A lipid molecule and its composition

Abstract

The present invention discloses the preparation and application of lipid molecules and compositions thereof for delivering active ingredients, and relates to the field of biomedicine. The novel lipid molecule comprises the general formula (I), (II) or (III): #imgabs0# and can be used to deliver active ingredients (such as nucleic acids, polypeptides, proteins) to cells and / or organs. The embodiments of the present invention provide a nucleic acid-lipid nanoparticle composition of a variety of novel lipid molecules, and the lipid nano delivery system composed of the composition is used to deliver mRNA; at both the cellular and animal levels, it shows better delivery efficiency than the currently marketed product DLin-MC3-DMA, and can be used as a new method for delivering nucleic acid drugs to promote the development of nucleic acid drugs.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to the preparation and application of lipid molecules and compositions thereof for delivering active ingredients. Background Art

[0002] Following small molecule drugs and antibody drugs, nucleic acid drugs have become the third wave of modern pharmaceutical development. Nucleic acid drugs typically introduce specific nucleic acid molecules into target cells or tissues to replace, compensate, block, or modify specific genes to prevent and treat diseases. While nucleic acid drugs offer significant advantages, the presence of nucleases in serum can lead to rapid degradation of nucleic acids. The negative charge of nucleic acid molecules also makes it difficult for them to cross cell membranes, resulting in an extremely short half-life and inability to enter cells, leading to a lack of therapeutic efficacy. Therefore, the development of specific compounds and delivery systems is needed to improve this situation and promote the use of nucleic acid drugs as an important means of disease prevention and treatment.

[0003] Nanoparticle compositions containing lipid molecules have been demonstrated to be safe and efficient vehicles for delivering active ingredients. These lipid-containing compositions can block RNA degradation in serum and promote the cellular uptake of oligonucleotides. In addition to delivering nucleic acid molecules, they can also effectively deliver small molecule drugs, peptide drugs, and protein drugs to target cells and / or organs. Although numerous lipid-containing compositions have been described, their safety, efficacy, and specificity require further improvement. Therefore, there is a need to design and screen new lipid molecules and their nanocomposites for the delivery of various specific nucleic acid molecules. Summary of the Invention

[0004] The object of the present invention is to provide a novel lipid molecule and a nanoparticle composition comprising the lipid molecule, wherein the nanoparticle composition can deliver active ingredients to cells and / or organs according to the relevant methods of the present invention.

[0005] The technical solutions adopted by the present invention to achieve the above-mentioned purpose are:

[0006] Lipid molecules for delivering active ingredients, comprising: lipid compounds represented by general formula (I), (II), (III), or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, chelates, and non-covalent complexes thereof;

[0007] in,

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

[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)-, wherein 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-

[0012] (CH2) y -(C=O)O-, -(CH2) y -(C=O)S-, -S-, -O-, wherein y is an integer between 0 and 4;

[0013] G1, G'1, and G2 are each independently connected to any site in M, where the site is a carbon or nitrogen atom;

[0014] X is selected from carbon or nitrogen atoms; n is selected from an integer between 0 and 6;

[0015] L2 is selected from H, OH, C 1-3 Alkyl, C 2-3 One of the alkenyl groups;

[0016] L3 and L4 are each independently selected from C 0-25 Alkyl, C 2-25 Alkenyl, C 3-25 One of the alkynyl groups;

[0017] G3 and G4 are each independently selected from one of -CH2-, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -(C=O)NH-, -NH(C=O)-, -S(C=O)-, -(C=O)S-, and -SS-;

[0018] L5 and L6 are each independently selected from C 1-25 Alkyl, C 2-25 Alkenyl, C3-25 One of the alkynyl groups;

[0019] 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, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of the following, wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl; X1, X2 are each independently selected from C 1-3 alkyl;

[0020] or

[0021] R1 and R2, R'1 and R'2 combine to form an optionally substituted or unsubstituted 4-8 membered heterocyclic ring, pyrimidine ring, or purine ring; wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl;

[0022] Z in formula (II) is selected from H, F, -OH, -SH-, -NH2, -CF3, -NH-(CH2) r CH3, -N(CH3)-(CH2) r One of CH3, wherein r is an integer between 0 and 4;

[0023] In formula (III), Z' is selected from any substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 One of cycloalkynyl, phenyl, 4-8 membered heterocyclic ring, wherein the substituent group is 1 or 2 independent OH, SH, C 1-3 Hydroxyl, C 1-3 Alkoxy, amino, nitro, cyano, -(C=O)OC 1-3 alkyl.

[0024] In certain embodiments, the lipid compound of the general formula (I) comprises the structure represented by formula (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, or non-covalent complex thereof;

[0025]

[0026] In certain embodiments, the lipid compound of the general formula (II) comprises a structure represented by formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or (IIh), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, or non-covalent complex thereof;

[0027]

[0028] In certain embodiments, the lipid compound of the general formula (III) comprises the structure represented by formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, or non-covalent complex thereof;

[0029]

[0030] wherein 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)-, wherein x is an integer between 0 and 4;

[0031] L1 and L'1 are each independently selected from unsubstituted C 1-6 One of the alkyl groups;

[0032] G1 and G'1 are independently connected to any position in the benzene ring;

[0033] Z' is selected from any substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8One of cycloalkynyl, phenyl, 4-8 membered heterocyclic ring; wherein the substituent group is 1 or 2 independent OH, SH, C 1-3 Hydroxyl, C 1-3 Alkoxy, amino, nitro, cyano, -(C=O)OC 1-3 alkyl;

[0034] 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, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of the following, wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl; X1, X2 are each independently selected from C 1-3 alkyl;

[0035] or

[0036] R1 and R2, R'1 and R'2 combine to form an optionally substituted or unsubstituted 4-8 membered heterocyclic ring, pyrimidine ring, or purine ring; wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl;

[0037] E is selected from oxygen or sulfur atoms;

[0038] m is an integer between 0 and 4;

[0039] T comprises one of the structures shown in formula (1) to formula (18):

[0040]

[0041] In certain embodiments, the above lipid compound, wherein Each is independently selected from one of the structures shown in formulas Y01-Y30:

[0042]

[0043] In certain embodiments, the lipid molecule is selected from one or more of the following compounds:

[0044]

[0045]

[0046]

[0047] The present invention also provides a nanoparticle composition comprising one or more of the above-mentioned lipid compounds.

[0048] In certain embodiments, the aforementioned nanoparticle compositions further comprise a therapeutic and / or prophylactic agent.

[0049] In certain embodiments, the therapeutic and / or prophylactic agents described above are encapsulated within or associated with nanoparticles.

[0050] In certain embodiments, the therapeutic and / or preventive agents comprise nucleic acids, small molecule compounds, polypeptides or proteins; the nucleic acids comprise single-stranded DNA, double-stranded DNA, short isomers, agomir, antagomir, antisense molecules, small interfering RNA (siRNA), asymmetric interfering RNA (aiRNA), microRNA (miRNA), Dicer-substrate

[0051] At least one of RNA (dsRNA), small hairpin RNA (shRNA), transfer RNA (tRNA), messenger RNA (mRNA), circular RNA (circRNA), and nucleic acid aptamer.

[0052] In certain embodiments, the nucleic acid further comprises mRNA.

[0053] In certain 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 for delivering the active ingredient is 20-100%; the molar percentage of the steroidal 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%.

[0054] Preferably, the molar percentage of the lipid molecules for delivering active ingredients is 20-95%; the molar percentage of the steroid 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%.

[0055] In certain embodiments, the neutral lipids include 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-diole ...,2-dioleoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC sn-glycero-3-phosphoethanolamine (DOPE), palmitoyloleoylphosphatidylethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-stearoylethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin (SM), ceramide, sterol and its derivatives.

[0056] In certain embodiments, the steroidal compounds include at least one of cholesterol, coprosterol, non-sterols, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, brassicasterol, tomatine, tomatine, ursolic acid, α-tocopherol, corticosteroids and derivatives thereof.

[0057] In certain embodiments, the polymer-conjugated lipid comprises 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.

[0058] In certain embodiments, the polymer-conjugated lipid comprises DMG-PEG2000 or DMPE-PEG2000.

[0059] The present invention also discloses a method for delivering nucleic acid to cells and / or organs using the nanoparticle composition containing the lipid compound.

[0060] In certain embodiments, the administration of the nanoparticle composition includes, but is not limited to, intravenous, intramuscular, intradermal, subcutaneous, or nasal administration.

[0061] The invention also discloses the application of the nanoparticle composition in the preparation of medicines.

[0062] It should be noted that the above-mentioned drugs include nucleic acid drugs, nucleic acid vaccines, small molecule drugs, polypeptide drugs, protein drugs, etc.

[0063] The present invention has developed a kind of novel lipid molecule, and this novel lipid molecule can be used for active component (such as nucleic acid, polypeptide, protein) is delivered to cell and / or organ.Embodiments of the present invention provide multiple nucleic acid-lipid nanoparticle compositions that comprise the novel lipid molecule described by the present invention, and the lipid nano delivery system of being made up of it is used for delivering mRNA.On cellular level and animal level, all show the product DLin-MC3-DMA delivery efficiency that is better than current listing, can be used as the novel method of nucleic acid drug delivery, promote the development of nucleic acid drug.

[0064] The lipid compounds prepared by the present invention are capable of delivering nucleic acid molecules, small molecule compounds, polypeptides or proteins, etc. The carriers prepared using the lipid compounds of the present invention have high encapsulation efficiency for nucleic acid molecules, can successfully transport nucleic acid molecules to cells and / or organs, and express them efficiently; and the nanoparticle compositions prepared by the present invention can effectively deliver mRNA in animals and express related proteins at high levels. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 is the nuclear magnetic resonance spectrum of IBMC-001;

[0066] Figure 2 is the nuclear magnetic resonance spectrum of IBMC-002;

[0067] Figure 3 is the nuclear magnetic resonance spectrum of IBMC-003;

[0068] Figure 4 is the nuclear magnetic resonance spectrum of IBMC-004;

[0069] Figure 5 is the nuclear magnetic resonance spectrum of IBMC-005;

[0070] Figure 6 is the nuclear magnetic resonance spectrum of IBMC-006;

[0071] Figure 7 is the nuclear magnetic resonance spectrum of IBMC-007;

[0072] Figure 8 is the nuclear magnetic resonance spectrum of IBMC-011;

[0073] Figure 9 is the nuclear magnetic resonance spectrum of IBMC-012;

[0074] Figure 10 is the nuclear magnetic resonance spectrum of IBMC-015;

[0075] Figure 11 is the nuclear magnetic resonance spectrum of IBMC-018;

[0076] Figure 12 is the nuclear magnetic resonance spectrum of IBMC-019;

[0077] Figure 13 is the nuclear magnetic resonance spectrum of IBMC-020;

[0078] Figure 14 is the nuclear magnetic resonance spectrum of IBMC-023;

[0079] Figure 15 is the nuclear magnetic resonance spectrum of IBMC-024;

[0080] Figure 16 is the nuclear magnetic resonance spectrum of IBMC-025;

[0081] Figure 17 is the nuclear magnetic resonance spectrum of IBMC-028;

[0082] Figure 18 is the nuclear magnetic resonance spectrum of IBMC-029;

[0083] Figure 19 is the nuclear magnetic resonance spectrum of IBMC-030;

[0084] Figure 20 is the nuclear magnetic resonance spectrum of IBMC-031;

[0085] Figure 21 is the nuclear magnetic resonance spectrum of IBMC-034;

[0086] Figure 22 is the nuclear magnetic resonance spectrum of IBMC-035;

[0087] Figure 23 is the nuclear magnetic resonance spectrum of IBMC-036;

[0088] Figure 24 is the nuclear magnetic resonance spectrum of IBMC-037;

[0089] Figure 25 is the nuclear magnetic resonance spectrum of IBMC-040;

[0090] Figure 26 is the nuclear magnetic resonance spectrum of IBMC-041;

[0091] Figure 27 is the nuclear magnetic resonance spectrum of IBMC-042;

[0092] Figure 28 is the nuclear magnetic resonance spectrum of IBMC-043;

[0093] Figure 29 is the nuclear magnetic resonance spectrum of IBMC-044;

[0094] Figure 30 is the nuclear magnetic resonance spectrum of IBMC-048;

[0095] Figure 31 is the nuclear magnetic resonance spectrum of IBMC-051;

[0096] Figure 32 is the nuclear magnetic resonance spectrum of IBMC-052;

[0097] Figure 33 is the nuclear magnetic resonance spectrum of IBMC-053;

[0098] Figure 34 is the nuclear magnetic resonance spectrum of IBMC-054;

[0099] Figure 35 is the nuclear magnetic resonance spectrum of IBMC-055;

[0100] Figure 36 is the nuclear magnetic resonance spectrum of IBMC-056;

[0101] Figure 37 is the nuclear magnetic resonance spectrum of IBMC-057;

[0102] Figure 38 is the nuclear magnetic resonance spectrum of IBMC-058;

[0103] Figure 39 is the nuclear magnetic resonance spectrum of IBMC-059;

[0104] Figure 40 is the nuclear magnetic resonance spectrum of IBMC-060;

[0105] Figure 41 is the nuclear magnetic resonance spectrum of IBMC-061;

[0106] Figure 42 is the nuclear magnetic resonance spectrum of IBMC-062;

[0107] Figure 43 is the nuclear magnetic resonance spectrum of IBMC-066;

[0108] Figure 44 The effect of lipid nanoparticle compositions on cells transfected with EGFP mRNA at different N / P ratios is shown;

[0109] Figure 45 The Hela cell transfection effect of the lipid nanoparticle composition;

[0110] Figure 46 The lipid nanoparticle composition 293T cell transfection effect;

[0111] Figure 47The results of in vivo delivery test of lipid nanoparticle compositions (LNP preparations) using different injection methods are shown;

[0112] Figure 48 The results of in vivo delivery level testing of lipid nanoparticle compositions (LNP preparations) at different time points;

[0113] Figure 49 In vivo delivery of SARS-CoV2 Spike-induced S protein expression levels in muscle by lipid nanoparticle compositions (LNP formulations);

[0114] Figure 50 In vivo delivery of SARS-CoV2 Spike by lipid nanoparticle compositions (LNP formulations) induced the expression level of S protein in the liver;

[0115] Figure 51 In vivo delivery of SARS-CoV2 Spike-induced S protein expression levels in the blood by lipid nanoparticle compositions (LNP formulations). DETAILED DESCRIPTION

[0116] The technical solution of the present invention is further described in detail below with reference to the specific embodiments and the accompanying drawings:

[0117] Lipid molecules represented by the general formulas (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), and (IIIc) were synthesized; all of the above lipid molecules can be synthesized in a modular manner. In the specific examples of the present invention, unless otherwise specified, all raw materials and reagents used were commercially obtained and did not require further purification.

[0118] Example 1: The synthetic route of IBMC-001 is as follows:

[0119]

[0120] The specific synthesis steps of IBMC-001 are as follows: Step 1: Synthesis of Bi-12: Dissolve 79 mmol Bi-01 (5-hydroxyisophthalic acid), 160 mmol benzyl bromide and 240 mmol sodium bicarbonate in 100 mL of DMF, stir at 40°C for 8 hours, dilute the reactant with dichloromethane and wash with saturated sodium bicarbonate, wash with sodium chloride, dry with anhydrous sodium sulfate and then spin-dry, and purify with a silica gel column 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).

[0121] Step 2: Synthesis of Bi-13: Dissolve 10 mmol of Bi-12, 20 mmol of tert-butyl bromoacetate and 30 mmol of potassium carbonate in 100 mL of acetonitrile, stir at 70°C for 8 h, dilute the reaction solution with ethyl acetate, wash with saturated sodium bicarbonate, wash with saturated sodium chloride, dry over anhydrous sodium sulfate and spin-dry, and purify with silica gel column 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).

[0122] Step 3: Synthesis of Bi-14: 6 mmol of Bi-13 was dissolved in 50 mL of a 4 / 1 mixed solvent of trifluoroacetic acid and dichloromethane, stirred at room temperature for 12 h, and the solvent was dried by spin-drying. The product was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then dried by spin-drying. The product was purified by silica gel column 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).

[0123] Step 4: Synthesis of Bi-140013: Dissolve 1.52 mmol of Bi-14 and 3.04 mmol of T-13 in 50 mL of dichloromethane, add 3.04 mmol of 4-dimethylaminopyridine and 4.56 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stir at room temperature for 8 h, extract with dichloromethane, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column 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).

[0124] Step 5: Synthesis of Bi-150013: 1.11 mmol Bi-140013 and 100 mg Pd / C were dissolved in 50 mL methanol, and hydrogen was passed through the mixture, and stirred at room temperature for 8 h. The filtrate was filtered and dried 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).

[0125] Step 6: Synthesis of IBMC-001: Dissolve 0.067 mmol Bi-150013 and 0.266 mmol N-methyldiethanolamine in 5 mL of dichloromethane, add 0.1995 mmol of 4-dimethylaminopyridine and 0.3325 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stir at room temperature for 8 h, extract with dichloromethane, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column to obtain IBMC-001 (41 mg, 55.79%). 1 H NMR (400 MHz, Chloroform-d) δ8.33 (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), H NMR spectrum as shown Figure 1 shown.

[0126] The synthetic route of T-13 is as follows:

[0127]

[0128] The specific synthesis steps of T-13 are as follows:

[0129] Step 1: Synthesis of T-3-3: In a three-necked flask, 48.7 mmol TosMIC was weighed and dissolved in 150 mL of DMSO. 166 mmol NaH, 107.2 mmol T-3-1 (5-bromopentyl acetate) and 9.7 mmol TBAI were added to the reaction flask under an ice bath. After the addition, the mixture was stirred at room temperature overnight. After the reaction was completed, ice water was added to the reaction solution, and then 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 directly processed into the next step. Dissolve 20.9 g of T-3-2 in 250 mL of dichloromethane, add 50 mL of saturated concentrated hydrochloric acid dropwise, stir for 1 h, add water to the reaction solution, extract with dichloromethane, wash with saturated sodium bicarbonate solution, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate, and separate 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).

[0130] Step 2: Synthesis of T-3-4: Dissolve 24.4 mmol of T-3-3 in 100 mL of a mixture of methanol and water (4:1), add 73 mmol of sodium hydroxide, stir at 40°C for 4 h, remove methanol by rotary evaporation, extract with ethyl acetate, concentrate, and separate 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).

[0131] Step 3: Synthesis of T-3-5: Dissolve 17.3 mmol of T-3-4 and 51.98 mmol of 2-hexyldecanoic acid in 100 mL of dichloromethane, then add 34.6 mmol of 4-dimethylaminopyridine and 34.6 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stir at room temperature overnight, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, spin dry and purify with silica gel column 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).

[0132] Step 4: Synthesis of T-13: Dissolve 14 mmol of T-3-5 in 150 mL of methanol, add 56 mmol of sodium borohydride, stir at room temperature for 3 h, then add 50 mL of ice water to quench, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate by evaporation 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).

[0133] Example 2: The synthetic route of IBMC-002 is as follows:

[0134]

[0135] The specific synthesis steps of IBMC-002 differ from those of Example 1:

[0136] 1) The difference between the synthesis steps of Bi-140011 and Bi-140013: T-11 is used instead of T-13;

[0137] 2) The difference between the synthesis steps of Bi-150011 and Bi-150013: Bi-140011 is used instead of Bi-140013.

[0138] Proton spectrum of IBMC-002: 1H NMR (400 MHz, Chloroform-d) δ8.31 (s, 1H), 7.78 (s, 2H), 5.00 (p, J = 6.0 Hz, 1H), 4.71 (s, 2H), 4.46 (t, J = 5.6 Hz, 4H), 4.03 (td, J = 6.5, 4.4 Hz, 4H), 3.64 (t, J = 5.3 Hz, 4H), 2.92 (t, J = 5.6 Hz, 4H), 2.70 (t, J = 5.3 Hz, 4H), 2.42 (s, 6H), 2.28 (q, J = 7.5, 6.8 Hz, 3H), 1.64–1.17 (m, 52H), 0.86 (t, J = 6.6 Hz, 9H), H NMR spectrum as shown Figure 2 shown.

[0139] The synthetic route of T-11 is as follows:

[0140]

[0141] The specific synthesis steps of T-11 are as follows:

[0142] 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 at room temperature overnight, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and then spin-dried. The mixture was purified by silica gel column 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).

[0143] Step 2: Synthesis of T-3-8: Dissolve 3.8 mmol of T-3-7 and 4.6 mmol of nonanoic acid in 50 mL of dichloromethane, then add 7.6 mmol of 4-dimethylaminopyridine and 7.6 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, stir at room temperature overnight, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column to obtain T-3-8 (0.9 g, 90%). 1H 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).

[0144] Step 3: Synthesis of T-11: Dissolve 1.3 mmol of T-3-8 in 50 mL of methanol, add 5.2 mmol of sodium borohydride, stir at room temperature for 3 h, then add 50 mL of ice water to quench, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate by evaporation to obtain T-11 (0.9 g, 99%). 1 H 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).

[0145] The specific synthesis steps of T-3-4 are the same as those in Example 1.

[0146] Example 3: The synthetic route of IBMC-003 is as follows:

[0147]

[0148] The specific synthesis steps of IBMC-003 differ from those of Example 2 in that T-08 is used instead of T-11.

[0149] Proton spectrum of IBMC-003: 1 H NMR (400MHz, Chloroform-d) δ8.33 (t, J=1.5Hz, 1H), 7.79 (d, J=

[0150] 1.5Hz,2H),5.00(p,J=6.2Hz,1H),4.72(s,2H),4.44(t,J=5.7Hz,4H),3.65–3.59(m,4H),2.87(t,J=5.6Hz,4H),2.70–2.63(m,4H),2.39(s,6H),1.18-1.25(m,68H),0.91–0.85(m,6H), H NMR spectrum as Figure 3 shown.

[0151] The synthetic route of T-08 is as follows:

[0152]

[0153] The specific synthesis steps of T-08 are as follows:

[0154] Step 1: Synthesis of T-1-1: Under an ice-water bath, dissolve 17.8 mmol of T-1-0 (linoleic acid) in 50 mL of THF and slowly add dropwise to 50 mL of tetrahydrofuran containing 17.8 mmol of LiAlH4 with stirring. After the addition is complete, stir at room temperature for 2 h. After the reaction is completed, add ice water to quench the LiAlH4. Filter, spin-dry, and separate by column chromatography to obtain T-1-1 (4.5 g, 94.7%). 1 H 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).

[0155] 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 continued for 2 h. The solvent was dried 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).

[0156] Step 3: Synthesis of T-08: Add 18.29 mmol of magnesium stick to a Shrek tube and evacuate, add ultra-dry THF, and finally dissolve 6 mmol of T-1-2 in 5 mL of THF and inject into the reaction flask. After stirring at room temperature for 1 h, add ethyl formate and stir overnight. Quench the reaction with water, extract with dichloromethane, concentrate, and separate 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).

[0157] Example 4: The synthetic route of IBMC-004 is as follows:

[0158]

[0159] 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 borane tetrahydrofuran were dissolved in 100 mL of ultra-dry THF, stirred at room temperature for 24 h, and the reactant was quenched with saturated ammonium chloride, washed with saturated sodium chloride, dried over anhydrous NaSO4, and purified on a silica gel column 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).

[0160] Step 2: Synthesis of Bi-04: Dissolve 64.6 mmol of Bi-02 and 77.2 mmol of methyl bromoacetate in 300 mL of acetonitrile, add 129.8 mmol of potassium carbonate, reflux at 80°C, and react for 4 h. The reaction solution is cooled to room temperature and filtered. The filtrate is dried and purified on a silica gel column 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).

[0161] Step 3: Synthesis of Bi-06: Dissolve 22.1 mmol Bi-04 and 88.4 mmol imidazole in 100 mL of anhydrous dichloromethane, dissolve tert-butyldimethylsilyl chloride in 50 mL of anhydrous dichloromethane and add dropwise to the reaction solution. React at room temperature for 4 h, spin dry, and purify by column to obtain the target product Bi-06 (7.56 g, 70%). 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).

[0162] Step 4: Synthesis of Bi-07: 11 mmol of Bi-06 was dissolved in 90 mL of methanol; 22 mmol of sodium hydroxide was dissolved in 30 mL of deionized water and added dropwise to the methanol solution. The reaction was allowed to proceed for 2 h. The solution was vortexed to one-third volume and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the product was purified by column chromatography to obtain the target product Bi-07 (2.9 g, 60%). 1 H 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).

[0163] Step 5: Synthesis of Bi-0713: Dissolve 0.227 mmol of Bi-07 in 50 mL of dichloromethane, and add 0.114 mmol of T-13, 0.341 mmol of 4-dimethylaminopyridine, and 0.272 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in sequence. Stir at room temperature for 8 h, wash with sodium chloride solution, dry over anhydrous sodium sulfate, and then dry and purify with silica gel column 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).

[0164] Step 6: Synthesis of Bi-070013: Dissolve 0.91 mmol of Bi-0713 in 50 mL of dichloromethane, add 5 mL of saturated concentrated hydrochloric acid dropwise, react for 8 h, spin dry, and purify on a silica gel column to obtain the target product Bi-070013 (0.71 g, 81%). 1H 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).

[0165] Step 7: Synthesis of IBMC-004: Dissolve 0.08 mmol of Bi-070013 in 8 mL of dichloromethane, and add 0.32 mmol of 3-(4-morpholinyl)propionic acid, 0.48 mmol of 4-dimethylaminopyridine, and 0.38 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in sequence. React at room temperature for 12 h, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column to obtain the target product IBMC-004 (42 mg, 45.38%). 1H NMR (400MHz, Chloroform-d) δ6.96 (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), H NMR spectrum as shown Figure 4 shown.

[0166] The specific synthesis steps of T-13 are the same as those in Example 1.

[0167] Example 5: The synthetic route of IBMC-005 is as follows:

[0168]

[0169] The specific synthesis steps of IBMC-005 are as follows: Step 1: Synthesis of Bi-0711: Dissolve 0.227 mmol of Bi-07 in 5 mL of dichloromethane, and add 0.114 mmol of T-11, 0.342 mmol of 4-dimethylaminopyridine, and 0.227 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in sequence, stir at room temperature for 12 hours, wash with sodium chloride solution, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column 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).

[0170] Step 2: Synthesis of Bi-070011: Dissolve 0.045 mmol of Bi-0711 in 5 mL of dichloromethane, add 0.6 mL of saturated concentrated hydrochloric acid dropwise, react for 8 h, spin dry, and purify on a silica gel column 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).

[0171] Step 3: Synthesis of IBMC-005: Dissolve 0.064 mmol of Bi-070011 in 5 mL of dichloromethane, and add 0.032 mmol of N,N-dimethylaminobutyric acid hydrochloride, 0.096 mmol of 4-dimethylaminopyridine, and 0.096 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in sequence. React at room temperature for 12 h, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column to obtain the target product IBMC-005 (7 mg, 10.1%). 1H NMR (400 MHz, Chloroform-d) δ7.01 (s, 1H), 6.83 (dt, J = 13.1, 2.3 Hz, 2H), 5.08 (s, 2H), 4.99 (tt, J = 7.2, 3.5 Hz, 1H), 4.64 (d, J = 15.2 Hz, 4H), 4.03 (td, J = 6.7, 4.1 Hz, 4H), 2.45 (dt, J = 16.9, 7.4 Hz, 6H), 2.36 (s, 4H), 2.28 (t, J = 7.6 Hz, 3H), 1.93 (p, J = 7.2 Hz, 2H), 1.70–1.16 (m, 52H), 0.88 (td, J = 6.9, 1.7 Hz, 9H). Figure 5 shown.

[0172] The specific synthesis steps of Bi-07 are the same as those in Example 4.

[0173] Example 6: The synthetic route of IBMC-006 is as follows:

[0174]

[0175] The specific synthesis steps of IBMC-006 differ from those of Example 5 in that T-08 is used instead of T-11. 1 H NMR (400 MHz, 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). Figure 6 shown.

[0176] The specific synthesis steps of T-08 are the same as those in Example 3.

[0177] Example 7: Specific synthesis steps of IBMC-007: 0.067mmol Bi-150013 and 0.266mmol N,N-dimethylpropanolamine were dissolved in 5mL of dichloromethane, 0.1995mmol of 4-dimethylaminopyridine and 0.3325mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 8h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain IBMC-007 (41mg, 55.79%). 1 H NMR (400 MHz, Chloroform-d) δ8.30 (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), H NMR spectrum as shown Figure 7 shown.

[0178] The specific synthesis steps of Bi-150013 are the same as those in Example 1.

[0179] Example 8: Specific synthesis steps of IBMC-011: 0.067 mmol Bi-150013 and 0.266 mmol morpholinopropanol were dissolved in 5 mL of dichloromethane, 0.1995 mmol of 4-dimethylaminopyridine and 0.3325 mmol of 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 to obtain IBMC-011 (41 mg, 55.79%). 1 H NMR (400 MHz, Chloroform-d) δ8.31–8.29 (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), H NMR spectrum as shown Figure 8 shown.

[0180] The specific synthesis steps of Bi-150013 are the same as those in Example 1.

[0181] Example 9: Specific synthesis steps of IBMC-012: Same as Example 8. Proton spectrum of IBMC-012: 1H NMR (400 MHz, Chloroform-d) δ8.33–8.30 (m, 1H), 7.79–7.73 (m, 2H), 5.01 (td, J = 7.1, 3.5 Hz, 1H), 4.70 (s, 2H), 4.39 (q, J = 7.0 Hz, 4H), 4.04 (t, J = 6.6 Hz, 4H), 3.71 (t, J = 4.6 Hz, 4H), 2.48 (dt, J = 10.2, 6.0 Hz, 4H), 2.29 (tt, J = 8.9, 5.3 Hz, 2H), 1.97 (p, J = 6.8 Hz, 2H), 1.68–1.16 (m, 64H), 0.90–0.83 (m, 12H), nuclear magnetic hydrogen spectrum as shown Figure 9 shown.

[0182] Example 10: Specific synthesis steps of IBMC-015: The specific synthesis steps of IBMC-015: 0.022mmolBi-150013, 0.067mmolEDCI and 0.067mmolHOBT were dissolved in 5mLdichloromethane. After 1h, 0.088mmolmorpholinopropanol and 0.088mmolDIEA were added thereto, and the mixture was stirred at room temperature for 8h. The mixture was extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by spin-drying with a silica gel column; 0.089mmolphenylethanol was added and dissolved in 5mLdichloromethane, 0.067mmol4-dimethylaminopyridine and 0.11mmol1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 8h. The mixture was extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by spin-drying with a silica gel column to obtain IBMC-015 (5mg, 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= 6.6Hz,4H),3.70(t,J=4.7Hz,4H),3.57(q,J=5.6Hz,2H),2.60–2.44(m,6H),2.29(tt,J=8.9,5.3Hz,2H),1.79(p,J=6.0Hz,2H),1.66–1.17(m,64H),0.90–0.84(m,12H), H NMR spectrum as shown Figure 10 shown.

[0183] 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 of dichloromethane, 0.225 mmol of 4-dimethylaminopyridine and 0.375 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, spin-dried and purified on a silica gel column to obtain IBMC-018 (21 mg, 25.3%). 1 H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.76 (s, 2H), 5.00 (q, J = 6.3 Hz, 1H), 4.70 (s, 2H), 4.46 (t, J = 5.8 Hz, 4H), 4.03 (q, J = 6.2 Hz, 4H), 3.70 (t, J = 5.2 Hz, 4H), 2.89–2.57 (m, 24H), 2.27 (t, J = 7.6 Hz, 3H), 1.64–1.18 (m, 52H), 0.86 (t, J = 6.6 Hz, 9H), H NMR spectrum as shown Figure 11 shown.

[0184] The specific synthesis steps of Bi-150011 are the same as those in Example 2.

[0185] Example 12: Specific synthesis steps of IBMC-019: 0.075 mmol Bi-150011 and 0.3 mmol morpholinopropanol were dissolved in 5 mL of dichloromethane, 0.225 mmol of 4-dimethylaminopyridine and 0.375 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, spin-dried and purified on a silica gel column to obtain IBMC-019 (36 mg, 45.57%). 1 H NMR (400 MHz, Chloroform-d) δ8.28 (t, J = 1.5 Hz, 1H), 7.75 (d, J = 1.4 Hz, 2H), 5.01 (dt, J = 7.1, 5.3 Hz, 1H), 4.69 (s, 2H), 4.39 (t, J = 6.6 Hz, 4H), 4.03 (td, J = 6.6, 4.6 Hz, 4H), 3.70 (t, J = 4.7 Hz, 8H), 2.47 (dt, J = 10.0, 6.0 Hz, 12H), 2.27 (dd, J = 9.2, 6.1 Hz, 3H), 1.96 (q, J = 6.9 Hz, 4H), 1.65–1.18 (m, 52H), 0.90–0.83 (m, 9H). Figure 12 shown.

[0186] The specific synthesis steps of Bi-150011 are the same as those in Example 2.

[0187] 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 of dichloromethane, 0.225 mmol of 4-dimethylaminopyridine and 0.375 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, spin-dried and purified on a silica gel column to obtain IBMC-020 (25 mg, 34.39%). 1 H NMR (400 MHz, Chloroform-d) δ8.30 (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), H NMR spectrum as shown Figure 13 shown.

[0188] The specific synthesis steps of Bi-150011 are the same as those in Example 2.

[0189] Example 14: Specific synthesis steps of IBMC-023: 0.377 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.189 mmol N,N-dimethylaminobutyric acid hydrochloride, 0.567 mmol 4-dimethylaminopyridine, and 0.227 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The target product IBMC-023 (100 mg, 53.6%) was obtained. 1 H NMR (400 MHz, Chloroform-d) δ 6.95 (s, 1H), 6.82–6.70 (m, 2H), 5.01 (s, 2H), 4.92 (td, J = 7.1, 3.5 Hz, 1H), 4.57 (d, J = 14.0 Hz, 4H), 3.97 (t, J = 6.7 Hz, 4H), 2.59 (t, J = 7.8 Hz, 2H), 2.43 (s, 6H), 2.39 (d, J = 6.9 Hz, 2H), 2.23 (tt, J = 8.8, 5.3 Hz, 2H), 1.95 (q, J = 7.4 Hz, 2H), 1.62–1.08 (m, 64H), 0.80 (t, J = 6.7 Hz, 12H), H NMR spectrum as shown Figure 14 shown.

[0190] The specific synthesis steps of Bi-070013 are the same as those in Example 4.

[0191] Example 15: Specific synthesis steps of IBMC-024: 0.235 mmol Bi-070013 was dissolved in 8 mL dichloromethane, and 0.118 mmol 3-(4-morpholinyl)propionic acid, 0.353 mmol 4-dimethylaminopyridine, and 0.142 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by silica gel column to obtain the target product IBMC-024 (62.7 mg, 50.93%). 1H NMR (400 MHz, Chloroform-d) δ 6.90 (s, 1H), 6.79 (dt, J = 7.8, 2.3 Hz, 2H), 5.02 (s, 2H), 4.98–4.87 (m, 1H), 4.58 (d, J = 16.4 Hz, 4H), 3.96 (t, J = 6.6 Hz, 4H), 3.67–3.55 (m, 4H), 2.64 (t, J = 7.2 Hz, 2H), 2.49 (t, J = 7.2 Hz, 2H), 2.38 (t, J = 4.6 Hz, 4H), 2.23 (tt, J = 8.9, 5.3 Hz, 2H), 1.66–1.08 (m, 64H), 0.80 (t, J = 6.7 Hz, 12H). Figure 15 shown.

[0192] The specific synthesis steps of Bi-070013 are the same as those in Example 4.

[0193] Example 16: The synthetic route of IBMC-025 is as follows:

[0194]

[0195] Specific synthesis steps of IBMC-025: Step 1: Synthesis of 1OH-02: Dissolve 65mmol 1OH-1 (3,5-dihydroxybenzoic acid) and 195mmol borane tetrahydrofuran in 100mL ultra-dry THF and stir at room temperature for 24h; quench the reactant with saturated ammonium chloride, wash with saturated sodium chloride, dry with anhydrous NaSO4, and purify on a silica gel column to obtain 1OH-02 (5.9g, 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).

[0196] 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. Potassium carbonate (71.4 mmol) was added at 50°C and reacted for 4 h. The reaction solution was cooled to room temperature and filtered. The filtrate was dried and purified on a silica gel column 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).

[0197] Step 3: Synthesis of 1OH-04: Dissolve 11.1 mmol 1OH-03 and 44.4 mmol imidazole in 100 mL of anhydrous dichloromethane. Dissolve tert-butyldimethylsilyl chloride in 20 mL of anhydrous dichloromethane and add dropwise to the reaction solution. React at room temperature for 4 h. Dry the mixture and purify by column to obtain the target product 1OH-04 (5.6 g, 97.7%). 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).

[0198] Step 4: Synthesis of 1OH-05: Dissolve 0.7 g of 1OH-04 and 0.07 g of Pd / C in 20 mL of methanol and stir at room temperature for 1 h. Filter and spin-dry the solvent, and purify on a silica gel column 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).

[0199] 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 in sequence. 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 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).

[0200] 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. The mixture was dried and purified on a silica gel column 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).

[0201] Step 7: Synthesis of 1OH-08: Dissolve 0.21 mmol of 1OH-07 in 15 mL of dichloromethane, and add 0.41 mmol of N,N-dimethylaminobutyric acid hydrochloride, 75.13 mmol of 4-dimethylaminopyridine, and 94.32 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in sequence. React at room temperature for 12 h, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and then spin-dry. Purify on a silica gel column 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).

[0202] Step 8: Synthesis of IBMC-025: Dissolve 0.046 mmol of 1OH-08 in 8 mL of tetrahydrofuran, add 1 mL of 1M TBAF in tetrahydrofuran, react at room temperature for 2 h, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column to obtain the target product IBMC-025 (20 mg, 44.7%). 1 H NMR (400 MHz, 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). Figure 16 shown.

[0203] 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 of dichloromethane, 0.1674 mmol of 4-dimethylaminopyridine and 0.279 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added, stirred at room temperature for 8 h, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate and then spin-dried, and purified by silica gel column to obtain IBMC-028 (18 mg, 26.73%). 1H NMR (400 MHz, 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), H NMR spectrum as shown Figure 17 shown.

[0204] The specific synthesis steps of Bi-150013 are the same as those in Example 1.

[0205] Example 18: The specific synthesis steps of IBMC-029 are the same as those of Example 17. Proton spectrum of IBMC-029: 1 H NMR (400 MHz, Chloroform-d) δ8.30 (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), H NMR spectrum as shown Figure 18 shown.

[0206] Example 19: Specific synthesis steps of IBMC-030: 0.057 mmol Bi-070013 was dissolved in 5 mL 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 in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The target product IBMC-030 (40 mg, 57.7%) was obtained. 1H NMR (400MHz, Chloroform-d) δ6.94 (s, 1H), 6.85 (s, 2H), 5.05 (s, 4H), 4.98 (q, J = 6.3 Hz, 1H), 4.60 (s, 2H), 4.03 (t, J = 6.6 Hz, 4H), 2.68–2.41 (m, 16H), 2.39 (t, J = 7.3 Hz, 8H), 2.33 (s, 6H), 1.83 (p, J = 7.3 Hz, 4H), 1.56 (dd, J = 13.4, 7.0 Hz, 12H), 1.45–1.18 (m, 54H), 0.86 (t, J = 6.6 Hz, 12H), H NMR spectrum as shown Figure 19 shown.

[0207] The specific synthesis steps of Bi-070013 are the same as those in Example 4.

[0208] Example 20: Specific synthesis steps of IBMC-031: 0.171 mmol Bi-070013 was dissolved in 8 mL 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 in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by silica gel column to obtain the target product IBMC-031 (89.68 mg, 50.3%). 1 H NMR (400 MHz, 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), H NMR spectrum as shown Figure 20 shown.

[0209] The specific synthesis steps of Bi-070013 are the same as those in Example 4.

[0210] Example 21: The synthetic route of IBMC-034 is as follows:

[0211]

[0212] Specific synthesis steps of IBMC-034: Step 1: Synthesis of m46-02: 0.017 mmol m46-01 and 0.0187 mmol potassium acetate were dissolved in 30 mL of DMF and stirred at room temperature for 5 h. The reactant was quenched with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous NaSO4, and purified by silica gel column 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).

[0213] Step 2: Synthesis of m46-03: Dissolve 3.09 mmol of m46-02 in 20 mL of 1 M NaOH solution and stir at room temperature for 5 h. Adjust the pH to 3.5 with 6 M hydrochloric acid, extract with ethyl acetate, wash with saturated sodium chloride, dry over anhydrous NaSO4, and purify on a silica gel column to yield 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).

[0214] Step 3: Synthesis of m46-04: Dissolve 3.16 mmol of m46-04 and 3.79 mmol of methyl bromoacetate in 20 mL of acetonitrile, add 4.75 mmol of potassium carbonate, and reflux at 80°C for 4 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was dried and purified on a silica gel column to yield 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).

[0215] Step 4: Synthesis of m46-05: Dissolve 1.16 mmol of m46-04 and 2.32 mmol of imidazole in 20 mL of anhydrous dichloromethane. Dissolve tert-butyldimethylsilyl chloride in 5 mL of anhydrous dichloromethane and add dropwise to the reaction solution. React at room temperature for 4 h. Dry the mixture and purify by column 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).

[0216] 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 continued for 2 h. The solution was vortexed to one-third and extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the target product m46-06 (180 g, 67.2%) was obtained by column purification. 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).

[0217] Step 6: Synthesis of m46-07: 1.39 mmol of m46-06 was dissolved in 40 mL of dichloromethane, and 2.78 mmol of T-13, 5.56 mmol of 4-dimethylaminopyridine, and 4.17 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. 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 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).

[0218] Step 7: Synthesis of m46-08: 0.22 mmol of m46-07 was dissolved in 20 mL of dichloromethane, 0.025 mL of saturated concentrated hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for 8 h. The mixture was dried and purified by silica gel column 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).

[0219] Step 8: Synthesis of m46-09: 0.15 mmol of m46-08 was dissolved in 10 mL of dichloromethane, and 0.3 mmol of N,N-dimethylaminobutyric acid hydrochloride, 0.75 mmol of 4-dimethylaminopyridine, and 0.36 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The mixture was purified by silica gel column 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).

[0220] Step 9: Synthesis of IBMC-034: Dissolve 0.05 mmol m46-09 in 8 mL methanol, add 0.056 mmol sodium borohydride, react at room temperature for 2 h, spin-dry the solvent, and purify with silica gel column 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), H NMR spectrum as shown Figure 21 shown.

[0221] Example 22: Specific synthesis steps of IBMC-035: 0.022mmol Bi-150013, 0.067mmol EDCI and 0.067mmol HOBT were dissolved in 5mL dichloromethane. After 1 hour, 0.088mmol N,N-dimethylpropanolamine and 0.088mmol DIEA were added. The mixture was stirred at room temperature for 8 hours, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain IBMC-035 (8mg, 32%).1 H NMR (400 MHz, Chloroform-d) δ8.74 (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). Figure 22 shown.

[0222] The specific synthesis steps of Bi-150013 are the same as those in Example 1.

[0223] Example 23: Specific synthesis steps of IBMC-036: 0.022mmol Bi-150013, 0.067mmol EDCI and 0.067mmol HOBT were dissolved in 5mL dichloromethane. After 1 hour, 0.088mmol morpholinopropanol and 0.088mmol DIEA were added thereto. The mixture was stirred at room temperature for 8 hours, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain IBMC-036 (14mg, 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 .6Hz,8H),3.57(q,J=5.8Hz,4H),2.53(dt,J=18.6,5.3Hz,12H),2.30(tt,J=8.8,5.4Hz,2H),1.81(q,J=6.1Hz,4H),1.65–1.20(m,64H),0.87(td,J=6.8,1.5Hz,12H), H NMR spectrum as shown Figure 23 shown.

[0224] The specific synthesis steps of Bi-150013 are the same as those in Example 1.

[0225] 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 of dichloromethane. After 1 hour, 0.088 mmol DIEA and 0.088 mmol morpholinoethanol were added thereto. The mixture was stirred at room temperature for 8 hours, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column to obtain IBMC-037 (14 mg, 56%). 1 H NMR (400 MHz, Chloroform-d) δ8.10–8.02 (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). Figure 24 shown.

[0226] The specific synthesis steps of Bi-150013 are the same as those in Example 1.

[0227] Example 25: The synthetic route of IBMC-040 is as follows:

[0228]

[0229] Specific synthesis steps for IBMC-040: Step 1: Synthesis of Si-H02: Dissolve 36.2 mmol of Si-H01 (p-hydroxybenzoic acid), 38.0 mmol of benzyl bromide, and 43.4 mmol of sodium carbonate in 150 mL of DMF and stir at 60°C for 5 hours. Dilute with dichloromethane, wash with water, then with saturated sodium chloride, dry over anhydrous sodium sulfate, concentrate by evaporation, and separate by column chromatography to obtain Si-H02 (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).

[0230] Step 2: Synthesis of Si-H0303: Dissolve 3.0 mmol Si-H02, 6.0 mmol cesium carbonate and 3.3 mmol T-13-Br in 100 mL of DMF, stir at 80°C for 5 h, extract with dichloromethane, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate by evaporation, and separate by column chromatography to obtain Si-H0303 (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).

[0231] Step 3: Synthesis of Si-H030003: Dissolve 2.5 mmol Si-H0303 and 80 mg palladium carbon in 20 mL of tetrahydrofuran, introduce hydrogen, and stir at 25°C for 12 h. Filter the reaction solution through celite and concentrate 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).

[0232] Step 4: Synthesis of IBMC-040: Dissolve 124.8 μmol Si-H030003, 282.6 μmol N,N-dimethylpropanolamine and 374.4 μmol DMAP in 15 mL of anhydrous DCM, stir at 25°C for 24 h, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate by evaporation, and separate by column chromatography to obtain IBMC-040 (18 mg, 10.3%). 1H NMR (400 MHz, Chloroform-d) δ8.03–7.89 (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), H NMR spectrum as shown Figure 25 shown.

[0233] The specific synthesis steps of T-13-Br are as follows: 3.7 mmol of carbon tetrabromide and 3.7 mmol of triphenylphosphine are dissolved in 20 mL of anhydrous tetrahydrofuran, stirred at room temperature, 1.2 mmol of T-13 is added, the temperature is raised to 45°C and the reaction is carried out for 1 hour, evaporated and concentrated, and T-13-Br (1.0 g, 92.9%) is 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).

[0234] Example 26: The specific synthesis steps of IBMC-041 differ from those of Example 24 in that morpholinopropanol is used instead of N,N-dimethylpropanolamine. Proton spectrum of IBMC-041: 1 H NMR (400 MHz, 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). Figure 26shown.

[0235] Example 27: The specific synthesis steps of IBMC-042 differ from those of Example 24 in that 3-(4-methyl-1-piperazinyl)-1-propanol is used instead of N,N-dimethylpropanolamine. Proton spectrum of IBMC-042: 1 H NMR (400 MHz, Chloroform-d) δ8.01–7.88 (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), H NMR spectrum as shown Figure 27 shown.

[0236] Example 28: The synthetic route of IBMC-043 is as follows:

[0237]

[0238] Specific synthesis steps of IBMC-043: Step 1: Synthesis of Si-H03: Dissolve 8.8mmol Si-H02, 17.5mmol cesium carbonate and 9.6mmol N,N-dimethyl-3-chloropropylamine in 100mL of DMF, stir at 80°C for 5h, dilute with dichloromethane, wash with water, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, concentrate by evaporation, and separate by column chromatography to obtain Si-H03 (1.8g, 65.6%). 1 HNMR(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).

[0239] Step 2: Synthesis of Si-H04: Dissolve 2.55 mmol Si-H03 and 80 mg palladium carbon in 20 mL of methanol, introduce hydrogen, stir at 25°C for 12 h, and concentrate by evaporation to obtain Si-H04 (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).

[0240] Step 3: Synthesis of IBMC-043: Dissolve 223.9 μmol Si-H04, 268.7 μmol T-13, 335.9 μmol EDCI and 671.8 μmol DMAP in 15 mL of DCM and stir at 30°C for 24 h. The reaction solution is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated by evaporation, and purified by column chromatography to obtain IBMC-043 (40 mg, 23.1%). 1 H NMR (400 MHz, Chloroform-d) δ7.97 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 5.10 (dq, J = 9.8, 3.7, 2.4 Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 4.04 (t, J = 6.6 Hz, 4H), 3.75 (t, J = 4.7 Hz, 2H), 2.53 (br, 6H), 2.29 (tt, J = 9.0, 5.4 Hz, 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). Figure 28 shown.

[0241] Example 29:

[0242] The specific synthesis steps of IBMC-044 differ from those of Example 28 in that T-11 is used instead of T-13. 1 H NMR (400 MHz, 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), H NMR spectrum as shown Figure 29 shown.

[0243] Example 30: The synthetic route of IBMC-048 is as follows:

[0244]

[0245] The synthesis steps of IBMC-048 differ from those of Example 29:

[0246] 1) The difference between the synthesis method of Si-HO5 and Si-HO3 is that morpholinopropanol is used instead of N,N-dimethyl-3-chloropropylamine;

[0247] 2) The difference between the synthesis method of Si-H06 and Si-H04: Si-H05 is used instead of Si-H03.

[0248] Proton spectrum of IBMC-048: 1 H NMR (400 MHz, Chloroform-d) δ7.97 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 5.19–4.98 (m, 1H), 4.08 (t, J = 6.3 Hz, 2H), 4.04 (t, J = 6.6 Hz, 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), H NMR spectrum as shown Figure 30 shown.

[0249] Example 31: The synthetic route of IBMC-051 is as follows:

[0250]

[0251] Specific synthesis steps of IBMC-051:

[0252] Step 1: Synthesis of Bi-070813: Dissolve 0.277 mmol of Bi-070013 in 10 mL of dichloromethane, and add 0.138 mmol of C3Y09, 0.415 mmol of 4-dimethylaminopyridine, and 0.166 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in sequence. React at room temperature for 12 h, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and then spin-dry. Purify on a silica gel column 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).

[0253] Step 2: Synthesis of IBMC-051: 0.075 mmol Bi-070813 was dissolved in 4 mL dichloromethane, 1.52 mL saturated concentrated hydrochloric acid was added dropwise, and the reaction was carried out for 12 h. The mixture was dried and purified by silica gel column 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=7.1Hz,2H),2.35(t,J=7.0Hz,2H),2.29–2.19(m,5H),1.81(p,J=7.0Hz,2H),1.58–1.10(m,64H),0.80(t,J=6.7Hz,12H), H NMR spectrum as shown Figure 31 shown.

[0254] The specific synthesis steps of Bi-070013 are the same as those in Example 4.

[0255] The synthetic route of C3Y09 is as follows:

[0256]

[0257] Specific synthesis steps of C3Y09: Step 1: Synthesis of C3-2: Dissolve 6.52mmol of C3-1 (methyl 4-(methylamino)butyrate hydrochloride) and 19.5mmol of potassium carbonate in 40mL of acetonitrile, heat to 50°C, add 8.5mmol of (2-bromoethoxy)-tert-butyldimethylsilane, heat to 80°C and reflux for 5h. After the reaction is complete, the solvent is dried and purified by column to obtain C3-2 (1.25g, 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).

[0258] Step 2: Synthesis of C3Y09: Dissolve 1.72 mmol of C3-2 and 5.2 mmol of sodium hydroxide in 10 mL of methanol and 5 mL of water, and stir at room temperature for 3 h. After the reaction is complete, remove the methanol by rotary evaporation, wash with ethyl acetate, acidify the aqueous phase with dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and spin dry 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).

[0259] Example 32: Specific synthesis steps of IBMC-052: Dissolve 0.125 mmol Bi-070013 in 10 mL dichloromethane, and add 0.498 mmol N,N-dimethylaminobutyric acid hydrochloride, 0.747 mmol 4-dimethylaminopyridine, and 0.597 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride in sequence, react at room temperature for 12 hours, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, and then spin-dry. Purify with silica gel column to obtain the target product IBMC-052 (40 mg, 33.8%). 1H NMR (400 MHz, Chloroform-d) δ 6.89 (d, J = 1.7 Hz, 1H), 6.79 (d, J = 1.4 Hz, 2H), 5.00 (s, 4H), 4.93 (td, J = 7.0, 3.5 Hz, 1H), 4.54 (s, 2H), 3.98 (t, J = 6.6 Hz, 4H), 2.34 (t, J = 7.4 Hz, 4H), 2.30–2.25 (m, 4H), 2.24–2.21 (m, 2H), 2.18 (s, 12H), 1.78 (h, J = 7.4, 6.9 Hz, 4H), 1.59–1.08 (m, 64H), 0.83–0.77 (m, 12H), H NMR spectrum as shown Figure 32 shown.

[0260] The specific synthesis steps of Bi-070013 are the same as those in Example 4.

[0261] Example 33: The synthetic route of IBMC-053 is as follows:

[0262]

[0263] Specific synthesis steps of IBMC-053: Step 1: Synthesis of JY-02: Dissolve 2.43 mmol of JY-01 (1,3-dimethyl 2-(4-methoxyphenyl)malonate) in 10 mL of anhydrous DCM, add 2.92 mmol of boron tribromide at -20°C and stir overnight, quench the reactant with an ice-water mixture, wash and extract three times with DCM, combine the organic phases, dry with anhydrous Na2SO4, and obtain JY-02 (0.84 g, 90.0%) by column chromatography. 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).

[0264] Step 2: Synthesis of JY-03: Dissolve 2.85 mmol of JY-02 in 15 mL of acetonitrile, add 4.28 mmol of Cs2CO3 and 3.43 mmol of (3-bromopropyl)dimethylamine, and stir at 60°C for 12 h. After the reaction is completed, filter, spin dry, and obtain JY-03 (0.31 g, 35.0%) by column chromatography. 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).

[0265] Step 3: Synthesis of IBMC-053: 1.21 mmol JY-03 was dissolved in 5 mL of EtOH, 7.26 mmol NaBH4 was added under ice bath, and the mixture was stirred at room temperature for 6 h. After the reaction, saturated NH4Cl aqueous solution was added to quench the reaction, and the mixture was extracted with DCM three times, spin-dried and dissolved in dichloromethane. 3.02 mmol ROH, 0.84 mmol EDC, and 0.84 mmol DMAP were added in sequence, and the mixture was stirred at room temperature for 24 h. After the reaction, the mixture was filtered, spin-dried, and column chromatography was performed to obtain IBMC-053 (367.0 mg, 39.0%). 1 H NMR (400 MHz, 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 = 6.4 Hz, 4H), 2.12-2.02 (m, 8H), 1.58 (br, 4H), 1.37-1.23 (m, 42H), 0.89 (t, J = 6.8 Hz, 6H), H NMR spectrum as shown Figure 33 shown.

[0266] 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 HNMR (400MHz, Chloroform-d) δ7.98 (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), H NMR spectrum as shown Figure 34 shown.

[0267] The specific synthesis steps of Si-H04 are the same as those in Example 28.

[0268] The specific synthesis steps of T-08 are the same as those in Example 3.

[0269] Example 35: The specific synthesis steps of IBMC-055 differ from those of Example 34 in that morpholinopropanol is used instead of N,N-dimethyl-3-chloropropylamine. Proton spectrum of IBMC-055: 1 H NMR (400 MHz, Chloroform-d) δ7.98 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.34 (tq, J = 10.9, 6.7, 5.8 Hz, 8H), 5.08 (p, J = 6.0 Hz, 1H), 4.08 (t, J = 6.2 Hz, 2H), 3.82–3.62 (m, 4H), 2.76 (t, J = 6.4 Hz, 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 = 6.7 Hz, 6H), H NMR spectrum as shown Figure 35 shown.

[0270] Example 36: The specific synthesis steps of IBMC-056 differ from those of Example 3 in that morpholinopropanol is used instead of N-methyldiethanolamine. Proton spectrum of IBMC-056: 1 H NMR (400 MHz, Chloroform-d) δ8.29 (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), H NMR spectrum as shown Figure 36 shown.

[0271] Example 37: The specific synthesis steps of IBMC-057 differ from those of Example 3 in that N,N-dimethylpropanolamine is used instead of N-methyldiethanolamine. Proton spectrum of IBMC-057: 1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 1.4 Hz, 2H), 5.01 (q, J = 6.1 Hz, 1H), 4.70 (s, 2H), 4.39 (t, J = 6.6 Hz, 4H), 2.44 (t, J = 7.3 Hz, 4H), 2.27 (s, 12H), 1.97 (h, J = 6.8, 6.0 Hz, 4H), 1.54 (t, J = 6.1 Hz, 4H), 1.24 (d, J = 5.4 Hz, 64H), 0.88 (t, J = 6.8 Hz, 6H), H NMR spectrum as shown Figure 37 shown.

[0272] Example 38: The specific synthesis steps of IBMC-058 differ from those of Example 3 in that 1,4-bis(2-hydroxyethyl)piperazine is used instead of N-methyldiethanolamine. Proton spectrum of IBMC-058: 1 H NMR (400 MHz, Chloroform-d) δ8.29 (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), H NMR spectrum as shown Figure 38 shown.

[0273] 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-dimethylaminopropionic acid hydrochloride, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The target product IBMC-059 (60 mg, 54.1%) was obtained. 1H NMR (400 MHz, Chloroform-d) δ 6.97 (s, 1H), 6.86 (dt, J = 13.6, 2.2 Hz, 2H), 5.09 (s, 2H), 5.02–4.97 (m, 1H), 4.64 (d, J = 16.0 Hz, 4H), 4.03 (t, J = 6.7 Hz, 4H), 2.69 (t, J = 7.1 Hz, 2H), 2.57 (t, J = 6.9 Hz, 2H), 2.34–2.24 (m, 8H), 1.62–1.52 (m, 12H), 1.42 (ddd, J = 13.6, 7.2, 3.4 Hz, 4H), 1.25 (s, 48H), 0.89–0.85 (m, 12H). Figure 39 shown.

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

[0275] 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-dimethylaminovaleric acid hydrochloride, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The mixture was purified by silica gel column 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=6.3Hz,2H),2.29(ddd,J=8.9,7.1,4.5Hz,2H),1.72–1.68(m,2H),1.61–1.51(m,12H),1.44–1.38(m,4H),1.24(d,J=7.9Hz,48H),0.85(t,J=6.7Hz,12H), H NMR spectrum as shown Figure 40 shown.

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

[0277] Example 41: Specific synthesis steps of IBMC-061: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol 1-piperidinepropionic acid, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The target product IBMC-061 (100 mg, 53.6%) was obtained. 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), H NMR spectrum as shown Figure 41 shown.

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

[0279] Example 42: Specific synthesis steps of IBMC-062: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol 3-pyrrolidin-1-ylpropionic acid, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The target product IBMC-062 (100 mg, 53.6%) was obtained. 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=7.5Hz,2H),2.78–2.63(m,6H),2.30(td,J=8.9,4.5Hz,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=6.7Hz,12H), H NMR spectrum as shown Figure 42 shown.

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

[0281] Example 43: Specific synthesis steps of IBMC-066: 0.23 mmol Bi-070013 was dissolved in 10 mL dichloromethane, and 0.11 mmol 4-(azepan-1-yl)butyric acid, 0.34 mmol 4-dimethylaminopyridine, and 0.14 mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride were added in sequence. The mixture was reacted at room temperature for 12 h, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The target product IBMC-066 (100 mg, 53.6%) was obtained. 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), H NMR spectrum as shown Figure 43 shown.

[0282] The specific synthesis steps of Bi-070013 are the same as those in Example 4.

[0283] Example 44: Preparation and testing of lipid nanoparticle compositions (LNP formulations)

[0284] To prepare nanoparticle compositions for delivering therapeutic and / or prophylactic agents to cells, a series of nanoparticle formulations were prepared and tested, and the lipid components of the nanoparticle compositions were optimized. Nanoparticles can be prepared using both manual and microfluidic methods, and these methods are not exhaustive. Any method capable of preparing the nanoparticle compositions of the present invention is within the scope of the present invention.

[0285] Lipid molecules represented by general formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), (IIIc), neutral lipids (such as DSPC, Avituo (Shanghai) Pharmaceutical Technology Co., Ltd.), steroid compounds (such as cholesterol, Avituo (Shanghai) Pharmaceutical Technology Co., Ltd.) and polymer-conjugated lipids (such as DMG-PEG2000, Avituo (Shanghai) Pharmaceutical Technology Co., Ltd.) are formulated into lipid compositions according to molar percentages (lipid molecules: DSPC: cholesterol: DMG-PEG2000 = 20%-100%: 0%-40%: 0%-80%: 0%-20%). Any formulation within this molar percentage range can be used to prepare nanoparticle compositions, and any LNP obtained by such a formulation is within the scope of protection of the present invention.

[0286] In this example, the lipid components were prepared at a molar ratio of 50:10:38.5:1.5 to a total concentration of 50 mM in ethanol. The lipid DLin-MC3-DMA (MC3) is a current standard in the field; therefore, a standard MC3 nanoparticle composition was prepared using a molar ratio of MC3:DSPC:cholesterol:DMG-PEG2000 of 50:10:38.5:1.5 as a control for this study.

[0287] The active ingredient (e.g., mRNA, EGFP, Luciferase, or SARS-CoV2 Spike) is added to a 10-50 mM buffer (citrate, acetate, pH 3-6) to prepare an aqueous mRNA solution for later use. The ethanolic lipid solution and the aqueous mRNA solution are mixed manually or using a microfluidic device to prepare a nanoparticle composition. The volume ratio of the aqueous phase to the ethanolic phase ranges from 1:1 to 5:1, with a volume ratio of 3:1 set in this example. The total lipid-to-mRNA mass ratio ranges from 5 to 65:1 (or, based on a lipid-to-mRNA ratio of 4 to 12:1). In this example, three N / P ratios of 8:1, 6:1, and 4:1 were set, yielding three sets of experimental data. Manual injection involves rapid vortexing for 30-60 seconds, with a vortex of 30 seconds set in this example. The total liquid flow rate in the microfluidic system ranges from 10 to 25 mL / min, with a total liquid flow rate of 20 mL / min set in this example.

[0288] The nanoparticle composition was purified by dialysis. The nanoparticle composition solution was dialyzed against DPBS multiple times to remove ethanol and free molecules, and then filtered through a 0.2 μm sterile filter to obtain a lipid nanoparticle composition (LNP preparation) encapsulating mRNA.

[0289] The nanoparticle composition was tested by dynamic light scattering using a Malvern Zetasizer Nano ZS ZEN3600 (Malvern, UK) to determine the particle size, polydispersity index (PDI), and potential of the lipid nanoparticle composition. The RNA quantification kit Quant-iT™ RiboGreen™ RNA Assay Kit (Thermo Fisher Scientific) was used to evaluate the mRNA encapsulation efficiency of the nanoparticle composition.

[0290] As shown in Tables 1A-1C, the particle size, PDI, potential and encapsulation efficiency of nanoparticle compositions of lipid molecules represented by general formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (III), (IIIa), (IIIb), and (IIIc) encapsulating mRNA (EGFP and / or Luciferase, SARS-CoV2 Spike) are compared.

[0291] Table 1A Physicochemical properties of nanoparticle compositions for cell transfection, wherein mRNA is a mixture of EGFP and Luciferase in equal mass ratios

[0292]

[0293]

[0294] #=N / P ratio of lipid molecules to mRNA is 6

[0295] Table 1B Physicochemical properties of nanoparticle compositions for animal administration, wherein the mRNA is Luciferase

[0296] lipid molecules Particle size (nm) PDI Potential (mV) Encapsulation efficiency% <![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

[0297] # = manual preparation of nanoparticle composition; * = microfluidic preparation of nanoparticle mixture

[0298] Table 1C Physicochemical properties of nanoparticle compositions for animal administration, wherein the mRNA is SARS-CoV2Spike

[0299]

[0300]

[0301] # = manual preparation of nanoparticle composition; * = microfluidic preparation of nanoparticle mixture

[0302] The test results are shown in Tables 1A, 1B, and 1C. As can be seen from Tables 1A, 1B, and 1C, the mRNA encapsulation efficiency of the nanoparticle composition is not much different from that of the marketed product, indicating that the nanoparticle composition prepared by this product meets the market requirements.

[0303] Example 45: Evaluation of cell transfection effects of lipid nanoparticle compositions (LNP preparations)

[0304] In a 96-well plate, 2 × 10 4 293T or Hela cells were cultured for 24 h, and when the cell confluence reached 70-90%, the cells were 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 h, 20X fluorescence images of EGFP were captured using an Olympus CKX53 fluorescence microscope.

[0305] The test results are as follows Figure 44 、 45 , 46, by Figure 44 、 45 ,46 It can be seen that at the cellular level, the new lipid molecules can effectively deliver mRNA to cells and express it, and some of the screened lipid materials are better than the lipid molecule MC3 that has been on the market.

[0306] Example 46: Evaluation of in vivo delivery levels of lipid nanoparticle compositions (LNP formulations)

[0307] Luciferase mRNA-loaded nanoparticle formulations were administered intramuscularly or intravenously to 6-8 week-old female Babl / c mice at a dose of 0.1 mg / kg, and small animal fluorescence imaging was performed using IVIS Lumina III (PE Company) at specific time points after administration (3h, 6h, and 24h).

[0308] The test results are as follows Figure 47 、 48 As shown by Figure 47 、 48 It can be seen that the nanoparticle composition of the lipid molecule IBMC-023 can effectively deliver mRNA in animals and express related proteins at high levels; at the same time, compared with MC3, no obvious liver enrichment phenomenon was observed for IBMC-023.

[0309] Example 47: Evaluation of the Level of S Protein Expression Induced by Lipid Nanoparticle Compositions (LNP Formulations) Delivering SARS-CoV2 Spike in Vivo

[0310] Nanoparticle formulations loaded with SARS-CoV2 Spike mRNA were administered intramuscularly to 6-8 week-old female Babl / c mice at a dose of 0.5 mg / kg. Six hours after administration, the expression of S protein in the blood, muscle, and liver of the mice was analyzed using a commercial SARS-CoV-2 (2019-nCoV) Spike ELISA kit (Sino Biological, KIT40591).

[0311] The test results are as follows Figure 49 、 50 , 51, by Figure 49 、 50 , 51 It can be seen that the nanoparticle composition of the lipid molecule IBMC-023 can effectively deliver mRNA in animals and express related proteins at high levels.

[0312] Experiments have shown that the cationic lipid compounds of the present invention are capable of delivering nucleic acid molecules, small molecule compounds, polypeptides or proteins, etc. The vectors prepared using the cationic lipid compounds of the present invention have high encapsulation efficiency for nucleic acid molecules, can successfully transport nucleic acid molecules to cells and / or organs, and express them efficiently.

[0313] The conventional techniques in the above embodiments are prior art known to those skilled in the art and will not be described in detail here. The above description is only a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any person skilled in the art who can easily conceive of changes or substitutions within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. Use of a lipid molecule in the preparation of a drug, wherein the lipid molecule is used to deliver an active ingredient, the lipid molecule comprising: a lipid compound represented by general formula (III), or at least one of its pharmaceutically acceptable salts; in, M is selected from a benzene ring; 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)-, wherein x is an integer between 0 and 4; L1 is selected from unsubstituted C 1-6 One of the alkyl groups; 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 -(C=O)S-, -S-, -O-, wherein y is an integer between 0 and 4; G1, G'1, and G2 are each independently connected to any site in M, where the site is a carbon or nitrogen atom; X is selected from carbon or nitrogen atoms; n is selected from an integer between 0 and 6; 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 -CH2-, -O(C=O)-, -(C=O)O-, -O(C=O)O-, -(C=O)NH-, -NH(C=O)-, -S(C=O)-, -(C=O)S-, and -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 and R2 are each independently selected from any substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of the following, wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl; X1, X2 are each independently selected from C 1-3 alkyl; or R1 and R2 are combined to form an optionally substituted or unsubstituted 4-8 membered heterocyclic ring, pyrimidine ring, or purine ring; wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl; In formula (III), Z' is selected from any substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 One of cycloalkynyl, phenyl, 4-8 membered heterocyclic ring, wherein the substituent group is 1 or 2 independent OH, SH, C 1-3 Hydroxyl, C 1-3 Alkoxy, amino, nitro, cyano, -(C=O)OC 1-3 alkyl.

2. The use of a lipid molecule in preparing a medicine according to claim 1, characterized in that: The lipid compound of general formula (III) comprises the structure represented by formula (IIIa), (IIIb) or (IIIc), or a pharmaceutically acceptable salt thereof; in, G1 is 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)-, wherein x is an integer between 0 and 4; L1 is selected from unsubstituted C 1-6 One of the alkyl groups; G1 is connected to any position in the benzene ring; Z' is selected from any substituted or unsubstituted H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 One of cycloalkynyl, phenyl, 4-8 membered heterocyclic ring; wherein the substituent group is 1 or 2 independent OH, SH, C 1-3 Hydroxyl, C 1-3 Alkoxy, amino, nitro, cyano, -(C=O)OC 1-3 alkyl; R1 and R2 are each independently selected from any substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, C 3-8 Cycloalkynyl, phenyl, -(C=O)C 1-3 alkyl, One of the following, wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 Alkyl; X1, X2 are each independently selected from C 1-3 alkyl; or R1 and R2 are combined to form an optionally substituted or unsubstituted 4-8 membered heterocyclic ring, pyrimidine ring, or purine ring; wherein the substituent group is 1 or 2 or 3 or 4 or 5 independent OH, SH, nitro, cyano, amino, C 1-3 Hydroxyl, C 1-3 Alkoxy, -(C=O)OC 1-3 Alkyl, C 1-3 alkyl; E is selected from oxygen or sulfur atoms; m is an integer between 0 and 4; T is selected from one of the structures shown in formula (1)-(18): 。 3. The lipid compound according to any one of claims 1-2, characterized in that: described One selected from the structures shown in formulas Y01-Y30: 。 4. The use of a lipid molecule in preparing a medicine according to claim 1, characterized in that: Use of the lipid compound in preparing a nanoparticle composition.

5. Use of a lipid molecule in preparing a medicine according to claim 4, characterized in that: The nanoparticle composition also comprises a therapeutic and / or prophylactic agent.

6. Use of a lipid molecule in preparing a medicine according to claim 5, characterized in that: The therapeutic agent and / or preventive agent comprises a nucleic acid, a small molecule compound, a polypeptide or a protein; the nucleic acid comprises at least one of single-stranded DNA, double-stranded DNA, a short isomer, agomir, antagomir, antisense molecule, small interfering RNA, asymmetric interfering RNA, microRNA, Dicer-substrate RNA, small hairpin RNA, transfer RNA, messenger RNA, circular RNA, and nucleic acid aptamer.

7. Use of a lipid molecule in preparing a medicine according to claim 4, characterized in that: 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 for delivering the active ingredient according to claim 1 is 20-100%; the molar percentage of the steroidal 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%.

8. Use of a lipid molecule in preparing a medicine according to claim 4, characterized in that: Application of the nanoparticle composition in drug preparation.

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