Deuterated benzothiophene compounds and pharmaceutical compositions and uses thereof

Abstract

The present invention provides a deuterated benzothiophene compound having a structure shown in general formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and the structure thereof is as follows: The deuterated benzothiophene compound having a structure shown in general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof are suitable for preparing an interferon gene stimulating protein agonist, and can also treat cancer and prepare a vaccine adjuvant. The compound of the present invention overcomes the defects of the existing lack of small molecule interferon gene stimulating protein agonists and the poor drugability of nucleotide interferon gene stimulating protein agonists, and can increase blood drug concentration, prolong half-life, and reduce single administration dose.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, and in particular to deuterated benzothiophene compounds, pharmaceutical compositions and uses thereof. Background Art

[0002] Innate immunity is the first line of defense against invading pathogens and tissue damage. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns (PAMPs) from pathogens or damage-associated molecular patterns (DAMPs) from the body itself, initiate cascade reactions, and induce the expression of genes such as interferons (IFNs), chemokines, and inflammatory factors. This innate immune response can not only inhibit the proliferation and spread of pathogens in the early stages, but also induce acquired immune responses to ultimately clear the infection. In addition, this innate immune response monitors the occurrence and invasion of tumors. Currently, a variety of PRRs have been discovered, such as membrane-bound toll-like receptors (TLRs), C-type lectinreceptors (CLRs), non-binding intracellular nucleotide-binding oligomerization-domain (NOD)-like receptors (NLRs), retinoic acid-like receptors (RLRs) and cytoplasmic DNA receptors.

[0003] Pathogen DNA and DNA leaked from the nucleus or mitochondria into the cytoplasm are immune stimulatory molecules, and there are many DNA receptors in the cytoplasm, such as absent in melanoma 2 (AIM2), interferon-inducible protein 16 (IFI16), RNA polymerase III and cyclic GMP-AMP synthase (cGAS). The STimulator of INterferon Genes (STING) located in the endoplasmic reticulum of the cytoplasm is the convergence point of these DNA receptors, controlling the innate immune response mediated by DNA, an immune stimulatory molecule. Studies have shown that cGAS recognizes double-stranded DNA in the cytoplasm and catalyzes GTP and ATP to generate 2′3′-cGAMP. 2′3′-cGAMP binds to interferon gene-stimulating protein as a second messenger, inducing interferon gene-stimulating protein to dimerize and transfer from the endoplasmic reticulum membrane to the vesicles around the nucleus, recruiting TBK1 and then phosphorylating itself, so that IRF3 is close to interferon gene-stimulating protein. Then, TBK1 phosphorylates IRF3, which transfers to the nucleus to induce the expression of type I interferon (IFN) and other inflammatory factors. Type I interferon promotes the maturation of dendritic cells (DC), selectively stimulates the cross-presentation of antigens, and recruits CD8 + T cells, thereby activating the acquired immune system to kill tumor cells or resist pathogen infection. Therefore, interferon gene-stimulated proteins play an important role in the innate and acquired immune responses in tumors and pathogen infections.

[0004] Given the key role of interferon gene stimulating protein in the body's immune response, the application of interferon gene stimulating protein agonists in the immunotherapy of various diseases has attracted much attention. For example, intratumoral injection of 2′3′-cGAMP leads to tumor cell degeneration in mouse models, and can inhibit the growth of distal tumor cells and induce long-term immune memory. Interferon gene stimulating protein agonists are used in combination with immune checkpoint inhibitors to increase the efficacy of immune checkpoint inhibitors. In addition, the body's immune response induced by interferon gene stimulating protein agonists can effectively control viral infections such as influenza A virus, hepatitis B virus, herpes simplex virus and HIV. Therefore, the research and development of interferon gene stimulating protein agonists is of great significance for the immunotherapy of cancer and infectious diseases. However, the interferon gene stimulating protein agonists reported so far are mostly cyclic dinucleotide analogs, but the defects such as metabolic instability in the body, poor membrane permeability, and only intratumoral administration have greatly limited the application of interferon gene stimulating protein agonists. Therefore, the research and development of small molecule agonists of interferon gene stimulating protein is of great significance.

[0005] MSA-2 is the first STING small molecule agonist that can be administered orally, but it requires a higher dose to be effective. Deuterated drugs refer to drugs in which some hydrogen atoms in the drug molecule are replaced with deuterium. Since the shape and volume of deuterium in the drug molecule are similar to those of hydrogen, deuterated drugs generally retain the biological activity and selectivity of the original drug. Since the CD bond is more stable than the CH bond, the CD bond of deuterated drugs is less likely to break during the chemical reaction process, and its half-life will be extended. Since 2000, the deuteration strategy has been widely used in drug research. The present invention adopts the D-generation strategy to optimize the biological activity of MSA-2, significantly improve its pharmacokinetic properties, and reduce the single dosage.

[0006]

[0007] Deuterated drugs refer to drugs in which some hydrogen atoms in the drug molecule are replaced with deuterium. Since the shape and volume of deuterium in the drug molecule are similar to those of hydrogen, deuterated drugs generally retain the biological activity and selectivity of the original drug. The mass of deuterium is twice that of hydrogen, so the vibration and stretching frequency of the CD bond is smaller than that of CH, and the ground state energy is lower. This results in a higher activation energy for the CD bond to break than the CH bond, and the CD bond is less likely to break, making deuterated drugs generally more stable in the body and their half-life longer.

[0008] Due to the complexity of the metabolic process of biological systems, the pharmacokinetic properties of drugs in vivo are affected by many factors and also show corresponding complexity. Compared with the corresponding non-deuterated drugs, the changes in the pharmacokinetic properties of deuterated drugs show great randomness and unpredictability. Deuteration at certain sites not only fails to prolong the half-life, but may shorten it and deteriorate its pharmacokinetic properties; the effect of deuterated molecules on cell activity is even more unpredictable and inconclusive. On the other hand, hydrogen at certain positions on drug molecules is not easy to be deuterated due to steric hindrance and other reasons. Therefore, the deuteration of drugs is not arbitrary, and the effect of deuterated sites on drugs is unpredictable. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the defect of the single structure of the existing interferon gene stimulating protein small molecule agonist, and provide a deuterated benzothiophene compound, a pharmaceutical composition and use. The deuterated benzothiophene compound of the present invention has good agonist activity on interferon gene stimulating protein and has a good therapeutic effect on tumors.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a deuterated benzothiophene compound having a structure shown in general formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, the structure of which is as follows:

[0012]

[0013] Among them, R 1 Halogen or -OCR 1-1 R 1-2 R 1-3 ;

[0014] R 1-1 , R 1-2 and R 1-3 independently selected from hydrogen or deuterium;

[0015] R 2 , R 3 , R 4 or R 6 independently selected from hydrogen or deuterium;

[0016] At the same time, R 2 , R 3 , R 4 and R 6 At least one is selected from deuterium;

[0017] R 5 is hydrogen or halogen;

[0018] X is C3-6 Cycloalkyl or

[0019] The left end of Connected, The right end of connected;

[0020] Y is C 1-4 alkyl.

[0021] In one embodiment of the present invention, when R 1 When it is a halogen, the halogen is bromine or chlorine.

[0022] In one embodiment of the present invention, when X is C 3-6 When cycloalkyl, the C 3-6 Cycloalkyl is cyclopropyl or cyclobutyl.

[0023] In one embodiment of the present invention, when R 5 When it is a halogen, the halogen is fluorine.

[0024] In one embodiment of the present invention, when R 6 C 1-4 When the C 1-4 The alkyl group is methyl or ethyl.

[0025] In one embodiment of the present invention, the compound represented by the general formula I is any of the following compounds:

[0026]

[0027] The present invention provides a deuterated benzothiophene compound having a structure shown in general formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof for use in preparing an interferon gene stimulating protein agonist.

[0028] The present invention provides use of a deuterated benzothiophene compound having a structure as shown in I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a drug for preventing and / or treating cancer.

[0029] In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, liver cancer, gastric cancer, leukemia, melanoma, colon cancer, glioma, kidney cancer, ovarian cancer, pancreatic cancer, breast cancer, head and neck cancer, prostate cancer, multiple myeloma, or cervical cancer.

[0030] The present invention provides use of a deuterated benzothiophene compound having a structure as shown in I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for preventing and / or treating an infectious disease.

[0031] The present invention provides a pharmaceutical composition, which contains a deuterated benzothiophene compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or excipient.

[0032] In the pharmaceutical composition, the amount of the deuterated benzothiophene compound as shown in Formula I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is a therapeutically effective amount.

[0033] The present invention provides use of a pharmaceutical composition in preparing an interferon gene stimulating protein agonist.

[0034] The present invention provides use of a pharmaceutical composition in preparing a drug for preventing and / or treating cancer.

[0035] The present invention provides use of a deuterated benzothiophene compound having a structure as shown in I, or a pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for preventing and / or treating an infectious disease.

[0036] The pharmaceutical excipients can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0037] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0038] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral preparations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid preparations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical preparations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum preparations. Examples of preparations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0039] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the free form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonate or bicarbonate), phosphoric acid (forming phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid (forming sulfate or bisulfate), hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid. Acids such as tartaric acid and methanesulfonic acid; organic acid salts also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and can be converted into any base or acid addition salt. Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the free form of the compound. The free form of the compound differs from its various salt forms in certain physical properties, such as different solubility in polar solvents.

[0040] The "pharmaceutically acceptable salts" of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

[0041] The term "isomers" refers to compounds that have the same chemical formula but different arrangements of the atoms.

[0042] The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of Formula I or a salt thereof. Such a product may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a process of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain a metabolite thereof.

[0043] Metabolites are typically identified by preparing radiolabeled isotopes of the compounds of the invention, administering them parenterally to animals, such as rats, mice, guinea pigs, monkeys, or humans, at detectable doses (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies that can bind to antigenic epitopes present in the metabolites). The metabolite structure is determined in a conventional manner, for example, by MS, LC / MS or NMR analysis. Generally, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. As long as the metabolite products are not otherwise not found in vivo, they can be used in assays for therapeutic dosing of the compounds of the invention. The compounds of the invention may contain non-natural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds may be labeled with radioisotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0044] In addition to the form of salts, the compounds provided by the present invention also exist in the form of prodrugs. The prodrugs of the compounds described herein are easily chemically changed under physiological conditions to be converted into the compounds of the present invention. Any compound that can be converted in vivo to provide a bioactive substance (i.e., a compound shown in Formula I) is a prodrug within the scope and spirit of the present invention. For example, a carboxyl-containing compound can form a physiologically hydrolyzable ester, which acts as a prodrug by being hydrolyzed in vivo to obtain the compound shown in Formula I itself. The prodrug is preferably administered orally, because hydrolysis occurs mainly under the influence of digestive enzymes in many cases. When the ester itself is active or hydrolysis occurs in the blood, parenteral administration can be used.

[0045] When the linking group is listed without indicating its linking direction, it is linked in the same direction as reading from left to right.

[0046] Those skilled in the art will appreciate that, according to the conventions used in the art, the structural formulas used in this application to describe groups It means that the corresponding group is connected with other fragments and groups in the compound shown in formula I through this site.

[0047] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0048] The positive and progressive effects of the present invention are:

[0049] The compounds of the present invention overcome the defects of the existing interferon gene stimulating protein small molecule agonists, the poor drugability of nucleotide interferon gene stimulating protein agonists, etc. The blood drug concentration of the compounds of the present invention is increased, the half-life is prolonged, and the single dosage is reduced. The compounds of the present invention have good agonistic activity on interferon gene stimulating protein, and have good therapeutic effects on tumors and infectious diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 It shows the tumor volume growth curve of MC38 mouse transplanted tumor model after administration of compound S19 and MSA-2. DETAILED DESCRIPTION

[0051] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part 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 creative work are within the scope of protection of the present invention.

[0052] Example 1: Synthesis of Compound S1

[0053]

[0054] Step 1: Synthesis of compound 2

[0055] Cesium carbonate (300 mmol, 97.7 g), catalytic amount of potassium iodide and deuterated iodomethane (21.6 g, 150 mmol) were added to a solution of compound 1 (19.7 g, 100 mmol) in DMF (200 mL), the temperature was raised to 80°C, the reaction was stirred overnight, cooled to room temperature, water was added to quench the reaction, ethyl acetate was extracted (100 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 2 (16.1 g, 75%). MS (ESI, m / z): 215 (M + +1).

[0056] Step 2: Synthesis of compound 3

[0057] Compound 2 (15 g, 70 mmol) was dissolved in anhydrous DMF (150 mL) and protected by nitrogen. Potassium carbonate (29 g, 210 mmol) and ethyl thioglycolate (15.3 mL, 140 mmol) were added to the above solution. The reaction temperature was raised to 60°C and stirred for 3 h. After the reaction was complete, the mixture was cooled to room temperature and poured into a large amount of ice water. The mixture was filtered and the filter cake was collected and dried in vacuo to obtain compound 3 (12.2 g, 65%). MS (ESI, m / z): 270 (M + +1).

[0058] Step 3: Synthesis of compound 4

[0059] Compound 3 (10 g, 37.2 mmol) was dissolved in THF (100 mL). At 0°C, lithium hydroxide aqueous solution (80 mL, 160 mmol, 2 M) was added to the solution, and then the mixture was transferred to room temperature and stirred for 5 h. After the reaction was complete, the mixture was transferred to 0°C, and dilute hydrochloric acid was added to adjust the pH to 2-3. A large amount of solid precipitated, and the filter cake was collected by suction filtration and vacuum dried to obtain compound 4 (8.1 g, 90%). MS (ESI, m / z): 242 (M + +1).

[0060] Step 4: Synthesis of compound 5

[0061] Compound 4 (8 g, 33.3 mmol) was dissolved in anhydrous DMF (60 mL), dimethylhydroxylamine hydrochloride (4.9 g, 50.0 mmol), HATU (19.0 g, 50.0 mmol) and DIPEA (17.4 mL, 99.9 mmol) were added to the above solution, and the reaction was stirred at room temperature. The reaction was stopped after overnight reaction, and water was added to the above reaction to quench the reaction, and ethyl acetate was extracted (100 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 5 (6.6 g, 70%). MS (ESI, m / z): 285 (M + +1).

[0062] Step 5: Synthesis of compound 6

[0063] Compound 5 (6.0 g, 21.1 mmol) was dissolved in anhydrous THF (60 mL). Under nitrogen protection, methylmagnesium bromide THF solution (28 mL, 42.2 mmol, 1.5 M) was slowly added to the above solution at -10 ° C. The reaction was transferred to room temperature for 2 h. After the reaction was completed, the temperature was transferred to 0 ° C, saturated ammonium chloride solution was added to the reaction solution to quench the reaction, THF was removed under reduced pressure, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 6 (3.2 g, 63%). MS (ESI, m / z): 240 (M + +1).

[0064] Step 6: Synthesis of compound 7

[0065] Compound 6 (3 g, 12.6 mmol) was dissolved in anhydrous THF (25 mL), and under nitrogen protection, a tetrahydrofuran solution of LDA (16.5 mL, 16.3 mmol, 1 M) was slowly added to the reaction solution at -78 °C. After the addition was completed, the reaction solution was transferred to -20 °C for reaction for 1 h. Then, the reaction solution was transferred to -78 °C, and a THF (5 mL) solution of ethyl bromoacetate (2.1 mL, 18.8 mmol) was slowly added to the reaction solution. After the addition was completed, the reaction solution was slowly warmed to room temperature. After the reaction was allowed to proceed overnight, the reaction was stopped, the reaction solution was transferred to 0 °C, a saturated ammonium chloride solution was added to quench the reaction, THF was removed under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 7 (2.2 g, 53%). MS (ESI, m / z): 326 (M + +1).

[0066] Step 6: Synthesis of compound S1

[0067] Compound 7 (200 mg, 0.62 mmol) was dissolved in THF (5 mL), and the mixture was transferred to 0°C. Aqueous hydroxide solution (2.5 mL, 2.5 mmol, 1 M) was added to the reaction mixture, and the mixture was transferred to room temperature. The mixture was stirred for 2 h, and the reaction mixture was then transferred to 0°C. The pH value was adjusted to 2-3 with dilute hydrochloric acid. A white solid precipitated, and the mixture was filtered off. The filter cake was collected and dried in vacuo to obtain compound S1 (165 mg, 90%). 1 HNMR(500MHz,DMSO-d6)δ11.33(s,1H),7.88(d,J=2.3Hz,1H),7.34(d,J=2.1Hz,1H ),7.24(s,1H),3.85(s,3H),3.83(m,2H)2.71(t,J=8.4Hz,2H).MS(ESI,m / z):298(M + +1).

[0068] Example 2: Synthesis of Compound S2

[0069]

[0070] The synthesis method is the same as in Example 1. Replace with That's it. 1 H NMR (500MHz, DMSO-d6) δ11.39(s,1H),8.13(d,J=4.9Hz,1H),7.03(s,1H),3.84(s,3H),3.83(d t,J=14.5,8.4Hz,1H),3.50(dt,J=14.5,8.4Hz,1H),2.71(t,J=8.4Hz,2H).MS(ESI,m / z):316(M + +1).

[0071] Example 3: Synthesis of Compound S3

[0072]

[0073] Step 1: Synthesis of compound 9

[0074] Compound 4 (2.4 g, 10.1 mmol) was dissolved in anhydrous THF (50 mL), CDI (5.1 g, 31.6 mmol) was added to the above solution, and the mixture was stirred at room temperature for 1 h. Then, MgCl2 (3.0 g, 31.6 mmol) and potassium monoethyl malonate (5.4 g, 31.6 mmol) were added to the reaction solution, and the reaction was continued to stir at room temperature for 6 h. Water (50 mL) was added, and ethyl acetate was extracted (40 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 9 (2.5 g, 83%). MS (ESI, m / z): 298 (M + +1).

[0075] Step 2: Synthesis of compound 10

[0076] Compound 9 (149 mg, 0.5 mmol) was dissolved in DMF (5 mL), and methyl 2-bromopropionate (55 μL, 0.5 mmol) and K2CO3 (0.14 g, 1 mmol) were added to the above solution. The reaction was stirred at room temperature for 4 h, and then water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 10, which was directly used in the next step without purification.

[0077] Step 3: Synthesis of compound 10

[0078] Dissolve compound 10 in step 2 in acetic acid (2 mL), then add concentrated hydrochloric acid (1 mL) to the above solution, raise the temperature of the reaction solution to 100°C, and stir to react for 2 h. Stop the reaction, cool to room temperature, add water (10 mL), extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate and purify by column chromatography to obtain compound 11 (73 mg, 45%). MS (ESI, m / z): 326 (M + +1).

[0079] Step 4: Synthesis of compound S3

[0080] Compound 11 (70 mg, 0.22 mmol) was dissolved in THF (2 mL), and the mixture was transferred to 0°C. Aqueous hydroxide solution (1 mL, 1 mmol, 1 M) was added to the reaction mixture, and the mixture was transferred to room temperature. The reaction mixture was stirred for 2 h, and the reaction mixture was then transferred to 0°C. The pH value was adjusted to 2-3 with dilute hydrochloric acid. A white solid precipitated. The mixture was filtered, and the filter cake was collected and dried in vacuo to obtain compound S3 (63 mg, 92%). 1HNMR(500MHz,DMSO-d6)δ11.33(s,1H),7.87(d,J=2.3Hz,1H),7.34(d,J=2.1Hz,1H),7.25(s,1H),3.85(s,3H),3. 56(dd,J=15.2,7.7Hz,1H),3.40(dd,J=15.3,7.8Hz,1H),2.65(m,2H),1.19(d,J=7.3Hz,3H).MS(ESI,m / z):312(M + +1).

[0081] Example 4: Synthesis of Compound S4

[0082]

[0083] The synthesis method is the same as in Example 3, except that the 2-bromopropionic acid methyl ester in step 2 is replaced by 2-bromobutyric acid methyl ester. 1 HNMR(500MHz,DMSO-d6)δ11.32(s,1H),7.87(d,J=2.3Hz,1H),7.33(d,J=2.1Hz,1H),7.25(s,1H),3.85(s,3H),3.57-3 .43(m,2H),2.65(tt,J=7.9,6.5Hz,1H),1.59(qdd,J=7.5,6.4,1.1Hz,2H),0.97(t,J=7.4Hz,3H).MS(ESI,m / z):326(M + +1).

[0084] Example 5: Synthesis of Compound S5

[0085]

[0086] The synthesis method is as in Example 3, and only Replace with That's it. 1 HNMR(500MHz,DMSO-d6)δ11.32(s,1H),8.13(d,J=5.0Hz,1H),7.03(s,1H),3.82(s,3H),3.56(dd,J=15.2, 7.7Hz,1H),3.40(dd,J=15.3,7.8Hz,1H),2.65(h,J=7.4Hz,1H),1.19(d,J=7.3Hz,3H).MS(ESI,m / z):330(M + +1).

[0087] Example 6: Synthesis of Compound S6

[0088]

[0089] Step 1: Synthesis of compound 12

[0090] Compound 4 (723 mg, 3 mmol) was dissolved in quinoline (10 mL), copper powder (0.96 g, 15 mmol) was added, the temperature was raised to 170°C, and the mixture was stirred for 2 h. Then, the mixture was cooled to room temperature, diluted hydrochloric acid solution (25 mL, 4 N) was added, and ethyl acetate was used for extraction (30 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 12 (502 mg, 85%). MS (ESI, m / z): 198 (M + +1).

[0091] Step 2: Synthesis of compound S6

[0092] Compound 12 (99 mg, 0.5 mmol) and compound 13 (112 mg, 1 mmol) were dissolved in anhydrous DCM (5 mL), transferred to 0°C, and AlCl3 (100 mg, 0.75 mmol) was added to the above solution. The reaction solution was heated to room temperature and stirred for 12 h. Then, the reaction solution was transferred to 0°C, 1N dilute hydrochloric acid was added to quench the reaction, and DCM was extracted (20 mL×2). The organic phases were combined, washed with 1N dilute hydrochloric acid, washed with saturated brine, dried over anhydrous sodium sulfate, and prepared by HPLC to obtain compound S6 (39 mg, 25%). 1 H NMR (500MHz, DMSO-d6) δ11.45(s,1H),7.90(d,J=2.3Hz,1H),7.34(d,J=2.1Hz,1H),7.25(s,1H),3.85(s,3H),3.27( dt,J=8.6,7.2Hz,1H),2.19(dt,J=8.6,7.1Hz,1H),1.81(q,J=7.0Hz,1H),1.63(q,J=7.0Hz,1H).MS(ESI,m / z):310(M + +1).

[0093] Example 7: Synthesis of Compound S7

[0094]

[0095] The synthesis method is the same as in Example 4, except that Replace with That's it. 1H NMR (500MHz, DMSO-d6) δ11.55(s,1H),7.90(d,J=2.3Hz,1H),7.33(d,J=2.1Hz,1H),7.25(s,1 H),3.85(s,3H),3.14–3.06(m,1H),3.10–2.99(m,1H),2.27–2.01(m,4H).MS(ESI,m / z):324(M + +1).

[0096] Example 8: Synthesis of Compound S8

[0097]

[0098] (1) Synthesis of Compound 16

[0099]

[0100] Cesium carbonate (300 mmol, 97.7 g), catalytic amount of potassium iodide and deuterated iodomethane (21.6 g, 150 mmol) were added to a solution of compound 15 (19.7 g, 100 mmol) in DMF (200 mL), the temperature was raised to 80°C, the reaction was stirred overnight, cooled to room temperature, water was added to quench the reaction, ethyl acetate was extracted (100 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 16 (16.1 g, 75%). MS (ESI, m / z): 215 (M + +1).

[0101] (2) The synthesis of compound S8 can refer to the synthesis method of S1 in Example 1, except that compound 2 is replaced by the corresponding raw material compound 16. 1 H NMR (500MHz, DMSO-d6) δ11.33(s,1H),7.88(d,J=2.3Hz,1H),7.38(d,J=2.1Hz,1H),7.21(s ,1H),3.89(s,3H),3.87–3.78(m,1H),3.50(dt,J=14.5,8.4Hz,1H),2.71(t,J=8.4Hz,2H).

[0102] Example 9: Synthesis of Compound S9

[0103]

[0104] The synthesis method is the same as in Example 3. Replace with the corresponding raw material compound That's it. 1H NMR (500MHz, DMSO-d6) δ11.33(s,1H),7.87(d,J=2.3Hz,1H),7.40(d,J=2.1Hz,1H),7.21(s,1H),3.88(s,3H ), 3.56 (dd, J = 15.2, 7.7Hz, 1H), 3.40 (dd, J = 15.3, 7.8Hz, 1H), 2.65 (h, J = 7.4Hz, 1H), 1.19 (d, J = 7.3Hz, 3H).

[0105] Example 10: Synthesis of Compound S10

[0106]

[0107] (1) Synthesis of Compound 19

[0108]

[0109] Cesium carbonate (300 mmol, 97.7 g), catalytic amount of potassium iodide and deuterated iodomethane (21.6 g, 150 mmol) were added to a solution of compound 18 (21.7 g, 100 mmol) in DMF (200 mL), the temperature was raised to 80°C, the reaction was stirred overnight, cooled to room temperature, water was added to quench the reaction, ethyl acetate was extracted (100 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 19 (16.4 g, 70%). MS (ESI, m / z): 235 (M + +1).

[0110] (2) The synthesis of compound S10 can refer to the synthesis method of S1 in Example 1, except that compound 2 is replaced by the corresponding raw material compound 19. 1 H NMR (500MHz, DMSO-d6) δ11.23 (s, 1H), 8.09 (s, 1H), 7.92 (d, J = 2.2Hz, 1H), 7.12 (d, J=2.3Hz,1H),3.85(s,3H),3.83(m,2H)2.71(t,J=8.4Hz,2H).MS(ESI,m / z):345(M + +1).

[0111] Example 11: Synthesis of Compound S11

[0112]

[0113] The synthesis method is the same as in Example 3. Replace with the corresponding raw material compound That's it.1 H NMR (500MHz, DMSO-d6) δ11.23(s,1H),8.09(s,1H),7.92(d,J=2.1Hz,1H),7.12(d,J=2.3Hz,1H),3.57(dd,J=15 .2,7.7Hz,1H),3.40(dd,J=15.3,7.8Hz,1H),2.65(h,J=7.4Hz,1H),1.19(d,J=7.3Hz,3H).MS(ESI,m / z):359(M + +1).

[0114] Example 12: Synthesis of Compound S12

[0115]

[0116] (1) Synthesis of Compound 22

[0117]

[0118] Cesium carbonate (130 g, 400 mmol), catalytic amount of potassium iodide and deuterated iodomethane (36.0 g, 250 mmol) were added to a solution of compound 21 (18.3 g, 100 mmol) in DMF (200 mL), the temperature was raised to 80°C, the reaction was stirred overnight, cooled to room temperature, water was added to quench the reaction, ethyl acetate was extracted (100 mL×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 22 (15.2 g, 70%). MS (ESI, m / z): 218 (M + +1).

[0119] (2) The synthesis of compound S12 can refer to the synthesis method of S1 in Example 1, except that compound 2 is replaced by the corresponding raw material compound 22. 1 H NMR (500MHz, DMSO-d6) δ11.23 (s, 1H), 8.09 (s, 1H), 7.92 (d, J = 2.2Hz, 1H), 7.12 (d, J = 2.3Hz, 1H), 3.83 (m, 2H) 2.71 (t, J = 8.4Hz, 2H). MS (ESI, m / z): 301 (M + +1).

[0120] Example 13: Synthesis of Compound S13

[0121]

[0122] The synthesis method is the same as in Example 3. Replace with the corresponding raw material compound That's it. 1 HNMR(500MHz,DMSO-d6)δ11.33(s,1H),7.92(d,J=2.1Hz,1H),7.40(d,J=2.1Hz,1H),7.26(s,1H),3.5 5(dd,J=15.4,7.7Hz,1H), 3.38(dd,J=15.2,7.7Hz,1H), 2.65(h,J=7.4Hz,1H), 1.19(d,J=7.3Hz,3H).

[0123] Example 14: Synthesis of Compound S14

[0124]

[0125] (1) Synthesis of Compound 27

[0126]

[0127] Step 1: Synthesis of compound 25

[0128] Compound 24 (17 g, 70 mmol) was dissolved in anhydrous DMF (160 mL) and protected by nitrogen. Potassium carbonate (29 g, 210 mmol) and ethyl thioglycolate (15.3 mL, 140 mmol) were added to the above solution. The reaction temperature was raised to 60°C and stirred for 6 hours. After the reaction was complete, the mixture was cooled to room temperature and poured into a large amount of ice water. The mixture was filtered and the filter cake was collected and dried in vacuo to obtain compound 25 (10.2 g, 55%). MS (ESI, m / z): 267 (M + +1).

[0129] Step 2: Synthesis of compound 26

[0130] Compound 25 (532 mg, 2 mmol) was dissolved in toluene (10 mL), and Ag2CO3 (552 mg, 2 mmol), D2O (800 mg, 40 mmol), and MePhos (182 mg, 0.5 mmol) were added to the above solution. Then, the reaction solution temperature was raised to 100°C and the reaction was stirred for 12 h. Saturated ammonium chloride solution was added to quench the reaction, and dichloromethane was extracted (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain compound 26 (304 mg, 57%). MS (ESI, m / z): 268 (M + +1).

[0131] Step 3: Synthesis of compound 27

[0132] Compound 26 (267 mg, 1 mmol) was dissolved in THF (2 mL), and the mixture was transferred to 0°C. A lithium hydroxide aqueous solution (2 mL, 2 mmol, 1 M) was added to the solution, and the mixture was transferred to room temperature and stirred for 3 h. The reaction was stopped, the mixture was transferred to 0°C, and dilute hydrochloric acid was added to adjust the pH to 2-3. A white solid was precipitated, and the filter cake was collected by suction filtration and vacuum dried to obtain compound 27 (213 mg, 89%). MS (ESI, m / z): 240 (M + +1).

[0133] (2) The synthesis of compound S14 can refer to the synthesis method of S1 in Example 1, except that compound 2 is replaced by the corresponding raw material compound 27. 1 HNMR(500MHz,DMSO-d6)δ11.33(s,1H),7.23(d,J=16.8Hz,1H),3.89(s,3H),3 .86(s,3H),3.81(t,J=8.5Hz,2H),2.72(t,J=8.5Hz,1H).MS(ESI,m / z):296(M + +1).

[0134] Example 15: Synthesis of Compound S15

[0135]

[0136] The synthesis method is the same as in Example 3, except that the raw materials in step 1 are Replace with the corresponding raw material compound The 2-bromopropionic acid methyl ester in step 2 can be replaced by 2-bromobutyric acid methyl ester. 1 H NMR (500MHz, DMSO-d6) δ11.33(s,1H),7.23(d,J=16.9Hz,2H),3.87(d,J=18.1Hz,6H),3.58(dd,J=15.0,7.9Hz,1H) ,3.42(dd,J=15.2,7.9Hz,1H),2.65(tt,J=7.7,6.4Hz,1H),1.59(m,2H),0.97(t,J=7.4Hz,3H).MS(ESI,m / z):324(M + +1).

[0137] Example 16: Synthesis of Compound S16

[0138]

[0139] The synthesis method is the same as in Example 6. Replace with the corresponding raw material compound That's it.1 HNMR(500MHz,DMSO-d6)δ11.23(s,1H),7.23(d,J=15.9Hz,2H),3.89(s,3H),3.85(s,3H),3.23(dt,J=8.6, 7.1Hz,1H),2.19(dt,J=8.6,7.2Hz,1H),1.81(q,J=6.9Hz,1H),1.64(q,J=7.0Hz,1H).MS(ESI,m / z):308(M + +1).

[0140] Example 17: Synthesis of Compound S17

[0141]

[0142] (1) Synthesis of Compound 29 The synthesis of Compound 27 in Example 14 was similar, except that the starting compound 25 was replaced by the starting compound 3.

[0143]

[0144] (2) Synthesis of Compound S17 The synthesis method of Example 1 was used, except that the raw material compound 4 was replaced by the corresponding raw material compound 29. 1 H NMR (500MHz, DMSO-d6) δ11.33(s,1H),7.25(s,1H),7.10(s,1H),3.87–3.77(m,5H),2.72(t,J=8.4Hz,2H).MS(ESI,m / z):299(M + +1).

[0145] Example 18: Synthesis of Compound S18

[0146]

[0147] The synthesis method is the same as in Example 17. Replace with corresponding raw materials That's it. 1 H NMR (500MHz, DMSO-d6) δ11.33(s,1H),7.23(d,J=11.0Hz,2H),3.88(s,3H),3.81(t,J=8.5Hz,2H),2.72(t,J=8.4Hz,1H).MS(ESI,m / z):299(M + +1).

[0148] Example 19: Synthesis of Compound S19

[0149]

[0150] The synthesis method is the same as in Example 17. Replace with corresponding raw materials That's it. 1 H NMR (500MHz, DMSO-d6) δ11.33(s,1H),7.23(d,J=11.0Hz,2H),3.81(t,J=8.5Hz,2H),2.72(t,J=8.4Hz,1H).MS(ESI,m / z):302(M + +1).

[0151] Example 20: Synthesis of Compound S20

[0152]

[0153] The synthesis method is the same as in Example 3. Replace with corresponding raw materials That's it. 1 H NMR (500MHz, DMSO-d6) δ11.33(s,1H),7.25(s,1H),7.10(s,1H),3.57(dd,J=15.1,7.8Hz,1H),3.41(dd,J=1 5.2,7.9Hz,1H),2.65(tt,J=7.8,6.3Hz,1H),1.63–1.53(m,2H),0.97(t,J=7.3Hz,3H).MS(ESI,m / z):330(M + +1).

[0154] Example 21: Synthesis of Compound S21

[0155]

[0156] Step 1: Synthesis of compound 35

[0157] Compound 33 (83 mg, 0.22 mmol), compound 34 (66 mg, 0.42 mmol), cesium carbonate (210 mg, 0.64 mmol) and Pd(dppf)Cl2 (24 mg, 0.04 mmol) were dissolved in 1,4-dioxane (2.0 mL) and water (0.4 mL), protected by nitrogen, and the temperature was raised to 90°C. The reaction was stirred for 2 h. The mixture was cooled to room temperature, filtered, concentrated, and purified by column chromatography to obtain compound 35 (32 mg, 45%). MS (ESI, m / z): 322 (M + +1).

[0158] Step 2: Synthesis of compound S21

[0159] Compound 35 (30 mg, 0.09 mmol) was dissolved in THF (2 mL), and the mixture was transferred to 0°C. Aqueous LiOH solution (0.5 mL, 1 M) was added to the mixture, and the mixture was transferred to room temperature and stirred for 3 h. The mixture was transferred to 0°C, and dilute hydrochloric acid was added to adjust the pH to 2-3. A white solid precipitated, and the filter cake was collected and dried under vacuum to obtain compound S21 (25 mg, 95%). MS (ESI, m / z): 294 (M + +1). 1 HNMR(500MHz,DMSO-d6)δ11.33(s,1H),7.93–7.86(m,2H),7.35(d,J=2.2Hz,1H),7.06–6.96(m,1H),5.81(dd,J=13.5,1. 9Hz, 1H), 5.52 (dd, J = 13.5, 1.9Hz, 1H), 3.83 (dt, J = 14.5, 8.4Hz, 1H), 3.50 (dt, J = 14.5, 8.4Hz, 1H), 2.71 (t, J = 8.4Hz, 2H).

[0160] Biological experiments

[0161] Example 22: Testing of the binding ability of compounds to human interferon gene stimulator protein

[0162] The specific steps of the interferon gene stimulating protein competitive binding test experiment are based on the kit of CISBIO. Basic principle: specific Anti 6His-Tb 3+ The antibody is used as a donor, which binds to the 6His-labeled h-IFN-GSP protein, and the d2-labeled IFN-GSP ligand is used as a receptor (CISBIO, catalogue no. 64BDSTGPEG). The compound is dissolved in DMSO and set at 10 concentration points. It is co-incubated with the above ligand and receptor to detect the IC of the test compound for competitive binding to the ligand in the system. 50 .

[0163] The specific experimental steps are as follows

[0164] ① Set up negative control wells, standard wells, and compound wells in the experiment, and add 5 μL of negative control, different concentrations of standard cGAMP, and different concentrations of samples to be tested into the negative control wells, standard wells, and compound wells respectively;

[0165] ② Add 5 μL 1X detection buffer to the negative control wells, and add 5 μL 1X 6His-labeled h-interferon gene stimulating protein to the standard and compound wells;

[0166] ③ Add 10 μL of 1X interferon gene stimulating protein ligand-d2 and 1X Anti 6His-Tb to all wells. 3+ Mix the working fluid;

[0167] ④ Seal the plate with a film and incubate at room temperature for 4 hours;

[0168] ⑤Tear off the membrane and use an HTRF compatible reader to read the absorbance values ​​at 616nm and 665nm respectively.

[0169] ⑥ Calculate the ratio of the acceptor and donor emission signals: Ratio = Signal 665nm / Signal 616nm X 10 4

[0170] ⑦ Calculate IC using the Ratio value 50 The IC value of the compound was then determined by the standard cGAMP. 50 The value is converted.

[0171] The experimental results are shown in Table 1 below. 50 >100nM; B:IC 50 =100nM-10nM; A:IC 50 <10nM.

[0172] The research results show that the compound of the present invention has a strong affinity to interferon gene stimulating protein.

[0173] Table 1 Binding ability of the tested compounds to human interferon gene stimulating protein

[0174] Compound No. <![CDATA[IC 50 (nM)]]> Compound No. <![CDATA[IC 50 (nM)]]> S1 A S12 A S2 A S13 A S3 A S14 A S4 A S15 A S5 A S16 A S6 A S17 A S7 A S18 A S8 A S19 A S9 A S20 A S10 A MSA-2 A S11 A

[0175] Example 23: Testing of IFNβ Release

[0176] Experimental steps: THP-1 cells were plated (1×10 5 The next day, after changing the cell medium, the test compound was co-incubated with THP-1 cells for 5 h, and then the culture supernatant was collected and the IFN-β content was detected by ELISA according to the following steps.

[0177] ① Addition of standard samples: set up standard sample wells and sample wells, and add 50 μL of standard samples of different concentrations (0, 25, 50, 100, 200, 400 pg / ml) to each standard sample well.

[0178] ② Sample addition: Set up blank wells (blank control wells do not add samples and enzyme-labeled reagents, and the rest of the steps are the same) and test sample wells. First add 40μL of sample diluent to the test sample wells on the enzyme-labeled plate, and then add 10μL of the test sample (the final sample dilution is 5 times). Add the sample to the bottom of the well of the enzyme-labeled plate, try not to touch the well wall, and gently shake to mix.

[0179] ③ Add enzyme: Add 100 μL of enzyme-labeled reagent to each well, except for the blank well.

[0180] ④ Incubation: Seal the plate with a sealing film and incubate at 37°C for 60 minutes.

[0181] ⑤ Liquid preparation: Dilute the 20-fold concentrated washing solution with 20-fold distilled water and set aside.

[0182] ⑥ Washing: Carefully peel off the sealing film, discard the liquid, spin dry, fill each well with washing solution, let it stand for 30 seconds and then discard, repeat this 5 times and pat dry.

[0183] ⑦ Color development: First add 50μl of color developer A to each well, then add 50μl of color developer B, gently shake and mix, and color development at 37℃ in the dark for 15 minutes.

[0184] ⑧Termination: Add 50 μL of stop solution to each well to terminate the reaction (the blue color immediately turns to yellow).

[0185] ⑨ Determination: Use the blank well as zero setting, and measure the absorbance (OD value) of each well in sequence at a wavelength of 450nm. The determination should be performed within 15 minutes after adding the stop solution.

[0186] ⑩Calculation: Calculate the IFN-β content in each sample after obtaining the standard curve using the standard product, and calculate the EC according to the IFN-β content induced by the test compound at different concentrations. 50 value.

[0187] After the interferon gene stimulating protein protein is activated, the expression of IFNβ is induced to exert anti-tumor or anti-infection effects. The amount of IFNβ produced is an important indicator of the degree of activation of the interferon gene stimulating protein protein. This experiment used the ELISA method to explore the amount of IFNβ produced after co-incubation of different concentrations of the test compound with THP-1 cells. The results are shown in Table 2 below. The compounds of the present invention can significantly induce the production of IFNβ in THP-1 cells, and are better than the positive control MSA-2.

[0188] Table 2 The amount of IFNβ produced after co-incubation of the test compounds with THP-1 cells at different concentrations

[0189]

[0190]

[0191] Example 24: Pharmacokinetic property testing

[0192] Male SD rats were selected and the drug was administered orally (10 mg / kg) or intravenously (2 mg / kg). At 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 10 h, and 24 h after administration, blood was continuously collected from the retinal venous plexus and placed in EP tubes containing heparin. The blood was centrifuged and the upper plasma was collected for LC-MS / MS analysis. Based on the blood drug concentration-time data obtained from the test, WinNonlin software was used to calculate the pharmacokinetic parameters and the oral bioavailability.

[0193] As shown in Table 3, compared with MSA-2, the clearance rate of the compound S19 of the present invention is reduced, the half-life is prolonged, the oral exposure is increased, and the oral bioavailability is significantly improved.

[0194] Table 3 Pharmacokinetic parameters of compounds

[0195]

[0196] Example 25: Anti-tumor activity detection in MC38 mouse transplant tumor model

[0197] MC38 cells (1×10 6 cells) were suspended in 150uL of saline and inoculated into the armpits of male C57B / L6 mice (age about 5-6 weeks, weight about 20g). 3 The mice were randomly divided into parallel groups, with 6 mice in each group, and the positive drug MSA-2 (30 mg / kg) and compound S19 (30 mg / kg) were dissolved in 1% DMSO, 40% PEG 400, 59% PBS solution and administered on the 1st, 5th and 10th days. The vehicle was used as the control group. The tumor volume and body weight were measured every two days with a vernier caliper to observe the size of the tumor volume and the effect of the drug on the weight of the mice. The tumor volume was calculated based on the formula "1 / 2×long diameter×short diameter". 2 The drug administration was stopped after 21 days. Three hours after the last administration, the mice were killed by dislocating the cervical vertebrae, and the tumors were dissected, photographed and weighed.

[0198] like Figure 1 As shown, at the same dose, the compound S19 of the present invention can completely inhibit the growth of MC38 transplanted tumors, which is significantly better than the tumor inhibition effect of the positive drug MSA-2. Therefore, the compound S19 of the present invention shows better prospects for treating tumors.

[0199] For those skilled in the art, the present disclosure is not limited to the foregoing illustrative embodiments, but can be embodied in other specific forms without departing from its essential attributes. It is therefore intended that all aspects be considered as illustrative and not restrictive, that reference is made to the embodiments of the appended claims rather than to the foregoing embodiments, that references are made only to the appended claims rather than to the foregoing examples, and that all changes that come within the meaning and scope of equivalents of the claims are therefore intended to be included herein.

[0200] All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the event of inconsistency, the present disclosure, including the definitions, will control.

Claims

1. A deuterated benzothiophene compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is any of the following compounds:

2. A pharmaceutical composition comprising a therapeutically effective amount of one or more deuterated benzothiophene compounds having the structure as shown in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutical excipient or carrier.

3. Use of the deuterated benzothiophene compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of an interferon gene stimulating protein agonist.

4. Use of the deuterated benzothiophene compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a drug for preventing and / or treating cancer.

5. Use of the deuterated benzothiophene compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a medicament for preventing and / or treating infectious diseases.

6. Use of the deuterated benzothiophene compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a vaccine adjuvant.

7. The use according to claim 6, characterized in that The vaccine adjuvant is a vaccine adjuvant used for preventing and / or treating cancer.

8. The use according to claim 7, characterized in that The vaccine adjuvant is a vaccine adjuvant used for preventing and / or treating infectious diseases.

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