A water-soluble prodrug compound of STING agonist MSA-2 and its preparation method and application

Abstract

The present invention relates to the field of biomedical technology, and in particular to a water-soluble prodrug compound of the STING agonist MSA-2, a preparation method thereof, and an application thereof. The structural formula of the water-soluble prodrug compound of the STING agonist MSA-2 is shown in the following formula: MSA-2 plus, wherein n=2-6. The water-soluble prodrug compound of the STING agonist MSA-2 of the present invention modifies and optimizes the structure of the small molecule MSA-2, connects the STING agonist MSA-2 to an alkanolamine molecule of a specific structure via an ester group to improve water solubility. After entering the body, the STING agonist MSA-2 can be released by esterase response and is used to treat cancer. The water-soluble prodrug compound of the STING agonist MSA-2 of the present invention has good water solubility and can be administered by intravenous injection, thereby increasing its concentration in the blood circulation, reducing the dosage of the drug, and reducing side effects.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a water-soluble prodrug compound of a STING agonist MSA-2, and a preparation method and application thereof. Background Art

[0002] Innate immunity is key to initiating and maintaining adaptive immune responses, and anti-tumor immunity also relies on the innate immune system to provide a strong and lasting immune response. Growing evidence indicates that the cyclic guanosine monophosphate-adenosine synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a key innate immune activation pathway in tumor immunity. Specifically, the body's innate immune cells detect extracellular double-stranded DNA (dsDNA) derived from bacteria, viruses, tumors, and other extracellular sources through intracellular cGAS, which then catalyzes the synthesis of the second messenger cyclic 2',3'-cGAMP from guanosine triphosphate (GTP) and adenosine triphosphate (ATP). 2',3'-cGAMP binds to the STING protein located on the endoplasmic reticulum membrane, causing STING to undergo conformational changes and become activated. Activated STING transfers from the endoplasmic reticulum to the Golgi apparatus and interacts with TANK-binding kinase 1 (TBK1), further inducing the phosphorylation of interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates to the cell nucleus, promoting the secretion of type I interferon IFN-β and other proinflammatory cytokines, thereby activating the immune system, exerting an immunomodulatory effect, killing tumor cells, and achieving tumor treatment.

[0003] The STING protein plays a crucial role in innate immune signaling pathways. Activation of STING by exogenous pharmacological agents has been shown to be an effective cancer immunotherapy in various preclinical models. First-generation STING agonists, including ADU-S100 and MK-1454, have been evaluated in clinical trials. Both are cyclic dinucleotide (CDN)-based compounds that can be injected directly into tumors. However, these CDN compounds have very short half-lives in the blood (<60 minutes). Even after intratumoral injection, they rapidly diffuse out of the tumor, with a half-life of <15 minutes in humans, resulting in poor anti-tumor efficacy. Furthermore, the negative charge of CDN compounds makes it difficult for them to penetrate cell membranes and be internalized into the cytoplasm. Low intracellular uptake efficiency leads to insufficient presentation of STING agonists to antigen-presenting cells (APCs). Due to these properties, first-generation STING agonists have failed to produce significant clinical benefits. In 2020, Merck developed an orally available, non-CDN STING small molecule agonist, MSA-2. On the one hand, the small molecule MSA-2 has enhanced permeability in the weakly acidic tumor microenvironment (TME), enabling greater penetration of MSA-2 into tumors and reducing the adverse effects associated with STING activation in normal tissues. On the other hand, MSA-2 can form pharmacologically active non-covalent dimers under acidic conditions, selectively inducing immune activation within the TME. This allows MSA-2 to exhibit potent immunohistotoxicity at the tumor site and has demonstrated effective tumor eradication in preclinical studies. Due to its poor solubility, MSA-2 is currently only available for administration: oral, subcutaneous, and intratumoral. Inefficient gastrointestinal absorption requires a larger oral dose of MSA-2 to increase blood concentrations, but high doses can potentially cause toxic side effects. Furthermore, subcutaneous and intratumoral administration methods have drawbacks such as limited dosing and technical difficulties, limiting their clinical application. Summary of the Invention

[0004] The present invention provides a water-soluble prodrug compound of a STING agonist MSA-2, a preparation method thereof, and an application thereof, to solve the above-mentioned problems existing in the prior art.

[0005] According to a first aspect of the present invention, the present invention provides a water-soluble prodrug compound of the STING agonist MSA-2, the structural formula of which is shown in the following formula MSA-2plus:

[0006] Wherein, n=2-6.

[0007] In the above scheme, a water-soluble prodrug compound of the STING agonist MSA-2 of the present invention optimizes the structure of the small molecule MSA-2 by linking the STING agonist MSA-2 to an alkanolamine molecule of a specific structure via an ester group to improve water solubility. Upon entry into the body, the compound is released by esterases, allowing for cancer treatment. The water-soluble prodrug compound of the STING agonist MSA-2 of the present invention exhibits good water solubility and can be administered via intravenous injection, increasing its concentration in the bloodstream, reducing drug dosage, and minimizing side effects.

[0008] In order to achieve better water solubility and better tumor treatment effect, further, n=3-5, preferably n=4.

[0009] According to a second aspect of the present invention, the present invention also provides a method for preparing the water-soluble prodrug compound of the STING agonist MSA-2, characterized in that the synthesis route is as follows:

[0010]

[0011] The specific steps include:

[0012] (1) Compound MSA-2 was used as raw material, and Esterification reaction is carried out to obtain compound MSA-200; wherein n=2-6, and R is tert-butyloxycarbonyl;

[0013] (2) Compound MSA-200 is subjected to a reaction to remove the amino protecting group R to obtain a water-soluble prodrug compound having a structure as shown in the formula MSA-2plus.

[0014] In the above scheme, the preparation method of the water-soluble prodrug compound of the STING agonist MSA-2 of the present invention is to firstly react the STING agonist MSA-2 with The esterification reaction is carried out, and then the amino protecting group R is removed. The preparation method is simple and applicable to wide production.

[0015] Furthermore, the compound MSA-200 is prepared by the following method: in a first solvent, under the action of a carbonyl activation reagent and a catalyst, the compound MSA-2 and Carry out esterification reaction.

[0016] Further, the first solvent is selected from one or more of dichloromethane, acetonitrile and N,N-dimethylformamide;

[0017] and / or, the carbonyl activating reagent is selected from one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the amount of the carbonyl activating reagent is 1-2 times the molar amount of compound MSA-2;

[0018] And / or, the catalyst is selected from one or both of 4-dimethylaminopyridine and triethylamine; the amount of the catalyst used is 0.1-0.5 times the molar amount of compound MSA-2.

[0019] In the above scheme, by selecting appropriate types of solvents, carbonyl activating reagents and catalysts, the amounts of reactants are limited to a reasonable range, which is more conducive to the esterification reaction and improves the synthesis efficiency of the water-soluble prodrug compound.

[0020] Furthermore, the esterification reaction temperature is room temperature, and the time is 10-14h, preferably 12h.

[0021] It should be noted that room temperature generally refers to 20-30°C.

[0022] In the above scheme, the esterification reaction is carried out at room temperature under mild conditions.

[0023] Furthermore, when R is tert-butyloxycarbonyl, the method for removing the amino protecting group R is as follows: in a second solvent, compound MSA-200 reacts under the action of Lewis acid.

[0024] Further, the second solvent is selected from 1,4-dioxane;

[0025] And / or, the Lewis acid is one or more of hydrochloric acid, trifluoroacetic acid and thionyl chloride; the amount of the Lewis acid is 10-50 times the molar amount of the compound MSA-2.

[0026] Furthermore, the reaction temperature for removing the amino protecting group R is room temperature, and the reaction time is until the reaction is complete. Preferably, the reaction time for removing the amino protecting group R is 0.5-1.5 hours, preferably 1 hour. In the above scheme, the reaction for removing the amino protecting group R is carried out at room temperature, and the conditions are mild.

[0027] In the above scheme, by selecting appropriate types of solvents and Lewis acids, the amounts of reactants are limited to a reasonable range, which is more conducive to the reaction of removing the amino protecting group R and improving the synthesis efficiency of the water-soluble prodrug compound.

[0028] According to a third aspect of the present invention, the present invention also provides use of the water-soluble prodrug compound of the STING agonist MSA-2 in the preparation of anti-tumor drugs.

[0029] A water-soluble prodrug compound of the STING agonist MSA-2 is described. The structure of the small molecule MSA-2 is modified and optimized, connecting the STING agonist MSA-2 to an alkanolamine molecule of a specific structure via an ester group to enhance water solubility. Upon entry into the body, the compound is released via esterases, enabling its use in cancer treatment. The water-soluble prodrug compound of the STING agonist MSA-2 has excellent water solubility and can be administered via intravenous injection, increasing its concentration in the bloodstream, reducing drug dosage, and minimizing side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions in the present invention or the prior art, a brief introduction is given below to the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0031] Figure 1 This is a comparison chart of the anti-tumor effects of MSA-2plusC2-C6 obtained in Examples 1-5 of the present invention.

[0032] Figure 2 This is a graph showing the anti-tumor effects of MSA-2plusC4 obtained in Example 3 of the present invention at different dosages. DETAILED DESCRIPTION

[0033] To make the objectives, technical solutions, and advantages of the present invention more clear, the technical solutions of the present invention will be clearly and completely described below in conjunction with the accompanying drawings. Obviously, the embodiments described are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.

[0034] The beneficial effects of the present invention will be described below with reference to specific embodiments.

[0035] The synthetic route adopted in the following examples is as follows:

[0036]

[0037] Example 1

[0038] This embodiment provides a method for preparing a water-soluble prodrug compound MSA-2plusC2 of the STING agonist MSA-2, comprising the following steps:

[0039] Under nitrogen protection, 0.6 mmol of 4-(5,6-dimethoxybenzo[B]thiophen-2-yl)-4-oxobutanoic acid (MSA-2), 0.1 mmol of 4-dimethylaminopyridine (DAMP) and 1 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) were added to 10 ml of dichloromethane, and 0.6 mmol of N-Boc-ethanolamine (N-Boc-ethylenediamine) was added. The reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / CH3OH, v / v

[0040] =50:1) to obtain a pale yellow oily compound. This pale yellow oily compound was then dissolved in 20 ml of a 1 mol / L hydrogen chloride / 1,4-dioxane solution and allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure to obtain MSA-2plusC2 (165.2 mg, 81.5% yield), a white powder.

[0041] The characterization data of the H NMR and C NMR of compound MSA-2plusC2 are as follows:

[0042] 1 H NMR(400MHz,D2O)δ7.56(s,1H),7.00(s,1H),6.92(s,1H),4.40(t,J=5.2Hz,2H ),3.76(s,6H),3.37(t,J=5.1Hz,2H),3.20(t,J=6.3Hz,2H),2.84–2.71(m,2H).

[0043] 13 C NMR(101MHz,D2O)δ195.15,174.46,149.85,147.29,138.83,136.53,132 .22,131.46,105.72,103.04,61.13,55.49,55.22,38.45,32.86,27.82.

[0044] The mass spectrometry characterization results of compound MSA-2plusC2 are shown below:

[0045] HRMS (ESI) m / z: C 16 H 20 NO5S[M+H] + Calculated: 338.1057, Measured: 338.1051.

[0046] Example 2

[0047] This embodiment provides a method for preparing a water-soluble prodrug compound MSA-2plusC3 of the STING agonist MSA-2, comprising the following steps:

[0048] Under nitrogen, 0.6 mmol of 4-(5,6-dimethoxybenzo[B]thiophen-2-yl)-4-oxobutanoic acid (MSA-2), 0.1 mmol of 4-dimethylaminopyridine (DAMP), and 1 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) were added to 10 ml of dichloromethane. 0.6 mmol of 3-(Boc-amino)-1-propanol was also added, and the mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / CH3OH, v / v = 50:1) to obtain a pale yellow oily compound. This pale yellow oily compound was then dissolved in 20 ml of a 1 mol / L hydrogen chloride / 1,4-dioxane solution and allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain white powder MSA-2plusC3 (176.0 mg, yield: 83.3%).

[0049] The characterization data of the H NMR and C NMR of compound MSA-2plusC3 are as follows:

[0050] 1 H NMR(400MHz,D2O)δ7.46(s,1H),6.92(s,1H),6.85(s,1H),4.22(d,J=12.0Hz,2H),3. 73(d,J=2.8Hz,6H),3.10(q,J=7.8Hz,4H),2.68(t,J=6.5Hz,2H),2.10–2.01(m,2H).

[0051] 13 C NMR(101MHz,D2O)δ195.16,174.97,149.96,147.42,139.07,136.52,132.29 ,131.38,105.81,103.12,64.58,55.53,55.28,39.03,32.96,28.24,24.86.

[0052] The mass spectrometry characterization results of compound MSA-2plusC3 are shown below:

[0053] HRMS (ESI) m / z: C 17 H 22 NO5S[M+H] +Calculated: 352.1213, Measured: 352.1210.

[0054] Example 3

[0055] This embodiment provides a method for preparing a water-soluble prodrug compound MSA-2plusC4 of the STING agonist MSA-2, comprising the following steps:

[0056] Under nitrogen, 0.6 mmol of 4-(5,6-dimethoxybenzo[B]thiophen-2-yl)-4-oxobutanoic acid (MSA-2), 0.1 mmol of 4-dimethylaminopyridine (DAMP), and 1 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) were added to 10 ml of dichloromethane. 0.6 mmol of 4-(Boc-amino)-1-butanol was also added, and the mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / CH3OH, v / v = 60:1) to obtain a pale yellow oily compound. This pale yellow oily compound was then dissolved in 20 ml of a 1 mol / L hydrogen chloride / 1,4-dioxane solution and allowed to react at room temperature for 1 hour. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain white powder MSA-2plusC4 (180.1 mg, yield: 82.4%).

[0057] The characterization data of the H NMR spectrum and C NMR spectrum of compound MSA-2plusC4 are as follows:

[0058] 1 H NMR(400MHz,D2O)δ7.46(s,1H),6.92(s,1H),6.85(s,1H),4.22(d,J=12.0Hz,2H),3. 73(d,J=2.8Hz,6H),3.10(q,J=7.8Hz,4H),2.68(t,J=6.5Hz,2H),2.10–2.01(m,2H).

[0059] 13 C NMR(101MHz,D2O)δ195.16,174.97,149.96,147.42,139.07,136.52,132.29,13 1.38,105.81,103.12,64.58,55.53,55.28,39.03,32.96,28.24,24.86,23.45.

[0060] The mass spectrometry characterization results of compound MSA-2plusC4 are shown below:

[0061] HRMS (ESI) m / z: C 18 H 24 NO5S[M+H] + Calculated: 366.1370, Measured: 366.1358.

[0062] Example 4

[0063] This embodiment provides a method for preparing a water-soluble prodrug compound MSA-2plusC5 of the STING agonist MSA-2, comprising the following steps:

[0064] Under nitrogen protection, 0.6mmol 4-(5,6-dimethoxybenzo[B]thiophen-2-yl)-4-oxobutanoic acid (MSA-2), 0.1mmol 4-dimethylaminopyridine (DAMP) and 1mmol 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) were added to 10ml dichloromethane, and 0.6mmol 5-(Boc-amino)-1-pentanol (5-(Boc-amino)-1-pentanol) was added and reacted at room temperature for 12h. After the reaction was completed, the solvent was distilled off under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / CH3OH, v / v=60:1) to obtain a light yellow oily compound. Then, the light yellow oily compound was dissolved in 20ml 1mol / L hydrogen chloride / 1,4-dioxane solution and reacted at room temperature for 1h. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain a white powder MSA-2plusC5.

[0065] (179.1 mg, yield: 78.5%).

[0066] The characterization data of the H NMR and C NMR of compound MSA-2plusC5 are as follows:

[0067] 1 H NMR(400MHz,D2O)δ7.59(s,1H),7.04(s,1H),6.99(s,1H),4.06(s,2H),3.77(d,J=6.2Hz, 6H), 3.11 (s, 2H), 2.86 (t, J = 7.5Hz, 2H), 2.66 (s, 2H), 1.58 (s, 4H), 1.31 (d, J = 6.8Hz, 2H).

[0068] 13C NMR(101MHz,D2O)δ195.23,174.95,150.08,147.56,139.30,136.57,132.38,131.3 7,105.94,103.22,65.10,55.59,55.36,39.19,33.03,28.39,27.24,26.30,22.13.

[0069] The mass spectrometry characterization results of compound MSA-2plusC5 are shown below:

[0070] HRMS (ESI) m / z: C 19 H 26 NO5S[M+H] + Calculated: 380.1527, Measured: 380.1523.

[0071] Example 5

[0072] This embodiment provides a method for preparing a water-soluble prodrug compound MSA-2plusC6 of the STING agonist MSA-2, comprising the following steps:

[0073] Under nitrogen, 0.6 mmol of 4-(5,6-dimethoxybenzo[B]thiophen-2-yl)-4-oxobutanoic acid (MSA-2), 0.1 mmol of 4-dimethylaminopyridine (DAMP), and 1 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) were added to 10 ml of dichloromethane. 0.6 mmol of 6-(Boc-amino)-1-hexanol was also added, and the mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / CH3OH, v / v = 60:1) to obtain a pale yellow oily compound. This pale yellow oily compound was then dissolved in 20 ml of a 1 mol / L hydrogen chloride / 1,4-dioxane solution and allowed to react at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain white powder MSA-2plusC6 (187.5 mg, yield: 79.3%).

[0074] The characterization data of the H NMR spectrum and C NMR spectrum of compound MSA-2plusC6 are as follows:

[0075] 1H NMR(400MHz,D2O)δ7.56(s,1H),6.99(s,1H),6.96(s,1H),3.99(t,J=6.3Hz,2H),3.76(d, J=6.8Hz,6H),3.08(s,2H),2.86(t,J=7.5Hz,2H),2.63(s,2H),1.50(s,4H),1.20(s,4H).

[0076] 13C NMR(101MHz,D2O)δ194.95,174.80,150.07,147.58,139.44,136.53,132.40,131.21,1 05.91,103.15,65.40,55.58,55.36,39.28,33.02,28.45,27.55,26.54,25.20,24.64.

[0077] The mass spectrometry characterization results of compound MSA-2plusC6 are shown below:

[0078] HRMS (ESI) m / z: C 20 H 28 NO5S[M+H] + Calculated: 394.1683, Measured: 394.1680.

[0079] Example 6 Antitumor Effect of MSA-2plusC2-C6

[0080] 6-8 week old Balb / c female mice were selected and injected subcutaneously with CT26 cells (1.5×10 6 ) to establish a tumor model. 3The mice were divided into 7 groups: Control, MSA-2, MSA-2plusC2, MSA-2plusC3, MSA-2plusC4, MSA-2plusC5 and MSA-2plusC6 (n=8 / group). Except for the MSA-2 group, which was administered by oral gavage, the other groups were administered by tail vein injection, and all groups received a single dose. The MSA-2 group was orally gavaged with 2 μmol of MSA-2 (dissolved in 200 μl of 10% DMSO, 40% PEG300, 5% Tween-80 and 45% PBS solution), 200ul of 5% glucose solution were injected into the control group mice, 2umol of MSA-2plusC2 (dissolved in 200ul of 5% glucose solution) were injected into the MSA-2plusC2 group mice, 2umol of MSA-2plusC3 (dissolved in 200ul of 5% glucose solution) were injected into the MSA-2plusC4 group mice, 2umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution) were injected into the MSA-2plusC5 group mice, and 2umol of MSA-2plusC5 (dissolved in 200ul of 5% glucose solution) were injected into the MSA-2plusC6 group mice. After administration, the mice were cultured in the same environment and the survival rate and tumor size of the mice were observed. Figure 1 ag, after administration of MSA-2plus, the tumor size of mice decreased significantly compared with the control group and MSA-2 group, and the MSA-2plusC4 group showed the fastest decrease. Figure 1 h, After treatment with MSA-2plus, the survival rate of mice was significantly prolonged compared with that of the control group, and the mice in the MSA-2plusC4 administration group survived completely.

[0081] Example 7 Antitumor Effects of MSA-2plusC4 at Different Doses

[0082] 6-8 week old Balb / c female mice were selected and injected subcutaneously with CT26 cells (1.5×10 6 ) Establish a tumor model. When the tumor volume is 70-120mm 3At the same time, the mice were divided into 7 groups: Control, 0.5umol MSA-2plusC4, 1.0umol MSA-2plusC4, 1.5umol MSA-2plusC4, 2.0umol MSA-2plusC4, 2.5umol MSA-2plusC4 and 3.0umol MSA-2plusC4 (n=8 / group). Seven groups of mice were injected via the tail vein with 200 μl of 5% glucose solution, 0.5 μl of MSA-2plusC4 (dissolved in 200 μl of 5% glucose solution), 1.0 μl of MSA-2plusC4 (dissolved in 200 μl of 5% glucose solution), 1.5 μl of MSA-2plusC4 (dissolved in 200 μl of 5% glucose solution), 2.0 μl of MSA-2plusC4 (dissolved in 200 μl of 5% glucose solution), 2.5 μl of MSA-2plusC4 (dissolved in 200 μl of 5% glucose solution), and 3 μl of MSA-2plusC4 (dissolved in 200 μl of 5% glucose solution). All groups received a single dose. After the injection, the mice were cultured in the same environment and the survival rate and tumor size of the mice were observed. Figure 2 ag, after being administered with different doses of MSA-2plusC4, the tumor volume of mice decreased more significantly with the increase of the dosage, and the tumor completely disappeared when the dosage was 1.5umol / mouse. Figure 2 h. When the dosage reached or exceeded 1.5umol / mouse, the survival rate of mice was significantly prolonged compared with the control group, and the mice survived completely.

[0083] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A water-soluble prodrug compound of the STING agonist MSA-2, characterized in that: Its structural formula is shown below as MSA-2plus: MSA-2 plus, where n=2-6.

2. The water-soluble prodrug compound of the STING agonist MSA-2 according to claim 1, characterized in that n=3-5。 3. The method for preparing the water-soluble prodrug compound of the STING agonist MSA-2 according to claim 1 or 2, characterized in that: The synthetic route is as follows: The specific steps include: (1) Compound MSA-2 is used as raw material, and Esterification reaction is carried out to obtain compound MSA-200; wherein n = 2-6, and R is tert-butyloxycarbonyl; (2) Compound MSA-200 is subjected to a reaction to remove the amino protecting group R to obtain a water-soluble prodrug compound having a structure as shown in the formula MSA-2 plus.

4. The preparation method according to claim 3, characterized in that The compound MSA-200 is prepared by the following method: in a first solvent, under the action of a carbonyl activating agent and a catalyst, the compound MSA-2 is reacted with Carry out esterification reaction.

5. The preparation method according to claim 4, characterized in that The first solvent is selected from one or more of dichloromethane, acetonitrile and N,N-dimethylformamide; and / or, the carbonyl activating reagent is selected from one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; the amount of the carbonyl activating reagent is 1-2 times the molar amount of compound MSA-2; And / or, the catalyst is selected from one or both of 4-dimethylaminopyridine and triethylamine; the amount of the catalyst used is 0.1-0.5 times the molar amount of compound MSA-2.

6. The preparation method according to claim 3, characterized in that The esterification reaction temperature is room temperature and the time is 10-14 hours.

7. The preparation method according to claim 3, characterized in that When R is tert-butyloxycarbonyl, the method for removing the amino protecting group R is as follows: in a second solvent, compound MSA-200 reacts under the action of Lewis acid.

8. The preparation method according to claim 7, characterized in that The second solvent is selected from 1,4-dioxane; And / or, the Lewis acid is one or more of hydrochloric acid, trifluoroacetic acid and thionyl chloride; the amount of the Lewis acid is 10-50 times the molar amount of the compound MSA-2.

9. The preparation method according to claim 3, characterized in that The reaction temperature for removing the amino protecting group R is room temperature, and the reaction time is until the reaction is complete.

10. Use of the water-soluble prodrug compound of the STING agonist MSA-2 according to claim 1 or 2 in the preparation of anti-tumor drugs.

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