A benzothiomorpholin-3-one compound, and a preparation method and application thereof

Abstract

The application discloses a benzothiomorpholine-3-ketone compound and a preparation method and application thereof. The compound has a structure shown in formula I. The application provides a series of novel benzothiomorpholine-3-ketone compounds, and the compounds have the characteristics of anti-tumor activity.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a benzothiomorpholino-3-one compound, its preparation method, and its application. Background Technology

[0002] Benzothiomorpholino-3-ones are an important class of hexaaromatic heterocycles containing nitrogen and sulfur heteroatoms. Their unique structure gives these compounds broad application prospects in many fields such as pharmaceuticals and materials science, demonstrating great development value and attracting widespread attention. For example, benzothiazine acetate A has strong antidiabetic activity, 1,4-benzothiazine derivative B can act as an intracellular calcium antagonist with good antiarrhythmic effects, and compound C (NS6180) is a highly selective and efficient inhibitor of the KCa3.1 ion channel with an IC50 value of 9 nM, inhibiting T cell activation and inflammatory responses.

[0003]

[0004] Benzothiomorpholine-3-one compounds possess a unique molecular structure with significant theoretical and practical value. Therefore, research and exploration into the synthesis of compounds with the benzothiomorpholine-3-one skeleton are of great research value. Consequently, it is necessary to develop a series of novel benzothiomorpholine-3-one compounds with pharmaceutical activity. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. To this end, the first aspect of the present invention provides a benzothiomorpholine-3-one compound, which is characterized by antitumor activity.

[0006] A second aspect of the present invention also provides a method for preparing a benzothiomorpholine-3-one compound.

[0007] A third aspect of the present invention also provides an application of a benzothiomorpholine-3-one compound.

[0008] A benzothiomorpholino-3-one compound according to a first aspect of the present invention has the structure shown in Formula I: ; Wherein, R1 is one or more substitutions, each independently selected from H, halogen, nitro, cyano, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl halogenates; R2 is one or more substitutions, each independently selected from H, C 1~6 alkyl, C 1~6 alkoxy, C 1~6alkyl halogenates; R3 can be one or more substitutions, each independently selected from H, halogen, cyano, C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl, C 2~6 ester group; R4 is one or more substitutions, each independently selected from H, halogen, C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl halogenates.

[0009] According to a preferred embodiment of the present invention, R1 is one or more substitutions, each independently selected from H, halogen, C. 1~6 alkyl, C 1~6 Fluorinated alkyl groups.

[0010] According to a preferred embodiment of the invention, R4 is one or more substitutions, each independently selected from H, halogen, C. 1~3 alkyl, C 1~3 alkoxy, C 1~6 Fluorinated alkyl groups.

[0011] According to a preferred embodiment of the present invention, R2 is independently selected from H and C. 1~6 alkoxy groups.

[0012] According to a preferred embodiment of the present invention, R3 is independently selected from H, halogen, cyano, C. 1~3 alkyl, C 1~6 Halogenated alkyl, C 2~6 The ester group.

[0013] According to a preferred embodiment of the present invention, the benzothiomorpholine-3-one compound has the following structural formula: .

[0014] The benzothiomorpholino-3-one compound according to embodiments of the present invention has at least the following beneficial effects: This invention provides a series of novel benzothiomorpholino-3-one compounds, which are characterized by antitumor activity.

[0015] According to a second aspect of the present invention, a method for preparing the benzothiomorpholino-3-one compound as described in the first aspect of the present invention is provided, comprising the following steps: Compounds II, III, and IV, along with a metal catalyst and a solvent, were mixed and reacted to obtain the benzothiomorpholin-3-one compound. The structural formulas of compounds II, III, and IV are as follows: , , ; The definitions of R1, R2, R3 and R4 in this invention are the same as those of R1, R2, R3 and R4 described in the first aspect of this invention.

[0016] According to a preferred embodiment of the present invention, the molar ratio of compound II, compound III and compound IV is 1:(1~4):(1~4).

[0017] According to a preferred embodiment of the present invention, the solvent includes at least one of ethanol, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, or water.

[0018] According to a preferred embodiment of the present invention, the metal catalyst includes at least one selected from iron salt, cobalt salt, nickel salt, copper salt, palladium complex, or ruthenium complex.

[0019] According to a preferred embodiment of the present invention, the iron salt includes at least one of Fe2(SO4)3, (CH3COO)2Fe, FeCl3, FeBr3, FeBr2 or Fe(acac)3.

[0020] According to a preferred embodiment of the present invention, the cobalt salt includes at least one of CoCl2, (CH3COO)2Co, Co, Co(acac)2, (PPh3)3CoCl or Co(OH)2.

[0021] According to a preferred embodiment of the present invention, the nickel salt includes at least one of Ni, Ni(NO3)2·6H2O, NiCl2·6H2O, NiBr2 or Ni(PPh3)4.

[0022] According to a preferred embodiment of the present invention, the copper salt includes at least one of CuCl2, CuO, CuSCN, Cu2O, CH3COOCu, or Cu2S.

[0023] According to a preferred embodiment of the present invention, the palladium complex includes at least one of Pd(PPh3)2Cl2, Pd(PPh3)4, or PdO.

[0024] According to a preferred embodiment of the present invention, the ruthenium complex includes at least one of RuCl3 and Ru(bpy)3Cl2·6H2O.

[0025] According to a preferred embodiment of the present invention, the reaction temperature is 0~120°C. For example, it includes 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, or any sub-range composed of two of the above values.

[0026] According to a preferred embodiment of the present invention, the reaction temperature is 40°C to 100°C. For example, it includes 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, or any sub-range composed of any two of the above values.

[0027] According to a preferred embodiment of the present invention, the reaction temperature is 60°C to 80°C. For example, it includes 60°C, 65°C, 70°C, 75°C, 80°C, or any sub-range consisting of two of the above values.

[0028] According to a preferred embodiment of the present invention, the reaction time is 0.5h to 24h. For example, it includes 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, or any sub-range composed of any two of the above values.

[0029] According to a preferred embodiment of the present invention, the reaction time is 2h to 20h. For example, it includes 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, or any subrange consisting of two of the above values.

[0030] According to a preferred embodiment of the present invention, the reaction time is 4h to 12h. For example, it includes 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, or any subrange composed of two of the above values.

[0031] According to a preferred embodiment of the present invention, the molar volume ratio of compound II to solvent is 0.2 mmol: 1-3 mL.

[0032] According to a preferred embodiment of the present invention, the method further includes a post-reaction purification step, wherein the eluent for purification is a mixed solution of petroleum ether, dichloromethane and ethyl acetate.

[0033] According to a preferred embodiment of the present invention, the eluent for column chromatography purification is a mixed solution of petroleum ether: dichloromethane: ethyl acetate in a volume ratio of 2~50:1:1.

[0034] The preparation method according to embodiments of the present invention has at least the following beneficial effects: The preparation method of this invention has high reaction atom utilization and can efficiently synthesize functionalized benzothiomorpholine-3-one compounds. It has the advantages of simple synthesis steps, safe operation, and good compatibility of the synthesis method with functional groups. It yields benzothiomorpholine-3-one compounds with very high added value, high yield, and high purity, which greatly saves experimental or production costs and is easy to industrialize.

[0035] The third aspect of the present invention provides the use of the benzothiomorpholine-3-one compound described in the first aspect of the present invention in the preparation of therapeutic and / or preventive antitumor drugs.

[0036] Other features and advantages of the invention will be set forth in the description which follows, and will be apparent in part from the description, or may be learned by practicing the invention.

[0037] Definitions and general terms “C 1-6 "alkyl" indicates an alkyl group with a total number of 1-6 carbon atoms, including C64. 1-6 straight-chain alkyl, C 1-6 Branched alkyl groups and C 3-6 The cycloalkyl group can be, for example, a straight-chain alkyl group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; a branched-chain alkyl group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; or a cycloalkyl group with a total of 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, cyclopentyl, methylcyclopentyl, cyclohexyl, etc. Regarding "C 1-3 "alkyl" has a similar interpretation, except that the number of carbon atoms is different.

[0038] “C 1-6 "halogenated alkyl" and "C" 1-6 The definition of "alkyl" is similar, except that "C" is different. 1-6 At least one H atom in the "halogenated alkyl group" is substituted by any halogen.

[0039] “C 1~6 "Fluoroalkyl" and "C" 1-6 The definition of "alkyl" is similar, except that "C" is different. 1-6 At least one H atom in a fluoroalkyl group is replaced by fluorine. For example, trifluoromethyl.

[0040] “C 1-6 "alkoxy group" refers to an alkoxy group with a total number of 1-6 carbon atoms, including C64 and C64. 1-6 straight-chain alkoxy, C 1-6 Branched alkoxy groups and C 2-6The cycloalkoxy group can be, for example, a straight-chain alkoxy group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; a branched-chain alkoxy group with a total of 1, 2, 3, 4, 5, or 6 carbon atoms; or a cycloalkoxy group with a total of 2, 3, 4, 5, or 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, etc. Regarding "C 1-3 The "alkoxy group" has a similar explanation, except that the number of carbon atoms is different.

[0041] "Halogen" includes any one or more of fluorine, chlorine, bromine, and iodine.

[0042] “C 2~6 The ester group represents the structural formula as follows: Ester groups with a total number of carbon atoms of 2 to 6, representative examples include methyl formate, ethyl formate, ethyl acetate, methyl acetate, etc. Attached Figure Description

[0043] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 The proton NMR spectrum of the compound in Example 1; Figure 2 The carbon NMR spectrum of the compound in Example 1; Figure 3 The proton NMR spectrum of the compound in Example 2; Figure 4 The carbon NMR spectrum of the compound in Example 2; Figure 5 The proton NMR spectrum of the compound in Example 3; Figure 6 The carbon NMR spectrum of the compound in Example 3; Figure 7 The nuclear magnetic resonance fluorine spectrum of the compound in Example 3; Figure 8 The proton NMR spectrum of the compound in Example 4; Figure 9 The carbon NMR spectrum of the compound in Example 4; Figure 10 The proton NMR spectrum of the compound in Example 5; Figure 11 The carbon NMR spectrum of the compound in Example 5; Figure 12 The proton NMR spectrum of the compound in Example 6; Figure 13 The carbon NMR spectrum of the compound in Example 6; Figure 14The proton NMR spectrum of the compound in Example 7; Figure 15 The carbon NMR spectrum of the compound in Example 7; Figure 16 The proton NMR spectrum of the compound in Example 8; Figure 17 The carbon NMR spectrum of the compound in Example 8; Figure 18 The proton NMR spectrum of the compound in Example 9; Figure 19 The carbon NMR spectrum of the compound in Example 9; Figure 20 The proton NMR spectrum of the compound in Example 10; Figure 21 The carbon NMR spectrum of the compound in Example 10; Figure 22 The proton NMR spectrum of the compound in Example 11; Figure 23 The carbon NMR spectrum of the compound in Example 11; Figure 24 The nuclear magnetic resonance fluorine spectrum of the compound in Example 11; Figure 25 The proton NMR spectrum of the compound in Example 12; Figure 26 The carbon NMR spectrum of the compound in Example 12 is shown. Detailed Implementation

[0044] The following are specific embodiments of the present invention, and the technical solutions of the present invention will be further described in conjunction with the embodiments, but the present invention is not limited to these embodiments.

[0045] Unless otherwise specified, the reagents, methods and equipment used in this invention are all conventional reagents, methods and equipment in this technical field.

[0046] Example 1 Example 1 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0047] 30.5 mg of 3-benzylbenzothiazolium salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 1 mL of acetonitrile were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 63%, and the compound was a white solid.

[0048] The proton NMR spectrum of the obtained compound is as follows: Figure 1 Carbon NMR spectrum, such as Figure 2 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.56 – 7.52 (m, 3H), 7.22(s, 6H), 7.09 – 7.06 (m, 4H), 6.92 – 6.89 (m, 2H), 6.82 – 6.79 (m, 1H), 6.75– 6.71 (m, 3H), 6.03 (s, 1H), 5.56 (d, J = 16.4 Hz, 1H), 4.95 (d, J = 16.4 Hz, 1H).

[0049] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 165.9, 143.0, 139.1,136.6, 135.6, 128.8, 128.7, 128.4, 128.1, 128.1, 127.9, 127.5, 127.2, 125.9,124.4, 122.9, 119.0, 117.7, 116.1, 66.5, 50.8.

[0050] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 27 H 22 N2OS [M+H] + Theoretical calculated value: 423.1525; Test data: 423.1516.

[0051] Example 2 Example 2 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0052] 38.3 mg of 3-(4-bromobenzyl)benzothiazole salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 3 mL of dimethyl sulfoxide were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 51%, and the compound was a white solid.

[0053] The proton NMR spectrum of the obtained compound is as follows: Figure 3 Carbon NMR spectrum, such as Figure 4 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.59 – 7.49 (m, 3H), 7.32(d, J = 8.0 Hz, 2H), 7.27 – 7.19 (m, 3H), 7.15 – 7.03 (m, 4H), 6.78 – 6.69 (m,6H), 5.94 (s, 1H), 5.46 (d, J = 16.4 Hz, 1H), 4.91 (d, J = 16.4 Hz, 1H).

[0054] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 165.8, 143.0, 138.8,135.6, 135.5, 131.8, 128.8, 128.5, 128.2, 128.0, 128.0, 127.7, 127.6, 124.6,122.9, 121.0, 119.1, 117.5, 116.1, 66.4, 50.2.

[0055] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 27 H 21 BrN2OS [M+Na] + Theoretical calculated value: 523.0450; Test data: 523.0441.

[0056] Example 3 Example 3 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0057] 37.3 mg of 3-(4-trifluoromethylbenzyl)benzothiazole salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of methanol were mixed thoroughly and reacted under oxygen conditions at 80 °C for 8 hours to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 71%, and the compound was a white solid.

[0058] The proton, carbon, and fluorine NMR spectra of the obtained compounds are as follows: Figures 5-7 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.56 – 7.53 (m, 3H), 7.45(d, J = 8.0 Hz, 2H), 7.27 – 7.19 (m, 3H), 7.15 – 7.04 (m, 4H), 6.97 (d, J = 8.0Hz, 2H), 6.76 – 6.71 (m, 4H), 5.90 (s, 1H), 5.57 (d, J = 16.8 Hz, 1H), 5.01(d, J = 16.8 Hz, 1H).

[0059] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 165.9, 142.9, 140.7,138.8, 135.4, 129.7, 129.4, 128.8, 128.6, 128.2, 128.1, 128.0, 127.6, 126.2,125.7 (q, J = 3.8 Hz), 124.6, 123.0, 119.2, 117.4, 116.1, 66.4, 50.4.

[0060] Nuclear magnetic resonance fluorine spectrum data: 19 F NMR (376 MHz, CDCl3) δ -62.51.

[0061] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 28 H 21 F3N2OS [M+H] + Theoretical calculated value: 491.1399; Test data: 491.1398.

[0062] Example 4 Example 4 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0063] 33.5 mg of 6-methoxybenzothiazole salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of N,N-dimethylformamide were mixed thoroughly and reacted under oxygen conditions at 80 °C for 8 hours to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 75%, and the compound was a green solid.

[0064] The proton NMR spectrum of the obtained compound is as follows: Figure 8 Carbon NMR spectrum, such as Figure 9 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.58 – 7.52 (m, 2H), 7.24 –7.20 (m, 6H), 7.10 – 7.03 (m, 3H), 6.93 – 6.87 (m, 2H), 6.75 – 6.70 (m, 4H), 6.62 (dd, J = 9.2, 2.8 Hz, 1H), 6.09 (s, 1H), 5.51 (d, J = 16.4 Hz, 1H), 4.92(d, J = 16.4 Hz, 1H), 3.81 (s, 3H).

[0065] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 165.5, 156.0, 143.0,136.7, 135.8, 132.8, 128.7, 128.7, 128.3, 128.1, 128.0, 127.2, 125.9, 124.2,118.9, 118.8, 116.1, 113.6, 112.4, 66.8, 55.6, 50.8.

[0066] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 28 H 24 N₂O₂S [M+Na] + Theoretical calculated value: 475.1450; Test data: 475.1441.

[0067] Example 5 Example 5 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0068] 33.3 mg of 3-(3,5-dimethylbenzyl)benzothiazole salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of N,N-dimethylacetamide were mixed thoroughly and reacted under oxygen conditions at 80 °C for 8 hours to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 48%, and the compound was a green solid.

[0069] The proton NMR spectrum of the obtained compound is as follows: Figure 10 Carbon NMR spectrum, such as Figure 11 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (500 MHz, CDCl3)δ 7.58 – 7.53 (m, 3H), 7.24 –7.21 (m, 3H), 7.11 – 7.06 (m, 4H), 6.87 (s, 1H), 6.81 – 6.75 (m, 3H), 6.72(t, J = 7.5 Hz, 1H), 6.51 (s, 2H), 6.21 (s, 1H), 5.69 (d, J = 16.5 Hz, 1H), 4.70(d, J = 16.5 Hz, 1H), 2.20 (s, 6H).

[0070] Carbon NMR spectroscopy data: 13 C NMR (126 MHz, CDCl3) δ 165.8, 143.0, 139.3,138.3, 136.5, 135.6, 128.9, 128.8, 128.3, 128.2, 128.0, 127.6, 127.5, 124.4,123.3, 122.9, 118.8, 117.8, 116.0, 66.3, 51.0, 21.3.

[0071] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 29 H 26 N2OS [M+Na] + Theoretical calculated value: 473.1658; Test data: 473.1649.

[0072] Example 6 Example 6 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0073] 30.5 mg of 3-benzylbenzothiazole salt (0.1 mmol), 11.8 μL of p-chlorobenzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of dimethyl thionyl chloride were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 64%, and the compound was a white solid.

[0074] The proton NMR spectrum of the obtained compound is as follows: Figure 12 Carbon NMR spectrum, such as Figure 13 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (500 MHz, CDCl3) δ 7.53 – 7.45 (m, 3H), 7.26 –7.17 (m, 5H), 7.14 – 7.07 (m, 4H), 6.92 – 6.91 (m, 2H), 6.88 – 6.83 (m, 1H), 6.76 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 8.0 Hz, 2H), 5.96 (s, 1H), 5.50 (d, J =16.0 Hz, 1H), 5.00 (d, J = 16.5 Hz, 1H).

[0075] Carbon NMR spectroscopy data: 13 C NMR (126 MHz, CDCl3) δ 165.4, 142.7, 139.0,136.4, 134.4, 134.3, 129.5, 128.9, 128.8, 128.4, 127.9, 127.8, 127.3, 125.9,124.6, 122.5, 119.3, 117.9, 116.1, 65.9, 50.8.

[0076] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 27 H 21 ClN2OS [M+K] + Theoretical calculated value: 495.0694; Test data: 495.0685.

[0077] Example 7 Example 7 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0078] 30.5 mg of 3-benzylbenzothiazolium salt (0.1 mmol), 12.1 μL of p-methoxybenzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of acetonitrile were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 46%, and the compound was a green solid.

[0079] The proton NMR spectrum of the obtained compound is as follows: Figure 14 Carbon NMR spectrum, such as Figure 15 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.51 – 7.48 (m, 1H), 7.45 –7.41 (m, 2H), 7.23 – 7.19 (m, 3H), 7.10 – 7.04 (m, 4H), 6.93 – 6.90 (m, 2H),6.83 – 6.79 (m, 1H), 6.76 – 6.69 (m, 5H), 5.54 (d, J = 16.4 Hz, 1H), 4.95 (d, J = 16.4 Hz, 1H), 3.74 (s, 3H).

[0080] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 166.1, 159.4, 143.1,139.1, 136.6, 129.4, 128.7, 128.7, 127.8, 127.5, 127.4, 127.2, 125.9, 124.3, 123.0, 118.9, 117.7, 116.1, 113.4, 66.0, 55.2, 50.7.

[0081] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 28 H 24 N₂O₂S [M+Na] +Theoretical calculated value: 475.1450; Test data: 475.1445.

[0082] Example 8 Example 8 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0083] 30.5 mg of 3-benzylbenzothiazole salt (0.1 mmol), 13.7 μL of 4-ethylbenzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of dimethyl thionyl chloride were mixed thoroughly and reacted under oxygen conditions at 80 °C for 8 hours to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 63%, and the compound was a yellow solid.

[0084] The proton NMR spectrum of the obtained compound is as follows: Figure 16 Carbon NMR spectrum, such as Figure 17 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (500 MHz, CDCl3) δ 7.51 – 7.49 (m, 1H), 7.43(d, J = 8.0 Hz, 2H), 7.20 – 7.17 (m, 3H), 7.09 – 7.04 (m, 6H), 6.88 (d, J = 7.0Hz, 2H), 6.82 – 6.77 (m, 1H), 6.73 – 6.71 (m, 3H), 5.55 (d, J = 16.5 Hz, 1H), 4.95 (d, J = 16.5 Hz, 1H), 2.58 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H).

[0085] Carbon NMR spectroscopy data: 13C NMR (126 MHz, CDCl3)δ 165.9, 144.4, 143.1, 139.1,136.6, 132.8, 128.7, 128.6, 127.9, 127.8, 127.6, 127.4, 127.1, 125.9, 124.2,122.9, 118.8, 117.6, 116.0, 66.2, 50.6, 28.3, 15.2.

[0086] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 29 H 26 N2OS [M+Na] + Theoretical calculated value: 473.1658; Test data: 473.1648.

[0087] Example 9 Example 9 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0088] 30.5 mg of 3-benzylbenzothiazole salt (0.1 mmol), 13.7 μL of 4-ethylbenzaldehyde (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of dimethyl thionyl chloride were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 60%, and the compound was a white solid.

[0089] The proton NMR spectrum of the obtained compound is as follows: Figure 18 Carbon NMR spectrum, such as Figure 19 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.62 (m, 2H), 7.56 –7.47 (m, 3H), 7.26 – 7.04 (m, 7H), 6.90 – 6.86 (m, 3H), 6.76 (t, J = 7.2 Hz,1H), 6.66 – 6.63 (m, 2H), 5.88 (s, 1H), 5.42 (d, J = 16.4 Hz, 1H), 5.05 (d, J =16.4 Hz, 1H).

[0090] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 164.8, 142.4, 141.3,138.8, 136.2, 131.9, 129.0, 128.8, 128.1, 128.1, 127.4, 125.9, 124.8, 122.0,119.7, 118.3, 118.0, 116.1, 112.3, 66.1, 50.9.

[0091] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 28 H 21 N3OS [M+H] + Theoretical calculated value: 448.1478; Test data: 448.1470.

[0092] Example 10 Example 10 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0093] 30.5 mg of 3-benzylbenzothiazole salt (0.1 mmol), 16.4 mg of methyl p-formylbenzoate (0.1 mmol), 18.2 μL of aniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of dimethyl thionyl chloride were mixed thoroughly and reacted under oxygen conditions at 80 °C for 8 hours to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 58%, and the compound was a green solid.

[0094] The proton NMR spectrum of the obtained compound is as follows: Figure 20 Carbon NMR spectrum, such as Figure 21 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.92 – 7.85 (m, 2H), 7.64 –7.58 (m, 2H), 7.55 – 7.50 (m, 1H), 7.24 – 7.19 (m, 3H), 7.11 – 7.03 (m, 4H), 6.92 – 6.89 (m, 2H), 6.84 – 6.79 (m, 1H), 6.75 – 6.70 (m, 3H), 6.04 (s, 1H), 5.51 (d, J = 16.4 Hz, 1H), 4.98 (d, J= 16.4 Hz, 1H), 3.88 (s, 3H).

[0095] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3)δ 166.5, 165.3, 142.7, 140.7,138.9, 136.3, 130.1, 129.4, 128.9, 128.8, 128.2, 128.0, 127.8, 127.3, 125.9,124.7, 122.6, 119.4, 117.9, 116.2, 66.3, 52.2, 50.9.

[0096] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 29 H 24 N₂O₃S [M+Na] + Theoretical calculated value: 503.1399; Test data: 503.1389.

[0097] Example 11 Example 11 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0098] 30.5 mg of 3-benzylbenzothiazole salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 18.8 μL of 4-fluoroaniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of dimethyl thionyl chloride were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 73%, and the compound was a white solid.

[0099] The proton, carbon, and fluorine NMR spectra of the obtained compounds are as follows: Figures 22-24 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.49 (m, 3H), 7.29 –7.13 (m, 6H), 7.10 – 7.06 (m, 2H), 6.97 – 6.86 (m, 2H), 6.85 – 6.70 (m, 3H),6.68 – 6.64 (m, 2H), 5.87 (s, 1H), 5.55 (d, J = 16.8 Hz, 1H), 4.96 (d,J = 16.4Hz, 1H).

[0100] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3)δ 165.9, 158.0, 155.6, 139.3(d, J = 2.1 Hz), 139.1, 136.5, 135.4, 128.7, 128.5, 128.2 (d, J = 11.6 Hz),127.9, 127.6, 127.2, 125.9, 124.4, 122.8, 117.7 (d, J = 3.7 Hz), 117.6, 115.3 (d, J = 22.3 Hz), 67.0, 50.8.

[0101] Nuclear magnetic resonance fluorine spectrum data: 19 F NMR (376 MHz, CDCl3) δ -113.2.

[0102] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 27 H 21 FN2OS [M+K] + Theoretical calculated value: 479.0990; Test data: 479.0980.

[0103] Example 12 Example 12 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0104] 30.5 mg of 3-benzylbenzothiazolium salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 31.8 μL of 4-tert-butylaniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of acetonitrile were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 86%, and the compound was a white solid.

[0105] The proton NMR spectrum of the obtained compound is as follows: Figure 25 Carbon NMR spectrum, such as Figure 26 As shown, the structural characterization data are as follows: 1H NMR spectroscopy data: 1H NMR (400 MHz, CDCl3)δ 7.62 – 7.50 (m, 3H), 7.27 –7.17 (m, 6H), 7.15 – 7.05 (m, 4H), 6.96 – 6.88 (m, 2H), 6.84 – 6.78 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 5.93 (s, 1H), 5.58 (d, J = 16.4 Hz, 1H), 4.95 (d, J =16.8 Hz, 1H), 1.27 (s, 9H).

[0106] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 165.9, 141.5, 140.4,139.1, 136.6, 136.0, 128.7, 128.3, 128.1, 128.1, 127.9, 127.4, 127.2, 125.9,125.6, 124.4, 123.1, 117.7, 115.5, 66.5, 50.8, 33.9, 31.5.

[0107] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 31 H 30 N2OS [M+Na] + Theoretical calculated value: 501.1971; Test data: 501.1963.

[0108] Example 13 Example 13 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0109] 30.5 mg of 3-benzylbenzothiazole salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 21.4 mg of 4-methylaniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of N,N-dimethylformamide were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 83%, and the compound was a yellow solid.

[0110] The structural characterization data of the obtained compounds are as follows: 1H NMR spectroscopy data: 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.47 (m, 3H), 7.23 –7.19 (m, 6H), 7.11 – 7.04 (m, 2H), 6.99 – 6.83 (m, 4H), 6.82 – 6.79 (m, 1H),6.68 – 6.54 (m, 2H), 5.54 (d, J = 16.8 Hz, 1H), 4.96 (d, J = 16.4 Hz, 1H), 2.19(s, 3H).

[0111] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 165.9, 140.6, 139.1,136.6, 135.8, 129.3, 128.7, 128.4, 128.3, 128.2, 128.1, 127.9, 127.4, 127.1,125.9, 124.3, 123.0, 117.7, 116.4, 66.8, 50.7, 20.5.

[0112] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 28 H 24 N2OS [M+H] + Theoretical calculated value: 437.1682; Test data: 437.1677.

[0113] Example 14 Example 14 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0114] 30.5 mg of 3-benzylbenzothiazole salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 24.6 mg of 4-methoxyaniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of N,N-dimethylacetamide were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain a crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 81%, and the compound was a brown solid.

[0115] The structural characterization data of the obtained compounds are as follows: 1H NMR spectroscopy data: 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.46 (m, 3H), 7.24 –7.18 (m, 6H), 7.09 – 7.03 (m, 2H), 6.96 – 6.91 (m, 2H), 6.83 – 6.79 (m, 1H), 6.65 (s, 4H), 5.58 (s, 1H), 5.51 (d, J = 16.4 Hz, 1H), 4.99 (d, J = 16.4 Hz, 1H), 3.70 (s, 3H).

[0116] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 166.1, 153.4, 139.2,136.8, 136.6, 135.9, 128.7, 128.4, 128.1, 128.1, 128.0, 127.4, 127.2, 126.0,124.3, 123.0, 118.5, 117.7, 114.2, 67.7, 55.5, 50.7.

[0117] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 28 H 24 N₂O₂S [M+Na] + Theoretical calculated value: 475.1450; Test data: 475.1443.

[0118] Example 15 Example 15 provides a benzothiomorpholino-3-one compound with the following structural formula: Preparation method is as follows:

[0119] 30.5 mg of 3-benzylbenzothiazolium salt (0.1 mmol), 10.2 μL of benzaldehyde (0.1 mmol), 25.0 μL of 4-trifluoromethylaniline (0.2 mmol), Raney nickel (10 mol %), and 2 mL of acetonitrile were mixed thoroughly and stirred at 80 °C for 8 hours under oxygen conditions to obtain the crude product. The crude product was purified by column chromatography to obtain the compound. The yield of this preparation method was 66%, and the compound was a white solid.

[0120] The structural characterization data of the obtained compounds are as follows: 1H NMR spectroscopy data: 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.50 (m, 3H), 7.31(d, J = 8.4 Hz, 2H), 7.27 – 7.17 (m, 6H), 7.15 – 7.08 (m, 2H), 6.91 – 6.88 (m,2H), 6.83 – 6.79 (m, 3H), 6.52 (s, 1H), 5.60 (d, J = 16.4 Hz, 1H), 4.94 (d, J =16.4 Hz, 1H).

[0121] Carbon NMR spectroscopy data: 13 C NMR (101 MHz, CDCl3) δ 165.4, 145.7, 138.9,136.3, 134.8, 128.7, 128.7, 128.3, 127.9, 127.8, 127.8, 127.3, 126.2 (q, J =3.8 Hz), 125.8, 124.7, 123.4, 122.4, 120.3 (q, J = 32.9 Hz), 117.8, 114.9, 65.4, 50.9.

[0122] Nuclear magnetic resonance fluorine spectrum data: 19 F NMR (376 MHz, CDCl3) δ -61.24.

[0123] High-resolution mass spectrometry (electrospray ionization mass spectrometry): C 28 H 21 F3N2OS [M+H] + Theoretical calculated value: 491.1399; Test data: 491.1390.

[0124] Activity test The anti-tumor cell activity of the products obtained in Examples 1-15 was tested.

[0125] (1) Test method: Each compound was prepared into a solution of 100 μg·mL -1 The methanol solution, and the positive control drugs 5-fluorouracil (5-FU) and docetaxel were prepared to a concentration of 100 μg / mL. -1 The inhibitory effects of each compound on K562 and HL-60 cells were tested using DMSO solution, with methanol and DMSO solvent as blank controls, respectively, and the MTT assay was used.

[0126] (2) Preparation of cell culture medium: Pour one packet of RPMI-1640 culture medium powder (Net wt 10.4g) into a clean beaker, dissolve it in 900mL of ultrapure water, and add 100mg·mL⁻¹ -1 1 mL of streptomycin, 0.5 mL of penicillin, and 2 g of NaHCO3 were mixed magnetically and then filtered through a 0.22 μm filter in a clean bench using a pre-sterilized Zeiss filter. The filtrate was stored directly in a 450 mL / bottle after moist heat sterilization. Before using the culture medium, frozen serum was inactivated at 56 °C for 30 min and then added to the prepared RPMI-1640 culture medium (50 mL serum in 450 mL of culture medium). The mixture was gently shaken, capped, sealed with aluminum foil, and stored at 4 °C. MTT solution preparation: 50 mg of MTT (3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazolium bromide) powder was dissolved in 10 mL of PBS solution, filtered through a 0.22 μm filter, and stored at 4 °C.

[0127] (3) Antitumor activity test: K562 cells and HL-60 cells in the logarithmic growth phase were centrifuged at 3000 rpm for 3 min at 4℃. The supernatant was removed, and the cells were diluted with fresh RPMI-1640 medium to a cell suspension of 1×10⁵ cells / mL. 200 μL of the suspension was seeded into each well of a 96-well plate and cultured for 1 h at 37℃ with 5% CO₂. 2 μL of sample solution was added to each well, with 3 parallel wells for each sample. Two blank control groups of 3 wells each were also included. After adding the sample, the cells were cultured under the same conditions for 24 h. After 24 h, the morphological changes of the cells were observed under an optical microscope to preliminarily determine whether the sample had cytotoxic activity. Photographs were taken if necessary. 5 mg·mL⁻¹ of the solution was added to each well. -1 Add 20 μL of MTT solution to each well and incubate for 4 h. Centrifuge the 96-well plate (4℃, 2000 rpm, 20 min) to remove the supernatant. Add 150 μL of DMSO to each well and shake thoroughly to completely dissolve the purple precipitate. Measure the optical density (OD) at 570 nm using a microplate reader. Take the average value for each sample and calculate IR% = (OD). 空白 -OD 样品 ) / OD 空白 The inhibition rate (IR%) is calculated using the formula ×100%.

[0128] The inhibitory activity of the compounds in Examples 1-15 against the proliferation of four types of tumor cells was tested using the MTT assay, and the results are shown in Table 1.

[0129] Table 1. MTT assay results (%) of the inhibitory activity against the proliferation of two types of tumor cells in Examples 1-15.

[0130] As shown in Table 1, the benzothiomorpholine-3-one compound prepared in this invention has a certain inhibitory effect on K562 cells and HL-60 cells, indicating that it has certain anti-tumor cell activity and has potential application value in anti-tumor cell drugs.

[0131] The present invention has been described in detail above with reference to the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A benzothiomorpholino-3-one compound, characterized in that, It has the structure shown in Equation I: ； Wherein, R1 is one or more substitutions, each independently selected from H, halogen, nitro, cyano, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl halogenates; R2 is one or more substitutions, each independently selected from H, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl halogenates; R3 can be one or more substitutions, each independently selected from H, halogen, cyano, C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 Halogenated alkyl, C 2~6 ester group; R4 is one or more substitutions, each independently selected from H, halogen, C. 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl halogenates.

2. The benzothiomorpholino-3-one compound according to claim 1, characterized in that, R1 is one or more substitutions, each independently selected from H, halogen, C. 1~6 alkyl, C 1~6 Fluorinated alkyl groups.

3. The benzothiomorpholino-3-one compound according to claim 1 or 2, characterized in that, R4 is one or more substitutions, each independently selected from H, halogen, C. 1~3 alkyl, C 1~3 alkoxy, C 1~6 Fluorinated alkyl groups.

4. The benzothiomorpholino-3-one compound according to any one of claims 1 to 3, characterized in that, The benzothiomorpholino-3-one compound has the following structural formula: 。 5. A method for preparing the benzothiomorpholino-3-one compound as described in any one of claims 1 to 4, characterized in that, Includes the following steps: Compounds II, III, and IV, along with a metal catalyst and a solvent, were mixed and reacted to obtain the benzothiomorpholin-3-one compound. The structural formulas of compounds II, III, and IV are as follows: 、 、 。 6. The preparation method according to claim 5, characterized in that, The molar ratio of compound II, compound III and compound IV is 1:(1~4):(1~4).

7. The preparation method according to claim 5, characterized in that, The metal catalyst includes at least one of iron salt, cobalt salt, nickel salt, copper salt, palladium complex, or ruthenium complex.

8. The preparation method according to claim 5, characterized in that, The solvent includes at least one of ethanol, tetrahydrofuran, acetonitrile, 1,2-dichloroethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, or water.

9. The preparation method according to claim 5, characterized in that, The reaction temperature is 0~120℃.

10. The use of the benzothiomorpholino-3-one compound according to any one of claims 1 to 4 in the preparation of therapeutic and / or preventive antitumor drugs.

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