Water-soluble prodrug compound of STING agonist MSA-2 as well as preparation method and application of water-soluble prodrug compound

Abstract

The invention relates to the technical field of biomedicine, in particular to a water-soluble prodrug compound of an STING agonist MSA-2 as well as a preparation method and application of the water-soluble prodrug compound. The structural formula of the water-soluble prodrug compound of the STING agonist MSA-2 is shown as the following formula MSA-2 plus: # imgabs0 # MSA-2 plus, and n is equal to 2 to 6. According to the water-soluble prodrug compound of the STING agonist MSA-2, the structure of a small molecule MSA-2 is modified and optimized, the STING agonist MSA-2 is connected with an alkanolamine molecule of a specific structure through an ester group, so that the water solubility is improved, the STING agonist MSA-2 can be released through esterase response after entering a living body, and the water-soluble prodrug compound of the STING agonist MSA-2 is used for treating cancers. The water-soluble prodrug compound of the STING agonist MSA-2 is good in water solubility and can be administrated in an intravenous injection mode, the concentration of the water-soluble prodrug compound in blood circulation is increased, the dosage of the water-soluble prodrug compound is reduced, and side effects are reduced.

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 the 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. Increasing evidence shows that the cyclic guanosine monophosphate-adenosine synthetase (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 bacteria, viruses, tumors, and other extracellular derived double-stranded DNA (dsDNA) through intracellular cGAS, and then catalyze guanosine triphosphate (GTP) and adenosine triphosphate (ATP) to synthesize the second messenger cyclic 2',3'-cGAMP. 2',3'-cGAMP binds to the STING protein located on the endoplasmic reticulum membrane, causing STING to undergo conformational changes and become activated. The 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). The phosphorylated IRF3 dimerizes and translocates to the 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] STING protein plays an important role in the innate immune signaling pathway, and exogenous drug molecules to activate STING have been shown to be an effective cancer immunotherapy in multiple preclinical models. The first generation of STING agonists have been evaluated in clinical trials, including ADU-S100 and MK-1454. Both are cyclic dinucleotide (CDN)-based compounds that can be directly injected into tumors. However, these CDN compounds have a very short half-life in the blood (<60 minutes), and even after intratumoral injection, they quickly diffuse out of the tumor, with a half-life of <15 minutes in the human body, resulting in poor anti-tumor effects. In addition, because CDN compounds are negatively charged, it is difficult for them to penetrate the cell membrane and internalize into the cytoplasm, and the low intracellular uptake efficiency leads to insufficient presentation of STING agonists to antigen presenting cells (APCs). Due to these properties, the first generation of STING agonists 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 a higher permeability in the weakly acidic tumor microenvironment (TME), which enables MSA-2 to enter the tumor site more and reduce 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, which can selectively induce immune activation in the tumor microenvironment. This allows MSA-2 to exhibit efficient immune killing ability at the tumor site and show effective tumor eradication effects in preclinical studies. Due to the poor solubility of MSA-2, there are currently only three ways of administration: oral, subcutaneous, and intratumoral. The gastrointestinal absorption efficiency of drugs is low, and the oral dose of MSA-2 needs to be increased to increase the drug concentration in the blood, but high-dose drug intake may cause toxic side effects in the organism. Furthermore, based on the subcutaneous and intratumoral injection methods, there are disadvantages such as limited dosage or high technical difficulty, which limits its clinical application. Summary of the invention

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

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

[0006] Among them, n=2-6.

[0007] In the above scheme, a water-soluble prodrug compound of a STING agonist MSA-2 of the present invention transforms and optimizes the structure of the small molecule MSA-2, connects the STING agonist MSA-2 with an alkanolamine molecule of a specific structure through an ester group to improve water solubility, and can be released by esterase response after entering the body for the treatment of 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 to increase its concentration in the blood circulation, reduce the dosage of the drug, and reduce 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 the second aspect of the present invention, the present invention also provides a method for preparing the water-soluble prodrug compound of the above-mentioned STING agonist MSA-2, characterized in that the synthesis route is as follows:

[0010]

[0011] The specific steps include:

[0012] (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;

[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 firstly reacts 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 suitable for wide production.

[0015] Further, 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 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 agent 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 agent 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 suitable types of solvents, carbonyl activating agents and catalysts, the amounts of reactants are limited within a reasonable range, which is more conducive to the esterification reaction and improves the synthesis efficiency of water-soluble prodrug compounds.

[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, the 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 dichlorothionyl; the amount of the Lewis acid is 10-50 times the molar amount of the compound MSA-2.

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

[0027] In the above scheme, by selecting suitable types of solvents and Lewis acids, the amount of reactants is limited within 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 the third aspect of the present invention, the present invention also provides the use of the water-soluble prodrug compound of the STING agonist MSA-2 in the preparation of anti-tumor drugs.

[0029] The water-soluble prodrug compound of the STING agonist MSA-2 of the present invention transforms and optimizes the structure of the small molecule MSA-2, connects the STING agonist MSA-2 with an alkanolamine molecule of a specific structure through an ester group to improve water solubility, and can be released by esterase response after entering the body, 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, can be administered by intravenous injection, increases its concentration in the blood circulation, reduces the dosage of the drug, and reduces 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 will be 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 diagram showing the anti-tumor effect of MSA-2plusC4 obtained in Example 3 of the present invention at different dosages. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the drawings of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] The beneficial effects of the present invention will be described below in conjunction with 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 a STING agonist MSA-2, comprising the following steps:

[0039] Under nitrogen protection, 0.6mmol 4-(5,6-dimethoxybenzo[B]thiophene-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 N-Boc-ethanolamine (N-Boc-ethylenediamine) was added, and the reaction was carried out 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

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

[0041] The characterization data of the H NMR and C NMR of the 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 a STING agonist MSA-2, comprising the following steps:

[0048] Under nitrogen protection, 0.6mmol 4-(5,6-dimethoxybenzo[B]thiophene-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 3-(Boc-amino)-1-propanol (3-(Boc-amino)-1-propanol) was added, and the reaction was carried out 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=50:1) 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 white powder MSA-2plusC3 (176.0 mg, yield: 83.3%).

[0049] The characterization data of the H NMR spectrum and C NMR spectrum of the 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 a STING agonist MSA-2, comprising the following steps:

[0056] Under nitrogen protection, 0.6mmol 4-(5,6-dimethoxybenzo[B]thiophene-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 4-(Boc-amino)-1-butanol (4-(Boc-amino)-1-butanol) was added, and the reaction was carried out 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 white powder MSA-2plusC4 (180.1 mg, yield: 82.4%).

[0057] The characterization data of the nuclear magnetic resonance hydrogen spectrum and carbon 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 a STING agonist MSA-2, comprising the following steps:

[0064] Under nitrogen protection, 0.6mmol 4-(5,6-dimethoxybenzo[B]thiophene-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 the reaction was carried out 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 spectrum and C NMR spectrum 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 a STING agonist MSA-2, comprising the following steps:

[0073] Under nitrogen protection, 0.6mmol 4-(5,6-dimethoxybenzo[B]thiophene-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 6-(Boc-amino)-1-hexanol (6-(Boc-amino)-1-hexanol) was added, and the reaction was carried out at room temperature for 12h. 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=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 white powder MSA-2plusC6 (187.5 mg, yield: 79.3%).

[0074] The characterization data of the H NMR spectrum and C NMR spectrum of the 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 female Balb / c mice were subcutaneously injected with CT26 cells (1.5×10 6 ) to establish a tumor model. When the tumor volume is 70-120mm 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 were given a single dose. The MSA-2 group mice were gavaged with 2umol of MSA-2 (dissolved in 200ul of 10% DMSO, 40% PEG300, 5% Tween-80 and 45% PBS solution), 200ul of 5% glucose solution was injected into the Control group mice, 2umol of MSA-2plusC2 (dissolved in 200ul of 5% glucose solution) was injected into the MSA-2plusC2 group mice, 2umol of MSA-2plusC3 (dissolved in 200ul of 5% glucose solution) was injected into the MSA-2plusC4 group mice, 2umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution) was injected into the MSA-2plusC5 group mice, 2umol of MSA-2plusC5 (dissolved in 200ul of 5% glucose solution) was injected into the MSA-2plusC6 group mice, 2umol of MSA-2plusC6 (dissolved in 200ul of 5% glucose solution) was injected into the MSA-2plusC6 group mice. After the administration, the mice were cultured in the same environment to observe the survival rate and tumor volume of the mice. Please refer to 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 decreased the fastest. 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-treated group survived completely.

[0081] Example 7 Anti-tumor effects of MSA-2plusC4 at different dosages

[0082] 6-8 week old female Balb / c mice were subcutaneously injected with CT26 cells (1.5×10 6 ) to 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). 200ul of 5% glucose solution, 0.5umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution), 1.0umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution), 1.5umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution), 2.0umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution), 2.5umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution) and 3umol of MSA-2plusC4 (dissolved in 200ul of 5% glucose solution) were injected into the corresponding 7 groups of mice through the tail vein. All groups were given a single dose. After the injection, the mice were cultured in the same environment and the survival rate and tumor volume of the mice were observed. Please refer to Figure 2 ag, after administration of 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 embodiments of the present invention.

Claims

1. A water-soluble prodrug compound of a STING agonist MSA-2, characterized in that: Its structural formula is shown in the following formula 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) Using compound MSA-2 as raw material, 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 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 and 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 activation 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 activation 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 temperature of the esterification reaction 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, the 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 dichlorothionyl; 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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