Morpholine ring compound and derivatives, and preparation method and application thereof

Abstract

The present application relates to a kind of morpholine ring compound and derivative and preparation method and application.The morpholine ring compound is the compound with the structure shown in formula A or formula B, or their enantiomers.The present application starts from ethynyl carbonate and 4-amino dienone or N-benzyl oxetane-3-amine, develops a continuous asymmetric propargyl amination and desymmetrization Michael addition reaction using cuprous iodide and chiral pyridine oxazoline ligand as catalyst, and desymmetrization ring-opening reaction of butylene oxide with diphenyl phosphate, efficiently, with high enantioselectivity and excellent diastereoselectivity Synthesis of multiple quaternary carbon center and multifunctional morpholine ring derivatives and nitrogen-containing adjacent quaternary carbon and hydroxyl-containing morpholine derivatives;And further develop a derivative with antitumor activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to the asymmetric synthesis of morpholine ring compounds containing nitrogen α-quaternary carbon. BACKGROUND

[0002] Chiral morpholine ring is widely distributed in natural products, pharmaceutical agents, and chiral catalysts. For example, Aprepitant can be used in clinic to prevent acute and delayed nausea and vomiting during the initial and repeat treatment of highly emetogenic anti-neoplastic chemotherapy. γ-Secretase inhibitor can be used for the treatment of neurological diseases. Nitrogen-containing morpholine ring aza-cyclic carbene catalysts are involved in asymmetric synthesis reactions. At present, various efficient strategies and methods have been developed for the construction of morpholine ring, especially the asymmetric catalytic strategy has been successfully applied in this field. The methods for synthesizing morpholine ring can be roughly divided into intermolecular and intramolecular types, including intramolecular asymmetric hydrogenation and intermolecular asymmetric alkylation. Although the construction of morpholine ring has made certain progress, the asymmetric construction of morpholine ring containing quaternary carbon and multiple functional groups through intermolecular method has not been developed, especially the asymmetric construction of morpholine ring by intermolecular cycloaddition reaction catalyzed by transition metal has not been reported in the literature.

[0003] Based on the above analysis, the present application develops a method for synthesizing morpholine ring derivatives containing multiple quaternary carbon centers and multiple functional groups, and morpholine derivatives containing nitrogen adjacent quaternary carbon and hydroxyl groups, by using cuprous iodide and chiral pyridine oxazoline ligand as catalyst, through continuous asymmetric propargyl amination and desymmetrization Michael addition reaction, and phosphoric acid diphenyl ester involved desymmetrization oxetane ring opening reaction, starting from ethynyl carbonate and 4-aminodienone or N-benzyl oxetane-3-amine. SUMMARY

[0004] The present application aims to explore the asymmetric propargylation and desymmetrization Michael addition tandem cyclization reaction of cuprous iodide and pyridine oxazoline ligand and the desymmetrization ring opening reaction of butylene oxide with diphenyl phosphate, to synthesize highly functionalized morpholine ring derivatives containing multiple quaternary carbons with high enantioselectivity and excellent diastereoselectivity, using simple and readily available ethynyl carbonate and 4-amino dienone or N-benzyl oxetan-3-amine as starting materials. And a series of derivatization transformations are made for the product, and the anti-tumor activity test is carried out on the derivatized product. Derivatization includes: 1) using Sonogashira coupling to convert the terminal alkyne to internal alkyne; 2) converting the terminal alkyne to a triazole fragment in the presence of a copper catalyst with a benzyl azide; 3) using DDQ to oxidize the benzyl position of VI-9 product to an amide; 4) hydrogenation of VI-1 to remove benzyl group, followed by cyclization of -OH and -NH groups, three kinds of fused nitrogen heterocyclic products can be obtained. Specifically,

[0005] The first aspect of the present application provides a morpholine ring compound, which is a compound having a structure shown in formula A or formula B, or an enantiomer thereof:

[0006]

[0007] wherein, R 1 and R 4 are each independently selected from thienyl, pyridyl, gem-dimethyl vinyl, 1,2-dimethyl vinyl or a group shown in formula C;

[0008]

[0009] R 2 is H, halogen, unsubstituted or halogen-substituted C1-C4 alkyl, C1-C4 alkoxy, cyano, C1-C4 alkyl ester, C6-C 10 aryl or 2,3-dioxolyl;

[0010] R 3 is C1-C4 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl;

[0011] R 5 is substituted or unsubstituted C6-C 14 aryl, substituted or unsubstituted C4-C 16 heteroaryl or C6-C 10 cycloalkenyl.

[0012] The term C1-C4 alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

[0013] The term C1-C4alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy.

[0014] The term C1-C4alkyl ester group includes, but is not limited to, methyl ester group, ethyl ester group, n-propyl ester group, isopropyl ester group, n-butyl ester group, isobutyl ester group, t-butyl ester group.

[0015] The term C6-C 10 Aryl includes, but is not limited to, benzene, alkyl-substituted benzene.

[0016] 2,3-dioxolyl means R 2 forms a fused ring structure with the benzene ring body, as shown in formula I-12.

[0017] According to the present application, preferably, R 2 is H, methyl, fluorine, chlorine, trifluoromethyl, methoxy, cyano, phenyl, t-butyl ester group or 2,3-dioxolyl; more preferably H, 3-methyl, 3-trifluoromethyl, 3-fluorine, 3-chlorine, 3-phenyl, 3-methoxy, 3-cyano, 3-t-butyl ester group, 2-fluorine, 2-methoxy, 1-fluorine or 2,3-dioxolyl.

[0018] According to the present application, preferably, R 3 is methyl, ethyl, n-butyl, 3-alkenyl n-butyl, cyclopropyl or propynyl.

[0019] According to a specific embodiment of the present application, in the compound shown in formula B, R 4 is a group shown in formula C and R 2 is H, methyl, fluorine, chlorine, trifluoromethyl, methoxy, cyano, phenyl, t-butyl ester group or 2,3-dioxolyl, R 5 is phenyl, 3-methoxyphenyl, 6-methoxynaphthyl, furanyl, thienyl, N-p-toluenesulfonyl pyrrolyl, benzofuran, or cyclohexenyl.

[0020] The second aspect of the present application provides a method for preparing a morpholine ring compound, for preparing the above-mentioned compound, comprising the following steps:

[0021] Under the protection of inert gas, the cuprous iodide, ligand and solvent are mixed and stirred, then the dicyclohexylmethylamine, the first reactant, the second reactant are added, the first reaction is carried out at-50℃ to-10℃, after the reaction is completed, the ring-closing reagent is added, the second reaction is continued to stir until the uncyclized product is completely reacted, to obtain the morpholine ring compound;

[0022] The first reactant is a compound shown in formula II; the second reactant is a compound shown in formula III or a compound shown in formula V.

[0023]

[0024]

[0025] wherein R 1 , R 3 and R 5 are as defined above;

[0026] When the second reactant is a compound of formula III, the ligand is L1, and the ring-closing reagent is trifluoroacetic acid;

[0027]

[0028] When the second reactant is a compound of formula V, the ligand is L2, and the ring-closing reagent is diphenyl phosphate;

[0029]

[0030] The preparation method of the present application includes two types corresponding to compounds of formula A and compounds of formula B respectively.

[0031] For the compound of formula A, when the second reactant is a compound of formula III, the ligand is L1, and the ring-closing reagent is trifluoroacetic acid.

[0032] For the compound of formula B, according to one specific embodiment, the first reactant is a compound of formula IV, the second reactant is a compound of formula V, the ligand is L2, and the ring-closing reagent is diphenyl phosphate;

[0033]

[0034] wherein R 2 are as defined above.

[0035] According to the present application, the inert gas is preferably argon, and the solvent is preferably toluene.

[0036] According to the present application, preferably, the temperature for mixing and stirring the cuprous iodide, the ligand and the solvent is 30-50°C.

[0037] According to the present application, preferably, after adding the trifluoroacetic acid, the temperature for continuing stirring the reaction is 10-30°C.

[0038] According to the present application, preferably, the amount of the cuprous iodide added is 4-6 mol%, the amount of the ligand added is 4-8 mmol%, the amount of the dicyclohexylmethylamine added is 1-3 equivalents, and the amount of the trifluoroacetic acid added is 3-5 equivalents.

[0039] According to the present application, preferably, when the second reactant is a compound of formula III, the temperature of the first reaction is from -30°C to -10°C, and when the second reactant is a compound of formula V, the temperature of the first reaction is from -50°C to -40°C.

[0040] The method of the present application also preferably comprises, after the reaction of the uncyclized product is complete, quenching the reaction system with saturated potassium carbonate solution, extracting with ethyl acetate, and then purifying by column chromatography.

[0041] According to the present application, a synthetic route for preparing a class of highly functionalized morpholine ring derivatives (compounds of formula A) containing multiple quaternary carbon centers is as follows:

[0042]

[0043] R 1 , R 3 are defined as R 1 , R 3 in formula A; wherein Cul is copper(I) iodide, PhMe is toluene, L1 is a 2-nucleophilic group-substituted 4-iodopyridine oxazoline ligand, Cy2NMe is dicyclohexylmethylamine, and d.r. is diastereomeric ratio.

[0044] According to one embodiment of the present application, the synthesis method is as follows: copper(I) iodide and ligand L1 are dissolved in 1 mL of toluene at room temperature, and stirred at 40°C for 30 minutes under argon protection. Subsequently, base dicyclohexylmethylamine, 4-aminodienone III, and alkynyl carbonate II are added in sequence, and the reaction mixture is continuously reacted at -20°C until the reaction is complete as determined by TLC. Subsequently, 4.0 equivalents of trifluoroacetic acid are added, and stirred at room temperature for 6 hours until the reaction of the uncyclized product is complete. Subsequently, the reaction system is quenched with saturated potassium carbonate solution, and extracted with ethyl acetate three times. The target product is directly obtained by column chromatography with V 石油醚 / V 乙酸乙酯 = 4:1. The ee value (enantiomeric excess) of the product is determined by chiral HPLC; HPLC analysis is performed using a Chiral AD-H column; and the racemate is obtained by reacting copper(I) iodide and a racemic ligand.

[0045] According to another type of the present application, a class of nitrogen-ortho quaternary carbon and hydroxyl-containing morpholine derivatives is synthesized in high yield, high enantioselectivity, and excellent diastereoselectivity by using a tandem cyclization reaction of asymmetric propargylation with copper(I) iodide and pyridine oxazoline ligand, and starting from a simple and readily available ethynyl carbonate and N-benzyloxyazetidine-3-amine. Specifically, a synthetic route for preparing a class of nitrogen-ortho quaternary carbon center, primary hydroxyl-containing morpholine ring derivatives (compounds of formula B) is as follows:

[0046]

[0047] In the reaction formula, R 2 R 5 Definition and formula C of R 2 In formula B, R 5 The definitions are the same; where CuI is cuprous iodide (I), PhMe is toluene, L2: 1-neyl-substituted pyridine oxazoline ligand, Cy2NMe: dicyclohexylmethylamine, and dr diastereomeric ratio.

[0048] According to a specific embodiment of the present invention, the synthesis method is as follows: Cuprous iodide and ligand L2 are dissolved in 1 mL of toluene at room temperature and stirred at 40 °C for 30 minutes under argon protection. Then, dicyclohexylmethylamine, N-benzyloxetane-3-amine V, and ethynyl carbonate II are added sequentially, and the reaction mixture continues to react at -44 °C until TLC detection shows complete reaction. Subsequently, 4.0 equivalents of diphenyl phosphate are added, and the mixture is stirred at room temperature for 8 hours until the uncyclized product reacts completely. The reaction system is then quenched using saturated potassium carbonate solution, and the mixture is extracted three times with ethyl acetate. 石油醚 / V 乙酸乙酯 The target product was obtained directly by 3:1 column chromatography. The ee value of the product was determined by chiral HPLC; HPLC analysis was performed using a chiral AS-H column; the racemic mixture was obtained by reacting cuprous iodide with the racemic ligand.

[0049] A third aspect of the present invention provides a morpholine ring compound derivative derived from the above-mentioned compounds, comprising: (1) an endoyne derivative having the structure shown in formula A-1 or formula B-1:

[0050]

[0051] Among them, R 1 R 3 R 4 and R 5 The definition is the same as above, where K is any derivatable group;

[0052] (2) Triazole derivatives having the structure shown in formula A-2 or formula B-2:

[0053]

[0054] Among them, R 1 R 3 R 4 and R 5 The definition is the same as above, where L is any derivatizable group;

[0055] (3) Amide derivatives, having the structure shown in formula B-3:

[0056]

[0057] wherein R 4 and R 5 are as defined above;

[0058] (4) ester derivatives having the structure of Formula B-4:

[0059]

[0060] wherein R 4 and R 5 are as defined above, and Q is an arbitrary group which can be derivatized;

[0061] (5) fused nitrogen heterocycle derivatives having the structures of Formula B-5 to Formula B-8:

[0062]

[0063] wherein R 4 is as defined above, and W is an arbitrary group which can be derivatized;

[0064]

[0065] wherein R 4 is as defined above, and X is an arbitrary group which can be derivatized;

[0066]

[0067] wherein R 4 is as defined above, and Y and Z are arbitrary groups which can be derivatized.

[0068] In the present application, the term "arbitrary group which can be derivatized" means that, for each derivatization method, the group can be any group suitable for the derivatization method, provided that the reaction is possible, and the present application is not particularly limited in this regard. Preferably, K, L, Q, W, X, Y, and Z are each independently at least one of a C1-C 12 alkyl group, a C2-C 12 alkenyl group, a C2-C 12 alkynyl group, a C3-C 12 cycloalkyl group, a C2-C 12 heterocycloalkyl group, a C6-C 20 aryl group, a C7-C 12 alkylaryl group, a C7-C 12 aralkyl group, and a C2-C 12 heteroaryl group. According to a specific embodiment of the present application, K is a phenyl group, L is a benzyl group, Q is a diazacyclohexane group, W is an ethyl group, X is an ethyl group, Y is a phenyl group, and Z is an ethyl group.

[0069] According to a most specific embodiment of the present application, in the formula B-4, R4 is meta-fluorophenyl, R5 is phenyl, Q is hydrazinocyclohexyl, and the morpholine ring derivative has a structure shown in the formula VIII-7:

[0070]

[0071] The present application tests the anti-tumor activity of the compound, and finds that the compound can effectively inhibit a plurality of tumor cells, including but not limited to at least one of lung cancer cells, human glioma cells and breast cancer cells, and can be used for preparing a tumor cell inhibitor.

[0072] The present application discloses the anti-tumor activity research of morpholine ring derivatives with optically active nitrogen-containing alpha quaternary carbon and synthetic conversion products thereof. General formula A is a kind of chiral quaternary carbon-containing, highly functionalized morpholine ring compound, which can be synthesized efficiently and selectively by transition metal copper-catalyzed propargyl carbonate and 4-amino dienone asymmetric propargyl amination and desymmetrization Michael addition reaction. General formula B is a kind of chiral quaternary carbon-containing and hydroxyl-containing morpholine ring compound, which can be synthesized efficiently and selectively by transition metal copper-catalyzed propargyl carbonate and N-benzyl oxetan-3-amine asymmetric propargyl amination and desymmetrization oxetane ring opening reaction with diphenyl phosphate.

[0073] Other features and advantages of the present application will be described in detail in the following specific embodiments. DETAILED DESCRIPTION

[0074] The preferred embodiments of the present application will be described in more detail below. Although the preferred embodiments of the present application are described below, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments described herein.

[0075] Preparation of compound I-1 of example 1

[0076]

[0077] The metal catalyst, copper iodide (0.005 mmol, 5 mol%) and L1(0.006 mmol, 6 mol%) were dissolved in 1 mL of toluene and stirred at 40 °C for 30 min under argon. Then dicyclohexylmethylamine (0.2 mmol, 2.0 equiv), 4-aminodienone III-1 (0.15 mmol, 1.5 equiv) were added successively, followed by ethynyl carbonate II-1 (0.1 mmol, 1.0 equiv). The reaction mixture was stirred at -20 °C until the reaction was complete by TLC. Then trifluoroacetic acid (4.0 equiv) was added and the reaction mixture was stirred at room temperature for 6 h until the uncyclized product was consumed. The reaction mixture was quenched with saturated potassium carbonate solution and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (V 石油醚 / V 乙酸乙酯 = 4:1 to give the product of formula I-1 in 75% yield.

[0078] 1 H NMR (400 MHz, CDC13) δ 7.81 (d, J = 7.0 Hz, 2H), 7.40 - 7.33 (m, 3H), 7.05 (dd, J = 10.3, 2.7 Hz, 1H), 6.00 (d, J = 10.3 Hz, 1H), 3.93 - 3.84 (m, 2H), 3.48 (d, J = 11.0 Hz, 1H), 2.91 - 2.65 (m, 2H), 2.60 (s, 1H), 2.01 (s, 1H), 1.38 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 196.0, 157.8, 140.6, 128.4, 127.0, 126.5, 86.6, 79.9, 77.7, 75.64, 55.7, 52.9, 41.1, 27.0. High resolution: calculated [M+H]: 268.1338, found 268.1339. + : 268.1338, found 268.1339. D 25 = 118 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 91%, chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times ti = 12.58 min, t2= 15.06 min.

[0079] Preparation of compound I-2 of example 2

[0080]

[0081] The preparation method is the same as Example 1, except that ethynyl carbonate II-2 (0.1 mmol, 1.0 equiv) is added to obtain the product of formula I-2, with a yield of 65%.

[0082] 1 H NMR (400 MHz, CDC13) δ 7.94 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.02 (dd, J = 10.3, 2.7 Hz, 1H), 6.00 (d, J = 10.3 Hz, 1H), 4.00-3.75 (m, 2H), 3.44 (d, J = 10.9 Hz, 1H), 2.88-2.66 (m, 2H), 2.64 (s, 1H), 2.04 (s, 1H), 1.39 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 195.7, 157.1, 144.6, 131, 130, 127.2, 127.0, 125.2 (q, J = 3.7 Hz), 85.8, 79.8, 77.4, 76.1, 55.2, 52.8, 40.9, 26.8. 19 F NMR (376 MHz, CDC13) δ -62.58. High resolution: calculated [M+H] + : 336.1211, found: 336.1207. [a] D 25 = 66.2 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 90%, chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 210 nm, 20°C, retention times t1= 13.928 min, t2= 15.415 min.

[0083] Preparation of compound I-3 of Example 3

[0084]

[0085] The preparation method is the same as Example 1, except that ethynyl carbonate II-3 (0.1 mmol, 1.0 equiv) is added to obtain the product of formula I-3, with a yield of 40%.

[0086] 1H NMR (400 MHz, CDC13) δ 7.96 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.00 (dd, J = 10.3, 2.7 Hz, 1H), 6.01 (d, J = 10.3 Hz, 1H), 3.93 - 3.81 (m, 2H), 3.42 (d, J = 10.9 Hz, 1H), 2.88 - 2.67 (m, 2H), 2.66 (s, 1H), 2.03 (s, 1H), 1.39 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 195.7, 156.8, 145.8, 132.2, 127.5, 127.3, 118.5, 112.2, 85.4, 79.8, 77.2, 76.4, 55.7, 52.8, 40.9, 26.9. High resolution: calculated [M+H] C26H28N2O6: 293.1290, found: 293.1297. + : 293.1290, found: 293.1297. D 25 = 22.70 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 94%, Chiral IC-H column (isopropanol: n-hexane 20:80, v:v), 1.0 mL / min, 230 nm, 20 °C, retention times ti = 30.461 min, t2= 33.521 min.

[0087] Preparation of compound I-4 of example 4

[0088]

[0089] Preparation method as in example 1, except that ethynyl carbonate II-4 (0.1 mmol, 1.0 equiv) was added, obtaining the product of formula I-4 in 48% yield.

[0090] 1 H NMR (400 MHz, CDC13) δ 7.98 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.04 (dd, J = 10.2, 2.7 Hz, 1H), 6.02 (s, 1H), 3.93 - 3.82 (m, 1H), 3.44 (d, J = 10.9 Hz, 1H), 3.02 - 2.67 (m, 1H), 2.62 (s, 2H), 2.02 (s, 1H), 1.60 (s, 9H), 1.39 (s, 3H). 13C NMR (100 MHz, CDC13) δ 195.9, 165.4, 157.4, 145.0, 132.0, 129.4, 127.2, 126.4, 86.1, 81.2, 79.8, 77.4, 75.9, 55.7, 52.8, 40.9, 28.2, 26.9. High resolution: calculated [M+H] 368.1862, found 368.1857. + : 368.1862, found 368.1857. [a] D 25 = 60.53 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 89%, chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 254 nm, 20°C, retention times ti = 13.607 min, t2= 18.660 min.

[0091] Example 5 Preparation of compound I-5

[0092]

[0093] Preparation method as in example 1, except that ethynyl carbonate II-5 (0.1 mmol, 1.0 equiv) was added, to give the product of formula I-5 in 60% yield.

[0094] 1 H NMR (400 MHz, CDC13) δ 7.78 (dd, J = 8.7, 5.5 Hz, 2H), 7.09 - 6.97 (m, 3H), 5.99 (dd, J = 10.3, 1.1 Hz, 1H), 3.92 - 3.79 (m, 2H), 3.43 (d, J = 11.0 Hz, 1H), 2.87 - 2.63 (m, 2H), 2.61 (s, 1H), 1.97 (s, 1H), 1.36 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 195.8, 157.4, 128.3 (d, J = 8.3 Hz), 127.1, 115.2, 114.9, 86.3, 79.8, 77.6, 75.8, 52.8, 40.9, 26.9, 25.7. 19 F NMR (376 MHz, CDC13) δ -114.14. High resolution: calculated [M+H] + : 286.1243, found 286.1235. [a] D 25= 76.57 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 91 %, chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times ti = 15.463 min, t2= 17.709 min.

[0095] Example 6 Preparation of compound I-6

[0096]

[0097] Preparation as in example 1, except that ethynyl carbonate II-6 (0.1 mmol, 1.0 equiv) was added to give the product I-6 in 50% yield.

[0098] 1 H NMR (400 MHz, CDCI3) δ 7.74 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 7.01 (dd, J = 10.3, 2.7 Hz, 1 H), 5.99 (dd, J = 10.3, 1.1 Hz, 1 H), 3.93 - 3.77 (m, 2H), 3.42 (d, J = 1 1.0 Hz, 1 H), 2.88 - 2.65 (m, 2H), 2.61 (s, 1 H), 1.96 (s, 1 H), 1.37 (s, 3H). 13 C NMR (100 MHz, CDCI3) δ 195.8, 157.3, 139.2, 134.2, 128.4, 128.0, 127.2, 86.1, 79.8, 77.5, 75.9, 55.3, 52.8, 40.9, 26.9. High resolution: calculated [M+H]: 302.0948, found: 302.0935. [a] + : 302.0948, found: 302.0935. [a] D 25 = 76.57 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 91 %, chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times ti = 15.463 min, t2= 17.709 min.

[0099] Example 7 Preparation of compound I-7

[0100]

[0101] Preparation as in example 1, except that ethynyl carbonate II-7 (0.1 mmol, 1.0 equiv) was added to give the product I-7 in 75% yield.

[0102] 1 H NMR (400 MHz, CDC13) δ 7.67 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.04 (dd, J = 10.3, 2.7 Hz, 1H), 5.99 (d, J = 10.6 Hz, 1H), 3.91 - 3.82 (m, 2H), 3.46 (d, J = 10.9 Hz, 1H), 2.88 - 2.64 (m, 2H), 2.58 (s, 1H), 2.35 (s, 3H), 1.89 (s, 1H), 1.36 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 196.0, 157.8, 138.1, 137.7, 129.0, 127.1, 126.3, 86.8, 79.8, 77.7, 75.4, 55.4, 52.8, 41.0, 26.9, 21.0. High resolution: calculated [M+H] 282.1494, found 282.1485. + : 282.1494, found 282.1485. [a] D 25 = 103.50 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 90%, Chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 11.517 min, t2= 14.347 min.

[0103] Example 8 Preparation of compound I-8

[0104]

[0105] Preparation method as in example 1, except that ethynyl carbonate II-8 (0.1 mmol, 1.0 equiv) was added, to give the product of formula I-8 in 88% yield.

[0106] 1 H NMR δ 7.86 (d, J = 8.4 Hz, 2H), 7.63 - 7.55 (m, 4H), 7.49 - 7.35 (m, 2H), 7.36 (s, 1H), 7.05 (dd, J = 10.2, 2.7 Hz, 1H), 6.00 (d, J = 10.2 Hz, 1H), 3.95 - 3.83 (m, 2H), 3.52 (d, J = 11.0 Hz, 1H), 2.87 - 2.65 (m, 2H), 2.62 (s, 1H), 2.04 (s, 1H), 1.38 (s, 3H). 13C NMR (100 MHz, CDC13) δ 195.94, 157.67, 141.20, 140.44, 139.60, 128.78, 127.06, 127.01, 126.87, 86.55, 79.81, 77.57, 75.65, 55.45, 52.81, 40.98, 26.87. High resolution: calculated [M+H] 344.1651, found 344.1642. [a] + : 298.1443, found 298.1439. [a] D 25 = 63.83 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 90%, chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 210 nm, 20°C, retention times ti = 20.414 min, t2= 24.518 min.

[0107] Example 9 Preparation of compound I-9

[0108]

[0109] The procedure of Example 1 was followed except that ethynyl carbonate II-9 (0.1 mmol, 1.0 equiv) was added to give the product of formula I-9 in 85% yield.

[0110] 1 H NMR (400 MHz, CDC13) δ 7.71 (d, J = 8.8 Hz, 2H), 7.04 (dd, J = 10.3, 2.7 Hz, 1H), 6.89 (d, J = 8.9 Hz, 2H), 5.99 (d, J = 9.7 Hz, 1H), 3.91 - 3.82 (m, 2H), 3.81 (s, 3H), 3.45 (d, J = 11.0 Hz, 1H), 2.86 - 2.65 (m, 2H), 2.59 (s, 1H), 1.94 (s, 1H), 1.36 (s, 3H). 13 C NMR δ 196.0, 159.5, 157.8, 132.7, 127.7, 127.1, 113.6, 86.8, 79.8, 77.7, 75.5, 55.3, 55.2, 52.9, 41.0, 26.9. High resolution: calculated [M+H] 298.1443, found 298.1439. [a] + : 298.1443, found 298.1439. [a] D 25= 56.8 (c = 0.5, CHCI3). Enantiomeric excess analysis of the product: enantiomeric excess of the product = 88%, Chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 210 nm, 20°C, retention times ti = 13.965 min, t2= 16.822 min.

[0111] Example 10 Preparation of compound I-10

[0112]

[0113] Preparation method as in example 1 except that ethynyl carbonate II-10 (0.1 mmol, 1.0 equiv) was added to give the product of formula I-10 in 78% yield.

[0114] 1 H NMR (400 MHz, CDCI3) δ 7.64-7.46 (m, 2H), 7.33 (td, J = 8.0, 6.0 Hz, 1H), 7.07-7.01 (m, 1H), 7.00 (d, J = 2.7 Hz, 1H), 6.00 (d, J = 10.2 Hz, 1H), 3.95-3.77 (m, 2H), 3.44 (d, J = 10.9 Hz, 1H), 2.87-2.64 (m, 2H), 2.61 (s, 1H), 2.00 (s, 1H), 1.38 (s, 3H). 13 C NMR (100 MHz, CDCI3) δ 164.0, 161.5, 143.4 (d, J = 7.1 Hz), 129.8 (d, J = 8.1 Hz), 127.2, 122.2 (d, J = 2.8 Hz), 115.2 (d, J = 21.4 Hz), 113.6 (d, J = 23.7 Hz), 86.1, 79.8, 77.5, 75.8, 55.4, 52.8, 40.9, 26.9. 19 F NMR (376 MHz, CDCI3) δ -57.84. High resolution: calculated [M+H]: 286.1243, found: 286.1233. [a] + : 286.1243, found: 286.1233. [a] D 25 = 56.8 (c = 0.5, CHCI3). Enantiomeric excess analysis of the product: enantiomeric excess of the product = 88%, Chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 210 nm, 20°C, retention times ti = 13.965 min, t2= 16.822 min.

[0115] Example 11 Preparation of compound I-11

[0116]

[0117] The preparation method is the same as Example 1, except that ethynyl carbonate II-11 (0.1 mmol, 1.0 equiv) is added to obtain the product of formula I-11, with a yield of 38%.

[0118] 1 H NMR (400 MHz, CDC13) δ = 7.76-7.68 (major, m, 1H), 7.43 (minor, t, J = 8.6, 1H), 7.36-7.30 (major, m, 1H), 7.17 (t, J = 7.7, 1H), 7.13-7.05 (major + minor, m, 2H), 6.00 (major, d, J = 10.4, 1H), 5.81 (minor, dd, J = 10.5, 2.7, 1H), 5.28 (minor, d, J = 10.2, 1H), 4.61 (minor, d, J = 12.0, 1H), 4.25 (major, d, J = 10.8, 1H), 4.03-3.92 (minor, m, 2H), 3.87 (major, q, J = 3.0, 1H), 3.74 (major, d, J = 10.9, 1H), 2.85-2.61 (major + minor, m, 2H), 2.55 (major, s, 1H), 2.45 (minor, s, 1H), 2.26 (major, s, 1H), 1.37 (major, s, 3H), 1.27 (minor, s, 3H). 13 CNMR (100 MHz, CDC13) δ 195.8, 157.2, 130.2, 130.1, 127.5, 127.4, 127.3, 127.2, 127.1, 126.1, 124.4, 124.3, 116.9, 116.6, 85.4, 79.8, 74.9, 74.9, 74.0, 73.93, 53.0, 53.0, 52.9, 41.1, 26.8, 26.4. 19 F NMR (376 MHz, CDC13) δ -109.92 (major), -112.88 (minor). High resolution: calculated [M+H]: 286.1243, found: 286.1235. + :286.1243, found: 286.1235. D 25= 20.35 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 84%, Chiral AD-H column (isopropanol: n-hexane 5:95, v:v), 1.0 mL / min, 215 nm, 20°C, retention times ti = 13.965 min, t2= 16.822 min.

[0119] Example 12 Preparation of compound I-12

[0120]

[0121] Preparation as in example 1 except that ethynyl carbonate II-12 (0.1 mmol, 1.0 equiv) was added to give the product I-12 in 56% yield.

[0122] 1 H NMR (400 MHz, CDC13) δ 7.31 (dd, J = 4.6, 2.7 Hz, 2H), 7.03 (dd, J = 10.3, 2.7 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.99 (m, J = 10.8 Hz, 3H), 3.90 - 3.78 (m, 2H), 3.43 (d, J = 11.0 Hz, 1H), 2.89 - 2.63 (m, 2H), 2.59 (s, 1H), 1.97 (s, 1H), 1.36 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 194.9, 156.6, 146.6, 146.4, 133.6, 126.0, 119.0, 106.8, 106.1, 100.2, 85.6, 78.8, 76.7, 74.5, 54.4, 51.8, 39.9, 25.9. High resolution: calculated [M+H] + : 312.1236, found: 312.1230. [a] D 25 = 65.63 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 88%, Chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 254 nm, 20°C, retention times ti = 22.871 min, t2= 29.062 min.

[0123] Example 13 Preparation of compound I-13

[0124]

[0125] The preparation method is the same as Example 1, except that ethynyl carbonate II-13 (0.1 mmol, 1.0 equiv) is added to obtain the product of formula I-13, with a yield of 83%.

[0126] 1 H NMR (400 MHz, CDC13) δ 7.41 - 7.35 (m, 2 H), 7.34 - 7.25 (m, 1 H), 7.03 (dd, J = 10.3, 2.7 Hz, 1 H), 6.86 (dd, J = 8.0, 2.3 Hz, 1 H), 5.99 (dd, J = 10.3, 1.2 Hz, 1 H), 3.91 - 3.85 (m, 2 H), 3.83 (s, 3 H), 3.47 (d, J = 11.0 Hz, H), 2.85 - 2.64 (m, 2 H), 2.58 (s, 1 H), 1.99 (s, 1 H), 1.37 (s, 3 H). 13 C NMR (100 MHz, CDC13) δ 195.9, 159.6, 157.6, 142.4, 129.3, 127.1, 118.8, 113.1, 112.8, 86.6, 79.8, 77.6, 75.5, 55.6, 55.3, 52.8, 40.99, 26.9. High resolution: calculated [M+H] 298.1443, found 298.1436. + : 298.1443, found 298.1436. [a] D 25 = 81 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 90%, chiral AD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 210 nm, 20°C, retention times t1= 15.986 min, t2= 18.151 min.

[0127] Preparation of compound I-14 of Example 14

[0128]

[0129] The preparation method is the same as Example 1, except that ethynyl carbonate II-14 (0.1 mmol, 1.0 equiv) is added to obtain the product of formula I-14, with a yield of 62%.

[0130] 1H NMR (400 MHz, CDC13) δ 7.55-7.50 (m, 1H), 7.30 (m, J = 7.7, 4.5 Hz, 2H), 7.01 (dd, J = 10.4, 2.7 Hz, 1H), 5.98 (d, J = 10.3 Hz, 1H), 3.99-3.82 (m, 2H), 3.55 (d, J = 10.9 Hz, 1H), 2.91-2.64 (m, 2H), 2.55 (s, 1H), 2.11 (s, 1H), 1.33 (s, 3H). 13 C NMR (100 MHz, CDC13) δ (ppm) δ 195.8, 157.3, 142.5, 127.1, 126.2, 126.0, 122.7, 86.6, 79.8, 76.9, 74.4, 53.2, 52.8, 40.9, 26.7. High resolution: [M+H] calculated: 274.0902, found: 274.0893. + : 274.0902, found: 274.0893. [a] D 25 = 76.57 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 84%, Chiral OD-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, retention times t1= 30.377 min, t2= 47.504 min.

[0131] Preparation of compound I-15

[0132]

[0133] Preparation method as in example 1, except that 4-aminodienone III-2 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-1 (0.1 mmol, 1.0 equiv) were added, obtaining the product of formula I-15 in 86% yield.

[0134] 1 H NMR (400 MHz, CDC13) δ 7.55-7.50 (m, 1H), 7.30 (m, J = 7.7, 4.5 Hz, 2H), 7.01 (dd, J = 10.4, 2.7 Hz, 1H), 5.98 (d, J = 10.3 Hz, 1H), 3.99-3.82 (m, 2H), 3.55 (d, J = 10.9 Hz, 1H), 2.91-2.64 (m, 2H), 2.55 (s, 1H), 2.11 (s, 1H), 1.33 (s, 3H). 13C NMR (100MHz, CDCl3) δ 195.9, 157.7, 140.9, 128.3, 128.3, 127.4, 126.5, 86.9, 78.2, 77.5, 75.4, 55.4, 54.8, 40.8, 33.2, 7.4. High resolution: Calculated values: [M+H] + :282.1494, Measured value: 282.1485.[α] D 25 =80.33 (c=0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 90%, chiral AD-H column (isopropanol:n-hexane = 10:90, v:v), 1.0 mL / min, 210 nm, 20 °C, retention times t1 = 11.056 min, t2 = 13.114 min.

[0135] Example 16 Preparation of compound I-16

[0136]

[0137] The preparation method was the same as in Example 1, except that 4-aminodienone III-3 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-1 (0.1 mmol, 1.0 equiv) were added to obtain the product of formula I-16, with a yield of 81%.

[0138] 1 H NMR (400MHz, CDCl3) δ7.81 (d, J=7.1Hz, 2H), 7.40-7.31 (m, 3H), 7.11 (dd, J=1 0.4,2.7Hz,1H),6.02(d,J=10.3Hz,1H),4.08-3.77(m,2H),3.45(d,J=11.0H z,1H),2.89-2.63(m,2H),2.60(s,1H),2.04(s,1H),1.65(ddd,J=16.9,11.9 ,4.4Hz,2H),1.59-1.41(m,2H),1.36(q,J=7.2Hz,2H),0.95(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3) δ 196.0, 157.9, 140.9, 128.3, 128.3, 127.3, 126.5, 86.8, 78.5, 77.5, 75.5, 55.4, 54.9, 40.8, 40.4, 25.0, 23.3, 13.9. High resolution: Calculated values: [M+H] + 310.1807, Measured value: 310.1807.[α] D25 = 53.97 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 91 %, chiral AD-H column (isopropanol: n-hexane 5:95, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times ti = 16.651 min, t2= 19.258 min.

[0139] Example 17 Preparation of compound I-17

[0140]

[0141] Preparation according to example 1, except that 4-amino dienone III-4 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-1 (0.1 mmol, 1.0 equiv) were added, to give product I-17 in 73% yield.

[0142] 1 H NMR (400 MHz, CDCI3) δ 7.81 (d, J = 6.7 Hz, 2H), 7.40-7.31 (m, 3H), 7.09 (dd, J = 10.4, 2.7 Hz, 1 H), 6.03 (d, J = 9.9 Hz, 1 H), 5.92-5.74 (m, 1 H), 5.20-4.86 (m, 2H), 4.07-3.76 (m, 2H), 3.45 (d, J = 1 1.0 Hz, 1 H), 2.87-2.63 (m, 2H), 2.60 (s, 1 H), 2.49-2.34 (m, 1 H), 2.33-2.21 (m, 1 H), 2.03 (s, 1 H), 1.76 (dtd, J = 24.7, 13.8, 5.6 Hz, 2H). 13 C NMR (100 MHz, CDCI3) δ 195.9, 157.4, 140.7, 137.7, 128.3, 127.4, 126.5, 1 15.6, 86.7, 78.1, 77.5, 75.5, 55.4, 54.9, 40.7, 39.5, 27.3. High resolution: calculated [M+H]: 308.1651, found: 308.1645. + : 308.1651, found: 308.1645. D 25 = 66.9 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 91 %, chiral AD-H column (isopropanol: n-hexane 5:95, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times ti = 17.945 min, t2= 22.403 min.

[0143] Example 18 Preparation of compound I-18

[0144]

[0145] The preparation method was the same as in Example 1, except that 4-aminodienone III-5 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-1 (0.1 mmol, 1.0 equiv) were added to obtain the product of formula I-18, with a yield of 74%.

[0146] 1 H NMR (400MHz, CDCl3) δ7.82 (d, J=6.9Hz, 2H), 7.40-7.33 (m, 3H), 6.75 (dd, J=10 .4,2.6Hz,1H),6.08(d,J=10.3Hz,1H),4.07-3.78(m,2H),3.46(d,J=11.0Hz,1 H),3.07-2.64(m,2H),2.59(s,1H),2.07(s,1H),1.10(ddd,J=13.9,8.4,5.5H z,1H),0.53(ddt,J=19.5,8.6,4.3Hz,2H),0.37(ddt,J=10.7,9.3,5.0Hz,2H). 13 C NMR (100MHz, CDCl3) δ 196.4, 153.5 140.8, 129.6, 128.3, 126.5, 87.0, 80.5, 77.4, 75.4, 55.3, 54.7, 41.1, 19.2, 0.6, -1.1. High resolution: Calculated values: [M+H] + :294.1494, Measured value: 294.1492.[α] D 25 =89.03 (c=0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 94%, chiral AD-H column (isopropanol:n-hexane = 5:95, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times t1 = 19.705 min, t2 = 25.693 min.

[0147] Example 19 Preparation of compound I-19

[0148]

[0149] The preparation method was the same as in Example 1, except that 4-aminodienone III-6 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-1 (0.1 mmol, 1.0 equiv) were added to obtain the product of formula I-19, with a yield of 52%.

[0150] 1 H NMR(400MHz, CDCl3) δ7.81(d,J=8.1Hz,2H),7.48-7.31(m,3H),7.07-6.96(m,1H),6.01(d,J=10.1Hz,1H),4.30-3 .74(m,2H),3.56(d,J=11.1Hz,1H),2.90(ddd,J=151.1,16.9,3.1Hz,2H),2.60(s,1H),2.41(s,1H),1.88(s,3H). 13 C NMR (100MHz, CDCl3) δ 196.0, 152.4, 139.9, 128.4, 128.39, 126.9, 126.4, 86.5, 82.3, 78.8, 77.56, 77.19, 75.91, 54.61, 51.58, 41.65, 3.80. High resolution: Calculated values: [M+Na] + :292.1338, Measured value: 292.1334.[α] D 25 = -6.63 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 90%, chiral AD-H column (isopropanol:n-hexane = 5:95, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times t1 = 18.235 min, t2 = 21.593 min.

[0151] Example 20 Preparation of compound I-20

[0152]

[0153] The preparation method was the same as in Example 1, except that 4-aminodienone III-5 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-15 (0.1 mmol, 1.0 equiv) were added to obtain product of formula I-20, with a yield of 60%.

[0154] 1H NMR (400 MHz, CDC13) δ 6.67 (dd, J = 10.4, 2.6 Hz, 1H), 6.02 (d, J = 10.4 Hz, 1H), 5.06 (s, 1H), 3.97 (d, J = 10.9 Hz, 1H), 3.90 (dd, J = 5.2, 2.3 Hz, 1H), 3.38 (d, J = 11.0 Hz, 1H), 2.91 (dd, J = 17.4, 3.4 Hz, 1H), 2.66 - 2.60 (m, 1H), 2.41 (s, 1H), 1.93 (s, 3H), 1.74 (s, 3H), 0.98 - 0.94 (m, 1H), 0.55 - 0.40 (m, 2H), 0.31 - 0.26 (m, 2H). 13 C NMR (100 MHz, CDC13) δ 195.50, 151.91, 137.59, 128.85, 124.24, 86.44, 79.58, 73.64, 72.60, 54.04, 49.42, 40.24, 26.02, 18.62, 18.11, -0.00, -2.21. High resolution: Calculated for [M+H] 272.1651, Found 272.1644. + : 272.1651, Found 272.1644. [a] D 25 = 12.20 (c = 0.05, CHCl3). Optical purity analysis: Enantiomeric excess of product = 79%, Chiral AZ-H column (i-PrOH: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, Retention times t1= 29.868 min, t2= 34.256 min.

[0155] Example 21 Preparation of compound I-21

[0156]

[0157] Preparation as in example 1, except that 4-amino dienone III-1 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-16 (0.1 mmol, 1.0 equiv) were added, to give product I-21 in 52% yield.

[0158] 1H NMR (400 MHz, CDC13) δ 6.99 (dd, J = 10.3, 2.7 Hz, 1H), 6.01 - 5.90 (m, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.73 (q, J = 3.0 Hz, 1H), 3.42 (d, J = 10.8 Hz, 1H), 2.89 - 2.57 (m, 2H), 2.43 (s, 1H), 1.74 (s, 3H), 1.65 (d, J = 6.7 Hz, 3H), 1.29 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 196.0, 158.0, 134.4, 126.8, 121.4, 86.5, 79.8, 74.9, 74.7, 56.3, 52.7, 41.0, 26.8, 13.5, 12.6. High resolution: [M+H] calculated: 246.1494, found: 246.1486. + :246.1494, found: 246.1486. [a] D 25 = 64.75 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 85%, Chiral AZ-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 20.330 min, t2= 33.616 min.

[0159] Preparation of compound I-22

[0160]

[0161] Preparation method as in example 1, except that 4-aminodienone III-5 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-16 (0.1 mmol, 1.0 equiv) were added, to give the product of formula I-22 in 56% yield.

[0162] 1 H NMR (400 MHz, CDC13) δ 6.99 (dd, J = 10.3, 2.7 Hz, 1H), 6.01 - 5.90 (m, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.73 (q, J = 3.0 Hz, 1H), 3.42 (d, J = 10.8 Hz, 1H), 2.89 - 2.57 (m, 2H), 2.43 (s, 1H), 1.74 (s, 3H), 1.65 (d, J = 6.7 Hz, 3H), 1.29 (s, 3H). 13C NMR (100 MHz, CDC13) δ 196.5, 153.9, 134.5, 129.4, 121.7, 87.1, 80.4, 74.7, 74.5, 56.3, 54.6, 41.1, 19.1, 13.6, 12.7, 0.6, -1.2. High resolution: calculated for [M+H] 406.1986, found 406.1988. + : 272.1651, found: 272.1644. [a] D 25 = 49.05 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 85%, Chiral AZ-H column (i-PrOH: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 15.708 min, t2= 23.054 min.

[0163] Preparation of compound I-23

[0164]

[0165] Preparation method as in example 1, except that 4-aminodienone III-4 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-16 (0.1 mmol, 1.0 equiv) were added, to give the product of formula I-23 in 45% yield.

[0166] 1 H NMR (400 MHz, CDC13) δ 7.04 (dd, J = 10.3, 2.7 Hz, 1H), 6.05-5.94 (m, 2H), 5.86-5.75 (m, 1H), 5.11-4.97 (m, 2H), 3.88-3.77 (m, 2H), 3.40 (d, J = 10.9 Hz, 1H), 2.90-2.57 (m, 2H), 2.44 (s, 1H), 1.75 (t, J = 1.3 Hz, 3H), 1.72-1.62 (m, 5H). 13 C NMR (100 MHz, CDC13) δ 196.3, 158.0, 138.2, 134.9, 127.6, 122.0, 115.8, 87.1, 78.5, 75.1, 75.0, 56.5, 55.1, 41.0, 39.9, 27.6, 13.9, 13.0. High resolution: calculated for [M+H] 406.1986, found 406.1988. + : 286.1807, found: 286.1810. [a] D 25= 16.47 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 84%, Chiral AZ-H column (i-PrOH: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 14.356 min, t2= 18.664 min.

[0167] Example 24 Preparation of compound I-24

[0168]

[0169] Preparation method as in example 1, except that 4-amino dienone III-1 (0.15 mmol, 1.5 equiv) and ethynyl carbonate II-17 (0.1 mmol, 1.0 equiv) were added, to give the product of formula I-24 in 26% yield.

[0170] 1 H NMR (400 MHz, CDC13) δ 9.06 (s, 1H), 8.59 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 6.8 Hz, 1H), 7.01 (dd, J = 10.4, 2.7 Hz, 1H), 6.01 (d, J = 10.3 Hz, 1H), 3.97 - 3.82 (m, 2H), 3.49 (d, J = 10.9 Hz, 1H), 2.87 - 2.68 (m, 2H), 2.66 (s, 1H), 2.01 (s, 1H), 1.39 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 195.8, 157.0, 149.7, 148.5, 136.1, 134.5, 127.3, 123.1, 85.2, 79.8, 77.4, 76.4, 54.4, 52.8, 40.9, 26.9. High resolution: calculated [M+H]: [M+H] + : 269.1290, found: 269.1285. [a] D 25 = 4.35 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 26%, Chiral AD-H column (i-PrOH: n-hexane 10:90, v:v), 1.0 mL / min, 254 nm, 20°C, retention times ti = 29.580 min, t2= 32.561 min.

[0171] Example 25 Preparation of compound VI-1

[0172]

[0173] Copper iodide and ligand L2 were dissolved in 1 mL of toluene at room temperature and stirred for 30 minutes at 40 °C under argon. Subsequently, base dicyclohexylmethylamine, N-benzyloxetan-3-amine V-1, ethynyl carbonate II-1 were added sequentially and the reaction mixture was allowed to continue to react at -44 °C until the reaction was complete by TLC. Subsequently, 4.0 equivalents of diphenyl phosphate were added and stirred at room temperature for 8 hours until the uncyclized product was completely reacted. Subsequently, the reaction system was quenched with saturated potassium carbonate solution and extracted with ethyl acetate three times. The target product of formula VI-1 was obtained directly by column chromatography with V 石油醚 / V 乙酸乙酯 = 3:1 column chromatography to give the target product of formula VI-1 in a yield of 82%.

[0174] 1 H NMR (400 MHz, CDC13) δ 7.95 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.36-7.24 (m, 5H), 7.19 (t, J = 7.3 Hz, 1H), 3.99 (dd, J = 11.6, 3.5 Hz, 1H), 3.87 (t, J = 11.2 Hz, 1H), 3.80-3.70 (m, 3H), 3.55-3.45 (m, 1H), 3.33 (d, J = 15.8 Hz, 1H), 3.26 (t, J = 10.9 Hz, 1H), 3.05-3.09 (m, 1H), 2.84 (s, 1H), 1.15 (d, J = 9.5 Hz, 1H). 13 C NMR δ 141.4, 139.0, 128.8, 128.6, 128.4, 128.0, 127.2, 126.8, 80.5, 77.5, 77.5, 70.5, 65.8, 62.0, 61.0, 57.1. High resolution: calculated [M+H]: 308.1645, found: 308.1647. + [α] D 25 = -54.2 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 92%, chiral AD-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 20 °C, retention times ti = 4.781 min, t2= 7.031 min.

[0175] Preparation of compound VI-2 of Example 26

[0176]

[0177] Preparation method as in Example 25, except that N-benzyloxetan-3-amine V-1, ethynyl carbonate II-5 were added to give the target product of formula VI-2 in a yield of 81%.

[0178] 1 H NMR (400 MHz, CDC13) δ 7.92 (dd, J = 8.7, 5.5 Hz, 2H), 7.36 - 7.24 (m, 4H), 7.20 (t, J = 7.0 Hz, 1H), 7.07 (t, J = 8.6 Hz, 2H), 4.00 (dd, J = 11.6, 3.5 Hz, 1H), 3.84 (t, J = 11.3 Hz, 1H), 3.73 (d, J = 12.7 Hz, 3H), 3.51 (dd, J = 12.7, 4.1 Hz, 1H), 3.34 (d, J = 15.9 Hz, 1H), 3.28 (dd, J = 12.7, 2.2 Hz, 1H), 3.08 - 3.03 (m, 1H), 2.84 (s, 1H), 1.21 (br, 1H). 13 C NMR δ 162.7 (d, J = 247.8 Hz), 141.1, 134.8 (d, J = 3.3 Hz), 129.7, 128.9, 127.2, 126.6, 115.3 (d, J = 21.4 Hz), 80.3, 77.7, 77.5, 70.5, 65.2, 61.9, 61.0, 56.9. 19 F NMR (376 MHz, CDC13) δ -113.62. High resolution: calculated [M+H] + : 326.1551, found: 326.1548. [a] D 25 = -57.1 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 89%, chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 4.832 min, t2= 6.573 min.

[0179] Example 27 Preparation of compound VI-3

[0180]

[0181] Preparation as in example 25, except that ethynyl carbonate II-6 is added, to give the target product of formula VI-3, in 76% yield.

[0182] 1H NMR (400 MHz, CDC13) δ 7.88 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.33-7.24 (m, 4H), 7.20 (t, J = 7.0 Hz, 1H), 4.00 (dd, J = 11.6, 3.5 Hz, 1H), 3.83 (t, J = 11.3 Hz, 1H), 3.77-3.08 (m, 3H), 3.50 (dd, J = 12.7, 4.1 Hz, 1H), 3.35 (d, J = 15.9 Hz, 1H), 3.31-3.25 (m, 1H), 3.08-3.03 (m, 1H), 2.84 (s, 1H), 1.16 (br, 1H). 13 C NMR δ 141.0, 137.7, 134.4, 129.4, 128.9, 128.6, 127.3, 126.6, 80.1, 77.8, 77.4, 70.5, 65.4, 61.9, 61.0, 57.0. High resolution: Calculated: [M+H] + : 342.1255, Found: 342.1252. [a] D 25 = -34.1 (c = 0.5, CHCl3). Optical purity analysis: Enantiomeric excess of product = 88%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 20 °C, Retention times t1= 4.756 min, t2= 5.493 min.

[0183] Preparation of compound VI-4 of example 28

[0184]

[0185] Preparation method as in example 25, except that ethynyl carbonate II-19 is added, to obtain the target product of formula VI-4, in 85% yield.

[0186] 1 H NMR (400 MHz, CDC13) δ 7.88 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.33-7.24 (m, 4H), 7.20 (t, J = 7.0 Hz, 1H), 4.00 (dd, J = 11.6, 3.5 Hz, 1H), 3.83 (t, J = 11.3 Hz, 1H), 3.77-3.08 (m, 3H), 3.50 (dd, J = 12.7, 4.1 Hz, 1H), 3.35 (d, J = 15.9 Hz, 1H), 3.31-3.25 (m, 1H), 3.08-3.03 (m, 1H), 2.84 (s, 1H), 1.16 (br, 1H).13 C NMR (100 MHz, CDC13) δ 141.0, 138.2, 131.6, 129.7, 128.9, 127.3, 126.6, 122.6, 79.9, 77.9, 77.4, 70.5, 65.5, 61.9, 61.0, 57.1. High resolution: calculated [M+H] 386.0750, found 386.0745. + : 386.0750, found 386.0745. [a] D 25 = -48.0 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 86%, chiral AS-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 10.154 min, t2= 12.372 min.

[0187] Example 29 Preparation of compound VI-5

[0188]

[0189] Preparation as in example 25 except that ethynyl carbonate II-7 was added to give the target product of formula VI-5 in 55% yield.

[0190] 1 H NMR δ 7.82 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.32 - 7.23 (m, 2H), 7.22 - 7.16 (m, 3H), 3.98 (dd, J = 11.6, 3.6 Hz, 1H), 3.90 - 3.70 (m, 4H), 3.50 (dd, J = 12.7, 3.9 Hz, 1H), 3.27 (dd, J = 27.7, 13.8 Hz, 2H), 3.05 (dq, J = 10.0, 3.4 Hz, 1H), 2.81 (s, 3H), 1.14 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 141.0, 138.2, 131.6, 129.7, 128.9, 127.3, 126.6, 122.6, 79.9, 77.9, 77.4, 70.5, 65.5, 61.9, 61.0, 57.1. High resolution: calculated [M+H] 386.0750, found 386.0745. + : 386.0750, found 386.0745. [a] D 25= -52.5 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 86%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 5.222 min, t2= 6.040 min.

[0191] Example 30 Preparation of compound VI-6

[0192]

[0193] Preparation as in example 25 except that ethynyl carbonate II-8 was added to give the target product of formula VI-6 in 69% yield.

[0194] 1 H NMR (400 MHz, CDC13) δ 8.07 (d, J = 8.4 Hz, 2H), 7.69 - 7.61 (m, 4H), 7.48 (t, J = 7.6 Hz, 2H), 7.45 - 7.37 (m, 3H), 7.36 - 7.30 (m, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.07 (dd, J = 11.7, 3.5 Hz, 1H), 4.01 - 3.77 (m, 4H), 3.59 (ddH), 3.34 (d, J = 12.7 Hz, 1H), 3.15 (dd, J = 8.6, 4.2 Hz, 1H), 2.92 (s, 1H), 1.31 (br, 1H). 13 C NMR (100 MHz, CDC13) δ 141.5, 141.4, 140.4, 138.0, 128.9, 128.8, 128.4, 127.5, 127.2, 127.1, 126.8, 80.5, 77.6, 77.5, 70.5, 65.6, 61.9, 61.1, 57.1. High resolution: calculated [M+H]: 384.1958, found: 384.1957. [a] + : 384.1958, found: 384.1957. [a] D 25 = -52.5 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 86%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 5.222 min, t2= 6.040 min.

[0195] Example 31 Preparation of compound VI-7

[0196]

[0197] The preparation method is the same as that in Example 25, except that ethynyl carbonate II-10 is added to obtain the target product of formula VI-7, with a yield of 83%.

[0198] 1 H NMR δ 7.73 (d, J = 7.9 Hz, 1H), 7.66 (dd, J = 10.3, 2.2 Hz, 1H), 7.40-7.31 (m, 2H), 7.29 (d, J = 7.3 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 4.00 (dd, J = 11.7, 3.5 Hz, 1H), 3.84 (t, J = 11.3 Hz, 1H), 3.73 (d, J = 4.7 Hz, 2H), 3.71 (s, 1H), 3.50 (dd, J = 12.3, 4.0 Hz, 1H), 3.37 (d, J = 15.9 Hz, 1H), 3.27 (d, J = 12.7 Hz, 1H), 3.06 (d, J = 10.3 Hz, 1H), 2.84 (s, 1H), 1.57 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 163.9, 141.9 (d, J = 6.8 Hz), 141.0, 130.0 (d, J = 8.3 Hz), 128.9, 127.3, 126.7, 123.5, 115.5 (d, J = 21.4 Hz), 77.8, 77.4, 70.5, 65.6, 61.9, 61.0, 57.2. 19 F NMR (376 MHz, CDC13) δ -112.43. High resolution: calculated [M+H] + : 326.1556, found: 326.1546. [a] D 25 = 86.67 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 91%, chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 210 nm, 20°C, retention times ti = 4.888 min, t2= 6.196 min.

[0199] Preparation of compound VI-8 of Example 32

[0200]

[0201] The preparation method is the same as that in Example 25, except that ethynyl carbonate II-14 is added to obtain the target product of formula VI-8, with a yield of 70%.

[0202] 1H NMR (400MHz, CDCl3) δ7.66 (dd, J=3.2, 1.2Hz, 1H), 7.44 (dd, J=5.1, 1.3Hz, 1H), 7.36-7.32 (m,1H),7.30(d,J=5.5Hz,2H),7.26(d,J=7.3Hz,2H),7.20(t,J=7.0Hz,1H),3.97(dd,J=11 .6,3.6Hz,1H),3.92-3.83(m,2H),3.80(s,2H),3.52(dd,J=12.7,3.9Hz,1H),3.33(d,J=1 5.8Hz,1H),3.25(d,J=12.9Hz,1H),3.01(dq,J=9.5,3.2Hz,1H),2.74(s,1H),1.10(s,1H). 13 C NMR (100MHz, CDCl3) δ 141.4, 141.0, 128.9, 127.2, 126.8, 126.4, 126.4, 125.0, 81.2, 76.6, 75.6, 70.4, 62.5, 61.8, 60.9, 56.5. High resolution: Calculated values: [M+H] + 314.1215, Measured value: 314.1210. [α] D 25 = -52.5 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 86%, chiral AS-H column (isopropanol:n-hexane = 30:70, v:v), 1.0 mL / min, 230 nm, 20 °C, retention times t1 = 5.392 min, t2 = 7.784 min.

[0203] Example 33 Preparation of compound VI-9

[0204]

[0205] The preparation method is the same as in Example 25, except that N-benzyloxetane-3-amine V-2 and ethynyl carbonate II-1 are added to obtain the target product of formula VI-9, with a yield of 79%.

[0206] 1H NMR (400 MHz, CDC13) δ 7.95 - 7.91 (m, 2H), 7.45 - 7.36 (m, 2H), 7.34 - 7.27 (m, 1H), 7.23 (d, J = 8.3 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 3.98 (dd, J = 11.6, 3.6 Hz, 1H), 3.86 (t, J = 11.2 Hz, 1H), 3.78 - 3.67 (m, 6H), 3.57 (dd, J = 12.7, 3.9 Hz, 1H), 3.27 (dd, J = 14.6, 6.2 Hz, 2H), 3.06 (d, J = 10.8 Hz, 1H), 2.83 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 158.7, 139.1, 133.1, 128.6, 128.4, 127.9, 114.2, 80.5, 77.5, 77.3, 70.5, 65.7, 61.9, 60.9, 56.4, 55.2. High resolution: Calculated [M+H] 338.1751, Found 338.1748. + : 338.1751, Found 338.1748. [a] D 25 = -60.1 (c = 0.5, CHCI3). Optical purity analysis: Enantiomeric excess of product = 89%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, Retention times ti = 5.766 min, t2= 7.736 min.

[0207] Preparation of compound VI-10 of example 34

[0208]

[0209] Preparation method as in example 25, except that N-benzyloxetan-3-amine V-3, ethynyl carbonate II-1 were added, to obtain the target product of formula VI-10, in 71% yield.

[0210] 1 H NMR (400 MHz, CDC13) δ 7.82 - 7.69 (m, 5H), 7.57 (d, J = 8.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.31 (t, J = 7.1 Hz, 1H), 7.21 - 7.10 (m, 2H), 4.92 (t, J = 6.3 Hz, 1H), 4.59 (t, J = 6.8 Hz, 1H), 4.51 - 4.32 (m, 4H), 4.27 (d, J = 16.6 Hz, 1H), 3.92 (s, 3H), 3.62 (d, J = 3.8 Hz, 2H), 2.70 (s, 1H).13 C NMR (100 MHz, CDC13) δ 157.6, 139.8, 136.7, 133.8, 129.2, 128.9, 128.5, 128.4, 127.7, 127.3, 126.0, 125.4, 119.1, 105.8, 82.1, 77.2, 76.7, 76.5, 69.9, 69.8, 55.9, 55.4, 50.3. High resolution: Calculated: [M+H] 388.1907, Found: 388.1908. [a] + :388.1907, Found: 388.1908. [a] D 25 = -102.7 (c = 0.5, CHCI3). Optical purity analysis: Enantiomeric excess of product = 91%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 20°C, retention times ti = 7.265 min, t2= 11.212 min.

[0211] Preparation of compound VI-11 of example 35

[0212]

[0213] Preparation method as in example 25, except that N-benzyloxyazetidin-3-amine V-4, ethynyl carbonate II-1 were added, to give the target product of formula VI-11 in 85% yield.

[0214] 1 H NMR (400 MHz, CDC13) δ 7.88 (dd, J = 7.5, 1.7 Hz, 2H), 7.40 (dd, J = 8.3, 6.7 Hz, 2H), 7.36 - 7.29 (m, 2H), 7.26 (d, J = 2.6 Hz, 1H), 6.25 (d, J = 1.7 Hz, 1H), 3.98 (dd, J = 11.6, 3.6 Hz, 1H), 3.89 - 3.77 (m, 2H), 3.68 (q, J = 11.4 Hz, 2H), 3.53 - 3.36 (m, 2H), 3.30 (d, J = 15.8 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.79 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 143.5, 139.5, 139.1, 128.6, 128.4, 127.9, 125.4, 109.9, 80.6, 77.5, 77.3, 70.3, 65.6, 61.4, 60.8, 47.7. High resolution: Calculated: [M+H] + :298.1438, Found: 298.1439. [a] D25 = -30.3 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 92%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 5.386 min, t2= 7.786 min.

[0215] Example 36 Preparation of compound VI-12

[0216]

[0217] Preparation as in example 25, except that N-benzyloxyazetidin-3-amine V-5, ethynyl carbonate II-1 were added, to give the target product of formula VI-12 in 65% yield.

[0218] 1 H NMR (400 MHz, CDC13) δ 7.96 - 7.88 (m, 2H), 7.47 - 7.37 (m, 2H), 7.32 (dt, J = 8.6, 4.1 Hz, 1H), 7.24 (dd, J = 5.0, 2.6 Hz, 1H), 7.17 - 7.09 (m, 1H), 6.96 (d, J = 4.9 Hz, 1H), 3.98 (dd, J = 11.7, 3.4 Hz, 1H), 3.85 (t, J = 11.3 Hz, 1H), 3.76 - 3.57 (m, 4H), 3.47 (d, J = 15.7 Hz, 1H), 3.33 (d, J = 12.7 Hz, 1H), 3.06 (d, J = 11.0 Hz, 1H), 2.81 (s, 1H), 1.40 (br, 1H). 13 C NMR (100 MHz, CDC13) δ 142.6, 139.1, 128.6, 128.4, 127.9, 126.9, 126.7, 120.9, 80.5, 77.5, 77.4, 70.4, 65.7, 61.7, 61.0, 52.3. High resolution: calculated [M+H]: 314.1209, found: 314.1202. + : 314.1209, found: 314.1202. D 25 = -30.3 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 92%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 5.386 min, t2= 7.786 min.

[0219] Example 37 Preparation of compound VI-13

[0220]

[0221] The procedure was the same as in Example 25 except that N-benzyloxyazetidine-3-amine V-6, ethynyl carbonate II-1 were added to give the target product of formula VI-13 in 65% yield.

[0222] 1 H NMR (400 MHz, CDC13) δ 7.85 (d, J = 7.5 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.40 - 7.24 (m, 5H), 6.99 (d, J = 15.6 Hz, 2H), 6.13 (s, 1H), 3.96 (dd, J = 11.6, 3.5 Hz, 1H), 3.79 (t, J = 11.2 Hz, 1H), 3.66 (q, J = 9.2, 7.0 Hz, 3H), 3.43 (d, J = 16.0 Hz, 1H), 3.28 (dd, J = 32.4, 14.1 Hz, 2H), 3.02 (d, J = 10.8 Hz, 1H), 2.75 (s, 1H), 2.39 (s, 3H), 1.33 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 145.1, 139.1, 136.0, 130.0, 129.3, 128.5, 128.4, 127.9, 126.7, 121.5, 117.8, 113.3, 80.5, 77.4, 77.3, 70.3, 65.6, 61.4, 60.9, 49.4, 21.6. High resolution: [M+H] calculated: 451.1686, found: 451.1685. + :451.1686, found: 451.1685.[α] D 25 = -34.7 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 93%, chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 10.385 min, t2= 15.468 min.

[0223] Preparation of compound VI-14 of Example 38

[0224]

[0225] The procedure was the same as in Example 25 except that N-benzyloxyazetidine-3-amine V-7, ethynyl carbonate II-1 were added to give the target product of formula VI-14 in 82% yield.

[0226] 1H NMR (400 MHz, CDC13) δ 7.99 (d, J = 8.1 Hz, 2H), 7.91 (d, J = 8.5 Hz, 1H), 7.83 - 7.73 (m, 2H), 7.56 (dd, J = 3.7, 1.4 Hz, 1H), 7.51 (s, 1H), 7.47 - 7.37 (m, 2H), 7.35 - 7.30 (m, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.61 (d, J = 3.6 Hz, 1H), 4.04 (dd, J = 11.7, 3.4 Hz, 1H), 3.95 - 3.69 (m, 4H), 3.57 - 3.40 (m, 2H), 3.27 (d, J = 12.8 Hz, 1H), 3.15 - 3, 13 (m, 1H), 2.88 (s, 1H), 2.36 (s, 3H), 1.14 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 145.0, 139.0, 136.4, 135.3, 133.9, 131.1, 129.9, 128.5, 128.4, 127.9, 126.9, 126.8, 123.4, 119.3, 113.7, 108.8, 80.5, 77.6, 77.5, 70.5, 65.8, 61.9, 61.0, 56.9, 21.6. High resolution: Calculated: [M+H] + : 501.1843, Found: 501.1842. [a] D 25 = -83.9 (c = 0.5, CHCl3). Optical purity analysis: Enantiomeric excess of product = 87%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20 °C, Retention times t1 = 17.579 min, t2 = 21.413 min.

[0227] Example 39 Preparation of compound VI-15

[0228]

[0229] Preparation as in example 25, except that N-benzyloxyazetidin-3-amine V-8, ethynyl carbonate II-1 were added to give the target product of formula VI-15 in 84% yield.

[0230] 1H NMR (400 MHz, CDC13) δ 7.98 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 12.7 Hz, 2H), 7.46 - 7.36 (m, 3H), 7.35 - 7.20 (m, 2H), 6.70 (s, 1H), 4.00 (dd, J = 11.6, 3.5 Hz, 1H), 3.95 - 3.69 (m, 4H), 3.61 - 3.51 (m, 1H), 3.43 (dd, J = 15.6, 1.7 Hz, 1H), 3.25 (t, J = 10.6 Hz, 1H), 3.15 - 3.08 (m, 1H), 2.85 (s, 1H), 1.36 - 0.81 (m, 1H). 13 C NMR (100 MHz, CDC13) δ 154.2, 145.6, 139.1, 135.8, 128.6, 128.4, 128.0, 127.8, 123.0, 119.1, 111.6, 106.5, 80.5, 77.6, 77.5, 70.5, 65.8, 62.0, 61.0, 57.1. High resolution: calculated [M+H] 348.1594, found 348.1593. + [α] D 25 = -86.67 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 90%, Chiral AS-H column (isopropanol: n-hexane 30:70, v:v), 1.0 mL / min, 254 nm, 20°C, retention times ti = 6.209 min, t2= 8.533 min.

[0231] Example 40 Preparation of compound VI-16

[0232]

[0233] Preparation method as in example 25, except that N-benzyloxyazetidin-3-amine V-9, ethynyl carbonate II-1 were added, to give the target product of formula VI-16, in 71% yield.

[0234] 1H NMR (400 MHz, CDC13) δ 7.81 (d, J = 7.4 Hz, 2H), 7.40-7.26 (m, 3H), 5.84 (s, 1H), 3.99 (dd, J = 11.5, 3.5 Hz, 1H), 3.80 (t, J = 11.2 Hz, 1H), 3.75-3.58 (m, 3H), 3.51 (d, J = 7.7 Hz, 1H), 3.07-2.87 (m, 2H), 2.75 (s, 1H), 2.64 (d, J = 16.2 Hz, 1H), 1.97-1.79 (m, 4H), 1.58-1.39 (m, 4H). 13 C NMR (100 MHz, CDC13) δ 139.1, 137.9, 128.3, 128.1, 127.9, 121.9, 80.8, 77.6.77.1, 70.4, 65.6, 61.7, 61.2, 58.8, 27.7, 25.0, 22.6, 22.4. High resolution: Calculated: [M+H] + : 312.1958, Found: 312.1959. [a] D 25 = -76.5 (c = 0.5, CHCl3). Optical purity analysis: Enantiomeric excess of product = 84%, Chiral AS-H column (i-PrOH: n-hexane 30:70, v:v), 1.0 mL / min, 220 nm, 20°C, Retention times t1= 3.899 min, t2= 4.822 min.

[0235] Synthesis of internal alkyne compounds represented by compounds VII-1 and VII-2

[0236]

[0237] Preparation of compound VII-1 of example 41

[0238]

[0239] Chiral morpholine VI-1 (0.10 mmol, 1.0 eq.), methyl 4-iodobenzoate (0.12 mmol, 1.2 eq.), Pd(PPh3)2Cl2(0.005 mmol, 0.05 eq.) and Cul (0.01 mmol, 0.1 eq.) were added successively into a Schlenk tube under argon atmosphere. Et3N (0.3 mmol, 3.0 eq.) and THF (1.0 mL) were added by syringe at room temperature, then the resulting solution was stirred at room temperature for 12 hours, followed by TLC. Subsequently, purification by silica gel column chromatography (hexane / EtOAc = 3:1) afforded the desired product VII-1 in 90% yield.

[0240] 1 H NMR (400 MHz, CDC13) δ 7.99 (d, J = 6.3 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 7.4 Hz, 2H), 7.21 (dd, J = 16.3, 9.1 Hz, 3H), 7.12 (t, J = 7.3 Hz, 1H), 3.95 (dd, J = 11.7, 3.5 Hz, 1H), 3.87 (s, 3H), 3.86 - 3.74 (m, 4H), 3.46 (dt, J = 12.6, 3.8 Hz, 1H), 3.33 (d, J = 15.7 Hz, 1H), 3.22 (t, J = 10.0 Hz, 1H), 3.07 (d, J = 7.2 Hz, 1H), 1.13 (dd, J = 9.9, 3.6 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 166.5, 141.3, 139.3, 132.0, 129.7, 129.5, 128.8, 128.6, 128.5, 128.0, 127.6, 127.1, 126.7, 89.6, 89.1, 77.5, 70.4, 66.4, 62.2, 61.1, 57.2, 52.2. High resolution: Calculated: [M+H] 442.2018, Found: 442.2011. + :442.2018, Found: 442.2011. [a] D 25 = -81.03 (c = 0.5, CHCI3). Optical purity analysis: Enantiomeric excess of product = 92%, Chiral AD-H column (isopropanol: n-hexane 20:80, v:v), 1.0 mL / min, 220 nm, 20°C, Retention times ti = 7.709 min, t2= 9.856 min.

[0241] Preparation of compound VII-2 of example 42

[0242]

[0243] Chiral morpholine I-1 (0.10 mmol, 1.0 eq.), methyl 4-iodobenzoate (0.12 mmol, 1.2 eq.), Pd(PPh3)2Cl2 (0.005 mmol, 0.05 eq.), and CuI (0.01 mmol, 0.1 equivalence) were sequentially added to a Schlenk tube under an argon atmosphere. Et3N (0.3 mmol, 3.0 eq.) and THF (1.0 mL) were added via syringe at room temperature, and the resulting solution was stirred at room temperature for 12 hours, followed by TLC. The solution was then purified by silica gel column chromatography (hexane / EtOAc = 3:1) to give the desired product VII-2 in 91% yield.

[0244] 1 H NMR (400MHz, CDCl3) δ7.99(d,J=7.5Hz,2H),7.84(d,J=8.0Hz,2H),7.48(d,J=8.7Hz,2H),7.38(dt,J=15.5,7.2Hz,3H),7.05(dd,J =9.7,1.9Hz,1H),5.98(d,J=10.2Hz,1H),3.98-3.90(m,5H),3.56(d,J=10.9Hz,1H),2.90-2.66(m,2H),2.18(s,1H),1.40(s,3H). 13 C NMR (100MHz, CDCl3) δ 196.0, 166.4, 158.0, 140.6, 131.3, 129.6, 129.5, 128.42 128.4, 127.5, 126.5, 126.3, 95.8, 86.4, 79.8, 77.6, 56.4, 52.9, 52.2, 41.1, 26.7. High resolution: Calculated values: [M+H] + 402.1705, measured value: 402.1709. [α] D 25 =159.13 (c=0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 91%, chiral AD-H column (isopropanol:n-hexane = 10:90, v:v), 1.0 mL / min, 210 nm, 20 °C, retention times t1 = 20.522 min, t2 = 29.676 min.

[0245] Synthesis of triazole compounds represented by compounds VII-3 and VII-4

[0246]

[0247] Example 43 Preparation of compound VII-3

[0248]

[0249] To a solution of VI-1 (0.1 mmol) and CuTc (0.03 mmol, 0.3 eq.) in toluene (0.5 mL) was added benzyl azide (0.3 mmol, 3.0 eq.) at 0 °C. Then heated to room temperature, after stirring for 2 hours, the reaction was monitored to end by TLC. The reaction was quenched with saturated NH4Cl (aq), extracted with DCM, dried over Na2SO4, and concentrated under reduced pressure. And purified by silica gel column chromatography (PE / EA = 3:1) to give the desired product VII-3 in 92% yield.

[0250] 1 H NMR (400 MHz, CDC13) δ 7.55 - 7.41 (m, 4 H), 7.44 - 7.32 (m, 5 H), 7.29 (q, J = 7.8 Hz, 4 H), 7.24 - 7.16 (m, 2 H), 5.80 - 5.34 (m, 2 H), 4.52 (d, J = 16.6 Hz, 1 H), 3.99 - 3.83 (m, 4 H), 3.49 (d, J = 16.6 Hz, 1 H), 3.36 (dd, J = 12.5, 4.8 Hz, 1 H), 3.17 (d, J = 11.9 Hz, 1 H), 2.57 - 2.47 (m, 1 H), 1.18 (s, 1 H). 13 C NMR (100 MHz, CDC13) δ 146.3, 142.4, 141.5, 134.8, 129.1, 128.7, 128.6, 128.2, 128.0, 127.9, 127.7, 126.7, 126.5, 125.6, 70.9, 65.9, 61.5, 60.6, 56.8, 54.1. High resolution: calculated [M+H] 441.2291, found 441.2276. [a] + : 441.2291, found 441.2276. [a] D 25 = -42.80 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 92%, Chiral AS-H column (isopropanol: n-hexane as 20:80, v:v), 1.0 mL / min, 220 nm, 20 °C, retention times ti = 16.120 min, t2= 20.615 min.

[0251] Preparation of compound VII-4 of example 44

[0252]

[0253] To a solution of I-1 (0.1 mmol) and CuTc (0.03 mmol, 0.3 eq.) in toluene (0.5 mL) was added benzyl azide (0.3 mmol, 3.0 eq.) at 0 °C. Then heated to room temperature, after stirring for 2 hours, the reaction was monitored to end by TLC. The reaction was quenched with saturated NH4Cl (aq), extracted with DCM, dried over Na2S04, and concentrated under reduced pressure. And purified by silica gel column chromatography (PE / EA = 3:1) to give the desired product VII-4 in 89% yield.

[0254] 1 H NMR (400 MHz, CDC13) δ 7.51 (s, 1H), 7.41 (p, J = 7.3 Hz, 3H), 7.35 - 7.19 (m, 7H), 5.97 (dd, J = 10.2, 2.7 Hz, 1H), 5.60 - 5.43 (m, 2H), 5.10 (d, J = 10.2 Hz, 1H), 4.20 - 3.79 (m, 2H), 3.59 (d, J = 11.6 Hz, 1H), 2.61 (ddd, J = 60.5, 17.3, 3.2 Hz, 2H), 1.32 (s, 3H). 13 C NMR (100 MHz, CDC13) δ 195.9, 156.4, 151.2, 142.9, 134.6, 129.2, 128.7, 128.1, 127.9, 127.5, 126.5, 125.1, 123.6, 79.8, 75.1, 57.2, 54.0, 52.2, 41.1, 26.8. High resolution: Calculated: [M+H] + : 401.1978, Found: 401.1964. [a] D 25 = 151.30 (c = 0.5, CHCl3). Optical purity analysis: Enantiomeric excess of product = 91%, Chiral AD-H column (isopropanol: n-hexane as 10:90, v:v), 1.0 mL / min, 220 nm, 20 °C, Retention times t1= 32.295 min, t2= 43.109 min.

[0255] Synthesis of amide compounds represented by compound VII-5

[0256]

[0257] Example 45 Preparation of compound VII-1

[0258]

[0259] VII-9 was prepared according to the procedure described in Example 1.1H NMR (400 MHz, CDC13) δ 7.98 (d, J = 8.8 Hz, 2H), 7.85 - 7.79 (m, 2H), 7.40 - 7.33 (m, 3H), 6.92 (d, J = 8.9 Hz, 2H), 4.35 (dd, J = 11.0, 5.0 Hz, 1H), 4.18 (dd, J = 11.1, 7.1 Hz, 1H), 4.08 (dd, J = 10.8, 3.2 Hz, 1H), 4.00 - 3.88 (m, 1H), 3.86 (s, 3H), 3.79 (d, J = 10.8 Hz, 1H), 3.45 - 3.35 (m, 2H), 2.69 (s, 1H), 2.22 (s, 1H).

[0260] 1 H NMR (400 MHz, CDC13) δ 7.98 (d, J = 8.8 Hz, 2H), 7.85 - 7.79 (m, 2H), 7.40 - 7.33 (m, 3H), 6.92 (d, J = 8.9 Hz, 2H), 4.35 (dd, J = 11.0, 5.0 Hz, 1H), 4.18 (dd, J = 11.1, 7.1 Hz, 1H), 4.08 (dd, J = 10.8, 3.2 Hz, 1H), 4.00 - 3.88 (m, 1H), 3.86 (s, 3H), 3.79 (d, J = 10.8 Hz, 1H), 3.45 - 3.35 (m, 2H), 2.69 (s, 1H), 2.22 (s, 1H). 13 C NMR (100 MHz, CDC13) δ 166.0, 163.6, 140.3, 131.7, 128.4, 126.7, 122.1, 113.7, 84.9, 77.1, 74.5, 69.4, 65.2, 57.9, 55.4, 50.4. High resolution: calculated [M+H]: 352.1549, found: 352.1557. + :352.1549, found: 352.1557.[α] D 25 = 4.40 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 89%, Chiral AS-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 254 nm, 20 °C, retention times ti = 12.893 min, t2= 14.585 min.

[0261] Synthesis of fused nitrogen heterocycle product compounds represented by compound VIII-1

[0262]

[0263] Example 46 Preparation of compound VIII-1

[0264]

[0265] VI-1 (0.10 mmol, 1.0 eq.) was dissolved in 2 mL MeOH, and 14 mg of carbon-supported 20% Pd(OH)2 (14 mg, 1.0 eq.) was added. The solution was placed under hydrogen atmosphere at 1 atm. After 8 hours, TLC was performed, the solution was filtered, and the residue was purified by silica gel chromatography (DCM / EtOH = 50:1) to give the desired product VIII-1 in 70% yield.

[0266] 1 H NMR (400MHz, CDCl3) δ7.45(d,J=7.7Hz,2H),7.35(t,J=7.7Hz,2H),7.29-7.21(m,1H),3.93-3.80(m,2H),3.65(dd,J=10.9 ,3.1Hz,1H),3.51(dd,J=11.0,4.5Hz,1H),3.37-3.24(m,3H),2.51-2.41(m,1H),2.12-1.73(m,3H),0.65(t,J=7.5Hz,3H). 13 C NMR (100MHz, CDCl3) δ 143.6, 128.3, 126.8, 125.6, 75.9, 69.1, 63.6, 57.5, 50.3, 25.2, 7.0. High resolution: Calculated values: [M+H] + 222.1494, Measured value: 222.1492.

[0267] Synthesis of fused nitrogen heterocycle product compounds represented by compound VIII-2

[0268]

[0269] Example 47 Preparation of compound VIII-2

[0270]

[0271] Under an argon atmosphere, VIII-1 (0.10 mmol, 1.0 eq.), Et3N (0.6 mmol, 6.0 eq.), and DCM (1.0 mL) were sequentially added to a Schlenk tube. Then, triphosgene (0.1 mmol, 1.0 eq.) was added at 0 °C. The mixture was stirred at room temperature for 10 hours. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by silica gel chromatography (PE / EA = 3:1) to give the desired product VIII-2 in 70% yield.

[0272] 1H NMR (400 MHz, CDC13) δ 7.47 - 7.34 (m, 4H), 7.31 (d, J = 6.5 Hz, 1H), 4.43 (t, J = 6.5 Hz, 1H), 4.18 (d, J = 9.4 Hz, 2H), 3.86 (t, J = 9.4 Hz, 1H), 3.55 (d, J = 11.7 Hz, 1H), 3.48 - 3.35 (m, 2H), 2.56 - 2.46 (m, 1H), 2.23 - 2.14 (m, 1H), 1.03 (t, J = 7.6 Hz, 1H). 13 C NMR (100 MHz, CDC13) δ 155.9, 137.1, 128.2, 127.6, 126.9, 77.4, 69.9, 64.4, 62.2, 50.9, 23.2, 8.2. High resolution: Calculated [M+H] + : 248.1287, found: 248.1286. [a] D 25 = 23.47 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 91%, Chiral AS-H column (isopropanol: n-hexane 15:85, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 17.721 min, t2= 29.524 min.

[0273] Synthesis of fused nitrogen heterocycle product compounds represented by compound VIII-4

[0274]

[0275] Preparation of compound VIII-4 of example 48

[0276]

[0277] To VIII-1 (0.12 mmol) and iTo a solution of Pr2NEt (0.48 mmol, 4.0 eq.) in DCM (1.0 mL) was added dropwise thionyl chloride (0.144 mmol, 1.2 eq.). After 3 hours of reaction at -20 °C. After completion of the reaction, the reaction mixture was concentrated and the residue was purified by silica gel chromatography (PE / EA = 3:1) to give the desired product VIII-3. To a solution of VIII-3 in acetonitrile (0.5 mL) and water (0.5 mL) at 0 °C was added ruthenium (III) chloride (0.1 mol%) followed by sodium periodate (0.135 mmol, 1.5 eq.). After 5 hours, the mixture was extracted with EA. The organic extract was washed with water, brine, dried over Na2S04and concentrated. The residue was purified by silica gel chromatography (PE / EA = 3:1) to give the desired product VIII-4 in 62% yield.

[0278] 1 H NMR (400 MHz, CDC13) δ 7.41 (d, J = 6.7 Hz, 2H), 7.38 - 7.27 (m, 3H), 4.48 (dd, J = 8.6, 5.9 Hz, 1H), 4.34 - 4.23 (m, 1H), 4.17 (dd, J = 11.7, 1.7 Hz, 1H), 4.06 - 3.96 (m, 2H), 3.90 (dd, J = 11.4, 4.0 Hz, 1H), 3.70 (t, J = 11.4 Hz, 1H), 2.54 - 2.45 (m, 1H), 2.22 - 2.13 (m, 1H), 0.68 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ 134.6, 129.0, 128.3, 128.0, 68.1, 66.9, 66.7, 63.4, 53.1, 26.3, 8.7. High resolution: Calculated: [M+H] + : 306.0770, Found: 306.0777. [a] D 25 = -28.37 (c = 0.5, CHCI3). Optical purity analysis: Enantiomeric excess of product = 92%, Chiral AS-H column (i-PrOH: n-hexane 20:80, v:v), 1.0 mL / min, 220 nm, 20 °C, Retention times ti = 16.547 min, t2= 30.403 min.

[0279] Synthesis of fused nitrogen heterocycle product compounds represented by compound VIII-5

[0280]

[0281] Example 49 Preparation of compound VIII-5

[0282]

[0283] DMAP (0.03 mmol, 0.3 eq.) and 10 (0.1 mmol) were dissolved in DCM (1.0 mL) in an ice water bath. Then imidazole (0.3 mmol, 3.0 eq.) and PhP(O)Cl2(0.15 mmol, 1.5 eq.) were added successively. The mixture was stirred at room temperature for 10 h. After the reaction was completed, it was quenched with saturated NaHCO3 aqueous solution and extracted with EA. Then the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (PE / EA = 1 : 1) to give the desired product VIII-5 in 96% yield.

[0284] 1 H NMR (400 MHz, CDC13) δ 7.47 - 7.39 (major + minor, m, 1H), 7.35 - 7.21 (major + minor, m, 4H), 7.21 - 7.13 (minor, m, 1H), 7.14 - 7.06 (major, m, 1H), 7.02 - 6.92 (major + minor, m, 4H), 4.61 - 4.54 (minor, m, 1H), 4.46 - 4.38 (major + minor, m, 2H), 4.30 - 4.20 (major, m, 1H), 4.14 - 4.05 (major + minor, m, 2H), 4.00 (major + minor, dd, J = 11.2, 3.8 Hz, 1H), 3.85 (major, t, J = 11.4 Hz, 1H), 3.74 (minor, t, J = 11.4 Hz, 1H), 2.69 - 2.61 (major + minor, m, 1H), 1.80 - 1.71 (major + minor, m, 1H), 0.85 (minor, t, J = 7.4 Hz, 3H), 0.53 (major, t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDC13) δ (ppm, major) 136.2, 132.1, 132.0, 131.6 (d, J = 3.1 Hz), 128.2, 127.8 (d, J = 3.2 Hz), 127.7, 127.6, 69.3, 69.2, 66.7 (d, J = 2.5 Hz), 59.8, 52.4 (d, J = 8.3 Hz), 26.8 (d, J = 6.3 Hz), 8.6. High resolution: calculated [M+H] 306.0770, found 306.0777. + :306.0770, found 306.0777. 31P NMR (162 MHz, CDC13) δ 32.05 (major), 31.33 (minor). High resolution: calculated [M+H] 344.1416, found 344.1414. [a] + :344.1416, found 344.1414. [a] D 25 = 11.50 (c = 0.5, CHCI3). Optical purity analysis: enantiomeric excess of product = 91%, chiral AS-H column (isopropanol: n-hexane 10:90, v:v), 1.0 mL / min, 220 nm, 20°C, retention times ti = 15.040 min, t2= 19.944 min.

[0285] Synthesis of core structure compounds of γ-secretase inhibitors represented by compound VIII-7

[0286]

[0287] Preparation of compound VIII-7 of example 50

[0288]

[0289] To a solution of ent-VI-7 (0.61 mmol) in acetonitrile / THF (1 : 1) was added pyridine (2.9 mmol, 4.8 eq.) followed by 4-nitrophenyl chloroformate (1.22 mmol, 2.0 eq.) and the reaction was heated at 68 °C overnight. The mixture was concentrated and then purified by silica gel column chromatography (PE / EA = 5: 1) to give 281 mg of product VIII-6.

[0290] To a solution of VIII-6 (0.57 mmol) in DCE (20 mL) was added 4-piperidyl piperidine (5.7 mmol, 10.0 eq.) and the reaction was stirred at room temperature overnight. The final mixture was diluted with DCM and 0.5 N NaOH, extracted with EtOAc, dried over sodium sulfate and concentrated, the residue was purified by silica gel column chromatography (DCM / MeOH = 30: 1) to give 190 mg of product VIII-7 in 68% yield.

[0291] 1H NMR (400 MHz, CDC13) δ 7.63 (dd, J = 27.3, 8.8 Hz, 1H), 7.33 - 7.24 (m, 4H), 7.21 (t, J = 7.5 Hz, 2H), 7.15 - 7.12 (m, 1H), 4.11 - 4.07 (m, 3H), 3.82 - 3.64 (m, 3H), 3.64 - 3.46 (m, 3H), 3.36 - 3.30 (m, 1H), 2.84 (s, 1H), 2.80 - 2.62 (m, 2H), 2.60 - 2.35 (m, 5H), 1.93 - 1.79 (m, 2H), 1.60 - 1.62 (m, 5H), 1.47 - 1.36 (m, 4H). 13 C NMR (100 MHz, CDC13) δ 161.4, 154.4, 141.6, 129.8 (d, J = 8.1 Hz), 128.1, 126.6, 125.1, 123.3, 122.3, 115.5, 115.3, 80.1, 77.7, 77.6, 70.9, 65.6, 64.2, 62.5, 59.3, 56.8, 50.2, 50.1, 43.6, 26.2, 24.6. 19 F NMR (376 MHz, CDC13) δ -112.49. High resolution: calculated [M+H] + : 520.2975, found: 520.2965. [a] D 25 = 0.139 (c = 0.5, CHCl3). Optical purity analysis: enantiomeric excess of product = 90%, Chiral AD-H column (isopropanol: n-hexane as 10:90, v:v), 1.0 mL / min, 210 nm, 20°C, retention times t1= 12.384 min, t2= 14.477 min.

[0292] Test Example

[0293] The anti-cancer activity of compound VIII-7 in the present application, and the reference drug SAHA, was tested using the standard MTT assay in vitro, and the specific results are shown in Table 1.

[0294] Table 1: Anti-cancer activity data of compound VIII-7

[0295]

[0296] It can be seen that compound VIII-7 has inhibitory activity on a variety of tumor cells, and for lung cancer cells and human glioma cells, compound VIII-7 shows lower IC 50In addition, among the inhibition of various types of tumor cells, the racemic compound VIII-7 had the most optimal inhibitory activity.

[0297] Having described various embodiments of the application, it is to be understood that the above description is meant not to be exhaustive or limited by the various embodiments disclosed. Many modifications and variations are possible in light of the above teachings without departing from the scope and spirit of the described embodiments.

Claims

1. A morpholine ring compound of the formula: ###00001### wherein, The morpholine ring compound has a structure shown in formula VIII-7:

2. Use of the morpholine ring compound of claim 1 in the preparation of a tumor cell inhibitor; the tumor cell is at least one of lung cancer cell, human glioma cell and breast cancer cell.

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