Ionizable lipids and uses thereof

Abstract

The present invention relates to a novel ionizable lipid compound represented by formula (I) or a salt thereof, and lipid nanoparticles comprising the compound or the salt thereof. The lipid nanoparticles comprising the novel ionizable lipid compound according to the present invention have excellent nucleic acid encapsulation efficiency and high cellular delivery efficiency to nucleic acids.

Description

Technical Field

[0001] The present invention relates to a novel ionizable lipid or a salt thereof, a lipid nanoparticle comprising the ionizable lipid or a salt thereof, and a composition comprising an ionic drug and the ionizable lipid or a salt thereof or the lipid nanoparticle. Background Art

[0002] In the pharmaceutical field, various particulate drug carriers in the form of structures such as emulsions, liposomes, microparticles, and nanoparticles have been actively studied to improve the efficiency of drug delivery to the body.

[0003] Meanwhile, with the progress of biotechnology, the development and commercialization of drugs using nucleic acids such as RNA as active ingredients are being actively realized. However, nucleic acids are easily degraded by enzymes (such as nucleases) in the body and are difficult to be delivered to target cells due to their size and anionic properties. Therefore, there is a great need for drug carriers to protect nucleic acids from being decomposed in the body and at the same time promote their delivery to target cells, and lipid nanoparticles (LNPs) are being actively studied.

[0004] LNPs generally consist of ionizable lipids as the main component, co-lipids (such as phospholipids), cholesterol, and PEG-lipids. It is known that ionizable lipids play a key role in determining the nucleic acid delivery efficiency by electrostatically binding to nucleic acids, encapsulating nucleic acids, and enabling nucleic acids to escape from endosomes inside cells. In addition, cholesterol keeps the LNP particles firm and stable, PEG-lipids play a role in preventing aggregation between LNP particles and ensuring structural stability, and co-lipids (such as phospholipids) play a role in maintaining the lipid bilayer membrane structure of LNP particles.

[0005] Meanwhile, recently, mRNA-based COVID-19 virus vaccines (such as Spikevax TM , Comirnaty TM ) have been developed and achieved commercial success. It is known that mRNA is easily degraded in the blood due to attacks by ribonucleases and has the disadvantage of being difficult to be delivered to cells due to its large molecular weight and negative charge. However, with the success of developing COVID-19 virus vaccines using the LNP system to overcome the above disadvantages, the importance of LNP technology in the pharmaceutical field is emerging.

[0006] In addition, in addition to mRNA, the development of therapies using various nucleic acids (such as antisense oligonucleotides (ASO), microRNAs (miRNA), etc.) is also being actively carried out. In order for nucleic acid therapies to be used clinically, their inherent challenges (such as instability in the body and low delivery efficiency to cells) must be addressed, and there is a need to develop novel ionizable lipids that can exhibit excellent cell delivery efficiency and nucleic acid encapsulation efficiency and at the same time minimize nucleic acid degradation.

[0007] The present inventors synthesized and prepared a novel ionizable lipid compound having a branched ester structure, which was prepared by adding an ester group to the terminal region of the ionizable lipid or introducing hydrocarbons of various lengths at various positions around the ester functional group in the terminal region of the ionizable lipid. Then, a novel ionizable lipid having excellent cellular delivery efficiency for nucleic acids was discovered.

[0008] [Related Technical Literature]

[0009] (Patent Document 1) US Published Patent US2020 / 0140378 A1 Summary of the Invention

[0010] Technical Problem

[0011] An object of the present invention is to provide a novel ionizable lipid compound having excellent cellular delivery efficiency and nucleic acid encapsulation efficiency and simultaneously minimizing nucleic acid degradation, and to provide lipid nanoparticles containing the compound and a composition containing the compound for drug delivery.

[0012] Solution to the Problem

[0013] In an embodiment of the present invention, there is provided a compound represented by formula (I) or a salt thereof.

[0014] In another embodiment of the present invention, there are provided lipid nanoparticles comprising a compound or a salt thereof, a helper lipid, cholesterol, and a PEG lipid.

[0015] In another embodiment of the present invention, there is provided a composition comprising an ionic drug and (i) a compound or a salt thereof or a composition comprising an ionic drug and (ii) lipid nanoparticles.

[0016] Advantageous Effects of the Invention

[0017] The novel ionizable lipid compound or a salt thereof of the present invention has excellent cellular delivery efficiency for nucleic acids and in vivo stability, thereby contributing to improving the in vivo stability and therapeutic efficacy of nucleic acid therapies. Brief Description of the Drawings

[0018] Figure 1 is a view showing the Z-average diameter and PI of F1-type LNPs containing any of the following compounds herein: ionizable lipid compounds 2 to 7, 9 to 13, 27 to 30, 32, 33, 36 to 38, 40 to 43, and 46 to 49.

[0019] Figure 2Views showing the encapsulation efficiency of F1-type LNPs containing any of the following compounds herein: ionizable lipid compounds 2 to 7, 9 to 13, 27 to 30, 32, 33, 36 to 38, 40 to 43, and 46 to 49.

[0020] Figure 3 Views showing the z-average diameter and PI of F2-type LNPs containing any of the following compounds herein: ionizable lipid compounds 1 to 7, 9, 10, 12 to 26, and 28 to 49.

[0021] Figure 4 Views showing the encapsulation efficiency of F2-type LNPs containing any of the following compounds herein: ionizable lipid compounds 1 to 7, 9, 10, 12 to 26, and 28 to 49.

[0022] Figure 5 Views showing the luminescence signal in the liver when using firefly luciferase mRNA administered via the tail vein to a control group (MC3 LNP) and an experimental group (F1-type LNPs containing ionizable lipid compounds 3, 4, 6, 32, or 46 herein).

[0023] Figure 6 Views showing the luminescence signal in the liver when using firefly luciferase mRNA administered via the tail vein to a control group (MC3 LNP) and an experimental group (F2-type LNPs containing ionizable lipid compounds 3, 4, 6, 19, 22, 25, 44, or 45 herein).

[0024] Figure 7 Views showing the luminescence signal in the liver when using firefly luciferase mRNA administered via the tail vein to a control group (MC3 LNP) and an experimental group (F1-type LNPs containing ionizable lipid compounds 4, 6, 32, or 46).

[0025] Figure 8 Views showing the luminescence signal in the liver when using firefly luciferase mRNA administered intramuscularly to a control group (MC3 LNP) and an experimental group (F2-type LNPs containing ionizable lipid compounds 6, 19, 21, 22, 25, 44, 45, or 46 herein). Detailed Description

[0026] In one aspect of the present invention, the present invention relates to a compound represented by formula (I) or a salt thereof:

[0027] (Terminal Region 1) j -Linker 1-Head k-Linker 2-(Terminal Region 2) m (I),

[0028] The terminal regions 1 and 2 are each independently represented by formula (II) or formula (III),

[0029]

[0030] wherein J and K are each independently -C(=O)-O- or -O-C(=O)-,

[0031] R1, R2, and R3 are each independently a linear C 1-25 alkyl or a branched C 3-35 alkyl, R1 and R2 being the same as or different from each other, the linear C 1-25 alkyl or the branched C 3-35 alkyl being unsubstituted or substituted by at least one selected from C 1-6 alkyl, Rx'-S-S-, Rx'-CH=CH-, Rx'-C(=O)-O-, Rx'-O-C(=O)-, -S-S-, -CH=CH-, -C(=O)-O-, -O-C(=O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, a 3- to 6-membered saturated or unsaturated carbocycloalkyl, a 3- to 6-membered saturated or unsaturated heterocyclic group, and a 3- to 6-membered saturated or unsaturated heterocycloalkyl which is unsubstituted or substituted by Rx″,

[0032] R4 is hydrogen, a linear C 1-25 alkyl, a branched C 3-30 alkyl, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocycloalkyl, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocycloalkyl, and is unsubstituted or substituted by one or more groups selected from Rx″, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)-,

[0033] Rx' is hydrogen, a linear C 1-25 alkyl, a branched C 3-25 alkyl, a linear C 5-30 alkenyl, a branched C 5-30 alkenyl, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocycloalkyl, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocycloalkyl, and is unsubstituted or substituted by one or more Rx″,

[0034] Rx″ is a hydroxyl group, a linear C 1-15 alkyl, a branched C 3-15alkyl, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group,

[0035] The wavy line indicates the bonding position,

[0036] The terminal regions 1 and 2 are the same as or different from each other,

[0037] The linking parts 1 and 2 are each independently a single bond, a straight-chain C 1-6 alkyl group, a branched-chain C 3-6 alkyl group, or a C 1-6 alkylene group, which may be unsubstituted or substituted by a hydroxyl group, -NR A R B or an amino group, and R A and R B are each independently a straight-chain C 1-6 alkyl group, and the linking parts 1 and 2 are the same as or different from each other,

[0038] The head is a 6-membered heterocyclic amine or an aliphatic amine,

[0039] j and m are each independently an integer from 0 to 2, and cannot both be the integer 0,

[0040] p and n are each independently an integer from 1 to 20,

[0041] k is an integer of 0 or 1,

[0042] The heterocyclic amine is a cyclic amine group containing one or more heteroatoms selected from N, S, or O and containing at least one nitrogen atom,

[0043] The carbocyclic group is a cyclic group composed of carbon and hydrogen atoms,

[0044] The heterocyclic group is a cyclic group containing one or more heteroatoms selected from N, S, or O,

[0045] The carbocyclic alkyl group is a carbocyclic group - straight-chain C 1-6 alkyl group or a carbocyclic group - branched-chain C 3-6 alkyl group, and

[0046] The heterocyclic alkyl group is a heterocyclic group - straight-chain C 1-6 alkyl group or a heterocyclic group - branched-chain C 3-6 alkyl group.

[0047] As used herein, the term "aliphatic amine" refers to a straight-chain or branched-chain hydrocarbon functional group having an amine terminus, which may have an aliphatic group with one or more unsaturated regions. Aliphatic amines are functional groups containing at least one amine group and at least one aliphatic group, and include but are not limited to triethylamine, tripropylamine, tributylamine, diisopropylamine, triisopropylamine, triisobutylamine, N,N-diisopropylethylamine, stearylamine, ethylenediamine, propylenediamine, hexamethylenediamine, bis(6-aminohexyl)amine, decylamine, undecylamine, dodecylamine, tridecylamine, tetradecylamine, hexadecylamine, octadecylamine, oleylamine, docosylamine, etc.

[0048] As used herein, the term "substituted" means replacing one or more atoms (such as hydrogen atoms, carbon atoms) of an organic compound with another atomic group, and the substituent refers to the introduced atomic group. In addition, unless stated to the contrary, each substituent may optionally be further substituted (i.e., further substituted or unsubstituted). For example, the terminal regions 1 and 2 of formula (I) are represented by formula (II), where R1 and R2 are straight-chain alkyl groups respectively. When the straight-chain alkyl groups are substituted by Rx'-CH=CH- and Rx'-C(=O)-O-, a compound having the same structure as compound 34 of the present application is obtained. In addition, the term "substituted" includes replacing a hydrogen atom in the molecular structure with a substituent so that a chemically stable compound is produced by such substitution without exceeding the valence of the specified atom. For example, "group A is substituted by substituent B" or "group A has substituent B" may mean that the hydrogen atom bonded to the atom (such as carbon) constituting the skeleton of group A is replaced by substituent B, so that group A and substituent B form a covalent bond.

[0049] As used herein, the term "alkyl" refers to a functional group derived from a straight-chain or branched-chain hydrocarbon, and includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0050] In addition, as used herein, the term "carbocyclic group" refers to a saturated carbocyclic group of carbon atoms (which has a monocyclic ring (such as cyclohexyl) and multiple fused rings (such as norbornyl, adamantyl)) and groups having a partially unsaturated (such as cycloalkenyl) carbocyclic or aromatic ring (such as aryl, phenyl), and includes but is not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, etc. In addition, as used herein, the term "heterocyclic group" refers to a monocyclic or polycyclic ring containing at least one (preferably 1 to 4) heteroatoms O, N or S, and does not include an aromatic ring. Examples include pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, morpholine, piperazine, tetrahydropyridyl, etc.

[0051] [1] In an embodiment of the present invention, the compound of the present invention refers to a compound of formula (I) or a salt thereof.

[0052] [2] In the embodiment of [1] above, k can be the integer 1.

[0053] [3] In the embodiment of [1] or [2] of the present invention, the head can be a 6-membered heterocyclic amine, or an optionally nitrogen atom-containing 6-membered heterocyclic amine, or a 6-membered heterocyclic amine containing at least 2 nitrogen atoms, or piperidine, pyridine, pyrimidine or piperazine.

[0054] [4] In the embodiment of [1] to [3] of the present invention, the connecting part 1 can be a straight-chain C 1-6 alkyl group, a straight-chain C A R B or an amine group-substituted straight-chain C 1-6 alkyl group, a branched-chain C 3-6 alkyl group, a branched-chain C A R B or an amine group-substituted branched-chain C 3-6 alkyl group, a C 1-6 alkylene group, or a C A R B or an amine group-substituted C 1-6 alkylene group, R A and R B can each independently be a straight-chain C 1-6 alkyl group or a branched-chain C 1-3 alkyl group.

[0055] [5] In the embodiment of [1] to [4] of the present invention, the connecting part 2 can be a straight-chain C 1-6 alkyl group or a straight-chain alkyl group substituted by a hydroxyl group.

[0056] [6] In the embodiment of [1] to [5] of the present invention, j and m can each be the integer 0 or 1 and not both be the integer 0.

[0057] [7] In the embodiment of [1] to [6] of the present invention, R1 is a straight-chain C 1-18 alkyl group, a straight-chain C 2-18 alkyl group, a straight-chain C 3-18 alkyl group, a straight-chain C 4-18 alkyl group, a straight-chain C 5-18 alkyl group, a straight-chain C 6-18 alkyl group, a branched-chain C 3-26 alkyl group, a branched-chain C 4-26 alkyl group, a branched-chain C 5-26 alkyl group, a branched-chain C 6-26 alkyl group, a branched-chain C 7-26 alkyl group or a branched-chain C 8-26 alkyl group, and the straight-chain alkyl group or the branched-chain alkyl group can be unsubstituted or substituted by a group selected from C 1-6Substituted by at least one of an alkyl group, Rx'-S-S-, Rx'-CH=CH-, Rx'-C(=O)-O-, Rx'-O-C(=O)-, -S-S-, -CH=CH-, -C(=O)-O-, -O-C(=O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group which is unsubstituted or substituted by Rx″, a 3- to 6-membered saturated or unsaturated heterocyclic group which is unsubstituted or substituted by Rx″, and a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group which is unsubstituted or substituted by Rx″.

[0058] [8] In the embodiments [1] to [7] of the present invention, R1 may be substituted by at least one selected from a straight-chain C 2-18 alkyl group, Rx'-C(=O)-O-, -CH=CH-, -C(=O)-O-, Rx'-O-C(=O)-, -O-C(=O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, and a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group which is unsubstituted or substituted by Rx″, and optionally may be substituted by at least one selected from a straight-chain C 2-18 alkyl group, Rx'-C(=O)-O-, -CH=CH-, -C(=O)-O-, Rx'-O-C(=O)-, -O-C(=O)-, and a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, or may be substituted by at least one selected from a straight-chain C 2-18 alkyl group, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, -O-C(=O)-, and a 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″.

[0059] [9] In the embodiments [1] to [8] of the present invention, R2 is a straight-chain C 1-18 alkyl group, a straight-chain C 2-18 alkyl group, a straight-chain C 3-18 alkyl group, a straight-chain C 4-18 alkyl group, a straight-chain C 5-18 alkyl group, a straight-chain C 6-18 alkyl group, a branched-chain C 3-26 alkyl group, a branched-chain C 4-26 alkyl group, a branched-chain C 5-26 alkyl group, a branched-chain C 6-26 alkyl group, a branched-chain C 7-26 alkyl group or a branched-chain C 8-26 alkyl group, and the straight-chain alkyl group or the branched-chain alkyl group may be unsubstituted or substituted by a group selected from C 1-6substituted by at least one of an alkyl group, Rx'-S-S-, Rx'-CH═CH-, -CH═CH-, Rx'-C(═O)-O-, -C(═O)-O-, Rx'-O-C(═O)-, -O-C(═O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group which is unsubstituted or substituted by Rx″, a 3- to 6-membered saturated or unsaturated heterocyclic group which is unsubstituted or substituted by Rx″, and a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group which is unsubstituted or substituted by Rx″.

[0060]

[10] In the embodiments [1] to [9] of the present invention above, R2 may be selected from straight-chain C 2-18 alkyl group, -CH═CH-, Rx'-C(═O)-O-, -C(═O)-O-, Rx'-O-C(═O)-, -O-C(═O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, and a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group which is unsubstituted or substituted by Rx″, and optionally may be selected from straight-chain C 2-18 alkyl group, -CH═CH-, Rx'-C(═O)-O-, -C(═O)-O-, Rx'-O-C(═O)-, -O-C(═O)-, and a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, or may be selected from straight-chain C 2-18 alkyl group, -CH═CH-, Rx'-C(═O)-O-, -C(═O)-O-, Rx'-O-C(═O)-, -O-C(═O)-, and a 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″.

[0061]

[11] In the embodiments [1] to

[10] of the present invention above, p and / or n may each independently be an integer from 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, or 1 to 6.

[0062]

[12] In the embodiments [1] to

[11] of the present invention above, R3 is a straight-chain C 1-18 alkyl group, straight-chain C 2-18 alkyl group, straight-chain C 3-18 alkyl group, straight-chain C 4-18 alkyl group, straight-chain C 5-18 alkyl group, straight-chain C 6-18 alkyl group, branched-chain C 3-32 alkyl group, branched-chain C 4-32 alkyl group, branched-chain C 5-32 alkyl group, branched-chain C 6-32Alkyl, branched C 7-32 Alkyl or branched C 8-32 Alkyl, wherein the straight-chain alkyl or branched-chain alkyl is straight-chain C 1-14 Alkyl, straight-chain C 2-14 Alkyl, straight-chain C 3-14 Alkyl, straight-chain C 4-14 Alkyl, straight-chain C 5-14 Alkyl, straight-chain C 6-14 Alkyl or branched C 12-21 Alkyl, wherein the straight-chain alkyl or branched-chain alkyl may be unsubstituted or substituted with at least one selected from straight-chain C 1-14 Alkyl, straight-chain C 2-14 Alkyl, straight-chain C 3-14 Alkyl, straight-chain C 4-14 Alkyl, straight-chain C 5-14 Alkyl, straight-chain C 6-14 Alkyl, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, -O-C(=O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted with Rx″, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group which is unsubstituted or substituted with Rx″, a 3- to 6-membered saturated or unsaturated heterocyclic group which is unsubstituted or substituted with Rx″, and a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group which is unsubstituted or substituted with Rx″.

[0063]

[13] In the above [1] to

[12] embodiments of the present invention, R3 may be unsubstituted or substituted with at least one selected from straight-chain C 1-14 Alkyl, straight-chain C 2-14 Alkyl, straight-chain C 3-14 Alkyl, straight-chain C 4-14 Alkyl, straight-chain C 5-14 Alkyl, straight-chain C 6-14 Alkyl, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)-.

[0064]

[14] In the above [1] to

[13] embodiments of the present invention, R4 may be hydrogen, straight-chain C 1-25 Alkyl, branched C 3-30An alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group. R4 may be unsubstituted or substituted by one or more groups selected from Rx″, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)-, and Rx' may be a straight-chain C 1-25 alkyl group, a branched-chain C 3-30 alkyl group, a straight-chain C 5-30 alkenyl group or a branched-chain C 5-30 alkenyl group, and is unsubstituted or substituted by one or more Rx″, and Rx″ may be a hydroxyl group, a straight-chain C 1-15 alkyl group, a branched-chain C 3-15 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, or a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group.

[0065]

[15] In the above [1] to

[14] embodiments of the present invention, R4 may be hydrogen, a straight-chain C 1-25 alkyl group, a straight-chain C alkyl group substituted by a hydroxyl group 1-25 alkyl group, a straight-chain C alkyl group substituted by a 6-membered saturated or unsaturated carbocyclic group 1-25 alkyl group, a straight-chain C alkyl group substituted by a 6-membered saturated or unsaturated carbocyclic alkyl group 1-25 alkyl group, a straight-chain C alkyl group substituted by a 6-membered saturated or unsaturated heterocyclic group 1-25 alkyl group, or a straight-chain C alkyl group substituted by a 6-membered saturated or unsaturated heterocyclic alkyl group 1-25 alkyl group or a branched-chain C 3-30 alkyl group, and the straight-chain alkyl group or the branched-chain alkyl group may be unsubstituted or substituted by one or more groups selected from Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)-, and Rx' may be a straight-chain C 1-25 alkyl group, a branched-chain C 3-30 alkyl group, a straight-chain C 5-30 alkenyl group or a branched-chain C 5-30 alkenyl group, and is unsubstituted or substituted by one or more Rx″.

[0066]

[16] In the above [1] to

[15] embodiments of the present invention, X and X1 may each independently be an oxygen atom (O).

[0067]

[17] In the above embodiments [1] to

[16] of the present invention, both the terminal regions 1 and 2 may be represented by formula (II), or both the terminal regions 1 and 2 may be represented by formula (III), or either of the terminal regions 1 and 2 may be represented by formula (II) and the remaining terminal region may be represented by formula (III), or j of the terminal region 1 is 0 and the terminal region 2 may be formula (II) or formula (III).

[0068]

[18] In the above embodiment [1] of the present invention, the present invention may be a compound represented by the following formula (V) or a salt thereof:

[0069]

[0070] wherein r is an integer from 1 to 10,

[0071] Q is -C(=O)-O- or -O-C(=O)-,

[0072] R 10 is a straight-chain C 1-25 alkyl or a branched-chain C 3-35 alkyl, or a group represented by formula (VI), the straight-chain C 1-25 alkyl or the branched-chain C 3-35 alkyl is unsubstituted or substituted by one or more groups selected from hydroxyl, straight-chain C 5-30 alkenyl, branched-chain C 5-30 alkenyl, -NR C R D and amine groups, R C and R D are each independently a straight-chain C 1-6 alkyl, and

[0073] R 12 is hydrogen, a straight-chain C 1-25 alkyl, a straight-chain C 1-25 alkyl substituted by hydroxyl, a straight-chain C 1-25 alkyl substituted by a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclic alkyl or a group represented by formula (VI),

[0074]

[0075] The wavy line indicates the bonding position,

[0076] q is an integer of 0 or 1,

[0077] s is an integer from 1 to 10,

[0078] U is -C(=O)-O- or -O-C(=O)-,

[0079] R 11, R 13 and R 14 are each independently hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-35 alkyl group, or a 6-membered saturated or unsaturated carbocyclic alkyl group, wherein the straight-chain C 1-25 alkyl group, the branched-chain C 3-35 alkyl group, or the 6-membered saturated or unsaturated carbocyclic alkyl group is unsubstituted or substituted with at least one selected from the group consisting of a hydroxyl group, a C 1-6 alkyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, R a -S-S-, -S-S-, R a -CH=CH-, -CH=CH-, R a -C(=O)-O-, -C(=O)-O-, R a -O-C(=O)-, -O-C(=O)-, an unsubstituted or R b -substituted 3- to 6-membered saturated or unsaturated carbocyclic group, an unsubstituted or R b -substituted 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, an unsubstituted or R b -substituted 3- to 6-membered saturated or unsaturated heterocyclic group, and an unsubstituted or R b -substituted 3- to 6-membered saturated or unsaturated heterocyclic alkyl group,

[0080] R a is hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-25 alkyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, and R a is unsubstituted or substituted with R b .

[0081] R b is a straight-chain C 1-15 alkyl group, a straight-chain C 1-15 alkyl group substituted with a hydroxyl group, a branched-chain C 3-15 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated cycloalkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group,

[0082] A carbocyclic group is a cyclic group composed of carbon and hydrogen atoms,

[0083] A heterocyclic group is a cyclic group containing one or more heteroatoms selected from N, S, or O,

[0084] A carbocyclic alkyl group is a carbocyclic group - straight-chain C 1-6 alkyl group or a carbocyclic group - branched-chain C 3-6 alkyl group,

[0085] A heterocyclic alkyl group is a heterocyclic group - straight-chain C 1-6 alkyl group or a heterocyclic group - branched-chain C 3-6 alkyl group, and preferably, r and s can each independently be an integer from 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, or 1 to 4.

[0086]

[19] In the embodiment of the above

[18] of the present invention, R 10 can be a straight-chain C 1-25 alkyl group, a branched-chain C 3-35 alkyl group, or a group represented by formula (VI), and the straight-chain C 1-25 alkyl group or the branched-chain C 3-35 alkyl group can be unsubstituted or substituted by a hydroxyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, -NR C R D or an amino group, and R C and R D can each independently be a straight-chain C 1-6 alkyl group or a branched-chain C 1-3 alkyl group, and

[0087] R 12 can be hydrogen, a straight-chain C 1-6 alkyl group, a straight-chain C 1-25 alkyl group substituted by a hydroxyl group, a straight-chain C 1-6 alkyl group substituted by a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclic alkyl group, or a group represented by formula (VI).

[0088] In another aspect of the present invention, the present invention can be a compound or a salt thereof, wherein k is the integer 1, and the 6-membered heterocyclic amine at the head is piperidine, pyridine, pyrimidine, or piperazine.

[0089] In another aspect of the present invention, the present invention can be a compound or a salt thereof, wherein k is the integer 1, and the head is an aliphatic amine.

[0090] In one aspect of the present invention, the present invention can be a compound or a salt thereof, wherein k is the integer 1, the head is piperazine or piperidine, and the connecting parts 1 and 2 are each independently a straight-chain C A alkyl group that is unsubstituted or substituted by a hydroxyl group, -NR B R 1-6 or an amino group, a branched-chain C A alkyl group that is unsubstituted or substituted by a hydroxyl group, -NR B or an amino group, or a straight-chain C 3-6An alkyl group or an unsubstituted or hydroxy-, -NR A R B or amino-substituted C 1-6 alkylene group.

[0091] In another aspect of the present invention, the present invention may be a compound or a salt thereof, wherein both terminal regions 1 and 2 are represented by formula (II), a compound or a salt thereof wherein both terminal regions 1 and 2 are represented by formula (III), or a compound or a salt thereof wherein either one of terminal regions 1 and 2 is represented by formula (II) and the remaining terminal region is represented by formula (III).

[0092] In one aspect of the present invention, the present invention may be a compound or a salt thereof, wherein p and / or n is an integer from 1 to 10.

[0093] In another aspect of the present invention, the present invention may be a compound or a salt thereof, wherein R1, R2, and R3 are each independently an unsubstituted or straight-chain C 1-18 alkyl group, a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclylalkyl group, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)-substituted straight-chain C 1-25 alkyl group or a branched-chain C 3-32 alkyl group, Rx' is hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-25 alkyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclylalkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclylalkyl group, and is unsubstituted or substituted by one or more Rx″, Rx″ is hydroxy, a straight-chain C 1-15 alkyl group, a branched-chain C 3-15 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclylalkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclylalkyl group.

[0094] In another aspect of the present invention, the present invention may be a compound or a salt thereof, wherein R1, R2, and R3 are each independently an unsubstituted or straight-chain C 2-18 alkyl group, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, -O-C(=O)-, a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclylalkyl group-substituted straight-chain C 1-25alkyl or branched C 3-32 alkyl, Rx' is hydrogen, straight-chain C 1-25 alkyl, branched C 3-25 alkyl, straight-chain C 5-30 alkenyl, branched C 5-30 alkenyl, 6-membered saturated or unsaturated carbocyclic group, 6-membered saturated or unsaturated carbocyclic group, 6-membered saturated or unsaturated carbocyclic group alkyl, 6-membered saturated or unsaturated heterocyclic group or 6-membered saturated or unsaturated heterocyclic group alkyl and Rx' is unsubstituted or substituted by one or more Rx″, Rx″ is hydroxy, straight-chain C 1-15 alkyl, 6-membered saturated or unsaturated carbocyclic group, 6-membered saturated or unsaturated carbocyclic group alkyl, 6-membered saturated or unsaturated heterocyclic group or 6-membered saturated or unsaturated heterocyclic group alkyl(heterocyclylalkyl).

[0095] In another aspect of the present invention, the present invention may be a compound or a salt thereof, wherein one of the linking moieties 1 and 2 is an unsubstituted or hydroxy-, -NR A R B - or amine-substituted straight-chain C 1-6 alkyl, hydroxy-, NR A R B - or amine-substituted branched C 3-6 alkyl or an unsubstituted or hydroxy-, NR A R B - or amine-substituted straight-chain C 1-6 alkylene, R A and R B are each independently straight-chain C 1-6 alkyl or branched C 1-3 alkyl.

[0096] In one aspect of the present invention, the present invention may be a compound or a salt thereof, wherein any one of the terminal regions 1 and 2 is represented by formula (II) or j or m is 0, and the remaining terminal region is represented by formula (III). At this time, R4 in formula (III) is hydrogen, straight-chain C 1-25 alkyl, branched C 3-30 alkyl, 3- to 6-membered saturated or unsaturated carbocyclic group, 3- to 6-membered saturated or unsaturated carbocyclic group alkyl, 3- to 6-membered saturated or unsaturated heterocyclic group or 3- to 6-membered saturated or unsaturated heterocyclic group alkyl, and R4 is unsubstituted or substituted by one or more groups selected from Rx″, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)- and -O-C(=O)-, Rx' is straight-chain C 1-25 alkyl or branched C 3-30 alkyl, Rx″ is hydroxy, straight-chain C 1-15 alkyl, branched C3-15 alkyl, a 3- to 6-membered saturated or unsaturated carbocyclic group, or a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group.

[0097] In another aspect of the present invention, the present invention may be a compound represented by the following formula (IV) or a salt thereof:

[0098]

[0099] The definition of X2 is the same as that of X above,

[0100] R5 to R8 have the same definition as that of R1 or R2 described above, and R5 to R8 may be the same as or different from each other.

[0101] In another aspect of the present invention, in the compound of formula (IV) or a salt thereof, X2 is each independently O or NH, R5 to R8 are each independently a linear C which is unsubstituted or substituted by at least one selected from Rx'-C(=O)-O-, Rx'-OC(=O)-, Rx'-SS- and Rx'-CH=CH- 3-15 Alkyl or branched C 3-15 Alkyl, Rx' is a straight chain C 1-10 Alkyl, Rx″ is hydroxyl, straight chain C 1-6 Alkyl, 6-membered saturated or unsaturated carbocyclic group or 6-membered saturated or unsaturated carbocyclic alkyl group.

[0102] In one aspect of the present invention, the present invention may be a compound represented by the following formula (V) or a salt thereof:

[0103]

[0104] wherein r is an integer from 0 to 10, Q is -C(=O)-O- or -OC(=O)-, R 10 For straight chain C 1-25 Alkyl or branched C 3-35 Alkyl, or a group represented by formula (VI), the straight chain C 1-25 Alkyl or branched C 3-35 The alkyl group is unsubstituted or substituted with hydroxyl, -NR C R D , Straight chain C 5-30 Alkenyl, branched C 5-30 Alkenyl or amine substituted, R C and R D Each independently is a straight chain C 1-6 Alkyl, R 12 For hydrogen, straight chain C 1-25 Alkyl, straight chain C substituted by hydroxyl 1-25 Alkyl, straight chain C substituted by 6-membered saturated or unsaturated carbocyclic group1-25 an alkyl group, a 6-membered saturated or unsaturated carbocyclic alkyl group, or a group represented by formula (VI),

[0105]

[0106] wherein the wavy line represents the bonding position, U is -C(=O)-O- or -O-C(=O)-, q is an integer of 0 or 1, s is an integer from 1 to 10, and R 11 , R 13 and R 14 are each independently hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-35 alkyl group, or a 6-membered saturated or unsaturated carbocyclic alkyl group, and the straight-chain C 1-25 alkyl group, the branched-chain C 3-35 alkyl group, or the 6-membered saturated or unsaturated carbocyclic alkyl group is unsubstituted or substituted with at least one selected from the group consisting of a hydroxyl group, a C 1-6 alkyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, R a -S-S-, -S-S-, R a -CH=CH-, -CH=CH-, R a -C(=O)-O-, -C(=O)-O-, R a -O-C(=O)-, -O-C(=O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted with R b , a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group which is unsubstituted or substituted with R b , a 3- to 6-membered saturated or unsaturated heterocyclic group which is unsubstituted or substituted with R b , and a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group which is unsubstituted or substituted with R b , R a is hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-25 alkyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, and R a is unsubstituted or substituted with R b , R b is a straight-chain C 1-15 alkyl group, a straight-chain C 1-15 alkyl group substituted with a hydroxyl group, a branched-chain C 3-15alkyl, 3- to 6-membered saturated or unsaturated carbocyclic group, 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, 3- to 6-membered saturated or unsaturated heterocyclic group, or 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, wherein the carbocyclic group is a cyclic group composed of carbon and hydrogen atoms, the heterocyclic group is a cyclic group containing one or more heteroatoms selected from N, S, or O, and the carbocyclic alkyl group is a carbocyclic group - straight-chain C 1-6 alkyl or carbocyclic group - branched-chain C 3-6 alkyl, and the heterocyclic alkyl group is a heterocyclic group - straight-chain C 1-6 alkyl or heterocyclic group - branched-chain C 3-6 alkyl.

[0107] In an embodiment of the present invention, the present invention may be a compound or a salt thereof, wherein R of formula (V) 10 is a straight-chain C 1-25 alkyl, branched-chain C 3-35 alkyl, or a group represented by formula (VI), and the straight-chain C 1-25 alkyl or branched-chain C 3-35 alkyl is unsubstituted or substituted with a hydroxyl group, -NR C R D , straight-chain C 5-30 alkenyl, branched-chain C 5-30 alkenyl, or an amino group, and R 12 is hydrogen, straight-chain C 1-6 alkyl, straight-chain C 1-25 alkyl substituted with a hydroxyl group, straight-chain C 1-6 alkyl substituted with a 6-membered saturated or unsaturated carbocyclic group, 6-membered saturated or unsaturated carbocyclic alkyl group, or a group represented by formula (VI).

[0108] In another aspect of the present invention, the present invention may be a compound or a salt thereof selected from the following:

[0109] (1) Tetrakis(2-ethylhexyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate;

[0110] (2) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetra(butane-4,1-diyl)tetrapentanoate;

[0111] (3) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetra(butane-4,1-diyl)tetraheptanoate;

[0112] (4) ((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butane-4,1-diyl) tetranonanoate;

[0113] (5) Tetrakis(octan-3-yl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionate);

[0114] (6) Tetrakis(4-(2-cyclohexylacetoxy)butyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionate);

[0115] (7) ((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butane-4,1-diyl) tetrahentriacontanoate;

[0116] (8) Tetrakis(4-(propionyloxy)butyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionate);

[0117] (9) ((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(ethane-2,1-diyl) tetraheptanoate;

[0118] (10) ((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(propane-3,1-diyl) tetrahexanoate;

[0119] (11) ((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(pentane-5,1-diyl) tetrabutanoate;

[0120] (12) Tetrakis(2-ethylhexyl) 4,4',4”,4”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrabutanoate;

[0121] (13) Tetrakis(2-ethylhexyl) 6,6',6”,6”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrahexanoate;

[0122] (14) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(hexane-6,1-diyl) tetra(2-hexyldecanoate);

[0123] (15) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(octane-8,1-diyl) tetra(2-hexyldecanoate);

[0124] (16) ((((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl) octakis(decanoate);

[0125] (17) Tetrakis(2-ethylhexyl) 8,8',8”,8”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetraoctanoate;

[0126] (18) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butane-4,1-diyl) tetra(2-hexyldecanoate);

[0127] (19) ((((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl) octakis(hexanoate);

[0128] (20) ((((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl) octakis(octanoate);

[0129] (21) Tetrakis(2-propylhexyl) 4,4',4”,4”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrabutanoate;

[0130] (22) Tetrakis(2-ethylpentyl) 4,4',4”,4”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrabutanoate;

[0131] (23) Tetrakis(2-propylhexyl) 6,6',6”,6”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrahexanoate;

[0132] (24) Tetrakis(2-propylhexyl) 8,8',8”,8”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetraoctanoate;

[0133] (25) Tetrakis(2-ethylpentyl) 6,6',6”,6”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrahexanoate;

[0134] (26) Tetrakis(2-ethylpentyl) 8,8',8”,8”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetraoctanoate;

[0135] (27) Di(heneicosan-10-yl) 3,3'-((3-(4-(3-hydroxypropyl)piperazin-1-yl)propyl)azanediyl)dipropanoate;

[0136] (28) ((3,3'-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl)azanediyl)bis(propionyl))bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate);

[0137] (29) ((3,3'-((3-(4-(3-hydroxypropyl)piperazin-1-yl)propyl)azanediyl)bis(propionyl))bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate);

[0138] (30) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanediyl))dipropionate;

[0139] (31) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(benzylazanediyl))dipropionate;

[0140] (32) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate;

[0141] (33) Tetrakis((Z)-non-2-en-1-yl) 9,9',9”,9”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate;

[0142] (34) Tetrakis((Z)-non-2-en-1-yl) 6,6',6”,6”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetrahexanoate;

[0143] (35) Tetrakis((Z)-non-2-en-1-yl) 4,4',4”,4”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetrabutanoate;

[0144] (36) Bis(heneicosan-10-yl) 3,3'-((3-(4-(3-((3-(heneicosan-10-yloxy)-3-oxopropyl)amino)propyl)piperazin-1-yl)propyl)azanediyl)dipropionate;

[0145] (37) (6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl 3-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl)(methyl)amino)propionate;

[0146] (38) (6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl 3-((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)(methyl)amino)propionate;

[0147] (39) Bis((6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate;

[0148] (40) Tetrakis(2-(2-cyclohexylacetoxy)ethyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate;

[0149] (41) Bis(4-(2-cyclohexylacetoxy)butyl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate;

[0150] (42) ((((3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))bis(propionyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl) tetrahexanoate;

[0151] (43) Bis(octan-3-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate;

[0152] (44) ((((3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis((3-(octan-3-yloxy)-3-oxopropyl)azanediyl))bis(propionyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl) tetrahexanoate;

[0153] (45) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetra(butane-4,1-diyl) tetra(3-ethylpentanoate);

[0154] (46) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis((4-hydroxybutyl)azanediyl))dipropionate;

[0155] (47) Bis(2-ethylhexyl) 3,3'-((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)azanediyl)dipropionate;

[0156] (48) ((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)azanediyl)bis(hexane-6,1-diyl) bis(2-hexyldecanoate); and

[0157] (49)Bis((Z)-non-2-en-1-yl) 9,9'-((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)azanediyl)dinonanoate.

[0158] In one aspect of the present invention, the present invention can be a lipid nanoparticle comprising a compound or a salt thereof, a helper lipid, cholesterol, and a PEG lipid.

[0159] As used herein, the term "lipid nanoparticle (LNP)" refers to a structure in which lipids are mixed with a drug (such as a nucleic acid-based drug) at room temperature to form a homogeneous phase and dispersed in an aqueous solution so that the drug exists in the form of a solid solution between lipid crystals. Since substances present in living organisms such as phospholipids, lipids, and cholesterol are used, lipid nanoparticles are particulate drug carriers with high bioavailability and affinity, capable of releasing and controlling drugs, and having high stability against decomposition by enzymes and the like. In addition, lipid nanoparticles are positively (+) charged at acidic pH to encapsulate RNA and neutrally charged at physiological pH to minimize toxicity.

[0160] In another aspect of the present invention, the helper lipid can be a phospholipid. A phospholipid is a lipid containing a phosphate ester group and one or more fatty acid chains, which may contain one or more double bonds and can interact with one or more negatively charged phospholipids of a membrane (such as a cell membrane).

[0161] In an embodiment of the present invention, phospholipids can be used without limitation as long as they are phospholipids capable of promoting the fusion of lipid nanoparticles. As phospholipids, one or more selected from DOPE (dioleoylphosphatidylethanolamine; 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DSPC (distearoylphosphatidylcholine), POPC (palmitoyloleoylphosphatidylcholine; 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine), EPC (egg phosphatidylcholine), DOPC (dioleoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DOPG (dioleoylphosphatidylglycerol), DPPG (dipalmitoylphosphatidylglycerol), DSPE (distearoylphosphatidylethanolamine), PE (phosphatidylethanolamine), DPPE (dipalmitoylphosphatidylethanolamine), POPE (1-palmitoyl-2-palmitoyl-sn-glycero-3-phosphoethanolamine), DOPS (1,2-dioleoyl-sn-glycero-3-[phospho-L-serine]), 2-octadecanoyl-sn-glycero-3-phosphoserine (DSPS; 18:0PS), 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phospho-L-serine (DOPS; 18:1Ps), sphingomyelin, etc. can be used, and one or more selected from DSPC, DOPC, DSPE, DOPE or sphingomyelin can be preferably used, but are not limited thereto.

[0162] In another aspect of the present invention, the PEG-lipid can comprise a linker moiety suitable for attaching PEG to the lipid nanoparticle. The linker moiety can be one or more selected from a carbonate group (-OC(O)O-), a succinyl group, a phosphate group (-O-(O)POH-O-), a sulfonate group, an amide group (-C(O)NH-), an amino group (-NR-), a carbonyl group (-C(O)-), a carbamate group (-NHC(O)O-), a urea group (-NHC(O)NH-), a disulfide group (-SS-), an ether group (-O-), a succinyl group (-(O)CCH2CH2C(O)-) and a succinamido group (-NHC(O)CH2CH2C(O)NH-), but is not limited thereto.

[0163] In one aspect of the present invention, the helper lipid and / or cholesterol of the lipid nanoparticle can be used as the lipid constituting the PEG-lipid, but any lipid capable of binding to PEG can be used without limitation.

[0164] In one aspect of the present invention, the molar ratio, weight ratio or volume ratio of the combination of the helper lipid, cholesterol and PEG-lipid component of the lipid nanoparticles of the present invention to the compound or its salt can be 1:10 to 10:1, but is not limited thereto.

[0165] In another aspect of the present invention, the lipid nanoparticles of the present invention may comprise 5 to 20 mol% of a helper lipid, 20 to 60 mol% of cholesterol, and 0.5 to 5 mol% of a PEG-lipid. Herein, mol% refers to the percentage obtained by dividing the number of moles of a specific component by the total number of moles of all components.

[0166] In one aspect of the present invention, the present invention may be a composition comprising an ionic drug and (i) a compound or a salt thereof, or a composition comprising an ionic drug and (ii) lipid nanoparticles.

[0167] In another aspect of the present invention, the ionic drug may be any one or more selected from nucleic acids or nucleic acid-based drugs, peptides, protein drugs, protein-nucleic acid constructs, and ion biopolymer-drug conjugates.

[0168] In an embodiment of the present invention, the nucleic acid may be, but is not limited to, any one or more selected from antisense oligonucleotides (ASO), small interfering RNAs (siRNA), microRNAs (miRNA), self-amplifying RNAs (SAM), circular RNAs, messenger RNAs (mRNA), crRNAs, tracrRNAs, single guide RNAs (sgRNA), transfer RNAs (tRNA), asymmetric interfering RNAs (aiRNA), antagomirs, ribozymes, dicer substrate RNAs, short hairpin RNAs (shRNA), plasmid DNAs (pDNA), double-stranded DNAs (dsDNA), partial double-stranded DNAs, triple-stranded DNAs, partial triple-stranded DNAs, single-stranded DNAs (ssDNA), double-stranded RNAs (dsRNA), locked nucleic acids (LNA), peptide nucleic acids (PNA), miRNA analogs, or anti-miRNAs.

[0169] In another embodiment of the present invention, the ionic drug may be a therapeutic agent for treating or preventing a disease.

[0170] In another aspect of the present invention, the composition may be used as a pharmaceutical composition for treating a disease.

[0171] In another aspect of the present invention, compared with a composition comprising an ionic drug and a previously known ionic lipid (such as MC3), a composition comprising an ionic drug and (i) a compound or a salt thereof, or a composition comprising an ionic drug and (ii) lipid nanoparticles may exhibit a biologically equivalent or enhanced drug delivery effect.

[0172] In another aspect of the present invention, compared with a composition containing the same ionic drug and a previously known lipid (such as MC3), a composition containing an ionic drug and (i) a compound or its salt or a composition containing an ionic drug and (ii) lipid nanoparticles may have a biologically equivalent or enhanced disease treatment or prevention effect, or may have improved immunogenicity.

[0173] In one aspect of the present invention, the composition may contain conventional non-toxic and pharmaceutically acceptable additives. Additives that can be used in the compositions of the present invention include sweeteners, binders, solubilizers, cosolvents, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavorings, etc., such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth, arginine, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, citrus essence, strawberry essence, vanilla essence, etc.

[0174] The compositions of the present invention can be prepared into various oral dosage forms, such as tablets, pills, powders, capsules, syrups or emulsions, or prepared into parenteral dosage forms, such as intramuscular, intravenous or subcutaneous administration.

[0175] When the composition of the present invention is formulated into an oral dosage form, cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. can be used as additives.

[0176] In addition, when the composition of the present invention is formulated into an injectable form, water, saline solution, aqueous glucose solution, similar aqueous sugar solutions, alcohols, diols, ethers, oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers, etc. can be used as additives.

[0177] Hereinafter, for the purpose of assisting understanding, the present invention will be described in detail by way of examples, etc. However, the embodiments according to the present invention can be modified into various other forms, and the scope of the present invention should not be construed as being limited to the following embodiments.

[0178] Preparation Example 1: Synthesis of Ionizable Lipids

[0179] The following synthetic formula only illustrates the method for preparing the novel ionizable lipid compound of the present invention and is not intended to limit the scope of the present invention as defined in the appended claims.

[0180] Novel ionizable lipid compounds were synthesized based on the following general [Synthesis Formulas 1] to [Synthesis Formula 7].

[0181] [Synthesis Formula 1] Overall reaction formula for ionizable lipid compounds 1 to 26, 33 to 36, 40, 44, and 45

[0182]

[0183] n is an integer of 1 or greater

[0184] R: straight-chain alkyl, branched-chain alkyl, or oxycarbonyl alkyl

[0185] Step 1: Synthesis of Compound B

[0186] To a stirred solution of diol (1.2 equivalents) in dichloromethane (DCM), add triethylamine (Et3N, 1.0 equivalent), 4-dimethylaminopyridine (DMAP, 0.1 equivalent), then add alkyloyl chloride. Add Compound A (1.0 equivalent) dropwise at 0 °C, and stir the reaction mixture at room temperature for 2 hours. Monitor the reaction progress by TLC. After the reaction is complete, dilute the reaction mixture with water and extract with dichloromethane (twice). Dry the combined organic layers over anhydrous Na2SO4, filter, and then concentrate the filtrate under reduced pressure to obtain the crude compound. Purify the crude compound by silica gel (100 to 200 mesh) column chromatography to obtain Compound B.

[0187] Step 2: Synthesis of Compound C

[0188] To a stirred solution of Compound B (1.0 equivalent) in dichloromethane, add triethylamine (2.0 equivalents). Add acryloyl chloride (0.38 mL, 4.65 mmol, 1.2 equivalents) dropwise at 0 °C, and stir the reaction mixture at room temperature for 2 hours. Monitor the reaction progress by TLC. After the reaction is complete, dilute the reaction mixture with water and extract with dichloromethane. Dry the combined organic layers over anhydrous Na2SO4, filter, and then concentrate the filtrate under reduced pressure to obtain the crude compound. Purify the crude compound by silica gel (100 to 200 mesh) column chromatography to obtain Compound C.

[0189] Step 3: Synthesis of ionizable lipid compounds 1 to 26, 33 to 36, 40, 44, and 45

[0190] To a stirred mixture of 3,3'-(piperazine-1,4-diyl)bis(prop-1-amine) (1.0 equiv), Compound C (4.0 equiv) in acetonitrile (ACN) at room temperature was added a catalytic amount of hydroquinone (0.1 equiv). The reaction mixture was heated to 70 °C and stirred at the same temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (100 to 200 mesh) column chromatography to give ionizable lipid compounds 1 to 26, 33 to 36, 40, 44, 45.

[0191] [Synthesis Formula 2] Overall reaction formula for ionizable lipid compounds 27 to 29

[0192]

[0193] n is an integer of 1 or greater

[0194] R: straight-chain alkyl, branched-chain alkyl or oxycarbonyl alkyl

[0195] Step 1: Synthesis of Compound E

[0196] To a stirred solution of Compound D (1.0 equiv) in dichloromethane at 0 °C was added dropwise imidazole (1.0 equiv) and TBDMS-Cl (TBSCI, tert-butyldimethylchlorosilane, 1.5 equiv). The reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with dichloromethane (twice). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (100 to 200 mesh) column chromatography (eluted with 10% methanol / DCM) to give Compound E.

[0197] Step 2: Synthesis of Compound G

[0198] To a stirred solution of Compound E (1.0 equiv) in DMF (N,N-dimethylformamide) was added K2CO3 (3.0 equiv) and Compound F (1.2 equiv), and the mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel (100 to 200 mesh) column chromatography (eluted with 3% ethyl acetate / petroleum ether) to give Compound G.

[0199] Step 3: Synthesis of Compound H

[0200] Hydrazine hydrate (10 equiv) was added to a stirred solution of compound G (1.0 equiv) in methanol, and the mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography on silica gel (100 - 200 mesh) eluting with 4% ethyl acetate / petroleum ether to give compound H.

[0201] Step 4: Synthesis of compound I

[0202] A catalytic amount of hydroquinone (0.1 equiv) was added to a stirred mixture of compound C (2.5 equiv) and compound H (1.0 equiv) in acetonitrile at room temperature. The reaction mixture was heated to 70 °C and stirred at the same temperature for 48 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain crude compound I.

[0203] Step 5: Synthesis of ionizable lipid compounds 27 to 29

[0204] TFA (trifluoroacetic acid, 5 equiv) was added to a stirred solution of compound I (1.00 equiv) in DCM at room temperature. Then the reaction mixture was stirred at the same temperature for 12 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with DCM (twice). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography on silica gel (100 - 200 mesh) eluting with 6% methanol / dichloromethane to give ionizable lipid compounds 27 to 29.

[0205] [Synthesis formula 3] Overall reaction formula for ionizable lipid compound 37

[0206]

[0207] n is an integer of 1 or greater

[0208] R: straight-chain alkyl, branched-chain alkyl or oxycarbonylalkyl

[0209] Step 1: Synthesis of compound K

[0210] Compound J (0.5 equiv) was added to a stirred solution of compound H (1.0 equiv) in acetonitrile at room temperature, then hydroquinone (0.1 equiv) was added, and the reaction mixture was stirred at 80 °C for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain crude compound K.

[0211] Step 2: Synthesis of compound L

[0212] To a stirred solution of compound K (1.0 equiv) in methanol was added paraformaldehyde (10 equiv) and acetic acid (1 drop), and the mixture was stirred at room temperature for 16 h. NaCNBH3 (10 equiv) was added and the mixture was stirred at room temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane (twice). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by NH-silica column chromatography (eluting with 20% ethyl acetate in petroleum ether) to give compound L.

[0213] Step 3: Synthesis of ionizable lipid compound 37

[0214] To a stirred solution of compound L (1.0 equiv) in dichloromethane at room temperature was added 4M HCl in 1,4-dioxane (5 equiv), and the reaction mixture was stirred at the same temperature for 16 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give ionizable lipid compound 37.

[0215] [Synthesis formula 4] Overall reaction formula for ionizable lipid compounds 30 to 32, 39, and 41 to 43

[0216]

[0217] R: straight-chain alkyl, branched-chain alkyl or oxycarbonylalkyl

[0218] Step 1: Synthesis of compound M

[0219] To a stirred solution of 3,3'-(piperazine-1,4-diyl)bis(prop-1-amine) (1.0 equiv) in ethanol was added benzaldehyde (2.1 equiv) and molecular sieves, and the mixture was stirred at room temperature (RT) for 12 h. Sodium borohydride (20 equiv) was added and the mixture was stirred at RT for 12 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give the crude residue. The residue was acidified with 1N HCl and washed with dichloromethane (twice). The aqueous layer was basified with 1N NaOH and extracted with dichloromethane (twice). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by neutral alumina column chromatography (eluting with 5% ethyl acetate / petroleum ether) to give compound M.

[0220] Step 2-1: Synthesis of ionizable lipid compound 31

[0221] To a stirred solution of compound J (2.5 equiv) in acetonitrile at room temperature was added compound M (1.0 equiv) and a catalytic amount of hydroquinone (0.1 equiv). The reaction mixture was heated to 80 °C and stirred at the same temperature for 72 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography on silica gel (100 - 200 mesh) eluting with 5% methanol / dichloromethane to give the ionizable lipid compound to 31.

[0222] Step 2-2: Synthesis of ionizable lipid compound 30

[0223] To a stirred solution of ionizable lipid compound 31 (1.0 equiv) in methanol was added Pd / C (0.1 equiv), and the mixture was stirred under a hydrogen balloon pressure (60 psi) for 8 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure to give the crude compound. The crude product was purified by preparative HPLC to give the ionizable lipid compound 30.

[0224] Step 2-3: Synthesis of ionizable lipid compounds 32, 39 and 41 - 43

[0225] To a stirred solution of ionizable lipid compound 30 (1.0 equiv) in methanol was added paraformaldehyde (10 equiv) and acetic acid (1 drop), and the mixture was stirred at RT for 4 h. NaCNBH3 (10 equiv) was added and the mixture was stirred at RT for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with dichloromethane (twice). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the ionizable lipid compounds 32, 39, 41 - 43.

[0226] [Synthesis formula 5] Overall reaction formula for ionizable lipid compound 38

[0227]

[0228] R: straight-chain alkyl, branched-chain alkyl or oxycarbonylalkyl

[0229] Step 1: Synthesis of compound N

[0230] At room temperature, compound J (0.8 equivalent) was added to a stirred solution of 3,3'-(piperazine-1,4-diyl)bis(prop-1-amine) (1.0 equivalent) in acetonitrile, and then hydroquinone (0.1 equivalent) was added. The reaction mixture was stirred at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give compound N.

[0231] Step 2: Synthesis of ionizable lipid compound 38

[0232] At room temperature, formaldehyde (10.0 equivalents) was added to a stirred solution of compound N (1.0 equivalent) in methanol, and then acetic acid (1 drop) was added. The reaction mixture was stirred at room temperature for 1 h. NaCNBH3 (10 equivalents) was added and the mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with 10% methanol in dichloromethane (twice). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure to give a crude compound. The crude compound was purified by preparative HPLC to give ionizable lipid compound 38.

[0233] [Synthesis formula 6] Overall reaction formula for ionizable lipid compound 46

[0234]

[0235] R: linear alkyl, branched alkyl or oxycarbonylalkyl

[0236] Step 1: Synthesis of compound P

[0237] To a stirred solution of ionizable lipid compound 30 (1.0 equivalent) in tetrahydrofuran (THF) was added compound O (2.50 equivalents) and acetic acid (1 drop). The mixture was stirred at room temperature for 1 h. Na(OAc)3BH (4 equivalents) was added and the mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with 10% methanol in dichloromethane (3 * 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give a crude compound. The crude compound was purified by column chromatography on NH-silica gel (100 - 200 mesh) eluted with 15% ethyl acetate / petroleum ether to give compound P.

[0238] Step 2-1: Synthesis of ionizable lipid compound 46

[0239] To a stirred solution of compound P (1.0 eq) in DCM at 0 °C was added 1,4-dioxane-HCl (4 M) (10 eq). The reaction mixture was then stirred at room temperature for 2 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was quenched with NaHCO3 solution (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by preparative HPLC to give the ionizable lipid compound 46.

[0240] [Synthesis Scheme 7] Overall reaction scheme for ionizable lipid compounds 47 to 49

[0241]

[0242] R: linear alkyl, branched alkyl or oxycarbonyl alkyl

[0243] Step 1: Synthesis of compound R

[0244] To a stirred solution of compound Q (1.0 eq) in dichloromethane at room temperature was added 4 M HCl in 1,4-dioxane (5 eq), and the reaction mixture was stirred at the same temperature for 16 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give compound R.

[0245] Step 2: Synthesis of compound T

[0246] To a stirred solution of compound R (1.0 eq) in DMF was added K2CO3 (3.0 eq) and compound S (1.2 eq), and the mixture was stirred at room temperature for 5 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate (twice). The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography on silica gel (100 - 200 mesh) eluting with 3% ethyl acetate / petroleum ether to give compound T.

[0247] Step 3: Synthesis of compound U

[0248] To a stirred solution of compound T (1.0 eq) in methanol was added hydrazine hydrate (10 eq), and the mixture was stirred at room temperature for 12 h. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography on silica gel (100 - 200 mesh) eluting with 4% ethyl acetate / petroleum ether to give compound U.

[0249] Step 4: Synthesis of Ionizable Lipid Compounds 47 to 49

[0250] To a stirred solution of Compound J (2.5 equiv) in acetonitrile at room temperature was added Compound U (1.0 equiv) and a catalytic amount of hydroquinone (0.1 equiv). The reaction mixture was heated to 80 °C and stirred at the same temperature for 72 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography on silica gel (100 - 200 mesh) eluting with 5% methanol / dichloromethane to give Ionizable Lipid Compounds 47 to 49.

[0251] The structures of Ionizable Lipid Compounds 1 to 49 synthesized by the synthesis of Formulas 1 to 7 are listed in Table 1 below.

[0252] [Table 1]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266] Meanwhile, among the synthesized ionizable lipids, for Compounds 1 to 49, measurements were made using a Bruker Ultrashield 400 or a spectrometer 11H NMR spectra. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in Hertz (Hz), the splitting patterns interpret the variations, and are shown by using s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), or br (broad peak). For compounds 1 to 49 1 1H NMR (400 MHz, CDCl3) data are shown in Table 2.

[0267] [Table 2]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273] Experimental Example 1. Properties of Ionizable Lipids

[0274] To prepare the LNPs, cholesterol purchased from Sigma Aldrich (USA) was used, and DMG-PEG2000 (1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol-2000) purchased from Avanti Polar Lipids (USA) was used as the PEG lipid. In addition, DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and DSPC (1,2-distearoyl-sn-glycero-3-PC) purchased from Avanti Polar Lipids (USA) were used as co-lipids.

[0275] The selected ionizable lipids 2 to 7, 9 to 13, 27 to 30, 32, 33, 36 to 38, 40 to 43, and 46 to 49 were mixed with DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), cholesterol, and PEG-lipid to prepare F1-type lipid nanoparticles (LNPs). F2-type LNPs were prepared by mixing the selected ionizable lipids 1 to 7, 9, 10, 12 to 26, and 28 to 49 with DOPE, cholesterol, and PEG-lipid. Table 3 lists the compositional information of F1-type LNPs and F2-type LNPs.

[0276] [Table 3]

[0277]

[0278]

[0279] For LNP preparation, NanoAssemblr Ignite TM (Precision Nanosystems, Inc., Canada) was used with a total flow rate (TFR) of 12 mL / min. Ethanol was removed using an Amicon ultrafiltration filter MWCO 10 kDa (Millipore, USA), the buffer was exchanged, and then it was concentrated. During dilution, concentration, and exchange, the prepared LNP was diluted with 1X DPBS to remove ethanol while concentrating the LNP.

[0280] [Method for analyzing the physicochemical properties of LNP]

[0281] Particle size, Z-average diameter, and polydispersity index (PI) were analyzed using a Zetasizer Pro (Malvern Instruments, UK). "PI" is the ratio describing the uniformity of the particle size distribution of the system. A PI close to 0 means monodisperse, and close to 1 means polydisperse.

[0282] [mRNA quantification and encapsulation efficiency (EE%) measurement method]

[0283] The mRNA content and EE% were measured using a Ribogreen RNA Assay Kit (Invitrogen, USA). Briefly, the mRNA concentration of the prepared mRNA / LNP in the Triton X-100 solution-treated group and the untreated group was measured, and the ratio of the mRNA encapsulated in the LNP to the total mRNA was calculated as EE%.

[0284] Table 4 below lists the measured values of the Z-average diameter, PI, and EE (%) of each prepared LNP, which are shown respectively in Figures 1 to 4 .

[0285] [Table 4]

[0286]

[0287]

[0288]

[0289] As can be seen in Table 4, it was confirmed that the LNP containing the ionizable lipid compound in this article has a Z-average diameter of less than 200 nm and a narrow particle size distribution with a PI of less than 0.2.

[0290] Experimental Example 2. Nucleic acid delivery efficacy of the novel ionizable lipid compound (in vivo)

[0291] To evaluate the in vivo transfection efficiency and distribution, the prepared materials were administered by intravenous and intramuscular injection. PBS was used as the control material, and the F1-type LNP or F2-type LNP prepared in Experimental Example 1 was used as the experimental group material.

[0292] Experimental Example 2.1. Nucleic Acid Delivery Efficacy of Novel Ionizable Lipid Compounds by Intravenous Administration

[0293] For the intravenous administration group, lipid nanoparticles equivalent to 0.5 mg / kg of mRNA were injected into Balb / c mice (male, 5 weeks old) via the tail vein. Six hours after injection, 150 mg / kg of D-luciferin (Perkin Elmer, USA) was administered intraperitoneally. Fifteen minutes later, the luminescence intensity (total flux) in the liver tissue of each mouse was quantitatively analyzed using an IVIS imaging system Luminar XR (Perkin Elmer, USA) device to measure the in vivo nucleic acid delivery efficacy of the novel ionizable lipid compound.

[0294] The quantified luminescence intensities of the experimental group and the control group are summarized in Table 5. In addition, the relative luminescence intensities of the experimental group and the control group are shown in Figure 5 and Figure 6 .

[0295] [Table 5]

[0296] LNP of F1 type Average total flux LNP containing ionizable lipid compound 3 (lipid 3) <![CDATA[6.4X10 10 > LNP containing ionizable lipid compound 4 (lipid 4) <![CDATA[4.4X10 10 > LNP containing ionizable lipid compound 6 (lipid 6) <![CDATA[5.5X10 10 > LNP containing ionizable lipid compound 32 (lipid 32) <![CDATA[2.8X10 10 > LNP containing ionizable lipid compound 46 (lipid 46) <![CDATA[5.4X10 10 > Control group (MC3 LNP) <![CDATA[1.8X10 10 > LNP of F2 type Average total flux LNP containing ionizable lipid compound 3 (lipid 3) <![CDATA[3.6X10 10 > LNP containing ionizable lipid compound 4 (lipid 4) <![CDATA[4.1X10 10 > LNP containing ionizable lipid compound 6 (lipid 6) <![CDATA[2.6X10 10 > LNP containing ionizable lipid compound 19 (lipid 19) <![CDATA[3.2X10 10 > LNP containing ionizable lipid compound 22 (lipid 22) <![CDATA[3.2X10 10 > LNP containing ionizable lipid compound 25 (lipid 25) <![CDATA[3.5X10 10 > LNP containing ionizable lipid compound 44 (lipid 44) <![CDATA[2.7X10 10 > LNP containing ionizable lipid compound 45 (lipid 45) <![CDATA[3.5X10 10 > Control group (MC3 LNP) <![CDATA[1.8X10 10 >

[0297] As confirmed in Table 5 above, compared with the control group, the LNP containing the ionizable lipid compound herein showed excellent in vivo mRNA delivery efficacy regardless of its composition.

[0298] Experimental Example 2.2. Nucleic Acid Delivery Efficacy of Novel Ionizable Lipid Compounds after Intramuscular Administration

[0299] For the intramuscular administration group, lipid nanoparticles equivalent to 0.25 mg / kg of mRNA were administered to the thigh muscle of Balb / c mice (male, 5 weeks old). The control group mice were treated with PBS in the same manner. Six hours after injection, 150 mg / kg of D-luciferin (Perkin Elmer, USA) was administered intraperitoneally. Fifteen minutes later, the luminescence intensity (total flux) in the thigh muscle tissue of each mouse was quantitatively analyzed using an IVIS imaging system Luminar XR (Perkin Elmer, USA) device to measure the in vivo nucleic acid delivery efficacy of the novel ionizable lipid compound.

[0300] The quantified luminescence intensities of the experimental group and the control group are summarized in Table 6. In addition, the relative luminescence intensities of the experimental group and the control group are shown in Figure 7 andFigure 8 in

[0301] [Table 6]

[0302]

[0303]

[0304] As confirmed in Table 6 above, compared with the control group, it was found that the LNPs containing the ionizable lipid compounds herein had significantly improved in vivo mRNA delivery efficacy regardless of their composition.

Claims

1. A compound represented by the following formula (I) or a salt thereof: (Terminal Region 1) j -Connection Portion 1-Head k-Connection Portion 2-(Terminal Region 2) m (I), wherein terminal regions 1 and 2 are each independently represented by the following formula (II) or formula (III), J and K are each independently -C(=O)-O- or -O-C(=O)-, R1, R2, and R3 are each independently a straight-chain C 1-25 alkyl or a branched-chain C 3-35 alkyl, R1 and R2 being the same as or different from each other, the straight-chain C 1-25 alkyl or the branched-chain C 3-35 alkyl being unsubstituted or substituted by at least one selected from C 1-6 alkyl, Rx'-S-S-, Rx'-CH=CH-, Rx'-C(=O)-O-, Rx'-O-C(=O)-, -S-S-, -CH=CH-, -C(=O)-O-, -O-C(=O)-, a 3- to 6-membered saturated or unsaturated carbocyclic group which is unsubstituted or substituted by Rx″, a 3- to 6-membered saturated or unsaturated carbocyclic group alkyl which is unsubstituted or substituted by Rx″, a 3- to 6-membered saturated or unsaturated heterocyclic group which is unsubstituted or substituted by Rx″, and a 3- to 6-membered saturated or unsaturated heterocyclic group alkyl which is unsubstituted or substituted by Rx″, R4 is hydrogen, a linear C 1-25 alkyl group, a branched C 3-30 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, and R4 is unsubstituted or substituted by one or more groups selected from Rx″, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)- Rx' is hydrogen, a linear C 1-25 alkyl group, a branched C 3-25 alkyl group, a linear C 5-30 alkenyl group, a branched C 5-30 alkenyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, and is unsubstituted or substituted by one or more Rx″, Rx″ is a hydroxyl group, a straight-chain C 1-15 alkyl group, a branched-chain C 3-15 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, The wavy line represents the bonding position, Terminal regions 1 and 2 are the same as or different from each other, The connecting parts 1 and 2 are each independently a single bond, a straight-chain C 1-6 alkyl group, a branched-chain C 3-6 alkyl group or a C 1-6 alkylene group, unsubstituted or substituted by a hydroxyl group, -NR A R B or an amino group, where R A and R B are each independently a straight-chain C 1-6 alkyl group. Linking parts 1 and 2 are the same as or different from each other, The head is a 6-membered heterocyclic amine or an aliphatic amine, j and m are each independently an integer from 0 to 2 and cannot both be the integer 0, p and n are each independently an integer from 1 to 20, k is an integer of 0 or 1, The heterocyclic amine is a cyclic amine group containing one or more heteroatoms selected from N, S or O and containing at least one nitrogen atom, The carbocyclic group is a cyclic group composed of carbon and hydrogen atoms, The heterocyclic group is a cyclic group containing one or more heteroatoms selected from N, S or O, Carbocyclic alkyl is carbocyclic - straight-chain C 1-6 alkyl or carbocyclic - branched-chain C 3-6 alkyl, and Heterocyclic alkyl is heterocyclic - straight-chain C 1-6 alkyl or heterocyclic - branched-chain C 3-6 alkyl.

2. The compound or a salt thereof according to claim 1, wherein k is the integer 1, and The 6-membered heterocyclic amine of the head is piperidine, pyridine, pyrimidine or piperazine.

3. The compound or a salt thereof according to claim 1, wherein k is the integer 1, and The head is an aliphatic amine.

4. The compound or a salt thereof according to claim 1, wherein k is 1, The head is piperazine or piperidine, The connecting parts 1 and 2 are each independently an unsubstituted or hydroxyl group-, -NR A R B - or amine group-substituted straight-chain C 1-6 alkyl group, an unsubstituted or hydroxyl group-, -NR A R B - or amine group-substituted branched-chain C 3-6 alkyl group or an unsubstituted or hydroxyl group-, -NR A R B - or amine group-substituted C 1-6 alkylene group, R A and R B are each independently a straight-chain C 1-3 alkyl group.

5. The compound or a salt thereof according to claim 1, wherein Both terminal regions 1 and 2 are represented by formula (II), or both terminal regions 1 and 2 are represented by formula (III).

6. The compound or a salt thereof according to claim 1, wherein Either one of terminal regions 1 and 2 is represented by formula (II), and the other terminal region is represented by formula (III).

7. The compound or a salt thereof according to claim 1, wherein, R1, R2, and R3 are each independently unsubstituted or straight-chain C 1-18 alkyl, 6-membered saturated or unsaturated carbocyclic group, 6-membered saturated or unsaturated carbocyclic alkyl group, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)-substituted straight-chain C 1-25 alkyl or branched-chain C 3-32 alkyl, Rx' is hydrogen, a straight-chain C 1-25 alkyl, a branched-chain C 3-25 alkyl, a straight-chain C 5-30 alkenyl, a branched-chain C 5-30 alkenyl, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, and Rx' is unsubstituted or substituted by one or more Rx″, Rx″ is a hydroxyl group, a straight-chain C 1-15 alkyl group, a branched-chain C 3-15 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered monounsaturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group.

8. The compound or a salt thereof according to claim 1, wherein R1, R2, and R3 are each independently an unsubstituted or a linear C 2-18 alkyl group, a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclic alkyl group, -Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)-, or a linear C 1-25 alkyl group or a branched C 3-32 alkyl group, Rx' is hydrogen, straight-chain C 1-25 alkyl, branched-chain C 3-25 alkyl, straight-chain C 5-30 alkenyl, branched-chain C 5-30 alkenyl, 6-membered saturated or unsaturated carbocyclic group, 6-membered saturated or unsaturated carbocyclic group, 6-membered saturated or unsaturated carbocyclic group alkyl, 6-membered saturated or unsaturated heterocyclic group or 6-membered saturated or unsaturated heterocyclic group alkyl, and Rx' is unsubstituted or substituted by one or more Rx″, and Rx″ is a hydroxyl group, a linear C 1-15 alkyl group, a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclic alkyl group, a 6-membered saturated or unsaturated heterocyclic group, or a 6-membered saturated or unsaturated heterocyclic alkyl group.

9. The compound or its salt according to claim 1, wherein p and / or n is an integer from 1 to 10.

10. The compound or its salt according to claim 1, wherein, R4 is hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-30 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, and R4 is unsubstituted or substituted by one or more groups selected from Rx″, Rx'-CH=CH-, -CH=CH-, Rx'-C(=O)-O-, -C(=O)-O-, Rx'-O-C(=O)-, and -O-C(=O)- Rx' is a straight-chain C 1-25 alkyl, branched-chain C 3-30 alkyl, straight-chain C 5-30 alkenyl or branched-chain C 5-30 alkenyl, and is unsubstituted or substituted by one or more Rx″, and Rx″ is a hydroxyl group, a straight-chain C 1-15 alkyl group, a branched-chain C 3-15 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group or a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group.

11. The compound or a salt thereof according to claim 1, wherein One of the linking groups 1 and 2 is an unsubstituted or hydroxyl, -NR A R B - or amine-substituted straight-chain C 1-3 alkyl, an unsubstituted or hydroxyl, NR A R B - or amine-substituted branched-chain C 3-6 alkyl or an unsubstituted or hydroxyl, NR A R B - or amine-substituted straight-chain C 1-3 alkylene group.

12. The compound or a salt thereof according to claim 1, wherein The compound or a salt thereof is represented by formula (V): wherein r is an integer from 1 to 10, Q is -C(=O)-O- or -O-C(=O)-, R 10 is a straight-chain C 1-25 alkyl or a branched C 3-35 alkyl, or is a group represented by formula (VI), wherein the straight-chain C 1-25 alkyl or the branched C 3-35 alkyl is unsubstituted or substituted by one or more groups selected from a hydroxyl group, a straight-chain C 5-30 alkenyl, a branched C 5-30 alkenyl, -NR C R D and an amine group, and R C and R D are each independently a straight-chain C 1-6 alkyl, R 12 is hydrogen, a straight-chain C 1-25 alkyl group, a straight-chain C 1-25 alkyl group substituted by a hydroxyl group, a straight-chain C 1-25 alkyl group substituted by a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclic alkyl group or a group represented by formula (VI), where the wavy line represents the bonding position, U is -C(=O)-O- or -O-C(=O)-, q is an integer of 0 or 1, s is an integer from 1 to 10, R 11 、R 13 and R 14 are each independently hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-35 alkyl group or a 6-membered saturated or unsaturated carbocyclic alkyl group, wherein the straight-chain C 1-25 alkyl group, the branched-chain C 3-35 alkyl group or the 6-membered saturated or unsaturated carbocyclic alkyl group is unsubstituted or substituted with at least one selected from the group consisting of a hydroxyl group, a C 1-6 alkyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, R a -S-S-, -S-S-, R a -CH=CH-, -CH=CH-, R a -C(=O)-O-, -C(=O)-O-, R a -O-C(=O)-, -O-C(=O)-, an unsubstituted or R b -substituted 3- to 6-membered saturated or unsaturated carbocyclic group, an unsubstituted or R b -substituted 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, an unsubstituted or R b -substituted 3- to 6-membered saturated or unsaturated heterocyclic group and an unsubstituted or Rb-substituted 3- to 6-membered saturated or unsaturated heterocyclic alkyl group. R a is hydrogen, a straight-chain C 1-25 alkyl group, a branched-chain C 3-25 alkyl group, a straight-chain C 5-30 alkenyl group, a branched-chain C 5-30 alkenyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, and R a is unsubstituted or substituted by R b substituent, R b is a straight-chain C 1-15 alkyl group, a straight-chain C 1-15 alkyl group substituted by a hydroxyl group, a branched-chain C 3-15 alkyl group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic group, a 3- to 6-membered saturated or unsaturated carbocyclic alkyl group, a 3- to 6-membered saturated or unsaturated heterocyclic group, or a 3- to 6-membered saturated or unsaturated heterocyclic alkyl group, The carbocyclic group is a cyclic group composed of carbon and hydrogen atoms, The heterocyclic group is a cyclic group containing one or more heteroatoms selected from N, S or O, The carbocyclic group alkyl is a carbocyclic group - straight-chain C 1-6 alkyl or a carbocyclic group - branched-chain C 3-6 alkyl, and Heterocyclic alkyl is heterocyclic group-linear C 1-6 alkyl or heterocyclic group-branched C 3-6 alkyl.

13. The compound or a salt thereof according to claim 12, wherein R 10 is a straight-chain C 1-25 alkyl or a branched C 3-35 alkyl and is unsubstituted or substituted with a hydroxyl group, a straight-chain C 5-30 alkenyl, a branched C 5-30 alkenyl, -NR C R D or an amino group, or is a group represented by formula (VI), R C and R D are each independently a straight-chain C 1-3 alkyl, and R 12 is hydrogen, a straight-chain C 1-6 alkyl group, a straight-chain C 1-25 alkyl group substituted with a hydroxyl group, a straight-chain C 1-6 alkyl group substituted with a 6-membered saturated or unsaturated carbocyclic group, a 6-membered saturated or unsaturated carbocyclic alkyl group, or a group represented by formula (VI).

14. The compound or its salt according to claim 1, wherein, The compound is selected from: (1) Tetrakis(2-ethylhexyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (2) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetrakis(butane-4,1-diyl)tetrapentanoate; (3) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetrakis(butane-4,1-diyl)tetraheptanoate; (4) ((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butane-4,1-diyl) tetranonanoate; (5) Tetrakis(octan-3-yl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (6) Tetrakis(4-(2-cyclohexylacetoxy)butyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (7) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butane-4,1-diyl) tetrahentriacontanoate; (8) Tetrakis(4-(propionyloxy)butyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (9) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(ethane-2,1-diyl) tetraheptanoate; (10) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(propane-3,1-diyl) tetrahexanoate; (11) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(pentane-5,1-diyl) tetrabutanoate; (12) Tetrakis(2-ethylhexyl) 4,4',4”,4”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrabutanoate; (13) Tetrakis(2-ethylhexyl) 6,6',6”,6”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrahexanoate; (14) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(hexane-6,1-diyl) tetra(2-hexyldecanoate); (15) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(octane-8,1-diyl) tetra(2-hexyldecanoate); (16) (((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl) octakis(decanoate)); (17) Tetrakis(2-ethylhexyl) 8,8',8”,8”'-((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(octanoate); (18) ((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butane-4,1-diyl) tetrakis(2-hexyldecanoate); (19) (((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl) octakis(hexanoate); (20) (((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(methylene))tetrakis(propane-2,1,3-triyl) octakis(octanoate); (21) Tetrakis(2-propylhexyl) 4,4',4”,4”'-((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butanoate); (22) Tetrakis(2-ethylpentyl) 4,4',4”,4”'-((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(butanoate); (23) Tetrakis(2-propylhexyl) 6,6',6”,6”'-((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(hexanoate); (24) Tetrakis(2-propylhexyl) 8,8',8”,8”'-((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(octanoate); (25) Tetrakis(2-ethylpentyl) 6,6',6”,6”'-((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(hexanoate); (26) Tetrakis(2-ethylpentyl) 8,8',8”,8”'-((3,3',3”,3”'-((Piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrakis(propionyl))tetrakis(oxy))tetrakis(octanoate); (27) Bis(heneicosan-10-yl) 3,3'-((3-(4-(3-hydroxypropyl)piperazin-1-yl)propyl)azanediyl)dipropionate; (28) ((3,3'-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl)azanediyl)bis(propionyl))bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate); (29) ((3,3'-((3-(4-(3-hydroxypropyl)piperazin-1-yl)propyl)azanediyl)bis(propionyl))bis(oxy))bis(hexane-6,1-diyl) bis(2-hexyldecanoate); (30) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanediyl))dipropionate; (31) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(benzylazanediyl))dipropionate; (32) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate; (33) Tetrakis((Z)-non-2-en-1-yl) 9,9',9”,9”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate; (34) Tetrakis((Z)-non-2-en-1-yl) 6,6',6”,6”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetrahexanoate; (35) Tetrakis((Z)-non-2-en-1-yl) 4,4',4”,4”'-((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetrabutanoate; (36) Bis(heneicosan-10-yl) 3,3'-((3-(4-(3-((3-(heneicosan-10-yloxy)-3-oxopropyl)amino)propyl)piperazin-1-yl)propyl)azanediyl)dipropionate; (37) (6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl 3-((3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl)(methyl)amino)propionate; (38) (6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl 3-((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)(methyl)amino)propionate; (39) Bis((6Z,16Z)-12-((Z)-dec-4-en-1-yl)docosa-6,16-dien-11-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate; (40) Tetrakis(2-(2-cyclohexylacetoxy)ethyl) 3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetrapropionate; (41) Bis(4-(2-cyclohexylacetoxy)butyl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate; (42) (((3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))bis(propionyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl) tetrahexanoate; (43) Bis(octan-3-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(methylazanediyl))dipropionate; (44) (((3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis((3-(octan-3-yloxy)-3-oxopropyl)azanediyl))bis(propionyl))bis(oxy))bis(methylene))bis(propane-2,1,3-triyl) tetrahexanoate; (45) ((3,3',3”,3”'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis(azanetriyl))tetra(propionyl))tetra(oxy))tetra(butane-4,1-diyl) tetra(3-ethylvalerate); (46) Bis(heneicosan-10-yl) 3,3'-((piperazine-1,4-diylbis(propane-3,1-diyl))bis((4-hydroxybutyl)azanediyl))dipropionate; (47) Bis(2-ethylhexyl) 3,3'-((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)azanediyl)dipropionate; (48) ((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)azanediyl)bis(hexane-6,1-diyl) bis(2-hexyldecanoate); and (49) Bis((Z)-non-2-en-1-yl) 9,9'-((3-(4-(3-(dimethylamino)propyl)piperazin-1-yl)propyl)azanediyl)dinonanoate.

15. A lipid nanoparticle comprising a compound or a salt thereof according to any one of claims 1 to 14, a helper lipid, cholesterol, and a PEG lipid.

16. The lipid nanoparticle according to claim 15, wherein, The helper lipid is a phospholipid.

17. A composition comprising: An ionizable drug; and (i) a compound or a salt thereof according to any one of claims 1 to 14, or (ii) a lipid nanoparticle comprising a compound or a salt thereof according to any one of claims 1 to 14, a helper lipid, cholesterol, and a PEG lipid.

18. The composition according to claim 17, wherein, The ionizable drug is one or more selected from nucleic acids or nucleic acid-based drugs, peptides, protein drugs, protein-nucleic acid constructs, and ionizable biopolymer-drug conjugates.

19. The composition according to claim 18, wherein, The nucleic acid is selected from one or more of antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA), self-amplifying RNA (SAM), circular RNA, messenger RNA (mRNA), crRNA, tracrRNA, single guide RNA (sgRNA), transfer RNA (tRNA), asymmetric interfering RNA (aiRNA), antagomir, ribozyme, dicer substrate RNA, short hairpin RNA (shRNA), plasmid DNA (pDNA), double-stranded DNA (dsDNA), partial double-stranded DNA, triple-stranded DNA, partial triple-stranded DNA, single-stranded DNA (ssDNA), double-stranded RNA (dsRNA), locked nucleic acid (LNA), peptide nucleic acid (PNA), miRNA mimics or anti-miRNA.

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