Chiral cis-cyclopropane compounds, processes for their preparation and uses thereof

Abstract

This invention discloses chiral cis-cyclopropane compounds, their preparation methods, and applications. The chiral cis-cyclopropane compound synthesis involves the following steps: using but-3-enoic acid derivatives and thioylide reagents as raw materials, reacting them in a solvent under the action of chiral ligands and a metal catalyst to generate the chiral cis-cyclopropane compound. The synthetic strategy of this invention utilizes a newly designed chiral monodentate oxazoline ligand to coordinate the olefinic moiety and directing group in the substrate molecule with a Pd(II) catalyst to form a complex intermediate containing a β-chiral center. Then, stereoselective nucleophilic palladiumization occurs under the action of thioylide reagents, followed by S... N Type II dimethyl sulfoxide elimination and reductive elimination form chiral cis-cyclopropane compounds. This method offers excellent yields and enantioselectivity, and is compatible with various electron-deficient and electron-rich sulfur ylides, as well as biorelated molecules. This invention provides a novel and efficient route for the synthesis of chiral cyclopropane compounds.

Description

Technical Field

[0001] This invention belongs to the field of asymmetric catalytic synthesis, specifically relating to chiral cis-cyclopropane compounds, their preparation methods, and applications. Background Technology

[0002] Cyclopropanes are a special class of structural units in organic synthesis and medicinal chemistry, widely found in various natural products and drugs, thanks to their unique three-membered ring strain, conformational rigidity, and favorable physicochemical properties. Besides direct biological activity, cyclopropane units are also versatile synthetic intermediates used in ring-opening reactions and functional group transformations; therefore, their enantioselective construction has been a long-term goal in synthetic organic chemistry. To date, most catalytic strategies for asymmetric cyclopropanation have focused on three types of reactions: Simmons-Smith cyclopropanation, transition metal-catalyzed carbene-to-olefin transfer reactions, and Michael-initiated cyclization reactions (MIRC). However, the vast majority of reported studies are still limited to activated olefins (such as styrene, allyl alcohol, or α,β-unsaturated carbonyl compounds). These substrates can effectively promote regio- and stereoselective functionalization through electronic effects or coordination-directing effects. In stark contrast, the asymmetric cyclopropanation of electronically neutral, unactivated olefins remains a significant challenge due to their low reactivity and high conformational flexibility. Although a few asymmetric transformations have been reported, most are limited to transition metal-catalyzed carbene transfer reactions and require the use of highly reactive, potentially explosive, or toxic diazo reagents. Therefore, further development of synthetic methods for chiral cyclopropanes is needed. Summary of the Invention

[0003] The purpose of this invention is to provide a chiral cyclopropane compound, its preparation method, and its applications. The synthetic strategy of this invention involves the coordination of the olefin moiety and directing group in the substrate molecule with a Pd(II) catalyst to form a complex intermediate containing a β-chiral center, under the action of a newly designed chiral monodentate oxazoline (MOX) ligand. This intermediate then undergoes stereoselective nucleophilic palladiumization under thioylide action, followed by S… N Type II dimethyl sulfoxide elimination and reductive elimination form chiral cis-cyclopropane compounds. This method exhibits excellent yields and enantioselectivity (>90% ee, >80% yield in most cases) and is compatible with various electron-deficient and electron-rich sulfur ylides as well as biorelated molecules. This invention provides a novel and efficient route for the synthesis of chiral cyclopropane compounds.

[0004] To achieve the above objectives, the technical solution of the present invention is as follows:

[0005] The first aspect of this invention is to provide a method for preparing a chiral cis-cyclopropane compound, comprising the following steps: using a but-3-enoic acid derivative and a thioylide reagent as raw materials, reacting them in a solvent under the action of a chiral ligand and a metal catalyst to generate a chiral cis-cyclopropane compound; wherein the but-3-enoic acid derivative is selected from at least one compound of the general formula shown in Formula I: ; wherein, the R 1 The sulfur ylide reagent is selected from hydrogen, halogen, and alkoxy groups; the sulfur ylide reagent is selected from at least one compound of the general formula shown in Formula II. ; wherein, the R 2 Selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted alkyl groups; the chiral ciscyclopropane compound is selected from at least one compound of the general formula shown in Formula III: ; where R in Equation III 1 With R in Equation I 1 The corresponding values ​​are the same; R in Equation III 2 With R in Equation II 2 The correspondence is the same.

[0006] The reaction of this invention, catalyzed by a metal catalyst, utilizes butyric acid derivatives and thioylide reagents as substrates, and a chiral monodentate oxazoline ligand as the chiral ligand, to prepare a chiral cis-cyclopropane compound (Formula III) under mild conditions. The chiral monodentate oxazoline ligand, as a chiral ligand, not only accelerates the reaction by promoting the dissociation of the trimer Pd(OAc)2 precatalyst into catalytically active monomeric species (thus promoting olefin coordination and insertion), but also, as a transient chiral ligand, achieves stereochemical control through selective surface recognition of olefins.

[0007] In a preferred embodiment, in formula I, the R 1 Selected from hydrogen, chlorine, and C1-C5 alkoxy groups; preferably, the R 1 Selected from hydrogen, chlorine, and C1-C3 alkoxy groups; more preferably, the R 1 The compounds are selected from hydrogen, chlorine, and methoxy; more preferably, Formula I is selected from at least one of the following compounds:

[0008] .

[0009] As a preferred embodiment, in Formula II, the R 2 Selected from phenyl, naphthyl, furanyl, thiophene, halogen-substituted phenyl, nitro-substituted phenyl, alkyl-substituted phenyl, haloalkyl-substituted phenyl, alkoxy-substituted phenyl, cyano-substituted phenyl, ester-substituted phenyl, sulfonyl-substituted phenyl, phenyl-substituted naphthyl, and C3-C15 alkyl; preferably, R 2The compound is selected from phenyl, naphthyl, furanyl, thiophene, halogen-substituted phenyl, nitro-substituted phenyl, C1-C3 alkyl-substituted phenyl, C1-C3 haloalkyl-substituted phenyl, C1-C3 alkoxy-substituted phenyl, cyano-substituted phenyl, C1-C3 ester-substituted phenyl, C1-C5 sulfonyl-substituted phenyl, phenyl-substituted naphthyl, and C3-C7 alkyl; more preferably, Formula II is selected from at least one of the following compounds:

[0010] .

[0011] In a preferred embodiment, the chiral ligand is selected from chiral monodentate oxazoline ligands; preferably, the chiral ligand is selected from any one of the following compounds:

[0012] .

[0013] In a preferred embodiment, the metal catalyst is at least one of palladium catalysts; preferably, the palladium catalyst is selected from at least one of palladium acetate, palladium chloride, palladium trifluoroacetate, and palladium bis(hexafluoroacetylacetone); and / or, the solvent is selected from alcohol solvents; preferably, the solvent is selected from at least one of hexafluoroisopropanol or trifluoroethanol.

[0014] In a preferred embodiment, the reaction temperature is room temperature to 60°C. o C; and / or, the reaction time is 12 to 24 hours.

[0015] In a preferred embodiment, the concentration of the butyric acid derivative in the solvent is 0.05~1.0 mol / L; and / or, the molar ratio of the butyric acid derivative to the sulfur ylide reagent is 1:(1.2-1.5); and / or, the molar ratio of the butyric acid derivative to the metal catalyst is 1:(0.05-0.2); and / or, the molar ratio of the butyric acid derivative to the chiral ligand is 1:(0.1~0.4).

[0016] A second aspect of the present invention is to provide a chiral cis-cyclopropane compound, said chiral cyclopropane compound being selected from at least one of the general structural formulas shown in Formula III: ; where R in Equation III 1 With R in Equation I 1 The corresponding values ​​are the same; R in Equation III 2 With R in Equation II 2 The correspondence is the same.

[0017] In a preferred embodiment, the chiral cis-cyclopropane compound is selected from at least one of the following compounds:

[0018] .

[0019] A third aspect of the invention is to provide the use of the chiral ciscyclopropane compound according to the second aspect of the invention as a synthetic chemical intermediate.

[0020] Chiral cyclopropane skeletons are widely found in various bioactive molecules, such as the plant growth regulator chlorhexidine, the antidepressant levamisole, and the oral hypoglycemic agent saxagliptin. This invention provides an efficient method for constructing chiral cyclopropane structural units, resulting in compounds with potential biological activity and applications. Furthermore, the rigid conformation of the cyclopropane ring effectively restricts molecular freedom, achieving a good spatial match with the target active pocket. This invention allows for the convenient introduction of chiral cyclopropane fragments into biologically relevant molecular skeletons, providing a new starting point for the subsequent discovery and structural optimization of lead compounds.

[0021] Advantages of this invention:

[0022] 1. The method of this invention has excellent yield and enantioselectivity (>90% ee, >80% yield in most cases); 2. It has broad substrate applicability and is compatible with various electron-deficient and electron-rich thioylides as well as biologically related molecules; 3. It efficiently constructs bioactive molecules, demonstrating the important application value of this method in the synthesis of complex molecules. Detailed Implementation

[0023] The present invention will be further described in detail below through specific embodiments.

[0024] A method for synthesizing chiral cyclopropane compounds, comprising the following general reaction formula:

[0025] Example 1: Following the synthesis steps of Method A, with a feed amount of 0.2 mmol (i.e., 1 equivalent), using A1 and B1 as raw materials, the target product P1 was synthesized in 91% yield. Specifically:

[0026] ;

[0027] Method A is as follows: Pd(OAc)2 (0.1 equiv.), chiral monodentate oxazoline ligand L13 (0.2 equiv.), and anhydrous hexafluoroisopropanol (4.0 mL) are added sequentially to an 8 mL screw-lined glass bottle (equipped with a rod-shaped polytetrafluoroethylene stir bar) that has been dried in an oven. The mixture is stirred at 60°C for 30 minutes and then cooled to room temperature. Subsequently, a but-3-enoic acid derivative (1.0 equiv.) and a thioyl ylide (1.2 equiv.) are added. The reaction tube is sealed and placed in an oil bath preheated to 60°C, and reacted at a low stirring speed of 200 rpm for 12 hours. After the reaction is complete, the mixture is concentrated under reduced pressure, and the crude product is purified by silica gel column chromatography to obtain the target chiral cyclopropanated product.

[0028] Method B: Compared with Method A, Method B is the same except that the amount of Pd(OAc)2 is 0.2 equiv and the amount of chiral monodentate oxazoline ligand is 0.4 equiv.

[0029] P1 is an unknown compound (prepared by method A). The detection data are as follows: yellow solid (R... f =0.41, petroleum ether / ethyl acetate = 3:1, v / v / ), product (60.3 mg).

[0030] 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.86 (dd, J = 4.3, 1.7 Hz,1H), 8.50 (dd, J = 7.7, 1.5 Hz, 1H), 8.38-8.32 (m, 1H), 8.03-7.97 (m, 2H),7.62-7.57 (m, 2H), 7.56-7.46 (m, 2H), 7.42 (t, J = 7.6 Hz, 2H), 3.16-3.06 (m,1H), 2.82 (dd, J = 16.1, 6.2 Hz, 1H), 2.65 (dd, J = 16.2, 8.2 Hz, 1H), 2.07-1.95 (m, 1H), 1.35-1.24 (m, 2H). 13C NMR (151 MHz, DMSO-d6) δ 198.6, 170.3,148.8, 138.2, 137.9, 136.5, 134.3, 132.8, 128.5, 128.0, 127.7, 126.9, 122.1,121.7, 116.2, 34.4, 22.0, 21.2, 14.1. HRMS (ESI) m / z Calcd for C 21 H 19 N2O2+ [M+H]+: 331.1441, found: 331.1448.

[0031] HPLC: The er value of P1 (92.8:7.2) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 10.77 min and 17.28 min.

[0032] Examples 1-12

[0033] It uses essentially the same preparation method as method A, but the different reaction conditions and results are shown in Table 1:

[0034] .

[0035] In Table 1, for Examples 1-12, the yields and diastereomeric proportions (dr) were determined by HPLC analysis at a reaction scale of 0.2 mmol (i.e., 1 equivalent), using 2-methoxynaphthalene as an internal standard and a Syncronis silica gel column. The enantiomeric proportions (er) were determined by chiral column HPLC. HFIP with a purity of 99.7% d was used in the experiments. b represents the separation yield; TFE: trifluoroethanol, HFIP: hexafluoroisopropanol, Trace: trace, rac: racemic; NA: not analyzed.

[0036] Examples 13-40

[0037] It uses the same raw materials and reaction conditions as Example 1, the only difference being the different chiral ligands. The specific chiral ligands and reaction results are shown in Table 2:

[0038]

[0039] Of the chiral ligands of this invention, L1, L2, L3, L4, L5, L6, L7, L10, L17, and L28 are previously reported compounds; the others are not. The synthetic methods for the unreported chiral monodentate oxazoline ligands have the following general reaction formula:

[0040] ;

[0041] (RI in the structural formula represents a haloalkane, which corresponds to XI or YI; X and Y correspond to the same X and Y in Table 2, and I represents a halogen, specifically iodine.)

[0042] Method C involves adding L1, a haloalkane, and potassium hydroxide sequentially to N,N-dimethylformamide (DMF) in a molar ratio of 1:1.5:1.5, with L1 having a concentration of 0.5 mol / L. The mixture is stirred for 12 hours under a nitrogen atmosphere at room temperature. After the reaction is complete, the DMF is evaporated to dryness, and the chiral monodentate oxazoline ligand product is obtained by silica gel column chromatography.

[0043] Method D involves sequentially adding L1, a haloalkane, cuprous iodide, N,N'-dimethylcyclohexane-1,2-diamine, and potassium phosphate to toluene in a molar ratio of 1:1.5:0.05:0.2:2. The concentration of L1 is 0.5 mol / L. The mixture is stirred for 24 h under a nitrogen atmosphere at 80°C. After the reaction is complete, the toluene is evaporated to dryness, and the chiral monodentate oxazoline ligand product is obtained by silica gel column chromatography.

[0044] The corresponding synthesized chiral monodentate oxazoline ligand products and their corresponding NMR data are as follows:

[0045] L8 is an unknown compound, a yellow solid (R). f = 0.31, petroleum ether / ethyl acetate = 5:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method C, the target product (408.0 mg) can be synthesized in 67% yield.

[0046] 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.7 Hz, 1H), 7.30-7.20 (m, 4H), 7.19-7.04 (m, 4H), 6.94 (s, 1H), 5.24 (s, 2H), 4.52-4.41 (m, 1H), 4.14 (t, J = 8.9 Hz, 1H), 3.95 (t, J = 7.9 Hz, 1H), 3.22 (dd, J = 14.6, 4.9 Hz, 1H), 2.78 (dd, J = 14.6, 8.6 Hz, 1H), 1.93 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ164.9, 137.7, 136.7, 128.8, 128.4, 127.6, 126.8, 126.4, 121.9, 119.2, 119.1,111.4, 109.8, 72.3, 66.7, 49.9, 31.3, 14.0.

[0047] L9 is an unknown compound, a yellow solid (R). f = 0.33, petroleum ether / ethyl acetate = 1:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method C, the target product (449.1 mg) can be synthesized in 59% yield.

[0048] 1 H NMR (400 MHz, CDCl3) δ 7.66-7.60 (m, 1H), 7.34-7.25 (m, 6H), 7.21-7.17 (m, 1H), 7.14-7.03 (m, 6H), 6.78 (s, 1H), 6.64 (s, 1H), 4.48-4.37 (m,1H), 4.05 (t, J = 8.9 Hz, 1H), 3.87 (t, J = 7.7 Hz, 1H), 3.20 (dd, J = 14.5,4.4 Hz, 1H), 2.72 (dd, J = 14.5, 8.5 Hz, 1H), 1.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.9, 140.0, 139.9, 136.9, 128.7, 128.4, 128.4, 128.0, 125.1,121.8, 119.5, 119.1, 110.7, 110.3, 71.9, 66.5, 63.5, 31.0, 14.0.

[0049] L11 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (530.3 mg) can be synthesized in 86% yield.

[0050] 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.46-7.38 (m, 3H), 7.23-7.12 (m, 5H), 4.56-4.46 (m, 1H), 4.22 (t, J = 8.9 Hz, 1H), 4.00 (d, J =7.3 Hz, 1H), 3.24 (dd, J = 14.6, 5.2 Hz, 1H), 2.84 (dd, J = 14.6, 8.5 Hz, 1H), 1.98 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.1, 161.0 (d, J = 246.2 Hz), 136.4, 135.8 (d, J = 2.9 Hz), 129.0, 126.1, 126.0 (d, J = 8.0 Hz), 122.8, 120.2, 119.3, 116.5 (d, J = 22.7 Hz), 113.5, 110.3, 72.4, 66.6, 31.4, 14.1. 19 FNMR (376 MHz, CDCl3) δ -115.5.

[0051] L12 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (526.2 mg) can be synthesized in 86% yield.

[0052] 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.51-7.37 (m, 5H), 7.24-7.13 (m, 3H), 4.56-4.45 (m, 1H), 4.27-4.19 (m, 1H), 4.04-3.97 (m, 1H), 3.23 (dd, J = 14.6, 5.3 Hz, 1H), 2.84 (dd, J = 14.6, 8.4 Hz, 1H), 1.99 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.1, 138.3, 136.0, 131.7, 129.8, 129.2,125.7, 125.3, 122.9, 120.4, 119.4, 114.0, 110.4, 72.4, 66.5, 31.4, 14.1.

[0053] L13 is an unknown compound, a yellow solid (R). f = 0.47, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (628.0 mg) can be synthesized in 85% yield.

[0054] 1 H NMR (400 MHz, CDCl3) δ 7.69-7.64 (m, 1H), 7.62-7.56 (m, 2H), 7.49(d, J = 7.9 Hz, 1H), 7.37-7.31 (m, 2H), 7.24-7.13 (m, 3H), 1.98 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ165.1, 138.8, 135.9, 132.7, 129.2, 125.6, 125.6, 122.9, 120.4, 119.4, 119.4,114.0, 110.4, 72.4, 66.5, 31.4, 14.1.

[0055] L14 is an unknown compound, a yellow solid (R). f = 0.47, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (598.7 mg) can be synthesized in 72% yield.

[0056] 1 H NMR (400 MHz, CDCl3) δ 7.84-7.78 (m, 2H), 7.67 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.25-7.14 (m, 5H), 4.57-4.46 (m, 1H), 4.24 (t, J =8.9 Hz, 1H), 4.00 (t, J = 7.9 Hz, 1H), 3.24 (dd, J = 14.6, 5.3 Hz, 1H), 2.84 (dd, J = 14.6, 8.4 Hz, 1H), 1.99 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.1,139.4, 138.6, 135.7, 129.2, 125.7, 125.5, 122.9, 120.4, 119.3, 114.0, 110.4,90.3, 72.3, 66.4, 31.3, 14.1.

[0057] L15 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (516.9 mg) can be synthesized in 85% yield.

[0058] 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.9Hz, 1H), 7.37-7.32 (m, 2H), 7.30-7.26 (m, 2H), 7.22-7.12 (m, 3H), 4.57-4.46(m, 1H), 4.21 (t, J = 8.9 Hz, 1H), 4.01 (t, J = 7.8 Hz, 1H), 3.27 (dd, J =14.6, 5.0 Hz, 1H), 2.82 (dd, J = 14.6, 8.8 Hz, 1H), 2.41 (s, 3H), 1.98 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.1, 137.2, 136.3, 136.2, 130.2, 130.2,129.0, 126.1, 124.2, 122.5, 120.0, 119.2, 113.0, 110.6, 72.5, 66.6, 31.5,21.1, 14.1.

[0059] L16 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (541.0 mg) can be synthesized in 78% yield.

[0060] 1 H NMR (400 MHz, CDCl3) δ 7.69-7.65 (m, 1H), 7.57-7.48 (m, 3H), 7.43-7.37 (m, 2H), 7.24-7.13 (m, 3H), 4.57-4.46 (m, 1H), 4.21 (t, J = 8.9 Hz, 1H), 4.01 (dd, J = 7.2 Hz, 1H), 3.29 (dd, J = 14.6, 4.9 Hz, 1H), 2.82 (dd, J =14.6, 8.9 Hz, 1H), 1.99 (s, 3H), 1.38 (s, 9H). 13C NMR (101 MHz, CDCl3) δ165.1, 149.4, 137.2, 136.3, 129.0, 126.6, 126.1, 123.8, 123.8, 122.6, 120.0,119.2, 113.1, 110.8, 72.5, 66.7, 34.7, 31.5, 14.1.

[0061] L18 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (538.3 mg) can be synthesized in 81% yield.

[0062] 1 H NMR (400 MHz, CDCl3) δ 7.68-7.64 (m, 1H), 7.45-7.41 (m, 1H), 7.33-7.29 (m, 2H), 7.21-7.09 (m, 3H), 6.83-6.78 (m, 2H), 4.57-4.46 (m, 1H), 4.20 (t, J = 8.9 Hz, 1H), 4.02 (dd, J = 8.5, 7.2 Hz, 1H), 3.29 (dd, J = 14.5, 4.8,1H), 3.00 (s, 6H), 2.81 (dd, J = 14.5, 9.0 Hz, 1H), 1.99 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 165.0, 149.4, 136.8, 129.1, 128.5, 126.6, 125.7, 122.2, 119.6,119.0, 113.0, 112.1, 110.7, 72.5, 66.7, 40.8, 31.5, 14.1.

[0063] L19 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (547.9 mg) can be synthesized in 72% yield.

[0064] 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 7.8, 1H), 7.60-7.54 (m, 2H), 7.52-7.48 (m, 2H), 7.46-7.41 (m, 2H), 7.21-7.16 (m, 4H), 7.13-7.08 (m, 3H),4.47-4.36 (m, 1H), 4.25 (t, J = 8.8 Hz, 1H), 3.94 (t, J = 7.8 Hz, 1H), 3.05(dd, J = 14.6, 5.4 Hz, 1H), 2.78 (dd, J = 14.6, 8.1 Hz, 1H), 1.87 (s, 3H). 13 CNMR (101 MHz, DMSO-d6) δ 163.4, 156.5, 154.8, 135.4, 134.5, 130.2, 128.8,126.5, 125.4, 123.7, 122.4, 119.8, 119.7, 119.3, 118.8, 113.1, 110.2, 71.6,66.1, 30.9, 13.5.

[0065] L20 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (521.9 mg) can be synthesized in 73% yield.

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 7.7Hz, 1H), 7.64-7.56 (m, 3H), 7.29-7.19 (m, 3H), 4.58-4.47 (m, 1H), 4.25 (t, J = 8.9 Hz, 1H), 4.01 (t, J = 7.8 Hz, 1H), 3.23 (dd, J = 14.7, 5.5 Hz, 1H), 2.87 (dd, J = 14.7, 8.2 Hz, 1H), 1.99 (s, 3H). 13C NMR (101 MHz, CDCl3) δ165.2, 142.8, 135.9, 129.7, 128.01 (q, J = 33.1 Hz), 127.0 (q, J = 3.8 Hz), 125.5, 124.1 (q, J = 272.1 Hz), 123.8, 123.3, 120.9, 119.6, 114.9, 110.6,72.4, 66.5, 31.5, 14.1. 19 F NMR (376 MHz, CDCl3) δ -62.2.

[0067] L21 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (471.3 mg) can be synthesized in 75% yield.

[0068] 1 H NMR (400 MHz, DMSO-d6) δ 8.03-7.98 (m, 2H), 7.83-7.78 (m, 2H), 7.72-7.62 (m, 3H), 7.28-7.15 (m, 2H), 4.48-4.37 (m, 1H), 4.25 (t, J = 8.4 Hz, 1H), 3.94 (t, J = 7.3 Hz, 1H), 3.03 (dd, J = 14.7, 5.6 Hz, 1H), 2.79 (dd, J =14.7, 8.0 Hz, 1H), 1.87 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.4, 142.9,134.7, 134.1, 129.7, 125.9, 123.3, 123.1, 120.8, 119.6, 118.7, 115.3, 110.7,107.7, 71.6, 65.9, 30.9, 13.5.

[0069] L22 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (494.7 mg) can be synthesized in 69% yield.

[0070] 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.1Hz, 1H), 7.37 (d, J = 1.7 Hz, 2H), 7.26-7.12 (m, 4H), 4.54-4.43 (m, 1H), 4.22(t, J = 8.9 Hz, 1H), 3.96 (t, J = 7.9 Hz, 1H), 3.18 (dd, J = 14.7, 5.6 Hz, 1H), 2.82 (dd, J = 14.7, 8.1 Hz, 1H), 1.97 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ165.0, 141.5, 135.8, 135.6, 129.5, 125.9, 125.1, 123.3, 122.1, 120.9, 119.5,115.0, 110.3, 72.2, 66.3, 31.3, 14.0.

[0071] L23 is an unknown compound, a yellow solid (R). f = 0.48, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (624.8 mg) can be synthesized in 69% yield.

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.82-7.75 (m, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.63-7.56 (m, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.30-7.15 (m, 3H), 4.56-4.44 (m,1H), 4.24 (t, J = 8.9 Hz, 1H), 3.99 (t, J = 7.8 Hz, 1H), 3.20 (dd, J = 14.7,5.3 Hz, 1H), 2.84 (dd, J = 14.7, 7.9 Hz, 1H), 1.99 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 141.9, 137.2, 135.8, 132.1, 131.6, 131.4, 129.6, 126.3, 125.6,125.3, 123.6, 123.4, 121.0, 119.6, 115.1, 110.4, 94.7, 72.3, 66.4, 31.4,14.1.

[0073] L24 is an unknown compound, a yellow solid (R). f = 0.47, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (647.1 mg) can be synthesized in 73% yield.

[0074] 1 H NMR (400 MHz, CDCl3) δ 7.74-7.59 (m, 9H), 7.46-7.38 (m, 4H), 7.37-7.31 (m, 2H), 7.27-7.14 (m, 3H), 4.58-4.45 (m, 1H), 4.23-4.15 (m, 1H), 4.03-3.96 (m, 1H), 3.26 (dd, J = 14.6, 5.3 Hz, 1H), 2.85 (dd, J = 14.6, 8.4 Hz, 1H), 1.96 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 164.9, 143.3, 140.6, 140.2,136.1, 129.2, 128.9, 127.9, 127.2, 125.9, 123.9, 122.8, 121.6, 120.2, 119.3,113.6, 110.7, 72.3, 66.5, 31.4, 14.0.

[0075] L25 is an unknown compound, a yellow solid (R). f = 0.47, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (447.2 mg) can be synthesized in 70% yield.

[0076] 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.0Hz, 1H), 7.23-7.14 (m, 3H), 7.10 (s, 2H), 6.97 (s, 1H), 4.58-4.46 (m, 1H), 4.22 (t, J = 8.9 Hz, 1H), 4.02 (t, J = 7.9 Hz, 1H), 3.28 (dd, J = 14.6, 4.9Hz, 1H), 2.82 (dd, J = 14.6, 8.9 Hz, 1H), 2.39 (s, 6H), 1.99 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ 165.1, 139.7, 139.5, 136.2, 129.1, 128.1, 126.1, 122.5,122.0, 120.0, 119.2, 113.1, 110.9, 72.5, 66.7, 31.5, 21.5, 14.1.

[0077] L26 is an unknown compound, a yellow solid (R). f = 0.47, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (594.7 mg) can be synthesized in 74% yield.

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.0Hz, 1H), 7.40 (s, 1H), 7.30 (s, 2H), 7.25-7.14 (m, 3H), 4.60-4.48 (m, 1H), 4.23 (t, J = 8.9 Hz, 1H), 4.04 (t, J = 7.9 Hz, 1H), 3.30 (dd, J = 14.6, 4.9Hz, 1H), 2.85 (dd, J = 14.6, 8.9 Hz, 1H), 2.00 (s, 3H), 1.38 (s, 18H). 13C NMR(101 MHz, CDCl3) δ 165.1, 152.5, 139.2, 136.4, 129.1, 126.4, 122.6, 120.5,120.0, 119.3, 118.9, 112.9, 110.8, 72.5, 66.7, 35.2, 31.6, 31.5, 14.2.

[0079] L27 is an unknown compound, a yellow solid (R). f = 0.47, dichloromethane / methanol = 50:1, v / v), by feeding at a scale of 2.0 mmol according to the synthesis steps of method D, the target product (469.0 mg) can be synthesized in 74% yield.

[0080] 1 H NMR (400 MHz, CDCl3) δ 7.68-7.59 (m, 2H), 7.24-7.14 (m, 3H), 6.64(d, J = 2.3 Hz, 2H), 6.45-6.42 (m, 1H), 4.57-4.46 (t, J = 7.4 Hz, 1H), 4.22(t, J = 8.9 Hz, 1H), 4.01 (t, J = 7.8 Hz, 1H), 3.83 (s, 6H), 3.26 (dd, J =14.6, 5.0 Hz, 1H), 2.83 (dd, J = 14.6, 8.7 Hz, 1H), 1.99 (s, 3H). 13 C NMR (101MHz, CDCl3) δ 165.1, 161.6, 141.4, 136.1, 129.2, 125.9, 122.7, 120.2, 119.3,113.4, 111.0, 102.6, 102.6, 98.3, 72.4, 66.6, 55.6, 31.4, 14.1.

[0081] Examples 41-42

[0082] It uses the same raw materials and reaction conditions as Method A, the only difference being the different but-3-enoic acid derivatives (different directing groups). The specific directing groups and reaction results are shown in Table 3:

[0083] .

[0084] Examples 43-83

[0085] Examples 43-83 were prepared using method A or method B, wherein formula I is selected from any of the following compounds: ;

[0086] Formula II is selected from any one of the following compounds:

[0087] ;

[0088] Compounds B17, B20, and B22 are unreported compounds. The preparation methods for these substances are as follows, with the following general reaction formula:

[0089] ;

[0090] Method E is as follows: Trimethyl sulfoxide and potassium tert-butoxide (tBuOK) are added sequentially to tetrahydrofuran (THF) in a molar ratio of 3:4. The concentration of trimethyl sulfoxide is 2.04 mol / L. The mixture is refluxed and stirred for 2 h under a nitrogen atmosphere. The reaction system is then cooled to 0°C, and an acyl chloride is added. The molar ratio of the acyl chloride to trimethyl sulfoxide and potassium tert-butoxide is 1:3:4. The reaction system is then heated to room temperature and stirred for another 3 h. After the reaction is complete, the THF is evaporated, and the product is obtained by silica gel column chromatography. The synthesized thioyl ylide products are as follows:

[0091] B17 is an unknown compound, a yellow solid (R). f = 0.33, dichloromethane / methanol = 30:1, v / v), by feeding at a scale of 6.8 mmol according to the synthesis steps of method E, the target product (1.92 g) can be synthesized in 88% yield.

[0092] 1 H NMR (400 MHz, CDCl3) δ 8.05 (t, J = 1.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.04 (t, J = 7.8 Hz, 1H), 4.98 (s, 1H), 3.43 (s, 6H). 13 C NMR (101 MHz, CDCl3)δ 180.3, 140.9, 139.3, 135.5, 129.9, 125.7, 94.1, 69.7, 42.0.

[0093] B20 is an unknown compound, a yellow solid (R). f= 0.37, dichloromethane / methanol = 30:1, v / v), by feeding at a scale of 6.8 mmol according to the synthesis steps of method E, the target product (1.84 g) can be synthesized in 84% yield.

[0094] 1 H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.84(d, J = 7.3 Hz, 1H), 8.15-8.10 (m, 1H), 7.39 (t, J = 7.5 Hz, 1H), 5.06 (s,1H), 3.48 (s, 6H), 1.32 (s, 12H). 13 C NMR (101 MHz, CDCl3) δ 182.5, 138.3,137.1, 133.0, 129.5, 127.8, 84.0, 68.6, 42.5, 25.0.

[0095] B22 is an unknown compound, a yellow solid (R). f = 0.40, dichloromethane / methanol = 30:1, v / v), by feeding at a scale of 6.8 mmol according to the synthesis steps of method E, the target product (1.36 g) can be synthesized in 83% yield.

[0096] 1 H NMR (400 MHz, CDCl3) δ 8.60 (t, J = 2.0 Hz, 1H), 8.31-8.24 (m, 1H), 8.15-8.11 (m, 1H), 7.57 (t, J = 7.9 Hz, 1H), 5.08 (s, 1H), 3.55 (s, 6H). 13 CNMR (101 MHz, CDCl3) δ 179.2, 148.3, 140.7, 132.6, 129.4, 125.3, 121.8, 69.9,42.4.

[0097] The corresponding synthesized chiral cis-cyclopropane products are as follows (excluding compound P1, which has already been prepared above):

[0098] .

[0099] The NMR data for the chiral ciscyclopropane products are as follows:

[0100] P2 is an unknown compound, a yellow solid (R).f = 0.43, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B2 as raw materials, the target product (66.3 mg) can be synthesized in 95% yield.

[0101] 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.48 (dd, J = 7.7, 1.4 Hz, 1H), 8.35 (dd, J = 8.3, 1.7 Hz, 1H), 8.10-8.03 (m, 2H), 7.62-7.56 (m, 2H), 7.49 (t, J = 7.9 Hz, 1H), 7.21 (t, J = 8.9Hz, 2H), 3.13-3.06 (m, 1H), 2.84 (dd, J = 16.1, 6.1 Hz, 1H), 2.60 (dd, J =16.2, 8.4 Hz, 1H), 2.07-1.94 (m, 1H), 1.33-1.22 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 197.1, 170.2, 164.8 (d, J = 251.2 Hz), 148.8, 137.9, 136.5, 134.8 (d, J = 3.0 Hz), 134.3, 130.9 (d, J = 9.5 Hz), 127.7, 126.9, 122.1, 121.7,116.2, 115.4 (d, J = 21.8 Hz), 34.4, 22.0, 21.2, 13.9. 19 F NMR (376 MHz, DMSO-d6) δ -106.8.HRMS (ESI) m / z Calcd forC 21 H 18 FN2O2 + [M+H] + : 349.1347, found:349.1351.

[0102] HPLC: The er value of P2(93:7) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ®OD-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 13.13 min and 15.20 min.

[0103] P3 is an unknown compound, a yellow solid (R). f = 0.42, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B3 as raw materials, the target product (69.4 mg) can be synthesized in 95% yield.

[0104] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.83 (dd, J = 4.2, 1.7 Hz, 1H), 8.49 (dd, J = 7.6, 1.4 Hz, 1H), 8.31 (dd, J = 8.4, 1.4 Hz, 1H), 7.99-7.94 (m, 2H), 7.59-7.53 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.43-7.38 (m, 2H), 3.10-3.01 (m, 1H), 2.85 (dd, J = 16.1, 6.0 Hz, 1H), 2.60 (dd, J = 16.1, 8.5Hz, 1H), 2.08-1.95 (m, 1H), 1.33-1.24 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ197.4, 170.2, 148.7, 137.8, 137.7, 136.7, 136.4, 134.2, 129.8, 128.4, 128.4,127.7, 126.8, 122.0, 121.6, 116.1, 34.4, 22.1, 21.4, 14.0. HRMS (ESI) m / zCalcd for C 21 H 18 ClN2O2 + [M+H] + 365.1051, found: 365.1060.

[0105] HPLC: The er value of P3 (95:5) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ®AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 10.04 min and 24.00 min.

[0106] P4 is an unknown compound, a yellow solid (R). f = 0.43, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B4 as raw materials, the target product (73.6 mg) can be synthesized in 90% yield.

[0107] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.83 (dd, J = 4.2, 1.8 Hz, 1H), 8.49 (dd, J = 7.7, 1.4 Hz, 1H), 8.30 (dd, J = 8.3, 1.6 Hz, 1H), 7.90-7.84 (m, 2H), 7.58-7.51 (m, 4H), 7.46 (t, J = 8.0 Hz, 1H), 3.08-2.99 (m, 1H), 2.86 (dd, J = 16.1, 6.0 Hz, 1H), 2.59 (dd, J = 16.1, 8.5 Hz, 1H), 2.07-1.95(m, 1H), 1.28 (t, J = 7.4 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 197.6, 170.1,148.6, 137.8, 137.0, 136.4, 134.2, 131.3, 129.9, 127.6, 126.8, 126.8, 122.0,121.6, 116.1, 34.4, 22.1, 21.4, 14.0. HRMS (ESI) m / z Calcd for C 21 H 18 BrN2O2 + [M+H] + : 409.0546, found: 409.0554.

[0108] HPLC: The er value of P4 (95:5) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ®AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 11.85 min and 28.99 min.

[0109] P5 is an unknown compound, a yellow solid (R). f = 0.47, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B5 as raw materials, the target product (60.7 mg) can be synthesized in 88% yield.

[0110] 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.51 (dd, J = 7.6, 1.4 Hz, 1H), 8.31 (dd, J = 8.3, 1.7 Hz, 1H), 7.90-7.85 (m, 2H), 7.59-7.54 (m, 2H), 7.47 (t, J = 7.9 Hz, 1H), 7.15 (d, J = 8.0Hz, 2H), 3.09-3.01 (m, 1H), 2.81 (dd, J = 16.2, 6.3 Hz, 1H), 2.63 (dd, J =16.2, 8.2 Hz, 1H), 2.25 (s, 3H), 2.04-1.93 (m, 1H), 1.26 (dd, J = 7.7, 6.5Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 197.9, 170.2, 148.7, 143.0, 137.8,136.4, 135.7, 134.3, 128.9, 128.1, 127.7, 126.8, 122.0, 121.6, 116.1, 34.5,21.8, 21.0, 20.9, 13.8. HRMS (ESI) m / z Calcd for C 22 H 21 N2O2 + [M+H] + : 345.1598, found: 345.1596.

[0111] HPLC: The er value of P5(91:9) was analyzed by liquid chromatography using a chiral column, CHIRALPAK.® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 15.03 min and 22.10 min.

[0112] P6 is an unknown compound, a yellow oily liquid (R). f = 0.53, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B6 as raw materials, the target product (72.8 mg) can be synthesized in 94% yield.

[0113] 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.48 (dd, J = 7.7, 1.3 Hz, 1H), 8.34 (dd, J = 8.3, 1.7 Hz, 1H), 7.94-7.89 (m, 2H), 7.59 (dd, J = 8.2, 4.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.41-7.35 (m, 2H), 3.12-3.04 (m, 1H), 2.80 (dd, J = 16.1, 6.2 Hz, 1H), 2.61 (dd, J= 16.1, 8.2 Hz, 1H), 2.06-1.93 (m, 1H), 1.31-1.24 (m, 2H), 1.21 (s, 9H). 13 CNMR (101 MHz, DMSO-d6) δ 197.9, 170.2, 155.7, 148.7, 137.8, 136.4, 135.6,134.2, 127.9, 127.7, 126.8, 125.1, 122.0, 121.6, 116.1, 34.6, 34.5, 30.7,21.8, 20.8, 13.6. HRMS (ESI) m / z Calcd for C 25 H 27 N2O2 + [M+H] + : 387.2067, found:387.2074.

[0114] HPLC: The er value of P6(91:9) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 11.11 min and 13.55 min.

[0115] P7 is an unknown compound, a yellow oily liquid (R). f = 0.38, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B7 as raw materials, the target product (65.1 mg) can be synthesized in 80% yield.

[0116] 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.87-8.82 (m, 1H), 8.54 (d,J = 7.6 Hz, 1H), 8.28 (dd, J = 8.2, 1.7 Hz, 1H), 8.09-8.02 (m, 2H), 7.67-7.58(m, 4H), 7.57-7.51 (m, 2H), 7.49-7.42 (m, 3H), 7.41-7.35 (m, 1H), 3.16-3.06(m, 1H), 2.85 (dd, J = 16.2, 6.2 Hz, 1H), 2.67 (dd, J = 16.1, 8.2 Hz, 1H), 2.09-1.96 (m, 1H), 1.35-1.26 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 197.9,170.2, 148.6, 144.1, 138.9, 137.8, 136.9, 136.4, 134.3, 129.0, 128.7, 128.2,127.7, 126.9, 126.9, 126.8, 126.6, 122.0, 121.6, 116.1, 34.5, 22.0, 21.1,13.9. HRMS (ESI) m / z Calcd for C 27 H 23 N2O2 + [M+H] + : 407.1754, found: 407.1762.

[0117] HPLC: The er value of P7(94:6) was analyzed by liquid chromatography using a Phenomenex chiral column. ® LuxTM Cellulose-1 column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 14.66 min and 15.96 min.

[0118] P8 is an unknown compound, a yellow oily liquid (R). f = 0.39, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B8 as raw materials, the target product (55.6 mg) can be synthesized in 77% yield.

[0119] 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.59 (dd, J = 7.6, 1.4 Hz, 1H), 8.33 (dd, J = 8.3, 1.7 Hz, 1H), 7.63-7.50 (m, 3H), 7.41 (dd, J = 7.6, 1.8 Hz, 1H), 7.39-7.32 (m, 1H), 6.99 (d, J =8.4 Hz, 1H), 6.86-6.78 (m, 1H), 3.73 (s, 3H), 2.98-2.90 (m, 1H), 2.81 (dd, J= 15.9, 6.6 Hz, 1H), 2.68 (dd, J = 15.9, 7.9 Hz, 1H), 2.01-1.88 (m, 1H), 1.32-1.23 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 200.8, 170.3, 157.7, 148.6,137.8, 136.4, 134.4, 132.8, 130.0, 129.0, 126.9, 122.0, 121.6, 120.0, 116.1,112.0, 55.6, 34.6, 26.3, 21.3, 14.7. HRMS (ESI) m / z Calcd for C 22 H 21 N2O3 + [M+H] +: 361.1547, found: 361.1555.

[0120] HPLC: The er value of P8 (87:13) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (n-hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 23.80 min and 27.89 min.

[0121] P9 is an unknown compound, a yellow oily liquid (R). f = 0.42, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B9 as raw materials, the target product (69.4 mg) can be synthesized in 87% yield.

[0122] 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.81 (dd, J = 4.2, 1.7 Hz, 1H), 8.47 (dd, J = 7.7, 1.4 Hz, 1H), 8.28 (dd, J = 8.3, 1.7 Hz, 1H), 8.11 (d,J = 8.1 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.57-7.50 (m, 2H), 7.44 (t, J =8.0 Hz, 1H), 3.09 (dd, J = 8.8, 6.5 Hz, 1H), 2.91 (dd, J = 16.1, 5.8 Hz, 1H),2.59 (dd, J = 16.1, 8.8 Hz, 1H), 2.13-2.01 (m, 1H), 1.32 (t, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 197.9, 170.1, 148.6, 141.2 (q, J = 1.3 Hz), 137.8, 136.4, 134.2, 132.1 (q, J = 32.0 Hz), 128.6, 127.6, 126.7, 125.2 (q, J= 3.7 Hz), 123.7 (q, J = 272.6 Hz), 121.9, 121.6, 116.1, 34.3, 22.6, 21.9,14.3.19 F NMR (376 MHz, DMSO-d6) δ -61.5. HRMS (ESI) m / z Calcd for C 22 H 18 F3N2O2 + [M+H] + : 399.1315, found: 399.1321.

[0123] HPLC: The er value of P9(95:5) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 7.06 min and 21.96 min.

[0124] P10 is an unknown compound, a yellow oily liquid (R). f = 0.44, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (59.2 mg) can be synthesized in 76% yield by feeding at a scale of 0.2 mmol using A1 and B10 as raw materials.

[0125] 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.46 (dd, J = 7.7, 1.4 Hz, 1H), 8.34 (dd, J = 8.3, 1.7 Hz, 1H), 8.07 (d,J = 8.5 Hz, 2H), 7.92 (d, J = 8.5 Hz, 2H), 7.62-7.56 (m, 2H), 7.47 (t, J =7.9 Hz, 1H), 3.86 (s, 3H), 3.17-3.09 (m, 1H), 2.88 (dd, J = 16.1, 5.9 Hz,1H), 2.59 (dd, J = 16.1, 8.7 Hz, 1H), 2.12-1.99 (m, 1H), 1.37-1.27 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 198.3, 170.2, 165.5, 148.7, 141.5, 137.8, 136.5,134.2, 132.7, 129.1, 128.2, 127.7, 126.8, 122.0, 121.7, 116.2, 52.4, 34.3,22.6, 21.8, 14.3. HRMS (ESI) m / z Calcd for C 23 H 21 N2O4 + [M+H] + : 389.1496, found:389.1500.

[0126] HPLC: The er value of P10 (95:5) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 20.50 min and 24.69 min.

[0127] P11 is an unknown compound, a yellow oily liquid (R). f = 0.27, petroleum ether / ethyl acetate = 3:1, v / v), according to the synthesis steps of method B, the target product (47.7 mg) can be synthesized in 67% yield by feeding at a scale of 0.2 mmol with A1 and B11 as raw materials.

[0128] 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dd, J = 7.6, 1.3 Hz, 1H), 8.35 (dd, J = 8.3, 1.7 Hz, 1H), 8.08 (d,J = 8.5 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.63-7.57 (m, 2H), 7.49 (t, J =8.0 Hz, 1H), 3.17-3.09 (m, 1H), 2.91 (dd, J = 16.1, 5.7 Hz, 1H), 2.55 (dd, J= 16.1, 7.7 Hz, 1H), 2.12-1.99 (m, 1H), 1.37-1.28 (m, 2H).13 C NMR (101 MHz, DMSO-d6) δ 198.0, 170.2, 148.8, 141.2, 137.8, 136.5, 134.2, 132.4, 128.5,127.7, 126.9, 122.1, 121.8, 118.1, 116.2, 114.6, 34.3, 22.7, 22.1, 14.3. HRMS(ESI) m / z Calcd for C 22 H 18 N3O2 + [M+H] + : 356.1394, found: 356.1396.

[0129] HPLC: The er value of P11 (87:13) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 23.35 min and 27.78 min.

[0130] P12 is an unknown compound, a yellow oily liquid (R). f = 0.27, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method B, the target product (36.9 mg) can be synthesized in 49% yield by feeding at a scale of 0.2 mmol using A1 and B12 as raw materials.

[0131] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.43 (dd, J = 7.7, 1.4 Hz, 1H), 8.34 (dd, J = 8.2, 1.7 Hz, 1H), 7.62-7.56 (m, 2H), 7.47 (t, J = 8.0 Hz, 1H), 3.20-3.12 (m, 1H), 2.94 (dd, J =16.1, 5.5 Hz, 1H), 2.56 (dd, J = 16.1, 9.1 Hz, 1H), 2.14-2.02 (m, 1H), 1.40-1.29 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 197.7, 170.2, 149.4, 148.8, 142.7,137.8, 136.5, 134.2, 129.3, 127.7, 126.8, 123.5, 122.1, 121.7, 116.2, 34.3,22.9, 22.2, 14.4. HRMS (ESI) m / z Calcd for C 21 H 18 N3O4 + [M+H] + : 376.1292, found:376.1299.

[0132] HPLC: The er value of P12 (82:18) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 26.14 min and 31.56 min.

[0133] P13 is an unknown compound, a yellow oily liquid (R). f = 0.27, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (75.1 mg) can be synthesized in 76% yield by feeding at a scale of 0.2 mmol using A1 and B13 as raw materials.

[0134] 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.86 (dd, J = 4.2, 1.7 Hz,1H), 8.47 (dd, J = 7.8, 1.4 Hz, 1H), 8.34-8.30 (m, 1H), 8.20-8.14 (m, 2H),7.84-7.79 (m, 2H), 7.60-7.54 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 3.20-3.10 (m,1H), 2.97-2.87 (m, 5H), 2.61 (dd, J = 16.2, 8.8 Hz, 1H), 2.14-2.01 (m, 1H),1.45-1.28 (m, 6H), 0.74 (t, J = 7.4 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) δ197.9, 170.1, 148.7, 142.7, 140.8, 137.8, 136.5, 134.2, 128.9, 127.7, 126.8,126.8, 122.0, 121.67, 116.1, 49.5, 34.3, 22.5, 21.9, 21.5, 14.5, 10.9. HRMS(ESI) m / z Calcd for C 27 H 32 N3O4S + [M+H] + : 494.2108, found: 494.2114.

[0135] HPLC: The er value of P13 (90:10) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 20.65 min and 26.23 min.

[0136] P14 is an unknown compound, a yellow oily liquid (R). f = 0.47, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (62.1 mg) can be synthesized in 89% yield by feeding at a scale of 0.2 mmol using A1 and B14 as raw materials.

[0137] 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.89-8.84 (m, 1H), 8.48 (d,J = 7.6 Hz, 1H), 8.38-8.32 (m, 1H), 8.10-8.03 (m, 2H), 7.63-7.57 (m, 2H),7.53-7.46 (m, 1H), 7.25-7.17 (m, 2H), 3.14-3.05 (m, 1H), 2.83 (dd, J = 16.1,6.1 Hz, 1H), 2.60 (dd, J = 16.1, 8.4 Hz, 1H), 2.07-1.94 (m, 1H), 1.33-1.23 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 197.5, 170.2, 162.0 (d, J = 245.2 Hz), 148.7, 140.3 (d, J = 6.3 Hz), 137.8, 136.5, 134.2, 130.6 (d, J = 7.7 Hz),127.7, 126.8, 124.2 (d, J = 2.8 Hz), 122.0, 121.7, 119.6 (d, J = 21.4 Hz),116.2, 114.5 (d, J = 22.2 Hz), 34.4, 22.2, 21.6, 14.2. 19 F NMR (376 MHz, DMSO-d6) δ -112.7. HRMS (ESI) m / z Calcd for C 21 H 18 FN2O2 + [M+H] + : 349.1347, found:349.1355.

[0138] HPLC: The er value of P14 (95:5) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 13.67 min and 15.94 min.

[0139] P15 is an unknown compound, a yellow oily liquid (R). f = 0.47, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B15 as raw materials, the target product (65.0 mg) can be synthesized in 89% yield.

[0140] 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.83 (dd, J = 4.2, 1.7 Hz,1H), 8.53-8.46 (m, 1H), 8.28 (dd, J = 8.3, 1.7 Hz, 1H), 7.95-7.86 (m, 2H),7.56-7.47 (m, 4H), 7.45 (t, J = 7.9 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 3.12-3.03 (m, 1H), 2.87 (dd, J = 16.1, 5.9 Hz, 1H), 2.61 (dd, J = 16.1, 8.6 Hz, 1H), 2.10-1.98 (m, 1H), 1.30 (t, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ197.4, 170.1, 148.6, 139.8, 137.8, 136.4, 134.2, 133.5, 132.3, 130.2, 127.6,127.6, 126.8, 126.5, 121.9, 121.6, 116.1, 34.4, 22.2, 21.7, 14.3. HRMS (ESI)m / z Calcd for C 21 H 18 ClN2O2 + [M+H] + : 365.1051, found:365.1056.

[0141] HPLC: The er value of P15 (96:4) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 14.43 min and 15.84 min.

[0142] P16 is an unknown compound, a yellow oily liquid (R). f = 0.47, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (65.0 mg) can be synthesized in 89% yield by feeding at a scale of 0.2 mmol using A1 and B16 as raw materials.

[0143] 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.87-8.80 (m, 1H), 8.49 (d,J = 7.7 Hz, 1H), 8.29 (d, J = 8.7 Hz, 1H), 8.06 (s, 1H), 7.95 (d, J = 7.9 Hz,1H), 7.63 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 8.6, 3.0 Hz, 2H), 7.50-7.42 (m,1H), 7.35-7.27 (m, 1H), 3.12-3.02 (m, 1H), 2.87 (dd, J = 16.1, 4.2 Hz, 1H), 2.61 (dd, J = 16.1, 8.5 Hz, 1H), 2.11-1.98 (m, 1H), 1.31 (t, J = 7.5 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 197.3, 170.0, 148.6, 140.0, 137.8, 136.3, 135.1,134.2, 130.4, 130.4, 127.6, 126.9, 126.7, 121.9, 121.6, 116.1, 34.4, 22.2,21.7, 14.3. HRMS (ESI) m / z Calcd for C 21 H 18 BrN2O2+ [M+H] + : 409.0546, found:409.0549.

[0144] HPLC: The er value of P16 (96:4) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 14.84 min and 16.36 min.

[0145] P17 is an unknown compound, a yellow oily liquid (R). f = 0.48, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B17 as raw materials, the target product (80.4 mg) can be synthesized in 88% yield.

[0146] 1 H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.86 (dd, J = 4.3, 1.7 Hz,1H), 8.48 (dd, J = 7.8, 1.2 Hz, 1H), 8.36-8.32 (m, 1H), 8.24 (t, J = 1.8 Hz,1H), 7.98 (dd, J = 8.0, 1.4 Hz, 1H), 7.84 (dd, J = 7.7, 1.7 Hz, 1H), 7.58(dd, J = 8.2, 4.1 Hz, 2H), 7.48 (t, J = 8.0 Hz, 1H), 7.18 (t, J = 7.8 Hz,1H), 3.13-3.04 (m, 1H), 2.86 (dd, J = 16.1, 5.9 Hz, 1H), 2.58 (dd, J = 16.1,8.7 Hz, 1H), 2.09-1.96 (m, 1H), 1.34-1.24 (m, 2H). 13 C NMR (101 MHz, DMSO-d6)δ 197.5, 170.2, 148.8, 141.1, 140.0, 137.8, 136.5, 136.2, 134.2, 130.5,127.3, 126.9, 122.1, 121.7, 116.2, 95.0, 34.4, 22.2, 21.7, 14.3. HRMS (ESI)m / z Calcd for C 21 H 18 IN2O2 + [M+H] + : 457.0407, found: 457.0412.

[0147] HPLC: The er value of P17 (92:8) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 14.78 min and 17.25 min.

[0148] P18 is an unknown compound, a yellow oily liquid (R). f= 0.50, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (62.1 mg) can be synthesized in 90% yield by feeding at a scale of 0.2 mmol using A1 and B18 as raw materials.

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.84 (dd, J = 4.0, 2.0 Hz,1H), 8.53 (d, J = 7.6 Hz, 1H), 8.32-8.27 (m, 1H), 7.82-7.74 (m, 2H), 7.58-7.52 (m, 2H), 7.50-7.43 (m, 1H), 7.28-7.22 (m, 2H), 3.11-3.02 (m, 1H), 2.83(dd, J = 16.1, 6.2 Hz, 1H), 2.65 (dd, J = 16.1, 8.2 Hz, 1H), 2.19 (s, 3H), 2.08-1.96 (m, 1H), 1.32-1.24 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 198.6,170.2, 148.6, 138.2, 137.8, 137.7, 136.4, 134.3, 133.2, 128.3, 128.2, 127.7,126.8, 125.2, 121.9, 121.5, 116.0, 34.5, 22.0, 21.1, 20.7, 14.0. HRMS (ESI)m / z Calcd for C 22 H 21 N2O2 + [M+H] + : 345.1598, found: 345.1597.

[0150] HPLC: The er value of P18 (94:6) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 10.45 min and 15.63 min.

[0151] P19 is an unknown compound, a yellow oily liquid (R). f= 0.40, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (90.1 mg) can be synthesized in 97% yield by feeding at a scale of 0.2 mmol using A1 and B19 as raw materials.

[0152] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.86 (dd, J = 4.3, 1.7 Hz, 1H), 8.49 (dd, J = 7.7, 1.4 Hz, 1H), 8.36 (dd, J = 8.3, 1.7 Hz, 1H), 7.60(dd, J = 8.1, 4.6 Hz, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.44 (dd, J = 2.8, 1.6Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.08 (dd, J = 8.1, 2.7 Hz, 1H), 3.71 (s,3H), 3.14-3.06 (m, 1H), 2.82 (dd, J = 16.1, 6.2 Hz, 1H), 2.62 (dd, J = 16.1,8.2 Hz, 1H), 2.07-1.95 (m, 1H), 1.33-1.23 (m, 2H). 13 C NMR (101 MHz, DMSO-d6)δ 198.4, 170.2, 159.2, 148.8, 139.6, 137.9, 136.5, 134.3, 129.6, 127.7,126.9, 122.1, 121.7, 120.6, 118.7, 116.2, 112.5, 55.2, 34.4, 22.2, 21.2,14.0. HRMS (ESI) m / z Calcd for C 22 H 21 N2O3 + [M+H] + : 361.1547, found: 361.1554.

[0153] HPLC: The er value of P19 (95:5) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) oC, 254 nm), retention times were 17.29 min and 19.25 min.

[0154] P20 is an unknown compound, a yellow oily liquid (R). f = 0.48, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B20 as raw materials, the target product (69.5 mg) can be synthesized in 76% yield.

[0155] 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.48 (dd, J = 7.7, 1.4 Hz, 1H), 8.34 (dd, J = 8.3, 1.7 Hz, 1H), 8.25 (t,J = 1.4 Hz, 1H), 8.16-8.11 (m, 1H), 7.82-7.77 (m, 1H), 7.61-7.55 (m, 2H), 7.51-7.39 (m, 2H), 3.15-3.06 (m, 1H), 2.84 (dd, J = 16.1, 6.1 Hz, 1H), 2.64(dd, J = 16.1, 8.4 Hz, 1H), 2.09-1.97 (m, 1H), 1.28 (s, 14H). 13 C NMR (101MHz, DMSO-d6) δ 198.5, 170.3, 148.7, 138.5, 137.9, 137.6, 136.5, 134.3,133.6, 131.1, 128.1, 127.7, 126.9, 122.0, 121.7, 116.2, 84.0, 34.4, 25.0,24.7, 24.7, 21.9, 21.4, 14.3. HRMS (ESI) m / z Calcd for C 27 H 30 BN2O4 + [M+H] + :457.2293, found: 457.2291.

[0156] HPLC: The er value of P20 (96:4) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ®IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 12.98 min and 13.84 min.

[0157] P21 is an unknown compound, a yellow oily liquid (R). f = 0.44, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B21 as raw materials, the target product (69.4 mg) can be synthesized in 87% yield.

[0158] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.79 (dd, J = 4.2, 1.7 Hz,1H), 8.47 (dd, J = 7.7, 1.4 Hz, 1H), 8.28-8.22 (m, 2H), 8.18 (t, J = 1.9 Hz,1H), 7.80-7.75 (m, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.54-7.49 (m, 2H), 7.42 (t,J = 7.9 Hz, 1H), 3.18-3.10 (m, 1H), 2.92 (dd, J = 16.1, 5.8 Hz, 1H), 2.61(dd, J = 16.1, 8.8 Hz, 1H), 2.14-2.02 (m, 1H), 1.37-1.28 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ 197.6, 170.2, 148.7, 138.8, 137.8, 136.5, 134.2, 132.0 (q, J= 1.3 Hz), 129.8, 129.4, 129.1, 128.99 (q, J = 3.5 Hz), 127.7, 126.8, 124.21(q, J = 3.9 Hz), 123.8 (q, J = 272.3 Hz), 122.42, 122.0, 121.7, 116.2, 34.4,22.4, 21.9, 14.3. 19 F NMR (376 MHz, DMSO-d6) δ -61.3. HRMS (ESI) m / z Calcd forC 22 H 18F3N2O2 + [M+H] + : 399.1315, found: 399.1323.

[0159] HPLC: The er value of P21(92:8) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 11.19 min and 12.04 min.

[0160] P22 is an unknown compound, a yellow oily liquid (R). f = 0.44, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method B, with a feed scale of 0.2 mmol, using A1 and B22 as raw materials, the target product can be synthesized in 87% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.59 (t, J = 2.0 Hz, 1H), 8.42-8.37 (m, 2H), 8.33 (dd, J = 8.3, 1.7 Hz, 1H),8.28-8.24 (m, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.59-7.55 (m, 2H), 7.44 (t, J =8.0 Hz, 1H), 3.24-3.16 (m, 1H), 2.93 (dd, J = 16.1, 5.6 Hz, 1H), 2.53 (dd, J= 16.1, 9.2 Hz, 1H), 2.15-2.04 (m, 1H), 1.39-1.31 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 196.9, 170.2, 148.7, 147.6, 139.1, 137.8, 136.4, 134.2, 134.1,130.2, 127.6, 126.8, 122.2, 122.0, 121.7, 116.1, 34.5, 22.5, 22.1, 14.3. HRMS(ESI) m / z Calcd for C 21 H 18 N3O4 + [M+H]+ : 376.1292, found: 376.1297.

[0161] HPLC: The er value of P22 (97:3) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 13.89 min and 31.78 min.

[0162] P23 is an unknown compound, a yellow oily liquid (R). f = 0.62, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B23 as raw materials, the target product (62.1 mg) can be synthesized in 89% yield.

[0163] 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.80 (dd, J = 4.2, 1.7 Hz, 1H), 8.56 (dd, J = 7.6, 1.4 Hz, 1H), 8.31 (dd, J = 8.3, 1.4 Hz, 1H), 7.76-7.69 (m, 1H), 7.60-7.45 (m, 4H), 7.23-7.12 (m, 2H), 2.93-2.83 (m, 2H), 2.68(dd, J = 16.1, 8.3 Hz, 1H), 2.09-1.97 (m, 1H), 1.36-1.27 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ 197.2, 170.2, 160.4 (d, J = 253.0 Hz), 148.7, 137.9, 136.5,134.3, 134.2 (d, J = 8.7 Hz), 130.1 (d, J = 2.6 Hz), 127.7, 126.9, 124.4 (d,J = 3.5 Hz), 121.9 (d, J = 34.8 Hz), 116.5 (d, J = 22.8 Hz), 116.3, 34.3,25.9, 25.8, 21.9, 14.8. 19F NMR (376 MHz, DMSO-d6) δ -112.7. HRMS (ESI) m / zCalcd for C 21 H 18 FN2O2 + [M+H] + : 349.1347, found: 349.1352.

[0164] HPLC: The er value of P23 (93:7) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 12.42 min and 14.13 min.

[0165] P24 is an unknown compound, a yellow oily liquid (R). f = 0.53, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B24 as raw materials, the target product (45.3 mg) can be synthesized in 62% yield.

[0166] 1 H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.82 (d, J = 4.1 Hz, 1H), 8.61 (d, J = 7.6 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.68-7.50 (m, 4H), 7.45-7.37 (m, 2H), 7.31 (t, J = 7.3 Hz, 1H), 2.93 (dd, J = 16.3, 6.2 Hz, 1H), 2.83-2.71 (m, 2H), 2.13-2.00 (m, 1H), 1.43-1.27 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 200.8, 170.2, 148.6, 139.9, 137.9, 136.4, 134.3, 131.9, 130.1,129.7, 129.3, 127.7, 127.1, 126.9, 122.0, 121.7, 116.3, 34.1, 26.2, 22.7,15.8. HRMS (ESI) m / z Calcd for C 21 H18 ClN2O2 + [M+H] + 365.1051, found: 365.1059.

[0167] HPLC: The er value of P24(77:23) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 14.09 min and 15.25 min.

[0168] P25 is an unknown compound, a yellow oily liquid (R). f = 0.52, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (47.7 mg) can be synthesized in 65% yield by feeding at a scale of 0.2 mmol using A1 and B25 as raw materials.

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.82 (dd, J = 4.3, 1.6 Hz, 1H), 8.49 (dd, J = 7.7, 1.3 Hz, 1H), 8.27 (dd, J = 8.3, 1.7 Hz, 1H), 7.63-7.56 (m, 2H), 7.55-7.50 (m, 2H), 7.44 (t, J = 7.9 Hz, 1H), 7.33-7.25 (m, 1H), 3.13-3.04 (m, 1H), 2.89 (dd, J = 16.1, 5.8 Hz, 1H), 2.58 (dd, J = 16.1, 8.7Hz, 1H), 2.12-1.99 (m, 1H), 1.31 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 196.3, 170.1, 163.4 (d, J = 12.6 Hz), 161.0 (d, J = 12.6 Hz), 148.7, 141.1 (t, J = 7.7 Hz), 137.8, 136.5, 134.2, 127.7, 126.8, 122.0, 121.7,116.2, 111.3 (d, J = 7.2 Hz), 111.1 (d, J = 7.2 Hz), 107.9 (t, J = 26.0 Hz),34.4, 22.4, 22.0, 14.4. 19 F NMR (376 MHz, DMSO-d6) δ -108.9. HRMS (ESI) m / zCalcd for C 21 H 17 F2N2O2 + [M+H] + 367.1253, found: 367.1260.

[0170] HPLC: The er value of P25 (95:5) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 12.76 min and 16.27 min.

[0171] P26 is an unknown compound, a yellow oily liquid (R). f = 0.53, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B26 as raw materials, the target product (68.6 mg) can be synthesized in 86% yield.

[0172] 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.81 (dd, J = 4.3, 1.7 Hz, 1H), 8.47 (d, J = 7.4 Hz, 1H), 8.26 (dd, J = 8.3, 1.7 Hz, 1H), 7.83 (d, J =2.0 Hz, 2H), 7.56-7.49 (m, 3H), 7.42 (t, J = 7.9 Hz, 1H), 3.12-3.04 (m, 1H), 2.90 (dd, J = 16.0, 5.6 Hz, 1H), 2.54 (dd, J = 16.0, 9.0 Hz, 1H), 2.12-2.00(m, 1H), 1.31 (t, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 196.2, 170.0,148.6, 140.7, 137.7, 136.4, 134.4, 134.1, 131.6, 127.6, 126.7, 126.5, 121.9,121.6, 116.0, 34.5, 22.4, 22.1, 14.4. HRMS (ESI) m / z Calcd for C 21 H 17 Cl2N2O2 + [M+H] + : 399.0662, found: 399.0668.

[0173] HPLC: The er value of P26 (96:4) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 80:20, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 12.70 min and 14.03 min.

[0174] P27 is an unknown compound, a yellow oily liquid (R). f = 0.52, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B27 as raw materials, the target product (63.9 mg) can be synthesized in 89% yield.

[0175] 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.86 (dd, J = 4.3, 1.7 Hz, 1H), 8.50 (dd, J = 7.7, 1.4 Hz, 1H), 8.33 (dd, J = 8.3, 1.8 Hz, 1H), 7.61-7.53 (m, 4H), 7.47 (t, J = 8.0 Hz, 1H), 7.03 (s, 1H), 3.10-3.01 (m, 1H), 2.81 (dd, J = 16.0, 6.1 Hz, 1H), 2.60 (dd, J = 16.1, 8.4 Hz, 1H), 2.14 (s, 6H), 2.06-1.95 (m, 1H), 1.27 (t, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, DMSO-d6) δ198.6, 170.2, 148.7, 138.3, 137.8, 137.5, 136.5, 134.2, 133.9, 127.7, 126.8,125.7, 122.0, 121.6, 116.0, 34.6, 22.0, 21.0, 20.6, 13.9. HRMS (ESI) m / zCalcd for C 23 H 23 N2O2 + [M+H] + : 359.1754, found: 359.1761. HPLC: The er value of P27 (94:6) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 6.11 min and 11.83 min.

[0176] P28 is an unknown compound, a yellow oily liquid (R). f = 0.49, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method B, with a feed scale of 0.2 mmol, using A1 and B28 as raw materials, the target product (43.9 mg) can be synthesized in 47% yield.

[0177] 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.80 (dd, J = 4.2, 1.7 Hz,1H), 8.45 (d, J = 1.7 Hz, 2H), 8.37 (dd, J = 7.7, 1.3 Hz, 1H), 8.32 (dd, J =8.3, 1.7 Hz, 1H), 8.20-8.15 (m, 1H), 7.60-7.54 (m, 2H), 7.43 (t, J = 8.0 Hz,1H), 3.33-3.25 (m, 1H), 2.98 (dd, J = 15.9, 5.3 Hz, 1H), 2.49-2.42 (m, 1H),2.18-2.06 (m, 1H), 1.41-1.31 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 196.6,170.2, 148.7, 140.0, 137.7, 136.5, 134.0, 130.5 (q, J = 33.6 Hz), 128.3 (q, J= 3.2 Hz), 127.7, 126.7, 125.7 (q, J = 2.3 Hz), 122.9 (q, J = 272.9 Hz), 122.0, 121.7, 116.1, 34.5, 22.8, 22.6, 14.4. 19 F NMR (376 MHz, DMSO-d6) δ -56.73. HRMS (ESI) m / z Calcd for C 23 H 17 F6N2O2 + [M+H] + : 467.1189, found: 467.1189.

[0178] HPLC: The er value of P28 (94:6) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 2.81 min and 3.31 min.

[0179] P29 is an unknown compound, a yellow oily liquid (R). f= 0.53, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B29 as raw materials, the target product (70.2 mg) can be synthesized in 88% yield.

[0180] 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 7.7, 1.3 Hz, 1H), 8.32 (dd, J = 8.3, 1.7 Hz, 1H), 8.07 (d,J = 2.0 Hz, 1H), 7.86 (dd, J = 8.3, 2.1 Hz, 1H), 7.60-7.53 (m, 3H), 7.46 (t,J = 7.9 Hz, 1H), 3.14-3.06 (m, 1H), 2.89 (dd, J = 16.0, 5.7 Hz, 1H), 2.52(dd, J = 16.0, 9.0 Hz, 1H), 2.10-1.98 (m, 1H), 1.35-1.26 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ 196.5, 170.1, 148.7, 138.1, 137.7, 136.4, 135.5, 134.1,131.5, 130.6, 129.7, 127.9, 127.7, 126.8, 122.0, 121.7, 116.1, 34.5, 22.3,21.9, 14.1. HRMS (ESI) m / z Calcd for C 21 H 17 Cl2N2O2 + [M+H] + : 399.0662, found:399.0667.

[0181] HPLC: The er value of P29 (96:4) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 11.85 min and 14.83 min.

[0182] P30 is an unknown compound, a yellow oily liquid (R).f = 0.16, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (55.6 mg) can be synthesized in 66% yield by feeding at a scale of 0.2 mmol using A1 and B30 as raw materials.

[0183] 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.84 (dd, J = 4.3, 1.7 Hz, 1H), 8.50 (dd, J = 7.6, 1.3 Hz, 1H), 8.36 (dd, J = 8.3, 1.7 Hz, 1H), 7.62-7.57 (m, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.24 (s, 2H), 3.73 (s, 6H), 3.61 (s,3H), 3.17-3.09 (m, 1H), 2.82 (dd, J = 16.0, 6.2 Hz, 1H), 2.58 (dd, J = 15.9,8.4 Hz, 1H), 2.07-1.95 (m, 1H), 1.31-1.24 (m, 2H). 13 C NMR (101 MHz, DMSO-d6)δ 197.5, 170.3, 152.5, 148.8, 141.4, 137.8, 136.6, 134.3, 133.7, 127.7,126.9, 122.1, 121.7, 116.1, 105.6, 60.1, 55.9, 34.7, 21.9, 21.1, 13.8. HRMS(ESI) m / z Calcd for C 24 H 25 N2O5 + [M+H] + : 421.1758, found: 421.1757.

[0184] HPLC: The er value of P30 (94:6) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 33.40 min and 41.86 min.

[0185] P31 is an unknown compound, a yellow oily liquid (R).f = 0.44, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (71.3 mg) can be synthesized in 95% yield by feeding at a scale of 0.2 mmol using A1 and B31 as raw materials.

[0186] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.51 (dd, J = 7.7, 1.4 Hz, 1H), 8.32 (dd, J = 6.8, 1.9 Hz, 1H), 7.64(dd, J = 8.2, 1.8 Hz, 1H), 7.59-7.54 (m, 2H), 7.48 (t, J = 7.9 Hz, 1H), 7.42(d, J = 1.7 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.02 (d, J = 9.6 Hz, 2H),3.06-2.97 (m, 1H), 2.78 (dd, J = 16.0, 6.2 Hz, 1H), 2.59 (dd, J = 16.0, 8.3Hz, 1H), 2.02-1.90 (m, 1H), 1.28-1.20 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ196.2, 170.3, 151.1, 148.7, 147.5, 137.8, 136.4, 134.3, 132.8, 127.7, 126.9,124.4, 122.0, 121.6, 116.1, 107.7, 107.5, 101.9, 34.6, 21.7, 20.7, 13.5. HRMS(ESI) m / z Calcd for C 22 H 19 N2O4 + [M+H] + : 375.1339, found: 375.1348. HPLC: The er value of P31 (89:11) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC50 column (n-hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 15.74 min and 17.16 min.

[0187] P32 is an unknown compound, a yellow oily liquid (R). f = 0.53, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B32 as raw materials, the target product (73.2 mg) can be synthesized in 96% yield.

[0188] 1 H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 8.70-8.60 (m, 2H), 8.53 (d, J= 1.7 Hz, 1H), 8.07-7.96 (m, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.75 (t, J = 9.1Hz, 2H), 7.56-7.44 (m, 2H), 7.43-7.31 (m, 3H), 3.15-3.07 (m, 1H), 2.90 (dd, J= 15.9, 6.7 Hz, 1H), 2.78 (dd, J = 15.9, 7.6 Hz, 1H), 2.26-2.14 (m, 1H),1.64-1.57 (m, 1H), 1.47-1.39 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 199.2, 170.6,148.1, 138.3, 136.1, 136.0, 135.4, 134.4, 132.5, 129.9, 129.6, 128.2, 128.2,127.8, 127.7, 127.2, 126.6, 124.1, 121.5, 121.4, 116.3, 35.5, 22.8, 21.5,14.5. HRMS (ESI) m / z Calcd for C 25 H 21 N2O2 + [M+H] + : 381.1598, found: 381.1606.

[0189] HPLC: The er value of P32 (86:14) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) oC, 254 nm), retention times were 16.42 min and 35.59 min.

[0190] P33 is an unknown compound, a yellow oily liquid (R). f = 0.55, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (67.1 mg) can be synthesized in 88% yield by feeding at a scale of 0.2 mmol using A1 and B33 as raw materials.

[0191] 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.75 (dd, J = 4.2, 1.7 Hz,1H), 8.59 (d, J = 7.5 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.28 (dd, J = 8.3,1.8 Hz, 1H), 8.09 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.88 (d, J =8.2 Hz, 1H), 7.59-7.43 (m, 5H), 7.41-7.34 (m, 1H), 3.01 (dd, J = 16.4, 6.1Hz, 1H), 2.96-2.84 (m, 2H), 2.16-2.04 (m, 1H), 1.44-1.33 (m, 2H). 13 C NMR (101MHz, DMSO-d6) δ 202.3, 170.4, 148.6, 137.8, 137.4, 136.4, 134.3, 133.2,131.8, 129.2, 128.3, 128.1, 127.7, 127.3, 126.8, 126.2, 125.2, 124.7, 121.9,121.6, 116.3, 34.3, 25.9, 22.0, 15.2. HRMS (ESI) m / z Calcd for C 25 H 21 N2O2 + [M+H] + : 381.1598, found: 381.1606.

[0192] HPLC: The er value of P33 (93:7) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ®IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 17.22 min and 22.14 min.

[0193] P34 is an unknown compound, a yellow oily liquid (R). f = 0.42, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B34 as raw materials, the target product (96.9 mg) can be synthesized in 78% yield.

[0194] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.87 (dd, J = 4.3, 1.7 Hz, 1H), 8.73 (d, J = 1.6 Hz, 1H), 8.47 (dd, J = 7.7, 1.4 Hz, 1H), 8.30 (dd, J =8.4, 1.8 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.06-7.93 (m, 3H), 7.84 (dd, J =8.6, 1.8 Hz, 1H), 7.62 (dd, J = 8.5, 2.3 Hz, 1H), 7.59-7.52 (m, 3H), 7.43 (t,J = 8.0 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 3.85 (s, 3H), 3.34-3.28 (m, 1H), 2.87 (dd, J = 16.1, 6.2 Hz, 1H), 2.69 (dd, J = 16.2, 8.2 Hz, 1H), 2.16-2.10(m, 6H), 2.09-2.03 (m, 4H), 1.78-1.72 (m, 6H), 1.39-1.31 (m, 2H). 13C NMR (101MHz, DMSO-d6) δ 198.1, 170.3, 158.6, 148.7, 140.3, 138.0, 137.8, 136.4,135.4, 135.1, 134.2, 131.5, 130.8, 130.0, 129.6, 128.2, 127.7, 126.8, 125.9,125.7, 125.0, 124.1, 124.0, 122.0, 121.6, 116.1, 112.7, 40.1, 36.6, 36.5,34.5, 28.4, 22.0, 21.1, 14.1. HRMS (ESI) m / z Calcd for C 42 H 41 N2O3 + [M+H] + :621.3112, found: 621.3123.

[0195] HPLC: The er value of P34 (89:11) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 22.60 min and 24.98 min.

[0196] P35 is an unknown compound, a yellow oily liquid (R). f = 0.31, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B35 as raw materials, the target product (46.9 mg) can be synthesized in 73% yield.

[0197] 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.53 (dd, J = 7.7, 1.4 Hz, 1H), 8.37 (dd, J = 8.3, 1.7 Hz, 1H), 7.93 (d,J = 1.7 Hz, 1H), 7.65-7.58 (m, 2H), 7.55-7.48 (m, 2H), 6.66 (dd, J = 3.6, 1.7Hz, 1H), 2.99-2.91 (m, 1H), 2.87 (dd, J = 16.2, 6.3 Hz, 1H), 2.72 (dd, J =16.3, 8.0 Hz, 1H), 1.99-1.86 (m, 1H), 1.36-1.26 (m, 1H), 1.23-1.15 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 186.5, 170.3, 153.0, 148.8, 147.5, 147.5, 137.9,136.5, 134.3, 127.7, 126.9, 122.1, 121.7, 118.3, 116.2, 112.5, 112.4, 34.2,21.5, 20.7, 14.1. HRMS (ESI) m / z Calcd for C 19 H 17 N2O3 + [M+H] + : 321.1234, found:321.1235.

[0198] HPLC: The er value of P35 (90:10) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 11.06 min and 13.69 min.

[0199] P36 is an unknown compound, a yellow oily liquid (R). f = 0.47, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B36 as raw materials, the target product (66.7 mg) can be synthesized in 99% yield.

[0200] 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.53 (dd, J = 7.7, 1.4 Hz, 1H), 8.34 (dd, J = 8.3, 1.7 Hz, 1H), 8.07(dd, J = 3.9, 1.2 Hz, 1H), 7.90 (dd, J = 4.9, 1.1 Hz, 1H), 7.62-7.55 (m, 2H), 7.50 (t, J = 7.9 Hz, 1H), 7.17 (dd, J = 5.0, 3.7 Hz, 1H), 3.11-3.03 (m, 1H),2.86 (dd, J = 16.2, 6.5 Hz, 1H), 2.74 (dd, J = 16.2, 7.9 Hz, 1H), 2.02-1.90(m, 1H), 1.37-1.29 (m, 1H), 1.26-1.19 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ191.1, 170.2, 148.7, 145.3, 137.9, 136.5, 134.4, 134.3, 133.2, 128.6, 127.7,126.9, 122.0, 121.6, 116.2, 34.3, 22.1, 20.9, 14.4. HRMS (ESI) m / z Calcd forC 19 H 17 N2O2S + [M+H] + : 337.1005, found: 337.1013.

[0201] HPLC: The er value of P36 (82:18) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 25.03 min and 31.12 min.

[0202] P37 is an unknown compound, a yellow oily liquid (R). f= 0.43, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B37 as raw materials, the target product (50.2 mg) can be synthesized in 71% yield.

[0203] 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.82 (dd, J = 4.2, 1.7 Hz, 1H), 8.57 (dd, J = 7.7, 1.4 Hz, 1H), 8.27 (dd, J = 8.3, 1.7 Hz, 1H), 7.55-7.49 (m, 2H), 7.45 (t, J = 7.9 Hz, 1H), 2.78 (dd, J = 16.3, 5.5 Hz, 1H), 2.55-2.46 (m, 2H), 2.44-2.38 (m, 1H), 2.28-2.19 (m, 1H), 1.77-1.65 (m, 1H),1.35-1.22 (m, 2H), 1.06-0.99 (m, 1H), 0.99-0.79 (m, 9H), 0.61 (t, J = 7.2 Hz,3H). 13 C NMR (101 MHz, DMSO-d6) δ 208.7, 170.2, 148.6, 137.8, 136.4, 134.4,127.7, 126.8, 122.0, 121.5, 115.9, 43.9, 34.2, 31.0, 28.5, 24.5, 23.2, 21.9,19.7, 13.7, 13.4. HRMS (ESI) m / z Calcd for C 22 H 29 N2O2 + [M+H] + : 353.2224, found:353.2226.

[0204] HPLC: The er value of P37 (88:12) was analyzed by liquid chromatography using a chiral column, CHIRALCEL. ® OD-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 7.98 min and 9.96 min.

[0205] P38 is an unknown compound, a yellow oily liquid (R). f = 0.31, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A1 and B38 as raw materials, the target product (56.1 mg) can be synthesized in 95% yield.

[0206] 1 H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.92 (dd, J = 4.2, 1.8 Hz, 1H), 8.61 (dd, J = 7.6, 1.4 Hz, 1H), 8.40 (dd, J = 8.3, 1.7 Hz, 1H), 7.68-7.60 (m, 2H), 7.56 (t, J = 8.0 Hz, 1H), 2.75 (dd, J = 16.2, 6.2 Hz, 1H), 2.62-2.51 (m, 2H), 2.28-2.19 (m, 1H), 1.89-1.77 (m, 1H), 1.22-1.13 (m, 1H),1.07-1.00 (m, 1H), 0.90-0.72 (m, 3H), 0.68-0.59 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 208.5, 170.3, 148.9, 148.8, 137.9, 136.6, 134.4, 127.8, 127.0, 122.1, 121.7, 116.1, 34.4, 24.8, 24.7, 22.0, 20.1, 14.0, 10.2. HRMS (ESI) m / zCalcd for C 18 H 19 N2O2 + [M+H] + : 295.1441, found: 295.1450.

[0207] HPLC: The er value of P38 (86:14) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® AY-H column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 6.28 min and 13.00 min.

[0208] P39 is an unknown compound, a yellow oily liquid (R).f = 0.44, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, the target product (49.9 mg) was synthesized in 74% yield by feeding at a scale of 0.2 mmol using A1 and B39 as raw materials.

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.88 (dd, J = 4.3, 1.7 Hz, 1H), 8.64 (dd, J = 7.6, 1.4 Hz, 1H), 8.33 (dd, J = 8.4, 1.7 Hz, 1H), 7.62-7.48 (m, 3H), 2.73 (dd, J = 16.2, 6.3 Hz, 1H), 2.57 (dd, J = 16.2, 8.1 Hz, 1H), 2.49-2.43 (m, 1H), 2.36-2.28 (m, 1H), 1.83-1.68 (m, 3H), 1.62-1.54 (m, 1H), 1.51-1.40 (m, 2H), 1.19-0.90 (m, 7H). 13 C NMR (101 MHz, DMSO-d6) δ 211.3,170.3, 148.6, 137.8, 136.4, 134.4, 127.7, 126.9, 122.0, 121.6, 116.0, 51.2,34.3, 27.8, 27.7, 25.4, 25.1, 25.1, 23.3, 20.0, 13.6. HRMS (ESI) m / z Calcdfor C 21 H 25 N2O2 + [M+H] + : 337.1911, found: 337.1918.

[0210] HPLC: The er value of P39(72:28) was analyzed by liquid chromatography using a Phenomenex chiral column. ® Lux™ Cellulose-1 column (n-hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 8.07 min and 8.56 min.

[0211] P40 is an unknown compound, a yellow oily liquid (R).f = 0.31, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A2 and B1 as raw materials, the target product (64.9 mg) can be synthesized in 89% yield.

[0212] 1 H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.69 (dd, J = 4.2, 1.6 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.42 (dd, J = 8.5, 1.6 Hz, 1H), 7.97 (dd, J =8.3, 1.3 Hz, 2H), 7.50-7.39 (m, 3H), 7.37-7.29 (m, 2H), 2.99-2.92 (m, 1H), 2.86 (dd, J = 16.0, 6.7 Hz, 1H), 2.76 (dd, J = 16.0, 7.5 Hz, 1H), 2.16-2.04(m, 1H), 1.56-1.49 (m, 1H), 1.41-1.34 (m, 1H). 13 C NMR (101 MHz, DMSO-d6) δ199.3, 170.5, 148.5, 138.7, 138.6, 133.6, 133.1, 132.7, 128.3, 128.1, 127.0,125.7, 124.0, 122.2, 116.1, 35.3, 22.5, 21.3, 14.6.

[0213] HPLC: The er value of P40 (89.6:10.4) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (hexane:isopropanol = 70:30, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 27.38 min and 29.08 min.

[0214] P41 is an unknown compound, a yellow oily liquid (R). f = 0.41, petroleum ether / ethyl acetate = 3:1, v / v), following the synthesis steps of method A, with a feed scale of 0.2 mmol, using A3 and B1 as raw materials, the target product (56.7 mg) can be synthesized in 74% yield.

[0215] 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.50 (dd, J = 8.4, 1.7 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.00 (d, J =7.3 Hz, 2H), 7.62-7.50 (m, 2H), 7.46-7.39 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 3.92 (s, 3H), 3.14-3.06 (m, 1H), 2.77 (dd, J = 16.1, 6.3 Hz, 1H), 2.65-2.56(m, 1H), 2.07-1.95 (m, 1H), 1.34-1.23 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ199.0, 170.1, 150.1, 149.6, 138.7, 133.2, 131.1, 128.9, 128.4, 128.1, 121.7,120.1, 117.4, 105.0, 56.3, 56.2, 34.7, 22.5, 21.7, 14.4.

[0216] HPLC: The er value of P41 (82.6:17.4) was analyzed by liquid chromatography using a chiral column, CHIRALPAK. ® IC column (n-hexane:isopropanol = 90:10, 1.0 mL / min, T = 30) o C, 254 nm), retention times were 13.98 min and 15.49 min.

[0217] The chiral cis-cyclopropane compound of the present invention can be further transformed as follows:

[0218] 1. A C=O bond can be converted to a C=S bond using method F:

[0219] Method F involves adding P1 and Lawston's reagent sequentially to dichloromethane (DCM) at a molar ratio of 1:0.5, with P1 concentration of 0.2 mol / L. The mixture is stirred for 24 h under air atmosphere and at room temperature. After the reaction is complete, the DCM is evaporated to dryness, and the thioamide product is obtained by silica gel column chromatography.

[0220] 2. A C=O bond can be converted to a C=C bond using method G:

[0221] The method G described therein involves adding P1, triphenylmethylphosphine bromide, and potassium tert-butoxide sequentially to tetrahydrofuran (THF) in a molar ratio of 1:1.3:2.6, with P1 concentration of 0.1 mol / L. The mixture is stirred for 12 h under air atmosphere and at room temperature. After the reaction is complete, the DCM is evaporated to dryness, and the olefin product is obtained by silica gel column chromatography.

[0222] The above embodiments are merely illustrative examples and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A method for preparing a chiral cis-cyclopropane compound, characterized in that, Includes the following steps: Using but-3-enoic acid derivatives and thioylide reagents as raw materials, chiral ligands and metal catalysts are reacted in a solvent to generate chiral cis-cyclopropane compounds. The buty-3-enoic acid derivative is selected from at least one compound of the general structural formula shown in Formula I: ; wherein, the R 1 Selected from hydrogen, halogens, and alkoxy groups; The sulfur ylide reagent is selected from at least one compound of the general formula shown in Formula II: ; wherein, the R 2 Selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, and substituted or unsubstituted alkyl groups; Chiral cis-cyclopropane compounds are selected from at least one compound of the general formula shown in Formula III: ; where R in Equation III 1 With R in Equation I 1 The corresponding values ​​are the same; R in Equation III 2 With R in Equation II 2 The correspondence is the same.

2. The method for preparing the chiral cis-cyclopropane compound according to claim 1, characterized in that: In formula I, R 1 Selected from hydrogen, chlorine, and C1-C5 alkoxy groups; preferably, the R 1 Selected from hydrogen, chlorine, and C1-C3 alkoxy groups; more preferably, the R 1 Selected from hydrogen, chlorine, and methoxy groups; More preferably, Formula I is selected from at least one of the following compounds: 。 3. The method for preparing the chiral cis-cyclopropane compound according to claim 1, characterized in that: In Formula II, R 2 Selected from phenyl, naphthyl, furanyl, thiophene, halogen-substituted phenyl, nitro-substituted phenyl, alkyl-substituted phenyl, haloalkyl-substituted phenyl, alkoxy-substituted phenyl, cyano-substituted phenyl, ester-substituted phenyl, sulfonyl-substituted phenyl, phenyl-substituted naphthyl, and C3-C15 alkyl; preferably, R 2 Selected from phenyl, naphthyl, furanyl, thiophene, halogen-substituted phenyl, nitro-substituted phenyl, C1-C3 alkyl-substituted phenyl, C1-C3 haloalkyl-substituted phenyl, C1-C3 alkoxy-substituted phenyl, cyano-substituted phenyl, C1-C3 ester-substituted phenyl, C1-C5 sulfonyl-substituted phenyl, phenyl-substituted naphthyl, and C3-C7 alkyl; More preferably, Formula II is selected from at least one of the following compounds: 。 4. The method for preparing the chiral cis-cyclopropane compound according to claim 1, characterized in that: The chiral ligand is selected from chiral monodentate oxazoline ligands; preferably, the chiral ligand is selected from any one of the following compounds: 。 5. The method for preparing the chiral cis-cyclopropane compound according to claim 1, characterized in that: The metal catalyst is at least one of palladium catalysts; preferably, the palladium catalyst is selected from at least one of palladium acetate, palladium chloride, palladium trifluoroacetate, and palladium bis(hexafluoroacetylacetone); and / or, The solvent is selected from alcohol solvents; preferably, the solvent is selected from at least one of hexafluoroisopropanol or trifluoroethanol.

6. The method for preparing the chiral cis-cyclopropane compound according to claim 1, characterized in that: The reaction temperature is room temperature to 60°C. o C; and / or, The reaction time is 12 to 24 hours.

7. The method for preparing the chiral cis-cyclopropane compound according to claim 1, characterized in that: The concentration of butyric acid derivatives in the solvent is 0.05~1.0 mol / L; and / or, The molar ratio of butyric acid derivative to thioylide reagent is 1:(1.2-1.5); and / or, The molar ratio of butyric acid derivative to metal catalyst is 1 : (0.05-0.2); and / or, The molar ratio of but-3-enoic acid derivative to chiral ligand is 1:(0.1~0.4).

8. A chiral cis-cyclopropane compound, characterized in that: The chiral cyclopropane compound is selected from at least one of the general structural formulas shown in Formula III: ; where R in Equation III 1 With R in Equation I 1 The corresponding values ​​are the same; R in Equation III 2 With R in Equation II 2 The correspondence is the same.

9. The chiral cis-cyclopropane compound according to claim 8, characterized in that: The chiral cis-cyclopropane compound is selected from at least one of the following compounds: 。 10. The use of the chiral ciscyclopropane compound according to any one of claims 8 to 9 as a synthetic chemical intermediate.

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