Cationic lipid and preparation method thereof

Abstract

The present invention provides cationic lipids and lipid nanoparticle formulations comprising these lipids, alone or in combination with other lipids. These lipid nanoparticles can be formulated with nucleic acids to facilitate their intracellular delivery in vitro and in therapeutic applications. The invention also provides a chemical synthesis method of the lipids.

Description

TECHNICAL FIELD

[0001] The present invention provides novel cationic lipids and compositions, such as lipid nanoparticles comprising such cationic lipids, which are useful for intracellular delivery of therapeutic agents. These lipid nanoparticles can be formulated with nucleic acids to facilitate their intracellular delivery in therapeutic applications in vitro and in vivo. The present invention also provides methods of chemical synthesis of the cationic lipids. BACKGROUND

[0002] The research and development of therapeutic nucleic acids, including circular RNA (cRNA), small interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides, messenger RNA (mRNA) as drugs, has stimulated exponential growth over the past decade. Nucleic acid-based drugs, including large nucleic acid molecules, must be delivered into the appropriate cellular compartment to exert their effects.

[0003] In gene therapy applications, cationic lipids have proven to be excellent nucleic acid carriers for the treatment of various diseases. Lipid nanoparticles (LNPs) are formed from cationic lipids and other helper lipids, including but not limited to cholesterol, DSPC, and PEGylated lipids, which encapsulate oligonucleotides, protecting them from degradation and facilitating cellular uptake.

[0004] Despite these efforts, there remains a need for improved lipid nanoparticle formulations that provide high potency upon administration and are capable of being used for the administration of various types of nucleic acids. SUMMARY

[0005] In some aspects, the present invention provides a cationic lipid represented by the structure of Formula (I): (I) or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically-labeled compound, or mixture thereof wherein: X is -O-, -NH-, or -S-; Y is -O-, -NH-, or -S-; L and L' are each independently selected at each occurrence from a direct bond, -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C 1-6alkylene-W-, -C 2-6 alkenylene-W-, -W-W'-C 1-6 alkylene-, -C 1-6 alkylene-W-W'-, -W-W'-C 1-6 alkenylene-, -C 2-6 alkenylene-W-W'-, -W-C 1-6 alkylene-W'- and -W-C 2-6 alkylene-W'-, wherein the alkylene and alkenylene are optionally further interrupted by one or more W; W and W' are each independently at each occurrence selected from -0-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene- and -C 2-6 alkenylene-; R 1 selected from: (a) NR 4 R 5 , wherein R 4 and R 5 are each independently H, C1-C6 alkyl, -NH2, halogen, -OH, 3- to 10-membered ring or C 6-12 aralkyl, wherein the C1-C6 alkyl, 3- to 10-membered ring or C 6-12 aralkyl is optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N and S; (b) a side chain of a natural or unnatural amino acid; (c) a 3- to 10-membered ring, for example a C 6-12 aromatic ring, a 3- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S, or a fused ring (for example a 4- to 10-membered fused ring), wherein the above rings are optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; and (d) -OH or -C 1-6 alkyl optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-10 alkyl; R2 and R 3 each is independently selected from: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; Z is -0-C(=0)-, -C(=0)-0- or -0-.

[0006] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (IA): (IA) wherein: X is -0-, -NH- or -S-; L is selected from a direct bond, -0-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene-, -C 2-6 alkenylene-, -W-C 1-6 alkylene-, -W-C 2-6 alkenylene-, -C 1-6 alkylene-W-, -C 2-6 alkenylene-W-, -W-W'-C 1-6 alkylene-, -C 1-6 alkylene-W-W'-, -W-W'-C 1-6 alkenylene-, -C 2-6 alkenylene-W-W'-, -W-C 1-6 alkylene-W'- and -W-C 2-6 alkenylene-W'-, wherein the alkylene and alkenylene groups are optionally further interrupted by one or more W; W and W' are each independently at each occurrence selected from -0-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene- and -C 2-6 alkenylene-; R 1 is selected from: (a) NR 4 R 5 wherein R 4 and R 5 are each independently H, Ci-C6alkyl, -NH2, halogen, -OH, 3- to 10-membered ring or C 6-12 aralkyl, wherein said Ci-C6alkyl, 3- to 10-membered ring or C 6-12 aralkyl is optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N and S; (b) a side chain of a natural or non-natural amino acid; (c) a 3- to 10-membered ring, for example a C 6-12 aromatic ring, a 3- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S, or a fused ring (e.g. a 4- to 10-membered fused ring), wherein said rings are optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; and (d) -OH or -C 1-6 alkyl optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-10 alkyl; R 2 and R 3 are each independently selected from: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22Alkyl; and (e)C4-C 15 Alkylene-Z-C4-C 22 alkenyl; Z is -OC(=O)-, -C(=O)-O- or -O-; m is 0, 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4, more preferably 3 or 4.

[0007] In some aspects, the present invention provides cationic lipids, or salts, hydrates, solvates, polymorphs, optical isomers, geometric isomers, enantiomers, diastereomers, tautomers, isotopically labeled compounds or mixtures thereof, wherein the cationic lipids are represented by a structure of formula (II) or (III):

[0008] in: L is selected from direct bonds, -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O-), -NH(S=O-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene-, -C 2-6 imidene-, -WC 1-6 Alkylene-, -WC 2-6 imidene-, -C 1-6 Alkylene-W-, -C 2-6 alkenyl-W-, -W-W'-C 1-6 alkylene-, -C 1-6 Alkylene -W-W'-, -W-W'-C 1-6 imidene-, -C 2-6 imidene-W-W'-, -WC 1-6 Alkylene-W'- and -WC 2-6 alkenyl-W'-, wherein the alkylene and alkenyl groups are optionally further interrupted by one or more W groups; W and W' are each independently selected from -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene- and -C 2-6 alkenyl-; R 1 Selected from: (a)NR 4 R 5 , where R 4 and R 5each independently H, C1-C6alkyl, -NH2, halogen, -OH, 3- to 10-membered ring, or C 6-12 aralkyl, wherein the C1-C6alkyl, 3- to 10-membered ring, or C 6-12 aralkyl is optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N, and S; (b) a side chain of a natural or unnatural amino acid; (c) a 3- to 10-membered ring, for example, C 6-12 aromatic ring, 3- to 10-membered heterocyclic ring containing one or more heteroatoms selected from O, N, and S, or 5- to 10-membered heteroaromatic ring, or a fused ring (e.g., 4- to 10-membered fused ring), wherein the above rings are optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; and (d) -OH or -C 1-6 alkyl optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-10 alkyl; R 2 and R 3 are each independently selected from: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; Z is -O-C(=O)-, -C(=O)-O-, or -O-; m is 0, 1, 2, 3, 4, 5, or 6, preferably 2, 3, or 4.

[0009] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (IV): wherein: L is -(CH2)n- where n = 1, 2, or 3; R 1 is -N(CH3)2, -N(C2H5)2, , or ; R 2 and R 3 are each independently selected from:

[0010] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (IV): wherein R 1 -L- is selected from , , , and , and wherein the other groups are as defined above.

[0011] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (V): wherein: L is -(CH2)n- where n = 1, 2, or 3; R 1 is -N(CH3)2, -N(C2H5)2, , or ; R 2 and R 3 are each independently selected from:

[0012] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (V): wherein R 1 -L- is selected from , , , and , and wherein the other groups are as defined above.

[0013] In some aspects, the present application provides an intermediate compound represented by the structure of Formula (VI): (VI) wherein R 6 is a leaving group, preferably , or ; and the remaining groups are as defined above.

[0014] In some aspects, the present application provides a method of making a cationic lipid of the present application, comprising the step of reacting a compound of Formula (VI) with a compound of Formula (VII) to obtain a cationic lipid of Formula (IA): wherein each group is as defined in aspects of the present application. In embodiments, the reaction is carried out in the presence of a base, such as TEA or DIPEA.

[0015] In some aspects, the present application provides a nanoparticle composition comprising a cationic lipid of the present application.

[0016] In some aspects, the present application provides a nanoparticle composition further comprising one or more of the following: a phospholipid, a PEG lipid, and a structural lipid. In some aspects, the present application provides a nanoparticle composition further comprising a phospholipid, a PEG lipid, and a structural lipid.

[0017] In some aspects, the present application provides a pharmaceutical composition comprising a nanoparticle composition of the present application and a pharmaceutically acceptable carrier.

[0018] In some aspects, the present application provides a method of delivering a therapeutic and / or prophylactic nucleic acid molecule to a cell, comprising the step of administering to an individual (i) a nanoparticle composition of the present application and (ii) a therapeutic and / or prophylactic nucleic acid molecule, wherein the administration involves contacting the cell with the nanoparticle composition, thereby delivering the therapeutic and / or prophylactic nucleic acid molecule to the cell. In embodiments, the therapeutic and / or prophylactic nucleic acid is encapsulated in a nanoparticle composition of the present application. In embodiments, the therapeutic and / or prophylactic nucleic acid is combined with a nanoparticle composition of the present application.

[0019] In some aspects, the present application provides a method of delivering a nucleic acid molecule encoding a protein to a cell, comprising the step of administering to an individual (i) a nanoparticle composition of the present application and (ii) a nucleic acid molecule encoding a protein, wherein the administration involves contacting the cell with the nanoparticle composition, thereby delivering the nucleic acid molecule to the cell. In embodiments, the nucleic acid molecule encoding a protein is encapsulated in a nanoparticle composition of the present application. In embodiments, the nucleic acid molecule encoding a protein is combined with a nanoparticle composition of the present application.

[0020] In some aspects, the present application provides a method of producing a polypeptide of interest in a cell, comprising the step of contacting the cell with a nanoparticle composition of the present application and (ii) a nucleic acid molecule encoding the polypeptide of interest, whereby the nucleic acid molecule is capable of being translated in the cell to produce the polypeptide. In embodiments, the nucleic acid molecule is an mRNA molecule, an siRNA molecule, or a circular RNA molecule. In embodiments, the nucleic acid molecule is a linear RNA. In embodiments, the nucleic acid molecule is a circular RNA.

[0021] In some aspects, the present application provides a nanoparticle composition for use in the preparation of a medicament for treating a disease or disorder in a mammal in need thereof, wherein the nanoparticle composition comprises (i) a lipid component comprising a phospholipid, a PEG lipid, a structural lipid, and a cationic lipid of the present application and (ii) a therapeutic and / or prophylactic nucleic acid molecule. In embodiments, the nucleic acid molecule is an mRNA, an siRNA, or a circular RNA. In embodiments, the nucleic acid molecule is a linear RNA. In embodiments, the nucleic acid molecule is a circular RNA.

[0022] In some aspects, the present application provides a nanoparticle composition for use in the preparation of a medicament for treating a disease or condition in a mammal in need thereof, wherein the nanoparticle composition comprises (i) a cationic lipid of the present application and (ii) a nucleic acid molecule encoding a therapeutic and / or prophylactic protein. In embodiments, the nucleic acid molecule is an mRNA, an siRNA, or a circular RNA. In embodiments, the nucleic acid molecule is a linear RNA. In embodiments, the nucleic acid molecule is a circular RNA.

[0023] In some aspects, the present application provides the use of a cationic lipid of the present application for the preparation of a nanoparticle composition.

[0024] In some aspects, the present application provides the use of a cationic lipid of the present application or a nanoparticle composition of the present application in the preparation of a medicament for treating a disease or condition in an individual in need thereof.

[0025] In some aspects, the present application provides a method of synthesizing a cationic lipid of formula (I), (IA), (II), (III), (IV), or (V) and a method of preparing a nanoparticle composition comprising a lipid component comprising a cationic lipid of formula (I), (IA), (II), (III), (IV), or (V). BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 . HPLC-ELSD chromatogram of LNP prepared from Lipid C showing the parent lipid at Rt 4.10 min and the hydrolyzed compound at Rt 5.56 min and the corresponding ratio.

[0027] Figure 2 . Mass spectrum of Lipid C and hydrolysis product.

[0028] Figure 3 . Overlay of chromatograms of Lipid 196 at t=0 and t=24 hours in EtOH PBS pH =7.4.

[0029] Figure 4 . Overlay of chromatograms of Lipid 68 at t=0 and t=24 hours in EtOH PBS pH =7.4.

[0030] Figure 5 . Overlay of chromatograms of Lipid 132 at t=0 and t=24 hours in EtOH PBS pH =7.4.

[0031] Figure 6 . Overlay of chromatograms of Lipid 90 at t=0 and t=24 hours in EtOH PBS pH =7.4. DETAILED DESCRIPTION

[0032] The present application provides novel lipid and lipid nanoparticle compositions comprising novel cationic lipids. The present application also provides methods of providing a nucleic acid molecule encoding a protein to a mammalian cell, in particular delivering the nucleic acid molecule encoding a protein to a mammalian organ and producing a polypeptide of interest in a mammalian cell. The present application also provides methods of delivering a therapeutic and / or prophylactic nucleic acid molecule to a mammalian cell, in particular delivering a therapeutic and / or prophylactic nucleic acid molecule to a mammalian organ, producing a polypeptide of interest in a mammalian cell, and treating a disease or disorder in a mammal in need thereof. For example, a method of producing a polypeptide of interest in a cell involves contacting a nanoparticle composition comprising a linear RNA (e.g., mRNA, siRNA, or circular RNA) with a mammalian cell, whereby the mRNA can be translated to produce a polypeptide of interest. A method of delivering a therapeutic and / or prophylactic nucleic acid molecule to a mammalian cell or organ can involve administering to an individual a nanoparticle composition comprising a therapeutic and / or prophylactic nucleic acid molecule, wherein the administration involves contacting a cell or organ with the composition, whereby the therapeutic and / or prophylactic nucleic acid molecule is delivered to the cell or organ.

[0033] As used herein, the term "alkyl" or "alkyl group" refers to a straight-chain or branched-chain saturated hydrocarbon comprising one or more carbon atoms (e.g., one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms), which is optionally substituted. The term "Ci-14 alkyl" refers to an optionally substituted straight-chain or branched-chain saturated hydrocarbon comprising 1-14 carbon atoms. Unless otherwise indicated, alkyl groups described herein refer to unsubstituted and substituted alkyl groups.

[0034] As used herein, the term "alkenyl" or "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon comprising two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one double bond, which is optionally substituted. The term "C2-14 alkenyl" refers to an optionally substituted straight-chain or branched-chain hydrocarbon comprising 2-14 carbon atoms and at least one carbon-carbon double bond. For example, an alkenyl group can comprise one, two, three, four, or more carbon-carbon double bonds. Unless otherwise indicated, alkenyl groups described herein refer to unsubstituted and substituted alkenyl groups. 2-14 The term "alkenyl" or "alkenyl group" refers to a straight-chain or branched-chain hydrocarbon comprising two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or more carbon atoms) and at least one double bond, which is optionally substituted. The term "C2-14 alkenyl" refers to an optionally substituted straight-chain or branched-chain hydrocarbon comprising 2-14 carbon atoms and at least one carbon-carbon double bond. For example, an alkenyl group can comprise one, two, three, four, or more carbon-carbon double bonds. Unless otherwise indicated, alkenyl groups described herein refer to unsubstituted and substituted alkenyl groups.

[0035] As used herein, the term "alkynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon containing two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more carbon atoms) and at least one carbon-carbon triple bond, which is optionally substituted. The term "C2-14alkynyl" refers to an alkynyl group having 2 to 14 carbon atoms. Unless otherwise specified, an alkynyl group as described herein refers to unsubstituted and substituted alkynyl groups. 2-14 As used herein, the term "alkynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon containing two or more carbon atoms (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty or more carbon atoms) and at least one carbon-carbon triple bond, which is optionally substituted. The term "C2-14alkynyl" refers to an alkynyl group having 2 to 14 carbon atoms. Unless otherwise specified, an alkynyl group as described herein refers to unsubstituted and substituted alkynyl groups.

[0036] As used herein, the term "carbocycle" or "carbocyclic group" refers to an optionally substituted monocyclic or polycyclic ring system containing one or more rings of carbon atoms. The ring can be a three-, four-, five-, six-, seven-, eight-, nine-, ten-, eleven-, twelve-, thirteen-, fourteen-, fifteen-, sixteen-, seventeen-, eighteen-, nineteen- or twenty-membered ring. The term "C3-6carbocycle" refers to a carbocycle containing a monocyclic ring having 3 to 6 carbon atoms. The carbocycle can contain one or more carbon-carbon double or triple bonds and can be non-aromatic or aromatic (e.g., cycloalkyl or aryl). Examples of carbocycles include cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and 1,2-dihydronaphthyl. As used herein, the term "cycloalkyl" means a non-aromatic carbocycle and can or can not contain any double or triple bonds. Unless otherwise specified, a carbocycle as described herein refers to unsubstituted and substituted carbocyclic groups, i.e., an optionally substituted carbocycle.

[0037] As used herein, the term "heterocycle" or "heterocyclic group" refers to an optionally substituted monocyclic or polycyclic ring system containing one or more rings, at least one of which contains at least one heteroatom. The heteroatom can be, for example, a nitrogen, oxygen or sulfur atom. The ring can be a three-, four-, five-, six-, seven-, eight-, nine-, ten-, eleven-, twelve-, thirteen- or fourteen-membered ring. The heterocycle can contain one or more double or triple bonds and can be non-aromatic or aromatic (e.g., heterocycloalkyl or heteroaryl). Examples of heterocycles include imidazolyl, imidazolidinyl, oxazolyl, oxazolidinyl, thiazolyl, thiazolidinyl, pyrazolidinyl, pyrazolyl, isoxazolidinyl, isoxazolyl, isothiazolidinyl, isothiazolyl, morpholinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thienyl, pyridyl, piperidinyl, quinolinyl and isoquinolinyl. As used herein, the term "heterocycloalkyl" means a non-aromatic heterocycle and can or can not contain any double or triple bonds. Unless otherwise specified, a heterocycle as described herein refers to unsubstituted and substituted heterocyclic groups, i.e., an optionally substituted heterocycle.

[0038] As used herein, unless otherwise indicated, alkyl, alkenyl, alkylene, alkenylene, and cyclic (e.g., carbocyclic and heterocyclic) groups can be optionally substituted. The optional substituents can be selected from, but are not limited to, halogen atoms (e.g., chloride, bromide, fluoride, or iodide groups), carboxylic acids (e.g., -C(O)OH), alcohols (e.g., hydroxyl, -OH), esters (e.g., -C(O)OR or -OC(O)R), aldehydes (e.g., -C(O)H), carbonyls (e.g., -C(O)R, or represented by C=O), acyl halides (e.g., -C(O)X, where X is a halide selected from bromide, fluoride, chloride, and iodide), carbonates (e.g., -OC(O)OR), alkoxys (e.g., -OR), acetals (e.g., -C(OR)2R, where each OR is an alkoxyl group, which can be the same or different, and R is an alkyl or alkenyl group), phosphates, thiols (e.g., -SH), sulfoxides (e.g., -S(O)R), sulfmic acid (e.g., -S(O)OH), sulfonic acids (e.g., -S(O)2OH), thioalcohols (e.g., -C(S)H), sulfates, sulfonyls, amides (e.g., -C(O)NR2or -N(R)C(O)R), azido (e.g., -N3), nitro (e.g., -NO2), cyano (e.g., -CN), isocyano (e.g., -NC), acyloxy (e.g., -OC(O)R), amino (e.g., -NR2, -NRH, or -NH2), carbamoyl (e.g., -OC(O)NR2, -OC(O)NRH, or -OC(O)NH2), sulfonamides (e.g., -S(O)2NR2, -S(O)2NRH, -S(O)2NH2, -N(R)S(O)2R, -N(H)S(O)2R, -N(R)S(O)2H, or -N(H)S(O)2H), alkyl, alkenyl, and cyclic (e.g., carbocyclic or heterocyclic) groups. In any of the foregoing, R is an alkyl or alkenyl group as defined herein. In some embodiments, the substituents themselves can be further substituted with, for example, one, two, three, four, five, or six substituents as defined herein. For example, as described herein, a C1-C6 alkyl group can be further substituted with one, two, three, four, five, or six substituents.

[0039] As used herein, the term “compound” is meant to include all isomers and isotopically labeled compounds of the depicted structures. An “isotope” refers to an atom having the same atomic number but a different mass number (due to a different number of neutrons in the nucleus). For example, isotopes of hydrogen include tritium and deuterium. In addition, the compounds, salts, or complexes of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates, respectively, by conventional methods.

[0040] The nitrogen-containing compounds of the present application can be converted to N-oxides by treatment with an oxidizing agent (for example, 3-chloroperoxybenzoic acid and / or hydrogen peroxide) to provide other compounds of the present disclosure. Thus, all shown and claimed nitrogen-containing compounds are considered to include the shown compounds and their N-oxide derivatives, where valence and structure permit. Furthermore, in other instances, the nitrogen in the compounds of the present disclosure can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine by an oxidizing agent such as m-CPBA. All shown and claimed nitrogen-containing compounds are also considered to encompass the shown compounds and their N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, where R is a substituted or unsubstituted C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, 3-14 membered carbocyclic ring, or 3-14 membered heterocyclic ring) derivatives, where valence and structure permit.

[0041] As used herein, the term "contacting" means establishing a physical connection between two or more entities. For example, contacting a mammalian cell with a nanoparticle composition means that the mammalian cell and the nanoparticle share a physical connection. Methods of contacting cells with external entities, both in vivo and ex vivo, are well known in the biological arts. For example, contacting a nanoparticle composition with a mammalian cell located within a mammal can be performed through different routes of administration (e.g., intravenous, intramuscular, intradermal, and subcutaneous), and can involve different amounts of the nanoparticle composition. Furthermore, more than one mammalian cell can be contacted with the nanoparticle composition.

[0042] As used herein, the term "delivering" means providing an entity to a destination. For example, delivering a therapeutic and / or prophylactic molecule to an individual can involve administering to the individual a nanoparticle composition comprising the therapeutic and / or prophylactic nucleic acid molecule (e.g., through an intravenous, intramuscular, intradermal, or subcutaneous route). Administering a nanoparticle composition to a mammal or a mammalian cell can involve contacting one or more cells with the nanoparticle composition.

[0043] As used herein, the term "isomer" means any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer, or diastereomer of a compound. A compound can contain one or more chiral centers and / or double bonds, and can therefore exist as stereoisomers, such as double-bond isomers (i.e., geometric E / Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The present disclosure encompasses any and all isomers of the compounds described herein, including stereoisomerically pure forms (e.g., geometrically pure, enantiomericly pure, or diastereomericly pure) as well as enantiomeric and stereoisomeric mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds and their resolution into their component enantiomers or stereoisomers are known per se.

[0044] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. The conversion involves the formal migration of a hydrogen atom accompanied by a switch in the bonding pattern of adjacent atoms. Tautomers exist as a mixture of tautomers in solution. In a solution where tautomeric interconversion is possible, a chemical equilibrium of tautomers is reached. The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is known as the tautomerism phenomenon.

[0045] It should be understood that the compounds of the present application can be described as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form.

[0046] As used herein, a "lipid component" is a component of a nanoparticle composition that comprises one or more lipids. For example, the lipid component can include one or more cationic / ionizable, pegylated, structural, or other lipids, such as a phospholipid.

[0047] As used herein, a "method of administration" can include intravenous, intramuscular, intradermal, subcutaneous, or other methods of delivering a composition to an individual. The method of administration can be selected to target delivery (e.g., specific delivery) to a particular region or system of the body.

[0048] As used herein, a "nanoparticle composition" is a composition that comprises one or more lipids. Nanoparticle compositions are typically microns or less in dimension, and can comprise a lipid bilayer. Nanoparticle compositions include lipid nanoparticles (LNPs), liposomes (e.g., lipid vesicles), and lipoplexes. For example, a nanoparticle composition can be a liposome having a lipid bilayer with a diameter of 500 nm or less.

[0049] In this specification, in some cases, a structural formula of a compound represents a certain isomer for convenience, but the present disclosure includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like, and it is understood that not all isomers can have the same level of activity. In addition, there can be crystal polymorphs of a compound represented by a formula. It should be noted that any crystal form, crystal form mixture, or anhydride or hydrate thereof is included within the scope of the present disclosure.

[0050] The term "crystal polymorph," "polymorph," or "crystal form" means a crystal structure in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all having the same elemental composition. Different crystal forms often have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. The recrystallization solvent, rate of crystallization, storage temperature, and other factors can cause one crystal form to dominate. Crystal polymorphs of a compound can be prepared by crystallization under different conditions.

[0051] The compositions can also include a salt of one or more of the compounds. The salt can be a pharmaceutically acceptable salt. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds in which the parent compound is altered by converting at least one of its existing acid or base moieties into its salt form (e.g., by reacting a free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compounds formed, for example, from non-toxic inorganic or organic acids. As used herein, the term "pharmaceutically acceptable salt" of a compound means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 1985, p. 1418, Pharmaceutical Salts: Properties, Selection, and Use, P. H. Stahl and C. G. Wermuth (eds.), Wiley-VCH, 2008, and Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977), each of which is incorporated herein by reference in its entirety. .

[0052] As used herein, a "phospholipid" is a lipid comprising a phosphate moiety and one or more carbon chains (e.g., unsaturated fatty acid chains). The phospholipid can comprise one or more multiple (e.g., double or triple) bonds (e.g., one or more degrees of unsaturation). Particular phospholipids can facilitate fusion with a membrane. For example, a cationic phospholipid can interact with one or more negatively charged phospholipids of a membrane (e.g., a cell or intracellular membrane). Fusion of the phospholipid with the membrane can allow one or more elements of the lipid-containing composition to pass through the membrane, thereby enabling, for example, delivery of the one or more elements to a cell.

[0053] As used herein, the lipid component of the nanoparticle composition can include one or more PEG or PEG-modified lipids. Such substances can alternatively be referred to as pegylated lipids. PEG lipids are lipids modified with polyethylene glycol. The PEG lipids can be selected from the following non-limiting group: PEG-modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides (PEG-CER), PEG-modified dialkylamines, PEG-modified diacylglycerols (PEG-DEG), PEG-modified dialkylglycerols, and mixtures thereof.

[0054] For example, the PEG lipid can be a PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, or PEG-DSPE lipid.

[0055] As used herein, the lipid component of the nanoparticle composition can include one or more structural lipids. The structural lipids can be selected from, but not limited to, cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatine, lycopersic acid, ursolic acid, a-tocopherol, and mixtures thereof. In some embodiments, the structural lipid is cholesterol. In some embodiments, the structural lipid includes cholesterol and a corticosteroid (e.g., prednisolone, dexamethasone, prednisone, and hydrocortisone) or a combination thereof.

[0056] As used herein, the lipid component of a nanoparticle composition can comprise one or more phospholipids, such as one or more (poly)unsaturated lipids. The phospholipids can assemble into one or more lipid bilayers. Generally, the phospholipids can comprise a phospholipid moiety and one or more fatty acid moieties. For example, the phospholipid moiety can be selected from the following non-limiting group: phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, 2-lysophosphatidylcholine, and sphingomyelin. The fatty acid moiety can be selected from the following non-limiting group: lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, a-linolenic acid, erucic acid, phytanic acid, eicosanoic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid. Non-natural substances including natural substances with modifications and substitutions including branching, oxidation, cyclization, and alkynes are also contemplated.

[0057] For example, the phospholipids can be functionalized or crosslinked with one or more alkynes (e.g., alkenyl groups in which one or more double bonds are replaced with a triple bond).

[0058] As used herein, the term “polypeptide” or “polypeptide of interest” refers to a polymer of amino acid residues typically linked by peptide bonds, which can be produced naturally (e.g., isolated or purified) or synthetically.

[0059] As used herein, “RNA” refers to a ribonucleic acid that is naturally or non-naturally occurring. For example, the RNA can include modified and / or non-naturally occurring components, such as one or more nucleobases, nucleosides, nucleotides, or linkages. The RNA can include a cap structure, a chain-terminating nucleoside, a stem loop, a poly-A sequence, and / or a polyadenylation signal. The RNA can have a nucleotide sequence that encodes a polypeptide of interest. For example, the RNA can be a messenger RNA (mRNA), a small interfering RNA (siRNA), or a circular RNA (cRNA). Translation of an mRNA or a circular RNA encoding a particular polypeptide (e.g., its in vivo translation within a mammalian cell) can generate the encoded polypeptide.

[0060] In some aspects, the present application provides a cationic lipid represented by the structure of Formula (I): (I) or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically-labeled compound, or mixture thereof wherein: X is -O-, -NH-, or -S-; Y is -O-, -NH-, or -S-; L and L' are each, independently at each occurrence, selected from a direct bond, -0-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene-, -C 2-6 alkylene-, -W-C 1-6 alkylene-, -W-C 2-6 alkylene-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C 1-6 alkylene-, -C 1-6 alkylene-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C W and W' are each, independently at each occurrence, selected from -0-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene-, and -C 2-6 alkylene-; R 1 is selected from: (a) NR 4 R 5 wherein R 4 and R 5 are each, independently, H, C1-C6 alkyl, -NH2, halogen, -OH, 3- to 10-membered ring or C 6-12 aralkyl, wherein said C1-C6 alkyl, 3- to 10-membered ring or C 6-12 aralkyl is optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N and S; (b) a side chain of a natural or non-natural amino acid; (c) a 3- to 10-membered ring, for example C 6-12an aromatic ring, a 3- to 10-membered heterocycle containing one or more heteroatoms selected from O, N, and S, a 5- to 10-membered heteroaromatic ring, or a fused ring (e.g., a 4- to 10-membered fused ring), wherein the above rings are optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered cyclic substituents; and (d) -OH or -C 1-6 alkyl and 3- to 4-membered cyclic substituents; and 1-10 alkyl; R 2 and R 3 each is independently selected from: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; Z is -O-C(=O)-, -C(=O)-O-, or -O-.

[0061] In embodiments, R 1 is selected from: (a) NR 4 R 5 wherein R 4 and R 5 each is independently H, C1-C6 alkyl, or C 6-12 aralkyl, optionally substituted with -NH2; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocycle or a 5- to 10-membered heteroaromatic ring, said heterocycle and heteroaromatic ring optionally containing one or more additional heteroatoms selected from O, N, and S; (b) a side chain of a natural or unnatural amino acid; (c) a 3- to 10-membered heterocycle or a 5- to 10-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, and S; and (d) -OH or -C 1-6 alkyl and 3- to 4-membered cyclic substituents; and 1-10 alkyl; R 2 and R 3 are each independently selected from: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; Z is -O-C(=O)-, -C(=O)-O- or -O-.

[0062] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (IA): (IA) wherein: X is -O-, -NH- or -S-; L is selected from a direct bond, -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene-, -C 2-6 alkenylene-, -W-C 1-6 alkylene-, -W-C 2-6 alkenylene-, -C 1-6 alkylene-W-, -C 2-6 alkenylene-W-, -W-W'-C 1-6 alkylene-, -C 1-6 alkylene-W-W'-, -W-W'-C 1-6 alkenylene-, -C 2-6 alkenylene-W-W'-, -W-C 1-6 alkylene-W'- and -W-C 2-6 alkenylene-W'-, wherein the alkylene and alkenylene groups are optionally further interrupted by one or more W; W and W' are each independently at each occurrence selected from the group consisting of -0-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene- and -C 2-6 alkenylene-; R 1 is selected from the group consisting of: (a) NR 4 R 5 wherein R 4 and R 5 are each independently H, C1-C6 alkyl, -NH2, halogen, -OH, 3- to 10-membered ring or C 6-12 aralkyl, wherein said C1-C6 alkyl, 3- to 10-membered ring or C 6-12 aralkyl is optionally substituted with one or more substituents selected from the group consisting of -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N and S; (b) a side chain of a natural or non-natural amino acid; (c) a 3- to 10-membered ring, for example a C 6-12 aromatic ring, a 3- to 10-membered heterocyclic ring containing one or more heteroatoms selected from O, N and S, a 5- to 10-membered heteroaromatic ring, or a fused ring (for example a 4- to 10-membered fused ring), wherein said rings are optionally substituted with one or more substituents selected from the group consisting of -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; and (d) -OH or -C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of -NH2, halogen, -OH, -C 1-10 alkyl; R 2 and R 3 are each independently selected from the group consisting of: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; Z is -O-C(=O)-, -C(=O)-O- or -O-; m is 0, 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4, more preferably 3 or 4.

[0063] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of formula (II) or (III):

[0064] wherein: L is selected from a direct bond, -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene-, -C 2-6 alkylene-, -W-C 1-6 alkylene-, -W-C 2-6 alkylene-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C 1-6 alkylene-, -C 1-6 alkylene-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C 1-6 alkylene-, -C 2-6 alkylene-, -C W and W' are each independently at each occurrence selected from -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene- and -C 2-6 alkylene-; R 1 is selected from: (a) NR 4 R 5 wherein R 4 and R 5Each of the following can be independently H, C1-C6 alkyl, -NH2, halogen, -OH, 3 to 10 membered ring or C 6-12 Aryl alkyl groups, wherein the C1-C6 alkyl group, 3- to 10-membered ring, or C 6-12 Aryl groups are optionally surrounded by one or more elements selected from -NH2, halogen, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents; or R 4 and R 5 Together with the nitrogen atoms to which they are attached, they form 4- to 10-membered heterocycles or 5- to 10-membered heteroaromatic rings, wherein the heterocycles and heteroaromatic rings optionally contain one or more additional heteroatoms selected from O, N and S; (b) Side chains of natural or non-natural amino acids; (c) 3- to 10-membered rings, such as C 6-12 Aromatic rings, 3- to 10-membered heterocycles containing one or more heteroatoms selected from O, N, and S, 5- to 10-membered heteroaromatic rings, or fused rings (e.g., 4- to 10-membered fused rings), wherein the aforementioned rings are optionally separated by one or more heteroatoms selected from -NH2, halogens, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents; and (d) -OH or optionally surrounded by one or more elements selected from -NH2, halogen, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents of -C 1-10 alkyl; R 2 and R 3 Each is selected independently from: (a)C 10 -C 22 alkyl; (b)C 10 -C 22 alkenyl; (c)C 10 -C 22 alkynyl group; (d)C4-C 15 Alkylene-Z-C4-C 22 Alkyl; and (e)C4-C 15 Alkylene-Z-C4-C 22 alkenyl; Z is -OC(=O)-, -C(=O)-O- or -O-; m can be 0, 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4.

[0065] In the implementation scheme, m is 2. In the implementation scheme, m is 3. In the implementation scheme, m is 4.

[0066] In the implementation plan, R1 selected from: (a) NR 4 R 5 wherein R 4 and R 5 are each independently H, C1-C6 alkyl, or C 6-12 aralkyl, optionally substituted with -NH2; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N, and S; (b) a side chain of a natural or unnatural amino acid; (c) a 3- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring containing one or more heteroatoms selected from O, N, and S, or a fused ring (e.g., a 4- to 10-membered fused ring); and (d) -OH or -C 1-6 alkyl optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-10 alkyl and a 3- to 4-membered ring.

[0067] In embodiments, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is selected from -C 1-6 alkylene-, -C 2-6 alkenylene-, -W-C 1-6 alkylene-, -W-C 2-6 alkenylene-, -C 1-6 alkylene-W-, -C 2-6 alkenylene-W-, -W-W'-C 1-6 alkylene-, -C 1-6 alkylene-W-W'-, -W-W'-C 1-6 alkylene-, -C 2-6 alkylene-W-W'-, -W-C 1-6 alkylene-W'- and -W-C 2-6 alkylene-W'-; W and W' are each independently at each occurrence selected from -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene- and -C 2-6 alkylene-.

[0068] In embodiments, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is -C 1-6 alkylene-, -W-C 1-6 alkylene-, -C 1-6 alkylene-W-, -W-W'-C 1-6 alkylene- or -W-C 1-6 alkylene-W'-; W and W' are each independently at each occurrence selected from -O-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene- and -C 2-6 alkylene.

[0069] In embodiments, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is -C 1-6 alkylene-, -W-C 1-6 alkylene-, -C 1-6 alkylene-W-, -W-W'-C 1-6 alkylene- or -W-C 1-6 alkylene-W'-; W and W' are each independently at each occurrence selected from -O-, -C(=0)-, -C(=0)0-, -C 1-6 alkylene- or -C 2-6 alkylene.

[0070] In embodiments, L is -C 1-6 alkylene-.

[0071] In embodiments, L is -(CH2)n- wherein n = 1, 2 or 3.

[0072] In embodiments, L is -(CH2)n- wherein n = 1. In embodiments, L is -(CH2)n- wherein n = 2. In embodiments, L is -(CH2)n- wherein n = 3.

[0073] In embodiments, R 1 is selected from: (a) NR 4 R 5 wherein R 4 and R 5each independently H, C1-C3 alkyl, or C 6-12 aralkyl, optionally substituted with -NH2; or R 4 and R 5 together with the nitrogen to which they are attached form a 5- to 6- membered heterocyclic or 5- to 6- membered heteroaromatic ring, optionally containing one or more additional heteroatoms selected from O, N, and S; and (b) a 5- to 6- membered heterocyclic or 5- to 6- membered heteroaromatic ring containing one or more heteroatoms selected from O, N, and S.

[0074] In embodiments, R 1 is NR 4 R 5 wherein R 4 and R 5 each independently H, C1-C3 alkyl, or benzyl, optionally substituted with -NH2.

[0075] In embodiments, R 1 is NR 4 R 5 , R 4 and R 5 together with the nitrogen to which they are attached form a 5- to 6- membered heterocyclic or 5- to 6- membered heteroaromatic ring, optionally containing one or more additional heteroatoms selected from O, N, and S.

[0076] In embodiments, R 1 is a 5- to 6- membered heterocyclic or 5- to 6- membered heteroaromatic ring containing one or more heteroatoms selected from O, N, and S.

[0077] In embodiments, R 1 is -OH.

[0078] In embodiments, R 1 is -C 1-10 alkyl, optionally substituted with one or more substituents selected from -NH2, halo, -OH, -C 1-6 alkyl, and a 3- to 4- membered ring.

[0079] In embodiments, R 1 is -OH, -C(CH3)3, -NH2, -N(CH3)2, -N(C2H5)2, , , , , , , , or , , , 、 、 .

[0080] In embodiments, R 2 and R 3 are each independently selected from: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; Z is -O-C(=O)-, -C(=O)-O- or -O-.

[0081] In embodiments, R 2 and R 3 are each independently selected from: (a) C 10 -C 22 alkyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkyl; (b) C 10 -C 22 alkenyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkenyl; (d) C p alkylene-Z-C q alkyl; and (e) C p alkylene-Z-C q alkenyl; Z is -O-C(=O)-, -C(=O)-O-, or -O-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

[0082] In embodiments, R 2 and R 3 are each independently selected from: (b) C 10 -C 22 alkenyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkenyl; and (c) C p alkylene-Z-C q alkyl; Z is -O-C(=O)- or -C(=O)-O-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

[0083] In embodiments, R 2 and R 3 are each independently selected from: (c) C p alkylene-Z-C q alkyl; Z is -O-C(=O)- or -C(=O)-O-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15; q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22, R 2 and R3 The Z in them is different.

[0084] In the implementation plan, R 2 For (b)C 10 -C 22 alkenyl groups, such as C 10 C 11 C 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 Or C 20 alkenyl; and R 3 For (c)C p Alkylene-ZC q alkyl, Z is -OC(=O)- or -C(=O)-O-. p is any integer from 4 to 15, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; q is any integer from 4 to 22, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22.

[0085] In the implementation plan, R 2 and R 3 For (c)C p Alkylene-ZC q alkyl, Z is -OC(=O)- or -C(=O)-O-. p is any integer from 4 to 15, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15; q is any integer from 4 to 22, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22; R 2 and R 3 The Z in R is the same, for example, R 2 and R 3 Z in the equation is -OC (=O)-.

[0086] In the implementation plan, R 2 and R 3 Each is selected independently from:

[0087] In embodiments, R 2 and R 3 are the same or different groups.

[0088] In embodiments, R 2 and R 3 are the same group and are .

[0089] In embodiments, R 2 and R 3 are the same group and are .

[0090] In embodiments, R 2 and R 3 are the same group and are .

[0091] In embodiments, R 2 and R 3 are the same group and are .

[0092] In embodiments, R 2 and R 3 are the same group and are .

[0093] In embodiments, R 2 and R 3 are different groups and are each or .

[0094] In embodiments, R 2 and R 3 are different groups and are each or .

[0095] In embodiments, R 2 and R 3 are different groups and are each or .

[0096] In embodiments, R 2 and R 3 are different groups and are each or . In embodiments, the cationic lipid of the application is a deuterated compound.

[0097] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or a mixture thereof, wherein the cationic lipid is represented by the structure of Formula (IV): wherein: L is -(CH2)n- where n = 1, 2, or 3; R 1 is -N(CH3)2, -N(C2H5)2, , or ; R 2 and R 3 are each independently selected from:

[0098] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or a mixture thereof, wherein the cationic lipid is represented by the structure of Formula (IV): wherein R 1 -L- is selected from , , , and , and wherein the other groups are as defined above.

[0099] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or a mixture thereof, wherein the cationic lipid is represented by the structure of Formula (V): wherein: L is -(CH2)n- where n = 1, 2, or 3; R 1 is -N(CH3)2, -N(C2H5)2, , or ; R 2 and R 3 are each independently selected from:

[0100] In some aspects, the present application provides a cationic lipid, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (V): wherein R 1 -L- is selected from , , , and , and wherein the other groups are as defined above.

[0101] In embodiments, the cationic lipid of the present application is selected from: Table 1

[0102] Table P1

[0103] In some aspects, the application provides an intermediate compound represented by the structure of formula (VI): (VI) wherein R 6 is a leaving group, preferably , or ; and the remaining groups are as defined above.

[0104] In embodiments, R 6 is .

[0105] In embodiments, R 2 and R 3 are as defined above.

[0106] In embodiments, the intermediate compound is: or .

[0107] In some aspects, the application provides a method of making a cationic lipid of the application comprising the step of reacting a compound of formula (VI) with a compound of formula (VII) to give a cationic lipid of formula (IA): wherein each group is as defined in aspects of the application. In embodiments, the reaction is carried out in the presence of a base, such as TEA or DIPEA.

[0108] In some aspects, the application provides a nanoparticle composition comprising a cationic lipid of the application.

[0109] In some aspects, the application provides a nanoparticle composition further comprising one or more selected from the group consisting of a phospholipid, a PEG lipid, and a structural lipid. In some aspects, the application provides a nanoparticle composition further comprising a phospholipid, a PEG lipid, and a structural lipid.

[0110] In some aspects, the present application provides a pharmaceutical composition comprising a nanoparticle composition of the present application and a pharmaceutically acceptable carrier.

[0111] As used herein, "therapeutic and / or prophylactic nucleic acid molecule" refers to a nucleic acid molecule that encodes a therapeutic and / or prophylactic protein that is translatable in a cell. Such a nucleic acid molecule can be any suitable form of nucleic acid molecule, for example any linear RNA or any circular RNA.

[0112] In some aspects, the present application provides a method of delivering a nucleic acid molecule to a cell comprising the step of administering to an individual (i) a nanoparticle composition of the present application and (ii) the nucleic acid molecule, wherein the administration involves contacting the cell with the nanoparticle composition, thereby delivering the nucleic acid molecule to the cell. In some aspects, the present application provides a method of delivering a nucleic acid molecule to a cell comprising the step of administering to an individual a composition comprising (i) a nanoparticle composition of the present application and (ii) the nucleic acid molecule, wherein the administration involves contacting the cell with the nanoparticle composition, thereby delivering the nucleic acid molecule to the cell. In embodiments, the nucleic acid molecule is a nucleic acid molecule encoding a protein. In embodiments, the nucleic acid molecule is a therapeutic and / or prophylactic nucleic acid molecule. In embodiments, the nucleic acid molecule encoding a protein is translatable in vivo. In some embodiments, the nucleic acid molecule is encapsulated in a nanoparticle composition of the present application. In embodiments, the nucleic acid molecule is attached to a nanoparticle composition of the present application. As used herein, "attached to" refers to the attachment of a nucleic acid to a nanoparticle composition of the present application via any physical or chemical means.

[0113] In some aspects, the present application provides a method of delivering a therapeutic and / or prophylactic nucleic acid molecule to a cell comprising the step of administering to an individual a pharmaceutical composition comprising (i) a nanoparticle composition of the present application and (ii) the therapeutic and / or prophylactic nucleic acid molecule, wherein the administration involves contacting the cell with the nanoparticle composition, thereby delivering the therapeutic and / or prophylactic nucleic acid molecule to the cell. In embodiments, the nucleic acid molecule is encapsulated in a nanoparticle composition of the present application. In embodiments, the nucleic acid molecule is attached to a nanoparticle composition of the present application. As used herein, "attached to" refers to the attachment of a nucleic acid to a nanoparticle composition of the present application via any physical or chemical means.

[0114] In embodiments, the individual is a mammal. In embodiments, the mammal is a human.

[0115] In some aspects, the present application provides a method of delivering a nucleic acid molecule encoding a protein to a cell, comprising the step of administering to an individual (i) a nanoparticle composition of the present application and (ii) a nucleic acid molecule encoding a protein, wherein the administration involves contacting the cell with the nanoparticle composition, thereby delivering the nucleic acid molecule to the cell. In embodiments, the nucleic acid molecule encoding a protein is encapsulated in a nanoparticle composition of the present application. In embodiments, the nucleic acid molecule encoding a protein is attached to a nanoparticle composition of the present application. As used herein, "attached to" means that the nucleic acid is attached to a nanoparticle composition of the present application via any physical or chemical means.

[0116] In some aspects, the present application provides a method of providing a polypeptide of interest in a cell, comprising the step of contacting the cell with a nanoparticle composition of the present application and (ii) a nucleic acid molecule encoding a polypeptide of interest, whereby the nucleic acid molecule is capable of being translated in the cell to generate the polypeptide. In embodiments, the nucleic acid molecule is an mRNA molecule, an siRNA molecule, or a circular RNA molecule. In embodiments, the nucleic acid molecule is a linear RNA. In embodiments, the nucleic acid molecule is a circular RNA.

[0117] In some aspects, the present application provides a nanoparticle composition for use in the preparation of a medicament for treating a disease or condition in an individual or mammal in need thereof, wherein the nanoparticle composition comprises (i) a lipid component comprising a phospholipid, a PEG lipid, a structural lipid, and a cationic lipid of the present application and (ii) a therapeutic and / or prophylactic nucleic acid molecule. In embodiments, the nucleic acid molecule is an mRNA, an siRNA, or a circular RNA. In embodiments, the nucleic acid molecule is a linear RNA. In embodiments, the nucleic acid molecule is a circular RNA.

[0118] In some aspects, the present application provides a nanoparticle composition for use in the preparation of a medicament for treating a disease or condition in an individual or mammal in need thereof, wherein the nanoparticle composition comprises (i) a cationic lipid of the present application and (ii) a nucleic acid molecule encoding a therapeutic and / or prophylactic protein. In embodiments, the nucleic acid molecule is an mRNA, an siRNA, or a circular RNA. In embodiments, the nucleic acid molecule is a linear RNA. In embodiments, the nucleic acid molecule is a circular RNA.

[0119] In embodiments of the present application, the individual is a mammal.

[0120] In embodiments of the present application, the mammal is a human.

[0121] In some aspects, the present application provides use of a cationic lipid of the present application for the preparation of a nanoparticle composition.

[0122] In some aspects, the application provides use of a cationic lipid of the application or a nanoparticle composition of the application in the manufacture of a medicament for treating a disease or disorder in an individual in need thereof.

[0123] In embodiments of the application, the individual is a mammal.

[0124] In embodiments of the application, the mammal is a human.

[0125] In some aspects, the application provides methods of synthesizing a cationic lipid of Formula (I), (IA), (II), (III), (IV), or (V) and methods of making a nanoparticle composition comprising a lipid component comprising a cationic lipid of Formula (I), (IA), (II), (III), (IV), or (V).

[0126] Examples The following examples are included to further illustrate the application described herein and to demonstrate embodiments of the application. Those skilled in the art will appreciate that the techniques disclosed in the following examples represent techniques discovered by the inventors to function well in the practice of the application, and, thus, can be considered to constitute examples of modes for its practice. However, it is not intended that this application be limited to the specific embodiments presented in the examples. Based on the disclosure provided herein, one skilled in the art can effect equivalent results and / or modifications in view of these teachings without undue experimentation.

[0127] General Synthetic Strategies wherein L" and L'" are each independently C3-C 14 alkylene; R a , R b , R c and R d are each independently C3-C 21 alkyl or C3-C 21 alkenyl, provided that R a and R b together comprise 3-21 carbon atoms, and R c and R d together comprise 3-21 carbon atoms; and the remaining groups are as defined herein.

[0128] The above general scheme describes a synthetic strategy. In the first row, the bromocarboxylic acid is esterified with the given alcohol to give the bromo-containing ester. The reaction is accomplished by refluxing in toluene with catalytic amounts of p-toluenesulfonic acid. The ester is then oxidized to the aldehyde and used directly in the next reaction.

[0129] In the second line, the carboxylic acid is esterified with a bromoethanol to form a bromine-containing ester on the alcohol (reaction conditions are similar), which is then oxidized to the corresponding aldehyde. In both cases, Kornblum oxidation is performed by heating the bromine-containing ester to 150°C in DMSO and adding NaHCO3. The aldehyde then reacts in a sequential manner. The first reaction is carried out in methanol, with reduction by adding sodium borohydride. A brief post-treatment is performed to remove excess ethanolamine, and a second aldehyde is added. The reaction is carried out in DCM, with sodium triacetoxyborohydride used as the reducing agent. Finally, the carbamate is prepared by reacting the resulting alcohol with phenyl p-nitrophenyl chloroformate, followed by the addition of an amine.

[0130] Representative synthetic route 1 Representative synthetic route 2 Intermediate Example 1. (Method 1) 8-Bromooctyl-2-hexyldecanoate was prepared by dissolving 2-hexyldecanoic acid (5 g, 19.50 mmol), 8-bromooct-1-ol (4.08 g, 19.50 mmol), and TsOH (0.185 g, 0.975 mmol) in 80 mL of dry toluene. The reaction was carried out overnight at 125 °C under Ar conditions with stirring. The solvent was removed by evaporation, and the crude material was purified by column chromatography (EtOAc 10% in hexane) to give the compound as a colorless oil (6.55 gr; 75%). 1 H NMR (400 MHz, CDCl3): δ 0.87 (6H,t, J = 6.61 Hz), 1.25 (29H, m), 1.60 (5H, m), 1.85 (2H, quint, J = 6.92 Hz), 2.31(1H, m), 3.40 (2H, t, J = 6.83 Hz), 4.06 (2H, t, J = 6.60 Hz). MS [ESI]: m / z: [M+H]calc. 447.5 obs. 447.5. Heptadecan-9-yl 8-bromooctanoate was synthesized from 8-bromooctanoic acid and heptadecan-9-ol according to method 1 to obtain the compound in the form of a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.90 (6H, t, J = 6.77 Hz), 1.28 (34H, m), 1.64 (2H, m), 1.86 (2H, quint, J = 6.92 Hz), 2.30 (2H, t, J = 7.44Hz), 3.41 (2H, t, J = 6.83 Hz), 4.89 (1H, quint, J = 6.24 Hz). Hexyl 11-bromoundecanoate is synthesized from 11-bromoundecanoic acid and hex-1-ol according to method 1 to obtain the compound in colorless oil form. 1 H NMR (400 MHz, CDCl3): δ 0.89 (3H, t, J = 6.86 Hz), 1.28 (20H,m), 1.59 (5H, m), 1.76 (1H, t, J = 7.35 Hz), 2.28 (2H, t, J = 7.51 Hz), 3.40 (1H,t, J = 6.86 Hz), 3.52 (1H, t, J = 6.75 Hz), 4.05 (2H, t, J 6.72 Hz). (Z)-Non-3-en-1-yl 6-bromohexanoate was synthesized from 6-bromohexanoic acid and (Z)-non-3-en-1-ol according to method 1 to obtain the title compound in colorless oil form. 1 H NMR (400 MHz, CDCl3): δ 0.90 (3H, t, J =6.79 Hz), 1.32 (6H, m), 1.49 (2H, m), 1.68 (2H, m), 1.89 (2H, quint, J = 6.89Hz), 2.05 (2H, q, J = 7.34 Hz), 2.30-2.44 (4H, 2.33 (t, J = 7.42 Hz), 2.39 (q, J =7.07 Hz), 3.42 (2H, t, J = 6.76 Hz), 4.09 (2H, t,J = 6.92 Hz), 5.36 (1H, m),5.52 (1H, m). 7-Bromoheptyl decanoate was synthesized according to Method 1 from decanoic acid and 7-bromoheptan-1-ol to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 0.87 (3H, t, J = 6.80 Hz), 1.20-1.48(18H, 1.21 (m), 1.26 (m), 1.35 (m)), 1.62 (4H, m), 1.80-1.91 (2H, 1.85 (t, J =7.34 Hz), 1.88 (s)), 2.28 (2H, t, J = 7.38 Hz), 3.39 (2H, t, J = 6.66 Hz), 4.05(2H, t, J = 6.46 Hz). Heptyl 10-bromodecanoate was synthesized according to Method 1 from heptan-1-ol and 10-bromodecanoic acid to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 0.87-0.93 (3H, 0.90 (t, J = 6.93 Hz),0.91 (s)), 1.31 (18H, m), 1.63 (4H, quint, J = 6.97 Hz), 1.86 (2H, quint, J =6.93 Hz), 2.30 (2H, t, J = 7.51 Hz), 3.41 (2H, t, J = 6.86 Hz), 4.07 (2H, t, J =6.73 Hz). Undecyl 6-bromohexanoate was synthesized according to Method 1 from undecan-1-ol and 6-bromohexanoic acid to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 0.90 (3H, t, J= 6.75 Hz), 1.28(16H, m), 1.49 (2H, m), 1.58-1.73 (4H, m), 1.89 (2H, quint, J = 6.89 Hz), 2.33(2H, t, J = 7.42 Hz), 3.42 (2H, t, J = 6.76 Hz), 4.08 (2H, t, J = 6.74 Hz). Intermediate Example 2. (Method 2) 8-oxooctyl 2-hexyl decanoate NaHCO3(3.84 gr; 46.0 mmol) was dissolved in 18 mL DMSO and heated to 150 o C. 8-bromooctyl 2-hexyl decanoate compound (3.54 g, 9.20 mmol) was added in one portion and the reaction stirred at 150 o C until completion. Then 6 volumes of water were added and the mixture extracted with hexanes (60 mL x 3). The organic phases were combined, dried over Na2SO4, filtered and evaporated. The crude oil was purified on silica gel (10% EtOAc in hexanes) to give the title compound as a colorless oil (1.6 gr; 44% yield) which was used directly in the next reaction. MS [ESI]: m / z: [M+H] calc. 383.6 obs. 383.5. Heptadecan-9-yl 8-oxooctanoate was synthesized according to Method 2 from heptadecan-9-yl 8-bromooctanoate to give a yellow oil which was used directly in the next reaction. MS [ESI]: m / z: [M+Na] calc. 419.6 obs. 419.5. Hexyl 11-oxoundecanoate was synthesized according to Method 2 from hexyl 11-bromoundecanoate to give the title compound as a yellow oil. MS [ESI]: m / z: [M+H] calc. 285.4 obs. 285.0. (Z)-Non-3-en-1-yl 6-oxohexanoate was synthesized according to Method 2 from (Z)-non-3-en-1-yl 6-bromohexanoate to give the compound as a yellow oil. MS [ESI]: m / z: [M+H] calc. 255.3 obs. 255.2. 7-oxoheptyl decanoate was synthesized according to method 2 from 7-bromoheptyl decanoate to give the compound as a colorless oil. MS [ESI]: m / z: [M+H] calc. 285.4 obs. 285.6. Heptyl 10-oxodecanoate was synthesized according to method 2 from heptyl 10-bromodecanoate to give the compound as a colorless oil. MS [ESI]: m / z: [M+H] calc. 285.4 obs. 285.6. Undecyl 6-oxohexanoate was synthesized according to method 2 from undecyl 6-bromohexanoate to give the compound as a colorless oil. MS [ESI]: m / z: [M+H] calc. 285.4 obs. 285.1. 2-Octyldodecyl 6-oxohexanoate was synthesized according to method 2 from 2- octyldodecyl 6-bromohexanoate to give the compound as a colorless oil. MS [ESI]: m / z: [M+H] calc. 411.6 obs. 411.5. Intermediate Example 5. (Method 3) (9Z,12Z)-Octadeca-9,12-dien-1-ol (3.5 g, 13.13 mmol) was dissolved in 100 mL DCM. Then sodium bicarbonate (11.03 g, 131 mmol) was added and the solution was stirred at room temperature. Then Dess-Martin Oxidizer (6.69 g, 15.76 mmol) was added in portions and the reaction was stirred at room temperature under argon. The reaction was monitored by TLC until the starting material was completely consumed. The reaction was washed with 100 mL water, 50 mL NaHC03(x2), 50 mL 10% Na2S203and 50 mL brine. The phases were separated and the organic phases were combined, dried over Na2S04, filtered and evaporated. The crude oil obtained was purified by column chromatography (hexane:EtOAc 90:10) to give the title compound as a yellowish oil (2.76 gr; 80% yield).

[0131] Intermediate Example 6. (Method 4) 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octyl 2- hexyldecanoate 8-oxooctyl 2-hexyldecanoate (1.3 g, 3.4 mmol, 1 equiv.) was dissolved in dry methanol (10 mL), ethanolamine (1.2 gr, 15.20 mmol, 5.0 equiv.) was added, and the resulting solution was stirred for 3 hours. After this time, the solution was cooled to 0 °C and sodium borohydride (128 mg, 3.4 mmol, 1 equiv.) was added, and the reaction was stirred for 20 minutes. The solvent was removed by evaporation, and the crude product was redissolved in 75 mL DCM. The organic phase was washed with a saturated solution of NaHC03(30 mL x 2), brine (30 mL x 1), filtered over Na2S04, and evaporated. The crude material was redissolved in 25 mL dry DCM. (9Z,12Z)-octadeca-9,12-dienal (1.5 g, 4.0 mmol, 1 equiv.) was added, and the solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (1.4 g, 6.8 mmol, 2.0 equiv.) was added, and the reaction was stirred under argon overnight. The reaction was quenched with a saturated solution of NaHC03, and extracted with DCM (3 times). The organic fraction was washed with a brine solution and dried over anhydrous Na2S04. The solvent was evaporated, and the crude material was purified by column chromatography to give a colorless oil (5.61 gr; 90% yield MS [ESI]: m / z: [M+H] calc. 691.2 obs. 690.9; 1 H NMR (500 MHz, CDCl3): δ 0.88(9H, m), 1.28 (47H, m), 1.50 (8H, m), 1.61 (2H, m), 2.05 (4H, q, J = 7.59Hz), 2.27 (2H, t, J = 7.61 Hz), 2.55 (4H, m), 2.67 (2H, m), 2.77 (2H, t, J =6.73 Hz), 3.60 (2H, m), 4.86 (1H, i, J = 6.79 Hz), 5.35 (4H, m). Intermediate Example 6. (Method 5) 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octyl 2- hexyldecanoate 8-oxooctyl 2-hexyldecanoate (1.3 g, 3.4 mmol, 1 equiv.) was dissolved in dry methanol (10 mL), ethanolamine (1.2 gr, 15.20 mmol, 5.0 equiv.) was added, and the resulting solution was stirred for 3 hours. After this time, the solution was cooled to 0°C, and sodium borohydride (128 mg, 3.4 mmol, 1 equiv) was added, the reaction was stirred for 20 minutes, the solvent was removed by evaporation, and the crude product was redissolved in 75 mL DCM. The organic phase was washed with a saturated solution of NaHC03(30 mL x 2), brine (30 mL x 1), dried with Na2S04, filtered, and evaporated. The crude material was redissolved in 25 mL dry DCM. Heptadecan-9-yl 8-oxooctanoate (1.34 g, 4.0 mmol, 1 equiv.) was added, and the solution was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (1.4 g, 6.8 mmol, 2.0 equiv.) was added, and the reaction was stirred under argon overnight. The reaction was quenched with a saturated solution of NaHC03, and extracted with DCM (3 times). The organic fraction was washed with a brine solution, and dried with anhydrous Na2S04. The solvent was evaporated, and the crude product was purified by column chromatography to obtain a colorless oil (5.61 gr; 90% yield). MS [ESI]: m / z: [M+H] calc. 809.4 obs. 809.3 1 H NMR (400 MHz, CDCl3): δ ppm 4.86 (p,1H); 4.06 (t, 2H); 3.53 (m, 2H); 2.58 (m, 2H); 2.44 (m, 4H); 2.27 (m+t, 3H),1.61 -1.28 (m, 74), 0.88 (m, 12H). Compound 1 Heptadecan-9-yl 8-((3-hydroxypropyl)((9Z,12Z)-octadeca-9,12-dien-1- yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 704.7 obs. 704.7; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.31 (54H, m), 1.64 (4H,m), 2.05 (4H, q, J= 7.43 Hz), 2.27 (2H, t, J = 7.51 Hz), 2.39 (4H, m), 2.62 (2H,t, J = 5.54 Hz), 2.77 (2H, t, J = 6.03 Hz), 3.79 (2H, t, J = 5.81 Hz), 4.86 (1H,quint, J = 6.21 Hz), 5.36 (4H, m). Compound 2 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(3-hydroxypropyl)amino)octan-2- yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 822.8 obs. 823.0; 1 H NMR (500 MHz, CDCl3): δ 0.87 (12H, m), 1.26 (75H, m), 2.27 (3H,m), 2.39 (4H, dd, J = 9.08, 6.30 Hz), 2.63 (2H, dd, J = 6.30, 4.49 Hz), 3.79 (2H,dd, J = 5.77, 4.27 Hz), 4.06 (2H, t, J = 6.52 Hz), 4.87 (1H, m), 5.66 (1H, m). Compound 3 8-((7-(decanoyloxy)heptyl)(3-hydroxypropyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 710.7 obs. 710.5; 1 HNMR (500 MHz, CDCl3): δ 0.87 (9H, m), 1.26 (46H, m), 1.61 (13H, m), 2.29 (4H,m), 2.40 (4H, m), 2.63 (2H, m), 3.64 (1H, m), 3.79 (2H, m), 4.06 (4H, m),5.65 (1H, m). Compound 4 Bis(2-octyldodecyl) 6,6'-((3-hydroxypropyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 864.8 obs. 864.9; 1 H NMR (400 MHz, CDC13): δ 0.88 (12H, t, J = 7.20 Hz), 1.27 (65H, m), 1.59 (14H, m),2.30 (4H, t, J = 7.68 Hz), 2.40 (4H, m), 2.62 (2H, t, J = 5.89 Hz), 3.78 (2H, t, J = 5.26 Hz), 3.97 (4H, d, J = 5.79 Hz), 5.46 (1H, bs). Compound 5 ((3-hydroxypropyl)azanediyl)bis(octan-8,1-diyl) bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 808.8 obs. 809.0; 1 H NMR (400 MHz, CDC13): δ 0.88 (12H, t, J = 6.70 Hz), 1.27 (52H, m), 1.44 (9H,m), 1.60 (12H, m), 2.31 (2H, tt, J = 8.98, 5.31 Hz), 2.36-2.43 (4H, 2.40 (t, J =7.63 Hz), 2.39 (d, J = 4.78 Hz)), 2.63 (2H, t, J = 5.42 Hz), 3.79 (2H, t, J = 5.06Hz), 4.06 (4H, t, J = 6.66 Hz), 5.65 (1H, m). Compound 7 2-octyldodecyl 6-((2-hydroxyethyl)((9Z,12Z)-octadeca-9,12-dien-1- yl)amino)hexanoate was synthesized according to Representative Synthetic Route 1 and Method 4. MS [ESI]: m / z: [M+H] calc. 705.2 obs. 705.2 1 H NMR (400 MHz, CDCl3): δ 0.90 (9H, m), 1.30 (53H, m), 1.68 (6H,m), 2.06 (4H, q, J = 7.08 MHz), 2.33 (2H, t, J = 7.31 MHz), 2.47 (1H, m),2.79 (3H, m), 2.92 (3H, m), 3.86 (1H, m), 3.98 (2H, m), 5.37 (4H, m). Compound 8 hexyl 11-((8-((2-hexyldodecanoyl)oxy)octyl)(2-hydroxyethyl)amino)undecanoate was synthesized according to Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 697.1 obs. 697.8 1 HNMR (400 MHz, CDCl3): δ 0.89 (9H, m), 1.31 (52H, m), 1.64 (11H, m), 2.30 (3H,m), 2.93 (2H, m), 3.02 (1H, m), 3.89 (2H, m), 4.07 (4H, t, J = 6.66 Hz). Compound 9 8-((2-hydroxyethyl)(6-((2-octyldodecyl)oxy)-6-oxohexyl)amino)octyl 2- hexyldodecanoate was synthesized according to Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 823.4 obs. 823.1 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H, m), 1.27 (69H, m), 1.62 (10H,m), 2.31 (3H, m), 2.75 (2H, m), 2.86 (1H, m), 3.76 (1H, m), 3.96 (2H, d, J =5.77 Hz), 4.05 (2H, t, J = 6.66 Hz). Compound 10 Undecyl 2-methyl-10-((9Z,12Z)-octadeca-9,12-dien-1-yl)-6-oxo-7-oxa- 2,5,10-triazahexadecanoate was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 578.9 obs. 578.9 1 H NMR (400 MHz, CDCl3): δ 0.90 (6H, h, J =4.22 Hz), 1.29 (40H, m), 1.64 (4H, m), 2.07 (4H, q, J = 6.77 Hz), 2.32 (2H,t, J = 7.48 Hz), 2.45 (4H, m), 2.58 (2H, t, J = 5.38 Hz), 2.79 (2H, t, J =6.32 Hz), 3.53 (2H, t, J = 5.37 Hz), 4.07 (2H, t, J = 6.76 Hz), 5.38 (3H, m). Compound 11 2-(((Z)-octadec-9-en-1-yl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethan-1- ol was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 561.0 obs. 560.6 1 H NMR (500 MHz, CDCl3): δ 0.88 (6H, m), 1.29 (45H, m), 1.55 (2H,m), 2.05 (7H, m), 2.63 (2H, m), 2.76 (3H, m), 3.67 (1H, m), 5.35 (4H, m). Compound 12 ((2-hydroxyethyl)azanediyl)bis(octan-8, 1 - diyl)bis(2-hexyldecanoate) was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 794.8 obs. 795.0; 1H NMR (400 MHz, CDCl3): δ 0.87 (12H, m), 1.25 (65H, m), 1.60 (10H, m), 2.30 (2H, m), 2.50 (3H, m), 2.62 (1H, m), 3.56 (1H, m), 4.06 (4H, t, J = 6.66 Hz). Compound 13 2-(di((9Z,12Z)-octadeca-9, 12-dien-1-yl)amino)ethan-1-ol was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 558.6 obs. 558.7; 1 H NMR (400MHz, CDCl3): δ 0.90 (6H, m), 1.32 (34H, m), 1.58 (3H, m), 2.06 (8H, m), 2.66(3H, m), 2.78 (6H, m), 3.69 (2H, m), 5.37 (8H, m). Compound 14 (Z)-non-3-en-1-yl 6-((2-hydroxyethyl)((9Z,12Z)-octadeca-9, 12-dien-1-yl)amino)hexanoate was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 548.5 obs. 548.6; 1H NMR (500 MHz, CDCl3): δ 0.88 (6H, t, J = 7.23 Hz), 1.30(25H, m), 1.51 (4H, m), 1.64 (2H, m), 2.04 (6H, m), 2.30 (2H, t, J = 7.43 Hz),2.37 (2H, q, J = 6.98 Hz), 2.55 (4H, m), 2.67 (2H, m), 2.77 (2H, t, J = 6.79 Hz),3.60 (2H, m), 4.06 (2H, t, J= 6.95 Hz), 5.35 (5H, m), 5.50 (1H, m). Compound 15 diheptyl 10,10'-((2-hydroxyethyl)azanediyl) bis(decanoate) was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 598.5 obs. 598.6; 1H NMR (500 MHz, CDC13): δ 0.88 (6H, m), 1.29 (36H, m), 1.58 (12H, m), 2.28 (4H, t, J = 7.77Hz), 2.59 (4H, m), 2.71 (2H, m), 3.64 (2H, m), 4.05 (4H, t, J = 6.73 Hz). Compound 16 (Z)-8-((2-hydroxyethyl)(6-(non-3-en-1- yloxy)-6-oxohexyl)amino)octyl 2-hexyl decanoate was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 666.6 obs. 666.7; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.30 (42H, m), 1.61 (7H,m), 2.03 (2H, q, J = 7.60 Hz), 2.37 (9H, m), 2.56 (2H, t, J = 5.58 Hz), 3.51 (2H,t, J = 5.49 Hz), 4.06 (4H, m), 5.34 (1H, m), 5.50 (1H, m). Compound 17 8-((7-(decanoyloxy)heptyl)(2-hydroxyethyl)amino)octan-2- yl hexyl decanoate was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 696.7 obs. 697.0; 1H NMR (500 MHz, CDC13): δ 0.87 (9H, m), 1.29 (48H, m), 1.60 (12H, m), 2.28 (3H, m), 2.70 (4H, m), 2.82 (2H, m), 3.64 (1H, t, J = 6.63 Hz), 3.72 (2H, m), 4.05 (4H, m). Compound 18 ((2-hydroxyethyl)azanediyl)bis(octane-8, 1-diyl)bis(decanoate) was synthesized according to the Representative Synthetic Route and Method 4. MS [ESI]: m / z: [M+H] calc 626.6 obs. 626.7; 1 H NMR (400MHz, CDC13): δ 0.88 (6H, t, J = 7.15 Hz), 1.30 (45H, m), 1.61 (8H, m), 2.28 (4H, t, J = 7.68 Hz), 2.43 (4H, m), 2.57 (2H, t, J = 5.37 Hz), 3.52 (2H, t, J =5.38 Hz), 4.05 (4H, t, J = 6.73 Hz). Intermediate Example P1. 8-hydroxyoctyl 2-hexyldecanoate compound

[001] 8-bromooctan-1-ol (2.05 g, 9.80 mmol) and 2-hexyldecanoic acid (2.51 g, 9.80 mmol) were placed in a 100 mL RBF. The flask was evacuated and purged with argon (x2). Then 40 mL of dry DMF was added followed by potassium carbonate (2.71 g, 19.61 mmol). The suspension was stirred at 60 °C overnight. Then the reaction was poured into 120 mL of 1M HCI. The resulting solution was extracted with 60 mL of hexane (x3), dried with Na2S04, filtered and evacuated under vacuum. The crude material was purified by column chromatography hexane 9:1 EtOAc to give compound

[001] as a yellowish oil (3.54 gr; 9.2 mmol; 94% yield). 1 H NMR (400 MHz, CDCl3): δ 4.06 (2H, t, J = 6.67 Hz); 3.62 (2H, t, J = 6.62 Hz); 2.35-2.25 (1H, m); 1.66-1.48 (6H, m); 1.46-1.16 (30H, m); 0.86 (6H, t, J = 6.87 Hz). MS [ESI]: m / z: [M+H] calc. 385.4 obs. 385.6 [M+Na] calc. 407.3 obs. 407.6 Intermediate Example P2. 8-oxooctyl 2-hexyldecanoate compound

[002] 8-hydroxyoctyl 2-hexyldecanoate (3.54 g, 9.20 mmol) was dissolved in 100 mL of DCM. PCC (2.98 g, 13.80 mmol) was added in portions over 10 minutes and the reaction was stirred at room temperature. After 2 hours the reaction mixture was passed through a plug of silica gel (eluted with DCM) to give compound 2 as a colorless oil (3.1 gr; 88% yield). It was used directly in the next reaction.

[0132] Intermediate Example P3. Heptadecan-9-yl 8-bromooctanoate Compound

[003] 8-Bromooctanoic acid (4.70 g, 21.05 mmol) and heptadecan-9-ol (4.5 g, 17.55 mmol) were dissolved in 75 mL of dry DCM. EDC (6.73 g, 35.1 mmol) and DMAP (0.429 g, 3.51 mmol) were added and the resulting solution was stirred at room temperature overnight. The solvent was evaporated and 60 mL of hexane was added. The reaction solution was stirred vigorously, washed with brine (100 mL x 2), dried over Na2S04, filtered and evaporated. The crude material was then purified by column chromatography (EtOAc 5:95 hexane) to give compound

[003] as a light brown oil (5.32 gr; 66% yield). 1 H NMR (400 MHz, CDCl3): δ ppm 4.89 (m, 1H); 3.42 (m, 2H); 2.31 (m, 2H); 1.89 (m, 2H); 1.73 - 1.18 (br m, 36H); 0.88 (m, 6H). Intermediate Example P4. Heptadecan-9-yl 8-((2-hydroxyethyl)amino)octanoate Compound

[004] Heptadecan-9-yl 8-bromooctanoate (5.32 g, 11.53 mmol) was dissolved in 10 mL of EtOH. Ethanolamine (20.91 ml, 346 mmol) was added and the resulting solution was stirred at 65 °C overnight. The reaction mixture was evaporated under vacuum and the crude material was dissolved in 40 mL of EtOAc. The organic layer was washed with water 30 mL x 2, dried over Na2S04, filtered and evaporated. The crude oil was purified by column chromatography (0.1% TEA, 10% MeOH in DCM) to give compound

[004] as a light yellow oil (3.84 gr 75% yield). 1 H NMR (400 MHz, CDCl3): δ ppm 4.86 (p. 1H); 3.67 (t, 2H); 2.83 (t, 2H) 2.67 (t,2H); 2.32 (t, 2H) 1.96 (br m, 2H); 1.72-1.41 (m, 37H); 0.88 (m, 6H). MS [ESI]: m / z: [M+H] calc. 442.4 obs. 442.6 Intermediate Example P5. 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octyl 2- hexyldecanoate Compound

[005] 8-oxooctyl 2-hexyldecanoate (3.09 g, 8.08 mmol) and heptadecan-9-yl 8-((2- hydroxyethyl)amino)octanoate (3.4 g, 7.70 mmol) were both dissolved in 120 mL dry DCM. The solution was stirred at room temperature for 2 hours. Then sodium triacetoxyborohydride (3.26 g, 15.39 mmol) was added and the resulting suspension was stirred at room temperature overnight under argon. 40 mL NaHC03saturated solution was added and the phases were separated. The organic phase was washed with brine (40 mL), dried over Na2S04, filtered and evaporated. The crude material was purified by column chromatography (CHCI3with 1-5% iPrOH) to give Compound

[005] as a colorless oil (5.61 gr; 90% yield). MS [ESI]: m / z: [M+H] calc. 809.4 obs. 809.3 1 H NMR (400 MHz, CDCl3): δ ppm 4.86 (p, 1H); 4.06 (t, 2H); 3.53 (m, 2H);2.58 (m, 2H); 2.44 (m, 4H); 2.27 (m+t, 3H), 1.61 -1.28 (m, 74), 0.88 (m, 12H) Intermediate Example P6. ((2-hydroxyethyl)azanediyl)bis(octane-8,1-diyl)bis(2-hexyldecanoate) Compound

[006] 8-oxooctyl 2-hexyldecanoate (1.391 g, 3.63 mmol) and ethanolamine (0.110 ml, 1.817 mmol) were dissolved in 25 mL DCM. The reaction mixture was stirred at room temperature under argon for 2 hours. Then sodium triacetoxyborohydride (1.155 g, 5.45 mmol) was added portionwise over 10 minutes and the reaction mixture was left overnight. Then the reaction was washed with 40 mL NaHC03(40 mL) and brine (40 mL x 2) and then the organic phase was dried over Na2S04, filtered and evaporated. The crude material was then purified by column chromatography (DCM with 2% iPrOH) to give Compound

[006] as a colorless oil (1.095 gr; 76% yield). 1H NMR (400 MHz, CDC13): δ ppm 4.05 (4H, t, J = 6.67 Hz); 3.54 (2H, t, J = 5.57 Hz) 2.59 (2H, t, J = 5.57 Hz); 2.46 (4H, t, J = 7.65 Hz); 2.34 - 2.24 (2H, m); 1.68 - 1.50 (8H, m); 1.48 - 1.36 (8H, m); 1.36 - 1.16 (56H, m); 0.86 (12H, t, J = 6.87 Hz); MS [ESI]: m / z: [M+H] calc. 795.4 obs. 795. Intermediate Example P7. 8-((2-hydroxyethyl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)octyl 2-hexyldecanoate compound

[007] Intermediate Example P7. Example 1 (Method 6) Octadecan-9-yl 10-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa- 2,5,10-triazaoctadecan-18-oate Lipid 66 8-((8-(Octadecan-9-yloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octan-2- yl hexyldecanoate (0.3 g; 0.37 mmol) and 4-nitrophenyl chloroformate (0.090 g; 0.45 mmol) were dissolved in 10 mL dry DCM. TEA (0.103 ml; 0.742 mmol) was added and the reaction was stirred at room temperature overnight. Then 2N 1,1-dimethylethane-1,2-diamine (0.083 g; 0.93 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was then directly subjected to column chromatography (DCM with 2% - 10% iPrOH) to give Lipid 66 as a yellow oil (297 mg; 83%); MS [ESI]: m / z: [M+H] calc. 923.5 obs. 923.5. 1 H NMR (400 MHz, CDCl3): δ 0.85 (12H, m), 1.23 (73H, m), 2.19 (6H, s),2.22-2.30 (3H, 2.25 (t, J = 7.54 Hz), 2.27 (m)), 2.34-2.45 (7H, 2.40 (m), 2.42(t, J = 7.58 Hz)), 2.64 (2H, t, J = 5.96 Hz), 3.23 (2H, q, J = 5.52 Hz), 4.03 (4H,m), 4.84 (1H, i, J = 6.21 Hz), 5.19-5.25 (1H, m). Lipid 6 10-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa-2,5,10- triazaoctadecan-18-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 908.8 obs. 909.3; 1 H NMR (500 MHz, CDCl3): δ 0.87 (12H, t, J= 6.84Hz), 1.26 (55H, m), 1.42 (4H, m), 1.58 (12H, m), 2.30 (3H, m), 2.39 (5H, m),2.65 (6H, m), 2.90 (3H, m), 3.35 (2H, m), 4.05 (4H, t, J = 6.68 Hz), 4.24 (2H,m), 5.24 (1H, m). Lipid 8 ((2-(((4-((tert-butoxycarbonyl)amino)benzyl)carbamoyl)oxy)ethyl)azanediyl)bis(octane-8, 1-diyl) bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1043.6 obs. 1043.2 1H NMR (500 MHz, CDCl3): δ 0.87 (12H, t, J = 6.84 Hz), 1.27 (53H, m), 1.42 (5H, m), 1.51 (6H, s), 1.61 (14H, m), 2.30 (2H, m), 2.91 (6H, m), 3.21 (6H, m), 3.79 (1H, m), 4.05 (4H, t, J = 6.94 Hz), 4.29 (2H, d, J = 5.98 Hz), 4.41 (2H, m), 7.21 (2H, d, J = 8.01 Hz), 7.32 (2H, d, J = 8.01 Hz). Lipid 35 2-(Di((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethyl(pyridin-4-ylmethyl)carbamate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 693.1 obs. 692.6 1H NMR (400 MHz, CDC13): δ 0.88 (6H, t, J = 6.66 Hz), 1.29 (33H, m), 1.49 (4H, m), 2.04 (8H, m), 2.58 (3H, m), 2.77 (6H, m), 4.22 (2H, t, J = 5.80 Hz), 4.37 (2H, d, J = 6.15 Hz), 5.35 (8H, m), 5.59 (1H, m), 7.21 (2H, d, J = 5.90 Hz), 8.54 (2H, d, J = 5.90 Hz). Lipid 36 2-(Di((9Z,12Z)-octadeca-9, 12-dien-1-yl)amino)ethyl (2- morpholinoethyl)carbamate was synthesized according to the general synthetic route and general procedure. MS [ESI]: m / z: [M+H] calc 715.1 obs. 714.9 1 H NMR (400 MHz, CDC13): δ 0.89 (6H, t, J = 6.66 Hz), 1.29 (33H, m), 1.49 (4H, m), 2.04 (8H, m), 2.45 (6H, m), 2.57 (5H, m), 2.77 (6H, m), 3.28 (2H, m), 3.69 (4H, m), 4.19 (2H, m), 5.35 (8H, m). J Lipid 37 2-(Di((9Z,12Z)-octadeca-9, 12-dien-1-yl)amino)ethyl (2-(4- methylpiperazin-1-yl)ethyl)carbamate was synthesized according to the general synthetic route and general procedure. MS [ESI]: m / z: [M+H] calc 728.7 obs. 727.9 1 H NMR (400 MHz, CDC13): δ 0.88 (6H, t, J = 6.66 Hz), 1.29 (33H, m), 1.49 (4H, m), 2.04 (8H, m), 2.35 (3H, s), 2.55 (13H, m), 2.78 (6H, m), 3.27 (2H, m), 4.18 (2H, t, J = 5.81 Hz), 5.35 (8H, m). ​ Lipid 39 2-(Di((9Z,12Z)-octadeca-9, 12-dien-1-yl)amino)ethyl((1H- imidazol-2-yl)methyl)carbamate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 728.7 obs. 727.9 1H NMR (400 MHz, CDCl3): δ 0.88 (6H, t, J = 6.75 Hz), 1.30 (32H, m), 1.56 (4H, m), 2.04 (8H, m), 2.67 (2H, m), 2.77 (6H, t, J = 6.41 Hz), 2.88 (1H, m), 2.97 (1H, m), 4.29 (2H, m), 4.38 (1H, m), 4.47 (1H, d, J = 6.15 Hz), 5.35 (8H, m), 6.01 (1H, m), 6.94 (2H, m). Lipid 41 2-(Di((9Z,12Z)-octadeca-9, 12-dien-1-yl)amino)ethyl(2- (dimethylamino)ethyl)carbamate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 672.1 obs. 672.6; 1 H NMR (400 MHz, CDCl3): δ 0.88 (6H, t, J = 6.66 Hz), 1.30 (32H, m), 1.48 (4H, m), 2.04 (8H, m), 2.27 (6H, m), 2.47 (2H, m), 2.56 (4H, m), 2.77 (6H, m), 3.28 (2H, m), 4.18 (2H, t, J = 6.06 Hz), 5.35 (8H, m), 5.47 (1H, m). Lipid 43 Hexyl 10-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa- 2,5,10-triazahenicosan-21-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 811.3 obs. 811.0; 1H NMR (500 MHz, CDC13): δ 0.88 (9H, m), 1.24-1.35 (46H, m), 1.40-1.46 (3H, m), 1.53-1.63 (11H, m), 2.29 (2H, s), 2.40 (5H, s), 2.46 (1H, s), 2.59-2.64 (2H, m), 2.65-2.71 (4H, m), 2.89-2.93 (2H, m), 3.31-3.38 (3H, m), 4.05-4.08 (4H, 4.06 (s), 4.07 (s)), 4.21-4.26 (2H, m), 5.86-5.91 (1H, m). Lipid 46 Hexyl 11-((8-((2-hexyldecanoyl)oxy)octyl)(2-(((2-(4- methylpiperazin-1-yl)ethyl)carbamoyl)oxy)ethyl)amino)undecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 866.4 obs. 866.0; 1 H NMR 1 H NMR (500 MHz, CDC13): δ 0.88 (9H, m), 1.24-1.35 (46H, m), 1.40-1.46 (3H, m), 1.53-1.63 (11H, m), 2.29 (2H, s), 2.40 (5H, s), 2.46 (1H, s), 2.59-2.64 (2H, m), 2.65-2.71 (4H, m), 2.89-2.93 (2H, m), 3.31-3.38 (3H, m), 4.05-4.08 (4H, 4.06 (s), 4.07 (s)), 4.21-4.26 (2H, m), 5.86-5.91 (1H, m). Lipid 51 2-Octyldodecyl 10-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa- 2,5,10-triazahexadecan-16-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 937.5 obs. 937.2; 1 H NMR (400 MHz, CDC13): δ 0.88 (12H, t, J =6.83 Hz), 1.26 (62H, s), 1.44 (4H, m), 1.63 (8H, m), 2.22 (6H, s), 2.30 (4H,t, J= 7.53 Hz), 2.39 (2H, t, J = 6.12 Hz), 2.42-2.47 (4H, m), 2.66 (2H, t, J =5.86 Hz), 3.20-3.27 (2H, m), 3.96 (4H, d, J = 5.81 Hz), 4.09 (1H, m), 5.22-5.27(1H, m). Lipid 52 2-octyldodecyl 11-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-7-oxo-8-oxa- 2,6,11-triazahexadecan-17-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 950.6 obs. 950.8; 1H NMR (400 MHz, CDCl3): δ 0.87 (12H, m), 1.26 (65H, m), 1.42 (3H, m), 1.58 (10H, m), 2.30 (4H, t, J = 7.60 Hz), 2.37 (4H, t, J = 1.62 Hz), 2.60 (4H, m), 2.82 (2H, m), 3.33 (2H, m), 3.57 (3H, m), 3.96 (2H, d, J = 5.81 Hz), 4.05 (2H, t, J = 6.75 Hz), 4.19 (2H, t, J = 5.89 Hz). Lipid 67 2-(((Z)-octadec-9-en-1-yl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethyl (2-(dimethylamino)ethyl)carbamate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 674.2 obs. 674.9; 1 H NMR (400 MHz): δ 0.88 (6H, td, J =6.70, 4.10 Hz), 1.22-1.55 (43H, 1.27 (m), 1.46 (br s)), 2.04 (8H, m), 2.24(5H, s), 2.43 (2H, t, J= 5.94 Hz), 2.48-2.55 (4H, 2.51 (t, J = 7.67 Hz), 2.51(d, J = 4.44 Hz)), 2.76 (4H, m), 3.26 (2H, m), 4.15 (2H, t, J = 5.97 Hz), 5.35(7H, m). Lipid 68 2-(((Z)-octadec-9-en-1-yl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethyl((1H- imidazol-2-yl)methyl)carbamate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 684.1 obs. 683.8; 1 H NMR (500 MHz, CDCl3): δ 0.88 (6H,m), 1.22-1.34 (39H, m), 1.47-1.56 (4H, m), 2.03 (8H, m), 2.59-2.68 (4H, m),2.77 (2H, m), 2.85 (2H, m), 4.28 (2H, m), 4.35 (1H, m), 4.42 (1H, m), 5.34(7H, m), 6.89-6.91 (1H, m), 6.96 (1H, s). Lipid 69 2-(((Z)-octadec-9-en-1-yl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethyl(3- (diethylamino)propyl)carbamate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 716.2 obs. 716.9; 1 H NMR (400 MHz, CDCl3): δ 0.88 (6H,m), 1.28 (42H, m), 1.40-1.50 (4H, m), 2.04 (7H, m), 2.47-2.54 (4H, 2.51 (t, J =7.65 Hz), 2.51 (d, J= 4.44 Hz)), 2.68-2.81 (9H, m), 4.13 (2H, m), 5.35 (6H,m), 1.77-1.85 (1H, m), 3.23-3.30 (2H, m), 1.15-1.20 (5H, m), 5.84-5.91 (1H,m). Lipid 70 2-(((Z)-octadec-9-en-1-yl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)ethyl (2-(4-methylpiperazin-1-yl)ethyl)carbamate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 729.2 obs 729.9;1H NMR (400 MHz, CDCl3): δ 0.90 (6H m), 1.31 (37H, m), 1.55 (4H, m), 2.04 (8H, m), 2.41 (3H, s), 2.53 (2H, m), 2.65 (9H, m), 2.79 (2H, t, J = 6.32 Hz), 2.88 (2H, m), 3.15 (3H, s), 3.29 (2H m), 4.23 (2H, m), 5.39 (7H, m). Lipid 75 2-octyldodecyl 2-methyl-10-((9Z,12Z)-octadeca-9,12-dien-1-yl)-6-oxo-7-oxa-2,5,10-triazahexadecan-16-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 819.3 obs. 819.1; 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H, m), 1.28 (52H, m), 1.43-1.54 (3H, m), 1.58-1.69 (3H, m), 2.06 (5H, q, J = 7.08Hz), 2.30 (8H, m), 2.43-2.58 (5H, m), 2.78 (3H, q, J = 6.12 Hz), 3.31 (1H, m),3.98 (2H, d, J= 5.75 Hz), 4.13-4.19 (2H, m), 5.37 (4H, m), 5.48-5.54 (1H, m). Lipid 76 2-Octyldodecyl 6-((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien- 1 -yl)amino)hexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 827.3 obs. 827.1 1 H NMR (400 MHz, CDCl3): δ 0.88(9H, m), 1.26 (49H, m), 1.62 (7H, m), 2.02 (4H, m), 2.24-2.33 (2H, m), 2.76(5H, m), 3.96 (2H, d, J = 5.78 Hz), 4.30 (9H, m), 4.46 (2H, t, J = 5.79 Hz),5.31-5.39 (4H, m), 6.96 (2H, m), 2.89-2.99 (1H, m). Lipid 78 2-Octyldodecyl 6-((2-(((2-(4-methylpiperazin-l-yl)ethyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien- 1 -yl)amino)hexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 873.5 obs. 873.0 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.88 (9H, m), 1.28 (46H, m), 1.46 (3H, sm), 1.62 (3H, m), 1.99(4H, m), 2.04 (5H, m), 2.32 (11H, m), 2.51 (3H, m), 2.75 (4H, m), 3.26 (2H,m), 3.35 (4H, q, J = 5.86 Hz), 3.52 (1H, m), 3.96 (2H, d, J = 5.81 Hz), 4.13 (2H,t,J = 6.15 Hz), 5.35 (4H, m), 6.11 (1H, m). Lipid 79 2-octyldodecyl 6-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien-1-yl)amino)hexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 860.4 obs. 861.0; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.26 (51H, s), 1.52-1.67 (6H, m), 2.04 (5H, dtd, J = 7.52, 6.58, 1.54 Hz),2.31 (2H, t, J = 7.39 Hz), 2.42-2.52 (7H, m), 2.76 (5H, m), 2.89-2.95 (1H, m),3.24-3.32 (2H, m), 3.68-3.74 (5H, m), 3.96 (2H, d, J = 5.79 Hz), 4.25-4.31 (1H,m), 5.30-5.38 (4H, m), 5.55-5.61 (1H, m). Lipid 81 2-octyldodecyl 2-methyl-11-((9Z,12Z)-octadeca-9, 12-dien-1-yl)-7-oxo-8-oxa- 2,6,11-triazahexadecan-17-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 832.4 obs. 833.0; 1 H NMR (400 MHz, CDCl3): δ 0.90 (9H,m), 1.28 (51H, m), 1.57-1.75 (7H, m), 2.07 (5H, m), 2.34 (1H, s), 2.70-2.73(4H, 2.72 (s), 2.73 (s)), 2.76-2.80 (2H, 2.77 (s), 2.79 (d, J= 2.56 Hz)),2.83-2.90 (5H, m), 3.01-3.09 (8H, m), 3.30-3.37 (2H, m) 3.98 (2H, d, J = 5.80Hz), 4.27-4.33 (2H, m), 5.37 (2H, m), 6.23 – 6.30 (1H, br s). Lipid 90 Undecyl 6-((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien- 1 -yl)amino)hexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 702.1 obs. 701.9; 1 H NMR (400 MHz): δ 0.88 (6H, m), 1.26(40H, m), 1.61 (4H, m), 2.04 (4H, q, J = 5.89 Hz), 2.28 (2H, m), 2.44 (2H, m),2.55-2.68 (3H, m) 2.77 (3H, m), 4.02-4.07 (2H, 4.04 (t, J = 5.90 Hz), 4.05 (t, J = 6.77 Hz)), 4.11-4.16 (1H, m), 4.25-4.28 (1H, m), 4.36 (2H, m), 5.35 (4H,m), 6.95 (2H, m). Lipid 99 (Z)-Non-3-en-1-yl 6-(((9Z,12Z)-octadeca-9,12-dien-1-yl)(2-(((pyridin-4- ylmethyl)carbamoyl)oxy)ethyl)amino)hexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 682.0 obs. 683.2; 1 H NMR (400 MHz, CDCl3): δ 0.88 (6H,m), 1.27 (26H, m), 1.62 (3H, m), 2.04 (7H, m), 2.29 (2H, s), 2.36 (2H, q, J= 6.78 Hz), 2.45 (4H, m), 2.68 (2H, t, J = 5.72 Hz), 2.77 (2H, t, J = 6.03 Hz),4.03 (2H, t, J = 6.93 Hz), 4.15 (2H, t, J = 5.92 Hz), 4.38 (2H, d, J = 6.20 Hz),5.35 (6H, m), 5.49 (1H, m), 7.21 (2H, dd, J = 4.26, 1.53 Hz), 8.55 (2H, dd, J =4.58, 1.42 Hz). Lipid 118 diheptyl 10,10'-((2-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)ethyl)azanediyl)bis(decanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 753.1 obs. 753.0. 1 H NMR (400 MHz, CDCl3): δ 0.88 (6H, t, J = 6.85 Hz), 1.27(43H, m), 1.53-1.64 (11H, m), 2.27 (4H, t, J = 7.57 Hz), 2.67 (2H, t, J = 6.35Hz), 3.24 (2H, m), 4.05 (4H, t, J = 6.75 Hz), 5.26 (1H, s), 2.42 (6H, m), 4.08-4.14 (2H, m), 2.31-2.36 (3H, m). Lipid 119 diheptyl 10,10'-((2-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)ethyl)azanediyl)bis(decanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 739.1, obs. 738.9. 1 H NMR (400 MHz, CDCl3): δ 0.88 (6H, t, J= 6.88 Hz), 1.28(39H, m), 1.56-1.65 (8H, 1.60 (quint, J = 7.24 Hz), 1.58 (s), 1.59 (s)), 1.75(4H, quint, J = 3.18 Hz), 2.28 (4H, t, J = 7.54 Hz), 2.46 (11H, m), 2.67 (2H, t, J = 5.97 Hz), 3.24-3.30 (2H, 3.27 (d, J = 6.67 Hz), 3.25 (d, J = 0.68 Hz)), 4.01-4.13 (7H, 4.10 (m), 4.05 (t, J = 6.74 Hz). Lipid 120 Heptyl 10-(10-(heptyloxy)-10-oxodecyl)-2-methyl-6-oxo-7-oxa-2,5,10- triazahenicosan-20-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H]calc 713.1 obs. 712.9; 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.88 (6H,t, J = 6.87 Hz), 1.23-1.36 (37H, m), 1.39-1.44 (3H, m), 1.60 (8H, m), 2.20-2.22(6H, 2.21 (s), 2.21 (s)), 2.28 (4H, t, J = 7.53 Hz), 2.38 (2H, t, J = 6.02 Hz),2.41-2.47 (4H, 2.44 (t, J = 7.62 Hz), 2.44 (d, J = 4.44 Hz)), 2.67 (2H, t, J = 6.00Hz), 3.23 (2H, m), 4.02-4.13 (6H, 4.05 (t, J = 6.74 Hz), 4.10 (t, J= 5.99 Hz). Lipid 122 Heptyl 3-ethyl-12-(10-(heptyloxy)-10-oxodecyl)-8-oxo-9-oxa-3,7,12- triazadocosan-22-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 755.2 obs. 754.9; 1H NMR (400 MHz, CDCl3): δ 0.88 (6H, t, J = 6.84 Hz),1.02 (6H, t, J = 7.14 Hz), 1.28 (40H, m), 1.61 (11H, m), 2.28 (4H, t, J = 7.54Hz), 2.48 (10H, m), 2.67 (2H, m), 3.24 (2H, m), 4.03-4.12 (6H, 4.05 (t, J =6.75 Hz), 4.09 (m)). Lipid 127 Heptadecan-9-yl 8-(((9Z,12Z)-octadeca-9,12-dien-1-yl)(2-(((2-(piperidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 845.4 obs. 844.8; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.14-1.64 (63H, 1.26 (m), 1.53 (m)), 2.05 (4H, q, J = 6.52 Hz), 2.24-2.48(12H, 2.27 (t, J = 7.53 Hz), 2.42 (m)), 2.67 (2H, t, J = 5.81 Hz), 2.77 (2H, m),3.25 (2H, m), 4.10 (2H, t, J = 6.01 Hz), 4.86 (1H, i, J = 6.22 Hz), 5.35 (4H, m). Lipid 128 Heptadecan-9-yl 8-(((9Z,12Z)-octadeca-9,12-dien-1-yl)(2-(((2-(pyrrolidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 831.3 obs. 833.1; 1 H NMR (400 MHz, CDCl3): δ 0.88(9H, m), 1.26 (60H, m), 1.61 (2H, m), 1.76 (4H, i, J = 3.16 Hz), 2.05 (4H, q, J =6.57 Hz), 2.27 (2H, t, J = 7.53 Hz), 2.47 (8H, m), 2.57 (2H, t, J = 6.11 Hz),2.67 (2H, t, J = 6.26 Hz), 2.77 (2H, t, J = 5.92 Hz), 3.27 (2H, m), 4.10 (2H, t, J = 6.23 Hz), 4.86 (1H, t, J = 6.23 Hz), 5.35 (4H, m), 5.19-5.25 (1H, m) Lipid 129 Heptadecan-9-yl 2-methyl-10-((9Z,12Z)-octadeca-9,12-dien-1-yl)-6-oxo-7-oxa- 2,5,10-triazaoctadecan-18-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 805.3 obs. 805.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H,m), 1.25 (56H, m), 1.61 (2H, m), 2.05 (4H, q, J = 6.79 Hz), 2.21 (5H, s), 2.27(2H, t, J = 7.53 Hz), 2.44 (6H, m), 2.67 (2H, t, J = 6.92 Hz), 2.77 (2H, t, J= 6.05 Hz), 3.24 (2H, m), 4.10 (2H, t, J = 6.32 Hz), 4.86 (1H, q, J = 6.20 Hz),5.35 (4H, m). Lipid 130 Heptadecan-9-yl 2-methyl-11-((9Z,12Z)-octadeca-9,12-dien-1-yl)-7-oxo-8-oxa- 2,6,11-triazanonadecanoate-19-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 819.3 obs. 819.1 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m),1.30 (54H, m), 1.62 (4H, q, J = 7.52 Hz), 2.20 (6H, s), 2.30 (4H,m), 2.44 (4H, m), 2.67 (2H, t, J = 6.32 Hz), 2.77 (2H, t, J = 6.49 Hz), 3.23 (2H,m), 4.10 (2H, t, J = 6.21 Hz), 4.86 (1H, i, J = 6.49 Hz), 5.35 (4H, m), 5.49 (1H,m). Lipid 131 Heptadecan-9-yl 3-ethyl-12-((9Z,12Z)-octadeca-9,12-dien-1-yl)-8-oxo-9-oxa- 3,7,12-triazicosa-20-oate octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 847.4 obs. 847.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.02 (6H, t, J = 7.14 Hz), 1.26 (53H, m), 1.62 (5H, h, J = 6.40 Hz), 2.05(4H, q, J = 6.83 Hz), 2.27 (2H, t,J = 7.52 Hz), 2.47 (10H, m), 2.66 (2H, m),2.77 (2H, t, J = 6.06 Hz), 3.24 (2H, m), 4.09 (2H, m), 4.86 (1H, q, J = 6.22 Hz),5.35 (4H, m). Lipid 132 Heptadecan-9-yl 8-((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien-1-yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 814.3 obs. 814.1; 1 H NMR (400 MHz, CDCl3): δ 0.87(9H, m), 1.25 (54H, m), 1.55-1.66 (3H, m), 2.04 (4H, q, J = 7.58 Hz), 2.26 (2H,t, J = 7.09 Hz), 2.43 (2H, m), 2.60 (2H, m), 2.77 (3H, m),4.09-4.17 (1H, m),4.27 (1H, m), 4.35 (2H, m), 4.86 (1H, br s), 5.22 (1H, m),5.35 (4H, m), 6.95(2H, s). Lipid 133 Heptadecan-9-yl 8-((2-(((3-(lH-imidazol-l-yl)propyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien-1-yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 842.3 obs. 842.1; 1 H NMR (400 MHz, CDCl3): δ 0.87(9H, m), 1.30 (53H, m), 1.60 (2H, m), 2.02 (6H, m), 2.27 (2H, t, J = 7.69 Hz),2.44 (4H, m), 2.66 (2H, t, J= 6.05 Hz), 2.77 (2H, t, J = 6.10 Hz), 3.18 (2H, q, J = 6.47 Hz), 4.00 (2H, m), 4.11 (2H, t, J = 6.06 Hz), 4.86 (2H, m), 5.35 (4H,m), 6.94 (1H, m), 7.06 (1H, m), 7.49 (1H, s). Lipid 134 heptadecan-9-yl 8-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien-1-yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 846.3 obs. 847.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H, m), 1.30(54H, m), 1.60 (2H, m), 2.04 (4H, q, J = 7.52 Hz), 2.27 (2H, t, J = 7.57 Hz),2.44 (10H, m), 2.67 (2H, t, J = 6.32 Hz), 2.77 (2H, t, J = 6.41 Hz), 3.27 (2H,m), 3.69 (4H, m), 4.11 (2H, t, J = 6.15 Hz), 4.86 (1H, i, J = 6.28 Hz), 5.20 (1H,m), 5.35 (4H, m). Lipid 135 heptadecan-9-yl 8-((2-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)ethyl)((9Z,12Z)- octadeca-9, 12-dien-1-yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 860.4 obs. 860.1 1H NMR (400 MHz, CDCl3): δ 0.88(9H, m), 1.30 (54H, m), 1.61 (2H, m), 2.04 (4H, q, J = 7.52 Hz), 2.28 (5H, m),2.45 (13H, m), 2.68 (2H, t, J = 6.23 Hz), 2.77 (2H, t, J = 6.67 Hz), 3.26 (2H,m), 4.11 (2H, t, J = 6.15 Hz), 4.86 (1H, i, J = 6.24 Hz), 5.20 (1H, m), 5.35 (4H,m). Lipid 136 Hexyl 10-(11-(hexyloxy)-11-oxoundecyl)-2-methyl-6-oxo-7-oxa-2,5,10- triazahenicosan-21-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 713.1 obs. 712.8 1 H NMR (500 MHz, CDCl3): δ 0.88 (6H, t, J = 7.08 Hz),1.29 (40H, m), 1.61 (8H, m), 2.21 (6H, s), 2.28 (4H, t, J = 7.54 Hz), 2.38 (2H,t, J = 5.96 Hz), 2.44 (4H, m), 2.67 (2H, t, J = 6.52 Hz), 3.23 (2H, m), 4.05 (4H,t, J = 6.73 Hz), 4.10 (2H, t, J = 6.46 Hz), 5.18 (1H, m). Lipid 137 Hexyl 3-ethyl-12-(11-(hexyloxy)-11-oxoundecyl)-8-oxo-9-oxa-3,7,12- triazatricosan-23-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 755.2 obs. 754.9 1H NMR (500 MHz, CDC13): δ 0.89 (6H, t, J = 6.73 Hz), 1.29 (40H, m), 1.60 (8H, m), 2.28 (7H, m), 2.45 (12H, m), 2.68 (2H, m), 3.26 (2H, m), 4.05 (4H, m), 4.11 (2H, m), 4.16 (1H, m), 5.21 (1H, m). J = 6.79 Hz), 1.02 (6H, t, J = 7.16 Hz), 1.29 (40H, m), 1.61 (8H, m), 2.28 (4H, t, J = 7.84 Hz), 2.46 (10H, m), 2.67 (2H, m), 3.24 (4H, m), 4.07 (6H, m), 5.11 (1H, m). J = 7.54 Hz), 2.44 (10H, m), 2.68 (2H, m), 3.27 (2H, m), 3.69 (4H, m), 4.05 (7H, m). J = 7.54 Hz), 2.44 (10H, m), 2.68 (2H, m), 3.27 (2H, m), 3.69 (4H, m), 4.05 (7H, m). Lipid 138, dihexyl 11,11'-((2-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)ethyl)azanediyl)heneicosanediyl ester was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 768.2 obs. 767.9 1 H NMR (500 MHz, CDC13): δ 0.89 (6H, t, J = 6.73 Hz), 1.29 (40H, m), 1.60 (8H, m), 2.28 (7H, m), 2.45 (12H, m), 2.68 (2H, m), 3.26 (2H, m), 4.05 (4H, m), 4.11 (2H, m), 4.16 (1H, m), 5.21 (1H, m). Lipid 139, dihexyl 11,11'-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)azanediyl)heneicosanediyl ester was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 755.2 obs. 755.0. 1 H NMR (500 MHz, CDC13): δ 0.89 (6H, t, J = 6.73 Hz), 1.29 (40H, m), 1.60 (8H, m), 2.28 (7H, m), 2.45 (12H, m), 2.68 (2H, m), 3.26 (2H, m), 4.05 (4H, m), 4.11 (2H, m), 4.16 (1H, m), 5.21 (1H, m). J = 6.84 Hz), 1.26 (40H, m), 1.61 (8H, m), 2.28 (4H, t, J = 7.54 Hz), 2.44 (10H, m), 2.68 (2H, m), 3.27 (2H, m), 3.69 (4H, m), 4.05 (7H, m). J = 7.54 Hz), 2.44 (10H, m), 2.68 (2H, m), 3.27 (2H, m), 3.69 (4H, m), 4.05 (7H, m). Lipid 146, heptadecan-9-yl-11-(8-(((2-hexyldecanoyl)oxy)octyl)-2-methyl-7-oxo-8-oxa-2,6,11-triazanonadecan-19-ester, was synthesized according to a general synthetic route and method. MS [ESI]: m / z: [M+H]calc 937.5, obs. 937.0; 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H, m), 1.25(68H, m), 1.54-1.67 (10H, m), 2.21 (12H, m), 2.41-2.47 (3H, 2.44 (t, J = 7.59Hz), 2.44 (d, J = 4.61 Hz)), 2.65-2.71 (1H, m), 3.21-3.25 (2H, m), 4.05 (4H,m), 4.5 (1H, i, J = 6.09 Hz). Lipid 147 8-((2-(((3-(1H-imidazol-1-yl)propyl)carbamoyl)oxy)ethyl)(8-(heptadecane-9-yloxy)-8-oxooctyl)amino)octyl-2-hexyldecanoate was synthesized according to a general synthetic route and method. MS [ESI]: m / z: [M+H]calc 960.5, obs. 960.2 1 H NMR (400 MHz, CDCl3): δ 0.87(12H, m), 1.25 (63H, s), 1.49 (3H, m), 1.60 (7H, m), 2.00 (2H, m), 2.27 (3H,m), 2.41-2.47 (3H, 2.44 (t, J = 7.58 Hz), 2.44 (d, J = 4.10 Hz), 2.66 (1H, t, J =6.07 Hz), 3.18 (2H, m), 4.03 (9H, m), 4.86 (1H, m), 6.94 (1H, s), 7.06 (1H,m), 7.49 (1H, s). Lipid 148 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(2-(((2-(pyrrolidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octyl 2-hexyl decanoate Hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 949.6, obs. 949.2 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H, m), 1.25 (76H, m), 1.76 (5H, m), 2.27 (3H, m), 2.50 (10H, m), 2.66(1H, m), 3.28 (1H, m), 4.03-4.11 (4H, 4.06 (t, J = 6.68 Hz), 4.10 (m), 4.85(1H, i, J = 6.38 Hz). Lipid 149 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(2-(((2-(piperidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octyl 2-hexyl decanoate Hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 963.6 obs. 963.2 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H,m), 1.25 (56H, m), 1.37-1.46 (8H, m), 1.49-1.65 (15H, m), 2.40 (14H, m), 2.67(1H, m), 3.22-3.29 (2H, m), 4.03-4.13 (5H, 4.06 (t, J = 6.64 Hz), 4.10 (t, J =6.06 Hz)), 4.86 (1H, i, J = 6.22 Hz). Lipid 150 Heneicosyl 6,6'-((2-(((2-(piperidin-1-yl)ethyl)carbamoyl)oxy)ethyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 753.2 obs 753.0 1H NMR (400 MHz, CDC13): δ 0.89 (6H, t, J = 6.85 Hz), 1.28 (36H,m), 1.45 (6H, m), 1.61 (13H, m), 2.30 (4H, t, J = 7.53 Hz), 2.42 (10H, m), 2.67(2H, t, J = 5.96 Hz), 3.27 (2H, d, J = 5.38 Hz), 4.04-4.13 (6H, 4.06 (t, J = 6.78Hz), 4.11 (t, J = 6.06 Hz)). Lipid 151 Heneicosyl 6,6'-((2-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)ethyl)azanediyl)dicarboxylate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 739.2 obs 738.9. 1 H NMR (400 MHz, CDC13): δ 0.88 (6H, t, J = 6.84 Hz), 1.26 (38H,m), 1.44 (5H, m), 1.62 (10H, m), 1.76 (5H, quint, J = 3.14 Hz), 2.29 (4H, t, J =7.52 Hz), 2.45 (8H, m), 2.58 (2H, t, J = 6.19 Hz), 2.65 (2H, m), 3.28 (2H, m),4.03-4.11 (6H, 4.05 (t, J = 6.78 Hz), 4.09 (t, J = 5.86 Hz)). Lipid 154 Undecyl 2-methyl-6-oxo-10-(6-oxo-6-(undecyloxy)hexyl)-7-oxa-2,5,10- triazahexadecan-16-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 713.1, obs. 712.95 1H NMR (400 MHz, CDC13): δ 0.88 (6H, t, J = 6.83Hz), 1.26 (39H, s), 1.44 (4H, m), 1.61 (9H, m), 2.22 (5H, s), 2.29 (4H, t, J =7.52 Hz), 2.44 (7H, m), 2.67 (2H, m), 3.25 (2H, m), 4.02-4.12 (6H, 4.05 (t, J =6.78 Hz), 4.07 (m)). Lipid 155 Heneicosyl 6,6' -((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 722.1, obs. 712.9 1 H NMR (400 MHz, CDC13): δ 0.88 (6H, t, J = 6.81 Hz), 1.26(52H, m), 2.28 (4H, t, J = 7.30 Hz), 2.43 (2H, m), 2.62 (2H, m), 4.05 (4H, t, J =6.78 Hz), 4.12 (1H, m), 4.37 (2H, m), 6.93 (2H, m). Lipid 156 Heneicosyl 6,6' -((2-(((2-(4-methylpiperazin-l- yl)ethyl)carbamoyl)oxy)ethyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 768.2 obs. 768.0. 1H NMR (400 MHz, CDCl3): δ 0.88 (6H, m), 1.28 (36H, m),1.46 (4H, m), 1.62 (8H, m), 2.31 (7H, m), 2.50 (13H, m), 2.69 (2H, t, J =6.06 Hz), 3.27 (2H, m), 4.05 (4H, t, J = 6.77 Hz), 4.11 (2H, t, J = 5.64 Hz),5.31 (1H, m). Lipid 157 Heneicosyl 6,6'-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 755.2 obs. 754.9 1 H NMR (400 MHz, CDCl3): δ 0.88 (6H, t, J = 6.83 Hz), 1.26 (35H, s),1.44 (5H, m), 1.62 (9H, m), 2.29 (4H, t, J = 7.51 Hz), 2.45 (10H, m), 2.66 (2H,t, J = 5.99 Hz), 3.27 (2H, m), 3.69 (4H, t, J = 4.62 Hz), 4.02-4.13 (6H, 4.05 (t, J = 6.78 Hz), 4.10 (t, J = 5.96 Hz)). Lipid 158 Heptadecan-9-yl 2-methyl-6-oxo-10-(6-oxo-6-(undecyloxy)hexyl)-7-oxa-2,5,10-triazaoctadecan-18- oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 825.3 obs. 825.0 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.88(9H, m), 1.26 (58H, m), 1.61 (6H, m), 2.28 (4H, q,J = 7.49 Hz), 2.44 (6H, m),2.66 (1H, s), 3.25 (1H, m), 4.05 (4H, m), 2.20-2.22 (6H, m), 4.86 (1H, i, J =6.15 Hz). Lipid 159 Heptadecan-9-yl 8-((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)(6- oxo-6-(undecyloxy)hexyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 833.7 obs. 834.0; 1 H NMR (500 MHz, CDCl3): δ 0.87 (9H,m), 1.30 (54H, m), 1.61 (7H, m), 2.27 (4H, m), 2.44 (3H, m), 2.63 (5H, m),2.82 (2H, m), 4.05 (2H, m), 4.14 (2H, m), 4.86 (1H, m), 5.11 (1H, m), 6.93(2H, m). Lipid 160 Heptadecan-9-yl 8-((2-(((2-(4-methylpiperazin-l- yl)ethyl)carbamoyl)oxy)ethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 879.8 obs. 880.1; 1 H NMR (400 MHz,, CDCl3): δ0.88 (9H, m), 1.27 (45H, m), 1.54 (18H, m), 2.28 (7H, m), 2.46 (10H, m), 2.67(2H, t, J = 6.06 Hz), 3.27 (2H, m), 4.07 (5H, m), 4.86 (2H, m), 5.23 (1H, m). Lipid 161 Heptadecan-9-yl 8-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)(6-oxo-6- (undecyloxy)hexyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 866.8 obs. 867.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.27(45H, m), 1.47 (10H, m), 1.62 (8H, m), 2.28 (4H, q, J = 7.86 Hz), 2.44 (10H,m), 2.67 (2H, t, J = 6.35 Hz), 3.28 (2H, m), 3.70 (4H, m), 4.07 (4H, m), 4.86(1H, i, J = 6.62 Hz), 5.22 (1H, m). Lipid 162 Heptadecan-9-yl 2-methyl-7-oxo-11-(6-oxo-6-(undecyloxy)hexyl)-8-oxa- 2,6,11-triazanonadecan-19-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 838.8 obs. 839.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.27(54H, s), 1.50 (4H, m), 1.62 (12H, m), 2.21-2.23 (6H, 2.21 (s), 2.22 (s)),2.28 (3H, q, J = 7.51 Hz), 2.33 (1H, t, J = 6.95 Hz), 2.43 (2H, m), 4.03 (1H, s),4.05 (1H, s), 4.86 (1H, i, J = 6.10 Hz), 2.64-2.69 (2H, m), 3.21-3.27 (2H, m). Lipid 163 Heptadecan-9-yl 8-((2-(((3-(1H-imidazol-1-yl)propyl)carbamoyl)oxy)ethyl)(6-oxo-6- (undecyloxy)hexyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 862.3 obs. 862.0; 1 H NMR (400 MHz, CDCl3): δ 0.88 (8H,m), 1.29 (61H, m), 1.58-1.66 (6H, m), 2.00 (2H, i, J = 6.86 Hz), 2.28 (3H, m),2.44 (3H, m), 2.66 (1H, m), 3.15-3.24 (2H, m),4.02 (4H, m), 4.11 (1H, t, J =5.71 Hz), 4.86 (1H, i, J = 6.10 Hz), 6.94 (1H, s), 7.06 (1H, s), 7.49 (1H, s), Lipid 164 Heptadecan-9-yl 8-((6-oxo-6-(undecyloxy)hexyl)(2-(((2-(pyrrolidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 851.4 obs. 851.1; 1 H NMR (400 MHz, CDCl3): 0.88 (9H, m),1.26 (54H, s), 1.51 (3H, m), 1.59-1.72 (9H, m), 2.25-2.36 (9H, 2.31 (dt, J =21.97, 7.46 Hz), 2.28 (s)), 2.98-3.07 (5H, m), 3.12-3.18 (3H, m), 3.20-3.28(3H, m), 3.59-3.66 (2H, m), 4.05 (1H, s), 4.41-4.47 (2H, m), 4.82-4.89 (1H,m). Lipid 165 Heptadecan-9-yl 8-((6-oxo-6-(undecyloxy)hexyl)(2-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)ethyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 864.8 obs. 865.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m),1.26 (56H, s), 1.51 (3H, m), 1.59-1.72 (9H, m), 2.25-2.36 (9H, 2.31 (dt, J = 21.97, 7.46 Hz), 2.28 (s)), 2.98-3.07 (5H, m), 3.12-3.18 (3H, m), 3.20-3.28(3H, m), 3.59-3.66 (2H, m), 4.05 (1H, s), 4.41-4.47 (2H, m), 4.82-4.89 (1H,m). Lipid 166 2-Octyldodecyl 2-methyl-11-(6-((2-octyldodecyl)oxy)-6-oxohexyl)-7-oxo-8-oxa- 2,6,11-triazaheneptadecan-17-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 979.3 obs. 979.3 1 H NMR (500 MHz, CDCl3): δ 0.88(12H, m), 1.27 (65H, m), 1.53 (4H, m), 1.64 (7H, m), 1.91 (2H, m), 2.04 (1H,m), 2.31 (4H, t, J = 7.53 Hz), 2.57 (9H, m), 2.80 (4H, m), 3.29 (3H, m), 3.96(4H, d, J = 5.77 Hz), 4.07 (1H, m), 4.17 (2H, t, J = 5.93 Hz), 5.89 (1H, m). Lipid 167 bis(2-octyldodecyl) 6,6'-((2-(((3-(1H-imidazol-1-yl)propyl)carbamoyl)oxy)ethyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1002.6 obs. 1002.4 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.88(12H, t, J = 6.81 Hz), 1.26 (74H, m), 1.62 (6H, m), 2.00 (2H, i, J = 6.86 Hz),2.30 (4H, t, J = 7.44 Hz), 2.45 (4H, t, J = 7.36 Hz), 2.65 (2H, t, J = 5.73 Hz),3.19 (2H, m), 3.96 (4H, d, J = 5.72 Hz), 4.01 (3H, m), 4.08-4.14 (2H, m), 6.94(1H, s), 7.49 (1H, s), 7.06 (1H, s). Lipid 168 bis(2-octyldodecyl) 6,6'-((2-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)ethyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 990.9 obs. 991.3; 1 H NMR (400 MHz, CDCl3): δ 0.88 (12H, t, J = 6.74 Hz),1.26 (64H, m), 1.44 (4H, m), 1.63 (11H, quint, J = 7.13 Hz), 1.76 (4H, m), 2.30(4H, t, J = 7.50 Hz), 2.46 (8H, m), 2.58 (2H, t, J = 6.13 Hz), 2.66 (2H, m),3.23-3.33 (2H, m), 3.96 (4H, d, J= 5.77 Hz), 4.09 (2H, m). Lipid 169 Bis(2-octyldodecyl) 6,6' -((2-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)ethyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1004.9 obs. 1005.3; 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.88 (12H, t, J = 6.76 Hz), 1.28 (63H, m), 1.44 (6H, m), 1.60 (17H, m), 2.37 (15H, m),2.67 (1H, m), 3.25 (1H, m), 3.96 (4H, d, J = 5.77 Hz), 4.09 (2H, m). Lipid 170 2-octyldodecyl 2-methyl-10-(6-((2-octyldodecyl)oxy)-6- oxohexyl)-6-oxo-7-oxa-2,5,10-triazahexadecan-16-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 964.9 obs. 965.4; 1 H NMR (400 MHz, CDCl3): 1 H NMR(400 MHz): δ 0.88 (12H, t, J = 6.83 Hz), 1.26 (70H, m), 1.44 (4H, m), 1.58-1.67(8H, 1.63 (quint, J = 7.57 Hz), 1.63 (d, J = 8.20 Hz)), 2.21-2.23 (6H, 2.22 (s),2.22 (s)), 2.30 (4H, t, J = 7.53 Hz), 2.37-2.48 (6H, 2.39 (m), 2.45 (t, J = 7.47Hz)), 2.66 (2H, m), 3.96 (4H, d, J= 5.81 Hz), 4.09 (1H, m), 3.21-3.27 (2H, m). Lipid 171 bis(2-octyldodecyl) 6,6' -((2-((((1H-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)azanediyl) dihexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 974.6 obs. 974.2 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.90 (12H,t, J = 6.83 Hz), 1.28 (79H, m), 2.31 (4H, t, J = 7.09 Hz), 2.42-2.49 (2H, m),2.59-2.68 (3H, m), 2.82-2.85 (1H, m), 3.98 (4H, d, J = 5.72 Hz), 4.11-4.17 (1H,m), 4.25-4.30 (1H, m), 4.35-4.42 (2H, m), 5.71-5.79 (1H, m), 6.97 (2H, s). Lipid 172 2-octyldodecyl 3-ethyl-12-(6-((2-octyldodecyl)oxy)-6-oxohexyl)-8-oxo-9-oxa-3,7,12-triazaoctadecan-18-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 1007.6 obs. 1007.2 1 H NMR (400 MHz, CDCl3): δ 0.88(12H, t, J = 6.82 Hz), 1.02 (6H, t, J = 7.14 Hz), 1.26 (68H, m), 1.43 (4H, m),1.63 (9H, m), 2.29 (4H, t, J = 7.53 Hz), 2.48 (10H, m), 2.65 (2H, m), 3.24 (2H,m), 3.96 (4H, d, J= 5.80 Hz), 4.08 (2H, m). Lipid 173 Bis(2-octyldodecyl) 6,6'-((2-(((2-(4-methylpiperazin-1- yl)ethyl)carbamoyl)oxy)ethyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 1020.7 obs. 1020.6 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ0.88 (12H, t, J = 6.82 Hz), 1.26 (69H, m), 1.42-1.47 (4H, m), 1.59-1.66 (6H,m), 2.28 (9H, m), 2.46 (13H, m), 2.66 (2H, m), 3.96 (4H, d, J = 5.80 Hz), 4.09(2H, m), 3.23-3.29 (2H, m). Lipid 173 Bis(2-octyldodecyl) 6,6'-((2-(((2-(4-methylpiperazin-1- yl)ethyl)carbamoyl)oxy)ethyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 1020.7 obs. 1020.6 1 H NMR (400 MHz, CDCl3): δ 0.90 (12H, t, J = 6.83 Hz), 1.29(67H, m), 1.46 (4H, m), 1.65 (6H, m), 2.31 (4H, t, J = 7.51 Hz), 2.47 (11H, m),2.68 (2H, t, J = 5.93 Hz), 3.30 (2H, m), 3.71 (4H, t, J = 4.60 Hz), 3.98 (4H, d, J = 5.81 Hz), 4.12 (2H, t, J = 5.89 Hz), 5.31 (1H, m). Lipid 176 ((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)azanediyl)bis(heptane-7, 1-diyl)bis(decanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 722.1 obs. 721.9 1 H NMR (400 MHz, CDC13): δ 0.88 (6H, t, J = 6.83 Hz), 1.23-1.37 (39H, m), 1.60 (12H, m), 2.28 (4H, t, J = 6.83 Hz),1.23-1.37 (39H, m), 1.60 (12H, m), 2.28 (4H, t, J = 7.55 Hz), 2.69 (2H, m),2.86-2.94 (2H, m), 4.05 (6H, m), 4.27 (1H, m), 4.35-4.40 (1H), 4.46 (1H, d, J = 6.14 Hz), 6.93 (2H, m), m). Lipid 178 ((2-(((2-(4-methylpiperazin-l-yl)ethyl)carbamoyl)oxy)ethyl)azanediyl)bis(heptane-7, 1-diyl)bis(decanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 768.2 obs. 768.0 1 H NMR (400 MHz, CDC13): δ 0.87 (6H, m), 1.26 (43H,m), 2.28 (5H, m), 4.05 (5H, t, J = 6.79 Hz), 1.61 (8H, m), 2.40-2.51 (13H, m),2.64-2.69 (2H, m), 3.23-3.29 (2H, m), 4.09-4.13 (2H, m). Lipid 184 (Z)-non-3-en-l-yl 10-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa-2,5,10-triazahexadecan-16-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 781.2 obs. 781.1 1H NMR (400 MHz, CDCl3): δ 0.87 (9H, m),1.25 (49H, m), 2.03 (2H, q, J = 7.43 Hz), 2.21-2.22 (6H, 2.21 (s), 2.22 (s)),2.37 (12H, m), 2.66 (2H, t, J = 5.80 Hz), 3.24 (1H, q, J = 2.18 Hz), 4.06 (7H,m), 5.31-5.37 (1H, m), 5.46-5.53 (1H, m). Lipid 185 (Z)-8-((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)(6-(non-3-en- 1-yloxy)-6-oxohexyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 790.2 obs. 789.9; 1 H NMR (400 MHz, CDCl3): 1 H NMR(400 MHz): δ 0.87 (9H, m), 1.25 (54H, m), 2.00 (2H, q, J = 7.02 Hz), 2.28 (7H,m), 2.61 (2H, m), 4.06 (4H, t, J = 6.91 Hz), 4.36 (2H, m), 5.31-5.36 (1H, m),5.46-5.54 (1H, m), 6.95 (2H, m). Lipid 186 (Z)-non-3-en-1-yl 3-ethyl-12-(8-((2-hexyldecanoyl)oxy)octyl)-8-oxo-9-oxa- 3,7,12-triazaoctadecan-18-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 823.3 obs. 822.9 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.02 (6H, t,J = 7.14 Hz), 1.26 (36H, m), 1.62 (15H, m), 2.03 (2H, q, J =7.86 Hz), 2.45 (16H, m), 2.66 (1H, m), 3.24 (2H, m), 4.06 (6H, t, J = 6.56 Hz),5.30-5.38 (1H, m), 5.50 (1H, m). Lipid 187 (Z)-8-((2-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)ethyl)(6-(non-3-en-1-yloxy)-6- oxohexyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 836.3 obs. 836.1 1 H NMR (400 MHz, CDCl3): δ0.88 (9H, m), 1.26 (44H, m), 1.62 (6H, m), 2.04 (2H, q, J = 7.42 Hz), 2.30(20H, m), 2.68 (2H, t, J = 5.98 Hz), 3.28 (2H, m), 4.07 (6H, m), 5.26 (1H,m), 5.35 (1H, m), 5.51 (1H, m). Lipid 188 (Z)-8-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)(6-(non-3-en-1-yloxy)-6-oxohexyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 823.3 obs. 823.0 1 H NMR (400 MHz, CDCl3): 1 H NMR (400MHz): δ 0.88 (9H, m), 1.25 (29H, m), 1.42-1.48 (4H, m), 1.61 (13H, m), 2.03(2H, q, J= 7.94 Hz), 2.45 (16H, m), 2.67 (2H, m), 3.28 (3H, m), 3.69 (5H, m),4.06 (6H, m), 5.33 (1H, m), 5.49 (1H, m). Lipid 189 (Z)-Non-3-en-1-yl 11-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-7- oxo-8-oxa-2,6,11-triazheptadecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 795.3 obs. 795.1 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H,m), 1.31 (39H, m), 1.64 (8H, m), 2.05 (2H, m), 2.22-2.24 (6H, 2.23 (s), 2.24(s)), 2.39 (14H, m), 2.68 (2H, m), 3.25 (2H, q, J = 6.48 Hz), 4.08 (7H, m),5.36 (1H, m), 5.52 (1H, m). Lipid 191 (Z)-8-((6-(non-3-en-1-yloxy)-6-oxohexyl)(2-(((2-(pyrrolidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 807.3 obs. 807.1 1 H NMR (400 MHz, CDCl3): δ 0.90(9H, m), 1.31 (40H, m), 1.63 (7H, m), 1.78 (4H, m), 2.05 (2H, q, J = 7.53 Hz),2.49 (14H, m), 2.59 (2H, t, J = 6.15 Hz), 2.68 (2H, t, J = 6.00 Hz), 3.30 (2H,m), 4.08 (7H, m), 5.35 (1H, m), 5.51 (1H, m). Lipid 192 (Z)-8-((6-(non-3-en-1-yl oxy)-6-oxohexyl)(2-(((2-(piperidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octan-2-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 821.3 obs. 821.2; 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.88 (9H, m), 1.25 (43H, m), 1.61 (7H, m), 1.76 (4H, quint, J = 7.53 Hz), 2.43 (16H, m), 2.66 (2H, t, J = 6.00 Hz),3.28 (2H, m), 4.06 (7H, m), 5.34 (1H, m), 5.49 (1H, m). J Lipid 193 11-(7-(decanoyloxy)heptyl)-2-methyl-7-oxo-8-oxa-2,6,11- triazanonadec-19-yl 2-hexyldecanoate Hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 825.3 obs. 825.0 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H, t, J = 6.45Hz), 1.31 (48H, m), 1.63 (11H, m), 2.22 (6H, s), 2.32 (6H, m), 2.46 (5H, m),2.69 (2H, m), 3.25 (2H, m), 4.07 (8H, m). Lipid 195 8-((7-(decanoyloxy)heptyl)(2-(((2-(pyrrolidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octan-2-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 836.7 obs. 837.1; 1 H NMR (400 MHz, CDCl3):​1 H NMR (400 MHz): δ 0.87(9H, t, J = 6.71 Hz), 1.25 (51H, m), 1.59 (15H, m), 2.37 (13H, m), 2.67 (2H,m), 3.24 (2H, m), 4.02-4.13 (6H, 4.05 (td, Lipid 196 8-((7-(decanoyloxy)heptyl)(2-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)ethyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 850.8 obs. 851.2; 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ 0.87(9H, t, J = 6.71 Hz), 1.25 (51H, m), 1.59 (15H, m), 2.37 (13H, m), 2.67 (2H,m), 3.24 (2H, m), 4.02-4.13 (6H, 4.05 (td, J = 6.63, 3.50 Hz), 4.10 (t, J = 6.40Hz)), 5.26 (1H, m). Lipid 197 10-(7-(decanoyloxy)heptyl)-2-methyl-6-oxo-7-oxa-2,5,10- triazaoctadec-18-yl 2-hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 810.7 obs. 811.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H, t, J = 6.44 Hz), 1.26(46H, m), 1.62 (15H, m), 2.20-2.23 (6H, 2.21 (s), 2.22 (s)), 2.25-2.34 (3H,2.29 (t, J= 7.61 Hz), 2.29 (m)), 2.44 (6H, m), 2.66 (2H, m), 3.24 (2H, m),4.02-4.12 (6H, 4.05 (td, J = 6.72, 3.49 Hz), 4.10 (m)). Lipid 198 8-((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)(7- (decanoyloxy)heptyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 820.3 obs. 820.0 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H, m), 1.27(62H, m), 2.27-2.36 (3H, 2.30 (t, J = 7.63 Hz), 2.31 (m)), 2.45 (2H, m), 2.62(3H, m), 2.84 (1H, m), 4.06 (5H, m), 4.37 (3H, m), 6.98 (2H, m). Lipid 199 12-(7-(Decanoyloxy)heptyl)-3-ethyl-8-oxo-9-oxa-3,7,12- triazadocosa-20-yl 2-hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 853.4 obs. 853.2; 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H, t, J = 6.40 Hz),1.04 (6H, t, J = 7.12 Hz), 1.27 (50H, m), 1.63 (12H, m), 2.27-2.36 (3H, 2.30(t, J = 7.61 Hz), 2.32 (m)), 2.50 (10H, m), 2.68 (2H, m), 3.26 (2H, m), 4.07(6H, m), 5.92 (1H, m). Lipid 200 8-((7-(decanoyloxy)heptyl)(2-(((2-(4-methylpiperazin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 866.4 obs. 866.1; 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H,t, J = 7.11 Hz), 1.28 (54H, m), 1.63 (8H, m), 2.31 (6H, m), 2.48 (12H, m), 2.70(2H, m), 3.28 (2H, m), 4.04-4.16 (7H, 4.07 (td, J = 6.70, 3.63 Hz), 4.13 (m)). Lipid 202 10-(8-(decanoyloxy)octyl)-2-methyl-6-oxo-7-oxa-2,5,10- triazaoctadec-18-yl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 741.2 obs. 704.9; 1 H NMR (400 MHz, CDCl3): δ 0.89 (6H, t, J = 6.53 Hz), 1.29(45H, m), 1.63 (8H, m), 2.23 (6H, s), 2.30 (4H, t, J = 7.36 Hz), 2.46 (6H, m),2.69 (2H, m), 3.26 (2H, m), 4.07 (4H, t, J = 6.66 Hz), 4.12 (2H, t, J = 5.85 Hz). Lipid 203 ((2-((((1H-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)azanediyl)bis(octane-8,1-diyl) bis(decanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 750.1 obs. 749.9; 1 H NMR (400 MHz, CDCl3): δ 0.89 (6H, t,J = 6.96 Hz),1.29 (53H, m), 2.30 (4H, t, J = 7.53 Hz), 2.45 (2H, m), 2.63 (3H, m), 2.83 (1H,m), 4.06 (5H, m), 4.16 (1H, m), 4.37 (3H, m), 6.94 (1H, m), 7.12 (1H, m). Lipid 205 ((2-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)ethyl)azanediyl)bis(octane-8,1-diyl)bis(decanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 795.7 obs. 796.0; 1H NMR (400 MHz, CDCl3): δ 0.87 (6H, t, J = 6.78Hz), 1.28 (44H, m), 1.43 (4H, m), 1.61 (8H, m), 2.28 (7H, m), 2.46 (12H, m),2.69 (2H, m), 3.27 (1H, m), 4.05 (4H, t, J = 6.75 Hz), 4.11 (2H, m). Lipid 209 ((2-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)ethyl)azanediyl)bis(octane-8,1-diyl)bis(decanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 766.7 obs. 767.0; 1H NMR (400 MHz, CDCl3): δ 0.89 (6H, t, J = 6.84 Hz),1.29 (44H, m), 1.63 (8H, m), 1.78 (4H, m), 2.30 (4H, t, J = 7.54 Hz), 2.49(10H, m), 2.69 (2H, m), 3.30 (2H, m), 4.07 (4H, t, J = 6.74 Hz), 4.12 (2H, m),5.26 (1H, m). Lipid 211 (Z)-2-methyl-10-(octadec-9-en-1-yl)-6-oxo-7-oxa-2,5,10- triazaoctadecadecyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 792.8 obs. 793.1; 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H, t, J = 1.44 Hz),1.28 (57H, m), 1.61 (4H, m), 2.02 (4H, m), 2.23 (6H, s), 2.32 (1H, m), 2.46(6H, m), 2.69 (2H, m), 3.26 (2H, m), 4.08 (4H, m), 5.36 (2H, m). Lipid 212 (Z)-8-((2-((((1H-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)(octadec-9-en-1-yl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 801.7 obs. 802.1; 1 H NMR (400 MHz, CDCl3): 1 H NMR (400 MHz): δ0.87 (9H, m), 1.25 (51H, m), 1.60 (4H, m), 1.74 (3H, m), 2.00 (3H, m), 2.43(1H, m), 2.60 (2H, m), 4.02 (3H, m), 4.35 (3H, m), 5.34 (1H, m), 6.88-6.96(2H, m). Lipid 213 (Z)-3-ethyl-12-(octadec-9-en-1-yl)-8-oxo-9-oxa-3,7,12-triazaeicosan-20-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 834.8 obs. 835.2; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.01 (6H,t, J= 7.14 Hz), 1.25 (53H, m), 1.61 (8H, m), 2.00 (4H, m), 2.30 (1H, m), 2.47(11H, m), 2.66 (2H, m), 3.24 (2H, m), 4.06 (4H, m), 5.34 (2H, m), 5.86-5.91(1H, m). Lipid 214 (Z)-8-((2-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)ethyl)(octadec-9-en-1- yl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 847.8 obs. 848.1; 1 H NMR (400 MHz, CDC13): δ 0.86-0.92 (9H, m), 1.31 (54H, m), 1.62 (6H, m), 2.03 (4H, m), 2.32 (1H, m), 2.47 (10H, m), 2.69 (2H, m), 3.30 (2H, m), 3.71 (4H, t, Lipid 215 (Z)-8-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)(octadec-9-en-1-yl)amino)octan-2- yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 834.8 obs. 835.2; 1 H NMR (400 MHz, CDC13): δ 0.86-0.92 (9H, m), 1.31 (54H, m), 1.62 (6H, m), 2.03 (4H, m), 2.32 (1H, m), 2.47 (10H, m), 2.69 (2H, m), 3.30 (2H, m), 3.71 (4H, t, J = 4.61 Hz), 4.08 (5H, m), 5.36 (2H, m). Lipid 216 (Z)-2-methyl-11-(octadec-9-en-1-yl)-7-oxo-8-oxa-2,6,11- triazanonadec-19-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 806.8 obs. 807.2; 1 H NMR (400 MHz, CDCl3): δ 0.86-0.92 (9H, m), 1.30(58H, m), 1.63 (6H, m), 2.02 (3H, m), 2.22 (6H, s), 2.34 (3H, m), 2.46 (4H,m), 2.69 (2H, m), 3.25 (2H, m), 4.09 (4H, m), 5.36 (2H, m). Lipid 217 (Z)-8-((2-(((3-(1H-imidazol-1-yl)propyl)carbamoyl)oxy)ethyl)(octadec-9-en-1-yl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 829.8 obs. 830.2; 1 H NMR (400 MHz, CDCl3): δ 0.83-0.90 (9H, m),1.26 (57H, m), 1.59 (4H, m), 2.00 (6H, m), 2.30 (1H, m), 2.45 (4H, m), 2.67(2H, t, J = 6.35 Hz), 3.18 (2H, m), 4.00 (2H, t, J = 7.00 Hz), 4.05 (2H, t, J =6.62 Hz), 4.11 (2H, t, J = 5.94 Hz), 5.34 (2H, m), 6.94 (1H, s), 7.06 (1H, s),7.49 (1H, s). Lipid 218 (Z)-8-(octadec-9-en-1-yl(2-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)ethyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 818.8 obs. 819.2; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.25(51H, m), 1.63 (9H, m), 1.76 (4H, m), 2.02 (4H, m), 2.46 (8H, m), 2.57 (2H,t, J = 6.12 Hz), 2.67 (2H, m), 3.25-3.32 (2H, m), 4.06 (4H, m), 5.35 (2H, m),2.31 (1H, m), 5.20-5.26 (1H, m). Lipid 219 (Z)-8-(octadec-9-en-1-yl(2-(((2-(piperidin-1-yl)ethyl)carbamoyl)oxy)ethyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 832.8 obs. 833.2; 1 H NMR (400 MHz, CDCl3): δ 0.89 (9H, m), 1.28(55H, m), 1.57 (12H, m), 2.03 (4H, m), 2.42 (11H, m), 2.69 (2H, m), 3.27 (2H,m), 4.08 (4H, m), 5.36 (2H, m). Lipid 220 undecyl 10-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa-2,5,10-triazahexadecan-16-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 810.7 obs. 811.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H, m), 1.27(46H, m), 1.43 (6H, m), 1.61 (8H, m), 2.22 (6H, s), 2.29 (3H, t,J = 7.07 Hz), 2.43 (6H, m), 2.67 (2H, m), 3.25 (2H, m), 4.05 (7H, m). Lipid 221 8-((2-((((1H-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octyl-2-hexyldecanoate was synthesized according to a general synthetic route and method. MS [ESI]: m / z: [M+H]calc. 819.7 obs. 820.0; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.33 (63H, m), 2.29 (3H, m), 2.44 (2H, m), 2.62 (3H, m), 4.06 (5H, m), 4.34 (3H, m), 6.95 (2H, m). Lipid 222 8-((2-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)ethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octyl-2-hexyldecanoate was synthesized according to a general synthetic route and method. MS [ESI]: m / z: [M+H]calc. 865.8 obs. 866.1; 1 H NMR (400 MHz, CDCl3): δ 0.89(9H, m), 1.31 (53H, m), 1.63 (7H, m), 2.32 (7H, m), 2.49 (13H, m), 2.71 (2H,m), 3.29 (2H, m), 4.07 (7H, m). Lipid 223 8-((2-(((2-morpholinoethyl)carbamoyl)oxy)ethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octyl-2-hexyldecanoate was synthesized according to a general synthetic route and method. MS [ESI]: m / z: [M+H]calc. 852.7 obs. 853.1; 1H NMR (400 MHz, CDC13): δ 0.89 (9H, m), 1.30 (50H, m), 1.63 (8H, m), 2.31 (3H, m), 2.47 (11H, m), 2.70 (2H, m), 3.29 (2H, m), 3.71 (5H, m), 4.07 (7H, m). Lipid 224 Undecyl 11 -(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-7-oxo-8-oxa-2,6,11 - triazahexadecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 824.7 obs. 825.0; 1 H NMR (400 MHz, CDC13): δ 0.89 (9H, m), 1.30 (52H, m), 1.64 (14H, m), 2.22 (6H, s), 2.33 (6H, m), 2.46 (4H, m), 3.25 (1H, m), 4.09 (3H, m), 2.68 (2H, m). Lipid 226 8-((6-oxo-6-(undecyloxy)hexyl)(2-(((2-(pyrrolidin-1 -yl)ethyl)carbamoyl)oxy)ethyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 836.7 obs. 837.0; 1 H NMR (400 MHz, CDC13): 1 H NMR (400 MHz, CDC13): δ 0.89 (9H, m), 1.30 (52H, m), 1.64 (14H, m), 2.22 (6H, s), 2.33 (6H, m), 2.46 (4H, m), 3.25 (1H, m), 4.09 (3H, m), 2.68 (2H, m). J = 7.43 Hz), 2.28 (m)), 2.47 (10H, m), 2.66 (1H, m), 3.23-3.29 (2H, m), 4.03-4.12 (6H, 4.05 (td, J = 6.74, 3.08 Hz), 4.09 (m)), 5.24-5.28 (1H, m), 1.76 (5H, m). Lipid 227 8-((6-oxo-6-(undecyloxy)hexyl)(2-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)ethyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 850.8 obs. 851.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H,s), 1.29 (54H, m), 1.58 (12H, m), 2.38 (13H, m), 2.67 (2H, t, J = 6.45 Hz),3.25 (2H, m), 4.07 (6H, m), 5.29 (1H, m). Lipid 244 (Z)-non-3-en-1-yl 6-((6-((2-octyldodecyl)oxy)-6-oxohexyl)(2-(((2- (pyrrolidin-1-yl)ethyl)carbamoyl)oxy)ethyl)amino)hexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc. 834.7 obs. 835.0; 1 H NMR (400 MHz, CDCl3):δ 0.88 (9H, m), 1.28 (47H, m), 1.62 (5H, m), 1.76 (4H, m), 2.03 (2H, q, J =7.86 Hz), 2.29 (4H, tds, J = 7.58, 2.51 Hz), 2.37 (2H, q, J = 7.17 Hz), 2.47 (8H,m), 2.58 (2H, t, J = 5.98 Hz), 2.66 (2H, t, J = 6.75 Hz), 3.28 (2H, m), 3.96 (2H,d, J = 5.72 Hz), 4.07 (4H, m), 5.33 (1H, m), 5.49 (1H, m). Lipid 245 (Z)-Non-3-en-1-yl 6-((6-((2-octyldodecyl)oxy)-6-oxohexyl)(2-(((2-(piperidin-1- yl)ethyl)carbamoyl)oxy)ethyl)amino)hexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 848.7 obs. 848.9; 1 H NMR (400 MHz, CDCl3): δ 0.90 (9H, m), 1.28 (45H, m), 1.61 (13H, m), 2.05 (2H, q, J = 7.34 Hz), 2.38(16H, m), 2.68 (2H, t, J = 7.26 Hz), 3.27 (2H, m), 3.98 (2H, d, J = 5.80 Hz),4.08 (4H, m), 5.33-5.37 (1H, m), 5.47-5.55 (1H, m). Lipid 270 Heptadecan-9-yl 2-methyl-11-((9Z,12Z)-octadeca-9,12-dien-1-yl)-6-oxo-7-oxa-2,5,11- triazanonadecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 818.8 obs. 819.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.26 (49H, m), 1.50 (4H, m), 1.61 (5H, m), 2.05 (4H, q, J = 6.94 Hz), 2.22(6H, s), 2.27 (2H, t, J = 7.53 Hz), 2.38 (6H, m), 2.46 (1H, m), 2.76 (2H, t, J =6.57 Hz), 4.06-4.09 (1H, m), 5.36 (4H, m), 3.22-3.28 (2H, m), 1.69-1.76 (2H,m), 4.86 (1H, i, J = 6.41 Hz), 5.08-5.15 (1H, m). Lipid 271 Heptadecan-9-yl 8-((3-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)propyl)((9Z, 12Z)- octadeca-9, 12-dien-1-yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 827.7 obs. 828.1; 1 H NMR (400 MHz, CDCl3): δ 0.90(9H, m), 1.28 (56H, m), 1.62 (5H, m), 1.72-1.79 (1H, m), 2.07 (4H, q, J = 6.77Hz), 2.29 (2H, t, J = 7.49 Hz), 2.37 (3H, m), 2.44-2.49 (2H, m), 2.78 (2H, t, J =6.52 Hz), 4.15 (1H, m), 4.37-4.40 (2H, 4.39 (d, J = 6.13 Hz), 4.38 (s)), 4.88(1H, i, J = 5.95 Hz), 5.38 (4H, m), 6.98 (2H, s). Lipid 272 Heptadecan-9-yl 3-ethyl-13-((9Z, 12Z)-octadeca-9, 12-dien-1-yl)-8-oxo-9-oxa-3, 7, 13- triazahenicosan-21-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 860.8 obs. 861.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.02 (6H, t, J = 7.13 Hz), 1.29 (49H, m), 1.50 (4H, m), 1.62 (5H, m), 1.73(2H, m), 2.04 (4H, q, J = 6.99 Hz), 2.27 (2H, t, J = 7.43 Hz), 2.37 (4H, m), 2.48(8H, m), 2.77 (2H, t, J= 6.49 Hz), 3.24 (2H, m), 4.06 (2H, m), 4.86 (1H,quint, J = 6.29 Hz), 5.35 (4H, m), 6.01 (1H, m). Lipid 273 Heptadecan-9-yl 8-((3-(((2-(4-methylpiperazin-1- yl)ethyl)carbamoyl)oxy)propyl)((9Z,12Z)-octadeca-9,12-dien-1- yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 873.8 obs. 874.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.27 (53H, m), 1.50 (3H, m), 1.61 (2H, m), 1.75 (2H, m), 2.04 (4H,q, J = 7.39 Hz), 2.28 (5H, m), 2.44 (14H, m), 2.77 (2H, t, J = 6.58 Hz), 3.26(2H, m), 4.08 (2H, t, J = 6.58 Hz), 4.86 (1H, quint, J = 6.25 Hz), 5.11 (1H, m),5.35 (4H, m). Lipid 274 Heptadecan-9-yl 8-((3-(((2-morpholinoethyl)carbamoyl)oxy)propyl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 860.8 obs. 861.0; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, m), 1.28(50H, m), 1.50 (4H, m), 1.61 (2H, m), 1.75 (2H, m), 2.04 (4H, q, J = 7.13 Hz),2.27 (2H, t, J = 7.50 Hz), 2.43 (12H, m), 2.77 (2H, t,J = 6.41 Hz), 3.27 (2H,m), 3.70 (4H, m), 4.09 (2H, t, J = 7.34 Hz), 4.86 (1H, quint, J = 6.26 Hz), 5.11(1H, m), 5.35 (4H, m). Lipid 275 Heptadecan-9-yl 2-methyl-12-((9Z,12Z)-octadeca-9,12-dien-1-yl)-7- oxo-8-oxa-2,6,12-triazahexacosa-20-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 832.8 obs. 833.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.29 (48H, m), 1.50 (4H, m), 1.63 (5H, m), 1.74 (3H, m), 2.05 (4H, q, J =6.72 Hz), 2.21 (6H, s), 2.27 (2H, t, J = 7.83 Hz), 2.36 (6H, m), 2.47 (2H, t, J =7.01 Hz), 2.77 (2H, t, J = 6.49 Hz), 3.24 (2H, q, J = 6.96 Hz), 4.07 (2H, t, J =6.83 Hz), 4.86 (1H, quint, J = 6.75 Hz), 5.36 (4H, m), 5.47 (1H, m). Lipid 276 Heptadecan-9-yl 8-((3-(((3-(1H-imidazol-1-yl)propyl)carbamoyl)oxy)propyl)((9Z,12Z)-octadeca-9,12-dien-1-yl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 855.8 obs. 856.0; 1 H NMR (400 MHz, CDCl3): 1H NMR (400 MHz): δ 0.87 (9H, m), 1.25 (53H, m), 1.57-1.64 (2H, m), 1.73 (3H, m),2.04 (6H, m), 2.27 (2H, t, J = 7.50 Hz), 2.34-2.40 (4H, 2.37 (t, J = 7.48 Hz),2.37 (d, J = 4.10 Hz)), 2.46 (2H, t, J = 7.26 Hz), 2.77 (2H, t, J = 6.17 Hz), 3.19(2H, q, J = 6.32 Hz), 4.00 (2H, t, J = 7.01 Hz), 4.10 (2H, t, J = 5.97 Hz), 4.86(1H, i, J = 6.24 Hz), 5.35 (4H, m), 6.93 (1H, s), 7.07 (1H, s), 7.49 (1H, s). Lipid 277 Heptadecan-9-yl 8-(((9Z,12Z)-octadeca-9,12-dien-1-yl)(3-(((2-(pyrrolidin-1- yl)ethyl)carbamoyl)oxy)propyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 844.8 obs. 844.9; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.30 (53H, m), 1.61 (3H, m), 1.76 (6H, m), 2.05 (4H, q, J = 7.21 Hz), 2.27(2H, t, J = 7.67 Hz), 2.37 (4H, m), 2.49 (6H, m), 2.58 (2H, t, J = 6.15 Hz), 2.77(2H, t, J = 6.41 Hz), 3.28 (2H, m), 4.08 (2H, t, J = 6.88 Hz), 4.86 (1H, quint,J = 6.26 Hz), 5.15 (1H, m), 5.35 (4H, m). Lipid 278 Heptadecan-9-yl 8-(((9Z,12Z)-octadeca-9,12-dien-1-yl)(3-(((2-(piperidin-1- yl)ethyl)carbamoyl)oxy)propyl)amino)octanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 858.8 obs. 859.0; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H,m), 1.34 (62H, m), 1.74 (2H, m), 2.05 (4H, q, J = 6.80 Hz), 2.27 (2H, t, J = 7.56Hz), 2.37 (10H, m), 2.47 (2H, t, J = 7.11 Hz), 2.77 (2H, t, J = 6.41 Hz), 3.25(2H, m), 4.08 (2H, t, J = 6.28 Hz), 4.86 (1H, quint, J = 6.27 Hz), 5.15 (1H, m),5.36 (4H, m). Lipid 279 Heptadecan-9-yl 10-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-5-oxa- 2,7,10-triazaoctadecan-18-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 922.9 obs. 923.2; 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H, t, J = 7.20Hz), 1.32 (74H, m), 2.28 (9H, m), 2.37 (4H, m), 2.50 (2H, t, J = 6.31 Hz), 2.55(2H, t, J = 6.06 Hz), 3.20 (2H, m), 4.06 (2H, t, J= 6.81 Hz), 4.16 (2H, t, J =5.58 Hz), 4.86 (1H, i, J = 5.68 Hz), 5.24 (1H, m). Lipid 344 Heptadecan-9-yl 11-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa- 2,5,11-triazononadecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 936.9 obs. 937.2; 1 H NMR (500 MHz, CDCl3): δ 0.87 (12H, m), 1.25(71H, m), 1.73 (2H, m), 2.22 (6H, m), 2.34 (10H, m), 2.46 (2H, m), 3.24 (2H,m), 4.06 (5H, m), 4.86 (2H, m), 5.12 (1H, m). Lipid 345 8-((3-((((1H-imidazol-2-yl)methyl)carbamoyl)oxy)propyl)(8- (heptadecan-9-yloxy)-8-oxooctyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 945.8 obs. 946.1; 1 H NMR (500 MHz, CDCl3): δ 0.88 (12H,m), 1.27 (62H, m), 1.50 (4H, m), 1.61 (8H, m), 1.73 (2H, m), 2.32 (7H, m),2.44 (2H, t, J = 6.92 Hz), 4.06 (2H, t, J = 6.63 Hz), 4.13 (2H, t, J = 6.41 Hz),4.37 (2H, d, J = 5.88 Hz), 4.86 (2H, quint, J = 6.68 Hz), 5.47 (1H, m), 6.96 (2H,s). Lipid 346 Heptadecan-9-yl 3-ethyl-13-(8-((2-hexyldecanoyl)oxy)octyl)-8-oxo-9-oxa- 3,7,13-triazahenicosan-21-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 978.9 obs. 979.3; 1 H NMR (500 MHz, CDC13): δ 0.88 (12H, m), 1.02 (5H, t, J = 7.14 Hz), 1.27 (56H, m), 1.40 (6H, m), 1.50 (4H, q, J = 6.41 Hz),1.60 (10H, m), 1.72 (2H, m), 2.28 (7H, m), 2.48 (8H, m), 3.24 (3H, m), 4.06(4H, t, J = 6.57 Hz), 4.86 (2H, m). Lipid 347 8-((8-(Heptadecan-9-yloxy)-8-oxooctyl)(3-(((2-(4- methylpiperazin-1-yl)ethyl)carbamoyl)oxy)propyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 991.9 obs. 992.2; 1 H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.25 (61H, m), 1.50 (5H, m), 1.61 (7H, m), 1.72 (3H, m), 2.39 (22H, m), 3.27 (2H, m), 4.07 (4H, m), 4.86 (1H, quint, J = 6.84 Hz), 5.11 (1H, m). Lipid 348 Heptadecan-9-yl 12-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-7-oxo-8-oxa- 2,6,12-triazaheneicosan-20-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 950.9 obs. 951.2; 1H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.28 (61H, m), 1.50 (4H, m), 1.61 (9H, m), 1.73 (3H, m), 2.21 (6H, s), 2.33 (9H, m), 2.46 (2H, t, J = 8.55 Hz), 3.23 (2H, m), 4.06 (4H, m), 4.86 (1H, m), 5.47(1H, m). Lipid 349 8-((3-(((3-(lH-imidazol-l-yl)propyl)carbamoyl)oxy)propyl)(8-(heptadecan-9-yloxy)-8- oxooctyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 973.9 obs. 974.2; 1 H NMR (500 MHz, CDC13): δ 0.88 (12H, m), 1.25 (74H, m), 1.75 (1H, m), 2.00 (2H, m), 2.27 (3H, m), 2.40 (3H, m), 2.49 (2H, m), 3.19 (2H, m), 3.77 (1H, m), 4.00 (5H, m), 4.86 (2H, m), 6.94 (1H, m), 7.06 (1H, m), 7.49 (1H, d, J = 1.60 Hz). Lipid 350 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(3-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)propyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 962.9 obs. 963.2; 1 H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.31 (74H, m), 1.75 (6H, m), 2.33 (7H, m), 2.48 (6H, m), 2.57 (2H, t, J = 6.19 Hz), 3.28 (2H, m), 4.07 (4H, m), 4.86 (1H, quint,J = 6.77 Hz), 5.15 (1H,m). Lipid 351 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(3-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)propyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 976.9 obs. 977.2; 1 H NMR (500 MHz, CDCl3): δ 0.87 (12H, m), 1.33 (81H, m), 1.74 (2H, m), 2.37 (15H, m), 3.25 (2H, m), 4.07 (4H, m),4.86 (1H, quint J = 6.73 Hz), 5.16 (1H, m). Lipid 351 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(3-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)propyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 976.9 obs. 977.2; 1 H NMR (500 MHz, CDCl3): δ 0.87 (12H, m), 1.32 (72H, m), 1.72 (2H, m), 2.06 (2H, i, J = 7.27 Hz), 2.33 (7H, m),2.47 (4H, m), 3.12 (2H, m), 3.19 (4H, t, J = 7.00 Hz), 4.06 (5H, m), 4.87 (2H,m), 5.03 (1H, m). Lipid 351 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(3-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)propyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 976.9 obs. 977.2; 1H NMR (500 MHz, CDCl3): δ 0.87(12H, m), 1.25 (83H, m), 1.74 (2H, m), 2.36 (6H, m), 2.46 (2H, m), 2.61 (5H,m), 3.21 (2H, m), 4.06 (4H, m), 4.86 (2H, ddt, J = 6.95, 5.88, 2.08 Hz), 5.20(1H, m). Lipid 355 12-(7-(decanoyloxy)heptyl)-2-methyl-7-oxo-8-oxa-2,6,12- triazadocosan-20-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 838.8 obs. 839.1; 1 H NMR (400 MHz, CDCl3): δ 0.88 (9H, t, J = 0.95 Hz),1.26 (50H, m), 1.61 (12H, m), 2.21 (6H, s), 2.29 (9H, m), 2.47 (2H, m), 3.23(2H, m), 4.06 (6H, td, J = 6.67, 3.04 Hz), 5.46 (1H, m). Lipid 356 8-((3-(((3-(1H-imidazol-1-yl)propyl)carbamoyl)oxy)propyl)(7- (decanoyloxy)heptyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 861.7 obs. 862.0; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H, t, J = 0.96Hz), 1.26 (53H, m), 1.61 (8H, m), 2.00 (2H, t, J = 6.87 Hz), 2.28 (3H, t, J =7.58 Hz), 2.33-2.40 (4H, 2.34 (s), 2.36 (t, J= 2.05 Hz), 2.38 (s)), 2.45 (2H,m), 3.19 (3H, m), 4.00 (2H, t, J = 7.00 Hz), 4.06 (7H, m), 6.93 (1H, s), 7.06(1H, s), 7.48 (1H, s). Lipid 357 8-((7-(decanoyloxy)heptyl)(3-(((2-(pyrrolid-1-yl)ethyl)carbamoyl)oxy)propyl)amino)octyl-2-hexyldecanoate was synthesized according to a general synthetic route and method. MS [ESI]: m / z: [M+H]calc 850.8 obs. 851.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H, m), 1.26(56H, m), 1.61 (9H, m), 1.76 (5H, m), 2.28 (3H, t, J = 7.59 Hz), 2.33-2.40 (4H,2.36 (t, J = 7.45 Hz), 2.36 (s)), 2.50 (6H, m), 2.58 (2H, t, J = 6.12 Hz), 4.05(5H, td, J = 6.71, 3.12 Hz). Lipid 358 8-((7-(decanoyloxy)heptyl)(3-(((2-(piperidin-1-yl)ethyl)carbamoyl)oxy)propyl)amino)octyl-2-hexyldecanoate was synthesized according to a general synthetic route and method. MS [ESI]: m / z: [M+H]calc 864.8 obs. 864.9; 1 H NMR (400 MHz, CDCl3): δ 0.87 (9H, m), 1.26 (52H,m), 1.59 (13H, m), 1.74 (2H, m), 2.37 (16H, m), 3.26 (2H, m), 4.08 (6H, m), 5.16 (1H, m). Lipid 359 11-(7-(decanoyloxy)heptyl)-2-methyl-6-oxo-7-oxa-2,5,11- triazanonadecan-19-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 824.7 obs. 825.0; 1 H NMR (400 MHz, CDC13): δ 0.87 (9H, m), 1.29 (52H, m), 1.60 (9H, m), 1.73 (2H, m), 2.22 (6H, s), 2.28 (3H, t, J = 7.59 Hz), 2.38 (6H, m), 2.46 (2H, t, J = 7.40 Hz), 3.24 (2H, m), 4.06 (6H, m). Lipid 360 8-((3-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)propyl)(7- (decanoyloxy)heptyl)amino)octyl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 833.7 obs. 834.0; 1 H NMR (400 MHz, CDC13): δ 0.87 (9H, m), 1.26 (52H, m), 1.61 (9H, m), 1.73 (2H, m), 2.28 (7H, m), 2.44 (2H, m), 4.06 (4H, td, J = 6.70, 3.24 Hz), 4.13 (2H, t, J = 6.43 Hz), 4.37 (2H, d, J = 6.08 Hz), 5.46 (IH, m), 6.96 (2H, s). Lipid 361 13-(7-(decanoyloxy)heptyl)-3-ethyl-8-oxo-9-oxa-3,7,13-triazahenicosan- 21-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 866.8 obs. 867.1; 1H NMR (400 MHz, CDC13): δ 0.88 (9H, m), 1.02 (6H, t, J = 7.14 Hz), 1.26 (53H, m), 1.61 (11H, quint, J = 6.95 Hz), 1.72 (2H, m), 2.28(3H, t, J = 7.58 Hz), 2.36 (4H, t, J = 7.46 Hz), 2.48 (8H, m), 3.24 (1H, s), 4.05(6H, td, J = 6.69, 3.37 Hz). Lipid 362 8-((7-(decanoyloxy)heptyl)(3-(((2-(4-methylpiperazin-l- yl)ethyl)carbamoyl)oxy)propyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 879.8 obs. 880.1; 1 H NMR (400 MHz, CDC13): δ 0.87 (9H, t, J = 6.53 Hz), 1.26 (53H, m), 1.61 (8H, m), 1.74 (2H, m), 2.28 (7H, m), 2.37(5H, m), 2.46 (10H, m), 3.26 (2H, m), 4.06 (6H, m). Lipid 363 8-((3-((2-(dimethylamino)ethyl)amino)propyl)(8-(heptadecan-9-yloxy)-8- oxooctyl)amino)octan-2-yl hexyl decanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 892.9 obs. 893.0; 1 H NMR (400 MHz, CDC13): δ 0.87 (12H, t, J = 7.16Hz), 1.27 (57H, m), 1.45 (10H, m), 1.61 (7H, m), 1.76 (3H, m), 2.25 (10H, m),2.44 (9H, m), 2.74 (2H, m), 4.06 (2H, t,J = 6.58 Hz), 4.86 (1H, quint, J = 6.66Hz). Lipid 364 2-Octyldodecyl 2-methyl-11-(6-((2-octyldodecyl)oxy)-6- oxohexyl)-6-oxo-7-oxa-2,5,11-triazahexadecan-17-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 978.9 obs. 979.3; 1 H NMR (400 MHz, CDCl3): δ 0.88 (12H, t, J = 6.82 Hz), 1.26 (68H, m), 1.42 (4H, m), 1.63 (8H, quint, J = 7.55Hz), 1.72 (2H, m), 2.22 (5H, s), 2.30 (4H, t, J = 7.53 Hz), 2.38 (7H, m), 3.24(2H, m), 3.96 (4H, d, J = 5.80 Hz), 4.07 (2H, m), 5.14 (1H, m). Lipid 365 Bis(2-octyldodecyl) 6,6'-((3-((((1H-imidazol-2-yl)methyl)carbamoyl)oxy)propyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 987.9 obs. 988.2; 1 H NMR (400 MHz, CDCl3): δ 0.88 (12H, t, J = 6.82 Hz),1.26 (68H, m), 1.41 (3H, m), 1.61 (9H, m), 1.73 (1H, m), 2.30 (8H, m), 2.43(2H, m), 3.96 (4H, d, J = 5.80 Hz), 4.13 (2H, m), 4.37 (2H, d, J = 6.05 Hz), 5.51(1H, m), 6.96 (2H, s). Lipid 366 2-octyldodecyl 3-ethyl-13-(6-((2-octyldodecyl)oxy)-6-oxohexyl)-8-oxo-9-oxa- 3,7,13-triazanonadecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1021.0 obs. 1021.3; 1 H NMR (400 MHz, CDC13): δ 0.88 (12H, t, J = 7.20 Hz), 1.02 (6H, t, J = 7.20 Hz), 1.26 (67H, m), 1.42 (4H, m), 1.64 (11H, m), 2.29 (4H, t, J = 7.20 Hz), 2.37 (4H, m), 2.47 (8H, m), 3.24 (2H, m), 3.96 (4H, d, J = 5.80 Hz), 4.06 (2H, t, J = 5.80 Hz), 5.12 (1H, m), 7.20 (1H, m). J = 7.20 Hz), 1.02 (6H, t, J = 7.00 Hz), 1.26 (67H, m), 1.42 (4H, m),1.64 (11H, m), 2.29 (4H, t, J = 7.68 Hz), 2.37 (4H, m), 2.47 (8H, m), 3.24 (2H,m), 3.96 (4H, d, J = 5.81 Hz), 4.06 (2H, t, J = 6.58 Hz), 5.99 (1H, m). Lipid 367 Bis(2-octyldodecyl) 6,6'-( (3-(((2-(4-methylpiperazin-l- yl)ethyl)carbamoyl)oxy)propyl)azanediyl)dicarboxylate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1034.0 obs. 1034.3; 1 H NMR (400 MHz, CDC13): δ 0.88 (12H, t, J = 7.20 Hz), 1.02 (6H, t, J = 7.20 Hz), 1.26 (67H, m), 1.42 (4H, m), 1.64 (11H, m), 2.29 (4H, t, J = 7.20 Hz), 2.37 (4H, m), 2.47 (8H, m), 3.24 (2H, m), 3.96 (4H, d, J = 5.80 Hz), 4.06 (2H, t, J = 5.80 Hz), 5.12 (1H, m), 7.20 (1H, m). J =7.00 Hz), 1.27 (66H, m), 1.42 (4H, m), 1.62 (8H, m), 1.73 (2H, m), 2.39 (23H,m), 3.27 (2H, m), 3.96 (4H, d, J = 5.80 Hz), 4.08 (2H, m), 5.12 (1H, m). Lipid 368 2-octyldodecyl 2-methyl-12-(6-((2-octyldodecyl)oxy)-6-oxohexyl)-7- oxo-8-oxa-2,6,12-triazaoctadecan-18-oate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 992.9 obs. 993.3; 1 H NMR (400 MHz, CDCl3): δ 0.88 (12H, t, J = 7.07 Hz), 1.27 (66H, m), 1.42 (4H, m), 1.64 (12H, m), 2.21 (6H,s), 2.32 (10H, m), 2.46 (2H, t, J = 7.25 Hz), 3.23 (2H, m), 3.96 (4H, d, J = 5.81Hz), 4.07 (2H, t, J = 6.41 Hz), 5.48 (1H, m). Lipid 369 Bis(2-octyldodecyl) 6,6'-((3-(((2-(pyrrolidin-l- yl)ethyl)carbamoyl)oxy)propyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1004.9 obs. 1005.2; 1 H NMR (400 MHz, CDCl3): δ 0.88 (12H, t, J = 7.09Hz), 1.27 (66H, m), 1.42 (4H, m), 1.62 (8H, m), 1.75 (6H, m), 2.30 (4H, t, J =7.43 Hz), 2.37 (4H, m), 2.49 (6H, m), 2.58 (2H, t, J = 6.30 Hz), 3.28 (2H, m),3.96 (4H, d, J = 5.81 Hz), 4.07 (2H, t, J = 6.75 Hz), 5.17 (1H, m). Lipid 370 Bis(2-octyldodecyl) 6,6' -((3-(((2-(piperidin-l- yl)ethyl)carbamoyl)oxy)propyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1018.9 obs. 1019.3; 1 H NMR (400 MHz, CDC13): δ 0.88 (12H, t, J = 6.92 Hz), 1.26 (66H, m), 1.42 (4H, m), 1.65 (12H, m), 2.33 (10H, m), 2.45 (2H, t, J = 7.43 Hz), 3.25 (2H, m), 3.96 (4H, d, J = 5.64 Hz), 4.07 (2H, m), 5.18 (1H, m). J = 7.13 Hz),1.27 (67H, m), 1.42 (6H, m), 1.60 (12H, m), 1.73 (2H, m), 2.30 (4H, t, J = 7.43Hz), 2.39 (11H, m), 3.25 (2H, m), 3.96 (4H, d, J = 5.64 Hz), 4.07 (2H, m), 5.18(1H, m). Lipid 371 Bis(2-octyldodecyl) 6,6' -((3-(((2-(aziridin-l- yl)ethyl)carbamoyl)oxy)propyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 976.9 obs. 977.2; 1 H NMR (400 MHz, CDC13): δ 0.88 (12H, t, J = 6.92 Hz), 1.26 (66H, m), 1.42 (4H, m), 1.65 (12H, m), 2.33 (10H, m), 2.45 (2H, t, J = 7.43 Hz), 3.25 (2H, m), 3.96 (4H, d, J = 5.64 Hz), 4.07 (2H, m), 5.18 (1H, m). J = 7.05Hz), 1.15 (2H, m), 1.26 (66H, m), 1.42 (4H, m), 1.65 (12H, m), 2.33 (10H, m),2.45 (2H, t, J = 7.42 Hz), 3.34 (2H, m), 3.96 (4H, d, J = 5.81 Hz), 4.08 (2H, t, J = 6.92 Hz), 5.17 (1H, m). Lipid 372 Bis(2-octyldodecyl) 6,6' -((3-(((2-(azetidin-l- yl)ethyl)carbamoyl)oxy)propyl)azanediyl) diohexanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 990.9 obs. 991.2;1 H NMR (400 MHz, CDCl3): δ 0.88 (12H, t, J = 6.81Hz), 1.26 (65H, m), 1.42 (4H, m), 1.61 (9H, m), 1.71 (2H, dt, J = 6.41, 1.67Hz), 2.06 (2H, t, J = 7.00 Hz), 2.30 (4H, t, J = 7.53 Hz), 2.37 (4H, t, J = 7.38Hz), 2.47 (4H, m), 3.12 (2H, m), 3.19 (4H, t, J = 6.99 Hz), 3.96 (4H, d, J = 5.80Hz), 4.06 (2H, m), 5.06 (1H, m). Lipid 373 bis(2-octyldodecyl) 6,6' -((3-(((2-(azepan-1-yl)ethyl)carbamoyl)oxy)propyl)azanediyl)dicaproate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 1033.0 obs. 1033.3; 1 H NMR (400 MHz, CDCl3): δ 0.88 (12H, t, J =6.95 Hz), 1.27 (64H, m), 1.43 (4H, m), 1.61 (20H, m), 2.30 (4H, t, J = 7.58Hz), 2.37 (4H, m), 2.46 (2H, t, J = 7.33 Hz), 2.61 (6H, m), 3.21 (2H, m), 3.96(4H, d, J = 5.64 Hz), 4.08 (2H, t, J = 6.41 Hz), 5.20 (1H, m). Lipid 374 11-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-6-oxo-7-oxa-2,5,11- triazanonadec-19-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 922.9 obs. 923.2; 1 H NMR (500 MHz): δ 0.87 (12H, m), 1.28 (62H,m), 1.60 (10H, m), 1.73 (2H, m), 2.22 (6H, s), 2.36 (8H, m), 2.46 (2H, t, J =7.24 Hz), 3.25 (2H, m), 4.06 (6H, m), 5.12 (1H, m). Lipid 375 ((3-((((1H-imidazol-2-yl)methyl)carbamoyl)oxy)propyl)aza-diyl)bis(octane-8,1-diyl) bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 931.8 obs. 932.2; 1 H NMR (500 MHz, CDCl3): δ 0.87 (12H, m), 1.25(62H, m), 1.60 (9H, m), 1.74 (2H, m), 2.31 (6H, m), 2.44 (2H, m), 4.06 (8H,m), 4.37 (2H, m), 5.44 (1H, m), 6.96 (2H, s). Lipid 376 3-ethyl-13-(8-((2-hexyldecanoyl)oxy)octyl)-8-oxo-9-oxa-3,7,13-triazahenicos-21-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 964.9 obs. 965.3; 1H NMR (500 MHz, CDCl3): δ 0.87 (12H, m), 1.02(6H, m), 1.25 (63H, m), 1.60 (10H, m), 1.73 (2H, m), 2.36 (6H, m), 2.48 (8H,m), 3.24 (2H, m), 4.06 (7H, m), 6.01 (1H, m). Lipid 377 ((3-(((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)oxy)propyl)azanediyl)bis(octane-8,1-diyl)bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 977.9 obs. 978.2; 1 H NMR (500 MHz, CDCl3): δ 0.87 (12H, m), 1.25(63H, m), 1.60 (9H, m), 1.74 (2H, m), 2.40 (21H, m), 3.27 (2H, m), 4.06 (6H,m), 5.11 (1H, m). Lipid 378 12-(8-((2-hexyldecanoyl)oxy)octyl)-2-methyl-7-oxo-8-oxa-2,6,12- triazadocosa-20-yl 2-hexyldecanoate was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 936.9 obs. 937.2; 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H, m), 1.25(63H, m), 1.61 (12H, m), 1.73 (2H,), 2.21 (5H, s), 2.34 (8H, m), 2.46 (2H,m), 3.23 (2H, m), 4.06 (6H, t, J = 6.65 Hz), 5.46 (1H, m). Lipid 379 ((3-(((2-(pyrrolidin-1-yl)ethyl)carbamoyl)oxy)propyl)azanediyl)bis(octane-8, 1-diyl)bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 948.9 obs. 949.2; 1 H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.25 (63H, m), 1.61 (9H, m), 1.76 (6H, m), 2.37 (6H, m), 2.50 (6H, m), 2.58 (2H, m), 3.28 (2H, m), 4.06 (6H, m), 5.15 (1H, m). Lipid 380 ((3-(((2-(piperidin-1-yl)ethyl)carbamoyl)oxy)propyl)azanediyl)bis(octane-8, 1-diyl)bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 962.9 obs. 963.1; 1 H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.29 (64H, m), 1.58 (14H, m), 1.74 (2H, m), 2.36 (12H, m), 2.47 (2H, t, = 7.48 Hz), 3.25 (2H, m), 4.06 (6H, m), 5.16 (1H, m). J Lipid 381 ((3-(((2-(aziridin-1-yl)ethyl)carbamoyl)oxy)propyl)azanediyl)bis(octane-8, 1-diyl)bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 920.8 obs. 921.1; 1 ​H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.16(2H, m), 1.26 (62H, m), 1.61 (8H, m), 1.74 (4H, m), 2.21 (1H, m), 2.34 (8H,m), 2.46 (2H, m), 3.00 (1H, m), 3.34 (2H, m), 4.06 (6H, m), 5.14 (1H, m). Lipid 382 ((3-(((2-(azetidin-l-yl)ethyl)carbamoyl)oxy)propyl)azanediyl)bis(octane-8, 1-diyl) bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 934.9 obs. 935.1; 1 H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.25(61H, m), 1.60 (9H, m), 1.72 (2H, m), 2.06 (2H, m), 2.36 (6H, m), 2.48 (4H,m), 3.12 (3H, m), 3.19 (5H, t, J = 6.95 Hz), 4.06 (6H, m), 5.03 (1H, m). Lipid 382 ((3-(((2-(azetidin-l-yl)ethyl)carbamoyl)oxy)propyl)azanediyl)bis(octane-8, 1-diyl) bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 934.9 obs. 935.1; 1 H NMR (500 MHz, CDC13): δ 0.87 (12H, m), 1.25(61H, m), 1.60 (9H, m), 1.72 (2H, m), 2.06 (2H, m), 2.36 (6H, m), 2.48 (4H,m), 3.12 (3H, m), 3.19 (5H, t, J = 6.75 Hz),2.60 (6H, m), 3.21 (2H, m), 4.07 (6H, m), 5.19 (1H, m). Lipid 384 ((3-((2-(dimethylamino)ethyl)amino)propyl)azanediyl)bis(octane-8, 1-diyl) bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 878.9 obs. 879.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H, d, J = 6.62 Hz), 1.28(62H, m), 1.59 (13H, m), 2.22 (6H, s), 2.37 (10H, m), 2.62 (2H, t, J = 7.13Hz), 2.67 (2H, t, J = 6.24 Hz), 4.06 (4H, t, J = 6.65 Hz). Lipid 385 ((3-((3-(diethylamino)propyl)amino)propyl)azanediyl)bis(octane-8, 1-diyl) bis(2-hexyldecanoate) was synthesized according to the general synthetic route and general methods. MS [ESI]: m / z: [M+H] calc 920.9 obs. 921.1; 1 H NMR (400 MHz, CDCl3): δ 0.87 (12H, m), 1.01 (6H, t, J = 7.14Hz), 1.27 (55H, m), 1.42 (1H, m), 1.58 (16H, m), 2.22 (1H, s), 2.41 (13H, m),2.61 (2H, m), 4.06 (4H, t, J = 6.66 Hz). Example P1 Heptadecan-9-yl 3-ethyl-12-(8-((2-hexyldecanoyl)oxy)octyl)-8-oxo-9-oxa-3,7,12- triazadocosa-20-ate lipid

[006] 8-((8-(Heptadecan-9-yloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octan-2-yl hexyldecanoate (0.3 g; 0.37 mmol) and 4-nitrophenyl chloroformate (0.090 g; 0.45 mmol) were dissolved in 10 mL dry DCM. TEA (0.103 ml; 0.742 mmol) was added and the reaction was stirred at room temperature overnight. Then N1,N1-dimethylpropane-1,3-diamine (0.121 g; 0.93 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was then directly subjected to column chromatography (DCM with 2% - 10% iPrOH) to give the lipid

[006] as a yellow oil (297 mg; 83%) 1 H NMR (400 MHz, CDCl3): δ ppm 5.87 (br, 1H);4.83 (p, 1H); 4.03 (m, 4 H) 3.24 (m, 2H); 2.61 (m, 8); 2.43 (m, 4H); 2.25 (m,3H); 1.72 – 1.43 (m, 19H); 1.22 (m, 59H); 1.08 (m, 6H); 0.85 (m, 12H); MS[ESI]: m / z: [M+H]calc. 965.6 obs. 965.5 Example P2 8-((2-(((2-(1H-imidazol-5-yl)ethyl)carbamoyl)oxy)ethyl)(8-(heptadecan-9-yloxy)-8- oxooctyl)amino)octyl 2-hexyldecanoate Lipid

[007] 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octyl 2-hexyldecanoate (0.3 g, 0.37 mmol), 4-nitrophenyl chloroformate (0.090 g, 0.445 mmol) were dissolved in 10 mL DCM. Then TEA (0.103 ml, 0.742 mmol) was added and the reaction was stirred at room temperature overnight. Then 2-(1H-imidazol-5-yl)ethan-1-amine (0.041 g, 0.371 mmol) was added and the reaction was stirred at room temperature overnight. Then the reaction was directly subjected to column chromatography (10% iPrOH in DCM with 0.1% TEA) to give the lipid

[007] as a yellow oil (160 mg; 45%). 1 H NMR (400 MHz, CDCl3): δ ppm 7.56 (s, 1H); 6.81 (s, 1H); 5.38 (brs, 1H); 4.86 (p, 1H); 4.17 (brm, 2H); 4.03 (m, 3 H); 3.46 (m, 2H); 2.81 (m, 4H); 2.56 (brm, 4H); 2.27 (m, 4H); 1.60 - 1.19 (m, 73H); 0.87 (m, 12H); MS [ESI]: m / z: [M+H] calc. 946.5 obs. 946.3 Example P3 8-((2-((((lH-imidazol-2-yl)methyl)carbamoyl)oxy)ethyl)(8-(heptadecan-9-yloxy)-8- oxooctyl)amino)octyl 2-hexyldecanoate lipid

[008] 8-((8-(heptadecan-9-yloxy)-8-oxooctyl)(2-hydroxyethyl)amino)octyl 2-hexyldecanoate (0.3 g, 0.371 mmol), 4-nitrophenyl chloroformate (0.090 g, 0.445 mmol) were dissolved in 10 mL DCM. Then TEA (0.103 ml, 0.742 mmol) was added and the reaction was stirred at room temperature overnight. (lH-imidazol-2-yl)methanamine (63 mg; 0.371) was dissolved in 5 mL DMF, then TEA (0.103 ml, 0.742 mmol) was added. The suspension was heated to form a clear solution and the resulting mixture was added to the reaction, which was stirred at room temperature overnight. The reaction was then directly subjected to column chromatography (10% iPrOH in DCM with 0.1% TEA) to give lipid

[008] as a yellow oil (160 mg; 45%) MS [ESI]: m / z: [M+H] calc. 932.5 obs. 932.3. Experimental Example 1 Materials and Methods 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethyleneglycol-2000 (DMG-PEG 2000) were from Avanti Lipids. Quant-it™ RiboGreen RNA assay kit was from ThermoFisher Scientific. Luciferase assay system, CellTiter-Glo® luminescent cell viability assay and lysis buffer were from Promega. Reference lipids, i.e. lipids A, B and C with the following structures were prepared according to the method described in US 11851389 B2.

[0133] Lipid A Lipid B Lipid C Long-term stability analysis The lipids of the present application were compared to reference lipids and found to have improved stability. After incorporation of the lipids into lipid nanoparticles, the purity of the lipids was tested and only the reference lipids were found to be cleaved by transesterification or hydrolysis under LNP synthesis conditions. Long-term stability studies also showed the formation of degradation products over time. Figures 1-6 Examples of stability testing of the ester moieties of reference lipid C and the lipids of the present application in ethanol and PBS pH = 7.4 (simulating LNP synthesis conditions) are depicted.

[0134] Lipid nanoparticle (LNP) preparation The ionizable lipid, DSPC, cholesterol, and DMG-PEG 2000 were mixed in a molar ratio of 50:10:38.5:1.5 in anhydrous ethanol. The circular RNA and linear mRNA payloads were suspended in 25 mM acetate buffer (pH 4.5). To form the LNP, three volumes of RNA encoding luciferase in the form of cirRNA (SEQ ID NO: 1) and mRNA (SEQ ID NO: 2) were mixed with one volume of lipids in ethanol solution (by microfluidic mixing with Nanoassemblr Ignite (Precision Nanosystems) at a flow rate of 12 ml / min). The molar ratio of ionizable lipid to ribonucleotides was 15 or 6. The final lipid concentration in solution was 1.5 mM to 6 mM. After encapsulation, the particles were dialyzed twice against PBS.

[0135] cirRNA: SEQ ID NO: 1 mRNA SEQ ID NO: 2 Lipid nanoparticle (LNP) physicochemical characterization LNP size and polydispersity index (PDI) were determined by dynamic light scattering (DLS) and zeta potential was measured by Zetasizer machine (Malvern). RNA concentration and encapsulation efficiency were analyzed by Quant-IT Ribogreen kit by calculating the percentage of encapsulation of 100% - (RNA-LNP / RNA-LNP with Triton X-100).

[0136] In vitro expression RAW 264.7 and Hep G2 cells were transfected with 100 ng / mL of RNA-LNP encoding for firefly luciferase. 72 hours post-transfection, cells were washed and lysed. Luciferase expression was determined in cell lysates with Luciferase Assay Reagent Kit (Promega) according to the kit protocol, and luciferase activity was measured by luminometer.

[0137] In vitro toxicity RAW 264.7 and Hep G2 cells were transfected with 1 pg / mL RNA-LNP. 72 hours post-transfection, cell viability was determined by luminometer with CellTiter-Glo® kit according to the kit protocol.

[0138] Cell viability was calculated according to the following formula: In vivo expression 6-8 weeks old female BALB / C mice were injected by intravenous injection with 0.05 -1 of RNA LNP. 2 and 24 hours post-injection, animals were bled and serum concentration of MCP-I was determined by immunoassay (Luminex).

[0139] Serum elevation of MCP-I cytokine 6-8 weeks old female BALB / C mice were injected by intravenous injection with 0.5 -1 of RNA LNP. 2 and 24 hours post-injection, animals were bled and serum concentration of MCP-I was determined by immunoassay (Luminex).

[0140] Serum elevation of liver enzymes 6-8 weeks old female BALB / C mice were injected by intravenous injection with 0.5 -1 RNA LNPs. Two hours and 24 hours after injection, animals were bled and serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined by a blood chemistry analyzer. PBS control data for the mice are as follows: 1. PBS control

[0141] Local tolerability assay by footpad injection The 0.175 Six to eight week old female BALB / C mice were injected with -1 RNA LNPs subcutaneously into the scruff of the neck. Prior to injection and 24 hours after injection, the thickness of the injected scruff was measured with calipers. The results in Table D show a slight increase in scruff thickness.

[0142] Test results are shown in Tables A1, A2, B1, B2, C, and D.

[0143] Table A1

[0144] Table A2

[0145] Table B1

[0146] Table B2

[0147] Table C

[0148] Table D

Claims

1. A cationic lipid represented by the structure of Formula (I): ###0001### or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof ， (I) wherein: X is -0-, -NH- or -S-; Y is -0-, -NH- or -S-; (b) a side chain of a natural or unnatural amino acid; L and L' are each independently selected from direct bonds, -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene-, -C 2-6 imidene-, -WC 1-6 Alkylene-, -WC 2-6 imidene-, -C 1-6 Alkylene-W-, -C 2-6 alkenyl-W-, -W-W'-C 1-6 alkylene-, -C 1-6 Alkylene -W-W'-, -W-W'-C 1-6 imidene-, -C 2-6 imidene-W-W'-, -WC 1-6 Alkylene-W'- and -WC 2-6 alkenyl-W'-, wherein the alkylene and alkenyl groups are optionally further interrupted by one or more W groups; W and W' are each independently selected from -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene- and -C 2-6 alkenyl-; R 1 selected from the group consisting of: (a) NR 4 R 5 , wherein R 4 and R 5 are each independently H, Ci-C6alkyl, -NH2, halogen, -OH, 3- to 10-membered ring, or C 6-12 aralkyl, wherein the Ci-C6alkyl, 3- to 10-membered ring, or C 6-12 aralkyl is optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl, and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached collectively form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N, and S; (b) a side chain of a natural or unnatural amino acid; and (c) 3- to 10-membered ring, for example C 6-12 aromatic ring, 3- to 10-membered heterocyclic ring containing one or more heteroatoms selected from O, N and S, 5- to 10-membered heteroaromatic ring, or fused ring (e.g. 4- to 10-membered fused ring), wherein the above rings are optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; and (d) -OH or optionally surrounded by one or more elements selected from -NH2, halogen, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents of -C 1-10 alkyl; Preferably, R 1 is selected from the group consisting of: (a) NR 4 R 5 wherein R 4 and R 5 are each independently H, C1-C6 alkyl, or C 6-12 aralkyl, optionally substituted with -NH2; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N, and S; (c) a 3- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S; Z is -0-C(=0)-, -C(=0)-0- or -0-. (d) -OH or optionally surrounded by one or more elements selected from -NH2, halogen, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents of -C 1-10 alkyl; R 2 and R 3 are each independently selected from the group consisting of: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; 2. The cationic lipid of claim 1, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (IA) ###0002### (IA) wherein: ， X is -0-, -NH- or -S-; (b) a side chain of a natural or unnatural amino acid; (b) a side chain of a natural or unnatural amino acid; and L is selected from the group consisting of a direct bond, -0-, -C(=0)-, -C(=0)0-, -NH-, -NHC(=0)-, -NH(S=0)-, -NHS(=0)2-, -S-, -S=0-, -S(=0)2-, -C 1-6 alkylene-, -C 2-6 alkenylene-, -W-C 1-6 alkylene-, -W-C 2-6 alkenylene-, -C 1-6 alkylene-W-, -C 2-6 alkenylene-W-, -W-W'-C 1-6 alkylene-, -C 1-6 alkylene-W-W'-, -W-W'-C 1-6 alkenylene-, -C 2-6 alkenylene-W-W'-, -W-C 1-6 alkylene-W'- and -W-C 2-6 alkenylene-W'-, wherein said alkylene and alkenylene are optionally further interrupted by one or more W; W and W' are each independently selected from -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene- and -C 2-6 alkenyl-; R 1 selected from the group consisting of: (a) NR 4 R 5 , wherein R 4 and R 5 are each independently H, Ci-C6alkyl, -NH2, halogen, -OH, 3- to 10-membered ring, or C 6-12 aralkyl, wherein the Ci-C6alkyl, 3- to 10-membered ring, or C 6-12 aralkyl is optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl, and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached collectively form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N, and S; (c) a 3- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S; (c) 3- to 10-membered ring, for example C 6-12 aromatic ring, 3- to 10-membered heterocyclic ring containing one or more heteroatoms selected from O, N and S, 5- to 10-membered heteroaromatic ring, or fused ring (e.g. 4- to 10-membered fused ring), wherein the above rings are optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; and (d) -OH or optionally surrounded by one or more elements selected from -NH2, halogen, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents of -C 1-10 alkyl; Preferably, R 1 is selected from the group consisting of: (a) NR 4 R 5 wherein R 4 and R 5 are each independently H, C1-C6 alkyl or C 6-12 aralkyl, optionally substituted with -NH2; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10- membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N and S; Z is -0-C(=0)-, -C(=0)-0- or -0-; m is 0, 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4, more preferably 3 or 4. R 2 and R 3 are each independently selected from the group consisting of: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; 3. The cationic lipid of claim 1, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of Formula (II) or (III): ###0003### (II) (III) wherein: (b) a side chain of a natural or unnatural amino acid; (b) a side chain of a natural or unnatural amino acid; and (c) a 3- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S; L is selected from direct bonds, -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O-), -NH(S=O-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene-, -C 2-6 imidene-, -WC 1-6 Alkylene-, -WC 2-6 imidene-, -C 1-6 Alkylene-W-, -C 2-6 alkenyl-W-, -W-W'-C 1-6 alkylene-, -C 1-6 Alkylene -W-W'-, -W-W'-C 1-6 imidene-, -C 2-6 imidene-W-W'-, -WC 1-6 Alkylene-W'- and -WC 2-6 alkenyl-W'-, wherein the alkylene and alkenyl groups are optionally further interrupted by one or more W groups; W and W' are each independently selected from -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene- and -C 2-6 alkenyl-; R 1 selected from the group consisting of: (a) NR 4 R 5 wherein R 4 and R 5 are each independently H, Ci-C6alkyl, -NH2, halo, -OH, 3- to 10-membered ring, or C 6-12 aralkyl, wherein the Ci-C6alkyl, 3- to 10-membered ring, or C 6-12 aralkyl is optionally substituted with one or more substituents selected from -NH2, halo, -OH, -C 1-6 alkyl, and 3- to 4-membered ring; or R 4 and R 5 together with the nitrogen to which they are attached collectively form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N, and S; Z is -0-C(=0)-, -C(=0)-0- or -0-; (c) 3- to 10-membered ring, for example C 6-12 aromatic ring, 3- to 10-membered heterocyclic ring containing one or more heteroatoms selected from O, N and S, 5- to 10-membered heteroaromatic ring, or fused ring (e.g. 4- to 10-membered fused ring), wherein the above rings are optionally substituted with one or more substituents selected from -NH2, halogen, -OH, -C 1-6 alkyl and 3- to 4-membered ring; and (d) -OH or optionally surrounded by one or more elements selected from -NH2, halogen, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents of -C 1-10 alkyl; Preferably, R 1 is selected from the group consisting of: (a) NR 4 R 5 wherein R 4 and R 5 are each independently H, C1-C6 alkyl or C 6-12 aralkyl, optionally substituted with -NH2; or R 4 and R 5 together with the nitrogen to which they are attached form a 4- to 10-membered heterocyclic ring or a 5- to 10-membered heteroaromatic ring, said heterocyclic and heteroaromatic rings optionally containing one or more additional heteroatoms selected from O, N and S; m is 0, 1, 2, 3, 4, 5 or 6, preferably 2, 3 or 4, more preferably 3 or 4.

7. The cationic lipid of any one of claims 1 to 6, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is -(CH2)n- wherein n = 1, 2 or 3. (d) -OH or optionally surrounded by one or more elements selected from -NH2, halogen, -OH, -C 1-6 Alkyl groups and 3- to 4-membered ring substituents of -C 1-10 alkyl R 2 and R 3 are each independently selected from the group consisting of: (a) C 10 -C 22 alkyl; (b) C 10 -C 22 alkenyl; (c) C 10 -C 22 alkynyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; (b) a 5- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaromatic ring containing one or more heteroatoms selected from O, N and S, or a fused ring (e.g. a 4- to 10-membered fused ring); and (c) -OH.

4. The cationic lipid of any one of claims 1 to 3, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is selected from -C 1-6 alkylene-, -C 2-6 alkenylene-, -W-C 1-6 alkylene-, -W-C 2-6 alkenylene-, -C 1-6 alkylene-W-, -C 2-6 alkenylene-W-, -W-W'-C 1-6 alkylene-, -C 1-6 alkylene-W-W'-, -W-W'-C 1-6 alkylene-, -C 2-6 alkenylene-W-W'-, -W-C 1-6 alkylene-W'- and -W-C 2-6 alkenylene-W'-; W and W' are each independently selected from -O-, -C(=O)-, -C(=O)O-, -NH-, -NHC(=O)-, -NH(S=O)-, -NHS(=O)2-, -S-, -S=O-, -S(=O)2-, -C 1-6 alkylene- and -C 2-6 Alkenyl-.

5. The cationic lipid of any one of claims 1 to 4, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is -C 1-6 alkylene-, -W-C 1-6 alkylene-, -C 1-6 alkylene-W-, -W-W'-C 1-6 alkylene- or -W-C 1-6 alkylene-W'-; W and W' are each independently selected from -O-, -C(=O)-, -C(=O)O-, and -C respectively each time they appear. 1-6 alkylene- or -C 2-6 Alkenyl group.

6. The cationic lipid of any one of claims 1 to 5, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is -C 1-6 alkylene-. Z is -0-C(=0)-, -C(=0)-0- or -0-.

8. The cationic lipid of any one of claims 1 to 7, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 1 is selected from the group consisting of: (a) NR 4 R 5 wherein R 4 and R 5 each independently is H, C1-C3 alkyl or C 6-12 aralkyl, optionally substituted with -NH2; or R 4 and R 5 together with the nitrogen to which they are attached form a 5- to 6- membered heterocyclic or 5- to 6- membered heteroaromatic ring, optionally containing one or more additional heteroatoms selected from O, N and S; Z is -0-C(=0)-, -C(=0)-0- or -0-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, 9. The cationic lipid of any one of claims 1 to 8, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 1 is NR 4 R 5 is NR 4 and R 5 are each independently H, C1-C3 alkyl or benzyl, optionally substituted with -NH2.

10. The cationic lipid of any one of claims 1 to 9, wherein R 1 is selected from -OH, -NH2, -N(CH3)2, -N(C2H5)2, , , , , , , , , , , , , and .

11. The cationic lipid of any one of claims 1 to 10, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are each independently selected from the group consisting of: (a) C 10 -C 22 alkyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkyl; (b) C 10 -C 22 alkenyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkenyl; (d) C4-C 15 alkylene-Z-C4-C 22 alkyl; and (e) C4-C 15 alkylene-Z-C4-C 22 alkenyl; ​ 12. The cationic lipid of any one of claims 1 to 10, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are each independently selected from the group consisting of: (a) C 10 -C 22 alkyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkyl; (b) C 10 -C 22 alkenyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkenyl; (c) C p alkylene-Z-C q alkyl; and (d) C p alkylene-Z-C q alkenyl; ​ ​ q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

13. The cationic lipid of any one of claims 1 to 12, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are each independently selected from the group consisting of: (b) C 10 -C 22 alkenyl, for example C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 or C 20 alkenyl; and (c) C p alkylene-Z-C q alkyl; Z is -O-C(=O)- or -C(=O)-O-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

14. The cationic lipid of any one of claims 1 to 13, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are each independently selected from the group consisting of: (c) C p alkylene-Z-C q alkyl; Z is -O-C(=O)- or -C(=O)-O-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22. R 2 and Z in R 3 are different.

15. The cationic lipid of any one of claims 1 to 14, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are each (b) C 16 -C 20 alkenyl, for example C 16 , C 17 , C 18 , C 19 or C 20 alkenyl, and (c) C p alkylene-Z-C q alkyl, Z is -O-C(=O)- or -C(=O)-O-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

16. The cationic lipid of any one of claims 1 to 15, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are (c) C p alkylene-Z-C q alkyl, Z is -O-C(=O)- or -C(=O)-O-, p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22. R 2 and Z in R 3 is the same, e.g., Z in R 2 and R 3 is -O-C(=O)-.

17. The cationic lipid of any one of claims 1 to 16, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are each independently selected from the group consisting of: 。 18. The cationic lipid of any one of the preceding claims, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically-labeled compound or mixture thereof, wherein R 2 and R 3 are each independently selected from the group consisting of: 、 、 、 、 and .

19. The cationic lipid of any one of the preceding claims, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein R 2 and R 3 are the same group and are , , or . Z is -O-C(=O)- or -C(=O)-O-, wherein R 2 and R 3 are different radicals and each is or , or wherein R 2 and R 3 are different radicals and each is or . p is any integer from 4 to 15, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, wherein R 2 and R 3 are different radicals and each is or , or wherein R 2 and R 3 are different radicals and each is or . q is any integer from 4 to 22, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22.

20. The cationic lipid of any one of the preceding claims, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or mixture thereof, ， 21. The cationic lipid of any one of the preceding claims, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or mixture thereof, 22. The cationic lipid of any one of the preceding claims, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or mixture thereof, wherein the cationic lipid is selected from Table 1 and Table P1.

23. A cationic lipid represented by the structure of formula (IV): (IV) or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound, or mixture thereof, wherein L is -(CH2)n- and wherein n = 1, 2, or 3; R 1 -N(CH3)2, -N(C2H5)2, , or ; R 2 and R 3 are each independently selected from the group consisting of: 。 24. The cationic lipid of claim 23, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of formula (IV): ， (IV) wherein R 1 -L- is selected from 、 、 、 and .

25. A cationic lipid represented by the structure of formula (V): ， or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein L is -(CH2)n- wherein n = 1, 2 or 3; R 1 -N(CH3)2, -N(C2H5)2, , or ; R 2 and R 3 are each independently selected from the group consisting of: 。 26. The cationic lipid of claim 25, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is represented by the structure of formula (V): ， (V) wherein R 1 -L- is selected from , , , and .

27. The cationic lipid of any one of claims 1 to 26, or a salt, hydrate, solvate, polymorph, optical isomer, geometric isomer, enantiomer, diastereomer, tautomer, isotopically labeled compound or mixture thereof, wherein the cationic lipid is a compound listed in Table PI.

28. An intermediate compound represented by the structure of formula (VI): ， (VI) wherein R 6 is a leaving group, preferably , or ; and the remaining groups are as defined in any one of claims 1-27.

29. A method of making the cationic lipid of any one of claims 1-27, comprising the step of reacting a compound of formula (VI) with a compound of formula (VII) to give a cationic lipid of formula (IA): ， wherein each group is as defined in any one of claims 1-27; and Preferably, the reaction is carried out in the presence of a base, such as TEA or DIPEA.

30. A nanoparticle composition comprising the cationic lipid of any one of claims 1-27.

31. A pharmaceutical composition comprising the cationic lipid of any one of claims 1-27 or the nanoparticle composition of claim 30 and a pharmaceutically acceptable carrier.

32. A method of delivering a nucleic acid molecule to a cell, comprising the step of administering to an individual a composition comprising (i) the nanoparticle composition of claim 30 and (ii) the nucleic acid molecule, wherein the administration involves contacting the cell with the nanoparticle composition, thereby delivering the nucleic acid molecule to the cell.

33. The method of claim 32, wherein the individual is a mammal.

34. The method of claim 33, wherein the mammal is a human.

35. A method of providing a polypeptide of interest in a cell, comprising the step of contacting the cell with a nucleic acid molecule encoding the polypeptide of interest, the nucleic acid molecule being encapsulated by or combined with the nanoparticle composition of claim 30, such that the nucleic acid molecule is capable of being translated in the cell to produce the polypeptide, for example, the nucleic acid molecule is an mRNA molecule, an siRNA molecule or a circular RNA molecule.

36. The cationic lipid of any one of claims 1-27 or the nanoparticle composition of claim 30 for use in the preparation of a medicament for the treatment of a disease or disorder in a mammal in need thereof, wherein the medicament comprises a therapeutic and / or prophylactic nucleic acid molecule, such as an mRNA, siRNA, or circular RNA.

37. Use of the cationic lipid of any one of claims 1-27 for the preparation of a nanoparticle composition.

38. Use of the cationic lipid of any one of claims 1-27 or the nanoparticle composition of claim 30 in the preparation of a medicament for the treatment of a disease or disorder in an individual in need thereof.

39. The use of claim 38, wherein the individual is a mammal.

40. The use of claim 39, wherein the mammal is a human.

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