Synthesis method and application of a benzothiaselenazole-1-ketone compound and derivatives thereof

Abstract

The application discloses a synthesis method and application of a benzothiaselenazol-1-ketone compound and derivatives thereof, and relates to the following steps: taking a sulfoximine and elemental selenium as raw materials, and realizing synthesis of a series of benzothiaselenazol-1-ketone compounds through rhodium catalysis direct C-H functionalization reaction, which has the advantages of strong functional group compatibility, wide substrate universality, mild conditions, simple operation, high efficiency and universality; meanwhile, taking the sulfoximine and the elemental selenium as starting raw materials, and realizing synthesis of chiral benzothiaselenazol-1-ketone compounds through direct C-H functionalization reaction with the aid of chiral phosphoric acid, which has a good application prospect, can specifically mark a mercapto structure in a polypeptide, a saccharide, a drug molecule and a protein and other biological macromolecules, shows good anti-SARS-CoV-2 virus activity, and a trastuzumab bioconjugate thereof can effectively image a cell surface HER 2 receptor, shows strong fluorescence, and is applied to preparation of an imaging reagent for the cell surface HER 2 receptor.

Description

TECHNICAL FIELD

[0001] The present application relates to a synthesis method and application of a benzothiaselenazole-1-ketone compound and its derivatives. BACKGROUND

[0002] Selenium (Se) is an essential trace element for human metabolism, and selenium deficiency can increase the incidence of diseases such as cancer, cardiovascular disease, and Kashin-Beck disease. At the same time, selenium is one of the important elements in proteins, and animals, especially vertebrates, have more than 25 specific selenium proteins. Due to the unique nucleophilic and electrophilic properties of selenium atoms, several selenium proteins, including glutathione peroxidase (GPxs) and thioredoxin reductase (TrxRs), play a crucial role in maintaining various physiological functions in the body. They mainly resist the generation of reactive oxygen species (ROS) through reversible redox processes, thereby achieving a balance between oxidation and reduction and providing a basis for targeted treatment of diseases caused by abnormal ROS. Because of the important role of selenium, selenium-deficient populations need additional selenium supplementation. The earliest selenium supplementation compounds are mostly inorganic compounds, which have been inhibited due to their high toxicity. Organic selenium compounds have received extensive attention due to their low toxicity and strong pharmacological activity. Currently, organic selenium compounds have been developed as more effective and highly selective therapeutic agents for treating many diseases caused by abnormal expression of corresponding selenium proteins, among which selenium-containing heterocycles occupy a particularly important position. Among them, benzothiaselenazole ketone is the most studied species because it can act as a GPx and TrxR mimic to exert strong anti-inflammatory, anticancer, antimicrobial, antiviral, and neuroprotective effects. Its mechanism is to form a Se-S bond through biochemical reactions with the thiol group of cysteine (Cys) on the protein, such as SARS-CoV-2M pro proteins. In addition, organic selenium compounds have been widely used as fluorescent probes and DNA compounds for construction, further highlighting their value.

[0003] Based on the important role of the above organic selenium compounds, the academic circles are committed to developing effective synthesis methods. The traditional cross-coupling method can be used for the synthesis of organic selenium compounds, but this method is based on the pre-functionalization of substrates, so there are some inherent shortcomings, such as harsh reaction conditions, low atom economy, poor substrate / functional group tolerance and complicated preparation of starting materials. In order to overcome these shortcomings, transition metal-catalyzed C-H functionalization strategies have been used to achieve the synthesis of organic selenium compounds. However, the pre-activated selenium source (such as dichloroselenide and diselenide) is usually involved, which will inevitably lead to low atom economy and cause handling complexity. From the perspective of green and sustainable chemistry, it is an ideal solution to use elemental selenium as a selenide reagent to construct organic selenium compounds by direct C-H functionalization. So far, Nishihara and Miura have reported three pioneering solutions respectively. Miura reported the rhodium-catalyzed oxidative cyclization of phenylimine with elemental selenium to directly construct isoselenazol ring compounds, and the product structure is relatively simple. Nishihara reported the rhodium-catalyzed cyclization of phenylamides with elemental selenium to construct benziselenazolone compounds, which requires the use of 8-aminoquinoline bidentate directing group, greatly limiting the scope of substrates. Therefore, there is an urgent need for a mild, convenient, efficient and universal synthesis method to synthesize novel organic selenium compounds. SUMMARY

[0004] The purpose of the present application is to provide a benzothiaselenazol-1-one compound or its derivative and a synthesis method and application thereof.

[0005] The present application is realized by the following technical solutions:

[0006] A benzothiaselenazol-1-one compound shown in formula I:

[0007]

[0008] R 1 selected from any one of the following groups: H, C1-C4 alkyl, halogen, phenyl, -CF3, -OCF3, -NO2, -CO2Me, -OTf, -OTs, -OMe; R 2 selected from any one of the following groups: halogen, C1-C3 alkyl, cycloalkyl, chloroalkyl, phenyl or substituted phenyl, naphthyl. Preferably, the chloroalkyl is chloro C1-C4 alkyl.

[0009] Preferably, the benzothiaselenazol-1-one compound shown in formula I is selected from the following compounds:

[0010]

[0011]

[0012] A synthesis method of a benzothiaselenazol-1-one compound shown in formula I, the method comprising the following steps: taking selenium and a sulfoximine shown in formula III as raw materials, and obtaining by rhodium catalysis at 90-110 DEG C:

[0013]

[0014] Wherein, R 1 is selected from any one of the following groups: H, C1-C4 alkyl, halogen, phenyl, -CF3, -OCF3, -NO2, -CO2Me, -OTf, -OTs, -OMe; R 2 is selected from any one of the following groups: halogen, C1-C3 alkyl, cycloalkyl, chloroalkyl, phenyl or substituted phenyl, naphthyl.

[0015] Preferably, the chloroalkyl is chloro C1-C4 alkyl.

[0016] When the reaction temperature is 100 DEG C, the reaction equation is as follows:

[0017]

[0018] Specifically comprising the following steps: adding [Cp*Rh(MeCN)3(SbF6)2], AgF, selenium and sulfoximine dissolved in dichloroethane into a sealed tube, and reacting under an oil bath at 100 DEG C; wherein the molar ratio of AgF, selenium and sulfoximine is 2.5: (3-4): 1.

[0019] The application also provides a synthesis method of an enantiomeric benzothiaselenazol-1-one compound shown in formula II, the method comprising the following steps: taking selenium and a sulfoximine shown in formula IV as raw materials, and obtaining by direct C-H functionalization reaction at 55-65 DEG C with the aid of a chiral phosphoric acid ligand;

[0020]

[0021] R 3 is selected from any one of the following groups: H, C1-C4 alkyl, halogen, phenyl, -CF3, -OCF3, -NO2, -CO2Me, -OTf, -OTs, -OMe; R 4 is selected from any one of the following groups: phenyl or substituted phenyl, naphthyl.

[0022] When the reaction temperature is 60 DEG C, the reaction equation is as follows:

[0023]

[0024] Specifically comprising the following steps: adding [Cp* 2phRh(MeCN)3(SbF6)2], AgF, selenium, sulfoximine, chiral phosphoric acid ligand (CPA3) were dissolved in trichloroethylene, and the reaction was carried out at 60 DEG C in an oil bath; wherein the molar ratio of AgF, selenium, sulfoximine was 2.5: (3-4): 1.

[0025] Preferably, the enantiomer of the benzothiaselenazol-1-one compound shown in formula II is selected from the following:

[0026]

[0027] The benzothiaselenazol-1-one compound shown in formula I or the enantiomer of the benzothiaselenazol-1-one compound shown in formula II provided by the present application exhibits good anti-SARS-CoV-2 virus activity, specifically, it exhibits excellent inhibitory activity in SARS-CoV-2 virus infected primate Vero cells, and the effective inhibition rate at a concentration of 10 μM is > 90%; at the same time, the compound 1 and its enantiomer have better inhibitory activity on SARS-CoV-2 virus M pro protein than the EBS control group. Further studies show that the benzothiaselenazol-1-one compound provided by the present application exerts activity by covalently binding to the key Cys145 site in the SARS-CoV-2 virus M pro protein.

[0028] Therefore, the present application also protects the application of the benzothiaselenazol-1-one compound shown in formula I or the enantiomer of the benzothiaselenazol-1-one compound shown in formula II, and the application in the preparation of anti-SARS-CoV-2 virus drugs.

[0029] The present application also protects the application of the benzothiaselenazol-1-one compound shown in formula I or the enantiomer of the benzothiaselenazol-1-one compound shown in formula II based on Se-S covalent connection in modified thiol-containing molecules, including amino acids, polypeptides and their derivatives, sugar compounds and other drug molecules.

[0030] The benzothiaselenazol-1-one derivative compound 12 provided by the present application is used as a starting material, and a bifunctional selenium linker compound L1 is synthesized through hydrolysis, amide condensation and other processes, the compound can be further connected with trastuzumab through Se-S bond to obtain a bioconjugate C1, and then connected with Alexa Fluor@555DIBO dye through the "click" reaction of azide and alkyne to obtain a trastuzumab-Alexa Fluor@555 conjugate C2. The fluorescence microscope image clearly shows that C2 can effectively image the cell surface HER2 receptor, and compared with negative MCF-7 (HER2 - ) cells, the HER2 high expression BT474 (HER2+ ) The cells show strong fluorescence.

[0031] Compound 12 as starting material, through hydrolysis, amide condensation synthesis of bifunctional selenium connector compound L1, the reaction equation is as follows:

[0032]

[0033] The process of bifunctional selenium connector L1 labeled trastuzumab is shown as follows:

[0034]

[0035] Therefore, the application also protects the use of the trastuzumab bioconjugate of the benzothiaselenazol-1-one compound shown in formula I or the enantiomer of the benzothiaselenazol-1-one compound shown in formula II in the preparation of an imaging reagent for the cell surface HER2 receptor.

[0036] The application also protects the use of the benzothiaselenazol-1-one compound shown in formula I or the enantiomer of the benzothiaselenazol-1-one compound shown in formula II or its derivative as a selenylation reagent, with indole or its derivative as a reactant, and tris (pentafluorophenyl) borane as a catalyst to react to obtain a novel indole selenide compound based on the benzothiaselenazol-1-one compound.

[0037] When it is the benzothiaselenazol-1-one compound shown in formula I or the enantiomer of the benzothiaselenazol-1-one compound shown in formula II, the reaction equation is as follows:

[0038]

[0039] The derivative of the benzothiaselenazol-1-one compound shown in formula I is selected from the following compounds:

[0040]

[0041] In particular, the indole derivative is a DNA-labeled indole.

[0042] The reaction equation is as follows:

[0043]

[0044] The application also protects a novel organic selenium compound based on the benzothiaselenazol-1-one compound shown in formula V:

[0045]

[0046] R 5 is selected from any one of the following groups: alkyl, acyl, substituted indole group, substituted seleno group or mercapto compound.

[0047] The alkyl group is preferably a C1-C100 alkyl group, more preferably a C1-C10 alkyl group.

[0048] In particular, the substituted indole group includes indole N, C2-C7 position differently substituted indole substrate, and the substituent includes alkyl, alkoxy, ester, alkynyl, halogen, nitro and the like functional groups, and the indole compound labeled with a DNA tag at different sites.

[0049] The alkyl group is preferably a C1-C100 alkyl group, more preferably a C1-C10 alkyl group.

[0050] The beneficial effects of the present application are as follows:

[0051] 1) The present application provides a novel organic selenium compound (benzothiacyl-1-ketone compound) or its derivative and a synthesis method thereof, which uses sulfoximine and elemental selenium as raw materials, realizes the synthesis of a series of benzothiacyl-1-ketone compounds through rhodium-catalyzed direct C-H functionalization reaction, and has the advantages of strong functional group compatibility, wide substrate universality, mild conditions, simple operation, high efficiency and universality.

[0052] 2) The present application uses sulfoximine and elemental selenium as starting materials, realizes the synthesis of chiral benzothiacyl-1-ketone compounds through direct C-H functionalization reaction with the aid of chiral phosphoric acid ligand. So far, there is no report on the construction of chiral organic selenium compounds by direct C-H functionalization based on elemental selenium as selenide reagent.

[0053] 3) The benzothiacyl-1-ketone compound or its derivative obtained by the present application has good application prospect, can specifically label mercapto group through Se-S bond, shows good anti-SARS-CoV-2 virus activity, and its trastuzumab bioconjugate can effectively image the cell surface HER2 receptor and show strong fluorescence, and is applied to the preparation of an imaging reagent for the cell surface HER2 receptor. BRIEF DESCRIPTION OF DRAWINGS

[0054] Figure 1 is the evaluation of the in vitro antiviral activity of Example 77, wherein a, the antiviral activity of the compound on SARS-CoV-2 infected primate Vero cells; b, the inhibition rate of different compounds on SARS-CoV-2 virus; c, the half-inhibitory concentration of a representative compound; d, the M pro MS-MS analysis results of the labeled protein.

[0055] Figure 2 is the bio-orthogonal labeling of trastuzumab and the imaging of cell surface HER2 receptor in Example 78, wherein a, SDS-PAGE analysis of the labeled protein; b, imaging of the cell surface HER2 receptor. DETAILED DESCRIPTION:

[0056] The following is further illustration of the application, but not limitation of the application.

[0057] Example 1: Synthesis of 1-phenylbenzo[d][1,3,2]thiaselenazole-1-one (Compound 1)

[0058]

[0059] In a 10 mL sealed tube, [Cp*Rh(MeCN)3(SbF6)2] (5 mol%), AgF (0.25 mmol, 2.5 equiv), selenium (0.3 mmol, 3 equiv), sulfoximine (0.1 mmol, 1 equiv) were dissolved in dichloroethane (0.5 ml) and reacted at 100 °C oil bath for 10 hours. After the reaction was completed, EA was added to dilute the reaction tube, and the reaction solution was transferred to a round-bottom flask, concentrated to obtain the crude product, separated by column chromatography, and eluted with eluent PE:EA=3:1 to obtain the product 23.4 mg, yield: 81%. 1 H NMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.6 Hz, 2H), 7.66 (m, 2H), 7.57 (t, J = 7.6 Hz, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 141.4, 140.6, 134.7, 133.9, 131.6, 129.8, 129.4, 126.4, 125.7, 124.2.

[0060] Example 2: Synthesis of 5-methyl-1-(p-tolyl)benzo[d][1,3,2]thiaselenazole-1-one (Compound 2)

[0061]

[0062] The preparation method refers to Example 1, except that imino-di-p-tolyl-λ 6 sulfone was used as the substrate to obtain the target compound 21.0 mg, yield: 65%. 1 H NMR (400 MHz, CDCl3): δ 7.85 (d, J = 8.2 Hz, 2H), 7.41 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.28-7.24 (m, 1H), 7.08 (d, J = 8.1 Hz, 1H), 2.44 (s, 3H), 2.41 (s, 3H). 13C NMR (101 MHz, CDC13): δ 144.9, 142.6, 141.7, 137.8, 132.7, 130.0, 129.7, 127.8, 125.2, 124.0, 21.8, 21.7.

[0063] Example 3: Synthesis of 5-propyl-l-(p-propylphenyl)benzo[d][l,3,2]thiasele- nazole-l-one (Compound 3)

[0064]

[0065] The preparation method refers to Example 1, except that imino bis-p-tert- butylphenyl-λ 6 The target compound 24.3 mg was obtained with a yield of 64% using sulfone as the substrate. 1 H NMR (400 MHz, CDC13): δ 7.86 (d, J = 8.1 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 2.64 (q, J = 8.4 Hz, 4H), 1.68-1.60 (m, 4H), 0.92 (t, J = 7.2 Hz, 6H). 13 C NMR (101 MHz, CDC13): δ 149.6, 147.3, 141.6, 137.8, 132.8, 129.8, 129.4, 127.3, 125.3, 123.5, 38.0, 38.0, 24.4, 24.3, 13.9.

[0066] Example 4: Synthesis of 5-tert-butyl-l-(p-phenyl)benzo[d][l,3,2]thiasele- nazole-l-one (Compound 4)

[0067]

[0068] The preparation method refers to Example 1, except that imino bis-p-tert- butylphenyl-λ 6 The target compound 24.3 mg was obtained with a yield of 64% using sulfone as the substrate. 1 H NMR (400 MHz, CDC13): δ 7.86 (d, J = 8.1 Hz, 2H), 7.40 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 2.64 (q, J = 8.4 Hz, 4H), 1.68-1.60 (m, 4H), 0.92 (t, J = 7.2 Hz, 6H). 13C NMR (101 MHz, CDC13): δ 157.8, 155.7, 141.7, 137.7, 132.4, 129.5, 126.4, 125.2, 124.7, 120.4, 31.3, 31.2.

[0069] Example 5: Synthesis of 5-methoxy-l-(4-methoxyphenyl)benzo[d][l,3,2]thiasele- nazole-l-one (Compound 5)

[0070]

[0071] Preparation method refers to Example 1, except that imino bis-p-methoxyphenyl-λ 6 sulfone as the substrate to obtain the target compound 25.3 mg, yield: 71%. 1 H NMR (400 MHz, CDC13): δ 7.89 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.02 (m, 3H), 6.81 (m, J = 8.8 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 163.9, 162.5, 143.9, 132.2, 131.7, 127.9, 126.5, 115.1, 114.5, 106.7, 56.0, 55.9.

[0072] Example 6: Synthesis of 5-fluoro-l-(4-fluorophenyl)benzo[d][l,3,2]thiasele- nazole-l-one (Compound 6)

[0073]

[0074] Preparation method refers to Example 1, except that imino bis-p-fluorophenyl-λ 6 sulfone as the substrate to obtain the target compound 29.7 mg, yield: 90%. 1 H NMR (400 MHz, CDC13): δ 8.00 (dd, J = 8.7, 5.1 Hz, 2H), 7.33 (m, 2H), 7.25 (t, J = 8.4 Hz, 2H), 7.05-6.99 (m, 1H). 13 C NMR (101 MHz, CDC13): δ 166.3 (d, J = 247.2 Hz), 163.9, 162.5, 143.9, 132.2, 131.7, 127.9, 126.5, 115.1, 114.5, 106.7, 56.0, 55.9.

[0075] 259.6 Hz), 164.7 (d, J = 257.6 Hz), 144.6 (d, J = 9.5 Hz), 136.4, 132.6 (d, J = 9.8 Hz), 130.9, 127.4 (d, J = 10.4 Hz), 116.8 (d, J = 22.8 Hz), 115.2 (d, J = 25.0 Hz), 110.9 (d, J = 25.7 Hz). 19 F NMR (376 MHz, CDCb): δ -103.1, -106.9.

[0076] Example 7: Synthesis of 5-chloro-l-(4-chlorophenyl)benzo[d][l,3,2]thiasele- nazole-l-one (Compound 7)

[0077]

[0078] The preparation method refers to Example 1, except that imino bis-p-chlorophenyl- λ 6 - sulfone as the substrate to obtain the target compound 33.3 mg, yield: 92%. 1 H NMR (400 MHz, CDCb): δ 7.90 (d, J = 8.6 Hz, 2H), 7.63 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 2.3 Hz, 2H). 13 C NMR (101 MHz, CDCb): δ 143.7, 141.2, 139.0, 138.8, 132.9, 131.1, 129.8, 127.2, 126.4, 124.0.

[0079] Example 8: Synthesis of 5-bromo-l-(4-bromophenyl)benzo[d][l,3,2]thiasele- nazole-l-one (Compound 8)

[0080]

[0081] The preparation method refers to Example 1, except that imino bis-p-chlorophenyl- λ 6 - sulfone as the substrate to obtain the target compound 33.3 mg, yield: 92%. 1 H NMR (400 MHz, CDCb): δ 7.90 (d, J = 8.6 Hz, 2H), 7.63 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 2.3 Hz, 2H). 13 C NMR (101 MHz, CDCb): δ 143.7, 141.2, 139.0, 138.8, 132.9, 131.1, 129.8, 127.2, 126.4, 124.0.

[0082] Example 9: Synthesis of 5-trifluoromethyl-1-(4-trifluoromethylphenyl)benzo[d][1,3,2]selenazol-1-one (Compound 9)

[0083]

[0084] The preparation method refers to Example 1, except that imino bis-p-trifluoromethylphenyl-λ 6 - sulfone as the substrate to obtain the target compound 31.1 mg, yield: 72%. 1 H NMR (400 MHz, CDC13): δ 8.13 (d, J = 8.2 Hz, 2H), 7.97 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H). 13 C NMR (101 MHz, CDC13): δ 143.6, 143.2, 136.3, 136.1 (q, J = 33.2 Hz), 134.0 (q, J = 33.0 Hz), 130.5, 126.7 (d, J = 3.4 Hz), 126.4, 124.6, 123.9 (d, J = 3.1 Hz), 121.8 (d, J = 4.1 Hz), 119.1. 19 F NMR (376 MHz, CDC13): δ -62.7, -63.1.

[0085] Example 10: Synthesis of 5-trifluoromethoxy-1-(4-trifluoromethoxyphenyl)benzo[d][1,3,2]selenazol-1-one (Compound 10)

[0086]

[0087] The preparation method refers to Example 1, except that imino bis-p-trifluoromethoxyphenyl-λ 6 - sulfone as the substrate to obtain the target compound 25.4 mg, yield: 55%. 1 H NMR (400 MHz, CDC13): δ 8.05 (d, J = 8.6 Hz, 2H), 7.49 (s, 1H), 7.45-7.38 (m, 3H), 7.17 (d, J = 8.5 Hz, 1H). 13 C NMR (101 MHz, CDC13): δ 153.5, 151.7, 144.4, 138.2, 132.3, 132.1, 127.1, 121.6 (d, J = 2.4 Hz), 121.1, 119.6, 119.0 (d, J = 2.4 Hz), 115.9.19 F NMR (376 MHz, CDC13): δ -57.6.

[0088] Example 11: Synthesis of 5-nitro-l-(4-nitrophenyl)benzo[d][l,3,2]thiaselenoxole-l- one (Compound 11)

[0089]

[0090] Preparation method refers to Example 1, except that imino bis p-nitrophenyl-λ 6 sulfone as the substrate to obtain the target compound 23.9 mg, yield: 62%. 1 H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.46 (d, J = 8.7 Hz, 2H), 8.15 (dd, J = 11.9, 5.0 Hz, 3H), 7.85 (d, J = 8.7 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6): δ 150.7, 149.3, 145.3, 144.7, 136.7, 130.7, 126.8, 124.9, 122.2, 121.9.

[0091] Example 12: Synthesis of 5-methylcarboxylate-l-(4-methylcarboxylate phenyl)benzo[d][l,3,2]thiaselenoxole-l-one (Compound 12)

[0092]

[0093] Preparation method refers to Example 1, except that imino bis p-methylcarboxylate phenyl-λ 6 sulfone as the substrate to obtain the target compound 23.9 mg, yield: 58%. 1 H NMR (400 MHz, CDC13): δ 8.36 (s, 1H), 8.23 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 3.97 (m, 6H). 13 C NMR (101 MHz, CDC13): δ 165.6, 165.5, 143.9, 142.4, 136.8, 135.3, 133.3, 130.6, 129.9, 127.8, 125.9, 125.5, 53.0, 52.9.

[0094] Example 13: Synthesis of 5-trifluoromethylsulfonate-l-(4- trifluoromethylsulfonate phenyl)benzo[d][l,3,2]selenazol-l-one (Compound 13)

[0095]

[0096] Preparation method refers to Example 1, except that imino bis-p-trifluoromethylsulfonate phenyl-λ 6 - sulfone as the substrate to obtain the target compound 40.6 mg, yield: 69%. 1 H NMR (400 MHz, CDC13): δ 8.11 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.7, 1.9 Hz, 1H). 13 C NMR (101 MHz, CDC13): δ 153.4, 151.6, 145.1, 140.2, 133.4, 132.4, 127.5, 122.7, 120.4, 117.4, 117.2, 117.1. 19 F NMR (376 MHz, CDC13): δ -72.40, -72.45.

[0097] Example 14: Synthesis of 5-p-tolylsulfonyloxy-l-(4-p-tolylsulfonyloxyphenyl)benzo[d][l,3,2]selenazol-l-one (Compound 14)

[0098]

[0099] Preparation method refers to Example 1, except that imino bis-p-tolylsulfonyloxy phenyl-λ 6 - sulfone as the substrate to obtain the target compound 37.7 mg, yield: 58%. 1 H NMR (400 MHz, CDC13): δ 8.11 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.7 Hz, 1H), 7.24 (dd, J = 8.7, 1.9 Hz, 1H). 13C NMR (101 MHz, CDC13): δ 153.9, 152.1, 146.3, 144.0, 138.6, 132.5, 131.9, 131.83, 131.76, 130.3, 128.6, 126.8, 123.4, 121.2, 118.0, 21.9.

[0100] Example 15: Synthesis of 5-phenyl-1-biphenylbenzo[d][1,3,2]thiasele- nazole-1-one (Compound 15)

[0101]

[0102] Preparation method refers to Example 1, except that imino-bis-m-methylphenyl-λ 6 - sulfone as the substrate to obtain the target compound 30.0 mg, yield: 68%. 1 H NMR (400 MHz, CDC13): δ 8.08 (d, J = 8.4 Hz, 2H), 7.82-7.76 (m, 3H), 7.62 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 7.0 Hz, 2H), 7.52-7.41 (m, 8H). 13 C NMR (101 MHz, CDC13): δ 146.9, 145.1, 142.4, 139.3, 139.2, 139.0, 133.5, 130.3, 129.22, 129.21, 128.9, 128.8, 128.0, 127.7, 127.6, 126.1, 125.9, 122.4.

[0103] Example 16: Synthesis of 6-methyl-1-m-methylphenylbenzo[d][1,3,2]thiase- lenazole-1-one (Compound 16)

[0104]

[0105] Preparation method refers to Example 1, except that imino-bis-m-methylphenyl-λ 6 - sulfone as the substrate to obtain the target compound 30.0 mg, yield: 68%. 1 H NMR (400 MHz, CDC13): δ 8.08 (d, J = 8.4 Hz, 2H), 7.82-7.76 (m, 3H), 7.62 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 7.0 Hz, 2H), 7.52-7.41 (m, 8H). 13C NMR (101 MHz, CDC13): δ 140.4, 139.7, 137.8, 136.9, 135.0, 134.8, 133.2, 130.1, 129.2, 127.0, 125.5, 123.8, 21.5, 20.9.

[0106] Example 17: Synthesis of 6-methoxy-l-m-methoxyphenylbenzo[d][l,3,2]thiasele- nazole-l-one (Compound 17)

[0107]

[0108] Preparation method refers to Example 1, except that imino di-m-methoxyphenyl-λ 6 sulfone is used as the substrate to obtain the target compound 22.1 mg, yield: 62%. 1 H NMR (400 MHz, CDC13): δ 7.55 (d, J = 7.8 Hz, 1H), 7.50-7.44 (m, 3H), 7.18 (dd, J = 8.1, 1.7 Hz, 1H), 7.13 (dd, J = 8.7, 2.3 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 160.2, 159.2, 141.8, 135.3, 131.8, 130.3, 124.7, 122.0, 121.1, 120.5, 114.1, 108.5, 56.0, 55.9.

[0109] Example 18: Synthesis of 6-chloro-l-m-chlorophenylbenzo[d][l,3,2]thiasele- nazole-l-one (Compound 18)

[0110]

[0111] Preparation method refers to Example 1, except that imino di-m-chlorophenyl-λ 6 sulfone is used as the substrate to obtain the target compound 31.9 mg, yield: 88%. 1 H NMR (400 MHz, CDC13): δ 7.94 (m, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.68-7.64 (m, 1H), 7.60-7.52 (m, 2H), 7.47 (dd, J = 8.5, 1.8 Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H). 13C NMR (101 MHz, CDC13): δ 141.8, 134.0, 135.8, 135.4, 134.5, 132.8, 132.3, 130.7, 129.8, 127.9, 125.4, 125.2.

[0112] Example 19: Synthesis of 7-methyl-l-o-tolylbenzo[d][l,3,2]thiasele- nazole-l-one (Compound 19)

[0113]

[0114] Preparation method refers to Example 1, except that imino-di-o-tolyl-λ 6 - sulfone as the substrate to obtain the target compound 17.5 mg, yield: 54%. 1 HNMR (400 MHz, CDC13): δ 8.40 (d, J = 7.9 Hz, 1H), 7.48 (m, 4H), 7.26 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 7.0 Hz, 1H), 2.07 (s, 3H), 1.85 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 142.6, 140.5, 139.1, 137.0, 134.0, 133.0, 132.2, 131.1, 130.5, 128.4, 126.8, 121.8, 19.48, 17.89.

[0115] Example 20: Synthesis of 4,6-dimethyl-l-(3,5-dimethylphenyl)benzo[d][l,3,2]thiase- nazole-l-one (Compound 20)

[0116]

[0117] Preparation method refers to Example 1, except that imino-di-3,5-dimethylphenyl- λ 6 - sulfone as the substrate to obtain the target compound 11.6 mg, yield: 33%. 1 H NMR (400 MHz, CDC13): δ 7.58 (s, 2H), 7.27 (s, 1H), 7.13 (s, 1H), 7.03 (s, 1H), 2.39 (s, 6H), 2.32 (s, 6H). 13 C NMR (101 MHz, CDC13): 140.5, 139.4, 138.7, 138.0, 135.6, 134.6, 133.4, 133.3, 127.2, 122.8, 21.4, 21.3, 20.9.

[0118] Example 21 : Synthesis of 1 -(2-naphthyl)naphtho[2,3-d][1,3,2]selenazol-1 - one (Compound 21 )

[0119]

[0120] Preparation method refers to Example 1, except that imino di-2-naphthyl-λ 6 - sulfone as substrate to get the target compound 12.0 mg, yield: 30%. 1 HNMR (400 MHz, CDC13): δ 8.80 (s, 1 H), 8.06 (d, J = 6.0 Hz, 2H), 7.96 (m, 3H), 7.88 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.70 (t, J = 7.4 Hz, 1 H), 7.67-7.63 (m, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 1 H). 13 CNMR (101 MHz, CDC13): δ 136.8, 136.4, 135.6, 134.8, 134.7, 132.4, 131.8, 131.3, 129.83, 129.80, 129.7, 129.4, 129.3, 128.1, 127.9, 127.4, 126.6, 126.1, 124.5, 122.4.

[0121] Example 22: Synthesis of 1 -methylbenzo[d][1,3,2]selenazol-1 -one (Compound 22)

[0122]

[0123] Preparation method refers to Example 1, except that imino (methyl)(phenyl)-λ 6 - sulfone as substrate to get the target compound 12.0 mg, yield: 30%. 1 HNMR (400 MHz, CDC13): δ 8.80 (s, 1 H), 8.06 (d, J = 6.0 Hz, 2H), 7.96 (m, 3H), 7.88 (d, J = 8.8 Hz, 1 H), 7.83 (d, J = 8.4 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.70 (t, J = 7.4 Hz, 1 H), 7.67-7.63 (m, 1 H), 7.58 (t, J = 7.5 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 1 H). 13 C NMR (101 MHz, CDC13): δ 142.4, 133.5, 132.1, 126.5, 124.7, 124.6, 45.6.

[0124] Example 23: Synthesis of 5-methyl-1-methylbenzo[d][1,3,2]thiasele-1-one (Compound 23)

[0125]

[0126] Preparation method refers to Example 1, except that imino(methyl)(p- methylphenyl)-λ 6 - sulfone as the substrate to obtain the target compound 23.7 mg, yield: 48%. 1 H NMR (400 MHz, CDC13): δ 7.65 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 3.52 (s, 3H), 2.46 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 143.4, 142.8, 131.1, 127.9, 124.5, 124.4, 45.7, 21.7.

[0127] Example 24: Synthesis of 5-methoxy-1-methylbenzo[d][1,3,2]thiasele-1-one (Compound 24)

[0128]

[0129] Preparation method refers to Example 1, except that imino(methyl)(p- methoxyphenyl)-λ 6 - sulfone as the substrate to obtain the target compound 22.0 mg, yield: 42%. 1 H NMR (400 MHz, CDC13): δ 7.64 (d, J = 8.4 Hz, 1H), 7.03 (s, 1H), 6.95 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H), 3.49 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 163.0, 145.3, 126.0, 125.8, 115.0, 107.3, 56.0, 46.0.

[0130] Example 25: Synthesis of 5-fluoro-1-methylbenzo[d][1,3,2]thiasele-1-one (Compound 25)

[0131]

[0132] Preparation method refers to Example 1, except that imino(methyl)(p- fluorophenyl)-λ 6 - sulfone as the substrate to obtain the target compound 23.6 mg, yield: 47%. 1H NMR (400 MHz, CDC13): δ 7.73 (dd, J = 8.7, 4.6 Hz, 1H), 7.30 (dd, J = 8.0, 2.0 Hz, 1H), 7.15 (td, J = 8.4, 2.0 Hz, 1H), 3.55 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 165.0 (d, J = 257.2 Hz), 145.9 (d, J = 5.9 Hz), 129.9, 126.6 (d, J = 10.5 Hz), 115.1 (d, J = 25.0 Hz), 111.4 (d, J = 25.7 Hz), 45.9. 19 F NMR (376 MHz, CDC13): δ -106.3 (dd, J = 12.2, 7.2 Hz).

[0133] Example 26: Synthesis of 5-methoxy-l-methylbenzo[d][l,3,2]thiaselenoxole-l- one (Compound 26)

[0134]

[0135] Preparation method refers to Example 1, except that imino(methyl)(p- chlorophenyl)-λ 6 sulfone as the substrate to obtain the target compound 27.2 mg, yield: 51%. 1 H NMR (400 MHz, CDC13): δ 7.68 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 3.56 (s, 3H). 13 C NMR (100 MHz, CDC13): δ 144.7, 139.3, 132.2, 127.1, 125.5, 124.4, 45.8.

[0136] Example 27: Synthesis of 5-bromo-l-methylbenzo[d][l,3,2]thiaselenoxole-l-one (Compound 27)

[0137]

[0138] Preparation method refers to Example 1, except that imino(methyl)(p- chlorophenyl)-λ 6 sulfone as the substrate to obtain the target compound 27.2 mg, yield: 51%. 1 HNMR (400 MHz, CDC13): δ 7.79 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 3.55 (s, 3H). 13C NMR (101 MHz, CDC13): δ 144.9, 132.6, 129.9, 127.7, 127.3, 125.6, 45.7.

[0139] Example 28: Synthesis of 5-carbomethoxy-l-methylbenzo[d][l,3,2]thiaselenoxepin-l- one (Compound 28)

[0140]

[0141] Preparation method refers to Example 1, except that imino(methyl)(p-carbomethoxyphenyl)- lambda 6 - sulfone as the substrate to obtain the target compound 35.6 mg, yield: 61%. 1 H NMR (400 MHz, CDC13): δ 8.32 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.62 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 165.4, 142.9, 136.4, 133.4, 127.6, 126.1, 124.4, 53.0, 45.4.

[0142] Example 29: Synthesis of 5-nitro-l-methylbenzo[d][l,3,2]thiaselenoxepin-l-one (Compound 29)

[0143]

[0144] Preparation method refers to Example 1, except that imino(methyl)(p-nitrophenyl)- lambda 6 - sulfone as the substrate to obtain the target compound 19.5 mg, yield: 35%. 1 H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H). 13 C NMR (101 MHz, DMSO-d6): δ 149.0, 144.2, 138.5, 125.7, 121.6, 44.4.

[0145] Example 30: Synthesis of 5-methyl-l-methylbenzo[d][l,3,2]thiaselenoxepin-l-one (Compound 30)

[0146]

[0147] Preparation method as in example 1 except that imino(methyl)(p-tolyl)-lambda 6 - sulfone as substrate to get the target compound 28.9 mg, yield: 55%. 1 HNMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.23 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H). 13 C NMR (101 MHz, DMSO-d6): δ 158.7, 135.5, 131.6, 126.2, 120.5, 108.0, 56.0, 44.5.

[0148] Example 31 : Synthesis of 6-methoxy-l-methylbenzo[d][l,3,2]thiaselenoxepin-l-one (Compound 31)

[0149]

[0150] Preparation method as in example 1 except that imino(methyl)(p-tolyl)-lambda 6 - sulfone as substrate to get the target compound 28.9 mg, yield: 55%. 1 HNMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.23 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H). 13 C NMR (101 MHz, DMSO-d6): δ 158.7, 135.5, 131.6, 126.2, 120.5, 108.0, 56.0, 44.5.

[0151] Example 32: Synthesis of 6-chloro-l-methylbenzo[d][l,3,2]thiaselenoxepin-l-one (Compound 32)

[0152]

[0153] Preparation method as in example 1 except that imino(methyl)(p-tolyl)-lambda 6 - sulfone as substrate to get the target compound 28.9 mg, yield: 55%. 1 HNMR (400 MHz, DMSO-d6): δ 7.82 (d, J = 8.7 Hz, 1H), 7.71 (s, 1H), 7.23 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ 140.6, 136.3, 131.3, 131.0, 127.3, 124.3, 44.4.

[0154] Example 33: Synthesis of 7-chloro-l-methylbenzo[d][l,3,2]thiaselenoxepin-l-one (Compound 33)

[0155]

[0156] Preparation method refers to Example 1, except that imino(methyl)(o-chlorophenyl)-λ 6 - sulfone as the substrate to obtain the target compound 26.6 mg, yield: 66%. 1 H NMR (400 MHz, CDC13): δ 7.58 (dd, J = 7.5, 3.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 3.75 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 145.3, 134.0, 133.0, 130.7, 123.7, 119.5, 48.2.

[0157] Example 34: Synthesis of Compound 34

[0158]

[0159] Preparation method refers to Example 1, except that imino(methyl)(o-chlorophenyl)-λ 6 - sulfone as the substrate to obtain the target compound 26.6 mg, yield: 66%. 1 H NMR (400 MHz, CDC13): δ 7.58 (dd, J = 7.5, 3.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 3.75 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 145.3, 134.0, 133.0, 130.7, 123.7, 119.5, 48.2.

[0160] Example 35: Synthesis of l-methylnaphtho[2,3-d][l,3,2]thiaselenoxepin-l-one (Compound 35)

[0161]

[0162] Preparation method refers to Example 1, except that imino(methyl)(o-chlorophenyl)-λ 6 - sulfone as the substrate to obtain the target compound 26.6 mg, yield: 66%.1 H NMR (400 MHz, CDC13): δ 8.32 (s, 1H), 8.02-7.95 (m, 2H), 7.85 (d, J = 8.3 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 1H), 3.61 (s, 3H). 13 C NMR (101 MHz, CDC13): δ 135.1, 134.9, 131.2, 129.6, 129.5, 127.5, 126.9, 125.0, 123.0, 44.8.

[0163] Example 36: Synthesis of 1-ethylbenzo[d][1,3,2]thiaselenoxide-1-one (Compound 36)

[0164]

[0165] The preparation method refers to Example 1, except that imino(cyclopropyl)(phenyl)-λ 6 sulfone as the substrate to obtain the target compound 36.7 mg, yield: 74%. 1 H NMR (400 MHz, CDC13): δ 7.72 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 3.80-3.67 (m, 2H), 1.28 (dd, J = 9.4, 5.3 Hz, 3H). 13 C NMR (101 MHz, CDC13): δ 143.7, 132.1, 131.1, 126.4, 125.2, 124.6, 52.5, 9.0.

[0166] Example 37: Synthesis of 1-cyclopropylbenzo[d][1,3,2]thiaselenoxide-1-one (Compound 37)

[0167]

[0168] The preparation method refers to Example 1, except that imino(cyclopropyl)(phenyl)-λ 6 sulfone as the substrate to obtain the target compound 27.4 mg, yield: 81%. 1H NMR (400 MHz, CDC13): δ 7.77 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 2.82 (tt, J = 7.7, 4.6 Hz, 1H), 1.38 - 1.16 (m, 4H). 13 C NMR (101 MHz, CDC13): δ 142.7, 133.8, 131.9, 126.3, 125.2, 124.5, 33.2, 6.8, 5.0.

[0169] Example 38: Synthesis of 1-chloromethylbenzo[d][l,3,2]thiaselenoxole-l-one (Compound 38)

[0170]

[0171] Preparation method refers to Example 1, except that imino(chloromethyl)(phenyl)-λ 6 - sulfone as the substrate to obtain the target compound 41.9 mg, yield: 78%. 1 H NMR (400 MHz, CDC13): δ 7.85 (d, J = 8.0 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.52 - 7.46 (m, 1H), 5.12 (d, J = 12.6 Hz, 1H), 4.86 (d, J = 12.6 Hz, 1H). 13 C NMR (100 MHz, CDC13): δ 145.0, 133.1, 128.1, 126.8, 126.7, 124.6, 60.5.

[0172] Example 39: Synthesis of (R)-l-chloromethylbenzo[d][l,3,2]thiaselenoxole-l-one (Compound (R)-l)

[0173]

[0174] In a 10 mL sealed tube, [Cp*Rh(MeCN)3(SbF6)2] (5 mol%), AgF (0.25 mmol, 2.5 equiv), selenium (0.3 mmol, 3 equiv), sulfoximine (0.1 mmol, 1 equiv), CPA3 (30 mol%) dissolved in trichloroethylene (1 ml), 60 °C oil bath for 36 hours. After the reaction was completed, ethyl acetate was added to dilute the reaction tube, and the reaction solution was transferred to a round-bottom flask, concentrated to obtain the crude product, separated by column chromatography, eluted with eluent PE:EA = 3:1 to obtain the product 25.1 mg, yield: 85%, e.r. = 6:94, [a]D 25 = -174.0 (c = 0.1, CH2Cl2).

[0175] Example 40: Synthesis of (S)-1-chloromethylbenzo[d][1,3,2]thiasele- nazole-1-one (compound (R)-1)

[0176]

[0177] The procedure was adapted from Example 39 except that (S)-CPA 3 was used as catalyst to give the target compound 41.9 mg, yield: 84%, e.r. = 95:5, [a] D 25 = +176.0 (c = 0.1, CH2Cl2).

[0178] Example 41 : Synthesis of (R)-5-methyl-1-(p-tolyl)benzo[d][1,3,2]thiase- nazole-1-one (compound (R)-2)

[0179]

[0180] The procedure was adapted from Example 39 except that imino-di-p-tolyl- λ 6 sulfone was used as substrate to give the target compound 22.8 mg, yield: 71 %, e.r. = 8:92, [a] D 25 = -146.0 (c = 0.1, CH2Cl2).

[0181] Example 42: Synthesis of (R)-5-propyl-1-(p-propylphenyl)benzo[d][1,3,2]thiase- nazole-1-one (compound (R)-3)

[0182]

[0183] The procedure was adapted from Example 39 except that imino-di-p- propylphenyl-λ 6 sulfone was used as substrate to give the target compound 31.3 mg, yield: 83%, e.r. = 13:87, [a] D 25 = -98.0 (c = 0.1, CH2Cl2).

[0184] Example 43: Synthesis of (R)-5-tert-butyl-1-(p-tert-butylphenyl)benzo[d][1,3,2]thiase- nazole-1-one (compound (R)-4)

[0185]

[0186] Reference example 39, except that imino-di-p-methoxyphenyl-λ 6 - sulfone as substrate to give the target compound 24.1 mg, yield: 68%, e.r. = 11 : 89, [a] D 25 = -79.0 (c = 0.1, CH2CI2).

[0187] Example 44: Synthesis of (R)-5-methoxy-l-(p-methoxyphenyl)benzo[d][l,3,2]thiasele- nazole-l-one (compound (R)-5)

[0188]

[0189] Reference example 39, except that imino-di-p-methoxyphenyl-λ 6 - sulfone as substrate to give the target compound 24.1 mg, yield: 68%, e.r. = 11 : 89, [a] D 25 = -79.0 (c = 0.1, CH2CI2).

[0190] Example 45: Synthesis of (R)-5-fluoro-l-(4-fluorophenyl)benzo[d][l,3,2]thiasele- nazole-l-one (compound (R)-6)

[0191]

[0192] Reference example 39, except that imino-di-p-fluorophenyl-λ 6 - sulfone as substrate to give the target compound 24.1 mg, yield: 68%, e.r. = 11 : 89, [a] D 25 = -79.0 (c = 0.1, CH2CI2).

[0193] Example 46: Synthesis of (R)-5-chloro-l-(4-chlorophenyl)benzo[d][l,3,2]thiasele- nazole-l-one (compound (R)-7)

[0194]

[0195] Reference example 39, except that imino-di-p-chlorophenyl-λ 6 - sulfone as substrate to give the target compound 24.1 mg, yield: 68%, e.r. = 11 : 89, [a] D 25 = -79.0 (c = 0.1, CH2CI2).

[0196] Example 47: Synthesis of (R)-5-bromo-l-(4-bromophenyl)benzo[d][l,3,2]thiasele- nazole-l-one (compound (R)-8)

[0197]

[0198] The procedure was adapted from Example 39 except that imino-di-p-bromophenyl- λ 6 - sulfone as the substrate to give the target compound 37.0 mg, yield: 82%, e.r. = 13:87, [a] D 25 = -89.0 (c = 0.1, CH2CI2).

[0199] Example 48: Synthesis of (R)-5-trifluoromethyl-l-(4-trifluoromethylphenyl)benzo[d][l,3,2]thiase- nazole-l-one (compound (R)-9)

[0200]

[0201] The procedure was adapted from Example 39 except that imino-di-p-trifluoromethylphenyl- λ 6 - sulfone as the substrate to give the target compound 17.2 mg, yield: 43%, e.r. = 21:79, [a] D 25 = -117.0 (c = 0.1, CH2CI2).

[0202] Example 49: Synthesis of (R)-5-trifluoromethoxy-l-(4-trifluoromethoxyphenyl)benzo[d][l,3,2]thiase- nazole-l-one (compound (R)-10)

[0203]

[0204] The procedure was adapted from Example 39 except that imino-di-p-trifluoromethoxyphenyl- λ 6 - sulfone as the substrate to give the target compound 10.9 mg, yield: 24%, e.r. = 23:77, [a] D 25 = -139.0 (c = 0.1, CH2CI2).

[0205] Example 50: Synthesis of (R)-5-nitro-l-(4-nitrophenyl)benzo[d][l,3,2]thiasele- nazole-l-one (compound (R)-11)

[0206]

[0207] The preparation method refers to example 39, except that imino-di-p-nitrophenyl-λ 6 - sulfone as substrate to give the target compound 21.9 mg, yield: 53%, e.r. = 21 : 79, [a] D 25 = -287.0 (c = 0.1, CH2CI2).

[0208] Example 51 : Synthesis of (R)-5-carbomethoxy-1-(4-carbomethoxyphenyl)benzo[d][1,3,2]thiasele- nazole-1 -one (compound (R)-12)

[0209]

[0210] The preparation method refers to example 39, except that imino-di-p-nitrophenyl-λ 6 - sulfone as substrate to give the target compound 21.9 mg, yield: 53%, e.r. = 21 : 79, [a] D 25 = -287.0 (c = 0.1, CH2CI2).

[0211] Example 52: Synthesis of (R)-5-triflate-1-(4-triflate-phenyl)benzo[d][1,3,2]thiasele- nazole-1 -one (compound (R)-13)

[0212]

[0213] The preparation method refers to example 39, except that imino-di-p-nitrophenyl-λ 6 - sulfone as substrate to give the target compound 21.9 mg, yield: 53%, e.r. = 21 : 79, [a] D 25 = -287.0 (c = 0.1, CH2CI2).

[0214] Example 53: Synthesis of (R)-5-p-tosyloxy-1-(4-p-tosyloxyphenyl)benzo[d][1,3,2]thiasele- nazole-1 -one (compound (R)-14)

[0215]

[0216] The preparation method refers to example 39, except that imino-di-p-nitrophenyl-λ 6 - sulfone as substrate to give the target compound 21.9 mg, yield: 53%, e.r. = 21 : 79, [a] D 25= -115.0 (c = 0.1, CH2Cl2).

[0217] Example 54: Synthesis of (R)-5-phenyl-1-biphenylylbenzo[d][1,3,2]thiase lenozole-1 -one (compound (R)-15)

[0218]

[0219] The procedure was adapted from Example 39 except that imino-di-m-methoxyphenyl-λ 6 sulfone was used as the substrate to give the target compound 16.1 mg in 50% yield, e.r. = 83: 17, [a]D= -222.0 (c = 0.1, CH2Cl2). D 25 = -130.0 (c = 0.1, CH2Cl2).

[0220] Example 55: Synthesis of (R)-6-methyl-1-m-methylphenylbenzo[d][1,3,2]thiase lenozole-1 -one (compound (R)-16)

[0221]

[0222] The procedure was adapted from Example 39 except that imino-di-m-methoxyphenyl-λ 6 sulfone was used as the substrate to give the target compound 16.1 mg in 50% yield, e.r. = 83: 17, [a]D= -222.0 (c = 0.1, CH2Cl2). D 25 = -130.0 (c = 0.1, CH2Cl2).

[0223] Example 56: Synthesis of (R)-6-methoxy-1-m-methoxyphenylbenzo[d][1,3,2]thiase lenozole-1 -one (compound (R)-17)

[0224]

[0225] The procedure was adapted from Example 39 except that imino-di-m-methoxyphenyl-λ 6 sulfone was used as the substrate to give the target compound 16.1 mg in 50% yield, e.r. = 83: 17, [a]D= -222.0 (c = 0.1, CH2Cl2). D 25 = -130.0 (c = 0.1, CH2Cl2).

[0226] Example 57: Synthesis of (R)-6-chloro-1-m-chlorophenylbenzo[d][1,3,2]thiase lenozole-1 -one (compound (R)-18)

[0227]

[0228] The preparation method refers to example 39, except that imino-di-2-naphthyl-λ 6 - sulfone as substrate to give the target compound 7.7 mg, yield: 24%, e.r. = 23:77, [a] D 25 = -191.0 (c = 0.1, CH2Cl2).

[0229] Example 58: Synthesis of (R)-7-methyl-1-o-tolylbenzo[d][1,3,2]thiaphen-1-one (compound (R)-19)

[0230]

[0231] The preparation method refers to example 39, except that imino-di-2-naphthyl-λ 6 - sulfone as substrate to give the target compound 7.7 mg, yield: 24%, e.r. = 23:77, [a] D 25 = -144.0 (c = 0.1, CH2Cl2).

[0232] Example 59: Synthesis of (R)-4,6-dimethyl-1-(3,5-dimethylphenyl)benzo[d][1,3,2]thiaphen-1-one (compound (R)-21)

[0233]

[0234] The preparation method refers to example 39, except that imino-di-2-naphthyl-λ 6 - sulfone as substrate to give the target compound 7.7 mg, yield: 24%, e.r. = 23:77, [a] D 25 = -158.0 (c = 0.1, CH2Cl2).

[0235] Example 60: Synthesis of 1,2-bis(2-(phenylsulfonylimino)phenyl)diselenide (compound 39)

[0236]

[0237] To a sealed tube under N2atmosphere was added a solution of compound 1 prepared in example 1 (0.2 mmol, 1.0 eq) in methanol (0.7 mL). Hydrazine monohydrate (10 μL, 0.2 mmol, dissolved in 0.2 mL of methanol) was added via a syringe and the syringe was rinsed with 0.1 mL of methanol. The reaction mixture was stirred in an oil bath at 65 °C for 1 h. Then, the mixture was poured into water and extracted with dichloromethane three times. The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. The reaction mixture was then concentrated and purified by column chromatography (eluent: PE / EA = 3 / 1) to give compound 39 in 91% yield (53.9 mg). 1 HNMR (400 MHz, CDC13): δ 8.15-8.12 (m, 6H), 7.62-7.56 (m, 2H), 7.52-7.50 (m, 4H), 7.44 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.09-7.01 (m, 2H), 3.51 (br s, 2H). 13 C NMR (101 MHz, CDC13): δ 141.6, 141.5, 140.8, 140.7, 133.5, 133.0, 131.8, 131.7, 131.1, 131.0, 130.5, 129.0, 128.3, 127.2.

[0238] Example 61: Synthesis of methyl (2-(phenylsulfonamidophenyl)selenyl)phenyl) selenide (compound 40)

[0239]

[0240] To a 10 mL Schlenk tube was added compound 1 (0.2 mmol, 1.0 eq) and tetrahydrofuran solvent under N2atmosphere. Then methyl magnesium bromide (1.0 M tetrahydrofuran solution, 0.6 mL, 0.6 mmol) was added dropwise at 0 °C. After stirring at room temperature for 2 h, the mixture was poured into water and extracted with dichloromethane three times. The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. After evaporation of the volatiles, compound 40 was obtained in 92% yield (57.1 mg) by column chromatography (eluent: PE / EA = 3 / 1). 1 HNMR (400 MHz, CDC13): δ 8.15-8.12 (m, 6H), 7.62-7.56 (m, 2H), 7.52-7.50 (m, 4H), 7.44 (d, J = 7.9 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.09-7.01 (m, 2H), 3.51 (br s, 2H). 13C NMR (101 MHz, CDC13): δ 141.0, 140.8, 135.1, 132.9, 132.8, 130.9, 128.8, 128.7, 128.4, 125.4, 7.6.

[0241] Example 62: Synthesis of Se-(2-(N-benzoylphenylsulfonimidoyl)phenyl)benzoselenoate (Compound 41)

[0242]

[0243] To a dry 10 mL Schlenk tube under N2atmosphere was added sodium borohydride (0.24 mmol, 1.2 equiv.) and ethanol (1 mL). Then compound 1 (0.2 mmol, 1.0 equiv.) was added to the above solution at 0 °C and stirred for 1 h, followed by the addition of benzoyl chloride (0.3 mmol, 1.5 equiv.) and the mixture was allowed to warm to room temperature for 12 h. After the reaction was completed, the mixture was poured into water (10 mL) and the product was extracted with dichloromethane (10 mL) three times. The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: DCM / EA = 50 / 1) to give compound 41 in 53% isolated yield (53.3 mg). 1 H NMR (400 MHz, CDC13): δ 8.30-8.21 (m, 3H), 8.17-8.11 (m, 4H), 7.71-7.52 (m, 5H), 7.51-7.40 (m, 4H), 7.38-7.34 (m, 1H), 7.20 (t, J = 6.8 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H). 13 C NMR (101 MHz, CDC13): δ 173.4, 171.9, 138.19, 138.17, 137.6, 137.5, 135.2, 134.2, 134.1, 133.9, 133.8, 132.7, 132.6, 131.9, 130.70, 130.66, 130.3, 129.93, 129.91, 129.53, 129.51, 129.40, 129.36, 129.35, 128.61, 128.57, 128.49, 128.3, 127.8, 127.7.

[0244] Example 63: Synthesis of 1-phenylbenzo[d][1,3,2]thiaselenazole 1,3-dioxide (Compound 42)

[0245]

[0246] To a 10 mL Schlenk tube was added a solution of compound 1 (0.2 mmol, 1.0 equiv) in chloroform (0.1 M) under N2atmosphere. Then 30% hydrogen peroxide (1.2 equiv) was added dropwise at 0 °C. After stirring at room temperature for 12 h, the mixture was poured into water and extracted with dichloromethane three times. The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. After evaporation of the volatiles, the resulting residue was purified by column chromatography (eluent: DCM / EA = 10 / 1) to give compound 42 in 90% isolated yield (55.9 mg). This compound is a mixture of two inseparable diastereoisomers with a dr value of 85:15 determined by H-NMR analysis. 1 H-NMR analysis determined a dr value of 85:15. 1 H NMR (400 MHz, CDC13): δ 8.23 (d, J = 7.5 Hz, 1.70 H), 8.07 (d, J = 7.6 Hz, 0.15 H), 7.99 (t, J = 10.4 Hz, 1.15 H), 7.83 (t, J = 7.2 Hz, 1 H), 7.74-7.65 (m, 3 H), 7.62 (t, J = 7.3 Hz, 2 H). 13 C NMR (101 MHz, CDC13): δ 147.4, 140.6, 138.4, 135.1, 134.9 (minor isomer), 134.7 (minor isomer), 134.6, 133.0, 130.0, 129.4, 129.0 (minor isomer), 127.1 (minor isomer), 126.7, 126.2.

[0247] Example 64: Synthesis of 2-((2-(phenylsulfonylimino)phenyl)selenyl)-1- (pyrimidin-2-yl)-1H-indole (compound 43)

[0248]

[0249] A mixture of compound 1 (0.1 mmol, 1.0 equiv), 1-(pyrimidin-2-yl)-1H-indole (0.11 mmol, 1.1 equiv) and [Cp*Rh(MeCN)3(SbF6)2] (5 mol%) in 1,2-dichloroethane (0.5 mL) was stirred at 100 °C for 12 h. Then, it was diluted with ethyl acetate and filtered through a short silica gel column to remove metal residues. The reaction mixture was concentrated and purified by column chromatography (eluent: PE / EA = 3 / 1) to give compound 43 in 64% isolated yield (31.5 mg). 1HNMR (400 MHz, CDC13): δ 8.80 (d, J = 8.4 Hz, 1H), 8.72 (d, J = 4.6 Hz, 2H), 8.54 (s, 1H), 8.28-8.23 (m, 3H), 7.65-7.52 (m, 3H), 7.34 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.12-7.04 (m, 4H), 6.93 (d, J = 7.8 Hz, 1H), 3.40 (brs, 1H). 13 C NMR (101 MHz, CDC13): δ 158.4, 157.3, 141.5, 140.4, 136.2, 135.5, 133.3, 132.91, 132.86, 132.5, 131.0, 130.6, 128.9, 128.5, 126.0, 124.7, 122.9, 120.4, 117.0, 116.5, 104.8.

[0250] Example 65: Synthesis of 3-((2-(phenylsulfonamidophenyl)seleno)-1H-indole (Compound 44)

[0251]

[0252] A solution of compound 1 (0.1 mmol, 1.0 equiv), 1H-indole (0.12 mmol, 1.2 equiv) and B(C6F5)3(5 mol%) in 1,2-dichloroethane (1.0 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed and the residue was purified by column chromatography (eluent: PE / EA = 3 / 1) to give compound 44 in 89% isolated yield (36.5 mg). 1 H NMR (400 MHz, CDC13): δ 9.37 (brs, 1H), 8.23 (d, J = 7.5 Hz, 2H), 8.17 (d, J = 7.7 Hz, 1H), 7.58-7.53 (m, 1H), 7.49 (t, J = 6.8 Hz, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 7.19-7.11 (m, 2H), 7.01-6.91 (m, 4H), 3.13 (brs, 1H). 13 C NMR (101 MHz, CDC13): δ 141.2, 139.7, 136.82, 136.76, 133.0, 132.8, 132.6, 130.7, 130.5, 129.6, 128.9, 128.4, 125.7, 122.8, 120.7, 119.8, 111.8, 98.2.

[0253] Example 66: Synthesis of 2-(l-((((2-(phenylsulfonylimino)phenyl)selanyl)thio)methyl)cyclopropyl)acetic acid (Compound 45)

[0254]

[0255] To a 10 mL Schlenk tube was added compound 1 (0.1 mmol, 1.0 eq) and a solution of mesalazine intermediate in dichloromethane (0.12 mmol, 1.2 eq, dissolved in 1 mL dichloromethane) under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 12 hours, after the end of the reaction the solvent was removed under reduced pressure and the resulting mixture was purified by column chromatography (eluent: DCM / EA / AcOH = 10 / 1 / 0.1) to obtain compound 45 with 95% isolated yield (41.9 mg). 1 H NMR (400 MHz, CDC13): δ 8.21 (d, J = 7.9 Hz, 1H), 8.10-8.07 (m, 3H), 7.57-7.45 (m, 4H), 7.36 (t, J = 7.4 Hz, 1H), 5.53 (br s, 2H), 2.87 (q, J = 13.5 Hz, 2H), 2.53-2.42 (m, 2H), 0.45-0.41 (m, 4H). 13 C NMR (101 MHz, CDC13): δ 177.9, 141.8, 140.1, 134.1, 133.3, 133.2, 130.8, 129.4, 129.1, 128.0, 127.0, 46.5, 39.7, 18.2, 12.6, 12.5.

[0256] Example 67: Synthesis of (2-(((2-(phenylsulfonylaminyl)phenyl)selanyl)thio)propanoyl)glycine (Compound 46)

[0257]

[0258] The preparation method refers to Example 66, except that tiopronin was used as the substrate to obtain compound 46 with 90% isolated yield. This compound is a mixture of two inseparable diastereoisomers, which were identified by H-NMR analysis with a dr value of 1:1. 1 H-NMR analysis determined a dr value of 1:1. 1H NMR (400 MHz, CDC13): δ 8.16-8.02 (m, 3H), 7.99 (d, J = 7.6 Hz, 1H), 7.57-7.43 (m, 4H), 7.34 (t, J = 7.2 Hz, 1H), 6.95-6.91 (m, 1H), 6.08 (br s, 3H), 3.81-3.73 (m, 1H), 3.65-3.59 (m, 1H), 3.54-3.49 (m, 1H), 1.40 (d, J = 6.8 Hz, 1.5H), 1.37 (d, J = 6.8 Hz, 1.5H). 13 C NMR (101 MHz, CDC13): δ 172.5, 172.4, 172.3, 141.2, 139.5, 133.6, 133.24, 133.18, 133.1, 131.9, 131.8, 130.8, 130.6, 129.51, 129.45, 129.35, 129.1, 128.3, 127.93, 127.88, 127.5, 127.3, 47.8, 47.6, 41.6, 18.31, 18.26.

[0259] Example 68: Synthesis of ((2S)-2-methyl-3-((2-(phenylsulfonamidophenyl)seleno)phenyl)seleno)propanoyl)-L-proline (Compound 47)

[0260]

[0261] The preparation method refers to Example 66, except that captopril is used as the substrate to obtain Compound 47 in a separation yield of 60%. The compound is a mixture of two inseparable diastereoisomers, which are separated by HPLC to obtain Compound 47a and Compound 47b. 1 The dr value is 1:1 determined by H-NMR analysis. 1 H NMR (400 MHz, DMSO-d6): δ 8.15-7.93 (m, 4H), 7.67-7.54 (m, 4H), 7.50 (t, J = 7.4 Hz, 1H), 5.85 (s, 0.5H), 5.77 (s, 0.5H), 4.16 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 8.4 Hz, 1H), 3.18-3.13 (m, 0.5H), 2.98-2.91 (m, 1H), 2.80-2.64 (m, 1H), 2.60-2.50 (m, 1H), 2.24-2.18 (m, 0.5H), 2.00-1.58 (m, 4H), 1.43-1.37 (m, 0.5H), 1.01-0.94 (m, 0.5H), 0.91 (d, J = 6.6 Hz, 1.5H), 0.84 (d, J = 6.6 Hz, 1.5H).13 C NMR (101 MHz, DMSO-d6): δ 173.3, 171.7, 171.4, 142.3, 140.4, 133.5, 133.3, 133.2, 132.9, 132.8, 130.5, 129.9, 129.6, 129.0, 128.9, 127.7, 127.5, 127.32, 127.28, 58.2, 58.1, 45.9, 45.3, 37.5, 37.0, 28.5, 28.3, 24.1, 23.8, 16.7, 16.6.

[0262] Example 69: Synthesis of N-(tert-butoxycarbonyl)-S-((2-(phenylsulfonamido)phenyl)seleno)-L-cysteine (Compound 48)

[0263]

[0264] The procedure of Preparation Example 66 was followed except that Boc-L-Cys was used as the substrate to give Compound 48 in 92% isolated yield. The compound was a mixture of two inseparable diastereomers in a 1:1 ratio as determined by H-NMR analysis. 1 H-NMR analysis determined the dr value to be 1:1. 1 H NMR (400 MHz, CDC13): δ 8.15 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 6.9 Hz, 2H), 8.00 (d, J = 7.6 Hz, 1H), 7.49-7.39 (m, 4H), 7.29 (t, J = 7.8 Hz, 1H), 6.64 (br s, 2H), 5.78-5.56 (m, 1H), 4.35 (br s, 1H), 3.33-3.02 (m, 2H), 1.40 (s, 4.5H), 1.39 (s, 4.5H). 13 C NMR (101 MHz, CDC13): δ 175.1, 155.7, 141.9, 139.8, 133.5, 133.3, 130.8, 129.3, 129.2, 128.3, 127.8, 127.1, 80.3, 54.7, 54.5, 40.0, 39.7, 28.5.

[0265] Example 70: Synthesis of N-((tert-butoxycarbonyl)-L-alanine)-S-((2-(phenylsulfonamido)phenyl)seleno)-L-cysteine ethyl ester (Compound 49)

[0266]

[0267] The preparation method refers to Example 66, except that Boc-Ala-Cys-OEt is used as the substrate to obtain compound 49 in an isolated yield of 80%. The compound is a mixture of two inseparable diastereomers, which are separated by 1 The dr value is determined to be 1 : 1 by H-NMR analysis. 1 H NMR (400 MHz, CDC13): δ 8.20-8.01 (m, 4H), 7.58-7.44 (m, 4H), 7.38 (t, J = 7.4 Hz, 1H), 7.07 (br s, 1H), 5.30-5.10 (m, 1H), 4.89-4.73 (m, 1H), 4.34-4.15 (m, 3.5H), 3.33-3.05 (m, 2.5H), 1.47-1.44 (m, 9H), 1.32-1.23 (m, 6H). 13 C NMR (101 MHz, CDC13): δ 172.6, 172.4, 170.1, 167.0, 155.6, 142.4, 142.3, 134.0, 133.5, 133.4, 133.3, 133.2, 133.0, 130.9, 130.8, 130.6, 129.23, 129.19, 129.0, 128.3, 128.0, 127.2, 80.3, 62.1, 53.2, 52.9, 50.1, 39.3, 39.0, 28.4, 18.2, 14.3, 14.2.

[0268] Example 71: Synthesis of l-((N,4-dimethylphenyl)sulfonamido)vinyl N-(tert- butoxycarbonyl)-S-((2-(phenylsulfonimidoyl)phenyl)seleno)-L-cysteine (compound 50)

[0269]

[0270] The preparation method refers to Example 66, except that Boc-Ala-Cys-OEt is used as the substrate to obtain compound 49 in an isolated yield of 80%. The compound is a mixture of two inseparable diastereomers, which are separated by 1 The dr value is determined to be 1 : 1 by H-NMR analysis. 1H NMR (400 MHz, CDC13): δ 8.20 (d, J = 7.8 Hz, 1H), 8.14-7.96 (m, 3H), 7.78-7.67 (m, 2H), 7.58-7.45 (m, 4H), 7.40-7.30 (m, 3H), 5.45-5.16 (m, 1H), 4.93 (s, 1H), 4.63 (s, 1H), 4.51-4.40 (m, 1H), 3.29-3.03 (m, 3H), 2.98 (s, 1.5H), 2.96 (s, 1.5H), 2.43 (s, 3H), 1.46-1.44 (m, 9H). 13 C NMR (101 MHz, CDC13): δ 170.5, 168.43, 168.39, 155.1, 155.0, 146.7, 145.1, 144.5, 142.2, 134.0, 136.1, 133.5, 133.3, 133.1, 130.8, 130.1, 129.7, 129.3, 129.2, 128.1, 127.8, 127.4, 127.3, 101.5, 80.5, 54.3, 54.2, 39.4, 39.1, 37.4, 33.2, 28.4, 25.1, 21.7.

[0271] Example 72: Synthesis of N-(tert-butoxycarbonyl)-S-((2-(phenylsulfonamidophenyl)phenyl)seleno)-L-cysteine-L-isoleucine methyl ester (Compound 51)

[0272]

[0273] The preparation method refers to Example 66, except that Boc-Cys-Ile-OMe is used as the substrate to obtain Compound 51 in a separation yield of 86%. The compound is a mixture of two inseparable diastereoisomers, which are separated by HPLC to obtain Compound 51a and Compound 51b. 1 The dr value is 1:1 determined by H-NMR analysis. 1 H NMR (400 MHz, CDC13): δ 8.20 (d, J = 7.8 Hz, 1H), 8.14-7.96 (m, 3H), 7.78-7.67 (m, 2H), 7.58-7.45 (m, 4H), 7.40-7.30 (m, 3H), 5.45-5.16 (m, 1H), 4.93 (s, 1H), 4.63 (s, 1H), 4.51-4.40 (m, 1H), 3.29-3.03 (m, 3H), 2.98 (s, 1.5H), 2.96 (s, 1.5H), 2.43 (s, 3H), 1.46-1.44 (m, 9H). 13C NMR (101 MHz, CDC13): δ 172.0, 170.1, 155.6, 142.1, 140.1, 133.5, 133.2, 130.8, 129.3, 129.2, 127.8, 127.2, 80.7, 56.7, 54.8, 52.3, 39.0, 38.6, 37.9, 37.9, 28.3, 25.0, 15.5, 11.6.

[0274] Example 73: N 2 -(tert-butoxycarbonyl)-N 4 Synthesis of methyl (2-(((2-(phenylsulfonamidophenyl)seleno)yloxy)ethyl)-L- aspartamidyl-L-phenylalaninate (Compound 52)

[0275]

[0276] The procedure of Preparation Example 66 was followed except that the aspartame derivative was used as the substrate to give Compound 52 in 88% isolated yield. The compound was a mixture of two inseparable diastereomers in a 1:1 dr value as determined by H-NMR analysis. 1 H-NMR analysis determined the dr value to be 1:1. 1 H NMR (400 MHz, CDC13): δ 8.18 (d, J = 7.7 Hz, 1H), 8.09-8.06 (m, 3H), 7.56-7.39 (m, 5H), 7.35 (t, J = 7.3 Hz, 1H), 7.29-7.20 (m, 3H), 7.14-7.11 (m, 2H), 6.70-6.62 (m, 1H), 6.18-6.12 (m, 1H), 4.75 (q, J = 6.1 Hz, 1H), 4.48-4.40 (m, 1H), 3.64 (s, 3H), 3.39-3.21 (m, 2H), 3.07-3.05 (m, 2H), 2.82-2.70 (m, 3H), 2.53-2.49 (m, 1H), 1.40 (s, 9H). 13 C NMR (101 MHz, CDC13): δ 171.5, 171.1, 155.6, 141.9, 140.1, 135.8, 133.4, 133.3, 133.1, 130.7, 129.3, 129.0, 128.6, 127.8, 127.1, 80.2, 53.6, 52.3, 51.1, 39.4, 37.8, 37.3, 36.0, 28.3.

[0277] Example 74: Synthesis of 2-(acetyloxymethyl)-6-(((2-(phenylsulfonamidophenyl) phenyl)selanyl)thio)tetrahydro-2H-pyran-3,4,5-triacetic acid (Compound 53)

[0278]

[0279] The preparation method was according to Example 66, except that D-glucopyranose derivative was used as the starting material to give Compound 53 in 95% isolated yield. This compound is a mixture of two inseparable diastereomers. 1 H NMR (400 MHz, CDC13): δ 8.37 (d, J = 8.0 Hz, 0.5H), 8.31 (d, J = 8.0 Hz, 0.5H), 8.12 (t, J = 7.6 Hz, 2H), 8.02 (d, J = 7.8 Hz, 1H), 7.63-7.39 (m, 4H), 7.39-7.27 (m, 1H), 5.46-5.27 (m, 2H), 5.14-4.97 (m, 1H), 4.63-4.57 (m, 1H), 4.27-3.90 (m, 2H), 3.86-3.76 (m, 1H), 3.64-3.54 (m, 1H), 2.20-2.08 (m, 6H), 2.06-1.85 (m, 6H). 13 C NMR (101 MHz, CDC13): δ 170.36, 170.30, 170.25, 170.1, 170.0, 169.6, 169.5, 169.4, 142.6, 142.4, 141.6, 140.7, 139.7, 139.6, 134.3, 134.1, 133.5, 133.3, 133.2, 133.0, 132.9, 131.7, 131.0, 130.7, 130.6, 130.5, 130.3, 129.2, 129.1, 128.9, 128.2, 127.8, 127.24, 127.17, 90.7, 88.9, 88.4, 74.8, 74.7, 71.8, 71.7, 68.6, 67.6, 67.2, 67.1, 61.5, 61.2, 60.9, 60.4, 21.1, 20.92, 20.85, 20.7, 20.64, 20.60, 20.57, 14.2.

[0280] Example 75: (2-((((3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6- methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl)thio)selanyl)phenyl)(imino)(phenyl)-λ 6Synthesis of sulfonamidone (compound 54)

[0281]

[0282] The procedure of Preparation Example 66 was followed, except that the cholestanol derivative was used as the substrate to give compound 54 in 83% isolated yield. The compound was a mixture of two inseparable diastereomers, which were separated by 1 The dr value was determined by H-NMR analysis to be 1 : 1. 1 H NMR (400 MHz, CDC13): δ 8.13 (d, J = 7.8 Hz, 1H), 8.04-8.02 (m, 3H), 7.49-7.34 (m, 4H), 7.27 (t, J = 7.3 Hz, 1H), 3.03-2.99 (m, 1H), 2.80 (br s, 1H), 1.89 (d, J = 11.6 Hz, 1H), 1.80-0.87 (m, 29H), 0.86-0.72 (m, 11H), 0.65-0.62 (m, 3H), 0.56 (s, 3H). 13 C NMR (100 MHz, CDC13): δ 141.73, 141.65, 140.5, 134.5, 133.0, 130.62, 130.55, 130.1, 129.9, 128.92, 128.88, 128.11, 128.07, 126.8, 56.6, 56.3, 54.2, 48.6, 42.7, 40.3, 40.2, 40.1, 39.6, 36.40, 36.39, 36.3, 35.9, 35.51, 35.50, 33.4, 33.2, 33.1, 32.0, 28.39, 28.35, 28.3, 28.1, 27.0, 24.3, 24.0, 23.0, 22.7, 20.9, 18.8, 12.2, 11.8.

[0283] Example 76: Synthesis of a library of organoselenium DNA-encoded compounds

[0284] To the solution of DNA-labeled indole (4 pL, 500 mM, pH 4.2 PBS), hexafluoroisopropanol (HFIP, 13 pL), B(C6F5)3 (1 pL, 40 mM in HFIP), benzo-thia-selenazole-1 -oxide (10 pL, 200 mM in HFIP) were added, the resulting mixture was vortexed and left to stand at room temperature for 6 hours. After incubation, 5 M NaCl solution (10% by volume) and ice ethanol (2.5-3 times by volume, ethanol stored at -20 °C) were added, vortexed, and incubated at -80 °C for at least 30 minutes. The sample was centrifuged at 12000 rpm for 15 minutes in a microcentrifuge at 4 °C to remove the supernatant. The resulting precipitate was redissolved in ddH2O (5 pL) for LC-MS detection.

[0285] Example 77: Evaluation of antiviral activity in vitro

[0286] (1) SARS-CoV-2 virus inhibition experiment

[0287] Primate Vero E6 cells were seeded in 96-well plates at a density of 1.5 x 10 4 cells / well. After overnight culture, the cells were pretreated with different concentrations of drugs prepared in Examples 1-59 for 2 hours at 37 °C. When performing antiviral detection, 0.05 MOI of virus was co-incubated with different concentrations of drugs for 1 hour, and 50 pL of the mixture was transferred to Vero E6 cells pretreated with drugs, and incubated for another 1 hour. Then the mixture was removed, and DMEM medium containing serially diluted drugs and 2% FBS was added, and incubated at 37 °C. After 24 hours, 200 pL of 4% PFA was added to each well to fix the cells for 1 hour, and the fixing solution was discarded, and the cells were washed with PBS for 3 times. Then the cells were permeabilized with 0.2% Triton X-100 and blocked with 1% BSA for 30 minutes, respectively. SARS-CoV / SARS-CoV-2 Nucleocapsid Rabbit PAb antibody (Sino Biological, cat#40143-T62) was added and incubated at 37 °C for 1 hour, and then Alexa Fluor 488 AffiniPure Donkey Anti-Rabbit IgG (h+L) fluorescent secondary antibody (Alexa Fluor 488, Jackson, cat#711-545-152) was further incubated at 37 °C for 1 hour in the dark. The cells were washed with PBST for 3 times, and the nuclei were stained with DAPI for 15 minutes at room temperature in the dark, and finally the cells were scanned and analyzed by Nexcelom Celigo imaging cytometer, and the virus inhibition rate was calculated.

[0288] (2) M pro protein inhibition test ​

[0289] Based on the antiviral results in Vero E6 cells, we further determined the effects of benzothiaseleno-1-one compounds and their (R)- / (S)-isomers on M... pro The inhibition level of the enzyme was determined using ebuselenium (EBS) as a positive control. The inhibition level of M by the compound was measured using the TR-FRET method. pro IC50 value of the protein. Specific steps: Pre-incubate 3CLpro (P132H mutant) with the target compound in a 96-well plate for 30 minutes. Initiate the reaction by adding the FRET-compatible peptide substrate MCA-AVLQSGFR-Lys(Dnp)-Lys-NH2. Perform fluorescence measurements at 40 detection points at 10-second intervals using a 340 / 405 excitation / emission filter on a multimode microplate reader (Thermo Scientific™ Varioskn™ LUX). Calculate the IC50 value using a four-parameter equation fitting curve in GraphPadPrism. 50 value.

[0290] The results show that ( Figure 1 ):

[0291] 1) It exhibited excellent inhibitory activity in Vero primate cells infected with SARS-CoV-2 virus, with an effective inhibition rate of >90% at a concentration of 10 μM; simultaneously, compound 1 and its enantiomers showed anti-SARS-CoV-2 virus M pro The inhibitory activity against the protein was superior to that of the ebuselenol (EBS) control group.

[0292] 2) The benzothiaseleno-1-one compound provided by this invention covalently binds to the SARS-CoV-2 virus M pro It exerts its activity at the key Cys145 site in the protein.

[0293] Example 78: Bioorthogonal labeling of trastuzumab and imaging of HER2 receptor on cell surface

[0294] (1) Synthesis method of bifunctional selenium-based linker L1

[0295] Into a round bottom flask containing 2.5 mL of DMF and 0.5 mL of water, 1-(4- carboxyphenyl)-1 λ4-benzo[d][1,3,2]thi azol-5-carboxylic acid 1 -oxide (0.05 g, 0.13 mmol) and sodium salt of N-hydroxysulfosuccinimide (NHSS) (0.062 g, 0.286 mmol) were added, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.055 g, 0.286 mmol) dissolved in 1 mL of DMF solution was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min, then 2-[2-(2-azidoethoxy)ethoxy]ethanolamine (0.045 g, 0.26 mmol) was added slowly into the reaction mixture, stirred at 40 °C for 24 h. The resulting crude mixture was purified by HPLC to give L1 as a yellow solid (0.043 g, yield 48%).

[0296]

[0297] (2) The process of labeling trastuzumab with bifunctional selenium linker L1

[0298] Into a 1.5 mL tube, 50 μL of 1 mg / mL trastuzumab (prepared from Hepes buffer, pH = 8.0) and 3.37 μL of 1 mM tris(2-carboxyethyl)phosphine (TCEP) were added, and the reaction was allowed to proceed at room temperature for 2 hours to obtain reduced trastuzumab, then 1.69 μL of 10 mM L1 was added, and the reaction was allowed to proceed at room temperature for 12 hours. The resulting conjugate C1 was purified using a Zeba TM The excess reagent was removed by purifying the conjugate C1 using a Zeba TM The resulting conjugate product C2 was characterized by SDS-PAGE: 20 μL of C2 was transferred to another 1.5 mL tube, 4 μL of protein buffer solution (6x TRANS) was added, and the sample was heated at 95 °C for 5 minutes. Two control samples were prepared in the same way. For the unreduced sample, 10 μL of trastuzumab (1 mg / mL) was mixed with 4 μL of 4x NuPAGE LDS sample buffer, and the sample was loaded onto a precast protein gel and electrophoresed at 130 V for 1 hour. The buffer system was 1x MOPS SDS running buffer (ABCONE). The fluorescence intensity was analyzed using a ChemiDoc MP imaging system. Then 0.5% Coomassie brilliant blue was added, and the gel was analyzed after washing 2-3 times.

[0299]

[0300] (3) Cell staining and imaging procedure

[0301] a) 4 x 10 5 BT474 (Her2+) or MCF-7 (Her2-) cells were seeded in 24-well plates;

[0302] b) 1 ml PBS was added and gently shaken for 5 min, and 150 μΐ of fixation buffer (BioLegend) was added and incubated at room temperature for 20 min in the dark; c) The buffer solution was discarded, and 1 ml PBS was added to wash the plate;

[0303] d) Incubation was performed under the conditions shown in the table below, respectively, with gentle shaking at room temperature;

[0304] Table. Conditions for imaging of cell surface Her2 receptor

[0305]

[0306] a NC: negative control; b C2 was obtained by mixing equal amounts of L1 and Click-IT @ Alexa Fluor @ 555 DIBO alkyne (Thermo Scientific) for 12 h at room temperature. After that, the mixture was combined with trastuzumab according to the procedure for labeling trastuzumab with bifunctional selenium linker L1.

[0307] e) 1 ml PBS containing 0.1% Triton was added, gently shaken, and washed twice for 5 min each time;

[0308] f) DAPI was diluted with PBS containing 0.1% Triton at a ratio of 1 :2000, 1 ml of DAPI solution was added to each well, and incubated at room temperature for 5 min in the dark.

[0309] Results are shown in Figure 2 . Fluorescence microscopy images clearly showed that C2 could effectively image cell surface HER2 receptor, and HER2 high-expressing BT474 (HER2 - ) cells showed strong fluorescence compared with negative MCF-7 (HER2 + ) cells.

Claims

1. A benzothiaseleno-1-one compound, characterized in that, Selected from the following compounds:

2. A method for synthesizing the benzothiaseleno-1-one compound according to claim 1, characterized in that, The method includes the following steps: using selenium and sulfoxide imine of formula III as raw materials, a reaction is carried out by rhodium catalysis at 90-110℃ to obtain: Among them, R 1 The substituents on the benzene ring of the benzothiaseleno-1-one compound as described in claim 1 are identical; R 2 It is consistent with the single bond linking group of S in the benzothiaseleno-1-one compound of claim 1.

3. The synthesis method according to claim 2, characterized in that, Specifically, the following steps are included: [Cp*Rh(MeCN)3(SbF6)2], AgF, selenium, and sulfoxide imide were added to the sealed tube and dissolved in dichloroethane. The reaction was carried out in an oil bath at 100°C. The molar ratio of AgF, selenium, and sulfoxide imide was 2.5:(3-4):

1.

4. Enantiomers of benzothiaseleno-1-one compounds, characterized in that, Selected from the following compounds:

5. A method for synthesizing the enantiomer of the benzothiaseleno-1-one compound according to claim 4, characterized in that, The method includes the following steps: using selenium and sulfoxide imine of formula IV as raw materials, the mixture is obtained by direct CH functionalization reaction with the aid of chiral phosphoric acid at 55-65°C; R 3 The substituent groups on the benzene ring of the enantiomer of the benzothiaseleno-1-one compound described in claim 4 are consistent; R 4 The single bond linking group of S is consistent with that of the enantiomer of the benzothiaseleno-1-one compound according to claim 4.

6. The synthesis method according to claim 5, characterized in that, Specifically, the following steps are included: Add [Cp*] to the sealing tube 2ph Rh(MeCN)3(SbF6)2], AgF, selenium, sulfoxide imine, and chiral phosphate ligand are dissolved in trichloroethylene and reacted in an oil bath at 60°C; wherein the molar ratio of AgF, selenium, and sulfoxide imine is 2.5:(3-4):

1.

7. The use of the enantiomer of the benzothiaseleno-1-one compound of claim 1 or the benzothiaseleno-1-one compound of claim 4 in the preparation of anti-SARS-CoV-2 virus drugs.

8. The use of trastuzumab bioconjugate C2 of compound 12 of claim 1 or compound (R)-12 of claim 4 in the preparation of imaging reagents for the HER2 receptor on the cell surface, characterized in that, The structure of trastuzumab bioconjugate C2 is as follows:

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