Lipid molecules for delivering active ingredients and use thereof

Abstract

The application discloses preparation and application of lipid molecules and compositions thereof for delivering active ingredients, and relates to the field of biological medicine. The novel lipid molecules comprise general formula (I), (II) or (III): and can be used for delivering active ingredients (such as nucleic acids, polypeptides, proteins) to cells and / or organs. Embodiments of the application provide nucleic acid-lipid nanoparticle compositions of various novel lipid molecules, and a lipid nanoparticle delivery system composed of the same is used for delivering mRNA; the delivery efficiency is superior to that of the currently marketed product DLin-MC3-DMA at both a cell level and an animal level, and the lipid molecules can be used as a novel method for delivering nucleic acid drugs and promote development of nucleic acid drugs.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to the preparation and application of lipid molecules and their compositions for delivering active ingredients. Background Technology

[0002] Following small molecule drugs and antibody drugs, nucleic acid drugs have become the third wave of modern pharmaceutical development. Nucleic acid drugs typically involve introducing specific nucleic acid molecules into target cells or tissues to replace, compensate for, block, or modify specific genes, thereby achieving the purpose of disease prevention and treatment. Although nucleic acid drugs have significant advantages, the presence of nucleases in serum leads to the rapid degradation of nucleic acids, and the negative charge of nucleic acid molecules makes it difficult for them to cross cell membranes, resulting in extremely short half-lives that prevent them from entering cells and achieving therapeutic effects. Therefore, it is necessary to develop specific compounds and delivery systems to improve this situation and promote nucleic acid drugs as an important means of disease prevention and treatment.

[0003] Currently, lipid-containing nanoparticle compositions have been validated as a safe and efficient carrier for delivering active ingredients. These compositions can block RNA degradation in serum and promote cellular uptake of oligonucleotides, effectively delivering not only nucleic acid molecules but also small molecule drugs, peptide drugs, and protein drugs to target cells and / or organs. Although various lipid-containing compositions have been disclosed, their safety, efficacy, and specificity require further improvement. Therefore, the design and screening of new lipid molecules and their nanoparticle compositions for the delivery of various specific nucleic acid molecules remains crucial. Summary of the Invention

[0004] The purpose of this invention is to provide a novel lipid molecule and a nanoparticle composition comprising the lipid molecule, such nanoparticle composition being capable of delivering active ingredients to cells and / or organs according to the relevant methods of this invention.

[0005] The technical solution adopted by the present invention to achieve the above objectives is as follows:

[0006] Lipid molecules used for delivering active ingredients include: lipid compounds represented by general formulas (I), (II), and (III), or their pharmaceutically available salts, stereoisomers, tautomers, solvates, chelates, and non-covalent complexes;

[0007] in,

[0008] M is selected from benzene ring, cyclobutane, cyclopentyl, cyclohexyl, pyrrole ring, pyridine, piperazine, imidazole, biphenyl, naphthalene ring, anthracene ring, pyrimidine ring, or 4-8 membered heterocycles;

[0009] G1 and G'1 are each independently selected from -(CH2) x-O(C=O)-, -(CH2) x -(C=O)O-, -(CH2) x -(C=O)S-、-(CH2) x -(C=O)NH-, -(CH2) x -O-、-(CH2) x -O(C=O)NH-, -(CH2) x -O(C=O)O-、-(CH2) x One of NH(C=O)-, where x is an integer between 0 and 4;

[0010] L1 and L'1 are each independently selected from unsubstituted C 1-6 One of the alkyl groups;

[0011] G2 is selected from -(CH2) 0-3 -、-O-(CH2) y -(C=O)O-, -(CH2) y -(C=O)O-, -(CH2) y -(C=O)NH-, -S-(CH2) y -(C=O)O-, -(CH2) y One of -(C=O)S-, -S-, and -O-, where y is an integer between 0 and 4;

[0012] G1, G'1, and G2 are each independently connected to any site in M, where the sites are either carbon or nitrogen atoms.

[0013] X is selected from carbon or nitrogen atoms; n is selected from an integer between 0 and 6.

[0014] L2 is selected from H, OH, C 1-3 Alkyl, C 2-3 One of the alkenyl groups;

[0015] L3 and L4 are each independently selected from C 0-25 Alkyl, C 2-25 alkenyl, C 3-25 One of the alkynyl groups;

[0016] G3 and G4 are each independently selected from one of the following: -CH2-, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -(C=O)NH-, -NH(C=O)-, -S(C=O)-, -(C=O)S-, -SS-;

[0017] L5 and L6 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl, C 3-25 One of the alkynyl groups;

[0018] R1, R2 and R'1, R'2 are each independently selected from any substituted or unsubstituted C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of them, wherein the substituents are 1, 2, 3, 4, or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl group; X1 and X2 are each independently selected from C1. 1-3 alkyl;

[0019] or

[0020] R1 and R2, R'1 and R'2 combine to form substituted or unsubstituted 4-8 membered heterocycles, pyrimidine rings, or purine rings; wherein the substituents are 1, 2, 3, 4, or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl;

[0021] In formula (II), Z is selected from H, F, -OH, -SH-, -NH2, -CF3, and -NH-(CH2). r CH3, -N(CH3)-(CH2) r One of CH3, where r is an integer between 0 and 4;

[0022] In formula (Ⅲ), Z' is selected from H or C with arbitrary substitution or no substitution. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 One of cycloalkynyl, phenyl, or 4-8 membered heterocycles, wherein the substituents are one or two independent OH, SH, or C groups. 1-3 Hydroxyl group, C 1-3 Alkoxy, amino, nitro, cyano, -(C=O)OC 1-3 alkyl.

[0023] In some embodiments, the lipid compound of general formula (I) above comprises the structure shown in formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically available salt, stereoisomer, tautomer, solvate, chelate, or non-covalent complex thereof;

[0024]

[0025] In some embodiments, the lipid compounds of general formula (II) above include structures shown in formulas (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), or (IIh), or pharmaceutically available salts, stereoisomers, tautomers, solvates, chelates, or non-covalent complexes thereof.

[0026]

[0027] In some embodiments, the lipid compound of general formula (III) above comprises the structure shown in formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically available salt, stereoisomer, tautomer, solvate, chelate or non-covalent complex thereof;

[0028]

[0029] Among them, G1 and G'1 are each independently selected from -(CH2). x -O(C=O)-, -(CH2) x -(C=O)O-, -(CH2) x -(C=O)S-、-(CH2) x -(C=O)NH-, -(CH2) x -O-、-(CH2) x -O(C=O)NH-, -(CH2) x -O(C=O)O-、-(CH2) x One of NH(C=O)-, where x is an integer between 0 and 4;

[0030] L1 and L'1 are each independently selected from unsubstituted C 1-6 One of the alkyl groups;

[0031] G1 and G'1 are each independently attached to any site in the benzene ring;

[0032] Z' is selected from H or C, whether substituted or unsubstituted. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8One of the following: cycloalkynyl, phenyl, or 4-8 membered heterocycles; wherein the substituents are one or two independent OH, SH, or C groups. 1-3 Hydroxyl group, C 1-3 Alkoxy, amino, nitro, cyano, -(C=O)OC 1-3 alkyl;

[0033] R1, R2 and R'1, R'2 are each independently selected from any substituted or unsubstituted C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of them, wherein the substituents are 1, 2, 3, 4, or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl group; X1 and X2 are each independently selected from C1. 1-3 alkyl;

[0034] or

[0035] R1 and R2, R'1 and R'2 combine to form substituted or unsubstituted 4-8 membered heterocycles, pyrimidine rings, or purine rings; wherein the substituents are 1, 2, 3, 4, or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl;

[0036] E is selected from oxygen or sulfur atoms;

[0037] m is an integer between 0 and 4;

[0038] T includes one of the structures shown in equations (1) to (18):

[0039]

[0040] In some embodiments, the above-mentioned lipid compound, wherein and Each is independently selected from one of the structures shown in formulas Y01-Y30:

[0041]

[0042] In some embodiments, the lipid molecules are selected from one or more of the following compounds:

[0043]

[0044]

[0045]

[0046] The present invention also provides a nanoparticle composition comprising one or more of the lipid compounds described above.

[0047] In some embodiments, the above-described nanoparticle composition further comprises therapeutic and / or preventative agents.

[0048] In some embodiments, the therapeutic and / or preventive agents described above are encapsulated within or associated with nanoparticles.

[0049] In some embodiments, the therapeutic and / or preventive agents comprise nucleic acids, small molecule compounds, peptides, or proteins; the nucleic acids comprise at least one of single-stranded DNA, double-stranded DNA, short isomers, agomir, antagomir, antisense molecules, small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer-substrate RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), circular RNA (circRNA), and aptamers.

[0050] In some implementations, the aforementioned nucleic acid also includes mRNA.

[0051] In some embodiments, the nanoparticle composition further comprises one or more neutral lipids, one or more steroidal compounds, and one or more polymer-conjugated lipids; wherein the molar percentage of the lipid molecules used to deliver the active ingredient is 20-100%; the molar percentage of the steroidal compounds is 0-80%; the molar percentage of the neutral lipids is 0-40%; and the molar percentage of the polymer-conjugated lipids is 0-20%.

[0052] Preferably, the molar percentage of lipid molecules used for delivering the active ingredient is 20-95%; the molar percentage of the steroidal compound is 5-80%; the molar percentage of the neutral lipid is 5-40%; and the molar percentage of the polymer-conjugated lipid is 10-20%.

[0053] In some embodiments, the aforementioned neutral lipids comprise 1,2-distearyl-sn-glycerol-3-phosphate choline (DSPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphate choline (DPPC), 1,2-dimyristoyl-sn-glycerol-3-phosphate choline (DMPC), 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphate choline (POPC), 1,2-dioleoyl-sn-glycerol-3-phosphate choline (DOPC), and 1,2-dioleoyl- At least one of the following: sn-glycerol-3-phosphate ethanolamine (DOPE), palmitoyl oleoyl phosphatidyl ethanolamine (POPE), distearate-phosphatidyl-ethanolamine (DSPE), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoyl phosphate ethanolamine (DMPE), 1-stearoyl-2-oleoyl-stearoyl ethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin (SM), ceramide, sterol and its derivatives.

[0054] In some embodiments, the aforementioned steroidal compounds comprise at least one of cholesterol, coprosterol, nonsterol, sitosterol, ergosterol, campesterol, stigmasterol, brassosterol, tomatine, ursolic acid, α-tocopherol, corticosteroids and their derivatives.

[0055] In some embodiments, the polymer-conjugated lipids comprise at least one of polyethylene glycol-modified phosphatidylethanolamine, polyethylene glycol-modified phosphatidic acid, polyethylene glycol-modified ceramide, polyethylene glycol-modified dialkylamine, polyethylene glycol-modified diacylglycerol, and polyethylene glycol-modified dialkylglycerol.

[0056] In some embodiments, the polymer-conjugated lipids described above comprise DMG-PEG2000 or DMPE-PEG2000.

[0057] The present invention also discloses a method for delivering nucleic acids to cells and / or organs using a nanoparticle composition containing the above-mentioned lipid compounds.

[0058] In some embodiments, the above-described nanoparticle compositions are administered via methods including, but not limited to, intravenous, intradermal, subcutaneous, or nasal administration.

[0059] The present invention also discloses the application of the above-mentioned nanoparticle composition in drug preparation.

[0060] It should be noted that the above-mentioned drugs include nucleic acid drugs, nucleic acid vaccines, small molecule drugs, peptide drugs, protein drugs, etc.

[0061] This invention develops a novel lipid molecule that can be used to deliver active ingredients (such as nucleic acids, peptides, and proteins) to cells and / or organs. Embodiments of this invention provide various nucleic acid-lipid nanoparticle compositions comprising the novel lipid molecule described herein, forming lipid nanodelivery systems for mRNA delivery. These systems demonstrate superior delivery efficiency compared to currently marketed products like DLin-MC3-DMA at both cellular and animal levels, and can serve as a novel method for nucleic acid drug delivery, thus promoting the development of nucleic acid drugs.

[0062] The lipid compounds prepared by this invention can deliver nucleic acid molecules, small molecule compounds, peptides or proteins, etc. The carriers prepared using the lipid compounds of this invention have high encapsulation efficiency for nucleic acid molecules, which can successfully transport nucleic acid molecules into cells and / or organs and express them efficiently. Furthermore, the nanoparticle compositions prepared by this invention can effectively deliver mRNA in animals and express related proteins at high levels. Attached Figure Description

[0063] Figure 1 The nuclear magnetic resonance spectrum of IBMC-001;

[0064] Figure 2 The nuclear magnetic resonance spectrum of IBMC-002;

[0065] Figure 3 The nuclear magnetic resonance spectrum of IBMC-003;

[0066] Figure 4 The nuclear magnetic resonance spectrum of IBMC-004;

[0067] Figure 5 The nuclear magnetic resonance spectrum of IBMC-005;

[0068] Figure 6 The nuclear magnetic resonance spectrum of IBMC-006;

[0069] Figure 7 The nuclear magnetic resonance spectrum of IBMC-007;

[0070] Figure 8 The nuclear magnetic resonance spectrum of IBMC-011;

[0071] Figure 9 The nuclear magnetic resonance spectrum of IBMC-012;

[0072] Figure 10 The nuclear magnetic resonance spectrum of IBMC-015;

[0073] Figure 11 The nuclear magnetic resonance spectrum of IBMC-018;

[0074] Figure 12 The nuclear magnetic resonance spectrum of IBMC-019;

[0075] Figure 13 The nuclear magnetic resonance spectrum of IBMC-020;

[0076] Figure 14 The nuclear magnetic resonance spectrum of IBMC-023;

[0077] Figure 15 The nuclear magnetic resonance spectrum of IBMC-024;

[0078] Figure 16 The nuclear magnetic resonance spectrum of IBMC-025;

[0079] Figure 17 The nuclear magnetic resonance spectrum of IBMC-028;

[0080] Figure 18 The nuclear magnetic resonance spectrum of IBMC-029;

[0081] Figure 19 The nuclear magnetic resonance spectrum of IBM C-030;

[0082] Figure 20 The nuclear magnetic resonance spectrum of IBMC-031;

[0083] Figure 21 The nuclear magnetic resonance spectrum of IBMC-034;

[0084] Figure 22 The nuclear magnetic resonance spectrum of IBMC-035;

[0085] Figure 23 The nuclear magnetic resonance spectrum of IBMC-036;

[0086] Figure 24 The nuclear magnetic resonance spectrum of IBMC-037;

[0087] Figure 25 The nuclear magnetic resonance spectrum of IBMC-040;

[0088] Figure 26 The nuclear magnetic resonance spectrum of IBMC-041;

[0089] Figure 27 The nuclear magnetic resonance spectrum of IBMC-042;

[0090] Figure 28 The nuclear magnetic resonance spectrum of IBMC-043;

[0091] Figure 29 The nuclear magnetic resonance spectrum of IBMC-044;

[0092] Figure 30 The nuclear magnetic resonance spectrum of IBMC-048;

[0093] Figure 31 The nuclear magnetic resonance spectrum of IBMC-051;

[0094] Figure 32 The nuclear magnetic resonance spectrum of IBMC-052;

[0095] Figure 33 The nuclear magnetic resonance spectrum of IBMC-053;

[0096] Figure 34 The nuclear magnetic resonance spectrum of IBMC-054;

[0097] Figure 35 The nuclear magnetic resonance spectrum of IBMC-055;

[0098] Figure 36 The nuclear magnetic resonance spectrum of IBMC-056;

[0099] Figure 37 The nuclear magnetic resonance spectrum of IBMC-057;

[0100] Figure 38 The nuclear magnetic resonance spectrum of IBMC-058;

[0101] Figure 39 The nuclear magnetic resonance spectrum of IBMC-059;

[0102] Figure 40 The nuclear magnetic resonance spectrum of IBM C-060;

[0103] Figure 41 The nuclear magnetic resonance spectrum of IBMC-061;

[0104] Figure 42 The nuclear magnetic resonance spectrum of IBMC-062;

[0105] Figure 43 The nuclear magnetic resonance spectrum of IBMC-066;

[0106] Figure 44 Graphs showing the effect of lipid nanoparticle compositions on EGFP mRNA transfection in cells under different N / P ratios;

[0107] Figure 45 The transfection effect of the lipid nanoparticle composition on HeLa cells;

[0108] Figure 46 The transfection effect of the lipid nanoparticle composition on 293T cells;

[0109] Figure 47Results of in vivo delivery level tests for lipid nanoparticle compositions (LNP formulations) using different injection methods;

[0110] Figure 48 Results of in vivo delivery level testing of lipid nanoparticle compositions (LNP formulations) at different time points;

[0111] Figure 49 To deliver SARS-CoV2 in vivo using a lipid nanoparticle composition (LNP formulation), Spike induced the expression level of the S protein in muscle;

[0112] Figure 50 In vivo delivery of SARS-CoV2 Spike to the liver to induce the expression level of S protein;

[0113] Figure 51 Spike induces the expression level of SARS-CoV2 S protein in blood by delivering SARS-CoV2 in vivo using a lipid nanoparticle composition (LNP formulation). Detailed Implementation

[0114] The technical solution of the present invention will be further described in detail below with reference to specific embodiments and accompanying drawings:

[0115] Lipid molecules represented by general formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), and (IIIc) are synthesized; all of the above lipid molecules can be synthesized using a modular approach. In specific embodiments of the present invention, unless otherwise specified, all raw materials and reagents used are commercially available and require no further purification.

[0116] Example 1: The synthesis route of IBMC-001 is shown in the following formula:

[0117]

[0118] The specific synthesis steps of IBMC-001 are as follows: Step 1: Synthesis of Bi-12: 79 mmol Bi-01 (5-hydroxyisophthalic acid), 160 mmol benzyl bromide and 240 mmol sodium bicarbonate were dissolved in 100 mL DMF and stirred at 40 °C for 8 h. The reactants were diluted with dichloromethane and washed with saturated sodium bicarbonate, washed with sodium chloride, dried with anhydrous sodium sulfate and evaporated to dryness. The solution was purified by silica gel column chromatography to obtain Bi-12 (14.2 g, 49.58%). 1H NMR (400MHz, Chloroform-d) δ8.31 (s, 1H), 7.79 (d, J = 1.5Hz, 2H), 7.51–7.29 (m, 10H), 6.41 (s, 1H), 5.37 (s, 4H).

[0119] Step 2: Synthesis of Bi-13: 10 mmol Bi-12, 20 mmol tert-butyl bromoacetate and 30 mmol potassium carbonate were dissolved in 100 mL acetonitrile and stirred at 70 °C for 8 h. The reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness, and purified by silica gel column chromatography to obtain Bi-13 (4.35 g, 90.52%). 1 H NMR (400MHz, Chloroform-d) δ8.39(t,J=1.4Hz,1H),7.77(d,J=1.4Hz,2H),7.47–7.32(m,10H),5.37(s,4H),4.58(s,2H),1.47(s,9H).

[0120] Step 3: Synthesis of Bi-14: 6 mmol of Bi-13 was dissolved in 50 mL of a 4 / 1 mixture of trifluoroacetic acid and dichloromethane. The mixture was stirred at room temperature for 12 h, the solvent was evaporated to dryness, the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then evaporated to dryness. The mixture was purified by silica gel column chromatography to obtain Bi-14 (1.92 g, 77.05%). 1 H NMR (400MHz, Chloroform-d) δ8.40(t,J=1.4Hz,1H),7.80(d,J=1.4Hz,2H),7.48–7.30(m,11H),5.37(s,4H),4.75(s,2H).

[0121] Step 4: Synthesis of Bi-140013: 1.52 mmol Bi-14 and 3.04 mmol T-13 were dissolved in 50 mL dichloromethane, and 3.04 mmol of 4-dimethylaminopyridine and 4.56 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain Bi-140013 (1.56 g, 83.78%). 1H NMR(400MHz,Chloroform-d)δ8.39(s,1H),7.80(d,J=1.4Hz,2H),7.46–7.34(m,10H),5.37(s,4H),5.04–4.97(m,1H),4 .69(s,2H),4.05(dt,J=13.4,6.6Hz,4H),2.30(td,J=9.0,4.4Hz,2H),1.68–1.19(m,64H),0.87(tt,J=7.1,2.2Hz,12H).

[0122] Step 5: Synthesis of Bi-150013: 1.11 mmol Bi-140013 and 100 mg Pd / C were dissolved in 50 mL methanol, hydrogen gas was introduced, and the mixture was stirred at room temperature for 8 h. After filtration, the filtrate was dried under rotary evaporation to obtain Bi-150013 (682 mg, 79.95%). 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H),7.80(s,2H),5.01(s,1H),4.74(s,2 H), 4.05 (d, J = 7.1Hz, 4H), 2.31 (s, 2H), 1.67–1.16 (m, 64H), 0.90-0.83 (m, 12H).

[0123] Step 6: Synthesis of IBMC-001: 0.067 mmol Bi-150013 and 0.266 mmol N-methyldiethanolamine were dissolved in 5 mL dichloromethane, and 0.1995 mmol 4-dimethylaminopyridine and 0.3325 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain IBMC-001 (41 mg, 55.79%). 1 ¹H NMR (400MHz, Chloroform-d) δ 8.33 (s, 1H), 7.78 (d, J = 1.4 Hz, 2H), 5.01 (t, J = 6.3 Hz, 1H), 4.72 (s, 2H), 4.44 (t, J = 5.6 Hz, 4H), 4.04 (t, J = 6.6 Hz, 4H), 3.61 (t, J = 5.3 Hz, 4H), 2.86 (t, J = 5.6 Hz, 4H), 2.65 (t, J = 5.3 Hz, 4H), 2.38 (s, 6H), 2.30 (s, 2H), 1.66–1.19 (m, 64H), 0.87 (t, J = 6.7 Hz, 12H), [NMR spectrum is shown in the original text]. Figure 1 As shown.

[0124] The synthesis route for the T-13 is shown in the following formula:

[0125]

[0126] The specific steps for synthesizing the T-13 are as follows:

[0127] Step 1: Synthesis of T-3-3: In a three-necked flask, 48.7 mmol of TosMIC was weighed and dissolved in 150 mL of DMSO. Under ice bath conditions, 166 mmol of NaH, 107.2 mmol of T-3-1 (5-bromopentyl acetate) and 9.7 mmol of TBAI were added to the reaction flask. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was completed, ice water was added to the reaction solution, and the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain intermediate T-3-2 (20.9 g, 95%), which was then directly proceeded to the next step. 20.9 g of T-3-2 was dissolved in 250 mL of dichloromethane, and 50 mL of saturated concentrated hydrochloric acid was added dropwise. After stirring for 1 h, water was added to the reaction solution, and the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain T-3-3 (7.5 g, 53.9%). 1 H NMR (400MHz, CDCl3) δ4.05 (t, J = 6.76 Hz, 4H), 2.42 (t, J = 7.44, 4H), 2.04 (s, 6H), 1.56-1.67 (m, 8H), 1.30-1.39 (m, 4H).

[0128] Step 2: Synthesis of T-3-4: 24.4 mmol of T-3-3 was dissolved in 100 mL of a methanol / water (4:1) mixture, 73 mmol of sodium hydroxide was added, the mixture was stirred at 40 °C for 4 h, methanol was removed by rotary evaporation, the mixture was extracted with ethyl acetate, concentrated and separated by column chromatography to obtain T-3-4 (3.5 g, 71%). 1 H NMR (400MHz, CDCl3) δ3.65 (t, J = 6.50 Hz, 4H), 2.42 (t, J = 7.31, 4H), 1.54-1.64 (m, 8H), 1.30-1.39 (m, 4H).

[0129] Step 3: Synthesis of T-3-5: 17.3 mmol of T-3-4 and 51.98 mmol of 2-hexyldecanoic acid were dissolved in 100 mL of dichloromethane, and then 34.6 mmol of 4-dimethylaminopyridine and 34.6 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was stirred overnight at room temperature, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain T-3-5 (9.5 g, 80.9%). 1H NMR (400MHz, CDCl3) δ (ppm) 4.06 (t, J = 6.63Hz, 4H), 2.40 (t, J = 7.42Hz, 4H), 2.27 -2.34(m,2H),1.55-1.66(m,16H),1.25-1.28(m,44H),0.87(t,J=13.38Hz,12H).

[0130] Step 4: Synthesis of T-13: 14 mmol of T-3-5 was dissolved in 150 mL of methanol, 56 mmol of sodium borohydride was added, and the mixture was stirred at room temperature for 3 h. Then, 50 mL of ice water was added to quench the mixture, followed by extraction with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, and evaporation and concentration to obtain T-13 (9.5 g, 99%). 1 H NMR (400MHz, CDCl3) δ4.00 (t, J = 6.61Hz, 4H), 3.51-3.52 (m, 1H), 2.20-2.27 (m, 2H), 1.48-1.60(m,8H),1.26-1.42(m,12H),1.18-1.25(s,44H),0.80(t,J=13.31,12H).

[0131]

[0132] The specific synthesis steps of IBMC-002 differ from those in Example 1:

[0133] 1) The difference between the synthesis steps of Bi-140011 and Bi-140013 is that T-11 is used instead of T-13;

[0134] 2) The difference between the synthesis steps of Bi-150011 and Bi-150013: Bi-140011 is used instead of Bi-140013.

[0135] The proton spectrum of IBMC-002: 1 ¹H NMR (400MHz, Chloroform-d) δ 8.31 (s, 1H), 7.78 (s, 2H), 5.00 (p, J = 6.0Hz, 1H), 4.71 (s, 2H), 4.46 (t, J = 5.6Hz, 4H), 4.03 (td, J = 6.5, 4.4Hz, 4H), 3.64 (t, J = 5.3Hz, 4H), 2.92 (t, J = 5.6Hz, 4H), 2.70 (t, J = 5.3Hz, 4H), 2.42 (s, 6H), 2.28 (q, J = 7.5, 6.8Hz, 3H), 1.64–1.17 (m, 52H), 0.86 (t, J = 6.6Hz, 9H), ¹H NMR spectrum as shown. Figure 2 As shown.

[0136] The T-11 synthesis route is shown in the following formula:

[0137]

[0138] The specific steps for the synthesis of the T-11 are as follows:

[0139] Step 1: Synthesis of T-3-7: 17.3 mmol of T-3-4 and 4.32 mmol of 2-hexyldecanoic acid were dissolved in 50 mL of dichloromethane, and then 8.64 mmol of 4-dimethylaminopyridine and 8.64 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was stirred overnight at room temperature, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain T-3-7 (1.7 g, 90%). 1 H NMR(400MHz, CDCl3)δ4.06(t,J=6.63Hz,2H),3.65(t,J=6.51,2H),2.39-2.43(m,4H ),2.27-2.34(m,1H),1.54-1.66(m,10H),1.25-1.44(m,26H),0.87(t,J=6.67,6H).

[0140] Step 2: Synthesis of T-3-8: 3.8 mmol of T-3-7 and 4.6 mmol of nonanoic acid were dissolved in 50 mL of dichloromethane, and then 7.6 mmol of 4-dimethylaminopyridine and 7.6 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was stirred overnight at room temperature, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain T-3-8 (0.9 g, 90%). 1 H NMR (400MHz, CDCl3) δ4.06 (td, J=6.6, 2.9Hz, 4H), 2.40 (t, J=7.4Hz, 4H), 2.30 (q, J=8.4,7.5Hz,3H),1.67–1.52(m,12H),1.48–1.18(m,36H),0.87(t,J=6.6Hz,9H).

[0141] Step 3: Synthesis of T-11: 1.3 mmol of T-3-8 was dissolved in 50 mL of methanol, 5.2 mmol of sodium borohydride was added, and the mixture was stirred at room temperature for 3 h. Then, 50 mL of ice water was added to quench the mixture, followed by extraction with dichloromethane, washing with saturated brine, drying with anhydrous sodium sulfate, and evaporation and concentration to obtain T-11 (0.9 g, 99%). 1H NMR (400MHz, CDCl3) δ4.07 (td, J=6.7, 3.2Hz, 4H), 3.59 (dd, J=7.5, 4.0Hz, 1H) ,2.38–2.21(m,3H),1.67–1.56(m,8H),1.48–1.22(m,44H),0.92–0.83(m,9H).

[0142] The specific synthesis steps for T-3-4 are the same as in Example 1.

[0143] Example 3: The synthesis route of IBMC-003 is shown in the following formula:

[0144]

[0145] The specific synthesis steps of IBMC-003 differ from those in Example 2: T-08 is used instead of T-11.

[0146] The proton spectrum of IBMC-003: 1 H NMR (400MHz, Chloroform-d) δ8.33 (t, J=1.5Hz, 1H), 7.79 (d, J=

[0147] 1.5 Hz, 2H), 5.00 (p, J = 6.2 Hz, 1H), 4.72 (s, 2H), 4.44 (t, J = 5.7 Hz, 4H), 3.65–3.59 (m, 4H), 2.87 (t, J = 5.6 Hz, 4H), 2.70–2.63 (m, 4H), 2.39 (s, 6H), 1.18–1.25 (m, 68H), 0.91–0.85 (m, 6H), 1H NMR spectrum as follows Figure 3 As shown.

[0148] The synthesis route for T-08 is shown in the following formula:

[0149]

[0150] The specific steps for synthesizing the T-08 are as follows:

[0151] Step 1: Synthesis of T-1-1: Under an ice-water bath, 17.8 mmol of T-1-0 (linoleic acid) was dissolved in 50 mL of THF and slowly added dropwise to 50 mL of tetrahydrofuran containing 17.8 mmol of LiAlH4. After the addition was complete, the mixture was stirred at room temperature for 2 h. After the reaction was complete, LiAlH4 was quenched with ice water, filtered, evaporated to dryness, and separated by column chromatography to obtain T-1-1 (4.5 g, 94.7%). 1H NMR (400MHz, CDCl3) δ5.29-5.42(m,4H),3.64(t,J=6.64Hz,2H),2.77(t,J=6.64Hz,2 H), 2.02-2.07 (m, 4H), 1.53-1.60 (m, 2H), 1.25-1.39 (m, 16H), 0.89 (t, J = 6.89Hz, 3H).

[0152] Step 2: Synthesis of T-1-2: Under ice-water bath, 16.9 mmol T-1-1 and 17.7 mmol CBr4 were dissolved in 100 mL of dichloromethane, and PPh3 was added. The reaction was carried out for 2 h, the solvent was evaporated, and T-1-2 (5.7 g, 90%) was obtained by column chromatography. 1 H NMR (400MHz, CDCl3) δ5.32-5.44(m,4H),3.43(t,J=6.87Hz,2H),2.79(t,J=6.49Hz,2H),2. 07(dd,J=6.81Hz,4H),1.87(t,J=14.74Hz,2H),1.26-1.46(m,16H),0.91(t,J=6.86Hz,3H).

[0153] Step 3: Synthesis of T-08: 18.29 mmol magnesium strip was added to a Shrek tube and vacuum was applied. Ultra-dry THF was added. Finally, 6 mmol of T-1-2 was dissolved in 5 mL of THF and injected into a reaction flask. After stirring at room temperature for 1 h, ethyl formate was added and stirred overnight. The reaction was quenched with water, extracted with dichloromethane, concentrated, and separated by column chromatography to obtain T-08 (0.9 g, 28%). 1 HNMR (400MHz, CDCl3) δ 5.29-5.42 (m, 8H), 3.56-3.59 (m, 1H), 2.77 (t, J = 6.41Hz, 4H), 2.02-2.07 (m, 8H), 1.23-1.47 (m, 40H), 0.89 (t, J = 6.89Hz, 6H).

[0154] Example 4: The synthesis route of IBMC-004 is shown in the following formula:

[0155]

[0156] The specific synthesis steps of IBMC-004 are as follows: Step 1: Synthesis of Bi-02: 55 mmol Bi-01 (5-hydroxyisophthalic acid) and 330 mmol boranetetrahydrofuran were dissolved in 100 mL of ultradry THF and stirred at room temperature for 24 h. The reactants were quenched with saturated ammonium chloride, washed with saturated sodium chloride, dried with anhydrous NaSO4, and purified by silica gel column chromatography to obtain Bi-02 (5.25 g, 61%). 1 H NMR (400MHz, Methanol-d4) δ6.77 (q, J=1.1Hz, 1H), 6.67 (d, J=1.5Hz, 2H), 4.49 (s, 4H).

[0157] Step 2: Synthesis of Bi-04: 64.6 mmol Bi-02 and 77.2 mmol methyl bromoacetate were dissolved in 300 mL acetonitrile, 129.8 mmol potassium carbonate was added, and the mixture was refluxed at 80 °C for 4 h. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was purified by silica gel column chromatography to obtain Bi-04 (10.97 g, 75%). 1 H NMR (400MHz, Chloroform-d) δ 6.99 (tt, J = 1.3, 0.7Hz, 1H), 6.85 (d, J = 1.4Hz, 2H), 4.67 (d, J = 0.7Hz, 4H), 4.66 (s, 2H), 3.81 (s, 3H).

[0158] Step 3: Synthesis of Bi-06: 22.1 mmol Bi-04 and 88.4 mmol imidazole were dissolved in 100 mL of anhydrous dichloromethane. Tert-butyldimethylchlorosilane was dissolved in 50 mL of anhydrous dichloromethane and added dropwise to the reaction solution. The reaction was carried out at room temperature for 4 h. The product Bi-06 (7.56 g, 70%) was obtained by rotary evaporation and column purification. 1 H NMR (400MHz, Chloroform-d) δ6.89 (dt, J = 1.9, 0.9Hz, 1H), 6.84–6.72 (m, 2H), 4.75–4.65 (m, 4H), 4.64 (s, 2H), 3.80 (s, 3H), 0.94 (s, 18H), 0.15 (s, 12H).

[0159] Step 4: Synthesis of Bi-07: 11 mmol Bi-06 was dissolved in 90 mL methanol; 22 mmol sodium hydroxide was dissolved in 30 mL deionized water and added dropwise to the methanol solution. The reaction was carried out for 2 h. The solution was then rotated to one-third and extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the solution was purified by rotary evaporation and column chromatography to obtain the target product Bi-07 (2.9 g, 60%). 1H NMR (400MHz, Chloroform-d) δ 6.94 (s, 1H), 6.75 (s, 2H), 4.67 (d, J = 12.8Hz, 4H), 3.48 (d, J = 1.1Hz, 2H), 0.93 (d, J = 7.2Hz, 18H), 0.08 (d, J = 7.1Hz, 12H).

[0160] Step 5: Synthesis of Bi-0713: 0.227 mmol Bi-07 was dissolved in 50 mL of dichloromethane, and 0.114 mmol T-13, 0.341 mmol 4-dimethylaminopyridine, and 0.272 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was stirred at room temperature for 8 h, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the target product Bi-0713 (2.29 g, 71%). 1 H NMR(400MHz,Chloroform-d)δ6.83(d,J=6.7Hz,1H),6.73–6.66(m,2H),4.91(td,J=7.2,3.5Hz,1H),4.62(s,4H),4.54(d,J=5.8 Hz,2H),3.97(t,J=6.7Hz,4H),2.23(tt,J=8.8,5.3Hz,2H),1.58–1.07(m,64H),0.87(s,18H),0.83–0.78(m,12H),0.02(s,12H).

[0161] Step 6: Synthesis of Bi-070013: 0.91 mmol Bi-0713 was dissolved in 50 mL of dichloromethane, 5 mL of saturated concentrated hydrochloric acid was added dropwise, the reaction was carried out for 8 h, the product was evaporated to dryness and purified by silica gel column chromatography to obtain the target product Bi-070013 (0.71 g, 81%). 1 H NMR(400MHz,Chloroform-d)δ7.04–6.92(m,1H),6.85(d,J=1.3Hz,2H),5.09–4.93(m,1H),4.66(s,4H),4.6 4(s,2H),4.03(td,J=6.8,1.5Hz,4H),2.30(tt,J=8.9,5.4Hz,2H),1.69–1.16(m,64H),0.94–0.79(m,12H).

[0162] Step 7: Synthesis of IBMC-004: 0.08 mmol Bi-070013 was dissolved in 8 mL of dichloromethane, and 0.32 mmol of 3-(4-morpholino)propionic acid, 0.48 mmol of 4-dimethylaminopyridine, and 0.38 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product IBMC-004 (42 mg, 45.38%). ¹H NMR (400MHz, Chloroform-d) δ 6.96 (d, J = 1.5Hz, 1H), 6.87 (d, J = 1.6Hz, 2H), 5.09 (s, 4H), 5.01 (q, J = 6.0Hz, 1H), 4.61 (s, 2H), 4.04 (t, J = 6.6Hz, 4H), 3.69 (t, J = 4.6Hz, 8H), 2.71 (s, 4H), 2.57 (s, 4H), 2.47 (s, 8H), 2.33–2.26 (m, 2H), 1.82–1.20 (m, 64H), 0.91–0.83 (m, 12H), ¹H NMR spectrum as shown. Figure 4 As shown.

[0163] The specific synthesis steps for T-13 are the same as in Example 1.

[0164] Example 5: The synthesis route of IBMC-005 is shown in the following formula:

[0165]

[0166] The specific synthesis steps of IBMC-005 are as follows: Step 1: Synthesis of Bi-0711: 0.227 mmol Bi-07 was dissolved in 5 mL of dichloromethane, and 0.114 mmol T-11, 0.342 mmol 4-dimethylaminopyridine, and 0.227 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was stirred at room temperature for 12 h, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was purified by silica gel column chromatography to obtain the target product Bi-0711 (90 mg, 78.95%). 1H NMR(400MHz,Chloroform-d)δ6.81(d,J=6.4Hz,1H),6.72–6.63(m,2H),4.89(p,J=6.0Hz,1H),4.62–4.58(m,4H),4.54(s,1H),4.51(s ,1H),3.94(td,J=6.7,3.6Hz,4H),3.71(s,1H),2.29–2.09(m,2H),1.59–1.06(m,52H),0.85(s,18H),0.82–0.75(m,9H),0.01(s,12H).

[0167] Step 2: Synthesis of Bi-070011: 0.045 mmol Bi-0711 was dissolved in 5 mL of dichloromethane, and 0.6 mL of saturated concentrated hydrochloric acid was added dropwise. The reaction was carried out for 8 h, and the product was purified by silica gel column chromatography after drying to obtain the target product Bi-070011 (53 mg, 75%). 1 HNMR(400MHz,Chloroform-d)δ6.98(t,J=1.4Hz,1H),6.85(d,J=1.4Hz,2H),5.30(s,2H),5.05–4.94(m, 1H), 4.65 (d, J = 9.0Hz, 4H), 4.11–3.91 (m, 4H), 2.35–2.19 (m, 3H), 1.74–1.12 (m, 52H), 0.93–0.81 (m, 9H).

[0168] Step 3: Synthesis of IBMC-005: 0.064 mmol Bi-070011 was dissolved in 5 mL of dichloromethane, and 0.032 mmol N,N-dimethylaminobutyrate, 0.096 mmol 4-dimethylaminopyridine, and 0.096 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product IBMC-005 (7 mg, 10.1%). 1¹H NMR (400MHz, Chloroform-d) δ 7.01 (s, 1H), 6.83 (dt, J = 13.1, 2.3Hz, 2H), 5.08 (s, 2H), 4.99 (tt, J = 7.2, 3.5Hz, 1H), 4.64 (d, J = 15.2Hz, 4H), 4.03 (td, J = 6.7, 4.1Hz, 4H), 2.45 (dt, J = 16.9, 7.4Hz, 6H), 2.36 (s, 4H), 2.28 (t, J = 7.6Hz, 3H), 1.93 (p, J = 7.2Hz, 2H), 1.70–1.16 (m, 52H), 0.88 (td, J = 6.9, 1.7Hz, 9H). The ¹H NMR spectrum is as follows: Figure 5 As shown.

[0169] The specific synthesis steps for Bi-07 are the same as in Example 4.

[0170] Example 6: The synthesis route of IBMC-006 is shown in the following formula:

[0171]

[0172] The specific synthesis steps of IBMC-006 differ from those in Example 5: T-08 is used instead of T-11. The proton NMR spectrum of IBMC-006 is as follows: 1 1H NMR (400MHz, Chloroform-d) δ 6.96 (d, J = 1.6 Hz, 1H), 6.75 (dt, J = 12.2, 2.2 Hz, 2H), 5.36–5.21 (m, 8H), 5.02 (s, 2H), 4.92 (p, J = 6.1 Hz, 1H), 4.57 (d, J = 19.0 Hz, 4H), 2.74–2.68 (m, 4H), 2.61 (t, J = 7.9 Hz, 2H), 2.45 (s, 6H), 2.40 (t, J = 6.9 Hz, 2H), 1.98 (td, J = 7.2, 4.2 Hz, 8H), 1.53–1.08 (m, 42H), 0.85–0.75 (m, 6H). The 1H NMR spectrum is as follows: Figure 6 As shown.

[0173] The specific synthesis steps for T-08 are the same as in Example 3.

[0174] Example 7: Specific synthesis steps of IBMC-007: 0.067 mmol Bi-150013 and 0.266 mmol N,N-dimethylpropanolamine were dissolved in 5 mL dichloromethane, 0.1995 mmol 4-dimethylaminopyridine and 0.3325 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, the mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain IBMC-007 (41 mg, 55.79%). 1 ¹H NMR (400MHz, Chloroform-d) δ 8.30 (t, J = 1.4 Hz, 1H), 7.76 (d, J = 1.4 Hz, 2H), 5.04–4.97 (m, 1H), 4.70 (s, 2H), 4.38 (t, J = 6.6 Hz, 4H), 4.04 (t, J = 6.6 Hz, 4H), 2.42 (dd, J = 7.9, 6.7 Hz, 4H), 2.29 (ddd, J = 8.9, 5.4, 3.6 Hz, 2H), 2.25 (s, 12H), 1.99–1.90 (m, 4H), 1.64–1.19 (m, 64H), 0.86 (td, J = 6.8, 1.2 Hz, 12H). The ¹H NMR spectrum is as follows: Figure 7 As shown.

[0175] The specific synthesis steps for Bi-150013 are the same as in Example 1.

[0176] Example 8: Specific synthesis steps of IBMC-011: 0.067 mmol Bi-150013 and 0.266 mmol morpholinopropanol were dissolved in 5 mL dichloromethane, 0.1995 mmol 4-dimethylaminopyridine and 0.3325 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 8 h. The mixture was extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain IBMC-011 (41 mg, 55.79%). 1 ¹H NMR (400MHz, Chloroform-d) δ 8.31–8.29 (m, 1H), 7.77 (d, J = 1.5 Hz, 2H), 5.05–4.99 (m, 1H), 4.71 (s, 2H), 4.41 (t, J = 6.6 Hz, 4H), 4.05 (t, J = 6.6 Hz, 4H), 3.74–3.68 (m, 8H), 2.53–2.42 (m, 12H), 2.30 (tt, J = 8.9, 5.3 Hz, 2H), 1.97 (p, J = 6.8 Hz, 4H), 1.65–1.19 (m, 64H), 0.90–0.85 (m, 12H), [The remaining text appears to be incomplete and requires further context.] Figure 8 As shown.

[0177] The specific synthesis steps for Bi-150013 are the same as in Example 1.

[0178] Example 9: Specific synthesis steps of IBMC-012: Same as Example 8. The proton NMR spectrum of IBMC-012 is as follows: ¹H NMR (400MHz, Chloroform-d) δ 8.33–8.30 (m, 1H), 7.79–7.73 (m, 2H), 5.01 (td, J = 7.1, 3.5Hz, 1H), 4.70 (s, 2H), 4.39 (q, J = 7.0Hz, 4H), 4.04 (t, J = 6.6Hz, 4H), 3.71 (t, J = 4.6Hz, 4H), 2.48 (dt, J = 10.2, 6.0Hz, 4H), 2.29 (tt, J = 8.9, 5.3Hz, 2H), 1.97 (p, J = 6.8Hz, 2H), 1.68–1.16 (m, 64H), 0.90–0.83 (m, 12H). The proton NMR spectrum is as follows: Figure 9 As shown.

[0179] Example 10: Specific synthesis steps of IBMC-015: 0.022 mmol Bi-150013, 0.067 mmol EDCI and 0.067 mmol HOBT were dissolved in 5 mL dichloromethane. After 1 h, 0.088 mmol morpholinopropanol and 0.088 mmol DIEA were added. The mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography. 0.089 mmol phenylethanol was added and dissolved in 5 mL dichloromethane. 0.067 mmol 4-dimethylaminopyridine and 0.11 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added. The mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain IBMC-015 (5 mg, 20.15%). 1H(400MHz,Chloroform-d)δ8.26(t,J=4.8Hz,1H),8.03(s,1H),7.76–7.68(m,2H),7.4 7–7.34(m,5H),5.38(s,2H),5.00(dq,J=12.4,6.6,5.9Hz,1H),4.70(s,2H),4.03(t,J= 6.6 Hz, 4H), 3.70 (t, J = 4.7 Hz, 4H), 3.57 (q, J = 5.6 Hz, 2H), 2.60–2.44 (m, 6H), 2.29 (tt, J = 8.9, 5.3 Hz, 2H), 1.79 (p, J = 6.0 Hz, 2H), 1.66–1.17 (m, 64H), 0.90–0.84 (m, 12H), 1H NMR spectrum as follows Figure 10 As shown.

[0180] Example 11: Specific synthesis steps of IBMC-018: 0.075 mmol Bi-150011 and 0.3 mmol 1,4-bis(2-hydroxyethyl)piperazine were dissolved in 5 mL dichloromethane, 0.225 mmol 4-dimethylaminopyridine and 0.375 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, the mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and purified by silica gel column chromatography to obtain IBMC-018 (21 mg, 25.3%). 1 ¹H NMR (400MHz, Chloroform-d) δ 8.27(s, 1H), 7.76(s, 2H), 5.00(q, J = 6.3Hz, 1H), 4.70(s, 2H), 4.46(t, J = 5.8Hz, 4H), 4.03(q, J = 6.2Hz, 4H), 3.70(t, J = 5.2Hz, 4H), 2.89–2.57(m, 24H), 2.27(t, J = 7.6Hz, 3H), 1.64–1.18(m, 52H), 0.86(t, J = 6.6Hz, 9H), ¹H NMR spectrum as shown Figure 11 As shown.

[0181] The specific synthesis steps for Bi-150011 are the same as in Example 2.

[0182] Example 12: Specific synthesis steps of IBMC-019: 0.075 mmol Bi-150011 and 0.3 mmol morpholinopropanol were dissolved in 5 mL dichloromethane, 0.225 mmol 4-dimethylaminopyridine and 0.375 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, the mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and purified by silica gel column chromatography to obtain IBMC-019 (36 mg, 45.57%). 1 ¹H NMR (400MHz, Chloroform-d) δ 8.28 (t, J = 1.5Hz, 1H), 7.75 (d, J = 1.4Hz, 2H), 5.01 (dt, J = 7.1, 5.3Hz, 1H), 4.69 (s, 2H), 4.39 (t, J = 6.6Hz, 4H), 4.03 (td, J = 6.6, 4.6Hz, 4H), 3.70 (t, J = 4.7Hz, 8H), 2.47 (dt, J = 10.0, 6.0Hz, 12H), 2.27 (dd, J = 9.2, 6.1Hz, 3H), 1.96 (q, J = 6.9Hz, 4H), 1.65–1.18 (m, 52H), 0.90–0.83 (m, 9H), ¹H NMR spectrum as shown. Figure 12 As shown.

[0183] The specific synthesis steps for Bi-150011 are the same as in Example 2.

[0184] Example 13: Specific synthesis steps of IBMC-020: 0.075 mmol Bi-150011 and 0.3 mmol N,N-dimethylpropanolamine were dissolved in 5 mL dichloromethane, 0.225 mmol 4-dimethylaminopyridine and 0.375 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, the mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness and purified by silica gel column chromatography to obtain IBMC-020 (25 mg, 34.39%). 1 ¹H NMR (400MHz, Chloroform-d) δ 8.30 (d, J = 1.6 Hz, 1H), 7.77 (d, J = 1.4 Hz, 2H), 5.01 (q, J = 6.4 Hz, 1H), 4.71 (s, 2H), 4.40 (t, J = 6.5 Hz, 4H), 4.04 (q, J = 6.4 Hz, 4H), 2.52 (t, J = 7.4 Hz, 4H), 2.32 (s, 12H), 2.28 (t, J = 7.6 Hz, 3H), 2.00 (q, J = 6.9 Hz, 4H), 1.66–1.18 (m, 52H), 0.91–0.84 (m, 9H), ¹H NMR spectrum as shown Figure 13 As shown.

[0185] The specific synthesis steps for Bi-150011 are the same as in Example 2.

[0186] Example 14: Specific synthesis steps of IBMC-023: 0.377 mmol Bi-070013 was dissolved in 10 mL of dichloromethane, and 0.189 mmol of N,N-dimethylaminobutyrate, 0.567 mmol of 4-dimethylaminopyridine, and 0.227 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was purified by silica gel column chromatography to obtain the target product IBMC-023 (100 mg, 53.6%). 1 ¹H NMR (400MHz, Chloroform-d) δ 6.95 (s, 1H), 6.82–6.70 (m, 2H), 5.01 (s, 2H), 4.92 (td, J = 7.1, 3.5Hz, 1H), 4.57 (d, J = 14.0Hz, 4H), 3.97 (t, J = 6.7Hz, 4H), 2.59 (t, J = 7.8Hz, 2H), 2.43 (s, 6H), 2.39 (d, J = 6.9Hz, 2H), 2.23 (tt, J = 8.8, 5.3Hz, 2H), 1.95 (q, J = 7.4Hz, 2H), 1.62–1.08 (m, 64H), 0.80 (t, J = 6.7Hz, 12H). The ¹H NMR spectrum is as follows: Figure 14 As shown.

[0187] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0188] Example 15: Specific synthesis steps of IBMC-024: 0.235 mmol Bi-070013 was dissolved in 8 mL of dichloromethane, and 0.118 mmol of 3-(4-morpholino)propionic acid, 0.353 mmol of 4-dimethylaminopyridine, and 0.142 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the target product IBMC-024 (62.7 mg, 50.93%). 1¹H NMR (400MHz, Chloroform-d) δ 6.90 (s, 1H), 6.79 (dt, J = 7.8, 2.3Hz, 2H), 5.02 (s, 2H), 4.98–4.87 (m, 1H), 4.58 (d, J = 16.4Hz, 4H), 3.96 (t, J = 6.6Hz, 4H), 3.67–3.55 (m, 4H), 2.64 (t, J = 7.2Hz, 2H), 2.49 (t, J = 7.2Hz, 2H), 2.38 (t, J = 4.6Hz, 4H), 2.23 (tt, J = 8.9, 5.3Hz, 2H), 1.66–1.08 (m, 64H), 0.80 (t, J = 6.7Hz, 12H). The ¹H NMR spectrum is as follows: Figure 15 As shown.

[0189] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0190] Example 16: The synthesis route of IBMC-025 is shown in the following formula:

[0191]

[0192] The specific synthesis steps of IBMC-025 are as follows: Step 1: Synthesis of 1OH-02: 65 mmol of 1OH-1 (3,5-dihydroxybenzoic acid) and 195 mmol of boranetetrahydrofuran were dissolved in 100 mL of ultra-dry THF and stirred at room temperature for 24 h; the reactants were quenched with saturated ammonium chloride, washed with saturated sodium chloride, dried with anhydrous NaSO4, and purified by silica gel column chromatography to obtain 1OH-02 (5.9 g, 65%). 1 H NMR (400MHz, DMSO-d6) δ9.05 (s, 2H), 6.17 (d, J = 2.2Hz, 2H), 6.05 (t, J = 2.2Hz, 1H), 4.98 (t, J = 5.8Hz, 1H), 4.30 (d, J = 5.8Hz, 2H).

[0193] Step 2: Synthesis of 1OH-03: 71.4 mmol of 1OH-02 and 35.7 mmol of benzyl bromoacetate were dissolved in 200 mL of acetonitrile. At 50 °C, 71.4 mmol of potassium carbonate was added and the reaction was carried out for 4 h. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was evaporated to dryness and purified by silica gel column chromatography to obtain 1OH-03 (3.61 g, 59%). 1H NMR(400MHz,Chloroform-d)δ7.39–7.27(m,5H),7.13(s,1H),6.44–6.36(m,1H),6.32(dd, J=2.3,1.2Hz,1H),6.25(t,J=2.3Hz,1H),5.18(s,2H),4.52(s,2H),4.42(d,J=2.8Hz,2H).

[0194] Step 3: Synthesis of 1OH-04: 11.1 mmol of 1OH-03 and 44.4 mmol of imidazole were dissolved in 100 mL of anhydrous dichloromethane. Tert-butyldimethylchlorosilane was dissolved in 20 mL of anhydrous dichloromethane and added dropwise to the reaction solution. The reaction was carried out at room temperature for 4 h. The product 1OH-04 (5.6 g, 97.7%) was obtained by rotary evaporation and column purification. 1 H NMR(400MHz,Chloroform-d)δ7.39–7.31(m,5H),6.48(tq,J=2.1,0.9Hz,2H),6.30(t,J=2.3Hz ,1H),5.24(s,2H),4.63(d,J=1.7Hz,4H),0.97(s,9H),0.94(s,9H),0.18(s,6H),0.09(s,6H).

[0195] Step 4: Synthesis of 1OH-05: 0.7 g of 1OH-04 and 0.07 g of Pd / C were dissolved in 20 mL of methanol and stirred at room temperature for 1 h. The solvent was evaporated by filtration and purified by silica gel column chromatography to obtain 1OH-05 (0.44 g, 76%). 1 H NMR (400MHz, Chloroform-d) δ6.52–6.44(m,2H),6.31(s,1H),4.64(s,2H),4.60(s,2H),0.96(s,9H),0.93(s,9H),0.18(s,6H),0.08(s,6H).

[0196] Step 5: Synthesis of 1OH-06: 3.3 mmol of 1OH-05 was dissolved in 50 mL of dichloromethane, and 4.95 mmol of T-13, 14.85 mmol of 4-dimethylaminopyridine, and 9.9 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was stirred at room temperature for 8 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain the target product 1OH-06 (3.07 g, 86%). 1H NMR(400MHz,Chloroform-d)δ6.47(ddt,J=3.4,2.2,1.2Hz,2H),6.28(t,J=2.3Hz,1 H),4.99(qd,J=7.2,5.2Hz,1H),4.63(s,2H),4.55(s,2H),4.04(t,J=6.6Hz,4H),2.3 0(tt,J=8.9,5.3Hz,2H),1.59(dq,J=11.2,6.6Hz,12H),1.46–1.38(m,4H),1.33–1. 21(m,48H),0.96(s,9H),0.93(s,9H),0.90–0.84(m,12H),0.18(s,6H),0.08(s,6H).

[0197] Step 6: Synthesis of 1OH-07: 0.92 mmol of 1OH-06 was dissolved in 50 mL of dichloromethane, and 1.2 mL of saturated concentrated hydrochloric acid was added dropwise. The reaction was carried out for 6 h, and the product was purified by silica gel column chromatography after drying to obtain the target product 1OH-07 (0.68 g, 76%). 1 H NMR(400MHz,Chloroform-d)δ6.52(dd,J=2.2,1.3Hz,1H),6.48(dd,J=2.2,1.3 Hz,1H),6.33(t,J=2.3Hz,1H),4.99(qd,J=7.2,5.1Hz,1H),4.58(d,J=5.3Hz,4H ),4.03(t,J=6.7Hz,4H),2.30(tt,J=8.9,5.4Hz,2H),1.62–1.52(m,12H),1.46– 1.38(m,4H),1.33–1.20(m,48H),0.97(s,9H),0.90–0.84(m,12H),0.19(s,6H).

[0198] Step 7: Synthesis of 1OH-08: 0.21 mmol of 1OH-07 was dissolved in 15 mL of dichloromethane, and 0.41 mmol of N,N-dimethylaminobutyrate, 75.13 mmol of 4-dimethylaminopyridine, and 94.32 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was purified by silica gel column chromatography to obtain the target product 1OH-08 (0.16 g, 71.7%). 1H NMR(400MHz,Chloroform-d)δ6.50(t,J=1.9Hz,1H),6.45(t,J=1.8Hz,1H),6.35(t,J=2.3Hz ,1H),5.04–4.94(m,3H),4.56(s,2H),4.04(t,J=6.6Hz,4H),2.51(t,J=7.6Hz,2H),2.43(t, J=7.2Hz,2H),2.38(s,6H),2.29(ddd,J=8.9,5.4,3.6Hz,2H),1.91(p,J=7.3Hz,2H),1.63–1 .50(m,12H),1.45–1.37(m,4H),1.24(s,48H),0.96(s,9H),0.90–0.83(m,12H),0.18(s,6H).

[0199] Step 8: Synthesis of IBMC-025: 0.046 mmol 1OH-08 was dissolved in 8 mL of tetrahydrofuran, 1 mL of 1 MTBAF tetrahydrofuran was added, and the mixture was reacted at room temperature for 2 h. After washing with saturated sodium chloride solution and drying with anhydrous sodium sulfate, the product was evaporated to dryness and purified by silica gel column chromatography to obtain the target product IBMC-025 (20 mg, 44.7%). 1 ¹H NMR (400MHz, Chloroform-d) δ 6.39 (d, J = 1.8 Hz, 1H), 6.34 (t, J = 1.8 Hz, 1H), 6.26 (t, J = 2.3 Hz, 1H), 4.96–4.88 (m, 3H), 4.51 (s, 2H), 3.99 (tt, J = 6.7, 3.2 Hz, 4H), 2.32 (td, J = 8.2, 7.7, 5.8 Hz, 4H), 2.27–2.18 (m, 8H), 1.79 (q, J = 7.5 Hz, 2H), 1.58–1.43 (m, 12H), 1.40–1.33 (m, 4H), 1.18 (d, J = 3.5 Hz, 48H), 0.80 (t, J = 6.7 Hz, 12H). The ¹H NMR spectrum is as follows: Figure 16 As shown.

[0200] Example 17: Specific synthesis steps of IBMC-028: 0.0558 mmol Bi-150013 and 0.223 mmol 1,4-bis(2-hydroxyethyl)piperazine were dissolved in 5 mL dichloromethane, 0.1674 mmol 4-dimethylaminopyridine and 0.279 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, the mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by silica gel column chromatography to obtain IBMC-028 (18 mg, 26.73%). 1¹H NMR (400MHz, Chloroform-d) δ 8.28 (d, J = 1.6 Hz, 1H), 7.76 (d, J = 1.4 Hz, 2H), 5.00 (td, J = 7.0, 3.5 Hz, 1H), 4.70 (s, 2H), 4.46 (t, J = 5.9 Hz, 4H), 4.04 (t, J = 6.6 Hz, 4H), 3.65–3.56 (m, 4H), 2.78 (t, J = 5.9 Hz, 4H), 2.65–2.52 (m, 16H), 2.34–2.18 (m, 6H), 1.65–1.17 (m, 64H), 0.86 (t, J = 6.7 Hz, 12H), ¹H NMR spectrum as shown. Figure 17 As shown.

[0201] The specific synthesis steps for Bi-150013 are the same as in Example 1.

[0202] Example 18: The specific synthesis steps for IBMC-029 are the same as in Example 17. The proton NMR spectrum of IBMC-029 is as follows: 1 ¹H NMR (400MHz, Chloroform-d) δ 8.30 (d, J = 1.6 Hz, 1H), 7.76 (dt, J = 14.5, 2.2 Hz, 2H), 5.01 (p, J = 6.1 Hz, 1H), 4.70 (s, 2H), 4.46 (t, J = 6.0 Hz, 2H), 4.04 (t, J = 6.6 Hz, 4H), 3.93 (s, 2H), 3.62 (t, J = 5.4 Hz, 2H), 2.79 (t, J = 6.0 Hz, 2H), 2.71–2.50 (m, 8H), 2.31 (dt, J = 14.3, 5.7 Hz, 2H), 1.65–1.18 (m, 64H), 0.86 (t, J = 6.7 Hz, 12H). The ¹H NMR spectrum is as follows: Figure 18 As shown.

[0203] Example 19: Specific synthesis steps of IBMC-030: 0.057 mmol Bi-070013 was dissolved in 5 mL of dichloromethane, and 0.229 mmol of 4-(4-methyl-1-piperazinyl)butyric acid, 0.342 mmol of 4-dimethylaminopyridine, and 0.229 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was purified by silica gel column chromatography to obtain the target product IBMC-030 (40 mg, 57.7%). ¹H NMR (400MHz, Chloroform-d) δ 6.94 (s, 1H), 6.85 (s, 2H), 5.05 (s, 4H), 4.98 (q, J = 6.3Hz, 1H), 4.60 (s, 2H), 4.03 (t, J = 6.6Hz, 4H), 2.68–2.41 (m, 16H), 2.39 (t, J = 7.3Hz, 8H), 2.33 (s, 6H), 1.83 (p, J = 7.3Hz, 4H), 1.56 (dd, J = 13.4, 7.0Hz, 12H), 1.45–1.18 (m, 54H), 0.86 (t, J = 6.6Hz, 12H). The ¹H NMR spectrum is as follows: Figure 19 As shown.

[0204] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0205] Example 20: Specific synthesis steps of IBMC-031: 0.171 mmol Bi-070013 was dissolved in 8 mL of dichloromethane, and 0.086 mmol of 4-(4-methyl-1-piperazinyl)butyric acid, 0.258 mmol of 4-dimethylaminopyridine, and 0.103 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the target product IBMC-031 (89.68 mg, 50.3%). 1 ¹H NMR (400MHz, Chloroform-d) δ 6.99 (s, 1H), 6.91–6.77 (m, 2H), 5.07 (s, 2H), 5.06–4.95 (m, 1H), 4.64 (d, J = 15.0 Hz, 4H), 4.04 (t, J = 6.7 Hz, 4H), 2.69–2.16 (m, 17H), 1.84 (p, J = 7.2 Hz, 2H), 1.71–1.12 (m, 64H), 0.87 (t, J = 6.7 Hz, 12H), ¹H NMR spectrum as shown Figure 20 As shown.

[0206] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0207] Example 21: The synthesis route of IBMC-034 is shown in the following formula:

[0208]

[0209] The specific synthesis steps of IBMC-034 are as follows: Step 1: Synthesis of m46-02: 0.017 mmol m46-01 and 0.0187 mmol potassium acetate were dissolved in 30 mL DMF and stirred at room temperature for 5 h. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried with anhydrous NaSO4, and purified by silica gel column chromatography to obtain m46-02 (1.81 g, 54.7%). 1 H NMR(400MHz,Chloroform-d)δ11.04(d,J=0.5Hz,1H),9.90(d,J=0.6Hz,1H),7.60 –7.57(m,1H),7.56–7.52(m,1H),7.00(d,J=8.5Hz,1H),5.08(s,2H),2.10(s,3H).

[0210] Step 2: Synthesis of m46-03: 3.09 mmol of m46-02 was dissolved in 20 mL of 1 M NaOH solution and stirred at room temperature for 5 h. The reaction mixture was adjusted to pH 3.5 with 6 M hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous NaSO4, and purified by silica gel column chromatography to obtain m46-03 (0.42 g, 89.4%). 1 H NMR (400MHz, Chloroform-d) δ 11.00 (s, 1H), 9.90 (s, 1H), 7.58 (d, J = 2.2Hz, 1H), 7.53 (dd, J = 8.5, 2.3Hz, 1H), 6.99 (d, J = 8.6Hz, 1H), 4.69 (s, 2H).

[0211] Step 3: Synthesis of m46-04: 3.16 mmol m46-04 and 3.79 mmol methyl bromoacetate were dissolved in 20 mL acetonitrile, and 4.75 mmol potassium carbonate was added. The mixture was refluxed at 80 °C for 4 h. After cooling the reaction solution to room temperature, it was filtered. The filtrate was evaporated to dryness and purified by silica gel column chromatography to obtain m46-04 (0.42 g, 59.4%). 1H NMR(400MHz,Chloroform-d)δ10.54(s,1H),7.84(d,J=2.4Hz,1H),7.58(dd,J= 8.5, 2.4Hz, 1H), 6.87 (d, J = 8.5Hz, 1H), 4.78 (s, 2H), 4.67 (s, 2H), 3.82 (s, 3H).

[0212] Step 4: Synthesis of m46-05: 1.16 mmol m46-04 and 2.32 mmol imidazole were dissolved in 20 mL of anhydrous dichloromethane. Tert-butyldimethylchlorosilane was dissolved in 5 mL of anhydrous dichloromethane and added dropwise to the reaction solution. The reaction was carried out at room temperature for 4 h. The product was purified by rotary evaporation and column chromatography to obtain the target product m46-05 (0.28 g, 71.4%). 1 H NMR(400MHz,Chloroform-d)δ10.55(s,1H),7.83–7.71(m,1H),7.55(ddt,J=8.5,2.2,0.7Hz,1H), 6.84(d,J=8.6Hz,1H),4.76(s,2H),4.69(d,J=0.9Hz,2H),3.81(s,3H),0.93(s,9H),0.09(s,6H).

[0213] Step 5: Synthesis of m46-06: 0.83 mmol m46-05 was dissolved in 10 mL methanol, and 1.24 mmol sodium hydroxide was dissolved in 20 mL deionized water and added dropwise to the methanol solution. The reaction was carried out for 2 h. The solution was then evaporated to one-third and extracted with ethyl acetate. After drying with anhydrous sodium sulfate, the solution was evaporated to dryness and purified by column chromatography to obtain the target product m46-06 (180 g, 67.2%). 1 H NMR (400MHz, DMSO-d6) δ10.43(s,1H),7.61(d,J=2.3Hz,1H),7.47(dd,J=8.6,2.4Hz,1H ), 6.98 (d, J = 8.6Hz, 1H), 4.64 (s, 2H), 4.41 (d, J = 5.2Hz, 2H), 0.89 (s, 9H), 0.06 (s, 6H).

[0214] Step 6: Synthesis of m46-07: 1.39 mmol m46-06 was dissolved in 40 mL dichloromethane, and 2.78 mmol T-13, 5.56 mmol 4-dimethylaminopyridine, and 4.17 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was stirred at room temperature for 8 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain the target product m46-07 (0.84 g, 61%). 1H NMR(400MHz,Chloroform-d)δ10.55(s,1H),7.78(d,J=2.3Hz,1H),7.57–7.50( m,1H),6.85(d,J=8.6Hz,1H),4.99(p,J=6.2Hz,1H),4.74(s,2H),4.69(s,2H),4 .04(t,J=6.7Hz,4H),2.30(tt,J=8.9,5.3Hz,2H),1.61–1.54(m,12H),1.46–1.3 9(m,4H),1.25(d,J=3.6Hz,48H),0.92(s,9H),0.89–0.84(m,12H),0.09(s,6H).

[0215] Step 7: Synthesis of m46-08: 0.22 mmol m46-07 was dissolved in 20 mL dichloromethane, and 0.025 mL saturated concentrated hydrochloric acid was added dropwise. The mixture was stirred at room temperature for 8 h, evaporated to dryness, and purified by silica gel column chromatography to obtain the target product m46-08 (0.13 g, 66.8%). 1 HNMR(400MHz,Chloroform-d)δ10.55(s,1H),7.84(d,J=2.4Hz,1H),7.59(dd, J=8.5,2.4Hz,1H),6.87(d,J=8.6Hz,1H),5.03–4.96(m,1H),4.76(s,2H),4.67 (s,2H),4.02(t,J=6.7Hz,4H),2.30(tt,J=8.9,5.3Hz,2H),1.60–1.53(m,12H ), 1.42 (td, J = 8.0, 3.9 Hz, 4H), 1.26 ( d, J = 9.0 Hz, 48H), 0.87 ( t, J = 6.7 Hz, 12H).

[0216] Step 8: Synthesis of m46-09: 0.15 mmol m46-08 was dissolved in 10 mL dichloromethane, and 0.3 mmol N,N-dimethylaminobutyrate, 0.75 mmol 4-dimethylaminopyridine, and 0.36 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product IBMC-004 (0.12 g, 81.6%). 1H NMR (400MHz, Chloroform-d) δ10.54 (s, 1H), 7.86 (d, J = 2.4Hz, 1H), 7.53 (dd, J = 8.6, 2. 4Hz,1H),6.85(d,J=8.5Hz,1H),5.06(s,2H),4.99(p,J=6.1Hz,1H),4.75(s,2H),4.04( t,J=6.6Hz,4H),2.38(t,J=7.4Hz,2H),2.33–2.26(m,4H),2.21(s,6H),1.80(p,J=7.4H z,2H),1.63–1.52(m,12H),1.46–1.39(m,4H),1.32–1.20(m,48H),0.89–0.84(m,12H).

[0217] Step 9: Synthesis of IBMC-034: 0.05 mmol m46-09 was dissolved in 8 mL methanol, 0.056 mmol sodium borohydride was added, the reaction was carried out at room temperature for 2 h, the solvent was evaporated, and the product was purified by silica gel column chromatography to obtain the target product IBMC-034 (17.5 g, 35%). 1 H NMR(400MHz,Chloroform-d)δ7.34(d,J=2.2Hz,1H),7.23(dd,J=8.3,2.3Hz,1H),6.76(d,J=8.3Hz,1 H),5.05(s,2H),4.98(p,J=6.3Hz,1H),4.71(d,J=14.1Hz,4H),4.04(t,J=6.6Hz,4H),3.64(s,1H),2. 52 (t, J = 7.7 Hz, 2H), 2.41 (d, J = 7.7 Hz, 8H), 2.30 (tt, J = 8.9, 5.3 Hz, 2H), 1.91 (p, J = 7.2 Hz, 2H), 1.58 (dt, J = 13.4, 6.5 Hz, 12H), 1.42 (t, J = 6.9 Hz, 4H), 1.25 (d, J = 7.3 Hz, 48H), 0.87 (t, J = 6.7 Hz, 12H), 1H NMR spectrum as follows Figure 21 As shown.

[0218] Example 22: Specific synthesis steps of IBMC-035: 0.022 mmol Bi-150013, 0.067 mmol EDCI and 0.067 mmol HOBT were dissolved in 5 mL dichloromethane. After 1 h, 0.088 mmol N,N-dimethylpropanolamine and 0.088 mmol DIEA were added. The mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain IBMC-035 (8 mg, 32%).1 ¹H NMR (400MHz, Chloroform-d) δ 8.74 (t, J = 4.8 Hz, 2H), 7.96 (s, 1H), 7.52 (s, 2H), 4.99 (t, J = 6.2 Hz, 1H), 4.70 (s, 2H), 4.04 (t, J = 6.6 Hz, 4H), 3.56 (q, J = 5.6 Hz, 4H), 2.59 (t, J = 6.1 Hz, 4H), 2.40 (s, 12H), 2.30 (ddd, J = 8.8, 5.3, 3.5 Hz, 2H), 1.83 (p, J = 6.1 Hz, 4H), 1.64–1.19 (m, 64H), 0.87 (t, J = 6.7 Hz, 12H). The ¹H NMR spectrum is as follows: Figure 22 As shown.

[0219] The specific synthesis steps for Bi-150013 are the same as in Example 1.

[0220] Example 23: Specific synthesis steps of IBMC-036: 0.022 mmol Bi-150013, 0.067 mmol EDCI and 0.067 mmol HOBT were dissolved in 5 mL dichloromethane. After 1 h, 0.088 mmol morpholinopropanol and 0.088 mmol DIEA were added. The mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain IBMC-036 (14 mg, 54.73%). 1 H NMR(400MHz,Chloroform-d)δ8.06(t,J=4.8Hz,2H),7.87(d,J=1.6Hz,1H),7.52(d,J= 1.4Hz,2H),5.04–4.96(m,1H),4.72(s,2H),4.06(dt,J=10.4,6.6Hz,4H),3.74(t,J=4 0.6 Hz, 8 H), 3.57 (q, J = 5.8 Hz, 4 H), 2.53 (dt, J = 18.6, 5.3 Hz, 12 H), 2.30 (tt, J = 8.8, 5.4 Hz, 2 H), 1.81 (q, J = 6.1 Hz, 4 H), 1.65–1.20 (m, 64 H), 0.87 (td, J = 6.8, 1.5 Hz, 12 H), 1H NMR spectrum as follows Figure 23 As shown.

[0221] The specific synthesis steps for Bi-150013 are the same as in Example 1.

[0222] Example 24: Specific synthesis steps of IBMC-037: 0.022 mmol Bi-150013, 0.067 mmol EDCI and 0.067 mmol HOBT were dissolved in 5 mL dichloromethane. After 1 h, 0.088 mmol DIEA and 0.088 mmol morpholinoethanol were added. The mixture was stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain IBMC-037 (14 mg, 56%). 1 ¹H NMR (400MHz, Chloroform-d) δ 8.10–8.02 (m, 2H), 7.88 (s, 1H), 7.53 (d, J = 1.4 Hz, 2H), 5.00 (p, J = 6.5 Hz, 1H), 4.71 (s, 2H), 4.04 (t, J = 6.6 Hz, 4H), 3.74 (t, J = 4.7 Hz, 8H), 3.57 (q, J = 5.8 Hz, 4H), 2.62–2.43 (m, 10H), 2.30 (tt, J = 8.8, 5.4 Hz, 2H), 1.80 (p, J = 6.0 Hz, 4H), 1.66–1.20 (m, 62H), 0.87 (td, J = 6.8, 1.5 Hz, 12H), [NMR spectrum is shown in the original text]. Figure 24 As shown.

[0223] The specific synthesis steps for Bi-150013 are the same as in Example 1.

[0224] Example 25: The synthesis route of IBMC-040 is shown in the following formula:

[0225]

[0226] The specific synthesis steps of IBMC-040 are as follows: Step 1: Synthesis of Si-HO2: 36.2 mmol Si-HO1 (p-hydroxybenzoic acid), 38.0 mmol benzyl bromide, and 43.4 mmol sodium carbonate were dissolved in 150 mL of DMF and stirred at 60 °C for 5 h. The solution was diluted with dichloromethane, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation, and separated by column chromatography to obtain Si-HO2 (7.1 g, 85.9%). 1 H NMR (400MHz, Chloroform-d) δ 8.00 (d, J = 8.8 Hz, 2H), 7.48–7.30 (m, 5H), 6.85 (d, J = 8.8 Hz, 2H), 5.34 (s, 1H), 5.18 (s, 1H).

[0227] Step 2: Synthesis of Si-H03O3: 3.0 mmol Si-H02, 6.0 mmol cesium carbonate and 3.3 mmol T-13-Br were dissolved in 100 mL DMF, stirred at 80 °C for 5 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation, and separated by column chromatography to obtain Si-H03O3 (1.2 g, 44.6%). 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J=8.9Hz,2H),7.46–7.27(m,5H),6.87(d,J=8.9Hz,2H),5.33(s,2H),4.31(p,J=5.8Hz,1H ),4.05(t,J=6.6Hz,4H),2.30(tt,J=9.0,5.3Hz,2H),1.76–1.50(m,11H),1.50–1.33(m,9H),1.24(br,42H),0.94–0.77(m,12).

[0228] Step 3: Synthesis of Si-H030003: 2.5 mmol Si-H0303 and 80 mg palladium on carbon were dissolved in 20 mL tetrahydrofuran, hydrogen gas was introduced, and the mixture was stirred at 25 °C for 12 h. The reaction solution was filtered through diatomaceous earth and concentrated by evaporation to obtain Si-H030003 (450.0 mg, 67.0%). 1 H NMR(400MHz,Chloroform-d)δ8.02(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),4.33(p,J=5.9Hz,1H),4.05(t,J=6. 6Hz,4H),2.29(tt,J=8.9,5.3Hz,2H),1.79–1.51(m,8H),1.51–1.32(m,12H),1.25(m,44H),0.94–0.81(m,12H).

[0229] Step 4: Synthesis of IBMC-040: 124.8 μmol Si-H030003, 282.6 μmol N,N-dimethylpropanolamine and 374.4 μmol DMAP were dissolved in 15 mL of anhydrous DCM, stirred at 25 °C for 24 h, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by evaporation, and separated by column chromatography to obtain IBMC-040 (18 mg, 10.3%). 1¹H NMR (400MHz, Chloroform-d) δ 8.03–7.89 (m, 2H), 6.92–6.81 (m, 2H), 4.33 (dt, J = 14.9, 6.0 Hz, 3H), 4.05 (t, J = 6.6 Hz, 4H), 2.60 (t, J = 7.6 Hz, 2H), 2.39 (s, 6H), 2.32–2.24 (m, 2H), 2.09–1.98 (m, 2H), 1.62 (ddq, J = 22.2, 14.7, 8.4, 6.9 Hz, 12H), 1.48–1.33 (m, 12H), 1.25 (d, J = 3.8 Hz, 40H), 0.87 (td, J = 6.9, 2.3 Hz, 12H), ¹H NMR spectrum as follows Figure 25 As shown.

[0230] The specific synthesis steps of T-13-Br are as follows: 3.7 mmol carbon tetrabromide and 3.7 mmol triphenylphosphine were dissolved in 20 mL of anhydrous tetrahydrofuran, stirred at room temperature, 1.2 mmol T-13 was added, the temperature was raised to 45 °C and reacted for 1 h, the mixture was evaporated and concentrated, and T-13-Br (1.0 g, 92.9%) was obtained by column chromatography. 1 H NMR(400MHz,Chloroform-d)δ4.07(t,J=6.6Hz,4H),4.00(tt,J=8.0,5.0Hz,1H),2.31(tt,J=8.9,5.3Hz, 2H),1.93–1.73(m,4H),1.71–1.52(m,9H),1.51–1.33(m,8H),1.32–1.08(m,42H),0.87(t,J=6.7Hz,12H).

[0231] Example 26: The specific synthesis steps of IBMC-041 differ from those in Example 24: Morpholinylpropanol is used instead of N,N-dimethylpropanolamine. Proton NMR spectrum of IBMC-041: 1 ¹H NMR (400MHz, Chloroform-d) δ 8.00–7.89 (m, 2H), 6.94–6.80 (m, 2H), 4.33 (dt, J = 14.0, 6.1 Hz, 3H), 4.05 (t, J = 6.6 Hz, 4H), 3.74–3.70 (m, 4H), 2.50 (dd, J = 13.3, 5.9 Hz, 4H), 2.29 (tt, J = 8.9, 5.4 Hz, 2H), 2.00–1.89 (m, 2H), 1.70–1.52 (m, 12H), 1.48–1.33 (m, 12H), 1.30–1.19 (m, 42H), 0.87 (td, J = 6.9, 2.3 Hz, 12H). The ¹H NMR spectrum is as follows: Figure 26As shown.

[0232] Example 27: The specific synthesis steps of IBMC-042 differ from those in Example 24: 3-(4-methyl-1-piperazinyl)-1-propanol is used instead of N,N-dimethylpropanolamine. The proton NMR spectrum of IBMC-042 is as follows: 1 ¹H NMR (400MHz, Chloroform-d) δ 8.01–7.88 (m, 2H), 6.95–6.78 (m, 2H), 4.32 (dt, J = 8.8, 6.0 Hz, 3H), 4.05 (t, J = 6.6 Hz, 4H), 2.66–2.44 (m, 8H), 2.33 (s, 3H), 2.32–2.25 (m, 2H), 1.99–1.91 (m, 2H), 1.71–1.52 (m, 12H), 1.48–1.33 (m, 12H), 1.25 (d, J = 3.8 Hz, 42H), 0.87 (td, J = 6.9, 2.3 Hz, 12H), ¹H NMR spectrum as follows Figure 27 As shown.

[0233] Example 28: The synthesis route of IBMC-043 is shown in the following formula:

[0234]

[0235] The specific synthesis steps of IBMC-043 are as follows: Step 1: Synthesis of Si-HO3: 8.8 mmol Si-HO2, 17.5 mmol cesium carbonate and 9.6 mmol N,N-dimethyl-3-chloropropane were dissolved in 100 mL DMF and stirred at 80 °C for 5 h. The solution was diluted with dichloromethane, washed with water, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation, and separated by column chromatography to obtain Si-HO3 (1.8 g, 65.6%). 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J=9.0Hz,2H),7.47–7.30(m,5H),6.91(d,J=8.9Hz, 2H), 5.33 (s, 2H), 4.07 (t, J = 6.4Hz, 2H), 2.46 (t, J = 7.2Hz, 2H), 2.26 (s, 4H), 1.98 (p, 2H).

[0236] Step 2: Synthesis of Si-HO4: 2.55 mmol Si-HO3 and 80 mg palladium on carbon were dissolved in 20 mL methanol, hydrogen gas was introduced, and the mixture was stirred at 25 °C for 12 h. The mixture was then evaporated and concentrated to obtain Si-HO4 (550 mg, 96.5%). 1H NMR (400MHz, Methanol-d4) δ7.87 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.13 (t, J = 5.9 Hz, 2H), 3.14 (t, J = 7.7 Hz, 2H), 2.77 (s, 6H), 2.16 (p, 2H).

[0237] Step 3: Synthesis of IBMC-043: 223.9 μmol Si-H04, 268.7 μmol T-13, 335.9 μmol EDCI and 671.8 μmol DMAP were dissolved in 15 mL of DCM and stirred at 30 °C for 24 h. The reaction solution was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation, and obtained by column chromatography (40 mg, 23.1%). 1 ¹H NMR (400MHz, Chloroform-d) δ 7.97 (d, J = 8.9Hz, 2H), 6.91 (d, J = 8.9Hz, 2H), 5.10 (dq, J = 9.8, 3.7, 2.4Hz, 1H), 4.08 (t, J = 6.3Hz, 2H), 4.04 (t, J = 6.6Hz, 4H), 3.75 (t, J = 4.7Hz, 2H), 2.53 (br, 6H), 2.29 (tt, J = 9.0, 5.4Hz, 2H), 2.02 (br, 2H), 1.73–1.47 (m, 8H), 1.48–1.31 (m, 12H), 1.24 (s, 44H), 0.90–0.83 (m, 12H), ¹H NMR spectrum as shown Figure 28 As shown.

[0238] Example 29:

[0239] The specific synthesis steps of IBMC-044 differ from those in Example 28: T-11 is used instead of T-13. The proton NMR spectrum of IBMC-044 is as follows: 1 1H NMR (400MHz, Chloroform-d) δ 2.13 (s, 6H), 2.29 (t, 2H), 1.85 (m, 2H), 3.97–4.05 (t, 6H), 7.05–7.93 (dd, 4H), 4.42 (m, 1H), 2.15 (m, 1H), 2.29 (t, 2H), 1.29–1.63 (m, 52H), 0.93 (t, 9H), [NMR spectrum details omitted]. Figure 29 As shown.

[0240] Example 30: The synthesis route of IBMC-048 is shown in the following formula:

[0241]

[0242] The synthesis steps for IBMC-048 differ from those in Example 29 as follows:

[0243] 1) The difference between the synthesis method of Si-HO5 and Si-HO3: Morpholinylpropanol is used instead of N,N-dimethyl-3-chloropropane;

[0244] 2) The difference between the synthesis method of Si-HO6 and Si-HO4: Si-HO5 is used instead of Si-HO3.

[0245] The proton spectrum of IBMC-048: 1 H NMR(400MHz,Chloroform-d)δ7.97(d,J=8.9Hz,2H),6.91(d,J

[0246] =8.9Hz, 2H), 5.19–4.98(m, 1H), 4.08(t, J = 6.3Hz, 2H), 4.04(t, J = 6.6Hz, 4H), 3.84–3.59(m, 4H), 2.53(br, 6H), 2.02(br, 2H), 1.72–1.50(m, 12H), 1.47–1.32(m, 12H), 1.24(m, 40H), 0.92–0.81(m, 12H), ¹H NMR spectrum as follows Figure 30 As shown.

[0247] Example 31: The synthesis route of IBMC-051 is shown in the following formula:

[0248]

[0249] The specific synthesis steps of IBMC-051:

[0250] Step 1: Synthesis of Bi-070813: 0.277 mmol Bi-070013 was dissolved in 10 mL of dichloromethane, and 0.138 mmol C3Y09, 0.415 mmol 4-dimethylaminopyridine, and 0.166 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product Bi-070813 (71 mg, 45.5%). 1H NMR(400MHz,Chloroform-d)δ6.93(s,1H),6.80(dt,J=13.8,2.1Hz,2H),5.02(s,2H),5.01–4.91(m,1H),4.59(d,J=14.8Hz,4H),3.98(t,J=6.7 Hz,4H),3.64(t,J=6.5Hz,2H),2.45(t,J=6.5Hz,2H),2.39–2.21(m,6H) ,2.20(s,3H),1.75(p,J=7.4Hz,2H),1.61–1.11(m,64H),0.83(m,18H).

[0251] Step 2: Synthesis of IBMC-051: 0.075 mmol Bi-070813 was dissolved in 4 mL of dichloromethane, and 1.52 mL of saturated concentrated hydrochloric acid was added dropwise. The reaction was carried out for 12 h, and the product was purified by silica gel column chromatography after rotary evaporation to obtain the target product IBMC-051 (23 mg, 30.1%). 1 H NMR(400MHz,Chloroform-d)δ6.94(s,1H),6.77(dt,J=10.1,2.2Hz,2H),5.01(s,2H ),4.92(td,J=7.2,3.6Hz,1H),4.57(d,J=10.8Hz,4H),3.97(t,J=6.7Hz,4H),3.60–3 .44 (m, 2H), 2.56–2.47 (m, 2H), 2.45 (t, J = 7.1 Hz, 2H), 2.35 (t, J = 7.0 Hz, 2H), 2.29–2.19 (m, 5H), 1.81 (p, J = 7.0 Hz, 2H), 1.58–1.10 (m, 64H), 0.80 (t, J = 6.7 Hz, 12H), 1H NMR spectrum as follows Figure 31 As shown.

[0252] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0253] The synthesis route of C3Y09 is shown in the following formula:

[0254]

[0255] The specific synthesis steps of C3Y09 are as follows: Step 1: Synthesis of C3-2: 6.52 mmol of C3-1 (methyl 4-(methylamino)butyrate hydrochloride) and 19.5 mmol of potassium carbonate were dissolved in 40 mL of acetonitrile, heated to 50 °C, and 8.5 mmol of (2-bromoethoxy)-tert-butyldimethylsilane were added. The mixture was then refluxed at 80 °C for 5 h. After the reaction was complete, the solvent was evaporated and purified by column chromatography to obtain C3-2 (1.25 g, 66.4%).1 H NMR(400MHz,Chloroform-d)δ3.68(td,J=6.6,1.3Hz,2H),3.65(d,J=1.4Hz,3H),2.50(td,J=6.6,1.4Hz,2H),2.40(dd,J=7.9,6.5H z, 2H), 2.33 (td, J = 7.5, 1.4Hz, 2H), 2.25 (d, J = 1.4Hz, 3H), 1.77 (pd, J = 7.4, 1.3Hz, 2H), 0.88 (d, J = 1.4Hz, 9H), 0.06 (d, J = 1.2Hz, 6H).

[0256] Step 2: Synthesis of C3Y09: 1.72 mmol C3-2 and 5.2 mmol sodium hydroxide were dissolved in 10 mL methanol and 5 mL water. The mixture was stirred at room temperature for 3 h. After the reaction was complete, the methanol was removed by rotary evaporation, the mixture was washed with ethyl acetate, the aqueous phase was acidified with dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then evaporated to dryness to obtain C3Y09 (0.35 g, 74%). 1 H NMR(400MHz,Chloroform-d)δ3.93–3.82(m,2H),2.83(qd,J=5.4,3.1Hz,4H),2.64 –2.56(m,2H),2.53(s,3H),1.87–1.77(m,2H),0.89(s,9H),0.07(d,J=2.7Hz,6H).

[0257] Example 32: Specific synthesis steps of IBMC-052: 0.125 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.498 mmol N,N-dimethylaminobutyrate, 0.747 mmol 4-dimethylaminopyridine, and 0.597 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was purified by silica gel column chromatography to obtain the target product IBMC-052 (40 mg, 33.8%). 1¹H NMR (400MHz, Chloroform-d) δ 6.89 (d, J = 1.7Hz, 1H), 6.79 (d, J = 1.4Hz, 2H), 5.00 (s, 4H), 4.93 (td, J = 7.0, 3.5Hz, 1H), 4.54 (s, 2H), 3.98 (t, J = 6.6Hz, 4H), 2.34 (t, J = 7.4Hz, 4H), 2.30–2.25 (m, 4H), 2.24–2.21 (m, 2H), 2.18 (s, 12H), 1.78 (h, J = 7.4, 6.9Hz, 4H), 1.59–1.08 (m, 64H), 0.83–0.77 (m, 12H). The ¹H NMR spectrum is as follows: Figure 32 As shown.

[0258] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0259] Example 33: The synthesis route of IBMC-053 is shown in the following formula:

[0260]

[0261] The specific synthesis steps of IBMC-053 are as follows: Step 1: Synthesis of JY-02: 2.43 mmol of JY-01 (2-(4-methoxyphenyl)malonic acid-1,3-dimethyl ester) was dissolved in 10 mL of anhydrous DCM. 2.92 mmol of boron tribromide was added at -20 °C and stirred overnight. The reactants were quenched with an ice-water mixture and then washed and extracted three times with DCM. The organic phases were combined, dried with anhydrous Na2SO4, and column chromatography was used to obtain JY-02 (0.84 g, 90.0%). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.27 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 4.58 (s, 1H), 3.75 (s, 6H).

[0262] Step 2: Synthesis of JY-03: 2.85 mmol JY-02 was dissolved in 15 mL of acetonitrile, and 4.28 mmol Cs2CO3 and 3.43 mmol (3-bromopropyl)dimethylamine were added. The mixture was stirred at 60 °C for 12 h. After the reaction was completed, the mixture was filtered, evaporated to dryness, and column chromatography was used to obtain JY-03 (0.31 g, 35.0%). 1 H NMR (400MHz, CDCl3) δ (ppm) 7.16 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.12 (t, J = 6.1 Hz, 2H), 4.02-3.99 (m, 4H), 3.48 (s, 1H), 3.33 (br, 12H).

[0263] Step 3: Synthesis of IBMC-053: 1.21 mmol JY-03 was dissolved in 5 mL EtOH, and 7.26 mmol NaBH4 was added under ice bath conditions. The mixture was stirred at room temperature for 6 h. After the reaction was completed, the reaction was quenched with saturated NH4Cl aqueous solution. The mixture was extracted three times with DCM, evaporated to dryness, dissolved in dichloromethane, and then 3.02 mmol ROH, 0.84 mmol EDC, and 0.84 mmol DMAP were added sequentially. The mixture was stirred at room temperature for 24 h. After the reaction was completed, the mixture was filtered, evaporated to dryness, and column chromatography was used to obtain IBMC-053 (367.0 mg, 39.0%). 1 1H NMR (400MHz, CDCl3) δ (ppm) 7.16-7.12 (m, 2H), 6.87-6.82 (m, 2H), 5.42-5.28 (m, 8H), 3.81-3.78 (m, 7H), 2.77 (t, J = 6.4Hz, 4H), 2.12-2.02 (m, 8H), 1.58 (br, 4H), 1.37-1.23 (m, 42H), 0.89 (t, J = 6.8Hz, 6H), [NMR spectrum is shown below] Figure 33 As shown.

[0264] Example 34: Specific synthesis steps of IBMC-054: 223.9 μmol Si-H04, 268.7 μmol T-08, 335.9 μmol EDCI and 671.8 μmol DMAP were dissolved in 15 mL of DCM, stirred at 30 °C for 24 h, washed with saturated NaCl, dried over anhydrous sodium sulfate, concentrated by evaporation, and separated by column chromatography to obtain IBMC-054 (30 mg, 18.3%). 1 ¹H NMR (400MHz, Chloroform-d) δ 7.98 (d, J = 8.5Hz, 2H), 6.90 (d, J = 8.5Hz, 2H), 5.47–5.24 (m, 8H), 5.08 (q, J = 6.2Hz, 1H), 4.08 (t, J = 6.2Hz, 2H), 2.76 (t, J = 6.5Hz, 2H), 2.62 (t, J = 7.4Hz, 2H), 2.37 (s, 6H), 2.12–1.95 (m, 8H), 1.76–1.50 (m, 4H), 1.45–1.15 (m, 40H), 0.95–0.76 (m, 6H), ¹H NMR spectrum as follows: Figure 34 As shown.

[0265] The specific synthesis steps for Si-H04 are the same as in Example 28.

[0266] The specific synthesis steps for T-08 are the same as in Example 3.

[0267] Example 35: The specific synthesis steps of IBMC-055 differ from those in Example 34: Morpholinylpropanol is used instead of N,N-dimethyl-3-chloropropane. The proton NMR spectrum of IBMC-055 is as follows: 1 ¹H NMR (400MHz, Chloroform-d) δ 7.98 (d, J = 8.5Hz, 2H), 6.90 (d, J = 8.7Hz, 2H), 5.34 (tq, J = 10.9, 6.7, 5.8Hz, 8H), 5.08 (p, J = 6.0Hz, 1H), 4.08 (t, J = 6.2Hz, 2H), 3.82–3.62 (m, 4H), 2.76 (t, J = 6.4Hz, 2H), 2.62–2.47 (m, 4H), 2.16–1.90 (m, 8H), 1.74–1.52 (m, 4H), 1.41–1.16 (m, 40H), 0.88 (t, J = 6.7Hz, 6H), ¹H NMR spectrum as shown Figure 35 As shown.

[0268] Example 36: The specific synthesis steps of IBMC-056 differ from those in Example 3: Morpholinylpropanol is used instead of N-methyldiethanolamine. The proton NMR spectrum of IBMC-056 is as follows: 1 ¹H NMR (400MHz, Chloroform-d) δ 8.29 (t, J = 1.4 Hz, 1H), 7.76 (d, J = 1.4 Hz, 2H), 5.00 (p, J = 6.2 Hz, 1H), 4.70 (s, 2H), 4.40 (t, J = 6.6 Hz, 4H), 3.75–3.68 (m, 8H), 2.55–2.36 (m, 12H), 1.96 (p, J = 6.8 Hz, 4H), 1.24 (q, J = 3.5, 2.8 Hz, 68H), 0.90–0.85 (m, 6H), ¹H NMR spectrum as follows: Figure 36 As shown.

[0269] Example 37: The specific synthesis steps of IBMC-057 differ from those in Example 3: N,N-dimethylpropanolamine is used instead of N-methyldiethanolamine. Proton NMR spectrum of IBMC-057: 1¹H NMR (400MHz, Chloroform-d) δ 8.31 (d, J = 1.5Hz, 1H), 7.77 (d, J = 1.4Hz, 2H), 5.01 (q, J = 6.1Hz, 1H), 4.70 (s, 2H), 4.39 (t, J = 6.6Hz, 4H), 2.44 (t, J = 7.3Hz, 4H), 2.27 (s, 12H), 1.97 (h, J = 6.8, 6.0Hz, 4H), 1.54 (t, J = 6.1Hz, 4H), 1.24 (d, J = 5.4Hz, 64H), 0.88 (t, J = 6.8Hz, 6H), ¹H NMR spectrum as shown below. Figure 37 As shown.

[0270] Example 38: The specific synthesis steps of IBMC-058 differ from those in Example 3: 1,4-bis(2-hydroxyethyl)piperazine is used instead of N-methyldiethanolamine. The proton NMR spectrum of IBMC-058 is as follows: 1 ¹H NMR (400MHz, Chloroform-d) δ 8.29 (t, J = 1.5 Hz, 1H), 7.77 (d, J = 1.5 Hz, 2H), 5.00 (p, J = 6.2 Hz, 1H), 4.70 (s, 2H), 4.47 (t, J = 5.9 Hz, 4H), 3.66–3.58 (m, 4H), 2.78 (q, J = 7.0, 6.5 Hz, 4H), 2.54 (d, J = 5.3 Hz, 20H), 1.25 (d, J = 4.9 Hz, 68H), 0.90–0.85 (m, 6H), [NMR spectrum details omitted]. Figure 38 As shown.

[0271] Example 39: Specific synthesis steps of IBMC-059: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol N,N-dimethylaminopropionate, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product IBMC-059 (60 mg, 54.1%). 1¹H NMR (400MHz, Chloroform-d) δ 6.97 (s, 1H), 6.86 (dt, J = 13.6, 2.2Hz, 2H), 5.09 (s, 2H), 5.02–4.97 (m, 1H), 4.64 (d, J = 16.0Hz, 4H), 4.03 (t, J = 6.7Hz, 4H), 2.69 (t, J = 7.1Hz, 2H), 2.57 (t, J = 6.9Hz, 2H), 2.34–2.24 (m, 8H), 1.62–1.52 (m, 12H), 1.42 (ddd, J = 13.6, 7.2, 3.4Hz, 4H), 1.25 (s, 48H), 0.89–0.85 (m, 12H). The ¹H NMR spectrum is as follows: Figure 39 As shown.

[0272] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0273] Example 40: Specific synthesis steps of IBMC-060: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol N,N-dimethylaminovalerate, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product IBMC-060 (100 mg, 53.6%). 1 H NMR(400MHz,Chloroform-d)δ7.02(s,1H),6.80(dt,J=13.9,2.1Hz,2H),5.06(s,2H),4.98 (td,J=7.2,3.6Hz,1H),4.62(d,J=12.7Hz,4H),4.02(t,J=6.7Hz,4H),2.79–2.73(m,2H),2 .57 (s, 6H), 2.41 (t, J = 6.3 Hz, 2H), 2.29 (ddd, J = 8.9, 7.1, 4.5 Hz, 2H), 1.72–1.68 (m, 2H), 1.61–1.51 (m, 12H), 1.44–1.38 (m, 4H), 1.24 (d, J = 7.9 Hz, 48H), 0.85 (t, J = 6.7 Hz, 12H), 1H NMR spectrum as follows Figure 40 As shown.

[0274] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0275] Example 41: Specific synthesis steps of IBMC-061: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol 1-piperidinonic acid, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The product was purified by silica gel column chromatography to obtain the target product IBMC-061 (100 mg, 53.6%). 1 H NMR(400MHz,Chloroform-d)δ6.97(s,1H),6.85(d,J=18.1Hz,2H),5.07(s,2H),5.00(p ,J=6.1Hz,1H),4.64(d,J=14.3Hz,4H),4.04(t,J=6.7Hz,4H),2.72(t,J=7.4Hz,2H),2. 59 (t, J = 7.4 Hz, 2H), 2.49–2.37 (m, 4H), 2.30 (tt, J = 9.2, 5.3 Hz, 2H), 1.64–1.52 (m, J = 5.5, 5.0 Hz, 16H), 1.43 (p, J = 6.8 Hz, 6H), 1.33–1.20 (m, 48H), 0.87 (t, J = 6.5 Hz, 12H), 1H NMR spectrum as follows Figure 41 As shown.

[0276] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0277] Example 42: Specific synthesis steps of IBMC-062: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol 3-pyrrolidone-1-ylpropionic acid, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product IBMC-062 (100 mg, 53.6%). 1H NMR(400MHz,Chloroform-d)δ6.98(s,1H),6.85(dt,J=16.9,2.1Hz,2H),5.09(s,2H) ,5.00(tt,J=7.2,3.6Hz,1H),4.65(d,J=15.6Hz,4H),4.03(t,J=6.7Hz,4H),2.96(t, J = 7.5 Hz, 2H), 2.78–2.63 (m, 6H), 2.30 (td, J = 8.9, 4.5 Hz, 2H), 1.91–1.82 (m, 4H), 1.63–1.52 (m, 12H), 1.47–1.39 (m, 4H), 1.33–1.21 (m, 48H), 0.87 (t, J = 6.7 Hz, 12H), 1H NMR spectrum as follows Figure 42 As shown.

[0278] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0279] Example 43: Specific synthesis steps of IBMC-066: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol 4-(azacycloheptane-1-yl)butyric acid, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added sequentially. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then evaporated to dryness. The solution was purified by silica gel column chromatography to obtain the target product IBMC-066 (100 mg, 53.6%). 1 H NMR(400MHz,Chloroform-d)δ7.04(s,1H),6.82(dt,J=16.6,2.2Hz,2H),5.08(s,2H),5.01–4.95(m,1H ),4.64(d,J=19.0Hz,4H),4.03(t,J=6.6Hz,4H),3.11(s,4H),2.97–2.89(m,2H),2.48(t,J=6.6Hz,2H) ,2.30(tt, J=8.9, 5.3Hz, 2H), 2.16(dq, J=14.1, 6.7Hz, 2H), 1.92(s, 4H), 1.70(s, 4H), 1.57(dq, J=14.3, 6.6Hz, 12H), 1.42(td, J=8.4, 7.8, 4.6Hz, 4H), 1.26(d, J=14.1Hz, 48H), 0.86(t, J=6.7Hz, 12H), 1H NMR spectrum as follows Figure 43 As shown.

[0280] The specific synthesis steps for Bi-070013 are the same as in Example 4.

[0281] Example 44: Preparation and testing of lipid nanoparticle compositions (LNP formulations)

[0282] To prepare nanoparticle compositions for delivering therapeutic and / or preventative agents to cells, a series of nanoparticle formulations were prepared and tested, and the lipid components of the nanoparticle compositions were optimized. The nanoparticles can be prepared manually and via microfluidics; these methods are not exhaustive, and any nanoparticle composition capable of producing the formulations of this invention is within the scope of this invention.

[0283] Lipid compositions are formulated using lipid molecules represented by general formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), and (IIIc), neutral lipids (such as DSPC, Aivitol (Shanghai) Pharmaceutical Technology Co., Ltd.), steroidal compounds (such as cholesterol, Aivitol (Shanghai) Pharmaceutical Technology Co., Ltd.), and polymer-conjugated lipids (such as DMG-PEG2000, Aivitol (Shanghai) Pharmaceutical Technology Co., Ltd.) in molar percentages (lipid molecules:DSPC:cholesterol:DMG-PEG2000 = 20%-100%:0%-40%:0%-80%:0%-20%). Formulations within this molar percentage range can prepare nanoparticle compositions, and any LNPs obtained through such formulations are within the scope of protection of this invention.

[0284] In this embodiment, the above-mentioned lipid components were prepared into an ethanol phase solution with a total concentration of 50 mM at a molar percentage of 50:10:38.5:1.5 for later use. Lipid DLin-MC3-DMA (MC3) is a current standard in the art; therefore, a standard MC3 nanoparticle composition was prepared using a molar percentage of MC3:DSPC:cholesterol:DMG-PEG2000 = 50:10:38.5:1.5 as a control in this study.

[0285] Active ingredients (such as mRNA, EGFP, Luciferase, or SARS-CoV2 Spike) were added to 10-50 mM buffer (citrate, acetate, pH 3-6) to prepare an aqueous mRNA solution. The ethanol-phase lipid solution and the aqueous mRNA solution were mixed manually or via a microfluidic device to prepare the nanoparticle composition. The volume ratio of the aqueous phase to the ethanol phase was between 1:1 and 5:1; in this embodiment, the volume ratio was set to 3:1. The mass ratio of total lipids to mRNA was between 5 and 65:1 (or based on the N / P ratio of lipid molecules to mRNA was between 4 and 12:1); in this embodiment, three N / P ratios were set at 8:1, 6:1, and 4:1, yielding three sets of experimental data. Manual operation involved rapid injection followed by vortexing for 30-60 seconds; in this embodiment, vortexing for 30 seconds was set. The total liquid flow rate of the microfluidic system was between 10 and 25 mL / min; in this embodiment, the total liquid flow rate was set to 20 mL / min.

[0286] The nanoparticle composition was purified by dialysis. The nanoparticle composition solution was dialyzed multiple times with DPBS to remove ethanol and free molecules, and then filtered through a 0.2 μm sterile filter to obtain a lipid nanoparticle composition (LNP formulation) encapsulating mRNA.

[0287] The nanoparticle composition was tested using a Malvern Zetasizer Nano ZS ZEN3600 (Malvern UK) to determine the particle size, polydispersity index (PDI), and potential of the lipid nanoparticle composition via dynamic light scattering. The encapsulation efficiency of the nanoparticle composition for mRNA was evaluated using the Quant-iT™ RiboGreen™ RNA Assay Kit (Thermo Fisher Scientific).

[0288] As shown in Tables 1A-1C, the particle size, PDI, potential, and encapsulation efficiency of nanoparticle compositions encapsulating mRNA (EGFP and / or Luciferase, SARS-CoV2 Spike) based on lipid molecules represented by general formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), and (IIIc) are compared.

[0289] Table 1A contains physicochemical properties of the nanoparticle composition for cell transfection, wherein the mRNA is a mixture of EGFP and Luciferase in equal mass ratios.

[0290]

[0291]

[0292] #=The N / P ratio of lipid molecules to mRNA is 6

[0293] Table 1B contains physicochemical properties of nanoparticle compositions for animal administration, where the mRNA is Luciferase.

[0294] lipid molecules Particle size (nm) PDI Potential (mV) Encapsulation rate % <![CDATA[MC3 # N / P=6]]> 161.13 0.18 -4.35 94.3 MC3*N / P=6 121.97 0.20 -7.53 96.4 <![CDATA[SM-102 # N / P=6]]> 168.90 0.20 -5.29 95.8 SM-102*N / P=6 91.80 0.15 -2.61 97.2 <![CDATA[IBMC-023 # N / P=6]]> 147.23 0.23 -3.61 93.2 IBMC-023*N / P=6 97.33 0.20 -1.41 96.7 <![CDATA[IBMC-023 # N / P=8]]> 157.23 0.22 -2.01 95.4 <![CDATA[IBMC-023 # N / P=4]]> 157.43 0.24 -2.52 95.3

[0295] # = Manual preparation of nanoparticle compositions; * = Microfluidic preparation of nanoparticle mixtures

[0296] Table 1C contains physicochemical properties of nanoparticle compositions for animal administration, where the mRNA is SARS-CoV-2 Spike.

[0297]

[0298]

[0299] # = Manual preparation of nanoparticle compositions; * = Microfluidic preparation of nanoparticle mixtures

[0300] The test results are shown in Tables 1A, 1B, and 1C. As can be seen from Tables 1A, 1B, and 1C, the encapsulation efficiency of the nanoparticle composition for mRNA is not much different from that of commercially available products, indicating that the nanoparticle composition prepared by this product meets the requirements for market launch.

[0301] Example 45: Evaluation of Cell Transfection Efficacy of Lipid Nanoparticle Composition (LNP Formulation)

[0302] In a 96-well plate, 2×10⁻⁶ ohms are laid in each well. 4 After culturing 293T or HeLa cells for 24 hours until the cell confluence reaches 70-90%, the cells are incubated with a lipid nanoparticle composition containing a mixed mRNA dose of 0.1 μg EGFP and 0.1 μg Luciferase per well. After 24 hours, 20X fluorescence images of EGFP are captured using an Olympus CKX53 fluorescence microscope.

[0303] Test results are as follows Figure 44 , 45 As shown in Figure 46, by Figure 44 , 45 As shown in 46, at the cellular level, the new lipid molecules can effectively deliver mRNA to cells and express it, and some of the selected lipids are superior to the already marketed lipid molecule MC3.

[0304] Example 46: Evaluation of in vivo delivery levels of lipid nanoparticle compositions (LNP formulations)

[0305] The nanoparticle formulation containing Luciferase mRNA was administered to 6-8 week old female Babl / c mice via intramuscular or intravenous injection at a dose of 0.1 mg / kg, and small animal fluorescence imaging was performed at specific time points after administration using IVIS Lumina III (PE).

[0306] Test results are as follows Figure 47 , 48 As shown, by Figure 47 , 48 It is known that the nanoparticle composition of the lipid molecule IBMC-023 can effectively deliver mRNA in animals and express related proteins at a high level; at the same time, compared with MC3, no obvious liver enrichment phenomenon was observed in IBMC-023.

[0307] Example 47: Evaluation of Spike-induced S protein expression levels in vivo after delivery of SARS-CoV2 using a lipid nanoparticle composition (LNP formulation).

[0308] Six- to eight-week-old female Babl / c mice were administered a nanoparticle formulation containing SARS-CoV2 Spike mRNA via intramuscular injection at a dose of 0.5 mg / kg. Six hours after administration, the expression levels of the S protein in the blood, muscle, and liver of the mice were analyzed according to the steps of a commercially available SARS-CoV-2 Spike ELISA kit (Sino Bioscience, KIT40591).

[0309] Test results are as follows Figure 49 , 50 As shown in Figure 51, by Figure 49 , 50 As can be seen from 51, the nanoparticle composition of the lipid molecule IBMC-023 can effectively deliver mRNA in animals and express related proteins at high levels.

[0310] Experiments have shown that the cationic lipid compounds of the present invention can deliver nucleic acid molecules, small molecule compounds, peptides or proteins, etc. The carriers prepared using the cationic lipid compounds of the present invention have high encapsulation efficiency for nucleic acid molecules, and can successfully transport nucleic acid molecules into cells and / or organs, and express them efficiently.

[0311] The conventional techniques described in the above embodiments are existing technologies known to those skilled in the art, and therefore will not be elaborated upon here. The above descriptions are merely specific embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A lipid molecule for delivering an active ingredient, comprising: a lipid compound represented by general formula (I), or a pharmaceutically available salt thereof; in, M is selected from the benzene ring; G1 and G'1 are each independently selected from -(CH2) x -O(C=O)-, where x is an integer between 0 and 4; L1 and L'1 are each independently selected from unsubstituted C 1-6 One of the alkyl groups; G2 is selected from -O-; G1, G'1, and G2 are each independently connected to the meta site in the benzene ring; X is selected from carbon or nitrogen atoms; L2 is selected from H, OH, C 1-3 Alkyl, C 2-3 One of the alkenyl groups; L3 and L4 are each independently selected from C 0-25 Alkyl, C 2-25 alkenyl, C 3-25 One of the alkynyl groups; G3 and G4 are each independently selected from one of the following: -CH2-, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -(C=O)NH-, -NH(C=O)-, -S(C=O)-, -(C=O)S-, -SS-; L5 and L6 are each independently selected from C 1-25 Alkyl, C 2-25 alkenyl, C 3-25 One of the alkynyl groups; R1, R2 and R'1, R'2 are each independently selected from any substituted or unsubstituted C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of them, wherein the substituents are 1, 2, 3, 4, or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl group; X1 and X2 are each independently selected from C1. 1-3 alkyl; or R1 and R2, R'1 and R'2 combine to form 4-8 membered heterocycles with or without substitution; wherein the substituents are 1, 2, 3, 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl.

2. The lipid molecule for delivering an active ingredient according to claim 1, characterized in that: The lipid compounds of general formula (I) comprise the structures shown in formula (Ia), (Ib), (Ic) or (Id), or pharmaceutically available salts thereof; in, G1 and G'1 are each independently selected from -(CH2) x -O(C=O)-, where x is an integer between 0 and 4; L1 and L'1 are each independently selected from unsubstituted C 1-6 One of the alkyl groups; G1 and G'1 are each independently connected to the meta site in the benzene ring; R1, R2 and R'1, R'2 are each independently selected from any substituted or unsubstituted C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of them, wherein the substituents are 1, 2, 3, 4, or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl group; X1 and X2 are each independently selected from C1. 1-3 alkyl; or R1 and R2, R'1 and R'2 combine to form 4-8 membered heterocycles with or without substitution; wherein the substituents are 1, 2, 3, 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl group, C 1-3 Alkyl group, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl; m is an integer between 0 and 4; T is selected from one of the structures shown in equations (1) to (18): 。 3. The lipid compound according to any one of claims 1-2, characterized in that: The and Each is independently selected from one of the structures shown in formulas Y01-Y30: 。 4. The lipid compound according to any one of claims 1-2, characterized in that: The 4-8 membered heterocycle is a pyrimidine ring or a purine ring.

5. A nanoparticle composition comprising one or more of the lipid compounds described in any one of claims 1-3.

6. The nanoparticle composition according to claim 5, characterized in that: The nanoparticle composition also contains therapeutic and / or preventative agents.

7. A nanoparticle composition according to claim 6, characterized in that: The therapeutic and / or preventive agents comprise nucleic acids, small molecule compounds, polypeptides, or proteins; the nucleic acids comprise at least one of single-stranded DNA, double-stranded DNA, agomir, antagomir, small interfering RNA, asymmetric interfering RNA, microRNA, Dicer-substrate RNA, small hairpin RNA, transfer RNA, messenger RNA, circular RNA, and nucleic acid aptamers.

8. The nanoparticle composition according to claim 5, characterized in that: The nanoparticle composition further comprises one or more neutral lipids, one or more steroid compounds, and one or more polymer-conjugated lipids; wherein, the molar percentage of the lipid molecules for delivering the active ingredient according to claim 1 is 20-100%; the molar percentage of the steroid compound is 0-80%; the molar percentage of the neutral lipid is 0-40%; and the molar percentage of the polymer-conjugated lipid is 0-20%.

9. The use of the nanoparticle composition of claim 5 in pharmaceutical preparation.

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