗粒或药物组合物可以通过包括以下步骤的方法制备:
(1)配料:配制包含所述核酸的水相;以及配制包含本公开的氨基脂质化合物和任选存在的辅助脂质、结构脂质和/或PEG-脂质的有机相(例如乙醇相);
(2)包封:将合适量的所述水相与所述有机相混合;
(3)透析:任选地对步骤(2)的混合物进行透析;
(4)除菌:任选地对步骤(3)的产物进行除菌,例如通过除菌过滤器,例如0.22μm的微孔滤膜。
本公开的氨基脂质化合物可以形成具有优良的生物活性成分包封性能的递送载体,例如脂质纳米颗粒,可以用于生物活性成分、特别是水难溶性药剂或者易分解或降解的活性成分(例如核酸)的递送,提高其生物利用度和效力、或免疫活性、或转染效率(对于核酸)、或安全性、或组织和\或细胞靶向性或特异性、或特定器官和\或组织的偏好性。
图1~图2为含不同氨基脂质化合物的脂质纳米颗粒的体内安全性(ALT酶活)检测结果;
图3~图4为含不同氨基脂质化合物的脂质纳米颗粒的体内安全性(AST酶活)检测结果;
图5为含不同氨基脂质化合物的脂质纳米颗粒的体内递送结果;
图6为含有不同氨基脂质化合物的脂质纳米颗粒在脾的不同免疫细胞群中的递送效率;
图7为含有不同氨基脂质化合物的脂质纳米颗粒在PBMC的不同免疫细胞群中的递送效率。
为了使本发明的目的、技术方案和优点更加清楚,下面结合具体实施例对本发明进行描述。以下实施例仅仅是用于说明本发明,而不是限制。
实施例
提供了以下实施例,其目的在于例示而并非限定。
实施例中未注明具体条件的实验方法,通常为常规条件,或按照原料或商品制造厂商所建议的条件;未注明来源的试剂,通常为通过商业途径可购得的常规试剂。
在实施例中施用的缩写具有如下含义:
Pd/C 钯/碳;
EA 乙酸乙酯;
DCM 二氯甲烷;
TEA 三乙胺;
MPa 兆帕;
DMF N,N-二甲基甲酰胺;
EDCI 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;
DMAP 4-二甲氨基吡啶;
TBAF 四丁基氟化铵
TEMPO 2,2,6,6-四甲基哌啶氮氧化物;
NaDCC 二氯异氰尿酸钠;
TBSCl 叔丁基二甲基氯硅烷;
h 小时;
min 分。
实施例1氨基脂质化合物383的合成
第一步:合成DFSGN-T
反应式:
实验过程:
向100mL圆底烧瓶,依次加入EDCI(4.43g,23.13mmol),DCM(26mL),TEA(2.34g,23.13mmol),摇匀搅拌5min后加入DMAP(0.47g,3.86mmol),BHB(4,4-双(庚氧基)丁醇)(4.2g,13.88mmol),DTN(10-氧代十九烷二酸)(2.64g,7.71mmol),室温下搅拌过夜。反应结束,加DCM(100mL),水(150mL),搅拌萃取,分液,收集有机相,有机相用50mL饱和氯化钠溶液洗,无水硫酸钠干燥,减压浓缩,得到DFSGN-T粗品7.7g,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得到5.13g DFSGN-T,收率81%。
第二步:合成DFSGN-C
实验过程:
向250mL单口瓶,加入DFSGN-T(5.13g,5.62mmol),溶于甲醇(50mL),冷却至0℃。搅拌下分批加入硼氢化钠(0.23g,6.18mmol),加料完成后保温反应1h。反应结束,减压蒸除溶剂,加水(100mL),DCM(100mL),搅拌萃取,分液,收集有机相,有机相用水(50mL)洗涤,有机相于45℃减压浓缩,得到DFSGN-C粗品5.2g,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得到4.5g DFSGN-C,收率88%。
第三步:合成383-D
反应式:
实验过程:
向50mL单口圆底烧瓶,加入DFSGN-C(1.8g,1.97mmol),DCM(18mL),加入DMAP(72mg,0.60mmol),吡啶(0.39g,4.93mmol),室温搅拌,分批加入对硝苯基氯甲酸酯(0.79g,3.94mmol),继续搅拌1h。反应结束,加水(150mL)稀释,用DCM(100mL)萃取,收集有机相,有机相用水(80mL)洗涤后,减压浓缩,得到383-D粗品3.0g,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得到1.74g 383-D,收率82%。
第四步:合成氨基脂质化合物383
反应式:
实验过程:
向50mL单口圆底烧瓶,加入383-D(1.74g,1.61mmol),DCM(18mL),DMAP(59mg,
0.48mmol),三乙胺(0.49mg,4.84mmol),二乙氨基丙醇(1.27g,9.68mmol),室温下搅拌2天。反应结束,加水(100mL)稀释,用DCM(100mL)萃取,收集有机相,有机相用水(80mL)洗涤后,减压浓缩,得到氨基脂质化合物383粗品2.8g,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得到945mg氨基脂质化合物383,收率55%,纯度96.55%。
氨基脂质化合物383
1H NMR in CDCl3δ4.69-4.65(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.6Hz,2H),4.07(t,J=6.1Hz,4H),3.58-3.54(m,4H),3.42-3.38(m,4H),2.53-2.49(m,6H),2.28(t,J=7.5Hz,4H),1.83-1.79(m,2H),1.71-1.66(m,12H),1.61-1.52(m,12H),1.36-1.28(m,52H),1.01(t,J=7.2Hz,6H)0.88(t,J=7.1Hz,12H).
LC-MS(ESI):Calculated for(M+H)1070.92,Found 1071.5.
实施例2氨基脂质化合物382的合成
根据一般合成方法,将化合物BSB替换BHB,按照实施例1的方法制备氨基脂质化合物382,得到655mg氨基脂质化合物382,收率58%,纯度97.63%。
BSB
氨基脂质化合物382
1H NMR in CDCl3δ4.69-4.65(m,1H),4.48(t,J=5.1Hz,2H),4.17(t,J=6.5Hz,2H),4.07(t,J=6.0Hz,4H),3.58-3.55(m,4H),3.42-3.38(m,4H),2.53-2.49(m,6H),2.28(t,J=7.6Hz,4H),1.84-1.79(m,2H),1.74-1.65(m,12H),1.61-1.52(m,12H),1.37-1.27(m,44H),1.01(t,J=7.2Hz,6H)0.89(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for(M+H)1014.85,Found 1015.4.
实施例3氨基脂质化合物1245的合成
第一步:合成3-溴丙醛
反应式:
实验过程:
向500mL的单口瓶中加入3-溴丙醇(10.0g,72mmol),DCM(150mL),搅拌下,加入TEMPO(225mg,1.44mmol),碳酸氢钾(5.05g,50.4mmol),溴化钠(296mg,2.88mmol),将反应液降至5℃,滴加NaDCC的水溶液(9.5g,43.2mmol),滴加完成后,于5℃反应3h,过滤,滤饼用20mL水和20mL DCM各洗涤一次,收集有机相,减压浓缩,得到3-溴丙醛粗品,粗品经硅胶柱层析,使用DCM洗脱,得到9.0g 3-溴丙醛,收率91.2%。
第二步:合成3,3-二辛氧基溴丙烷
反应式:
实验过程:
向250mL的单口瓶中加入3-溴丙醛(9.0g,65.7mmol),环戊基甲醚(80mL),1-辛醇(21.4g,164.3mmol),溴化铵(322mg,3.3mmol),搅拌下,反应液加热至130℃回流分水,反应6h,过滤,收集滤液,减压浓缩,得到3,3-二辛氧基溴丙烷粗品,粗品经硅胶柱层析,使用正己烷洗脱,得到9.63g 3,3-二辛氧基溴丙烷,收率38.6%。
第三步:合成1245-A
反应式:
实验过程:
向500mL的两口瓶中加入2-羟甲基-1,3-丙二醇(4.5g,42.7mmol),DMF(250mL),搅拌下,将反应液降至0℃,分批加入氢化钠(1.5g,37.0mmol),0℃反应1h,缓慢滴入3,3-二辛氧基-1-溴丙烷DMF溶液(11.2g,29.5mmol,溶于20mL DMF),滴加完成,将反应液升温至10℃反应6h,加入200mL水淬灭反应,然后转入1L分液漏斗中,再加入300mL水,用乙酸乙酯200mL萃取两次,合并有机相,有机相用300mL水洗涤后,减压浓缩,得到1245-A粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=3:1洗脱,得到5.87g 1245-A,收率49.2%。
第四步:合成1245-B
反应式:
实验过程:
向500mL的两口瓶中加入1245-A(5.87g,14.0mmol),DCM(280mL),搅拌下,将反应液降
至-10℃,加入亚油酸(4.32g,15.4mmol),EDCI(4.03g,21.0mmol),DMAP(171mg,1.4mmol),吡啶(1.66g,21.0mmol),滴加完成后,-10℃反应8h,反应液升至室温,加入200mL水淬灭反应,然后用200mL DCM萃取两次,合并有机相,减压浓缩,得到1245-B粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=5:1洗脱,得到5.6g 1245-B,收率58.7%。
第五步:合成氨基脂质化合物1245
反应式:
实验过程:
向250mL的两口瓶中加入1245-B(4.85g,7.12mmol),DCM(70mL),DMAP(261mg,2.14mmol),吡啶(1.41g,17.8mmol),室温下搅拌,然后分批缓慢加入对硝基苯基氯甲酸酯(2.87g,15.54mmol),室温反应1h,加入3-二乙氨基-1-丙醇(2.8g,21.4mmol),室温反应12h,减压蒸除溶剂,加入100mL水,用100mL正己烷萃取两次,合并有机相,有机相用150mL水洗涤后,减压浓缩,得到氨基脂质化合物1245粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=1:1洗脱,得到3.28g氨基脂质化合物1245,收率55.0%,纯度96.30%。
LC-MS(ESI):Calculated for(M+H)838.7,Found 839.1.
实施例4氨基脂质化合物1246的合成
第一步:合成4-(叔丁基二甲基甲硅烷基)氧代-1-丁醇
反应式:
实验过程:
向1L的单口瓶中加入1,4-丁二醇(20.0g,222mmol),DCM(660mL),咪唑(22.67g,333mmol),搅拌下,将反应液降至0℃,加入TBSCl(36.7g,244mmol),0℃反应6h,加入400mL水,用DCM300mL萃取两次,合并有机相,减压浓缩,得到4-(叔丁基二甲基甲硅烷基)氧代-1-丁醇粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=5:1洗脱,得到22.5g 4-(叔丁基二甲基甲硅烷基)氧代-1-丁醇,收率49.5%。
第二步:合成4-(叔丁基二甲基甲硅烷基)氧代-1-丁醛
反应式:
实验过程:
向1L的单口瓶中加入4-(叔丁基二甲基甲硅烷基)氧代-1-丁醇(22.5g,110mmol),DCM(300mL),搅拌下,加入TEMPO(344mg,2.2mmol),碳酸氢钾(7.7g,77mmol),溴化钠(453mg,4.4mmol),将反应液降至5℃,滴加NaDCC的水溶液(14.5g,66mmol,溶于150mL水),5℃反应3h,过滤,滤饼用50mL水和50mL DCM各洗涤一次,收集滤液,滤液分相,收集有机相,水相用150mL DCM萃取两次,合并有机相,减压浓缩,得到4-(叔丁基二甲基甲硅烷基)氧代-1-丁醛粗品,粗品经硅胶柱层析,使用DCM洗脱,得到11.4g 4-(叔丁基二甲基甲硅烷基)氧代-1-丁醛,
收率51.2%。
第三步:合成4,4-二辛氧基-1-TBS丁醇
反应式:
实验过程:
向250mL的单口瓶中加入4-(叔丁基二甲基甲硅烷基)氧代-1-丁醛(10.0g,49.4mmol)、环戊基甲醚(80mL)、1-辛醇(16.1g,123.5mmol)、溴化铵(242mg,2.47mmol),搅拌下,反应液加热至130℃回流分水,反应6h,过滤,收集滤液,减压浓缩,得到4,4-二辛氧基-1-TBS丁醇粗品,粗品经硅胶柱层析,使用正己烷洗脱,得到10.2g 4,4-二辛氧基-1-TBS丁醇,收率46.4%。
第四步:合成4,4-二辛氧基-1-丁醇
反应式:
实验过程:
向250mL的单口瓶中加入4,4-二辛氧基-1-TBS丁醇(10.0g,22.5mmol)、四氢呋喃(110mL)、TBAF(10.6g,33.7mmol),搅拌下,室温反应6h,加入80mL饱和碳酸氢钠溶液,然后用乙酸乙酯80mL萃取两次,合并有机相,有机相用100mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,收集滤液,减压浓缩,得到4,4-二辛氧基-1-丁醇粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=5:1洗脱,得到6.5g 4,4-二辛氧基-1-丁醇,收率87.4%。
第五步:合成1246-A1
反应式:
实验过程:
向500mL的两口瓶中加入5-羟甲基-2,2-二甲基-1,3-二恶烷(13.0g,88.9mmol)、DCM(270mL),搅拌下,将反应液降至-10℃,加入亚油酸(25.0g,88.9mmol)、EDCI(25.6g,133.5mmol)、DMAP(2.18g,17.8mmol)、吡啶(10.6g,134.0mmol),升至室温,反应8h,加入200mL水淬灭反应,用200mL DCM萃取两次,合并有机相,减压浓缩,得到1246-A1粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=20:1洗脱,得到23.6g 1246-A1,收率64.9%。
第六步:合成1246-A
反应式:
实验过程:
向1L的圆底瓶中加入1246-A1(23.6g,57.8mmol)、乙醇(360mL),室温下搅拌,滴加盐酸(120mL),室温反应1h,加入600mL饱和碳酸氢钠溶液淬灭反应,用500mL DCM萃取两次,合并有机相,减压浓缩,得到1246-A粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=3:1洗脱,得到17.5g 1246-A,收率82.2%。
第七步:合成1246-A-TBS
反应式:
实验过程:
向1L的圆底瓶中加入1246-A(21.3g,57.8mmol)、DCM(600mL),搅拌下,将反应液降至0℃,加入咪唑(5.9g,86.7mmol)、TBSCl(9.6g,63.7mmol),0℃反应8h,加入500mL饱和碳酸氢钠溶液淬灭反应,用DCM(500mL)萃取两次,合并有机相,有机相用400mL饱和氯化钠溶液洗涤后,减压浓缩,得到粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=10:1洗脱,得到12.4g1246-A-TBS,收率44.4%。
第八步:合成1246-B
反应式:
实验过程:
向100mL的两口瓶中加入1246-A-TBS(4.5g,9.32mmol)、DCM(45mL)、DMAP(0.34g,2.79mmol),搅拌下,滴加吡啶(1.62g,20.5mmol),分批缓慢加入对硝基苯基氯甲酸酯(3.75g,18.6mmol),室温反应1h,加入3-二乙氨基-1-丙醇(3.66g,27.9mmol)与三乙胺(0.93g,9.32mmol)的混合液,室温反应16h,减压蒸除溶剂,加入200mL水,用正己烷200mL萃取两次,合并有机相,有机相用200mL水、150mL饱和碳酸氢钠溶液洗涤后,减压浓缩,得到5.72g油状物。
在250mL的圆底瓶中加入上述油状物(5.72g)、四氢呋喃(57mL),室温下搅拌,滴加三乙胺三氟化氢(14.35g),室温反应16h,浓缩反应液,加入100mL乙酸乙酯稀释,使用饱和碳酸氢钠溶液调pH=8,加200mL水洗涤,水相用200mL乙酸乙酯萃取两次,合并有机相,减压浓缩,得到1246-B粗品,粗品经硅胶柱层析,使用DCM:甲醇=10:1洗脱,得到960mg 1246-B,收率19.6%。
第九步:合成1246-C
反应式:
实验过程:
向25mL的单口瓶中加入4,4-二辛氧基-1-丁醇(1.0g,3.02mmol)、DCM(10mL)、DMAP(74mg,0.6mmol)、吡啶(0.36g,4.5mmol),室温下搅拌,分批缓慢加入对硝基苯基氯甲酸酯(0.91g,4.5mmol),室温反应1h,浓缩反应液,加入100mL水,用100mL正己烷萃取两次,合并有机相,有机相用150mL水、150mL饱和碳酸氢钠溶液洗涤后,减压浓缩,得到1246-C粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=1:1洗脱,得到905mg 1246-C,收率60.3%。
第十步:合成氨基脂质化合物1246
反应式:
实验过程:
向25mL的两口瓶中加入1246-B(0.96g,1.82mmol)、DCM(10mL)、DMAP(67mg,0.55mmol)、三乙胺(0.45mL,3.65mmol),室温下搅拌,加入1246-C(0.91g,1.82mmol),室温反应12h,加入100mL水,50mL DCM萃取,水相用100mL DCM萃取二次,合并有机相,有机相用150mL饱和碳酸氢钠溶液洗涤后,减压浓缩,得到氨基脂质化合物1246粗品,粗品经硅胶柱层析,使用正己烷:乙酸乙酯=1:1洗脱,得到1.25g氨基脂质化合物1246,收率77.6%,纯度94.13%。
1H NMR(600MHz,CDCl3)δ5.41-5.29(m,4H),4.47(t,J=5.5Hz,1H),4.22-4.12(m,10H),3.55(dt,J=9.2,6.7Hz,2H),3.40(dt,J=9.2,6.7Hz,2H),2.76(t,J=6.9Hz,2H),2.50(q,J=7.2Hz,6H),2.45(dt,J=11.9,5.9Hz,1H),2.30(t,J=7.6Hz,2H),2.04(q,J=7.0Hz,4H),1.84-1.77(m,2H),1.77-1.64(m,4H),1.63-1.58(m,2H),1.58-1.51(m,4H),1.39-1.20(m,34H),1.00(t,J=7.1Hz,6H),0.88(q,J=6.9Hz,9H).
13C NMR(151MHz,CDCl3)δ173.60,155.13,155.11,130.36,130.18,128.18,128.05,102.70,68.30,67.12,66.00,65.03,65.00,61.39,49.21,47.01,37.75,34.23,31.98,31.66,30.02,29.93,29.75,29.58,29.49,29.41,29.32,29.26,27.34,26.60,26.40,25.77,24.98,24.20,22.80,22.71,14.24,14.22,11.87.
LC-MS(ESI):Calculated for(M+H)882.7,Found 883.1.
实施例5氨基脂质化合物1247的合成
根据一般合成方法以及实施例3的方法,按照如下反应路线制备氨基脂质化合物1247,得到2.0g氨基脂质化合物1247,收率54.9%,纯度95.75%。
1H NMR(600MHz,CDCl3)δ5.41-5.29(m,4H),4.58(t,J=5.8Hz,1H),4.22-4.14(m,5H),4.11(dd,J=11.1,6.4Hz,1H),3.56(dt,J=9.2,6.7Hz,2H),3.46(dd,J=13.7,6.1Hz,4H),3.40(dt,J=9.3,6.7Hz,2H),2.77(t,J=6.9Hz,2H),2.62-2.49(m,6H),2.33-2.28(m,3H),2.04(q,J=7.0Hz,4H),1.85(q,J=6.2Hz,2H),1.83-1.78(m,2H),1.63-1.58(m,2H),1.58-1.52(m,4H),1.38-1.22(m,34H),1.00(t,J=7.1Hz,6H),0.88(q,J=7.0Hz,9H).
13C NMR(151MHz,CDCl3)δ173.74,155.31,130.36,130.18,128.19,128.05,100.79,68.34,67.59,66.95,66.28,66.27,65.88,62.18,49.23,47.01,38.65,34.33,34.09,31.99,31.67,30.07,29.76,29.60,29.49,29.44,29.34,29.29,29.28,27.34,26.62,26.42,25.77,25.05,22.81,22.72,14.24,14.22,11.88.
LC-MS(ESI):Calculated for(M+H)824.7,Found 825.1.
实施例6氨基脂质化合物1248的合成
根据一般合成方法以及实施例3的方法,按照如下反应路线制备氨基脂质化合物1248,得到5.47g氨基脂质化合物1248,收率82.6%,纯度96.52%。
1H NMR(600MHz,CDCl3)δ5.41-5.19(m,4H),4.44(t,J=5.7Hz,1H),4.23-4.14(m,5H),4.11(dd,
J=11.2,6.4Hz,1H),3.55(dt,J=9.2,6.7Hz,2H),3.44(d,J=5.9Hz,2H),3.42-3.36(m,4H),2.77(t,J=6.8Hz,2H),2.62-2.49(m,6H),2.33-2.28(m,3H),2.04(q,J=7.0Hz,4H),1.83-1.77(m,2H),1.63-1.58(m,4H),1.58-1.52(m,6H),1.41-1.21(m,36H),1.00(t,J=7.1Hz,6H),0.88(q,J=6.9Hz,9H).
13C NMR(151MHz,CDCl3)δ173.75,155.31,130.36,130.18,128.18,128.05,103.14,71.44,68.26,66.93,65.93,65.73,62.23,49.23,47.02,38.69,34.34,33.42,31.99,31.67,30.06,29.76,29.59,29.57,29.49,29.43,29.34,29.28,27.34,26.62,26.42,25.77,25.05,22.81,22.72,21.52,14.25,14.22,11.89.
LC-MS(ESI):Calculated for(M+H)852.7,Found 853.1.
实施例7氨基脂质化合物387的合成
根据一般合成方法,将化合物387-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物387,其中387-A5(1.7g,1.76mmol),3-二乙氨基-1-丙醇(1.39g,10.56mmol),得到0.37g氨基脂质化合物387,收率21.93%,纯度95.40%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.5Hz,2H),4.07(t,J=6.2Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.40(dt,J=9.3,6.7Hz,4H),2.55-2.47(m,6H),2.28(t,J=7.6Hz,4H),1.85-1.76(m,2H),1.74-1.63(m,8H),1.63-1.48(m,16H),1.38-1.20(m,36H),1.00(t,J=7.1Hz,6H),0.90(m,12H).
LC-MS(ESI):Calculated for(M+H)958.79,Found 959.3.
实施例8氨基脂质化合物388的合成
根据一般合成方法,将化合物388-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物388,其中388-A5(1.2g,1.17mmol),3-二甲氨基-1-丙醇(0.72g,7.02mmol),得到0.37g氨基脂质化合物388,收率31.95%,纯度94.45%。
1H NMR(600MHz,CDCl3)δ4.71-4.63(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.6Hz,2H),4.08(t,J=6.2Hz,4H),3.57(dt,J=9.3,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.39-2.34(m,2H),2.28(t,J=7.6Hz,4H),2.22(s,6H),1.88-1.80(m,2H),1.74-1.63(m,10H),1.63-1.47(m,16H),1.39-1.22(m,42H),0.95-0.81(m,12H).
LC-MS(ESI):Calculated for(M+H)986.82,Found 987.4.
实施例9氨基脂质化合物389的合成
根据一般合成方法,将化合物389-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物389,其中389-A5(2.4g,2.23mmol),3-二乙氨基-1-丙醇(1.75g,13.35mmol),得到1.05g氨基脂质化合物389,收率43.97%,纯度92.22%。
1H NMR(600MHz,CDCl3)δ4.72-4.62(m,1H),4.45(t,J=5.7Hz,2H),4.17(t,J=6.5Hz,2H),4.05(t,J=6.7Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.40(dt,J=9.3,6.7Hz,4H),2.61-2.43(m,6H),2.28(t,J=7.6Hz,4H),1.87-1.76(m,2H),1.57(m,26H),1.43-1.16(m,50H),1.01(t,J=7.1Hz,6H),0.89(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for(M+H)1070.67,Found.
实施例10氨基脂质化合物390的合成
根据一般合成方法,将化合物390-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物390,其中390-A5(1.2g,1.17mmol),3-二乙氨基-1-丙醇(0.92g,7.02mmol),得到0.44g氨基脂质化合物390,收率37.06%,纯度91.06%。
1H NMR(600MHz,CDCl3)δ4.71-4.61(m,1H),4.45(t,J=5.7Hz,2H),4.17(t,J=6.5Hz,2H),4.05(t,J=6.7Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.40(dt,J=9.3,6.7Hz,4H),2.51(td,J=7.1,3.4Hz,6H),2.28(t,J=7.6Hz,4H),1.85-1.76(m,2H),1.76-1.47(m,26H),1.43-1.17(m,42H),1.01(t,J=7.1Hz,6H),0.90(m,12H).
LC-MS(ESI):Calculated for(M+H)1014.85,Found 1015.3.
实施例11氨基脂质化合物391的合成
根据一般合成方法,将化合物391-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物391,其中391-A5(2g,2.03mmol),3-二乙氨基-1-丙醇(1.6g,12.18mmol),得到0.847g氨基脂质化合物391,收率43.53%,纯度92.68%。
1H NMR(600MHz,CDCl3)δ4.71-4.61(m,1H),4.45(t,J=5.7Hz,2H),4.17(t,J=6.5Hz,2H),4.05(t,J=6.7Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.40(dt,J=9.3,6.7Hz,4H),2.51(td,J=7.1,3.4Hz,6H),2.28(t,J=7.6Hz,4H),1.85-1.76(m,2H),1.76-1.47(m,26H),1.43-1.17(m,34H),1.01(t,J=7.1Hz,6H),0.90(m,12H).
LC-MS(ESI):Calculated for(M+H)958.46,Found 959.1.
实施例12氨基脂质化合物392的合成
根据一般合成方法,将化合物392-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物392,其中392-A5(0.86g,0.85mmol),3-二乙氨基-1-丙醇(0.67g,5.1mmol),得到0.29g氨基脂质化合物392,收率33.9%,纯度97.93%。
1H NMR(600MHz,CDCl3)δ5.62-5.48(m,8H),4.69-4.65(m,1H),4.62-4.53(m,2H),4.20-4.11(m,6H),4.09-4.06(m,8H),2.54-2.45(m,6H),2.28(t,J=7.6Hz,4H),2.06-2.03(m,8H),1.84-1.76(m,2H),1.75-1.66(m,8H),1.64-1.46(m,8H),1.43-1.35(m,8H),1.35-1.22(m,20H),1.00(t,J=7.1Hz,6H),0.90(t,J=7.4Hz,
12H).
LC-MS(ESI):Calculated for(M+H)1006.50,Found 1007.1.
实施例13氨基脂质化合物396的合成
根据一般合成方法,将化合物396-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物396,其中396-A5(1.3g,1.27mmol),1-(3-羟丙基)吡咯烷(0.67g,5.18mmol),得到0.29g氨基脂质化合物396,收率22.55%,纯度95.18%。
1H NMR(600MHz,CDCl3)δ4.71-4.62(m,1H),4.48(t,J=5.2Hz,2H),4.18(t,J=6.6Hz,2H),4.07(t,J=6.1Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.40(dt,J=9.3,6.7Hz,4H),2.55-2.49(m,6H),2.28(t,J=7.6Hz,4H),1.92-1.97(m,2H),1.80-1.63(m,14H),1.63-1.45(m,16H),1.43-1.16(m,42H),0.89(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for(M+H)1012.55,Found 1013.2.
实施例14氨基脂质化合物398的合成
根据一般合成方法,将化合物398-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物398,其中398-A5(1g,0.98mmol),N-甲基-2-(2-羟乙基)吡咯烷(0.76g,5.88mmol),得到0.29g氨基脂质化合物398,收率29.23%,纯度96.77%。
1H NMR(600MHz,CDCl3)δ4.72-4.62(m,1H),4.48(d,J=5.3Hz,2H),4.25-4.18(m,1H),4.18-4.12(m,1H),4.07(t,J=6.0Hz,4H),3.56(dt,J=8.5,6.7Hz,4H),3.40(dt,J=8.9,6.8Hz,4H),3.05(t,J=8.6Hz,1H),2.28(dd,J=16.8,9.3Hz,7H),2.20-2.02(m,3H),2.00-1.94(m,1H),1.83-1.63(m,12H),1.63-1.43(m,18H),1.40-1.19(m,42H),0.88(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for(M+H)1012.55,Found 1013.2.
实施例15氨基脂质化合物399的合成
根据一般合成方法,将化合物399-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物399,其中399-A5(1g,0.98mmol),3-(2-甲基哌啶-1-基)丙-1-胺(0.92g,5.88mmol),得到0.7g氨基脂质化合物399,收率68.71%,纯度96.77%。
1H NMR(600MHz,CDCl3)δ4.69(s,1H),4.48-4.47(m,2H),4.08-4.06(t,J=5.9Hz,4H),3.56(dt,J=13.6,6.7Hz,4H),3.40(dt,J=13.8,6.8Hz,4H),3.32-3.21(m,1H),3.17-3.16(m,1H),2.85-2.83(m,1H),2.79-2.74(m,1H),2.28(t,J=7.5Hz,6H),2.06(t,J=10.7Hz,1H),1.81-1.41(m,30H),1.37-1.27(m,46H),1.04(d,J=6.2Hz,3H),0.89(t,J=6.8Hz,12H).
LC-MS(ESI):Calculated for(M+H)1039.62,Found 1040.3
实施例16氨基脂质化合物416的合成
根据一般合成方法,将化合物416-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物416,其中416-A5(1g,0.98mmol),1-甲基哌啶-3-甲醇(0.76g,5.88mmol),得到0.6g氨基脂质化合物416,收率60.47%,纯度96.77%。
1H NMR(600MHz,CDCl3)δ4.70-4.62(m,1H),4.48(t,J=5.2Hz,2H),4.08-4.03(m,5H),3.94(dd,J=10.6,7.4Hz,1H),3.56(dt,J=9.2,6.7Hz,4H),3.40(dt,J=9.2,6.7Hz,4H),2.85(d,J=10.2Hz,1H),2.74(d,J=10.5Hz,1H),2.29-2.25(m,7H),2.06-1.94(m,1H),1.90(t,J=10.8Hz,1H),1.80-1.44(m,29H),1.42-1.08(m,44H),0.89(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for(M+H)1012.55,Found 1013.2
实施例17氨基脂质化合物423的合成
根据一般合成方法,将化合物423-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物423,其中423-A5(1g,0.98mmol),3-二甲氨基-2,2-二甲基-1-丙醇(0.77g,5.88mmol),得到0.7g氨基脂质化合物423,收率70.4%,纯度91.78%。
1H NMR(600MHz,CDCl3)δ4.72-4.63(m,1H),4.48(t,J=5.2Hz,2H),4.08(t,J=6.1Hz,4H),3.94(s,2H),3.57(dt,J=9.1,6.7Hz,4H),3.41(dt,J=9.2,6.7Hz,4H),2.30-2.23(m,10H),2.17(s,2H),1.75-1.47(m,26H),1.42-1.17(m,42H),0.92(s,6H),0.89(t,J=6.9Hz,12H)
LC-MS(ESI):Calculated for(M+H)1014.57,Found 1015.2
实施例18氨基脂质化合物429的合成
根据一般合成方法,将化合物429-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物429,其中429-A5(2g,1.94mmol),3-二乙氨基-1-丙醇(1.53g,11.64mmol),得到0.84g氨基脂质化合物429,收率42.35%,纯度97.22%。
1H NMR(600MHz,CDCl3)δ4.71-4.62(m,1H),4.48(t,J=5.1Hz,2H),4.17(t,J=6.5Hz,2H),4.07(t,J=6.0Hz,4H),3.67(dt,J=9.3,6.3Hz,4H),3.55-3.36(m,20H),2.53(td,J=7.1,3.4Hz,6H),2.28(t,J=7.6Hz,4H),1.86-1.81(m,10H),1.73-1.63(m,8H),1.63-1.45(m,8H),1.27(m,20H),1.19(t,J=7.0Hz,12H),1.03-1.00(m,6H).
LC-MS(ESI):Calculated for(M+H)1022.45,Found 1023.1
实施例19氨基脂质化合物430的合成
根据一般合成方法,将化合物430-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物430,其中430-A5(2.3g,1.7mmol),3-二乙氨基-1-丙醇(1.34g,10.2mmol),得到0.84g氨基脂质化合物430,收率36.7%,纯度98.29%。
1H NMR(600MHz,CDCl3)δ4.70-4.63(m,1H),4.43(t,J=5.2Hz,2H),4.17(t,J=6.5Hz,2H),4.07(t,J=6.2Hz,4H),3.46(dd,J=9.2,5.8Hz,4H),3.27(dd,J=9.2,5.8Hz,4H),2.57-2.45(m,6H),2.28(t,J=7.6Hz,4H),1.86-1.76(m,2H),1.74-1.45(m,24H),1.42-1.18(m,80H),1.01(t,J=7.1Hz,6H),0.89(q,J=6.9Hz,24H).
LC-MS(ESI):Calculated for(M+H)1351.21,Found 1351.8
实施例20氨基脂质化合物490的合成
根据一般合成方法,将化合物490-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物490,其中490-A5(2.9g,2.69mmol),3-二甲氨基-1-丙醇(1.67g,16.14mmol),得到1.3g氨基脂质化合物490,收率46.35%,纯度93.50%。
1H NMR(600MHz,CDCl3)δ4.67(s,1H),4.47(t,J=5.3Hz,2H),4.17(t,J=6.6Hz,2H),4.07(t,J=6.2Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.40(dt,J=9.3,6.7Hz,4H),2.37-2.34(m,2H),2.28(t,J=7.6Hz,4H),2.22(s,6H),1.87-1.81(m,2H),1.68(t,J=6.6Hz,12H),1.56(dt,J=14.5,4.6Hz,12H),1.34-1.24(m,52H),0.88(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for 1042.62,Found(M+H):1043.4.
实施例21氨基脂质化合物849的合成
根据一般合成方法,将化合物849-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物849,其中849-A5(2.0g,1.68mmol),3-二甲氨基-1-丙醇(1.04g,10.08mmol),得到0.8g氨基脂质化合物849,收率41.2%,纯度93.97%。
1H NMR(600MHz,CDCl3)δ4.66(m,1H),4.47(t,J=5.2Hz,2H),4.17(t,J=6.6Hz,2H),4.07(t,J=6.1Hz,4H),3.55(dt,J=9.2,6.7Hz,4H),3.40(dt,J=9.2,6.7Hz,4H),2.38-2.33(m,2H),2.27(t,J=7.6Hz,4H),2.22(s,6H),1.87-1.80(m,2H),1.71-1.63(m,8H),1.63-1.49(m,16H),1.37-1.20(m,66H),0.87(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for(M+H)1154.84,Found 1155.5.
实施例22氨基脂质化合物859的合成
根据一般合成方法,将化合物859-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物859,其中859-A5(1.1g,0.97mmol),3-二乙氨基-1-丙醇(0.76g,5.82mmol),得到270mg氨基脂质化合物859,收率24.72%,纯度95.67%。
1H NMR(600MHz,CDCl3)δ4.72-4.59(m,1H),4.48(t,J=5.1Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=6.1Hz,4H),3.56(dt,J=9.1,6.7Hz,4H),3.40(dt,J=9.1,6.7Hz,4H),2.51(td,J=7.1,3.4Hz,6H),2.28(t,J=7.6Hz,4H),1.84-1.77(m,2H),1.73-1.50(m,28H),1.31(dd,J=30.6,6.5Hz,56H),1.01(t,J=7.1Hz,6H),0.88(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for 1126.78,Found(M+H):1127.4.
实施例23氨基脂质化合物2021的合成
第一步:合成2021-A2
取EDCI(8.0g,41.75mmol),加入DCM(120ml),TEA(4.18g,41.75mmol),室温搅拌下加入2021-A1(9.6g,33.4mmol),待反应液澄清后,加入2-羟甲基-1,3-丙二醇(1.8g,16.7mmol),DMAP(377mg,3.09mmol),室温反应16h,反应液使用饱和碳酸氢钾溶液(150ml)洗涤,分液,收集有机相,水相再用DCM(80ml)萃取一次,合并有机相,减压蒸除溶剂,得到2021-A2粗品,粗品经硅胶柱层析,用正己烷:乙酸乙酯=20:1洗脱,得到4.5g 2021-A2,收率41.65%。
第二步:合成2021-A3
向50mL单口圆底烧瓶,加入2012-A2(2.0g,3.09mmol),溶于DCM(20mL),加入DMAP
(113mg,0.93mmol),吡啶(0.61g,7.73mmol),室温搅拌,分批加入对硝苯基氯甲酸酯(1.25g,6.18mmol),继续搅拌1h,加水(150mL)稀释,用DCM(100mL)萃取,收集有机相,有机相用水(80mL)洗涤,浓缩,得到3.5g 2021-A3粗品,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得2.13g 2021-A3,收率85%。
第三步:合成2021
向50mL单口圆底烧瓶,加入2021-A3(2.0g,2.46mmol),溶于DCM(20mL),加入DMAP(92mg,0.75mmol),三乙胺(0.75mg,7.38mmol),二甲氨基丙醇(1.52g,14.76mmol),室温下搅拌2天,加水(100mL)稀释,用二氯甲烷(100mL)萃取,收集有机相,有机相用水(80mL)洗涤,减压浓缩,得到2.6g 2021粗品,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得到1.16g氨基脂质化合物2021,收率61%,纯度95.32%。
1H NMR(600MHz,CDCl3)δ4.47(t,J=5.6Hz,2H),4.18(t,J=6.1Hz,4H),4.13(dd,J=6.0,1.8Hz,4H),3.55(dt,J=9.3,6.7Hz,4H),3.39(dt,J=9.3,6.7Hz,4H),2.43-2.37(m,5H),2.36-2.32(m,2H),2.21(s,6H),1.91(td,J=7.6,5.7Hz,4H),1.85-1.80(m,2H),1.57-1.51(m,8H),1.35-1.24(m,24H),0.88(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for 776.11,Found(M+H):776.7.
实施例24氨基脂质化合物2035的合成
根据一般合成方法,将化合物2035-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2035,其中2035-A5(4.1g,4.12mmol),3-二甲氨基-1-丙醇(2.55g,24.6mmol),得到3.0g氨基脂质化合物2035,收率75.97%,纯度92.02%。
1H NMR(600MHz,CDCl3)δ4.71-4.63(m,1H),4.60(t,J=5.8Hz,2H),4.23-4.10(m,6H),3.58(dt,J=9.2,6.7Hz,4H),3.42(dt,J=9.2,6.7Hz,4H),2.47-2.38(m,2H),2.32-2.24(m,10H),1.94(q,J=6.4Hz,4H),1.90-1.81(m,2H),1.63-1.49(m,16H),1.38-1.22(m,44H),0.89(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for(M+H)958.46,Found 959.2.
实施例25氨基脂质化合物2036的合成
根据一般合成方法,将化合物2036-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2036,其中2036-A5(4.85g,4.62mmol),3-二甲氨基-1-丙醇(2.86g,27.7mmol),得到0.9g氨基脂质化合物2036,收率19.2%,纯度92.23%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.46(t,J=5.7Hz,2H),4.17(t,J=6.6Hz,2H),4.06(t,J=6.7Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.40(dt,J=9.3,6.7Hz,4H),2.39-2.34(m,2H),2.28(t,J=7.6Hz,4H),2.22(s,6H),1.84(dd,J=14.2,7.1Hz,2H),1.66-1.54(m,30H),1.45-1.27(m,42H),0.89(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for(M+H)1014.57,Found 1015.3.
实施例26氨基脂质化合物2038的合成
根据一般合成方法,将化合物2038-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2038,其中2038-A5(0.91g,1.02mmol),3-二甲氨基-1-丙醇(0.63g,6.12mmol),得到425mg氨基脂质化合物2038,收率47.77%,纯度94.67%。
1H-NMR(600MHz,CDCl3)δ4.70-4.63(m,1H),4.48(t,J=5.2Hz,2H),4.22(t,J=5.8Hz,2H),4.07(t,J=6.2Hz,4H),3.57(dt,J=9.2,6.7Hz,4H),3.41(dt,J=9.2,6.7Hz,4H),2.65-2.57(m,4H),2.30(ddd,J=15.3,11.8,6.9Hz,14H),1.70-1.54(m,20H),1.38-1.27(m,28H),0.89(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for 874.29,Found(M+H):875.1.
实施例27氨基脂质化合物2039的合成
根据一般合成方法,将化合物2039-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2039,其中2039-A5(5.0g,5.33mmol),3-二甲氨基-1-丙醇(3.3g,31.97mmol),得到1.05g氨基脂质化合物2039,收率21.83%,纯度94.51%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.6Hz,2H),4.08(t,J=6.2Hz,4H),3.57(dt,J=9.3,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.38-2.35(m,2H),2.31-2.26(m,4H),2.23(s,6H),1.85(dt,J=13.8,6.7Hz,4H),1.73-1.65(m,8H),1.58(m,16H),1.57–1.39-1.25(m,30H),0.89(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for 902.35,Found(M+H):903.30.
实施例28氨基脂质化合物2040的合成
根据一般合成方法,将化合物2040-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2040,其中2040-A5(2.0g,2.07mmol),3-二甲氨基-1-丙醇(1.28g,12.42mmol),得到0.77g氨基脂质化合物2040,收率40.0%,纯度92.49%。
1H NMR(600MHz,CDCl3)δ4.68(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.6Hz,2H),4.08(t,J=6.2Hz,4H),3.57(dt,J=9.3,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.38-2.35(m,2H),2.31-2.26(m,4H),
2.23(s,6H),1.85(dt,J=13.8,6.7Hz,4H),1.73-1.65(m,8H),1.58(m,16H),1.39-1.25(m,34H),0.89(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for 930.40,Found(M+H):931.2.
实施例29氨基脂质化合物2041的合成
根据一般合成方法,将化合物2041-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2041,其中2041-A5(2.5g,2.51mmol),3-二甲氨基-1-丙醇(1.56g,15.08mmol),得到0.66g氨基脂质化合物2041,收率27.43%,纯度91.97%。
1H NMR(600MHz,CDCl3)δ4.68(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.6Hz,2H),4.07(t,J=6.2Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.56-2.46(m,6H),2.32-2.24(m,4H),1.71-1.66(m,12H),1.62(m,4H),1.59-1.54(m,10H),1.40-1.25(m,40H),1.01(t,J=7.1Hz,6H),0.89(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for(M+H)958.46,Found 959.0.
实施例30氨基脂质化合物2042的合成
根据一般合成方法,将化合物2038-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2042,其中2038-A5(1.0g,1.10mmol),3-二乙氨基-1-丙醇(0.86g,6.60mmol),得到0.35g氨基脂质化合物2042,收率35.26%,纯度96.36%。
1H NMR(600MHz,CDCl3)δ4.68(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.6Hz,2H),4.07(t,J=6.2Hz,4H),3.57(dt,J=9.3,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.56-2.46(m,6H),2.32-2.24(m,4H),1.71-1.66(m,12H),1.62(m,4H),1.59-1.54(m,10H),1.40-1.25(m,28H),1.01(t,J=7.1Hz,6H),0.89(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for 902.35,Found(M+H):903.2
实施例31氨基脂质化合物2043的合成
根据一般合成方法,将化合物2039-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2043,其中2039-A5(1.2g,1.28mmol),3-二乙氨基-1-丙醇(1.01g,7.67mmol),得到0.56g氨基脂质化合物2043,收率47.02%,纯度90.21%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.4Hz,2H),4.07(t,J=6.2Hz,4H),3.57(dt,J=9.3,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.56-2.47(m,6H),2.28(t,J=7.6Hz,4H),1.86-1.78(m,4H),1.72-1.65(m,8H),1.62-1.52(m,16H),1.37-1.24(m,30H),1.01(t,J=7.1Hz,6H),0.89(t,J=7.0Hz,12H).
LC-MS(ESI):Calculated for 930.40,Found(M+H):931.3.
实施例32氨基脂质化合物2044的合成
根据一般合成方法,将化合物2040-A5替换383-D,按照实施例1第三步方法合成氨基脂质化合物2044,其中2044-A5(0.93g,0.96mmol),3-二乙氨基-1-丙醇(0.76g,5.76mmol),得到0.4g氨基脂质化合物2044,收率43.50%,纯度90.45%。
1H NMR(600MHz,CDCl3)δ4.71-4.60(m,1H),4.48(t,J=5.1Hz,2H),4.20-4.12(m,2H),4.08(t,J=6.0Hz,4H),3.57(dt,J=9.2,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.57-2.45(m,6H),2.28(t,J=7.6Hz,4H),1.93-1.84(m,4H),1.73-1.65(m,8H),1.65-1.51(m,16H),1.35-1.25(m,34H),1.02(t,J=7.1Hz,6H),0.89(t,J=6.8Hz,12H).
LC-MS(ESI):Calculated for 958.46,Found(M+H):959.3.
实施例33氨基脂质化合物2045的合成
根据一般合成方法,将化合物2041-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2045,其中2045-A5(2.5g,2.51mmol),3-二乙氨基-1-丙醇(1.98g,15.08mmol),得到1.2g氨基脂质化合物2045,收率48.46%,纯度90.78%。
1H NMR(600MHz,CDCl3)δ4.71-4.61(m,1H),4.47(t,J=5.1Hz,2H),4.16(t,J=6.5Hz,2H),4.06(t,J=6.1Hz,4H),3.56(dt,J=9.3,6.7Hz,4H),3.39(dt,J=9.3,6.7Hz,4H),2.58-2.43(m,6H),2.27(t,J=7.6Hz,4H),1.90-1.74(m,6H),1.74-1.45(m,20H),1.42-1.16(m,40H),1.00(t,J=7.1Hz,6H),0.88(t,J=6.8Hz,12H).
LC-MS(ESI):Calculated for(M+H)986.51,Found 987.1.
实施例34氨基脂质化合物2061的合成
根据一般合成方法,将化合物2061-A5替换383-D,按照实施例1第四步方法合成氨基脂质化合物2061,其中2061-A5(1.87g,1.99mmol),3-二乙氨基-1-丙醇(1.23g,11.94mmol),得到0.942g氨基脂质化合物2061,收率53.29%,纯度94.25%。
1H-NMR(600MHz,CDCl3)δ4.70-4.63(m,1H),4.48(t,J=5.2Hz,2H),4.22(t,J=5.8Hz,2H),4.07(t,J=6.2Hz,4H),3.57(dt,J=9.2,6.7Hz,4H),3.41(dt,J=9.2,6.7Hz,4H),2.65-2.57(m,4H),2.30(ddd,J=15.3,11.8,6.9Hz,14H),1.70-1.54(m,22H),1.38-1.27(m,28H),0.89(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for 888.32,Found(M+H):888.7.
实施例35氨基脂质化合物851的合成
第一步:合成851-A1
反应式:
实验过程:
向100mL圆底烧瓶,依次加入EDCI(2.8g,14.6mmol),DCM(50mL),TEA(1.47g,14.6mmol),摇匀搅拌5min后加入DMAP(0.89g,7.3mmol),BHB(4,4-双(庚氧基)丁醇)(3.09g,10.22mmol),DTN(10-氧代十九烷二酸)(5.00g,14.6mmol),室温下搅拌过夜。加DCM(100mL),水(150mL),搅拌萃取,分液,收集有机相,有机相用50mL饱和氯化钠溶液洗涤后,减压浓缩,得到851-A1粗品8.2g,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=2:1洗脱,得3.36g851-A1,收率52.3%。
第二步:合成851-A2
反应式:
实验过程:
向100mL圆底烧瓶,依次加入EDCI(1.1g,5.74mmol),DCM(30mL),TEA(0.58g,5.74mmol),摇匀搅拌5min后加入DMAP(0.29g,2.39mmol),BPB(4,4-双(戊氧基)丁醇)(1.41g,
5.74mmol),851-A1(3.00g,4.78mmol),室温下搅拌过夜。加DCM(100mL),水(150mL),搅拌萃取,分液,收集有机相,用50mL饱和氯化钠溶液洗涤后,减压浓缩,得到4.8g 851-A2粗品,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得3.42g 851-A2,收率83.6%。
第三步:合成851-A3
反应式:
实验过程:
向250mL单口瓶,加入851-A2(3.00g,3.51mmol),溶于甲醇(30mL),冷却至0℃。搅拌下分批加入硼氢化钠(0.135g,3.51mmol),加料完成后保温反应1h。减压蒸除溶剂,加水(100mL),DCM(100mL),搅拌萃取,收集有机相,有机相用水(50mL)洗涤后,减压浓缩,得到3.1g 851-A3粗品,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得2.86g 851-A3,收率95.1%。
第四步:合成851-A4
反应式:
实验过程:
向50mL单口圆底烧瓶,加入851-A3(2.86g,3.34mmol),溶于DCM(30mL),加入DMAP(122mg,1.00mmol),吡啶(0.66g,8.35mmol),室温搅拌,分批加入对硝苯基氯甲酸酯(1.35g,6.68mmol),继续搅拌1h,加水(150mL),DCM(100mL),搅拌萃取,收集有机相,有机相用水(80mL)洗涤后,减压浓缩,得到5.0g 851-A4粗品,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得3.06g 851-A4,收率89.6%。
第五步:合成氨基脂质化合物851
反应式:
实验过程:
向50mL单口圆底烧瓶,加入851-A4(3.00g,2.93mmol),溶于DCM(30mL),加入DMAP(108mg,0.88mmol),三乙胺(0.88mg,8.8mmol),二甲氨基丙醇(1.81g,17.58mmol),室温下搅拌2天,加水(100mL),DCM(100mL)搅拌萃取,收集有机相,有机相用水(80mL)洗涤后,减
压浓缩,得到3.6g氨基脂质化合物851粗品,粗品经硅胶柱层析,使用乙酸乙酯:正庚烷=1.5:1洗脱,得1.69g氨基脂质化合物851,收率58.3%,纯度97.21%。
1H NMR(600MHz,CDCl3)δ4.66(m,1H),4.47(dd,J=5.3,4.5Hz,2H),4.16(t,J=6.6Hz,2H),4.07(t,J=5.9Hz,4H),3.56(dtd,J=8.8,6.7,2.0Hz,4H),3.40(dt,J=9.2,6.7Hz,4H),2.37-2.33(m,2H),2.27(t,J=7.6Hz,4H),2.22(s,6H),1.87-1.80(m,2H),1.68(dt,J=13.0,7.4Hz,8H),1.62-1.50(m,16H),1.35-1.24(m,44H),0.92-0.85(m,12H).
LC-MS(ESI):Calculated for 986.51,Found(M+H):987.2.
实施例36氨基脂质化合物854的合成
根据一般合成方法,将化合物854-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物854,其中854-A4(2.37g,2.26mmol),3-二甲氨基-1-丙醇(1.40g,13.53mmol),得到1.2g氨基脂质化合物854,收率52.33%,纯度91.41%。
1H NMR(600MHz,CDCl3)δ4.66(s,1H),4.47(t,J=5.2Hz,2H),4.16(t,J=6.6Hz,2H),4.06(t,J=6.2Hz,4H),3.55(dtd,J=8.3,6.7,1.5Hz,4H),3.39(dtd,J=7.4,6.7,0.6Hz,4H),2.39-2.34(m,2H),2.27(t,J=7.6Hz,4H),2.22(s,6H),1.87-1.80(m,2H),1.71-1.63(m,8H),1.62-1.48(m,16H),1.34-1.22(m,48H),0.87(m,12H).
LC-MS(ESI):Calculated for 1014.57,Found(M+H):1015.2.
实施例37氨基脂质化合物856的合成
根据一般合成方法,将化合物856-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物856,其中856-A4(1.5g,1.36mmol),3-二甲氨基-1-丙醇(0.84g,8.13mmol),得到500mg氨基脂质化合物856,收率34.45%,纯度94.85%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.47(t,J=5.0Hz,2H),4.17(t,J=6.6Hz,2H),4.07(t,J=6.0Hz,4H),3.59-3.53(m,4H),3.43-3.36(m,4H),2.38-2.32(m,2H),2.28(t,J=7.6Hz,4H),2.22(s,6H),1.86-1.80(m,2H),1.68(dd,J=18.0,8.4Hz,8H),1.61-1.49(m,16H),1.36-1.24(m,56H),0.88(m,12H).
LC-MS(ESI):Calculated for 1070.67,Found(M+H):1071.4.
实施例38氨基脂质化合物861的合成
根据一般合成方法,将化合物861-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物861,其中861-A4(1.5g,1.51mmol),3-二乙氨基-1-丙醇(1.19g,9.06mmol),得到900mg氨基脂质化合物861,收率60.48%,纯度94.43%。
1H NMR(600MHz,CDCl3)δ4.71-4.63(m,1H),4.48(t,J=5.2Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=6.1Hz,4H),3.57(dt,J=9.2,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),2.54-2.46(m,6H),2.28(t,J=7.6Hz,
4H),1.85-1.77(m,2H),1.74-1.49(m,24H),1.40-1.23(m,40H),1.01(t,J=7.1Hz,6H),0.95-0.83(m,12H).
LC-MS(ESI):Calculated for 986.51,Found(M+H):987.2.
实施例39氨基脂质化合物862的合成
根据一般合成方法,按照实施例35第五步方法合成氨基脂质化合物862,其中851-A4(2.2g,2.15mmol),3-二乙氨基-1-丙醇(1.69g,12.91mmol),得到910mg氨基脂质化合物862,收率41.69%,纯度93.61%。
1H NMR(600MHz,CDCl3)δ4.71-4.62(m,1H),4.48(t,J=4.7Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=5.9Hz,4H),3.57(m,4H),3.41(dt,J=9.0,6.8Hz,4H),2.56-2.45(m,6H),2.33-2.25(m,4H),1.85-1.76(m,2H),1.74-1.49(m,26H),1.39-1.22(m,42H),1.01(t,J=7.1Hz,6H),0.93-0.83(m,12H).
LC-MS(ESI):Calculated for 1014.57,Found(M+H):1015.3.
实施例40氨基脂质化合物863的合成
根据一般合成方法,将化合物863-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物863,其中863-A4(1.81g,1.72mmol),3-二乙氨基-1-丙醇(1.36g,10.34mmol),得到950mg氨基脂质化合物863,收率52.88%,纯度93.08%。
1H NMR(600MHz,CDCl3)δ4.71-4.62(m,1H),4.48(t,J=4.7Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=5.7Hz,4H),3.65-3.51(m,4H),3.41(dt,J=9.0,6.8Hz,4H),2.60-2.44(m,6H),2.28(t,J=7.5Hz,4H),1.83-1.76(m,2H),1.74-1.50(m,26H),1.42-1.19(m,46H),1.01(t,J=7.1Hz,6H),0.89(dt,J=13.7,7.0Hz,12H).
LC-MS(ESI):Calculated for 1042.62,Found(M+H):1043.2.
实施例41氨基脂质化合物864的合成
根据一般合成方法,将化合物864-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物864,其中864-A4(2.81g,2.61mmol),3-二乙氨基-1-丙醇(2.08g,15.63mmol),得到1.2g氨基脂质化合物864,收率42.94%,纯度92.67%。
1H NMR(400MHz,CDCl3)δ4.73-4.60(m,1H),4.48(dd,J=5.1,4.5Hz,2H),4.12(dt,J=11.4,6.3Hz,6H),3.57(dtd,J=8.8,6.7,2.0Hz,4H),3.41(dt,J=9.2,6.7Hz,4H),2.60-2.43(m,6H),2.28(t,J=7.6Hz,4H),1.86-1.77(m,2H),1.74-1.50(m,24H),1.41-1.20(m,52H),1.01(t,J=7.1Hz,6H),0.90(dt,J=13.7,4.4Hz,12H).
LC-MS(ESI):Calculated for 1070.67,Found(M+H):1071.3.
实施例42氨基脂质化合物865的合成
根据一般合成方法,将化合物854-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物865,其中854-A4(1.5g,1.43mmol),3-二乙氨基-1-丙醇(1.12g,8.57mmol),得到0.65g氨基脂质化合物865,收率43.60%,纯度96.53%。
1H NMR(600MHz,CDCl3)δ4.71-4.63(m,1H),4.48(t,J=5.2Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=6.2Hz,4H),3.57(m,4H),3.44-3.36(m,4H),2.51(td,J=7.1,3.4Hz,6H),2.28(t,J=7.6Hz,4H),1.85-1.77(m,2H),1.74-1.50(m,24H),1.41-1.20(m,48H),1.32(m,6H),0.89(td,J=7.0,3.5Hz,12H).
LC-MS(ESI):Calculated for 1042.62,Found(M+H):1043.3
实施例43氨基脂质化合物867的合成
根据一般合成方法,将化合物856-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物867,其中856-A4(2.0g,1.81mmol),3-二乙氨基-1-丙醇(1.42g,10.84mmol),得到0.60g氨基脂质化合物867,收率30.17%,纯度91.94%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.48(dd,J=5.3,4.7Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=6.0Hz,4H),3.57(m,4H),3.41(m,4H),2.55-2.48(m,6H),2.28(t,J=7.6Hz,4H),1.86-1.50(m,28H),1.38-1.22(m,54H),1.01(t,J=7.1Hz,6H),0.91-0.85(m,12H).
LC-MS(ESI):Calculated for 1098.73,Found(M+H):1099.3。
实施例44氨基脂质化合物868的合成
根据一般合成方法,将化合物868-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物868,其中868-A4(1.0g,0.90mmol),3-二乙氨基-1-丙醇(0.71g,5.4mmol),得到84mg氨基脂质化合物868,收率8.49%,纯度92.68%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=6.2Hz,4H),3.56(dt,J=9.1,6.7Hz,4H),3.40(dt,J=9.2,6.7Hz,4H),2.54-2.46(m,6H),2.28(t,J=7.6Hz,4H),1.84-1.77(m,2H),1.73-1.50(m,28H),1.37-1.23(m,52H),1.01(t,J=7.1Hz,6H),0.88(td,J=6.9,1.4Hz,12H).
LC-MS(ESI):Calculated for 1098.73,Found(M+H):1099.4.
实施例45氨基脂质化合物869的合成
根据一般合成方法,将化合物869-A4替换851-A4,按照实施例35第五步方法合成氨基脂质化合物869,其中869-A4(1.25g,1.08mmol),3-二乙氨基-1-丙醇(0.85g,6.48mmol),得到50mg氨基脂质化合物869,收率4.00%,纯度93.28%。
1H NMR(600MHz,CDCl3)δ4.67(m,1H),4.48(t,J=5.3Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=6.2Hz,4H),3.56(dt,J=9.1,6.7Hz,4H),3.40(dt,J=9.2,6.7Hz,4H),2.54-2.46(m,6H),2.28(t,J=7.6Hz,4H),1.84-1.77(m,2H),1.73-1.50(m,28H),1.37-1.23(m,60H),1.01(t,J=7.1Hz,6H),0.88(td,J=6.9,1.4Hz,12H).
LC-MS(ESI):Calculated for 1154.84,Found(M+H):1155.3.
实施例46氨基脂质化合物434的合成
根据一般合成方法,将化合物434-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物434,其中434-A4(2.0g,1.74mmol),3-二乙氨基-1-丙醇(1.37g,10.46mmol),得到1.1g氨基脂质化合物434,收率55.51%,纯度95.69%。
1H NMR(600MHz,CDCl3)δ4.70-4.62(m,1H),4.48(t,J=5.2Hz,2H),4.17(t,J=6.5Hz,2H),4.08(t,J=6.2Hz,4H),3.57(m,4H),3.44-3.36(m,6H),2.49-2.44(m,6H),2.28(t,J=7.6Hz,4H),1.73-1.48(m,22H),1.32(m,62H),0.95(m,6H),0.89(td,J=7.0,3.5Hz,12H).
LC-MS(ESI):Calculated for 1038.98,Found(M+H):1039.4.
实施例47氨基脂质化合物436的合成
根据一般合成方法,将化合物436-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物436,其中436-A4(2.0g,2.14mmol),3-二乙氨基-1-丙醇(1.68g,12.84mmol),得到0.79g氨基脂质化合物436,收率39.6%,纯度90.91%。
1H NMR(600MHz,CDCl3)δ4.70-4.62(m,1H),4.58-4.53(t,J=7.0Hz,1H),4.48(t,J=5.2Hz,2H),4.08(t,J=6.2Hz,4H),3.95(q,J=7.1Hz,2H),3.57(m,4H),3.44-3.36(m,6H),2.49-2.44(m,6H),2.28(t,J=7.6Hz,4H),1.73-1.48(m,18H),1.32(m,41H),0.95(m,6H),0.89(t,J=7.0,6H).
LC-MS(ESI):Calculated for 928.39,Found(M+H):929.1
实施例48氨基脂质化合物437的合成
根据一般合成方法,将化合物437-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物437,其中437-A4(1.3g,1.24mmol),3-二乙氨基-1-丙醇(0.98g,7.44mmol),得到0.6g氨基脂质化合物437,收率46.7%,纯度94.75%。
1H NMR(600MHz,CDCl3)δ4.70-4.62(m,1H),4.58-4.53(t,J=7.0Hz,1H),4.48(t,J=5.2Hz,2H),4.08
(t,J=6.2Hz,4H),3.95(q,J=7.1Hz,2H),3.57(m,4H),3.44-3.36(m,6H),3.25-3.16(t,J=6.7,2H),2.98-2.89(t,J=7.5,2H),2.49-2.44(m,6H),2.28(t,J=7.6Hz,4H),1.73-1.48(m,18H),1.32(m,46H),1.05(m,3H),0.89(t,J=7.0,12H).
LC-MS(ESI):Calculated for 1036.57,Found(M+H):1037.3
实施例49氨基脂质化合物438的合成
根据一般合成方法,将化合物438-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物438,其中438-A4(1.6g,1.72mmol),3-二乙氨基-1-丙醇(1.35g,10.32mmol),得到0.82g氨基脂质化合物438,收率51.6%,纯度92.59%。
1H NMR(600MHz,CDCl3)δ5.53-5.51(dt,J=11.0,7.8Hz,3H),5.48-5.46(dt,J=10.7,7.4Hz,3H),4.71-4.63(m,1H),4.58-4.53(t,J=7.0Hz,1H),4.48(t,J=5.2Hz,2H),4.15(d,J=9.66Hz,2H),4.08(t,J=6.2Hz,4H),3.57(d,J=7.8Hz,4H),3.44-3.36(m,6H),3.25-3.16(m,6H),2.49-2.44(q,J=7.6Hz,6H),2.28(m,6H),1.73-1.48(m,20H),1.32(m,16H),0.96(m,3H),0.89(t,J=7.0,12H).
LC-MS(ESI):Calculated for 922.34,Found(M+H):923.1
实施例50氨基脂质化合物439的合成
根据一般合成方法,将化合物439-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物439,其中439-A4(1.2g,1.15mmol),3-二乙氨基-1-丙醇(0.91g,6.90mmol),得到0.37g氨基脂质化合物439,收率31.6%,纯度95.92%。
1H NMR(600MHz,CDCl3)δ4.86(t,J=4.9Hz,1H),4.71(m,1H),4.26(s,4H),4.24-4.16(m,2H),4.16-4.04(m,4H),3.40(t,J=6.6Hz,2H),3.37(s,3H),2.58-2.50(m,6H),2.32(td,J=7.6,1.9Hz,4H),2.25(t,J=7.2Hz,4H),1.76(t,J=7.8Hz,4H),1.70-1.51(m,20H),1.44-1.26(m,46H),1.05(t,J=7.1Hz,6H),0.92(t,J=6.8Hz,6H).
LC-MS(ESI):Calculated for 1032.58,Found(M+H):1033.3
实施例51氨基脂质化合物440的合成
根据一般合成方法,将化合物440-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物440,其中440-A4(1.0g,1.08mmol),3-二乙氨基-1-丙醇(0.85g,6.48mmol),得到0.52g氨基脂质
化合物440,收率52.5%,纯度92.61%。
1H NMR(600MHz,CDCl3)δ4.70(m,1H),4.51(t,J=5.3Hz,1H),4.21(t,J=6.6Hz,2H),4.10(dt,J=13.5,6.5Hz,4H),3.60(dt,J=9.3,6.7Hz,2H),3.48-3.40(m,2H),3.35(t,J=6.6Hz,4H),2.43(t,J=7.8Hz,2H),2.31(t,J=7.8Hz,4H),2.28(m,4H),1.75-1.54(m,24H),1.37-1.25(m,38H),1.05(t,J=7.1Hz,6H),0.92(t,J=6.8Hz,9H).
LC-MS(ESI):Calculated for 914.40,Found(M+H):914.6。
实施例52氨基脂质化合物441的合成
根据一般合成方法,将化合物441-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物441,其中441-A4(1.8g,1.74mmol),3-二乙氨基-1-丙醇(1.37g,10.44mmol),得到0.6g氨基脂质化合物441,收率33.2%,纯度94.67%。
1H NMR(600MHz,CDCl3)δ4.70-4.62(m,1H),4.58-4.53(t,J=7.0Hz,1H),4.48(t,J=5.2Hz,2H),4.08(t,J=6.2Hz,4H),3.95(q,J=7.1Hz,2H),3.57(m,4H),3.44-3.36(m,6H),2.49-2.44(m,6H),2.28(t,J=7.6Hz,4H),1.73-1.48(m,20H),1.32(m,50H),0.95(m,6H),0.89(t,J=7.0,9H).
LC-MS(ESI):Calculated for 1026.58,Found(M+H):1027.3
实施例53氨基脂质化合物442的合成
根据一般合成方法,将化合物442-A4替换383-D,按照实施例1第四步方法合成氨基脂质化合物442,其中442-A4(1.3g,1.19mmol),3-二乙氨基-1-丙醇(0.94g,7.14mmol),得到0.29g氨基脂质化合物442,收率22.8%,纯度94.29%。
1H NMR(600MHz,CDCl3)δ4.70-4.62(m,1H),4.58-4.53(t,J=7.0Hz,1H),4.48(t,J=5.2Hz,2H),4.08(t,J=6.2Hz,4H),3.97-3.94(m,2H),3.66-3.62(t,J=6.75Hz,2H),3.44-3.36(m,6H),2.49-2.44(m,6H),2.28(t,J=7.6Hz,6H),1.73-1.48(m,16H),1.32(m,56H),1.25(d,J=6.17Hz,6H),0.95(m,6H),0.89(t,J=7.0,9H).
LC-MS(ESI):Calculated for 1081.70,Found(M+H):1082.3
实施例54氨基脂质化合物393的合成
第一步:合成DLSGN-T
反应式:
实验过程:
向250mL单口烧瓶,依次加入EDCI(8.40g,43.80mmol),DMAP(0.64g,5.26mmol),三乙胺(4.44g,43.80mmol),溶于DCM(60mL),室温搅拌,再加入DTN(6.00g,17.5mmol),BSB(8.66g,31.54mmol),室温反应过夜,加入饱和氯化铵(100mL)水溶液淬灭,分相,收集有机相,水相用DCM(100mL)萃取二次,合并有机相,有机相用饱和氯化钠溶液100mL洗涤后,蒸除溶剂,得到15.9g DFSGN-T粗品,粗品经硅胶柱层析,用乙酸乙酯:正庚烷=1:10洗脱,得到13.6g DSLGN-T。
第二步:合成393-A1
反应式:
实验过程:
向100mL单口烧瓶,依次加入DSLGN-T(4g,4.71mmol),DCM(20mL),甲醇(20mL),醋酸铵(3.63g,47.1mmol)室温下搅拌1h,加氰基硼氢化钠(0.89g,14.13mmol),室温过夜,减压蒸除溶剂,加水(50mL),使用DCM(50mL×2)萃取,收集有机相,减压蒸除溶剂,得到4.1g 393-A1粗品,粗品经硅胶柱层析,用正己烷:乙酸乙酯=5:1洗脱,得2.46g 393-A1,收率61%。
第三步:合成393-A2
反应式:
实验过程:
向250mL单口瓶中,加入对硝基苯基氯甲酸酯(5.53g,27.43mmol),DCM(15mL),再将DMAP(0.28g,2.29mmol),3-二乙氨基-1-丙醇(3g,22.86mmol),吡啶(2.17g,27.43mmol)溶于DCM(15mL)中,缓慢滴加到反应体系中,滴加完毕后,反应2h,加入50mL水淬灭反应,收集有机相,水相再用50mL DCM萃取一次,合并有机相,减压浓缩,得到粗品,粗品经硅胶柱层析,
经正己烷:乙酸乙酯=20:1纯化,得到6.48g 393-A1,收率95.6%。
第四步:合成氨基脂质化合物393
反应式:
实验过程:
向100mL单口瓶中加入383-A1(1g,1.17mmol),DCM(10mL),DMAP(72mg,0.59mmol),吡啶(0.28g,3.51mmol)及393-A2(1.04g,3.51mmol),室温反应过夜,加水(20mL),使用DCM(20mL×2)萃取,收集有机相,减压浓缩,得到氨基脂质化合物393粗品,粗品经硅胶柱层析,用正己烷:乙酸乙酯=3:1洗脱,得到700mg氨基脂质化合物393,纯度94.11%,收率59%。
1H NMR(600MHz,CDCl3)δ4.48(t,J=5.2Hz,2H),4.07(t,J=6.1Hz,6H),3.56(dt,J=9.2,6.7Hz,5H),3.40(dt,J=9.2,6.7Hz,4H),2.56-2.47(m,6H),2.28(t,J=7.6Hz,4H),1.76(m,2H),1.72-1.63(m,8H),1.57(m,12H),1.45(m,2H),1.38-1.21(m,46H),1.02(t,J=7.1Hz,6H),0.89(t,J=6.9Hz,12H).
LC-MS(ESI):Calculated for(M+H)1013.87,Found 1014.3.
实施例55氨基脂质化合物394的合成
实验过程:
向100mL单口瓶中加入三光气(214mg,0.73mmol),DCM(10mL),-10℃下滴加3-二乙氨基丙胺(190mg,1.46mmol)的DCM(5mL)溶液,室温下搅1h,滴加三乙胺(295mg,2.92mmol),搅拌10min,减压蒸除溶剂,得到白色固体,加DCM(10mL),393-A1(1.2g,1.4mmol),搅拌过夜,加水(20mL)搅拌,分液,收集有机相,水相用DCM(20mL)萃取一次,合并有机相,减压浓缩,得氨基脂质化合物394粗品,粗品经硅胶柱层析,用乙酸乙酯:甲醇=30:1洗脱,得到1.18g氨基脂质化合物394,收率83.16%。
1H NMR(600MHz,CDCl3)δ4.48(t,J=5.3Hz,2H),4.07(t,J=6.2Hz,4H),3.66-3.59(m,1H),3.57(dt,J=9.3,6.7Hz,4H),3.41(dt,J=9.3,6.7Hz,4H),3.38-3.32(m,2H),3.11-3.07(m,4H),3.03(t,J=6.4Hz,2H),2.28(t,J=7.6Hz,4H),2.02-1.94(m,2H),1.73-1.63(m,8H),1.63-1.51(m,12H),1.43(m,2H),1.38-1.23(m,52H),0.89(t,J=6.8Hz,12H).
LC-MS(ESI):Calculated for(M+H)1012.89,Found 1013.6
试验例1.包封荧光素酶mRNA(Fluc mRNA)的脂质纳米颗粒的制备
(1)配料:
将指定量的Fluc mRNA原液、0.2M醋酸钠缓冲液、DEPC水加入容器中,混匀制得水相。
分别将本公开的氨基脂质化合物、辅助脂质(DSPC)、结构脂质(胆固醇)和PEG-脂质溶于无水乙醇,制备各自的溶液,浓度依次为20mg/mL、10mg/mL、20mg/mL和25mg/mL。按摩尔比,Lipid:DSPC:CHO-HP:M-DMG-2000为48:10:40.5:1.5,分别移取前述4种溶液,混匀,制得醇相。
(2)包封:使用微流控制备仪(MPE-L2)以水相:醇相=9mL/min:3mL/min流速分别吸入到水相、醇相注射器中,以水相:醇相=12ml/min:4ml/min流速进行包封,获得包封mRNA的脂质纳米
颗粒(mRNA-LNP)。
(3)透析:将步骤(2)的产物装载于透析袋中,并置于Tris Buffer-8%(m/V)蔗糖溶液中进行置换,以除去残留的乙醇、未组装的脂质等成分。在室温避光下和磁力搅拌下透析2小时(每隔1小时更换一次透析液)。
(4)使步骤(3)的产物通过0.22μm的微孔滤膜以除菌,然后分装。
制备得到包封Fluc mRNA的多种脂质纳米颗粒制剂(LNP制剂),其中,各种LNP制剂中包含的氨基脂质化合物各不相同,每种LNP制剂中的Fluc mRNA的浓度为0.2μg/μL,Fluc mRNA:Lipid的质量比为1:10,粒径为80nm~130nm,包封率为85%以上。
试验例2.脂质纳米颗粒的体内递送性能评价
动物准备:选取6~8周龄的雌性BALB/c小鼠,在SPF级饲养室中饲养。动物试验严格按照国家健康机构的指南以及动物伦理要求进行。
体内递送:受试LNP制剂注射前,轻轻反复颠倒LNP制剂,使制剂样品完全混匀。用1ml的胰岛素注射器吸取对应量的LNP制剂,采用尾静脉注射(IV)的方式注射LNP制剂,每种LNP制剂3只小鼠重复,每只小鼠注射70μL相应的由试验例1制备得到的包封荧光素酶mRNA(Fluc mRNA)的LNP制剂;
小鼠在注射LNP制剂6h之后,注射200μL的D-Luciferin荧光素酶显影底物(货号:122799;厂家:Perkin Elmer),底物注射完之后,采用异氟烷吸入麻醉的方式麻醉小鼠,并记录荧光素酶显影底物的注射时间,底物注射10min之后,将动物仰卧位放置,在IVIS活体成像系统下观察活体动物体内以及各器官luciferase的信号分布及表达强度。
使用代表性氨基脂质化合物包封的荧光素酶mRNA(Fluc mRNA)的脂质纳米颗粒的包封率及其所诱导的荧光表达强度见表4,其中,含SM-102、1001或ALC-0315的LNP制剂作为对照LNP制剂。对照LNP制剂的制备方法与试验例1的LNP制剂的制备方法大致相同,其区别在于,制备对照LNP制剂时将本公开的氨基脂质化合物替换为SM-102、1001或ALC-0315。
表4
试验例3.脂质纳米颗粒的体内安全性评价
按照试验例1所示方法,将荧光素酶mRNA(Fluc mRNA)替换为人促红细胞生成素mRNA(hEPO mRNA),制备得到包封人促红细胞生成素mRNA(hEPO mRNA)的多种脂质纳米颗粒制剂(LNP制剂),其中,每种LNP制剂中人促红细胞生成素mRNA(hEPO mRNA)的浓度为0.5μg/μL,hEPO mRNA:Lipid的质量比为1:10,粒径为90nm~130nm,包封率为90%以上;含MC3的LNP制剂中的MC3为
动物准备:选取6-8周龄,雌性SD大鼠,在SPF级饲养室中饲养。动物试验严格按照国家健康机构的指南以及动物伦理要求进行。
体内递送:受试LNP制剂注射前,轻轻反复颠倒LNP制剂,使制剂样品完全混匀。2mL注射器吸取对应量的制剂样品,采用尾静脉注射(IV)的方式注射LNP制剂,每种制剂4只大鼠重复,每只大鼠注射(1200μL-hEPO 3mpk)包封人促红细胞生成素mRNA(hEPO mRNA)的LNP制剂。采用Tris缓冲溶液作为空白对照。
血清获取:采集注射后12h的大鼠血液样本,并将其置于不含抗凝剂的试管内;室温下自然凝集30min~60min,待血液凝固后以3500rpm的速度离心10min,得到上清液即为血清。
谷丙转氨酶的检测按照试剂盒说明书(南京建成生物研究所,货号为C009-2-1)进行,并使用试剂盒中提供的标准品作标准曲线。实验中使用D-PBS,购买自生工生物工程(上海)股份有限公司,货号为E607009-0600。
小鼠血清中谷丙转氨酶(ALT)酶活检测方法具体如下:
ALT标准曲线的制备:
(1)酶促反应:依次加入0、2、4、6、8、10μL体积的2μmol/mL丙酮酸钠标准液至5μL的0.1mol/L磷酸缓冲液中,并用ALT基质液(谷丙转氨酶基质液)将体积补齐至25μl。用移液枪反复吸打混匀。
(2)加成反应:向(1)中所有反应孔中,加入20μL的2,4-二硝基苯肼液,吸打混匀后置于37℃培养箱中反应20min。
(3)显色:向(2)中所有反应孔中加入200μL的0.4mol/L NaOH溶液终止反应,吸打混匀后室温下孵育15min。使用酶标仪测定各孔在510nm处的OD值。
(4)标准曲线的数据处理:各孔所测得的OD值减去丙酮酸钠为0μl孔的OD值获得各孔对应的绝对OD值,对应ALT卡门式单位依次为0、28、57、97、150、200。以绝对OD值为横坐标,相应的卡门式单位为纵坐标,获得标准曲线。
血清样本中ALT酶活检测:
(1)试剂准备:将ALT基质液放在37℃培养箱中预温。
(2)酶促反应:吸取5μL稀释后的血清加至96孔板,再向对应样本孔中加入20μL基质液,并反复吸打混匀,避免产生气泡,置于37℃培养箱中反应30min。
(3)加成反应:向(2)中所有反应孔中加入20μL的2,4-二硝基苯肼,吸打混匀后37℃培养箱中反应20min。
(4)显色:向(3)中所有反应孔中加入200μL 0.4mol/L NaOH溶液终止反应,吸打混匀后室温下孵育15min。使用酶标仪读取波长510nm下各孔的OD值。
(5)血清ALT酶活计算:样本孔所得OD值减去对照孔(未发生生化反应样品孔)OD值得到对应样品孔的绝对OD值。将其代入标准曲线公式计算对应血清样品的ALT酶活(卡门氏单位),
将卡门氏单位换算成活力单位:1卡门单位=0.482U/L)。
小鼠血清中谷草转氨酶(AST)酶活检测方法具体如下:
AST标准曲线的制备:
(1)酶促反应:依次加入0、2、4、6、8μL体积的2μmol/mL丙酮酸钠标准液至5μL的0.1mol/L磷酸缓冲液中,并用AST基质液(谷草转氨酶基质液)将体积补齐至25μL。用移液枪反复吸打混匀。
(2)加成反应:向(1)中所有反应孔中,加入20μL的2,4-二硝基苯肼液,吸打混匀后置于37℃培养箱中反应20min。
(3)显色:向(2)中所有反应孔中加入200μL的0.4mol/L NaOH溶液终止反应,吸打混匀后室温下孵育15min。使用酶标仪测定各孔在510nm处的OD值。
(4)标准曲线的数据处理:各孔所测得的OD值减去丙酮酸钠为0μL孔的OD值获得各孔对应的绝对OD值,对应AST卡门式单位依次为0、24、61、114、190。以绝对OD值为横坐标,相应的卡门式单位为纵坐标,获得标准曲线。
血清样本中AST酶活检测:
(1)试剂准备:将AST基质液放在37℃培养箱中预温。
(2)酶促反应:吸取5μL稀释后的血清加至96孔板,再向对应样本孔中加入20μL基质液,并反复吸打混匀,避免产生气泡,置于37℃培养箱中反应30min。
(3)加成反应:向(2)中所有反应孔中加入20μL的2,4-二硝基苯肼,吸打混匀后37℃培养箱中反应20min。
(4)显色:向(3)中所有反应孔中加入200μL 0.4mol/L NaOH溶液终止反应,吸打混匀后室温下孵育15min。使用酶标仪读取波长510nm下各孔的OD值。
(5)血清AST酶活计算:样本孔所得OD值减去对照孔(未发生生化反应样品孔)OD值得到对应样品孔的绝对OD值。将其代入标准曲线公式计算对应血清样品的AST酶活(卡门氏单位),将卡门氏单位换算成活力单位:1卡门单位=0.482U/L)。
使用代表性氨基脂质化合物包封的含人促红细胞生成素(hEPO)mRNA的脂质纳米颗粒的体内递送及安全性评价结果见图1~图5,其中Tris、ALC-0315和MC3为对照,“Tris”是指只注射Tris缓冲液溶液的对照组。
从图1~图4可以看出,与已上市的ALC-0315和MC3相比,代表性氨基脂质化合物表现出更低的ALT酶活和AST酶活。
试验例4.脂质纳米颗粒对不同组织器官的免疫细胞群的递送效率评价
对C57BL/6小鼠(每组3只),每只静脉注射包封有eGFP的mRNA-LNP,12小时后解剖小鼠,取脾和外周血,制备各组织器官的单细胞悬液,经Fc阻断抗体封闭,以及流式荧光抗体表面染色后,进行流式检测,分析各免疫细胞群中eGFP的表达水平,从而确认含不同氨基脂质化合物的脂质纳米颗粒对不同组织器官的免疫细胞群的递送效率。
试验结果见图6~图7,图6和图7中的“Blank”是指注射100μL Tris缓冲液的对照组。由图6~图7可知,含有氨基脂质化合物382、388、2039、2041、2042、2043和2045的脂质纳米颗粒对不同免疫细胞具有不同的递送偏好性。
除本公开中描述的那些外,根据前述描述,对本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。
Claims (106)
- 具有式(II-I)的结构的氨基脂质化合物,
或其药学上可接受的盐,或其立体异构体,其中,A1、A2和A3为以下情形之一:(1)当连接A1和A2的虚线以及连接A1和A3的虚线为不存在时,A1为H、C1‐C5烃基或C1‐C5杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基或键;(2)当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基或键,A1和A2连同它们共同连接的氮原子一起形成含N的杂环;(3)当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为H、C1‐C5烃基或C1‐C5杂烃基,A3为C1‐C5亚烃基,A1和A3连同它们共同连接的氮原子一起形成含N的杂环;(4)当连接A1和A2的虚线以及连接A1和A3的虚线为键时,A1为C1‐C5亚烃基或C1‐C5亚杂烃基,A2为C1‐C5亚烃基或C1‐C5亚杂烃基,A3为C1‐C5亚烃基,A1、A2和A3连同它们共同连接的氮原子一起形成含N的螺环杂环、稠合杂环或桥环杂环;A4为C1‐C5亚烃基或键;A5、A6、A7、A8和A12各自独立地为C1‐C18亚烃基、C1‐C18亚杂烃基或键;Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;Y1为-Z3C(=O)Z4-、-N(R5)-、-Z3C(=S)Z4-、-OS(=O)2O-、-OS(=O)O-、-OS(=O)2NH-、-NHS(=O)2NH-、-NHS(=O)2-、-S(=O)2NH-、-S(=O)2O-、-OS(=O)2-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-O-、-S-、-NHS(=O)2O-、-NHP(=O)O-、-OP(=O)NH-、-NHP(=O)(OH)O-、-OP(=O)(OH)NH-、-OC(=O)S-或-SC(=O)O-;X为C或N;R1为H、C1‐C24的烃基、C1‐C24的杂烃基、Z6R8、-C(R6)(OA13Z8R9)2、-C(R6)(SA13Z8R9)2或-C(R6)(SA13Z8R9)(OA13Z8R9);R2为H、C1‐C24的烃基、C1‐C24的杂烃基、Z7R10、-C(R6)(OA14Z9R11)2、-C(R6)(SA14Z9R11)2或-C(R6)(SA14Z9R11)(OA14Z9R11);Z3和Z4各自独立地为-O-、-N(R6)-、‐S‐或键;Z6和Z7各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-或-NHS(=O)2O-;R5为-C(=O)A9Z5A10、-C(=O)A11、H或C1‐C8烃基;Z5为-O-或‐S‐;Z8和Z9各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-S-、-C(=O)S-、-SC(=O)-、-C(=O)N(R6)-、-N(R6)C(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-SC(=O)N(R6)-、-N(R6)C(=O)S-、-N(C(=O)A9OA10)-、-N(C(=O)A9SA10)-、-N(C(=O)A11)、-N(A9OA10)-、-N(A9SA10)-、-N(A11)-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-、-OP(=O)(H)O-、-OS(=O)2NH-、-NHS(=O)2O-或键;R6各自独立地为H或C1‐C8烃基;R8和R10各自独立地为H、C1‐C24烃基或含有O或者S的C1‐C24杂烃基;R9和R11各自独立地为C1‐C24烃基或含有O或者S的C1‐C24杂烃基;A9为C1‐C8亚烃基或键;A10和A11各自独立地为C1‐C8烃基;A13和A14各自独立地为C1‐C8亚烃基、C1‐C8亚杂烃基或键;优选地,所述烃基为烷基、烯基或炔基;优选地,所述亚烃基为亚烷基、亚烯基或亚炔基;优选地,所述杂烃基为杂烷基、杂烯基或杂炔基;优选地,所述亚杂烃基为亚杂烷基、亚杂烯基或亚杂炔基。 - 根据权利要求1所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,具有式(II-VIa)所示的结构:
- 根据权利要求1所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,具有式(II-IVa)所示的结构:
- 根据权利要求1所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,具有式(II-VIa-c)所示的结构:
- 根据权利要求1和2中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-Z3C(=O)Z4-或-N(R5)-。
- 根据权利要求1、2和5中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(R6)C(=O)O-、-OC(=O)N(R6)-或-OC(=O)O-。
- 根据权利要求1、2、5和6中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)O-。
- 根据权利要求1、2、5和6中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(H)C(=O)O-。
- 根据权利要求1、2、5和6中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)N(H)-。
- 根据权利要求1、2和5中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(R5)-。
- 根据权利要求1、2、5和10中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(C(=O)A9OA10)-。
- 根据权利要求1、2、5和10中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(C(=O)A10)-。
- 根据权利要求1、2、5至12中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2各自独立地为-C(=O)O-或-OC(=O)-。
- 根据权利要求1、2、5至13中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-C(=O)O-。
- 根据权利要求1、2、5至13中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-OC(=O)-。
- 根据权利要求1、2、5至13中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z2为-C(=O)O-。
- 根据权利要求1、2、5至13中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z2为-OC(=O)-。
- 根据权利要求1、2、5至14、16中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2为-C(=O)O-。
- 根据权利要求1、2、5至13、15和17中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2为-OC(=O)-。
- 根据权利要求1、2、5至14和17中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-C(=O)O-,Z2为-OC(=O)-。
- 根据权利要求1、2、5至20中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(R6)(OR9)2。
- 根据权利要求1、2、5至21中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(H)(OR9)2。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为-C(R6)(OR11)2。
- 根据权利要求1、2、5至23中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为-C(H)(OR11)2。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为Z7R10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为-C(=O)OR10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为-OC(=O)R10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为-OR10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为-N(H)C(=O)R10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为-C(=O)N(R6)R10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R2为被取代的C1‐C24烷基。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(R6)(OR9)2,R2为-C(R6)(OR11)2。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(H)(OR9)2,R2为-C(=O)OR10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(H)(OR9)2,R2为-OC(=O)R10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(H)(OR9)2,R2为-OR10。
- 根据权利要求1、2、5至22中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R1为-C(H)(OR9)2,R2为被羟基取代的C1‐C24烷基。
- 根据权利要求1、2、5至7、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为-C(=O)OR10。
- 根据权利要求1、2、5至7、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为-OC(=O)R10。
- 根据权利要求1、2、5至7、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为-OR10。
- 根据权利要求1、2、5至7、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)O-,R1为-C(H)(OR9)2,R2为被羟基取代的C1‐C24烷基。
- 根据权利要求1、2、5至7、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)O-,A7和A8为未被取代的C1-C5亚烷基,R1为-C(H)(OR9)2,R2为-C(=O)OR10。
- 根据权利要求1、2、5至7、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)O-,A7和A8为未被取代的C1-C5亚烷基,R1为-C(H)(OR9)2,R2为-OC(=O)R10。
- 根据权利要求1、2、5、6、8、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(H)C(=O)O-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
- 根据权利要求1、2、5、6、9、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-OC(=O)N(H)-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
- 根据权利要求1、2、5、6、11、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(C(=O)A9OA10)-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
- 根据权利要求1、2、5、6、12、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(C(=O)A10)-,R1为-C(H)(OR9)2,R2为-C(H)(OR11)2。
- 根据权利要求1、2、5、6、12、13至37中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Y1为-N(C(=O)A10)-,R1为-C(H)(OR9)2,R2为被羟基取代的C1‐C24烷基。
- 根据权利要求1、2、5至48中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A9为C1‐C5亚烷基。
- 根据权利要求1、2、5至49中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A10为C1‐C8烷基。
- 根据权利要求1、2、5至50中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R10为C1‐C24烷基、C2‐C24烯基或C2‐C24炔基。
- 根据权利要求1、2、5至51中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R10为直链的C2‐C8烷基。
- 根据权利要求1、2、5至51中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R10为支化的C7‐C18烷基。
- 根据权利要求1、2、5至51中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R10为C5‐C12烯基。
- 根据权利要求1、2、5至51中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R10为C5‐C12炔基。
- 根据权利要求1、2、5至55中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R9为C9‐C11炔基,例如C10炔基。
- 根据权利要求1、2、5至56中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R14为C1‐C5烷基。
- 根据权利要求1、2、5至56中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:R14为具有1个双键的C4‐C8烯基。
- 根据权利要求1和3中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A12为C2-C3亚烷基。
- 根据权利要求1和3中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A12为C1-C3亚烷基(例如C1亚烷基),A5和A6各自独立地为C3-C9亚烷基(例如C4- C9亚烷基、C5-C9亚烷基、C6亚烷基、C7亚烷基、C8亚烷基)。
- 根据权利要求1、3和4中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2各自独立地为-C(=O)O-、-OC(=O)-、-O-、‐C(=O)‐、-C(=O)N(R6)-、-N(R6)C(=O)-、-N(R6)C(=O)O-、-OC(=O)N(R6)-、-N(R6)C(=O)N(R6)-、-C(=O)S-、-SC(=O)-、-OC(=O)O-、-OC(=O)S-、-SC(=O)O-、-SC(=O)S-、-OS(=O)O-、-OS(=O)2O-、-OP(=O)O-、-OP(=O)(OH)O-或-OP(=O)(H)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-C(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-OC(=O)-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-OC(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-N(H)C(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-OC(=O)N(H)-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z2为-C(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z2为-OC(=O)-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z2为-OC(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z2为-N(H)C(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z2为-OC(=O)N(H)-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2为-C(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2为-OC(=O)-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2为-OC(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2为-N(H)C(=O)O-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1和Z2为-OC(=O)N(H)-。
- 根据权利要求1、3、4和59至61中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:Z1为-C(=O)O-,Z2为-OC(=O)-。
- 根据权利要求1至77中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A4为键。
- 根据权利要求1至78中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A5和A6各自独立地为C3-C10亚烷基。
- 根据权利要求1至79中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A7和A8各自独立地为C2-C4亚烷基或C5-C10亚烷基。
- 根据权利要求1至80中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:各R9各自独立地为C3-C9烷基。
- 根据权利要求1至80中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:各R9各自独立地为C5‐C8烯基。
- 根据权利要求1至82中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:各R11各自独立地为C3-C9烷基。
- 根据权利要求1至82中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:各R11各自独立地为C5‐C8烯基。
- 根据权利要求1至84中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:连接A1和A2的虚线以及连接A1和A3的虚线为不存在。
- 根据权利要求1至84中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在。
- 根据权利要求1至84中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在。
- 根据权利要求1至87中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A1和A2各自独立地为C1-C5烷基,或C1-C5亚烷基。
- 根据权利要求1至85和88中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A1和A2各自独立地为C1-C3烷基。
- 根据权利要求89中所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A1和A2各自独立地为C1-C2烷基。
- 根据权利要求88中所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A2为C1-C3烷基。
- 根据权利要求88中所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A2为C1-C2烷基。
- 根据权利要求1至92中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A3为C1-C5亚烷基。
- 根据权利要求1至93中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:A3为C2-C4亚烷基。
- 根据权利要求1至84、86、88、93和94中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:当连接A1和A2的虚线为键以及连接A1和A3的虚线为不存在时,A1和A2连同它们共同连接的氮原子一起形成含N的四元、五元或六元的杂环。
- 根据权利要求1至84、87、88、91至94中任一项所述的氨基脂质化合物,或其药学上可接受的盐,或其立体异构体,其中:当连接A1和A3的虚线为键以及连接A1和A2的虚线为不存在时,A1和A3连同它们共同连接的氮原子一起形成含N的四元、五元或六元的杂环。
- 根据权利要求1至96中任一项所述的氨基脂质化合物,所述的氨基脂质化合物具有以下所示的结构之一:
- 脂质纳米颗粒,其中含有权利要求1至97中任一项所述的氨基脂质化合物。
- 根据权利要求98所述的脂质纳米颗粒,其还含有生物活性成分;优选地,所述生物活性成分为核酸。
- 药物组合物,其含有权利要求1至97中任一项所述的氨基脂质化合物,或权利要求98和99中任一项所述的脂质纳米颗粒,以及药学上可接受的载体、稀释剂或赋形剂。
- 权利要求1至97中任一项所述的氨基脂质化合物用于制备活性成分的递送载体的用途;优选地,所述活性成分为药物活性成分,优选为核酸。
- 权利要求1至97中任一项所述的氨基脂质化合物、权利要求98和99中任一项所述的脂质纳米颗粒或权利要求100所述的药物组合物在制备药物中的用途。
- 根据权利要求101所述的用途,其中所述药物用于疾病的治疗和/或预防;优选地,所述药物用于基因治疗、蛋白质替代疗法、反义治疗、通过干扰RNA进行的治疗或基因疫苗接种。
- 根据权利要求101和102中任一项所述的用途,其中所述药物为核酸药物。
- 权利要求1至97中任一项所述的氨基脂质化合物、权利要求98和99中任一项所述的脂质纳米颗粒或权利要求100所述的药物组合物在制备用于核酸转移的药物中的用途。
- 根据权利要求105所述的用途,其中所述核酸选自RNA、反义寡核苷酸、DNA;优选地,所述RNA选自信使RNA(mRNA)、核糖体RNA(rRNA)、微RNA(miRNA)、转移RNA(tRNA)、小的抑制RNA(siRNA)、小的核RNA(snRNA)、小发夹RNA(shRNA)、单链向导RNA(sgRNA)、cas9 mRNA或其混合物;优选地,所述DNA为质粒。
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