Compounds and compositions and methods thereof for intracellular delivery of nucleic acid drugs

Abstract

The present disclosure provides compounds according to Formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIII, and XIV for use as a component in a lipid nanoparticle composition for the delivery of biological and / or therapeutic agents. The present disclosure also provides novel, stable lipid nanoparticle compositions comprising one or more biological and / or therapeutic agents, as well as methods of making and delivering lipid nanoparticle compositions.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 375,007, filed on September 8, 2022, and U.S. Provisional Patent Application No. 63 / 503,714, filed on May 22, 2023, under 35 U.S.C.§119(e), and incorporates by reference in its entirety the disclosures thereof herein. Technical field

[0003] The present disclosure relates to certain compounds and their lipid nanoparticle (LNP) compositions, as well as methods of using these compounds and LNP compositions to transfect and deliver biomolecules and therapeutic agents (such as nucleic acid molecules) into cells. Background art

[0004] Currently, many diseases associated with protein deficiency or misfolding, such as Alzheimer's disease, Parkinson's disease, cystic fibrosis, Fabry disease, etc., require new therapies. For certain protein - related diseases, proteins or enzymes normally secreted by cells are needed for replacement. Gene therapy can treat or even cure such diseases; however, there are some limitations in using traditional gene therapy to achieve this goal.

[0005] One major obstacle of previous gene therapies is that delivering nucleic acids encoding the desired proteins usually has difficulty reaching high enough levels and cannot maintain such levels for a long time, requiring multiple booster doses. Another major obstacle of traditional gene therapy is that once DNA is introduced into cells, only a small fraction is integrated into the genome, and this integration may bring long - term benefits but may also cause unexpected consequences, such as inducing certain mutations that hinder or disrupt the function of endogenous genes.

[0006] In contrast, mRNA - based gene therapy eliminates the risk of inducing genomic mutations, and since the half - life of RNA is relatively short, any confounding effects only last for a limited time. In addition, mRNA can perform its intended function without entering the cell nucleus, which greatly alleviates the defects of traditional gene therapy.

[0007] Due to the inherent instability of mRNA, delivering it into cells is a major challenge. Due to the steric hindrance caused by the presence of 2 - hydroxyl on the ribose of mRNA, mRNA lacks a stable double - helix structure similar to DNA. This makes it more prone to hydrolysis and degradation. In addition, once mRNA reaches the cytoplasm of the cell, it is exposed to degradative enzymes (RNases). Currently, mRNA - based solutions and products need to be stored at ultra - low temperatures (such as minus 80 degrees Celsius) and avoid ubiquitous RNases.

[0008] Studies have shown that encapsulating mRNA within microparticles composed of lipids (lipid nanoparticles, LNPs) can significantly improve the stability of mRNA, protect it from RNases, and facilitate transfection (see, for example, Nat. Rev. Mater. 2021, 6, 1078 - 1094). Early versions of LNPs were composed of cationic lipids (DOTAP, DOTMA, DDAB, etc.), helper lipids (HSPC, DSPC, etc.), cholesterol, and PEG - modified lipids. Due to the permanent cations in the cationic lipids, these LNPs were shown to be toxic. In addition, these early - formulated LNPs did not degrade fast enough in vivo, leading to accumulation upon repeated dosing.

[0009] Replacing the cationic lipids in lipid nanoparticle formulations with amino - ionizable lipids has shown a significant reduction in toxicity. This has driven the development of novel RNA - based therapies (e.g., Alnylam's Onpattro, Pfizer / BioNTech's Comirnaty, and Moderna's Spikevax). Amino - ionizable lipids include, for example, amino - containing lipids that are readily protonated under physiological conditions.

[0010] However, there is still an urgent need for more effective formulations to introduce mRNA into cells to improve its biological performance. In addition, new formulations are needed to deliver nucleic - acid - based therapies. This disclosure meets these and other needs. SUMMARY OF THE INVENTION

[0011] This disclosure provides novel compounds and compositions for facilitating the intracellular delivery of bioactive molecules and / or therapeutic molecules. This disclosure also provides methods for manufacturing nanoparticles and methods for delivering and / or administering nanoparticles (for treating diseases or disorders).

[0012] In one aspect of this disclosure, the structure of the compounds described herein is of Formula I, or a salt thereof, or an isomer thereof:

[0013]

[0014] Wherein:

[0015] R 1 and R 2 may be the same or different and are each independently an alkyl, alkenyl, or alkynyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocycle;

[0016] R 3is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms, or together with the adjacent nitrogen atom forms a ring structure containing 3 to 18 carbon atoms;

[0017] R 4 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms;

[0018] R 5 and R 8 may be the same or different and are each independently a chemical bond, or an alkylene group having 1 to 28 carbon atoms,

[0019] an alkenylene group having 2 to 28 carbon atoms, or an alkynylene group having 2 to 28 carbon atoms;

[0020] R 6 and R 9 may be the same or different and are each independently a hydrogen atom or a straight-chain alkyl group having 1 to 28 carbon atoms or

[0021] an alkenyl group having 2 to 28 carbon atoms;

[0022] R 7 and R 10 may be the same or different and are each independently a hydrogen atom or a straight-chain alkyl group having 1 to 28 carbon atoms or an alkenyl group having 2 to 28 carbon atoms;

[0023] X 1 is a chemical bond, -O-, -CO-, -OC-O- or -O-CO-;

[0024] X 2 and X 4 may be the same or different and are each independently methylene (-CH 2 -), -S-, -SS-, -O-,

[0025] OCO-, -CO-O- or -NR-, where R is a lower alkyl group; and

[0026] X 3 and X 5 may be the same or different and are each independently methylene (-CH 2 -), -S-, -SS-, -O-,

[0027] OCO-, -CO-O- or -NR-, where R is a lower alkyl group,

[0028] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0029] Another aspect of the present disclosure, the structural formula of the compounds described herein is Formula II, or a salt thereof, or an isomer thereof:

[0030]

[0031] Wherein:

[0032] R 1 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms, or an alkynylene group having 2 to 18 carbon atoms;

[0033] R 2 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms, an alkynylene group having 3 to 18 carbon atoms, a carbocyclic alkylene group having 3 to 8 carbon atoms, a heterocyclic alkylene group having 3 to 8 atoms, or a heteroalkylene group having 1 to 18 carbon atoms;

[0034] ;

[0035] R 3 and R 5 may be the same or different and are each independently a chemical bond or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms, or an alkynylene group having 2 to 28 carbon atoms;

[0036] R 4 , R 6 and R 7 may be the same or different and are each independently a hydrogen atom or an alkyl group having 2 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms, or an alkynyl group having 2 to 28 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -CO-OR, -CO-NR

[0037] R a R b、 -NR a -CO-R, -O-

[0038] CO-NR a R b、 -NR a -CO-OR, -NR a R b and -S-CO-R, wherein each occurrence of R is independently a hydrogen atom or methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,

[0039] nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl; R

[0040] and R a and R bIndependently a hydrogen atom or a lower alkyl group;

[0041] X 1 is -OH, -SH, -N(R) 2 , a carbocyclic or heterocyclic group having 5 - 8 carbon atoms, a hydrogen atom or absent, wherein each occurrence of R is independently a lower alkyl group or a hydrogen atom;

[0042] X 2 is -O-CO-, -CO-O-, -NR-CO- or -CO-NR-, wherein R is a lower alkyl group or hydrogen; and

[0043] X 3 、X 4 and X 5 are each independently -O-CO-, -CO-O-, -NR-CO-, -CO-NR-, a bond or absent, wherein R is a lower alkyl group or a hydrogen atom.

[0044] Wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0045] Another aspect of the present disclosure, the structural formula of the compound described herein is Formula III, or a salt thereof, or an isomer thereof:

[0046]

[0047]

[0048]

[0048] Wherein:

[0049] R 1 is an alkylene group having 1 - 18 carbon atoms, an alkenylene group having 2 - 18 carbon atoms or an alkynylene group having 2 - 18 carbon atoms;

[0050] R 2 and R 4 may be the same or different, and are each independently a chemical bond or an alkylene group having 1 - 28 carbon atoms, an alkenylene group having 2 - 28 carbon atoms or an alkynylene group having 2 - 28 carbon atoms;

[0051] R 3 and R 5 may be the same or different, and are each independently a hydrogen atom or an alkyl group having 1 - 28 carbon atoms, an alkenyl group having 2 - 28 carbon atoms or an alkynyl group having 2 - 28 carbon atoms;

[0052] X 1 is -OH, -OR, -CO-OR, -CO-R, -O-CO-R, -SH, -SR, -N(R) 2, a carbocyclic or heterocyclic group having 5 to 8 carbon atoms, a hydrogen atom or absent, wherein each occurrence of R is independently hydrogen or an optionally substituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl; and

[0053] X 2 and X 3 may be the same or different and are each independently -O-CO-, -CO-O-, -CO-, -NRCO-, -

[0054] CO-NR-, a chemical bond or absent, wherein R is a lower alkyl or hydrogen,

[0055] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0056] Another aspect of the present disclosure, the structural formula of the compound described herein is Formula IV, or a salt thereof, or an isomer thereof:

[0057]

[0058] Wherein:

[0059] R 1 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -

[0060] CO-OR, -CO-NR a R b , -NR a -CO-R, -O-CO-NR a R b , -NR a -CO-OR, -NR a R b and -S-

[0061] CO-R, wherein each occurrence of R is independently a hydrogen atom or a lower alkyl; and R a and R b are independently a hydrogen atom or a lower alkyl;

[0062] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0063] R 2 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms;

[0064] R 3 is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or an alkynyl group having 2 to 18 carbon atoms,

[0065] or a carbocyclic group or a heterocyclic group having 5 to 8 carbon atoms, a hydrogen atom or absent;

[0066] R 4 、R 6 and R 8 may be the same or different and are each independently a chemical bond or an alkylene group having 1 to 28 carbon atoms,

[0067] an alkenylene group having 2 to 28 carbon atoms or an alkynylene group having 2 to 28 carbon atoms;

[0068] R 5 、R 7 、R 9 are the same or different and are each independently a chemical bond or an alkyl group having 2 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms;

[0069] X 1 is methylene (-CH 2 -), -O-, -S-, -SS-, -NR- (wherein R is a lower alkyl group), -CO-NR- (wherein

[0070] R is a lower alkyl group), -NR-CO- (wherein R is a lower alkyl group or a hydrogen atom), -O-CO-, -CO-O-, -

[0071] CO-, -O-CO-O-, a carbocyclic subunit or a heterocyclic subunit having 5 to 8 carbon atoms, a chemical bond or absent; and

[0072] X 2 、X 3 and X 4 are the same or different and are each independently methylene (-CH 2 -), -O-, -S-, -SS-, -NR-

[0073] (wherein R is a lower alkyl group), -CO-NR- (wherein R is a lower alkyl group), -NR-CO- (wherein R

[0074] is a lower alkyl group or a hydrogen atom), -O-CO-, -COO-, -CO-, -O-CO-O-, a carbocyclic subunit or a heterocyclic subunit having 5 to 8 carbon atoms, a chemical bond or absent,

[0075] wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0076] In another aspect of the present disclosure, the structural formula of the compound described herein is Formula V, or a salt or an isomer thereof:

[0077]

[0078] Wherein:

[0079] R 1 is an alkyl group having 2 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or an alkynyl group having 2 to 18 carbon atoms, a carbocyclic group or a heterocyclic group having 5 to 8 carbon atoms, a hydrogen atom or absent;

[0080] R 2 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms;

[0081] R 3 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -

[0082] CO-OR, -CO-NR a R b 、-NR a -CO-R, -O-CO-NR a R b 、-NR a -CO-OR, -NR a R b and -S-

[0083] CO-R, where R is independently a hydrogen atom or a lower alkyl each time it appears; and R a and

[0084] R b are independently a hydrogen atom or a lower alkyl;

[0085] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0086] R 4 and R 8 may be the same or different and are each independently a chemical bond or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28

[0087] carbon atoms or an alkynylene group having 2 to 28 carbon atoms;

[0088] R 5 and R 9 may be the same or different and are each independently a hydrogen atom or an alkyl group having 1 to 28 carbon atoms, 2 to 28

[0089] an alkenyl group of carbon atoms or an alkynyl group of 2 to 28 carbon atoms;

[0090] R 6 and R 7 may be the same or different and are each independently a chemical bond or an alkylene group of 1 to 18 carbon atoms, an alkenylene group of 2 to 18

[0091] carbon atoms or an alkynylene group of 2 to 18 carbon atoms;

[0092] X 1 is methylene (-CH 2 -), -O-, -S-, -SS-, -NR- (wherein R is a lower alkyl group), -CO-NR- (wherein

[0093] R is a lower alkyl group), -NR-CO- (wherein R is a lower alkyl group or a hydrogen atom), -O-CO-, -CO-O-, -

[0094] CO-, -O-CO-O-, a carbocyclic subunit or a heterocyclic subunit of 5 to 8 carbon atoms, a chemical bond or absent; and

[0095] X 2 and X 3 may be the same or different and are each independently methylene (-CH 2 -), -O-, -S-, -SS-, -NR-

[0096] (wherein R is a lower alkyl group), -CO-NR- (wherein R is a lower alkyl group), -NR-CO- (wherein R

[0097] is a lower alkyl group or a hydrogen atom), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit or a heterocyclic subunit of 5 to 8 carbon atoms, a chemical bond or absent,

[0098] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0099] In another aspect of the present disclosure, the compound described herein has the structural formula of Formula VI, or a salt thereof, or an isomer thereof

[0100]

[0101] wherein:

[0102] Y 1 and Y 2may be the same or different and are each independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, and alkynylene, where R is independently hydrogen, or alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group;

[0103] X is selected from -S-, -SS-, -O-, -CH 2 -, alkenylene, alkynylene, -NR-, where R is a hydrogen atom or alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group;

[0104] R 1 and R 2 are the same or different and are each independently selected from carbocyclic group, alkyl, alkenyl, and alkynyl, each optionally substituted;

[0105] R 3 is selected from a hydrogen atom, a halogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl, and heteroaryl, and each group other than hydrogen and halogen is optionally substituted;

[0106] Z is selected from alkylene, alkenylene, alkynylene, and carbocyclic subunit;

[0107] m is from 1 to 24.

[0108] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0109] In another aspect of the present invention, the structure of the compound described herein is Formula VII or its salt or its isomer

[0110]

[0111] wherein:

[0112] Y 1 and Y 2 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom, or alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group each time it appears;

[0113] X 1 and X 2 are the same or different and are independently selected from -S-, -SS-, -O-, -CH 2-, alkenylene, alkynylene and -NR-, where R is a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group;

[0114] R 1 and R 2 may be the same or different and are independently selected from alkyl, alkenyl, alkynyl and heterocyclic groups, each optionally substituted;

[0115] R 3 is selected from a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group, each optionally substituted;

[0116] m and n are each independently an integer selected from 1 to 24,

[0117] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0118] In another aspect of the present invention, the compound described herein has the structural formula of Formula VIII, or a salt thereof, or an isomer thereof

[0119]

[0120] wherein:

[0121] X 1 、X 2 and X 3 are independently selected from -CH 2 -, -O-, -S- and -NR-, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group;

[0122] R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group, and each group other than hydrogen and halogen may be optionally substituted;

[0123] R 3 and R 4 are selected from carbocyclic, alkyl, alkenyl and alkynyl groups, each optionally substituted;

[0124] m is 0, 1, 2, 3, 4 or 5,

[0125] where the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0126] In another aspect of the present invention, the compound described herein has the structural formula of Formula IX, or a salt thereof, or an isomer thereof

[0127]

[0128] wherein:

[0129] X 1 and X 2 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenes and alkynes, where each occurrence of R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group;

[0130] R 1 and R 2 may be the same or different and are independently a hydrogen atom, halogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl, each of which may be optionally substituted except for hydrogen and halogen atoms;

[0131] R 3 and R 4 may be the same or different and are independently a carbocyclic group, alkyl, alkenyl and alkynyl;

[0132] m and n may be the same or different and are each an integer from 1 to 24,

[0133] where the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0134] In another aspect of the present invention, the compound described herein has the structural formula of Formula X, or a salt thereof, or an isomer thereof

[0135]

[0136] wherein:

[0137] R 1 、R 2 、R 3 、R 4 and R 5 may be the same or different and are independently selected from a hydrogen atom, halogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl. Each group may be optionally substituted except for hydrogen and halogen atoms;

[0138] X 1 、X 2 and X 3 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2-, -NR-, alkenylene, and alkynylene, where R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group;

[0139] X 4 selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, (C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkenylene, and alkynylene, where R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; or X 4 is a straight-chain alkyl containing 0 to 10 methylene units;

[0140] Y 1 and Y 2 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene, and carbocyclic-subylene, where R is independently, each time it appears, a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; and

[0141] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,

[0142] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0143] In another aspect of the present invention, the structural formula of the compound described herein is Formula XI, or its salt, or its isomer

[0144]

[0145] where:

[0146] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group, where each may be optionally substituted except for hydrogen and halogen atoms;

[0147] X 1 、X 2 、X 3 、X 4 、X 5 and X6 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene, carbocyclic group and chemical bond, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group each time it appears;

[0148] X 7 and X 8 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene and carbocyclic group, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group each time it appears; or X 7 and X 8 each independently is a straight-chain alkyl group containing 0 to 10 methylene units;

[0149] Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene and alkynylene, where R is independently a hydrogen atom or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group each time it appears; and

[0150] n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10,

[0151] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0152] In another aspect of the present invention, the structural formula of the compound described herein is Formula XII, or its salt, or its isomer

[0153]

[0154] wherein:

[0155] R 1 、R 2 、R 3 and R 4may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, each of which may be optionally substituted except for the hydrogen and halogen atoms;

[0156] X 1 、X 2 、X 3 and X 4 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, an alkenylene group, an alkynylene group, or a chemical bond, wherein each occurrence of R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group;

[0157] X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, an alkenylene group,

[0158] an alkynylene group, and a bond, wherein each occurrence of R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group; or X 5 and X 6 are each independently a straight-chain alkyl group containing 0 to 10 methylene units;

[0159] Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, an alkenylene group, an alkynylene group, and a bond, wherein each occurrence of R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group;

[0160] The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic, or anti-aromatic ring system; and

[0161] n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10,

[0162] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0163] Another aspect of the present invention, the chemical structure formula of the compound described herein is Formula XIII, or its salt, or its isomer

[0164]

[0165] Wherein:

[0166] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be optionally substituted except for a hydrogen atom and a halogen atom;

[0167] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, an alkenylene group, an alkynylene group, a cyclic alkylene group or a heteroalkylene group, where R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group each time it appears;

[0168] X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, an alkenylene group, an alkynylene group, a cyclic alkylene group or a heteroalkylene group, where R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group; or X 7 and X 8 are each a straight-chain alkyl group containing 0 to 10 methylene units;

[0169] Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH2 - An alkenylene, alkynylene, and cyclic alkylene or heteroalkylene, wherein each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group;

[0170] The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic, or anti-aromatic ring system; and

[0171] n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10,

[0172] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0173] Another aspect of the present invention, the compound described herein has the structural formula of Formula XIV, or a salt thereof, or an isomer thereof

[0174]

[0175] wherein:

[0176] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group, each of which may be optionally substituted except for the hydrogen and halogen atoms;

[0177] X 1 、X 2 、X 3 、X 4 and X 5 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, an alkylene, alkenylene, alkynylene, cycloalkylene, and heterocycloalkylene, wherein R is independently a hydrogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, and heterocyclic group;

[0178] Y 1 、Y 2 and Y 3 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2- An alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene group, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl,

[0179] carbocyclic or heterocyclic group; and

[0180] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10,

[0181] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0182] Another aspect of the present disclosure provides methods for synthesizing and characterizing compounds of structural formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII and XIV, and methods for manufacturing nanoparticle compositions, the nanoparticle compositions comprising a lipid component (e.g., a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV) and a biomolecule or therapeutic agent (including but not limited to nucleic acids (e.g., mRNA)).

[0183] Examples of bioactive and / or therapeutic molecules include but are not limited to: (1) polynucleotides, such as mRNA, rRNA, RNAi, microRNA, plasmid, aptamer, DNA, cDNA; (2) antisense polynucleotides; (3) low molecular weight compounds (synthetic or naturally occurring), such as peptides, hormones and antibiotics; and (4) proteins.

[0184] In some embodiments, the active molecule is completely encapsulated in the lipid nanoparticle composition such that the active molecule can resist enzymatic degradation (e.g., by nucleases). In other embodiments, the lipid particles are non-toxic to mammals (e.g., humans).

[0185] In one example, the lipid nanoparticle composition may include one or more ionizable lipids, neutral lipids, PEG-modified lipids or cholesterol. For example, the lipid nanoparticle composition may include at least one of the following ionizable lipids: DLin-MC3-DMA, DODMA, DODAP, SM-102, ALC-0315, C12-200, or one of the ionizable lipids described in formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV. In some examples, the lipid nanoparticle composition includes PEG 2000 -DMG or other PEG-conjugated lipids. In some examples, the lipid nanoparticle composition includes cholesterol. In certain examples, the lipid nanoparticle composition includes at least one neutral lipid (e.g., DSPE, DOPE, DSPC, HSPC).

[0186] In another aspect, the present disclosure provides lipid nanoparticle compositions comprising (a) one or more active molecules; (b) one or more ionizable lipids, present in the composition in an amount of about 10 mol% to about 85 mol% of the total lipids present; (c) one or more neutral "helper" lipids, present in the composition in an amount of about 5 mol% to about 40 mol% of the total lipids present; (d) one or more PEG-conjugated lipids that inhibit nanoparticle aggregation, present in the composition in an amount of about 0 mol% to about 10 mol% of the total lipids present; and (e) cholesterol, present in the composition in an amount of about 10 mol% to 50 mol% of the total lipids present.

[0187] The present disclosure also provides compositions and methods for facilitating transfection and delivery of one or more nucleic acid molecules to cells. In some embodiments, the secretion of the protein persists for a period of time. For example, the secreted protein can be produced for more than 1 hour, more than 3 hours, more than 6 hours, more than 10 hours, more than 24 hours, more than 48 hours, or more than 72 hours after administration. In some embodiments, protein expression above the therapeutic level is sustainable.

[0188] In another aspect, the present disclosure describes lipid nanoparticle compositions and acceptable pharmaceutically relevant carriers according to the foregoing aspects. For example, the lipid nanoparticle composition can be suspended in a buffer or other solution that is intended to promote stability during storage and / or transportation. In some embodiments, the lipid nanoparticle composition can be refrigerated (e.g., stored at a temperature of about 2 to 8 degrees Celsius). In other embodiments, the lipid nanoparticle composition can be frozen (e.g., at a temperature below 0 degrees Celsius (e.g., about -5 degrees Celsius, -10 degrees Celsius, -15 degrees Celsius, -20 degrees Celsius, -30 degrees Celsius, -40 degrees Celsius, -50 degrees Celsius, -60 degrees Celsius, -70 degrees Celsius, -80 degrees Celsius, -90 degrees Celsius, -100 degrees Celsius, -120 degrees Celsius, -140 degrees Celsius, or -160 degrees Celsius)). In other embodiments, the lipid nanoparticle composition can be lyophilized in the presence of sucrose, lactose, or other sugars or excipients (e.g., bulking agents, disintegration temperature regulators, amino acids, polyols, buffers, complexing agents, tonicity regulators, or antioxidants). The lyophilized lipid nanoparticle composition cake can preferably be stored in a sterile lyophilized vial and subsequently rehydrated with sterile water for injection.

[0189] In another aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a therapeutic agent by delivery with a lipid nanoparticle composition according to any aspect or embodiment disclosed herein.

[0190] In another aspect, the present disclosure provides a method of delivering a therapeutic agent to a subject in need thereof to treat a disease or disorder of the subject using a lipid nanoparticle composition according to any aspect or embodiment disclosed herein.

[0191] In another aspect, the present disclosure provides the use of a lipid nanoparticle composition (LNP) according to any aspect or embodiment disclosed herein in the manufacture of a medicament for treating a disease or disorder of a subject in need thereof.

[0192] Such disease or disorder can be any disease or disorder that can be treated by a therapeutic agent delivered to a subject in need thereof by the LNP.

[0193] Other aspects or advantages of the present disclosure will be better understood by those skilled in the art from the following drawings, detailed description, examples and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0194] Figure 1 A representative dynamic light scattering (DLS) curve of a novel lipid nanoparticle composition is shown.

[0195] Figure 2 Additional representative dynamic light scattering (DLS) curves of a novel lipid nanoparticle composition are shown.

[0196] Figure 3 Additional representative dynamic light scattering (DLS) curves of a novel lipid nanoparticle composition are shown.

[0197] Figure 4 Additional representative dynamic light scattering (DLS) curves of a novel lipid nanoparticle composition are shown.

[0198] Figure 5 A representative in vitro transfection efficiency of a novel lipid nanoparticle composition relative to a naked mRNA standard is shown.

[0199] Figure 6 Additional representative in vitro transfection efficiencies of a novel lipid nanoparticle composition relative to a naked mRNA standard are shown.

[0200] Figure 7 Additional representative in vitro transfection efficiencies of a novel lipid nanoparticle composition relative to a naked mRNA standard are shown. DETAILED DESCRIPTION

[0201] This disclosure relates to novel lipids and lipid nanoparticle compositions comprising the novel lipids. This disclosure also provides methods for delivering a biological and / or therapeutic agent to mammalian cells or organs and for treating a disease or disorder using a lipid nanoparticle composition (LNP). A method for delivering a biological and / or therapeutic agent to mammalian cells or organs may involve administering a nanoparticle composition comprising the biological and / or therapeutic agent to a subject, wherein the cells or organs are contacted with the composition, thereby delivering the biological and / or therapeutic agent to the cells or organs.

[0202] I. Ionizable Lipids

[0203] This disclosure provides lipids comprising an amine moiety and one or more biodegradable groups. The lipids described herein can be used in nanoparticle compositions for delivering a biological and / or therapeutic agent to mammalian cells or organs.

[0204] In one aspect of this disclosure, the compounds described herein have the structural formula of Formula I, or a salt thereof, or an isomer thereof.

[0205]

[0206] Wherein:

[0207] R 1 and R 2 may be the same or different and are each independently an alkyl, alkenyl, or alkynyl group; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0208] R 3 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms, or an alkynylene group having 2 to 18 carbon atoms, or together with the adjacent nitrogen atom forms a ring structure having 3 to 18 carbon atoms;

[0209] R 4 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms, or an alkynylene group having 2 to 18 carbon atoms;

[0210] R 5 and R 8 may be the same or different and are each independently a chemical bond, or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms, or an alkynylene group having 2 to 28 carbon atoms;

[0211] R 6 and R 9 may be the same or different and are each independently a hydrogen atom or a straight-chain alkyl group having 1 to 28 carbon atoms or an alkenyl group having 2 to 28 carbon atoms;

[0212] R7 and R 10 may be the same or different and each independently is a hydrogen atom or an alkyl group having 1 to 28 carbon atoms in a straight chain or an alkenyl group having 2 to 28 carbon atoms;

[0213] X 1 is a chemical bond, -O-, -CO-, -OC-O- or -O-CO-;

[0214] X 2 and X 4 may be the same or different and each independently is methylene (-CH 2 -), -S-, -SS-, -O-, OCO-, -CO-O- or -NR-, where R is a lower alkyl group; and

[0215] X 3 and X 5 may be the same or different and each independently is methylene (-CH 2 -), -S-, -SS-, -O-, OCO-, -CO-O- or -NR-, where R is a lower alkyl group,

[0216] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0217] In some embodiments, R 1 and R 2 together with the atoms to which they are attached form part of a 5- to 8-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S and P. In certain embodiments, the heterocycle formed by R 1 and R 2 is substituted by one or more carbocyclic groups having 3 to 7 carbon atoms or 3- to 8-membered heterocyclic groups or other functional groups, such as alkyl, alkenyl, alkynyl, -OH, -SH, -OR, -SR, -NR 2 , -oxo or combinations thereof.

[0218] In some embodiments, R 3 , X 1 and R 4 may form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, olefins or alkynes. In certain embodiments, the ring may optionally be substituted by one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2, NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0219] In some embodiments, R 5 , X 2 and X 3 may together with the atoms to which they are attached form part of a 4- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group of 3-7 carbon atoms, 3-8 membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0220] In some embodiments, R 8 , X 4 and X 5 may together with the atoms to which they are attached form part of a 4- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group of 3-7 carbon atoms, 3-8 membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0221] In some embodiments, R 1 and R 2 are each independently selected from methyl, ethyl and isopropyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group.

[0222] In some embodiments, R 3 is a straight-chain alkyl group containing at least 3 carbons.

[0223] In some embodiments, in the compound of formula I:

[0224] R 1 and R 2 are each independently methyl, ethyl, propyl, isopropyl, butyl or isobutyl; or R1 and

[0225] R 2 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0226] R 3 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms;

[0227] R 4 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms;

[0228] R 5 and R 8 may be the same or different and are each independently a chemical bond, an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms;

[0229] R 6 and R 9 may be the same or different and are each independently a hydrogen atom, a straight-chain alkyl group having 1 to 14 carbon atoms or a straight-chain alkenyl group having 2 to

[0230] 14 carbon atoms;

[0231] R 7 and R 10 may be the same or different and are each independently a hydrogen atom, a straight-chain alkyl group having 1 to 14 carbon atoms or a straight-chain alkenyl group having 2 to 14 carbon atoms;

[0232] X 1 is a chemical bond, -CO-, -OC-O- or -O-CO-;

[0233] X 2 and X 4 may be the same or different and are each independently methylene (-CH 2 -), -O-, -OCO- or -CO-O-;

[0234] and

[0235] X 3 and X 5 may be the same or different and are each independently methylene (-CH 2 -), -O-, -OCO- or -CO-O-.

[0236] In some embodiments, the compound of formula I may be selected from the compounds of List 1:

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] and its salts and isomers.

[0251] In another aspect of the present disclosure, the structural formula of the compound described herein is Formula II, or its salt, or its isomer

[0252]

[0253]

[0254] Wherein:

[0255] R 1 is an alkylene group having 1 - 18 carbon atoms, an alkenylene group having 2 - 18 carbon atoms or an alkynylene group having 2 - 18 carbon atoms;

[0256] R 2 is an alkylene group having 1 - 18 carbon atoms, an alkenylene group having 2 - 18 carbon atoms, an alkynylene group having 2 - 18 carbon atoms, a carbocyclic subunit having 3 - 8 carbon atoms, a heterocyclic subunit having 3 - 8 members or a heteroalkylene group having 1 - 18 carbon atoms;

[0257] R 3 and R 5 may be the same or different and are each independently a chemical bond or an alkylene group having 1 - 28 carbon atoms, an alkenylene group having 2 - 28 carbon atoms or an alkynylene group having 2 - 28 carbon atoms;

[0258] R 4 、R6 and R 7 may be the same or different and each independently is a hydrogen atom or an alkyl group having 1 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms, each optionally being substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -CO-OR, -CO-NR a R b -, -NR a -CO-R, -O-CO-NR a R b -, -NR a -CO-OR, -NR a R b and -S-CO-R, where R is independently a hydrogen atom or methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl each time it appears; R a and R b are independently a hydrogen atom or a lower alkyl group;

[0259] X 1 is -OH, -SH, -N(R) 2 , a carbocyclic group or a heterocyclic group having 5 to 8 carbon atoms, a hydrogen atom or absent, where R is independently a lower alkyl group or a hydrogen atom each time it appears;

[0260] X 2 is -O-CO-, -CO-O-, -NR-CO- or -CO-NR-, where R is a lower alkyl group or a hydrogen atom; and

[0261] X 3 , X 4 and X 5 are each independently -O-CO-, -CO-O-, -NR-CO-, -CO-NR-, a chemical bond or absent, where R is a lower alkyl group or a hydrogen atom,

[0262] where the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0263] In some embodiments, X 2 , X 3 and R 2Form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which may optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, or alkynes. In certain embodiments, the heterocyclic ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0264] In some embodiments, R 1 , X 1 and R 7 Form part of a 5- to 20-membered heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which may optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, or alkynes. In certain embodiments, the heterocyclic ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0265] In some embodiments, X 5 , R 5 , R 3 and X 4 Together with the carbon atom to which they are attached, form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which may optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, or alkynes. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, NR 2 , NHR, -oxo, -OCO-, -NR-CO-, or other functional groups.

[0266] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7Optionally substituted by one or more substituents such as, but not limited to, alkyl, alkenyl or alkynyl, a carbocyclic group having 3 to 7 carbon atoms, a heterocyclic group having 3 to 8 members, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0267] In some embodiments, R 5 is a chemical bond; and R 6 is a hydrogen atom; and X 5 is absent.

[0268] In some embodiments, X 1 is a hydrogen atom.

[0269] In some embodiments, X 2 is -O-CO- or -CO-O-.

[0270] In some embodiments, R 7 is an alkenyl group having 18 straight-chain carbon atoms.

[0271] In some embodiments, R 1 and X 1 together are a 1,2-dihydroxypropane moiety, a pyrrolidinoethylamine moiety or a (2-hydroxyethyl)(ethyl)amino)ethylamine moiety.

[0272] In some embodiments, R 7 is a 2-hexyldecyl hexanoate moiety; X 2 is -O-CO- or -CO-O-; and R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl or ((2-hexyldecyl)thio)ethyl.

[0273] In some embodiments, in the compound of formula II:

[0274] R 1 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms;

[0275] R 2 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or

[0276] a heteroalkylene group having 1 to 8 carbon atoms;

[0277] R 3 and R 5may be the same or different and each independently is a key or an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms;

[0278] atoms, or an alkenylene group having 2 to 14 carbon atoms;

[0279] R 4 、R 6 and R 7 may be the same or different and each independently is hydrogen or an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms;

[0280] X 1 is -OH, -N(R) 2 、a carbocyclic group having 5 to 8 carbon atoms or hydrogen, where R is independently a lower alkyl group or a hydrogen atom each time it appears;

[0281] X 2 is -O-CO- or -CO-O-; and

[0282] X 3 、X 4 and X 5 are each independently a chemical bond, -OCO- or -CO-O-,

[0283] wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0284] In some embodiments, the compounds of formula II may be selected from the compounds of List 2:

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297] and its salts and isomers.

[0298] In another aspect of the present disclosure, the compound described herein has the structural formula of Formula III, or its salt, or its isomer.

[0299]

[0300] Wherein:

[0301] R 1 is an optionally substituted alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms;

[0302] R 2 and R 4 may be the same or different and are each independently a bond or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms or an alkynylene group having 2 to 28 carbon atoms;

[0303] R 3 and R 5 may be the same or different and are each independently hydrogen or an alkyl group having 1 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms;

[0304] X 1 is -OH, -OR, -CO-OR, -CO-R, -O-CO-R, -SH, -SR, -N(R) 2 , a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group, a hydrogen atom or absent, wherein each occurrence of R is independently a hydrogen atom or an optionally substituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl; and

[0305] X 2 and X 3 may be the same or different and are each independently -O-CO-, -CO-O-, -CO-, -NRCO-, -CO-NR-, a chemical bond or absent, wherein R is a lower alkyl group or a hydrogen atom,

[0306] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0307] In some embodiments, R 1 and X 1can together form a 5- to 8-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P. In certain embodiments, R 1 and X 1 form a heterocyclic ring that may optionally be substituted with one or more substituents such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0308] In some embodiments, R 2 and R 4 can independently be a carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P and having 3 to 8 carbon atoms. The carbocyclic or heterocyclic ring group may optionally be substituted with one or more substituents such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0309] In some embodiments, R 2 and X 2 and / or R 4 and X 3 can together with the atoms to which they are attached form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which may optionally be part of a functional group such as, but not limited to, ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, or alkyne. In certain embodiments, the ring may optionally be substituted with one or more substituents such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0310] In some embodiments, R 4 and X 3may, together with the atoms to which they are attached, form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally form part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes or alkynes. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0311] In some embodiments, X 2 and X 3 are independently -O-CO- or -CO-O-.

[0312] In some embodiments, R 3 and R 5 are straight-chain alkylene groups of 10 carbon atoms.

[0313] In some embodiments, X 2 is -CO-O- and X 3 is -OCO-.

[0314] In some embodiments, in the compounds of formula III:

[0315] R 1 is an optionally substituted alkylene group of 1 to 8 carbon atoms, an alkenylene group of 2 to 8 carbon atoms or an alkynylene group of 2 to 8 carbon atoms;

[0316] R 2 and R 4 may be the same or different and are each independently a bond or an alkylene group of 1 to 14 carbon atoms, an alkenylene group of 2 to 14 carbon atoms or an alkynylene group of 2 to 14 carbon atoms;

[0317] R 3 and R 5 may be the same or different and are each independently hydrogen or an alkyl group of 1 to 8 carbon atoms, an alkenyl group of 2 to 8 carbon atoms or an alkynyl group of 2 to 8 carbon atoms;

[0318] X 1is -OH, -CO-OR, -O-CO-R, a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group or a hydrogen atom, wherein each occurrence of R is independently a hydrogen atom or an optionally substituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl; and X 2 and X 3 may be the same or different and are each independently -O-CO-, -CO-O-, -NR-CO-, -CO-NR- or a chemical bond, wherein R is a lower alkyl or a hydrogen atom,

[0319] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0320] In some embodiments, the compounds of formula III may be selected from the compounds of List 3:

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328] or a salt thereof, or an isomer thereof.

[0329] In another aspect of the present disclosure, the compound described herein has the structural formula of formula IV, or a salt thereof, or an isomer thereof.

[0330]

[0331] Wherein:

[0332] R 1 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms, each optionally substituted by one, two or three independently selected from -OR, -SR, -SSR, -O-CO-R, -CO-OR, -CO-NR a R b 、-NR a -CO-R, -O-CO-NR a Rb 、 -NR a -CO-OR, -NR a R b and the substituents in -S-CO-R, where each occurrence of R is independently hydrogen or a lower alkyl; and R a and R b are independently a hydrogen atom or a lower alkyl;

[0333] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0334] R 2 is an alkylene group having 1 - 18 carbon atoms, an alkenylene group having 2 - 18 carbon atoms or an alkynylene group having 2 - 18 carbon atoms;

[0335] R 3 is an alkyl group having 1 - 18 carbon atoms, an alkenyl group having 2 - 18 carbon atoms, or an alkynyl group having 2 - 18 carbon atoms, or a carbocyclic group having 5 - 8 carbon atoms, a heterocyclic group, a hydrogen atom or absent;

[0336] R 4 、R 6 and R 8 may be the same or different and are each independently a bond or an alkylene group having 1 - 28 carbon atoms, an alkenylene group having 2 - 28 carbon atoms or an alkynylene group having 2 - 28 carbon atoms;

[0337] R 5 、R 7 、R 9 may be the same or different and are each independently a bond or an alkyl group having 2 - 28 carbon atoms, an alkenyl group having 2 - 28 carbon atoms or an alkynyl group having 2 - 28 carbon atoms;

[0338] X 1 is methylene (-CH 2 -), -O-, -S-, -SS-, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or hydrogen), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 - 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent; and X 2 、X 3 and X 4 may be the same or different and are each independently methylene (-CH 2-), -O-, -S-, -SS, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or a hydrogen atom), -O-CO-, COO-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent,

[0339] wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0340] In some embodiments, R 1 can together with one or two atoms to which it is attached form part of a 3- to 10-membered heterocycle having one or more heteroatoms selected from N, O, S or P, which can optionally form part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes or alkynes. In certain embodiments, the ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0341] In some embodiments, R 2 and X 1 can together form a 5- to 8-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S and P. In certain embodiments, the formed heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0342] In some embodiments, R 4 , R 6 and R 8 can independently be a carbocyclic or heterocyclic ring having 3 to 8 carbon atoms and one or more heteroatoms selected from N, O, S and P. The carbocyclic or heterocyclic ring group can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0343] In some embodiments, R 4 and X2 can together with the atoms to which they are attached form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes or alkynes. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 2, -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0344] In some embodiments, R 6 and X 3 can together with the atoms to which they are attached form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes or alkynes. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 2, -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0345] In some embodiments, R 8 and X 4 can together with the atoms to which they are attached form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes or alkynes. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 2, -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0346] In some embodiments, n is 3.

[0347] In some embodiments, R 1 is methyl, ethyl, propyl, butyl, or methoxymethyl, ethoxyethyl, or methoxyethyl.

[0348] In some embodiments, R 2 is ethyl.

[0349] In some embodiments, X 1 is -O-CO- or -COO-.

[0350] In some embodiments, R 5 , R 7 and R 9 are the same and each is a straight-chain alkyl group having 10 carbon atoms.

[0351] In some embodiments, in the compound of formula IV:

[0352] R 1 is an alkylene group having 1-8 carbon atoms, an alkenylene group having 2-8 carbon atoms or an alkynylene group having 2-8 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -O-CO-R, -CO-OR, -CO-NR a R b , -NR a -CO-R, -O-CO-NR a R b , -NR a -CO-OR and -NR a R b wherein R is independently a hydrogen atom or a lower alkyl group each time it appears; and R a and R b are independently a hydrogen atom or a lower alkyl group;

[0353] n is 0, 1, 2, 3, 4 or 5;

[0354] R 2 is an alkylene group having 1-8 carbon atoms, an alkenylene group having 2-8 carbon atoms or an alkynylene group having 2-8 carbon atoms;

[0355] R 3 is an alkyl group having 1-8 carbon atoms, an alkenyl group having 2-8 carbon atoms, or an alkynyl group having 2-8 carbon atoms, or a carbocyclic group, a heterocyclic group having 5-8 carbon atoms, or a hydrogen atom;

[0356] R 4 , R 6 and R 8 may be the same or different and are each independently a chemical bond or an alkylene group having 1-14 carbon atoms, an alkenylene group having 2-14 carbon atoms or an alkynylene group having 2-14 carbon atoms;

[0357] R 5 , R 7 , R 9may be the same or different and each independently is a chemical bond or an alkyl group having 2 to 14 carbon atoms, an alkenyl group having 2 to 14 carbon atoms or an alkynyl group having 2 to 14 carbon atoms;

[0358] X 1 is methylene (-CH 2 -), -O-, -NR-, where R is a lower alkyl group, -O-CO-, -CO-O-, C 5-8 carbocyclic subunit, heterocyclic subunit or bond; and

[0359] X 2 、X 3 and X 4 are the same or different and each independently is methylene (-CH 2 -), -O-, -NR- (where R is a lower alkyl group), O-CO-, COO-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit or a chemical bond,

[0360] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0361] In some embodiments, the compounds of Formula IV may be selected from the compounds of List 4:

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368] or a salt thereof, or an isomer thereof.

[0369] Another aspect of the present disclosure, the chemical structure of the compounds described herein is Formula V, or a salt thereof, or an isomer thereof.

[0370]

[0371] Wherein:

[0372] R 1 is an alkyl group having 2 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or an alkynyl group having 2 to 18 carbon atoms, a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group, a hydrogen atom or absent;

[0373] R2 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms;

[0374] R 3 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -CO-OR, -CO-NR a R b , -NR a -CO-R, -O-CO-NR a R b , -NR a -CO-OR, -NR a R b and -S-CO-R, where R is independently a hydrogen atom or a lower alkyl each time it appears; and R a and R b are independently a hydrogen atom or a lower alkyl;

[0375] n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0376] R 4 and R 8 may be the same or different and are each independently a chemical bond or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms or an alkynylene group having 2 to 28 carbon atoms;

[0377] R 5 and R 9 may be the same or different and are each independently a hydrogen atom or an alkyl group having 1 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms;

[0378] R 6 and R 7 may be the same or different and are each independently a chemical bond or an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms;

[0379] X 1 is methylene (-CH 2 -), -O-, -S-, -SS-, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or a hydrogen atom), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent; and X 2 and X 3Identical or different, each independently being methylene (-CH 2 -), O-, -S-, -SS-, NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl- ) ), -NR-CO- (where R is a lower alkyl or hydrogen), O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent,

[0380] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0381] In some embodiments, R 2 and X 1 together with the atoms to which they are attached form part of a 3- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0382] In some embodiments, R 3 may together with one or two atoms to which it is attached form part of a 3- to 10-membered heterocyclic ring having one or more heteroatoms selected from N, O, S or P, said heteroatoms may optionally be part of a functional group, said functional group such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the ring may optionally be substituted with one or more substituents, said substituents such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0383] In some embodiments, R 6 and R 7 are optionally substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 7-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2, -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0384] In some embodiments, R 4 and X 2 can together with the atoms to which they are attached form part of a 3-10 membered carbon ring or 3-10 membered heterocycle having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, 3-7 membered carbocyclic group, 3-8 membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0385] In some embodiments, R 8 and X 3 can together with the atoms to which they are attached form part of a 3-10 membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which may optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the ring may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, 3-7 membered carbocyclic group, 3-8 membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0386] In some embodiments, n is 3.

[0387] In some embodiments, R 3 is methyl, ethyl, propyl, butyl, methoxymethyl, ethoxyethyl or methoxyethyl.

[0388] In some embodiments, R 2 consists of ethyl.

[0389] In some embodiments, X 1 is -O-CO- or -CO-O-.

[0390] In some embodiments, R 1 is an alkyl group of 10 carbon atoms.

[0391] In some embodiments, R 6 and R7 Each is independently an ethylene group, a propylene group or a butylene group.

[0392] In some embodiments, X 2 and X 3 are independently -O-CO- or -CO-O-.

[0393] In some embodiments, in the compound of formula V:

[0394] R 1 is an alkyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an alkynyl group having 2 to 8 carbon atoms, a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group, or a hydrogen atom;

[0395] R 2 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms;

[0396] R 3 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -O-CO-R, -CO-OR and -NR a R b wherein each occurrence of R is independently a hydrogen atom or a lower alkyl group; and R a and R b are independently a hydrogen atom or a lower alkyl group;

[0397] n is 0, 1, 2, 3, 4 or 5;

[0398] R 4 and R 8 may be the same or different and are each independently a chemical bond or an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms;

[0399] R 5 and R 9 may be the same or different and are each independently a hydrogen atom or an alkyl group having 1 to 14 carbon atoms, an alkenyl group having 2 to 14 carbon atoms or an alkynyl group having 2 to 14 carbon atoms;

[0400] R 6 and R 7 may be the same or different and are each independently a bond or an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms;

[0401] X 1 is a methylene group (-CH 2-), -O-, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or a hydrogen atom), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit, a heterocyclic subunit or a chemical bond having 5 to 8 carbon atoms; and

[0402] X 2 and X 3 may be the same or different and are each independently a methylene group (-CH 2 -), -O-, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or a hydrogen atom), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit, a heterocyclic subunit or a chemical bond,

[0403] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0404] In some embodiments, the compound of formula V may be selected from the compounds of List 5:

[0405]

[0406]

[0407]

[0408] or a salt thereof, or an isomer thereof.

[0409] In one aspect of the present disclosure, the compound described herein has the structural formula of formula VI, or a salt thereof, or an isomer thereof

[0410]

[0411] wherein:

[0412] Y 1 and Y 2 may be the same or different and are each independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene and alkynylene, wherein R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group;

[0413] X is selected from -S-, -SS-, -O-, -CH 2-, alkenylene, alkynylene, -NR-, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group;

[0414] R 1 and R 2 may be the same or different and are each independently selected from carbocyclic, alkyl, alkenyl, and alkynyl groups, each optionally substituted;

[0415] R 3 is selected from a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group, and each group other than the hydrogen and halogen atoms is optionally substituted;

[0416] Z is selected from alkylene, alkenylene, alkynylene, and carbocyclic-subylene;

[0417] m is from 1 to 24.

[0418] Wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0419] In some embodiments, R 2 、Y 2 and R 3 can together form part of a 4- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which can optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, or alkyne. In certain embodiments, the carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, 3- to 7-carbon atom carbocyclic group, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 、-NHR、-oxo、-O-CO-、-NR-CO- or other functional groups.

[0420] In some embodiments, X, Y 1 and R 1 can together form part of a 4- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which can optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, or alkyne. In certain embodiments, the carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, 3- to 7-carbon atom carbocyclic group, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 、-NHR、-oxo、-O-CO-、-NR-CO- or other functional groups.

[0421] In some embodiments, Y 1 , X, and Y 2 can together form part of a 5- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which can optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, or alkyne. In certain embodiments, the carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, heterocyclic group of 3 to 8 members, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0422] In some embodiments, Y 1 and Y 2 are independently selected from -(C═O)O-, -O(C═O)-, -(C═O)S-, -S(C═O)-, -NR(C═O)-, and -(C═O)NR-.

[0423] In some embodiments, R 3 is selected from an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl, or heteroaryl, each optionally substituted with -OH.

[0424] In some embodiments, X is an oxygen atom or a nitrogen atom with or without substituents.

[0425] In some embodiments, in the compound of formula VI:

[0426] Y 1 and Y 2 can be the same or different and are each independently selected from -(C═O)O-, -O(C═O)-, -NR(C═O)-, -(C═O)NR-, -O-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group;

[0427] X is selected from -S-, -O-, -CH 2 -, alkenylene, alkynylene, -NR-, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group;

[0428] R 1 and R 2 can be the same or different and are each independently selected from a carbocyclic group, alkyl, alkenyl, and alkynyl, each optionally substituted;

[0429] R 3Selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, and each group may be optionally substituted except for the hydrogen atom;

[0430] Z is selected from an alkylene group, an alkenylene group, an alkynylene group, and a carbocyclic subunit; and

[0431] m is 1 - 14,

[0432] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0433] In some embodiments, the compounds of Formula VI may be selected from the compounds in List 6:

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443] and their salts and isomers.

[0444] In another aspect of the present disclosure, the compounds described herein have the structural formula of Formula VII, or their salts, or their isomers

[0445]

[0446] wherein:

[0447] Y 1 and Y 2 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, an alkenylene group, and an alkynylene group, where R is independently a hydrogen atom, or an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group each time it appears;

[0448] X 1and X 2 are the same or different and are independently selected from -S-, -SS-, -O-, -CH 2 -, alkenylene, alkynylene and -NR-, where R is hydrogen, or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group;

[0449] R 1 and R 2 may be the same or different and are independently selected from alkyl, alkenyl, alkynyl and heterocyclic group, each optionally substituted;

[0450] R 3 is selected from a hydrogen atom, a halogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl, each optionally substituted;

[0451] m and n are each independently an integer selected from 1 - 24,

[0452] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0453] In some embodiments, X 1 , Y 1 and R 1 can together form part of a 4 - 10 membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 - 7 carbon atoms, 3 - 8 membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0454] In some embodiments, X 2 , Y 2 and R 2 can together form part of a 4 - 10 membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S or P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene or alkyne. In certain embodiments, the carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 - 7 carbon atoms, 3 - 8 membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , 0NHR, -oxo, -O-CO-, -NR-CO- or other functional groups.

[0455] In some embodiments, Y 1 , X 1 , X 2 and Y 2 may together form part of a 5- to 10-membered carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, or P, which may optionally be part of a functional group, such as, but not limited to, ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, or alkyne. In certain embodiments, the carbocyclic or heterocyclic ring may optionally be substituted with one or more substituents, such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, heterocyclic group of 3 to 8 members, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0456] In some embodiments, X 1 and X 2 are each independently -S- or -O-.

[0457] In some embodiments, X 1 and X 2 are each independently an oxygen atom, a sulfur atom, or a nitrogen atom with or without substituents, or a methylene group.

[0458] In some embodiments, R 3 is selected from alkyl, cycloalkyl, or aryl, each optionally substituted with -OH.

[0459] In some embodiments, Y 1 and Y 2 are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, and -(C=O)NR-.

[0460] In some embodiments, in the compound of formula VII:

[0461] Y 1 and Y 2 may be the same or different and are each independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom, or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group;

[0462] X 1 and X 2 may be the same or different and are independently selected from -S-, -O-, -CH2 - alkenylene, alkynylene, -NR-, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group;

[0463] R 1 and R 2 may be the same or different and are each independently selected from carbocyclic, alkyl, alkenyl, and alkynyl groups, each optionally substituted;

[0464] R 3 is selected from a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group, and each group other than the hydrogen atom is optionally substituted; and

[0465] m and n are each independently an integer selected from 1 - 14,

[0466] where the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0467] In some embodiments, the compounds of formula VII may be selected from the compounds in List 7:

[0468]

[0469]

[0470]

[0471]

[0472] and their salts and isomers.

[0473] In another aspect of the present disclosure, the compounds described herein have the structural formula of formula VIII, or their salts, or their isomers.

[0474]

[0475] Wherein:

[0476] X 1 、X 2 and X 3 are independently selected from -CH 2 -, -O-, -S-, and -NR-, where R is hydrogen or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group;

[0477] R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, halogen atom, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group, and each group other than the hydrogen and halogen atoms is optionally substituted;

[0478] R3 and R 4 is selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group, each optionally substituted; and

[0479] m is 0, 1, 2, 3, 4, or 5,

[0480] wherein the longest atomic chain length in the compound is between 18 and 70 atoms.

[0481] In some embodiments, R 1 and R 2 can together form part of a 4- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to an ether, a sulfide, a disulfide, an ester, a sulfonate, a thioester, a sulfone, a sulfoxide, an amine, an amide, a carbamate, a carbonate, an alkene, or an alkyne. In certain embodiments, the heterocycle formed by R 1 and R 2 can optionally be substituted with one or more substituents, such as but not limited to an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group having 3 to 7 carbon atoms, a heterocyclic group having 3 to 8 members, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0482] In some embodiments, R 1 and X can together form part of a 5- to 10-membered aromatic or non-aromatic carbocycle or heterocycle having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to an ether, a sulfide, a disulfide, an ester, a sulfonate, a thioester, a sulfone, a sulfoxide, an amine, an amide, a carbamate, a carbonate, an alkene, or an alkyne. In certain embodiments, the heterocycle formed by R 1 and X can optionally be substituted with one or more substituents, such as but not limited to an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group having 3 to 7 carbon atoms, a heterocyclic group having 3 to 8 members, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0483] In some embodiments, R 3 and R 4 can together form part of a 5- to 10-membered aromatic or non-aromatic carbocycle or heterocycle having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to an ether, a sulfide, a disulfide, an ester, a sulfonate, a thioester, a sulfone, a sulfoxide, an amine, an amide, a carbamate, a carbonate, an alkene, or an alkyne. In certain embodiments, R 3 and R4 The heterocycle formed may optionally be substituted with one or more substituents such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, heterocyclic group having 3 to 8 members, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NRCO- or other functional groups.

[0484] In some embodiments, R 1 and R 2 are independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl, each optionally substituted with -OH, or together form part of a ring structure.

[0485] In some embodiments, X 1 , X 2 and X 3 are independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom with or without substituents.

[0486] In some embodiments, in the compound of Formula VIII:

[0487] X 1 , X 2 and X 3 are independently selected from -CH 2 -, -O- and -NR-, where R is a hydrogen atom or an alkyl, alkenyl, carbocyclic group, heterocyclic group;

[0488] R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, an alkyl, alkenyl, alkynyl, carbocyclic group and heterocyclic group, and each group other than the hydrogen atom is optionally substituted;

[0489] R 3 and R 4 are selected from carbocyclic group, alkyl, alkenyl and alkynyl, each optionally substituted;

[0490] m is 0, 1, 2, 3, 4 or 5.

[0491] In some embodiments, the compound of Formula VIII may be selected from the compounds in List 8:

[0492]

[0493]

[0494]

[0495]

[0496] or a salt thereof, or an isomer thereof.

[0497] In another aspect of the present disclosure, the compound described herein has the structural formula of Formula IX, or a salt thereof, or an isomer thereof

[0498]

[0499] wherein:

[0500] X 1 and X 2 are the same or different moieties selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenes, and alkynes, where R is independently, each time it appears, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group;

[0501] R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, each of which may be optionally substituted except for hydrogen and halogen atoms;

[0502] R 3 and R 4 may be the same or different and are independently selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group; and

[0503] m and n are the same or different and are each an integer from 1 to 24,

[0504] wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0505] In some embodiments, R 1 and R 2 may together form part of a 4- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which may optionally be part of a functional group, such as, but not limited to, an ether, a sulfide, a disulfide, an ester, a sulfonate, a thioester, a sulfone, a sulfoxide, an amine, an amide, a carbamate, a carbonate, an alkene, or an alkyne. In certain embodiments, the formed heterocycle may be optionally substituted with one or more substituents, such as, but not limited to, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group having 3 to 7 carbon atoms, a 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2, -NHR, -oxo, -O-CO-, -NRCO- or other functional groups.

[0506] In some embodiments, X 1 and X 2 can together form part of a 4- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, or alkyne. In certain embodiments, the formed heterocycle can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NRCO- or other functional groups.

[0507] In some embodiments, wherein R 1 and R 2 are each independently an alkyl group having 1 to 20 carbon atoms, each optionally substituted with -OH.

[0508] In some embodiments, X 1 and X 2 are independently selected from an oxygen atom, a sulfur atom, a nitrogen atom with or without substituents, ester, thioester, amide, alkene, and alkyne.

[0509] In some embodiments, in the compound of formula IX:

[0510] X 1 and X 2 are the same or different moieties selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -CH 2 -, alkene, and alkyne, wherein R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group each time it appears;

[0511] R 1 and R 2 can be the same or different and are independently selected from a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, and heterocyclic group, and each group other than the hydrogen atom can optionally be substituted;

[0512] R 3 and R 4 can be the same or different and are independently selected from carbocyclic group, alkyl, alkenyl, and alkynyl; and

[0513] m and n can be the same or different and are each an integer from 1 to 14,

[0514] The longest atomic chain in the compound is between 18 and 70 atoms.

[0515] In some embodiments, the compound of Formula IX may be selected from the compounds of List 9:

[0516]

[0517]

[0518]

[0519]

[0520] or a salt thereof, or an isomer thereof.

[0521] In another aspect of the present disclosure, the compound described herein has the structural formula of Formula X, or a salt thereof, or an isomer thereof

[0522]

[0523] Wherein:

[0524] R 1 、R 2 、R 3 、R 4 and R 5 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, and each group may be optionally substituted except for the hydrogen and halogen atoms;

[0525] X 1 、X 2 and X 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, an alkenylene group, and an alkynylene group, where R is independently a hydrogen atom, or an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group each time it appears;

[0526] X 4 is selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, an alkenylene group, and an alkynylene group, where R is independently a hydrogen atom, or an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group each time it appears; or X 4is a straight-chain alkyl group containing 0 to 10 methylene units;

[0527] Y 1 and Y 2 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene, and carbocyclic subunit, where R is independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group each time it appears; and

[0528] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,

[0529] wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

[0530] In some embodiments, R 3 , R 4 and X 3 may together with the atoms to which they are attached form part of a 4- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which may optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the heterocycle formed may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0531] In some embodiments, R 4 and R 5 may together with the atoms to which they are attached form part of a 4- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which may optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the heterocycle formed may optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0532] In some embodiments, Y 1 , X 1 and R 1 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0533] In some embodiments, Y 2 , X 2 and R 2 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0534] In some embodiments, R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, or eicosyl, each optionally substituted with -OH, or R 3 fuses with R 4 to form a ring system.

[0535] In some embodiments, R 4 and R 5Independently selected from linear, branched or cyclic alkyl, selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl, each optionally substituted with -OH, or R 4 and R 5 are fused into a ring system.

[0536] In some embodiments, X 1 and X 2 are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, an oxygen atom, a sulfur atom, -NR-, an alkene, an alkyne, or a cyclic alkyl or heteroalkyl, and X 3 is selected from -O-, -S-, an alkylene, an amine, an alkenylene and an alkynylene, wherein R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group each time it appears.

[0537] In some embodiments, X 4 is -O-, -S-.

[0538] In some embodiments, Y 1 and Y 2 are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, an alkene, an alkyne, a cycloalkylene or a heteroalkylene, wherein R is independently a hydrogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group each time it appears.

[0539] In some embodiments, in the compound of formula X:

[0540] R 1 、R 2 、R 3 、R 4 and R 5 may be the same or different and are independently selected from a hydrogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group, and each is optionally substituted except for the hydrogen atom;

[0541] X 1 、X 2 and X 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, an alkenylene and an alkynylene, wherein R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group each time it appears;

[0542] X 4 selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, (C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, and alkynylene, where R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; or X 4 is a straight-chain alkyl group containing 0-8 methylene units;

[0543] Y 1 and Y 2 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene, and carbocyclic subunit, where R is independently, each time it appears, a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; and

[0544] m is 0, 1, 2, 3, 4, or 5,

[0545] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0546] In some embodiments, the compound of formula X may be selected from the compounds of List 10:

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558] or a salt thereof, or an isomer thereof.

[0559] In another aspect of the present disclosure, the compound described herein has the structural formula of Formula XI, or a salt thereof, or an isomer thereof

[0560]

[0561] Wherein:

[0562] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, each of which may be optionally substituted except for the hydrogen and halogen atoms;

[0563] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, an alkylene group, an alkenylene group, an alkynylene group, a carbocyclic group, and a chemical bond, where R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group each time it appears;

[0564] X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, an alkylene group, an alkenylene group, an alkynylene group, and a carbocyclic group, where R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group each time it appears; or X 7 and X 8 are each independently a straight-chain alkyl group containing 0 - 10 methylene units;

[0565] Y 1 、Y 2 、Y 3 and Y 4may be the same or different and are independently selected from -(C═O)O-, -O(C═O)-, -(C═O)S-, -S(C═O)-, -NR(C═O)-, -(C═O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group each time it appears; and

[0566] n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10,

[0567] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0568] In some embodiments, R 3 and R 4 may together with the atoms to which they are attached form part of a 5- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which may optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the heterocycle formed may optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, SH, -OR, -SR, -NR 2 -, -NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0569] In some embodiments, R 4 and R 5 may together with the atoms to which they are attached form part of a 5- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which may optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the heterocycle formed may optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 -, -NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0570] In some embodiments, R 1 , X 1 and Y 1can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group such as, but not limited to, an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents such as, but not limited to, an alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 、-NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0571] In some embodiments, R 2 、X 2 and Y 2 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group such as, but not limited to, an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents such as, but not limited to, an alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 、-NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0572] In some embodiments, R 6 、X 5 and Y 3 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group such as, but not limited to, an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents such as, but not limited to, an alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 、-NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0573] In some embodiments, R 7 、X 6 and Y 4can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, esters, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, alkynes, or imines. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 、-NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0574] In some embodiments, R 3 、R 4 and R 5 are independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl, each optionally substituted with -OH, or R 3 、R 4 and R 5 together form part of a ring system.

[0575] In some embodiments, R 3 and R 4 form part of a ring system.

[0576] In some embodiments, X 7 and X 8 are independently selected from an oxygen atom, a sulfur atom, a substituted or unsubstituted nitrogen atom, an alkenylene, an alkynylene, a cyclic alkylene or heteroalkylene, an ester, a thioester, or an amide.

[0577] In some embodiments, Y 1 、Y 2 、Y 3 and Y 4 are independently selected from an oxygen atom, a sulfur atom, a substituted or unsubstituted nitrogen atom, an ester, a thioester, an amide, an alkenylene, an alkynylene, or a cyclic alkylene or heteroalkylene.

[0578] In some embodiments, in the compound of formula XI:

[0579] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7may be the same or different and are independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, and each is optionally substituted, except for the hydrogen atom;

[0580] X 1 and X 2 and X 3 and X 4 and X 5 and X 6 may be the same or different and are independently selected from -(C═O)O-, O(C═O)-, -NR(C═O)-, -(C═O)NR-, -O-, -S-, -CH 2 -, -NR-, an alkylene group, an alkenylene group, an alkynylene group, a carbocyclic group, and a bond, where R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group each time it appears;

[0581] X 7 and X 8 may be the same or different and are independently selected from -(C═O)O-, -O(C═O)-, -O-, -S-, -CH 2 ]-, -NR-, an alkylene group, an alkenylene group, an alkynylene group, a carbocyclic group, and a chemical bond, where R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group each time it appears; or X 7 and X 8 are each independently a straight-chain alkyl group containing 0 to 5 methylene units;

[0582] Y 1 and Y 2 and Y 3 and Y 4 may be the same or different and are independently selected from -(C═O)O-, -O(C═O)-, -NR(C═O)-, -(C═O)NR-, -O-, -S-, -CH 2 -, an alkenylene group, and an alkynylene group, where R is independently a hydrogen atom or an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group each time it appears; and

[0583] n and m are independently selected from 0, 1, 2, 3, 4, or 5,

[0584] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0585] In some embodiments, the compounds of formula XI may be selected from the compounds of List 11:

[0586]

[0587]

[0588]

[0589]

[0590] or a salt thereof, or an isomer thereof.

[0591] Another aspect of the present disclosure is that the structural formula of the compound described herein is Formula XII, or a salt thereof, or an isomer thereof.

[0592]

[0593] Wherein:

[0594] R 1 、R 2 、R 3 and R 4 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, each of which may be optionally substituted except for hydrogen and halogen atoms;

[0595] X 1 、X 2 、X 3 and X 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, an alkenylene group, an alkynylene group, and a chemical bond, where each occurrence of R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, or a heterocyclic group;

[0596] X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, an alkenylene group, an alkynylene group, and a bond, where R is independently a hydrogen atom, or an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group each time it appears; or X 5 and X 6 are each independently a straight-chain alkyl group containing 0-10 methylene units;

[0597] Y 1 、Y 2 、Y 3 and Y 4may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, alkynylene and a bond, where each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group;

[0598] The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic or anti-aromatic ring system; and

[0599] n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10,

[0600] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0601] In some embodiments, the central heterocycle may contain more unsaturation (e.g., double bonds or triple bonds) or may optionally be substituted. In certain embodiments, the heterocycle may be substituted such that two substituents are not directly attached to the nitrogen of the ring, but to an atom adjacent to the nitrogen. In certain embodiments, the heterocycle may be aromatic such that there is no permanent cationic charge.

[0602] In some embodiments, R 1 、X 1 and Y 1 may together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S and P, which may optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring may optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, 3- to 7-carbon atom carbocyclic group, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 、-NHR、-oxo, -O-CO-, -NR-CO- or other functional groups.

[0603] In some embodiments, R 2 、X 2 and Y 2can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, esters, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, alkynes, or imines. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0604] In some embodiments, R 3 , X 3 and Y 3 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, esters, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, alkynes, or imines. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0605] In some embodiments, R 4 , X 4 and Y 4 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, esters, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, alkynes, or imines. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0606] In some embodiments, X 1 , X 2 , X 3 and X4 Independently selected from an oxygen atom, a sulfur atom, a substituted or unsubstituted nitrogen atom, an ester, a thioester, an amide, a cyclic alkylene or heteroalkylene, an alkenylene or an alkynylene.

[0607] In some embodiments, X 5 and X 6 are independently selected from an oxygen atom, a sulfur atom, a nitrogen atom, an alkenyl, an alkynyl, a cyclic alkylene or heteroalkylene moiety, or a methylene chain.

[0608] In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 are independently selected from an oxygen atom, a sulfur atom, a substituted or unsubstituted nitrogen atom, an ester, a thioester, an amide, an alkenylene, an alkynylene, or a cyclic alkylene or heteroalkylene.

[0609] In some embodiments, in the compound of formula XII:

[0610] R 1 , R 2 , R 3 and R 4 are the same or different and are independently selected from a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a carbocyclic group, a heterocyclic group, each of which may be optionally substituted except for the hydrogen atom;

[0611] X 1 , X 2 , X 3 and X 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, an alkenylene, an alkynylene and a bond, wherein each occurrence of R is independently a hydrogen atom, an alkyl, an alkenyl, an alkynyl, a carbocyclic group or a heterocyclic group;

[0612] X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, an alkenylene, an alkynylene and a bond, wherein R is independently a hydrogen atom, or an alkyl, an alkenyl, an alkynyl, a carbocyclic group, a heterocyclic group each time it appears; or X 5 and X 6 are each independently a straight-chain alkyl containing 0-5 methylene units;

[0613] Y 1 , Y 2 , Y 3and Y 4 may be the same or different and are independently selected from -(C═O)O-, -O(C═O)-, -NR(C═O)-, -(C═O)NR-, -O-, -S-, -CH 2 -, alkenylene, alkynylene, and a chemical bond, where R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group;

[0614] The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic, or anti-aromatic ring system; and

[0615] n and m are independently selected from 0, 1, 2, 3, 4, or 5,

[0616] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0617] In some embodiments, the compounds of formula XII may be selected from the compounds of List 12:

[0618]

[0619]

[0620] or a salt thereof, or an isomer thereof.

[0621] In another aspect of the present invention, the compounds described herein have the structural formula of formula XIII, or a salt thereof, or an isomer thereof

[0622]

[0623] wherein:

[0624] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group, wherein each may be optionally substituted except for hydrogen and halogen atoms;

[0625] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 may be the same or different and are independently selected from -(C═O)O-, O(C═O)-, -(C═O)S-, -S(C═O)-, -NR(C═O)-, -(C═O)NR-, -O-, -S-, -SS-, -CH 2-, -NR-, alkenylene, alkynylene, cyclic alkylene or heteroalkylene, where each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group;

[0626] X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, alkenylene, alkynylene, cyclic alkylene or heteroalkylene, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group; or X 7 and X 8 each is a straight-chain alkyl containing 0-10 methylene units;

[0627] Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, alkynylene and cyclic alkylene or heteroalkylene, where each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group;

[0628] The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic or anti-aromatic ring system; and

[0629] n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10,

[0630] where the longest atomic chain in the compound is between 18 and 70 atoms.

[0631] In some embodiments, the central heterocycle may contain more unsaturation (such as double bonds or triple bonds) or may optionally be substituted. In certain embodiments, the heterocycle may be substituted such that the two substituents are not directly attached to the nitrogen atom of the ring, but are attached to an atom adjacent to the nitrogen. In certain embodiments, the heterocycle may be aromatic such that there is no permanent cationic charge.

[0632] In some embodiments, R 1 、X 1 and Y 1can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group such as, but not limited to, ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0633] In some embodiments, R 2 , X, and Y 2 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group such as, but not limited to, ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0634] In some embodiments, R 5 , X 5 and Y 3 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group such as, but not limited to, ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents such as, but not limited to, alkyl, alkenyl, alkynyl, carbocyclic group of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0635] In some embodiments, R 6 , X 6 and Y 4can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, esters, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, alkynes, or imines. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 、-NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0636] In some embodiments, R 3 and X 3 can together form part of a 3- to 10-membered aromatic or non-aromatic heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, esters, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, alkynes, or imines. In certain embodiments, the formed heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 、-NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0637] In some embodiments, R 4 and X 4 can together form part of a 3- to 10-membered aromatic or non-aromatic heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ethers, sulfides, disulfides, esters, sulfonates, esters, thioesters, sulfones, sulfoxides, amines, amides, carbamates, carbonates, alkenes, alkynes, or imines. In certain embodiments, the formed heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic groups of 3 to 7 carbon atoms, 3- to 8-membered heterocyclic groups, -OH, -SH, -OR, -SR, -NR 2 、-NHR, -oxo, -O-CO-, -NRCO-, or other functional groups.

[0638] In some embodiments, R 3 and R 4independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl, each optionally substituted by -OH;

[0639] In some embodiments, X 1 , X 2 , X 5 and X 6 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkenylene, alkynylene, or cyclic alkylene or heteroalkylene, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group each time it appears.

[0640] In some embodiments, X 3 and X 4 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkenyl, alkynyl, or cyclic alkyl or heteroalkyl, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic each time it appears.

[0641] In some embodiments, X 7 and X 8 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkenyl, alkynyl, or cyclic alkylene or heteroalkylene, or a methylene chain, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group each time it appears.

[0642] In some embodiments, Y 1 , Y 2 , Y 3 and Y 4 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkenylene, alkynylene, or cyclic alkylene or heteroalkylene, where R is independently hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group each time it appears.

[0643] In some embodiments, in the compound of formula XIII:

[0644] R 1 , R 2 , R 3 , R 4 , R 5 and R6 may be the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclic group, and heterocyclic group, and each group may be optionally substituted except hydrogen and halogen;

[0645] X 1 、X 2 、X 3 、X 4 、X 5 and X 6 are the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, alkynylene, cyclic alkylene or heteroalkylene, wherein each occurrence of R is independently hydrogen, or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group;

[0646] X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, alkynylene, cyclic alkylene or heteroalkylene, wherein R is independently hydrogen, or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group; or X 7 and X 8 each is a straight-chain alkyl containing 0-10 methylene units;

[0647] Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, alkenylene, alkynylene, cyclic alkylene or heteroalkylene, wherein each occurrence of R is independently a hydrogen atom, or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group;

[0648] The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic or anti-aromatic ring system; and

[0649] n and m are independently selected from 0, 1, 2, 3, 4 or 5,

[0650] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0651] In some embodiments, the compounds of formula XIII may be selected from the compounds of List 13:

[0652]

[0653]

[0654] or a salt thereof, or an isomer thereof.

[0655] In another aspect of the present invention, the compound described herein has the structural formula of Formula XIV, or a salt thereof, or an isomer thereof

[0656]

[0657] Wherein:

[0658] R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be optionally substituted except for a hydrogen atom and a halogen atom;

[0659] X 1 、X 2 、X 3 、X 4 and X 5 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, an alkylene group, an alkenylene group, an alkynylene group, a cycloalkylene group and a heterocycloalkylene group, wherein R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group and a heterocyclic group;

[0660] Y 1 、Y 2 and Y 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, an alkylene group, an alkenylene group, an alkynylene group, a cycloalkylene group and a heterocycloalkylene group, wherein R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group or a heterocyclic group; and

[0661] m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10,

[0662] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0663] In some embodiments, R 1 , X 1 and Y 1 can together form part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0664] In some embodiments, R 2 , X 2 and Y 2 can together form - part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0665] In some embodiments, R 3 , X 3 and Y 3 can together form - part of a 3- to 10-membered aromatic or non-aromatic carbocyclic or heterocyclic ring having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed carbocyclic or heterocyclic ring can optionally be substituted with one or more substituents, such as but not limited to alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0666] In some embodiments, R 4 , X 5 and Y 5 can together form part of a 4- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed heterocycle can optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0667] In some embodiments, X 4 and X 5 can together form part of a 3- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed heterocycle can optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR=CO-, or other functional groups.

[0668] In some embodiments, R 5 and R 6 can together form part of a 3- to 10-membered aromatic or non-aromatic heterocycle having one or more heteroatoms selected from N, O, S, and P, which can optionally be part of a functional group, such as but not limited to an ether, sulfide, disulfide, ester, sulfonate, ester, thioester, sulfone, sulfoxide, amine, amide, carbamate, carbonate, alkene, alkyne, or imine. In certain embodiments, the formed heterocycle can optionally be substituted with one or more substituents, such as but not limited to an alkyl, alkenyl, alkynyl, carbocyclic group having 3 to 7 carbon atoms, 3- to 8-membered heterocyclic group, -OH, -SH, -OR, -SR, -NR 2 , -NHR, -oxo, -O-CO-, -NR-CO-, or other functional groups.

[0669] Y 1 and Y 2The two-carbon chain therebetween may have a certain degree of unsaturation (e.g., alkene or alkyne).

[0670] In some embodiments, X 1 , X 2 and X 3 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, wherein each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group.

[0671] In some embodiments, X 4 and X 5 are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkylene, alkenylene, alkynylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene ring, wherein each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group.

[0672] In some embodiments, Y 1 , Y 2 and Y 3 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, wherein each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic group.

[0673] In some embodiments, in the compound of formula XIV:

[0674] R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, an alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic group, and each group other than hydrogen is optionally substituted;

[0675] X 1 , X 2 , X 3 , X 4 and X 5 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -

[0676] NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2-, -NR-, alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, wherein R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group and heterocyclic group;

[0677] Y 1 , Y 2 and Y 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, wherein R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group; and m is selected from 0, 1, 2, 3, 4 or 5,

[0678] wherein the longest atomic chain in the compound is between 18 and 70 atoms.

[0679] In some embodiments, the compounds of formula XIV may be selected from the compounds of List 14:

[0680]

[0681]

[0682]

[0683] or a salt thereof, or an isomer thereof.

[0684] The amino moiety of the lipid according to formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XI, XII, XIII or XIV may be protonated at physiological pH. The lipid may be positively charged or partially positively charged at physiological pH. Such lipids may be referred to as ionizable lipids. Some lipids may also be zwitterionic (neutral molecules with positive and negative charges).

[0685] Those skilled in the art should understand that the present disclosure encompasses any and all reasonable combinations of any two or more embodiments described in various aspects of the present disclosure, such as compounds according to formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XI, XII, XIII or XIV, including isomers and salts, or pharmaceutical compositions thereof (hereinafter), as shown in certain claims.

[0686] In some embodiments, the pK a of the ionizable lipid may be in the range of about 5.0 to about 8.0, more preferably between about 5.5 and about 7.5, even more preferably between about 6.0 and about 7.0. In some embodiments, pKa It can be between about 4.0 and about 9.5.

[0687] II. Lipid nanoparticle compositions

[0688] Another aspect of the present disclosure provides a method for encapsulating and / or inserting a biological and / or therapeutic agent within or on the surface of a lipid nanoparticle composition, the lipid nanoparticle composition comprising one or more ionizable lipids (e.g., amino lipids), helper lipids (e.g., neutral lipids), PEG-conjugated or other modified lipids, and cholesterol, as well as various pharmaceutically acceptable additives, such as but not limited to pH control compositions (e.g., citric acid, sodium phosphate, sodium hydroxide, hydrochloric acid, acetic acid, tromethamine, histidine, succinic acid, and combinations thereof), osmotic agents (e.g., sodium chloride, mannitol, sucrose, lactose, sorbitol), and antioxidants (e.g., α-tocopherol, ascorbic acid). Examples of bioactive molecules and / or therapeutic agents include but are not limited to: (1) polynucleotides, such as mRNA, rRNA, RNAi, microRNA, plasmid, aptamer, DNA, cDNA; (2) antisense polynucleotides; (3) low molecular weight compounds (synthetic or naturally occurring), such as peptides, hormones, and antibiotics; and (4) proteins, etc.

[0689] In some embodiments, the biomolecule and / or therapeutic agent is completely encapsulated within the lipid nanoparticle composition such that the biomolecule and / or therapeutic agent is resistant to enzymatic degradation (e.g., by nucleases). In certain embodiments, the biomolecule and / or therapeutic agent can be partially encapsulated within the lipid nanoparticle composition such that the biological and / or therapeutic agent extends through the surface layer of the lipid nanoparticle composition but is fully inserted into a surface feature matrix, such as but not limited to surface proteins, PEG, or other polymer chains bound to lipids, such that the biological and / or therapeutic agent is completely resistant to enzymatic degradation (e.g., by nucleases). In some preferred embodiments, the lipid nanoparticle composition is non-toxic to mammals (e.g., humans).

[0690] In another aspect, the present disclosure provides a method for treating a disease or disorder in a mammalian (e.g., human) subject in need thereof. The method comprises the step of administering to the mammalian a therapeutically effective amount of a lipid nanoparticle composition comprising (a) a lipid component, including phospholipids, PEG-conjugated lipids, structural lipids, or compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, or XIV, and (b) a biomolecule and / or therapeutic agent (e.g., mRNA).

[0691] In another aspect, the present disclosure provides the use of a lipid compound according to any one of Formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV, or a pharmaceutically acceptable salt thereof, in combination with a biomolecule and / or a therapeutic agent (e.g., mRNA), in the manufacture of a medicament for treating a disease or disorder in a subject in need thereof.

[0692] In some embodiments, the diameter of the lipid nanoparticle composition can be 1 μm or less, as measured by any method known in the art (e.g., dynamic light scattering (DLS), transmission electron microscopy, scanning electron microscopy, atomic force microscopy, or other methods). In some embodiments, the diameter of the lipid nanoparticle composition can be 500 nm or less. In some preferred embodiments, the diameter of the lipid nanoparticle composition can be 250 nm or less. In some embodiments, the lipid nanoparticle composition is a vesicle comprising one or more lipid bilayers. In certain embodiments, the lipid nanoparticle composition comprises two or more concentric spherical, ellipsoidal, or amorphous bilayers separated by an aqueous compartment. The lipid bilayers can be functionalized with one or more ligands, proteins, and / or channels. The lipid bilayers can be cross-linked to each other.

[0693] In some embodiments, the lipid nanoparticle composition can comprise one or more ionizable lipids (e.g., amino lipids), neutral lipids, PEG, and other modified lipids (e.g., polyglycerol modification, polyacrylamide modification, polydimethylacrylamide modification, polyvinylpyrrolidone modification, hyaluronic acid modification, heparin modification, or polysialic acid modification) or cholesterol. For example, the lipid nanoparticle composition can comprise at least one of the following ionizable lipids: DLin-MC3-DMA, DODMA, DODAP, SM-102, ALC-0315, C12-200, or one of the ionizable lipids described in Formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV. In some embodiments, the lipid nanoparticle composition comprises PEG 2000 -DMG or other PEG-conjugated lipids. In some embodiments, the lipid nanoparticle composition comprises cholesterol. In certain embodiments, the lipid nanoparticle composition comprises at least one neutral lipid (e.g., DSPE, DOPE, DSPC, HSPC, etc.).

[0694] In some embodiments, the lipid nanoparticle composition comprises (a) one or more active agents; (b) one or more ionizable lipids of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV, present in the composition in an amount of about 10 mol% to about 85 mol% of the total lipids present; (c) one or more neutral "helper" lipids, present in the composition in an amount of about 5 mol% to about 40 mol% of the total lipids present; (d) one or more PEG-conjugated lipids that inhibit particle aggregation, present in the composition in an amount of about 0 mol% to about 10 mol% of the total lipids present; and (e) cholesterol, present in the composition in an amount of about 10 mol% to 50 mol% of the total lipids present.

[0695] In some embodiments of the lipid nanoparticle composition, the phospholipid is selected from 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-docosanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), palmitoyl oleoyl-phosphatidylethanolamine (POPE), 1,2-diphytoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphate-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof.

[0696] In some embodiments of the lipid nanoparticle composition, the binding lipids that inhibit nanoparticle aggregation include polyethylene glycol-lipid conjugates (PEG-lipids), polyglycerol-lipid conjugates, polyoxazoline-lipid conjugates, polyvinylpyrrolidone-lipid conjugates, polyacrylamide-lipid conjugates, polydimethylacrylamide-lipid conjugates, hyaluronic acid-lipid conjugates, heparin-lipid conjugates, polysialic acid-lipid conjugates, and the like.

[0697] In some embodiments of the lipid nanoparticle composition, the PEG-lipid is selected from PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol, PEG-modified glycerol ester, PEG-modified sterol, and mixtures thereof.

[0698] In some embodiments of the lipid nanoparticle composition, the biomolecule / therapeutic agent is ribonucleic acid (RNA).

[0699] In some embodiments of the lipid nanoparticle composition, the RNA is selected from small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), messenger RNA (mRNA), self-amplifying mRNA (sa mRNA), and mixtures thereof.

[0700] In some embodiments of the lipid nanoparticle composition, the biomolecule and / or therapeutic agent comprises mRNA.

[0701] In some embodiments, the mRNA comprises from about 300 to about 20,000 nucleotides.

[0702] In some embodiments of the lipid nanoparticle composition, the mRNA comprises at least one modified nucleotide. In some embodiments, the neutral phospholipid comprises distearoyl phosphatidylcholine (DSPC).

[0703] In some embodiments, the binding lipid that inhibits particle aggregation comprises a polyethylene glycol-lipid conjugate (PEG-lipid).

[0704] In some embodiments, the PEG-lipid conjugate comprises 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG).

[0705] In some embodiments of the lipid nanoparticle composition, the average molecular weight of the PEG is 2000 daltons.

[0706] In some embodiments of the lipid nanoparticle composition, the biomolecule and / or therapeutic agent is an oligonucleotide.

[0707] In some embodiments of the lipid nanoparticle composition, the oligonucleotide comprises from about 10 to about 200 nucleotides.

[0708] In some embodiments of the lipid nanoparticle composition, the oligonucleotide comprises one or more modified nucleotides.

[0709] In some embodiments of the lipid nanoparticle composition, the oligonucleotide comprises at least one 2'-O-methyl (2'OMe) nucleotide.

[0710] In some embodiments, the lipid nanoparticle composition comprises a biomolecule and / or therapeutic agent, a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV (10 mol% to 85 mol% of the total lipids present in the composition), a neutral "helper" phospholipid or derivative thereof (5 mol% to 40 mol% of the total lipids in the composition), cholesterol or a derivative thereof (10 mol% to 50 mol% of the total lipids in the composition), and an aggregation-inhibiting conjugate lipid (0 mol% to 10 mol% of the total lipids in the composition). In some embodiments, the molar ratio of ionizable nitrogen atoms in the compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV to the phosphate groups in the biologic and / or therapeutic agent (N:P ratio) is from 1 to 15.

[0711] In some embodiments, the lipid nanoparticle composition comprises a biomolecule and / or therapeutic agent, a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV (20 mol% to 70 mol% of the total lipids present in the composition), a neutral "helper" phospholipid or derivative thereof (5 mol% to 30 mol% of the total lipids in the composition), cholesterol or a derivative thereof (20 mol% to 50 mol% of the total lipids in the composition), and an aggregation-inhibiting conjugate lipid (0.25 mol% to 5 mol% of the total lipids in the composition). In some embodiments, the molar ratio of ionizable nitrogen atoms in the compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV to the phosphate groups in the biomolecule and / or therapeutic agent (N:P ratio) is from 2 to 12.

[0712] In some embodiments, the lipid nanoparticle composition comprises a biomolecule and / or therapeutic agent, a compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV (40 mol% to 60 mol% of the total lipids present in the composition), a neutral "helper" phospholipid or derivative thereof (5 mol% to 15 mol% of the total lipids in the composition), cholesterol or derivative thereof (30 mol% to 45 mol% of the total lipids in the composition), and an aggregation-inhibiting conjugating lipid (0.5 mol% to 2 mol% of the total lipids in the composition). In some embodiments, the molar ratio of the ionizable nitrogen atom in the compound according to Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV to the phosphate group in the biomolecule and / or therapeutic agent (N:P ratio) is from 3 to 9.

[0713] In addition to the lipids described in Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV, the lipid nanoparticle composition may further comprise one or more ionizable lipids. The ionizable lipids may be selected from, but are not limited to: 1,2-dioleoyl-oxy-N,N-dimethylaminopropane (DODMA), 1,2-dioleoyl-3-dimethylammonium propane (DODAP), N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propyl-1-ammonium (DOBAQ), 1,2-dilinoleoyl-oxy-N,N-dimethyl-3-aminopropane (Dlin-DMA), 17-cis,trans,cis,trans-heptadeca-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butyrate (Dlin-MC3-DMA), 2-[2,2-bis[(9Z,12Z)-octadeca-9,12-dienyl]-1,3-dioxolan-4-yl]-N,N-dimethylethylamine (Dlin-K-DMA), 2,2-dilinoleoyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (Dlin-KC2-DMA), 9-heptadecyl 8-{(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino}octanoate (SM-102), [(4-hydroxybutyl)azanediyl]bis(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315), 1,1-((2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethyl)azanediyl)bis(dodecan-2-ol) (C12-200), 3,6-bis[4-[bis(2-hydroxydodecyl)amino]butyl]-2,5-piperazinedione (cKK-E12), and 1,1,4,10,10-penta(N-dodecylpropionamide)-1,4,7,10-tetraazadecane (98N12-5), etc.

[0714] Lipid nanoparticle compositions can comprise one or more neutral "helper" lipids. The neutral lipids can be selected from, but are not limited to: phospholipids such as lecithin, phosphatidylethanolamine, sphingomyelin, egg sphingomyelin (ESM), cephalin, cardiolipin, phosphatidic acid, cerebroside, cetyl phosphate, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-docosanoyl-sn-glycero-phosphocholine (DUPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-sn-glycero-3-phosphate-rac-(1-glycerol) sodium salt (DOPG), 1,2-dipalmitoyl-sn-glycero-3-phosphate-rac-(1-glycerol) sodium salt (DPPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphate-rac-(1-glycerol) sodium salt (POPG), N-(3-maleimid-1-oxopropyl)-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE-mal), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine, monomethylphosphatidylethanolamine, dimethylphosphatidylethanolamine, 1,2-dierucoyl-sn-glycero-3-phosphoethanolamine (DEPE), 1-stearoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (SOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLOPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) and others and mixtures thereof. Other diacyl phosphatidylcholines, diacyl phosphatidylethanolamines and diacyl phosphatidylserine phospholipids can also be used. In some embodiments, the acyl groups in these lipids are acyl groups of fatty acids having chains of 10-24 carbon atoms (e.g., lauroyl, myristoyl, palmitoyl, stearoyl or oleoyl).

[0715] The lipid nanoparticle composition may also comprise one or more sterols. The sterol may be selected from the non-limiting list of cholesterol, cholesterol derivatives, ergosterol, and ergosterol derivatives. Non-limiting examples of cholesterol derivatives include 5α-cholestanol, 5α-coprostanol, cholesterol-(2'-hydroxy)ethyl ether, cholesterol-(4'-hydroxy)butyl ether, 6-ketocholestanol, thiocholesterol, cholesterol acetate, cholesterol sulfate, cholest-3,5-diene, 5α-coprostane, cholestenone, 5α-cholestanone, cholesteryl laurate, etc. and mixtures thereof.

[0716] The lipid nanoparticle composition may also comprise one or more PEG conjugates or another polymer conjugate (e.g., polyglycerol-modified, polyacrylamide-modified, polydimethylacrylamide-modified, polyvinylpyrrolidone-modified, hyaluronic acid-modified, heparin-modified, polysialic acid-modified, etc.). PEG-conjugated lipids may be selected from the following non-limiting list: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol 2000)] sodium salt (PEG2000-DSPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol 2000)] sodium salt (PEG2000-DPPE), 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 2000 (PEG2000-DMG), distearoyl-rac-glycerol-polyethylene glycol 2000 (PEG2000-DSG), methoxypolyethylene glycol 2000-oxy-N,N-ditetradecylethylacetamide (ALC-0159), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol 1000)] sodium salt (DOPE-PEG1000-amine), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol 2000)] sodium salt (DOPE-PEG2000-amine), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol 1000)] sodium salt (DOPE-PEG1000-COOH), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol 2000)] sodium salt (DOPE-PEG2000-COOH), and cholesterol-(polyethylene glycol 600) (PEG600-Chol), polyethylene glycolylated ceramide, polyethylene glycolylated phosphatidic acid, polyethylene glycolylated phosphatidylethanolamine, polyethylene glycolylated dialkylamine, polyethylene glycolylated diacylglycerol, polyethylene glycolylated dialkylglycerol, polyethylene glycolylated glycerol ester, polyethylene glycolylated sterol, etc. and mixtures thereof. In some embodiments, the average molecular weight of the polyethylene glycol chain is 2000 atomic mass units.

[0717] Lipid nanoparticle compositions can include additional components such as bilayer stabilizing components (e.g., polyamide oligomers [see, e.g., U.S. Patent No. 6,320,017]), peptides, proteins, detergents, lipids, and ceramide derivatives (see, e.g., U.S. Patent No. 5,885,613).

[0718] In some embodiments of the present disclosure, the lipid component includes an ionizable lipid, a neutral lipid, a sterol, and a polyethylene glycol-conjugated lipid. In certain embodiments, the lipid component composition includes one or more ionizable lipids, neutral lipids, sterols, polyethylene glycol-conjugated lipids, and antioxidant excipients (e.g., α-tocopherol, N-acetylcysteine, ascorbic acid).

[0719] In some embodiments, the biomolecule and / or therapeutic agent encapsulated by the lipid nanoparticle composition is a nucleic acid. In some embodiments, the nucleic acid is RNA or an oligonucleotide that is fully or partially encapsulated within the lipid nanoparticle composition. The oligonucleotide can contain up to about 200 nucleotides and can be a deoxyribooligonucleotide or a ribooligonucleotide. Deoxyribooligonucleotides are composed of a 5-carbon sugar called deoxyribose, and the 5' and 3' carbons of this sugar are covalently linked to phosphates to form an alternating unbranched polymer. Ribooligonucleotides consist of a similar repeating structure, where the 5-carbon sugar is ribose.

[0720] In some embodiments, the biological nucleic acid and / or nucleic acid is selected from fomivirsen, mipomersen, nusinersen, eteplirsen, inotersen, golodirsen, milasen, casimersen, patisiran, givosiran, lumasiran, inclisiran, pegaptanib, defibrotide, tozinameran, elsomeren, defibrotide, viltolarsen, volanesorsen, Cas9 mRNA with or without a guide RNA, erythropoietin mRNA, etc., and combinations thereof.

[0721] The RNA of the present disclosure can have various lengths, typically depending on the specific RNA form (e.g., mRNA, siRNA, dsRNA, RNAi, microRNA, etc.). For example, in a particular embodiment, the length of the mRNA can be from about 500 to about 100,000 nucleotide residues, while the length of the oligonucleotide can be from about 10 to about 200 nucleotides.

[0722] In some embodiments, the lipid nanoparticle composition may comprise one or more buffering agents. Other components may be added to enhance or maintain chemical stability, including but not limited to preservatives, surfactants, dispersants, and / or gases. In some embodiments, the pH of the lipid nanoparticle composition may be from about pH 4.5 to 9.0. In some embodiments, the pH of the lipid nanoparticle composition may be from about pH 5.0 to 8.5. In some preferred embodiments, the pH may be from about pH 5.5 to 8.0. In some more preferred embodiments, the pH may be from about pH 6.0 to 7.5.

[0723] In some embodiments, the lipid nanoparticle composition is produced by mixing an alcoholic lipid solution (e.g., lipids dissolved in ethanol or isopropanol) with an aqueous solution consisting of a biological and / or therapeutic agent and a buffering agent. In some embodiments, the lipid nanoparticle composition is produced by a microfluidic device having chaotic mixing characteristics. In some preferred embodiments, the lipid nanoparticle composition is produced by mixing an alcoholic lipid solution with an aqueous solution consisting of a biological and / or therapeutic agent and a buffering agent in an impinging jet mixing device.

[0724] In some embodiments, the flow rate ratio of the aqueous solution (e.g., biomolecules and / or therapeutic agents dissolved in a buffer solution) to the alcoholic lipid solution (e.g., lipids dissolved in ethanol or isopropanol) is from about 12:1 to about 1:1.

[0725] In some embodiments, the flow rate ratio of the aqueous solution (e.g., biological and / or therapeutic agents dissolved in a buffer solution) to the alcoholic lipid solution (e.g., lipids dissolved in ethanol or isopropanol) is from about 6:1 to about 1:1. In some preferred embodiments, the flow rate ratio of the aqueous solution (e.g., biomolecules and / or therapeutic agents dissolved in a buffer solution) to the alcoholic lipid solution (e.g., lipids dissolved in ethanol or isopropanol) is from about 4:1 to about 1:1.

[0726] In some embodiments, the aqueous solution used to form the lipid nanoparticle composition is removed or diluted to a negligible amount by methods well known in the art (e.g., simple dilution, dialysis, ultracentrifugation, etc.). In some embodiments, the solution used to replace the removed aqueous solution may consist of one or more tonicity regulators (e.g., sodium chloride, potassium chloride, mannitol, or glucose), a buffering agent, or a cryoprotectant (e.g., sucrose, trehalose, mannitol, glycerol, etc.).

[0727] In some embodiments, the lipid nanoparticle composition can be stored in an acceptable pharmaceutically relevant carrier (e.g., a buffer or other solution designed to promote stability during storage or transportation). In some embodiments, the lipid nanoparticle composition can be refrigerated (e.g., stored at a temperature of about 2 degrees Celsius to about 8 degrees Celsius). In other embodiments, the lipid nanoparticle composition can be stored in a carrier composed of a buffer and a cryoprotectant, such as but not limited to sucrose, trehalose, or mannitol. In some embodiments, the lipid nanoparticle composition can be frozen (e.g., at a temperature below 0 degrees Celsius (e.g., about -5 degrees Celsius, -10 degrees Celsius, -15 degrees Celsius, -20 degrees Celsius, -30 degrees Celsius, -40 degrees Celsius, -50 degrees Celsius, -60 degrees Celsius, -70 degrees Celsius, -80 degrees Celsius, -90 degrees Celsius, -100 degrees Celsius, -120 degrees Celsius, -140 degrees Celsius, or -160 degrees Celsius)). In other embodiments, the lipid nanoparticle composition can be lyophilized in the presence of sucrose, lactose, or other sugars or excipients (e.g., swelling agents, disintegration temperature regulators, amino acids, polyols, buffers, complexing agents, tonicity regulators, or antioxidants). The lyophilized lipid nanoparticle composition cake can preferably be stored in a sterile lyophilization vial and subsequently rehydrated with sterile water for injection.

[0728] III. Application and Administration

[0729] As used herein, the terms "subject" and "patient" refer to any animal (e.g., a mammal) that receives administration of the lipid nanoparticle composition, including but not limited to humans, rodents, dogs, cats, horses, sheep, pigs, non-human primates (e.g., monkeys), and the like.

[0730] 1. The lipid nanoparticle compositions and methods of the present disclosure are used to deliver biological and / or therapeutic agents for treating a variety of diseases. The lipid nanoparticle compositions of the present disclosure are suitable for treating diseases or disorders related to the deficiency or dysfunction of proteins and / or enzymes excreted or secreted by cells into the surrounding extracellular fluid (e.g., components of coagulation factors, complement pathway cytokines, chemokines, chemotactic agents, protein hormones, serum protein components, antibodies, secretable Toll-like receptors, etc.). In some embodiments, the disease or disorder may involve protein deficiency or misfolding (e.g., Alzheimer's disease, Parkinson's disease, cystic fibrosis, or Fabry disease). In other embodiments, the disease or disorder may not be caused by protein defects or deficiencies, but would benefit from the provision of secreted proteins (e.g., spinal muscular atrophy or Leber congenital amaurosis). Diseases or conditions for which the present disclosure may be useful include, but are not limited to, Alzheimer's disease, Parkinson's disease, cystic fibrosis, Fabry disease, SMN1-related spinal muscular atrophy, Huntington's disease, muscular dystrophies (e.g., Duchenne muscular dystrophy and Becker muscular dystrophy), human immunodeficiency virus (HIV), influenza, heart disease, cancer (e.g., breast cancer, prostate cancer, colorectal cancer, kidney cancer, bladder cancer, lymphoma, thyroid cancer, endometrial cancer, pancreatic cancer), tuberculosis, multiple sclerosis, transthyretin amyloidosis, hemophilia diseases (e.g., hemophilia B, hemophilia A), amyotrophic lateral sclerosis, GALT-related galactosemia, VEGF-related heart failure, propionic acidemia, ornithine transcarbamylase deficiency, Zika virus, rabies, SARS-CoV-2, malaria, tuberculosis, hepatitis B, Gaucher's disease, Creutzfeldt-Jakob disease, nephrogenic diabetes insipidus, spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, sickle cell anemia, Machado-Joseph atrophy, retinitis pigmentosa, alpha-1 antitrypsin deficiency, galactocerebrosidase deficiency, Bardet-Biedl syndrome, Charlevoix-Saguenay, ethylmalonic encephalopathy, familial hypercholesterolemia, Ellis-van Creveld syndrome, Marfan syndrome, McKusick-Kaufman syndrome, osteogenesis imperfecta, phenylketonuria, Tay-Sachs disease, cataracts, familial amyloidosis, Wilson's disease, Santavuori-Haltia disease, Jansky-Bielschowsky disease, juvenile Batten disease, juvenile neuronal ceroid lipofuscinosis, and Pelizaeus-Merzbacher disease.

[0731] Lipid nanoparticle compositions can be administered to a patient. In some embodiments, the lipid nanoparticle compositions comprise one or more additional biomolecules and / or therapeutic agents, carriers, buffers, tonicity modifiers, cryoprotectants, or other suitable excipients to produce two or more different proteins or enzymes. In some embodiments, the delivery of multiple bio- and / or therapeutic agents (e.g., mRNA) can be utilized to treat a disease or disorder, wherein the defective or missing protein is composed of subunits encoded by multiple genes. In some embodiments, the bio- and / or therapeutic agents (e.g., mRNA) can be engineered such that a single mRNA strand can encode more than one subunit of the target protein.

[0732] Definitions

[0733] Unless otherwise defined, all professional terms, symbols, and other scientific terms or terminology used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In certain instances, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from what is commonly understood in the art. Many of the techniques and procedures described or cited herein are well understood by those skilled in the art and are commonly used using conventional methods. Where appropriate, procedures involving the use of commercially available kits and reagents are generally carried out according to the protocols and / or parameters defined by the manufacturer, unless otherwise indicated. All patents, applications, published applications, and other publications cited herein are incorporated by reference in their entirety. If the definitions set forth in this section are contrary to or inconsistent with the definitions set forth in the patents, applications, published applications, and other publications incorporated by reference herein, the definitions set forth in this section shall control.

[0734] As used herein, the singular forms "a," "an," and "the" include plural referents, and vice versa, and any plural form includes the singular referent, unless the context clearly dictates otherwise.

[0735] The term "about" or "approximately" as used herein, unless otherwise defined, generally includes plus or minus 10% of the indicated number. For example, "about 10%" may represent a range from 9% to 11%, and "about 30" may represent from 27 to 33. Sometimes preferably, "about" includes plus or minus 5% of the indicated value. When "about" is used before a range, it applies to both the lower and upper limits of the range.

[0736] The term "substantially" as used herein means "mostly" or "essentially," as would be understood by one of ordinary skill in the art, and if measurable quantitatively, means at least 90%, preferably at least 95%, more preferably at least 98%.

[0737] Unless otherwise specified, the terms "comprising", "having", "including", and "containing" and the like shall be construed as open-ended terms (i.e., meaning "including but not limited to").

[0738] As used herein, the term "compound" is intended to include all isomers and isotopes of the structures shown. "Isotope" refers to atoms having the same atomic number but different mass numbers, which is due to the different number of neutrons in the atomic nucleus. For example, isotopes of hydrogen include deuterium and tritium. The compounds, salts or complexes of the present disclosure can be prepared with solvents or water molecules by conventional methods to form solvates and hydrates.

[0739] As used herein, the term "isomer" refers to any geometric isomer, tautomer, zwitterion, stereoisomer, enantiomer or diastereoisomer (where applicable) of a compound. A compound may include one or more chiral centers (with absolute configuration R or S, whether specified or not) and / or double bonds, and thus may exist in the form of stereoisomers, such as double bond isomers (i.e., geometric E / Z isomers) or diastereoisomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). The present disclosure encompasses any and all isomers of the compounds described herein, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and mixtures of enantiomers and stereoisomers (e.g., racemates). Methods for identifying mixtures of enantiomers and stereoisomers of a compound and separating them into their component enantiomers or stereoisomers are well known in the art.

[0740] As used herein, the terms "alkyl" and "alkyl group" refer to straight-chain or branched-chain fully saturated hydrocarbons having one or more carbon atoms, preferably 1 to 28, sometimes preferably 1 to 22, sometimes preferably 1 to 20, sometimes preferably 1 to 18, sometimes preferably 1 to 16, sometimes preferably 1 to 14, sometimes preferably 1 to 12, sometimes preferably 12 to 22, sometimes preferably 12 to 20, sometimes preferably 12 to 18, sometimes preferably 12 to 16, sometimes preferably 1 to 8, sometimes preferably 1 to 6, sometimes preferably 1 to 4. The term "lower alkyl" or similar terms refers to an alkyl group having 1 - 6 carbon atoms, sometimes preferably 1 - 4 carbon atoms, and sometimes more preferably methyl or ethyl. The alkyl groups described herein may be optionally substituted.

[0741] As used herein, the terms "alkenyl" and "alkenyl group" refer to straight-chain or branched-chain hydrocarbons having two or more carbon atoms and at least one double bond, preferably 2 to 28 carbon atoms, sometimes preferably 2 to 22 carbon atoms, sometimes preferably 2 to 20 carbon atoms, sometimes preferably 2 to 18 carbon atoms, sometimes preferably 2 to 16 carbon atoms, sometimes preferably 2 to 14 carbon atoms, sometimes preferably 2 to 12 carbon atoms, sometimes preferably 12 to 22 carbon atoms, sometimes preferably 12 to 20 carbon atoms, sometimes preferably 12 to 18 carbon atoms, sometimes preferably 12 to 16 carbon atoms, sometimes preferably 2 to 8 carbon atoms, sometimes preferably 2 to 6 carbon atoms, sometimes preferably 2 to 4 carbon atoms. The alkenyl group may include one or more carbon-carbon double bonds. The alkenyl groups described herein may be optionally substituted.

[0742] As used herein, the terms "alkynyl" and "alkynyl group" refer to straight-chain or branched-chain hydrocarbons having two or more carbon atoms and at least one carbon-carbon triple bond, preferably 2 to 28 carbon atoms, sometimes preferably 2 to 22 carbon atoms, sometimes preferably 2 to 20 carbon atoms, sometimes preferably 2 to 18 carbon atoms, sometimes preferably 2 to 16 carbon atoms, sometimes preferably 2 to 14 carbon atoms, sometimes preferably 2 to 12 carbon atoms, sometimes preferably 12 to 22 carbon atoms, sometimes preferably 12 to 20 carbon atoms, sometimes preferably 12 to 18 carbon atoms, sometimes preferably 12 to 16 carbon atoms, sometimes preferably 2 to 8 carbon atoms, sometimes preferably 2 to 6 carbon atoms, sometimes preferably 2 to 4 carbon atoms. The alkynyl groups described herein may be optionally substituted.

[0743] As used herein, the terms "aryl" and "aryl group" refer to monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic groups of 6 to 14 carbon atoms. Representative aromatic rings include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, and biphenyl groups, sometimes preferably phenyl or naphthyl, and sometimes more preferably phenyl.

[0744] The terms "heteroaryl", "heteroaryl group", etc. refer to aromatic monocyclic or polycyclic (e.g., bicyclic or tricyclic) moieties having 5 to 14 ring atoms, wherein one or more (preferably one, two, or three) ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Representative heteroaryl rings include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolyl, etc.

[0745] As used herein, the term "heteroalkyl", etc. refers to an alkyl group in which one or more of the backbone chain atoms are heteroatoms independently selected from N, O, S, or combinations thereof. The heteroatoms are located at any internal position of the heteroalkyl or at the position where the heteroalkyl is attached to the remainder of the molecule. In some embodiments, at most two heteroatoms are consecutive. The heteroalkyls described herein may be optionally substituted.

[0746] The terms "carbocyclic", "carbocyclic group" or "carbocyclic moiety" refer to non-aromatic monocyclic or polycyclic groups having one or more carbon atom rings, sometimes preferably one or two, and sometimes more preferably one. The size of the ring can range from 3 to 18 carbon atoms, sometimes preferably 3 to 10 carbon atoms in the ring, and sometimes more preferably 3 to 8 carbon atoms in the ring. The carbocyclic ring can also include one or more carbon-carbon double bonds or triple bonds, sometimes preferably one or two, and sometimes more preferably one.

[0747] The terms "cycloalkyl" or "cyclic alkyl" as used herein and the like refer to saturated monocyclic carbon rings, preferably having 3 to 8 carbon atoms in the ring (sometimes more preferably 3 to 6 carbon atoms in the ring). The carbocyclic ring and cycloalkyl can be unsubstituted or substituted. Thus, cycloalkyl is a particular subset of carbocyclic groups and is generally a more preferred subset.

[0748] The terms "heterocyclic", "heterocyclic group", "heterocyclic moiety" and the like refer to monocyclic or polycyclic groups having one or more (preferably 1 to 3, sometimes more preferably 1 or 2, and sometimes more preferably 1) carbon atom rings, wherein the carbon atom rings contain one or more (sometimes preferably 1 to 3, sometimes more preferably 1 or 2) heteroatoms independently selected from N, O and S, and at least one of the rings containing heteroatoms is non-aromatic. The size of the ring can range from 3 to 18 members, sometimes preferably 3 to 10 members, and sometimes more preferably 3 to 8 members. The heterocyclic ring can also include one or more carbon-carbon, carbon-heteroatom and / or heteroatom-heteroatom double bonds or triple bonds. The heterocyclic rings described herein can be optionally substituted.

[0749] The terms "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "carbocyclic", "cycloalkylene" and "heterocyclic" refer to divalent linking groups of the parent prefixes (e.g., alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclic, cycloalkylene and heterocyclic, respectively). For example, alkylene is the divalent portion of an alkyl group, and heterocyclic is the divalent portion of a heterocyclic group. Sometimes, for simplicity or convenience, the suffix "ene" may be omitted. For example, "alkylene" may be referred to as "alkyl", "alkenylene" may be referred to as "alkenyl", "heteroalkylene" may be referred to as "heteroalkyl", "carbocyclic" may be referred to as "carbocyclic", "heterocyclic" may be referred to as "heterocyclic", and so on. Sometimes, for convenience or simplicity, "alkenyl" or "alkenylene" may be abbreviated as "olefin", "alkynyl" or "alkynylene" may be abbreviated as "alkyne", "carbocyclic" or "carbocyclic" may be abbreviated as "carbocyclic" or "carbocyclic", "cycloalkyl" or "cycloalkylene" may be abbreviated as "cycloalkyl", "heterocyclic" or "heterocyclic" may be abbreviated as "heterocyclic" or "heterocyclic", and so on. A person of ordinary skill in the art should be able to easily determine the exact meaning and structure of the group in a particular structural environment and context. Therefore, such nomenclature should not be regarded as ambiguous or as a disclosure defect. If it is considered necessary and the context is reasonable, renaming such groups to more appropriate terms should not be regarded as adding new content.

[0750] As used herein, the term "biodegradable group" refers to a functional group that can promote lipid metabolism in an animal model (i.e., humans). Biodegradable groups can be selected from, but are not limited to, the group consisting of -CO-, -CS-, -CO-O-, -OCO-, -CS--O-, -CO-S-, -CS-S-, -O-CS-, -S-CO-, -S-CS- and -SS-.

[0751] Alkyl, alkenyl, alkynyl, carbocyclic and heterocyclic groups may be optionally substituted. Optional substituents can be selected from, but are not limited to, halogen molecules (e.g., chlorine, bromine, fluorine, iodine groups), carboxylic acids, carbonyls, carbonates, alkoxys, acetals, phosphates, thiols, disulfides, sulfoxides, sulfinic acids, sulfonic acids, thioaldehydes, sulfates, sulfonyls, amides, azides, nitros, cyanos, isocyanos, acyloxys, aminos, carbamoyls, sulfonamides, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic groups. In some embodiments, the substituent group may be further substituted by one or more substituents defined herein.

[0752] In this specification, phrases such as "substituted or unsubstituted" and "optionally substituted" can be used interchangeably. When any group in any compound or structure is indicated as "substituted" and / or "unsubstituted", this means that the group can optionally be substituted with one or more, preferably 1 to 5, sometimes more preferably 1 to 3 substituents independently selected from halogen atoms, cyano group, nitro group, amino group, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, aryl group, alkylthio group, alkylamino group, alkylsulfonyl (alkyl sulfone), alkylsulfinyl (alkyl sulfoxide), acyloxy group, carboxylic acid, carboxylic acid ester, and carboxamide group, etc. The alkyl group can have 1 - 10 carbon atoms, sometimes preferably 1 - 6 carbon atoms, and sometimes more preferably 1 - 4 carbon atoms. The esters can be esters of alcohols having 1 to 10 carbon atoms, sometimes preferably alcohols having 1 to 6 carbon atoms, and sometimes more preferably alcohols having 1 to 4 carbon atoms. Expressions such as "optionally substituted alkylene, alkenylene, or alkynylene" should be understood to mean that each of alkylene, alkenylene, and alkynylene is optionally substituted.

[0753] In some embodiments, when an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, etc. or a part thereof is substituted, the substituent can be substituted at any available attachment point, and the substituent can be one or more, sometimes preferably 1 to 5, sometimes more preferably 1 to 3, independently selected from alkyl groups having 1 - 6 carbon atoms, halogen molecules, alkoxy groups having 1 - 6 carbon atoms, alkenyl groups having 1 - 6 carbon atoms, alkynyl groups having 1 - 6 carbon atoms, alkylthio groups having 1 - 6 carbon atoms, alkylamino groups having 1 - 6 carbon atoms 、 bis(alkyl groups having 1 - 6 carbon atoms)amino group, mercapto group, hydroxy group, nitro group, cyano group, amino group, cycloalkyl groups having 3 - 6 carbon atoms, 5 - 10 - membered heterocyclic groups, aryl groups having 6 - 10 carbon atoms, 5 - 10 - membered heteroaryl groups, cycloalkoxy groups having 3 - 6 carbon atoms, cycloalkylthio groups having 1 - 6 carbon atoms, 5 - 10 - membered heterocyclic thio groups, and oxo group. In some embodiments, sometimes preferably, the substituents are independently selected from alkyl groups having 1 - 6 carbon atoms, halogen atoms, alkoxy groups having 1 - 6 carbon atoms, alkylthio groups having 1 - 6 carbon atoms, alkylamino groups having 1 - 6 carbon atoms, bis(alkyl groups having 1 - 6 carbon atoms)amino group, mercapto group, hydroxy group, nitro group, cyano group, amino group, and oxo group. In some embodiments, sometimes more preferably, the substituents are independently selected from alkyl groups having 1 - 4 carbon atoms, halogen atoms, alkoxy groups having 1 - 4 carbon atoms, alkylthio groups having 1 - 4 carbon atoms, alkylamino groups having 1 - 4 carbon atoms, bis(alkyl groups having 1 - 4 carbon atoms)amino group, mercapto group, hydroxy group, nitro group, cyano group, and amino group. Those of ordinary skill in the art should understand that the oxo (=O) group cannot be a substituent of an aryl or heteroaryl group, nor can it be located on an unsaturated carbon of any other group.

[0754] As used herein, the term "linker" refers to a moiety that connects two other moieties. The linker can include one or more groups, including but not limited to phosphate groups, alkylene groups, alkenylene groups, carbocyclic groups, heterocyclic groups, amides, or glycerol.

[0755] Terms such as "the longest chain of atoms in a compound" refer to the maximum length (counted by the number of atoms) from the end of one substituted chain (excluding hydrogen atoms) to the end of another substituted chain (excluding hydrogen atoms) in a compound molecule, including any atoms that most directly connect the two substituted chains (i.e., the fewest number of atoms inserted between the two substituted chains). For example, the maximum length from the end of one substituted chain to the end of another substituted chain in Compound 1 is 19 atoms; the maximum length from the end of one substituted chain to the end of another substituted chain in Compound 128 is 40 atoms; the maximum length from the end of one substituted chain to the end of another substituted chain in Compound 206 is 52 atoms. While not intending to be bound by theory, for maintaining the properties and characteristics of the disclosed LNP compounds, the preferred range of "the longest chain of atoms in a compound" is from about 18 to about 70 atoms. In some embodiments, the longest chain of atoms is between 18 and 60 atoms. In some embodiments, the longest chain of atoms is between 18 and 50 atoms.

[0756] As used herein, the term "lipid component" is a component of a lipid nanoparticle composition that includes one or more lipids. For example, the lipid component can include one or more ionizable, polyethylene glycol-conjugated, structural, or other lipids (such as phospholipids).

[0757] As used herein, the term "N:P ratio" refers to the molar ratio of ionizable nitrogen atoms in the lipid (within the physiological pH range) to phosphate groups in the nucleic acid (such as RNA).

[0758] As used herein, the term "lipid nanoparticle composition" refers to a composition that includes one or more lipids. The lipid nanoparticle composition is typically of micron or nano size or smaller and may include a lipid bilayer. Lipid nanoparticle compositions include particles such as lipid nanoparticles (LNPs), liposomes, lipid complexes, nanoemulsions, and polymer nanoparticles. For example, the lipid nanoparticle composition can be a liposome with a diameter of 600 nm or less.

[0759] The lipid nanoparticle composition may further comprise a salt of one or more compounds. The salt may be a pharmaceutically acceptable salt, and sometimes preferably a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound in which the existing acidic or basic moiety is modified by converting it into its salt form (e.g., by reacting the free base with an organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues (e.g., amines); base or organic salts of acidic residues (e.g., carboxylic acids); and the like. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, dodecyl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), undecanoate, and the like. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing acidic or basic moieties by conventional chemical methods well known in the art.A list of suitable salts can be found in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Co., Easton, PA, 1985, p. 1418; Pharmaceutical Salts: Properties, Selection, and Use, P. H. Stahl and C. G. Wermuth (Eds.), Wiley-VCH, 2008; Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977); and The Orange Book (on the website of the Food & Drug Administration, Washington, DC), each of which is hereby incorporated by reference in its entirety.

[0760] Those of ordinary skill in the art will understand that the synthetic methods described herein can utilize various protecting groups. As used herein, the term "protecting group" refers to a particular functional moiety (e.g., O, S, N) that is temporarily blocked so that a reaction can be selectively carried out at another reaction site in a multifunctional compound. In some embodiments, the protecting group selectively reacts in good to excellent yield to provide a protected substrate that is stable to the reaction conditions of subsequent reactions, but can be readily and selectively removed in good to excellent yield by readily available, preferably non-toxic reagents that do not react with other functional groups. In some embodiments, the protecting group does not create new stereocenters and has little or no additional functionality to avoid further reaction sites. Protecting groups can be used to form derivatives that are readily separable. Oxygen, sulfur, nitrogen, and carbon protecting groups can be utilized as described herein.Protecting groups for hydroxyl functional groups can be selected from the following non-limiting list: methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (MBom), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenoxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methano-benzofuran-2-yl, 1-ethoxyethyl, 2-bromoethyl, 2,2,2-trichloroethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl, 2-trimethylsilylethyl, 4-methoxybenzoylmethyl, tert-butyl, cyclohexyl, allyl, p-methoxyphenyl, p-chlorophenyl, p-nitrophenyl, 2,4-dinitrophenyl, benzyl, p-methoxybenzyl, halobenzyl, 2-pyridyl, 4-pyridyl, 2-quinolylmethyl, diphenylmethyl, bis(4-methoxyphenyl)methyl, triphenylmethyl, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, haloacetate, pivalate, adamantate, crotonate, benzoate, methanesulfonate, alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl-2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), methanesulfonate (mesylate), benzylsulfonate and tosylate (TS).Protecting groups for amino functional groups can be selected from the following non-limiting list: methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxybenzoyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1-methyl-1-(4-biphenyl)ethyl carbamate (Bpoc), tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), 4-methylsulfinylbenzyl carbamate (Msz), [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), tert-amyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, picolinamide, benzamide, acetoacetamide, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), quaternary ammonium salts, N-benzylamine, N-triphenylmethylamine (Tr), N-[(4-methylphenyl)diphenylmethyl]amine (MMTr), N-ferrocenylmethylamine (Fcm), N-benzylideneamine, N-diphenylmethyleneamine, diphenylphosphonamide (Dpp), dimethylthiophosphonamide (Mpt), diphenylthiophosphonamide (Ppt), diphenylphosphoramide, benzenesulfinamide, o-nitrobenzenesulfinamide (Nps), p-toluenesulfonamide (Ts), benzenesulfonamide, methanesulfonamide (Ms), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylsulfonamide. Additionally, various protecting groups are described in Greene's Protective Groups in Organic Synthesis, 5th Edition. Wuts, PGM, editor, John Wiley & Sons, New Jersey: 2014, the entire content of which is hereby incorporated by reference into this document.

[0761] As used herein, the term "independently selected" means that one or more R groups are selected independently of other R groups in the same structure (e.g., the R groups can be the same or different).

[0762] As used herein, the term "pharmaceutically acceptable" describes non-biological or other adverse materials that do not cause unacceptable levels of adverse biological effects or harmful interactions (e.g., toxicity, irritation, allergic reactions, or other problems or complications).

[0763] As used herein, the term "polypeptide" refers to a polymer of amino acid residues, typically joined by peptide bonds, which may be produced naturally or synthetically.

[0764] As used herein, the terms "biological agent" and "therapeutic agent" refer to any agent that has a therapeutic or diagnostic effect and / or causes a desired pharmacological or biological effect when administered to a subject (e.g., a cell, mouse, rat, human). Biological molecules and therapeutic agents also refer to "active agents", which may include, but are not limited to, chemotherapeutic agents, small molecule drugs, nucleic acids, proteins, radiopharmaceuticals, and cytotoxins.

[0765] As used herein, the term "nucleic acid" refers to a biopolymer and macromolecule composed of nucleotides, such as RNA, DNA, or oligonucleotides.

[0766] As used herein, the term "DNA" refers to deoxyribonucleic acid, which may be naturally or non-naturally occurring. For example, DNA may include modified and / or non-naturally occurring components, such as one or more nucleobases, nucleotides, or linkers. DNA may have a nucleotide sequence encoding an RNA sequence for producing a target polypeptide. For example, DNA may encode messenger RNA (mRNA). DNA may be selected from, but not limited to, plasmids, aptamers, complementary DNA (cDNA), and mixtures thereof.

[0767] As used herein, the term "plasmid" refers to a small extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently.

[0768] As used herein, the term "aptamer" refers to a short single-stranded DNA (ssDNA) or RNA (ssRNA) molecule that selectively binds to a specific target (e.g., a protein, peptide, carbohydrate, small molecule, toxin, or living cell).

[0769] As used herein, the term "RNA" refers to ribonucleic acid, whether naturally occurring or non-naturally occurring. For example, RNA can include modified and / or non-naturally occurring components, such as one or more nucleobases, nucleotides, or linkers. RNA can include a cap structure, a chain-terminating nucleoside, a stem-loop, a poly-adenylate sequence, and / or a polyadenylation signal. RNA can have a nucleotide sequence encoding a target polypeptide. For example, RNA can be messenger RNA (mRNA). Translation of an mRNA encoding a specific polypeptide, such as in vivo translation of an intracellular mRNA, can produce the encoded polypeptide. RNA can be selected from, but not limited to, small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), endonuclease substrate RNA (dsRNA), small hairpin RNA (shRNA), mRNA, ribosomal RNA (rRNA), aptamers, and mixtures thereof. Nucleic acids can contain any number of modifications, including but not limited to the following modifications: modified backbone structures (e.g., phosphorothioates, chiral phosphorothioates, dithiophosphates, phosphotriesters, aminoalkyl phosphotriesters, alkyl phosphonates, phosphonates, amino phosphates, and boranophosphates), salt form modifications (e.g., sodium, potassium, ammonium, etc.), pseudouridine (ψ) substitution, N6-methyladenylation (m 6 A), N5-methylcytidinylation (m 5 C), ribose methylation (2'-OMe)), and sugar type (e.g., deoxyribose versus ribose). For more information on nucleic acid modifications, see McKenzie, LK, et al. Chemical Society Reviews, 50, 5126 - 5164 (2021), Ochoa, S., et al. Molecules, 25(20)4659 (2020), Prakash, TP et al., Journal of Medicinal Chemistry 48, 4247 - 4253 (2005), and Zhang, HY et al., Current Topics in Medicinal Chemistry 6, 893 - 900 (2006), the entire contents of which are incorporated herein by reference.

[0770] As used herein, the term "polydispersity index" is a ratio that describes the uniformity of the particle size distribution in a system or sample. A smaller value (e.g., less than 0.2) indicates a narrower particle size distribution, while a larger value (e.g., 0.8) indicates a wider particle size distribution.

[0771] As used herein, the term "size" or "average size" in a lipid nanoparticle composition refers to the average diameter of the lipid nanoparticle composition.

[0772] As used herein, the term "zeta potential" refers to the electrokinetic potential of a lipid or lipid nanoparticle composition.

[0773] As used herein, the term "subject" or "patient" refers to a human patient or a mammal such as a cat, dog, cow, horse, monkey, etc.

[0774] As used herein, the term "contact" means establishing a physical connection between two or more entities. For example, contacting a cell with a lipid nanoparticle composition means bringing the cell and the nanoparticle into a shared physical connection. Methods of contacting a cell with an external entity are well known in the art.

[0775] As used herein, the terms "delivery" and "transport" mean providing an entity to a destination. For example, delivering a biological or therapeutic agent to a subject may involve administering to the subject a lipid nanoparticle composition comprising the biological or therapeutic agent by methods well known in the biological arts (e.g., intravenous, intradermal, subcutaneous, or intramuscular routes).

[0776] As used herein, the term "encapsulation efficiency" refers to the amount of a biological or therapeutic agent that becomes part of a lipid nanoparticle composition, relative to the total amount of the initial biological or therapeutic agent used to prepare the lipid nanoparticle composition. For example, if the total amount of a biological or therapeutic agent initially provided to the composition is 40 micrograms and 30 micrograms of the biological or therapeutic agent are encapsulated in the lipid nanoparticle composition, the encapsulation efficiency can be set at 75%.

[0777] As used herein, the term "encapsulate" can refer to completely, substantially, or partially enclosing, confining, surrounding, or wrapping. Encapsulation efficiency can be determined by assay. is a hypersensitive fluorescent nucleic acid stain used to quantify oligonucleotides and single-stranded DNA or RNA in solution (available from Invitrogen Corporation, Waltham, Massachusetts).

[0778] As used herein, the term "fully encapsulated" means that a biomolecule and / or therapeutic agent resides within a lipid nanoparticle composition in such a way that it does not degrade significantly upon exposure to serum or nuclease assays that would significantly degrade free biomolecules and / or therapeutic agents. In some embodiments, in a treatment where there would typically be 100% degradation of free biomolecules and / or therapeutic agents, less than 25% of the biomolecules and / or therapeutic agents degrade. In some preferred embodiments, less than 10% of the biomolecules and / or therapeutic agents degrade. In some more preferred embodiments, less than 5% of the biomolecules and / or therapeutic agents degrade. In even more preferred embodiments, less than 1% of the biomolecules and / or therapeutic agents degrade. Full encapsulation also indicates that the particles are serum stable, i.e., they do not rapidly break down into their components upon in vivo administration.

[0779] As used herein, the term "expression" refers to the translation of mRNA or a similar nucleic acid into a polypeptide or protein, as well as the post-translational modification of the polypeptide or protein.

[0780] As used herein, the term "transfection" refers to the introduction of a species (i.e., a biomolecule or therapeutic agent, such as RNA) into a cell.

[0781] As used herein, the term "enhanced delivery" refers to the delivery of a greater amount of a biomolecule and / or therapeutic agent to a tissue or cell by a lipid nanoparticle composition, compared to the level of biomolecule and / or therapeutic agent delivered to the tissue or cell by a control lipid nanoparticle composition (e.g., Dlin-MC3-DMA, SM-102, ALC-0315, or DODMA). The level of delivery can refer to at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 10-fold higher than the control lipid nanoparticle composition. The level of delivery of a biomolecule and / or therapeutic agent to a particular tissue or cell of interest can be measured by comparing the amount of the desired protein produced in the tissue or cell of interest to the total protein mass in the tissue or cell. Enhanced delivery of a lipid nanoparticle formulation to a tissue or cell can be determined in a subject other than the subject being treated (e.g., a rat, pig, dog, non-human primate, etc.).

[0782] Use the following abbreviations:

[0783] ACN: Acetonitrile

[0784] aiRNA: Asymmetric interfering RNA

[0785] BCA assay: Bicinchoninic acid assay

[0786] CDCl 3 : Deuterochloroform

[0787] cDNA: Complementary DNA

[0788] Chol: Cholesterol

[0789] DCM: Dichloromethane

[0790] DIEA: N,N-Diisopropylethylamine

[0791] DMAP: 4-Dimethylaminopyridine

[0792] DMPC: 1,2-Dimyristoyl-sn-glycero-3-phosphocholine

[0793] DNA: Deoxyribonucleic acid

[0794] DPPC: 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine

[0795] DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine

[0796] dsRNA: Dicer-substrate RNA

[0797] EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0798] EtOH: Ethanol

[0799] HFIP: Hexafluoroisopropanol

[0800] HSPC: L-α-hydrogenated phosphatidylcholine

[0801] IPA: Isopropanol

[0802] LNP: Lipid nanoparticle

[0803] mCPBA: m-chloroperoxybenzoic acid

[0804] MeOH: Methanol

[0805] miRNA: MicroRNA

[0806] mRNA: Messenger RNA

[0807] O / N: Overnight

[0808] PC: Phosphatidylcholine

[0809] PEG: Polyethylene glycol

[0810] PEG-DMG: 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol 2000

[0811] PG: Phosphatidylglycerol

[0812] RNA: Ribonucleic acid

[0813] RNAi: RNA interference

[0814] rRNA: Ribosomal RNA

[0815] rt: Room temperature

[0816] shRNA: Small hairpin RNA

[0817] siRNA: Small interfering RNA

[0818] TEA: Triethylamine

[0819] TFA: Trifluoroacetic acid

[0820] THF: Tetrahydrofuran

[0821] TLC: Thin Layer Chromatography

[0822] Examples

[0823] The present disclosure will be described in more detail by way of specific examples. The following examples are for illustrative purposes only and are not intended to limit the present disclosure in any way. Those skilled in the art will readily recognize that various non-critical parameters can be modified or changed to produce similar results.

[0824] It should be understood that all the above descriptions and the following examples are for illustration rather than limitation. Those skilled in the art will understand many embodiments after reading the description or examples. Therefore, the scope of the present disclosure should not be determined with reference to the description or examples, but should be determined with reference to the appended claims and the full scope of the equivalents thereof. The disclosures of all articles and references, including patent applications, patents, PCT publications, and GenBank accession numbers, are incorporated herein by reference for reference purposes.

[0825] Example 1

[0826] Materials and Methods

[0827] All commercial chemical reagents and solvents were purchased from Sigma Aldrich (St. Louis, MO) and Fisher Scientific (Hampton, NH) and used without further purification. 1 1H NMR spectra were recorded at room temperature using an Agilent 500 MHz spectrometer. Chemical shifts (δ) are expressed in parts per million, referenced to the residual solvent signal; all coupling constants (J) are reported in Hz.

[0828] mRNA: All mRNA molecules used in these studies were purchased from TriLink BioTechnologies (San Diego, CA) without further modification.

[0829] Lipid encapsulation of mRNA: In some embodiments, the mRNA molecules were encapsulated into nucleic acid-lipid particles composed of one or more of the following lipids: lipid conjugate PEG-DMG, ionizable lipids DODMA, DODAP, Dlin-MC3-DMA, SM-102, ALC-0315, DSPC, compounds of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV, and / or cholesterol.

[0830] Example 2

[0831] Synthesis of Compounds with Structure Conforming to Formula I

[0832]

[0833] Representative Synthesis Step 1

[0834]

[0835] 1,1'-{[(5-Dimethylamino)pentyl]azanediyl}bis(2-octanol) (Method A)

[0836]

[0837] Add 5-(dimethylamino)pentanamine (143 μL, 1 mmol) and 1,2-epoxyoctane (306 μL, 2 mmol) to a dry flask equipped with a stir bar. Seal the flask and stir the mixture at 90 °C for 3 days. Cool the reaction mixture to room temperature. Collect the title compound as a pale yellow viscous oil and use it without further purification. 1,1'-{[5-(Dimethylamino)pentyl]azanediyl}bis(2-octyl) dioctanoate (Method B)

[0838]

[0839] Add hexanoyl chloride (232.2 μL, 1.5 mmol) dropwise to a solution of 1,1'-{[5-dimethylamino)pentyl]aza-diyl}bis(2-octanol) (193 mg, 0.5 mmol) and triethylamine (153.3 μL, 1.1 mmol) in dichloromethane (2 mL). Stir the reactants at room temperature overnight. Dilute the reaction mixture with dichloromethane and wash with saturated sodium bicarbonate. Separate the organic layer, wash with brine, and dry with Na 2 SO 4 Dry. Filter the organic layer and evaporate it to dryness under reduced pressure. Collect the title compound as a pale yellow viscous oil and use it without further purification.

[0840] Example 3

[0841] Synthesis of Compounds with Structure Conforming to Formula II

[0842]

[0843] Representative Synthesis Step 2

[0844]

[0845] Octadecyl 3-[octadecyl(methyl)amino]propionate (Method C)

[0846]

[0847] Octadecyl prop-2-enoate (162 mg, 0.5 mmol) was charged into a vial and a stir bar was added. N-Methyloctadecylamine (142 mg, 0.5 mmol) and 1.0 mL of isopropanol / hexafluoroisopropanol (v:v = 3:1) were added and the vial was sealed. The mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure and the crude product was used without further purification.

[0848] Synthesis of intermediates

[0849] Aliphatic acrylate: Oleyl acrylate

[0850]

[0851] Oleyl alcohol (134 mg, 5 mmol) and triethylamine (55 mg, 5.5 mmol) were mixed in a glass vial and 1.0 mL of anhydrous dichloromethane was added. Acryloyl chloride (46 mg, 0.5 mmol) was slowly added to the resulting mixture. The vial was capped and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The resulting crude product was used directly without further purification.

[0852] Example 4

[0853] Synthesis of the compound with the structural formula conforming to formula III

[0854]

[0855] Representative synthesis step 3

[0856]

[0857] 2-{Methyl[3-oxo-3-(dodecyloxy)propyl]amino}ethyl nonanoate (Method D)

[0858]

[0859] 3-[(2-Hydroxyethyl)(methyl)amino]propyl dodecanoate (315 mg, 1.0 mmol) and triethylamine (110 mg, 1.1 mmol) were charged into a glass vial. Anhydrous dichloromethane (1 mL) was added to the mixture. Nonanoyl chloride was dissolved in anhydrous dichloromethane (1 mL) and added dropwise to the mixture. The solution was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The product was then treated with hexane (5 mL) and mixed well to precipitate white needle-like crystals. The mixture was filtered and hexane was removed by distillation under reduced pressure to give the title compound as a pale purple viscous liquid, which was used without further purification.

[0860] Synthesis of intermediates

[0861] Dodecyl 3-[(2-hydroxyethyl)(methyl)amino]propionate

[0862]

[0863] 2-(Methylamino)ethanol (300 mg, 4.0 mmol) and dodecyl acrylate (960 mg, 4.0 mmol) were charged into a glass vial. A mixture of 1.0 mL of isopropanol and hexafluoroisopropanol (v:v = 3:1) was added, and the reaction mixture was thoroughly mixed. The reaction was heated to 50 °C and vigorously stirred for 3 hours. Then the solvent was removed by distillation under reduced pressure. The title compound was collected as a pale yellow viscous oil and used without further purification.

[0864] Example 5

[0865] Synthesis of compounds with a structural formula conforming to Formula IV

[0866]

[0867] Representative synthesis step 4

[0868]

[0869] Didodecyl 3,3'-({3-[(nonanoylethyl)(3-dodecyloxy-3-oxopropyl)amino]ethyl}azanediyl)dipropionate (Method E)

[0870]

[0871] Didodecyl 3,3'-({[(2-hydroxyethyl)(3-dodecyloxy-3-oxopropyl)amino]ethyl}azanediyl)dipropionate (410 mg, 0.5 mmol) and triethylamine (55 mg, 0.55 mmol) were charged into a glass vial. Anhydrous dichloromethane (1 mL) was added and the mixture was stirred. Nonanoyl chloride (93 mg, 1.05 mmol) was diluted with anhydrous dichloromethane (1 mL) and added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction product was concentrated under reduced pressure, and the residue was mixed with hexane (5 mL) to precipitate white needle-like crystals. The mixture was filtered and hexane was removed by distillation under reduced pressure to give the title compound as a colorless viscous oil, which was used directly without further purification.

[0872] Synthesis of the intermediate didodecyl 3,3'-({[(2-hydroxyethyl)(3-dodecyloxy-3-oxopropyl)amino]ethyl}azanediyl)dipropionate

[0873]

[0874] 2-(2-Aminoethylamino)ethanol (104 mg, 1.0 mmol) and dodecyl acrylate (790 mg, 3.3 mmol) were charged into a glass vial. A mixture of isopropanol and hexafluoroisopropanol (v:v = 3:1) (1 mL) was added, and the reaction mixture was thoroughly mixed. The reaction was heated to 50 °C and stirred vigorously for 40 h. The solvent was removed by distillation under reduced pressure to give the title compound as a colorless viscous oil, which was used directly without further purification.

[0875] Example 6

[0876] Synthesis of Compound 125

[0877]

[0878] 2-Hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for another 3 h. The solvent was removed by distillation under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 The hexane layer was dried and the hexane was removed by distillation under reduced pressure to give 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0879] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 3-aminopropane-1,2-diol (3.64 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 h. The solvent was removed by distillation under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed by distillation under reduced pressure to give 2-hexyldecyl 6-((2,3-dihydroxypropyl)amino)hexanoate as a colorless oil (1.2 g, 70%).

[0880] 2-Hexyldecyl 6-((2,3-dihydroxypropyl)amino)hexanoate (0.430 mg, 1 mmol) and dodecyl acrylate (240 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v = 3:1, 2 mL) and stirred at 60 °C for 16 h. The solvent was removed, and the residue was purified by silica gel chromatography (0.1% NH 4A mixture of OH and 5% MeOH in DCM was used to obtain a light brown oily product (312 mg, 46%). 1 H NMR (500 MHz, CDCl 3 ) δ = 4.07 (td, J = 7.3, 2.8 Hz, 2H), 3.96 (t, J = 4.7 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.50 - 3.43 (m, 1H), 2.92 (dt, J = 13.7, 7.7 Hz, 1H), 2.71 (dd, J = 13.4, 6.9 Hz, 1H), 2.58 (dd, J = 13.1, 9.5 Hz, 1H), 5.54 - 2.37 (m, 5H), 2.30 (td, J = 8.0, 2.6 Hz, 2H), 1.62 (dq, J = 11.3, 5.9 Hz, 5H), 1.46 (s, 2H), 1.38 - 1.09 (m, 46H), 0.88 (td, J = 7.4, 2.6 Hz, 9H).

[0881] Example 7

[0882] Synthesis of Compound 226

[0883]

[0884] 2-Hexyl-1-decanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for another 3 hours. The solvent was removed by distillation under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 The hexane was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0885] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-pyrrolidinoethylamine (4.56 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 Dry. The mixture was filtered and the solvent was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate as a colorless oil (1.22 g, 67%).

[0886] 2-Hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate (452 mg, 1 mmol) and 2-decyltetradecyl acrylate (409 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL). The mixture was stirred at 60 °C for 16 h, the solvent was removed, and the residue was purified by silica gel chromatography (a mixture of 0.1% NH 4 OH, 7.5% MeOH in DCM) to give the product (422 mg, 49%). 1 1H NMR (500 MHz, CDCl 3 ) δ = 3.95 (dt, J = 5.7, 2.6 Hz, 4H), 2.77 (J = 21.9, 14.9 Hz, 8H), 2.43 (t, J = 7.4 Hz, 4H), 2.29 (t, J = 7.5 Hz, 2H), 1.89 (s, 4H), 1.61 (q, J = 7.6 Hz, 4H), 1.45 (q, J = 7.8 Hz, 2H), 1.26 (d, J = 6.1 Hz, 68H), 0.92 - 0.77 (m, 12H).

[0887] Example 8

[0888] Synthesis of Compound 227

[0889]

[0890] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise with stirring to a solution of 2-(2-aminoethylamino)ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL). After stirring for 3 h, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined, dried over anhydrous Na 2 SO 4 and the solvent was removed by distillation under reduced pressure to obtain a crude pale yellow oil. 10% NaOH solution (20 mL) was added to the above crude oil. The resulting solution was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with DCM (30 mL × 6). The DCM layers were combined, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4Dry. The organic solvent was removed by distillation under reduced pressure to obtain 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g, total yield 30%).

[0891] 2-Hexyldecan-1-ol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 3 hours. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 and the hexane was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0892] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (4.22 g, 32 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-((2-hydroxyethyl)(ethyl)aminoethyl)aminohexanoate as a colorless oil (1.18 g, 63%).

[0893] 2-Hexyldecyl 6-((2-hydroxyethyl)(ethyl)aminoethyl)aminohexanoate (470 mg, 1 mmol) and 2-decyltetradecyl acrylate (408 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed, and the residue was purified by silica gel chromatography (NH 4 OH, 7.5% MeOH in DCM) to give the product (415 mg, 47%). 1 1H NMR (500 MHz, CDCl 3) δ = 3.96 (d, J = 5.7 Hz, 4H), 3.59 (s, 2H), 2.81 (t, J = 7.4 Hz, 2H), 2.68 (d, J = 17.2 Hz, 5H), 2.58 (s, 2H), 2.46 (dt, J = 15.9, 7.6 Hz, 4H), 2.30 (q, J = 7.2 Hz, 2H), 1.63 (dt, J = 15.7, 7.7 Hz, 4H), 1.48 (pent, J = 7.7 Hz, 2H), 1.26 (s, 68H), 1.09 (t, J = 7.1 Hz, 3H), 0.88 (t, J = 6.7 Hz, 12H).

[0894] Example 9

[0895] Synthesis of Compound 228

[0896]

[0897] Mix 2-hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) in anhydrous DCM (20 mL) and cool to 0 °C. Slowly add 6-bromohexanoyl chloride (4.39 g, 2.06 mmol) to the resulting mixture. Stir the reaction mixture at 0 °C for 30 minutes and then at room temperature for another 3 hours. Remove the solvent under reduced pressure, and add hexane (150 mL) to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), dry with anhydrous Na 2 SO 4 Dry the hexane layer and remove hexane under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0898] Dissolve 2-hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-pyrrolidinoethylamine (4.56 g, 40 mmol) in ethanol (8 mL) and stir at 60 °C for 16 hours. Remove the solvent by distillation under reduced pressure, and re-suspend the residue in ethyl acetate (100 mL). Wash the suspension with water (50 mL × 2), brine (50 mL × 2), and dry with anhydrous Na 2 SO 4 Dry. Filter the mixture and remove the solvent under reduced pressure to obtain 2-hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate as a colorless oil (1.22 g, 67%).

[0899] Dissolve 2-hexyldecyl 6-(2-pyrrolidinoethyl)aminohexanoate (453 mg, 1 mmol) and 2-octyldodecyl acrylate (352 mg, 1 mmol) in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL). Stir at 60 °C for 16 h. Remove the solvent. Purify the residue by silica gel chromatography (a mixture of 0.1% NH 4 OH, 7.5% MeOH in DCM) to give the product (398 mg, 49%). 1 H NMR (500 MHz, CDCl 3 ) δ = 3.95 (d, J = 5.7 Hz, 4H), 2.80 (t, J = 7.3 Hz, 2H), 2.56 (d, J = 26.0 Hz, 6H), 2.43 (t, J = 7.5 Hz, 4H), 2.29 (t, J = 7.5 Hz, 2H), 1.78 (s, 4H), 1.62 (pent, J = 7.6 Hz, 4H), 1.45 (pent, J = 7.5 Hz, 2H), 1.26 (d, J = 5.5 Hz, 60H), 0.87 (t, J = 6.7 Hz, 12H).

[0900] Example 10

[0901] Synthesis of Compound 229

[0902]

[0903] Stir 2-hexyldecanoic acid (3.84 g, 15 mmol), EDC·HCl (3.74 g, 19.5 mmol), and DMAP (2.38 g, 19.5 mmol) in anhydrous DCM at room temperature for 20 min. Add 6-bromo-1-hexanol (2.72 g, 15 mmol) to the resulting mixture and stir for 24 h. Remove DCM under reduced pressure. Resuspend the residue in 150 mL of hexane. Wash the suspension with water (50 mL × 2), brine (50 mL × 2), and acetonitrile (50 mL). Separate the hexane layer, dry over anhydrous Na 2 SO 4 and evaporate under reduced pressure. Purify the residue by silica gel chromatography (a hexane solution of 3% ethyl acetate) to give 6-bromohexyl 2-hexyldecanoate as a colorless oil (2.58 g, 41%).

[0904] 6-Bromohexyl 2-hexyldecanoate (2.09 g, 5 mmol) and 2-pyrrolidinoethylamine (5.70 g, 50 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 h. The solvent was removed under reduced pressure and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2) and dried over anhydrous Na 2 SO 4 . The mixture was filtered and the solvent was removed under reduced pressure to give 6-((2-pyrrolidinoethyl)amino)hexyl 2-hexyldecanoate as a colorless oil (1.61 g, 71%).

[0905] 6-((2-Pyrrolidinoethyl)amino)hexyl 2-hexyldecanoate (452 mg, 1 mmol) and 2-decyltetradecyl acrylate (408 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 h. The solvent was removed and the residue was purified by silica gel chromatography (0.1% NH 4 OH, 7.5% MeOH in DCM) to give the product (442 mg, 51%). 1 H NMR (500 MHz, CDCl 3 3) δ = 4.04 (t, J = 6.7 Hz, 2H), 3.95 (d, J = 5.8 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 2.63 (s, 6H), 2.43 (td, J = 7.4, 3.2 Hz, 4H), 2.30 (tt, J = 9.4, 5.3 Hz, 1H), 1.81 (s, 3H), 1.59 (tt, J = 14.4, 7.4 Hz, 5H), 1.43 (h, J = 7.6 Hz, 4H), 1.35 (pent, J = 7.4 Hz, 66H), 0.87 (td, J = 6.9, 2.9 Hz, 12H).

[0906] Example 11

[0907] Synthesis of Compound 230

[0908]

[0909] 2-Hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for another 3 hours. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 and the hexane was removed under reduced pressure to give 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0910] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-pyrrolidinoethylamine (4.56 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed by distillation under reduced pressure to give 2-hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate as a colorless oil (1.22 g, 67%).

[0911] 2-Hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate (453 mg, 1 mmol) and 2-((2-hexyldecyl)thio)ethyl acrylate (357 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed, and the residue was purified by silica gel chromatography (0.1% NH 4 OH, 7.5% MeOH in DCM) to give the product (439 mg, 54%). 1 1H NMR (500 MHz, CDCl 3 ) δ = 4.19 (td, J = 7.2, 1.8 Hz, 1H), 3.95 (dd, J = 5.7, 1.8 Hz, 2H), 2.90 - 2.60 (m, 11H), 2.52 (dd, J = 6.4, 1.8 Hz, 2H), 2.48 - 2.39 (m, 4H), 2.29 (tt, J = 7.5, 4.1 Hz, 2H), 1.87 (s, 4H), 1.62 (pent, J = 7.7 Hz, 3H), 10.47 (dq, J = 30.7, 6.9 Hz, 3H), 1.26 (d, J = 10.2 Hz, 51H), 0.87 (t, J = 6.7 Hz, 12H).

[0912] Example 12

[0913] Synthesis of Compound 231

[0914]

[0915] Mix 2-hexyldecan-1-ol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) in anhydrous DCM (20 mL), and cool to 0 °C. Slowly add 6-bromohexanoyl chloride (4.39 g, 2.06 mmol) to the resulting mixture. Stir the reaction mixture at 0 °C for 30 minutes and then at room temperature for another 3 hours. Remove the solvent under reduced pressure, and add hexane (150 mL) to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), dry the hexane layer with anhydrous Na 2 SO 4 Dry the hexane layer and remove hexane under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0916] Dissolve 2-hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 3-(N,N-diethylamino)ethylamine (5.20 g, 40 mmol) in ethanol (8 mL), and stir at 60 °C for 16 hours. Remove the solvent under reduced pressure, and re-suspend the residue in ethyl acetate (100 mL). Wash the suspension with water (50 mL × 2) and brine (50 mL × 2), and dry with anhydrous Na 2 SO 4 Dry. Filter the mixture and remove the solvent under reduced pressure to obtain 2-hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate as a colorless oil (1.24 g, 66%).

[0917] Dissolve 2-hexyldecyl 6-((3-(N,N-diethylamino)ethyl)amino)hexanoate (468 mg, 1 mmol) and 3-((2-hexyldecyl)thio)propyl acrylate (370 mg, 1 mmol) in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), stir at 60 °C for 16 hours, remove the solvent, and purify the residue by silica gel chromatography (a mixture of 0.1% NH 4 OH, 7.5% MeOH in DCM) to obtain the product (395 mg, 47%).

[0918] Example 13

[0919] Synthesis of Compound 232

[0920]

[0921] 2-Hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 3 hours. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 and the hexane was removed by distillation under reduced pressure to give 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0922] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-pyrrolidinoethylamine (4.56 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed under reduced pressure to give 2-hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate as a colorless oil (1.22 g, 67%).

[0923] 2-Hexyldecyl 6-((2-pyrrolidinoethyl)amino)hexanoate (452 mg, 1 mmol) and 2-hexyldecyl acrylate (296 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed, and the residue was purified by silica gel chromatography (0.1% NH 4 OH, 7.5% MeOH in DCM mixture) to give the product (348 mg, 46%). 1 1H NMR (500 MHz, CDCl 3 ) δ = 3.95 (d, J = 5.8 Hz, 4H), 2.79 (t, J = 7.2 Hz, 2H), 2.67 (s, 6H), 2.43 (t, J = 7.4 Hz, 4H), 2.29 (t, J = 7.5 Hz, 4H), 1.84 (s, 4H), 1.62 (pent, J = 7.6 Hz, 4H), 1.45 (pent, J = 7.7 Hz, 2H), 1.26 (d, J = 4.7 Hz, 52H), 0.87 (t, J = 6.7 Hz, 12H).

[0924] Example 14

[0925] Synthesis of Compound 233

[0926]

[0927] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise to a solution of 2-(2-aminoethylamino)ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL) with stirring. After stirring for 3 h, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined and dried over anhydrous Na 2 SO 4 The solvent was removed by distillation under reduced pressure to obtain a crude pale yellow oil. 10% NaOH solution (20 mL) was added to the above crude oil. The resulting solution was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with DCM (30 mL × 6). The combined DCM layers were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 The organic solvent was removed by distillation under reduced pressure to obtain 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g, total yield 30%).

[0928] 2-Hexyldecan-1-ol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for another 3 h. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 The hexane was removed under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0929] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (4.22 g, 32 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 h. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2SO 4 Dry. The mixture was filtered and the solvent was removed under reduced pressure to obtain 2-hexyldecyl 6-((2-hydroxyethyl)(ethyl)aminoethyl)amino)hexanoate as a colorless oil (1.18 g, 63%).

[0930] 2-Hexyldecyl-6-((2-hydroxyethyl)(ethyl)aminoethyl)amino)hexanoate (470 mg, 1 mmol) and 2-octyldodecyl acrylate (352 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), stirred at 60 °C for 16 h, the solvent was removed, and the residue was purified by silica gel chromatography (a mixture of 0.1% NH 4 OH, 7.5% MeOH in DCM) to give the product (356 mg, 43%). 1 1H NMR (500 MHz, CDCl 3 ) δ = 3.96 (d, J = 5.7 Hz, 4H), 3.63 (s, 2H), 2.82 (t, J = 7.3 Hz, 2H), 2.79 - 2.66 (m, 6H), 2.62 (s, 2H), 2.47 (dt, J = 14.0, 7.4 Hz, 3H), 2.30 (d, J = 7.9 Hz, 2H), 1.63 (dt, J = 16.1, 7.7 Hz, 5H), 1.48 (pent, J = 8.1 Hz, 2H), 1.26 (d, J = 11.0 Hz, 59H), 1.14 - 1.06 (m, 3H), 0.87 (t, J = 6.8 Hz, 12H).

[0931] Example 15

[0932] Synthesis of Compound 234

[0933]

[0934] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise to a solution of 2-(2-aminoethylamino)ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL) with stirring. After stirring for 3 h, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined and dried over anhydrous Na 2 SO 4Dry, and remove the solvent by distillation under reduced pressure to obtain a crude product as a pale yellow oil. Add 10% NaOH solution (20 mL) to the above crude oil. Stir the resulting solution at 60 °C for 2 hours. Cool the reaction mixture to room temperature and extract with DCM (30 mL × 6). Combine the DCM layers, wash with brine (20 mL), and dry with anhydrous Na 2 SO 4 Dry. Remove the organic solvent by distillation under reduced pressure to obtain 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g, total yield 30%).

[0935] Mix 2-hexyldecan-1-ol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) in anhydrous DCM (20 mL), and cool to 0 °C. Slowly add 6-bromohexanoyl chloride (4.39 g, 2.06 mmol) to the resulting mixture. Stir the reaction mixture at 0 °C for 30 minutes and then at room temperature for another 3 hours. Remove the solvent under reduced pressure, add hexane (150 mL) to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), dry with anhydrous Na 2 SO 4 Dry the hexane layer and remove hexane by distillation under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0936] Dissolve 2-hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (4.22 g, 32 mmol) in ethanol (8 mL), and stir at 60 °C for 16 hours. Remove the solvent by distillation under reduced pressure, and re-suspend the residue in ethyl acetate (100 mL). Wash the suspension with water (50 mL × 2) and brine (50 mL × 2), and dry with anhydrous Na 2 SO 4 Dry. Filter the mixture and remove the solvent under reduced pressure to obtain 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate as a colorless oil (1.18 g, 63%).

[0937] Dissolve 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate (470 mg, 1 mmol) and 2-((2-hexyldecyl)thio)ethyl acrylate (356 mg, 1 mmol) in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), stir at 60 °C for 16 hours, remove the solvent, and purify the residue by silica gel chromatography (a mixture of 0.1% NH 4 OH, 7.5% MeOH in DCM) to obtain the product (332 mg, 40%). 11H NMR (500 MHz, CDCl 3 ) δ = 4.20 (t, J = 7.1 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.52 (t, J = 5.1 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.59 (td, J = 16.5, 6.5 Hz, 6H), 2.54 - 2.45 (m, 6H), 2.42 (t, J = 7.8 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H), 1.63 (pent, J = 7.5 Hz, 3H), 1.49 (dq, J = 23.6, 6.9 Hz, 3H), 1.27 (d, J = 9.8 Hz, 51H), 1.04 (t, J = 7.0 Hz, 3H), 0.88 (t, J = 6.7 Hz, 12H).

[0938] Example 16

[0939] Synthesis of Compound 235

[0940]

[0941] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise to a solution of 2-(2-aminoethylamino)ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL) with stirring. After stirring for 3 h, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined, dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure to obtain a crude pale yellow oil. 10% NaOH solution (20 mL) was added to the above crude oil. The resulting solution was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with DCM (30 mL × 6). The DCM layers were combined, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4 . The organic solvent was removed under reduced pressure to obtain 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g, total yield 30%).

[0942] 2-Hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for an additional 3 hours. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried with anhydrous Na 2 SO 4 The hexane was removed by distillation under reduced pressure to give 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0943] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (4.22 g, 32 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried with anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed under reduced pressure to give 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate as a colorless oil (1.18 g, 63%).

[0944] 2-Hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate (470 mg, 1 mmol) and 2-[(2-hexyldecyl)thio]propyl acrylate (370 mg, 1 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed, and the residue was purified by silica gel chromatography (0.1% NH 4 OH, 7.5% MeOH in DCM) to give the product (365 mg, 43%).

[0945] Example 17

[0946] Synthesis of Compound 236

[0947]

[0948] At 0 °C, while stirring, trifluoroacetate (7.1 g, 60 mmol) was slowly added to a solution of 2-(2-aminoethylamino)ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL). After stirring for 3 hours, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. To the residue was added H 2 O (100 mL), and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined and dried over anhydrous Na 2 SO 4 The solvent was removed by distillation under reduced pressure to obtain a crude pale yellow oil. To the above crude oil was added 10% NaOH solution (20 mL). The resulting solution was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with DCM (30 mL × 6). The DCM layers were combined, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4 The organic solvent was removed by distillation under reduced pressure to obtain 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g, total yield 30%).

[0949] 2-Hexyl-1-decanoic acid (3.84 g, 15 mmol), EDC·HCl (3.74 g, 19.5 mmol), and DMAP (2.38 g, 19.5 mmol) were stirred in anhydrous DCM at room temperature for 20 minutes. 6-Bromo-1-hexanol (2.72 g, 15 mmol) was added to the resulting mixture and stirred for 24 hours. DCM was removed under reduced pressure. The residue was resuspended in 150 mL of hexane. The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and acetonitrile (50 mL). The hexane layer was separated, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane solution of 3% ethyl acetate) to obtain 6-bromohexyl 2-hexyldecanoate as a colorless oil (2.58 g, 41%). 6-Bromohexyl 2-hexyldecanoate (2.10 g, 5 mmol) and 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (5.2 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered, and the solvent was removed under reduced pressure to obtain 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexyl 2-hexyldecanoate as a colorless oil (1.54 g, 66%).

[0950] Dissolve 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexyl 2-hexyldecanoate (470 mg, 1 mmol) and 2-[(2-hexyldecyl)thio]ethyl acrylate (356 mg, 1 mmol) in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), stir at 60 °C for 16 h, remove the solvent, and purify the residue by silica gel chromatography (a mixture of 0.1% NH 4 OH, 7.5% MeOH in DCM) to obtain the product (376 mg, 45%).

[0951] Example 18

[0952] Synthesis of Compound 237

[0953]

[0954] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise to a solution of 2-[(3-aminopropyl)amino]ethanol (7.08 g, 60 mmol) in acetonitrile (30 mL) with stirring. After stirring for 3 h, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. Add H 2 O (100 mL) to the residue, and extract the aqueous solution with ethyl acetate (30 mL × 5). Combine the organic layers, dry over anhydrous Na 2 SO 4 and distill off the solvent under reduced pressure to obtain a crude pale yellow oil. Add 10% NaOH solution (20 mL) to the above crude oil. Stir the resulting solution at 60 °C for 2 h. Cool the reaction mixture to room temperature, extract with DCM (30 mL × 6), combine the DCM layers, wash with brine (20 mL), dry over anhydrous Na 2 SO 4 and distill off the organic solvent under reduced pressure to obtain 2-[(3-aminopropyl)(ethyl)amino]ethanol as a colorless oil (2.8 g, total yield 31%).

[0955] Mix 2-hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) in anhydrous DCM (20 mL) and cool to 0 °C. Slowly add 6-bromohexanoyl chloride (4.39 g, 2.06 mmol) to the resulting mixture. Stir the reaction mixture at 0 °C for 30 min and then at room temperature for 3 h. Distill off the solvent under reduced pressure, add hexane (150 mL) to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), dry over anhydrous Na2 SO 4 The hexane layer was dried, and hexane was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0956] 2-Hexyldecyl 6-bromohexanoate (0.84 g, 2 mmol) and 2-[(3-aminopropyl)(ethyl)amino]ethanol (2.33 g, 16 mmol) were dissolved in ethanol (8 mL), and the mixture was stirred at 60 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was redissolved in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2) and brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered, and the solvent was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminopropyl]aminohexanoate as a colorless oil (0.66 g, 68%).

[0957] 2-Hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminopropyl]aminohexanoate (97 mg, 0.2 mmol) and 2-decyltetradecyl acrylate (82 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), and the mixture was stirred at 60 °C for 16 hours. The solvent was removed to obtain the product.

[0958] Example 19

[0959] Synthesis of Compound 238

[0960]

[0961] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise to a solution of 2-[(3-aminopropyl)amino]ethanol (7.08 g, 60 mmol) in acetonitrile (30 mL) with stirring. After stirring for 3 hours, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined, dried over anhydrous Na 2 SO 4 The solvent was removed under reduced pressure to obtain a crude pale yellow oil. 10% NaOH solution (20 mL) was added to the above crude oil. The resulting solution was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, extracted with DCM (30 mL × 6), the DCM layers were combined, washed with brine (20 mL), and dried over anhydrous Na 2 SO4 It was dried and the organic solvent was removed by distillation under reduced pressure to obtain 2-[(3-aminopropyl)(ethyl)amino]ethanol as a colorless oil (2.8 g, total yield 31%).

[0962] 2-Hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for another 3 hours. The solvent was removed under reduced pressure and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), it was dried with anhydrous Na 2 SO 4 The hexane layer was dried and hexane was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0963] 2-Hexyldecyl 6-bromohexanoate (0.84 g, 2 mmol) and 2-[(3-aminopropyl)(ethyl)amino]ethanol (2.33 g, 16 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2) and brine (50 mL × 2), and dried with anhydrous Na 2 SO 4 It was dried. The mixture was filtered and the solvent was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminopropyl]aminohexanoate as a colorless oil (0.66 g, 68%).

[0964] 2-Hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminopropyl]aminohexanoate (96 mg, 0.2 mmol) and 2-octyldodecyl acrylate (70 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed to obtain the product.

[0965] Example 20

[0966] Synthesis of Compound 239

[0967]

[0968] 2-Hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for another 3 hours. The solvent was removed by distillation under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 dried, and hexane was removed under reduced pressure to give 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0969] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-(4-methylpiperazin-1-yl)ethylamine (5.72 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 dried. The mixture was filtered, and the solvent was removed by distillation under reduced pressure to give 2-hexyldecyl 6-[2-(4-methylpiperazin-1-yl)ethyl]aminohexanoate as a colorless oil (1.26 g, 65%).

[0970] 2-Hexyldecyl 6-[2-(4-methylpiperazin-1-yl)ethyl]aminohexanoate (96 mg, 0.2 mmol) and 2-decyltetradecyl acrylate (82 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed to obtain the product.

[0971] Example 21

[0972] Synthesis of Compound 240

[0973]

[0974] 2-Hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for another 3 hours. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na2 SO 4 The hexane layer was dried, and hexane was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0975] 2-Hexyldecyl-6-bromohexanoate (1.68 g, 4 mmol) and 2-(3-hydroxypyrrolidinyl)ethylamine (5.20 g, 40 mmol) were dissolved in ethanol (8 mL), and the mixture was stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2) and brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered, and the solvent was removed by distillation under reduced pressure to obtain 6-[2-(3-hydroxypyrrolidinyl)ethyl]aminohexanoate as a colorless oil (1.18 g, 63%).

[0976] 2-Hexyldecyl 6-[2-(3-hydroxypyrrolidinyl)ethyl]aminohexanoate (94 mg, 0.2 mmol) and 2-octyldodecyl acrylate (70 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), and the mixture was stirred at 60 °C for 16 hours. The solvent was removed to obtain the product.

[0977] Example 22

[0978] Synthesis of Compound 241

[0979]

[0980] 2-Hexyl-1-decanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 3 hours. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), it was dried over anhydrous Na 2 SO 4 The hexane layer was dried, and hexane was removed under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0981] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-pyrrolidinoethylamine (4.56 g, 40 mmol) were dissolved in ethanol (8 mL), and the mixture was stirred at 60 °C for 16 h. The solvent was removed by distillation under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2) and brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 . The mixture was filtered, and the solvent was removed under reduced pressure to give 2-hexyldecyl 6-[(2-pyrrolidinoethyl)amino]hexanoate as a colorless oil (1.22 g, 67%).

[0982] 2-Hexyldecyl 6-[(2-pyrrolidinoethyl)amino]hexanoate (91 mg, 0.2 mmol) and 2-[(2-hexyldecyloxy)ethyl] acrylate (71 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), and the mixture was stirred at 60 °C for 16 h. The solvent was removed to obtain the product.

[0983] Example 23

[0984] Synthesis of Compound 242

[0985]

[0986] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise to a solution of 2-[(2-aminoethyl)amino]ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL) with stirring. After stirring for 3 h, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined, dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure to obtain a crude pale yellow oil. 10% NaOH solution (20 mL) was added to the above crude oil. The resulting solution was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and extracted with DCM (30 mL × 6). The DCM layers were combined, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4 . The organic solvent was removed by distillation under reduced pressure to give 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g, total yield 30%).

[0987] 2-Hexyl-1-decanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 3 hours. The solvent was removed under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 The hexane was removed under reduced pressure to give 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[0988] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (4.22 g, 32 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2) and brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed by distillation under reduced pressure to give 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate as a colorless oil (1.18 g, 63%).

[0989] 2-Hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate (93 mg, 0.2 mmol) and 2-[(2-hexyldecyl)oxy]ethyl acrylate (71 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed to obtain the product.

[0990] Example 24

[0991] Synthesis of Compound 243

[0992]

[0993] 9 - heptadecanol (2.56 g, 10 mmol) and TEA (1.21 g, 12 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6 - Bromohexanoyl chloride (2.14 g, 10 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for another 3 hours. The solvent was removed by distillation under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 and the hexane was removed by distillation under reduced pressure to give 9 - heptadecyl - 6 - bromohexanoate as a colorless liquid (3.68 g, 85%).

[0994] 9 - Heptadecyl 6 - bromohexanoate (1.72 g, 4 mmol) and 2 - pyrrolidinoethylamine (4.56 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed by distillation under reduced pressure to give 9 - heptadecyl 6 - (2 - pyrrolidinoethyl)aminohexanoate as a colorless oil (1.32 g, 71%).

[0995] 9 - Heptadecyl 6 - (2 - pyrrolidinoethyl)aminohexanoate (93 mg, 0.2 mmol) and 2 - octyldodecyl acrylate (70 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed to give the crude product. 1 H NMR (500 MHz, CDCl 3 ) δ 4.89 - 4.82 (m, 1H), 3.96 (t, J = 4.1 Hz, 2H), 2.80 (t, J = 7.4 Hz, 2H), 2.59 (d, J = 21.4 Hz, 7H), 2.43 (t, J = 7.5 Hz, 4H), 2.30 - 2.24 (m, 2H), 1.79 (s, 4H), 1.61 (q, J = 7.7 Hz, 3H), 1.54 - 1.40 (m, 6H), 1.26 (d, J = 9.2 Hz, 59H), 0.87 (td, J = 6.9, 3.3 Hz, 12H).

[0996] Example 25

[0997] Synthesis of Compound 244

[0998]

[0999] 9-Heptadecanol (2.56 g, 10 mmol) and TEA (1.21 g, 12 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (2.14 g, 10 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for an additional 3 hours. The solvent was removed by distillation under reduced pressure, and hexane (150 mL) was added to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), the hexane layer was dried over anhydrous Na 2 SO 4 and the hexane was removed by distillation under reduced pressure to give 9-heptadecyl-6-bromohexanoate as a colorless liquid (3.68 g, 85%).

[1000] 9-Heptadecyl 6-bromohexanoate (1.72 g, 4 mmol) and 2-pyrrolidinoethylamine (4.56 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed under reduced pressure to give 9-heptadecyl 6-(2-pyrrolidinoethyl)aminohexanoate as a colorless oil (1.32 g, 71%).

[1001] 9-Heptadecyl 6-(2-pyrrolidinoethyl)aminohexanoate (93 mg, 0.2 mmol) and 2-[(2-hexyldecyl)thio]ethyl acrylate (52 mg, 0.2 mmol) were dissolved in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL) and stirred at 60 °C for 16 hours. The solvent was removed to give the crude product. 1 1H NMR (500 MHz, CDCl 3 ) δ 4.85 (pent, J = 6.3 Hz, 1H), 4.19 (t, J = 7.1 Hz, 2H), 2.80 (t, J = 7.3 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 2.62 - 2.50 (m, 8H), 2.44 (dt, J = 11.7, 7.5 Hz, 4H), 2.27 (t, J = 7.6 Hz, 2H), 1.79 (s, 4H), 1.61 (pent, J = 7.6 Hz, 2H), 1.48 (tdd, J = 17.3, 13.6, 7.0 Hz, 7H), 1.40 - 1.16 (m, 52H), 0.89 - 0.84 (m, 12H).

[1002] Example 26

[1003] Synthesis of Compound 245

[1004]

[1005] Mix 2-hexyldecanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) in anhydrous DCM (20 mL) and cool to 0 °C. Slowly add 6-bromohexanoyl chloride (4.39 g, 20.6 mmol) to the resulting mixture. Stir the reaction mixture at 0 °C for 30 minutes and then at room temperature for another 3 hours. Remove the solvent under reduced pressure, and add hexane (150 mL) to the residue. After washing with water (50 mL × 2) and acetonitrile (50 mL × 2), dry the hexane layer with anhydrous Na 2 SO 4 dry, and distill off hexane under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[1006] Dissolve 2-hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 3-aminopropane-1,2-diol (3.64 g, 40 mmol) in ethanol (8 mL), and stir at 60 °C for 16 hours. Remove the solvent under reduced pressure, and re-suspend the residue in ethyl acetate (100 mL). Wash the suspension with water (50 mL × 2), brine (50 mL × 2), and dry with anhydrous Na 2 SO 4 dry. Filter the mixture, remove the solvent under reduced pressure to obtain 2-hexyldecyl 6-(2,3-dihydroxypropyl)aminohexanoate as a colorless oil (1.2 g, 70%).

[1007] Dissolve 2-hexyldecyl 6-(2,3-dihydroxypropyl)aminohexanoate (0.430 mg, 1 mmol) and tetradecyl acrylate (0.268 mg, 1 mmol) in a mixture of isopropanol / hexafluoroisopropanol (v:v, 3:1, 2 mL), stir at 60 °C for 16 hours, remove the solvent, and purify the residue by silica gel column chromatography (NH 4 OH, 5% MeOH in DCM mixture) to obtain the product (0.352 g, 50%). 1 1H NMR (500 MHz, CDCl 3)δ = 4.07 (t, J = 6.8 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.78 - 3.70 (m, 2H), 3.50 - 3.42 (m, 1H), 2.92 (dt, J = 14.0, 7.4 Hz, 1H), 2.71 (dt, J = 12.9, 6.1 Hz, 1H), 2.54 (ddd, J = 37.1, 14.3, 8.6 Hz, 3H), 2.47 - 2.38 (m, 4H), 2.30 (t, J = 7.4 Hz, 2H), 1.69 - 1.55 (m, 5H), 1.44 (dd, J = 16.5, 8.7 Hz, 2H), 1.26 (dd, J = 9.5, 4.6 Hz, 49H), 0.87 (t, J = 6.7 Hz, 9H).

[1008] Example 27

[1009] Synthesis of Compound 247

[1010]

[1011] (±)-Epichlorohydrin (2.04 g, 22 mmol) and 2-mercaptoethanol (1.56 g, 20 mmol) were stirred overnight at 60 °C in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 10 mL). The reaction mixture was cooled to room temperature and NaOH (880 mg, 22 mmol) dissolved in 25 mL of H 2 O was added slowly. The reaction mixture was stirred at room temperature for 2 hours and then extracted with DCM (50 mL × 3). The combined DCM layers were dried over anhydrous Na 2 SO 4 and DCM was removed under reduced pressure to give the crude product as a colorless oil (1.82 g, 70%). The crude 2-[(oxiran-2-yl)methyl]sulfanylethanol was used without further purification.

[1012] 2-Hexyldecanoic acid (2.58 g, 10 mmol), EDC·HCl (2.30 g, 12 mmol) and DMAP (1.46 g, 12 mmol) were stirred in anhydrous DCM at room temperature for 20 minutes. 2-[(oxiran-2-yl)methyl]sulfanylethanol (1.34 g, 10 mmol) was added to the resulting mixture and stirred for 24 hours. DCM was removed under reduced pressure. The residue was resuspended in 150 mL of hexane. The suspension was washed with H 2 O (50 mL × 2), brine (50 mL × 2) and acetonitrile (50 mL × 2). The hexane layer was separated and dried over anhydrous Na 2 SO 4It was dried and distilled under reduced pressure to obtain a colorless oily product (2.32 g, 62%). The crude 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate can be used without further purification.

[1013] 2-[(Oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate (0.372 g, 1 mmol) and 2-hexyldecyl 6-(4-hydroxybutyl)aminohexanoate (0.428 g, 1 mmol) were dissolved in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 2 mL), heated to 90 °C and stirred for 24 h. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography (5% MeOH in DCM containing 0.1% ammonia) to obtain a colorless oily product (0.482 g, 60%). 1 1H NMR (500 MHz, CDCl 3 ) δ = 4.23 (td, J = 7.0, 2.3 Hz, 2H), 3.96 (d, J = 5.7 Hz, 2H), 3.83 (q, J = 6.2 Hz, 1H), 3.60 (dq, J = 18.2, 6.7 Hz, 2H), 2.81 (t, J = 7.0 Hz, 2H), 2.63 (d, J = 5.9 Hz, 2H), 2.54 (dq, J = 12.5, 6.3 Hz, 2H), 2.50 - 2.36 (m, 4H), 2.35 - 2.26 (m, 3H), 1.62 (ddq, J = 21.7, 15.0, 7.1 Hz, 10H), 1.53 - 1.46 (m, 2H), 1.42 (q, J = 6.6 Hz, 2H), 1.25 (m, J = 5.6 Hz, 47H), 0.87 (td, J = 6.9, 3.8 Hz, 12H).

[1014] Example 28

[1015] Synthesis of Compound 249

[1016]

[1017] (±)-Epichlorohydrin (2.04 g, 22 mmol) and 2-mercaptoethanol 1 (1.56 g, 20 mmol) were stirred in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 10 mL) at 60 °C overnight. The reaction mixture was cooled to room temperature, and NaOH (880 mg, 22 mmol) dissolved in 25 mL of H 2 O was slowly added. The reaction mixture was stirred at room temperature for 2 h and then extracted with DCM (50 mL × 3). The combined DCM layers were dried over anhydrous Na 2 SO4干燥 , DCM was removed under reduced pressure to obtain the crude product, which was a colorless oil (1.82 g, 70%). The crude 2-(((oxiran-2-yl)methyl)thio)ethanol can be used without further purification.

[1018] 2-Hexyldecanoic acid (2.58 g, 10 mmol), EDC·HCl (2.30 g, 12 mmol) and DMAP (1.46 g, 12 mmol) were stirred in anhydrous DCM at room temperature for 20 minutes. 2-(((oxiran-2-yl)methyl)thio)ethanol (1.34 g, 10 mmol) was added to the resulting mixture and stirred for 24 hours. DCM was removed under reduced pressure. The residue was resuspended in 150 mL of hexane. The suspension was washed with H 2 O (50 mL×2), brine (50 mL×2) and acetonitrile (50 mL×2). The hexane layer was separated and dried over anhydrous Na 2 SO 4干燥 and evaporated under reduced pressure to obtain the product as a colorless oil (2.32 g, 62%). The crude 2-((oxiran-2-ylmethyl)thio)ethyl 2-hexyldecanoate can be used without further purification.

[1019] 2-Hexyl-1-decanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for another 3 hours. The solvent was removed under reduced pressure and hexane (150 mL) was added to the residue. After washing with water (50 mL×2) and acetonitrile (50 mL×2), the hexane layer was dried over anhydrous Na 2 SO 4 The hexane layer was dried, and hexane was removed under reduced pressure to obtain 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[1020] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-pyrrolidinoethylamine (4.56 g, 40 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL×2), brine (50 mL×2), and dried over anhydrous Na 2 SO 4 The mixture was filtered and the solvent was removed by distillation under reduced pressure to obtain 2-hexyldecyl 6-(2-pyrrolidinoethyl)aminohexanoate as a colorless oil (1.22 g, 67%).

[1021] Dissolve 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate (74 mg, 0.2 mmol) and 2-hexyldecyl 6-(2-pyrrolidinoethyl)aminohexanoate (90 mg, 0.2 mmol) in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 2 mL), heat to 90 °C, and stir for 24 h. Remove the solvent under reduced pressure to obtain a crude product as a colorless oil.

[1022] Example 29

[1023] Synthesis of Compound 250

[1024]

[1025] Stir (±)-epichlorohydrin (2.04 g, 22 mmol) and 2-mercaptoethanol (1.56 g, 20 mmol) in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 10 mL) at 60 °C overnight. Cool the reaction mixture to room temperature and slowly add NaOH (880 mg, 22 mmol) dissolved in 25 mL H 2 O. Stir the reaction mixture at room temperature for 2 h, then extract with DCM (50 mL × 3). Combine the DCM layers, dry over anhydrous Na 2 SO 4 and remove DCM under reduced pressure to obtain a crude product as a colorless oil (1.82 g, 70%). The crude 2-[(oxiran-2-yl)methyl]thioethanol can be used without further purification.

[1026] Stir 2-hexyldecanoic acid (2.58 g, 10 mmol), EDC·HCl (2.30 g, 12 mmol), and DMAP (1.46 g, 12 mmol) in anhydrous DCM at room temperature for 20 min. Add 2-[(oxiran-2-yl)methylthio]ethanol (1.34 g, 10 mmol) to the resulting mixture and stir for 24 h. Distill off DCM under reduced pressure. Resuspend the residue in 150 mL of hexane. Wash the suspension with H 2 O (50 mL × 2), brine (50 mL × 2), and acetonitrile (50 mL × 2). Separate the hexane layer, dry over anhydrous Na 2 SO 4 and evaporate under reduced pressure to obtain a colorless oil product (2.32 g, 62%). The crude 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate can be used without further purification.

[1027] 2-Hexyl-1-decanoic acid (3.84 g, 15 mmol), EDC·HCl (3.74 g, 19.5 mmol), and DMAP (2.38 g, 19.5 mmol) were stirred in anhydrous DCM at room temperature for 20 minutes. 6-Bromo-1-hexanol (2.72 g, 15 mmol) was added to the resulting mixture and stirred for 24 hours. DCM was removed under reduced pressure. The residue was resuspended in 150 mL of hexane. The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and acetonitrile (50 mL). The hexane layer was separated, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane solution of 3% ethyl acetate) to give 6-bromohexyl 2-hexyl decanoate as a colorless oil (2.58 g, 41%).

[1028] 6-Bromohexyl 2-hexyl decanoate (2.09 g, 5 mmol) and 2-pyrrolidinoethylamine (5.70 g, 50 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 hours. The solvent was removed by distillation under reduced pressure, and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL × 2), brine (50 mL × 2), and dried over anhydrous Na 2 SO 4 The mixture was filtered, and the solvent was removed by distillation under reduced pressure to give 6-[(2-pyrrolidinoethyl)amino]hexyl 2-hexyl decanoate as a colorless oil (1.61 g, 71%).

[1029] 2-[(Oxiran-2-yl)methylthio]ethyl 2-hexyl decanoate (74 mg, 0.2 mmol) and 6-[(2-pyrrolidinoethyl)amino]hexyl 2-hexyl decanoate (90 mg, 0.2 mmol) were heated to 90 °C in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 2 mL) and stirred for 24 hours. The solvent was removed by distillation under reduced pressure to give a crude product as a colorless oil.

[1030] Example 30

[1031] Synthesis of Compound 251

[1032]

[1033] (±)-Epichlorohydrin (2.04 g, 22 mmol) and 2-mercaptoethanol (1.56 g, 20 mmol) were stirred in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 10 mL) at 60 °C overnight. The reaction mixture was cooled to room temperature, and a solution of... in 25 mL of H2 880 mg (22 mmol) of NaOH in O. The reaction mixture was stirred at room temperature for 2 h and then extracted with DCM (50 mL×3). The DCM layers were combined and dried over anhydrous Na 2 SO 4 and concentrated in vacuo to remove DCM to give the crude product as a colorless oil (1.82 g, 70%). The crude 2-[(oxiran-2-yl)methyl]thioethanol was used without further purification.

[1034] 2-Hexyldecanoic acid (2.58 g, 10 mmol), EDC·HCl (2.30 g, 12 mmol) and DMAP (1.46 g, 12 mmol) were stirred in anhydrous DCM at room temperature for 20 min. 2-[(Oxiran-2-yl)methyl]thioethanol (1.34 g, 10 mmol) was added to the resulting mixture and stirred for 24 h. DCM was removed in vacuo. The residue was resuspended in 150 mL of hexane. The suspension was washed with H 2 O (50 mL×2), brine (50 mL×2) and acetonitrile (50 mL×2). The hexane layer was separated and dried over anhydrous Na 2 SO 4 and evaporated in vacuo to give the product as a colorless oil (2.32 g, 62%). The crude 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate was used without further purification.

[1035] 2-Hexyl-1-decanol (4.84 g, 20 mmol) and TEA (2.42 g, 24 mmol) were mixed in anhydrous DCM (20 mL) and cooled to 0 °C. 6-Bromohexanoyl chloride (4.39 g, 2.06 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 3 h. The solvent was removed in vacuo and hexane (150 mL) was added to the residue. After washing with water (50 mL×2) and acetonitrile (50 mL×2), the hexane layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 2-hexyldecyl 6-bromohexanoate as a colorless liquid (4.7 g, 56%).

[1036] 2-Hexyldecyl 6-bromohexanoate (1.68 g, 4 mmol) and 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (4.22 g, 32 mmol) were dissolved in ethanol (8 mL) and stirred at 60 °C for 16 h. The solvent was removed by distillation in vacuo and the residue was resuspended in ethyl acetate (100 mL). The suspension was washed with water (50 mL×2), brine (50 mL×2) and dried over anhydrous Na 2 SO4 Dry. Filter the mixture and remove the solvent under reduced pressure to obtain 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate as a colorless oil (1.18 g, 63%).

[1037] Dissolve 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate (74 mg, 0.2 mmol) and 2-hexyldecyl 6-[(2-hydroxyethyl)(ethyl)aminoethyl]aminohexanoate (94 mg, 0.2 mmol) in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 2 mL), heat to 90 °C, and stir for 24 hours. Distill off the solvent under reduced pressure to obtain a crude product as a colorless oil.

[1038] Example 31

[1039] Synthesis of Compound 253

[1040]

[1041] Stir (±)-epichlorohydrin (2.04 g, 22 mmol) and 2-mercaptoethanol (1.56 g, 20 mmol) in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 10 mL) at 60 °C overnight. Cool the reaction mixture to room temperature and slowly add NaOH (880 mg, 22 mmol) dissolved in 25 mL H 2 O. Stir the reaction mixture at room temperature for 2 hours, then extract with DCM (50 mL × 3). Combine the DCM layers, dry over anhydrous Na 2 SO 4 and remove DCM under reduced pressure to obtain a crude product as a colorless oil (1.82 g, 70%). The crude 2-[(oxiran-2-yl)methylthio]ethanol can be used without further purification.

[1042] Stir 2-hexyldecanoic acid (2.58 g, 10 mmol), EDC·HCl (2.30 g, 12 mmol), and DMAP (1.46 g, 12 mmol) in anhydrous DCM at room temperature for 20 minutes. Add 2-[(oxiran-2-yl)methylthio]ethanol (1.34 g, 10 mmol) to the resulting mixture and stir for 24 hours. Remove DCM under reduced pressure. Resuspend the residue in 150 mL of hexane. Wash the suspension with H 2 O (50 mL × 2), brine (50 mL × 2), and acetonitrile (50 mL × 2). Separate the hexane layer and dry over anhydrous Na 2 SO 4Dry and evaporate under reduced pressure to obtain a colorless oily product (2.32 g, 62%). The crude 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate can be used without further purification.

[1043] Dissolve 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate (75 mg, 0.2 mmol) and 6-[(4-hydroxybutyl)amino]hexyl 2-hexyldecanoate (86 mg, 0.2 mmol) in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 1 mL), heat to 90 °C and stir for 24 h. Remove the solvent under reduced pressure, and purify the residue by silica gel chromatography (5% MeOH in DCM containing 0.1% ammonia) to obtain a light brown oily product (205 mg, 51%). 1 H NMR (500 MHz, CDCl 3 ) δ 4.23 (td, J = 7.0, 2.6 Hz, 2H), 4.14 - 4.08 (m, 1H), 4.05 (t, J = 6.7 Hz, 2H), 3.82 (q, J = 6.1 Hz, 1H), 3.61 (td, J = 11.4, 5.0 Hz, 2H), 2.81 (td, J = 6.8, 1.5 Hz, 2H), 2.68 - 2.59 (m, 2H), 2.59 - 2.50 (m, 2H), 2.50 - 2.35 (m, 4H), 2.30 (tt, J = 9.4, 5.3 Hz, 2H), 1.68 - 1.51 (m, 10H), 1.52 - 1.38 (m, 6H), 1.35 (q, J = 7.1 Hz, 3H), 1.32 - 1.15 (m, 42H), 0.86 (t, J = 6.7 Hz, 12H).

[1044] Example 32

[1045] Synthesis of Compound 254

[1046]

[1047] Stir (±)-epichlorohydrin (2.04 g, 22 mmol) and 2-mercaptoethanol (1.56 g, 20 mmol) in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 10 mL) at 60 °C overnight. Cool the reaction mixture to room temperature, and slowly add NaOH (880 mg, 22 mmol) dissolved in 25 mL H 2 O. Stir the reaction mixture at room temperature for 2 h, then extract with DCM (50 mL × 3). Combine the DCM layers, and dry over anhydrous Na 2 SO 4Dry it, and remove DCM under reduced pressure to obtain the crude product, which is a colorless oil (1.82 g, 70%). The crude 2-[(oxiran-2-yl)methylthio]ethanol can be used without further purification.

[1048] Stir 2-hexyldecanoic acid (2.58 g, 10 mmol), EDC·HCl (2.30 g, 12 mmol) and DMAP (1.46 g, 12 mmol) in anhydrous DCM at room temperature for 20 minutes. Add 2-[(oxiran-2-yl)methylthio]ethanol (1.34 g, 10 mmol) to the resulting mixture and stir for 24 hours. Remove DCM under reduced pressure. Resuspend the residue in 150 mL of hexane. Wash the suspension with H 2 O (50 mL × 2), brine (50 mL × 2) and acetonitrile (50 mL × 2). Separate the hexane layer, and dry it with anhydrous Na 2 SO 4 and evaporate it under reduced pressure to obtain a colorless oily product (2.32 g, 62%). The crude 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate can be used without further purification.

[1049] Dissolve 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate (75 mg, 0.2 mmol) and 2-hexyldecyl 6-(2-hydroxyethyl)aminohexanoate (80 mg, 0.2 mmol) in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 1 mL), heat to 90 °C and stir for 24 hours. Distill off the solvent under reduced pressure, and purify the residue by silica gel chromatography (5% MeOH in DCM containing 0.1% ammonia water) to obtain a light brown oily product (189 mg, 48%). 1 1H NMR (500 MHz, CDCl 3 ) δ 4.28 - 4.18 (m, 2H), 3.96 (dd, J = 5.8, 1.4 Hz, 2H), 3.81 (q, J = 6.0 Hz, 1H), 3.74 (td, J = 5.7, 1.6 Hz, 2H), 3.39 - 3.10 (m, 1H), 2.80 (td, J = 6.9, 1.5 Hz, 2H), 2.76 - 2.65 (m, 2H), 2.63 - 2.55 (m, 2H), 2.55 - 2.38 (m, 3H), 2.37 - 2.24 (m, 3H), 1.65 (dddq, J = 35.3, 20.3, 14.3, 7.3 Hz, 7H), 1.53 - 1.36 (m, 4H), 1.26 (dd, J = 10.9, 5.2 Hz, 48H), 0.93 - 0.80 (m, 12H).

[1050] Example 33

[1051] Synthesis of Compound 255

[1052]

[1053] (±)-Epichlorohydrin (2.04 g, 22 mmol) and 2-mercaptoethanol (1.56 g, 20 mmol) were stirred overnight at 60 °C in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 10 mL). The reaction mixture was cooled to room temperature, and NaOH (880 mg, 22 mmol) dissolved in 25 mL of H 2 O was added slowly. The reaction mixture was stirred at room temperature for 2 h and then extracted with DCM (50 mL × 3). The DCM layers were combined, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give the crude product as a colorless oil (1.82 g, 70%). The crude 2-[(oxiran-2-yl)methylthio]ethanol was used without further purification.

[1054] 2-Hexyldecanoic acid (2.58 g, 10 mmol), EDC·HCl (2.30 g, 12 mmol), and DMAP (1.46 g, 12 mmol) were stirred in anhydrous DCM at room temperature for 20 min. 2-[(Oxiran-2-yl)methylthio]ethanol (1.34 g, 10 mmol) was added to the resulting mixture and stirred for 24 h. DCM was removed by distillation under reduced pressure. The residue was resuspended in 150 mL of hexane. The suspension was washed with H 2 O (50 mL × 2), brine (50 mL × 2), and acetonitrile (50 mL × 2). The hexane layer was separated, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give the product as a colorless oil (2.32 g, 62%). The crude 2-[(oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate was used without further purification.

[1055] 2-[(Oxiran-2-yl)methylthio]ethyl 2-hexyldecanoate (75 mg, 0.2 mmol) and 2-hexyldecyl 6-(3-hydroxypropyl)aminohexanoate (82 mg, 0.2 mmol) were dissolved in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 1 mL), heated to 90 °C, and stirred for 24 h. The solvent was removed by distillation under reduced pressure to give the crude product as a colorless oil.

[1056] Example 34

[1057] Synthesis of Compound 256

[1058]

[1059] 2-Hexyldecanoic acid (5.12 g, 20 mmol), EDC·HCl (4.97 g, 26 mmol) and DMAP (3.17 g, 26 mmol) were stirred in anhydrous DCM at room temperature for 20 min. 5-Hexen-1-ol (2.0 g, 20 mmol) was added to the resulting mixture and stirred for 24 h. DCM was removed under reduced pressure. The residue was resuspended in 150 mL of hexane. The suspension was washed with water (50 mL×2), brine (50 mL×2) and acetonitrile (20 mL×2). The hexane layer was separated, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give hex-5-en-1-yl 2-hexyldecanoate as a colorless oil (4.21 g, 62%). The product was used without further purification.

[1060] mCPBA (2.51 g, 11 mmol) was added to a solution of hex-5-en-1-yl 2-hexyldecanoate (10 mmol) in anhydrous DCM. The resulting mixture was stirred at room temperature overnight. DCM was removed by distillation under reduced pressure. 100 mL of hexane was added to the residue, and the mixture was washed with saturated Na 2 S 2 O 3 , saturated Na 2 CO 3 , brine, and dried over anhydrous Na 2 SO 4 . The solvent was removed by distillation under reduced pressure to give 4-(oxiran-2-yl)butyl 2-hexyldecanoate as a colorless oil (2.12 g, 59%). The crude product was used without further purification.

[1061] 4-(Oxiran-2-yl)butyl 2-hexyldecanoate (71 mg, 0.2 mmol) and 2-hexyldecyl 6-(4-hydroxybutyl)aminohexanoate (86 mg, 0.2 mmol) were dissolved in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 1 mL), heated to 90 °C and stirred for 24 h. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography (5% MeOH in DCM containing 0.1% ammonia) to give the product as a light brown oil (175 mg, 44%). 1 1H NMR (500 MHz, CDCl 3) δ 4.06 (q, J = 6.0 Hz, 2H), 3.95 (d, J = 5.7 Hz, 2H), 3.73 - 3.53 (m, 3H), 2.56 (dd, J = 17.0, 11.6 Hz, 2H), 2.47–2.33 (m, 3H), 2.29 (t, J = 7.4 Hz, 3H), 1.60 (dh, J = 30.9, 7.6 Hz, 13H), 1.51–1.33 (m, 7H), 1.26 (dd, J = 11.8, 6.5 Hz, 48H), 0.86 (dtd, J = 7.1, 4.2, 2.0 Hz, 12H).

[1062] Example 35

[1063] Synthesis of Compound 257

[1064]

[1065] 2-Hexyldecanoic acid (5.12 g, 20 mmol), EDC·HCl (4.97 g, 26 mmol) and DMAP (3.17 g, 26 mmol) were stirred in anhydrous DCM at room temperature for 20 minutes. 5-Hexen-1-ol (2.0 g, 20 mmol) was added to the resulting mixture and stirred for 24 hours. DCM was removed under reduced pressure. The residue was resuspended in 150 mL of hexane. The suspension was washed with water (50 mL × 2), brine (50 mL × 2) and acetonitrile (20 mL × 2). The hexane layer was separated, dried over anhydrous Na 2 SO 4 and evaporated to dryness under reduced pressure to give hex-5-en-1-yl 2-hexyldecanoate as a colorless oil (4.21 g, 62%). The product was used without further purification.

[1066] mCPBA (2.51 g, 11 mmol) was added to a solution of hex-5-en-1-yl 2-hexyldecanoate (10 mmol) in anhydrous DCM. The resulting mixture was stirred overnight at room temperature. DCM was removed under reduced pressure. 100 mL of hexane was added to the residue, and the mixture was washed with saturated Na 2 S 2 O 3 , saturated Na 2 CO 3 , brine, and dried over anhydrous Na 2 SO 4 . The solvent was removed by distillation under reduced pressure to give 4-(oxiran-2-yl)butyl 2-hexyldecanoate as a colorless oil (2.12 g, 59%). The crude product was used without further purification.

[1067] 4-(oxiran-2-yl)butyl 2-hexyldecanoate (71 mg, 0.2 mmol) and 6-(4-hydroxybutyl)aminohexyl 2-hexyldecanoate (85.5 g, 0.2 mmol) were dissolved in a mixture of 1,4-dioxane and H 2 O (v:v, 1:1, 1 mL), heated to 90 °C, and stirred for 24 hours. The solvent was removed by distillation under reduced pressure to give a light brown oily product.

[1068] Example 36

[1069] Synthesis of Compound 297

[1070]

[1071] Boc-L-aspartic acid (4.60 g, 20 mmol), EDC·HCl (9.2 g, 48 mmol), and DMAP (5.91 g, 48 mmol) were dissolved in anhydrous DCM (50 mL), stirred at room temperature for 20 minutes, 2-octyldodecan-1-ol (11.90 g, 40 mmol) was added, and the mixture was stirred at room temperature for 48 hours. DCM was removed, and the residue was resuspended in H 2 O (100 mL), extracted with hexane (50 mL × 3), and the combined hexane layers were washed with acetonitrile (50 mL × 2) and brine (50 mL × 2), and dried over Na 2 SO 4 . The mixture was filtered, and the solvent was removed by distillation under reduced pressure to obtain (2S)-bis(2-octyldodecyl)-2-[(tert-butoxycarbonyl)amino]succinate as a pale yellow oil (10.2 g, 64%).

[1072] (2S)-Bis(2-octyldodecyl)-2-[(tert-butoxycarbonyl)amino]succinate (10.2 g, 12.8 mmol) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (v:v, 1:1, 20 mL), and stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 11 with 20% NaOH solution (monitored using pH test paper). 50 mL of saturated NaHCO 3 was added to the mixture, and then it was extracted with dichloromethane (50 mL × 4). The combined dichloromethane layers were washed with water (50 mL × 2) and brine (50 mL × 2), and dried over Na 2 SO 4 . The mixture was filtered, and the solvent was removed by distillation under reduced pressure to give (2S)-bis(2-octyldodecyl) 2-[(tert-butoxycarbonyl)amino]succinate as a pale yellow oil (8.2 g, 92%).

[1073] (2S)-Bis(2-octyldodecyl) 2-[(tert-butoxycarbonyl)amino]succinate (3.47 g, 5 mmol) and triethylamine (0.697 g, 6 mmol) were dissolved in anhydrous DCM (30 mL) and cooled to 0 °C. Acryloyl chloride (0.542 g, 6 mmol) was slowly added to the resulting mixture. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 3 hours. DCM was evaporated by distillation under reduced pressure and the residue was dissolved in hexane (150 mL). The hexane suspension was washed with H 2 O (50 mL × 2), brine (50 mL × 2) and acetonitrile (20 mL × 2). The hexane layer was separated, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure to give (2S)-bis(2-octyldodecyl)-2-acrylamidosuccinate as a light brown oil (2.45 g, 65%)

[1074] (2S)-Bis(2-octyldodecyl)-2-acrylamidosuccinate (0.745 mg, 1 mmol) and 2-(pyrrolidin-1-yl)ethylamine (0.114 g, 1 mmol) were dissolved in a mixture of isopropanol (2 mL) and reacted at 65 °C for 24 hours. The solvent was removed to give a colorless oily product (421 mg, 49%).

[1075] Example 37

[1076] Synthesis of Compound 341

[1077]

[1078] 4.8 g of 2-hexyldecan-1-ol (2 equivalents) and 3.9 g of diisopropylethylamine (3 equivalents) were mixed with 20 mL of anhydrous DCM in a 100 mL round-bottom flask. The mixture was cooled to ~0 °C using an ice bath. Then, 1.8 g of fumaryl chloride (1.2 equivalents) was added dropwise to the reaction mixture with vigorous stirring. After adding fumaryl chloride, the ice bath was removed and the temperature was allowed to rise to room temperature. The mixture was stirred at room temperature overnight. When the starting material was consumed, the end point of the reaction was confirmed by TLC. The reaction mixture was diluted with 60 mL of ethyl acetate and then washed three times with 1 M aqueous HCl, deionized water, and saturated NaCl solution. Then, the organic layer was separated and dried by distillation under reduced pressure. The residue was purified by silica gel column chromatography using hexane to give bis(2-hexyldecyl) fumarate (yield 85%, 4.8 g).

[1079] 2.0 g of bis(2-hexyldecyl) fumarate (1 equivalent) and 690 mg of 3-(diethylamino)propylamine (1.5 equivalents) were mixed with 4.5 mL of IPA (isopropanol) and 1.5 mL of HFIPA (hexafluoro-2-propanol) in a 25 mL round-bottom flask. The mixture was heated to 50 °C in an oil bath for about 6 hours. The reaction was monitored by TLC and terminated when the starting materials were consumed. The solvent was then removed by distillation under reduced pressure to give a yellow oily residue as the crude product. The crude product was purified by silica gel column chromatography with a mobile phase consisting of 0% to 33% ethyl acetate / hexane. The product obtained was a pale yellow oil (yield 40%, 980 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 3.99 (ddd, J = 27.6, 6.2, 2.9 Hz, 4H), 3.60 (dt, J = 6.5, 3.8 Hz, 1H), 2.74 - 2.57 (m, 3H), 2.48 (ddtd, J = 21.7, 17.8, 9.1, 4.7 Hz, 7H), 1.90 (s, 1H), 1.59 (pent, J = 7.6 Hz, 4H), 1.25 (d, J = 7.3 Hz, 48H), 0.99 (ddd, J = 8.3, 6.8, 2.4 Hz, 6H), 0.87 (td, J = 7.2, 2.5 Hz, 12H).

[1080] Example 38

[1081] Synthesis of Compound 347

[1082]

[1083] 4.8 g of 2-hexyldecan-1-ol (2 equivalents) and 3.9 g of diisopropylethylamine (3 equivalents) were mixed with 20 mL of anhydrous DCM in a 100 mL round-bottom flask. The mixture was cooled to ~0 °C in an ice bath. Then, 1.8 g of fumaryl chloride (1.2 equivalents) was added dropwise to the reaction mixture with vigorous stirring. After the addition of fumaryl chloride, the ice bath was removed and the temperature was allowed to rise to room temperature. The mixture was stirred overnight at room temperature. When the starting materials were consumed, the end point of the reaction was confirmed by TLC. The reaction mixture was diluted with 60 mL of ethyl acetate and then washed three times with 1 M aqueous HCl, deionized water, and saturated NaCl solution. The organic layer was then separated and dried by distillation under reduced pressure. The residue was purified by silica gel column chromatography with hexane to give bis(2-hexyldecyl) fumarate (yield 85%, 4.8 mg).

[1084] 1.7 g of bis(2-hexyldecyl) fumarate (1 equivalent) and 1.0 g of N,N,N′-trimethyl-1,3-propanediamine (3 equivalents) were mixed with 5 mL of IPA (isopropanol) in a 25 mL round-bottom flask. The mixture was heated to 60 °C in an oil bath for about 20 h. The reaction was monitored by TLC and terminated when the starting materials were consumed. The solvent was then removed by distillation under reduced pressure to give a yellow oily residue as the crude product. The crude product was purified by silica gel column chromatography with a mobile phase consisting of hexane from 0% to 33% ethyl acetate. The purified product was a pale yellow oil (30% yield, 610 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 4.06 - 3.92 (m, 4H), 3.80 (t, J = 7.6 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.62 - 2.54 (m, 2H), 2.49 (dt, J = 12.4, 6.8 Hz, 1H), 2.29 (d, J = 2.5 Hz, 3H), 2.24 (t, J = 7.7 Hz, 2H), 2.21 (d, J = 2.3 Hz, 6H), 1.60 (q, J = 7.8 Hz, 4H), 1.27 (d, J = 11.2 Hz, 48H), 0.87 (ddd, J = 7.5, 4.8, 2.0 Hz, 12H).

[1085] Example 39

[1086] Synthesis of Compound 348

[1087]

[1088] 6.0 g of 2-octyldodecan-1-ol (2 equivalents) and 3.9 g of diisopropylethylamine (3 equivalents) were mixed with 20 mL of anhydrous DCM in a 100 mL round-bottom flask. The mixture was cooled to ~0 °C in an ice bath. Then, 1.8 g of fumaryl chloride (1.2 equivalents) was added dropwise to the reaction mixture with vigorous stirring. After the addition of fumaryl chloride, the ice bath was removed and the temperature was allowed to rise to room temperature. The mixture was stirred overnight at room temperature. The end point of the reaction was confirmed by TLC when 2-octyldodecan-1-ol was consumed. The reaction mixture was diluted with 60 mL of ethyl acetate and then washed three times with 1 M aqueous HCl, deionized water, and saturated NaCl solution. The organic layer was then separated and dried by distillation under reduced pressure. The residue was purified by silica gel column chromatography with hexane (85% yield, 5.8 g).

[1089] 2.0 g of bis(2-octyldodecyl) fumarate (1 equivalent) and 1.0 g of N,N,N′-trimethyl-1,3-propanediamine (3 equivalents) were mixed with 5 mL of IPA (isopropanol) in a 25 mL round-bottom flask. The mixture was heated to 60 °C in an oil bath for about 20 h. The reaction was monitored by TLC and terminated when the starting materials were exhausted. The solvent was then removed by distillation under reduced pressure to give a yellow oily residue as the crude product. The crude product was purified by silica gel column chromatography with a mobile phase of 0% to 33% ethyl acetate / hexane. The product was a pale yellow oil (yield 30%, 700 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 3.99 (dddd, J = 22.8, 20.8, 10.9, 5.7 Hz, 4H), 3.80 (t, J = 7.5 Hz, 1H), 2.82 (dd, J = 15.9, 8.1 Hz, 1H), 2.62 - 2.53 (m, 2H), 2.49 (ddd, J = 12.4, 7.9, 6.1 Hz, 1H), 2.29 (s, 3H), 2.22 (d, J = 19.1 Hz, 8H), 1.67 - 1.55 (m, J = 6.6 Hz, 4H), 1.25 (s, 64H), 0.88 (t, J = 6.9 Hz, 12H).

[1090] Example 40

[1091] Synthesis of Compound 350

[1092]

[1093] 6.0 g of 2-octyl-1-dodecanol (2 equivalents) and 3.9 g of diisopropylethylamine (3 equivalents) were mixed with 20 mL of anhydrous DCM in a 100 mL round-bottom flask. The mixture was cooled to ~0 °C in an ice bath. Then, 1.8 g of fumaryl chloride (1.2 equivalents) was added dropwise to the reaction mixture with vigorous stirring. After the addition of fumaryl chloride, the ice bath was removed and the temperature was allowed to rise to room temperature. The mixture was stirred overnight at room temperature. When 2-octyl-1-dodecanol was consumed, the reaction endpoint was confirmed by TLC. The reaction mixture was diluted with 60 mL of ethyl acetate and then washed three times with 1 M aqueous HCl, deionized water, and saturated NaCl solution. The organic layer was then separated and dried by distillation under reduced pressure. The residue was purified by silica gel column chromatography with hexane (85% yield, 5.8 g).

[1094] 2.0 g of bis(2-octyldodecyl) fumarate (1 equivalent) and 1.5 g of N1,N3-dimethyl-N1-[3-(methylamino)propyl]propane-1,3-diamine (3 equivalents) were mixed with 5 mL of IPA (isopropyl alcohol) in a 25 mL round-bottom flask. The mixture was heated to 60 °C using an oil bath for about 20 h. The reaction was monitored by TLC and terminated when the starting materials were consumed. The solvent was then removed by distillation under reduced pressure to give a yellow oily residue as the crude product. The crude product was purified by silica gel column chromatography with a mobile phase of 0% to 33% ethyl acetate / hexane. The product collected was a pale yellow oil (yield 30%, 770 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 3.99 (ddt, J = 16.3, 11.0, 5.6 Hz, 4H), 3.88 (dd, J = 8.0, 6.7 Hz), 1H 2.82 (dd, J = 16.1, 8.0 Hz, 1H), 2.61 - 2.48 (m, 5H), 2.19 (s, 15H), 1.57 (dddd, J = 27.7, 13.8, 8.8, 5.0 Hz, 7H), 1.26 (d, J = 6.7 Hz, 64H), 0.87 (t, J = 6.8 Hz, 12H).

[1095] Example 41

[1096] Synthesis of Compound 354

[1097]

[1098] 4.8 g of 2-hexyldecan-1-ol (2 equivalents) and 3.9 g of diisopropylethylamine (3 equivalents) were mixed with 20 mL of anhydrous DCM in a 100 mL round-bottom flask. The mixture was cooled to ~0 °C using an ice bath. Then, 1.8 g of fumaryl chloride (1.2 equivalents) was added dropwise to the reaction mixture with vigorous stirring. After the addition of fumaryl chloride, the ice bath was removed and the temperature was allowed to rise to room temperature. The mixture was stirred overnight at room temperature. When the starting materials were consumed, the reaction endpoint was confirmed by TLC. The reaction mixture was diluted with 60 mL of ethyl acetate and then washed three times with 1 M aqueous HCl, deionized water, and saturated NaCl solution. The organic layer was then separated and dried by distillation under reduced pressure. The residue was purified by silica gel column chromatography with hexane to give bis(2-hexyldecyl) fumarate (yield 85%, 4.8 g).

[1099] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added with stirring to a solution of 2-(2-aminoethylamino)ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL). After stirring for 3 hours, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined and dried over anhydrous Na 2 SO 4 . The solvent was removed by distillation under reduced pressure to obtain a crude pale yellow oil. 10% NaOH solution (20 mL) was added to the above crude oil. The resulting solution was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with DCM (30 mL × 6). The DCM layers were combined, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4 . The organic solvent was removed by distillation under reduced pressure to obtain 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g).

[1100] 1.8 g of bis(2-hexyldecyl) fumarate (1 equivalent) and 650 mg of 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (1.5 equivalents) were mixed with 4.5 mL of IPA (isopropanol) and 1.5 mL of HFIPA (hexafluoro-2-propanol) in a 25 mL round-bottom flask. The mixture was heated to 50 °C in an oil bath for about 6 hours. The reaction was monitored by TLC and ended when the starting materials were consumed. Then the solvent was removed by distillation under reduced pressure to obtain a yellow oily residue as the crude product. The crude product was purified by silica gel column chromatography, and the mobile phase consisted of 0% to 33% ethyl acetate / hexane. The product collected was a pale yellow oil (yield 35%, 780 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 4.01 (dd, J = 27.6, 5.8 Hz, 4H), 3.64 (dd, J = 7.1, 5.8 Hz, 1H), 3.54 (t, J = 5.2 Hz, 2H), 2.81 - 2.50 (m, 11H), 1.61 (dd, J = 13.9, 6.9 Hz, 2H), 1.26 (d, J = 6.3 Hz, 49H), 1.01 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 6.8 Hz, 12H).

[1101] Example 42

[1102] Synthesis of Compound 355

[1103]

[1104] 6.0 g of 2-octyl-1-dodecanol (2 equivalents) and 3.9 g of diisopropylethylamine (3 equivalents) were mixed with 20 mL of anhydrous DCM in a 100 mL round-bottom flask. The mixture was cooled to ~0 °C using an ice bath. Then, 1.8 g of fumaryl chloride (1.2 equivalents) was added dropwise to the reaction mixture with vigorous stirring. After the addition of fumaryl chloride, the ice bath was removed and the temperature was allowed to rise to room temperature. The mixture was stirred overnight at room temperature. When the 2-octyl-1-dodecanol was consumed, the reaction endpoint was confirmed by TLC. The reaction mixture was diluted with 60 mL of ethyl acetate and then washed three times with 1 M aqueous HCl, deionized water, and saturated NaCl solution. Then, the organic layer was separated and dried by distillation under reduced pressure. The residue was purified by silica gel column chromatography using hexane (yield 85%, 5.8 g).

[1105] At 0 °C, trifluoroacetate (7.1 g, 60 mmol) was slowly added dropwise to a solution of 2-(2-aminoethylamino)ethanol (6.2 g, 60 mmol) in acetonitrile (30 mL) with stirring. After stirring for 3 hours, iodoethane (9.4 g, 60 mmol) and DIEA (8.5 g, 66 mmol) were added. The reaction mixture was heated to 40 °C and stirred overnight. The solvent was removed by distillation under reduced pressure. H 2 O (100 mL) was added to the residue, and the aqueous solution was extracted with ethyl acetate (30 mL × 5). The organic layers were combined and dried over anhydrous Na 2 SO 4 The solvent was removed by distillation under reduced pressure to obtain a crude pale yellow oil. 10% NaOH solution (20 mL) was added to the above crude oil. The resulting solution was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and extracted with DCM (30 mL × 6). The DCM layers were combined, washed with brine (20 mL), and dried over anhydrous Na 2 SO 4 The organic solvent was removed by distillation under reduced pressure to obtain 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol as a colorless oil (2.4 g).

[1106] Mix 2.0 g of bis(2-octyldodecyl) fumarate (1 equivalent) and 650 mg of 2-[(2-aminoethyl)(ethyl)amino]ethan-1-ol (1.5 equivalents) with 4.5 mL of IPA (isopropyl alcohol) and 1.5 mL of HFIPA (hexafluoro-2-propanol) in a 25 mL round-bottom flask. Heat the mixture to 50 °C in an oil bath for about 6 hours. Monitor the reaction by TLC and end when the starting materials are consumed. Then remove the solvent by distillation under reduced pressure to obtain a yellow oily residue as the crude product. Purify the crude product by silica gel column chromatography with a mobile phase consisting of 0% to 33% ethyl acetate / hexane. The product collected is a pale yellow oil (yield 35%, 840 mg). 1 H NMR (500 MHz, CDCl 3 ) δ 4.01 (dd, J = 27.8, 5.8 Hz, 4H), 3.64 (dd, J = 7.0, 5.8 Hz, 1H), 3.55 (t, J = 5.1 Hz, 2H), 2.81 - 2.52 (m, 11H), 1.62 (s, 2H), 1.33 - 1.20 (m, 67H), 1.02 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 6.9 Hz, 12H).

[1107] Example 43

[1108] Synthesis of Compound 356

[1109]

[1110] Mix 7.1 g of 2-decyl-1-tetrad...

Claims

1. A compound of formula I: or an isomer thereof, or a salt thereof, wherein: R 1 and R 2 may be the same or different and each independently is an alkyl, alkenyl or alkynyl group; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic group; R 3 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms, or an alkynylene group having 2 to 18 carbon atoms, or together with the adjacent nitrogen atom forms a ring structure containing 3 to 18 carbon atoms; R 4 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms; R 5 and R 8 may be the same or different and each independently is a chemical bond, or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms, or an alkynylene group having 2 to 28 carbon atoms; R 6 and R 9 may be the same or different and each independently is a hydrogen atom or an alkyl group having 1 to 28 carbon atoms in a straight chain or an alkenyl group having 2 to 28 carbon atoms; R 7 and R 10 may be the same or different and each independently is a hydrogen atom or an alkyl group having 1 to 28 carbon atoms in a straight chain or an alkenyl group having 2 to 28 carbon atoms; X 1 is a chemical bond, -O-, -CO-, -OC-O- or -O-CO-; X 2 and X 4 may be the same or different and each independently is a methylene (-CH 2 -), -S-, -SS-, -O-, OCO-, -CO-O- or -NR-, where R is a lower alkyl; and X 3 and X 5 may be the same or different and each independently is methylene (-CH 2 -), -S-, -SS-, -O-, OCO-, -CO-O- or -NR-, where R is a lower alkyl, where the longest atomic chain in the compound is between 18 and 70 atoms.

2. The compound according to claim 1, or an isomer thereof, or a salt thereof, wherein R 1 and R 2 are each independently selected from methyl, ethyl and isopropyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic group; and R 3 is a straight-chain alkyl group containing at least 3 carbons.

3. The compound according to claim 1, or an isomer thereof, or a salt thereof, wherein: R 1 and R 2 each independently is methyl, ethyl, propyl, isopropyl, butyl or isobutyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic group; R 3 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms; R 4 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms; R 5 and R 8 may be the same or different and each independently is a chemical bond, an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms; R 6 and R 9 may be the same or different and each independently is a hydrogen atom, a straight-chain alkyl group having 1 to 14 carbon atoms or a straight-chain alkenyl group having 2 to 14 carbon atoms; R 7 and R 10 may be the same or different and each independently is a hydrogen atom, a straight-chain alkyl group having 1 to 14 carbon atoms or a straight-chain alkenyl group having 2 to 14 carbon atoms; X 1 is a chemical bond, -CO-, -OC-O- or -O-CO-; X 2 and X 4 may be the same or different and each independently is methylene (-CH 2 -), -O-, -OCO- or -CO-O-; and X 3 and X 5 may be the same or different and each independently is methylene (-CH 2 -), -O-, -OCO- or -CO-O-.

4. A compound of formula II: or an isomer thereof, or a salt thereof, wherein: R 1 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms; R 2 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms, an alkynylene group having 2 to 18 carbon atoms, a carbocyclic group having 3 to 8 carbon atoms, a heterocyclic group having 3 to 8 members, or a heteroalkylene group having 1 to 18 carbon atoms; R 3 and R 5 may be the same or different and each independently is a chemical bond or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms or an alkynylene group having 2 to 28 carbon atoms; R 4 、R 6 and R 7 may be the same or different and each independently is a hydrogen atom or an alkyl group having 1 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms, each optionally being substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -CO-OR, -CO-NR a R b , -NR a -CO-R, -O-CO-NR a R b , -NR a -CO-OR, -NR a R b and -S-CO-R, where R is independently a hydrogen atom or methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl each time it appears; R a and R b are independently a hydrogen atom or a lower alkyl group; X 1 is -OH, -SH, -N(R) 2 , a carbocyclic or heterocyclic group having 5 to 8 carbon atoms, a hydrogen atom or absent, wherein each occurrence of R is independently a lower alkyl group or a hydrogen atom; X 2 is -O-CO-, -CO-O-, -NR-CO- or -CO-NR-, where R is a lower alkyl group or a hydrogen atom; and X 3 、 X 4 and X 5 are each independently -O-CO-, -CO-O-, -NR-CO-, -CO-NR-, a chemical bond or absent, where R is a lower alkyl or a hydrogen atom, where the length of the longest atomic chain in the compound is between 18 and 70 atoms.

5. The compound according to claim 4, or an isomer thereof, or a salt thereof, wherein R 5 is a chemical bond; and R 6 is a hydrogen atom; and X 5 is absent.

6. The compound according to claim 4 or 5, or an isomer thereof, or a salt thereof, wherein X 2 is -O-CO- or -CO-O-.

7. A compound as claimed in any one of claims 4 to 6, or an isomer thereof, or a salt thereof, wherein R 7 is an alkenyl group having 18 carbon atoms in a straight chain.

8. A compound as claimed in any one of claims 4 to 7, or an isomer thereof, or a salt thereof, wherein R 1 and X 1 together are a 1,2-dihydroxypropane moiety, a pyrrolidinoethylamine moiety or a (2-hydroxyethyl)(ethyl)amino)ethylamine moiety.

9. The compound according to claim 4, or an isomer thereof, or a salt thereof, wherein R 7 is a 2-hexyldecyl hexanoate moiety; X 2 is -O-CO- or -CO-O-; and R 2 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl or ((2-hexyldecyl)thio)ethyl.

10. The compound according to claim 4, or an isomer thereof, or a salt thereof, wherein: R 1 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms; R 2 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms, an alkynylene group having 2 to 8 carbon atoms or a heteroalkylene group having 1 to 8 carbon atoms; R 3 and R 5 may be the same or different and each independently is a key or an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms; R 4 、R 6 and R 7 may be the same or different and each independently is hydrogen or an alkylene group having 1 to 14 carbon atoms, an alkenylene having 2 - 14 carbon atoms or an alkynylene having 2 - 14 carbon atoms; X 1 is -OH, -N(R) 2 , a carbocyclic group having 5 to 8 carbon atoms or hydrogen, where R is independently a lower alkyl group or a hydrogen atom each time it appears; X 2 is -O-CO- or -CO-O-; and X 3 , X 4 and X 5 are each independently a chemical bond, -OCO- or -CO-O-, where the length of the longest atomic chain in the compound is between 18 and 70 atoms.

11. A compound of formula III: or a salt thereof, or an isomer thereof, wherein: R 1 is an optionally substituted alkylene having 1 to 18 carbon atoms, an alkenylene having 2 to 18 carbon atoms or an alkynylene having 2 to 18 carbon atoms; R 2 and R 4 may be the same or different and each independently is a key or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms or an alkynylene group having 2 to 28 carbon atoms; R 3 and R 5 may be the same or different and each independently is hydrogen or an alkyl group having 1 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms; X 1 is -OH, -OR, -CO-OR, -CO-R, -O-CO-R, -SH, -SR, -N(R) 2 , a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group, a hydrogen atom or absent, wherein each occurrence of R is independently a hydrogen atom or an optionally substituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl; and X 2 and X 3 may be the same or different and each independently is -O-CO-, -CO-O-, -CO-, -NRCO-, -CO-NR-, a chemical bond or absent, where R is a lower alkyl group or a hydrogen atom, where the longest atomic chain in the compound is between 18 and 70 atoms.

12. The compound according to claim 11, or an isomer thereof, or a salt thereof, wherein X 2 and X 3 are independently -O-CO- or -CO-O-.

13. The compound according to claim 11 or 12, or an isomer thereof, or a salt thereof, wherein R 3 and R 5 is a straight-chain alkylene group having 10 carbon atoms.

14. The compound according to claim 11, or an isomer thereof, or a salt thereof, wherein: R 1 is an optionally substituted alkylene of 1 to 8 carbon atoms, alkenylene of 2 to 8 carbon atoms or alkynylene of 2 to 8 carbon atoms; R 2 and R 4 may be the same or different and each independently is a bond or an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms; R 3 and R 5 may be the same or different and each independently is hydrogen or an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms or an alkynyl group having 2 to 8 carbon atoms; X 1 is -OH, -CO-OR, -O-CO-R, a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group or a hydrogen atom, wherein R is independently a hydrogen atom or an optionally substituted methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl each time it appears; and X 2 and X 3 may be the same or different and each independently is -O-CO-, -CO-O-, -NR-CO-, -CO-NR- or a chemical bond, where R is a lower alkyl group or a hydrogen atom, where the longest atomic chain in the compound is between 18 and 70 atoms.

15. A compound of formula IV: or a salt thereof, or an isomer thereof, wherein: R 1 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -CO-OR, -CO-NR a R b , -NR a -CO-R, -O-CO-NR a R b , -NR a -CO-OR, -NR a R b and -S-CO-R, wherein R is independently hydrogen or a lower alkyl each time it appears; and R a and R b are independently a hydrogen atom or a lower alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R 2 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms; R 3 is an alkyl group having 1 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, an alkynyl group having 2 to 18 carbon atoms, a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group, a hydrogen atom or absent; R 4 、R 6 and R 8 may be the same or different and each independently is a bond or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms or an alkynylene group having 2 to 28 carbon atoms; R 5 、R 7 、R 9 may be the same or different and each independently is a key or an alkyl group having 2 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms; X 1 is methylene (-CH 2 -), -O-, -S-, -SS-, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or hydrogen), -O-CO-, -CO-O-, - CO-, -O-CO-O-, a carbocyclic subunit having 5 - 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent; and X 2 、X 3 and X 4 may be the same or different and each independently is methylene (-CH 2 -), -O-, -S-, - SS, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or a hydrogen atom), -O-CO-, COO-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 - 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent, where the length of the longest atomic chain in the compound is between 18 and 70 atoms.

16. The compound according to claim 15, or an isomer thereof, or a salt thereof, wherein n is 3.

17. The compound according to claim 15, or an isomer thereof, or a salt thereof, wherein R 1 is methyl, ethyl, propyl, butyl, or methoxymethyl, ethoxyethyl, or methoxyethyl; and R 2 is ethyl.

18. A compound according to any one of claims 15 to 17, or an isomer or a salt thereof, wherein X 1 is -O-CO- or -COO-.

19. The compound according to any one of claims 15 to 18, or an isomer thereof, or a salt thereof, wherein R 5 、R 7 and R 9 are the same and each is a straight-chain alkyl group having 10 carbon atoms.

20. The compound according to claim 15, or an isomer thereof, or a salt thereof, wherein: R 1 is an alkylene of 1 - 8 carbon atoms, an alkenylene of 2 - 8 carbon atoms or an alkynylene of 2 - 8 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -O-CO-R, -CO-OR, -CO-NR a R b , -NR a -CO-R, -O-CO-NR a R b , -NR a -CO-OR and -NR a R b ; where R is independently a hydrogen atom or a lower alkyl each time it appears; and R a and R b are independently a hydrogen atom or a lower alkyl; n is 0, 1, 2, 3, 4 or 5; R 2 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms; R 3 is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, or a carbocyclic group, heterocyclic group having 5 to 8 carbon atoms, or a hydrogen atom; R 4 、R 6 and R 8 may be the same or different and each independently represents a chemical bond or an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms; R 5 、R 7 、R 9 may be the same or different and each independently is a chemical bond or an alkyl group having 2 to 14 carbon atoms, an alkenyl group having 2 to 14 carbon atoms or an alkynyl group having 2 to 14 carbon atoms; X 1 is methylene (-CH 2 -), -O-, -NR-, where R is lower alkyl, -O-CO-, -CO-O-, C 5-8 carbocyclic subunit, heterocyclic subunit or bond; and X 2 、X 3 and X 4 are the same as or different from each other and each independently is methylene (-CH 2 -), -O-, -NR- (wherein R is a lower alkyl), O-CO-, COO-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit or a chemical bond. where the longest atomic chain in the compound is between 18 and 70 atoms.

21. A compound of formula V: or an isomer thereof, or a salt thereof, wherein: R 1 is an alkyl group having 2 to 18 carbon atoms, an alkenyl group having 2 to 18 carbon atoms, or an alkynyl group having 2 to 18 carbon atoms, a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group, a hydrogen atom or absent; R 2 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms; R 3 is an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -SR, -SSR, -O-CO-R, -CO-OR, -CO-NR a R b , -NR a -CO-R, -O-CO-NR a R b , -NR a -CO-OR, -NR a R b and -S-CO-R, wherein R is independently a hydrogen atom or a lower alkyl each time it appears; and R a and R b are independently a hydrogen atom or a lower alkyl; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R 4 and R 8 may be the same or different and each independently is a chemical bond or an alkylene group having 1 to 28 carbon atoms, an alkenylene group having 2 to 28 carbon atoms or an alkynylene group having 2 to 28 carbon atoms; R 5 and R 9 may be the same or different and each independently is a hydrogen atom or an alkyl group having 1 to 28 carbon atoms, an alkenyl group having 2 to 28 carbon atoms or an alkynyl group having 2 to 28 carbon atoms; R 6 and R 7 may be the same or different and each independently is a chemical bond or an alkylene group having 1 to 18 carbon atoms, an alkenylene group having 2 to 18 carbon atoms or an alkynylene group having 2 to 18 carbon atoms; X 1 is methylene (-CH 2 -), -O-, -S-, -SS-, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or a hydrogen atom), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent; and X 2 and X 3 are the same or different and each independently is methylene (-CH 2 -), O-, -S-, -SS-, NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl- ) ), -NR-CO- (where R is a lower alkyl or hydrogen), O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit, a chemical bond or absent, where the longest atomic chain in the compound is between 18 and 70 atoms.

22. The compound according to claim 21, or an isomer thereof, or a salt thereof, wherein n is 3.

23. The compound according to claim 21 or 22, or an isomer thereof, or a salt thereof, wherein R 2 consists of ethyl; and R 3 is methyl, ethyl, propyl, butyl, methoxymethyl, ethoxyethyl or methoxyethyl.

24. A compound according to any one of claims 21 to 23, or an isomer thereof, or a salt thereof, wherein X 1 , X 2 and X 3 are each independently -O-CO- or -CO-O-.

25. The compound according to any one of claims 21 to 24, or an isomer thereof, or a salt thereof, wherein R 1 is an alkyl group having 10 carbon atoms, and R 6 and R 7 are each independently ethylene, propylene or butylene group.

26. The compound according to claim 21, or an isomer thereof, or a salt thereof, wherein: R 1 is an alkyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an alkynyl group having 2 to 8 carbon atoms, a carbocyclic group having 5 to 8 carbon atoms, a heterocyclic group, or a hydrogen atom; R 2 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms; R 3 is an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms, each optionally substituted by one, two or three substituents independently selected from -OR, -O-CO-R, -CO-OR and -NR a R b wherein each occurrence of R is independently a hydrogen atom or a lower alkyl group; and R a and R b are independently a hydrogen atom or a lower alkyl group; n is 0, 1, 2, 3, 4 or 5; R 4 and R 8 may be the same or different and each independently is a chemical bond or an alkylene group having 1 to 14 carbon atoms, an alkenylene group having 2 to 14 carbon atoms or an alkynylene group having 2 to 14 carbon atoms; R 5 and R 9 may be the same or different and each independently is a hydrogen atom or an alkyl group having 1 to 14 carbon atoms, an alkenyl group having 2 to 14 carbon atoms or an alkynyl group having 2 to 14 carbon atoms; R 6 and R 7 may be the same or different and each independently is a key or an alkylene group having 1 to 8 carbon atoms, an alkenylene group having 2 to 8 carbon atoms or an alkynylene group having 2 to 8 carbon atoms; X 1 is methylene (-CH 2 -), -O-, -NR- (where R is a lower alkyl), -CO-NR- (where R is a lower alkyl), -NR-CO- (where R is a lower alkyl or a hydrogen atom), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit or a chemical bond; and X 2 and X 3 may be the same or different and each independently is methylene (-CH 2 -), -O-, -NR- (where R is a lower alkyl group), -CO-NR- (where R is a lower alkyl group), -NR-CO- (where R is a lower alkyl group or a hydrogen atom), -O-CO-, -CO-O-, -CO-, -O-CO-O-, a carbocyclic subunit having 5 to 8 carbon atoms, a heterocyclic subunit or a chemical bond, where the longest atomic chain in the compound is between 18 and 70 atoms.

27. A compound of formula VI: or an isomer thereof, or a salt thereof, wherein: Y 1 and Y 2 may be the same or different and are each independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene and alkynylene, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group; X is selected from -S-, -SS-, -O-, -CH 2 -, alkenylene, alkynylene, -NR-, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group; R 1 and R 2 may be the same or different and are each independently selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group, each of which is optionally substituted; R 3 selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, and each group other than the hydrogen and halogen atoms may be optionally substituted; Z is selected from alkylene, alkenylene, alkynylene and carbocyclic subunit; m is from 1 to 24. wherein the longest atomic chain in the compound is between 18 and 70 atoms.

28. The compound according to claim 27, or an isomer thereof, or a salt thereof, wherein Y 1 and Y 2 are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)- and -(C=O)NR-.

29. A compound as claimed in claim 27 or 28, or an isomer thereof, or a salt thereof, wherein R 3 is selected from alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl or heteroaryl, each optionally substituted with -OH.

30. The compound according to any one of claims 27 to 29, or an isomer thereof, or a salt thereof, wherein X is an oxygen atom (-O-) or a nitrogen atom with or without substituents (-NR-).

31. The compound according to claim 27, or an isomer thereof, or a salt thereof, wherein: Y 1 and Y 2 may be the same or different and are each independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group; X is selected from -S-, -O-, -CH 2 -, alkenylene, alkynylene, -NR-, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group; R 1 and R 2 may be the same or different and each independently is selected from a carbocyclic group, an alkyl group, an alkenyl group and an alkynyl group, each optionally substituted; R 3 selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, and each group other than the hydrogen atom may be optionally substituted; Z is selected from alkylene, alkenylene, alkynylene and carbocyclic alkylene; and m is 1 - 14, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

32. The compound of formula VII: or an isomer thereof, or a salt thereof, wherein: Y 1 and Y 2 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, and alkynylene, where each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; X 1 and X 2 are the same or different and are independently selected from -S-, -SS-, -O-, -CH 2 -, alkenylene, alkynylene, and -NR-, where R is hydrogen, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; R 1 and R 2 may be the same or different and are each independently selected from alkyl, alkenyl, alkynyl and heterocyclic group, each optionally substituted; R 3 selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, each optionally substituted; m and n are each independently an integer selected from 1 - 24, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

33. The compound according to claim 32, or an isomer thereof, or a salt thereof, wherein X 1 and X 2 are each independently an oxygen atom (-O-), a sulfur atom (-S-), or a nitrogen atom with or without substituents (-NR-), or a methylene group.

34. A compound according to claim 32 or 33, or an isomer or a salt thereof, wherein Y 1 and Y 2 are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)- and -(C=O)NR-.

35. A compound according to any one of claims 32 to 34, or an isomer or a salt thereof, wherein R 3 is selected from alkyl, cycloalkyl or aryl, each optionally substituted by -OH.

36. The compound according to claim 32, or an isomer thereof, or a salt thereof, wherein: Y 1 and Y 2 may be the same or different and are each independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group; X 1 and X 2 may be the same or different and are independently selected from -S-, -O-, -CH 2 -, alkenylene, alkynylene, -NR-, where R is a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group; R 1 and R 2 may be the same or different and are each independently selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group, each optionally substituted; R 3 selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, and each group other than the hydrogen atom may be optionally substituted; and m and n are each independently an integer selected from 1 - 14, wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

37. The compound of formula VIII: or an isomer thereof, or a salt thereof, wherein: X 1 、X 2 and X 3 are independently selected from -CH 2 -, -O-, -S- and -NR-, where R is hydrogen or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group; R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, and each group may be optionally substituted, except for the hydrogen and halogen atoms; R 3 and R 4 is selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group, each optionally substituted; and m is 0, 1, 2, 3, 4 or 5, wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

38. The compound according to claim 37, or an isomer thereof, or a salt thereof, wherein R 1 and R 2 are independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl, each optionally substituted with -OH, or together form part of a ring structure.

39. The compound according to claim 37, or an isomer thereof, or a salt thereof, wherein: X 1 、 X 2 and X 3 are independently selected from -CH 2 -, -O-, and -NR-, where R is a hydrogen atom or an alkyl, alkenyl, carbocyclic group, or heterocyclic group; R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group and a heterocyclic group, and each group other than the hydrogen atom is optionally substituted; R 3 and R 4 selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group, each optionally substituted; m is 0, 1, 2, 3, 4 or 5.

40. The compound of formula IX: or an isomer thereof, or a salt thereof, wherein: X 1 and X 2 are the same or different moieties selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenes and alkynes, where R is independently, each time it appears, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group; R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be optionally substituted except for a hydrogen atom and a halogen atom; R 3 and R 4 may be the same or different and are independently selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group; and m and n are the same or different and are each an integer from 1 - 24, wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

41. The compound according to claim 40, or an isomer thereof, or a salt thereof, wherein R 1 and R 2 are each independently an alkyl group having 1 to 20 carbon atoms, each optionally substituted with -OH.

42. The compound according to claim 40, or an isomer thereof, or a salt thereof, wherein: X 1 and X 2 are the same or different moieties selected from -(C═O)O-, -O(C═O)-, -NR(C═O)-, -(C═O)NR-, -O-, -CH 2 -, alkenes and alkynes, where R is independently, each time it appears, a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group; R 1 and R 2 may be the same or different and are independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group and a heterocyclic group, and each group may be optionally substituted except for a hydrogen atom and a halogen atom; R 3 and R 4 may be the same or different and are independently selected from a carbocyclic group, an alkyl group, an alkenyl group, and an alkynyl group; and m and n may be the same or different and are each an integer from 1 - 14, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

43. The compound of formula X: or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 and R 5 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, and each group may be optionally substituted except for the hydrogen and halogen atoms; X 1 , X 2 and X 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, - S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkenylene and alkynylene, wherein R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group each time it appears; X 4 Selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkenylene and alkynylene, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group each time it appears; or X 4 is a straight-chain alkyl containing 0-10 methylene units; Y 1 and Y 2 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, - S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkylene alkenylene, or alkynylene and carbocyclic alkylene, wherein R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group each time it appears; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, wherein the length of the longest atomic chain in the compound is between 18 and 70 atoms.

44. The compound according to claim 43, or an isomer thereof, or a salt thereof, wherein R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl, each optionally substituted by -OH, or R 3 fuses with R 4 to form a ring system.

45. A compound as claimed in claim 43 or 44, or an isomer or a salt thereof, wherein R 4 and R 5 are independently selected from straight-chain, branched-chain or cyclic alkyl groups, selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl, each optionally substituted by -OH, or R 4 and R 5 are fused to form a ring system.

46. A compound as claimed in any one of claims 43 to 45, or an isomer thereof, or a salt thereof, wherein X 1 and X 2 are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, an oxygen atom, a sulfur atom, -NR-, an alkene, an alkyne, or a cyclic alkyl or heteroalkyl, and X 3 is selected from -O-, -S-, an alkylene, an amine, an alkenylene and an alkynylene, wherein R is independently, in each occurrence, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group.

47. A compound as claimed in any one of claims 43 to 46, or an isomer thereof, or a salt thereof, wherein X 4 is -O-, -S-.

48. A compound as claimed in any one of claims 43 to 47, or an isomer or a salt thereof, wherein Y 1 and Y 2 are each independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkene, alkyne, cycloalkylene or heteroalkylene, wherein R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group each time it appears.

49. The compound according to claim 43, or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 and R 5 may be the same or different and are independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, and each is optionally substituted, except for the hydrogen atom; X 1 , X 2 , and X 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, and alkynylene, where R is independently, each occurrence, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; X 4 Selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, (C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, and alkynylene, where R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; or X 4 is a straight-chain alkyl group containing 0 - 8 methylene units; Y 1 and Y 2 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkylene, alkenylene, or alkynylene and carbocyclic moiety, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group each time it appears; and m is 0, 1, 2, 3, 4 or 5, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

50. The compound of formula XI: or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 may be the same or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be optionally substituted except for hydrogen and halogen atoms; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene, carbocyclic group and chemical bond, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group each time it appears; X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, - S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkylene an alkenylene, or an alkynylene and a carbocyclic group, where each occurrence of R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group or a heterocyclic group; or X 7 and X 8 each independently is a straight-chain alkyl group containing 0 - 10 methylene units; Y 1 , Y 2 , Y 3 , and Y 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group each time it appears; and n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

51. The compound according to claim 50, or an isomer thereof, or a salt thereof, wherein R 3 , R 4 and R 5 are independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and eicosyl, each optionally substituted with -OH, or R 3 , R 4 and R 5 together form part of a ring system.

52. The compound according to claim 50, or an isomer or a salt thereof, wherein R 3 and R 4 form part of a ring system.

53. A compound according to any one of claims 50 to 52, or an isomer or salt thereof, wherein X 7 and X 8 are independently selected from an oxygen atom (-O-), a sulfur atom (-S-), a substituted or unsubstituted nitrogen atom (-NR-), an alkenylene, an alkynylene, a cyclic alkylene or heteroalkylene, an ester, a thioester or an amide.

54. A compound as claimed in any one of claims 50 to 53, or an isomer or a salt thereof, wherein Y 1 、Y 2 、Y 3 and Y 4 are independently selected from an oxygen atom (-O-), a sulfur atom (-S-), a substituted or unsubstituted nitrogen atom (-NR-), an ester, a thioester, an amide, an alkenylene, an alkynylene, or a cyclic alkylene or heteroalkylene.

55. The compound according to claim 50, or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 、R 6 and R 7 may be the same or different and are independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, and each is optionally substituted, except for the hydrogen atom; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, an alkylene group, an alkenylene group, an alkynylene group, a carbocyclic group and a bond, where R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group or a heterocyclic group each time it appears; X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -O-, -S-, -CH 2 -, -NR-, alkylene, alkenylene, or alkynylene, carbocyclic group, and chemical bond, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group each time it appears; or X 7 and X 8 are each independently a straight-chain alkyl group containing 0 to 5 methylene units; Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, alkenylene, and alkynylene, where R is independently a hydrogen atom or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group each time it appears; and n and m are independently selected from 0, 1, 2, 3, 4 or 5, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

56. The compound of formula XII: or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 and R 4 may be the same or different and are each independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, each of which may be optionally substituted except for the hydrogen and halogen atoms; X 1 , X 2 , X 3 and X 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkenylene, alkynylene and chemical bond, wherein each occurrence of R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group; X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, - S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkenylene, An alkynylene group and a bond, where R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; or X 5 and X 6 each independently is a straight-chain alkyl group containing 0 to 10 methylene units; Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, alkynylene and a bond, where R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group; The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic or anti-aromatic ring system; and n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

57. The compound according to claim 50, or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 and R 4 are the same or different and are independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, and each may be optionally substituted except for a hydrogen atom and a halogen atom; X 1 、X 2 、X 3 and X 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, alkynylene and a bond, wherein each occurrence of R is independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group or a heterocyclic group; X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, alkynylene and a bond, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group each time it appears; or X 5 and X 6 are each independently a straight-chain alkyl group containing 0 - 5 methylene units; Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, alkenylene, alkynylene and chemical bonds, where R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group each time it appears; The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic or anti-aromatic ring system; and n and m are independently selected from 0, 1, 2, 3, 4 or 5, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

58. A compound of formula XIII: or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, each of which may be optionally substituted except for hydrogen and halogen atoms; X 1 、X 2 、X 3 、X 4 、X 5 and X 6 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, -NR-, alkenylene, alkynylene, cyclic alkylene or heteroalkylene, wherein R is independently, each time it appears, a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic or heterocyclic group; X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -(C=O)S-, - S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, alkenylene, sub- An alkynyl group, a cyclic alkylene group or a heteroalkylene group, where R is independently a hydrogen atom, or an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group; or X 7 and X 8 Each is a straight-chain alkyl group containing 0-10 methylene units; Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkenylene, alkynylene, and cyclic alkylene or heteroalkylene, where R is independently a hydrogen atom, or alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group each time it appears; The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic or anti-aromatic ring system; and n and m are independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

59. The compound according to claim 58, or an isomer thereof, or a salt thereof, wherein R 3 and R 4 are independently methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl or eicosyl, each optionally substituted by -OH; 60. A compound according to claim 58 or 59, or an isomer or a salt thereof, wherein X 1 , X 2 , X 5 and X 6 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S- -NR-, alkenylene, alkynylene, or cyclic or heteroalkylene, where each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group; X 7 and X 8 are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -NR-, alkenylene, alkynylene, or cyclic or heteroalkylene, or a methylene chain, where each occurrence of R is independently a hydrogen atom, or an alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group.

61. The compound according to claim 58, or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, carbocyclic group and heterocyclic group, and each group may be optionally substituted except for hydrogen and halogen; X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 are the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, alkynylene, cycloalkylene or heteroalkylene, where R is independently hydrogen, or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group each time it appears; X 7 and X 8 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkenylene, alkynylene, cyclic alkylene or heteroalkylene, wherein R is independently hydrogen, or alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group; or X 7 and X 8 each is a straight-chain alkyl group containing 0-10 methylene units; Y 1 、Y 2 、Y 3 and Y 4 may be the same or different and are independently selected from –(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, alkenylene, alkynylene, and cyclic alkylene or heteroalkylene, where R is independently a hydrogen atom, or alkyl, alkenyl, alkynyl, carbocyclic group, or heterocyclic group each time it appears; The central ring structure is an optionally substituted aromatic, heteroaromatic, non-aromatic or anti-aromatic ring system; and n and m are independently selected from 0, 1, 2, 3, 4 or 5, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

62. A compound of formula XIV: or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, a halogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, and each may be optionally substituted except for the hydrogen and halogen atoms; X 1 、 X 2 、 X 3 、 X 4 and X 5 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, SS-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group and heterocyclic group; Y 1 、Y 2 and Y 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, –(C=O)S-, -S(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -SS-, -CH 2 -, alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group; and m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

63. The compound according to claim 62, or an isomer thereof, or a salt thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 and R 6 may be the same or different and are independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a carbocyclic group, and a heterocyclic group, and each group is optionally substituted, except for hydrogen; X 1 , X 2 , X 3 , X 4 and X 5 may be the same or different and are independently selected from -(C=O)O-, O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, -NR-, alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, wherein R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group and heterocyclic group; Y 1 、Y 2 and Y 3 may be the same or different and are independently selected from -(C=O)O-, -O(C=O)-, -NR(C=O)-, -(C=O)NR-, -O-, -S-, -CH 2 -, alkylene, alkenylene, alkynylene, cycloalkylene and heterocycloalkylene, where R is independently a hydrogen atom, alkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group; and m is selected from 0, 1, 2, 3, 4 or 5, wherein the longest atomic chain in the compound is between 18 and 70 atoms.

64. A compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XI, XII, XIII or XIV, selected from the compounds from List 1 to List 14, an isomer thereof, or a salt thereof.

65. A lipid nanoparticle composition comprising: a. A biological and / or therapeutic agent with an N:P ratio of 1 to 15; b. A compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII or XIV according to any one of claims 1 to 64, or an isomer thereof, or a salt thereof, accounting for 10 mol% to 85 mol% of the total lipids present in the composition; c. A neutral "helper" phospholipid or a derivative thereof, accounting for 5 mol% to 40 mol%; d. Cholesterol or a derivative thereof, accounting for 10 mol% to 50 mol% of the total lipids in the composition; e. An aggregation-inhibiting binding lipid, accounting for 0 mol% to 10 mol% of the total lipids in the composition.

66. The lipid nanoparticle composition according to claim 65, wherein the phospholipid is selected from 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-docosanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), palmitoyl oleoyl-phosphatidylethanolamine (POPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphate-rac-(1-glycerol) sodium salt (DOPG), sphingomyelin, and mixtures thereof.

67. The lipid nanoparticle composition according to claim 65 or 66, wherein the PEG-lipid is selected from PEG-modified phosphatidylethanolamine, PEG-modified phosphatidic acid, PEG-modified ceramide, PEG-modified dialkylamine, PEG-modified diacylglycerol, PEG-modified dialkylglycerol, PEG-modified glyceride, PEG-modified sterol, and mixtures thereof.

68. The lipid nanoparticle composition according to any one of claims 65 to 67, wherein the biomolecule / therapeutic agent is ribonucleic acid (RNA), and the RNA is optionally selected from small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer substrate RNA (dsRNA), small hairpin RNA (shRNA), messenger RNA (mRNA), self-amplifying mRNA (samRNA), and mixtures thereof.

69. The lipid nanoparticle composition according to any one of claims 65 to 68, wherein the biomolecule and / or therapeutic agent comprises mRNA, and optionally the mRNA comprises from about 300 to about 20,000 nucleotides; and optionally the mRNA comprises at least one modified nucleotide.

70. The lipid nanoparticle composition according to any one of claims 65 to 69, wherein the neutral phospholipid comprises distearoyl phosphatidylcholine (DSPC).

71. The lipid nanoparticle composition according to any one of claims 65 to 70, wherein the binding lipid that inhibits particle aggregation comprises a polyethylene glycol-lipid conjugate (PEG-lipid), and optionally the PEG-lipid conjugate comprises 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG), and optionally the average molecular weight of the PEG is 2000 daltons.

72. The lipid nanoparticle composition according to claim 65, wherein the biomolecule and / or therapeutic agent is an oligonucleotide, optionally wherein the oligonucleotide comprises from about 10 to about 200 nucleotides, optionally wherein the oligonucleotide comprises one or more modified nucleotides, and optionally wherein the oligonucleotide comprises at least one 2'-O-methyl (2'OMe) nucleotide.

73. A method of treating a disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of the lipid nanoparticle composition according to any one of claims 65-72, wherein optionally, the disease or disorder is selected from Leber congenital amaurosis, Alzheimer's disease, Parkinson's disease, cystic fibrosis, Fabry disease, SMN1-related spinal muscular atrophy, Huntington's disease, muscular dystrophy (such as Duchenne muscular dystrophy and Becker muscular dystrophy), human immunodeficiency virus (HIV), influenza, heart disease, cancer (such as breast cancer, prostate cancer, colorectal cancer, renal cancer, bladder cancer, lymphoma, thyroid cancer, endometrial cancer, pancreatic cancer), tuberculosis, multiple sclerosis, transthyretin amyloidosis, hemophilia diseases (such as hemophilia B, hemophilia A), amyotrophic lateral sclerosis, GALT-related galactosemia, VEGF-related heart failure, propionic academia, ornithine transcarbamylase deficiency, Zika virus, rabies, SARS-CoV-2, malaria, tuberculosis, hepatitis B, Gaucher disease, Creutzfeldt-Jakob disease, nephrogenic diabetes insipidus, spinocerebellar ataxia, dentatorubral-pallidoluysian atrophy, sickle cell anemia, Machado-Joseph atrophy, retinitis pigmentosa, alpha-1 antitrypsin deficiency, galactocerebrosidase deficiency, Bardet-Biedl syndrome, Charlevoix-Saguenay, ethylmalonic encephalopathy, familial hypercholesterolemia, Ellis-van Creveld syndrome, Marfan syndrome, McKusick-Kaufman syndrome, osteogenesis imperfecta, phenylketonuria, Tay-Sachs disease, cataracts, familial amyloidosis, Wilson's disease, Santavuori-Haltia disease, Jansky-Bielschowsky disease, juvenile Batten disease, juvenile neuronal ceroid lipofuscinosis, and Pelizaeus-Merzbacher disease.

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