Lipid compounds, compositions and uses thereof

Abstract

The present disclosure provides lipid compounds and compositions comprising the lipid compounds of the present disclosure (e.g., lipid nanoparticle (LNP) compositions). The present disclosure provides methods of delivering an active agent (e.g., a polynucleotide) to a cell or tissue, preferably an extrahepatic cell or tissue, of a subject comprising administering to the subject an effective amount of a lipid nanoparticle of the disclosure wherein the lipid nanoparticle comprises a lipid compound of the disclosure and an active agent (e.g., a polynucleotide).

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 504,967, filed May 30, 2023, the entire contents of which are hereby incorporated by reference. Technical Field

[0002] This disclosure provides lipid compounds and compositions comprising the lipid compounds disclosed herein (e.g., lipid nanoparticle (LNP) compositions). This disclosure also provides a method for delivering an active agent (e.g., a polynucleotide) to the cells or tissues of a subject, such as extrahepatic cells or tissues, comprising administering to the subject an effective amount of the lipid nanoparticles disclosed herein, wherein the lipid nanoparticles comprise the lipid compounds disclosed herein and the active agent (e.g., a polynucleotide). Background Technology

[0003] Many bioactive agents are difficult to deliver into cells. These include polynucleotide-based therapies (e.g., DNA-based therapies or RNA-based therapies, such as mRNA or siRNA), and CRISPR / Cas9-based gene editing therapies. Recently, lipid nanoparticles (LNPs) have been developed as encapsulation mediators for delivering these types of bioactive agents to cells and tissues of interest. For example, LNPs containing ionizable lipids can act as mediators to deliver bioactive agents across cell membranes and directly into target cells, and to guide these agents to preferred tissues of interest.

[0004] However, LNPs may benefit from improvements such as prolonged stability and enhanced cell or tissue specificity. For example, many LNPs strongly target hepatocytes and tissues, but have limited effectiveness in targeting extrahepatic (i.e., non-hepatic) cells and tissues. Therefore, there is a need for stable LNP compositions that can effectively target extrahepatic cells and tissues of subjects. Summary of the Invention

[0005] This disclosure provides lipid compounds and compositions comprising the lipid compounds disclosed herein (e.g., lipid nanoparticle (LNP) compositions) that can provide, in particular, improved stability and / or extrahepatic targeting.

[0006] This disclosure provides lipid compounds having the following formula: or its pharmaceutically acceptable salt; wherein: R 1 and R 1' Each is independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R5 or (C1-C8 alkoxy)-R 5 ; R 1'' Independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 (C1-C8 alkoxy)-R 5 、or R 12 -R 13 ; Each R 5 Independently: hydrogen, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, sterol, C(O)OR 6 OC(O)-R 6 OC(O)OR 6 CH(R) 7 )R 8 C(O)O-CH-(R) 7 )R 8 C(O)O-C1-C4 alkyl-(R 9 )R 10 OC(O)-C1-C4 alkyl-(R 9 )R 10 、or OC(O)CH(R) 9 )R 10 ; Each R 6 Independently: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, C7-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, or sterol; R 7 and R 8 Each independently is: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, or C7-C 12 Alkoxy; R 9 and R 10Each independently is: C1-C 12 Alkyl or C2-C 12 alkenyl; X 1 Is it O, NH, or CHR? 14 ; X 2 Is it O, NH, or CHR? 11 ; R 2 It is C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C1-C 12 Alkoxy, (C1-C4 alkyl)-(C1-C4 alkoxy), optionally substituted C3-C 12 Cycloalkyl, (C1-C4 alkyl)-(optionally substituted C3-C) 12 (Cycloalkyl), optionally substituted C3-C6 heterocycles, (C1-C4 alkyl)-(optionally substituted C3-C6 heterocycles), optionally substituted C5-C6 aryl, or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl); R 2' It is hydrogen, C1-C 12 Alkyl, alkenyl, or alkynyl, C1-C 12 Alkoxy, (C1-C4 alkyl)-(C1-C4 alkoxy); Where R 2 and R 2' They can be combined to form optionally substituted C4-C6 cycloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 heterocycles; R 3 and R 4 Each independently is: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl, or wherein R 3 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 11 It is hydrogen or C1-C6 alkyl, or R 11 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 12 It is a bonded or optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl group; R 13 It is hydrogen, optionally substituted C3-C 12 Cycloalkyl, or optionally substituted C5-C6 aryl; R 14 It is hydrogen or C1-C6 alkyl, or R 14 and R 2 They are linked together to form optionally substituted C5-C8 cycloalkyl groups; m is 1-4; p is 0-4; and n is 1-5.

[0007] This disclosure provides lipid compounds having the following formula: Or its pharmaceutically acceptable salt, wherein: R 1 and R 1' Each is independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 or (C1-C8 alkoxy)-R 5 ; R 1'' Independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 (C1-C8 alkoxy)-R 5 、or R 12 -R 13 ; Each R 5 Independently: hydrogen, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, sterol, C(O)OR 6 OC(O)-R 6 OC(O)OR 6 CH(R) 7 )R 8 C(O)O-CH(R) 7 )R 8 C(O)O-C1-C4 alkyl-(R 9 )R 10 OC(O)-C1-C4 alkyl-(R 9 )R 10 、or OC(O)CH(R) 9 )R 10 ; Each R 6 Independently: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, C7-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, or sterol; R 7 and R 8 Each independently is: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, or C7-C 12 Alkoxy; R 9 and R 10 Each independently is: C1-C 12 Alkyl or C2-C 12 alkenyl; X 1 Is it O, NH, or CHR? 14 ; X 2 Is it O, NH, or CHR? 11 ; R 2 It is C1-C 12 Alkyl, C2-C 12 alkenyl, or C2-C 12 alkynyl group, C1-C 12 Alkoxy, (C1-C4 alkyl)-(C1-C4 alkoxy), optionally substituted C3-C 12 Cycloalkyl, (C1-C4 alkyl)-(optionally substituted C3-C) 12 (Cycloalkyl), optionally substituted C3-C6 heterocycles, (C1-C4 alkyl)-(optionally substituted C3-C6 heterocycles), optionally substituted C5-C6 aryl, or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl); R 3 and R 4 Each independently is: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl, or wherein R 3 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 12 It is a bonded or optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl group; R 13It is hydrogen, optionally substituted C3-C 12 Cycloalkyl, or optionally substituted C5-C6 aryl; R 11 It is hydrogen or C1-C6 alkyl, or R 11 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 14 It is hydrogen or C1-C6 alkyl, or R 14 and R 2 They are linked together to form optionally substituted C5-C8 cycloalkyl groups; n is 1-5; and m is 1-4.

[0008] In some embodiments, R 1 R 1' and R 1'' The two in the equation are independently (C1-C9 alkyl)-R 5 And each R 5 Independently, it is C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' Each is independently (C1-C9 alkyl)-R 5 And each R 5 Independently, it is C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' And R 5' It is C6-C 10 Cycloalkyl. In some embodiments, R 5' It is 1-adamantyl or 2-adamantyl. In some embodiments, R 1 R 1' and R 1'' One of them is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group.

[0009] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5 ; Each R 5Independently, it is C(O)OR 6 And each R 6 Independently, it is C7-C 12 Alkyl or C7-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' Each is independently (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is C(O)OR 6 And each R 6 Independently, it is C7-C 12 Alkyl or C7-C 12 Alkenyl group.

[0010] In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' And R 5' It is C6-C 10 Cycloalkyl. In some embodiments, R 5' It is 1-adamantyl or 2-adamantyl.

[0011] In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group.

[0012] In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is OC(O)CH(R) 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0013] In some embodiments, R 1 and R 1' It is (C1-C9 alkyl)-R 5'R 5' It is C(O)OR 6 And each R 6 Independently, it is C7-C 12 Alkyl or C7-C 12 alkenyl; and R 1' It is R 12 -R 13 , where R 12 It is a bonded or optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 ynyl group; and R 13 It is hydrogen, optionally substituted C3-C 12 Cycloalkyl, or optionally substituted C5-C6 aryl.

[0014] In some embodiments, R 12 It is a key. In some embodiments, R 12 It is a C1-C6 alkyl group. In some embodiments, R 12 It is a C1 alkyl group. In some embodiments, R 12 It is optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl. In some embodiments, R 12 It is selected from pentyl, 1-methylpentyl, 4-methylpentyl, 5,5,5-trifluoropentyl, 4,4,5,5,5-pentafluoropentyl, and pent-4-ynyl.

[0015] In some embodiments, R 13 It is hydrogen.

[0016] In some embodiments, R 13 It is an optional replacement of C3-C 12 Cycloalkyl. In some embodiments, R 13 Selected from optionally substituted cyclopropane, optionally substituted cyclobutane, and optionally substituted cyclohexane, such as 4-pentylcyclohexyl.

[0017] In some embodiments, R 13 It is an optional substituted fused C3-C 12 cycloalkyl, optionally substituted bridging C3-C 12 Cycloalkyl, or optionally substituted spirocyclic C3-C 12 Cycloalkyl.

[0018] In some embodiments, R 13 It is an optionally substituted C5-C6 aryl group. In some embodiments, R 13 It is an optionally substituted phenyl group, such as 4-pentylphenyl or 3,5-di-tert-butylphenyl.

[0019] In some embodiments, R13 It is an optionally substituted bicyclic [2.2.2]pentane. In some embodiments, R 13 It is unsubstituted bicyclo[2.2.2]pentane, 1-(trifluoromethyl)bicyclo[1.1.1]pentane, or 1-methylbicyclo[1.1.1]pentane.

[0020] In some embodiments, R 13 It is an optionally substituted bicyclic [2.1.0]pentane. In some embodiments, R 13 It is an unsubstituted bicyclic [2.1.0]pentane.

[0021] In some embodiments, R 13 It is optionally substituted bicyclic [3.1.0]hexane. In some embodiments, R 13 It is 6,6-difluorobicyclo[3.1.0]hexane.

[0022] In some embodiments, R 13 It is optionally substituted bicyclic [2.1.1]hexane. In some embodiments, R 13 It is unsubstituted bicyclo[2.1.1]hexane or 1-fluorobicyclo[2.1.1]hexane.

[0023] In some embodiments, R 13 It is optionally substituted spiro[2,3]hexane. In some embodiments, R 13 It is optionally unsubstituted spiro[2,3]hexane or 1,1-difluorospiro[2,3]hexane.

[0024] In some embodiments, R 13 It is an optionally substituted 1,1'-bis(cyclohexane).

[0025] In some embodiments, R 13 It is a decahydronaphthalene that is optionally substituted.

[0026] In some embodiments, R 13 It is optionally substituted bicyclic [2.2.1]heptane. In some embodiments, R 13 It is unsubstituted bicyclic [2.2.1]heptane or 7,7-dimethylbicyclic [2.2.1]heptane.

[0027] In some embodiments, R 13 It is optionally substituted bicyclic [4.1.0]heptane. In some embodiments, R 13 It is unsubstituted bicyclic [4.1.0]heptane or 7,7-difluorobicyclic [4.1.0]heptane.

[0028] In some embodiments, R 13It is optionally substituted bicyclic [3.2.0]heptane. In some embodiments, R 13 It is an unsubstituted bicyclic [3.2.0]heptane.

[0029] In some embodiments, R 13 It is optionally substituted with spiro[3.3]heptane. In some embodiments, R 13 It is unsubstituted spiro[3.3]heptane or 2,2-difluorospiro[3.3]heptane.

[0030] In some embodiments, R 13 It is an optionally substituted bicyclic [2.2.2]octane. In some embodiments, R 13 It is unsubstituted bicyclo[2.2.2]octane or 1-methylbicyclo[2.2.2]octane.

[0031] In some embodiments, R 13 It is an optionally substituted bicyclic [3.2.1]octane. In some embodiments, R 13 It is unsubstituted bicyclic [3.2.1]octane or 8-oxabicyclic [3.2.1]octane.

[0032] In some embodiments, R 13 It is optionally substituted with spiro[2,5]octane. In some embodiments, R 13 It is unsubstituted spiro[2.5]octane or 1,1-difluorospiro[2.5]octane.

[0033] In some embodiments, R 13 It is optionally substituted bicyclic [3.2.2]nonane. In some embodiments, R 13 It is unsubstituted bicyclic [3.2.2]nonane or 1-fluorobicyclic [3.2.2]nonane.

[0034] In some embodiments, R 13 It is optionally substituted 1-bicyclo[3.3.1]nonane. In some embodiments, R 13 It is unsubstituted bicyclic [3.3.1]nonane or 1-methylbicyclic [3.3.1]nonane.

[0035] In some embodiments, R 13 It is adamantane.

[0036] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is OC(O)CH(R) 9 )R 10And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' Each is independently (C1-C9 alkyl)-R 5 ;R 5 It is OC(O)CH(R) 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0037] In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is C(O)O-C1-C4 alkyl-(R 9 )R 10 or OC(O)-C1-C4 alkyl-(R 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is C(O)O-C1-C4 alkyl-(R 9 )R 10 or OC(O)-C1-C4 alkyl-(R 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' Each is independently (C1-C9 alkyl)-R 5 ;R 5 It is C(O)O-C1-C4 alkyl-(R 9 )R 10or OC(O)-C1-C4 alkyl-(R 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0038] In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' And R 5' It is C6-C 10 cycloalkyl; optionally, wherein R 5' It is 1-adamantyl or 2-adamantyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is C(O)OR 6 And R 6 It is C7-C 12 Alkyl or C7-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group.

[0039] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group. In some embodiments, R 1 R 1' and R 1'' Each is independently (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is CH(R)7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group.

[0040] In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is OC(O)CH(R) 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0041] In some embodiments, R 2 It is C1-C 12 Alkyl, C2-C 12 alkenyl, or C2-C 12 Alkyne group. In some embodiments, R 2 It is a C4-C8 alkyl group. In some embodiments, R 2 It is methyl, ethyl, propyl, isopropyl, butyl, 1-isobutyl, 2-isobutyl, tert-butyl, C5 alkyl, C6 alkyl, C8 alkyl, or C 10 alkyl.

[0042] In some embodiments, R 2 It is C1-C 12 Alkoxy or (C1-C4 alkyl)-(C1-C4 alkoxy). In some embodiments, R 2 It is methoxy, ethoxy, methoxymethyl, or ethoxyethyl.

[0043] In some embodiments, R 2 It is an optional replacement of C3-C 12 Cycloalkyl, optionally substituted C3-C6 heterocyclic, or optionally substituted C5-C6 aryl. In some embodiments, R 2 It is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, such as 4-pentylcyclohexyl.

[0044] In some embodiments, R 2 It is an optionally substituted phenyl group. In some embodiments, R 2 It is 4-pentylphenyl.

[0045] In some embodiments, R 2It is optionally substituted (C1-C4 alkyl)-(optionally substituted C3-C 12 Cycloalkyl), (C1-C4 alkyl)-(optionally substituted C3-C6 heterocyclic), or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl). In some embodiments, R 2 It is -CH2-cyclopropyl, -(CH2)2-cyclopropyl, -CH2-cyclohexyl, -(CH2)2-cyclohexyl, -(CH2)2-(4-pentylcyclohexyl), -CH2-phenyl, or -(CH2)2-phenyl.

[0046] In some embodiments, R 2' It is hydrogen. In some embodiments, R 2' It is C1-C 12 Alkyl, C2-C 12 alkenyl, or C2-C 12 Alkyne group. In some embodiments, R 2 It is methoxy, ethoxy, methoxymethyl, or ethoxyethyl.

[0047] In some embodiments, R 2 and R 2' Combining them forms optionally substituted C4-C6 cycloalkyl or C4-C6 heterocyclic rings. In some embodiments, R 2 and R 2' They combine to form cyclohexane or pyran.

[0048] In some embodiments, X 1 It is CH2. In some embodiments, X 1 It is CHR 14 And R 14 and R 2 They are linked together to form optionally substituted C5-C8 cycloalkyl groups. In some embodiments, R 14 and R 2 They are linked together to form optionally substituted C5 cycloalkyl or optionally substituted C6 cycloalkyl.

[0049] In some embodiments, X 2 It is NH. In some embodiments, X 2 It is O. In some embodiments, R 3 and R 4 Each is independently a C1-C6 alkyl group.

[0050] In some embodiments, R 3 and R 4 They connect together to form a heterocycle containing nitrogen heteroatoms. In some embodiments, R 3 and R 4 They connect together to form pyrrolidine. In some embodiments, R3 and R 4 It connects with the preceding alkyl group to form a quinine ring.

[0051] In some embodiments, n is 1, 2, 3, or 4.

[0052] In some embodiments, m is 1, 2, 3, or 4.

[0053] In some embodiments, p is 0, 1, 2, 3, or 4.

[0054] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C2 alkyl)-R 5 .

[0055] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C3 alkyl)-R 5 .

[0056] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C4 alkyl)-R 5 .

[0057] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C5 alkyl)-R 5 .

[0058] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C6 alkyl)-R 5 .

[0059] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C7 alkyl)-R 5 .

[0060] In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C8 alkyl)-R 5 .

[0061] In some embodiments, the compound has the following formula: Or, or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound has the following formula: Or, or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the compound has the following formula: Or, or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the compound is any one of compounds 1-209 or a pharmaceutically acceptable salt thereof.

[0065] In some embodiments, the compound is any one of compounds 7, 8, 10, 13, 14, 26, 33, 38, 39, 40, 48, 60, 61, 89, 103, or 109, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 7 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 8 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 10 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 13 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 14 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 26 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 33 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 38 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 39 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 40 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 48 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 60 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 61 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 89 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 103 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 109 or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, this disclosure provides lipid nanoparticles comprising compounds disclosed herein (e.g., lipid compounds). In some embodiments, this disclosure provides lipid nanoparticles comprising: compounds disclosed herein (e.g., lipid compounds); phospholipids; cholesterol; and polyethylene glycol lipids. In some embodiments, the lipid nanoparticles comprise: about 20-80 mol% of compounds disclosed herein (e.g., lipid compounds), about 7.5-40 mol% of phospholipids, about 6-45 mol% of cholesterol, and about 1-4 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 45-65 mol% of compounds disclosed herein (e.g., lipid compounds), about 10 mol% of phospholipids, about 25-45 mol% of cholesterol, and about 1-4 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 45-50 mol% of the compounds disclosed herein (e.g., lipid compounds), about 10 mol% of phospholipids, about 38-42 mol% of cholesterol, and about 2-3 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 47.5 mol% of the compounds disclosed herein (e.g., lipid compounds), about 40 mol% of cholesterol, and about 2.5 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 47.5-52.5 mol% of the compounds disclosed herein (e.g., lipid compounds), about 10 mol% of phospholipids, about 37-40 mol% of cholesterol, and about 1-2 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 50 mol% of the compounds disclosed herein (e.g., lipid compounds), about 38.5 mol% of cholesterol, and about 1.5 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 57.5-62.5 mol% of the compounds disclosed herein (e.g., lipid compounds), about 10 mol% of phospholipids, about 26-29 mol% of cholesterol, and about 2-3 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 60 mol% of the compounds disclosed herein (e.g., lipid compounds), about 27.5 mol% of cholesterol, and about 2.5 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 45-50 mol% of the compounds disclosed herein (e.g., lipid compounds), about 10 mol% of phospholipids, about 37.5-40.5 mol% of cholesterol, and about 3-4 mol% of PEG lipids. In some embodiments, the lipid nanoparticles comprise: about 47.5 mol% of the compounds disclosed herein (e.g., lipid compounds), about 39 mol% of cholesterol, and about 3.5 mol% of PEG lipids.

[0067] In some embodiments, the lipid nanoparticles comprise a targeting component. In some embodiments, the targeting component is a targeting lipid. In some embodiments, the targeting component is an active targeting component. In some embodiments, the active targeting component is a protein, peptide, small molecule, or antibody or antigen-binding fragment thereof. In some embodiments, the active targeting component is a protein. In some embodiments, the active targeting component is a peptide. In some embodiments, the active targeting component is a small molecule. In some embodiments, the active targeting component is an antibody or antigen-binding fragment thereof.

[0068] In some embodiments, the lipid nanoparticles comprise one or more polynucleotides encapsulated within the lipid nanoparticles. In some embodiments, the one or more polynucleotides comprise RNA. In some embodiments, the one or more polynucleotides comprise DNA. In some embodiments, the one or more polynucleotides comprise both DNA and RNA.

[0069] In some embodiments, this disclosure provides pharmaceutical compositions comprising the lipid nanoparticles of this disclosure and pharmaceutically acceptable excipients. In some embodiments, this disclosure provides pharmaceutical compositions comprising the lipid nanoparticles of this disclosure, wherein the lipid nanoparticles comprise one or more polynucleotides encapsulated within the lipid nanoparticles; and pharmaceutically acceptable excipients.

[0070] In some embodiments, this disclosure provides a method of delivering polynucleotides to the cells or tissues of a subject, comprising administering to the subject an effective amount of the lipid nanoparticles or pharmaceutical composition of this disclosure. In some embodiments, this disclosure provides a method of delivering polynucleotides to the cells or tissues of a subject, comprising administering to the subject an effective amount of the lipid nanoparticles or pharmaceutical composition of this disclosure. In some embodiments, the cells or tissues comprise extrahepatic cells or tissues. In some embodiments, the cells or tissues comprise brain cells or tissues. In some embodiments, the cells or tissues comprise lung cells or tissues. In some embodiments, the cells or tissues comprise bone marrow cells or tissues. In some embodiments, the cells or tissues comprise spleen cells or tissues. In some embodiments, the cells or tissues comprise muscle cells or tissues. In some embodiments, the cells or tissues comprise kidney cells or tissues. In some embodiments, the cells or tissues comprise heart cells or tissues. In some embodiments, the cells or tissues comprise pancreatic cells or tissues. In some embodiments, the cells or tissues comprise immune cells or tissues.

[0071] In some embodiments, this disclosure provides a method of treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of this disclosure.

[0072] In some embodiments, this disclosure provides a method of producing a therapeutic composition comprising encapsulating an active agent within lipid nanoparticles, wherein the lipid nanoparticles contain compounds of this disclosure (e.g., lipid compounds). In some embodiments, the active agent comprises DNA. In some embodiments, the active agent comprises RNA. In some embodiments, the active agent comprises both DNA and RNA.

[0073] In some embodiments, this disclosure provides a method for producing a vaccine or prophylactic composition, the method comprising: encapsulating an active agent (e.g., RNA or DNA) within lipid nanoparticles, wherein the lipid nanoparticles contain compounds of this disclosure (e.g., lipid compounds). In some embodiments, the active agent comprises DNA. In some embodiments, the active agent comprises RNA. In some embodiments, the active agent comprises both DNA and RNA.

[0074] In some embodiments, this disclosure provides for the use of the lipid nanoparticles or pharmaceutical compositions of this disclosure in the manufacture of a medicament for delivering polynucleotides to extrahepatic cells or tissues of a subject. In some embodiments, this disclosure provides for the use of the lipid nanoparticles or pharmaceutical compositions of this disclosure in the manufacture of a medicament for treating a disease in a subject. Attached Figure Description

[0075] Figure 1A The stability of selected lipid nanoparticles (LNPs) prepared according to formulation F1 over four weeks is shown, as measured by particle size. Figure 1B The stability of selected LNPs prepared according to formulation F1 over four weeks is shown, as measured by the polydispersity index (PDI). N / P = molar ratio of ionizable nitrogen to phosphate groups. T = time. D = days. W = weeks.

[0076] Figure 1C The stability of selected LNPs prepared according to formulation F3 over two weeks is shown, as measured by particle size. Figure 1D The stability of selected LNPs prepared according to formulation F3 over two weeks is shown, as measured by the polydispersity index (PDI). N / P = molar ratio of ionizable nitrogen to phosphate groups. T = time. D = days. W = weeks.

[0077] Figure 2A , Figure 2B , Figure 2C and Figure 2D Mouse organ luciferase imaging results are provided 6 hours after IV administration of selected LNP compound pools. Results are shown as total throughput [p / s].

[0078] Figure 3Mouse brain luciferase imaging results are provided 6 hours after ICV administration of selected LNP compound pools. Results are shown as total flux [p / s].

[0079] Figure 4A and Figure 4B Mouse lung luciferase imaging results following intratracheal administration of LNP compound pools (compounds 2, 3, 5, and 7) are provided. Results are shown as total flux [p / s]. Figure 4A Live animal imaging results were provided. Figure 4B The results of the in vitro imaging were provided.

[0080] Figure 4C Mouse lung luciferase imaging results following intratracheal administration of LNP compound pools (compounds 8, 9, 11, and 20) are provided. Results are shown as total flux [p / s].

[0081] Figure 4D Mouse lung luciferase imaging results following intratracheal administration of LNP compound pools (compounds 12, 14, 16, and 18) are provided. Results are shown as total flux [p / s].

[0082] Figure 5A Mouse organ luciferase imaging results following IV administration of selected LNP compounds prepared according to formulation F2 are provided. Results are shown as total throughput [p / s]. Figure 5B These results are shown relative to MC3 activity normalization.

[0083] Figure 6A and Figure 6B Mouse lung and tracheal luciferase imaging results following intratracheal administration of selected LNP compounds prepared according to formulation F2 are provided. Results are shown as total flux [p / s]. Figure 6A Live animal imaging results were provided. Figure 6B The results of the in vitro imaging were provided.

[0084] Figure 7A , Figure 7B and Figure 7C Results of in vivo activity screening in the spleen, femur, and muscle of a group of mice following administration of certain LNP compounds disclosed herein are provided (average total throughput).

[0085] Figure 8A , Figure 8B and Figure 8C Results of in vivo screening of NHP activity in the spleen, femur, and muscle after administration of certain LNP compounds disclosed herein to a group of cynomolgus monkeys are provided (unique molecular identifier count).

[0086] Figure 9Results of in vivo screening of NHP activity in the spleen (unique molecular identifier count) after administration of certain LNP compounds disclosed herein to a group of cynomolgus monkeys are provided.

[0087] Figure 10 Results of in vivo screening (unique molecular identifier count) of NHP activity in the femur after administration of certain LNP compounds disclosed herein to a group of cynomolgus monkeys are provided.

[0088] Figure 11 Results of in vivo screening of NHP activity in muscle (unique molecular identifier count) after administration of certain LNP compounds disclosed herein to a group of cynomolgus monkeys are provided. Detailed Implementation I. Lipid compounds

[0089] Unbound by theory, when an active agent is encapsulated in an LNP containing a lipid compound disclosed herein, the lipid compound facilitates the delivery of the active agent to the desired target of the subject, such as to the subject's extrahepatic cells or tissues.

[0090] In some embodiments, this disclosure provides lipid compounds having formula (I): (I), or a pharmaceutically acceptable salt thereof; wherein: R 1 and R 1' Each is independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 or (C1-C8 alkoxy)-R 5 ; R 1'' Independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 (C1-C8 alkoxy)-R 5 、or R 12 -R 13 ; Each R 5 Independently: hydrogen, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkoxy, optionally substituted C3-C 12Cycloalkyl (including fused, bridged, or spirocycloalkyl), optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, sterol, C(O)OR 6 OC(O)-R 6 OC(O)OR 6 CH(R) 7 )R 8 C(O)O-CH-(R) 7 )R 8 C(O)O-C1-C4 alkyl-(R 9 )R 10 OC(O)-C1-C4 alkyl-(R 9 )R 10 、or OC(O)CH(R) 9 )R 10 ; Each R 6 Independently: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, C7-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, or sterol; R 7 and R 8 Each independently is: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, or C7-C 12 Alkoxy; R 9 and R 10 Each independently is: C1-C 12 Alkyl or C2-C 12 alkenyl; X 1 Is it O, NH, or CHR? 14 ; X 2 Is it O, NH, or CHR? 11 ; R 2 It is C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C1-C 12 alkoxy, or (C1-C4 alkyl)-(C1-C4 alkoxy), optionally substituted C3-C 12Cycloalkyl, (C1-C4 alkyl)-(optionally substituted C3-C) 12 (Cycloalkyl), optionally substituted C3-C6 heterocycles, (C1-C4 alkyl)-(optionally substituted C3-C6 heterocycles), optionally substituted C5-C6 aryl, or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl); R 2' It is hydrogen, C1-C 12 Alkyl, alkenyl, or alkynyl, C1-C 12 Alkoxy, (C1-C4 alkyl)-(C1-C4 alkoxy); Where R 2 and R 2' They can be combined to form optionally substituted C4-C6 cycloalkyl, optionally substituted C3-C6 cycloalkyl, or optionally substituted C3-C6 heterocycles; R 3 and R 4 Each independently is: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl, or wherein R 3 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 11 It is hydrogen or C1-C6 alkyl, or R 11 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 12 It is a bonded or optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl group; R 13 It is hydrogen, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), or optionally substituted C5-C6 aryl; R 14 It is hydrogen or C1-C6 alkyl, or R 14 and R 2 They are linked together to form optionally substituted C5-C8 cycloalkyl groups; m is 1-4; p is 0-4; and n is 1-5.

[0091] In some embodiments, this disclosure provides lipid compounds having formula (II): (II), or a pharmaceutically acceptable salt thereof; wherein: R 1 and R1' Each is independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 or (C1-C8 alkoxy)-R 5 ; R 1'' Independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 (C1-C8 alkoxy)-R 5 、or R 12 -R 13 ; Each R 5 Independently: hydrogen, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, sterol, C(O)OR 6 OC(O)-R 6 OC(O)OR 6 CH(R) 7 )R 8 C(O)O-CH(R) 7 )R 8 C(O)O-C1-C4 alkyl-(R 9 )R 10 OC(O)-C1-C4 alkyl-(R 9 )R 10 、or OC(O)CH(R) 9 )R 10 ; Each R 6 Independently: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, C7-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, or sterol; R 7 and R 8 Each independently is: C7-C 12Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, or C7-C 12 Alkoxy; R 9 and R 10 Each independently is: C1-C 12 Alkyl or C2-C 12 alkenyl; X 1 Is it O, NH, or CHR? 14 ; X 2 Is it O, NH, or CHR? 11 ; R 2 It is C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C1-C 12 alkoxy, or (C1-C4 alkyl)-(C1-C4 alkoxy), optionally substituted C3-C 12 Cycloalkyl, (C1-C4 alkyl)-(optionally substituted C3-C) 12 (Cycloalkyl), optionally substituted C3-C6 heterocycles, (C1-C4 alkyl)-(optionally substituted C3-C6 heterocycles), optionally substituted C5-C6 aryl, or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl); R 3 and R 4 Each independently is: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl, or wherein R 3 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 11 It is hydrogen or C1-C6 alkyl, or R 11 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms; R 12 It is a bonded or optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl group; R 13 It is hydrogen, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), or optionally substituted C5-C6 aryl; R 14 It is hydrogen or C1-C6 alkyl, or R 14 and R 2They are linked together to form optionally substituted C5-C8 cycloalkyl groups; n is 1-5; and m is 1-4.

[0092] In some embodiments, R 1 R 1' and R 1'' Each is independently: (C1-C9 alkyl)-R 5 (C2-C9 alkenyl)-R 5 (C2-C9 ynyl)-R 5 or (C1-C8 alkoxy)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are identical. In some embodiments, R 1 R 1' and R 1'' The two in are the same. In some embodiments, R 1 R 1' and R 1'' The three in the text are all different.

[0093] In some embodiments, R 1 R 1' and R 1'' At least one of them is (C2 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C2 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are (C2 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' At least one of them is (C3 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C3 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are (C3 alkyl)-R 5 In some embodiments, R 1 R 1' and R1'' At least one of them is (C4 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C4 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are (C4 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' At least one of them is (C5 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C5 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are (C5 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' At least one of them is (C6 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C6 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are (C6 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' At least one of them is (C7 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C7 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are (C8 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1''At least one of them is (C8 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C8 alkyl)-R 5 In some embodiments, R 1 R 1' and R 1'' All three are (C8 alkyl)-R 5 .

[0094] In some embodiments, each R 5 Independently: hydrogen, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, sterol, C(O)OR 6 OC(O)-R 6 OC(O)OR 6 CH(R) 7 )R 8 C(O)O-CH(R) 7 )R 8 C(O)O-C1-C4 alkyl-(R 9 )R 10 OC(O)-C1-C4 alkyl-(R 9 )R 10 、or OC(O)CH(R) 9 )R 10 In some embodiments, all R 5 The functional groups are all identical. In some embodiments, the two R groups are identical. 5 The functional groups are the same. In some embodiments, all R groups are identical. 5 The functional groups are all different.

[0095] In some embodiments, each R 6 Independently: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, C7-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, or sterol. In some embodiments, R 7and R 8 Each independently is: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, or C7-C 12 Alkyl group. In some embodiments, R 9 and R 10 Each independently is: C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0096] In some embodiments, R 1 R 1' and R 1'' At least one of them is (C1-C9 alkyl)-R 5 And R 5 It is C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' The two in the equation are independently (C1-C9 alkyl)-R 5 And each R 5 Independently, it is C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' All three are independently (C1-C9 alkyl)-R 5 And each R 5 Independently, it is C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' And R 5' It is C6-C 10 Cycloalkyl. In some embodiments, R 5' It is 1-adamantyl or 2-adamantyl. In some embodiments, R 1 R 1' and R 1'' One of them is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group.

[0097] In some embodiments, R 1 R 1' and R 1'' At least one of them is (C1-C9 alkyl)-R5 ;R 5 It is C(O)OR 6 And R 6 It is C7-C 12 Alkyl or C7-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is C(O)OR 6 And each R 6 Independently, it is C7-C 12 Alkyl or C7-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' All three are independently (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is C(O)OR 6 And each R 6 Independently, it is C7-C 12 Alkyl or C7-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' And R 5' It is C6-C 10 Cycloalkyl. In some embodiments, R 5' It is 1-adamantyl or 2-adamantyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is OC(O)CH(R) 9 )R 10 And R 9 and R 10Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0098] In some embodiments, R 1 R 1' and R 1'' At least one of them is (C1-C9 alkyl)-R 5 ;R 5 It is OC(O)CH(R) 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is OC(O)CH(R) 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' All three are independently (C1-C9 alkyl)-R 5 ; Each R 5 It is OC(O)CH(R) 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' And R 5' It is C6-C 10 cycloalkyl (e.g., R) 5' It is 1-adamantyl or 2-adamantyl). In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is C(O)OR 6And R 6 It is C7-C 12 Alkyl or C7-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group.

[0099] In some embodiments, R 1 and R 1' It is (C1-C9 alkyl)-R 5' R 5' It is C(O)OR 6 And each R 6 Independently, it is C7-C 12 Alkyl or C7-C 12 alkenyl; and R 1' It is R 12 -R 13 , where R 12 It is a bonded or optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl group; R 13 It is hydrogen, optionally substituted C3-C 12 Cycloalkyl (including fused, bridged, or spirocycloalkyl), or optionally substituted C5-C6 aryl.

[0100] In some embodiments, R 12 It is a key.

[0101] In some embodiments, R 12 It is optionally substituted, branched or unbranched C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl. In some embodiments, R 12 It is a C1 alkyl group. In some embodiments, R 12 It is an optionally substituted branched C1-C6 alkyl group. In some embodiments, R 12 It is pentyl. In some embodiments, R 12 It is 1-methylpentyl. In some embodiments, R 12 It is 4-methylpentyl. In some embodiments, R 12 It is 5,5,5-trifluoropentyl. In some embodiments, R 12 It is 4,4,5,5,5-pentafluoropentyl. In some embodiments, R 12It is an optionally substituted branched C1-C6 ynyl group. In some embodiments, R 12 It is pentyl-4-ynyl.

[0102] In some embodiments, R 13 It is hydrogen.

[0103] In some embodiments, R 13 It is an optional replacement of C3-C 12 Cycloalkyl groups (including fused, bridged, or spirocycloalkyl groups). In some embodiments, R 13 It is an optionally substituted cyclopropane. In some embodiments, R 13 It is an optionally substituted cyclobutane. In some embodiments, R 13 It is an optionally substituted cyclohexane. In some embodiments, R 13 It is 4-pentylcyclohexyl. In some embodiments, R 13 It is an optionally substituted C5-C6 aryl group. In some embodiments, R 13 It is an optionally substituted phenyl group. In some embodiments, R 13 It is 4-pentylphenyl. In some embodiments, R 13 It is 3,5-di-tert-butylphenyl.

[0104] In some embodiments, R 13 It is an optional substituted fused C3-C 12 Cycloalkyl. In some embodiments, R 13 It is an optional replacement for the bridging C3-C 12 Cycloalkyl. In some embodiments, R 13 The spiroring C3-C is optionally substituted. 12 Cycloalkyl. In some embodiments, R 13 It is an optionally substituted bicyclo[2.2.2]pentane, such as unsubstituted bicyclo[2.2.2]pentane, 1-(trifluoromethyl)bicyclo[1.1.1]pentane, or 1-methylbicyclo[1.1.1]pentane. In some embodiments, R 13 It is an optionally substituted bicyclic [2.1.0]pentane, such as unsubstituted bicyclic [2.2.2]pentane. In some embodiments, R 13 It is optionally substituted bicyclo[3.1.0]hexane, such as unsubstituted bicyclo[3.1.0]hexane or 6,6-difluorobicyclo[3.1.0]hexane. In some embodiments, R 13 It is optionally substituted bicyclo[2.1.1]hexane, such as unsubstituted bicyclo[2.1.1]hexane or 1-fluorobicyclo[2.1.1]hexane. In some embodiments, R 13It is optionally substituted spiro[2,3]hexane, such as unsubstituted spiro[2,3]hexane or 1,1-difluorospiro[2,3]hexane. In some embodiments, R 13 It is optionally substituted 1,1'-bis(cyclohexane). In some embodiments, R 13 It is optionally substituted decahydronaphthalene. In some embodiments, R 13 It is an optionally substituted bicyclic [2.2.1]heptane, such as unsubstituted bicyclic [2.2.1]heptane or 7,7-dimethylbicyclic [2.2.1]heptane. In some embodiments, R 13 It is an optionally substituted bicyclic [4.1.0]heptane, such as unsubstituted bicyclic [4.1.0]heptane or 7,7-difluorobicyclic [4.1.0]heptane. In some embodiments, R 13 It is an optionally substituted bicyclic [3.2.0]heptane, such as unsubstituted bicyclic [3.2.0]heptane. In some embodiments, R 13 It is optionally substituted spiro[3,3]heptane, such as unsubstituted spiro[3,3]heptane or 2,2-difluorospiro[3,3]heptane. In some embodiments, R 13 It is an optionally substituted bicyclo[2.2.2]octane, such as unsubstituted bicyclo[2.2.2]octane or 1-methylbicyclo[2.2.2]octane. In some embodiments, R 13 It is an optionally substituted bicyclic [3.2.1]octane, such as unsubstituted bicyclic [3.2.1]octane or 8-oxabicyclic [3.2.1]octane. In some embodiments, R 13 It is optionally substituted spiro[2.5]octane, such as unsubstituted spiro[2.5]octane or 1,1-difluorospiro[2.5]octane. In some embodiments, R 13 It is optionally substituted bicyclic [3.2.2]nonane, such as unsubstituted bicyclic [3.2.2]nonane or 1-fluorobicyclic [3.2.2]nonane. In some embodiments, R 13 It is optionally substituted bicyclic [3.3.1]nonane, such as unsubstituted bicyclic [3.3.1]nonane or 1-methylbicyclic [3.3.1]nonane. In some embodiments, R 13 It is adamantane.

[0105] In some embodiments, R 1 R 1' and R 1'' At least one of them is (C1-C9 alkyl)-R 5 ;R 5 It is CH(R) 7 )R 8 And R 7 and R 8 Independently, it is C7-C12 Alkyl group. In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group. In some embodiments, R 1 R 1' and R 1'' Each is independently (C1-C9 alkyl)-R 5 ; Each R 5 Independently, it is CH(R) 7 )R 8 And R 7 and R 8 Each is independently C7-C 12 Alkyl group. In some embodiments, R 1 R 1' and R 1'' One of them is (C1-C9 alkyl)-R 5' ;R 5' It is OC(O)CH(R) 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0106] In some embodiments, R 1 R 1' and R 1'' At least one of them is (C1-C9 alkyl)-R 5 ;R 5 It is C(O)O-C1-C4 alkyl-(R 9 )R 10 or OC(O)-C1-C4 alkyl-(R 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl. In some embodiments, R 1 R 1' and R 1'' The two independent ones are (C1-C9 alkyl)-R 5; Each R 5 Independently, it is C(O)O-C1-C4 alkyl-(R 9 )R 10 or OC(O)-C1-C4 alkyl-(R 9 )R 10 And R 9 and R 10 Each is independently C1-C 12 Alkyl or C2-C 12 Alkenyl group.

[0107] In some embodiments, X 1 It is O, NH, CHR 14 And R 14 It is hydrogen or a C1-C6 alkyl group. In some embodiments, X 1 It is CH2. In some embodiments, X 1 It is NH. In some embodiments, X 1 It is O. In some embodiments, X 1 It is CHR 14 And R 14 and R 2 They are linked together to form optionally substituted C5-C8 cycloalkyl groups. In some embodiments, R 14 and R 2 They are linked together to form optionally substituted C5 cycloalkyl groups. In some embodiments, R 14 and R 2 They are linked together to form optionally substituted C6 cycloalkyl groups.

[0108] In some embodiments, X 2 Is it O, NH, or CHR? 11 And R 11 It is hydrogen or a C1-C6 alkyl group. In some embodiments, X 2 It is CHR 11 And R 11 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms. In some embodiments, R 11 and R 4 They are linked together to form 1-methylpyrrolidine (where R 3 (as a methyl group). In some embodiments, R 11 and R 4 They are linked together to form 1-methylpiperidine (where R 3 As a methyl group).

[0109] In some embodiments, X 2 It is NH. In some embodiments, X 2 It is O.

[0110] In some embodiments, R 2 It is C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C1-C 12 Alkoxy, (C1-C4 alkyl)-(C1-C4 alkoxy), optionally substituted C3-C 12 Cycloalkyl, (C1-C4 alkyl)-(optionally substituted C3-C) 12 (Cycloalkyl), optionally substituted C3-C6 heterocycles, (C1-C4 alkyl)-(optionally substituted C3-C6 heterocycles), optionally substituted C5-C6 aryl, or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl).

[0111] In some embodiments, R 2 It is C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 Alkyne group. In some embodiments, R 2 It is C1-C 12 Alkyl group. In some embodiments, R 2 It is a C4-C8 alkyl group. In some embodiments, R 2 It is a methyl group. In some embodiments, R 2 It is trifluoromethyl. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is propyl or isopropyl. In some embodiments, R 2 It is butyl, 1-isobutyl, 2-isobutyl, or tert-butyl. In some embodiments, R 2 It is a C5 alkyl group. In some embodiments, R 2 It is a C6 alkyl group. In some embodiments, R 2 It is a C8 alkyl group. In some embodiments, R 2 It is C 10 alkyl.

[0112] In some embodiments, R 2 It is C1-C 12 Alkyl group. In some embodiments, R 2 It is (C1-C4 alkyl)-(C1-C4 alkoxy). In some embodiments, R 2 It is a methoxymethyl group. In some embodiments, R 2 It is ethoxyethyl.

[0113] In some embodiments, R 2 It is an optional replacement of C3-C 12Cycloalkyl, optionally substituted C3-C6 heterocyclic, or optionally substituted C5-C6 aryl. In some embodiments, R 2 It is an optionally substituted cyclopropyl group. In some embodiments, R 2 It is an optionally substituted cyclobutyl group. In some embodiments, R 2 It is an optionally substituted cyclopentyl group. In some embodiments, R 2 It is an optionally substituted cyclohexyl group. In some embodiments, R 2 It is 4-pentylcyclohexyl. In some embodiments, R 2 It is an optionally substituted phenyl group. In some embodiments, R 2 It is 4-pentylphenyl.

[0114] In some embodiments, R 2 It is (C1-C4 alkyl)-(optionally substituted C3-C) 12 Cycloalkyl), (C1-C4 alkyl)-(optionally substituted C3-C6 heterocyclic), or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl). In some embodiments, R 2 It is -CH2-cyclopropyl, -(CH2)2-cyclopropyl, -CH2-cyclohexyl, -(CH2)2-cyclohexyl, -CH2-phenyl, or -(CH2)2-phenyl.

[0115] In some embodiments, R 2' It is hydrogen. In some embodiments, R 2' It is C1-C 12 Alkyl, C2-C 12 alkenyl, or C2-C 12 Alkyne group. In some embodiments, R 2' It is a methyl group. In some embodiments, R 2' It is ethyl. In some embodiments, R 2' It is propyl. In some embodiments, R 2' It is butyl. In some embodiments, R 2' It is a C5 alkyl group. In some embodiments, R 2' It is a C6 alkyl group. In some embodiments, R 2' It is C1-C 12 Alkyl group. In some embodiments, R 2' It is (C1-C4 alkyl)-(C1-C4 alkoxy). In some embodiments, R 2' It is a methoxymethyl group. In some embodiments, R 2' It is ethoxyethyl. In some embodiments, R 2' With R 2 same.

[0116] In some embodiments, R2 and R 2' Combining them forms optionally substituted C4-C6 cycloalkyl groups. In some embodiments, R 2 and R 2' The combination forms optionally substituted cyclohexanes. In some embodiments, R 2 and R 2' The combination forms optionally substituted C4-C6 heterocycles. In some embodiments, R 2 and R 2' Combining to form optionally substituted pyrans.

[0117] In some embodiments, R 3 and R 4 Each is independently: hydrogen, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 hydroxyalkyl. In some embodiments, R 3 and R 4 Each is independently a C1-C6 alkyl group. In some embodiments, R 3 and R 4 They connect together to form a heterocycle containing one or more N, O, or S heteroatoms. In some embodiments, R 3 and R 4 They connect together to form a heterocycle containing nitrogen heteroatoms. In some embodiments, R 3 and R 4 They connect together to form pyrrolidine. In some embodiments, R 3 and R 4 It connects with the preceding alkyl group to form a quinine ring.

[0118] In some embodiments, n is 1-5. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0119] In some embodiments, m is 1-4. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0120] In some embodiments, p is 0-4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0121] Examples of lipid compounds having formulas (I) and (II) are presented in Table 1. Pharmaceutically acceptable salts of the compounds presented in Table 1 are also included. Table 1: Exemplary Compounds

[0122] In some embodiments, the lipid compound is any one of compounds 1-209.

[0123] In some embodiments, the lipid compound is any one of compound 7, 8, 10, 13, 14, 26, 33, 38, 39, 40, 48, 60, 61, 89, 103, or 109, or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the lipid compound is any one of compounds 1-20 or a pharmaceutically acceptable salt thereof.

[0125] In some embodiments, the lipid compound is compound 14 or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, the lipid compound is any one of compound 7, 8, 10, 13, or 18, or a pharmaceutically acceptable salt thereof.

[0127] In some embodiments, the lipid compound is any one of compounds 1-4 or 6-12, or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the lipid compound is any one of compound 17, 60, or 61, or a pharmaceutically acceptable salt thereof.

[0129] In some embodiments, the lipid compound is any one of compounds 50-58 or a pharmaceutically acceptable salt thereof.

[0130] In some embodiments, the lipid compound is any one of compound 31, 41-43, or 47, or a pharmaceutically acceptable salt thereof.

[0131] In some embodiments, the lipid compound is any one of compounds 24, 25, 28, 29, 33-36, 38, or 40, or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the lipid compound is any one of compounds 62-34 or 66, or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments, the lipid compound is any one of compounds 21, 23, 26, 27, 37, 39, or 44-46, or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the lipid compound is any one of compounds 13-14, 67, 73, 81, 91, 93, 96, or 98-101, or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the lipid compound is any one of compounds 14-15, 49-50, 59, or 102-103, or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments, the lipid compound is any one of compounds 8, 14, 7, 10, or 60-61, or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is an ionizable lipid compound. II. Lipid Compositions Lipid nanoparticles (LNP)

[0138] In some embodiments, this disclosure provides lipid compositions (e.g., lipid nanoparticles (LNPs)) comprising at least one lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid nanoparticles are microspherical vesicles (i.e., liposomes) comprising a liposomal layered phase lipid bilayer (monolayer or multilayer) encompassing the interlayer space. In some embodiments, the lipid nanoparticles are nanospherical vesicles comprising a liposomal layered phase lipid bilayer (monolayer or multilayer).

[0139] In some embodiments, the lipid nanoparticles (LNPs) comprise: (i) at least one lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) at least one phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) at least one accessory lipid (e.g., cholesterol); and (iv) at least one PEG lipid. In some embodiments, the LNPs comprise: (i) at least one lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) at least one phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) at least one cholesterol; and (iv) at least one PEG lipid. In some embodiments, the lipid nanoparticles (LNPs) comprise one or more additional lipid components.

[0140] In some embodiments, the lipid nanoparticles (LNPs) comprise a lipid compound selected from any one of compounds 1-209. In some embodiments, the lipid nanoparticles (LNPs) comprise a lipid compound selected from any one of compounds 7, 8, 10, 13, 14, 26, 33, 38, 39, 40, 48, 60, 61, 89, 103, or 109, or a pharmaceutically acceptable salt thereof.

[0141] The phospholipids used in the lipid compositions (e.g., LNP) disclosed herein may be neutral, uncharged, or zwitterionic phospholipids. Examples of phospholipids used in lipid compositions include, but are not limited to: dipalmitoylphosphatidylcholine (DPPC), distearylphosphatidylcholine (DSPC), phosphocholine (DOPC), dimyristoylphosphatidylcholine (DMPC), phosphatidylcholine (PLPC), 1,2-distearyl-sn-glycerol-3-phosphocholine (DAPC), phosphatidylethanolamine (PE), lecithinylcholine (EPC), dilauroylphosphatidylcholine (DLPC), dimyristoylphosphatidylcholine (DMPC), 1-myristoyl-2-palmitoylphosphatidylcholine (MPPC), 1-palmitoyl-2-myristoylphosphatidylcholine (PMPC), 1-palmitoyl-2-myristoylphosphatidylcholine (PMPC), 1-palmitoyl-2-myristoylphosphatidylcholine (MP ...MPPC), 1-palmitoyl-2-myristoylphosphatidylcholine (MP 2-Stearylphosphatidylcholine (PSPC), 1,2-disialanoyl-sn-glycerol-3-phosphatecholine (DBPC), 1-stearoyl-2-palmitoylphosphatidylcholine (SPPC), 1,2-di-eicosenoyl-sn-glycerol-3-phosphatecholine (DEPC), palmitoyloleoylphosphatidylcholine (POPC), lysophosphatidylcholine, dioleoylphosphatidylethanolamine (DOPE), dilinoleoylphosphatidylcholine, distearylphosphatidylethanolamine (DSPE), dimyristoylphosphatidylethanolamine (DMPE), dipalmitoylphosphatidylethanolamine (DPPE), palmitoyloleoylphosphatidylethanolamine (POPE), lysophosphatidylethanolamine, and combinations thereof. In some embodiments, the phospholipid is distearylphosphatidylcholine (DSPC).

[0142] The auxiliary lipids used in the lipid compositions (e.g., LNP) disclosed herein include steroids, sterols, and alkyl resorcinols. Examples of auxiliary lipids used in lipid compositions include, but are not limited to, cholesterol, cholesterol hemisuccinate, and 5-heptadecyl resorcinol. In some embodiments, the auxiliary lipid is cholesterol.

[0143] PEG lipids used in the lipid compositions (e.g., LNPs) disclosed herein comprise compounds containing a lipid portion bound to a PEG-based polymeric portion (i.e., the PEG portion). In some embodiments, the lipid portion of the PEG lipid is derived from diacylglycerol or diacylglycerol amide. In some embodiments, the lipid portion of the PEG lipid is derived from a dialkylglycerol or dialkylglycerol amide group. In some embodiments, the dialkylglycerol or dialkylglycerol amide group has an alkyl chain length of about C4 to about C40 saturated or unsaturated carbon atoms. In some embodiments, the alkyl chain length is about C10 to about C20. In some embodiments, the dialkylglycerol or dialkylglycerol amide group comprises one or more functional groups (e.g., amides or esters). In some embodiments, the dialkylglycerol or dialkylglycerol amide group comprises one or more substituted alkyl groups.

[0144] The PEG moiety of the PEG lipid may comprise any polyethylene glycol (PEG) or other polyalkylene ether polymer, including optionally substituted linear or branched polymers of ethylene glycol or ethylene oxide. The molecular weight of the PEG moiety may be: about 130 to about 50,000 Da; about 150 to about 25,000 Da; about 150 to about 15,000 Da; about 150 to about 10,000 Da; about 150 to about 5,000 Da; about 150 to about 4,000 Da; about 150 to about 3,000 Da; about 150 to about 2,500 Da; about 150 to about 2,000 Da; about 500 to about 3,000 Da; about 500 to about 2,000 Da; about 1,000 to about 3,000 Da; or about 1,000 to about 2,000 Da. In some embodiments, the PEG moiety comprises PEG2000 (having 2,000 Da).

[0145] In some embodiments, the lipid composition (e.g., LNP) comprises about 40-70 mol% of at least one lipid compound having formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 20-80 mol% of a lipid compound having formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 45-65 mol% of a lipid compound having formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 45-50 mol% (e.g., about 47.5 mol%) of a lipid compound having formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 47.5-52.5 mol% (e.g., about 50 mol%) of a lipid compound having formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 50-55 mol% (e.g., about 52.5 mol%) of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 52.5-57.5 mol% (e.g., about 55 mol%) of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 55-60 mol% (e.g., about 57.5 mol%) of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 57.5-62.5 mol% (e.g., about 60 mol%) of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 60-65 mol% (e.g., about 62.5 mol%) of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, the lipid composition comprises about 62.5-67.5 mol% (e.g., about 65 mol%) of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the lipid composition (e.g., LNP) comprises about 7.5-40 mol% of phospholipids (e.g., distearylphosphatidylcholine (DSPC)). In some embodiments, the lipid composition (e.g., LNP) comprises about 7.5-12.5 mol% of phospholipids (e.g., distearylphosphatidylcholine (DSPC)). In some embodiments, the lipid composition comprises about 10 mol% of phospholipids (e.g., distearylphosphatidylcholine (DSPC)).

[0147] In some embodiments, the lipid composition (e.g., LNP) comprises about 6-50 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition (e.g., LNP) comprises about 20-50 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition (e.g., LNP) comprises about 6-45 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 25-45 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 26-29 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 27.5 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 37-40 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 38.5 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 37.5-40.5 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 39 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 38-42 mol% of an accessory lipid (e.g., cholesterol). In some embodiments, the lipid composition comprises about 40 mol% of an accessory lipid (e.g., cholesterol).

[0148] In some embodiments, the lipid composition (e.g., LNP) comprises about 1-4 mol% of PEG lipids. In some embodiments, the lipid composition comprises about 1-2 mol% (e.g., 1.5 mol%) of PEG lipids. In some embodiments, the lipid composition comprises about 1.5-2.5 mol% (e.g., 2 mol%) of PEG lipids. In some embodiments, the lipid composition comprises about 2-3 mol% (e.g., 2.5 mol%) of PEG lipids. In some embodiments, the lipid composition comprises about 2.5-3.5 mol% (e.g., 3 mol%) of PEG lipids. In some embodiments, the lipid composition comprises about 3-4 mol% (e.g., 3.5 mol%) of PEG lipids.

[0149] In some embodiments, the lipid composition (e.g., LNP) comprises: (i) about 20-80 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 7.5-40 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 6-45 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 1-4 mol% of a PEG lipid. In some embodiments, the lipid composition (e.g., LNP) comprises: (i) about 40-70 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 7.5-12.5 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 20-50 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 1-4 mol% of a PEG lipid. In some embodiments, the lipid composition comprises: (i) about 45-65 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 25-45 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 1-4 mol% of a PEG lipid.

[0150] In some embodiments, the lipid composition (e.g., LNP) comprises: (i) about 45-50 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 38-42 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 2-3 mol% of a PEG lipid. In some embodiments, the lipid composition comprises: (i) about 47.5 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 40 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 2.5 mol% of a PEG lipid.

[0151] In some embodiments, the lipid composition (e.g., LNP) comprises: (i) about 47.5-52.5 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 37-40 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 1-2 mol% of a PEG lipid. In some embodiments, the lipid composition comprises: (i) about 50 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 38.5 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 1.5 mol% of a PEG lipid.

[0152] In some embodiments, the lipid composition (e.g., LNP) comprises: (i) about 57.5-62.5 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 26-29 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 2-3 mol% of a PEG lipid. In some embodiments, the lipid composition comprises: (i) about 60 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 27.5 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 2.5 mol% of a PEG lipid.

[0153] In some embodiments, the lipid composition (e.g., LNP) comprises: (i) about 45-50 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 37.5-40.5 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 3-4 mol% of a PEG lipid. In some embodiments, the lipid composition comprises: (i) about 47.5 mol% of a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof; (ii) about 10 mol% of a phospholipid (e.g., distearylphosphatidylcholine (DSPC)); (iii) about 39 mol% of an accessory lipid (e.g., cholesterol); and (iv) about 3.5 mol% of a PEG lipid.

[0154] In some embodiments, the lipid compositions disclosed herein (e.g., LNP) further comprise a targeting component. In some embodiments, the targeting component is a passive targeting component. In some embodiments, the passive targeting component comprises a targeting lipid. In some embodiments, the targeting lipid comprises at least one cationic targeting lipid. Examples of cationic targeting lipids used in the lipid compositions disclosed herein (e.g., LNP) include, but are not limited to, 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA). In some embodiments, the targeting lipid comprises at least one anionic targeting lipid. Examples of anionic targeting lipids used in the lipid compositions disclosed herein (e.g., LNP) include, but are not limited to, phosphatidic acid (PA), bis(monoacylglycerol) phosphate (BMP), hemi-bis(monoacylglycerol) phosphate (hemi-BMP), and bis(diacylglycerol) phosphate (BDP).

[0155] In some embodiments, the targeting component of the lipid compositions disclosed herein (e.g., lipid nanoparticles (LNPs)) is an actively targeting component. In some embodiments, the actively targeting component comprises a protein. In some embodiments, the actively targeting component comprises a peptide. In some embodiments, the actively targeting component comprises a small molecule. In some embodiments, the actively targeting component comprises an antibody. In some embodiments, the actively targeting component comprises an antigen-binding fragment of an antibody. Surfactant

[0156] In some embodiments, the lipid compositions disclosed herein (e.g., lipid nanoparticles (LNPs)) comprise at least one active agent (e.g., RNA, DNA). In some embodiments, this disclosure provides lipid compositions (e.g., lipid nanoparticles (LNPs)) comprising at least one lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and at least one active agent (e.g., RNA, DNA) within the lipid composition (e.g., within the LNP).

[0157] In some embodiments, the active agent comprises one or more polynucleotides. In some embodiments, the active agent comprises one or more RNAs. In some embodiments, the active agent comprises one or more DNAs. In some embodiments, the active agent comprises one or more RNAs and one or more DNAs.

[0158] In some embodiments, the active agent comprises mRNA. In some embodiments, the active agent comprises mRNA encoding an RNA-guided DNA binder (e.g., a Cas nuclease, such as Cas9).

[0159] In some embodiments, the active agent comprises gRNA. In some embodiments, the active agent comprises dgRNA or sgRNA.

[0160] In some embodiments, the active agent comprises an inhibitory polynucleotide, such as siRNA (i.e., a non-coding short interfering RNA molecule). Compositions and methods

[0161] In some embodiments, this disclosure provides pharmaceutical compositions comprising the lipid compositions of this disclosure (e.g., lipid nanoparticles (LNPs)). In some embodiments, the pharmaceutical composition comprises the lipid compositions of this disclosure (e.g., lipid nanoparticles (LNPs)) and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is an aqueous solution or suspension. In some embodiments, the pharmaceutical composition is an oil-based solution or suspension.

[0162] In some embodiments, this disclosure provides a method for delivering an active agent (e.g., a polynucleotide) to target cells or tissues (e.g., extrahepatic cells or tissues). In some embodiments, the method includes administering to a subject an effective amount of a lipid composition (e.g., LNP) disclosed herein. In some embodiments, the method includes administering to a subject an effective amount of a pharmaceutical composition comprising a lipid composition (e.g., LNP) disclosed herein.

[0163] In some embodiments, this disclosure describes a composition of this disclosure for use in delivering an active agent (e.g., a polynucleotide) to target cells or tissues (e.g., extrahepatic cells or tissues). In some embodiments, this disclosure describes the use of the composition of this disclosure in delivering an active agent (e.g., a polynucleotide) to target cells or tissues (e.g., extrahepatic cells or tissues). In some embodiments, this disclosure describes the use of the composition of this disclosure in manufacturing a medicament for use in delivering an active agent (e.g., a polynucleotide) to target cells or tissues (e.g., extrahepatic cells or tissues). In some embodiments, the use includes administering an effective amount of the lipid composition of this disclosure (e.g., LNP) to a subject. In some embodiments, the use includes administering an effective amount of a pharmaceutical composition comprising the lipid composition of this disclosure (e.g., LNP) to a subject.

[0164] In some embodiments, the target cells or tissues are extrahepatic cells or tissues. In some embodiments, the extrahepatic cells or tissues comprise one or more (e.g., all) of the following: brain cells or tissues; lung cells or tissues; bone marrow cells or tissues; spleen cells or tissues; lymph node cells or tissues; ovarian / testicular cells or tissues; muscle cells or tissues; kidney cells or tissues; pancreatic cells or tissues; and / or cardiac cells or tissues. In some embodiments, the extrahepatic cells or tissues comprise one or more (e.g., all) of the following: brain cells or tissues; lung cells or tissues; and / or bone marrow cells or tissues. In some embodiments, bone marrow cells or tissues are located in the femur. In some embodiments, the extrahepatic cells or tissues comprise brain cells or tissues. In some embodiments, the extrahepatic cells or tissues comprise lung cells or tissues. In some embodiments, the extrahepatic cells or tissues comprise bone marrow cells or tissues. In some embodiments, the extrahepatic cells or tissues comprise spleen cells or tissues. In some embodiments, the extrahepatic cells or tissues comprise lymph node cells or tissues. In some embodiments, the extrahepatic cells or tissues comprise ovarian or testicular cells or tissues. In some embodiments, the extrahepatic cells or tissue comprise muscle cells or tissue. In some embodiments, the extrahepatic cells or tissue comprise kidney cells or tissue. In some embodiments, the extrahepatic cells or tissue comprise pancreatic cells or tissue. In some embodiments, the extrahepatic cells or tissue comprise cardiac cells or tissue.

[0165] In some embodiments, this disclosure provides a method of treating a subject's disease, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a lipid composition (e.g., LNP) disclosed herein.

[0166] In some embodiments, this disclosure describes a composition of this disclosure for use in treating a subject’s disease by administering a therapeutically effective amount of the composition to the subject, wherein the composition comprises a lipid composition of this disclosure (e.g., LNP).

[0167] In some embodiments, this disclosure describes the use of the disclosed compositions in treating a subject’s disease by administering a therapeutically effective amount of the composition to the subject, wherein the composition comprises the disclosed lipid compositions (e.g., LNP).

[0168] In some embodiments, this disclosure describes the use of the disclosed compositions in the manufacture of a medicament for use in treating a subject’s disease by administering a therapeutically effective amount of the medicament to the subject, wherein the medicament comprises the disclosed lipid compositions (e.g., LNP).

[0169] In some embodiments, the lipid composition (e.g., LNP) comprises a lipid compound having formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, and an active agent (e.g., DNA, RNA).

[0170] In some embodiments, the lipid composition (e.g., LNP) comprises a lipid compound selected from any one of compounds 1-209 or a pharmaceutically acceptable salt thereof, and encapsulates an active agent (e.g., DNA, RNA).

[0171] In some embodiments, the lipid composition (e.g., LNP) comprises a lipid compound selected from any one of compounds 7, 8, 10, 13, 14, 26, 33, 38, 39, 40, 48, 60, 61, 89, 103, or 109, or a pharmaceutically acceptable salt thereof, and encapsulates an active agent (e.g., DNA, RNA).

[0172] In some embodiments, this disclosure provides a method for producing a therapeutic composition, the method comprising encapsulating an active agent (e.g., DNA, RNA) within lipid nanoparticles (LNPs) of this disclosure. In some embodiments, this disclosure provides a method for producing a prophylactic composition, the method comprising encapsulating an active agent (e.g., DNA, RNA) within lipid nanoparticles (LNPs) of this disclosure. In some embodiments, this disclosure provides a method for producing a vaccine, the method comprising encapsulating an active agent (e.g., DNA, RNA) within lipid nanoparticles (LNPs) of this disclosure.

[0173] In some embodiments, the lipid composition (e.g., LNP) of the therapeutic composition, prophylactic composition, or vaccine comprises a lipid compound having formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the active agent (e.g., DNA, RNA) is encapsulated into lipid nanoparticles (LNPs) by mixing a solution containing an active agent (e.g., DNA, RNA) with a solution / suspension containing lipid nanoparticles or lipid nanoparticle precursor elements. Examples of solutions or solvents that can be used to form LNPs or encapsulate active agents into LNPs include, but are not limited to: water, PBS, Tris buffer, NaCl, citrate buffer, acetate buffer, ethanol, chloroform, diethyl ether, cyclohexane, tetrahydrofuran, methanol, and isopropanol.

[0174] In some embodiments, the active agent comprises DNA. In some embodiments, the active agent comprises RNA. In some embodiments, the active agent comprises both DNA and RNA. In some embodiments, the RNA comprises mRNA. In some embodiments, the RNA comprises repressive RNA, such as siRNA. III. Definition

[0175] Unless otherwise stated, the following terms and phrases have the following meanings. These definitions are not intended to be restrictive in nature, but rather to provide clarity in understanding certain aspects of this disclosure.

[0176] Administration: As used herein, the term “administration” refers to the provision of the composition to a subject.

[0177] Alkenyl group: As used herein, the term "alkenyl group" refers to an alkenyl moiety attached by a divalent oxygen bridge (e.g., -OC). 1-20 (Alkenyl). Examples of such groups include, but are not limited to, ethyleneoxy and propenoxy groups.

[0178] Alkenyl: As used herein, the term "alkenyl" refers to an unsaturated hydrocarbon chain (branched or unbranched) having one or more carbon-carbon double bonds within its chain. In some embodiments, the alkenyl group may optionally be substituted with one or more substituents. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, etc.

[0179] Alkenyl: As used herein, the term "alkenyl" refers to a divalent alkenyl group. Examples of alkenyl groups include, but are not limited to, vinylidene, propenide, butenide, pentenide, and hexenide.

[0180] Alkoxy group: As used herein, the term "alkoxy group" refers to an alkyl moiety attached via a divalent oxygen bridge (e.g., ROC). 1-20 Examples of such groups include, but are not limited to, methoxy, ethoxy, propoxy, etc.

[0181] Alkyl: As used herein, the term "alkyl" refers to a saturated hydrocarbon chain (branched or unbranched). In some embodiments, the alkyl group may optionally be substituted with one or more substituents (i.e., the alkyl group may be unsubstituted or substituted with one or more substituents). In some embodiments, the alkyl group may optionally be substituted with one or more halogroups (e.g., F). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (n-propyl, isopropyl), butyl (n-butyl, sec-butyl, isobutyl, tert-butyl), pentyl (n-pentyl, isopentyl, neopentyl), etc.

[0182] Alkylene: As used herein, the term “alkylene” refers to a divalent alkyl group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (n-propylene, isopropylene), butylene (n-butylene, secondary butylene, isobutylene, tert-butylene), and pentylene (n-pentylene, isopentylene, neopentylene).

[0183] Alkynyl: As used herein, the term "alkynyl" refers to an unsaturated hydrocarbon chain (branched or unbranched) having one or more carbon-carbon triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, and hexynyl.

[0184] Iynyne: As used herein, the term "ynyne" refers to a divalent ynyne group. Examples of ynyne groups include, but are not limited to, ethynylene, propynylene, butynylene, penynylene, and hexynylene.

[0185] Approximately / about: As used herein, the terms “approximately” and “about” are used interchangeably and refer to a value within + / - 10% of the listed value when applied to one or more values ​​of interest. In some embodiments, unless explicitly stated otherwise or otherwise apparent from the context, the term refers to a range of values ​​falling within + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, + / - 1% or less of the reference value.

[0186] Aryl: As used herein, the term "aryl" refers to a monocyclic aromatic hydrocarbon ring or a polycyclic group containing at least one aromatic hydrocarbon ring. In some embodiments, the aryl group may optionally be substituted with one or more substituents. Examples of aryl groups include, but are not limited to, phenyl and naphthyl.

[0187] aryl: The term "aryl" refers to a polyvalent (e.g., divalent or trivalent) aryl group.

[0188] Cycloalkyl: As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic or tricyclic) hydrocarbon ring. In some embodiments, the cycloalkyl group may optionally be substituted with one or more substituents. In some embodiments, the cycloalkyl group may optionally be substituted with one or more C1-C1 substituents. 12 Alkyl groups (e.g., methyl, ethyl, n-pentyl, n-butyl, n-pentyl, etc.) are substituted. The number of ring atoms in a cycloalkyl ring can be indicated by "C". x -C y The nomenclature is used to designate cycloalkyl groups, where x and y are integers specifying the number of ring atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc. In some embodiments, the cycloalkyl group comprises a fused cycloalkyl group (e.g., a fused bicyclic or fused tricyclic group). In some embodiments, the cycloalkyl group comprises a bridged cycloalkyl group (e.g., a bridged bicyclic group). In some embodiments, the cycloalkyl group comprises a spirocycloalkyl group (e.g., a spirobicyclic group).

[0189] Cycloalkylene: As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl group. Examples of such groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and adamantylene.

[0190] Dienyl: As used herein, the term “dienyl” refers to an unsaturated hydrocarbon chain (branched or unbranched) having one or more carbon-carbon double bonds within the chain. Examples of dienyl groups include, but are not limited to, 1,3-pentadienyl, 1,4-hexadienyl, (2Z,5Z)-undec-2,5-dienyl, etc.

[0191] Effective amount: As used herein, the term “effective amount” or “therapeutic effective amount” for a pharmaceutical agent is an amount sufficient to produce a beneficial or desired outcome (e.g., biological, medical, or clinical results). Therefore, the effective amount depends on its context of application (e.g., route of administration, severity of illness, subject’s biochemistry and medical history, etc.) and can be determined by standard clinical techniques skilled in the art (e.g., inference from dose-response curves derived from tests).

[0192] Halogenated: As used herein, the term “halogenated” refers to fluorine, chlorine, bromine, and / or iodine.

[0193] Heterocyclic / Heterocyclic / Heterocyclic Group: As used herein, the terms “heterocyclic,” “heterocyclic,” or “heterocyclic group” refer to a saturated or unsaturated non-aromatic ring (monocyclic or bicyclic) containing one or more (e.g., 1 to 4) heteroatoms (e.g., N, O, or S). The number of ring atoms in a heterocycle can be specified using the “xy-membered” nomenclature, where x and y are integers specifying the number of ring atoms. For example, 3- to 6-membered heterocyclic groups refer to saturated or unsaturated 3- to 6-membered ring structures containing one or more heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolinyl, pyrrolylalkyl, pyrazolylalkyl, oxazolyl, thiazolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, etc.

[0194] Heterocyclic groups: As used herein, the term "hemeocyclic group" refers to a divalent heterocyclic group. Examples of such groups include, but are not limited to, pyrrolidine, pyrrolidinealkyl, pyrazolidinealkyl, oxazolyl, thiazolyl, piperidinyl, piperazine, morpholinyl, etc.

[0195] Hydroxyalkyl: As used herein, the term "hydroxyalkyl" refers to RC 1-20 -OH groups. Examples of such groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, etc.

[0196] Lipid nanoparticles: As used herein, the term "lipid nanoparticle" or "LNP" refers to a particle comprising a plurality of lipid molecules physically linked together by intermolecular forces. In some embodiments, lipid nanoparticles are microspherical vesicles comprising a liposome-like layered lipid bilayer (monolayer or multilayer). In other embodiments, lipid nanoparticles are nanospherical vesicles comprising a liposome-like layered lipid bilayer (monolayer or multilayer).

[0197] mol %: As used herein, the term "mol percentage" or "mol %" refers to the mole fraction of a particular element in a mixture, expressed as a percentage of the total number of moles in the mixture. The mole fraction is the number of moles of a particular component in a mixture relative to the total number of moles in that mixture.

[0198] Pharmaceutically acceptable: As used herein, the terms “pharmaceuticalally acceptable” or “therapeutically acceptable” are used to describe compounds, materials, compositions, and / or dosage forms that are suitable for contact with human and animal tissues within reasonable medical judgment without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0199] Pharmaceutically acceptable excipients: As used herein, the term "pharmaceutically acceptable excipient" refers to an ingredient in a composition that is capable of suspending, carrying, diluting, stabilizing, controlling, encapsulating, or otherwise supplementing the compound or composition disclosed herein (e.g., LNP). Pharmaceutically acceptable excipients are substantially non-toxic, non-inflammatory in subjects, and otherwise pharmaceutically acceptable (as defined above).

[0200] Pharmaceutically acceptable salts: As used herein, the phrase "pharmaceutically acceptable salts" refers to salts that, within reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without producing undue toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Compounds described herein may contain basic or acidic functional groups, or both, and may be converted into pharmaceutically acceptable salts as needed using appropriate acids or bases. These salts can be prepared in situ during the final separation and purification of the compound.

[0201] Phospholipids: As used herein, the term "phospholipid" refers to a lipid comprising a phosphate moiety and one or more carbon chains (e.g., unsaturated fatty acid chains). Phospholipids may include one or more double or triple bonds (e.g., one or more unsaturated bonds) in their carbon chains.

[0202] Prevention (or prophylaxis): As used herein, the term "preventing, prevention, or prophylaxis" means partially or completely delaying the onset of a disease or condition; partially or completely delaying the onset of one or more symptoms, features, or clinical manifestations of a disease or condition; partially or completely delaying the progression of a disease or condition; and / or reducing the risk of developing a pathology associated with a disease or condition. In some embodiments, "preventing, prevention, or prophylaxis" of a disease or condition may be considered a subset of the meaning of the term "treatment or treating" of that disease or condition.

[0203] Subject: As used herein, the term "subject" means any organism to which the compositions according to this disclosure may be administered, for example, for experimental, diagnostic, preventive, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and / or plants. The patient may be seeking or needing treatment, requesting treatment, receiving treatment, about to receive treatment, or under the supervision of a trained professional due to a particular disease or condition.

[0204] Identical substituents: As used herein, when two substituents are “identical,” they have the same molecular formula and bonded atomic sequence, but their atoms may have different or the same three-dimensional orientation in space. In some embodiments, when identical substituents each contain one or more double bonds, the configuration of each of the one or more double bonds in one substituent is the same as the configuration of the corresponding one or more double bonds in the other substituent.

[0205] Treatment: As used herein, the term "treatment" means the partial or complete relief, improvement, enhancement, reduction, or alleviation of one or more symptoms or features of a particular disease or condition, delaying its onset, inhibiting its progression, reducing its severity, decreasing its incidence, and / or preventing it. Treatment may be administered to subjects who do not exhibit signs of the disease or condition, and / or subjects who only exhibit early signs of the disease or condition, for the purpose of reducing the risk of developing pathology (or further pathology) associated with the disease or condition. General considerations

[0206] In various places within this disclosure, substituents or properties of the disclosed compounds are disclosed in the form of groups or ranges. This disclosure is intended to include every individual or subcombination of members in such groups and ranges, and such groups or ranges include endpoints. As a non-limiting example, if a group or range is from about 1 to about 10, then the group or range includes both values ​​of about 1 and about 10.

[0207] Unless otherwise indicated or apparent from the context, articles such as "a / an" and "the" may mean one or more. Unless otherwise indicated or apparent from the context, a claim or specification including "or" among one or more members of a group is considered satisfactory if one, more than one, or all of the members of that group are present in, used in, or otherwise associated with a given product or method. This disclosure may include embodiments in which exactly one member of the group is present in, used in, or otherwise associated with a given product or method. This disclosure may include embodiments in which more than one or all of the members of the group are present in, used in, or otherwise associated with a given product or method.

[0208] The term “includes” is intended to indicate openness, allowing but not requiring the inclusion of additional elements or steps. When the term “includes” is used herein, it also covers and discloses the terms “consisting of” and “substantially consisting of”.

[0209] The abbreviation “eg” is derived from the Latin word *exempli gratia* and is used herein to indicate a non-restrictive instance. Therefore, the abbreviation “eg” is synonymous with the term “for example”. The abbreviation “ie” is derived from the Latin word *id est* and is used herein to indicate a non-restrictive paraphrase or clarification. Therefore, the abbreviation “ie” is synonymous with the term “that is”.

[0210] If a variable is provided in the context of an organic chemical structure and has a series of numbers, then the variable should be understood as an integer value within that range, including the endpoints. For example, "n is 0-3" means that n is 0, 1, 2, or 3.

[0211] Any embodiment of the present disclosure that is prior art may be expressly excluded from any one or more claims. Any embodiment of the pharmaceuticals, methods, and / or compositions disclosed herein, for whatever reason (whether or not related to the existence of prior art), may be excluded from one or more claims.

[0212] If any publications, patent applications, patents and other references mentioned herein are incorporated by way of citation and conflict with this specification, this specification shall prevail.

[0213] Chapter titles, materials, methods, and examples are illustrative only and are not intended to be limiting. Example Example 1 - Preparation and Analysis of Lipid Nanoparticles (LNPs) a. LNP formulations

[0214] Formulations comprising the lipid compounds disclosed herein were prepared. Four common formulations were used, according to Table 2: Table 2: General Preparations

[0215] LNP formulations were prepared using the lipid compounds listed in Table 1: compounds 1-12, 14, 16, 18, and 20. Formulation results are shown in Table 3 (PDI = polydispersity index, N / P = molar ratio of ionizable nitrogen to phosphate groups, EE% = encapsulation efficiency (measured using a fluorescence-based assay)): Table 3: LNP formulations b. LNP preparation

[0216] Lipids and active ingredients (e.g., RNA, DNA, etc.) are assembled into LNPs using microfluidic mixing. The ethanol phase is prepared by dissolving ionizable lipids (i.e., lipid compounds), phospholipids (e.g., DSPC), cholesterol, and PEG lipids in ethanol at predetermined mol% ratios given in Table 2. The aqueous phase is prepared by diluting nucleic acid cargo (e.g., firefly luciferase mRNA) in an acidified buffer (50 mM citrate buffer, pH 4.0). The two phases are mixed using a chip with a microfluidic mixing architecture (e.g., a ring mixer) at a predetermined flow rate ratio (e.g., 9 ml / min for the aqueous phase and 3 ml / min for the ethanol phase). The resulting LNPs, containing lipids and encapsulated with nucleic acid cargo, are dialyzed against PBS at pH 7.4 for 2 hours at room temperature using a 20 kDa MWCO dialysis membrane. The PBS is then replaced, and dialyzing continues overnight at 2°C–8°C. After buffer exchange, the LNPs are optionally concentrated using an ultracentrifuge with a 10–100 kDa MWCO membrane. c. Plate-based fluorescence (RiboGreen) measurement

[0217] Nucleic acid cargo in LNPs was quantified using RiboGreen assays, referencing a nucleic acid standard curve. LNPs encapsulated with nucleic acid cargo were mixed with 1x Tris-EDTA (TE) and 2% triton in TE to achieve the required dilutions for assay. The samples were then heated at 30°C and vortexed at 300 rpm. Samples were seeded into 96-well plates, with RiboGreen reagent added to each well. After incubation in the dark, fluorescence in the wells was measured and plotted against a standard curve. The nucleic acid concentration obtained from the Triton-treated samples was used for quantification of the total cargo concentration. Unencapsulated (free) cargo was determined using only the fluorescence values ​​of the TE-diluted samples, and the encapsulation efficiency (EE%) was determined using their ratio. d. Dynamic light scattering

[0218] Based on the process steps and LNP concentration, LNP was diluted to the predetermined dilution range with PBS at pH 7.4. After mixing, particle size and PDI were measured using a dynamic light scattering instrument. Example 2 - Stability Study

[0219] The stability of LNPs prepared from selected lipid compounds was investigated at 2°C–8°C. Compounds 1–7 and 10 (N / P: 6) were tested for 4 weeks in formulation F1. Particle size and PDI results were shown in… Figure 1A and Figure 1B middle.

[0220] In formulation F3, compounds 2, 3, 5, and 7 were also tested over a two-week period. Particle size and PDI results were shown... Figure 1C and Figure 1D middle. Example 3 - In vivo activity in mice a. General Solution

[0221] Biodistribution studies of small rodents were conducted in mice (e.g., C57BL / 6J, Balb-c, CD-1, etc.). To assess the biodistribution and tissue activity of LNP following systemic administration, C57BL / 6J mice received a single intravenous injection of LNP formulations in PBS (alone or in combination) at varying doses of firefly luciferase mRNA (0.25–3 mg / kg) via tail vein. At predetermined time points (4–6 hours post-injection), animals were anesthetized with isoflurane, and in vivo imaging sessions of bioluminescence were performed using an in vivo imaging system (IVIS). All animals were administered D-luciferin at a dose of 15 mg / mL via subcutaneous (SC) injection, at a dose of 0.2 mL / animal. The fur on the abdomen of the animals was shaved using an animal shaver. They were then positioned with their shaved abdomens facing upwards towards the IVIS camera. Systemic imaging was performed 10–15 minutes after D-luciferin administration.

[0222] To gain a detailed understanding of the organ distribution and activity of the LNP formulation, an ex vivo imaging procedure was also performed. All animals received SC D-luciferin, were then euthanized by isoflurane overdose, and subsequently perfused with saline. After perfusion, organs were collected, and IVIS luminescence imaging was performed within 10–15 minutes following D-luciferin injection.

[0223] To deliver to the lungs, LNP formulation was administered to CD-1 mice via a single intratracheal administration under isoflurane anesthesia. D-fluorescein was then administered subcutaneously (SC) at a dose of 15 mg / mL per animal. Whole-body imaging was performed within 10–15 minutes following D-fluorescein injection. The animals were then perfused with saline, and the lungs and trachea were collected for luminescence imaging.

[0224] All IVIS images were processed using computer software to identify regions of interest for each organ, thereby detecting total flux (p / s) values ​​as quantification of luminescence. Total flux values ​​were then plotted to assess in vivo activity in each collected organ. b. General activity studies

[0225] The activity of LNPs prepared from selected lipid compounds in delivering mRNA in mice was investigated. LNPs were formulated using the lipid compounds described in Example 2, and these four LNP formulations were then mixed together. Additional pools were created by combining the four groups of LNPs corresponding to the four different lipid compounds shown, resulting in sixteen pools with different compositions. The formulation properties of the resulting LNPs are shown in Table 4. Table 4: LNP composition used in in vivo mouse studies

[0226] Each LNP compound pool (IV) was injected into mice (1 mg / kg), with PBS as a control. Organ imaging results of the mice 6 hours later (shown as total flux [p / s]) were displayed. Figure 2A , Figure 2B , Figure 2C and Figure 2D middle. c. Brain activity

[0227] LNP compound pools (ICV) of compounds 1, 4, 6, and 10 were locally administered intracerebrally (1 µg / animal) to mouse brains, with PBS as a control. Mouse brain imaging results (shown as total throughput [p / s]) are shown in... Figure 3 middle. d. Pulmonary activity

[0228] LNP compounds 2, 3, 5, and 7 were locally (intratracheally) administered into the lungs of mice (7 µg RNA / animal), with PBS as a control. Mouse lung imaging results (shown as total flux [p / s]) are shown in... Figure 4A (Live animal imaging) and Figure 4B In (extracellular imaging).

[0229] LNP compounds 8, 9, 11, and 20 were locally (intratracheally) administered into the lungs of mice (7 µg RNA / animal), with PBS as a control. Mouse lung imaging results (shown as total flux [p / s]) are shown in... Figure 4C middle.

[0230] LNP compounds 12, 14, 16, and 18 were locally (intratracheally) administered into the lungs of mice (7 µg RNA / animal), with PBS as a control. Mouse lung imaging results (shown as total flux [p / s]) are shown in... Figure 4D middle. Example 4 - Study of Formulation F2 a. Study and design of formulation F2

[0231] Following Example 1, LNPs containing lipid compounds 7, 8, 10, 14, and 18 were prepared in formulation F2. For comparison, an LNP formulation containing MC3 (Cayman Chemical) as a lipid compound was also prepared using formulation F2. PBS was used as a control. The formulation properties are shown in Table 5. Table 5: LNP composition used in the study of formulation F2 b. General formulation F2 activity

[0232] Each LNP formulation (IV) was injected into mice (0.3 mg / kg), with PBS as a control. Imaging results were collected according to the protocol in Example 4. Organ imaging results of mice after 6 hours (shown as total throughput [p / s]) are shown in... Figure 5A In the middle. Mouse organ imaging results normalized relative to MC3 activity showed Figure 5B middle. c. Lung studies of formulation F2

[0233] Each LNP formulation was administered topically (intratracheally) to the mouse lungs (7 µg RNA / animal), compared with MCS, and PBS was used as a control. Imaging results were collected according to the protocol in Example 4. Mouse lung and tracheal imaging results (shown as total flux [p / s]) are shown in... Figure 6A (Live animal imaging) and Figure 6B In (extracellular imaging). Example 5 - In vivo activity screening in mice

[0234] Following the general research protocol in Example 3(a), a small rodent biodistribution study was conducted on mice. LNPs containing lipid compounds were prepared in formulation F2, and MC3 (Kaiman Chemicals) was used as the lipid compound (prepared using formulation F2) for comparison. LNP pools (encapsulated with firefly luciferase mRNA) were injected into mice at different doses, and organ-average total flux (p / s) results (measuring luciferase activity) were collected according to Example 3(a).

[0235] LNP dosage, LNP pool composition, and organ-average total flux results for multiple mouse organs are shown in Table 6. LNPs containing MC3 were used as controls and for inter-mouse comparisons. Dosage units are in mg / kg; LC is based on lipid compounds in Table 1. Table 6: In vivo activity screening

[0236] Additional screening results for compounds 7, 13, 14, 26, 33, 38, 39, 40, 48, 60, 61, 89, 103, and 109 in the spleen, femur, and muscle showed... Figure 7A , Figure 7B and Figure 7C In the study, MC3 was used as a control for comparison. Example 6 - In vivo activity screening in non-human primates

[0237] Biodistribution studies of nonhuman primates (NHPs) were conducted in cynomolgus monkeys (e.g., long-tailed macaques) aged 4–6 years. Animals were pre-administered with dexamethasone, famotidine, and diphenhydramine (1, 0.5, and 5 mg / kg, respectively) on days 1 and 2 prior to administration of the test material. LNP formulations were prepared using ionizable lipids (according to formulation F2 in Example 1), such that each LNP formulation encapsulated one or more mRNAs with a predetermined unique barcode sequence as its cargo. LNPs in PBS identified by their unique barcode mRNA cargo were then mixed together at a predetermined ratio. To assess the biodistribution of LNPs in tissues following systemic administration, NHPs received a single intravenous infusion of LNP administration material in PBS (alone or in combination) (total dose levels varying (0.5–1 mg / kg)) over 30 minutes via a peripheral vein (cephalic vein, saphenous vein, or other available vein).

[0238] Animals were euthanized by exsanguination via the femoral artery after intravenous injection of ketamine (10 mg / kg) and Euthasol® (0.25 mL / kg) at predetermined time points (4–6 hours after administration of the mixed test material). All animals were then perfused with systemic PBS before tissue collection. 20–25 mg samples were collected from all treatment group animals for biodistribution analysis and placed in sample tubes containing RNALater™ solution. All tissue samples were stored at room temperature for 24 hours, then the supernatant was removed and the samples were frozen.

[0239] To identify unique LNPs distributed within a tissue, the sample was homogenized using a tissue homogenizer (e.g., TissueLyser). Total RNA was extracted from the tissue homogenate using standard methods. The normalized RNA levels were then sequenced using a targeted RNA sequencing method with unique molecular identifiers (UMIs) to ensure accurate RNA molecule counting. For each tissue, the resulting RNA molecule counts were normalized by mixing the RNA counts of the test items. The results were analyzed using an internal bioinformatics workflow.

[0240] The composition of LNP pools and UMI counts for multiple NHP organs are shown in Table 7. LNPs containing MC3 were used as controls and for inter-mouse comparisons. Dosage units are in mg / kg; LC is based on lipid compounds in Table 1. Table 7: In vivo activity screening

[0241] Screening results for NHP group 1 (spleen, femur, and muscle) showed Figure 8A , Figure 8B and Figure 8C In the middle. The screening results of NHP group 2 (spleen) showed that Figure 9 In the middle. The screening results of NHP group 3 (femur) are shown in Figure 10 In the middle. The screening results of NHP group 4 (muscle) are shown in Figure 11 middle. Example 7 - General Materials and Methods for Synthesis

[0242] All temperatures are in degrees Celsius and are uncorrected. Reagent-grade chemicals and anhydrous solvents were purchased from commercial sources and, unless otherwise mentioned, can be used without further purification. Product names were determined using the naming software included in the Biovia Electronic Lab Notebook. Silica gel chromatography was performed on a Teledyne Isco instrument using a pre-packed disposable SiO2 stationary column with eluent flow rates ranging from 15 to 200 mL / min and UV detection (254 and 280 nm). Reversed-phase purification was performed using a C18 column with UV detection (214 and 254 nm). Chemical shifts are reported in parts per million (ppm) with solvent peaks as a reference. 1 In 1H NMR, the solvent peak of CDCl3 appeared at 7.26 ppm, DMSO-d6 at 2.50 ppm, and CD3OD at 3.31 ppm. Terms and abbreviations: Example 8 - Compound 1: Dioleoyl 2-((oleoyloxy)methyl)-2-(((4-(((2-(pyrrolid-1-yl)ethyl)carbamoyl)oxy)decanoyl)oxy)methyl)propane-1,3-diyl ester Step 1:

[0243] NaOH (24.67 g, 616.75 mmol, 1.05 eq) was slowly added to a solution of 5-hexyltetrahydrofuran-2-one (100 g, 587.38 mmol, 1 eq) in H₂O (500 mL). The mixture was stirred at 100°C for 12 hr under N₂. The reaction mixture was concentrated under reduced pressure to remove the solvent. A white solid, sodium 4-hydroxydecanoyloxy (90 g, crude), was obtained and used directly in the next step. Step 2:

[0244] Bromomethylbenzene (8.13 g, 47.56 mmol, 1 eq) was added dropwise to a solution of sodium 4-hydroxydecanoyloxy (10 g, 47.56 mmol, 1 eq) in DMSO (100 mL). The mixture was stirred at 25°C for 5 min under N2. The reaction mixture was diluted with saturated NaCl (100 mL) and diluted with EtOAc (200 mL) (100 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. Benzyl 4-hydroxydecanoate (12 g, crude product), a pale yellow oil, was obtained and rapidly used in the next step. Step 3:

[0245] At 0°C, (4-nitrophenyl)chloroformate (17.38 g, 86.21 mmol, 1 eq) and Py (6.82 g, 86.21 mmol, 6.96 mL, 2 eq) were slowly added to a solution of 4-hydroxydecanoate benzyl ester (12 g, 43.11 mmol, 1 eq) in DCM (120 mL). The mixture was stirred at 25°C for 1 hr under N2. The reaction mixture was diluted with petroleum ether (100 mL), filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound 4-(4-nitrophenoxy)carbonyloxydecanoate benzyl ester (10 g, 22.55 mmol, 52.31% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.30-8.25 (m,2 H) 7.37-7.27 (m, 7 H) 5.14 (s, 2 H) 4.91-4.85 (m, 1 H) 2.53-2.50 (t, J=7.6Hz, 2 H) 2.16-2.07 (m, 1 H) 2.05-1.97 (m, 1 H) 1.77-1.72 (m, 1 H) 1.67-1.60 (m, 1 H) 1.43-1.30 (m, 8 H) 0.91-0.88 (t, J=6.0 Hz, 3 H). Step 4:

[0246] Add 2-pyrrolidone-1-ylethylamine (7.72 g, 67.65 mmol, 1 eq), DMAP (550.94 mg, 4.51 mmol, 0.2 eq), and DIPEA (8.74 g, 67.65 mmol, 11.78 mL, 3 eq) to a solution of 4-(4-nitrophenoxy)carbonyloxydecanoate benzyl ester (10 g, 22.55 mmol, 1 eq) in DCM (100 mL). Stir the mixture at 25°C for 12 hr under N2. Dilute the reaction mixture with H2O (100 mL) and mix with DCM (200 mL) (100 mL) 2) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1). The compound 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid benzyl ester (7 g, 16.72 mmol, 74.17% yield) was given as a colorless oil. Step 5:

[0247] Benzyl 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoate (7 g, 16.72 mmol, 1 eq) was added to a suspension of Pd / C (2 g, 1.88 mmol, 10% purity, 0.112 eq) in THF (140 mL). The mixture was stirred at 25°C for 12 hr under H2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 50 / 1 to 3 / 1). The compound 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (3 g, 9.13 mmol, 54.62% yield) was given as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 10.23 (s, 1 H) 6.27 (s, 1 H) 4.77-4.71 (m, 1 H) 3.68-3.60 (m, 1 H) 3.19-3.14 (m, 1 H) 3.08-2.95 (m, 5 H) 2.82-2.77 (m, 1 H) 2.37-2.21 (m, 2 H) 2.06-2.00 (m, 1 H) 1.96 (s, 4 H) 1.84-1.74 (m, 1 H) 1.64-1.58 (m, 1H) 1.52-1.45 (m, 1 H) 1.30-1.26 (m, 8H) 0.88-0.85 (t, J = 6.8 Hz, 3 H). Step 6:

[0248] The mixture of [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (8 g, 45.40 mmol, 0.45 eq), (Z)-octadec-9-enoic acid (28.50 g, 100.89 mmol, 28.50 mL, 1 eq), EDCI (23.21 g, 121.07 mmol, 1.2 eq), DIPEA (32.60 g, 252.22 mmol, 43.93 mL, 2.5 eq), and DMAP (1.23 g, 10.09 mmol, 0.1 eq) in DCM (285 mL) was degassed and purged three times with N2. The mixture was then stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with water (200 mL) and mixed with DCM (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound (Z)-octadec-9-enoic acid [2,2-dimethyl-5-[[(Z)-octadec-9-enoyl]oxymethyl]-1,3-dioxane-5-yl]methyl ester (20 g, 28.36 mmol, 56.23% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.37- 5.34 (m, 4 H) 4.11 (s, 4 H) 3.75 (s, 4 H) 2.34 - 2.30 (t, J=7.6 Hz, 4 H)2.05 - 1.99 (m, 8 H) 1.63 - 1.60 (m, 4 H) 1.43 (s, 6 H) 1.31 - 1.27 (m, 40 H) 0.91 - 0.87 (t, J=6.8 Hz, 6 H). Step 7:

[0249] At 0°C, HCl (3 M, 10.40 mL, 1.1 eq) was slowly added to a solution of (Z)-octadec-9-enoic acid [2,2-dimethyl-5-[[(Z)-octadec-9-enoyl]oxymethyl]-1,3-dioxane-5-yl]methyl ester (20 g, 28.36 mmol, 1 eq) in THF (200 mL). The mixture was then stirred at 20°C for 12 hr under a N2 atmosphere. The reaction mixture was adjusted to pH = 7 at 0°C with saturated Na2CO3 and then subjected to ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). The compound [2,2-bis(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxy-propyl](Z)-octadec-9-enolate (10 g, 15.04 mmol, 53.01% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.38 - 5.34 (m, 4 H) 4.15 (s, 4H) 3.58 (s, 4 H) 2.73 (s, 2 H) 2.38 - 2.34 (t, J=7.2 Hz, 4 H) 2.07 - 2.00 (m,8 H) 1.65 - 1.60 (m, 4H) 1.31 - 1.25 (m, 40H) 0.91 - 0.87 (t, J=6.8 Hz, 6H). Step 8:

[0250] Oleic acid (1.70 g, 6.01 mmol, 1 eq) was slowly added to a solution of [2,2-bis(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxypropyl](Z)-octadec-9-enoate (4 g, 6.01 mmol, 1 eq), EDCI (1.38 g, 7.22 mmol, 1.2 eq), DMAP (73.48 mg, 601.47 μmol, 0.1 eq), and DIPEA (1.94 g, 15.04 mmol, 2.62 mL, 2.5 eq) in DCM (40 mL). The reaction mixture was stirred at 20°C for 12 hr under a N2 atmosphere. The reaction mixture was diluted with water (100 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound [2-(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxy-2-[[(Z)-octadec-9-enoyl]oxymethyl]propyl](Z)-octadec-9-enolate (1.5 g, 1.61 mmol, 26.83% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δppm 5.40 - 5.31 (m, 6 H) 4.12 (s, 6 H) 3.50 - 3.49 (d, J=6.8 Hz, 2 H) 2.53 -2.49 (t, J=7.2 Hz, 1 H) 2.35 - 2.31 (t, J=7.2 Hz, 6 H) 2.07 - 2.00 (m, 12 H)1.64 - 1.58 (m, 6 H) 1.31 - 1.28 (m, 60 H) 0.90 -0.87 (t, J=6.8 Hz, 9 H). Step 9:

[0251] [2-(hydroxymethyl)-3-[(Z)-octadecyl-9-enoyl]oxy-2-[[(Z)-octadecyl-9-enoyl]oxymethyl]propyl](Z)-octadecyl-9-enoate (1.5 g, 1.61 mmol, 1 eq) was slowly added to a mixture of 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (477.04 mg, 1.45 mmol, 0.9 eq), EDCI (371.24 mg, 1.94 mmol, 1.2 eq), DMAP (19.72 mg, 161.38 μmol, 0.1 eq), and DIPEA (521.43 mg, 4.03 mmol, 702.74 μL, 2.5 eq) in a DCM (15 mL) solution. The mixture was stirred at 25°C for 12 hr under a N2 atmosphere. Dilute the reaction mixture with water (50 mL) and mix with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). The compound [2,2-bis[[(Z)-octadecano-9-enoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl](Z)-octadecano-9-enolate (104 mg, 83.88 μmol, 5.20% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm5.80 (s, 1 H) 5.39 - 5.32 (m, 6 H) 4.75 - 4.71 (m, 1 H) 4.17 - 4.08 (m, 8 H)3.52 - 3.50 (m, 2 H) 3.20 - 2.94 (m, 4 H) 2.39 - 2.35 (m, 2 H) 2.33 -2.29 (t,J=7.6 Hz, 6 H) 2.02 - 1.99 (m, 14 H) 1.94 - 1.86 (m, 2 H) 1.83 - 1.75 (m, 2H) 1.61 - 1.58 (m, 8 H) 1.49-1.42 (m, 2 H) 1.30 - 1.27 (m, 68 H) 0.90 -0.87 (m, 12 H). Example 9 - Compound 2: 2-((((9Z,12Z)-octadecano-9,12-dienoyl)oxy)methyl)-2-(((4-(((2-(pyrrolidone-1-yl)ethyl)carbamoyl)oxy)decanoyl)oxy)methyl)propane-1,3-diyl(9Z,9'Z,12Z,12'Z)-bis(octadecano-9,12-dienoate) Step 1:

[0252] In a 1000 mL single-necked round-bottom flask under N2, 2,2-bis(hydroxymethyl)propane-1,3-diol (50 g, 367.25 mmol, 1 eq) was dissolved in DMF (500 mL). The mixture was stirred at 90°C under N2 for 1 h. Then, under N2 at 70°C, 2,2-dimethoxypropane (38.25 g, 367.25 mmol, 45.00 mL, 1 eq) and 4-methylbenzenesulfonic acid hydrate (698.58 mg, 3.67 mmol, 0.01 eq) were added to the above reaction mixture. The mixture was stirred at 25°C under N2 for 12 hr. The reaction mixture was quenched by using TEA (10 mL) and stirred at 25°C under N2 for 1 hr. The mixture was then concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (28 g, 158.90 mmol, 43.27% yield) was given as a white solid. Step 2:

[0253] Add EDCI (11.05 g, 57.65 mmol, 1.2 eq), DMAP (586.93 mg, 4.80 mmol, 0.1 eq), and DIPEA (15.52 g, 120.11 mmol, 20.92 mL, 2.5 eq) to a mixture of [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (8.47 g, 48.04 mmol, 1 eq) and (9Z, 12Z)-octadec-9,12-dienoic acid (28.29 g, 100.89 mmol, 28.29 mL, 2.1 eq) in DCM (280 mL). Stir the mixture at 25°C for 12 hr under a nitrogen atmosphere. Dilute the reaction mixture with H2O (500 mL) and ethyl acetate (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound (9Z, 12Z)-octadec-9,12-dienoic acid [2,2-dimethyl-5-[[(9Z, 12Z)-octadec-9,12-dienoyl]oxymethyl]-1,3-dioxane-5-yl]methyl ester (15 g, 21.40 mmol, 44.54% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 11.79 – 11.42 (m, 1H), 5.40 – 5.36 (m, 4H), 2.80 – 2.77 (t, J = 6.32 Hz, 2H), 2.38 – 2.40 (t, J = 7.52 Hz, 2H), 2.08 –2.04 (q, J = 6.6 Hz, 4H), 1.66- 1.61 (m, 2H), 1.37 – 1.31 (m, 14H), 0.92 –0.88 (t, J = 6.72 Hz, 3H). Step 3:

[0254] Add HCl (3 M, 7.85 mL, 1.1 eq) to a solution of (9Z, 12Z)-octadecano-9,12-dienoic acid [2,2-dimethyl-5-[[(9Z, 12Z)-octadecano-9,12-dienoyl]oxymethyl]-1,3-dioxane-5-yl]methyl ester (15 g, 21.40 mmol, 1 eq) in THF (150 mL). Stir the mixture at 25°C for 7 hr. Dilute the reaction mixture with H2O (200 mL) and ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound [2,2-bis(hydroxymethyl)-3-[(9Z, 12Z)-octadec-9,12-dienoyl]oxy-propyl](9Z, 12Z)-octadec-9,12-dienoic acid ester (8 g, 12.10 mmol, 56.57% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.33 - 5.26 (m,8 H) 4.07 (s, 4 H) 3.50 (s, 4 H) 2.72 - 2.69 (t, J=6.8 Hz, 4 H) 2.30 - 2.26(t, J=7.2 Hz, 4 H) 2.01 - 1.96 (m, 8 H) 1.58 - 1.54 (t, J=7.2 Hz, 4 H) 1.32 -1.19 (m, 30 H) 0.84 - 0.80 (t, J=6.8 Hz, 6 H). Step 4:

[0255] To a mixture of (9Z,12Z)-octadec-9,12-dienoic acid (424.27 mg, 1.51 mmol, 424.27 μL, 0.5 eq) and [2,2-bis(hydroxymethyl)-3-[(9Z,12Z)-octadec-9,12-dienoyl]oxy-propyl](9Z,12Z)-octadec-9,12-dienoic acid ester (2 g, 3.03 mmol, 1 eq) in DCM (204 mL), DIPEA (977.63 mg, 7.56 mmol, 1.32 mL, 2.5 eq), EDCI (696.04 mg, 3.63 mmol, 1.2 eq), and DMAP (36.96 mg, 302.57 μmol, 0.1 eq) were added. The mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (20 mL) and ethyl acetate (60 mL) (20 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound [2-(hydroxymethyl)-3-[(9Z, 12Z)-octadec-9,12-dienoyl]oxy-2-[[(9Z, 12Z)-octadec-9,12-dienoyl]oxymethyl]propyl](9Z, 12Z)-octadec-9,12-dienoic acid ester (700 mg, 758.04 μmol, 25.05% yield) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 5.40 - 5.30 (m, 12 H) 4.12 (s, 6 H) 3.50 - 3.49 (d, J=6.8Hz, 2 H) 2.79 - 2.76 (t, J=6.4 Hz, 6 H) 2.54 - 2.50 (t, J=7.2 Hz, 1 H) 2.35 -2.31 (t, J=7.6 Hz, 6 H) 2.08 - 2.03 (m, 12 H) 1.64 - 1.60 (m, 6 H) 1.38 -1.28 (m, 42 H) 0.91- 0.88 (t, J=6.8 Hz, 9 H). Step 5:

[0256] Add DMAP (27.78 mg, 227.41 μmol, 0.3 eq), DIPEA (244.93 mg, 1.90 mmol, 330.09 μL, 2.5 eq), and EDCI (174.38 mg, 909.65 μmol, 1.2 eq) to a mixture of [2-(hydroxymethyl)-3-[(9Z, 12Z)-octadecano-9, 12-dienoic acid]oxy-2-[[(9Z, 12Z)-octadecano-9, 12-dienoic acid]oxymethyl]propyl](9Z, 12Z)-octadecano-9, 12-dienoic acid ester (700 mg, 758.04 μmol, 1 eq) and 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (497.95 mg, 1.52 mmol, 2 eq) in DCM (7 mL) to a mixture of [2-(hydroxymethyl)-3-[(9Z, 12Z)-octadecano-9, 12-dienoic acid]oxy-2-[[(9Z, 12Z)-octadecano-9, 12-dienoic acid]oxymethyl]propyl](9Z, 12Z)-octadecano-9, 12-dienoic acid ester (700 mg, 758.04 μmol, 1 eq) and 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (497.95 mg, 1.52 mmol, 2 eq) in DCM (7 mL). The mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O (30 mL) and diluted with ethyl acetate (30 mL) (10 mL). 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound [2,2-bis[[(9Z, 12Z)-octadecano-9,12-dienoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl](9Z, 12Z)-octadecano-9,12-dienoic acid ester (110 mg, 88.24 μmol, 11.64% yield, 98.98% purity) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.61 (s, 1 H)5.42 - 5.30 (m, 12 H) 4.75 (s, 1 H) 4.17 - 4.09 (m, 8 H) 3.46 (s, 2 H) 2.94 -2.85 (m, 2 H) 2.79 - 2.76 (t, J=6.8 Hz, 6 H) 2.39 - 2.35 (m, 2 H) 2.33 - 2.29 (t, J=7.6 Hz, 6 H) 2.08 - 2.03 (m, 12 H) 1.96 - 1.89 (m, 4 H) 1.87 - 1.74 (m, 2 H) 1.62 - 1.59 (m, 8 H) 1.49 - 1.27 (m, 54 H) 0.94 - 0.86 (m, 12 H). Example 10 - Compound 3: [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[(Z)-octadecano-9-enoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl](Z-octadecano-9-enolate Step 1:

[0257] To a mixture of [2,2-bis(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxypropyl](Z)-octadec-9-enolate (3 g, 4.51 mmol, 1 eq), EDCI (1.04 g, 5.41 mmol, 1.2 eq), DIPEA (1.46 g, 11.28 mmol, 1.96 mL, 2.5 eq), and DMAP (55.11 mg, 451.10 μmol, 0.1 eq) in DCM (30 mL), 2-(1-adamantyl)acetic acid (525.81 mg, 2.71 mmol, 0.6 eq) in DCM (30 mL) was slowly added. The reaction mixture was stirred at 20°C under N2 for 12 hr. The reaction mixture was diluted with water (50 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxypropyl](Z)-octadec-9-enolate (1.5 g, 1.78 mmol, 39.52% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.40 - 5.31 (m, 4 H) 4.12 - 4.09 (m, 6 H) 3.52 - 3.50 (d, J=6.8Hz, 2 H) 2.54 - 2.50 (t, J=7.2 Hz, 1 H) 2.35 - 2.31 (t, J=7.6 Hz, 4 H) 2.10 (s, 2 H) 2.04 - 1.98 (m, 9 H) 1.73 - 1.57 (m, 16 H) 1.31 - 1.28 (m, 42 H)0.91 - 0.87 (t, J=6.8 Hz, 6 H). Step 2:

[0258] Add EDCI (273.44 mg, 1.43 mmol, 1.2 eq), DMAP (43.56 mg, 356.60 μmol, 0.3 eq), and DIPEA (384.06 mg, 2.97 mmol, 517.60 μL, 2.5 eq) to a mixture of [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[(Z)-octadecano-9-enoyl]oxy-propyl](Z)-octadecano-9-enoic acid ester (1 g, 1.19 mmol, 1 eq) and 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (351.37 mg, 1.07 mmol, 0.9 eq) in DCM (10 mL) to a mixture of [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[(Z)-octadecano-9-enoyl]oxy-propyl](Z)-octadecano-9-enoic acid ester (1 g, 1.19 mmol, 1 eq) and 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (351.37 mg, 1.07 mmol, 0.9 eq) in DCM (10 mL). Stir the reaction mixture at 20°C for 12 hr under N2 atmosphere. Dilute the reaction mixture with water (50 mL) and mix with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). The compound [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[(Z)-octadecano-9-enoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl](Z)-octadecano-9-enolate (105 mg, 91.17 μmol, 7.67% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.39 - 5.31 (m, 4 H) 4.75 (s, 1 H) 4.16 - 4.09 (m, 8 H) 3.39 (s, 2 H) 2.86 - 2.63 (m, 4 H) 2.40 - 2.35 (m, 2 H) 2.33 -2.29 (t, J=7.6 Hz, 4 H)2.08 (s, 2 H) 2.02 - 1.97 (m, 10 H) 1.89 (s, 4 H) 1.82 - 1.77 (m, 2 H) 1.72 -1.69 (m, 4 H) 1.63 - 1.58 (m, 14H) 1.49 - 1.42 (m, 2 H) 1.30-1.27 (m, 50 H) 0.90 - 0.87 (m, 9 H). Example 11 - Compound 4: [2-(4,4-dioctyloxybutyryloxymethyl)-2-[[(Z)-octadecano-9-enoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl](Z-octadecano-9-enolate Step 1:

[0259] A mixture of 4,4-dimethoxybutyronitrile (30 g, 232.28 mmol, 1 eq), octyl-1-ol (90.75 g, 696.83 mmol, 110.13 mL, 3 eq), and PPTS (145.93 g, 580.69 mmol, 2.5 eq) in toluene (300 mL) was degassed and purged three times with N2. The mixture was then stirred at 110°C for 36 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 50 / 1). The compound 4,4-dioctyloxybutyronitrile (40 g, 122.88 mmol, 52.90% yield) was given as a colorless oil. Step 2:

[0260] NaOH (24.57 g, 614.39 mmol, 5 eq) was slowly added to a solution of 4,4-dioctyloxybutyronitrile (40 g, 122.88 mmol, 1 eq) in EtOH (100 mL) and H2O (100 mL). The reaction mixture was stirred at 110°C for 12 hr under a N2 atmosphere. The reaction mixture was adjusted to pH 5 using 1 M HCl and then mixed with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1). The compound 4,4-dioctyloxybutyric acid (30 g, 87.08 mmol, 70.86% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm4.54 - 4.51 (t, J=5.6 Hz, 1 H) 3.60 - 3.56 (m, 2 H) 3.45 - 3.40 (m, 2 H) 2.47- 2.44 (t, J=7.6 Hz, 2 H) 1.97 - 1.92 (m, 2 H) 1.58 - 1.55 (m, 4 H) 1.32 -1.28 (m, 20 H) 0.90 - 0.87 (t, J=6.8 Hz, 6 H). Step 3:

[0261] To a solution of [2,2-bis(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxypropyl](Z)-octadec-9-enoate (3 g, 4.51 mmol, 1 eq), EDCI (1.04 g, 5.41 mmol, 1.2 eq), DMAP (55.11 mg, 451.10 μmol, 0.1 eq), and DIPEA (1.46 g, 11.28 mmol, 1.96 mL, 2.5 eq) in DCM (30 mL), 4,4-dioctyloxybutyric acid (1.55 g, 4.51 mmol, 1 eq) was slowly added to the solution in DCM (30 mL). The reaction mixture was stirred at 20°C for 12 hours under a N2 atmosphere. The reaction mixture was diluted with water (50 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound [2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxy-propyl](Z)-octadec-9-enolate (1.5 g, 1.51 mmol, 33.54% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δppm 5.39 - 5.30 (m, 4 H) 4.50 - 4.47 (t, J=5.6 Hz, 1 H) 4.11 (s, 6 H)3.59 -3.50 (m, 4 H) 3.43 -3.38 (m, 2 H) 2.61 - 2.57 (t, J=6.8 Hz, 1 H) 2.44 - 2.40 (t, J=7.6 Hz, 2 H) 2.34 - 2.31 (t, J=7.6 Hz, 4 H) 2.02 - 1.91 (m, 10 H) 1.63- 1.54 (m, 8 H) 1.31 - 1.28 (m, 60 H) 0.90 - 0.87 (t, J=6.8 Hz, 12 H). Step 4:

[0262] The mixture of [2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[(Z)-octadec-9-enoyl]oxy-propyl](Z)-octadec-9-enolate (1.5 g, 1.51 mmol, 1 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (447.18 mg, 1.36 mmol, 0.9 eq), EDCI (348.00 mg, 1.82 mmol, 1.2 eq), DMAP (55.44 mg, 453.84 μmol, 0.3 eq) and DIPEA (488.79 mg, 3.78 mmol, 658.75 μL, 2.5 eq) in DCM (20 mL) was degassed and purged three times with N2. The mixture was then stirred at 20°C for 12 hours under N2 atmosphere. Dilute the reaction mixture with water (50 ml) and mix with DCM (150 mL) (50 ml) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). The compound [2-(4,4-dioctyloxybutyryloxymethyl)-2-[[(Z)-octadecano-9-enoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl](Z)-octadecano-9-enolate (110 mg, 84.49 μmol, 5.58% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.40 - 5.31 (m, 4 H) 4.76 (s, 1 H) 4.49 - 4.47 (t, J=5.2 Hz, 1 H) 4.15 - 4.11 (m, 8 H) 3.59 - 3.53 (m, 2 H) 3.43 - 3.38 (m, 4 H)2.69 (s, 4 H) 2.44 - 2.26 (m, 8 H) 2.02 - 1.99 (m, 8 H) 1.94 - 1.73 (m, 8 H)1.68 - 1.05 (m, 84 H) 0.90 - 0.87 (t, J=6.8 Hz, 15H) Example 12 - Compound 5: [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[(9Z, 12Z)-octadecano-9,12-dienoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl](9Z,12Z)-octadecano-9,12-dienoic acid ester Step 1:

[0263] The mixture of [2,2-bis(hydroxymethyl)-3-[(9Z, 12Z)-octadec-9,12-dienoyl]oxy-propyl](9Z,12Z)-octadec-9,12-dienoate (3 g, 4.54 mmol, 1 eq), 2-(1-adamantyl)acetic acid (529.02 mg, 2.72 mmol, 0.6 eq), DMAP (55.45 mg, 453.86 μmol, 0.1 eq), EDCI (1.04 g, 5.45 mmol, 1.2 eq), and DIPEA (1.47 g, 11.35 mmol, 1.98 mL, 2.5 eq) in DCM (30 mL) was degassed and purged three times with N2. The mixture was then stirred at 25°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (100 mL) and ethyl acetate (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[(9Z,12Z)-octadec-9,12-dienoyl]oxypropyl](9Z,12Z)-octadec-9,12-dienoic acid ester (800 mg, 955.50 μmol, 21.05% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J = 5.4Hz, 1H), 3.97 - 3.87 (m, 1H), 3.81 - 3.68 (m, 4H), 3.48 (s, 3H), 2.87 - 2.69(m, 6H), 2.40 – 2.37 (t, J = 6.6 Hz, 2H), 1.99 - 1.94 (m, 2H), 1.20 - 1.17 (t, J = 7.2 Hz, 6H). Step 2:

[0264] [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[(9Z, 12Z)-octadec-9,12-dienoyl]oxy-propyl](9Z,12Z)-octadec-9,12-dienoic acid ester (800 mg, 955.50 μmol, 1 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (627.66 mg, 1.91 mmol, 2 eq), DMAP (35.02 mg, 286.65 μmol, 0.3 eq), DIPEA (308.73 mg, 2.39 mmol, 416.08 μL, 2.5 eq), and EDCI (219.81 mg, 1.15 mmol, 1.2 eq) were administered in DCM (8 The mixture in 30 mL was degassed and purged three times with N2, then stirred at 25°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and purged with ethyl acetate (90 mL). 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound [2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[(9Z, 12Z)-octadecano-9,12-dienoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl](9Z,12Z)-octadecano-9,12-dienoic acid ester (140 mg, 121.98 μmol, 12.77% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.54 - 5.24 (m, 8H), 5.18 (d, J = 1.0 Hz, 1H), 4.75 (s, 1H), 4.16 - 4.03 (m, 8H), 3.39 - 3.21 (m, 2H), 2.79 – 2.76 (t, J = 6.4 Hz, 4H),2.69 - 2.44 (m, 6H), 2.40 - 2.28 (m, 6H), 2.10 - 2.01 (m, 10H), 2.00 (m, 1H),1.97 (s, 2H), 1.79 (s, 5H), 1.72 (s, 1H), 1.69 (s, 2H), 1.65 - 1.54 (m, 14H), 1.42 - 1.21 (m, 38H), 0.91 - 0.87 (q, J = 6.6 Hz, 9H). Example 13 - Compound 6: [2-(4,4-dioctyloxybutyryloxymethyl)-2-[[(9Z, 12Z)-octadecano-9,12-dienoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl](9Z, 12Z)-octadecano-9,12-dienoic acid ester Step 1:

[0265] The mixture of [2,2-bis(hydroxymethyl)-3-[(9Z, 12Z)-octadec-9,12-dienoyl]oxy-propyl](9Z,12Z)-octadec-9,12-dienoate (3 g, 4.54 mmol, 1 eq), 4,4-dioctyloxybutyric acid (938.19 mg, 2.72 mmol, 0.6 eq), EDCI (1.04 g, 5.45 mmol, 1.2 eq), DMAP (55.45 mg, 453.86 μmol, 0.1 eq) and DIPEA (1.47 g, 11.35 mmol, 1.98 mL, 2.5 eq) in DCM (60 mL) was degassed and purged three times with N2. The mixture was then stirred at 25°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (300 mL) and ethyl acetate (900 mL) (300 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound [2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[(9Z, 12Z)-octadec-9,12-dienoyl]oxy-propyl](9Z, 12Z)-octadec-9,12-dienoic acid ester (900 mg, 911.38 μmol, 20.08% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.41-5.32 (m, 8H), 4.50-4.47 (t, J = 5.2 Hz, 1H), 4.12 (s, 6H), 3.58-3.50 (m, 4H), 3.44-3.38 (m, 2H), 2.80-2.76 (t, J = 6.4 Hz, 4H), 2.60-2.56 (t, J = 6.8 Hz, 1H), 2.44-2.40(t, J = 7.2 Hz, 2H), 2.35-2.31 (t, J = 7.6 Hz, 4H), 2.08-2.03 (q, J = 6.8 Hz, J = 13.6 Hz, 8H), 1.96-1.91 (q, J = 7.6 Hz, J = 13.2 Hz, 2H), 1.64-1.55(m,8H), 1.40-1.28 (m, 48H), 0.92-0.87 (m, 12H) Step 2:

[0266] [2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[(9Z,12Z)-octadec-9,12-dienoyl]oxy-propyl](9Z,2Z)-octadec-9,12-dienoic acid ester (900 mg, 911.38 μmol, 1 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (598.68 mg, 1.82 mmol, 2 eq), EDCI (209.66 mg, 1.09 mmol, 1.2 eq), DIPEA (294.47 mg, 2.28 mmol, 396.86 μL, 2.5 eq) and DMAP (22.27 mg, 182.28 μmol, 0.2 eq) were administered in DCM (9 The mixture in 30 mL was degassed and purged three times with N2, then stirred at 25°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and purged with ethyl acetate (90 mL). 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound [2-(4,4-dioctyloxybutyryloxymethyl)-2-[[(9Z, 12Z)-octadecano-9,12-dienoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl](9Z, 12Z)-octadecano-9,12-dienoic acid ester (140 mg, 103.69 μmol, 11.38% yield, 96.13% purity). 1H NMR (400 MHz, chloroform-d) δppm 5.42-5.30(m, 8H), 5.18(s, 1H), 4.75(s, 1H), 4.49-4.47(t, J = 5.2 Hz, 1H), 4.12-4.11(d, J = 3.2 Hz, 8H), 3.59-3.53(m, 2H), 3.43-3.38(m, 2H), 3.302-3.289(d, J = 5.2 Hz, 2H), 2.79-2.76(t, J = 6.8 Hz, 4H), 2.62-2.59(t, J = 5.6 Hz, 2H), 2.53(s, 4H), 2.42-2.35(m, 4H), 2.32-2.29(t, J = 7.6 Hz, 4H), 2.08-2.03(q, J = 6.4 Hz, J = 13.2 Hz, 8H), 1.94-1.89(q, J = 6.4 Hz, J = 13.2 Hz, 3H),1.78(s, 3H), 1.62-1.53(m, 10H), 1.40-1.28(m, 58H), 0.91-0.87(m, 15H). Example 14 - Compound 7: O7-[2,2-bis[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptanoic acid ester Step 1:

[0267] The mixture of (Z)-non-3-en-1-ol (50 g, 351.52 mmol, 1 eq), pimelic acid (281.51 g, 1.76 mol, 5 eq), EDCI (80.87 g, 421.83 mmol, 1.2 eq), DMAP (4.29 g, 35.15 mmol, 0.1 eq), and DIPEA (113.58 g, 878.81 mmol, 153.07 mL, 2.5 eq) in DCM (500 mL) was degassed and purged three times with N2. The mixture was then stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with water (500 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound 7-[(Z)-non-3-enoxy]-7-oxo-heptanoic acid (140 g, 492.28 mmol, 35.01% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 11.63-10.83(m, 1H), 5.52-5.49(m,1H), 5.35-5.30(m, 1H), 4.09-4.05(t, J = 6.8 Hz, 2H), 2.04-2.29(m, 6H), 2.07-2.01(m, 2H), 1.70-1.62(m, 4H), 1.43-1.28(m, 8H), 0.91-0.87(t, J = 6.8 Hz, 3H) Step 2:

[0268] The mixture of 7-[(Z)-non-3-enoxy]-7-oxo-heptanoic acid (28.69 g, 100.89 mmol, 1 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (8 g, 45.40 mmol, 0.45 eq), EDCI (23.21 g, 121.07 mmol, 1.2 eq), DIPEA (32.60 g, 252.22 mmol, 43.93 mL, 2.5 eq), and DMAP (2.47 g, 20.18 mmol, 0.2 eq) in DCM (300 mL) was degassed and purged three times with N2. The mixture was then stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with water (200 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound O7-[[2,2-dimethyl-5-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]pimercate (70 g, 98.74 mmol, 65.24% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.54-5.49(m, 2H), 5.35-5.32(m, 2H), 4.10(s,4H), 4.08-4.05(t, J = 6.8 Hz, 4H), 3.75(s, 4H), 2.40-2.28(m, 12H), 2.06-2.01(q, J = 6.8 Hz, J = 13.6 Hz, 4H), 1.66-1.62(m, 8H), 1.42(s, 6H), 1.37-1.26(m,16H), 0.91-0.87(t, J = 6.4 Hz, 6H) Step 3:

[0269] To a solution of O7-[[2,2-dimethyl-5-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]peptidate (30 g, 42.32 mmol, 1 eq) in THF (300 mL), HCl (3 M, 15.52 mL, 1.1 eq) was slowly added, and the mixture was stirred at 20°C for 12 hr under a N2 atmosphere. Saturated Na2CO3 (300 mL) was added to the reaction mixture and ethyl acetate (600 mL) (200 mL) was added. 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). The compound O7-[2,2-bis(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]pimercate (20 g, 29.90 mmol, 35.33% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δppm 5.52-5.47(m, 2H), 5.36-5.30(m, 2H), 4.14(s, 4H), 4.08-4.04(t, J = 7.2Hz), 3.58(s, 4H), 2.84(s, 2H), 2.40-2.29(m, 12H), 2.06-2.00(q, J = 6.4 Hz, J= 14 Hz, 4H), 1.69-1.60(m, 8H), 1.38-1.28(m, 16H), 0.91-0.87(t, J = 6.8 Hz, 6H) Step 4:

[0270] Add 7-[(Z)-non-3-enoxy]-7-oxo-heptanoic acid (5.10 g, 17.94 mmol, 0.6 eq) in DCM (50 mL) to a mixture of O7-[2,2-bis(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]heptanedioic acid (20 g, 29.90 mmol, 1 eq), EDCI (6.88 g, 35.88 mmol, 1.2 eq), DIPEA (9.66 g, 74.75 mmol, 13.02 mL, 2.5 eq), and DMAP (365.28 mg, 2.99 mmol, 0.1 eq) in DCM (150 mL). Stir the mixture at 20°C for 12 hr under N2 atmosphere. Dilute the reaction mixture with water (200 mL) and mix with DCM (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). The compound O7-[2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]pimercate (8 g, 8.55 mmol, 28.61% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δppm 5.54-5.49(m, 3H), 5.35-5.30(m, 3H), 4.11(s, 6H), 4.08-4.05(t, J = 7.2 Hz,6H), 3.52-3.50(d, J = 6 Hz, 2H), 2.67-2.64(t, J = 13.6 Hz, 1H), 2.40-2.29(m,18H), 2.06-2.01(q, J = 6.4 Hz, 13.6 Hz, 6H), 1.68-1.60(m, 12H), 1.39-1.27(m,24H), 0.91-0.87(t, J = 6.8 Hz, 9H) Step 5:

[0271] O7-[2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]pimercinate (8 g, 8.55 mmol, 1 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (3.37 g, 10.26 mmol, 1.2 eq), EDCI (1.97 g, 10.26 mmol, 1.2 eq), DIPEA (2.76 g, 21.38 mmol, 3.72 mL, 2.5 eq) and DMAP (104.50 mg, 855.37 μmol, 0.1 eq) were prepared in DCM (80 The mixture in the solution was degassed and purged three times with N2, then stirred at 20°C for 12 hours under N2 atmosphere. The reaction mixture was diluted with water (200 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). The compound O7-[2,2-bis[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptanedioate (3.4 g, 2.73 mmol, 31.91% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.54-5.47(m, 3H), 5.35-5.30(m, 3H), 5.18(s, 1H), 4.75(s, 1H), 4.10(s, 8H), 4.08-4.04(t, J = 7.2 Hz, 6H), 3.29-3.28(d, J = 5.2 Hz, 2H), 2.61-2.58(t, J = 5.6 Hz, 2H), 2.52(s, 4H), 2.40-2.28(m, 22H), 2.06-2.01(q, J = 6.4 Hz, J = 13.6 Hz, 6H), 1.90-1.87(m,1H), 1.77(s, 3H), 1.67-1.59(m, 14H), 1.37-1.27(m, 32H), 0.91-0.86(m, 12H) Example 15 - Compound 8: O7-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptanoate Step 1:

[0272] Add EDCI (515.87 mg, 2.69 mmol, 1.2 eq), DIPEA (724.57 mg, 5.61 mmol, 976.51 μL, 2.5 eq), and DMAP (54.79 mg, 448.50 μmol, 0.2 eq) to a solution of O7-[2,2-bis(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]p-heptaester (1.5 g, 2.24 mmol, 1 eq) in DCM (15 mL). Then add dropwise a solution of 2-(1-adamantyl)acetic acid (392.08 mg, 2.02 mmol, 0.9 eq) in DCM (15 mL) to the above reaction mixture. Stir the mixture at 20°C under N2 for 12 hr. The reaction mixture was diluted with H2O (30 mL) and ethyl acetate (90 mL) (30 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1). The compound O7-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxoheptanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]pimercate (0.7 g, 828.26 μmol, 36.93% yield) was obtained as a colorless oil. 1 H NMR(400 MHz, CDCl3) δ ppm 5.54-5.48(m, 2H), 5.37-5.31(m, 2H), 4.12(s, 4H), 4.09-4.05(t, J = 6.4 Hz, 6H), 3.53-3.52(d, J = 4 Hz, 2H), 2.61(s, 1H), 2.40-2.29(m, 12H), 2.10(s, 2H), 2.07-2.02(q, J = 6.8 Hz, J = 14 Hz, 4H), 1.98(s, 3H),1.73-1.60(m, 20H), 1.40-1.27(m, 16H), 0.91–0.88 (t, J = 6.4 Hz, 6H) Step 2:

[0273] Add EDCI (190.53 mg, 993.91 μmol, 1.2 eq), DIPEA (267.62 mg, 2.07 mmol, 360.67 μL, 2.5 eq), and DMAP (20.24 mg, 165.65 μmol, 0.2 eq) to a solution of 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (272.04 mg, 828.26 μmol, 1 eq) in DCM (7 mL) to the above reaction mixture. Then add O7-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]pimecrocidol ester (0.7 g, 828.26 μmol, 1 eq) to the above reaction mixture. The mixture was stirred at 20°C under N2 for 12 hours. The reaction mixture was diluted with H2O (30 mL) and ethyl acetate (90 mL). 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1). The compound O7-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]pimercinate (0.15 g, 129.80 μmol, 15.67% yield). 1 H NMR (400MHz, CDCl3) δ ppm 5.54-5.48(m, 2H), 5.37-5.31(m, 2H), 5.28-5.23(m, 1H), 4.75(s, 1H), 4.11(s, 6H), 4.08-4.05(t, J = 6.8 Hz, 6H), 3.309(s, 2H), 2.63-2.56(d, J = 26.8 Hz, 6H), 2.40-2.29(m, 14H), 2.08-2.02(m, 6H), 1.97(s, 3H), 1.90-1.86(m, 1H), 1.80(s, 5H), 1.72-1.58(m, 22H), 1.39-1.27(m, 24H), 0.91-0.86(m,9H). Example 16 - Compound 9: O7-[2-(4,4-dioctyloxybutyryloxymethyl)-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptadiate Step 1:

[0274] The mixture of O7-[2,2-bis(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]pimercate (3.2 g, 4.78 mmol, 1 eq), 4,4-dioctyloxybutyric acid (824.11 mg, 2.39 mmol, 0.5 eq), DMAP (58.45 mg, 478.40 μmol, 0.1 eq), DIPEA (1.55 g, 11.96 mmol, 2.08 mL, 2.5 eq) and EDCI (1.10 g, 5.74 mmol, 1.2 eq) in DCM (32 mL) was degassed and purged three times with N2. The mixture was then stirred at 25°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and ethyl acetate (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound O7-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]pimercate (1.4 g, 1.41 mmol, 29.40% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.54-5.50(m, 2H),5.35-5.33(m, 2H), 4.50-4.47(t, J = 5.2 Hz, 1H), 4.11(s, 6H), 4.09-4.05(t, J =7.2 Hz, 4H), 3.59-3.51(m, 4H), 3.43-3.38(m, 2H), 2.67-2.64(t, J = 6.8 Hz,1H), 2.42-2.29(m, 14H), 2.07-2.02(q, J = 6.8 Hz, J = 14.0 Hz, 4H), 1.96-1.91(q, J = 7.6 Hz, J = 13.2 Hz, 2H), 1.68-1.54(m, 12H), 1.40-1.28(m, 36H), 0.91-0.87(m, 12H) Step 2:

[0275] O7-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptyl]oxy-propyl]O1-[(Z)-non-3-enyl]pimecrocidol (1.4 g, 1.41 mmol, 1 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (461.95 mg, 1.41 mmol, 1 eq), DMAP (17.18 mg, 140.65 μmol, 0.1 eq), EDCI (323.55 mg, 1.69 mmol, 1.2 eq), and DIPEA (454.44 mg, 3.52 mmol, 612.45 μL, 2.5 eq) were administered in DCM (14 The mixture in 50 mL was degassed and purged three times with N2, then stirred at 25°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (50 mL) and ethyl acetate (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1). The compound O7-[2-(4,4-dioctyloxybutyryloxymethyl)-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decyloxy]propyl]O1-[(Z)-non-3-enyl]pimercinate (150 mg, 114.87 μmol, 8.17% yield). 1H NMR (400 MHz, CDCl3) δ ppm 5.52-5.49(m, 2H), 5.35-5.32(m, 2H), 5.19(s, 1H), 4.74(s, 1H), 4.49-4.46(t, J= =5.6Hz, 1H), 4.11-4.10(d, J = 2 Hz, 8H), 4.08-4.04(t, J = 6.8 Hz, 4H), 3.58-3.53(m, 2H), 3.43-3.37(m, 2H), 3.30-3.28(d, J = 5.6 Hz, 2H), 2.61-2.58(t, J = 5.6Hz, 2H), 2.53(s, 4H), 2.41-2.28(m, 16H), 2.06-2.01(q, J = 6.8 Hz, J = 13.6Hz, 4H), 1.93-1.88(q, J = 7.6 Hz, J = 13.2 Hz, 3H), 1.78(s, 5H), 1.67-1.52(m,14H), 1.37-1.28(m, 44H), 0.91-0.86(m, 15H) Example 17 - Compound 10: O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester Step 1:

[0276] The mixture of (Z)-non-3-en-1-ol (40 g, 281.22 mmol, 1 eq), octanoic acid (244.93 g, 1.41 mol, 5 eq), EDCI (70.08 g, 365.58 mmol, 1.3 eq), DIPEA (109.04 g, 843.66 mmol, 146.95 mL, 3 eq), and DMAP (3.44 g, 28.12 mmol, 0.1 eq) in DCM (400 mL) was degassed and purged three times with N2. The mixture was then stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with water (500 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound 8-[(Z)-non-3-enoxy]-8-oxo-octanoic acid (140 g, 469.14 mmol, 33.36% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 11.33(s, 1H), 5.54-5.48(m, 1H), 5.37-5.31(m, 1H), 4.09-4.05(t, J = 6.8 Hz, 2H), 2.40-2.28(m, 6H), 2.07-2.01(q, J = 6.4 Hz, J = 14 Hz, 2H), 1.68-1.60(m, 4H), 1.39-1.27(m, 10H), 0.91-0.88(t, J = 6.8 Hz, 3H) Step 2:

[0277] The mixture of 8-[(Z)-non-3-enoxy]-8-oxo-octanoic acid (30.11 g, 100.89 mmol, 1 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (8 g, 45.40 mmol, 0.45 eq), EDCI (23.21 g, 121.07 mmol, 1.2 eq), DIPEA (32.60 g, 252.22 mmol, 43.93 mL, 2.5 eq), and DMAP (1.23 g, 10.09 mmol, 0.1 eq) in DCM (300 mL) was degassed and purged three times with N2. The mixture was then stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with water (500 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound O8-[[2,2-dimethyl-5-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]octanoic acid ester (70 g, 94.98 mmol, 62.76% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.54-5.47(m, 2H), 5.37-5.30(m, 2H), 4.11(s,4H), 4.08-4.05(t, J = 6.8 Hz, 4H), 3.74(s, 4H), 2.40-2.27(m, 12H), 2.07-2.01(q, J = 7.2 Hz, J = 14Hz, 4H), 1.64-1.59(m, 8H), 1.42(s, 6H), 1.37-1.27(m,20H), 0.91-0.88(t, J = 6.8 Hz, 6H). Step 3:

[0278] The solution of O8-[[2,2-dimethyl-5-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]octanoic acid ester (70 g, 94.98 mmol, 1 eq) and HCl (3 M, 34.83 mL, 1.1 eq) in THF (700 mL) was degassed and purged three times with N2. The mixture was then stirred at 20°C for 7 hr under N2 atmosphere. At 20°C, saturated Na2CO3 (500 mL) was slowly added to the reaction mixture. It was then diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1). The compound O8-[2,2-bis(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (38 g, 54.52 mmol, 57.41% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.53-5.47(m, 2H), 5.37-5.30(m, 2H), 4.14(s,1H), 4.08-4.05(t, J = 7.2 Hz, 4H), 3.58(s, 4H), 2.81(s, 2H), 2.40-2.28(m,12H), 2.06-2.01(q, J = 6.8 Hz, J = 14 Hz, 4H), 1.65-1.60(m, 8H), 1.37-1.27(m,20H), 0.90-0.87(t, J = 6.4 Hz, 6H). Step 4:

[0279] Add 8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid (23 g, 33.00 mmol, 1 eq), EDCI (7.59 g, 39.60 mmol, 1.2 eq), DIPEA (10.66 g, 82.50 mmol, 14.37 mL, 2.5 eq), and DMAP (403.17 mg, 3.30 mmol, 0.1 eq) in a solution of O8-[2,2-bis(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoic acid (5.91 g, 19.80 mmol, 0.6 eq) in DCM (230 mL) to a solution of O8-[2,2-bis(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoic acid (230 mL) in DCM (230 mL) in DCM (230 mL). Stir the mixture at 20°C for 12 hr under a nitrogen atmosphere. Dilute the reaction mixture with water (200 mL) and mix with DCM (800 mL) (400 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 10 / 1). The compound O8-[2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (11 g, 11.25 mmol, 34.10% yield) was obtained as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 5.54-5.48(m, 3H), 5.37-5.31(m, 3H), 4.11(s, 6H), 4.09-4.05(t, J = 6.8 Hz, 6H), 3.51-3.50(d, J = 6.8 Hz, 2H), 2.61-2.57(t, J = 6.8 Hz,1H), 2.40-2.28(m, 18H), 2.07-2.02(q, J = 6.8 Hz, J = 14 Hz, 6H), 1.64-1.61(t,J = 7.2 Hz, 12H), 1.38-1.27(m, 30H), 0.91-0.88 (t, J = 6.4Hz, 9H) Step 5:

[0280] O8-[2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (11 g, 11.25 mmol, 1 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (3.33 g, 10.13 mmol, 0.9 eq), EDCI (2.59 g, 13.51 mmol, 1.2 eq), DIPEA (3.64 g, 28.14 mmol, 4.90 mL, 2.5 eq), and DMAP (137.50 mg, 1.13 mmol, 0.1 eq) were placed in DCM (100 The mixture in the solution was degassed and purged three times with N2, then stirred at 20°C for 12 hours under N2 atmosphere. The reaction mixture was diluted with water (200 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1). The compound O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (3.5 g, 2.72 mmol, 24.15% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.54-5.48(m, 3H),5.37-5.31(m, 3H), 5.17(s, 1H), 4.75(s, 1H), 4.11(s, 8H), 4.08-4.05(t, J = 6.8Hz, 8H), 3.29-3.28(d, J = 4.8 Hz, 2H), 2.60-2.57(t, J = 6.0 Hz, 4H), 2.52(s,4H), 2.40-2.35(q, J = 7.2 Hz, J = 14.0 Hz, 8H), 2.33-2.28(q, J = 7.2 Hz, J =12.4 Hz, 12H), 2.07-2.01(q, J = 6.8 Hz, J = 14.0 Hz, 6H), 1.89(s, 1H), 1.78(s, 3H), 1.67-1.59(m, 14H), 1.39-1.28(m, 40H), 0.91-0.86 (m, 12H). Example 18 - Compound 11: O8-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester Step 1:

[0281] Add DIPEA (463.60 mg, 3.59 mmol, 624.80 μL, 2.5 eq), EDCI (330.07 mg, 1.72 mmol, 1.2 eq), DMAP (17.53 mg, 143.48 μmol, 0.1 eq), and 2-(1-adamantyl)acetic acid (278.74 mg, 1.43 mmol, 1 eq) to a solution of O8-[2,2-bis(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (1 g, 1.43 mmol, 1 eq) in DCM (10 mL). Stir the mixture at 20°C for 12 h under N2. Pour the reaction mixture into H2O (50 mL) and extract with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 5 / 1). The compound O8-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (450 mg) was obtained as a colorless oil. Step 2:

[0282] Add EDCI (171.24 mg, 893.26 μmol, 1 eq), DMAP (9.09 mg, 74.44 μmol, 0.1 eq), DIPEA (240.52 mg, 1.86 mmol, 324.15 μL, 2.5 eq) and 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (293.39 mg, 893.26 μmol, 1.2 eq) to a solution of O8-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxooctanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid (0.65 g, 744.39 μmol, 1 eq) in DCM (6.5 mL) to a solution of O8-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxooctanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid (2.5 eq) in DCM (6.5 mL). The mixture was stirred at 15°C under N2 for 12 h. The reaction mixture was diluted with H2O (50 mL) and then mixed with DCM (150 mL). 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 2 / 1). The compound O8-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (200 mg) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.51-5.47(m, 2H), 5.37-5.30(m, 2H), 5.17(s, 1H), 4.74(m, 1H),4.11-4.04(m, 12H), 3.29-3.28(d, J = 4.0 Hz, 2H), 2.60-2.57(t, J = 4.0 Hz,2H), 2.52(s, 4H), 2.39-2.34(q, J = 4.0 Hz, J = 12.0 Hz, 6H), 2.32-2.27(m,8H), 2.07-2.00(m, 6H), 1.96(s, 3H), 1.88-1.87(m, 1H), 1.78(s, 5H), 1.77-1.68(m, 9H), 1.62-1.57(m, 16H), 1.35-1.26(m, 30H), 0.90-0.86(m, 9H). Example 19 - Compound 12: O8-[2-(4,4-dioctyloxybutyryloxymethyl)-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decyloxy]propyl]O1-[(Z)-non-3-enyl]octyl ester Step 1:

[0283] Add DIPEA (695.40 mg, 5.38 mmol, 937.20 μL, 2.5 eq), EDCI (495.11 mg, 2.58 mmol, 1.2 eq), DMAP (26.29 mg, 215.22 μmol, 0.1 eq), and 4,4-dioctyloxybutyric acid (444.90 mg, 1.29 mmol, 0.6 eq) to a solution of O8-[2,2-bis(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octyl]oxy-propyl]O1-[(Z)-non-3-enyl]octyl ester (1.5 g, 2.15 mmol, 1 eq) in DCM (15 mL) to a solution of O8-[2,2-bis(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octyl]oxy-propyl]O1-[(Z)-non-3-enyl]octyl ester (1.5 g, 2.15 mmol, 1 eq), DMAP (26.29 mg, 215.22 μmol, 0.1 eq), and 4,4-dioctyloxybutyric acid (444.90 mg, 1.29 mmol, 0.6 eq). Stir the mixture at 20°C under N2 for 12 h. The reaction mixture was poured into H2O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 5 / 1). The compound O8-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (0.7 g) was obtained as a colorless oil. Step 2:

[0284] Add DIPEA (220.99 mg, 1.71 mmol, 297.83 μL, 2.5 eq), EDCI (157.34 mg, 820.74 μmol, 1.2 eq), DMAP (8.36 mg, 68.40 μmol, 0.1 eq) and 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (269.57 mg, 820.74 μmol, 1.2 eq) to a solution of O8-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid (700 mg, 683.95 μmol, 1 eq) in DCM (7 mL) to a solution of O8-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octyl]oxy-propyl]O1-[(Z)-non-3-enyl]octanoic acid (700 mg, 683.95 μmol, 1 eq) in DCM (7 mL). The mixture was stirred at 20°C for 12 h under N2. The reaction mixture was poured into H2O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 8 / 1 to 5 / 1). The compound O8-[2-(4,4-dioctyloxybutyryloxymethyl)-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (160 mg) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.54-5.48 (m, 2H), 5.38-5.31 (m, 2H), 5.17 (s, 1H), 4.75 (s, 1H), 4.50-4.47 (t, J = 8.0 Hz, 1H), 4.12-4.11(d, J =4.0 Hz, 8H), 4.09-4.05 (t, J = 6.8 Hz, 4H), 3.59-3.53 (m, 2H), 3.43-3.38 (m,2H), 3.30-3.28 (m, 2H), 2.61-2.58 (t, J = 6.0 Hz, 2H), 2.52 (s, 4H), 2.42-2.35 (m, 8H), 2.33-2.28 (m, 8H), 2.07-2.02 (q, J = 6.8 Hz, J = 14 Hz, 4H), 1.94-1.89 (m, 3H), 1.78 (s, 5H), 1.64 - 1.55 (m, 14H), 1.38 - 1.28 (m, 48H),0.91-0.87 (m, 15H) Example 20 - Compound 13: O6-[2,2-bis[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]adipate Step 1:

[0285] Add EDCI (48.52 g, 253.10 mmol, 1.2 eq), DIPEA (68.15 g, 527.29 mmol, 91.84 mL, 2.5 eq), adipic acid (154.12 g, 1.05 mol, 175.13 mL, 5 eq), and DMAP (2.58 g, 21.09 mmol, 0.1 eq) to a solution of (Z)-non-3-en-1-ol (30.00 g, 210.91 mmol, 1 eq) in DCM (300 mL) to a solution of (Z)-non-3-en-1-ol (30.00 g, 210.91 mmol, 1 eq), to a solution of (Z)-non-3-en-1-ol (30.00 g, 210.91 mmol, 1 eq), to a solution of (Z)-non-3-en-1-ol (30.00 g, 210.91 mmol, 1 eq), to a solution of (Z)-non-3-en-1-ol (300 mL) in DCM (300 mL) ... 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 6-[(Z)-non-3-enoxy]-6-oxo-hexanoic acid (30 g, 110.96 mmol, 52.61% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm5.54-5.50(m, 1H), 5.35-5.32(m, 1H), 4.09-4.06(t, J = 7.2Hz, 2H), 2.04-2.32(m,6H), 2.06-2.01(m, 2H), 1.70-1.67(m, 4H), 1.37-1.26(m, 6H), 0.91-0.88(t, J =6.8Hz, 3H) Step 2:

[0286] Add EDCI (22.85 g, 119.18 mmol, 1.2 eq), DIPEA (32.09 g, 248.28 mmol, 43.25 mL, 2.5 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (7 g, 39.73 mmol, 0.4 eq), and DMAP (1.21 g, 9.93 mmol, 0.1 eq) to a solution of 6-[(Z)-non-3-enoxy]-6-oxo-hexanoic acid (26.85 g, 99.31 mmol, 1 eq) in DCM (270 mL) to a solution of 6-[(Z)-non-3-enoxy]-6-oxo-hexanoic acid (26.85 g, 99.31 mmol, 1 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (7 g, 39.73 mmol, 0.4 eq), and DMAP (1.21 g, 9.93 mmol, 0.1 eq). Stir the mixture at 20°C for 12 hours under N2. Dilute the reaction mixture with H2O (300 mL) and mix with DCM (900 mL) (300 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O6-[[2,2-dimethyl-5-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]adipic acid ester (15 g, 22.03 mmol, 22.18% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.52-5.49(m, 2H),5.35-5.30(m, 2H), 4.11(S, 1H), 4.09-4.05(t, J = 7.2 Hz, 4H), 3.74(s, 4H),2.40-2.30(m, 12H), 2.06-2.01(q, J = 6.8 Hz, J = 14Hz, 4H), 1.67-1.64(m, 8H),1.42(s, 6H), 1.37-1.26(m, 12H), 0.91-0.88(t, J = 6.4Hz, 6H). Step 3:

[0287] To a solution of O6-[[2,2-dimethyl-5-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]adipic acid ester (15 g, 22.03 mmol, 1 eq) in THF (150 mL), HCl (3 M, 8.08 mL, 1.1 eq) was slowly added. The mixture was stirred at 20°C under N2 for 7 hr. The reaction mixture was diluted with saturated NaHCO3 (300 mL) and diluted with DCM (900 mL) (300 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O6-[2,2-bis(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid ester (6 g, 9.36 mmol, 42.50% yield) was given as a colorless oil. Step 4:

[0288] Add EDCI (717.93 mg, 3.75 mmol, 1.2 eq), DIPEA (1.01 g, 7.80 mmol, 1.36 mL, 2.5 eq), 6-[(Z)-non-3-enoxy]-6-oxo-hexanoic acid (506.27 mg, 1.87 mmol, 0.6 eq), and DMAP (38.13 mg, 312.09 μmol, 0.1 eq) to a solution of O6-[2,2-bis(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoic acid in DCM (20 mL). Stir the mixture at 20°C for 12 hr under N2. Dilute the reaction mixture with H2O (30 mL) and with DCM (90 mL) (30 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O6-[2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-2-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]adipic acid ester (0.9 g, 1.01 mmol, 32.29% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.54-5.48(m, 3H), 5.37-5.32(m,3H), 4.12(s, 6H), 4.09-4.05(t, J = 7.2 Hz, 6H), 3.53-3.51(d, J = 6.4 Hz, 2H),2.69-2.67(t, J = 6.4 Hz, 1H), 2.40-2.31(m, 18H), 2.07-2.01(m, 6H), 1.68-1.64(m, 12H), 1.38-1.27(m, 18H), 0.91-0.88(t, J = 6.8 Hz, 9H) Step 5:

[0289] Add EDCI (231.79 mg, 1.21 mmol, 1.2 eq), DIPEA (325.57 mg, 2.52 mmol, 438.77 μL, 2.5 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (397.14 mg, 1.21 mmol, 1.2 eq), and 4-pyrrolidine-1-ylpyridine (14.93 mg) to a solution of O6-[2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-2-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]adipic acid (0.9 g, 1.01 mmol, 1 eq) in DCM (9 mL) to a solution of O6-[2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-2-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]adipic acid (0.9 g, 1.01 mmol, 1 eq), EDCI (231.79 mg, 1.21 mmol, 1.2 eq), DIPEA (325.57 mg, 2.52 mmol, 438.77 μL, 2.5 eq), 4-(2-pyrrolidine-1-ylpyridine) (14.93 μL, 1.21 mmol, 1.2 eq), 4-pyrrolidine-1-ylpyridine (14.93 μL, 1.21 mg, 100.76 μmol, 0.1 eq). The mixture was stirred at 20°C under N2 for 12 hr. The reaction mixture was diluted with H2O (30 mL) and mixed with DCM (90 mL) (30 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O6-[2,2-bis[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]adipate (0.5 g, 415.41 μmol, 41.23% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.48(m, 3H), 5.37-5.19(m, 3H), 5.19(s,1H),4.75(s, 1H), 4.11(s, 8H), 4.09-4.05(t, J = 6.8 Hz, 6H), 3.23-3.29(d, J = 4Hz, 2H), 2.60(s, 2H), 2.52(s, 4H), 2.40-2.31(m, 20H), 2.07-2.01(q, J = 6.8Hz, 6H), 1.92-1.85(m, 1H), 1.78(s, 5H), 1.67-1.63(m, 14H), 1.38-1.27(m, 26H),0.91-0.86(m, 12H) Example 21 - Compound 14: O6-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]adipate Step 1:

[0290] Add EDCI (717.94 mg, 3.75 mmol, 1.2 eq), DIPEA (1.01 g, 7.80 mmol, 1.36 mL, 2.5 eq), 2-(1-adamantyl)acetic acid (363.78 mg, 1.87 mmol, 0.6 eq), and DMAP (38.13 mg, 312.09 μmol, 0.1 eq) to a solution of O6-[2,2-bis(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid ester (2 g, 3.12 mmol, 1 eq) in DCM (20 mL) to a solution of O6-[2,2-bis(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid ester (2 g, 3.12 mmol, 1 eq), 2-(1-adamantyl)acetic acid (363.78 mg, 1.87 mmol, 0.6 eq), and DMAP (38.13 mg, 312.09 μmol, 0.1 eq). Stir the mixture at 20°C for 12 hr under N2. Dilute the reaction mixture with H2O (100 mL) and mix with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O6-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipate (0.8 g, 979.08 μmol, 31.37% yield) was obtained as a colorless oil. 1H NMR (400MHz, CDCl3) δ ppm 5.52-5.48(m, 2H), 5.37-5.31(m, 2H), 4.12(s, 4H), 4.09-4.06(m, 6H), 5.53-5.52(d, J = 6.8 Hz, 2H), 2.63-2.59(t, J = 6.8 Hz, 1H), 2.40-2.31(m, 12H), 2.10(s, 2H), 2.07-2.01(q, J = 6.4 Hz, J = 14 Hz, 4H), 1.98(s,3H), 1.73-1.59(m, 20H), 1.38-1.27(m, 12H), 0.91–0.88 (t, J = 6.4 Hz, 6H) Step 2:

[0291] Add EDCI (204.75 mg, 1.07 mmol, 1.2 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (292.34 mg, 890.07 μmol, 1 eq), DIPEA (287.59 mg, 2.23 mmol, 387.59 μL, 2.5 eq) and DMAP (10.87 mg, 89.01 μmol, 0.1 eq) to a solution of O6-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipate (0.8 g, 979.08 μmol, 1.1 eq) in DCM (8 mL). The mixture was stirred at 20°C under N2 for 12 hours. The reaction mixture was diluted with H2O (10 mL) and mixed with DCM (30 mL) (10 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound O6-[2-[[2-(1-adamantyl)acetyl]oxymethyl]-2-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]adipate (0.1 g, 88.69 μmol, 9.96% yield). 1H NMR (400 MHz, CDCl3) δ ppm 5.52-5.48(m, 2H), 5.35-5.31(m, 2H), 5.21(s,1H), 4.75(s, 1H), 4.12(s, 6H), 4.09-4.05(t, J = 6.8 Hz, 6H), 3.31-3.30(d, J =3.2 Hz, 2H), 2.62-2.55(d, J = 30 Hz, 6H), 2.40-2.31(m, 14H), 2.08-2.01(m,6H), 1.97(s, 3H), 1.88(s, 1H), 1.80(s, 5H), 1.72-1.63(m, 14H), 1.60-1.58(m,8H), 1.40-1.27(m, 20H), 0.91-0.86(m, 9H) Example 22 - Compound 15: O6-[2-(4,4-dioctyloxybutyryloxymethyl)-2-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]adipate Step 1:

[0292] Add EDCI (717.93 mg, 3.75 mmol, 1.2 eq), 4,4-dioctyloxybutyric acid (645.14 mg, 1.87 mmol, 0.6 eq), DIPEA (1.01 g, 7.80 mmol, 1.36 mL, 2.5 eq), and DMAP (38.13 mg, 312.09 μmol, 0.1 eq) to a solution of O6-[2,2-bis(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid (2 g, 3.12 mmol, 1 eq) in DCM (20 mL) to a solution of O6-[2,2-bis(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid (2 g, 3.12 mmol, 1 eq), DIPEA (1.01 g, 7.80 mmol, 1.36 mL, 2.5 eq), and DMAP (38.13 mg, 312.09 μmol, 0.1 eq). Stir the mixture at 20°C for 12 hr under N2. Dilute the reaction mixture with H2O (100 mL) and mix with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O6-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid ester (0.6 g, 620.25 μmol, 19.87% yield) was given as a colorless oil. Step 2:

[0293] Add EDCI (142.68 mg, 744.30 μmol, 1 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (305.58 mg, 930.37 μmol, 1.5 eq), DIPEA (200.41 mg, 1.55 mmol, 270.09 μL, 2.5 eq) and 4-pyrrolidine-1-ylpyridine (9.19 mg, 62.02 μmol, 0.1 eq) to a solution of O6-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid (0.6 g, 620.25 μmol, 1 eq) in DCM (6 mL) to a solution of O6-[2-(4,4-dioctyloxybutyryloxymethyl)-2-(hydroxymethyl)-3-[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]adipic acid (0.6 g, 620.25 μmol, 1 eq) in DCM (6 mL). The mixture was stirred at 20°C under N2 for 12 hours. The reaction mixture was diluted with H2O (10 mL) and mixed with DCM (30 mL) (10 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O6-[2-(4,4-dioctyloxybutyryloxymethyl)-2-[[6-[(Z)-non-3-enoxy]-6-oxo-hexanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]adipate (0.15 g, 117.39 μmol, 18.93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 5.54-5.48(m, 2H), 5.35-5.33(m, 2H),5.19(s, 1H), 4.75(s, 1H), 4.50-4.47(t, J = 5.6 Hz, 1H), 4.11(s, 8H), 4.09-4.05(t, J = 7.2 Hz, 4H), 3.57-3.53(m, 2H), 3.43-3.38(m, 2H), 3.30-3.28(d, J =5.2 Hz, 2H), 2.61-2.58(t, J = 5.6 Hz, 2H), 2.52(s, 4H), 2.40-2.32(m, 14H), 2.07-2.02(q, J = 6.4 Hz, J = 14 Hz, 4H), 1.94-1.89(q, J = 7.6 Hz, J = 13.6Hz, 3H), 1.78(s, 5H), 1.69-1.63(m, 10H), 1.60-1.53(m, 6H), 1.36-1.28(m, 40H),0.91-0.87(m, 15H) Example 23 - Compound 16: O7-[2-[7-(2-Butyloctyloxy)heptayloxymethyl]-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptayl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptanediol ester Step 1:

[0294] Add DIPEA (40.32 g, 312.01 mmol, 54.35 mL, 2.5 eq), 2-butyloctanoic acid (25 g, 124.80 mmol, 1 eq), DMAP (1.52 g, 12.48 mmol, 0.1 eq), and EDCI (28.71 g, 149.76 mmol, 1.2 eq) to a solution of heptane-1,7-diol (49.50 g, 374.41 mmol, 3 eq) in DCM (500 mL). Stir the mixture at 25°C for 12 hr under N2. Dilute the reaction mixture with H2O (600 mL) and mix with DCM (1000 mL) (500 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound 2-butyloctanoic acid 7-hydroxyheptyl ester (100 g, 317.96 mmol, 63.69% yield) was given as a colorless oil. Step 2:

[0295] At 0°C, CrO3 / H2SO4 (238.47 mg, 119.24 mmol, 1.5 eq) was added dropwise to a solution of 2-butyloctanoic acid 7-hydroxyheptyl ester (25 g, 79.49 mmol, 1 eq) in acetone (250 mL). The mixture was stirred at 25°C under N2 for 12 hr. The reaction mixture was diluted with H2O (200 mL) and diluted with EtOAc (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound 7-(2-butyloctyloxy)heptanoic acid (50 g, 152.21 mmol, 47.87% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 11.27-10.80(m, 1H), 4.09-4.06(t, J = 6.8 Hz, 2H), 2.39-2.28(m,3H), 1.57-1.55(m, 6H), 1.47-1.37(m, 6H), 1.33-1.22(m, 12H), 0.90-0.86(m, 6H) Step 3:

[0296] Add EDCI (687.83 mg, 3.59 mmol, 1 eq), DIPEA (966.09 mg, 7.48 mmol, 1.30 mL, 2.5 eq), 7-(2-butyloctyloxy)heptanoic acid (589.30 mg, 1.79 mmol, 0.6 eq), and DMAP (36.53 mg, 299.00 μmol, 0.1 eq) to a solution of O7-[2,2-bis(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptyl]oxy-propyl]O1-[(Z)-non-3-enyl]heptanoic acid (2 g, 2.99 mmol, 1 eq) in DCM (20 mL). Stir the mixture at 20°C for 12 hr under N2. Dilute the reaction mixture with H2O (20 mL) and with DCM (30 mL) (10 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptyl]oxy-propyl]O1-[(Z)-non-3-enyl]pimercate (1 g, 1.02 mmol, 34.15% yield) was given as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 5.52-5.48(m, 2H), 5.37-5.33(m, 2H), 4.12(s, 6H), 4.09-4.05(t, J = 6.8 Hz, 6H), 3.52-3.50(d, J = 6.8 Hz, 2H), 2.64-2.61(t, J = 6.8Hz,1H), 2.39-2.29(m, 14H), 2.07-2.02(q, J = 6.4 Hz, J = 10.8 Hz, 4H), 1.68-1.57(m, 16H), 1.47-1.43(m, 2H), 1.38-1.26(m, 30H), 0.91-0.86 (m, 12H) Step 4: To be replaced

[0297] Add EDCI (234.89 mg, 1.23 mmol, 1 eq), DIPEA (329.92 mg, 2.55 mmol, 444.63 μL, 2.5 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (301.83 mg, 918.96 μmol, 0.9 eq) and DMAP (12.47 mg, 102.11 μmol, 0.1 eq) to a solution of O7-[2-[7-(2-butyloctyloxy)heptayloxymethyl]-2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptayl]oxy-propyl]O1-[(Z)-non-3-enyl]heptayl ester (1 g, 1.02 mmol, 1 eq) in DCM (10 mL). The mixture was stirred at 20°C under N2 for 12 hours. The reaction mixture was diluted with H2O (20 mL) and mixed with DCM (30 mL) (10 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[2-[7-(2-butyloctyloxy)heptanoyloxymethyl]-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]pimercinate (0.15 g, 116.30 μmol, 11.39% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.48(m, 2H), 5.37-5.31(m, 2H), 5.27-5.01(m, 1H), 4.75(s, 1H), 4.11(s, 8H), 4.08-4.05(t, J = 6.8 Hz, 6H), 3.31(s,2H), 2.62-2.55(m, 6H), 2.40-2.29(m, 18H), 2.07-2.02(q, J = 6.4 Hz, J = 14 Hz,4H), 1.91-1.80(m, 5H), 1.66-1.59(m, 14H), 1.46-1.27(m, 44H), 0.91-0.86(m,15H) Example 24 - Compound 17: O7-[2,2-bis[7-(2-butyloctyloxy)heptanoyloxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptadiate Step 1:

[0298] Add EDCI (17.41 g, 90.80 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (6 g, 34.05 mmol, 0.45 eq), DMAP (924.41 mg, 7.57 mmol, 0.1 eq), and DIPEA (24.45 g, 189.17 mmol, 32.95 mL, 2.5 eq) to a solution of 7-(2-butyloctanoyloxy)heptanoic acid (24.86 g, 75.67 mmol, 1 eq) in DCM (250 mL) to a solution of 7-(2-butyloctanoyloxy)heptanoic acid (24.86 g, 75.67 mmol, 1 eq), DMAP (924.41 mg, 7.57 mmol, 0.1 eq), and DIPEA (24.45 g, 189.17 mmol, 32.95 mL, 2.5 eq). Stir the mixture at 25°C for 12 hr under N2. Dilute the mixture with H2O (300 mL) and mix with DCM (500 mL) (100 mL) 5) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound [7-[[5-[7-(2-butyloctyloxy)heptyloxymethyl]-2,2-dimethyl-1,3-dioxane-5-yl]methoxy]-7-oxo-heptyl]2-butyloctyl ester (13 g, 16.31 mmol, 21.55% yield) was given as a colorless oil. Step 2:

[0299] At 0°C, HCl (3 M, 12.42 mL, 1.1 eq) was added dropwise to a solution of [7-[[5-[7-(2-butyloctyloxy)heptyloxymethyl]-2,2-dimethyl-1,3-dioxane-5-yl]methoxy]-7-oxo-heptyl]2-butyloctanoate (27 g, 33.87 mmol, 1 eq) in THF (270 mL). The mixture was stirred at 25°C under N2 for 5 hr. It was then poured into H2O (200 mL) and mixed with DCM (800 mL) (200 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound [7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-3-hydroxy-2-(hydroxymethyl)propoxy]-7-oxo-heptyl]2-butyloctyl ester (10 g, 13.21 mmol, 39.00% yield) was given as a colorless oil. Step 3:

[0300] Add EDCI (1.01 g, 5.28 mmol, 2 eq), 7-[(Z)-non-3-enoxy]-7-oxo-heptyl]2-butyloctanoate (2 g, 2.64 mmol, 1 eq), DMAP (32.27 mg, 264.17 μmol, 0.1 eq), and DIPEA (682.84 mg, 5.28 mmol, 920.28 μL, 2 eq) to a solution of [7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-3-hydroxy-2-(hydroxymethyl)propoxy]-7-oxo-heptanoic acid (450.77 mg, 1.59 mmol, 0.6 eq), DMAP (32.27 mg, 264.17 μmol, 0.1 eq), and DIPEA (682.84 mg, 5.28 mmol, 920.28 μL, 2 eq) to a solution of [7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-3-hydroxy-2-(hydroxymethyl)propoxy]-7-oxo-heptyl]-2-butyloctanoate (2 g, 2.64 mmol, 1 eq) in DCM (20 mL) to a solution of [7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-3-hydroxy-2-(hydroxymethyl)propoxy]-7-oxo-heptyl]-2-butyloctanoate (2 g, 2.64 mmol, 1 eq), DMAP (32.27 mg, 264.17 μmol, 0.1 eq), and DIPEA (682.84 mg, 5.28 mmol, 920.28 μL, 2 eq) in DCM (20 mL) to a 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound O7-[2,2-bis[7-(2-butyloctyloxy)heptyloxymethyl]-3-hydroxy-propyl]O1-[(Z)-non-3-enyl]pimercate (0.7 g, 683.95 μmol, 25.89% yield) was obtained as a colorless oil. Step 4:

[0301] Add EDCI (218.53 mg, 1.14 mmol, 2 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (187.20 mg, 569.96 μmol, 1 eq), DMAP (6.96 mg, 57.00 μmol, 0.1 eq), and DIPEA (147.33 mg, 1.14 mmol, 198.55 μL, 2 eq) to a solution of O7-[2,2-bis[7-(2-butyloctyloxy)heptanoyloxymethyl]-3-hydroxy-propyl]O1-[(Z)-non-3-enyl]peptidate (0.7 g, 683.95 μmol, 1.2 eq) in DCM (7 mL) to a solution of O7-[2,2-bis[7-(2-butyloctyloxy)heptanoyloxymethyl]-3-hydroxy-propyl]O1-[(Z)-non-3-enyl]peptidate (0.7 g, 683.95 μmol, 1.2 eq), DMAP (6.96 mg, 57.00 μmol, 0.1 eq), and DIPEA (147.33 mg, 1.14 mmol, 198.55 μL, 2 eq). Stir the mixture at 25°C for 12 hr under N2. Dilute the reaction mixture with H2O (50 mL) and with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound O7-[2,2-bis[7-(2-butyloctyloxy)heptyloxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decyloxy]propyl]O1-[(Z)-non-3-enyl]heptadiate (111 mg) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.48(m, 1H), 5.43-5.04(m, 2H), 4.75(s, 1H), 4.11(s, 8H), 4.08-4.05(t, J = 6.8Hz, 6H), 3.34(s, 2H), 2.67-2.60(m, 6H), 2.40-2.28(m, 14H), 2.07-2.01(q, J = 6.8 Hz, J = 13.6Hz, 2H), 1.90-1.76(m, 6H), 1.63-1.56(m, 16H), 1.47-1.24(m, 54H), 0.91-0.86 (m, 18H) Example 25 - Compound 18: [7-[2,2-bis[7-(2-butyloctyloxy)heptyloxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decyloxy]propoxy]-7-oxo-heptyl]2-butyloctanoate Step 1:

[0302] Add EDCI (911.56 mg, 4.76 mmol, 1 eq), DIPEA (51.21 mg, 396.26 μmol, 69.02 μL, 0.1 eq), 7-(2-butyloctyloxy)heptanoic acid (780.99 mg, 2.38 mmol, 0.6 eq), and DMAP (1.21 g, 9.91 mmol, 2.5 eq) to a solution of [7-[2-[7-(2-butyloctyloxy)heptanoic acid]-3-hydroxy-2-(hydroxymethyl)propoxy]-7-oxo-heptyl]2-butyloctyl ester (3 g, 3.96 mmol, 1 eq) in DCM (30 mL) to a solution of [7-[2-[7-(2-butyloctyloxy)heptanoic acid]-3-hydroxy-2-(hydroxymethyl)propoxy]-7-oxo-heptyl]2-butyloctyl ester (3 g, 3.96 mmol, 1 eq), 7-(2-butyloctyloxy)heptanoic acid (780.99 mg, 2.38 mmol, 0.6 eq), and DMAP (1.21 g, 9.91 mmol, 2.5 eq). Stir the mixture at 25°C for 12 hr under N2. Dilute the reaction mixture with H2O (100 mL) and mix with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound [7-[2,2-bis[7-(2-butyloctyloxy)heptyloxymethyl]-3-hydroxy-propoxy]-7-oxo-heptyl]2-butyloctanoate (1.5 g, 1.41 mmol, 35.46% yield) was given as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 4.12(s, 6H), 4.09-4.06(t, J = 6.8 Hz, 6H), 3.515-3.50(d, J= 6 Hz), 2.59-2.56(t, J = 6.4 Hz, 1H), 2.36-2.28(m, 9H), 1.67-1.55(m, 24H),1.45-1.26(m, 48H), 0.91-0.87(m, 18H) Step 2:

[0303] Add EDCI (466.88 mg, 2.44 mmol, 2 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (359.96 mg, 1.10 mmol, 0.9 eq), DMAP (14.88 mg, 121.77 μmol, 0.1 eq), and DIPEA (314.77 mg, 2.44 mmol, 424.21 μL, 2 eq) to a solution of [7-[2,2-bis[7-(2-butyloctyloxy)heptanoyloxymethyl]-3-hydroxy-propoxy]-7-oxo-heptyl]2-butyloctanoate (1.3 g, 1.22 mmol, 1 eq) in DCM (13 mL) to a solution of [7-[2,2-bis[7-(2-butyloctyloxy)heptanoyloxymethyl]-3-hydroxy-propoxy]-7-oxo-heptyl]2-butyloctanoate (1.3 g, 1.22 mmol, 1 eq), DMAP (14.88 mg, 121.77 μmol, 0.1 eq), and DIPEA (314.77 mg, 2.44 mmol, 424.21 μL, 2 eq). Stir the mixture at 25°C for 12 hr under N2. Dilute the reaction mixture with H2O (50 mL) and mix with DCM (100 mL) (50 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound [7-[2,2-bis[7-(2-butyloctyloxy)heptyloxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decyloxy]propoxy]-7-oxo-heptyl]2-butyloctyl ester (106 mg, 76.92 μmol, 6.32% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.86-0.90 (td, J=6.94, 2.2 Hz, 21 H) 1.23 - 1.33 (m, 42 H) 1.34 - 1.51 (m, 20 H) 1.51 - 1.69 (m, 20 H) 1.78 (m, 6 H) 1.84 - 1.96 (m, 1 H) 2.30 - 2.42 (m, 10 H) 2.53 (m, 4H) 2.60 (m, 2 H) 3.29 (d, J=4.8 Hz, 2 H) 4.07 (t, J=6.6 Hz, 6 H) 4.12 (s, 8H) 4.75 (br s, 1 H) 5.18 (br s, 1 H). Example 26 - Compound 19: [7-[2-[7-(2-Butyloctyloxy)heptayloxymethyl]-2-(4,4-dioctyloxybutyryloxymethyl)-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decyloxy]propoxy]-7-oxo-heptayl]2-butyloctyl ester Step 1:

[0304] Add EDCI (607.70 mg, 3.17 mmol, 1.2 eq), DIPEA (853.56 mg, 6.60 mmol, 1.15 mL, 2.5 eq), and DMAP (32.27 mg, 264.17 μmol, 0.1 eq) to a solution of [7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-3-hydroxy-2-(hydroxymethyl)propoxy]-7-oxoheptyl]2-butyloctyl ester (2 g, 2.64 mmol, 1 eq) in DCM (20 mL), then add dropwise a solution of 4,4-dioctyloxybutyric acid (728.11 mg, 2.11 mmol, 0.8 eq) in DCM (20 mL) to the above reaction mixture. Stir the mixture at 20°C under N2 for 12 hr. Dilute the reaction mixture with H2O (20 mL) and with DCM (60 mL) (20 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1). The compound [7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-2-(4,4-dioctyloxybutyryloxymethyl)-3-hydroxypropoxy]-7-oxo-heptyl]2-butyloctyl ester (1.4 g, 1.29 mmol, 48.91% yield, 100% purity) was given as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ ppm 0.70 - 0.90 (m, 18 H)1.12 - 1.43 (m, 58 H) 1.48 - 1.62 (m, 14 H) 1.79 - 1.92 (m, 2 H) 2.16 - 2.29(m, 6 H) 2.34 (t, J=7.6 Hz, 2 H) 2.54 (t, J=7.0 Hz, 1 H) 3.33 (dt, J=9.2, 6.8Hz, 2 H) 3.40 - 3.57 (m, 4 H) 3.99 (t, J=6.6 Hz, 4 H) 4.04 (s, 6 H) 4.41 (t,J=5.4 Hz, 1 H). Step 2:

[0305] Add EDCI (212.29 mg, 1.11 mmol, 1.2 eq), DIPEA (298.18 mg, 2.31 mmol, 401.86 μL, 2.5 eq), and DMAP (11.27 mg, 92.29 μmol, 0.1 eq) to a solution of [7-[2-[7-(2-butyloctyloxy)heptanoyloxymethyl]-2-(4,4-dioctyloxybutyryloxymethyl)-3-hydroxypropoxy]-7-oxo-heptyl]2-butyloctanoate (1 g, 922.85 μmol, 1 eq) in DCM (10 mL) to the above reaction mixture, and then add 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (272.80 mg, 830.57 μmol, 0.9 eq). Stir the mixture at 20°C under N2 for 12 hr. Dilute the reaction mixture with H2O (20 mL) and with DCM (30 mL) (10 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 1 / 1). The compound [7-[2-[7-(2-butyloctyloxy)heptyloxymethyl]-2-(4,4-dioctyloxybutyryloxymethyl)-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decyloxy]propoxy]-7-oxo-heptyl]2-butyloctyl ester (0.102 g, 73.17 μmol, 7.93% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 0.86-0.90 (td, J=7.0, 2.4 Hz, 6 H) 1.22 - 1.32(m, 12 H) 1.36 - 1.45 (m, 12 H) 1.59 - 1.67 (m, 6 H) 2.35-2.38 (m, 4 H) 3.50 (s, 2 H) 3.70 - 3.76 (m, 4 H) 4.05-4.09 (t, J=6.6 Hz, 2 H) 4.25 (s, 2 H). Example 27 - Compound 20: [7-[2,2-bis(4,4-dioctyloxybutyryloxymethyl)-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propoxy]-7-oxo-heptyl]2-butyloctanoate Step 1:

[0306] Add EDCI (4.08 g, 21.28 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (5 g, 28.38 mmol, 1.6 eq), DIPEA (5.73 g, 44.34 mmol, 7.72 mL, 2.5 eq), and DMAP (216.66 mg, 1.77 mmol, 0.1 eq) to a solution of 7-(2-butyloctanoyloxy)heptanoic acid (5.83 g, 17.73 mmol, 1 eq) in DCM (58 mL) to a solution of 7-(2-butyloctanoyloxy)heptanoic acid (5.83 g, 17.73 mmol, 1 eq), DIPEA (5.73 g, 44.34 mmol, 7.72 mL, 2.5 eq), and DMAP (216.66 mg, 1.77 mmol, 0.1 eq) to a solution of 7-(2-butyloctanoyloxy)heptanoic acid (5.83 g, 17.73 mmol, 1 eq) in DCM (300 mL) to a solution of 7-(2-butyloctanoyloxy)heptanoic acid (5.83 g, 17.73 mmol, 1 eq), ...2.23 mmol, 1 eq), to a solution of 7-(2-butyloctanoyloxy)heptanoic acid (5.83 g, 2.23 mmol, 1 eq 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound [7-[[5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methoxy]-7-oxo-heptyl]2-butyloctanoate (3 g, 6.16 mmol, 34.76% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3)δ ppm 0.86-0.90 (td, J=7.0, 2.4 Hz, 6 H) 1.22 - 1.32 (m, 12 H) 1.36 - 1.45(m, 12 H) 1.59 - 1.67 (m, 6 H) 2.35-2.38 (m, 4 H) 3.50 (s, 2 H) 3.70 - 3.76 (m, 4 H) 4.05-4.09 (t, J=6.6 Hz, 2 H) 4.25 (s, 2 H). Step 2:

[0307] At 0°C, HCl (3M, 2.26 mL, 1.1 eq) was slowly added to a solution of [7-[[5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methoxy]-7-oxo-heptyl]2-butyloctanoate (3 g, 6.16 mmol, 1 eq) in THF (30 mL). The mixture was stirred at 20°C under N2 for 7 hr. The reaction mixture was added to saturated NaHCO3 to adjust the pH to 9, and EtOAc (90 mL) (30 mL) was added to the solution. 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound [7-[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]-7-oxo-heptyl]2-butyloctanoate was given as a colorless oil (1.5 g, 3.36 mmol, 54.49% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 0.86-0.90 (td, J=6.94, 2.6 Hz, 6 H) 1.21 - 1.47 (m, 19 H) 1.63 - 1.66 (m, 6 H) 2.32 (s, 1 H)2.36-2.39 (t, J=7.4 Hz, 2 H) 2.53 - 2.65 (m, 2 H) 3.66 (s, 6 H) 4.06-4.09 (t,J=6.6 Hz, 2 H) 4.23 (s, 2 H). Step 3:

[0308] Add EDCI (772.62 mg, 4.03 mmol, 1.2 eq), 4,4-dioctyloxybutyric acid (2.31 g, 6.72 mmol, 2 eq), DIPEA (1.09 g, 8.40 mmol, 1.46 mL, 2.5 eq), and DMAP (41.03 mg, 335.86 μmol, 0.1 eq) to a solution of [7-[3-hydroxy-2,2-bis(hydroxymethyl)propoxy]-7-oxo-heptyl]2-butyloctanoate (1.5 g, 3.36 mmol, 1 eq) in DCM (30 mL). Stir the mixture at 20°C for 12 hr under N2. Concentrate the reaction mixture under reduced pressure to remove the solvent. Dilute the residue with H2O (50 mL) and mix with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound [7-[2,2-bis(4,4-dioctyloxybutyryloxymethyl)-3-hydroxy-propoxy]-7-oxo-heptyl]2-butyloctanoate (1.2 g, 1.09 mmol, 32.49% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.87 - 0.91 (m, 18 H) 1.28 - 1.38 (m, 56 H)1.53 - 1.65 (m, 16 H) 1.91 - 1.96 (m, 4 H) 2.29 - 2.35 (m, 3 H) 2.40-2.44 (t,J=7.4 Hz, 4 H) 2.64-2.67 (t, J=7.0 Hz, 1 H) 3.38-3.44 (dt, J=9.2, 6.8 Hz, 4H) 3.51 - 3.59 (m, 6 H) 4.05-4.09 (t, J=6.6 Hz, 2H) 4.11 (s, 6H) 4.47-4.50 (t, J=5.4 Hz, 2 H). Step 4:

[0309] Add EDCI (251.04 mg, 1.31 mmol, 1.2 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (322.58 mg, 982.14 μmol, 0.9 eq), DIPEA (141.04 mg, 1.09 mmol, 190.08 μL, 2.5 eq), and DMAP (13.33 mg, 109.13 μmol, 0.1 eq) to a solution of [7-[2,2-bis(4,4-dioctyloxybutyryloxymethyl)-3-hydroxy-propoxy]-7-oxo-heptyl]2-butyloctanoate (1.2 g, 1.09 mmol, 1 eq) in DCM (24 mL) to a solution of [7-[2,2-bis(4,4-dioctyloxybutyryloxymethyl)-3-hydroxy-propoxy]-7-oxo-heptyl]2-butyloctanoate (1.2 g, 1.09 mmol, 1 eq), DIPEA (141.04 mg, 1.09 mmol, 190.08 μL, 2.5 eq), and DMAP (13.33 mg, 109.13 μmol, 0.1 eq). Stir the mixture at 20°C for 12 hr under N2. Dilute the reaction mixture with H2O (50 mL) and mix with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound [7-[2,2-bis(4,4-dioctyloxybutyryloxymethyl)-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propoxy]-7-oxo-heptyl]2-butyloctanoate (0.12 g, 85.10 μmol, 7.80% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.81 - 0.94 (m, 21 H) 1.24 - 1.51 (m, 66 H) 1.52 - 1.66 (m, 18H) 1.79 (m, 4 H) 1.89 - 1.95 (m, 4 H) 2.25 - 2.43 (m, 9 H) 2.53 (m, 4 H) 2.61 (m, 2 H) 3.20 - 3.34 (m, 2 H) 3.41 (dt, J=9.2, 6.8 Hz, 4 H) 3.56 (dt, J=9.2,6.8 Hz, 4 H) 4.07 (t, J=6.6 Hz, 2 H) 4.12 (s, 8 H) 4.48 (t, J=5.4 Hz, 2 H)4.68 - 4.90 (m, 1 H) 5.20 (br s, 1 H). Example 28 - Compound 21: O9-[2,2-bis[[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-oct-3-enyl]azelate Step 1:

[0310] Under a nitrogen atmosphere, EDCI (35.88 g, 187.19 mmol, 1.2 eq), azelaic acid (146.80 g, 779.96 mmol, 5 eq), DIPEA (50.40 g, 389.98 mmol, 67.93 mL, 2.5 eq), and DMAP (1.91 g, 15.60 mmol, 0.1 eq) were added to a solution of (Z)-oct-3-en-1-ol (20 g, 155.99 mmol, 1 eq) in DCM (100 mL) and THF (100 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 9-[(Z)-oct-3-enoxy]-9-oxo-nonanoic acid was given as a colorless oil (20 g, 67.02 mmol, 42.96% yield). Step 2:

[0311] Under a nitrogen atmosphere, EDCI (8.70 g, 45.40 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (3 g, 17.03 mmol, 0.45 eq), DIPEA (12.22 g, 94.58 mmol, 16.47 mL, 2.5 eq), and DMAP (462.21 mg, 3.78 mmol, 0.1 eq) were added to a solution of 9-[(Z)-oct-3-enoxy]-9-oxo-nonanoic acid (11.29 g, 37.83 mmol, 1 eq) in DCM (110 mL) at N2 atmosphere. The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O9-[[2,2-dimethyl-5-[[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-oct-3-enyl]azelate (7 g, 9.50 mmol, 25.10% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.49 (m, 2H), 5.35-5.32 (m, 2H), 4.10 (s, 4H), 4.06 (t, J =12.0 Hz, 8H), 3.74(s, 4H), 2.40-2.35 (m, 4H), 2.33-2.27 (m, 4H), 2.05-2.02 (m, 4H), 1.60 (t, J= 8.0 Hz, 9H), 1.42 (s, 6 H), 1.34-1.31 (m, 20 H), 0.92-0.88(m, 6 H). Step 3:

[0312] Under a nitrogen atmosphere at 0°C, HCl (3 M, 3.48 mL, 1.1 eq) was added to a solution of O9-[[2,2-dimethyl-5-[[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-oct-3-enyl]azelate (7 g, 9.50 mmol, 1 eq) in THF (70 mL). The reaction mixture was stirred at 20°C for 2 hours under a nitrogen atmosphere. The reaction mixture was diluted with aqueous NaHCO3 (70 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O9-[2,2-bis(hydroxymethyl)-3-[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxy-propyl]O1-[(Z)-oct-3-enyl]azelate (2.5 g, 3.59 mmol, 37.77% yield) was given as a colorless oil. Step 4:

[0313] Under a nitrogen atmosphere, EDCI (330.07 mg, 1.72 mmol, 1.2 eq), 9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxy-propyl]O1-[(Z)-oct-3-enyl]azelate (1 g, 1.43 mmol, 1 eq) were added to a solution of O9-[2,2-bis(hydroxymethyl)-3-[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoic acid (256.91 mg, 860.90 μmol, 0.6 eq), DIPEA (463.60 mg, 3.59 mmol, 624.80 μL, 2.5 eq), and DMAP (17.53 mg, 143.48 μmol, 0.1 eq) were added to a solution of O9-[2,2-bis(hydroxymethyl)-3-[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoic acid (10 mL) in DCM, EDCI (330.07 mg, 1.72 mmol, 1.2 eq), 9-[(Z)-oct-3-enoxy]-9-oxo-nonanoic acid (256.91 mg, 860.90 μmol, 0.6 eq), DIPEA (463.60 mg, 3.59 mmol, 624.80 μL, 2.5 eq), DMAP (17.53 mg, 143.48 μmol, 0.1 eq) under a nitrogen atmosphere at 20°C for 12 hr. Dilute the reaction mixture with H2O (10 mL) and with DCM (30 mL) (10 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O9-[2-(hydroxymethyl)-3-[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxy-2-[[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxymethyl]propyl]O1-[(Z)-oct-3-enyl]azelate (0.5 g, 511.59 μmol, 35.66% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.49 (m, 3H), 5.36-5.33 (m, 3H), 4.11 (s, 6H), 4.06 (t, J = 4.0 Hz, 6H), 3.51(d, J = 4.0 Hz, 2H), 2.60 (t, J = 4.0 Hz, 1H), 2.40-2.27 (m, 18H), 2.07-2.02(m, 6H), 1.34-1.32 (m, 28H), 0.92-0.89 (m, 9H). Step 5:

[0314] Under a nitrogen atmosphere, EDCI (117.69 mg, 613.91 μmol, 1.2 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (201.63 mg, 613.91 μmol, 1.2 eq), and DIPEA (165.30 mg, 1.28 mmol, 222.77 μL, 2.5 eq) were added to a solution of O9-[2-(hydroxymethyl)-3-[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxy-2-[[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxymethyl]propyl]O1-[(Z)-oct-3-enyl]azelate (0.5 g, 511.59 μmol, 1 eq) in DCM (5 mL). eq) and 4-pyrrolidine-1-ylpyridine (7.58 mg, 51.16 μmol, 0.1 eq). The reaction mixture was stirred at 20°C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (10 mL) and mixed with DCM (30 mL) (10 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The compound O9-[2,2-bis[[9-[(Z)-oct-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-oct-3-enyl]azelate (133 mg) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm5.52-5.49 (m, 3H), 5.36-5.33 (m, 3H), 5.26-5.25(m, 1H), 4.75(s, 1H), 4.12 (d,J = 3.2 Hz, 8H), 4.06 (t, J = 1.81 (s, 6H), 1.63-1.49 (m, 16H), 1.36-1.27 (m, 36H), 0.92-0.86 (m, 12H). Example 29 - Compound 22: O9-[2,2-bis[[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]azelate Step 1:

[0315] Under a nitrogen atmosphere, EDCI (32.35 g, 168.73 mmol, 1.2 eq), azelaic acid (132.33 g, 703.05 mmol, 5 eq), DIPEA (45.43 g, 351.52 mmol, 61.23 mL, 2.5 eq), and DMAP (1.72 g, 14.06 mmol, 0.1 eq) were added to a solution of (Z)-non-3-en-1-ol (20 g, 140.61 mmol, 1 eq) in DCM (100 mL) and THF (100 mL). The mixture was stirred at 20°C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (300 mL) and mixed with DCM (900 mL) (300 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 9-[(Z)-non-3-enoxy]-9-oxo-nonanoic acid (20 g, 64.01 mmol, 45.52% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 11.21 (br s, 1 H), 5.56 -5.45 (m, 1 H), 5.39 - 5.29 (m, 1 H), 4.07 (t, J=6.8 Hz, 2 H), 2.42 - 2.27 (m,6 H), 2.08 - 1.99 (m, 2 H), 1.71 - 1.56 (m, 4 H), 1.38 - 1.20 (m, 12 H), 0.89 (t, J=6.8 Hz, 3 H). Step 2:

[0316] Under a nitrogen atmosphere, EDCI (2.90 g, 15.13 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (1 g, 5.68 mmol, 0.45 eq), DIPEA (4.07 g, 31.53 mmol, 5.49 mL, 2.5 eq), and DMAP (154.07 mg, 1.26 mmol, 0.1 eq) were added to a solution of 9-[(Z)-non-3-enoxy]-9-oxo-nonanoic acid (3.94 g, 12.61 mmol, 1 eq) in DCM (40 mL). The mixture was stirred at 20°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (50 mL) and mixed with DCM (90 mL) (30 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O9-[[2,2-dimethyl-5-[[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]azelate (2 g, 2.61 mmol, 20.73% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.51-5.49 (m,2H), 5.35-5.32 (m, 2H), 4.10 (s, 4H), 4.06 (t, J = 12.0 Hz, 8H), 3.74 (s,4H), 2.40-2.35(m, 4H), 2.33-2.27(m, 4H), 2.04 (t, J = 8. 0 Hz, 4H), 1.6 (t, J= 8.0 Hz, 9H), 1.42 (s, 6H), 1.34-1.31 (m, 20H), 0.92-0.88(m, 6H). Step 3:

[0317] Under a nitrogen atmosphere at 0°C, HCl (3 M, 3.12 mL, 1.1 eq) was added to a solution of O9-[[2,2-dimethyl-5-[[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O1-[(Z)-non-3-enyl]azelate (6.5 g, 8.50 mmol, 1 eq) in THF (65 mL). The reaction mixture was stirred at 20°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with saturated NaHCO3 (100 mL) and diluted with EtOAc (300 mL) (100 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O9-[2,2-bis(hydroxymethyl)-3-[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]azelate (2.5 g, 3.45 mmol, 40.59% yield) was given as a colorless oil. Step 4:

[0318] Under a N2 atmosphere, EDCI (190.38 mg, 993.10 μmol, 1.2 eq), 9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxy-propyl]O1-[(Z)-non-3-enyl]azelate (0.6 g, 827.58 μmol, 1 eq) were added to a solution of O9-[2,2-bis(hydroxymethyl)-3-[9-[(Z)-non-3-enoxy]-9-oxo-nonanoic acid (155.14 mg, 496.55 μmol, 0.6 eq), DIPEA (267.40 mg, 2.07 mmol, 360.38 μL, 2.5 eq) and DMAP (10.11 mg, 82.76 μmol, 0.1 eq) in DCM (6 mL). The reaction mixture was stirred at 20°C for 12 h under a nitrogen atmosphere. The reaction mixture was diluted with H₂O (30 mL) and then mixed with DCM (90 mL) (30 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O9-[2-(hydroxymethyl)-3-[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxy-2-[[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]azelate (0.3 g, 294.28 μmol, 35.56% yield). Step 5:

[0319] Under a nitrogen atmosphere, EDCI (338.49 mg, 1.77 mmol, 1.2 eq), DIPEA (475.42 mg, 3.68 mmol, 640.73 μL, 2.5 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (579.93 mg, 1.77 mmol, 1.2 eq) and 4-pyrrolidine-1-ylpyridine (21.81 mg) were added to a solution of O9-[2-(hydroxymethyl)-3-[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxy-2-[[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]azelate (1.5 g, 1.47 mmol, 1 eq) in DCM (20 mL). mg, 147.14 μmol, 0.1 eq). The reaction mixture was stirred at 20°C for 12 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (30 mL) and mixed with DCM (90 mL) (30 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O9-[2,2-bis[[9-[(Z)-non-3-enoxy]-9-oxo-nonanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]azelate (0.1 g, 75.20 μmol, 5.11% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.52 -5.48 (m, 3 H), 5.36 - 5.33 (m, 3 H), 4.76 (br s, 1 H), 4.11 (s, 8 H), 4.07(t, J=7.0 Hz, 6 H), 3.34 (br s, 2 H), 2.75 - 2.55 (m, 4 H), 2.38 (m, 8 H),2.30 (m, 12 H), 2.04 (m, 6 H), 1.90 - 1.73 (m, 6 H), 1.70- 1.58 (m, 16 H),1.38 - 1.27 (m, 44 H), 0.91 - 0.85 (m, 12 H). Example 30 - Compound 23: O8-[2,2-bis[(8-nonoxy-8-oxo-octanoyl)oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-nonyloctanoic acid ester Step 1:

[0320] Under a nitrogen atmosphere, nonan-1-ol (20 g, 138.64 mmol, 1 eq) was dissolved in DCM (600 mL) and THF (600 mL) with octanoic acid (120.76 g, 693.22 mmol, 5 eq), DIPEA (53.76 g, 415.93 mmol, 72.45 mL, 3 eq), EDCI (34.55 g, 180.24 mmol, 1.3 eq), and DMAP (3.39 g, 27.73 mmol, 0.2 eq). The reaction mixture was stirred at 20°C for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into H2O (1000 mL) and extracted with DCM (300 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1). The compound 8-nonoxy-8-oxo-octanoic acid (33 g, 109.84 mmol, 79.23% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 11.40 (br s, 1 H), 4.06 (t, J=6.8Hz, 2 H), 2.43 - 2.20 (m, 4 H), 1.73 - 1.55 (m, 6 H), 1.43 - 1.15 (m, 16 H), 0.96 - 0.81 (m, 3 H). Step 2:

[0321] Under a nitrogen atmosphere, DIPEA (20.37 g, 157.64 mmol, 27.46 mL, 2.5 eq), EDCI (14.51 g, 75.67 mmol, 1.2 eq), and DMAP (770.34 mg, 6.31 mmol, 0.1 eq) were added to a solution of 8-nonoxy-8-oxo-octanoic acid (18.94 g, 63.06 mmol, 1 eq) and [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (5 g, 28.38 mmol, 0.45 eq) in DCM (200 mL). The reaction mixture was stirred at 20°C for 12 hr under a nitrogen atmosphere. The reaction mixture was then poured into H2O (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1 to 10 / 1). The compound O8-[[2,2-dimethyl-5-[(8-nonoxy-8-oxo-octanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-nonyl octanoate was given as a colorless oil (17 g, 22.94 mmol, 72.65% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 4.11 (s, 4 H), 4.06 (t, J=6.8 Hz, 4 H), 3.74 (s, 4 H), 2.31 (m, 8 H), 1.70 - 1.55 (m, 12 H), 1.42 (s, 6 H), 1.39 - 1.09 (m, 32 H), 0.94 -0.80 (m, 6 H). Step 3:

[0322] At 0°C under N2 atmosphere, HCl (3 M, 9.18 mL, 1.2 eq) was added to a solution of O8-[[2,2-dimethyl-5-[(8-nonoxy-8-oxo-octanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-nonyl octanoate (17 g, 22.94 mmol, 1 eq) in THF (170 mL). The reaction mixture was stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with saturated NaHCO3 (100 mL) and diluted with EtOAc (300 mL) (100 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1). The compound O8-[2,2-bis(hydroxymethyl)-3-(8-nonoxy-8-oxo-octanoyl)oxy-propyl]O1-nonyl octanoic acid ester (8.7 g, 12.41 mmol, 54.10% yield) was given as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 4.13 (s, 4 H), 4.05 (t, J=6.8 Hz, 4 H), 3.58 (br s, 4 H), 2.86 (br s, 2 H), 2.40 - 2.16 (m, 8 H), 1.71 - 1.50 (m, 12 H), 1.41 - 1.13 (m, 32 H), 0.87 (t, J=6.8 Hz, 6 H). Step 4:

[0323] To a solution of 8-nonoxy-8-oxo-octanoic acid (2.24 g, 7.45 mmol, 0.6 eq) and O8-[2,2-bis(hydroxymethyl)-3-(8-nonoxy-8-oxo-octanoyl)oxy-propyl]O1-nonyl octanoic acid ester (8.7 g, 12.41 mmol, 1 eq) in DCM (87 mL), DIPEA (4.01 g, 31.03 mmol, 5.40 mL, 2.5 eq), EDCI (2.86 g, 14.89 mmol, 1.2 eq), and DMAP (151.62 mg, 1.24 mmol, 0.1 eq) were added. The reaction mixture was stirred at 20°C for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into H2O (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 8 / 1 to 5 / 1). The compound O₈-[2-(hydroxymethyl)-3-(8-nonoxy-8-oxo-octanoyl)oxy-2-[(8-nonoxy-8-oxo-octanoyl)oxymethyl]propyl]O₁-nonyl octanoic acid ester (3.4 g, 3.46 mmol, 27.85% yield) was given as a colorless oil. 1H NMR (400MHz, CDCl3) δ ppm 4.10 (s, 6 H), 4.04 (t, J=6.8 Hz, 6 H), 3.49 (br d, J=6.2Hz, 2 H), 2.65 (br t, J=6.6 Hz, 1 H), 2.30 (m, 12 H), 1.52 - 1.68 (m, 18 H),1.11 - 1.39 (m, 48 H),0.77 - 0.90 (m, 9 H), Step 5:

[0324] Under a N2 atmosphere, DIPEA (262.85 mg, 2.03 mmol, 354.25 μL, 2.5 eq), EDCI (187.14 mg, 976.21 μmol, 1.2 eq), and 4-pyrrolidine-1-ylpyridine (12.06 mg, 81.35 μmol, 0.1 eq) were added to a solution of O8-[2-(hydroxymethyl)-3-(8-nonoxy-8-oxo-octanoyl)oxy-2-[(8-nonoxy-8-oxo-octanoyl)-oxymethyl]propyl]O1-nonyl octanoic acid ester (800 mg, 813.51 μmol, 1 eq) and 4-(2-pyrrolidine-1-ylcarbamoyloxy)decanoic acid (534.39 mg, 1.63 mmol, 2 eq) in DCM (8 mL). The reaction mixture was stirred at 20°C for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into H2O (20 mL) and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, dichloromethane / methanol = 50 / 1 to 5 / 1). The compound O8-[2,2-bis[(8-nonoxy-8-oxo-octanoyl)oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-nonyl octanoic acid ester (110 mg, 81.64 μmol, 10.06% yield, 96.02% purity) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.19 (br s, 1 H), 4.75 (br s, 1H), 4.11 (s, 8 H), 4.06 (t, J=6.8 Hz, 6 H), 3.29 (br d, J=5.4 Hz, 2 H), 3.29(br d, J=5.4 Hz, 2 H), 2.59 (br t, J=5.8 Hz, 2 H), 2.52 (br s, 4 H), 2.42 -2.34 (m, 2 H), 2.33 - 2.19 (m, 12 H), 1.89 (br d, J=6.8 Hz, 1 H), 1.78 (br s,5 H), 1.70 (br s, 2 H), 1.61 (br d, J=3.2 Hz, 18 H), 1.43 - 1.22 (m, 56 H), 0.92 - 0.84 (m, 12 H). Example 31 - Compound 24: O7-[2,2-bis[(7-nonoxy-7-oxo-heptanoyl)oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-nonylheptane ester Step 1:

[0325] Under a nitrogen atmosphere, nonan-1-ol (20 g, 138.64 mmol, 1 eq) was mixed with a solution of DCM (200 mL) and THF (200 mL) in EDCI (34.55 g, 180.24 mmol, 1.3 eq), pimelic acid (111.03 g, 693.22 mmol, 5 eq), DMAP (1.69 g, 13.86 mmol, 0.1 eq), and DIPEA (44.80 g, 346.61 mmol, 60.37 mL, 2.5 eq). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (500 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). The compound 7-nonoxy-7-oxo-heptanoic acid (30 g, 104.75 mmol, 75.55% yield) was given as a colorless oil.1 HNMR (400 MHz, CDCl3) δ ppm 11.78-10.36 (br s, 1 H), 4.06 (t, J=6.8 Hz, 2 H), 2.49 - 2.24 (m, 4 H), 1.65 (m, 6 H), 1.50 - 1.49 (m, 14 H), 0.99 - 0.80 (m, 3H). Step 2:

[0326] Under a nitrogen atmosphere, EDCI (11.60 g, 60.53 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (4 g, 22.70 mmol, 0.45 eq), DMAP (616.27 mg, 5.04 mmol, 0.1 eq), and DIPEA (16.30 g, 126.11 mmol, 21.97 mL, 2.5 eq) were added to a solution of 7-nonoxy-7-oxo-heptanoic acid (14.45 g, 50.44 mmol, 1 eq) in DCM (145 mL) at N2 atmosphere. The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (300 mL) and mixed with DCM (800 mL) (200 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). The compound O7-[[2,2-dimethyl-5-[(7-nonoxy-7-oxo-heptanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-nonylpimercate (7.5 g, 10.52 mmol, 20.85% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.11 (s, 4H), 4.06 (t, J=6.8 Hz, 4 H), 3.74 (s, 4 H), 2.32 (m, 8 H), 1.72 - 1.55 (m, 12H), 1.42 (s, 6 H), 1.40 - 1.09 (m, 28 H), 0.88 (t, J=6.8 Hz, 6 H). Step 3:

[0327] Under a nitrogen atmosphere at 0°C, HCl (3 M, 3.60 mL, 1.1 eq) was added to a solution of O7-[[2,2-dimethyl-5-[(7-nonoxy-7-oxo-heptanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-nonylpimercinate (7 g, 9.82 mmol, 1 eq) in THF (70 mL). The reaction mixture was stirred at 25°C for 7 hours under a nitrogen atmosphere. The reaction mixture was diluted with saturated NaHCO3 (50 mL) and diluted with EtOAc (100 mL) (50 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[2,2-bis(hydroxymethyl)-3-(7-nonoxy-7-oxo-heptanoyl)oxy-propyl]O1-nonylpimercate (2.5 g, 3.72 mmol, 37.84% yield) was given as a colorless oil. Step 4:

[0328] Under a nitrogen atmosphere, EDCI (854.63 mg, 4.46 mmol, 1.2 eq), 7-nonoxy-7-oxo-heptanoic acid (638.42 mg, 2.23 mmol, 0.6 eq), DMAP (45.39 mg, 371.51 μmol, 0.1 eq), and DIPEA (1.20 g, 9.29 mmol, 1.62 mL, 2.5 eq) were added to a solution of O7-[2,2-bis(hydroxymethyl)-3-(7-nonoxy-7-oxo-heptanoyl)oxy-propyl]O1-nonyl heptanoic acid (2.5 g, 3.72 mmol, 1 eq) in DCM (25 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (200 mL) (50 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[2-(hydroxymethyl)-3-(7-nonoxy-7-oxo-heptanoyl)oxy-2-[(7-nonoxy-7-oxo-heptanoyl)oxymethyl]propyl]O1-nonylpimercate (1.2 g, 1.27 mmol, 34.31% yield) was given as a colorless oil.1 H NMR (400 MHz, CDCl3) δ ppm 4.11 (s, 6H), 4.05 (t, J =13.6 Hz, 6H), 3.51 (d, J =6.4 Hz, 2H), 2.66 (t, J =6.8Hz, 1H), 2.36-2.29 (m, 12H), 1.68-1.60 (m, 18H), 1.39-1.27 (m, 42H), 0.92-0.87 (m, 9H). Step 5:

[0329] Under a N2 atmosphere, EDCI (293.26 mg, 1.53 mmol, 1.2 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (251.22 mg, 764.89 μmol, 0.6 eq), 4-pyrrolidine-1-ylpyridine (18.89 mg, 127.48 μmol, 0.1 eq) and DIPEA (411.90 mg, 3.19 mmol, 555.12 μL, 2.5 eq) were added to a solution of O7-[2-(hydroxymethyl)-3-(7-nonoxy-7-oxo-heptanoyl)oxy-2-[(7-nonoxy-7-oxo-heptanoyl)oxymethyl]propyl]O1-nonylpimecroceta ester (1.2 g, 1.27 mmol, 1 eq) in DCM (12 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with 50 mL of H₂O and then diluted with 25 mL of DCM (50 mL). 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[2,2-bis[(7-nonoxy-7-oxo-heptanoyl)oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-nonylpimercate (120 mg, 91.78 μmol, 7.20% yield, 95.74% purity) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.20 (s, 1H), 4.76-4.75 (s, 1H), 4.11 (s, 8H), 4.06 (t, J=6.8 Hz, 6H), 3.30-3.29 (s, 2H), 2.57 (d, J=30.8 Hz, 6H), 2.40-2.29(m, 14H), 1.91-1.79 (m, 6H), 1.68-1.56 (m, 22H), 1.52-1.45(m, 2H), 1.39-1.28(m, 46H), 0.93-0.87 (m, 12H). Example 32 - Compound 25: O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)octanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester Step 1:

[0330] Under a nitrogen atmosphere, 5-butyltetrahydrofuran-2-one (50 g, 351.63 mmol, 50.97 mL, 1 eq) was added to a solution of NaOH (14.77 g, 369.21 mmol, 1.05 eq) in H2O (250 mL). The reaction mixture was stirred at 100°C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. A white solid, sodium 4-hydroxyoctanoyloxy (45 g, 246.99 mmol, 70.24% yield), was obtained and used directly in the next step. Step 2:

[0331] Under a nitrogen atmosphere, BnBr (8.45 g, 49.40 mmol, 1 eq) was added dropwise to a solution of sodium 4-hydroxyoctanoyloxy (9 g, 49.40 mmol, 1 eq) in DMSO (90 mL). The reaction mixture was stirred at 25°C for 5 min under a nitrogen atmosphere. The reaction mixture was diluted with saturated NaCl (100 mL) and diluted with EtOAc (200 mL) (100 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound 4-hydroxycaprylate benzyl ester (2.67 g, crude) was obtained as a pale yellow oil and was rapidly used in the next step. Step 3:

[0332] Under a nitrogen atmosphere at 0°C, (4-nitrophenyl)chloroformate (12.88 g, 63.91 mmol, 1 eq) and Py (5.06 g, 63.91 mmol, 5.16 mL, 2 eq) were slowly added to a solution of 4-hydroxybenzyl octanoate (8 g, 31.96 mmol, 1 eq) in DCM (201 mL). The reaction mixture was stirred at 25°C for 1 hr under a nitrogen atmosphere. The reaction mixture was diluted with petroleum ether (100 mL), filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound 4-(4-nitrophenoxy)carbonyloxybenzyl octanoate (5 g, 12.04 mmol, 37.66% yield) was given as a colorless oil. Step 4:

[0333] Under a nitrogen atmosphere, DIPEA (4.67 g, 36.11 mmol, 6.29 mL, 3 eq), 2-pyrrolidine-1-ylethylamine (2.75 g, 24.07 mmol, 2 eq), and DMAP (147.03 mg, 1.20 mmol, 0.1 eq) were added to a solution of 4-(4-nitrophenoxy)carbonyloxybenzyl octanoate (5 g, 12.04 mmol, 1 eq) in DCM (77 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (100 mL) and mixed with DCM (360 mL) (120 mL) 3) Extraction. The combined organic layers were filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)benzyl octanoate was given as a colorless oil (2 g, 5.12 mmol, 42.55% yield). Step 5:

[0334] Under a nitrogen atmosphere, benzyl 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)octanoic acid (2 g, 5.12 mmol, 1 eq) was added to a suspension of Pd / C (6.54 g, 6.15 mmol, 10% purity, 1.2 eq) in THF (40 mL). The reaction mixture was stirred at 25°C for 12 hr under H2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 50 / 1 to 3 / 1). The compound 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)octanoic acid (0.5 g, 1.66 mmol, 32.50% yield) was given as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 6.56 (d, J = 2.8 Hz, 1H), 4.75-4.68(m, 1H), 3.65-3.57(m, 1H), 3.22-3.16 (m, 1H), 3.07-2.83 (m, 6H), 2.34-2.23 (m, 2H), 2.00-1.95 (m, 5H), 1.83-1.76 (m, 1H), 1.62-1.46 (m, 2H), 1.33-1.29 (m, 4H), 0.86 (t, J = 6.4 Hz, 3H). Step 6:

[0335] Under a nitrogen atmosphere, EDCI (117.69 mg, 613.91 μmol, 1.2 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)octanoic acid (230.52 mg, 767.38 μmol, 1.5 eq), and DIPEA (165.30 mg, 1.28 mmol, 222.77 μL, 2.5 eq) were added to a solution of O8-[2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoic acid (0.5 g, 511.59 μmol, 1 eq) in DCM (5 mL). eq) and 4-pyrrolidine-1-ylpyridine (7.58 mg, 51.16 μmol, 0.1 eq). The reaction mixture was stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (30 mL) and mixed with DCM (60 mL) (20 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)octanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (105 mg, 83.35 μmol, 16.29% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.47 (m, 3 H), 5.37-5.33 (m, 3 H), 4.76 (s,1 H), 4.11(s, 8 H), 4.07 (t, J=7.2 Hz, 6 H), 3.39(s, 2H), 2.78(s, 4 H), 2.39-2.35 (m, 8 H), 2.33-2.27 (m,12 H), 2.07-1.99 (m, 6 H), 1.89-1.77 (m, 6 H),1.67-1.57(m, 14 H), 1.50-1.46(m, 1 H), 1.39-1.23(m, 36 H), 0.89 (t, J=6.8 Hz, 12 H). Example 33 - Compound 26: O7-[2,2-bis[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)octanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptanoic acid ester

[0336] Under a nitrogen atmosphere, EDCI (196.77 mg, 1.03 mmol, 1.2 eq), DIPEA (276.38 mg, 2.14 mmol, 372.47 μL, 2.5 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)octanoic acid (308.34 mg, 1.03 mmol, 1.2 eq), and 4-pyrrolidine-1-ylpyridine (12.68 mg, 85.54 μmol, 0.1 eq) were added to a solution of O7-[2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl in DCM (10 mL). The reaction mixture was stirred at 20°C for 12 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (30 mL) and mixed with DCM (90 mL) (30 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[2,2-bis[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)octanoyloxy]propyl]O1-[(Z)-non-3-enyl]pimercate (0.12 g, 98.55 μmol, 11.52% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.52-5.50 (m, 3 H), 5.35-5.33 (m, 3 H), 4.75 (s, 1 H), 4.11(s, 8 H), 4.07 (t, J=7.2 Hz, 6 H), 3.32 (d,J=5.2 Hz, 2H), 2.60(d, J=25.2 Hz, 6H), 2.40-2.29 (m, 21H), 2.07-2.01 (m, 6H), 2.07-1.99 (m, 6 H), 1.80 (s, 6 H), 1.68-1.59(m, 14 H), 1.39-1.29(m, 28H), 0.90(t, J = 6.8 Hz, 12 H). Example 34 - Compound 27: O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxooctanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)dodecanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester Step 1:

[0337] Under a nitrogen atmosphere, NaOH (10.59 g, 264.75 mmol, 1.05 eq) was added to a solution of 5-octyltetrahydrofuran-2-one (50 g, 252.14 mmol, 1 eq) in H2O (500 mL). The reaction mixture was stirred at 100°C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. Sodium 4-hydroxydodecanoyloxy, a white solid, was obtained (50 g, crude product) and used directly in the next step. Step 2:

[0338] Under a nitrogen atmosphere, BnBr (7.18 g, 41.96 mmol, 1 eq) was added to a solution of sodium 4-hydroxydodecanoyloxy (10 g, 41.96 mmol, 1 eq) in DMSO (100 mL). The reaction mixture was stirred at 20°C for 0.5 hr under a nitrogen atmosphere. The reaction mixture was diluted with saturated NaCl (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The compound 4-hydroxydecanoic acid benzyl ester (30 g, crude) was obtained as a pale yellow oil and was rapidly used in the next step. Step 3:

[0339] Under a nitrogen atmosphere at 0°C, Py (5.16 g, 65.27 mmol, 5.27 mL, 2 eq) and (4-nitrophenyl)chloroformate (7.89 g, 39.16 mmol, 1.2 eq) were added to a solution of 4-hydroxybenzyl dodecanoate (10 g, 32.63 mmol, 1 eq) in DCM (100 mL). The reaction mixture was stirred at 25°C for 1 hr under a nitrogen atmosphere. The reaction mixture was diluted with petroleum ether (100 mL), filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1). The compound 4-(4-nitrophenoxy)carbonyloxybenzyl dodecanoate (9 g, 19.09 mmol, 81.82% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 8.28 - 8.24 (m, 2 H), 7.41 - 7.33 (m, 7 H), 5.14 (s, 2 H), 4.92- 4.85 (m, 1 H), 2.52 (t, J=7.6 Hz, 2 H), 2.11 (m, 1 H), 2.04 - 1.94 (m, 1H), 1.82 - 1.69 (m, 1 H), 1.68 - 1.60 (m, 1 H), 1.48 - 1.25 (m, 12 H), 0.89 (t, J=6.8 Hz, 3 H). Step 4:

[0340] Under a nitrogen atmosphere, DIEA (7.40 g, 57.26 mmol, 9.97 mL, 3 eq) and DMAP (233.17 mg, 1.91 mmol, 0.1 eq) were added to a solution of 4-(4-nitrophenoxy)carbonyloxybenzyl dodecanoate (9 g, 19.09 mmol, 1 eq) and 2-pyrrolidine-1-ylethylamine (4.36 g, 38.17 mmol, 2 eq) in DCM (90 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (200 mL) (100 mL) 2) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1). The compound 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)benzyl dodecanoate was given as a yellow oil (3 g, 6.72 mmol, 35.21% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 10.55 (br s, 1 H), 7.49 - 7.29 (m, 5 H), 5.29 (br d, J=6.2 Hz, 1H), 5.11 (s, 2 H), 4.74 (br s, 1 H), 3.42 - 3.16 (m, 2 H), 2.78 - 2.56 (m, 6H), 2.38 (br t, J=7.6 Hz, 2 H), 2.01- 1.89 (m, 1 H), 1.83 (br s, 4 H), 1.55 -1.37 (m, 2 H), 1.36 - 1.22 (m, 12 H), 0.87 (t, J=6.8 Hz, 3 H). Step 5:

[0341] Under a nitrogen atmosphere, benzyl 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)dodecanoate (3 g, 6.72 mmol, 1 eq) was added to a suspension of Pd / C (714.83 mg, 671.71 μmol, 10% purity, 0.1 eq) in THF (180 mL). The reaction mixture was stirred at 25°C for 12 hr under H2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 50 / 1 to 3 / 1). The compound 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)dodecanoic acid (1.8 g, 5.05 mmol, 90.00% yield) was given as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 8.87 (br s, 1 H), 6.43 (brd, J=3.38 Hz, 1 H), 4.73 (br d, J=2.50 Hz, 1 H), 3.63-3.60 (m, 1 H), 3.24 -3.13 (m, 1 H), 3.10 – 2.89 (m, 5 H), 2.85-2.83 (m, 1 H), 2.40 – 2.17 (m, 2H), 2.11 – 1.89 (m, 5 H), 1.87 – 1.70 (m, 1 H), 1.69 – 1.54 (m, 1 H), 1.51 -1.46 (m, 1 H), 1.38 - 1.22 (m, 12 H), 0.87 (t, J=6.82 Hz, 3 H). Step 6:

[0342] Under a nitrogen atmosphere, DIEA (264.48 mg, 2.05 mmol, 356.44 μL, 2.5 eq) and EDCI (188.30 mg, 982.25 μmol, 1.2 eq) were added to a solution of O8-[2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (800 mg, 818.54 μmol, 1 eq) and 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)dodecanoic acid (437.71 mg, 1.23 mmol, 1.5 eq) in DCM (10 mL) were added. eq) and 4-pyrrolidine-1-ylpyridine (12.13 mg, 81.85 μmol, 0.1 eq). The reaction mixture was stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (30 mL) and DCM (90 mL) (30 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxooctanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)dodecanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (300 mg, 183.06 μmol, 22.30% yield, 80.29% purity). 1 H NMR(400 MHz, CDCl3) δ ppm 5.52 - 5.49 (m, 3 H), 5.37 - 5.33 (m, 3 H), 4.75 (brs, 1 H), 4.18 - 4.02 (m, 14 H), 3.35 (br d, J=4.8 Hz, 2 H), 2.81 - 2.48 (m, 6H), 2.37 (m, 8 H), 2.04 (m, 6 H), 2.30 (m, 12 H), 1.94 - 1.78 (m, 6 H), 1.71 -1.58 (m, 12 H), 1.43 - 1.10 (m, 46 H), 0.91 - 0.84 (m, 12H). Example 35 - Compound 28: O7-[2,2-bis[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)dodecanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptanoic acid ester

[0343] Under a nitrogen atmosphere, EDCI (196.77 mg, 1.03 mmol, 1.2 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)dodecanoic acid (274.44 mg, 769.83 μmol, 0.9 eq), DMAP (261.24 mg, 2.14 mmol, 2.5 eq), and 4-pyrrolidine-1-ylpyridine (12.68 g) were added to a solution of O7-[2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]peptidate (0.8 g, 855.37 μmol, 1 eq) in DCM (110 mL). mg, 85.54 μmol, 0.1 eq). The reaction mixture was stirred at 20°C for 12 hr under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (200 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[2,2-bis[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)dodecanoyloxy]propyl]O1-[(Z)-non-3-enyl]heptanediate (0.12 g, 94.21 μmol, 11.01% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.49-5.52 (m, 3 H), 5.35-5.32 (m, 3 H), 4.67(s, 1 H), 4.03(s, 8 H), 3.99 (t, J=7.2 Hz, 6 H), 3.70-3.26(m, 2H), 2.60-2.46(m, 6H), 2.33-2.21 (m, 20H), 1.99-1.91 (m, 6 H), 1.75 (s, 6 H), 1.58-1.53(m,14 H), 1.31-1.19(m, 36 H), 0.84-0.79(m, 12H). Example 36 - Compound 29: O8-[2-[4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoyloxymethyl]-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoyl ester Step 1:

[0344] Under a nitrogen atmosphere, N'-ethyl-N'-methyl-ethane-1,2-diamine (5.18 g, 50.73 mmol, 2.5 eq) was added to a mixture of 4-(4-nitrophenoxy)carbonyloxydecanoate benzyl ester (9 g, 20.29 mmol, 1 eq), DIPEA (7.87 g, 60.88 mmol, 10.60 mL, 3 eq), and DMAP (247.92 mg, 2.03 mmol, 0.1 eq) in DCM (90 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (40 mL) and diluted with ethyl acetate (120 mL) (40 mL) 3) Extraction. The combined organic layers were concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoic acid benzyl ester (5 g, 12.30 mmol, 60.60% yield) was given as a colorless oil. 1H NMR (400 MHz, MeOD) δ ppm 7.31 - 7.28 (m, 5 H), 4.86 (s, 2 H), 4.77 - 4.71 (m, 1 H), 3.23 (t, J=6.8 Hz, 2 H), 2.60 - 2.47 (m, 4 H), 2.42 (t, , 0.95 - 0.82 (m, 3H). Step 2:

[0345] Under a nitrogen atmosphere, benzyl 4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoic acid (5 g, 12.30 mmol, 1 eq) was added to a suspension of Pd / C (300 mg, 10% purity) in THF (100 mL). The reaction mixture was stirred at 25°C for 12 hr under H2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to DCM: MeOH = 0 : 1). The compound 4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoic acid (2.2 g, 6.95 mmol, 56.53% yield) was given as a pale yellow oil. 1 H NMR (400 MHz, MeOD) δ ppm 4.84-4.70(m, 1H), 3.31-3.26(m, 1H), 3.23-3.01(m, 5H), 2.75(s, 3H), 2.27-2.20(m, 1H), 2.14-1.98(m,2H),1.80-1.72(m,1H), 1.61-1.57(m,1H), 1.48-1.44(m,1H), 1.30-1.27(m,10H),0.88-0.84(m,3H). Step 3:

[0346] Under a nitrogen atmosphere, 4-pyrrolidine-1-ylpyridine (16.68 g) was added to a mixture of O8-[2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (1.1 g, 1.13 mmol, 1 eq), 4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoic acid (427.37 mg, 1.35 mmol, 1.2 eq), DIPEA (363.66 mg, 2.81 mmol, 490.10 μL, 2.5 eq), and EDCI (258.91 mg, 1.35 mmol, 1.2 eq) in DCM (20 mL). mg, 112.55 μmol, 0.1 eq). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (20 mL) and EtOAc (60 mL) (20 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). O8-[2-[4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoyloxymethyl]-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (100 mg, 78.38 μmol, 6.96% yield, 100% purity) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.49(m, 3H), 5.35-5.33(m, 3H), 4.75(s, 1H), 4.11(s, 8H), 4.06(t, J = 3.4 Hz, 6H), 3.29(s, 2H),2.53-2.37(m, 4H), 2.40-2.33(m, 8H), 2.31-2.78(m,14H), 2.07-2.01(m, 6H), 1.64-1.57(m, 14H), 1.50-1.40 (m,2H), 1.36-1.27(m, 40H), 1.10-1.05(m, 3H), 0.91-0.86 (m, 12H). Example 37 - Compound 30: O7-[2-[4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoyloxymethyl]-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]heptanediol ester

[0347] Under a N2 atmosphere, O7-[2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]pimercinate (0.8 g, 855.37 μmol, 1 eq), 4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoic acid (324.80 mg, 1.03 mmol, 1.2 eq), DIPEA (276.38 mg, 2.14 mmol, 372.47 μL, 2.5 eq) and EDCI (196.77 mg, 1.03 mmol, 1.2 eq) were reacted in DCM (10 4-pyrrolidine-1-ylpyridine (12.68 mg, 85.54 μmol, 0.1 eq) was added to the mixture in mL. The reaction mixture was stirred at 25°C for 12 hr under N2 atmosphere. The reaction mixture was diluted with H2O (20 mL) and EtOAc (60 mL) (20 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). O7-[2-[4-[2-[ethyl(methyl)amino]ethylcarbamoyloxy]decanoyloxymethyl]-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]pimercate (0.1 g, 81.06 μmol, 9.48% yield, 100% purity) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.52-5.50(m, 3H),5.36-5.33(m, 3H), 4.75(s, 1H), 4.11(s, 8H), 4.06(t, J = 3.4 Hz, 6H), 3.37(s,2H), 2.65-2.37(m, 3H), 2.40-2.34(m, 22H), 1.68-1.60(m, 22H), 1.38-1.24(m,32H), 0.89(m, 12H). Example 38 - Compound 31: O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(3-pyrrolidone-1-ylpropoxycarbonyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester Step 1:

[0348] Under a nitrogen atmosphere, Py (713.43 mg, 9.02 mmol, 727.99 μL, 2 eq), 3-pyrrolidine-1-ylprop-1-ol (873.98 mg, 6.76 mmol, 1.5 eq), and DMAP (55.09 mg, 450.97 μmol, 0.1 eq) were added to a solution of 4-(4-nitrophenoxy)carbonyloxydecanoate benzyl ester (2 g, 4.51 mmol, 1 eq) in ACN (28 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (100 mL) and diluted with EtOAc (400 mL) (100 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound 4-(3-pyrrolidine-1-ylpropoxycarbonyloxy)decanoic acid benzyl ester (1 g, 2.31 mmol, 51.14% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.37 - 7.27(m, 5 H), 5.12 (s, 2 H), 4.75 - 4.72 (m, 1 H), 4.20-4.16 (m, 2 H), 2.59 -2.55 (m, 2 H), 2.64 - 2.49 (m, 6 H), 1.99 (m, 1 H), 1.95 - 1.56 (m, 3 H), 1.89-1.81 (m, 4 H), 1.70 - 1.48 (m, 2 H), 1.38 - 1.25 (m, 8 H), 0.88 (t, J=6.6Hz, 3 H). Step 2:

[0349] Under a nitrogen atmosphere, benzyl 4-(3-pyrrolidine-1-ylpropoxycarbonyloxy)decanoate (1 g, 2.31 mmol, 1 eq) was added to a suspension of Pd / C (333.33 mg, 313.22 μmol, 10% purity, 1.36e-1 eq) in THF (20 mL). The reaction mixture was stirred at 25°C for 12 hr under H2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 100 / 1 to 0 / 1). The compound 4-(3-pyrrolidine-1-ylpropoxycarbonyloxy)decanoic acid (0.4 g, 1.16 mmol, 50.50% yield) was given as a pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ ppm 8.24 - 8.17 (m, 1 H), 4.84-4.82 (m,1 H), 4.34-4.32 (m, 1 H), 4.02 (m, 1 H), 3.32 - 3.05 (m, 3 H), 2.98 - 2.87(m, 2 H), 2.26 - 2.73 (m, 1 H), 2.39 - 2.20 (m, 2 H), 2.15 - 2.03 (m, 1 H), 2.01 - 1.83 (m, 7 H), 1.78 - 1.56 (m, 1 H), 1.52 (m, 1 H), 1.38 - 1.07 (m, 8H), 0.95 - 0.76 (m, 3 H). Step 3:

[0350] Under a nitrogen atmosphere, EDCI (235.37 mg, 1.23 mmol, 1.2 eq), 4-(3-pyrrolidine-1-ylpropoxycarbonyloxy)decanoic acid (316.27 mg, 920.86 μmol, 0.9 eq), 4-pyrrolidine-1-ylpyridine (15.16 mg, 102.32 μmol, 0.1 eq), and DIPEA (330.60 mg, 2.56 μmol, 1 g, 1 eq) were added to a solution of O8-[2-(hydroxymethyl)-3-[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxy-2-[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (1 g, 1.02 mmol, 1 eq) in DCM (1.13 mL). mmol, 445.55 μL, 2.5 eq). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O8-[2,2-bis[[8-[(Z)-non-3-enoxy]-8-oxo-octanoyl]oxymethyl]-3-[4-(3-pyrrolidine-1-ylpropoxycarbonyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]octanoic acid ester (0.1 g, 76.76 μmol, 7.50% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.54-5.48(m, 3H), 5.37-5.31(m, 3H), 4.72-4.70(m, 1H), 4.21-4.20(m, 2H), 4.11(d, J=4.0Hz, 8H), 4.06 (t, J=7.2Hz, 6H), 2.63(s, 4H), 2.40-2.35(m, 8H), 2.33-2.28(m, 12H), 2.05-2.01(m, 10H), 1.88-1.84(m, 4H), 1.64-1.59(m, 16H), 1.34-1.28(m, 38H), 0.91-0.87 (m, 12H). Example 39 - Compound 32:

[0351] Under a nitrogen atmosphere, EDCI (368.94 mg, 1.92 mmol, 1.2 eq), 4-(3-pyrrolidine-1-ylpropoxycarbonyloxy)decanoic acid (495.76 mg, 1.44 mmol, 0.9 eq), DMAP (19.59 mg, 160.38 μmol, 0.1 eq) and DIPEA (518.20 mg, 4.01 mmol, 698.39 μmol) were added to a solution of O7-[2-(hydroxymethyl)-3-[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxy-2-[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]propyl]O1-[(Z)-non-3-enyl]peptidate (1.5 g, 1.60 mmol, 1 eq) in DCM (20 mL) were added. μL, 2.5 eq). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and diluted with DCM (200) (100 mL). 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[2,2-bis[[7-[(Z)-non-3-enoxy]-7-oxo-heptanoyl]oxymethyl]-3-[4-(3-pyrrolidine-1-ylpropoxycarbonyloxy)decanoyloxy]propyl]O1-[(Z)-non-3-enyl]pimercate (100 mg, 78.88 μmol, 4.92% yield, 99.45% purity) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.52-5.50(m, 3H),5.35-5.33(m, 3H), 4.74-4.70(m, 1H), 4.22(t, J=6Hz, 2H), 4.11(s, 8H), 4.06 (t,J=7.2Hz, 6H), 3.04-2.88(m, 4H), 2.38(t, J=6.4Hz, 7H), 2.35-2.27(m, 12H), 2.20-2.18(m, 2H), 2.07-2.01(m, 10H), 1.66-1.60(m, 20H), 1.37-1.28(m, 30H), 0.91-0.87 (m, 12H). Example 40 - Compound 33: O8-[2,2-bis[(8-octyloxy-8-oxo-octylyl)oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-octyloctyl ester Step 1:

[0352] Under a nitrogen atmosphere, octanoic acid (133.76 g, 767.89 mmol, 5 eq) was added to a mixture of octano-1-ol (20 g, 153.58 mmol, 24.27 mL, 1 eq), DIPEA (59.55 g, 460.73 mmol, 80.25 mL, 3 eq), DMAP (3.75 g, 30.72 mmol, 0.2 eq), and EDCI (38.27 g, 199.65 mmol, 1.3 eq) in DCM (800 mL) and THF (800 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 8-octyloxy-8-oxo-octanoic acid (25 g, 87.29 mmol, 56.84% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 11.23 (br s, 1 H), 4.06 (t, J=6.8 Hz, 2 H), 2.42 - 2.22 (m, 4 H), 1.73 - 1.55 (m, 6 H), 1.46 - 1.26 (m, 14H), 0.89 (t, J=6.8 Hz, 3H). Step 2:

[0353] Under a nitrogen atmosphere, [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (4 g, 22.70 mmol, 0.45 eq) was added to a mixture of 8-octyloxy-8-oxo-octanoic acid (14.45 g, 50.44 mmol, 1 eq), DIPEA (16.30 g, 126.11 mmol, 21.97 mL, 2.5 eq), EDCI (11.60 g, 60.53 mmol, 1.2 eq), and DMAP (616.27 mg, 5.04 mmol, 0.1 eq) in DCM (200 mL), and the reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[[2,2-dimethyl-5-[(8-octyloxy-8-oxo-octanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-octyl octanoate was given as a colorless oil (6.5 g, 9.12 mmol, 18.07% yield). 1 H NMR (400 MHz, CDCl3)δ ppm 4.10 (s, 4 H), 4.06 (t, J=6.8 Hz, 4 H), 3.74 (s, 4 H), 2.30 (m, 8 H), 1.69 - 1.59 (m, 12 H), 1.42 (s, 6 H), 1.36 - 1.24 (m, 28 H), 0.94 - 0.83 (m, 6 H). Step 3:

[0354] Under a nitrogen atmosphere at 0°C, HCl (3 M, 3.75 mL, 1.1 eq) was added to a solution of O8-[[2,2-dimethyl-5-[(8-octyloxy-8-oxo-octanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-octyl octanoate (6.5 g, 9.12 mmol, 1 eq) in THF (65 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with aqueous NaHCO3 (200 mL) and diluted with EtOAc (250 mL) (50 mL) 5) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2,2-bis(hydroxymethyl)-3-(8-octoxy-8-oxo-octanoyl)oxy-propyl]O1-octyl octanoic acid ester (2.5 g, 3.72 mmol, 40.75% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.15 (s, 4 H), 3.98 (t, J=6.8Hz, 4 H), 3.57 (s, 4 H), 2.86 (br s, 2 H), 2.34 - 2.16 (m, 8 H), 1.59 - 1.46 (m, 12 H), 1.31 - 1.17 (m, 28 H), 0.90 - 0.72 (m, 6 H). Step 4:

[0355] Under a nitrogen atmosphere, 8-octyloxy-8-oxo-octanoic acid (331.98 mg, 1.16 mmol, 0.6 eq) was added to a mixture of O8-[2,2-bis(hydroxymethyl)-3-(8-octoxy-8-oxo-octanoyl)oxy-propyl]O1-octyl octanoic acid (1.3 g, 1.93 mmol, 1 eq), EDCI (444.41 mg, 2.32 mmol, 1.2 eq), DMAP (23.60 mg, 193.19 μmol, 0.1 eq), and DIPEA (624.20 mg, 4.83 mmol, 841.24 μL, 2.5 eq) in DCM (150 mL), and the reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2-(hydroxymethyl)-3-(8-octoxy-8-oxo-octanoyl)oxy-2-[(8-octoxy-8-oxo-octanoyl)oxymethyl]propyl]O1-octyl octanoic acid ester (500 mg, 531.17 μmol, 27.50% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.11 (s, 6 H), 4.06 (t, J=6.8 Hz, 6H), 3.50 (d, J=6.8 Hz, 2 H), 2.60 (t, J=6.8 Hz, 1 H), 2.38 - 2.27 (m, 12 H), 1.62 (m, 18 H), 1.36 - 1.23 (m, 42 H), 0.93 - 0.82 (m, 9 H). Step 5:

[0356] Under a nitrogen atmosphere, 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (498.96 mg, 1.52 mmol, 1 eq) was added to a mixture of O8-[2-(hydroxymethyl)-3-(8-octoxy-8-oxo-octanoyl)oxy-2-[(8-octoxy-8-oxo-octanoyl)oxymethyl]propyl]O1-octyl octanoic acid ester (1.1 g, 1.17 mmol, 1 eq), DIPEA (377.58 mg, 2.92 mmol, 508.86 μL, 2.5 eq), EDCI (268.82 mg, 1.40 mmol, 1.2 eq) and 4-pyrrolidine-1-ylpyridine (17.32 mg, 116.86 μmol, 0.1 eq) in DCM (15 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with 20 mL of H₂O and then diluted with 60 mL of ethyl acetate. 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2,2-bis[(8-octyloxy-8-oxo-octylyl)oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-octyl octanoic acid ester (150 mg, 119.83 μmol, 10.25% yield, 100% purity) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.18(s, 1H), 4.75(s, 1H), 4.14-4.11(m, 8H), 4.05(t, J = 3.4 Hz, 2H), 3.29(d, J = 2.6 Hz, 2H), 2.60-2.52(m, 6H), 2.33-2.29(m, 14H), 1.90 (d, J = 3.0 Hz, 1H), 1.18(s, 4H), 1.62-1.61(m, 20H), 1.35-1.25(m, 52H), 0.90-0.86(m,12H). Example 41 - Compound 34: O7-[2,2-bis[(7-octoxy-7-oxo-heptanoyl)oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-octylheptane ester Step 1:

[0357] Add EDCI (38.27 g, 199.65 mmol, 1.3 eq), DMAP (1.88 g, 15.36 mmol, 0.1 eq), DIPEA (49.62 g, 383.94 mmol, 66.88 mL, 2.5 eq), and octyl-1-ol (20 g, 153.58 mmol, 24.27 mL, 1 eq) to a solution of pimecrolic acid (122.99 g, 767.89 mmol, 5 eq) in DCM (615 mL) and THF (615 mL) to a solution of pimecrolic acid (122.99 g, 767.89 mmol, 5 eq), and stir at 25°C for 12 hr under a N2 atmosphere. Dilute the reaction mixture with H2O (300 mL) and mix with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound 7-octyloxy-7-oxo-heptanoic acid (30 g, 110.14 mmol, 71.72% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 11.02 (br s, 1 H), 4.06 (t, J=6.8 Hz, 2 H), 2.43 - 2.24 (m, 4H), 1.74 - 1.56 (m, 6 H), 1.45 - 1.16 (m, 12 H), 0.94 - 0.80 (m, 3H). Step 2:

[0358] Under a nitrogen atmosphere, EDCI (11.60 g, 60.53 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (4 g, 22.70 mmol, 0.45 eq), DMAP (616.27 mg, 5.04 mmol, 0.1 eq), and DIPEA (16.30 g, 126.11 mmol, 21.97 mL, 2.5 eq) were added to a solution of 7-octyloxy-7-oxo-heptanoic acid (13.74 g, 50.44 mmol, 1 eq) in DCM (130 mL) at N2 atmosphere. The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[[2,2-dimethyl-5-[(7-octoxy-7-oxo-heptanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-octyl pimecrolate (7 g, 10.22 mmol, 20.26% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.11 (s, 4 H), 4.06 (t, J=6.8 Hz, 4 H), 3.74 (s, 4 H), 2.32 (m, 8 H), 1.70 - 1.59 (m, 12 H), 1.42 (s, 6 H), 1.40 - 1.25 (m, 24 H), 0.95 - 0.81 (m, 6 H). Step 3:

[0359] Under a nitrogen atmosphere at 0°C, HCl (3 M, 3.75 mL, 1.1 eq) was added to a solution of O7-[[2,2-dimethyl-5-[(7-octyloxy-7-oxo-heptanoyl)oxymethyl]-1,3-dioxane-5-yl]methyl]O1-octyl pimecrolate (7 g, 10.22 mmol, 1 eq) in THF (70 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with aqueous NaHCO3 (200 mL) and diluted with EtOAc (250 mL) (50 mL) 5) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[2,2-bis(hydroxymethyl)-3-(7-octoxy-7-oxo-heptanoyl)oxy-propyl]O1-octyl pimecrolate (2.5 g, 3.88 mmol, 37.93% yield) was given as a colorless oil. Step 4:

[0360] Under a nitrogen atmosphere, EDCI (356.72 mg, 1.86 mmol, 1.2 eq), 7-octyloxy-7-oxo-heptanoic acid (253.43 mg, 930.41 μmol, 0.6 eq), DMAP (18.94 mg, 155.07 μmol, 0.1 eq), and DIPEA (501.04 mg, 3.88 mmol, 675.26 μL, 2.5 eq) were added to a solution of O7-[2,2-bis(hydroxymethyl)-3-(7-octoxy-7-oxo-heptanoyl)oxy-propyl]O1-octyl pimecroceta ester (1 g, 1.55 mmol, 1 eq) in DCM (10 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[2-(hydroxymethyl)-3-(7-octoxy-7-oxo-heptanoyl)oxy-2-[(7-octoxy-7-oxo-heptanoyl)oxymethyl]propyl]O1-octyl pimecrolate (0.4 g, 444.82 μmol, 28.69% yield) was given as a colorless oil. 1H NMR(400 MHz, CDCl3) δ ppm 4.16(s, 6H), 4.06 (t, J=6.4Hz, 6H), 3.52(d, J=6.8Hz,2H), 2.66(t, J=6.8Hz, 1H), 2.36-2.29(m, 12H), 1.69-1.59(m, 19H), 1.40-1.27(m,34H), 0.89(t, J=13.6Hz, 9H). Step 5:

[0361] Under a nitrogen atmosphere, EDCI (102.33 mg, 533.79 μmol, 1.2 eq), 4-(2-octyloxy-7-oxo-heptanoyl)oxy-2-[(7-octyloxy-7-oxo-heptanoyl)oxymethyl]propyl]O1-octyl pimecrolate (0.4 g, 444.82 μmol, 1 eq) was added to a solution of O7-[2-(hydroxymethyl)-3-(7-octoxy-7-oxo-heptanoyl)oxy-2-[(7-octoxy-7-oxo-heptanoyl)oxymethyl]propyl]O1-octyl pimecrolate (0.4 g, 444.82 μmol, 1 eq) in DCM (5 mL), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (131.49 mg, 400.34 μmol, 0.9 eq), DIPEA (143.72 mg, 1.11 mmol, 193.70 μL, 2.5 eq), and DMAP (5.43 mg, 44.48 μmol, 0.1 eq) were added. The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. Dilute the reaction mixture with H2O (50 mL) and with DCM (50 mL) (25 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O7-[2,2-bis[(7-octoxy-7-oxo-heptanoyl)oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-octylpimercate was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 5.19 (s, 1H), 4.76 (d, J=2.0 Hz, 1H), 4.12 (s, 8H), 4.06 (t, J=6.8 Hz, 6 H), 3.30 (d, J=5.2 Hz, 1H), 2.61(t, J=12 Hz, 2H), 2.52 (s, 4H), 2.40-2.29 (m, 14H), 1.95-1.78 (m, 6H), 1.68-1.60 (m, 22H), 1.39-1.28 (m, 42H), 0.90-0.87 (m, 12H). Example 42 - Compound 35: O8-[2,2-bis[(8-decoxy-8-oxo-octanoyl)oxymethyl]-3-[4-(2-pyrrolidone-1-ethylcarbamoyloxy)decanoyloxy]propyl]O1-decyloctanoate Step 1:

[0362] Under a nitrogen atmosphere, octanoic acid (110.05 g, 631.79 mmol, 5 eq) was added to a mixture of decanol (20 g, 126.36 mmol, 24.13 mL, 1 eq), DMAP (1.54 g, 12.64 mmol, 0.1 eq), EDCI (29.07 g, 151.63 mmol, 1.2 eq), and DIPEA (40.83 g, 315.90 mmol, 55.02 mL, 2.5 eq) in DCM (65 mL) and THF (65 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (600 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 8-decyloxy-8-oxo-octanoic acid (25 g, 79.50 mmol, 62.92% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 11.71-10.55(m, 1H), 4.06(t, J = 3.2Hz, 2H), 2.37-2.28(m, 4H), 1.69-1.58(m,6H), 1.43-1.27(m,18H), 0.89(t, J = 3.4Hz, 3H). Step 2:

[0363] Under a nitrogen atmosphere, [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (2 g, 11.35 mmol, 0.45 eq) was added to a mixture of 8-decyloxy-8-oxo-octanoic acid (7.93 g, 25.22 mmol, 1 eq), DIPEA (8.15 g, 63.06 mmol, 10.98 mL, 2.5 eq), EDCI (5.80 g, 30.27 mmol, 1.2 eq), and DMAP (616.27 mg, 5.04 mmol, 0.2 eq) in DCM (300 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[[5-[(8-decoxy-8-oxo-octanoyl)oxymethyl]-2,2-dimethyl-1,3-dioxane-5-yl]methyl]O1-decyl octanoate was given as a colorless oil (4 g, 5.20 mmol, 20.62% yield). 1 H NMR (400 MHz, CDCl3) δ ppm 4.10 (s,4 H), 4.05 (t, J=6.8 Hz, 4 H), 3.74 (s, 4 H), 2.30-2.90 (m, 8 H), 1.63-1.60 (m, 12 H), 1.42 (s, 6 H), 1.22 - 1.36 (m, 36 H), 0.88 (t, J=6.8 Hz, 6 H). Step 3:

[0364] Under a nitrogen atmosphere at 0°C, HCl (2 M, 2.86 mL, 1.1 eq) was added to a solution of O8-[[5-[(8-decoxy-8-oxo-octanoyl)oxymethyl]-2,2-dimethyl-1,3-dioxane-5-yl]methyl]O1-decyl octanoate (4 g, 5.20 mmol, 1 eq) in THF (40 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2-[(8-decoxy-8-oxo-octanoyl)oxymethyl]-3-hydroxy-2-(hydroxymethyl)propyl]O1-decyl octanoic acid ester (1.5 g, 2.06 mmol, 39.56% yield) was given as a colorless oil. Step 4:

[0365] Under a nitrogen atmosphere, 8-decyloxy-8-oxo-octanoic acid (388.20 mg, 1.23 mmol, 0.6 eq) was added to a mixture of O8-[2-[(8-decoxy-8-oxo-octanoyl)oxymethyl]-3-hydroxy-2-(hydroxymethyl)propyl]O1-decyl octanoic acid (1.5 g, 2.06 mmol, 1 eq), EDCI (473.32 mg, 2.47 mmol, 1.2 eq), DMAP (25.14 mg, 205.75 μmol, 0.1 eq), and DIPEA (664.80 mg, 5.14 mmol, 895.96 μL, 2.5 eq) in DCM (15 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2,2-bis[(8-decyloxy-8-oxo-octanoyl)oxymethyl]-3-hydroxy-propyl]O1-decyl octanoic acid ester (800 mg, 780.12 μmol, 37.92% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.11 (s, 6 H), 4.05 (t, J=6.8 Hz, 6 H), 3.50 (d, J=6.8 Hz, 1 H), 3.56 - 3.43 (m, 1 H), 2.61 (t, J=6.6 Hz, 1 H), 2.37 - 2.27 (m, 12 H), 1.67 -1.58 (m, 18 H), 1.37 - 1.20 (m, 54 H), 0.97 - 0.73 (m, 9 H). Step 5:

[0366] Under a nitrogen atmosphere, 4-(2-pyrrolidine-1-ylcarbamoyloxy)decanoic acid (576.51 mg, 1.76 mmol, 1.2 eq), DIPEA (472.62 mg, 3.66 mmol, 636.95 μL, 2.5 eq), 4-pyrrolidine-1-ylpyridine (216.78 mg, 1.46 mmol, 1 eq), and EDCI (336.49 mg, 1.76 mmol, 1.2 eq) were added to a solution of O8-[2,2-bis[(8-decoxy-8-oxo-octanoyl)oxymethyl]-3-hydroxy-propyl]O1-decyloctanoic acid (1.5 g, 1.46 mmol, 1 eq) in DCM (20 mL), in 25 °C. The reaction mixture was diluted with H2O (20 mL) and ethyl acetate (60 mL) (20 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O8-[2,2-bis[(8-decoxy-8-oxo-octanoyl)oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-decyl octanoic acid ester (110 mg, 82.34 μmol, 5.63% yield, 100% purity) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm5.18 (br s, 1 H), 4.75 (br s, 1 H), 4.14 - 4.09 (m, 8 H), 4.06 (t, J=6.8 Hz, 6 H), 3.29 (d, J=5.2 Hz, 2 H), 2.59 (t, J=5.9 Hz, 2 H), 2.52 (br s, 4 H), 2.40 - 2.34 (m, 2 H), 2.33 - 2.27 (m, 12 H), 1.94 - 1.84 (m, 1 H), 1.78 (brs, 4 H), 1.61 (m, 18 H), 1.44 - 1.11 (m, 66 H), 0.96 - 0.81 (m, 12 H). Example 43 - Compound 36: O7-[2,2-bis[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-decylheptanoate Step 1:

[0367] Under a nitrogen atmosphere, pimelic acid (101.19 g, 631.79 mmol, 5 eq) was added to a mixture of decanol (20 g, 126.36 mmol, 24.13 mL, 1 eq), EDCI (29.07 g, 151.63 mmol, 1.2 eq), DMAP (1.54 g, 12.64 mmol, 0.1 eq), and DIPEA (40.83 g, 315.90 mmol, 55.02 mL, 2.5 eq) in DCM (600 mL) and THF (600 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL). 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 7-decyloxy-7-oxo-heptanoic acid (30 g, 99.86 mmol, 79.03% yield) was given as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 11.27 (br s, 1 H), 4.06 (t, J=6.8 Hz, 2 H), 2.45 - 2.29 (m, 4 H), 1.71 - 1.56 (m, 6 H), 1.45 - 1.24 (m, 16H), 0.96 - 0.83 (m, 3H). Step 2:

[0368] Under a nitrogen atmosphere, 7-decyloxy-7-oxo-heptanoic acid (11.37 g, 37.83 mmol, 1 eq) was added to a mixture of [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (3 g, 17.03 mmol, 0.45 eq), DMAP (462.20 mg, 3.78 mmol, 0.1 eq), EDCI (8.70 g, 45.40 mmol, 1.2 eq), and DIPEA (12.22 g, 94.58 mmol, 16.47 mL, 2.5 eq) in DCM (150 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[[5-[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-2,2-dimethyl-1,3-dioxane-5-yl]methyl]O1-decyl pimecrolate (3.5 g, 4.72 mmol, 12.48% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.11(s, 4 H), 4.06 (t, J=6.8 Hz, 4 H), 3.74 (s, 4 H), 2.32 (m, 8 H), 1.73 - 1.59(m, 12 H), 1.42 (s, 6 H), 1.39 - 1.23 (m, 32 H), 0.90 - 0.86 (m, 6 H). Step 3:

[0369] Under a nitrogen atmosphere at 0°C, HCl (3 M, 1.73 mL, 1.1 eq) was added to a mixture of O7-[[5-[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-2,2-dimethyl-1,3-dioxane-5-yl]methyl]O1-decyl pimecrolate (3.5 g, 4.72 mmol, 1 eq) in THF (35 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with aqueous NaHCO3 (200 mL) and diluted with ethyl acetate (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[2-[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-3-hydroxy-2-(hydroxymethyl)propyl]O1-decyl pimecrolate (1.2 g, 1.71 mmol, 36.25% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.15 (s, 4 H), 4.06 (t, J=6.8 Hz, 4 H), 3.59 (br d, J=4.2 Hz, 4 H), 2.78 (br s, 2 H), 2.45 - 2.25 (m, 8 H), 1.69 - 1.59 (m, 12 H), 1.40 - 1.24 (m, 32 H), 0.97 - 0.82 (m, 6 H). Step 4:

[0370] Under a nitrogen atmosphere, 7-decyloxy-7-oxo-heptanoic acid (257.15 mg, 855.94 μmol, 0.6 eq) was added to a mixture of O7-[2-[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-3-hydroxy-2-(hydroxymethyl)propyl]O1-decyl heptanoic acid (1 g, 1.43 mmol, 1 eq), DIPEA (460.94 mg, 3.57 mmol, 621.21 μL, 2.5 eq), EDCI (328.17 mg, 1.71 mmol, 1.2 eq), and DMAP (17.43 mg, 142.66 μmol, 0.1 eq) in DCM (15 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (20 mL) and diluted with ethyl acetate (60 mL) (20 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[2,2-bis[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-3-hydroxy-propyl]O1-decyl pimecrolate (0.4 g, 406.75 μmol, 28.51% yield) was given as a colorless oil. 1 H NMR (400MHz, CDCl3) δ ppm 4.11 (s, 6 H), 4.05 (t, J=6.8 Hz, 6 H), 3.51 (br d, J=6.4Hz, 2 H), 2.68 (t, J=6.6 Hz, 1 H), 2.32 (m, 12 H), 1.68 - 1.59 (m, 18 H),1.40 - 1.24 (m, 48 H), 0.88 (t, J=6.6 Hz, 9 H) Step 5:

[0371] Under a nitrogen atmosphere, 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (280.55 mg, 854.18 μmol, 1.2 eq) was added to a mixture of O7-[2,2-bis[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-3-hydroxy-propyl]O1-decyl pimecrolate (0.7 g, 711.82 μmol, 1 eq), DIPEA (229.99 mg, 1.78 mmol, 309.96 μL, 2.5 eq), EDCI (163.75 mg, 854.18 μmol, 1.2 eq) and 4-pyrrolidine-1-ylpyridine (10.55 mg, 71.18 μmol, 0.1 eq) in DCM (10 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (20 mL) and ethyl acetate (60 mL) (20 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O7-[2,2-bis[(7-decoxy-7-oxo-heptanoyl)oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O1-decyl pimecrolate (130 mg, 100.48 μmol, 14.12% yield, 100% purity) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.21 (br s, 1 H), 4.75 (br s, 1 H), 4.11 (s, 8 H), 4.06 (t, J=6.8 Hz, 6 H), 3.30 (br d, J=4.8 Hz, 2 H), 2.60 (br s, 2 H), 2.53 (br s, 4 H), 2.42 - 2.36 (m, 2 H), 2.31 (d, J=7.4 Hz, 10 H), 1.90 (m, 1 H), 1.78 (br s, 6H), 1.71 - 1.59 (m, 20 H), 1.46 - 1.24 (m, 58 H), 0.98 - 0.82 (m, 12 H). Example 44 - Compound 37: O1-[2,2-bis[[8-(1-methyloctyloxy)-8-oxo-octyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O8-(1-methyloctyl)octyl ester Step 1:

[0372] Under a nitrogen atmosphere, EDCI (15.95 g, 83.19 mmol, 1.2 eq), DMAP (846.89 mg, 6.93 mmol, 0.1 eq), and DIPEA (22.40 g, 173.31 mmol, 30.19 mL, 2.5 eq) were added to a solution of octanoic acid (60.38 g, 346.61 mmol, 5 eq) in DCM (600 mL). Then, nonan-2-ol (10 g, 69.32 mmol, 1 eq) in DCM (100 mL) was added to the above reaction mixture, and the reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O (500 mL) and mixed with DCM (150 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound 8-(1-methyloctyloxy)-8-oxo-octanoic acid (6 g, 19.97 mmol, 28.81% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 10.42 (brs, 1 H), 4.80 - 5.00 (m, 1 H), 2.36 (t, J=7.4 Hz, 2 H), 2.28 (t, J=7.6 Hz, 2H), 1.71 - 1.41 (m, 5 H), 1.49 - 1.41 (m, 1 H), 1.40 - 1.33 (m, 4 H), 1.33 -1.22 (m, 10 H), 1.20 (d, J=6.2 Hz, 3 H), 0.96 - 0.80 (m, 3 H). Step 2:

[0373] Under a nitrogen atmosphere, EDCI (11.60 g, 60.53 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (4 g, 22.70 mmol, 0.45 eq), DMAP (616.27 mg, 5.04 mmol, 0.1 eq), and DIPEA (16.30 g, 126.11 mmol, 21.97 mL, 2.5 eq) were added to a solution of 8-(1-methyloctyloxy)-8-oxo-octanoic acid (15.16 g, 50.44 mmol, 1 eq) in DCM (200 mL) at N2 atmosphere. The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and mixed with DCM (800 mL) (200 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[[2,2-dimethyl-5-[[8-(1-methyloctyloxy)-8-oxo-octanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O8-(1-methyloctyl)octanoic acid ester (8 g, 10.80 mmol, 21.40% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92 - 4.87 (m, 2 H), 4.11 (s, 4 H), 3.74 (s, 4 H), 2.30 (m, 8H), 1.71 - 1.56 (m, 10 H), 1.48 (m, 2 H), 1.42 (s, 6 H), 1.39 - 1.31 (m, 10H), 1.31 - 1.25 (m, 18 H), 1.20 (d, J=6.2 Hz, 6 H), 0.93 - 0.83 (m, 6 H). Step 3:

[0374] Under a nitrogen atmosphere at 0°C, HCl (3 M, 3.46 mL, 1.1 eq) was added to a solution of O1-[[2,2-dimethyl-5-[[8-(1-methyloctyloxy)-8-oxo-octyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O8-(1-methyloctyl)octanoic acid ester (7 g, 9.45 mmol, 1 eq) in THF (70 mL). The reaction mixture was stirred at 25°C for 2 hr under a nitrogen atmosphere. The reaction mixture was diluted with aqueous NaHCO3 (200 mL) and diluted with EtOAc (600 mL) (200 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[2,2-bis(hydroxymethyl)-3-[8-(1-methyloctyloxy)-8-oxo-octanoyl]oxy-propyl]O8-(1-methyloctyl)octanoic acid ester (4 g, 5.71 mmol, 60.41% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92 -4.88 (m, 2 H), 4.15 (s, 4 H), 3.59 (s, 4 H), 2.78 (br s, 2 H), 2.36 (t, J=7.6Hz, 4 H), 2.28 (t, J=7.4 Hz, 4 H), 1.63 (m, 10 H), 1.52 - 1.42 (m, 2 H), 1.37- 1.23 (m, 28 H), 1.20 (d, J=6.2 Hz, 6 H), 0.96 - 0.80 (m, 6 H). Step 4:

[0375] Under a nitrogen atmosphere, EDCI (984.51 mg, 5.14 mmol, 1.2 eq), 8-(1-methyloctyloxy)-8-oxo-octanoic acid (771.46 mg, 2.57 mmol, 0.6 eq), DMAP (52.28 mg, 427.97 μmol, 0.1 eq), and DIPEA (1.38 g, 10.70 mmol, 1.86 mL, 2.5 eq) were added to a solution of O1-[2,2-bis(hydroxymethyl)-3-[8-(1-methyloctyloxy)-8-oxo-octanoyl]oxy-propyl]O8-(1-methyloctyl)octanoic acid (3 g, 4.28 mmol, 1 eq) in DCM (37 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. Dilute the reaction mixture with H2O (100 mL) and with DCM (400 mL) (100 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). The compound O1-[2-(hydroxymethyl)-3-[8-(1-methyloctyloxy)-8-oxo-octanoyl]oxy-2-[[8-(1-methyloctyloxy)-8-oxo-octanoyl]oxymethyl]propyl]O8-(1-methyloctyl)octanoic acid ester (1.5 g, 1.53 mmol, 35.64% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92-4.86 (m, 3H), 4.12(s, 6H), 3.51 (d, J=9.6Hz, 2H), 2.61 (t, J=6.8Hz, 1H), 2.35-2.26 (m, 12H), 1.64-1.61 (m, 12H), 1.49-1.43 (m, 4H), 1.36-1.32 (m,14H), 1.30-1.28(m, 30H), 1.20 (t, J=6.4Hz, 9H), 0.88 (t, J=13.6Hz, 9H). Step 5:

[0376] Under a N2 atmosphere, EDCI (421.07 mg, 2.20 mmol, 1 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (541.07 mg, 1.65 mmol, 0.9 eq), 4-pyrrolidine-1-ylpyridine (27.13 mg, 183.04 μmol, 0.1 eq) and DIPEA (591.41 mg, 4.58 mmol, 797.05 μL, 2.5 eq) were added to a solution of O1-[2-(hydroxymethyl)-3-[8-(1-methyloctyloxy)-8-oxo-octyl]oxy-2-[[8-(1-methyloctyloxy)-8-oxo-octyl]oxymethyl]propyl]O8-(1-methyloctyl)octanoic acid (1.8 g, 1.83 mmol, 1 eq) in DCM (19 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with 100 mL of H₂O and then diluted with 400 mL of DCM (100 mL). 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[2,2-bis[[8-(1-methyloctyloxy)-8-oxo-octyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O8-(1-methyloctyl)octyl ester (0.1 g, 61.83 μmol, 3.38% yield, 80% purity) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.40-5.35(m, 1H),4.94-4.74(m, 3H), 4.75(s, 1H), 4.11-4.09(s, 8H), 3.37(s, 2H), 2.72-2.60(s,6H), 2.40-2.25(m, 14H), 1.86-1.77(m, 6H), 1.64-1.55(m, 18H), 1.49-1.45(m,4H), 1.35-1.27(m, 48H), 1.20(d, J=6.4Hz, 9H), 0.88(t, J=13.6Hz, 12H). Example 45 - Compound 38: O1-[2,2-bis[[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O7-(1-methyloctyl)heptanediate Step 1:

[0377] Under a nitrogen atmosphere, a solution of nonan-2-ol (20 g, 138.64 mmol, 1 eq) in DCM (1310 mL) was mixed with EDCI (34.55 g, 180.24 mmol, 1.3 eq), pimelic acid (111.03 g, 693.22 mmol, 5 eq), DMAP (1.69 g, 13.86 mmol, 0.1 eq), and DIPEA (44.80 g, 346.61 mmol, 60.37 mL, 2.5 eq). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (500 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound 7-(1-methyloctyloxy)-7-oxo-heptanoic acid (30 g, 104.75 mmol, 75.55% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.93 - 4.88 (m, 1 H), 2.37 (t, J=7.6 Hz, 2 H), 2.29 (t, J=7.6 Hz, 2 H), 1.74 - 1.61 (m, 4 H), 1.61 - 1.52 (m, 1 H), 1.52 - 1.34 (m, 3 H), 1.33 - 1.23 (m, 10 H), 1.20 (d, J=6.2 Hz, 3 H), 0.96- 0.82 (m, 3H). Step 2:

[0378] Under a nitrogen atmosphere, EDCI (2.90 g, 15.13 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (1 g, 5.68 mmol, 0.45 eq), DMAP (154.07 mg, 1.26 mmol, 0.1 eq), and DIPEA (4.07 g, 31.53 mmol, 5.49 mL, 2.5 eq) were added to a solution of 7-(1-methyloctyloxy)-7-oxo-heptanoic acid (3.61 g, 12.61 mmol, 1 eq) in DCM (46 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[[2,2-dimethyl-5-[[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O7-(1-methyloctyl)pimercate (1.5 g, 2.10 mmol, 16.68% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92 - 4.88 (m, 2 H), 4.11 (s, 4 H), 3.75 (s, 4 H), 2.37 - 2.13 (m, 8 H), 1.69 - 1.60 (m, 8 H), 1.47 (br d, J=8.0 Hz, 2 H), 1.56 (s, 2 H), 1.42 (s, 6 H), 1.39 - 1.22 (m, 24 H), 1.20 (d, J=6.2 Hz, 6 H), 0.98 - 0.71 (m, 6 H). Step 3:

[0379] Under a nitrogen atmosphere at 0°C, HCl (3 M, 771.40 μL, 1.1 eq) was added to a solution of O1-[[2,2-dimethyl-5-[[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O7-(1-methyloctyl)pimercinate (1.5 g, 2.10 mmol, 1 eq) in THF (15 mL). The reaction mixture was stirred at 25°C for 2 hr under a nitrogen atmosphere. The reaction mixture was diluted with aqueous NaHCO3 (50 mL) and diluted with EtOAC (100 mL) (50 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[2,2-bis(hydroxymethyl)-3-[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxy-propyl]O7-(1-methyloctyl)pimercate (0.6 g, 891.63 μmol, 42.38% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm4.92-4.87(m, 2H), 4.15(s, 4H), 3.59(s, 4H), 2.37(t, J=7.2Hz, 4H), 2.29(t, J=7.6Hz, 4H), 1.70-1.55(m, 12H), 1.50-1.32(m, 8H), 1.28(s, 18H) 1.20(d, J =6.0Hz, 6H), 0.89(t, J =6.4Hz, 6H). Step 4:

[0380] Under a nitrogen atmosphere, EDCI (205.11 mg, 1.07 mmol, 1.2 eq), 7-(1-methyloctyloxy)-7-oxo-heptanoic acid (153.22 mg, 534.98 μmol, 0.6 eq), DMAP (10.89 mg, 89.16 μmol, 0.1 eq), and DIPEA (288.09 mg, 2.23 mmol, 388.26 μL, 2.5 eq) were added to a solution of O1-[2,2-bis(hydroxymethyl)-3-[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxy-propyl]O7-(1-methyloctyl)p-glucopyranoic acid (153.22 mg, 534.98 μmol, 0.6 eq), DMAP (10.89 mg, 89.16 μmol, 0.1 eq), and DIPEA (288.09 mg, 2.23 mmol, 388.26 μL, 2.5 eq) in DCM (1 mL) were added. The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. Dilute the reaction mixture with H2O (50 mL) and with DCM (100 mL) (50 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). The compound O1-[2-(hydroxymethyl)-3-[7-(1-methyloctyloxy)-7-oxo-heptanyl]oxy-2-[[7-(1-methyloctyloxy)-7-oxo-heptanyl]oxymethyl]propyl]O7-(1-methyloctyl)pimercinate (0.3 g, 318.70 μmol, 35.74% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92-4.87(m, 3H), 4.11(s, 6H), 3.51(d, J =6.4Hz, 2H), 2.69(t, J =13.6Hz, 1H), 2.36-2.26(m, 12H), 1.69-1.62(m, 12H), 1.58-1.44(m, 6H), 1.40-1.32(m, 8H), 1.27(s, 28H), 1.20(d, J =6Hz, 9H), 0.88(t, J =13.6Hz, 9H). Step 5:

[0381] Under a nitrogen atmosphere, EDCI (219.94 mg, 1.15 mmol, 1.2 eq), 4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoic acid (282.63 mg, 860.50 μmol, 0.9 eq), 4-pyrrolidone-1-ylpyridine (14.17 mg, 95.61 μmol, 0.1 eq), and DIPEA (308.93 mg, 2.39 mmol, 416.34 μL, 2.5 eq) were added to a solution of O1-[2-(hydroxymethyl)-3-[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxy-2-[[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxymethyl]propyl]O7-(1-methyloctyl)pimecrocidol (0.9 g, 956.11 μmol, 1 eq) in DCM (10 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[2,2-bis[[7-(1-methyloctyloxy)-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O7-(1-methyloctyl)pimercate (0.1 g, 79.82 μmol, 8.35% yield, 99.92% purity) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.35-5.32(s, 1H), 4.92-4.87(m, 3H), 4.75(s, 1H), 4.11(s, 8H), 3.34(d, J =4.0Hz,2H), 2.65(d, J =18.4Hz, 6H), 2.39-2.26(m, 14H), 1.83(s, 6H), 1.67-1.46(m,22H), 1.39-1.27(m, 42H), 1.20(d, J =6.4Hz, 9H), 0.88(t, J =6.4Hz, 12H). Example 46 - Compound 39: O1-[2,2-bis[[8-(1-methylnonoxy)-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O8-(1-methylnonyl)octanoic acid ester Step 1:

[0382] Under a nitrogen atmosphere, EDCI (31.49 g, 164.27 mmol, 1.3 eq), octanoic acid (110.05 g, 631.79 mmol, 5 eq), DMAP (1.54 g, 12.64 mmol, 0.1 eq), and DIPEA (40.83 g, 315.90 mmol, 55.02 mL, 2.5 eq) were added to a solution of decan-2-ol (20 g, 126.36 mmol, 1 eq) in DCM (1300 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (500 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound 8-(1-methylnonoxy)-8-oxo-octanoic acid (30 g, 95.40 mmol, 75.50% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.93- 4.88 (m, 1 H), 2.36 (t, J=7.6 Hz, 2 H), 2.28 (t,J=7.6 Hz, 2 H), 1.74 - 1.52 (m, 6 H), 1.51 - 1.42 (m, 1 H), 1.38 - 1.22 (m,16 H), 1.20 (d, J=6.2 Hz, 3 H), 0.94 - 0.81 (m, 3 H). Step 2:

[0383] Under a nitrogen atmosphere, EDCI (2.90 g, 15.13 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (1 g, 5.68 mmol, 0.45 eq), DMAP (154.07 mg, 1.26 mmol, 0.1 eq), and DIPEA (4.07 g, 31.53 mmol, 5.49 mL, 2.5 eq) were added to a solution of 8-(1-methylnonoxy)-8-oxo-octanoic acid (3.97 g, 12.61 mmol, 1 eq) in DCM (50 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (150 mL) (50 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O1-[[2,2-dimethyl-5-[[8-(1-methylnonoxy)-8-oxo-octanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O8-(1-methylnonyl)octanoic acid ester (1.5 g, 1.95 mmol, 15.47% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92- 4.88 (m, 2 H), 4.11 (s, 4 H), 3.75 (s, 4 H), 2.30 (m, 8H), 1.68 - 1.56 (m, 10 H), 1.48 (m, 2 H), 1.42 (s, 6 H), 1.36 - 1.23 (m, 32H), 1.20 (d, J=6.2 Hz, 6 H), 0.96 - 0.81 (m, 6 H), Step 3:

[0384] Under a nitrogen atmosphere at 0°C, HCl (3 M, 715.12 μL, 1.1 eq) was added to a solution of O1-[[2,2-dimethyl-5-[[8-(1-methylnonoxy)-8-oxo-octanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O8-(1-methylnonyl)octanoic acid ester (1.5 g, 1.95 mmol, 1 eq) in THF (15 mL). The reaction mixture was stirred at 25°C for 2 hr under a nitrogen atmosphere. The reaction mixture was diluted with saturated NaHCO3 (100 mL) and diluted with EtOAc (200 mL) (50 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[2,2-bis(hydroxymethyl)-3-[8-(1-methylnonoxy)-8-oxo-octanoyl]oxy-propyl]O8-(1-methylnonyl)octanoic acid ester (0.8 g, 1.10 mmol, 56.26% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92- 4.88 (m, 2 H), 4.15 (s, 4 H), 3.58 (br s, 4 H), 2.79 (br s, 2 H), 2.35 (t,J=7.4 Hz, 4 H), 2.27 (t, J=7.4 Hz, 4 H), 1.66 - 1.53 (m, 10 H), 1.49 - 1.41 (m, 2 H), 1.39 - 1.23 (m, 32 H), 1.20 (d, J=6.25 Hz, 6 H), 0.97 - 0.82 (m, 6H). Step 4:

[0385] Under a nitrogen atmosphere, EDCI (252.43 mg, 1.32 mmol, 1.2 eq), 8-(1-methylnonoxy)-8-oxo-octanoyl]oxy-propyl]O8-(1-methylnonyl)octanoic acid (207.04 mg, 658.41 μmol, 0.6 eq), DMAP (13.41 mg, 109.73 μmol, 0.1 eq), and DIPEA (354.56 mg, 2.74 mmol, 477.84 μL, 2.5 eq) were added to a solution of O1-[2,2-bis(hydroxymethyl)-3-[8-(1-methylnonoxy)-8-oxo-octanoyl]oxy-propyl]O8-(1-methylnonyl)octanoic acid (2.04 mg, 658.41 μmol, 0.6 eq), DMAP (13.41 mg, 109.73 μmol, 0.1 eq), and DIPEA (354.56 mg, 2.74 mmol, 477.84 μL, 2.5 eq) in DCM (10 mL) were added. The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. Dilute the reaction mixture with H2O (100 mL) and with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O1-[2-(hydroxymethyl)-3-[8-(1-methylnonoxy)-8-oxo-octanoyl]oxy-2-[[8-(1-methylnonoxy)-8-oxo-octanoyl]oxymethyl]propyl]O8-(1-methylnonyl)octanoic acid ester (0.3 g, 292.55 μmol, 26.66% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92-4.87(m, 3H), 4.12(s, 6H), 3.51(d, J=2.8Hz, 2H), 2.62(s, 1H), 2.33(t, J=7.6Hz,6H), 2.27(t, J=7.2Hz, 6H), 1.64-1.61(m, 10H), 1.49-1.42(m, 6H), 1.36-1.32(m,14H), 1.27(s, 34H), 1.20(d, J=6.4Hz, 9H), 0.88(t, J=6.4Hz, 9H). Step 5:

[0386] Under a nitrogen atmosphere, EDCI (224.33 mg, 1.17 mmol, 1.2 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (288.26 mg, 877.64 μmol, 0.9 eq), 4-pyrrolidine-1-ylpyridine (14.45 mg, 97.52 μmol, 0.1 eq) and DIPEA (315.08 mg, 2.44 mmol, 424.64 eq) were added to a solution of O1-[2-(hydroxymethyl)-3-[8-(1-methylnonoxy)-8-oxo-octanoyl]oxy-2-[[8-(1-methylnonoxy)-8-oxo-octanoyl]oxymethyl]propyl]O8-(1-methylnonyl)octanoic acid (1 g, 975.16 μmol, 1 eq) in DCM (13 mL). μL, 2.5 eq). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (50 mL) and mixed with DCM (100 mL) (25 mL). 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O1-[2,2-bis[[8-(1-methylnonoxy)-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O8-(1-methylnonyl)octanoic acid ester (0.1 g, 74.86 μmol, 7.68% yield) was obtained as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.31-5.29(s, 1H), 4.93-4.86(m, 3H), 4.75(s, 1H), 4.11(s, 8H), 3.33(d, J=4Hz, 2H), 2.61(d, J=25.6Hz,6H), 2.40-2.25(m, 14H), 1.90-1.81(m, 6H), 1.64-1.55(m, 18H), 1.49-1.42(m,4H), 1.35-1.32(m, 14H), 1.27(s, 40H), 1.20(d, J=6.4Hz, 9H), 0.88(t, J = 6.4 Hz, 12 Hz. Example 47 - Compound 40: O1-[2,2-bis[[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O7-(1-methylnonyl)heptanoic acid ester Step 1:

[0387] Under a nitrogen atmosphere, EDCI (29.07 g, 151.63 mmol, 1.2 eq), pimelic acid (101.19 g, 631.79 mmol, 5 eq), DMAP (1.54 g, 12.64 mmol, 0.1 eq), and DIPEA (40.83 g, 315.90 mmol, 55.02 mL, 2.5 eq) were added to a solution of decan-2-ol (20 g, 126.36 mmol, 1 eq) in DCM (1210 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (500 mL) and mixed with DCM (1500 mL) (500 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound 7-(1-methylnonoxy)-7-oxo-heptanoic acid (30 g, 99.86 mmol, 79.03% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92 - 4.88 (m, 1 H), 2.36 (t, J=7.47 Hz, 2 H), 2.29 (t, J=7.47 Hz, 2 H), 1.74 - 1.60 (m, 4 H), 1.59 - 1.36 (m, 4 H), 1.27 (br s,12 H), 1.20 (d, J=6.27 Hz, 3 H), 0.93 - 0.82 (m, 3 H). Step 2:

[0388] Under a nitrogen atmosphere, EDCI (2.90 g, 15.13 mmol, 1.2 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (1 g, 5.68 mmol, 0.45 eq), DMAP (154.07 mg, 1.26 mmol, 0.1 eq), and DIPEA (4.07 g, 31.53 mmol, 5.49 mL, 2.5 eq) were added to a solution of 7-(1-methylnonoxy)-7-oxo-heptanoic acid (3.79 g, 12.61 mmol, 1 eq) in DCM (50 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (200 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[[2,2-dimethyl-5-[[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O7-(1-methylnonyl)pimercate (1.5 g, 2.02 mmol, 16.05% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.92 - 4.88 (m, 2 H), 4.11 (s, 4 H), 3.74 (s, 4 H), 2.42 - 2.21 (m, 8 H), 1.71 - 1.57 (m, 10 H), 1.47 (br d, J=8.0 Hz, 2 H), 1.42 (s, 6 H), 1.38 - 1.21 (m, 28 H), 1.20 (d, J=6.2 Hz, 6 H), 0.97 - 0.77 (m, 6 H). Step 3:

[0389] Under a nitrogen atmosphere at 0°C, HCl (3 M, 742.20 μL, 1.1 eq) was added to a solution of O1-[[2,2-dimethyl-5-[[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O7-(1-methylnonyl)pimercinate (1.5 g, 2.02 mmol, 1 eq) in THF (15 mL). The reaction mixture was stirred at 25°C for 2 hr under a nitrogen atmosphere. The reaction mixture was diluted with saturated NaHCO3 (100 mL) and diluted with EtOAc (200 mL) (100 mL) 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[2,2-bis(hydroxymethyl)-3-[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxy-propyl]O7-(1-methylnonyl)pimercate (0.8 g, 1.14 mmol, 56.38% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm4.92- 4.87 (m, 2 H), 4.15 (s, 4 H), 3.59 (br d, J=4.50 Hz, 4 H), 2.80 (br s,2 H), 2.37 (t, J=7.44 Hz, 4 H), 2.29 (t, J=7.38 Hz, 4 H), 1.69- 1.60 (m, 10H), 1.48 - 1.34 (m, 6 H), 1.27 (br s, 24 H), 1.20 (d, J=6.25 Hz, 6 H), 0.89(t, J=6.75 Hz, 6 H). Step 4:

[0390] Under a nitrogen atmosphere, EDCI (262.54 mg, 1.37 mmol, 1.2 eq), 7-(1-methylnonoxy)-7-oxo-heptanoyl]oxy-propyl]O7-(1-methylnonyl)pimecroceta ester (0.8 g, 1.14 mmol, 1 eq) were added to a solution of O1-[2,2-bis(hydroxymethyl)-3-[7-(1-methylnonoxy)-7-oxo-heptanoic acid (205.72 mg, 684.76 μmol, 0.6 eq), DMAP (13.94 mg, 114.13 μmol, 0.1 eq), and DIPEA (368.75 mg, 2.85 mmol, 496.97 μL, 2.5 eq) in DCM (10 mL) were added. The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. Dilute the reaction mixture with H2O (100 mL) and with DCM (400 mL) (100 mL) 4) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1). The compound O1-[2-(hydroxymethyl)-3-[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxy-2-[[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxymethyl]propyl]O7-(1-methylnonyl)pimercate (0.3 g, 305.06 μmol, 26.73% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.93-4.86(m, 3H), 4.11(s, 6H), 3.52 (d, J=4.8Hz, 2H), 2.68(s, 1H), 2.34(t, J=7.6Hz, 6H), 2.90(t, J=7.6Hz, 6H), 1.68-1.60 (m, 14H), 1.49-1.42 (m, 4H), 1.40-1.27 (m, 42H), 1.20 (d, J=6.0Hz, 9H), 0.88(t, J=13.6Hz, 9H). Step 5:

[0391] Under a N2 atmosphere, EDCI (233.93 mg, 1.22 mmol, 1.2 eq), 4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoic acid (300.59 mg, 915.19 μmol, 0.9 eq), 4-pyrrolidine-1-ylpyridine (15.07 mg, 101.69 μmol, 0.1 eq) and DIPEA (328.56 mg, 2.54 mmol, 442.81 μL, 2.5 eq) were added to a solution of O1-[2-(hydroxymethyl)-3-[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxy-2-[[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxymethyl]propyl]O7-(1-methylnonyl)pimecrocidol (1 g, 1.02 mmol, 1 eq) in DCM (13 mL). The reaction mixture was stirred at 25°C for 12 hours under a nitrogen atmosphere. The reaction mixture was diluted with 50 mL of H₂O and then diluted with 25 mL of DCM (50 mL). 2) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1). The compound O1-[2,2-bis[[7-(1-methylnonoxy)-7-oxo-heptanoyl]oxymethyl]-3-[4-(2-pyrrolidine-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O7-(1-methylnonyl)pimercate (0.1 g, 77.29 μmol, 7.60% yield) was given as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 5.39-5.28(s, 1H), 4.92-4.87(m,3H), 4.75-4.74(s, 1H), 4.11(s, 8H), 3.34 (d, J=3.6Hz, 2H), 2.63(d, J=1.6Hz,6H), 2.39-2.26(m, 14H), 1.91-1.77(m, 6H), 1.67-1.44(m, 26H), 1.38-1.27(m,44H), 1.20(d, J=6.4Hz, 9H), 0.88(t, J=13.6Hz, 12H). Example 48 - Compound 41: O1-[2,2-bis[[8-(1-methyldecyloxy)-8-oxo-octanoyl]oxymethyl]-3-[4-(2-pyrrolidone-1-ylethylcarbamoyloxy)decanoyloxy]propyl]O8-(1-methyldecyl)octanoic acid ester Step 1:

[0392] Under a nitrogen atmosphere, EDCI (20.03 g, 104.46 mmol, 1.2 eq), octanoic acid (75.82 g, 435.27 mmol, 5 eq), DIPEA (28.13 g, 217.64 mmol, 37.91 mL, 2.5 eq), and DMAP (1.06 g, 8.71 mmol, 0.1 eq) were added to a solution of undecane-2-ol (15 g, 87.05 mmol, 1 eq) in DCM (450 mL) and THF (450 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (1000 mL) and mixed with DCM (2100 mL) (700 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound 8-(1-methyldecyloxy)-8-oxo-octanoic acid (15 g, 45.66 mmol, 52.45% yield) was given as a colorless oil. Step 2:

[0393] Under a nitrogen atmosphere, EDCI (2.90 g, 15.13 mmol, 1.2 eq), DIPEA (4.07 g, 31.53 mmol, 5.49 mL, 2.5 eq), [5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxane-5-yl]methanol (1 g, 5.68 mmol, 0.45 eq), and DMAP (154.07 mg, 1.26 mmol, 0.1 eq) were added to a solution of 8-(1-methyldecyloxy)-8-oxo-octanoic acid (4.14 g, 12.61 mmol, 1 eq) in DCM (50 mL). The reaction mixture was stirred at 25°C for 12 hr under a nitrogen atmosphere. The reaction mixture was diluted with H2O (100 mL) and mixed with DCM (300 mL) (100 mL) 3) Extraction. The combined organic layers were dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1). The compound O1-[[2,2-dimethyl-5-[[8-(1-methyldecyloxy)-8-oxo-octanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O8-(1-methyldecyl)octanoic acid ester (1.5 g, 1.88 mmol, 14.92% yield) was given as a colorless oil. Step 3:

[0394] Under a nitrogen atmosphere at 0°C, HCl (3 M, 689.96 μL, 1.1 eq) was added to a solution of O1-[[2,2-dimethyl-5-[[8-(1-methyldecyloxy)-8-oxo-octanoyl]oxymethyl]-1,3-dioxane-5-yl]methyl]O8-(1-methyldecyl)octanoic acid ester (1.5 g, 1.88...

Claims

1. A compound of the formula: , or a pharmaceutically acceptable salt thereof; wherein: R 1 and R 1' are each independently: (C1-C9 alkyl)-R 5 , (C2-C9 alkenyl)-R 5 , (C2-C9 alkynyl)-R 5 , or (C1-C8 alkoxy)-R 5 ; R 1'' independently: (C1-C9alkyl)-R 5 , (C2-C9alkenyl)-R 5 , (C2-C9alkynyl)-R 5 , (C1-C8alkoxy)-R 5 , or R 12 -R 13 ; Each R 5 Independently: hydrogen, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, sterol, C(O)OR 6 OC(O)-R 6 OC(O)OR 6 CH(R) 7 )R 8 C(O)O-CH-(R) 7 )R 8 C(O)O-C1-C4 alkyl-(R 9 )R 10 OC(O)-C1-C4 alkyl-(R 9 )R 10 、or OC(O)CH(R) 9 )R 10 ; Each R 6 Independently: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, C7-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, or sterol; R 7 and R 8 each independently is: C7-C 12 alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl, or C7-C 12 alkoxy; R 9 and R 10 each independently is: C1-C 12 alkyl or C2-C 12 alkenyl; X 1 is O, NH, or CHR 14 ; X 2 is O, NH, or CHR 11 ; R 2 is C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C1-C 12 alkoxy, (C1-C4 alkyl)-(C1-C4 alkoxy), optionally substituted C3-C 12 cycloalkyl, (C1-C4 alkyl)-(optionally substituted C3-C 12 cycloalkyl), optionally substituted C3-C6 heterocycle, (C1-C4 alkyl)-(optionally substituted C3-C6 heterocycle), optionally substituted C5-C6 aryl, or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl); R 2' is hydrogen, C1-C 12 alkyl, alkenyl, or alkynyl, C1-C 12 alkoxy, (C1-C4alkyl)-(C1-C4alkoxy); wherein R 2 and R 2' may combine to form an optionally substituted C4-C6cycloalkyl, optionally substituted C3-C6cycloalkyl, or optionally substituted C3-C6heterocycle; R 3 and R 4 are each independently: hydrogen, Ci-C6alkyl, Ci-C6alkoxy, or Ci-C6hydroxyalkyl, or wherein R 3 and R 4 are linked together to form a heterocyclic ring comprising one or more N, O, or S heteroatoms; R 11 is hydrogen or Ci-C6alkyl, or wherein R 11 and R 4 are linked together to form a heterocyclic ring comprising one or more N, O, or S heteroatoms; R 12 is a bond or optionally substituted, branched or unbranched C1-C6alkyl, C1-C6alkenyl, or C1-C6alkynyl; R 13 is hydrogen, optionally substituted C3-C 12 cycloalkyl, or optionally substituted C5-C6 aryl; R 14 is hydrogen or CrC6alkyl, or wherein R 14 and R 2 are linked together to form an optionally substituted C5-C8cycloalkyl; m is 1-4; p is 0-4; and n is 1-5.

2. A compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1' each independently is: (C1-C9 alkyl)-R 5 , (C2-C9 alkenyl)-R 5 , (C2-C9 alkynyl)-R 5 , or (C1-C8 alkoxy)-R 5 ; R 1'' independently: (C1-C9alkyl)-R 5 , (C2-C9alkenyl)-R 5 , (C2-C9alkynyl)-R 5 , (C1-C8alkoxy)-R 5 , or R 12 -R 13 ; Each R 5 Independently: hydrogen, C1-C 12 Alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl group, C2-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, sterol, C(O)OR 6 OC(O)-R 6 OC(O)OR 6 CH(R) 7 )R 8 C(O)O-CH(R) 7 )R 8 C(O)O-C1-C4 alkyl-(R 9 )R 10 OC(O)-C1-C4 alkyl-(R 9 )R 10 、or OC(O)CH(R) 9 )R 10 ; Each R 6 Independently: C7-C 12 Alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl group, C7-C 12 Alkoxy, optionally substituted C3-C 12 Cycloalkyl, optionally substituted C5-C6 aryl, 1-adamantyl, 2-adamantyl, or sterol; R 7 and R 8 each independently is: C7-C 12 alkyl, C7-C 12 alkenyl, C7-C 12 alkynyl, or C7-C 12 alkoxy; R 9 and R 10 each independently is: C1-C 12 alkyl or C2-C 12 alkenyl; X 1 is O, NH, or CHR 14 ; X 2 is O, NH, or CHR 11 ; R 2 is C1-C 12 alkyl, C2-C 12 alkenyl, or C2-C 12 alkynyl, C1-C 12 alkoxy, (C1-C4 alkyl)-(C1-C4 alkoxy), optionally substituted C3-C 12 cycloalkyl, (C1-C4 alkyl)-(optionally substituted C3-C 12 cycloalkyl), optionally substituted C3-C6 heterocycle, (C1-C4 alkyl)-(optionally substituted C3-C6 heterocycle), optionally substituted C5-C6 aryl, or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl); R 3 and R 4 are each independently: hydrogen, Ci-C6alkyl, Ci-C6alkoxy, or Ci-C6hydroxyalkyl, or wherein R 3 and R 4 are linked together to form a heterocyclic ring comprising one or more N, O, or S heteroatoms; R 12 is a bond or optionally substituted, branched or unbranched C1-C6alkyl, C1-C6alkenyl, or C1-C6alkynyl; R 13 is hydrogen, optionally substituted C3-C 12 cycloalkyl, or optionally substituted C5-C6 aryl; R 11 is hydrogen or Ci-C6alkyl, or wherein R 11 and R 4 are linked together to form a heterocyclic ring comprising one or more N, O, or S heteroatoms; R 14 is hydrogen or CrC6alkyl, or wherein R 14 and R 2 are linked together to form an optionally substituted C5-C8cycloalkyl; n is 1-5; and m is 1-4.

3. The compound of claim 1, wherein R 1 , R 1' , and R 1'' each independently is (Ci-C9 alkyl)-R 5 , and each R 5 independently is C2-C 12 alkenyl.

4. The compound of claim 3, wherein R 1 , R 1' , and R 1'' are each independently (Ci-C9 alkyl)-R 5 ; and each R 5 is independently C2-C 12 alkenyl.

5. The compound of claim 3, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; and R 5' is C6-C 10 cycloalkyl; optionally wherein the R 5' is 1-adamantyl or 2-adamantyl.

6. The compound of claim 3, wherein one of R 1 , R 1' , and R 1'' is CH(R 7 )R 8 ; and R 7 and R 8 are each independently C7-C 12 alkoxy.

7. The compound of claim 1, wherein two of R 1 , R 1' , and R 1'' are independently (Ci-C9 alkyl)-R 5 ; each R 5 is independently C(O)O-R 6 ; and each R 6 is independently C7-C 12 alkyl or C7-C 12 alkenyl.

8. The compound of claim 7, wherein R 1 , R 1' , and R 1'' are each independently (Ci-C9 alkyl)-R 5 ; each R 5 is independently C(O)O-R 6 ; and each R 6 is independently C7-C 12 alkyl or C7-C 12 alkenyl.

9. The compound of claim 6, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; and R 5' is C6-C 10 cycloalkyl; optionally wherein the R 5' is 1-adamantyl or 2-adamantyl.

10. The compound of claim 7, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; R 5' is CH(R 7 )R 8 ; and R 7 and R 8 are each independently C7-C 12 alkoxy.

11. The compound of claim 7, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; R 5' is OC(O)CH(R 9 )R 10 ; and R 9 and R 10 are each independently Ci-C 12 alkyl or C2-C 12 alkenyl.

12. The compound of claim 7, wherein R 1 and R 1' are (Ci-C9 alkyl)-R 5' , R 5' is C(O)O-R 6 , and each R 6 is independently C7-C 12 alkyl or C7-C 12 alkenyl; and R 1' is R 12 -R 13 , wherein R 12 is a bond or optionally substituted, branched or unbranched Ci-C6 alkyl, Ci-C6 alkenyl, or Ci-C6 alkynyl; and R 13 is hydrogen, optionally substituted C3-C 12 cycloalkyl, or optionally substituted C5-C6 aryl.

13. The compound of claim 12, wherein R 12 is a bond.

14. The compound of claim 12, wherein R 12 is Ci-C6alkyl; optionally Ci alkyl.

15. The compound of claim 12, wherein R 12 is optionally substituted, branched or unbranched Ci-C6alkyl, Ci-C6alkenyl, or Ci-C6alkynyl; optionally wherein R 12 is selected from pentyl, 1-methylpentyl, 4-methylpentyl, 5,5,5-trifluoropentyl, 4,4,5,5,5-pentafluoropentyl, and pent-4-ynyl.

16. The compound of any one of claims 12 to 14, wherein R 13 is hydrogen.

17. The compound of any one of claims 13 to 14, wherein R 13 is optionally substituted C3-C 12 cycloalkyl; optionally, wherein R 13 is selected from optionally substituted cyclopropane, optionally substituted cyclobutane, and optionally substituted cyclohexane, for example 4-pentylcyclohexyl.

18. The compound of 17, wherein R 13 is optionally substituted fused C3-C 12 cycloalkyl, optionally substituted bridged C3-C 12 cycloalkyl, or optionally substituted spiro C3-C 12 cycloalkyl.

19. The compound of any one of claims 13 to 14, wherein R 13 is optionally substituted C5-C6 aryl; optionally is optionally substituted phenyl, for example 4-pentylphenyl or 3,5-di-tert-butylphenyl.

20. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted bicyclo[2.2.2]pentane; optionally wherein R 13 is unsubstituted bicyclo[2.2.2]pentane, 1-(trifluoromethyl)bicyclo[l. l. l]pentane, or 1 -methylbicyclo[l. l. l]pentane.

21. The compound of any one of claims 13 to 14, wherein R 13 is an optionally substituted bicyclo[2.1.0]pentane; optionally wherein R 13 is unsubstituted bicyclo[2.1.0]pentane.

22. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted bicyclo[3.1.0]hexane; optionally wherein R 13 is 6,6-difluorobicyclo[3.1.0]hexane.

23. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted bicyclo[2.1.1]hexane; optionally wherein R 13 is unsubstituted bicyclo[2.1.1]hexane or 1-fluorobicyclo[2.1.1]hexane.

24. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted spiro[2.3]hexane; optionally unsubstituted spiro[2.3]hexane or 1,1-difluorospiro[2.3]hexane.

25. The compound of any one of claims 13-14, wherein R 13 is optionally substituted 1,1'-bis(cyclohexane).

26. The compound of any one of claims 13 to 14, wherein R 13 is an optionally substituted decahydronaphthalene.

27. The compound of any one of claims 13 to 14, wherein R 13 is an optionally substituted bicyclo[2.2.1]heptane; optionally wherein R 13 is unsubstituted bicyclo[2.2.1]heptane or 7,7-dimethylbicyclo[2.2.1]heptane.

28. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted bicyclo[4.1.0]heptane; optionally wherein R 13 is unsubstituted bicyclo[4.1.0]heptane or 7,7-difluorobicyclo[4.1.0]heptane.

29. The compound of any one of claims 13 to 14, wherein R 13 is an optionally substituted bicyclo[3.2.0]heptane; optionally wherein R 13 is an unsubstituted bicyclo[3.2.0]heptane.

30. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted spiro[3.3]heptane; optionally wherein R 13 is unsubstituted spiro[3.3]heptane or 2,2-difluorospiro[3.3]heptane.

31. The compound of any one of claims 13 to 14, wherein R 13 is an optionally substituted bicyclo[2.2.2]octane; optionally wherein R 13 is unsubstituted bicyclo[2.2.2]octane or 1-methylbicyclo[2.2.2]octane.

32. The compound of any one of claims 13 to 14, wherein R 13 is an optionally substituted bicyclo[3.2.1]octane; optionally wherein R 13 is unsubstituted bicyclo[3.2.1]octane or 8-oxabicyclo[3.2.1]octane.

33. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted spiro[2.5]octane; optionally wherein R 13 is unsubstituted spiro[2.5]octane or 1,1-difluorospiro[2.5]octane.

34. The compound of any one of claims 13 to 14, wherein R 13 is an optionally substituted bicyclo[3.2.2]nonane; optionally wherein R 13 is unsubstituted bicyclo[3.2.2]nonane or 1-fluorobicyclo[3.2.2]nonane.

35. The compound of any one of claims 13-14, wherein R 13 is an optionally substituted 1-bicyclo[3.3.1]nonane; optionally wherein R 13 is unsubstituted bicyclo[3.3.1]nonane or 1-methylbicyclo[3.3.1]nonane.

36. The compound of any one of claims 13 to 14, wherein R 13 is adamantane.

37. The compound of claim 1, wherein R 1 , R 1' , and R 1'' are each independently (Ci-C9 alkyl)-R 5 ; each R 5 is independently OC(O)CH(R 9 )R 10 ; and R 9 and R 10 are each independently Ci-C 12 alkyl or C2-C 12 alkenyl.

38. The compound of claim 37, wherein R 1 , R 1' , and R 1'' are each independently (Ci-C9 alkyl)-R 5 ; R 5 is OC(O)CH(R 9 )R 10 ; and R 9 and R 10 are each independently Ci-C 12 alkyl or C2-C 12 alkenyl.

39. The compound of claim 1, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; R 5' is C(O)O-Ci-C4 alkyl-(R 9 )R 10 or OC(O)-Ci-C4 alkyl-(R 9 )R 10 ; and R 9 and R 10 are each independently Ci-C 12 alkyl or C2-C 12 alkenyl.

40. The compound of claim 1, wherein R 1 , R 1' , and R 1'' are each independently H or (Ci-C9 alkyl)-R 5 ; each R 5 is independently C(O)O-Ci-C4 alkyl-(R 9 )R 10 or OC(O)-Ci-C4 alkyl-(R 9 )R 10 ; and R 9 and R 10 are each independently Ci-C 12 alkyl or C2-C 12 alkenyl.

41. The compound of claim 1, wherein R 1 , R 1' , and R 1'' are each independently (Ci-C9 alkyl)-R 5 ; R 5 is C(O)O-Ci-C4 alkyl-(R 9 )R 10 or OC(O)-Ci-C4 alkyl-(R 9 )R 10 ; and R 9 and R 10 are each independently Ci-C 12 alkyl or C2-C 12 alkenyl.

42. The compound of claim 37, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; and R 5' is C6-C 10 cycloalkyl; optionally wherein R 5' is 1-adamantyl or 2-adamantyl.

43. The compound of claim 37, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; R 5' is C(O)O-R 6 ; and R 6 is C7-C 12 alkyl or C7-C 12 alkenyl.

44. The compound of claim 37, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; R 5' is CH(R 7 )R 8 ; and R 7 and R 8 are each independently C7-C 12 alkoxy.

45. The compound of claim 1, wherein two of R 1 , R 1' , and R 1'' are independently (Ci-C9 alkyl)-R 5 ; each R 5 is independently CH(R 7 )R 8 ; and R 7 and R 8 are each independently C7-C 12 alkoxy.

46. The compound of claim 45, wherein R 1 , R 1' , and R 1'' are each independently (Ci-C9 alkyl)-R 5 ; each R 5 is independently CH(R 7 )R 8 ; and R 7 and R 8 are each independently C7-C 12 alkoxy.

47. The compound of claim 42, wherein one of R 1 , R 1' , and R 1'' is (Ci-C9 alkyl)-R 5' ; R 5' is OC(O)CH(R 9 )R 10 ; and R 9 and R 10 are each independently Ci-C 12 alkyl or C2-C 12 alkenyl.

48. The compound of any one of claims 1-47, wherein R 2 is Ci-C 12 alkyl, C2-C 12 alkenyl, or C2-C 12 alkynyl.

49. The compound of any one of claims 1-47, wherein R 2 is C4-C8alkyl.

50. The compound of any one of claims 1-47, wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl, 1-isobutyl, 2-isobutyl, tert-butyl, C5alkyl, C6alkyl, C8alkyl, or C 10 alkyl.

51. The compound of any one of claims 1-47, wherein R 2 is Ci-C 12 alkoxy or (Ci-C4alkyl)-(Ci-C4alkoxy); optionally, wherein R 2 is methoxy, ethoxy, methoxymethyl, or ethoxyethyl.

52. The compound according to any one of claims 1-47, wherein R 2 It is an optional replacement of C3-C 12 Cycloalkyl, optionally substituted C3-C6 heterocyclic, or optionally substituted C5-C6 aryl; optionally, wherein R 2 It is optionally substituted with cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, such as 4-pentylcyclohexyl.

53. The compound of any one of claims 1-47, wherein R 2 is optionally substituted phenyl; optionally wherein R 2 is 4-pentylphenyl.

54. The compound according to any one of claims 1-47, wherein R 2 It is optionally substituted (C1-C4 alkyl)-(optionally substituted C3-C 12 Cycloalkyl), (C1-C4 alkyl)-(optionally substituted C3-C6 heterocyclic), or (C1-C4 alkyl)-(optionally substituted C5-C6 aryl); optionally, wherein R 2 It is -CH2-cyclopropyl, -(CH2)2-cyclopropyl, -CH2-cyclohexyl, -(CH2)2-cyclohexyl, -(CH2)2-(4-pentylcyclohexyl), -CH2-phenyl, or -(CH2)2-phenyl.

55. The compound of any one of claims 48-54, wherein R 2' is hydrogen.

56. The compound of any one of claims 48-54, wherein R 2' is Ci-C 12 alkyl, C2-C 12 alkenyl, or C2-C 12 alkynyl; optionally wherein R 2 is methoxy, ethoxy, methoxymethyl, or ethoxyethyl.

57. The compound of any one of claims 1-47, wherein R 2 and R 2' in combination form an optionally substituted C4-C6 cycloalkyl or C4-C6 heterocycle; optionally, wherein R 2 and R 2' in combination form cyclohexane or pyran.

58. The compound of any one of claims 1-57, wherein X 1 is CH2.

59. The compound of any one of claims 1-57, wherein X 1 is CHR 14 and R 14 and R 2 are joined together to form an optionally substituted C5-C8 cycloalkyl; optionally wherein R 14 and R 2 are joined together to form an optionally substituted C5 cycloalkyl or an optionally substituted C6 cycloalkyl.

60. The compound of any one of claims 1-59, wherein X 2 is NH.

61. The compound of any one of claims 1-59, wherein X 2 is O.

62. The compound of any one of claims 1-61, wherein R 3 and R 4 each independently is C1-C6alkyl.

63. The compound of any one of claims 1-61, wherein R 3 and R 4 are linked together to form a heterocycle comprising a nitrogen heteroatom; optionally wherein R 3 and R 4 are linked together to form pyrrolidine, or wherein R 3 and R 4 are linked together with the preceding alkyl group to form a quinuclidine ring.

64. The compound of any one of claims 1-63, wherein n is 1, 2, 3, or 4.

65. The compound of any one of claims 1-64, wherein m is 1, 2, 3, or 4.

66. The compound of any one of claims 1-65, wherein p is 0, 1, 2, 3, or 4.

67. The compound of any one of claims 1-66, wherein two of R 1 , R 1' , and R 1'' are independently (C2alkyl)-R 5 .

68. The compound of any one of claims 1-66, wherein two of R 1 , R 1' , and R 1'' are independently (C3alkyl)-R 5 .

69. The compound of any one of claims 1-66, wherein two of R 1 , R 1' , and R 1'' are independently (C4alkyl)-R 5 .

70. The compound of any one of claims 1-66, wherein two of R 1 , R 1' , and R 1'' are independently (C5alkyl)-R 5 .

71. The compound of any one of claims 1-66, wherein two of R 1 , R 1' , and R 1'' are independently (C6alkyl)-R 5 .

72. The compound of any one of claims 1-66, wherein two of R 1 , R 1' , and R 1'' are independently (C7alkyl)-R 5 .

73. The compound of any one of claims 1-66, wherein two of R 1 , R 1' , and R 1'' are independently (C8alkyl)-R 5 .

74. The compound of any one of claims 1-66, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof.

75. The compound of any one of claims 1-66, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof.

76. The compound of any one of claims 1-66, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof.

77. The compound of claim 1, wherein the compound is any one of Compounds 1-209, or a pharmaceutically acceptable salt thereof.

78. The compound of claim 1, wherein the compound is any one of Compounds 7, 8, 10, 13, 14, 26, 33, 38, 39, 40, 48, 60, 61, 89, 103, or 109, or a pharmaceutically acceptable salt thereof.

79. A lipid nanoparticle comprising the compound of any one of claims 1-78.

80. A lipid nanoparticle comprising the compound of any one of claims 1-78; a phospholipid; cholesterol; and a polyethylene glycol lipid.

81. A lipid nanoparticle comprising: about 20-80 mol% of the compound of any one of claims 1-78, about 7.5-40 mol% of a phospholipid, about 6-45 mol% of cholesterol, and about 1-4 mol% of a PEG lipid.

82. A lipid nanoparticle comprising: about 45-65 mol% of the compound of any one of claims 1-78, about 10 mol% of a phospholipid, about 25-45 mol% of cholesterol, and about 1-4 mol% of a PEG lipid.

83. A lipid nanoparticle comprising: about 45-50 mol% of the compound of any one of claims 1-78, about 10 mol% of a phospholipid, about 38-42 mol% of cholesterol, and about 2-3 mol% of a PEG lipid.

84. The lipid nanoparticle of claim 83, comprising: about 47.5 mol% of the compound of any one of claims 1-78, about 40 mol% of cholesterol, and about 2.5 mol% of a PEG lipid.

85. A lipid nanoparticle comprising: about 47.5-52.5 mol% of the compound of any one of claims 1-78, about 10 mol% of a phospholipid, about 37-40 mol% of cholesterol, and about 1-2 mol% of a PEG lipid.

86. The lipid nanoparticle of claim 85, comprising: about 50 mol% of the compound of any one of claims 1-78, about 38.5 mol% cholesterol, and about 1.5 mol% PEG lipid.

87. The lipid nanoparticle, comprising: about 57.5-62.5 mol% of the compound of any one of claims 1-78, about 10 mol% phospholipid, about 26-29 mol% cholesterol, and about 2-3 mol% PEG lipid.

88. The lipid nanoparticle of claim 87, comprising: about 60 mol% of the compound of any one of claims 1-78, about 27.5 mol% cholesterol, and about 2.5 mol% PEG lipid.

89. The lipid nanoparticle, comprising: about 45-50 mol% of the compound of any one of claims 1-78, about 10 mol% phospholipid, about 37.5-40.5 mol% cholesterol, and about 3-4 mol% PEG lipid.

90. The lipid nanoparticle of claim 89, comprising: about 47.5 mol% of the compound of any one of claims 1-38, about 39 mol% cholesterol, and about 3.5 mol% PEG lipid.

91. The lipid nanoparticle of any one of claims 80-90, further comprising: a targeting component.

92. The lipid nanoparticle of claim 91, wherein the targeting component is a targeting lipid.

93. The lipid nanoparticle of claim 91, wherein the targeting component is an active targeting component.

94. The lipid nanoparticle of claim 91, wherein the active targeting component is a protein, a peptide, a small molecule, or an antibody or antigen-binding fragment thereof.

95. The lipid nanoparticle of any one of claims 79-94, further comprising one or more polynucleotides encapsulated within the lipid nanoparticle.

96. The lipid nanoparticle of claim 95, wherein the one or more polynucleotides comprise RNA.

97. The lipid nanoparticle of claim 95, wherein the one or more polynucleotides comprise DNA.

98. The lipid nanoparticle of claim 95, wherein the one or more polynucleotides comprise DNA and RNA.

99. A pharmaceutical composition, comprising the lipid nanoparticle of any one of claims 79-98, and a pharmaceutically acceptable excipient.

100. A pharmaceutical composition, comprising the lipid nanoparticle of any one of claims 95-98, and a pharmaceutically acceptable excipient.

101. A method of delivering a polynucleotide to a cell or tissue of a subject, comprising administering to the subject an effective amount of the lipid nanoparticle of any one of claims 79-98, or the pharmaceutical composition of claim 100.

102. The method of claim 101, wherein the cell or tissue comprises an extrahepatic cell or tissue.

103. The method of claim 101, wherein the cell or tissue comprises a brain cell or tissue.

104. The method of claim 101, wherein the cell or tissue comprises a lung cell or tissue.

105. The method of claim 101, wherein the cell or tissue comprises a bone marrow cell or tissue.

106. The method of claim 101, wherein the cell or tissue comprises a spleen cell or tissue.

107. The method of claim 101, wherein the cell or tissue comprises a muscle cell or tissue.

108. The method of claim 101, wherein the cell or tissue comprises a kidney cell or tissue.

109. The method of claim 101, wherein the cell or tissue comprises a heart cell or tissue.

110. The method of claim 101, wherein the cell or tissue comprises a pancreas cell or tissue.

111. The method of claim 101, wherein the cell or tissue comprises an immune cell or tissue.

112. A method of treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 99 or claim 100.

113. A method of producing a therapeutic composition, comprising encapsulating an active agent within a lipid nanoparticle, wherein the lipid nanoparticle comprises the compound of any one of claims 1-78.

114. A method of producing a vaccine or prophylactic composition, comprising encapsulating an active agent within a lipid nanoparticle, wherein the lipid nanoparticle comprises the compound of any one of claims 1-78.

115. The method of claim 113 or claim 114, wherein the active agent comprises DNA.

116. The method of claim 113 or claim 114, wherein the active agent comprises RNA.

117. The method of claim 113 or claim 114, wherein the active agent comprises DNA and RNA.

118. The lipid nanoparticle of any one of claims 79-98 or the pharmaceutical composition of claim 99 or claim 100, for use in delivering a polynucleotide to an extrahepatic cell or tissue of a subject.

119. Use of the lipid nanoparticle of any one of claims 79-98 or the pharmaceutical composition of claim 99 or claim 100 in the manufacture of a medicament for delivering a polynucleotide to an extrahepatic cell or tissue of a subject.

120. The lipid nanoparticle of any one of claims 79-98 or the pharmaceutical composition of claim 99 or claim 100, for use in treating a disease in a subject.

121. Use of the lipid nanoparticle of any one of claims 79-98 or the pharmaceutical composition of claim 99 or claim 100 in the manufacture of a medicament for treating a disease in a subject.

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