Preparation method for chiral dihydrothienopyrimidine sulfoxide and use thereof, and 2- and 4-substituted compound of chiral dihydrothienopyrimidine sulfoxide

Abstract

Provided are a preparation method for a chiral dihydrothienopyrimidine sulfoxide and a use thereof, and 2- and 4-substituted compound of the chiral dihydrothienopyrimidine sulfoxide. The preparation method for the chiral dihydrothienopyrimidine sulfoxide comprises: oxidizing 2,4-disubstituted-6,7-dihydrothienopyrimidine into (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide by means of an oxidizing agent under the action of a chiral biguanide catalyst and a molybdate catalyst. The reaction conditions are mild, the reaction process is green and environment-friendly, industrial production is facilitated, and the reaction product has excellent enantioselectivity.

Description

Preparation method of chiral dihydrothienopyrimidine sulfoxide and its application and 2- and 4-substituted compounds Technical Field

[0001] The present invention relates to the technical field of preparation of PDE4 inhibitors, in particular to a preparation method of chiral dihydrothienopyrimidine sulfoxide, its application and 2- and 4-substituted compounds thereof. Background Art

[0002] Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are two important intracellular second messengers. They participate in various metabolic activities through specific receptors. Their intracellular concentrations are primarily regulated by the synthesis of adenylate (guanylate) cyclase and the hydrolysis of phosphodiesterases (PDEs). PDEs specifically use 3,5-cyclic nucleotides as substrates, catalyzing the hydrolysis of intracellular cAMP and cGMP to the corresponding inactive 5-nucleotides, thereby affecting various metabolic functions. There are 11 major families of PDEs, and PDE4, as the largest, is widely distributed in the human body, significantly affecting central nervous system function, cardiovascular function, inflammatory responses, the immune system, and cell adhesion. PDE4, consisting of four AD isoforms and 25 splice variants, specifically hydrolyzes cAMP and is an important drug target. Therefore, the development of PDE4 inhibitors for regulating various physiological activities and treating related diseases has important scientific significance and application value.

[0003] In the central nervous system, PDE4 inhibitors block the hydrolysis of cAMP, thereby prolonging the transmission of cAMP-induced downstream signaling and indirectly promoting the expression of genes related to synaptic plasticity, memory, and cognition. Therefore, PDE4 inhibitors have the potential to improve memory and cognition. Furthermore, increasing evidence indicates that neurotransmission in the brain is also influenced by cAMP and cGMP. PDE4 inhibitors may protect dopaminergic neurons from the neurotoxic effects of the environmental toxin 1-methyl-4-phenyl-pyridinium by promoting cAMP elevation, potentially leading to the alleviation of neurodegenerative movement disorders such as Parkinson's disease, which are caused by the degeneration and death of midbrain dopaminergic neurons. Furthermore, by preventing cAMP hydrolysis and causing elevated cAMP levels, PDE4 inhibitors can indirectly downregulate proinflammatory cytokines. Furthermore, cAMP itself has a bronchodilating effect. Therefore, PDE4 inhibitors are widely used in the treatment of inflammatory diseases and asthma.

[0004] Given the wide range of pharmacological activities of PDE4 inhibitors, a large number of scientists have devoted themselves to the development of such drugs. Despite significant progress, the development of new PDE4 inhibitors is often hampered by dose-limiting side effects such as nausea, vomiting, and sedation, necessitating the urgent need for novel chemical entities to advance the development of such drugs. Patent WO2019057806 discloses the preparation of dihydrothieno[3,2-d]pyrimidines, which can act as PDE4 inhibitors and treat and ameliorate skin diseases. Patents WO2006111549 and WO2009050242 both disclose methods for the preparation of dihydrothieno[3,2-d]pyrimidines for the treatment of respiratory and inflammatory diseases. Patents BE663693A and US3318881A disclose methods for the preparation of dihydrothieno[3,2-d]pyrimidines, which exhibit cardiovascular therapeutic and sedative properties.

[0005] Given that dihydrothieno[3,2-d]pyrimidines are a new class of PDE4 inhibitors, their synthesis has attracted the attention of scientists. The monooxygenated forms of these compounds, known as sulfoxides, often exhibit greater activity, and asymmetric oxidation of dihydrothieno[3,2-d]pyrimidines is the simplest way to obtain them. Patent WO2009052138A1 discloses a method for the catalytic oxidation of 2-[4-(4-chlorophenyl)-piperazin-1-yl-4-chloro-6,7-dihydrothieno[3,2-d]pyrimidine] using a titanium isopropoxide-chiral hydrobenzoin ligand-tert-butyl hydrogen peroxide oxidation agent system. This oxidation method yields R-type oxo products, which readily undergo 4-substitution reactions with primary or secondary amines, yielding a series of (R)-2-[4-(4-chlorophenyl)-piperazin-1-yl]-4-substituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxides. The conversion of sulfoxide c to d occurs with little or no loss of enantioselectivity, enabling the synthesis of 4-amino-substituted derivatives d using this method. However, the fixed 4-(4-chlorophenyl)-piperazin-1-substituent at the 2-position of substrate b limits the versatility of subsequent transformations.

[0006] Patents CN111712502A and CN111108109A disclose the asymmetric oxidation of 2-chloro-4-substituted-6,7-dihydrothieno[3,2-d]pyrimidine compounds. Using a titanium isopropoxide-chiral Binaphthol ligand-tert-butyl hydrogen peroxide oxidation agent system and dichloromethane as solvent, the target product f is obtained in high yield and high enantioselectivity at room temperature. The chiral sulfoxide f can be further converted into a 2-amino-substituted derivative g. Compared to the method described in patent WO2009052138A1, this method has a wider substrate applicability and achieves high enantioselectivity at room temperature. It is currently the most commonly used and effective method for preparing (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxides.

[0007] However, its limitations are as follows:

[0008] (1) The first step is the preparation of the substrate. Substrate e is generally prepared by a 4-position substitution reaction of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine with an amine. However, during the preparation process, substitution reactions can occur at both the 2- and 4-positions, and the chemical selectivity is not high, resulting in a generally low yield of e (less than 85%).

[0009] (2) The second is the substrate scope. Although the methods provided by patents CN111712502A and CN111108109A have a wider scope of application than patent WO2009052138A1, the difference in the 4-position substituent in substrate e still leads to differences in the enantioselectivity of the products obtained by oxidation;

[0010] (3) Another issue is the difficulty of industrial production. The method is cumbersome and may result in poor repeatability when industrialized. The main reason is that this reaction uses chiral Binaphthol as a ligand. By adding Ti(O i The catalyst complex is prepared in situ using Pr4 and an appropriate amount of water for the catalytic reaction. Water, however, hydrolyzes the titanium alkoxide, potentially leading to the formation of oligomers on the water surface. Factors such as the water addition rate, droplet size, and stirring speed of the reaction system all influence the reaction outcome. Therefore, the reproducibility of the reaction is strictly dependent on the amount and rate of water addition. Furthermore, this reaction generally requires relatively low temperatures, placing high demands on industrial production conditions.

[0011] (4) Finally, there are economic and environmental factors. The oxidants used in this type of reaction are generally tert-butyl hydroperoxide or cumyl hydroperoxide, which are expensive. In addition, the by-products of the reaction, alkyl alcohols, are harmful to the human body and pollute the environment.

[0012] Research by Chris H. Senanayake et al. demonstrated that the sulfoxide form h of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine a, due to the introduction of a sulfoxide group, exhibits superior chemoselectivity compared to a during substitution reactions, affording the 4-substituted product in yields exceeding 90%, thereby increasing the overall yield of the two substitutions (Org. Process Res. Dev. 2016, 20, 982-988). However, the asymmetric oxidation of a by Chris H. Senanayake et al. yielded only 80% yield of 70% optical purity for the sulfoxide h, a moderate enantioselectivity that limits the practical application of this method. Therefore, achieving a green, simple, and efficient enantioselective synthesis of the sulfoxide h would not only increase the yield of the disubstituted product g but also significantly enrich the structural diversity of novel PDE4 inhibitors based on dihydrothieno[3,2-d]pyrimidines.

[0013] Summary of the Invention

[0014] Therefore, it is necessary to provide a preparation method of chiral dihydrothienopyrimidine sulfoxide and its application and its 2- and 4-substituted compounds to solve the problems of poor synthesis efficiency of existing dihydrothienopyrimidine sulfoxide and high requirements for industrial production conditions.

[0015] To achieve the above object, the present invention provides a method for preparing a chiral dihydrothienopyrimidine sulfoxide, comprising the following steps: oxidizing 2,4-disubstituted-6,7-dihydrothienopyrimidine to (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide by an oxidant in the presence of a chiral biguanide and a molybdate catalyst, according to the following chemical reaction formula:

[0016] Further, R1 is selected from Cl or R2 is selected from Cl.

[0017] Furthermore, the chiral biguanide catalyst is BG-TMS.

[0018] The structure of BG-TMS is as follows:

[0019] Preparation reference Journal of the American Chemical Society, 2018, 140, 1952-1955.

[0020] The application of the preparation method of chiral dihydrothienopyrimidine sulfoxide is to prepare (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide, and obtain a compound with chiral dihydrothienopyrimidine sulfoxide as the parent core and substitution at the 2 and 4 positions through a substitution reaction. The reaction formula is as follows:

[0021] 2. Chiral dihydrothienopyrimidine sulfoxide compounds substituted at the 2 and 4 positions, the compound structures are shown in formula (1) to formula (14):

[0022] The differences between the present invention and other existing routes of 2- and 4-substituted chiral dihydrothienopyrimidine sulfoxide compounds are as follows:

[0023] The above technical solution has the following beneficial effects:

[0024] (1) High efficiency: At room temperature and a catalyst dosage of 0.1 mol%, an enantioselectivity of up to 98% can be achieved. When the temperature drops to 0°C, the catalyst dosage is reduced to 0.05 mol%, and although the reaction rate slows down, the high yield and enantioselectivity (90% yield, 92% ee) are still maintained.

[0025] (2) Simple and easy to operate: It avoids the tedious operation of converting the catalyst precursor into the catalyst when using a noble metal catalytic system, and does not require strict water volume and water speed control. The presence of trace water in the system will not affect the reaction effect;

[0026] (3) Clean and environmentally friendly: The catalytic oxidation system uses green reagent hydrogen peroxide as the oxidant, avoiding the health hazards and environmental pollution risks caused by the use of tert-butyl hydroperoxide or cumyl hydroperoxide;

[0027] (4) Mild conditions and high yield: This method provides a simple route for preparing (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxides with high chemoselectivity and high enantioselectivity. The reaction yield is high, and the 4-substitution reaction is completed in two hours at room temperature, showing good chemoselectivity.

[0028] (5) The chiral synthesis of the innovative anti-pulmonary fibrosis drug BI 1015550 (Engl. J. Med., 2022, 386, 2178-2187.) was achieved with high yield and high enantioselectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG1 is a synthetic route of (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide according to a specific embodiment.

[0030] FIG2 is a hydrogen NMR spectrum of compound D described in a specific embodiment.

[0031] FIG3 is the NMR carbon spectrum of compound D described in the specific embodiment.

[0032] FIG4 is a chiral column chromatography analysis of compound D according to a specific embodiment.

[0033] FIG5 is a hydrogen NMR spectrum of compound G described in a specific embodiment.

[0034] FIG6 is the NMR carbon spectrum of compound G described in the specific embodiment.

[0035] FIG7 is a chiral column chromatography analysis of compound G according to a specific embodiment.

[0036] FIG8 is a hydrogen NMR spectrum of compound 14 described in a specific embodiment.

[0037] FIG9 is the NMR carbon spectrum of compound 14 described in the specific embodiment.

[0038] FIG10 is a chiral column chromatography analysis of compound 14 according to a specific embodiment. DETAILED DESCRIPTION

[0039] In order to explain the technical content, structural features, achieved objectives and effects of the technical solution in detail, the following is a detailed description in conjunction with specific embodiments and accompanying drawings.

[0040] Example 1

[0041] Compound C: Preparation of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine

[0042] Compound A: methyl 3-[(2-methoxy-2-oxoethyl)thio]propionate:

[0043] 3.6 g of methyl 3-mercaptopropionate (30 mmol, 1.0 eq) was added to a 100 mL round-bottom flask equipped with a stirrer. 20 mL of THF was added as the reaction solvent. The reaction system was stirred in an ice-water bath at 0°C. 1.32 g of sodium hydride (60 wt%, dispersed in mineral oil) (33 mmol, 1.1 eq) was slowly added. Stirring was continued for 5 minutes. Then, 5.0 g of methyl 2-bromoacetate (233 mmol, 1.1 eq) was slowly added dropwise to the reaction solution. Stirring was continued at 0°C for 0.5 hours, and the reaction system was allowed to react at room temperature for 4 hours. TLC monitoring indicated that the reaction was complete. The reaction was quenched by adding saturated brine to the reaction solution, and the organic layer was separated. The brine layer was washed with ethyl acetate, combined, dried, concentrated, and purified by column chromatography to obtain 5.5 g of a colorless oil (yield: 95%).

[0044] 1H NMR (600MHz, CDCl3) δ2.63 (d, J = 7.2 Hz, 2H), 2.89 (d, J = 7.2 Hz, 2H), 3.24 (s, 2H), 3.68 (s, 3H), 3.72 (s, 3H).

[0045] The preparation of compound B refers to patent WO2009052138.

[0046] Compound C was prepared as described in Org. Process Res. Dev. 2016, 20, 982-988.

[0047] The preparation of compound F refers to patent WO2006111549.

[0048] Example 2

[0049] Compound D: Preparation of (R)-2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide

[0050] Embodiment 1: 10.3 mg of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (0.05 mmol, 1.0 eq) was added to a reactor equipped with a stirrer at room temperature (20-30° C.), and then 5 μL of a toluene solution of TMS-BG (1×10 -5 M,5×10 -5 mmol, 0.001eq), 5 μL Na2MoO4 aqueous solution (4 mg / mL, 1×10 -4 mmol, 0.002eq), 2.5 μL H2SO4 solution (2M, 5×10 -3 mmol, 0.1eq), 0.5mL (nBu)2O solvent. After stirring at room temperature for 2-3 minutes, 4.5μL of 35wt% H2O2 solution (0.0525mmol, 1.05eq) was added to the reaction solution and monitored by TLC. After the reaction was completed, sodium sulfite solution was added to quench the reaction. The organic layer was then separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were dried and concentrated, and then purified by column chromatography to obtain 10mg of a white solid (yield: 91%). The chiral purity was analyzed by chiral column chromatography. Conditions: CHIRALCEL AD-H, n-hexane / isopropanol = 80 / 20, flow rate = 1mL / min, detection wavelength = 254nm, retention time = 8.5min (main peak), 10.7min (minor peak). The analysis results showed an enantioselectivity of 98%. Optical rotation [α] D 30 =+350 (c=2.0, CH2Cl2).

[0051] 1H NMR (600MHz, CDCl3) δ4.04(dt,J=18.5,8.0Hz,1H),3.53(ddd,J=18.5,8.1,2.7Hz,1H),3.47-3.39(m,1H),3.35(ddd,J=14.2,7.9,2.7Hz,1H);

[0052] 13 C NMR (151MHz, CDCl3) δ178.11, 163.89, 161.69, 135.49, 49.82, 34.13.

[0053] Embodiment 2: 10.3 mg of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (0.05 mmol, 1.0 eq) was added to a reactor equipped with a stirrer at room temperature (20-30° C.), and then 25 μL of a toluene solution of TMS-BG (1×10 -5 M,2.5×10 -4 mmol,0.005eq),0.5mg Ag2MoO4(1.25×10 -3 The reaction mixture was stirred at room temperature for 2-3 minutes, and then 4.5 μL of H2O2 solution (35 wt%, 0.0525 mmol, 1.05 eq) was added. The reaction mixture was monitored by TLC. After completion, sodium sulfite solution was added to quench the reaction. The organic layer was then separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were dried, concentrated, and purified by column chromatography to obtain 10 mg of a white solid (yield: 90%, enantioselectivity: 92%).

[0054] Embodiment 3: Gram-scale preparation: 1.03 g of 2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (5 mmol, 1.0 eq) was added to a reactor equipped with a stirrer at room temperature (20-30° C.), and then 0.5 mL of a toluene solution of TMS-BG (1×10 -5 M,5×10 -3 mmol, 0.001eq), 0.5mL 4mg / mL Na2MoO4 aqueous solution (1×10 -2mmol, 0.2eq), 0.25mL H2SO4 solution (2M, 0.5mmol, 0.1eq), and 50mL (nBu)2O solvent. After stirring at room temperature for 2-3 minutes, 450μL H2O2 (35wt%, 5.25mmol, 1.05eq) was added to the reaction solution and monitored by TLC. After completion of the reaction, sodium sulfite solution was added to quench the reaction. The organic layer was then separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were dried, concentrated, and purified by column chromatography to obtain 1g of a white solid (yield: 90%, enantioselectivity: 92%).

[0055] Implementation 4: The difference from Implementation 1 is that in an ice-salt bath (below 0° C.), the BG-TMS catalyst dosage is 0.05 mol%, the sodium molybdate dosage is 0.1 mol%, and the reaction time is 6 h. After the reaction, 10 mg of a white solid is obtained after purification and drying (yield: 90%, enantioselectivity: 92%).

[0056] Embodiment 5: Different from Embodiment 1, 30 wt% H2O2 was used for oxidation, and the reaction time was 0.5 h. After the reaction, 10 mg of white solid was obtained after purification and drying (yield: 90%, enantioselectivity: 95%).

[0057] Embodiment 6: Different from Embodiment 1, BG-TMS and ammonium heptamolybdate are used as catalysts, 35 wt% H2O2 is used for oxidation, potassium bisulfate is added, and the reaction time is 0.5 h. After the reaction, 10 mg of white solid is obtained after purification and drying (yield: 90%, enantioselectivity: 90%).

[0058] Embodiment 7: Different from Embodiment 1, 6M H2SO4 is used as an additive, 30wt% H2O2 is used for oxidation, and the reaction time is 0.5h. After the reaction, 10mg of white solid is obtained after purification and drying (yield: 90%, enantioselectivity: 93%).

[0059] Embodiment 8: Unlike Embodiment 1, 1M H2SO4 was used as an additive, 30 wt% H2O2 was used for oxidation, and the reaction time was 0.5 h. After the reaction, 10 mg of a white solid was obtained after purification and drying (yield: 90%, enantioselectivity: 90%).

[0060] Embodiment 9: Different from Embodiment 1, sodium bisulfate is used as an additive, 35 wt% H2O2 is used for oxidation, the solvent is isopropyl ether, the reaction time is 0.5 h, and after the reaction, 10 mg of a white solid is obtained after purification and drying (yield: 90%, enantioselectivity: 95%).

[0061] Embodiment 10: The difference from Embodiment 1 is that 0.25 mL of n-butyl ether is used as the solvent, the reaction time is 0.5 h, and after the reaction, 10 mg of a white solid is obtained after purification and drying (yield: 90%, enantioselectivity: 94%).

[0062] Implementation 11: Different from Implementation 1, ammonium bisulfate is used as an additive, silver molybdate is used as a co-catalyst, and ether is used as the solvent. The reaction time is 4 hours. After the reaction, 10 mg of a white solid is obtained after purification and drying (yield: 90%, enantioselectivity: 90%).

[0063] Embodiment 12: Different from embodiment 1, BG-TMS and lithium molybdate are used as catalysts, 30 wt% H2O2 is used for oxidation, the solvent is toluene, the reaction time is 2 h, and after the reaction, 10 mg of white solid is obtained after purification and drying (yield: 90%, enantioselectivity: 92%).

[0064] Embodiment 13: Different from Embodiment 2, the reaction is carried out in an ice-salt bath (below 0° C.) for 3 h. After the reaction, the product is purified and dried to obtain 10 mg of a white solid (yield: 92%, enantioselectivity: 95%).

[0065] Example 3

[0066] Compound G: Preparation of (R)-4-chloro-2-[4-(4-chlorophenyl)-piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide:

[0067] At room temperature, 9.2 mg of 4-chloro-2-[4-(4-chlorophenyl)-piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine (0.025 mmol, 1.0 eq) was added to a reactor equipped with a stirrer, and then 12.5 μL of a toluene solution of TMS-BG (1×10 -5 M,1.25×10 -4 mmol, 0.005eq), 12.5 μL Na2MoO4 aqueous solution (4 mg / mL, 2.5×10 -4 mmol, 0.01eq), 12.5 μL H2SO4 solution (1 M, 1.25×10 -2mmol, 0.5eq), and 0.5mL (nBu)2O solvent. After stirring at 0°C for 2-3 minutes, 2.2μL of 35wt% H2O2 solution (0.026mmol, 1.05eq) was added to the reaction solution and monitored by TLC. After completion of the reaction, sodium sulfite solution was added to quench the reaction. The organic layer was then separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were dried and concentrated, and purified by column chromatography to obtain 8.7mg of a white solid (yield: 90%). Chiral purity was analyzed by chiral column chromatography. Conditions: CHIRALCEL AD-H, n-hexane / isopropanol = 80 / 20, flow rate = 1mL / min, detection wavelength = 254nm, retention time = 17.6min (main peak), 24.5min (minor peak). The analysis results showed an enantioselectivity of 87%.

[0068] 1 H NMR (600MHz, CDCl3) δ7.28-7.22(m,2H), 6.97-6.85(m,2H), 4.21-3.95(m,4H), 3.90-3.77(m,1H), 3.30-3.12(m,7H).

[0069] The H NMR spectrum of compound G is shown in Figures 5-6, and the chiral column chromatography analysis is shown in Figure 7.

[0070] The prepared (R)-2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide is subjected to a substitution synthesis reaction to prepare compounds having structures shown in formula (1) to formula (14):

[0071] The following are examples of synthetic substitution reactions:

[0072] Example 4

[0073] Synthetic compound: (R)-2-(4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)-4-(tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothiophene[3,2-d]-pyrimidine 5-monooxide, with the following structural formula:

[0074] 22.3 mg (0.1 mmol, 1.0 eq) (R)-2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide and 13.7 mg (0.1 mmol, 1.0 eq) 4-aminotetrahydropyranyl hydrochloride were added to a reactor containing 1 mL of 1,4-dioxane at room temperature. Then, 42 μL (0.3 mmol, 3.0 eq) of triethylamine was added to the reactor and reacted at room temperature. TLC monitoring was performed. After the reaction was completed, the solvent was removed in vacuo, and water was added to the remaining mixture. The mixture was extracted with DCM and the organic phases were combined. The organic phases were washed with saturated brine and the solvent was dried to obtain a crude product.

[0075] The crude product was added to a reactor containing 1.5 mL of tetrahydrofuran, and 29.7 mg (0.11 mmol, 1.1 eq) of 2-(piperazin-1-yl)benzo[d]-oxazole was added. After stirring for 1-2 minutes, 68 μL of diisopropylethylamine (0.4 mmol, 4.0 eq) was added to the reactor. The mixture was heated to reflux and stirred for approximately 10 hours. After the temperature dropped to room temperature, water was added to the reaction mixture and stirred for 10 minutes. The organic layer was separated and the aqueous phase was extracted twice with DCM. The organic layers were combined and washed with saturated brine. The residue was dried, concentrated, and purified by column chromatography to yield 34 mg of a white solid (yield: 80%).

[0076] 1 H NMR (600MHz, CDCl3) δ7.38 (dd, J=7.8, 1.2Hz, 1H), 7.30–7.26 (m, 1H), 7.19 (td, J=7.7, 1.1Hz, 1H), 7.05 (td, J= 7.7,1.2Hz,1H),5.55(d,J=6.9Hz,1H),4.21(tdt,J=11.2,7.7,4.2Hz,1H),4.01(dp,J=8.3,4.4,3.9Hz,6H),3 .75(t,J=5.3Hz,4H),3.61(dt,J=17.1,7.4Hz,1H),3.52(ttd,J=11.6,6.1,2.5Hz,2H),3.41(dt,J=12.5,7.6H z,1H),3.09–2.97(m,2H),2.00(dtd,J=12.7,5.5,4.5,2.3Hz,2H),1.61(ddtd,J=19.5,13.0,11.3,4.4Hz,2H).

[0077] Example 5

[0078] Prepare the compound: (R)-1-(5-oxido-4-(tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothiophene[3,2-d]-pyrimidin-2-yl)azetidin-3-yl-2-iodobenzoate, the chemical structure of which is as follows:

[0079] 22.3 mg (0.1 mmol, 1.0 eq) (R)-2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide and 13.7 mg (0.1 mmol, 1.0 eq) 4-aminotetrahydropyranyl hydrochloride were added to a reactor containing 1 mL of 1,4-dioxane at room temperature. Then, 42 μL (0.3 mmol, 3.0 eq) of triethylamine was added to the reactor and reacted at room temperature. TLC monitoring was performed. After the reaction was completed, the solvent was removed in vacuo, and water was added to the remaining mixture. The mixture was extracted with DCM and the organic phases were combined. The organic phases were washed with saturated brine and the solvent was dried to obtain a crude product. The obtained product was added to a reactor containing 1 mL of DMF, and 11 mg (0.1 mmol, 1.0 eq) of 3-hydroxyazetidine hydrochloride was added thereto. After stirring for 1 to 2 minutes, 34 μL of diisopropylethylamine (0.2 mmol, 2.0 eq) was added to the reactor. The mixture was stirred at room temperature and monitored by TLC. After the reaction was complete, the solvent was removed in vacuo and the crude product was dried for later use.

[0080] 27.3 mg (0.11 mmol, 1.1 eq) of o-iodobenzoic acid was added to a reactor containing 1 mL of DCM. 25 mg (0.13 mmol, 1.3 eq) of EDAC and 12.2 mg (0.1 mmol, 1.0 eq) of DMAP were then added sequentially. After stirring at room temperature for 1-2 minutes, the crude product was added to the mixture and heated to 55°C. The reaction was monitored by TLC. Upon completion, the reaction solution was cooled to room temperature. Saturated ammonium chloride was added to the reaction solution, the organic layer was separated, and the aqueous phase was extracted twice with DCM. The organic layers were combined and washed with saturated brine. The residue was dried, concentrated, and purified by column chromatography to obtain 27 mg of a white solid (yield: 50%).

[0081] 1H NMR(600MHz, CDCl3)δ8.01(dd,J=8.0,1.1Hz,1H),7.87(dd,J=7.8,1.8Hz,1H),7.45–7.38(m,1H),7.18(td,J =7.7,1.7Hz,1H),6.18(s,1H),5.50(tt,J=6.6,4.1Hz,1H),4.57(dd,J=10.8,6.6Hz,2H),4.36–4.15(m,3H),3 .96(dddd,J=19.0,11.9,8.3,2.6Hz,2H),3.63(dt,J=17.9,7.8Hz,1H),3.45(tdd,J=11.4,8.5,2.3Hz,2H),3 .36(dt,J=13.1,8.2Hz,1H),3.14–2.95(m,2H),1.90(dddd,J=28.9,12.8,4.6,2.2Hz,2H),1.71–1.45(m,2H);

[0082] 13 C NMR (151MHz, CDCl3) δ173.68,165.77,163.44,158.90,141.64,133.65,133.26,131. 32,128.06,109.06,94.40,66.86,65.28,57.03,49.63,47.18,32.73,32.60,32.54.

[0083] Example 6

[0084] (R)-2-(4-(Benzo[d]oxazol-2-yl)piperazin-1-yl)-4-(piperidin-1-yl)-6,7-dihydrothiophene[3,2-d]-pyrimidine 5-monooxide, chemical structure is as follows:

[0085] The preparation method is as shown in Example 4. Piperidine and 2-(piperazin-1-yl)benzo[d]-oxazole are used as raw materials to prepare the target product as a white powder (yield: 85%).

[0086] 1H NMR (600MHz, CDCl3) δ7.37(dd,J=7.9,1.1Hz,1H),7.27(d,J=8.1Hz,1H),7.17(td,J=7.7,1.1Hz,1H),7.03(td,J=7.7,1.2Hz,1H) ,4.04–3.92(m,6H),3.87(ddd,J=13.6,7.0,3.7Hz,2H),3.80–3.65(m,5H),3.18–3.02(m,3H),1.69(ddt,J=21.7,8.9,4.7Hz,6H);

[0087] 13 C NMR (151MHz, CDCl3) δ176.87,161.96,161.42,159.29,148.72,142.72,124.12,1 20.95,116.38,109.96,108.85,47.98,47.78,45.45,43.55,32.40,25.80,24.50.

[0088] Example 7

[0089] Prepare the compound: (R)-2-(4-(benzo[d]oxazol-2-yl)piperazin-1-yl)-4-morpholino-6,7-dihydrothiopheno[3,2-d]-pyrimidine 5-monooxide, the chemical structure of which is as follows:

[0090] Preparation method: Refer to Example 4, using morpholine and 2-(piperazin-1-yl)benzo[d]-oxazole as raw materials, and the target product is a white powder (yield: 82%).

[0091] 1 H NMR (600MHz, CDCl3) δ7.38(d,J=7.8Hz,1H),7.27(d,J=7.9Hz,1H),7.18(t,J=7.6Hz,1H),7.04( t,J=7.8Hz,1H),4.07–3.90(m,8H),3.82(h,J=6.0Hz,4H),3.78–3.68(m,5H),3.19–3.05(m,3H);

[0092] 13 C NMR (151MHz, CDCl3) δ177.49,161.84,161.65,160.22,148.66,142.47,124.2 5,121.12,116.40,109.91,108.94,66.61,48.00,46.55,45.47,43.48,32.44.

[0093] Example 8

[0094] Prepare compound: (R)-2-(4-(benzo[d]oxazol-2-yl)piperazin-1-yl)-5-oxido-6,7-dihydrothiophene[3,2-d]-pyrimidin-4-yl)glycine methyl ester, the chemical structure is as follows

[0095] Preparation method: Refer to Example 4, using glycine methyl ester hydrochloride and 2-(piperazin-1-yl)benzo[d]-oxazole as raw materials, and the target product is a white powder (yield: 85%).

[0096] 1 H NMR(600MHz CDCl3)δ7.38(dd,J=7.9,1.2Hz,1H),7.28(d,J=7.9Hz,1H),7.18(td,J=7.7,1.1Hz,1H),7.05(td,J=7.7,1.2Hz,1H),6.86(s,1H),4.26(dd,J=17.4 ,5.5Hz,1H),4.14–3.89(m,5H),3.75(d,J=4.1Hz,7H),3.70–3.60(m,1H) ,3.38(dt,J=14.1,8.3Hz,1H),3.09(dddd,J=13.3,10.4,5.8,2.6Hz,2H);

[0097] 13 C NMR (151MHz, CDCl3) δ174.52,170.51,162.43,161.87,159.33,148.68,142.5 9,124.20,121.05,116.39,108.91,52.25,49.60,45.42,43.50,42.79,32.66.

[0098] Example 9

[0099] Prepare the compound: (R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-4-(tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothiopheno[3,2-d]-pyrimidine 5-monooxide, the chemical structure of which is as follows:

[0100] The target product was prepared using 4-aminotetrahydropyran hydrochloride and 4-(4-chlorophenoxy)piperidine hydrochloride as raw materials (yield: 78%).

[0101] 1H NMR (600MHz, CDCl3) δ7.25–7.21(m,2H),6.88–6.84(m,2H),5.66(s,1H),4.51(tt,J= 7.0,3.4Hz,1H),4.23–4.03(m,3H),3.97(tt,J=11.6,3.6Hz,2H),3.84–3.68(m,2H),3 .60(dt,J=16.2,8.3Hz,1H),3.47(tdd,J=11.6,7.1,2.2Hz,2H),3.36(dt,J=13.5,8. 0Hz,1H),3.09–2.92(m,2H),2.00–1.90(m,3H),1.86-1.72(m,3H),1.65–1.49(m,2H).

[0102] Example 10

[0103] Prepare the compound: (R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-4-(piperidin-1-yl)-6,7-dihydrothiopheno[3,2-d]-pyrimidine 5-monooxide, the chemical structure of which is as follows:

[0104] Preparation method: Refer to Example 4, using piperidine and 4-(4-chlorophenoxy)piperidine hydrochloride as raw materials, and the target product is a white powder (yield: 80%).

[0105] 1 H NMR (600MHz, CDCl3) δ7.25–7.21(m,2H),6.89–6.83(m,2H),4.50(tt,J=7.1,3.5H z,1H),4.09(ddd,J=12.5,7.3,3.3Hz,2H),3.94(ddd,J=13.6,7.1,3.1Hz,2H),3. 85(ddd,J=13.5,6.7,3.6Hz,2H),3.81–3.66(m,3H),3.18–3.03(m,3H),1.96(ddq ,J=14.2,7.0,3.5Hz,2H),1.79(dtd,J=13.8,7.2,3.6Hz,2H),1.74–1.61(m,6H);

[0106] 13 C NMR (151MHz, CDCl3) δ177.00,161.55,159.39,155.86,129.51,125.90,117.53,109.20,72.85,47.97,47.75,41.11,32.41,30.44,25.85,24.61.

[0107] Example 11

[0108] Prepare the compound: (R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-4-morpholino-6,7-dihydrothiopheno[3,2-d]-pyrimidine 5-monooxide, the chemical structure of which is as follows:

[0109] Preparation method: Refer to Example 4, using morpholine and 4-(4-chlorophenoxy)piperidine hydrochloride as raw materials, and the target product is a white powder (yield: 85%).

[0110] 1 H NMR (600MHz, CDCl3) δ7.25–7.20(m,2H),6.89–6.82(m,2H),4.51(tt,J=6.9,3.4Hz,1H),4.07(ddd,J=12.2,7.5,3.7Hz ,2H),4.01–3.88(m,4H),3.88–3.63(m,7H),3.21–2.95(m,3H),1.99–1.90(m,2H),1.79(dtd,J=13.9,7.2,3.7Hz,2H);

[0111] 13 C NMR (151MHz, CDCl3) δ177.41,161.46,160.24,155.79,129.50,125.93,117.51,109.20,72.68,66.63,48.00,46.53,41.02,32.37,30.39.

[0112] Example 12

[0113] Prepare the compound: (R)-2-(4-(4-chlorophenoxy)piperidin-1-yl)-5-oxido-6,7-dihydrothiopheno[3,2-d]-pyrimidin-4-yl)glycine methyl ester, the chemical structure of which is as follows:

[0114] Preparation method: Refer to Example 4, using glycine methyl ester hydrochloride and 4-(4-chlorophenoxy)piperidine hydrochloride as raw materials, and the target product is a white powder (yield: 82%).

[0115] 1H NMR (600 MHz CDCl3)δ7.26–7.17(m,2H),6.89–6.83(m,2H),4.50(tt,J=6.9,3.4Hz,1H),4.2 2(dd,J=17.4,5.5Hz,1H),4.16–3.95(m,3H),3.87–3.74(m,2H),3.72(s,3H),3 .65(dt,J=16.5,7.8Hz,1H),3.36(dt,J=13.5,8.2Hz,1H),3.08(ddd,J=13.9,8 .0,2.8Hz,2H),1.93(qd,J=6.8,3.1Hz,2H),1.79(qd,J=11.9,9.0,4.0Hz,2H);

[0116] 13 C NMR (151MHz, CDCl3) δ174.91,170.43,162.27,159.16,155.75,129.50,125.94,117.45,108.47,72.47,52.21,49.65,42.81,41.16,32.52,30.35.

[0117] Example 13

[0118] Prepare the compound: (R)-2-(4-(4-chlorophenyl)piperazin-1-yl)-4-(tetrahydro-2H-pyran-4-yl)amino)-6,7-dihydrothiophene[3,2-d]-pyrimidine 5-monooxide, the chemical structure of which is as follows:

[0119] Preparation method: Refer to Example 4, using 4-aminotetrahydropyran hydrochloride and 1-(4-chlorophenyl)piperazine hydrochloride as raw materials, and the target product is a white solid (yield: 80%).

[0120] 1H NMR (600MHz, CDCl3) δ7.24–7.17(m,2H),6.92–6.81(m,2H),5.93(s,1H),4.19(tdq,J= 11.3,7.8,4.1Hz,1H),4.09–3.91(m,6H),3.63(dt,J=16.6,7.7Hz,1H),3.48(tdd,J=1 1.8,9.8,2.3Hz,2H),3.37(dt,J=13.4,8.0Hz,1H),3.18(t,J=5.2Hz,4H),3.05(ddd,J =14.0,8.3,3.2Hz,2H),1.94(dddd,J=25.1,13.0,4.5,2.3Hz,2H),1.69–1.49(m,2H);

[0121] 13 C NMR (151MHz, CDCl3) δ173.44,162.29,158.70,149.70,129.09,125.19,117. 72,108.49,66.88,66.86,49.68,49.37,47.32,44.05,32.62,32.57,32.46.

[0122] Example 14

[0123] Prepare the compound: (R)-2-(4-(4-chlorophenyl)piperazin-1-yl)-4-(piperidin-1-yl)-6,7-dihydrothiophene[3,2-d]-pyrimidine 5-monooxide, the chemical structure of which is as follows:

[0124] Preparation method: Refer to Example 4, using piperidine and 1-(4-chlorophenyl)piperazine hydrochloride as raw materials, and the target product is a white powder (yield: 83%).

[0125] 1 H NMR (600MHz, CDCl3) δ7.19(d,J=8.4Hz,2H),6.84(d,J=8.7Hz,2H),4.02–3.89(m,6H),3.85(dq,J=10.9,3.7Hz,2H),3.69(d t,J=16.7,8.2Hz,1H),3.15(t,J=5.1Hz,4H),3.09(dd,J=8.5,4.7Hz,2H),3.03(dt,J=16.7,4.7Hz,1H),1.76–1.57(m,6H);

[0126] 13C NMR (151MHz, CDCl3) δ177.47,161.99,159.59,150.06,129.20,125.12,117.84,109.59,49.52,48.08,47.84,43.97,32.64,25.99,24.75.

[0127] Example 15

[0128] (R)-2-(4-(4-chlorophenyl)piperazin-1-yl)-4-morpholino-6,7-dihydrothiophene[3,2-d]-pyrimidine 5-monooxide, the chemical structure is as follows:

[0129] Preparation method: Refer to Example 4, using morpholine and 1-(4-chlorophenyl)piperazine hydrochloride as raw materials, and the target product is a white powder (yield: 80%).

[0130] 1 H NMR (600MHz, CDCl3) δ7.24–7.20(m,2H),6.90–6.84(m,2H),4.03–3.92(m,8H),3.86–3.76(m,4H),3.71(dt,J=16.7,7.8Hz,1H),3.22–3.02(m,7H);

[0131] 13 C NMR (151MHz, CDCl3) δ177.28,161.47,160.18,149.75,129.12,125.27,117.81,109.64,66.63,49.45,48.02,46.55,43.92,32.39.

[0132] Example 16

[0133] Prepare the compound: (R)-2-(4-(4-chlorophenyl)piperazin-1-yl)-5-oxido-6,7-dihydrothiophene[3,2-d]-pyrimidin-4-yl)glycine methyl ester, the chemical structure of which is as follows:

[0134] Preparation method: Refer to Example 4, using glycine methyl ester hydrochloride and 1-(4-chlorophenyl)piperazine hydrochloride as raw materials, and the target product is a white powder (yield: 85%).

[0135] 1H NMR (600MHz, CDCl3) δ7.22(d,J=8.8Hz,2H),6.86(d,J=8.6Hz,2H),4.25(dd,J=17.4,5.5Hz,1H),4.07–3.88(m,5H),3.73(s ,3H),3.65(dt,J=16.6,7.8Hz,1H),3.37(dt,J=13.5,8.0Hz,1H),3.16(t,J=5.2Hz,4H),3.09(ddd,J=14.1,8.3,2.9Hz,2H);

[0136] 13 C NMR (151MHz, CDCl3) δ174.44,170.49,162.38,159.30,149.73,129.13,125.28,117.80,108.70,52.31,49.74,49.40,43.95,42.81,32.65.

[0137] Example 17

[0138] Prepare the compound: (R)-1-(5-oxido-4-(piperidin-1-yl)-6,7-dihydrothiophene[3,2-d]-pyrimidin-2-yl)azetidin-3-yl-2-iodobenzoate, the chemical structure of which is as follows:

[0139] Preparation method: Refer to Example 5, using glycine methyl ester hydrochloride and 1-(4-chlorophenyl)piperazine hydrochloride as raw materials, and the target product is a white powder (yield: 85%).

[0140] 1 H NMR (600MHz, CDCl3) δ7.22(d,J=8.8Hz,2H),6.86(d,J=8.6Hz,2H),4.25(dd,J=17.4,5.5Hz,1H),4.07–3.88(m,5H),3.73(s ,3H),3.65(dt,J=16.6,7.8Hz,1H),3.37(dt,J=13.5,8.0Hz,1H),3.16(t,J=5.2Hz,4H),3.09(ddd,J=14.1,8.3,2.9Hz,2H);

[0141] 13C NMR (151MHz, CDCl3) δ174.44,170.49,162.38,159.30,149.73,129.13,125.28,117.80,108.70,52.31,49.74,49.40,43.95,42.81,32.65.

[0142] Example 18

[0143] Prepare the compound: (R)-1-(5-oxido-4-(piperidin-1-yl)-6,7-dihydrothiophene[3,2-d]-pyrimidin-2-yl)azetidin-3-yl-2-iodobenzoate, the chemical structure of which is as follows:

[0144] Preparation method: Refer to Example 5, using piperidine, 3-hydroxyazetidine hydrochloride and o-iodobenzoic acid as raw materials, and the target product is a white powder (yield: 60%).

[0145] 1 H NMR (600MHz, CDCl3) δ8.01(d,J=7.8Hz,1H),7.87(dd,J=7.8,1.7Hz,1H),7.42(t,J =7.6Hz,1H),7.18(td,J=7.7,1.7Hz,1H),5.50(ddd,J=10.8,6.8,4.1Hz,1H),4.57( dd,J=10.7,6.6Hz,2H),4.27(s,2H),3.96(ddd,J=13.2,7.0,3.1Hz,2H),3.87(ddd ,J=13.7,7.1,3.8Hz,2H),3.78–3.67(m,1H),3.21–3.04(m,3H),1.83–1.56(m,6H);

[0146] 13 C NMR (151MHz, CDCl3) δ176.89,165.82,162.46,159.15,141.62,133.79,133.22,1 31.33,128.07,110.25,94.40,65.38,56.97,47.89,47.70,32.36,25.88,24.57.

[0147] Example 19

[0148] Prepare the compound: (R)-1-(4-morpholine-5-oxido-6,7-dihydrothiophene[3,2-d]-pyrimidin-2-yl)azetidin-3-yl-2-iodobenzoate, the chemical structure of which is as follows:

[0149] Preparation method: Refer to Example 5, using morpholine, 3-hydroxyazetidine hydrochloride and o-iodobenzoic acid as raw materials, and the target product is a white powder (yield: 85%).

[0150] 1 H NMR(600MHz CDCl3)δ8.01(d,J=7.9Hz,1H),7.86(d,J=7.8Hz,1H),7.43(t,J=7.6Hz,1H),7.23–7.15(m,1H),5.51(tt,J=6.9 ,4.1Hz,1H),4.58(d,J=10.3Hz,2H),4.29(s,2H),3.97(t,J=4.9Hz,4H),3.88–3.67(m,5H),3.08–3.26(m,3H);

[0151] 13 C NMR (151MHz, CDCl3) δ176.87,165.81,161.91,159.91,141.65,133.73,133.2 8,131.33,128.10,110.44,94.40,66.64,65.27,57.04,47.98,46.53,32.28.

[0152] Example 20

[0153] Prepare the compound: (R)-1-(-4-(2-methoxy-2-oxoethyl)amino)-5-oxido-6,7-dihydrothiophene[3,2-d]-pyrimidin-2-yl)azetidin-3-yl-2-iodobenzoate, the chemical structure of which is as follows:

[0154] Preparation method: Refer to Example 5, using glycine methyl ester hydrochloride, 3-hydroxyazetidine hydrochloride and o-iodobenzoic acid as raw materials, and the target product is a white powder (yield: 54%).

[0155] 1H NMR (600MHz, CDCl3) δ8.02 (dd, J=8.0, 1.2Hz, 1H), 7.87 (dd, J=7.8, 1.7Hz, 1H), 7.43 (td, J=7.6 ,1.2Hz,1H),7.19(td,J=7.7,1.7Hz,1H),6.75(s,1H),5.52(tt,J=6.7,4.1Hz,1H),4.75–4.47 (m,2H),4.32(ddd,J=17.7,5.7,2.9Hz,3H),4.08(ddd,J=17.3,10.4,5.1Hz,1H),3.76(d,J=2. 7Hz, 3H), 3.68 (ddd, J=18.2, 8.7, 6.8Hz, 1H), 3.41 (dt, J=13.5, 7.9Hz, 1H), 3.23–3.06 (m, 2H).

[0156] 13 C NMR (151MHz, CDCl3) δ172.65,170.21,167.74,165.79,159.38,141.67,133.70,133. 31,131.36,128.12,109.79,94.42,65.17,57.12,52.48,52.47,49.91,42.47,32.44.

[0157] Example 21

[0158] Prepare the compound: (R)-2-(4-(5-chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutylamino)-6,7-dihydrothiophene[3,2-d]-pyrimidine 5-monooxide, the chemical structure of which is as follows:

[0159] Preparation method: Refer to Example 4, using (1-aminocyclobutyl)methanol and 5-chloro-2-(piperidin-4-yl)pyrimidine as raw materials, and the target product is a white powder (yield: 70%).

[0160] 1H NMR(600MHz,CDCl3)δ8.61(s,2H),6.38(s,1H),4.80(s,2H),4.43(s,1H),3.88–3.75(m,2H),3.59(dt,J=16.4,8.0Hz,1H),3.33(dt,J=13.7,8.2Hz,1H),3.16(tt,J=11.6,3.8Hz,1H),3.09–3.01(m,3H),2.39–2.30(m,2H),2.20(dtd,J=20.8,8.7,4.2Hz,2H),2.05(d,J=13.3Hz,3H),1.92–1.80(m,3H); 13 C NMR(151MHz,CDCl3)δ174.58,170.55,162.24,158.87,155.58,129.17,107.51,67.88,59.14,49.44,44.47,32.73,30.66,30.23,30.19,14.95;IR:2936,2846,2356,2337,1562,1521,1485,1428,1373,1143,1014cm -1 ;M.p.:215.3℃;HRMS(ESI)calcd for C 20 H 26 ClN6O2S m / z[M+H] + :449.1521;found:449.1518;[α] D 23 =+137(c=0.17,CH2Cl2);HPLC analysis:CHIRALCEL AD-H(Hex / IPA=70 / 30,1mL / min,220nm),15.0min,27.1min(major),97%ee。

[0161] It should be noted that, in this document, relational terms such as first and second, etc., are used solely to distinguish one entity or operation from another, and do not necessarily require or imply any actual relationship or order between these entities or operations. Furthermore, the terms "include," "comprise," or any other variations thereof are intended to encompass non-exclusive inclusion, such that a process, method, article, or terminal device comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or terminal device. Without further limitation, elements defined by the phrase "include..." or "comprising..." do not exclude the presence of additional elements in the process, method, article, or terminal device comprising the elements. Furthermore, in this document, "greater than," "less than," "exceeding," etc., are understood to exclude the number itself; "above," "below," "within," etc., are understood to include the number itself.

[0162] Although the above embodiments have been described, those skilled in the art may make additional changes and modifications to these embodiments once they know the basic creative concepts. Therefore, the above descriptions are merely embodiments of the present invention and do not limit the scope of patent protection of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention's description and drawings, or directly or indirectly applied in other related technical fields, are also included in the scope of patent protection of the present invention.

Claims

1. A method for preparing a chiral dihydrothienopyrimidine sulfoxide, characterized in that: The preparation steps are as follows: 2,4-disubstituted-6,7-dihydrothienopyrimidine is oxidized by an oxidant under the action of a chiral biguanide and a molybdate catalyst to form (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide, and the chemical reaction formula is as follows:

2. The method for preparing a chiral dihydrothienopyrimidine sulfoxide according to claim 1, characterized in that: R1 is selected from Cl or R2 is selected from Cl.

3. The method for preparing a chiral dihydrothienopyrimidine sulfoxide according to claim 1, characterized in that: A chiral biguanide catalyst and a molybdate catalyst are used to jointly catalyze an oxidation reaction, wherein the chiral biguanide catalyst is BG-TMS, the molybdate catalyst is one or more of molybdic acid, lithium molybdate, sodium molybdate, sodium molybdate dihydrate, potassium molybdate, rubidium molybdate, silver molybdate, ammonium heptamolybdate, diammonium molybdate, and ammonium dimolybdate, and the oxidant is an aqueous solution of hydrogen peroxide with a mass fraction of 30% or 35%.

4. The method for preparing a chiral dihydrothienopyrimidine sulfoxide according to claim 3, characterized in that: When the biguanide catalyst is BG-TMS, the dosage of BG-TMS catalyst is 0.05-0.1 mol%. When the reaction temperature is at room temperature, the dosage of BG-TMS catalyst is 0.1 mol%. When the reaction temperature is below 0° C., the dosage of BG-TMS catalyst is 0.05 mol%.

5. The method for preparing a chiral dihydrothienopyrimidine sulfoxide according to claim 1, characterized in that: Additives are added to the reaction system, wherein the additives are one or more of 1M-6M sulfuric acid, sodium bisulfate, potassium bisulfate, ammonium bisulfate, tetrabutylammonium bisulfate, and trioctylmethylammonium bisulfate.

6. The method for preparing a chiral dihydrothienopyrimidine sulfoxide according to claim 1, characterized in that: The reaction solvent is one or more of diethyl ether, isopropyl ether, n-butyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, n-hexane, cyclohexane, toluene, xylene, isopropyl benzene and tert-butyl benzene.

7. The use of the method for preparing chiral dihydrothienopyrimidine sulfoxide according to any one of claims 1 to 6, characterized in that: The prepared (R)-2,4-disubstituted-6,7-dihydrothieno[3,2-d]pyrimidine sulfoxide is subjected to a substitution reaction to obtain a compound having chiral dihydrothienopyrimidine sulfoxide as a parent core and substituted at the 2,4 positions. The reaction formula is as follows: Wherein, R1 is selected from Cl or R2 is selected from Cl, R3 is selected from H, R4 is selected from the following structures: Or NR3R4 represents a group selected from the following: NR5R6 is selected from the following groups:

8. The use of the method for preparing chiral dihydrothienopyrimidine sulfoxide according to claim 7, characterized in that: The conditions for the substitution reaction are: In the NR3R4 substitution reaction, the corresponding substituted organic amine is used, 1,4-dioxane is used as solvent, triethylamine is added, and the reaction is carried out at room temperature; In the NR5R6 substitution reaction, the corresponding substituted organic amine is used, tetrahydrofuran is used as solvent, diisopropylethylamine is added, and the reaction is heated under reflux.

9. A chiral dihydrothienopyrimidine sulfoxide compound substituted at the 2,4 position, characterized in that: The compound structures are shown in formula (1) to formula (14):

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