LAT1-mediated STING agonist prodrug as well as preparation method and medical application thereof

Abstract

The invention discloses an LAT1-mediated STING agonist prodrug as well as a preparation method and medical application thereof, and belongs to the technical field of medicines. In order to solve the problem of specific delivery of the STING agonist, a series of LAT1-mediated STING agonist prodrug molecules are designed and synthesized, the molecules enter tissues through recognition and transportation of LAT1, then the STING agonist molecules are subjected to hydrolysis bond breaking through esterase or aminopeptidase, and the STING agonist molecules are released, so that the STING-activated non-specific immunocompetence is realized.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a class of LAT1-mediated STING agonist prodrugs, their preparation methods, and pharmaceutical uses. Background Technology

[0002] The scope and application of prodrug-mediated drug delivery strategies have been significantly expanded. By altering the physicochemical properties and pharmacokinetic characteristics of drug molecules, they have become one of the main means to alleviate drug delivery challenges (such as low exposure and nonlinear exposure) (Chemical Society Reviews, 2024, 53(4)). Targeted prodrug strategies refer to the selective activation of prodrugs by utilizing abnormally expressed biomarkers or enzymes in cells and tumor microenvironments, thereby improving efficacy and reducing unnecessary toxicity by minimizing off-target interactions.

[0003] Targeted activation of STING is a promising new strategy for tumor immunotherapy. It can activate the body's own immune system, transforming "cold" tumors into "hot" tumors and enhancing their immunogenicity. However, its development still faces challenges such as delivery strategies, penetration, persistence, and drug toxicity limitations. In the tumor microenvironment, many STING agonists do not easily enter cells. Currently, most STING agonist analogs in clinical trials are designed for systemic administration, which can easily trigger systemic immune inflammation (Nature Reviews Bioengineering, 2025, 3). Therefore, specifically delivering STING agonists to tumor tissues is a major direction for future research.

[0004] LAT1 is highly expressed in the blood-brain barrier and in tumors such as glioblastoma (GBM). Furthermore, it can overcome the blood-brain barrier and circumvent the efflux substrate effects of certain transport proteins, making it a promising novel drug target for treating brain cancer (European Journal of Pharmaceutical Sciences, 2024, 192). Reversibly coupling a STING agonist with a LAT1 transport substrate creates a LAT1-like prodrug that actively enters the brain, accumulates at the tumor site, and then enters cells, releasing the drug molecules and ultimately achieving tumor regression. Given the lack of effective treatments for gliomas, especially GBM, STING-agonist LAT1 prodrugs have significant market potential.

[0005] Based on this, the present invention designs and synthesizes a series of LAT1-mediated STING agonist prodrug molecules. These molecules can utilize the selective expression and transport of LAT1 to deliver STING agonists to specific tissues such as the blood-brain barrier, thereby achieving non-specific immune activity activated by STING. Summary of the Invention

[0006] The first aspect of the invention provides a compound, stereoisomer, or pharmaceutically acceptable salt of formula (I) or formula (II):

[0007]

[0008] In formula (I):

[0009] R 1 Selected from hydrogen atom, halogen atom, cyano group, OR 9 、N(R 9 2. C1-C6 alkyl, C1-C6 haloalkyl, OR 9 Substituted C1-C6 alkyl or C3-C6 cycloalkyl;

[0010] R 9 Selected from hydrogen atom, hydroxyl group, amino group, hydroxymethyl group, methoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C6 10 Aryl;

[0011] R 2 Selected from hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, hydroxymethyl groups, methoxy groups, thiomethyl groups, N(CH2CH3)2, N(CH3)2, benzyloxy groups, benzoyloxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl;

[0012] M is selected from oxygen, carbon, nitrogen, or selenium atoms;

[0013] X is selected from oxygen or nitrogen atoms;

[0014] Y 1 Selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-6 membered heterocyclic, C5-C 10 Aryl or C5~C 10 Substitution of aryl groups;

[0015] In formula (II):

[0016] R 3 Selected from hydrogen atom, halogen atom, cyano group, OR 9 、N(R 9 2. C1-C6 alkyl, C1-C6 haloalkyl, OR 9 Substituted C1-C6 alkyl or C3-C6 cycloalkyl;

[0017] R 9Hydrogen atom, hydroxyl group, amino group, hydroxymethyl group, methoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C6 10 Aryl;

[0018] R 4 Selected from hydrogen atom, hydroxyl group, halogen atom, amino group, hydroxymethyl group, methoxy group, ethoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, pinacol ester group of borate, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C 10 Aryl;

[0019] R 5 Selected from hydrogen atom, hydroxyl group, halogen atom, amino group, hydroxymethyl group, methoxy group, ethoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, pinacol ester group of borate, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C 10 Aryl;

[0020] R 6 Selected from hydrogen atom, hydroxyl group, halogen atom, amino group, hydroxymethyl group, methoxy group, ethoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C6 alkyl group. 10 Aryl;

[0021] A 1 The ring is a five-membered ring or a heteroatom five-membered ring, and the heteroatom is selected from sulfur atom, oxygen atom or nitrogen atom;

[0022] M is selected from oxygen, carbon, nitrogen, or selenium atoms;

[0023] X is selected from oxygen or nitrogen atoms;

[0024] Y 2 Selected from hydrogen atoms or When one side Y 2 When X is a hydrogen atom, X is an oxygen atom, and Y on the other side... 2 It cannot be selected from hydrogen atoms at the same time;

[0025] Z is selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-6 membered heterocyclic, C5-C6 alkyl, C6-C6 alkyl, C7 ... 10 Aryl or C5~C 10 Replacement of aryl groups.

[0026] Furthermore, in equation (I): R1 Selected from hydrogen atom, halogen atom, cyano group, OR 9 、N(R 9 2. C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; preferably hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, methoxy, or ethoxy;

[0027] R 9 Selected from hydrogen atoms, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, and C5-C6 cycloalkyl groups. 10 Aryl;

[0028] R 2 Selected from hydrogen atoms, halogen atoms, hydroxyl groups, methoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl group; preferably hydrogen atom, fluorine atom, hydroxyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group;

[0029] M is selected from oxygen, nitrogen, or selenium atoms; selenium atoms are preferred.

[0030] X is selected from oxygen or nitrogen atoms; oxygen atoms are preferred.

[0031] Furthermore, in equation (II): R 3 Selected from hydrogen atoms, halogen atoms, OR 9 C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; preferably hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, methoxy, or ethoxy;

[0032] R 9 Selected from hydrogen atoms, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl;

[0033] R 4 Selected from hydrogen atoms, hydroxyl groups, halogen atoms, methoxy groups, ethoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl group; preferably hydrogen atom, hydroxyl group, fluorine atom, methoxy group, ethoxy group, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group;

[0034] R 5 Selected from hydrogen atoms, hydroxyl groups, halogen atoms, methoxy groups, ethoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10Aryl group; preferably hydrogen atom, hydroxyl group, fluorine atom, methoxy group, ethoxy group, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group;

[0035] R 6 Selected from hydrogen atoms, hydroxyl groups, halogen atoms, methoxy groups, ethoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl group; preferably hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, methoxy, ethoxy;

[0036] A 1 The ring is a five-membered ring or a heteroatom five-membered ring, and the heteroatom is selected from sulfur atoms or nitrogen atoms; preferably, selenophene ring or pyrrole ring;

[0037] M is selected from oxygen, nitrogen, or selenium atoms; selenium atoms are preferred.

[0038] X is selected from oxygen or nitrogen atoms; oxygen atoms are preferred.

[0039] In some specific instances, the present invention provides compounds as shown below:

[0040]

[0041]

[0042]

[0043] The present invention also provides a method for preparing the above-mentioned compound, as follows:

[0044] When the compounds are S1-S8 and S17-S26, the amino acid substrate A is selected and the amino group is replaced by Fmoc-Cl to obtain compound of general formula 1. Compound of general formula 1 is reacted with a tert-butyl protecting agent under reflux to obtain compound of general formula 2. Compound of general formula 2 is condensed with the monomeric STING agonist molecule (obtained according to patents CN113429387A, CN120025311A, and US20180093964A1) to obtain compound of general formula 3. Compound of general formula 3 is deprotected by Fmoc protecting group under basic conditions to obtain compound of general formula 4. Compound of general formula 4 is hydrolyzed under acidic conditions to obtain compound of general formula (Ⅰa).

[0045] When it is a compound shown in S9-S10, it is obtained by protecting the amino acid substrate A with a boron group to obtain compound of general formula 5. Compound of general formula 5 is condensed to obtain compound of general formula 6. Compound of general formula 6 is deprotected to obtain compound of general formula 7. Compound of general formula 7 is salted in TFA to obtain compound of general formula (Ⅰa).

[0046] When the compound is S11-S13, S27, it is obtained by protecting the amino acid substrate B with a boron group to obtain compound of general formula 8. Compound of general formula 8 is condensed to obtain compound of general formula 9. Compound of general formula 9 is deprotected to obtain compound of general formula 10. Compound of general formula 10 is salted in TFA to obtain compound of general formula (Ib).

[0047] When it is a compound as shown in S14-S16, S28, the amino acid substrate C is reduced to give compound of general formula 11. Compound of general formula 11 is protected with a boron group to give compound of general formula 8. Compound of general formula 8 is condensed to give compound of general formula 9. Compound of general formula 9 is deprotected to give compound of general formula 10. Compound of general formula 10 is salted in TFA to give compound of general formula (Ib).

[0048] The synthesis route is as follows:

[0049]

[0050] Among them, R 1 R 2 and Y 1 As mentioned earlier, R 7 Selected from m-CN, m-NO2, p-CN, R 8 Selected from m-CH2NH2, m-NH2, p-CH2NH2.

[0051] In some more specific embodiments, the process of preparing compound 1 from amino acid substrate A uses Fmoc-Cl as a protecting agent, which can also be replaced by Fmoc-OSu and Fmoc-OPfp; the reaction needs to be carried out under alkaline conditions such as sodium carbonate, sodium bicarbonate, Et3N or DIPEA, and the reaction solvent can be DMF, DCM, THF, 1,4-dioxane and water.

[0052] In some more specific embodiments, the process of preparing compound 2 from compound 1 uses tert-butyl 2,2,2-trichloroacetylimine ester as the reactant and DCM, THF, and DMF as the reaction solvent.

[0053] In some more specific embodiments, the condensing agent used in the preparation of compound 3 from compound 2 may be HATU, HBTU, HOAT, HOBT, DCC, EDC, and EDCI, the base used may be TEA, DIPEA, and DMAP, and the reaction solvent may be DCM, MeCN, and DMF.

[0054] In some more specific embodiments, the process of preparing compound 4 from compound 3 may use piperidine, diethylamine and DBU as the base and DMF, DCM and DMSO as the solvent.

[0055] In some more specific embodiments, the reaction reagents for preparing compound Ia from compound 4 can be trifluoroacetic acid, maleic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent can be DCM and acetic acid.

[0056] In some more specific embodiments, the reaction reagent for preparing compound 5 from amino acid substrate A can be 9-BBN-H, and the reaction solvent can be THF and MeOH.

[0057] In some more specific embodiments, the condensing agent used in the preparation of compound 6 from compound 5 may be HATU, HBTU, HOAT, HOBT, DCC, EDC, and EDCI, the base used may be TEA, DIPEA, and DMAP, and the reaction solvent may be DCM, MeCN, and DMF.

[0058] In some more specific embodiments, the reaction reagent for preparing compound 7 from compound 6 is chloroform, and the reaction solvent may be methanol.

[0059] In some more specific embodiments, the reaction reagents for preparing compound Ia from compound 7 can be trifluoroacetic acid, maleic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent can be DCM and acetic acid.

[0060] In some more specific embodiments, the reaction reagent for preparing compound 8 from amino acid substrate B can be tris-9-BBN-H, and the reaction solvent can be THF and MeOH.

[0061] In some more specific embodiments, the condensing agent used in the preparation of compound 9 from compound 8 may be HATU, HBTU, HOAT, HOBT, DCC, EDC, and EDCI; the base used may be TEA, DIPEA, and DMAP; and the reaction solvent may be DCM, MeCN, and DMF.

[0062] In some more specific embodiments, the reaction reagent for preparing compound 10 from compound 9 is chloroform, and the reaction solvent may be methanol.

[0063] In some more specific embodiments, the reaction reagents for preparing compound Ib from compound 10 may be trifluoroacetic acid, maleic acid, hydrochloric acid, and sulfuric acid, and the reaction solvent may be DCM.

[0064] In some more specific embodiments, the process of preparing compound 11 from amino acid substrate C may use Pd / C and H2, LiAlH4 as reaction reagents, and methanol and THF as reaction solvents.

[0065] In some more specific embodiments, the reaction reagent for preparing compound 8 from compound 11 may be 9-BBN-H, and the reaction solvent may be THF and MeOH.

[0066] When the compounds are D1-D11 and D15-D18, the compound of general formula 2 is condensed with a dimerized STING agonist molecule (obtained according to patents CN116332903A and CN119751440A) to obtain a compound of general formula 12 or general formula 13. The compound of general formula 12 or general formula 13 is hydrolyzed under alkaline conditions to obtain a compound of general formula 14 or general formula 15. The compound of general formula 14 or general formula 15 is hydrolyzed under acidic conditions to obtain a compound of general formula (IIa) or general formula (IIb).

[0067] When the compound is shown as D12-D14, the compound of general formula 8 condenses with a dimerized STING agonist molecule to give a compound of general formula 16 or general formula 17, the compound of general formula 16 or general formula 17 is deprotected to give a compound of general formula 18 or general formula 19, and the compound of general formula 18 or general formula 19 is salted in TFA to give a compound of general formula (IIc) or general formula (IId).

[0068] Its synthetic route is as follows:

[0069]

[0070] Among them, R 3 R 4 R 5 R 6 A 1 As mentioned before, R and Z 7 Selected from m-CN, m-NO2, p-CN, R 8 Selected from m-CH2NH2, m-NH2, and p-CH2NH2. When R 5 Selected from hydrogen atoms, R 3 and R 4 If the same substituents are selected, then compounds of general formula IIa and IIb are compounds with the same structure, and compounds of general formula IIc and IId are compounds with the same structure.

[0071] In some more specific embodiments, the condensing agent used in the preparation of compound 12 or compound 13 from compound 2 may be HATU, HBTU, HOAT, HOBT, DCC, EDC, and EDCI, the base used may be TEA, DIPEA, and DMAP, and the reaction solvent may be DCM, MeCN, and DMF.

[0072] In some more specific embodiments, the process of preparing compound 14 or compound 15 from compound 12 or compound 13 may use piperidine, diethylamine and DBU as the base and DMF, DCM and DMSO as the solvent.

[0073] In some more specific embodiments, the process of preparing general formula IIa or general formula IIb from compound 14 or compound 15 may use trifluoroacetic acid, maleic acid, hydrochloric acid and sulfuric acid as reaction reagents, and DCM and acetic acid as reaction solvents.

[0074] In some more specific embodiments, the process of preparing compound 16 or compound 17 from compound 8 may use HATU, HBTU, HOAT, HOBT, DCC, EDC and EDCI as condensing agents, TEA, DIPEA and DMAP as bases, and DCM, MeCN and DMF as reaction solvents.

[0075] In some more specific embodiments, the process of preparing compound 18 or compound 19 from compound 16 or compound 17 uses chloroform as the reaction reagent and methanol as the reaction solvent.

[0076] In some more specific embodiments, the process of preparing compound IIc or IId from compound 18 or compound 19 may use trifluoroacetic acid, maleic acid, hydrochloric acid and sulfuric acid as reaction reagents, and DCM and acetic acid as reaction solvents.

[0077] This invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of an active ingredient and a pharmaceutically acceptable excipient; the active ingredient comprises one or more of the above-mentioned compounds, stereoisomers, or pharmaceutically acceptable salts. In the pharmaceutical composition, the excipient comprises a pharmaceutically acceptable carrier.

[0078] The present invention also provides the use of the above-described compounds, stereoisomers, or pharmaceutically acceptable salts, or the above-described pharmaceutical compositions, in the preparation of drugs that activate the cGAS-STING pathway.

[0079] The present invention also provides the use of the above-described compounds, stereoisomers, or pharmaceutically acceptable salts, or the above-described pharmaceutical compositions, in the preparation of a medicament for the treatment of diseases associated with STING pathway activity.

[0080] The present invention also provides the use of the above-mentioned compounds, stereoisomers, or pharmaceutically acceptable salts, or the above-mentioned pharmaceutical compositions, in the preparation of tumor therapeutic drugs, wherein the tumors include adult diffuse glioma, pediatric diffuse glioma, high-grade glioma, esophageal squamous cell carcinoma, bladder cancer, bile duct cancer, pancreatic cancer, colorectal cancer, brain cancer, choriocarcinoma, etc.

[0081] Unless otherwise stated, the following terms used in the specification and claims have the meanings discussed below:

[0082] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule.

[0083] The term "pharmaceutically acceptable salt" refers to the salt prepared from compounds of formulas (I) and (II) of this invention with a pharmaceutically acceptable organic acid. Salts derived from pharmaceutically acceptable organic acids include aliphatic monocarboxylate salts, aliphatic dicarboxylate salts, glycoside salts, aromatic salts, sulfonates, and amino acid salts. Substituted acids include haloacids, hydroxy acids, amino acids, unsaturated acids, and alkoxyaryloxy acids. Examples include maleic acid, fumaric acid, succinic acid, malonic acid, citric acid, tartaric acid, malic acid, salicylic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, trichloroacetic acid, methoxyacetic acid, phenoxyacetic acid, etc.

[0084] The term "alkyl" refers to a monovalent, straight-chain or branched saturated aliphatic hydrocarbon group having a number of carbon atoms within a specified range. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one to three, and most preferably one or two.

[0085] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, or iodine, or fluorinated, chlorinated, bromine, or iodinated.

[0086] The term "halogenated alkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms have been replaced by a halogen.

[0087] The term "aromatic heterocycle" refers to a cyclic group with 5 to 6 ring atoms, one or two of which are heteroatoms selected from N, O or S, and the remaining ring atoms are C, and the ring has a fully conjugated π-electron system. Detailed Implementation

[0088] To further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention. They should not be construed as limiting the present invention.

[0089] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0090] abbreviation

[0091] 1 H NMR proton nuclear magnetic resonance spectrum

[0092] 13 C NMR 13 C nuclear magnetic resonance spectrum

[0093] CDCl3 (deuterated chloroform)

[0094] CDI N,N-carbonyldiimidazole

[0095] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0096] DCC N,N'-Dicyclohexylcarbodiimide

[0097] DMAP 4-Dimethylaminopyridine

[0098] DMF N,N-dimethylformamide

[0099] DMSO (dimethyl sulfoxide)

[0100] EDCI 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0101] HRMS (High Resolution Mass Spectrometry)

[0102] TLC (Thin Layer Chromatography)

[0103] Intermediate preparation 1

[0104]

[0105] Step 1: Preparation of (((9H-fluorene-9-yl)methoxy)carbonyl)-L-tyrosine (1a)

[0106] In a 100 mL round-bottom flask, 1.0 g of L-tyrosine (Al, 5.51 mmol, 1 eq) was added and suspended in 14 mL of dioxane. Then, 15 mL of 10% sodium carbonate solution was added, and the mixture was cooled in an ice bath. Subsequently, 1.72 g of Fmoc-Cl (6.62 mmol, 1.2 eq) was added, and the reaction was brought to room temperature for 6 h. The reaction was quenched with 78 mL of saturated sodium carbonate solution and extracted with diethyl ether (30 mL × 3). The pH of the aqueous phase was then adjusted to 1–2, filtered, and the filter cake was dried to obtain intermediate 1a, a white solid, 1.41 g, yield 67.2%. 1 H NMR (300MHz, DMSO-d6): δ = 9.34 (s, 1H), 7.82 (d, J = 7.4Hz, 2H), 7.58 (t, J = 6.8Hz, 2H), 7.42 (t, J = 7.2Hz, 2H), 7.28 (q, J = 7.0Hz, 2H), 7.09 (t, J = 7.9Hz,1H),6.71(s,2H),6.60(d,J=7.4Hz,1H),4.15-4.10(m,4H),2.89(dd,J1=13.5Hz,J2=3.9Hz,1H),2.77(t,J=10.8Hz,1H)ppm.HRMS(ESI+ ):cacld for C 24 H 22 NO5 + (M+H) + ,404.1492; found 404.1490.

[0107] As shown in Table 1 below, intermediates 1b to 1h can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 1a described above.

[0108] Table 1

[0109]

[0110] Step 2: Preparation of ((9H-fluorene-9-yl)methoxycarbonyl)-L-tyrosine tert-butyl ester (2a)

[0111] 1.00 g (2.48 mmol, 1.0 eq) of intermediate 1a was added to a 100 mL round-bottom flask, dissolved in 2 mL of THF, and diluted with 8 mL of DCM. The mixture was stirred in an ice bath for 30 min. Subsequently, 1.63 g (7.44 mmol, 3.0 eq) of tert-butyl trichloroacetylimine was slowly added dropwise. After the addition was complete, the reaction mixture was moved to room temperature and stirred for 20 min, then heated to 60 °C and refluxed overnight. The reaction mixture was monitored by TLC until the starting material was completely reacted. After the reaction mixture cooled to room temperature, it was diluted with 80 mL of EA, washed three times with saturated sodium bicarbonate solution, once with water, and once with saturated brine. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (PE:EA = 4:1) to obtain intermediate 2a, a white solid of 783 mg, in a yield of 68.6%. 1 H NMR (300MHz, DMSO-d6): δ = 9.26 (s, 1H), 7.89 (d, J = 7.5Hz, 2H), 7.75 (d, J = 8. 1Hz,1H),7.67(t,J=7.1Hz,2H),7.42(t,J=7.4Hz,2H),7.31(q,J=6.5Hz,2H) ,3.82(d,J=8.1Hz,1H),7.03(d,J=8.4Hz,2H),6.65(d,J=8.4Hz,2H),4.24-4 .18(m,3H),4.07-3.99(m,1H),2.89-2.71(m,2H),1.34(s,9H)ppm.HRMS(ESI + ):cacld for C 28 H 29 NNaO5 + (M+Na) +,482.1938; found482.1945.

[0112] As shown in Table 2 below, intermediates 2b to 2h can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 2a described above.

[0113] Table 2

[0114]

[0115] Intermediate preparation 2

[0116]

[0117] Step 1: Preparation of (R)-4-(5,6-dimethoxybenzo[b]selenophen-2-yl)-2-ethyl-4-oxobutyric acid-4-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(tert-butoxy)-3-propionyl)phenyl ester (3a)

[0118] 783 mg (1.70 mmol, 1.0 eq) of intermediate 2a and 628 mg (1.70 mmol, 1.0 eq) of I-15 (patent CN113429387A) were added to a 100 mL round-bottom flask and dissolved in 17 mL of DCM. Then, 526 mg of 1,3-dicyclohexylcarbodiimide (DCC, 2.55 mmol, 1.5 eq) and 4 mg of 4-dimethylaminopyridine (DMAP, 0.34 mmol, 0.02 eq) were added, and the mixture was reacted at room temperature for 5 h. The mixture was filtered, and the filtrate was diluted with 80 mL of EA, washed three times with dilute hydrochloric acid, once with water, and once with saturated brine. The filtrate was dried over anhydrous sodium sulfate and filtered again. After concentration, the filtrate was purified by silica gel column chromatography (PE:EA = 2:1) to obtain 954 mg of a pale yellow, foamy solid, with a yield of 69.2%. 1 H NMR (300MHz, DMSO-d6): δ = 8.52 (s, 1H), 7.84 (q, J = 7.6Hz, 3H), 7.72 (s, 1H), 7.66 (t,J=5.9Hz,2H),7.51(s,1H),7.44-7.37(m,2H),7.32-7.27(m,4H),6.98(d,J=8 .2Hz,2H),4.26-4.09(m,4H),8.4(d,J=8.2Hz,6H),3.48(d,J=9.5Hz,2H),3.07- 2.84(m,3H),1.81-1.72(m,2H),1.32(s,9H),1.04(t,J=7.3Hz,3H)ppm.HRMS(ESI + ):cacld for C29 H 36 NO7Se + (M+H) + ,834.2152; found 834.2130.

[0119] As shown in Table 3 below, intermediates 3b to 3h, 3q to 3z, 12a to 12j, and 13a to 13e can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 3a described above.

[0120] Table 3

[0121]

[0122]

[0123]

[0124]

[0125] Step 2: Preparation of (R)-4-(5,6-dimethoxybenzo[b]selenophen-2-yl)-2-ethyl-4-oxobutyric acid-4-((S)-2-amino-3-(tert-butoxy)-3-propionyl)phenyl ester (4a)

[0126] 200 mg (0.25 mmol) of intermediate 3a was added to a 50 mL round-bottom flask and dissolved in 5 mL of DCM. Then, 0.5 mL of piperidine was added with stirring at room temperature, and the reaction was carried out for 13 h at room temperature. After dilution with 30 mL of EA, the mixture was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and subjected to silica gel column chromatography (DCM:MeOH = 70:1) to obtain 117 mg of a pale yellow, foamy solid, with a yield of 79.6%. 1 H NMR (300MHz, DMSO-d6): δ=9.96(s,1H),8.46(s,1H),7.68(s,1H),7.51(d,J= 5.1Hz,1H),7.48(s,1H),7.09(d,J=8.4Hz,2H),3.83(d,J=6.1Hz,6H),3.48-3 .36(m,2H),3.09(dd,J1=17.0Hz,J2=4.5Hz,1H),2.99-2.90(m,1H),2.80-2.6 6(m,2H),1.68-1.55(m,2H),1.34(s,9H),0.92(t,J=9.3Hz,3H)ppm.HRMS(ESI + ):cacld for C 29 H 36NO7Se + (M+H) + ,590.1652; found 590.1774.

[0127] As shown in Table 4 below, intermediates 4b to 4h and 4q to 4u can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 4a described above.

[0128] Table 4

[0129]

[0130]

[0131]

[0132]

[0133] Intermediate preparation 3

[0134]

[0135] Step 1: (1R,4'S,5S)-4'-(4-hydroxy-3-iodobenzyl)-9λ 4 Preparation of -borozyro[bicyclo[3.3.1]nonane-9,2'-[1,3,2]oxazoborane]-5'-one (5a)

[0136] 0.50 g (1.6 mmol, 1 eq) of (S)-2-amino-3-(4-hydroxy-3-iodophenyl)propionic acid (A9) was added to a 100 mL three-necked round-bottom flask. After resuspending in 14 mL of methanol, the mixture was purged with nitrogen and refluxed for approximately 30 min. 4 mL of 0.5 M 9-BBN-H tetrahydrofuran solution was added vial, and the mixture was refluxed for another 24 h. After removing the solvent by rotary evaporation, hexane was added and the mixture was stirred to form a solid. The solid was then filtered to give intermediate 5a, a white solid, 0.55 g, with a yield of 79.1%. No further purification was required; it was used directly in the next reaction. HRMS(ESI) + ):cacld for C 17 H 24 BINO3 + (M+H) + ,428.0888; found 428.0893.

[0137] Compound 5b can be prepared using the same starting materials and reactants as intermediate 5a described above.

[0138] Step 2: (R)-4-(5,6-dimethoxybenzo[b]selenophen-2-yl)-2-ethyl-4-oxobutyric acid-2-iodo-4-(((1R,4'S,5S)-5'-oxo-9λ 4 Preparation of borspiro[bicyclo[3.3.1]nonane-9,2'-[1,3,2]oxazoborane]-4'-yl)methyl)phenyl ester (6a)

[0139] Intermediate 2a was replaced with 5a, and intermediate 6a was prepared using the same method as intermediate 3a, yielding a light yellow solid with a yield of 65.3%. HRMS(ESI) + ):cacld for C 33 H 40 BINO7Se + (M+H) + ,780.1102; found 780.1089.

[0140] Compound 6b can be prepared using the same starting materials and reactants as intermediate 6a and 6a described above.

[0141] Step 3: Preparation of (S)-2-amino-3-(4-(((R)-4-(5,6-dimethoxybenzo[b]selenophen-2-yl)-2-ethyl-4-oxobutyryl)oxy)-3-iodophenyl)propionic acid (7a)

[0142] 100 mg (0.13 mmol, 1 eq) of intermediate 6a was added to a round-bottom flask, dissolved in 10 mL of chloroform and 1 mL of methanol, and reacted at room temperature for 48 h. The mixture was diluted with 40 mL of diethyl ether, filtered, and the filter cake was dried to give intermediate 7a, a white solid, 58 mg, yield 66.7%. HRMS (ESI) + ):cacld for C 25 H 27 BINO7Se + (M+H) + ,659.9992; found659.9984.

[0143] Compound 7b can be prepared using the same starting materials and reactants as intermediate 7a described above.

[0144] Intermediate preparation 4

[0145]

[0146] Step 1: (1R,4'S,5S)-4'-(4-aminobenzyl)-9λ 4Preparation of -borozyro[bicyclo[3.3.1]nonane-9,2'-[1,3,2]oxazoborane]-5'-one (8a)

[0147] Intermediate A9 was replaced with (S)-2-amino-3-(4-aminophenyl)propionic acid (B1), and compound 8a was obtained by the same preparation method as intermediate 5a, as a white solid in 80.7% yield. No further purification was required, and the next reaction was carried out directly. HRMS (ESI) + ):cacld for C 17 H 26 BN2O2 + (M+H) + ,301.2082; found 301.2086.

[0148] As shown in Table 5 below, intermediates 8b and 8c can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 8a described above.

[0149] Table 5

[0150]

[0151]

[0152] Step 2: (R)-4-(5,6-dimethoxybenzo[b]selenobenzyl-2-yl)-2-ethyl-4-oxo-N-(4-(((1R,4'S,5S)-5'-oxo-9λ) 4 Preparation of -borozyro[bicyclo[3.3.1]nonane-9,2'-[1,3,2]oxazoborane]-4'-yl)methyl)phenyl)butyramide (9a)

[0153] 100 mg (0.27 mmol, 1 eq) of I-15 (patent CN113429387A) and 155 mg (0.41 mmol, 1.5 eq) of HATU were added to a 50 mL round-bottom flask and dissolved in 4 mL of DMF. Then, 53 mg (0.41 mmol, 1.5 eq) of DIPEA was added, and the reaction was carried out at room temperature for approximately 30 min. Next, 81 mg (0.27 mmol, 1 eq) of intermediate 8a was added, and the reaction was carried out at room temperature for 6 h. The reaction was quenched with 30 mL of water and extracted with EA (20 mL × 3). The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:MeOH = 80:1) to give intermediate 9a, a pale yellow solid, 131 mg, yield 74.5%. HRMS (ESI) + ):cacld for C 33 H40 BClNO7Se + (M+H) + ,653.2296; found 653.2302.

[0154] As shown in Table 6 below, intermediates 9b to 9h, 16a, 16b, and 17a can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 9a described above.

[0155] Table 6

[0156]

[0157]

[0158] Step 3: Preparation of (S)-2-amino-3-(4-((R)-4-(5,6-dimethoxybenzo[b]selenophen-2-yl)-2-ethyl-4-oxobutamido)phenyl)propionic acid (10a)

[0159] Intermediate 6a was replaced with 9a, and prepared using the same method as 7a, to obtain intermediate 10a, a pale yellow solid, with a yield of 68.1%. HRMS(ESI) + ):cacld for C 25 H 27 NO7Se + (M+H) + ,533.1185; found 533.1189.

[0160] As shown in Table 7 below, intermediates 10b to 10h, 18a, 18b, and 19a can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 10a described above.

[0161] Table 7

[0162]

[0163] Intermediate preparation 5

[0164]

[0165] Preparation of (S)-2-amino-3-(3-aminophenyl)propionic acid (11a)

[0166] 1.00 g (4.76 mmol, 1 eq) of 2-amino-3-(3-nitrophenyl)propionic acid (C1) and 0.10 g of 10% palladium on carbon were added to a 100 mL round-bottom flask and dissolved in 40 mL of methanol. After purging with hydrogen, the mixture was reacted at room temperature for 6 h. The mixture was filtered, and the filtrate was concentrated to give intermediate 11a, a white solid, 0.83 g, in 96.8% yield. HRMS (ESI) + ):cacld for C9H 13 N2O2 + (M+H) + ,181.0972; found 181.0978.

[0167] As shown in Table 8 below, intermediates 11b and 11c can be prepared using the corresponding starting materials and reactants according to the synthesis method of intermediate 11a described above.

[0168] Table 8

[0169]

[0170] Example 1

[0171]

[0172] Preparation of (S)-2-amino-3-(4-(((R)-4-(5,6-dimethoxybenzo[b]selenophen-2-yl)-2-ethyl-4-oxobutyryl)oxy)phenyl)propionate trifluoroacetate (S1)

[0173] In a 50 mL round-bottom flask, 96 mg (0.16 mmol) of intermediate 4a was added, dissolved in 4 mL of DCM, and then 1 mL of trifluoroacetic acid was added dropwise with stirring. The mixture was allowed to react overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, and tertiary methyl ether was added to form a slurry. The slurry was then beaten with EA to give compound S1, a pale yellow solid, 73 mg, with a yield of 70.6%. 1 H NMR (300MHz, DMSO-d6): δ = 8.51 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 7.31 (d, J = 8.2Hz, 2H), 7.02 (d, J = 8.2Hz, 2H) ,3.85(s,3H),3.82(s,3H),3.57-3.34(m,3H),3.12-2.96(m,3H),1.83-1.73(m,2H),1.04(t,J=7.3Hz,3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=193.46,173.54,170.61,150.51,149.50,148.46,144.30,137.03,135.04,134.93,1 33.83,130.67,121.54,108.91,107.97,55.85,55.60,54.41,41.76,35.76,26.87,24.75,11.39ppm.HRMS(ESI + ):cacld for C 25 H 28 NO7Se + (M+H) + ,534.1026; found 534.1024.

[0174] Example 2

[0175]

[0176] Following the preparation method described in Example 1, intermediate 4a was replaced with 4b, and compound S2 was obtained by using the same preparation method as compound S1. The compound was a yellow solid with a yield of 61.5%. 1 H NMR (300MHz, DMSO-d6): δ = 8.52 (s, 1H), 8.31 (s, 2H), 7.71 (s, 1H), 7.51 (s, 1H), 7.39 (t, J = 7.8Hz, 1H), 7.16 (d, J = 7.7Hz, 1H), 7.02 (d, J = 8.1Hz,2H),4.22(s,1H),3.85(s,3H),3.83(s,3H),3.52-3.37(m,2H),3.11-3.04(m,3H),1.84-1.74(m,2H),1.06(t,J=6.9Hz,3H)ppm. 13 C NMR (75MHz, DMSO-d6): δ=193.76,173.83,170.36,150.87,150.76,148.70,144.48,137.29,136.92,135.32,135.1 8,129.99,127.25,122.83,120.95,109.19,108.10,56.08,55.83,53.13,41.98,35.64,25.00,11.60ppm.HRMS(ESI + ):cacld for C 25 H 28 NO7Se + (M+H) +,534.1026; found 534.1025.

[0177] Example 3

[0178]

[0179] Following the preparation method described in Example 1, intermediate 4a was replaced with 4c, and compound S3 was obtained using the same preparation method as compound S1, as a yellow solid with a yield of 69.6%. HRMS (ESI) + ):cacld for C 27 H 29 N2O7Se + (M+H) + ,573.1134; found 573.1104.

[0180] Example 4

[0181]

[0182] Following the preparation method described in Example 1, intermediate 4a was replaced with 4d, and compound S4 was obtained using the same preparation method as compound S1, as a pale yellow solid with a yield of 62.3%. HRMS (ESI) + ):cacld for C 20 H 26 NO7Se + (M+H) + ,472.0869; found 472.0840.

[0183] Example 5

[0184]

[0185] Following the preparation method described in Example 1, intermediate 4a was replaced with 4e, and compound S5 was obtained using the same preparation method as compound S1, as a yellow solid with a yield of 57.3%. HRMS (ESI) + ):cacld for C 23 H 31 NO7Se + (M+H) + ,458.0713; found 458.0706.

[0186] Example 6

[0187]

[0188] Following the preparation method described in Example 1, intermediate 4a was replaced with 4f, and compound S6 was obtained by using the same preparation method as compound S1. The compound was a pale yellow solid with a yield of 49.2%. 1 H NMR (300MHz, DMSO-d6): δ=8.47(s,1H),7.70(s,1H),7.50(s,1H),4.21-4.09(m,2H),3.85(s,3H),3.82(s,3H),3.67(t,J=6.3Hz,1H),3.40(q,J =9.3Hz,1H),3.21(dd,J1=17.6Hz,J2=4.7Hz,1H),2.89-2.82(m,1H),2.16-1.95(m,2H),1.67-1.58(m,2H),0.92(t,J=7.3Hz,3H)ppm.HRMS(ESI + ):cacld forC 20 H 26 NO7Se + (M+H) + ,472.0869; found 472.0862.

[0189] Example 7

[0190]

[0191] Following the preparation method described in Example 1, intermediate 4a was replaced with 4g, and compound S7 was obtained using the same preparation method as compound S1, as a yellowish-white solid with a yield of 70.3%. HRMS(ESI) + ):cacld for C 25 H 26 I2NO7Se + (M+H) + ,785.8958; found 785.9023.

[0192] Example 8

[0193]

[0194] Following the preparation method described in Example 1, intermediate 4a was replaced with 4h, and compound S8 was obtained as a yellow solid with a yield of 74.4%, using the same preparation method as compound S1. HRMS(ESI) - ):cacld for C 31 H 26 I4NO8Se - (MH) - ,1127.7008; found 1127.7052.

[0195] Example 9

[0196]

[0197] Intermediate 7a, 58 mg (0.088 mmol, 1 eq), was added to a round-bottom flask, dissolved in 4 mL of DCM, and 20 mg of trifluoroacetic acid was added dropwise. The mixture was reacted at room temperature for 3 h. The reaction solution was concentrated, and EA was added to slurry the mixture to form a solid. The solid was filtered, and the filter cake was dried to give compound S9, a yellow solid, 47 mg, 69.2%. 1 H NMR (300MHz, DMSO-d6): δ = 8.53 (s, 1H), 8.29 (s, 3H), 7.78 (d, J = 1.5Hz, 1H), 7.71 (s, 1 H),7.51(s,1H),7.32(dd,J1=8.3Hz,J2=1.4Hz,1H),7.08(d,J=8.3Hz,1H),4.24(s,1H ),3.84(d,J=8.6Hz,6H),3.55(q,J=9.7Hz,1H),3.43(dd,J1=17.6Hz,J2=4.4Hz,1H),3 .16-3.08(m,3H),2.81(s,1H),1.94-1.83(m,2H),1.09(t,J=7.2Hz,3H)ppm.HRMS(ESI + ):cacld for C 25 H 27 BINO7Se + (M+H) + ,659.9992; found 660.0013.

[0198] Example 10

[0199]

[0200] Referring to the preparation method described in Example 9, intermediate 7a was replaced with (S)-2-amino-3-(3-chloro-4-(((R)-4-(5,6-dimethoxybenzo[b]selenophen-2-yl)-2-ethyl-4-oxobutyryl)oxy)phenyl)propionic acid (7b), and compound S10 was obtained by the same preparation method as S9, as a yellow solid with a yield of 81.4%. HRMS(ESI) + ):cacld forC 25 H 27 ClNO7Se + (M+H) + ,568.0636; found 568.0631.

[0201] Example 11

[0202]

[0203] Referring to the preparation method described in Example 9, intermediate 7a was replaced with 10a, and the same preparation method as S9 was used to obtain compound S11, a yellow solid, with a yield of 86.9%. HRMS (ESI) + ):cacld for C 25 H 29 N2O6Se + (M+H) + ,533.1185; found 533.1163.

[0204] Example 12

[0205]

[0206] Following the preparation method described in Example 9, intermediate 7a was replaced with 10b, and the same preparation method as in S9 was used to obtain compound S12, a yellow solid, with a yield of 82.1%. HRMS (ESI) + ):cacld for C 25 H 27 N2O7Se + (M+H) + ,533.1185; found 533.1188.

[0207] Example 13

[0208]

[0209] Following the preparation method described in Example 9, intermediate 7a was replaced with 10c, and the same preparation method as S9 was used to obtain compound S13, a yellow-brown solid, with a yield of 84.5%. HRMS (ESI) + ):cacld for C 22 H 31 N2O6Se + (M+H) + ,499.1342; found 499.1338.

[0210] Example 14

[0211]

[0212] Following the preparation method described in Example 9, intermediate 7a was replaced with 10d, and the same preparation method as S9 was used to obtain compound S14, a yellow-brown solid with a yield of 81.2%. 1H NMR (300MHz, DMSO-d6): δ = 10.14 (s, 1H), 8.42 (s, 1H), 7.62-7.44 (m, 4H), 7.24 (t, J = 7.5Hz, 1H), 6.91 (d, J = 6.6Hz, 1H), 4.11-4.0 9(m,1H),3.80(d,J=3.0Hz,6H),3.46(q,J=9.1Hz,1H),3.09-2.93(m,4H),1.64-1.57(m,2H),0.91(t,J=7.1Hz,3H)ppm.HRMS(ESI + ):cacld for C 25 H 29 N2O6Se + (M+H) + ,533.1185; found533.1189.

[0213] Example 15

[0214]

[0215] Following the preparation method described in Example 9, intermediate 7a was replaced with 10e, and the same preparation method as in S9 was used to obtain compound S15, a yellow solid, with a yield of 85.6%. HRMS (ESI) + ):cacld for C 26 H 31 N2O6Se + (M+H) + ,547.1342; found 547.1341.

[0216] Example 16

[0217]

[0218] Following the preparation method described in Example 9, intermediate 7a was replaced with 10f, and the same preparation method as S9 was used to obtain compound S16, a yellow solid with a yield of 89.1%. 1 H NMR (300MHz, DMSO-d6): δ=8.49(s,1H),8.42(s,1H),7.67(s,1H),7.53(s,1H),7.25-7.14(m,4H),,4.25(s,2H),3.94(s,1H),3.8 4(d,J=8.7Hz,6H),3.39(q,J=9.0Hz,1H),3.17-2.98(m,3H),2.81(s,1H),1.64-1.49(m,2H),0.89(t,J=6.8Hz,3H)ppm.HRMS(ESI+ ):cacld for C 26 H 31 N2O6Se + (M+H) + ,547.1342; found547.1339.

[0219] Example 17

[0220]

[0221] Following the preparation method described in Example 1, intermediate 4a was replaced with 4q, and compound S17 was obtained using the same preparation method as compound S1, as a white solid with a yield of 65.3%. HRMS (ESI) + ):cacld for C 24 H 26 NO7Se + (M+H) + ,520.0896; found 520.0888.

[0222] Example 18

[0223]

[0224] Following the preparation method described in Example 1, intermediate 4a was replaced with 4r, and compound S18 was obtained using the same preparation method as compound S1, as a white solid with a yield of 63.6%. HRMS (ESI) + ):cacld for C 27 H 28 F2NO7Se + (M+H) + ,591.1040; found 591.1030.

[0225] Example 19

[0226]

[0227] Following the preparation method described in Example 1, intermediate 4a was replaced with 4s, and compound S19 was obtained by using the same preparation method as compound S1, which was a white solid with a yield of 63.6%. 1H NMR (300MHz, DMSO-d6): δ = 9.59 (d, J = 6.8Hz, 1H), 8.03 (d, J = 4.7Hz, 1H), 7.81-7.75 (m,3H),7.72(s,1H),7.39(d,J=2.7Hz,1H),7.17-7.08(m,2H),4.32-4.25(m,1H),3 .86(d,J=13.4Hz,4H),3.79-3.64m,1H),3.40-3.34(m,1H),3.23-3.10m,2H),2.20- 2.14(m,1H),2.12-2.01(m,1H),1.93-1.85(m,1H),1.83-1.73(m,1H)ppm.HRMS(ESI + ):cacld for C 27 H 26 F2NO7Se + (M+H) + ,589.0884; found 589.0865.

[0228] Example 20

[0229]

[0230] Following the preparation method described in Example 1, intermediate 4a was replaced with 4t, and compound S20 was obtained using the same preparation method as compound S1, as a white solid with a yield of 67.6%. HRMS (ESI) + ):cacld for C 23 H 24 FNO7Se + (M+H) + ,524.0618; found 524.0609.

[0231] Example 21

[0232]

[0233] Following the preparation method described in Example 1, intermediate 4a was replaced with 4u, and compound S21 was obtained using the same preparation method as compound S1, as a white solid with a yield of 67.6%. HRMS (ESI) + ):cacld for C 27 H 28 BrNO7Se + (M+H) + ,651.0240; found 651.0231.

[0234] Example 22

[0235]

[0236] Following the preparation method described in Example 1, intermediate 4a was replaced with 4v, and compound S22 was obtained using the same preparation method as compound S1. The compound was a creamy white solid with a yield of 58.4%. HRMS (ESI) + ):cacld for C 25 H 25 N2O7S + (M+H) + ,497.1377; found 497.1364.

[0237] Example 23

[0238]

[0239] Following the preparation method described in Example 1, intermediate 4a was replaced with 4w, and compound S23 was obtained using the same preparation method as compound S1. The compound was a creamy white solid with a yield of 64.6%. HRMS (ESI) + ):cacld for C 23 H 24 NO7S + (M+H) + ,458.1268; found 458.1260.

[0240] Example 24

[0241]

[0242] Following the preparation method described in Example 1, intermediate 4a was replaced with 4x, and compound S24 was obtained using the same preparation method as compound S1, as a white solid with a yield of 62.1%. HRMS (ESI) + ):cacld for C 23 H 24 NO7S + (M+H) + ,458.1268; found 458.1256.

[0243] Example 25

[0244]

[0245] Following the preparation method described in Example 1, intermediate 4a was replaced with 4y, and compound S25 was obtained using the same preparation method as compound S1, as a white solid with a yield of 54.4%. HRMS (ESI) +):cacld for C 18 H 22 NO7S + (M+H) + ,396.1111; found 396.1109.

[0246] Example 26

[0247]

[0248] Following the preparation method described in Example 1, intermediate 4a was replaced with 4z, and compound S26 was obtained using the same preparation method as compound S1, as a white solid with a yield of 58.9%. HRMS (ESI) + ):cacld for C 23 H 23 I2NO7S + (M+H) + ,709.9201; found 709.9198.

[0249] Example 27

[0250]

[0251] Following the preparation method described in Example 9, intermediate 7a was replaced with 10g, and the same preparation method as S9 was used to obtain compound S27, a yellow solid, with a yield of 80.2%. HRMS (ESI) + ):cacld for C 26 H 31 N2O6Se + (M+H) + ,471.8514; found 471.8509.

[0252] Example 28

[0253]

[0254] Following the preparation method described in Example 9, intermediate 7a was replaced with 10h, and the same preparation method as S9 was used to obtain compound S28, a white solid with a yield of 76.4%. HRMS (ESI) + ):cacld for C 24 H 27 N2O6S + (M+H) + ,471.1584; found 471.1578.

[0255] Example 29

[0256]

[0257] Following the preparation method described in Example 1, intermediate 4a was replaced with 14a, and compound D1 was obtained by using the same preparation method as compound S1, which was a white solid with a yield of 30.1%. 1 H NMR (300MHz, DMSO-d6): δ = 9.59 (d, J = 6.8Hz, 1H), 8.04 (s, 1H), 7.81-7.75 (m, 2H),7.46(s,1H),7.37(d,J=1.6Hz,1H),7.17-7.08(m,1H),4.26(t,J=6.4Hz ,2H),3.85(s,3H),3.78-3.74(m,1H),3.39-3.32m,1H),3.16-3.10(m,3H),2 .73(t,J=7.9Hz,1H),2.60(t,J=8.4Hz,1H),2.28-2.24(m,1H)ppm.HRMS(ESI + ):cacld for C 40 H 39 N2O 12 Se2 + (M+H) + ,899.0828; found 899.0820.

[0258] Example 30

[0259]

[0260] Following the preparation method described in Example 1, intermediate 4a was replaced with 14b, and compound D2, a white solid, was obtained using the same preparation method as compound S1, with a yield of 36.4%. 1 H NMR (300MHz, DMSO-d6): δ = 9.65 (d, J = 6.8Hz, 1H), 8.24 (s, 2H), 7.95-7.88 (m, 3H), 7.46 ( s,1H),7.21(d,J=8.3Hz,4H),7.13-7.08(m,2H),4.18(t,J=6.4Hz,4H),3.85(s,6H),3. 71-3.66m,1H),3.21-3.17(m,2H),3.11-3.07(m,4H),2.73-2.64(m,1H),2.52(t,J=8.4 Hz,2H),2.36-2.28(m,2H),1.79-1.70(m,1H),1.51-1.47(m,1H),1.21-1.16(m,3H)ppm. 13C NMR (75MHz, DMSO-d6): δ=200.32,198.18,175.39,173.20,171.94,150.31,150.29,146.90 ,146.88,143.26,142.12,141.60,139.06,139.01,138.36,138.33,137.50,132.12,127.74 ,126.67,120.07,112.13,112.06,112.05,111.09,111.06,110.06,109.47,66.53,66.48, 56.17,56.16,55.33,42.61,42.37,38.12,29.30,28.97,27.44,24.96,11.69ppm.HRMS (ESI + ):cacld for C 42 H 43 N2O 12 Se2 + (M+H) + ,927.1141; found 927.1136.

[0261] Example 31

[0262]

[0263] Following the preparation method described in Example 1, intermediate 4a was replaced with 14c, and compound D3 was obtained using the same preparation method as compound S1, as a white solid with a yield of 31.6%. HRMS (ESI) + ):cacld for C 40 H 39 FI2NO 12 Se2 + (M+H) + ,1157.8871; found 1157.8866.

[0264] Example 32

[0265]

[0266] Following the preparation method described in Example 1, intermediate 4a was replaced with 14d, and compound D4 was obtained using the same preparation method as compound S1, as a white solid with a yield of 25.5%. HRMS (ESI) + ):cacld for C 40 H 41 FNO 12 Se2 + (M+H)+ ,906.0938; found 906.0926.

[0267] Example 33

[0268]

[0269] Following the preparation method described in Example 1, intermediate 4a was replaced with 14e, and compound D5 was obtained using the same preparation method as compound S1. The compound was a yellowish-white solid with a yield of 33.0%. HRMS(ESI) + ):cacld for C 40 H 44 FNO 12 Se2 + (M+H) + ,843.2038; found 843.2024.

[0270] Example 34

[0271]

[0272] Following the preparation method described in Example 1, intermediate 4a was replaced with 14f, and compound D6 was obtained as a white solid with a yield of 30.5%, using the same preparation method as compound S1. HRMS (ESI) + ):cacld for C 44 H 45 FN3O 12 Se2 + (M+H) + ,882.2147; found 882.2136.

[0273] Example 35

[0274]

[0275] Following the preparation method described in Example 1, intermediate 4a was replaced with 15a, and compound D7 was obtained using the same preparation method as compound S1. The compound was a yellowish-white solid with a yield of 34.7%. HRMS(ESI) + ):cacld for C 44 H 43 N3O 12 Se2 + (M+H) + ,927.1141; found 927.1133.

[0276] Example 36

[0277]

[0278] Following the preparation method described in Example 1, intermediate 4a was replaced with 15b, and compound D8 was obtained using the same preparation method as compound S1, as a white solid with a yield of 28.3%. HRMS (ESI) + ):cacld for C 40 H 39 FI2NO 12 Se2 + (M+H) + ,1157.8871; found 1157.8854.

[0279] Example 37

[0280]

[0281] Following the preparation method described in Example 1, intermediate 4a was replaced with 15c, and compound D9 was obtained using the same preparation method as compound S1, as a white solid with a yield of 25.9%. HRMS (ESI) + ):cacld for C 40 H 41 FNO 12 Se2 + (M+H) + ,906.0938; found 906.0944.

[0282] Example 38

[0283]

[0284] Following the preparation method described in Example 1, intermediate 4a was replaced with 15d, and compound D10 was obtained using the same preparation method as compound S1, as a yellowish-white solid with a yield of 32.3%. HRMS(ESI) + ):cacld for C 49 H 44 FN2O 12 Se2 + (M+H) + ,843.2038; found 843.2025.

[0285] Example 39

[0286]

[0287] Following the preparation method described in Example 1, intermediate 4a was replaced with 15e, and compound D11 was obtained using the same preparation method as compound S1, as a white solid with a yield of 37.8%. HRMS (ESI)+ ):cacld for C 44 H 45 FN3O 12 Se2 + (M+H) + ,882.2147; found 882.2136.

[0288] Example 40S

[0289]

[0290] Referring to the preparation method described in Example 9, intermediate 7a was replaced with 18a, and the same preparation method as in S9 was used to obtain compound D12, a yellow solid, with a yield of 24.6%. HRMS (ESI) + ):cacld for C 40 H 43 N2O 11 Se + (M+H) + ,887.1192; found 887.1185.

[0291] Example 41

[0292]

[0293] Following the preparation method described in Example 9, intermediate 7a was replaced with 18b, and the same preparation method as in S9 was used to obtain compound D13, a yellow solid, in a yield of 32.1%. HRMS (ESI) + ):cacld for C 39 H 41 N2O 11 Se + (M+H) + ,873.1035; found 873.1027.

[0294] Example 42

[0295]

[0296] Following the preparation method described in Example 9, intermediate 7a was replaced with 19a, and the same preparation method as in S9 was used to obtain compound D14, a yellow solid, in 28.5% yield. HRMS (ESI) + ):cacld for C 40 H 43 N2O 11 Se + (M+H) +,887.1192; found 887.1185.

[0297] Example 43

[0298]

[0299] Following the preparation method described in Example 1, intermediate 4a was replaced with 14g, and compound D15 was obtained as a white solid with a yield of 24.5%, using the same preparation method as compound S1. HRMS (ESI) + ):cacld for C 40 H 39 N2O 12 S2 + (M+H) + ,803.1939; found 803.1927.

[0300] Example 44

[0301]

[0302] Following the preparation method described in Example 1, intermediate 4a was replaced with 14h, and compound D16 was obtained as a white solid with a yield of 28.7%, using the same preparation method as compound S1. HRMS (ESI) + ):cacld for C 38 H 38 NO 12 S2 + (M+H) + ,764.1830; found 764.1827.

[0303] Example 45

[0304]

[0305] Following the preparation method described in Example 1, intermediate 4a was replaced with 14i, and compound D17 was obtained as a white solid with a yield of 25.6%, using the same preparation method as compound S1. HRMS (ESI) + ):cacld for C 40 H 39 N3O2SSe + (M+H) + ,851.1381; found 851.1376.

[0306] Example 46

[0307]

[0308] Following the preparation method described in Example 1, intermediate 4a was replaced with 14j, and compound D18 was obtained using the same preparation method as compound S1, as a white solid with a yield of 26.1%. HRMS (ESI) + ):cacld for C 38 H 38 NO 12 SSe + (M+H) + ,812.1274; found 812.1269.

[0309] Test Example 1

[0310] Compound binding ability test with LAT1

[0311] To verify the scientific validity of the compound design, the prodrugs S1-S28 and D1-D18 (50 μM) were first combined with known substrates of LAT1. 2 HL-Leu (0.76 μM) was used to competitively take up the compound in HEK 293T cells that stably overexpressed human LAT1, and the LAT1 affinity of the compound was tested.

[0312] Table 9. Affinity test of compounds with LAT1

[0313] Cpd. Inhibition % Cpd. Inhibition % Cpd. Inhibition % S1 63.7 S17 62.5 D5 65.9 S2 60.2 S18 71.45 D6 52.3 S3 34.5 S19 80.2 D7 60.5 S4 1.4 S20 62.1 D8 67.6 S5 0.7 S21 67.2 D9 69.9 S6 2.2 S22 56.4 D10 58.4 S7 84.4 S23 70.1 D11 60.3 S8 1.1 S24 45.4 D12 70.8 S9 0.7 S25 50.7 D13 56.6 S10 73.3 S26 49.5 D14 53.1 S11 71.4 S27 1.5 D15 48.8 S12 2.4 S28 2.1 D16 50.3 S13 59.7 D1 52.3 D17 62.5 S14 74.0 D2 45.6 D18 52.8 S15 73.5 D3 41.0 Cpd. 32.2 S16 76.1 D4 62.1

[0314] Note: The data in the table are expressed as mean ± SD, n = 3.

[0315] The results are shown in Table 9. Except for some compounds (S4-S6, S8-S9, S12, S27, S28) which showed weak or no uptake inhibition, most compounds had good uptake inhibition activity, which was significantly higher than that of the positive control BCH (a selective competitive inhibitor of LAT1), demonstrating that they have good affinity for LAT1.

[0316] Test Example 2

[0317] LAT1-mediated transport capacity testing and release of some compounds

[0318] To verify whether the prodrug molecules could enter cells and whether they could effectively release the STING agonist, a time-dependent uptake assay was performed in HEK 293T-hLAT1 cells. Compounds S11, S15, S16, D11–D13, and D17 showed weak cell uptake, with all uptake levels less than 1000 pmol / mg protein within 90 min. Compounds S11, S13–S16, S22, S24, D1–D13, and D17 failed to effectively release the STING agonist intracellularly, with all release levels less than 200 pmol / mg protein.

[0319] Table 10 LAT1-mediated time-dependent uptake of STING prodrug [a]

[0320]

[0321]

[0322] Note: Compound data in the table are expressed as mean ± SD, n = 3.

[0323] Test Example 3

[0324] Evaluation of STING pathway activity of representative compounds

[0325] The direct STING agonist activity of compounds S1, S3, and S7 was detected using a luciferase reporter gene assay. The results showed that S1, S3, and S7 had no direct STING agonist activity, consistent with the design concept, confirming that they are STING agonist prodrugs. After being taken up into cells, they can be hydrolyzed by esterases and other enzymes to release the STING agonist.

[0326] Table 11. LAT1-mediated STING prodrug STING agonistic activity

[0327] Inhibition % ISG-THP1 [a] ]]> S1 NA [b] ]] S3 BCH S7 Cpd. NA NA I-15 18.13

[0328] Note: [a] Magnitude of activation of compound (20 μM) and blank control in ISG-THP1 cells; [b] NA, noactivity; data are expressed as mean, n = 3.

[0329] Test Example 4

[0330] This invention represents the PK properties of compounds.

[0331] The pharmacokinetic properties of representative compounds were analyzed, and the results showed that compound S3 had high in vivo exposure and a short half-life (t) after injection. 1 / 2The duration of action was 2.27 h. The pharmacokinetic properties of S3 differed somewhat from those of I-15, while effective release of I-15 could be detected in the blood.

[0332] Table 12 Pharmacokinetic parameters of compounds S3 and I-15 [a]

[0333]

[0334] [a] In vivo pharmacokinetic parameters of compounds S3 and I-15, data are expressed as mean ± SD of three experiments. Solvent system: 5% DMSO + 15% PEG + 80% PBS.

[0335] Test Example 5

[0336] This invention represents the in vivo evaluation of compounds in a glioma model.

[0337] For the representative compound S3, three dose gradients of 5 mg / kg, 15 mg / kg, and 25 mg / kg were used, with temozolomide (TMZ) and the representative compound I-15 (5 mpk) from a previous patent (CN 113429387 A) as positive controls. The drugs were administered orally, and daily weight changes were recorded. Brain tumor tissue was collected the day after the last dose to examine changes in tumor volume and weight. Experimental data showed that compound S3 exerts a dose-dependent inhibitory effect against glioma.

[0338] Table 13 represents the in vivo evaluation of compound S3 in a glioma model.

[0339]

[0340] Note: Data in the table are expressed as mean ± SD, n = 6; ns indicates no effect; statistical significance was calculated using a one-way ANOVA test (**P < 0.01, ***P < 0.001, ****P < 0.0001).

[0341] This invention utilizes the structures of representative compounds such as I-15 from the inventors' previous research patents on STING agonists (CN113429387A, CN120025311A, CN116332903A, CN119751440A) to conduct research on LAT1-guided STING agonist prodrugs. Since STING agonists lack specific delivery advantages, they cannot solve the problem of targeted tumor therapy. LAT1, as a medium-to-large amino acid transporter in vivo, has a superior enrichment effect in the brain, kidneys, and other regions, especially selectively expressed at the BBB and GBM. Therefore, by using LAT1 to mediate the transport of STING agonists across the BBB to reach the lesion site and activate the STING pathway, reversing local immunosuppression, it is hoped that this can overcome the current treatment challenges of malignant brain tumors. This invention verifies that the invented compounds have no direct STING agonist activity, confirming them as STING agonist prodrug molecules. The LAT1 affinity, transport capacity, and release capacity of the compounds were also tested, and it was concluded that some of the representative compounds in this invention have the potential to be developed into drugs for the treatment of brain tumors.

Claims

1. A compound, stereoisomer, or pharmaceutically acceptable salt of formula (I) or formula (II): In formula (I): R 1 Selected from hydrogen atom, halogen atom, cyano group, OR 9 、N(R 9 2. C1-C6 alkyl, C1-C6 haloalkyl, OR 9 Substituted C1-C6 alkyl or C3-C6 cycloalkyl; R 9 Selected from hydrogen atom, hydroxyl group, amino group, hydroxymethyl group, methoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C6 10 Aryl; R 2 Selected from hydrogen atoms, halogen atoms, hydroxyl groups, amino groups, hydroxymethyl groups, methoxy groups, thiomethyl groups, N(CH2CH3)2, N(CH3)2, benzyloxy groups, benzoyloxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl; M is selected from oxygen, carbon, nitrogen, or selenium atoms; X is selected from oxygen or nitrogen atoms; Y 1 Selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-6 membered heterocyclic, C5-C 10 Aryl or C5~C 10 Substitution of aryl groups; In formula (II): R 3 Selected from hydrogen atom, halogen atom, cyano group, OR 9 、N(R 9 2. C1-C6 alkyl, C1-C6 haloalkyl, OR 9 Substituted C1-C6 alkyl or C3-C6 cycloalkyl; R 9 Selected from hydrogen atom, hydroxyl group, amino group, hydroxymethyl group, methoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C6 10 Aryl; R 4 Selected from hydrogen atom, hydroxyl group, halogen atom, amino group, hydroxymethyl group, methoxy group, ethoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, pinacol ester group of borate, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C 10 Aryl; R 5 Selected from hydrogen atom, hydroxyl group, halogen atom, amino group, hydroxymethyl group, methoxy group, ethoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, pinacol ester group of borate, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C 10 Aryl; R 6 Selected from hydrogen atom, hydroxyl group, halogen atom, amino group, hydroxymethyl group, methoxy group, ethoxy group, thiomethyl group, N(CH2CH3)2, N(CH3)2, benzyloxy group, benzoyloxy group, C1-C6 alkyl group, C1-C6 haloalkyl group, C3-C6 cycloalkyl group, 3-6 membered heterocyclic group or C5-C6 alkyl group. 10 Aryl; A 1 The ring is a five-membered ring or a heteroatom five-membered ring, and the heteroatom is selected from sulfur atom, oxygen atom or nitrogen atom; M is selected from oxygen, carbon, nitrogen, or selenium atoms; X is selected from oxygen or nitrogen atoms; Y 2 Selected from hydrogen atoms or When one side Y 2 When X is a hydrogen atom, X is an oxygen atom, and Y on the other side... 2 It cannot be both hydrogen atoms; Z is selected from C1-C4 alkyl, C1-C4 haloalkyl, 3-6 membered heterocyclic, C5-C6 alkyl, C6-C6 alkyl, C7 ... 10 Aryl or C5~C 10 Replacement of aryl groups.

2. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, In formula (I): R 1 Selected from hydrogen atom, halogen atom, cyano group, OR 9 、N(R 9 2. C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; preferably hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, methoxy, or ethoxy; R 9 Selected from hydrogen atoms, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, and C5-C6 cycloalkyl groups. 10 Aryl; R 2 Selected from hydrogen atoms, halogen atoms, hydroxyl groups, methoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl group; preferably hydrogen atom, fluorine atom, hydroxyl group, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; M is selected from oxygen, nitrogen, or selenium atoms; selenium atoms are preferred. X is selected from oxygen or nitrogen atoms; oxygen atoms are preferred.

3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, In formula (II): R 3 Selected from hydrogen atoms, halogen atoms, OR 9 C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl; preferably hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, methoxy, or ethoxy; R 9 Selected from hydrogen atoms, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl; R 4 Selected from hydrogen atoms, hydroxyl groups, halogen atoms, methoxy groups, ethoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl group; preferably hydrogen atom, hydroxyl group, fluorine atom, methoxy group, ethoxy group, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; R 5 Selected from hydrogen atoms, hydroxyl groups, halogen atoms, methoxy groups, ethoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl group; preferably hydrogen atom, hydroxyl group, fluorine atom, methoxy group, ethoxy group, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; R 6 Selected from hydrogen atoms, hydroxyl groups, halogen atoms, methoxy groups, ethoxy groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C6 cycloalkyl groups, 3-6 membered heterocyclic groups, or C5-C6 alkyl groups. 10 Aryl group; preferably hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, methoxy, ethoxy; A 1 The ring is a five-membered ring or a heteroatom five-membered ring, and the heteroatom is selected from sulfur atoms or nitrogen atoms; preferably, selenophene ring or pyrrole ring; M is selected from oxygen, nitrogen, or selenium atoms; selenium atoms are preferred. X is selected from oxygen or nitrogen atoms; oxygen atoms are preferred.

4. The following compounds:

5. A pharmaceutical composition, characterized in that, It includes an effective amount of the active ingredient and pharmaceutically acceptable excipients; the active ingredient includes one or more of the compounds, stereoisomers or pharmaceutically acceptable salts described in any one of claims 1 to 4.

6. The pharmaceutical composition according to claim 5, characterized in that, The excipients include pharmaceutically acceptable carriers.

7. Use of the compound, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 4, or the pharmaceutical composition of claim 5, in the preparation of a drug that activates the cGAS-STING pathway.

8. Use of the compound, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 4, or the pharmaceutical composition of claim 5, in the preparation of a medicament for the treatment of diseases associated with STING pathway activity.

9. Use of the compound, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 4, or the pharmaceutical composition of claim 5, in the preparation of a tumor therapeutic agent.

10. The use according to claim 9, characterized in that, The tumors include adult diffuse glioma, childhood diffuse glioma, high-grade glioma, esophageal squamous cell carcinoma, bladder cancer, bile duct cancer, pancreatic cancer, colorectal cancer, brain cancer, and choriocarcinoma.

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