Chiral 3, 3-disubstituted indolone compound as well as preparation method and application thereof

Abstract

The invention relates to a chiral 3, 3-disubstituted indolone compound as well as a preparation method and application thereof, and belongs to the technical field of organic chemistry. The chiral 3, 3-disubstituted indolone compound is characterized in that the structural formula is as shown in formula (I) or formula (II): # imgabs 0 #, formula (I) # imgabs 1 # and formula (II); a series of chiral 3, 3-disubstituted indolone compounds are prepared in a three-dimensional divergence mode at low cost, a pair of diastereoisomers or enantiomers can be synthesized by regulating and controlling a cheap achiral co-catalyst under the catalysis of the same chiral ligand, and the novel three-dimensional divergence synthesis method is never reported; the 3, 3-disubstituted indolone compound disclosed by the invention is a novel anticancer active compound, has obvious growth inhibition activity on human colorectal cancer cells, and provides a solid foundation for research and development of new anticancer drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and specifically relates to a chiral 3,3-disubstituted indole ketone compound and a preparation method and application thereof. Background Art

[0002] 3,3-disubstituted indolones are one of the most common heterocyclic structures in nature and widely exist between natural products and active pharmaceutical molecules. Chiral 3,3-disubstituted indolones, as an important branch, have been widely used in the fields of medicine and biological activity, and the social demand is increasing. Studies have shown that chiral 3,3-disubstituted indolones have excellent pharmacological activities in the fields of anti-inflammatory, antibacterial and anti-tumor. However, the synthesis of such compounds is mostly limited to the direct nucleophilic substitution reaction of the carbon at position 3 of indolones, and the stereo control method of this position is still limited, and is currently limited to chiral organic small molecule catalysts, transition metal catalysts and chiral Lewis acid catalysts. In addition, the configuration of the stereo center at position 3 of indolone is crucial to the drug activity effect, which leads to the fact that it is very important to achieve the inversion of the stereo center at position 3 in the synthesis of the structure of chiral 3,3-disubstituted indolone compounds in an asymmetric stereo divergent manner. Therefore, how to efficiently synthesize a series of chiral 3,3-disubstituted indolone compounds in a stereo divergent manner is still a difficult problem, and the current synthesis method is quite limited. In addition, the universal stereodivergent synthesis method also provides the possibility to find more pharmacological activities of such compounds.

[0003] According to the World Health Organization, colorectal cancer is the third most common cancer in the world, accounting for about 10% of all cancer cases. It is also the second leading cause of cancer-related deaths worldwide. Colorectal cancer mainly affects the elderly, with most cases occurring in people aged 50 years and above. It is generally believed that some lifestyle factors contribute to colorectal cancer, such as high intake of processed meat products and low intake of fruits and vegetables, sedentary lifestyle, obesity, smoking and excessive alcohol consumption. Since colorectal cancer is often diagnosed in the late stage when treatment options are limited, the incidence and impact of colorectal cancer can be significantly reduced by implementing primary prevention strategies, such as adopting a healthy lifestyle, avoiding risk factors and early detection through screening. In recent years, how to prevent and treat the disease has become a hot topic. Therefore, it is a significant and challenging task to extract natural products, synthesize molecular libraries, and screen out low cytotoxic and highly selective drug molecules with anti-tumor activity. Summary of the invention

[0004] The purpose of the present invention is to solve the deficiencies of the prior art, provide a chiral 3,3-disubstituted indolone compound and a stereodivergent preparation method and application thereof, the preparation method is low in cost, the prepared chiral 3,3-disubstituted indolone compound with different stereoisomers has excellent anti-colorectal cancer activity, and more than 20 of the 70 prepared compounds are significantly better than the commercially available drugs 5-fluorouracil (5-Fu, 5-Fluorouracil), irinotecan (Irinotecan), vorinostar (Vorinostar), oxaliplatin (Oxaliplatin) in anti-colorectal cancer. Therefore, it has a good application prospect and scientific value.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0006] Chiral 3,3-disubstituted indole ketone compounds, the structural formula is shown in formula (I) or formula (II):

[0007]

[0008] In formula (I), the carbon atom marked with "*" is a chiral center;

[0009] R 1 is tert-butoxy, ethoxy or benzyloxy;

[0010] R 2 is methyl, methoxy, chlorine, fluorine, β-chloroethyl or hydrogen;

[0011] R 3 is bromine, fluorine, methoxy or hydrogen;

[0012] R 4 is bromine or hydrogen;

[0013] R 5 is methyl or hydrogen;

[0014] R 6 is methoxy, fluorine, bromine, methyl or hydrogen, or simultaneously in both R 6 The position of a phenyl group;

[0015] R 7 is methyl or hydrogen;

[0016] R 8 is p-methylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-fluorophenyl, m-methoxyphenyl, m-fluorophenyl, 2-naphthyl, N-pyrrolyl, 2-thienyl, 6-benzofuranyl, p-fluorobenzyl, p-methylphenylmercapto or phenyl;

[0017]

[0018] In formula (II), the carbon atom marked with “*” is the chiral center;

[0019] R 1’ is N-pyrrolyl or phenyl;

[0020] R 2’ is methoxy, fluorine or hydrogen;

[0021] R 3’ for hydrogen, or simultaneously in both R 3’ There is a phenyl group in the position.

[0022] The present invention synthesized 70 3,3-disubstituted indolones (including 3,3-diaryl substituted indolones) compounds shown in Table 1 in a "stereo-divergent" manner. Structural formula of the synthesized compounds of the present invention and IC of their anti-colorectal cancer activity 50 The values ​​are shown in Table 1.

[0023] The present invention also provides a method for preparing the chiral 3,3-disubstituted indolones (including 3,3-diaryl substituted indolones) compounds, and the general reaction formula is as follows:

[0024]

[0025] The steps include:

[0026] Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I);

[0027] Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

[0028] Furthermore, preferably, in step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indolone compound represented by formula (IV) is 1.95 to 2.05:1;

[0029] The reaction temperature is 40-60°C and the reaction time is 30 minutes to 2 hours;

[0030] The rhodium catalyst is 1,5-cyclooctadiene acetylacetonate rhodium, and the molar ratio of 1,5-cyclooctadiene acetylacetonate rhodium to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1;

[0031] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine, (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1;

[0032] Zinc chloride is used as a co-catalyst, and the molar ratio of zinc chloride to the 3-substituted indole ketone compound represented by formula (IV) is 0.2-2.0:1;

[0033] The reaction solvent is toluene; the present invention does not limit the amount of the solvent, as long as it can satisfy the reaction. For example, the molar ratio of the volume of toluene to the 3-substituted indole ketone compound represented by formula (IV) is 0.8-2 ml: 0.1 mmol.

[0034] Furthermore, preferably, in step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indolone compound represented by formula (IV) is 1.95 to 2.05:1;

[0035] The reaction temperature is 40-60°C and the reaction time is 30 minutes to 2 hours;

[0036] The rhodium catalyst is di(1,5-cyclooctadiene) rhodium tetrafluoroborate, and the molar ratio of di(1,5-cyclooctadiene) rhodium tetrafluoroborate to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1;

[0037] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine; (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1;

[0038] Dysprosium chloride is used as a co-catalyst, and the molar ratio of dysprosium chloride to the 3-substituted indolone compound represented by formula (IV) is 0.2-2.0:1;

[0039] The reaction solvent is 1,2-dichloroethane; the present invention does not limit the amount of the solvent, as long as it can satisfy the reaction. For example, the molar ratio of the volume of 1,2-dichloroethane to the 3-substituted indole ketone compound represented by formula (IV) is 0.8-2 ml: 0.1 mmol.

[0040] Further, preferably, in step (2), chloroform is used as a solvent. The present invention does not limit the amount of the solvent, as long as it can satisfy the reaction; for example, the molar ratio of the volume of 1,2-dichloroethane to the 3-substituted indolone compound shown in formula (IV) is 0.8-2 ml: 0.1 mmol. The reaction temperature is 40-60°C, the reaction time is 10-24 hours, and zinc chloride is used as both a dehydrating agent and a deprotecting agent to dehydrate and deprotect the chiral 3,3-diaryl substituted indolone compound shown in formula (I) to obtain a chiral 3,3-diaryl substituted indolone compound shown in formula (II); wherein the molar ratio of zinc chloride to the chiral 3,3-disubstituted indolone compound shown in formula (I) is 1.0-2.0:1.

[0041] The present invention also provides the use of the chiral 3,3-disubstituted indolone (including 3,3-diaryl substituted indolone) compound in the preparation of anti-colorectal cancer active agents.

[0042] In the present invention, in step (1), a commercially available indolinone compound and a commercially available benzoxanorbornene compound undergo a "stereo-divergent" asymmetric ring-opening reaction to obtain 3,3-disubstituted indolinones of different stereo configurations.

[0043] In the present invention, the compound of formula I synthesized in step (2) is further dehydrated and deprotected under the action of an acidic additive to obtain 3,3-diaryl substituted indolones of different stereo configurations.

[0044] The 3,3-disubstituted indole ketone of formula (I) synthesized by using dysprosium chloride as a co-catalyst and the 3,3-disubstituted indole ketone of formula (I) synthesized by using zinc chloride as a co-catalyst should be diastereoisomers of each other, that is, diastereoselective divergent synthesis is achieved.

[0045] In step (2) of the present invention, zinc chloride is used as both a dehydrating agent and a protecting group removing agent to perform a dehydrating and protecting group removing treatment on the chiral 3,3-diaryl substituted indole one compound represented by formula (I) to obtain the chiral 3,3-diaryl substituted indole one compound represented by formula (II).

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] (1) The present invention uses a "stereodivergent" method to prepare a series of chiral 3,3-disubstituted indolone compounds at a relatively low cost. A pair of "diastereomers" or "enantiomers" can be synthesized by regulating a cheap achiral co-catalyst under the catalysis of the same chiral ligand. This novel "stereodivergent" synthesis method has never been reported. In the past, "stereodivergent" synthesis required switching expensive chiral catalysts to achieve the purpose.

[0048] (2) The present invention discloses that 3,3-disubstituted indolone compounds are a new type of anticancer active compounds, which have significant growth inhibitory activity against human colorectal cancer cells (HCT116). These compounds have simple structures and are very easy to obtain, but there are few studies on their anticancer biological activities. The present invention may provide a solid foundation for the research and development of new anticancer drugs;

[0049] (3) Under the same experimental conditions, compounds 15, 16, 17, 18, 21, 25, 28, 29, 32, 33, 35, 37, 38, 39, 40, 44, 46, 47, 49, 50, 52, 55, 52, 55, 60, 62, 63, 64, 67, 68, and 69 showed better anti-colorectal cancer activity than the commercial drug oxaliplatin (IC 50 =28.79 μM). Furthermore, the anti-colorectal cancer drug activity of compounds 16, 17, 18, 21, 25, 28, 29, 32, 33, 35, 38, 39, 44, 46, 47, 49, 52, 55, 60, 62, 63, 64, 67, 68, and 69 is superior to that of the commercially available drug 5-fluorouracil (5-Fu, 5-Fluorouracil, IC 50 =18.32 μM). Furthermore, the anti-colorectal cancer drug activity of compounds 16, 17, 18, 21, 25, 28, 29, 32, 35, 38, 39, 44, 46, 49, 52, 55, 52, 55, 60, 62, 63, 64, 67, 68, and 69 is superior to that of the commercially available drug irinotecan (IC 50 =12.87 μM). Furthermore, the anti-colorectal cancer drug activity of compounds 17 and 39 is superior to that of the commercially available drug Vorinostar (IC 50 =4.99 μM), showing the powerful anti-tumor drug activity of 3,3-disubstituted indolone compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 is the H NMR spectrum of compound 1;

[0051] Figure 2 is the carbon NMR spectrum of compound 1;

[0052] Figure 3 is the high performance liquid chromatogram of compound 1;

[0053] Figure 4 is the H NMR spectrum of compound 2;

[0054] Figure 5 is the carbon NMR spectrum of compound 2;

[0055] Figure 6 is the high performance liquid chromatogram of compound 2;

[0056] Figure 7 is the H NMR spectrum of compound 3;

[0057] Figure 8 is the carbon NMR spectrum of compound 3;

[0058] Fig. 9 is the high performance liquid chromatogram of compound 3;

[0059] Fig.10 The graph shows the results of the anticancer activity experiment of some compounds of the present invention and commercially available drugs 5-fluorouracil (5-Fu, 5-Fluorouracil), irinotecan, vorinostar, and oxaliplatin on the colorectal cancer cell line HCT116, wherein the concentration of 0 μM is the blank control group, i.e., no compound is added. DETAILED DESCRIPTION

[0060] The present invention is further described in detail below in conjunction with embodiments.

[0061] Those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the art or the product specifications are used. If the manufacturer of the materials or equipment used is not specified, they are all conventional products that can be purchased.

[0062] The compounds used in the embodiments of the present invention can be directly purchased from commercial sources and can be used without purification. The structures of the three compounds of 1,5-cyclooctadiene acetylacetonate rhodium, di(1,5-cyclooctadiene) tetrafluoroborate rhodium, and (R)-(-)-1-(Sp)-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine (chiral bisphosphine ligand) are shown below:

[0063]

[0064] The benzoxanorbornene compound represented by formula (III) used in the embodiment of the present invention has a structure as shown below:

[0065]

[0066] The 3-substituted indole ketone compounds represented by formula (IV) used in the examples of the present invention are all racemic, and their structures and compound numbers are shown below:

[0067]

[0068]

[0069] For 3,3-disubstituted indolone compounds represented by formula (I) having multiple chiral centers, the order of their absolute configurations is as follows according to the "Principles of Nomenclature of Organic Compounds-2017":

[0070] 3,3-disubstituted indolinone compounds and the order of their chiral centers, wherein the quaternary carbon in the present invention refers to the carbon atom at position 1 in formula (I), and the configuration of the quaternary carbon refers to the absolute configuration of the carbon atom at position 1 in formula (I).

[0071] Example 1

[0072] The preparation method of chiral 3,3-disubstituted indole ketone compounds comprises the following steps:

[0073] Step (1): 1,5-cyclooctadienyl acetylacetonate rhodium (1.6 mg, 0.005 mmol, 5 mol%) and the corresponding chiral bisphosphine ligand (R)-1-[(S P )-2-(diphenylphosphino)ferrocene]ethyl di-tert-butylphosphine (3.2 mg, 0.006 mmol, 6 mol%). Subsequently, toluene (1.0 ml) was added as a solvent. Zinc chloride (13.6 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene a-1 (28.8 mg, 0.2 mmol, 2.0 equiv), 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 (30.9 mg, 0.1 mmol, 1.0 equiv) were then added. Then, the mixture was stirred at 40°C for 1 hour. After the reaction was completed, the reaction mixture was quenched with water (2 ml) and extracted twice with 10 ml of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and the volatiles were removed to obtain a crude product. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give the desired compound 1 - tert-butyl 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoleline-1-carboxylate (42.1 mg, yield 93%, ee>99%).

[0074] The reaction formula of Example 1 is:

[0075]

[0076] The structural formula of compound 1 is: The absolute configuration is: (S,S,S).

[0077] Data characterization of chiral 3,3-disubstituted indolinone compound 1: [α] D20 =-544.12 (c = 0.17, CHCl3).

[0078] 1 H NMR (400MHz, CDCl3), δ7.80 (d, J=8.7Hz 1H),7.54–7.44(m,2H),7.42–7.29(m,3H),7.28–7.17(m,3H),7.21–7.1 1(m,1H),6.91–6.84(m,1H),6.61(td,J=7.6,1.1Hz,1H),6.45(dd,J=7.6 ,1.4Hz,1H),6.38(dd,J=9.8,1.3Hz,1H),5.80(ddd,J=9.8,5.0,1.3Hz,1 H), 4.73 (s, 1H), 4.02 (dt, J = 5.1, 1.6Hz, 1H), 1.60 (s, 9H), 1.26 (s, 1H). For example Figure 1 .

[0079] 13 C NMR (101MHz, CDCl3)δ175.4,149.1,140.0,136.8,135.0,131.8,129.3,128.9,128.9,128.4,128.4,128.3,128.0,128.0,126.9,126.8,126.0,123.7,122.9,114.5,84.5,68.0,60.0,50.2,28.1. Figure 2 .

[0080] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 27 NNaO4) + :476.1838, molecular weight captured by high-resolution mass spectrometry: 476.1835;

[0081] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: tR (minor) = 13.6 min, tR (major) = 15.0 min. Figure 3 .

[0082] Example 2

[0083] The difference between Example 2 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-phenylindolone-1-carboxylic acid ethyl ester b-2, and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 2 is obtained, namely, 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoleline-1-carboxylic acid ethyl ester (38.2 mg), with a yield of 90%.

[0084] The structural formula of compound 2 is: The absolute configuration is: (S,S,S).

[0085] Data characterization of chiral 3,3-disubstituted indolone compound 2: [α] D 20 =-43.48 (c = 1.0, CHCl3)

[0086] 1 H NMR(600MHz, CDCl3)δ7.87(d,J=8.2Hz,1H),7.48–7.42(m,2H),7.40–7.32(m,3H),7.25–7.21( m,3H),7.23–7.15(m,1H),6.90–6.86(m,1H),6.64(td,J=7.7,1.1Hz,1H),6.45(dd,J=7.7,1.3H z,1H),6.37(dd,J=9.8,1.3Hz,1H),5.80(ddd,J=9.8,5.1,1.3Hz,1H),4.73(d,J=5.3Hz,1H),4. 41(q,J=7.1Hz,2H),4.04(dd,J=4.9,1.6Hz,1H),1.72(d,J=6.1Hz,1H),1.41(t,J=7.1Hz,3H). Such as Figure 4 .

[0087] 13 C NMR (151MHz, CDCl3)δ175.4,150.8,139.6,136.6,135.0,131.8,129.4,129.0,129.0,128.5,128.4,128.3,128.0,127.9,126.9,126.9,126.0,123.6,123.2,114.6,68.0,63.5,60.1,50.1,14.2. Figure 5 .

[0088] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 27 H23 NNaO4) + :448.1525, Molecular weight captured by high-resolution mass spectrometry: 448.1524

[0089] HPLC: 99% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=11.0min,t R (major) = 17.5min. Figure 6 .

[0090] Example 3

[0091] The difference between Example 3 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-phenylindolone-1-carboxylic acid benzyl ester b-3 (34.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 3 is obtained, namely, 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindolone-1-carboxylic acid benzyl ester (43.8 mg), with a yield of 90%.

[0092] The structural formula of compound 3 is: The absolute configuration is: (S,S,S).

[0093] Data characterization of chiral 3,3-disubstituted indolinone compound 3: [α] D 20 =-470.78 (c = 0.10, CHCl3)

[0094] 1 H NMR(500MHz, CDCl3)δ7.86(dd,J=8.3,1.1Hz,1H),7.50–7.38(m,4H),7.42–7.29(m, 6H),7.22–7.12(m,4H),6.89–6.84(m,1H),6.64(td,J=7.6,1.1Hz,1H),6.47(dd,J= 7.7,1.3Hz,1H),6.37(dd,J=9.8,1.4Hz,1H),5.79(ddd,J=9.8,5.1,1.3Hz,1H),5.3 8(s,2H),4.72(d,J=6.3Hz,1H),4.04(dt,J=5.2,1.5Hz,1H),1.69(d,J=6.3Hz,1H). For example Figure 7 .

[0095] 13 C NMR (126MHz, CDCl3)δ175.2,150.7,139.5,136.6,134.9,134.8,131.8,129.5,129.0,129.0,128.6,128.5,128.4,128.4,128.3,128.1,128.1,127.9,127.0,126.9,125.9,123.5,123.3,114.7,68.7,68.0,60.0,50.0. Figure 8 .

[0096] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 32 H 26 NO4) + :488.1862, molecular weight captured by high-resolution mass spectrometry: 488.1853.

[0097] HPLC: 99% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=14.6min,t R (major) = 18.5min. Fig. 9 .

[0098] Example 4

[0099] The difference between Example 4 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-(p-tolyl)indolone-1-carboxylic acid tert-butyl ester b-4 (34.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 4 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(p-tolyl)indolone-1-carboxylic acid tert-butyl ester (43.8 mg), with a yield of 89%.

[0100] The structural formula of compound 4 is: The absolute configuration is: (S,S,S).

[0101] Data characterization of chiral 3,3-disubstituted indolone compound 4: [α] D 20=-317.27 (c = 0.75, CHCl3)

[0102] 1 H NMR(600MHz, CDCl3)δ7.79(d,J=8.2Hz,1H),7.34(d,J=8.4Hz,1H),7.23–7.12(m, 7H),6.88–6.84(m,1H),6.60(td,J=7.6,1.2Hz,1H),6.44(dd,J=7.7,1.4Hz,1H), 6.35(dd,J=9.8,1.5Hz,1H),5.78(ddd,J=9.8,5.1,1.4Hz,1H),4.74(d,J=5.9Hz, 1H),3.99(dt,J=5.0,1.6Hz,1H),2.34(s,3H),1.74(d,J=6.0Hz,1H),1.59(s,9H).

[0103] 13 C NMR (151MHz, CDCl3) δ175.6,149.1,140.0,137.7,135.0,133.8,131.8,129.6,129.2,128.8,128.4, 128.3,128.2,127.8,127.0,126.8,125.9,123.8,122.8,114.4,84.4,68.0,59.7,50.0,28.0,21.0.

[0104] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO4) + :490.1994, molecular weight captured by high-resolution mass spectrometry: 490.1985.

[0105] HPLC: 99% ee, Daicel chiral chromatographic column model: IF-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=21.4min,t R (major) = 15.4min.

[0106] Example 5

[0107] The difference between Example 5 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-(tert-butyl)phenyl)-2-oxoindolinone-1-carboxylic acid tert-butyl ester b-5 (36.5 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 5 is obtained - 3-(4-(tert-butyl)phenyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindolinone-1-carboxylic acid tert-butyl ester (46.3 mg) with a yield of 91%.

[0108] The structural formula of compound 5 is: The absolute configuration is: (S,S,S).

[0109] Data characterization of chiral 3,3-disubstituted indolone compound 5: [α] D 20 =-258.85 (c = 0.40, CHCl3)

[0110] 1 H NMR (500MHz, CDCl3) δ7.78(d,J=8.1Hz,1H),7.37(s,4H),7.25–7.02(m,4H),6.86(dd,J=5.7,2.4Hz,1H),6.60(td,J=7.6,0.9Hz,1H),6.48–6.43(m, 1H),6.39–6.33(m,1H),5.80(ddd,J=9.8,5.1,1.1Hz,1H),4.76(s,1H),4. 01(dt,J=5.0,1.3Hz,1H),1.73(d,J=5.5Hz,1H),1.60(s,9H),1.31(s,9H).

[0111] 13 C NMR (126MHz, CDCl3) δ175.6,150.7,149.1,140.0,135.1,133.7,131.8,129.2,128.8,128.5,128.2,12 8.2,127.6,127.0,126.8,126.0,125.9,123.9,122.8,114.4,84.4,68.0,59.7,50.1,34.4,31.2,28.1.

[0112] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 33 H 35 NNaO4) +:532.2464; Molecular weight captured by high-resolution mass spectrometry: 532.2460.

[0113] HPLC:>99%ee, Daicel chiral chromatographic column model: AD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=31.0min,t R (major) = 24.7min.

[0114] Example 6

[0115] The difference between Example 6 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-6 (33.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 6 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-3-(4-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (41.1 mg), with a yield of 85%.

[0116] The structural formula of compound 6 is: The absolute configuration is: (S,S,S).

[0117] Data characterization of chiral 3,3-disubstituted indole ketone compound 6: [α] D 20 =-269.05 (c = 0.22, CHCl3)

[0118] 1 H NMR(600MHz, CDCl3)δ7.79(d,J=8.1Hz,1H),7.37(d,J=8.8Hz,2H),7.24–7.19(m,3H),7. 14(td,J=7.9,1.4Hz,1H),6.92–6.78(m,3H),6.60(td,J=7.6,1.1Hz,1H),6.43(dd,J=7. 7,1.4Hz,1H),6.36(dd,J=9.8,1.4Hz,1H),5.78(ddd,J=9.8,5.1,1.3Hz,1H),4.76(d,J= 5.8Hz,1H),3.97(dt,J=5.1,1.5Hz,1H),3.80(s,3H),1.69(d,J=6.3Hz,1H),1.60(s,9H).

[0119] 13 C NMR (151MHz, CDCl3) δ175.8,159.2,149.1,140.0,135.1,131.8,129.2,129.1,128.9,128.6,128.4, 128.3,128.2,127.0,126.9,125.9,123.8,122.8,114.5,114.3,84.4,68.0,59.4,55.3,50.2,28.1.

[0120] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5) + :506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1941.

[0121] HPLC: 99% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=28.8min,t R (major) = 16.1min.

[0122] Example 7

[0123] The difference between Example 7 and Example 1 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-fluorophenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-7 (32.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 7 is obtained - 3-(4-fluorophenyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (42.4 mg) with a yield of 90%.

[0124] The structural formula of compound 7 is: The absolute configuration is: (S,S,S).

[0125] Data characterization of chiral 3,3-disubstituted indolone compound 7: [α] D 20 = -364.64 (c = 0.53, CHCl3);

[0126] 1H NMR (400MHz, CDCl3) δ7.80 (d, J=8.2Hz, 1H), 7.44 (dd, J=8.7, 5.3Hz, 2H), 7.2 8–7.11(m,4H),7.06(t,J=8.6Hz,2H),6.87(dd,J=7.4,2.2Hz,1H),6.60(t,J =7.6Hz,1H),6.38(dd,J=15.0,8.7Hz,2H),5.77(dd,J=9.8,5.1Hz,1H),4.69 (d,J=5.2Hz,1H),3.95(d,J=4.8Hz,1H),1.76(d,J=5.8Hz,1H),1.60(s,9H).

[0127] 13 C NMR (101MHz, CDCl3) δ175.4,163.6,161.2,149.0,140.0,134.9,132.5(d,J=3.1Hz),131.7,129.8(d,J=8.1Hz),129.4,1 29.0,128.5(d,J=7.2Hz),128.3,126.9,126.5,125.5,123.4,122.9,115.9,115.7,114.5,84.6,67.9,59.4,50.2,28.0.

[0128] 19 F NMR (376MHz,CDCl3)δ-114.35.

[0129] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1736.

[0130] HPLC: 99% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=17.8min,t R (major) = 11.6min.

[0131] Example 8

[0132] The difference between Example 8 and Example 1 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(3-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-8 (33.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 8 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-3-(3-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (41.0 mg), with a yield of 85%.

[0133] The structural formula of compound 8 is: The absolute configuration is: (S,S,S).

[0134] Data characterization of chiral 3,3-disubstituted indolone compound 8: [α] D 20 =-369.02 (c = 0.56, CHCl3)

[0135] 1 H NMR (600MHz, CDCl3) δ7.78(d,J=8.2Hz,1H),7.29(t,J=8.0Hz,1H),7.25–7.17(m,3H),7.14(td,J =7.9,1.3Hz,1H),7.08(dd,J=7.7,1.6Hz,1H),6.98(t,J=2.2Hz,1H),6.88–6.84(m,2H),6.60(td ,J=7.6,1.1Hz,1H),6.45(dd,J=7.7,1.4Hz,1H),6.36(dd,J=9.8,1.4Hz,1H),5.78(ddd,J=9.8,5 .0,1.3Hz,1H),4.75(d,J=5.5Hz,1H),3.99(d,J=5.1Hz,1H),3.77(s,3H),1.73(d,J=6.0Hz,1H),

[0136] 1.60(s,9H).

[0137] 13 C NMR (151MHz, CDCl3) δ175.3,159.8,149.0,139.9,138.4,135.0,131.8,129.8,129.2,128.9,128.4,128.4,128.2,126.8,126.8,

[0138] 125.9,123.7,122.9,120.3,114.4,114.3,112.9,84.5,68.0,60.0,55.2,50.1,28.0.

[0139] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5) + :506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1938.

[0140] HPLC:>99%ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 35°C, detector wavelength: 254 nm, retention time: t R (minor)=18.1min,t R (major) = 18.5min.

[0141] Example 9

[0142] The difference between Example 9 and Example 1 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(3-fluorophenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-9 (32.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 9 is obtained - 3-(3-fluorophenyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (41.9 mg), with a yield of 89%.

[0143] The structural formula of compound 9 is: The absolute configuration is: (S,S,S).

[0144] Data characterization of chiral 3,3-disubstituted indolinone compound 9: [α] D 20 =-406.41 (c = 0.85, CHCl3)

[0145] 1H NMR(600MHz, CDCl3)δ7.79(d,J=8.2Hz,1H),7.34(dt,J=10.5,6.9Hz,2H),7.25–7 .19(m,3H),7.19–7.11(m,2H),7.03(d,J=6.8Hz,1H),6.86(d,J=7.7Hz,1H),6.61 (t,J=7.6Hz,1H),6.43(d,J=7.6Hz,1H),6.37(d,J=9.7Hz,1H),5.82–5.73(m,1H) ,4.68(d,J=4.9Hz,1H),3.94(d,J=5.0Hz,1H),1.80(d,J=5.6Hz,1H),1.60(s,9H).

[0146] 13 C NMR (151MHz, CDCl3) δ174.9,163.8,162.1,148.9,139.9,139.4(d,J=6.9Hz),134.9,131.7,130.3(d,J=8.3Hz),129.5,129.0,128.6,128.4,1 28.3,126.9,126.2,125.9,123.6(d,J=2.8Hz),123.2,123.0,115.3(d ,J=23.2Hz),114.9(d,J=21.0Hz),114.5,84.7,67.9,59.8,50.2,28.0.

[0147] 19 F NMR(376MHz,CDCl3)δ-111.44.HRMS(ESI)m / z(M+Na) + : Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1743.

[0148] HPLC: 99% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 35°C, detector wavelength: 254 nm, retention time: t R (minor)=14.1min,t R (major) = 13.3min.

[0149] Example 10

[0150] The difference between Example 10 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(naphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-10 (35.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally white solid Compound 10--)-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-3-(naphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (46.2 mg) is obtained with a yield of 92%.

[0151] The structural formula of compound 10 is: The absolute configuration is: (S,S,S).

[0152] Characterization data of chiral 3,3-disubstituted indolone compound 10: [α] D 20 =-284.70 (c = 0.19, CHCl3)

[0153] 1 H NMR(500MHz, CDCl3)δ7.90(d,J=8.7Hz,1H),7.84(ddt,J=8.7,6.1,2.9Hz,3H),7.77–7.67(m,2H),7. 46(dddd,J=18.3,8.1,6.8,1.4Hz,2H),7.23–7.16(m,3H),7.16–7.10(m,1H),6.91–6.85(m,1H),6.66 (td,J=7.6,1.1Hz,1H),6.50(dd,J=7.6,1.3Hz,1H),6.38(dd,J=9.8,1.4Hz,1H),5.84(ddd,J=9.8,5. 1,1.3Hz,1H),4.75(d,J=5.3Hz,1H),4.17(dt,J=5.2,1.5Hz,1H),1.77(d,J=5.9Hz,1H),1.59(s,9H).

[0154] 13 C NMR (126MHz, CDCl3) δ175.3,149.1,140.0,135.0,134.3,133.1,132.7,131.8,129.3,128.87,128.85,128.5,128.4,128. 3,128.2,127.52,127.45,126.87,126.85,126.5,126.2,126.0,125.3,123.7,123.0,114.5,84.5,68.0,60.2,50.0,28.0.

[0155] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 33 H 29 NNaO4) + :526.1994, molecular weight captured by high-resolution mass spectrometry: 526.1986

[0156] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=24.2min,t R (major) = 25.6min.

[0157] Embodiment 11

[0158] The difference between Example 11 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-(1H-pyrrol-1-yl)indoline-1-carboxylic acid tert-butyl ester b-11 (29.8 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 11 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(1H-pyrrol-1-yl)indoline-1-carboxylic acid tert-butyl ester (38.9 mg) with a yield of 88%.

[0159] The structural formula of compound 11 is: The absolute configuration is: (S,S,S).

[0160] Data characterization of chiral 3,3-disubstituted indolone compound 11: [α] D 20 =-398.97 (c = 1.14, CHCl3)

[0161] 1H NMR(600MHz, CDCl3)δ7.81(d,J=8.2Hz,1H),7.33–7.25(m,2H),7.24–7.15(m, 2H),6.91(t,J=2.2Hz,2H),6.85(d,J=7.4Hz,1H),6.64–6.54(m,2H),6.39(d,J =9.7Hz,1H),6.26(t,J=2.2Hz,2H),5.66(ddd,J=9.8,5.2,1.4Hz,1H),4.75(d, J=5.1Hz,1H),4.00–3.96(m,1H),1.89(t,J=4.4Hz,1H),1.61(d,J=1.4Hz,9H).

[0162] 13 C NMR (101MHz, CDCl3) δ172.1,148.7,140.2,134.8,131.3,130.4,130.0,129.0,128.59,128 .57,127.0,126.0,123.0,122.7,120.9,119.5,114.7,109.6,85.0,68.4,66.4,49.4,28.0.

[0163] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 27 H 26 N2NaO4) + :465.1790, molecular weight captured by high-resolution mass spectrometry: 465.1791.

[0164] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=17.1min,t R (major) = 20.4min.

[0165] Example 12

[0166] The difference between Example 12 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-(thiophen-2-yl)indoline-1-carboxylic acid tert-butyl ester b-12 (29.8 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 12 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(thiophen-2-yl)indoline-1-carboxylic acid tert-butyl ester (41.3 mg) with a yield of 90%.

[0167] The structural formula of compound 12 is: The absolute configuration is: (S,S,S).

[0168] Data characterization of chiral 3,3-disubstituted indolone compound 12: [α] D 20 =-295.05 (c = 0.20, CHCl3)

[0169] 1 H NMR(500MHz, CDCl3)δ7.78(d,J=8.2Hz,1H),7.32(m,1H),7.29–7.27(m,1H),7.25–7.19(m,1H),7. 15(ddd,J=8.3,5.1,3.9Hz,2H),7.05(dd,J=3.7,1.3Hz,1H),7.02(dd,J=5.1,3.6Hz,1H),6.86(dd, J=7.2,1.4Hz,1H),6.61(dd,J=4.0,1.0Hz,2H),6.39(dd,J=9.8,1.3Hz,1H),5.79(ddd,J=9.8,5.2, 1.4Hz, 1H), 4.83 (d, J = 3.5Hz, 1H), 3.78 (dt, J = 5.2, 1.4Hz, 1H), 1.73 (d, J = 5.5Hz, 1H), 1.61 (s, 9H).

[0170] 13 C NMR (126MHz, CDCl3) δ174.3,149.0,140.8,139.8,136.0,131.6,129.6,129.0,128.8,128.6,128.3,127.2,126.9,126.9,126.6,

[0171] 126.3,125.6,122.9,122.9,114.4,84.7,67.9,57.7,52.3,28.1.

[0172] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 27 H 25 NNaO4S) + :482.1402, molecular weight captured by high-resolution mass spectrometry: 482.1398;

[0173] HPLC: 98% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=10.7min,t R (major) = 12.0min.

[0174] Embodiment 13

[0175] The difference between Example 13 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(benzofuran-6-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-13 (34.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 13 is obtained - 3-(benzofuran-6-yl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester 13 (46.8 mg) with a yield of 95%.

[0176] The structural formula of compound 13 is: The absolute configuration is: (S,S,S).

[0177] Data characterization of chiral 3,3-disubstituted indolone compound 13: [α] D 20 =-305.96 (c = 0.26, CHCl3)

[0178] 1H NMR (600MHz, CDCl3) δ7.82(dd,J=8.3,1.1Hz,1H),7.64(d,J=2.0Hz,1H),7.61(d,J=2.2Hz,1H ),7.52–7.45(m,2H),7.24–7.11(m,4H),6.90–6.84(m,1H),6.72(dd,J=2.2,0.9Hz,1H),6.62 (td,J=7.6,1.1Hz,1H),6.47(dd,J=7.7,1.4Hz,1H),6.39–6.34(m,1H),5.81(ddd,J=9.8,5.1 ,1.3Hz,1H),4.77(d,J=5.2Hz,1H),4.07(d,J=5.1Hz,1H),1.74(d,J=6.0Hz,1H),1.59(s,9H).

[0179] 13 C NMR (151MHz, CDCl3) δ175.8,154.5,149.1,145.6,140.0,135.0,131.8,131.3,129.2,128.9,128.4,128.4,128.2,127.9,127.2,

[0180] 126.9,126.0,124.2,123.8,122.9,121.0,114.5,111.7,106.9,84.5,67.9,60.0,50.4,28.0.

[0181] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 31 H 27 NNaO5) + :516.1787, Molecular weight captured by high-resolution mass spectrometry: 516.1782

[0182] HPLC: 99.9% ee, Daicel chiral chromatographic column model: IC-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=12.5min,t R (major) = 29.7min.

[0183] Embodiment 14

[0184] The difference between Example 14 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-fluorobenzyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-14 (34.1 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 14 is obtained - 3-(4-fluorobenzyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (40.7 mg) with a yield of 84%.

[0185] The structural formula of compound 14 is: The absolute configuration is: (S,S,S).

[0186] Data characterization of chiral 3,3-disubstituted indolone compound 14: [α] D 20 =-224.73 (c = 0.26, CHCl3)

[0187] 1 H NMR(400MHz, CDCl3)δ7.55(d,J=8.1Hz,1H),7.32–7.19(m,3H),7.14(ddd,J=8.2,7.4 ,1.5Hz,1H),7.12–6.99(m,2H),6.95(td,J=7.5,1.1Hz,1H),6.78–6.60(m,5H),5.99 (ddd,J=9.8,5.3,1.3Hz,1H),4.72(d,J=5.8Hz,1H),3.34(d,J=13.1Hz,1H),3.25(dd d,J=5.4,2.2,1.3Hz,1H),3.19(d,J=13.2Hz,1H),1.83(d,J=6.5Hz,1H),1.46(s,9H).

[0188] 13 C NMR (101MHz, CDCl3) δ174.9,162.8,160.4,148.5,139.7,134.9,132.1,131.6(d,J=7.9Hz),130.8(d,J=3.2Hz),129.5,129.1, 128.3,128.2,128.1,127.8,126.9,124.1,123.7,123.5,114.6,114.4(d,J=5.8Hz),83.8,67.9,57.0,56.7,49.7,40.3,27.9.

[0189] 19F NMR (376MHz,CDCl3)δ-116.23.

[0190] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 39 H 28 FNNaO4) + :508.1900, Molecular weight captured by high-resolution mass spectrometry: 508.1907

[0191] HPLC: 96% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=14.6min,t R (major) = 11.2min.

[0192] Embodiment 15

[0193] The difference between Example 15 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-(p-tolylthio)indoline-1-carboxylic acid tert-butyl ester b-15 (35.5 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 15 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(p-tolylthio)indoline-1-carboxylic acid tert-butyl ester (44.9 mg) with a yield of 90%.

[0194] The structural formula of compound 15 is: The absolute configuration is: (S,S,S).

[0195] Data characterization of chiral 3,3-disubstituted indolone compound 15: [α] D 20 =-216.42 (c = 0.38, CHCl3)

[0196] 1H NMR (400MHz, CDCl3) δ7.54–7.45(m,2H),7.32(td,J=7.5,1.4Hz,1H),7.25(td,J=7.5,1.4H z,1H),7.20–7.16(m,2H),7.05(ddd,J=8.5,7.0,1.9Hz,1H),6.95(dd,J=14.6,7.7Hz,3H), 6.74–6.63(m,2H),6.43(dt,J=9.7,0.9Hz,1H),5.75(ddd,J=9.7,5.1,1.3Hz,1H),5.54(d, J=5.2Hz,1H),3.46(dt,J=5.1,1.8Hz,1H),2.26(s,3H),1.89(d,J=6.3Hz,1H),1.56(s,9H).

[0197] 13 C NMR (101MHz, CDCl3) δ172.8,148.6,140.1,139.2,137.1,135.1,131.8,129.5,129.3,129.0,128.8, 128.5,128.4,127.0,125.9,125.1,124.8,123.3,123.3,114.0,84.1,67.8,61.0,46.9,28.0,21.2.

[0198] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO4S) + :522.1715, molecular weight captured by high-resolution mass spectrometry: 522.1708.

[0199] HPLC:>99%ee, Daicel chiral chromatographic column model: ID, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=26.7min,t R (major) = 11.7min.

[0200] Example 16

[0201] The difference between Example 16 and Example 1 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-methyl-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-16 (32.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 16 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-5-methyl-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (39.7 mg) with a yield of 85%.

[0202] The structural formula of compound 16 is: The absolute configuration is: (S,S,S).

[0203] Data characterization of chiral 3,3-disubstituted indolone compound 16: [α] D 20 =-335.21 (c = 1.16, CHCl3).

[0204] 1 H NMR(600MHz, CDCl3)δ7.64(d,J=8.2Hz,1H),7.48–7.38(m,2H),7.38–7.33(m,2H) ,7.29–7.32(m,1H),7.24–7.08(m,3H),6.94–6.88(m,1H),6.88–6.83(m,1H),6.3 3(dd,J=9.8,1.3Hz,1H),6.19(d,J=1.8Hz,1H),5.77(ddd,J=9.7,5.1,1.4Hz,1H) ,4.70(s,1H),3.99(dt,J=5.2,1.4Hz,1H),1.94(s,1H),1.81(s,3H),1.58(s,9H).

[0205] 13 C NMR (151MHz, CDCl3) δ175.5,149.0,137.4,136.8,135.1,132.5,131.9,129.2,128.8,128.7,128.6, 128.5,128.0,127.9,127.8,126.9,126.7,126.5,123.7,113.9,84.2,67.8,60.0,49.8,28.0,20.5.

[0206] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO4) +:490.1994, Molecular weight captured by high-resolution mass spectrometry: 490.1994.

[0207] HPLC: 98% ee, Daicel chiral chromatographic column model: IJ-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=24.9min,t R (major) = 18.3min.

[0208] Embodiment 17

[0209] The difference between Example 17 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-17 (33.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 17 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-5-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (41.0 mg) with a yield of 85%.

[0210] The structural formula of compound 17 is: The absolute configuration is: (S,S,S).

[0211] Data characterization of chiral 3,3-disubstituted indolone compound 17: [α] D 20 =-482.04 (c = 0.24, CHCl3)

[0212] 1 H NMR(400MHz, CDCl3) δ7.73(d,J=9.0Hz,1H),7.52–7.23(m,8H),6.97–6.93(m,1H),6.72(d,J=9.2Hz,1H),6.39(d,J=9.9Hz,1H),5.9 8(s,1H),5.80(dd,J=9.9,5.0Hz,1H),4.74(d,J=5.0Hz,1H),4.06(d,J=5.1Hz,1H),3.15(s,3H),1.82(d,J=5.8Hz,1H),1.59(s,9H).

[0213] 13C NMR (101MHz, CDCl3) δ175.6,155.5,149.1,136.8,135.1,133.2,132.0,129.0,128.5,128 .2,128.0,127.9,127.1,123.9,115.6,115.4,110.4,84.3,67.7,60.8,55.1,49.9,28.0.

[0214] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5) + :506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1938;

[0215] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=16.9min,t R (major) = 14.8min.

[0216] Embodiment 18

[0217] The difference between Example 18 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-chloro-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-18 (34.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 18 is obtained - 5-chloro-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (44.8 mg) with a yield of 92%.

[0218] The structural formula of compound 18 is: The absolute configuration is: (S,S,S).

[0219] Data characterization of chiral 3,3-disubstituted indolinone compound 18: [α] D 20 =-264.76 (c = 1.20, CHCl3)

[0220] 1H NMR (600MHz, CDCl3) δ7.74(d,J=8.7Hz,1H),7.43(d,J=7.3Hz,2H),7.39(t,J=7.6Hz,2H ),7.36–7.33(m,1H),7.28–7.25(m,2H),7.11(dd,J=8.8,2.2Hz,1H),6.92(dd,J=5.5,3 .3Hz,1H),6.39(d,J=9.8Hz,1H),6.34(d,J=2.2Hz,1H),5.77(ddd,J=9.7,5.2,1.4Hz,1 H),4.69–4.65(m,1H),3.99(dd,J=5.2,1.4Hz,1H),1.80(d,J=5.8Hz,1H),1.59(s,9H).

[0221] 13 C NMR (151MHz, CDCl3) δ174.8,148.9,138.5,136.0,134.6,131.6,129.7,129.4,129.1,128.63,128.6 0,128.50,128.47,128.36,128.2,127.8,127.0,126.4,123.1,115.5,84.8,67.8,60.1,49.7,28.0.

[0222] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 ClNNaO4) + :510.1448, molecular weight captured by high-resolution mass spectrometry: 510.1443.

[0223] HPLC:>99%ee, Daicel chiral chromatographic column model: IF-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=46.0min,t R (major) = 36.3min.

[0224] Embodiment 19

[0225] The difference between Example 19 and Example 1 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-fluoro-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-19 (32.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 19 is obtained - 5-fluoro-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (43.3 mg) with a yield of 92%.

[0226] The structural formula of compound 19 is: The absolute configuration is: (S,S,S).

[0227] Data characterization of chiral 3,3-disubstituted indolone compound 19: [α] D 20 =-347.58 (c = 0.53, CHCl3).

[0228] 1 H NMR (400MHz, CDCl3) δ7.79(dd,J=9.0,4.6Hz,1H),7.47–7.30(m,5H),7.19–7.27(m,3H),6.93–6.81(m,2H),6.40(d,J=9.8Hz,1H) ,6.10(dd,J=8.8,2.7Hz,1H),5.79(dd,J=9.9,5.1Hz,1H),4.68(s,1H),4.01(d,J=5.1Hz,1H),1.76(d,J=7.1Hz,1H),1.59(s,9H).

[0229] 13 C NMR (101MHz, CDCl3) δ175.0, 159.8, 157.4, 149.0, 136.2, 136.0 (d, J = 2.5Hz), 134.7, 131.7, 129.5, 129.3, 129.1, 128.7 (d, J = 8.3Hz), 128. 5,128.4,128.1,127.8,127.0,123.3,115.6(d,J=7.8Hz),115.0(d,J=22.8Hz),113.5(d,J=25.4Hz),84.7,67.8,60.27,60.25,49.8,28.0.

[0230] 19 F NMR (376MHz,CDCl3)δ-118.87.

[0231] HRMS (ESI) m / z (M+Na)+ : Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1732

[0232] HPLC:>99%ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 35°C, detector wavelength: 254 nm, retention time: t R (minor)=17.9min,t R (major) = 17.1min.

[0233] Embodiment 20

[0234] The difference between Example 20 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 6-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-20 (33.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 20 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-6-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (43.4 mg) with a yield of 90%.

[0235] The structural formula of compound 20 is: The absolute configuration is: (S,S,S).

[0236] Data characterization of chiral 3,3-disubstituted indolone compound 20: [α] D 20 =-355.45 (c = 0.49, CHCl3)

[0237] 1H NMR(600MHz, CDCl3)δ7.47–7.44(m,3H),7.38–7.29(m,3H),7.23–7.18(m,3H) ,6.92–6.87(m,1H),6.39(dd,J=9.8,1.4Hz,1H),6.30(d,J=8.4Hz,1H),6.15(d d,J=8.5,2.5Hz,1H),5.78(ddd,J=9.8,5.1,1.3Hz,1H),4.69(d,J=5.3Hz,1H) ,3.99(dt,J=5.1,1.5Hz,1H),3.74(s,3H),1.70(d,J=6.1Hz,1H),1.60(s,9H).

[0238] 13 C NMR (151MHz, CDCl3) δ175.9,159.6,149.0,141.0,137.2,135.0,131.9,129.3,128.9,128.4,128. 2,127.93,127.85,126.9,126.6,123.9,118.4,108.8,100.9,84.5,68.0,59.6,55.3,50.2,28.0.

[0239] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5) + :506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1938

[0240] HPLC: 99% ee, Daicel chiral chromatographic column model: IA-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=33.4min,t R (major) = 26.2min.

[0241] Embodiment 21

[0242] The difference between Example 21 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 6-bromo-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-21 (38.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 21 is obtained - 6-bromo-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (47.3 mg) with a yield of 89%.

[0243] The structural formula of compound 21 is: The absolute configuration is: (S,S,S).

[0244] Data characterization of chiral 3,3-disubstituted indolone compound 21: [α] D 20 =-151.89 (c = 0.88, CHCl3).

[0245] 1 H NMR (600MHz, CDCl3) δ8.04(d,J=1.9Hz,1H),7.44–7.32(m,5H),7.26–7.21(m,2H),7.18(dd,J=6.5,2.3Hz,1H),6.93–

[0246] 6.89(m,1H),6.74(dd,J=8.2,1.9Hz,1H),6.40(d,J=9.1Hz,1H),6.25(d,J=8.2Hz, 1H), 4.68 (s, 1H), 4.00 (dt, J=5.1, 1.5Hz, 1H), 1.74 (d, J=5.5Hz, 1H), 1.60 (s, 9H).

[0247] 13 C NMR (151MHz, CDCl3) δ174.9,148.8,141.1,136.2,134.8,131.7,129.6,129.2,129.1,128.44,128 .40,128.2,127.8,127.1,127.0,125.8,125.8,123.3,122.1,118.0,85.1,67.8,59.9,49.9,28.0.

[0248] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 BrNNaO4) +:554.0943, molecular weight captured by high-resolution mass spectrometry: 554.0939;

[0249] HPLC: 99% ee, Daicel chiral chromatographic column model: IC, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=12.4min,t R (major) = 48.3min.

[0250] Embodiment 22

[0251] The difference between Example 22 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 6-fluoro-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-22 (32.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 22 is obtained - 6-fluoro-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (44.7 mg) with a yield of 95%.

[0252] The structural formula of compound 22 is: The absolute configuration is: (S,S,S).

[0253] Data characterization of chiral 3,3-disubstituted indolone compound 22: [α] D 20 =-405.63 (c = 0.46, CHCl3)

[0254] 1 H NMR(400MHz, CDCl3) δ7.59(dd,J=10.3,2.4Hz,1H),7.45–7.33(m,5H),7.24–7.16(m,3H),6.89(dd,J=5.4,3.4Hz,1H),6.42–6. 24(m,3H),5.78(ddd,J=9.8,5.2,1.4Hz,1H),4.68(d,J=2.9Hz,1H),4.00(d,J=5.2Hz,1H),1.78(d,J=5.6Hz,1H),1.60(s,9H).

[0255] 13C NMR (101MHz, CDCl3) δ175.3,163.5,161.1,148.8,141.2(d,J=12.3Hz),136.5,134.8,131.7,129.5,129.1,129.0,128.5,128 .3,128.1,127.8,127.0,126.9,123.4,122.0,122.0,109.5(d,J=22.2Hz),103.2(d,J=29.5Hz),85.0,67.8,59.7,50.0,28.0.

[0256] 19 F NMR (376MHz,CDCl3)δ-110.81.

[0257] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1738;

[0258] HPLC: 96% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=15.7min,t R (major) = 20.5min.

[0259] Embodiment 23

[0260] The difference between Example 23 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 7-bromo-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-23 (38.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 23 is obtained - 7-bromo-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (50.5 mg) with a yield of 95%.

[0261] The structural formula of compound 23 is: The absolute configuration is: (S,S,S).

[0262] Data characterization of chiral 3,3-disubstituted indolone compound 23: [α] D20 =-114.34 (c = 0.97, CHCl3)

[0263] 1 H NMR (600MHz, CDCl3) δ7.80(d,J=8.3Hz,1H),7.46(d,J=7.8Hz,2H),7.39–7.31(m,3H),7.22–7.19(m,2H),7.15(t,J=8.1Hz,1H),6.86(d,J=6.5Hz,1H) ,6.61(t,J=7.7Hz,1H),6.45(d,J=7.6Hz,1H),6.37(d,J=9.8Hz,1H),5.79( dt,J=8.2,3.5Hz,1H),4.72(s,1H),4.02(s,1H),1.75(s,1H),1.60(s,9H).

[0264] 13 C NMR (151MHz, CDCl3) δ175.4,149.0,140.0,136.8,135.0,131.8,129.3,128.9,128.9,128.4,128. 3,128.2,127.94,127.91,126.9,126.8,126.0,123.7,122.7,114.4,84.5,68.0,60.0,50.1,28.0.

[0265] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 BrNNaO4) + :554.0943, molecular weight captured by high-resolution mass spectrometry: 554.0940.

[0266] HPLC: 99% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=17.0min,t R (major) = 19.3min.

[0267] Embodiment 24

[0268] The difference between Example 24 and Example 1 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-(2-chloroethyl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-24 (37.1 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 24 is obtained - 5-(2-chloroethyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (43.7 mg) with a yield of 85%.

[0269] The structural formula of compound 24 is: The absolute configuration is: (S,S,S).

[0270] Data characterization of chiral 3,3-disubstituted indolone compound 24: [α] D 20 =-350.50 (c = 0.10, CHCl3)

[0271] 1 H NMR(600MHz, CDCl3)δ7.74(d,J=8.3Hz,1H),7.46–7.43(m,2H),7.40–7.37(m,2H),7.35–7.33( m,1H),7.28–7.24(m,3H),7.01(dd,J=8.3,1.9Hz,1H),6.93–6.89(m,1H),6.36(dd,J=9.8,1.4H z,1H),6.26(d,J=1.9Hz,1H),5.80(ddd,J=9.8,5.1,1.4Hz,1H),4.75(d,J=5.1Hz,1H),4.04(d t,J=5.1,1.3Hz,1H),3.12–3.00(m,2H),2.60–2.48(m,2H),1.71(d,J=6.1Hz,1H),1.60(s,9H).

[0272] 13 C NMR (151MHz, CDCl3) δ175.5,149.0,138.9,136.6,135.2,133.0,131.9,129.11,129.05,129.00,128.9 ,128.7,128.3,128.04,127.97,127.1,126.4,123.9,114.5,84.6,67.8,60.2,50.1,44.5,38.3,28.0.

[0273] HRMS (ESI) m / z (M+Na) +: Calculated molecular weight (C 31 H 30 ClNNaO4) + :538.1761, molecular weight captured by high-resolution mass spectrometry: 538.1757.

[0274] HPLC:>99%ee, Daicel chiral chromatographic column model: IF-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=15.7min,t R (major) = 14.6min.

[0275] Embodiment 25

[0276] The difference between Example 25 and Example 1 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 1,4-dihydro-1,4-epoxyanthracene a-2 (38.8 mg, 0.2 mmol, 2.0 eq.), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 25 is obtained, namely, tert-butyl 3-(1-hydroxy-1,2-dihydroanthracene-2-yl)-2-oxo-3-phenylindoline-1-carboxylate (49.8 mg), with a yield of 99%.

[0277] The structural formula of compound 25 is: The absolute configuration is: (S,S,S).

[0278] Data characterization of chiral 3,3-disubstituted indolone compound 25: [α] D 20 =-289.85 (c = 0.13, CHCl3)

[0279] 1 H NMR (500MHz, CDCl3) δ7.81(d,J=8.1Hz,1H),7.73(t,J=8.7Hz,2H),7.63(s,1H),7.51–7.30(m,8H),7.15–7.08(m,1H),6.58(t, J=9.3Hz,2H),6.51(t,J=7.4Hz,1H),5.85(dd,J=9.8,4.6Hz,1H),4.89(s,1H),4.08(d,J=4.9Hz,1H),1.79(s,1H),1.53(s,9H).

[0280] 13C NMR (151MHz, CDCl3) δ175.2,149.0,139.9,137.2,134.1,133.7,133.2,129.8,129.6,128.9,128.4,127.9 0,127.85,127.83,127.4,127.2,126.5,126.0,125.6,124.4,123.2,114.5,84.4,68.5,59.8,50.3,27.9.

[0281] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 33 H 29 NNaO4) + :526.1994, Molecular weight captured by high-resolution mass spectrometry: 526.1994.

[0282] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=16.9min,t R (major) = 21.2min.

[0283] Embodiment 26

[0284] The difference between Example 26 and Example 1 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 6,7-dimethoxy-1,4-dihydro-1,4-epoxynaphthalene a-3 (40.8 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 26 is obtained, namely, tert-butyl 3-(1-hydroxy-6,7-dimethoxy-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylate (48.7 mg), with a yield of 95%.

[0285] The structural formula of compound 26 is: The absolute configuration is: (S,S,S).

[0286] Data characterization of chiral 3,3-disubstituted indolone compound 26: [α] D 20 =-300.15 (c = 0.24, CHCl3)

[0287] 1H NMR (600MHz, CDCl3) δ7.74(d,J=8.1Hz,1H),7.38(d,J=7.6Hz,2H),7.30(t,J=7.5Hz, 2H),7.25(t,J=7.2Hz,1H),7.13–7.07(m,1H),6.66(s,1H),6.62(t,J=7.4Hz,1H),6.4 2(d,J=7.4Hz,1H),6.33(s,1H),6.21(d,J=9.7Hz,1H),5.62(dd,J=9.6,4.5Hz,1H),4. 56(s,1H),3.90(d,J=5.0Hz,1H),3.78(s,3H),3.73(s,3H),1.75(s,1H),1.51(s,9H).

[0288] 13 C NMR (151MHz, CDCl3) δ175.2,149.10,149.05,148.8,139.9,137.0,128.9,128.7,128.3,128.0,127.8,1 27.5,127.2,125.7,125.2,123.0,121.6,114.4,111.4,109.8,84.4,67.9,60.0,56.0,55.9,50.1,28.0.

[0289] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 31 H 31 NNaO6) + :536.2049, molecular weight captured by high-resolution mass spectrometry: 536.2048;

[0290] HPLC:>99%ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=35.2min,t R (major) = 20.1min.

[0291] Embodiment 27

[0292] The difference between Example 27 and Example 1 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 6,7-difluoro-1,4-dihydro-1,4-epoxynaphthalene a-4 (36.0 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 27 is obtained, namely tert-butyl 3-(6,7-difluoro-1-hydroxy-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylate (35.7 mg), with a yield of 73%.

[0293] The structural formula of compound 27 is: The absolute configuration is: (S,S,S).

[0294] Data characterization of chiral 3,3-disubstituted indolone compound 27: [α] D 20 =-365.65 (c = 0.71, CHCl3)

[0295] 1 H NMR(600MHz, CDCl3)δ7.83(d,J=8.2Hz,1H),7.48–7.43(m,2H),7.38(t,J=7.5Hz,2H),7.34(d d,J=8.3,6.2Hz,1H),7.22(td,J=7.9,1.4Hz,1H),7.05(t,J=8.9Hz,1H),6.77(t,J=7.6Hz,1H) ,6.71(dd,J=10.4,7.8Hz,1H),6.56(d,J=7.5Hz,1H),6.29(d,J=9.8Hz,1H),5.82(dd,J=9.8, 4.9Hz,1H),4.66(d,J=4.0Hz,1H),3.99(d,J=4.9Hz,1H),1.76(d,J=13.8Hz,1H),1.60(s,9H).

[0296] 13 C NMR (151MHz, CDCl3) δ175.0,149.0,140.0,136.6,129.1,128.7,128.1,127.9,127.5,126.9,125.7, 124.7,124.6,123.2,117.4(d,J=17.4Hz),115.4(d,J=17.5Hz),114.8,84.7,67.2,59.7,50.0,28.0.

[0297] 19F NMR (376MHz, CDCl3) δ -137.47 (d, J = 21.1Hz), -137.63 (d, J = 23.4Hz).

[0298] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 25 F2NNaO4) + :512.1649, Molecular weight captured by high-resolution mass spectrometry: 512.1643

[0299] HPLC: 99% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=10.3min,t R (major) = 16.7min.

[0300] Embodiment 28

[0301] The difference between Example 28 and Example 1 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 6,7-dibromo-1,4-dihydro-1,4-epoxynaphthalene a-5 (60.0 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 28 is obtained, namely tert-butyl 3-(6,7-dibromo-1-hydroxy-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylate (52.4 mg), with a yield of 86%.

[0302] The structural formula of compound 28 is: The absolute configuration is: (S,S,S).

[0303] Data characterization of chiral 3,3-disubstituted indolone compound 28: [α] D 20 =-406.38 (c = 0.21, CHCl3)

[0304] 1H NMR (600MHz, CDCl3) δ7.83(d,J=8.2Hz,1H),7.49–7.43(m,3H),7.36(dt,J=25.6,7.4Hz,3H),7.23(t,J=7.9Hz,1H),7.16(s,1H),6.80(t,J=7.6Hz, 1H),6.61(d,J=7.6Hz,1H),6.29(d,J=9.8Hz,1H),5.86(dd,J=9.9,4.9Hz ,1H),4.67(s,1H),3.98(dt,J=4.1,2.0Hz,1H),1.78(s,1H),1.60(s,9H).

[0305] 13 C NMR (151MHz, CDCl3) δ175.0,148.9,139.9,136.5,135.7,133.2,132.4,131.4,129.1,128.8,128 .2,127.8,127.3,126.8,126.0,125.7,124.8,123.4,123.3,114.8,84.7,67.0,59.7,50.2,28.0.

[0306] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 25 Br2NNaO4) + :632.0048, molecular weight captured by high-resolution mass spectrometry: 632.0038;

[0307] HPLC: 97% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=18.2min,t R (major) = 25.2min.

[0308] Embodiment 29

[0309] The difference between Example 29 and Example 1 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 5,6,7,8-tetramethyl-1,4-dihydro-1,4-epoxynaphthalene a-6 (40.0 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 29 is obtained - 3-(1-hydroxy-5,6,7,8-tetramethyl-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (40.7 mg) with a yield of 80%.

[0310] The structural formula of compound 29 is: The absolute configuration is: (S,S,S).

[0311] Data characterization of chiral 3,3-disubstituted indolone compound 29: [α] D 20 =-186.17 (c = 0.12, CHCl3)

[0312] 1 H NMR(500MHz, CDCl3)δ7.78(d,J=8.3Hz,1H),7.51–7.46(m,1H),7.40–7.33(m,2H),7.34–7.27(m, 1H),7.13(td,J=7.8,1.4Hz,1H),6.71(dd,J=10.1,1.0Hz,1H),6.56(td,J=7.6,1.1Hz,1H),6.25( dd,J=7.7,1.3Hz,1H),5.82(ddd,J=10.1,5.6,1.5Hz,1H),4.82(dt,J=7.6,1.4Hz,1H),3.97(dt, J=5.7,1.1Hz,1H),2.23(s,3H),2.20(s,3H),2.07(s,3H),2.01(s,3H),1.58(s,1H),1.56(s,9H).

[0313] 13 C NMR (126MHz, CDCl3) δ175.1,149.2,139.9,137.1,135.5,135.3,131.6,130.6,130.2,128.8,128.1,127.9,127 .80,127.75,127.73,127.4,125.9,122.6,121.4,114.2,84.1,64.8,59.9,50.1,28.0,17.0,16.8,15.0,14.5.

[0314] HRMS (ESI) m / z (M+Na)+ : Calculated molecular weight (C 33 H 35 NNaO4) + :532.2464, molecular weight captured by high-resolution mass spectrometry: 532.2456.

[0315] HPLC: 99.9% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 94 / 6, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=13.4min,t R (major) = 14.1min.

[0316] Embodiment 30

[0317] The difference between Example 30 and Example 1 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 5,8-dimethyl-1,4-dihydro-1,4-epoxynaphthalene a-7 (34.4 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 30 is obtained - 3-(1-hydroxy-5,8-dimethyl-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (43.3 mg) with a yield of 90%.

[0318] The structural formula of compound 30 is: The absolute configuration is: (S,S,S).

[0319] Data characterization of chiral 3,3-disubstituted indolinone compound 30: [α] D 20 =-257.12 (c = 0.25, CHCl3)

[0320] 1H NMR(600MHz, CDCl3)δ7.79(d,J=8.2Hz,1H),7.53–7.47(m,2H),7.39–7.28(m, 3H),7.17–7.11(m,1H),6.94(s,2H),6.58(ddt,J=7.6,3.9,1.9Hz,2H),6.22( dd,J=7.6,1.3Hz,1H),5.85(ddd,J=10.0,5.5,1.5Hz,1H),4.77(d,J=6.4Hz,1 H),3.99(d,J=5.5Hz,1H),2.13(s,3H),2.05(s,3H),1.61(s,1H),1.58(s,9H).

[0321] 13 C NMR (151MHz, CDCl3) δ175.2,149.1,139.9,136.8,133.4,132.8,131.8,130.2,130.0,129.9,128.9,128 .2,127.80,127.77,126.9,126.8,125.8,122.7,122.6,114.2,84.3,64.1,59.9,50.1,28.0,19.0,17.9.

[0322] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 31 H 30 NNaO4) + :504.2151, molecular weight captured by high-resolution mass spectrometry: 504.2150.

[0323] HPLC: 99% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=6.4min,t R (major) = 8.0min.

[0324] Embodiment 31

[0325] The difference between Example 31 and Example 1 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene a-8 (34.4 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as those in Example 1, and finally a white solid compound 31 is obtained, namely tert-butyl 3-(1-hydroxy-1,4-dimethyl-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylate (43.3 mg), with a yield of 90%.

[0326] The structural formula of compound 31 is: The absolute configuration is: (S,S,S).

[0327] Data characterization of chiral 3,3-disubstituted indolinone compound 31: [α] D 20 =-73.78 (c = 0.72, CHCl3)

[0328] 1 H NMR (400MHz, CDCl3) δ8.01–7.94(m,1H),7.52–7.39(m,3H),7.36–7.18(m,9H),5.69– 5.64(m,1H),4.16–4.10(m,1H),2.02(s,3H),1.87(s,1H),1.62(s,9H),0.54(s,3H).

[0329] 13 C NMR (101MHz, CDCl3) δ177.8,149.3,146.2,140.3,139.0,134.2,133.7,128.9,128.8,128.7,128.4, 128.1,127.7,127.2,126.5,124.4,124.0,123.4,121.3,115.7,84.3,56.5,54.6,28.1,23.1,19.1.

[0330] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 31 H 30 NNaO4) + :504.2151, molecular weight captured by high-resolution mass spectrometry: 504.2143.

[0331] HPLC:>99%ee, Daicel chiral chromatographic column model: IC, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=11.5min,t R (major) = 7.3min.

[0332] Embodiment 32

[0333] Step (1): In a 10 ml test tube equipped with a magnetic stirrer, di(1,5-cyclooctadiene)rhodium tetrafluoroborate (2.0 mg, 0.005 mmol, 5 mol%) and the corresponding chiral bisphosphine ligand (R)-1-[(S P )-2-(diphenylphosphino)ferrocene]ethyl di-tert-butylphosphine (3.2 mg, 0.006 mmol, 6 mol%). Subsequently, 1,2-dichloroethane (1.0 ml) was added as a solvent. Then, dysprosium chloride (26.8 mg, 0.1 mmol, 1.0 equiv), 1,4-dihydro-1,4-epoxynaphthalene a-1 (28.8 mg, 0.2 mmol, 2.0 equiv), 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 (30.9 mg, 0.1 mmol, 1.0 equiv) were added. Then, the mixture was stirred at 40°C for 2 hours. After the reaction was completed, the reaction mixture was quenched with water (2 ml) and extracted twice with 10 ml of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, and the volatiles were removed to obtain a crude product. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give the desired compound 32 - (R)-3-((1S,2S)-1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoleline-1-carboxylic acid tert-butyl ester (42.1 mg, yield 90%, ee>99%).

[0334] The reaction formula of Example 32 is:

[0335]

[0336] The structural formula of compound 32 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 1, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0337] Data characterization of chiral 3,3-disubstituted indole ketone compound 32: [α] D 20 = +83.00 (c = 0.11, CHCl3)

[0338] 1H NMR (400MHz, CDCl3) δ7.97(d,J=8.2Hz,1H),7.40–7.25(m,8H),7.22–7.11(m,3H),7.05–6.99(m,1H),6.48(dd,J=9.9,2 .8Hz,1H),5.68(dd,J=9.8,2.7Hz,1H),4.45(t,J=11.0Hz,1H),3.99(dt,J=12.0,2.8Hz,1H),1.62(s,9H),1.26(s,1H).

[0339] 13 C NMR (126MHz, CDCl3) δ177.3,149.4,140.6,138.2,138.0,132.5,129.7,128.8,128.7,128.1,128.0,127.8,127.7,127.3,127.1,

[0340] 126.9,126.0,123.8,123.7,115.6,84.2,71.8,57.7,51.2,28.1.

[0341] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 27 NNaO4) + :476.1838, molecular weight captured by high-resolution mass spectrometry: 476.1829.

[0342] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=7.4min,t R (major) = 5.3min.

[0343] Embodiment 33

[0344] The difference between Example 33 and Example 32 is that in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-phenylindolone-1-carboxylic acid ethyl ester b-2, and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 33 is obtained, namely 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoleline-1-carboxylic acid ethyl ester (31.4 mg), with a yield of 74%.

[0345] The structural formula of compound 33 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 2, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0346] Data characterization of chiral 3,3-disubstituted indolinone compound 33: [α] D 20 = +122.40 (c = 0.10, CHCl3)

[0347] 1 H NMR (600MHz, CDCl3) δ8.04(d,J=8.1Hz,1H),7.39–7.37(m,1H),7.35–7.29(m,6H),7.28(dd,J=3.8,2.4Hz,1H),7.18(tdd,J=5 .6,3.9,2.0Hz,3H),7.04–7.01(m,1H),6.48(dd,J=9.9,2.9Hz,1H),5.68(dd,J=9.9,2.7Hz,1H),4.46(d,J=10.7Hz,1H),4.44–

[0348] 4.40(m,2H),4.00(dt,J=12.3,2.8Hz,1H),1.78(d,J=10.3Hz,1H),1.41(t,J=7.1Hz,3H).

[0349] 13 C NMR (151MHz, CDCl3) δ177.3,151.1,140.3,138.0,138.0,132.5,129.8,128.9,128.8,128.1,127.9,127.9,127.7,127.3,127.2,

[0350] 126.8,126.0,124.2,123.4,115.7,71.9,63.4,57.7,51.1,14.2.

[0351] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 27 H 23 NNaO4) + :448.1525, Molecular weight captured by high-resolution mass spectrometry: 448.1515

[0352] HPLC: 96% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=6.8min,t R (major) = 5.6min.

[0353] Embodiment 34

[0354] The difference between Example 34 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-phenylindolone-1-carboxylic acid benzyl ester b-3 (34.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 34 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindolone-1-carboxylic acid benzyl ester (40.0 mg) with a yield of 82%.

[0355] The structural formula of compound 34 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 3, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0356] Data characterization of chiral 3,3-disubstituted indolone compound 34: [α] D 20 = +38.90 (c = 0.10, CHCl3)

[0357] 1 H NMR (500MHz, CDCl3) δ8.03(d,J=8.2Hz,1H),7.48(d,J=7.2Hz,2H),7.41–7.27(m,8H),7.22–7.14(m,3H),7.05–7.00(m,1H),6.49(dd,J= 9.9,2.9Hz,1H),5.69(dd,J=9.9,2.7Hz,1H),5.44–5.36(m,2H),4.48–4.42(m,1H),4.01(dt,J=12.3,2.8Hz,1H),1.64(d,J=10.5Hz,1H).

[0358] 13C NMR (126MHz, CDCl3) δ177.1,151.0,140.2,138.0,137.9,135.0,132.5,129.8,128.9,128.9,128.6,1 28.4,128.2,128.0,127.7,127.3,127.2,126.7,126.1,124.3,123.4,115.7,71.9,68.6,57.7,51.2.

[0359] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 32 H 25 NNaO4) + :510.1681, molecular weight captured by high-resolution mass spectrometry: 510.1672.

[0360] Embodiment 35

[0361] The difference between Example 35 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-(p-tolyl)indolone-1-carboxylic acid tert-butyl ester b-4 (34.3 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 35 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(p-tolyl)indolone-1-carboxylic acid tert-butyl ester (40.0 mg) with a yield of 85%.

[0362] The structural formula of compound 35 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 4, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0363] Data characterization of chiral 3,3-disubstituted indolinone compound 35: [α] D 20 = +111.79 (c = 0.43, CHCl3)

[0364] 1H NMR(600MHz, CDCl3) δ7.96(d,J=8.2Hz,1H),7.36–7.24(m,3H),7.23–7.09(m,7H),7.01(dd,J=6.7,2.0Hz,1H),6.47(dd,J=9.9,2.8Hz,1 H),5.70(dd,J=9.9,2.7Hz,1H),4.43(d,J=11.9Hz,1H),3.95(dt,J=11.9,2.8Hz,1H),2.32(s,3H),1.76(d,J=11.4Hz,1H),1.61(s,9H).

[0365] 13 C NMR (151MHz, CDCl3) δ177.5,149.4,140.5,138.0,137.6,135.1,132.5,129.6,129.5,128.6,128.1, 127.8,127.6,127.4,127.1,127.0,126.0,123.8,123.7,115.5,84.1,71.8,57.3,51.0,28.1,20.9.

[0366] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO4) + :490.1994, Molecular weight captured by high-resolution mass spectrometry: 490.1988

[0367] HPLC: 99% ee, Daicel chiral chromatographic column model: IF-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=22.7min,t R (major) = 12.3min.

[0368] Embodiment 36

[0369] The difference between Example 36 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-(tert-butyl)phenyl)-2-oxoindolinone-1-carboxylic acid tert-butyl ester b-5 (36.5 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 36 is obtained - 3-(4-(tert-butyl)phenyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindolinone-1-carboxylic acid tert-butyl ester (43.3 mg) with a yield of 85%.

[0370] The structural formula of compound 36 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 5, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0371] Data characterization of chiral 3,3-disubstituted indole ketone compound 36: [α] D 20 =-258.85 (c = 0.40, CHCl3)

[0372] 1 H NMR (500MHz, CDCl3) δ7.78(d,J=8.1Hz,1H),7.37(s,4H),7.25–7.02(m,4H),6.86(dd,J=5.7,2.4Hz,1H),6.60(td,J=7.6,0.9Hz,1H),6.48–6.43(m, 1H),6.39–6.33(m,1H),5.80(ddd,J=9.8,5.1,1.1Hz,1H),4.76(s,1H),4. 01(dt,J=5.0,1.3Hz,1H),1.73(d,J=5.5Hz,1H),1.60(s,9H),1.31(s,9H).

[0373] 13 C NMR (126MHz, CDCl3) δ175.6,150.7,149.1,140.0,135.1,133.7,131.8,129.2,128.8,128.5,128.2,128.2,127.6,127.0,126.8,

[0374] 126.0,125.9,123.9,122.8,114.4,84.4,68.0,59.7,50.1,34.4,31.2,28.1.

[0375] HRMS (ESI) m / z (M+H) +: Calculated molecular weight (C 33 H 35 NNaO4) + :532.2464, molecular weight captured by high-resolution mass spectrometry: 532.2456.

[0376] HPLC:>99%ee, Daicel chiral chromatographic column model: AD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=31.0min,t R (major) = 24.7min.

[0377] Embodiment 37

[0378] The difference between Example 37 and Example 32 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-6 (33.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid compound 37 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-3-(4-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (43.4 mg) with a yield of 90%.

[0379] The structural formula of compound 37 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 6, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0380] Data characterization of chiral 3,3-disubstituted indolone compound 37: [α] D 20 = +111.88 (c = 1.08, CHCl3)

[0381] 1H NMR (400MHz, CDCl3) δ7.87(d,J=8.2Hz,1H),7.28–7.00(m,9H),6.92(dd,J=6.1,2.7Hz,1H),6.76–6.69(m,2H),6.38(dd,J=9.9,2.8Hz,1 H),5.60(dd,J=9.8,2.7Hz,1H),4.33(t,J=11.2Hz,1H),3.82(dt,J=12.1,2.9Hz,1H),3.67(s,3H),1.84(d,J=10.3Hz,1H),1.52(s,9H).

[0382] 13 C NMR (101MHz, CDCl3) δ177.5,159.0,149.4,140.4,138.0,132.4,129.9,129.5,129.0,128.6,128.0,127.5,127.4,127.0,126.9,

[0383] 125.9,123.7,123.7,115.5,114.0,84.1,71.7,56.9,55.2,50.9,28.0.

[0384] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5) + :506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1939.

[0385] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=11.0min,t R (major) = 8.6min.

[0386] Embodiment 38

[0387] The difference between Example 38 and Example 32 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-fluorophenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-7 (32.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 38 is obtained - 3-(4-fluorophenyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (42.3 mg) with a yield of 88%.

[0388] The structural formula of compound 38 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 7, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0389] Data characterization of chiral 3,3-disubstituted indolinone compound 38: [α] D 20 = +140.63 (c = 0.49, CHCl3)

[0390] 1 H NMR(400MHz, CDCl3) δ7.96(d,J=8.2Hz,1H),7.39–7.24(m,5H),7.14(dt,J=15.4,6.5Hz,3H),7.04–6.92(m,3H),6. 48(dd,J=9.9,2.8Hz,1H),5.62(dd,J=9.9,2.8Hz,1H),4.41(t,J=11.1Hz,1H),1.97(d,J=10.3Hz,1H),1.61(s,9H).

[0391] 13 C NMR (101MHz, CDCl3) δ177.2,163.5,161.1,149.3,140.4,137.9,133.8(d,J=3.1Hz),132.3,129.8,129.7(d,J=8.0Hz) ,128.8,128.1,127.6,126.98,126.95,126.4,126.0,123.9,123.7,115.7,115.6,115.5,84.3,71.7,57.0,51.1,28.0.

[0392] 19 F NMR (376MHz,CDCl3)δ-114.51.

[0393] HRMS (ESI) m / z (M+Na) +: Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1737

[0394] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=8.7min,t R (major) = 6.8min.

[0395] Embodiment 39

[0396] The difference between Example 39 and Example 32 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(3-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-8 (33.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid compound 39 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-3-(3-methoxyphenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (43.9 mg) with a yield of 91%.

[0397] The structural formula of compound 39 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 8, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0398] Data characterization of chiral 3,3-disubstituted indolone compound 39: [α] D 20 = +118.15 (c = 0.39, CHCl3)

[0399] 1H NMR(600MHz, CDCl3)δ7.94(d,J=8.2Hz,1H),7.37–7.30(m,2H),7.29–7.20(m,2H) ,7.19–7.10(m,3H),7.04–7.00(m,1H),6.94(d,J=8.0Hz,1H),6.90(t,J=2.2Hz,1H ),6.85–6.81(m,1H),6.48(dd,J=10.0,2.8Hz,1H),5.73–5.68(m,1H),4.43(t,J= 11.3Hz,1H),3.98–3.93(m,1H),3.74(s,2H),1.70(d,J=10.6Hz,1H),1.62(s,9H).

[0400] 13 C NMR (151MHz, CDCl3) δ177.2,159.7,149.3,140.4,139.7,138.0,132.5,129.62,129.60,128.7,128.1,127.6,127.1,127.1,126.9,

[0401] 126.0,123.8,123.5,120.3,115.5,114.2,112.8,84.2,71.8,57.5,55.1,51.1,28.1.

[0402] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5) + :506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1940;

[0403] HPLC:>99%ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 35°C, detector wavelength: 254 nm, retention time: t R (minor)=9.7min,t R (major) = 8.6min.

[0404] Embodiment 40

[0405] The difference between Example 40 and Example 32 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(3-fluorophenyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-9 (32.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 40 is obtained - 3-(3-fluorophenyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (33.4 mg) with a yield of 71%.

[0406] The structural formula of compound 40 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 9, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0407] Data characterization of chiral 3,3-disubstituted indolinone compound 40: [α] D 20 =-406.41 (c = 0.85, CHCl3)

[0408] 1 H NMR(600MHz, CDCl3)δ7.79(d,J=8.2Hz,1H),7.34(dt,J=10.5,6.9Hz,2H),7.25–7 .19(m,3H),7.19–7.11(m,2H),7.03(d,J=6.8Hz,1H),6.86(d,J=7.7Hz,1H),6.61 (t,J=7.6Hz,1H),6.43(d,J=7.6Hz,1H),6.37(d,J=9.7Hz,1H),5.82–5.73(m,1H) ,4.68(d,J=4.9Hz,1H),3.94(d,J=5.0Hz,1H),1.80(d,J=5.6Hz,1H),1.60(s,9H).

[0409] 13 C NMR (151MHz, CDCl3) δ174.9,163.8,162.1,148.9,139.9,139.4(d,J=6.9Hz),134.9,131.7,130.3(d,J=8.3Hz),129.5,129.0,128.6,128.4,1 28.3,126.9,126.2,125.9,123.6(d,J=2.8Hz),123.2,123.0,115.3(d ,J=23.2Hz),114.9(d,J=21.0Hz),114.5,84.7,67.9,59.8,50.2,28.0.

[0410] 19 F NMR (376MHz,CDCl3)δ-111.44.

[0411] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1743.

[0412] HPLC: 99% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 35°C, detector wavelength: 254 nm, retention time: t R (minor)=14.1min,t R (major) = 13.3min.

[0413] Embodiment 41

[0414] The difference between Example 41 and Example 32 is that: in the step, tert-butyl 2-oxo-3-phenylindolone-1-carboxylate b-1 is replaced with tert-butyl 3-(naphthalen-2-yl)-2-oxoindoline-1-carboxylate b-10 (35.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid compound 41 is obtained - tert-butyl 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-3-(naphthalen-2-yl)-2-oxoindoline-1-carboxylate (46.2 mg) with a yield of 92%.

[0415] The structural formula of compound 41 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 10, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0416] Data characterization of chiral 3,3-disubstituted indolinone compound 41: [α] D 20 = +106.3 (c = 0.16, CHCl3)

[0417] 1H NMR(500MHz, CDCl3)δ8.02(dd,J=8.7,1.1Hz,1H),7.87–7.79(m,2H),7.70(m,2H),7.56(d,J=1.9Hz,1H),7.50–7.37(m,4H), 7.32–7.26(m,1H),7.25–7.14(m,3H),7.05–6.99(m,1H),6.45(dd,J=9.9,2.8Hz,1H),5.68(dd,J=9.9,2.7Hz,1H),4.50(t,J=

[0418] 10.8Hz,1H),4.12(d,J=12.1Hz,1H),1.73(s,1H),1.60(s,9H).

[0419] 13 C NMR (126MHz, CDCl3) δ177.2,149.4,140.6,138.0,135.7,133.0,132.7,132.5,129.7,128.9,128.7,128.2,128 .1,127.7,127.5,127.2,126.8,126.4,126.2,126.0,125.3,124.0,123.6,115.7,84.2,72.0,57.8,51.0,28.1.

[0420] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 33 H 29 NNaO4) + :526.1994, Molecular weight captured by high-resolution mass spectrometry: 526.1992

[0421] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=11.7min,t R (major) = 9.1min.

[0422] Embodiment 42

[0423] The difference between Example 42 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-(1H-pyrrol-1-yl)indoline-1-carboxylic acid tert-butyl ester b-11 (29.8 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 42 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(1H-pyrrol-1-yl)indoline-1-carboxylic acid tert-butyl ester (40.1 mg) with a yield of 91%.

[0424] The structural formula of compound 42 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 11, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0425] Characterization data of chiral 3,3-disubstituted indolone compound 42: [α] D 20 = +94.23 (c = 0.82, CHCl3)

[0426] 1 H NMR(400MHz, CDCl3)δ7.99(d,J=8.3Hz,1H),7.49–7.37(m,2H),7.28–7.22(m,1H) ),7.22–7.11(m,3H),7.04(dd,J=6.7,2.1Hz,1H),6.80(t,J=2.2Hz,2H),6.55(dd ,J=9.9,2.7Hz,1H),6.20(t,J=2.2Hz,2H),5.46(dd,J=9.8,2.6Hz,1H),4.35(t,J =11.0Hz,1H),3.93(dt,J=12.2,2.7Hz,1H),1.93(d,J=10.4Hz,1H),1.62(s,9H).

[0427] 13 C NMR (101MHz, CDCl3) δ173.3,149.0,141.1,137.2,132.3,130.6,130.5,128.2,127.8,127. 5,126.2,124.12,124.05,123.4,123.1,119.3,115.9,109.2,84.7,70.8,66.9,50.7,28.0.

[0428] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 27 H26 N2NaO4) + :465.1790, Molecular weight captured by high-resolution mass spectrometry: 465.1790

[0429] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=8.2min,t R (major) = 5.7min.

[0430] Embodiment 43

[0431] The difference between Example 43 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 2-oxo-3-(thiophen-2-yl)indoline-1-carboxylic acid tert-butyl ester b-12 (29.8 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 43 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(thiophen-2-yl)indoline-1-carboxylic acid tert-butyl ester (39.0 mg) with a yield of 85%.

[0432] The structural formula of compound 43 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 12, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0433] Data characterization of chiral 3,3-disubstituted indolinone compound 43: [α] D 20 = +130.10 (c = 0.10, CHCl3)

[0434] 1H NMR (500MHz, CDCl3) δ7.93 (d, J=8.2Hz, 1H), 7.41 (dd, J=7.5, 1.4Hz, 1H), 7.34 (td, J=7.9, 1.4Hz, 1H), 7.31–7. 26(m,1H),7.25(d,J=2.3Hz,1H),7.17(ddd,J=6.4,3.7,1.8Hz,2H),7.12(td,J=7.6,1.0Hz,1H),7.03(dd,J=6 .9,1.9Hz,1H),6.96(dd,J=5.1,3.6Hz,1H),6.92(dd,J=3.6,1.3Hz,1H),6.54(dd,J=9.9,2.8Hz,1H),5.84(dd ,J=9.8,2.8Hz,1H),4.40(t,J=11.1Hz,1H),3.81(dt,J=11.8,2.8Hz,1H),1.71(d,J=10.6Hz,1H),1.63(s,9H).

[0435] 13 C NMR (126MHz, CDCl3) δ176.3,149.3,142.3,140.2,137.6,132.4,129.8,129.2,128.1,127.7,127. 3,126.9,126.7,126.4,126.32,126.31,126.1,124.0,123.7,115.5,84.4,71.6,55.7,52.8,28.1.

[0436] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 27 H 25 NNaO4S) + :482.1402, Molecular weight captured by high-resolution mass spectrometry: 482.1402.

[0437] HPLC: 98% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=6.0min,t R (major) = 5.3min.

[0438] Embodiment 44

[0439] The difference between Example 44 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(benzofuran-6-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-13 (34.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid compound 44 is obtained - 3-(benzofuran-6-yl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (44.9 mg) with a yield of 91%.

[0440] The structural formula of compound 44 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 13, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0441] Data characterization of chiral 3,3-disubstituted indolone compound 44: [α] D 20 = +106.30 (c = 0.33, CHCl3)

[0442] 1 H NMR (600MHz, CDCl3) δ7.99(d,J=7.9Hz,1H),7.59(d,J=2.2Hz,1H),7.49(d,J=2.0Hz,1H),7.4 7–7.42(m,1H),7.42–7.34(m,3H),7.30–7.26(m,1H),7.21–7.13(m,3H),7.04–6.99(m,1H),6. 67(dd,J=2.2,1.0Hz,1H),6.46(dd,J=9.9,2.8Hz,1H),5.68(dd,J=9.9,2.7Hz,1H),4.46(dd, J=12.0,10.3Hz,1H),4.02(dt,J=12.0,2.8Hz,1H),1.78(dd,J=10.5,4.1Hz,1H),1.60(s,9H).

[0443] 13C NMR (151MHz, CDCl3) δ177.7,154.4,149.4,145.6 140.5,138.0,132.7,132.5,129.6,128.7,128.1,127.7,127.7,127.62,127.60,127.2,127.0 ,126.0,124.2,123.9,123.9,123.6,121.0,115.6,111.6,106.8,84.2,71.9,57.5,51.3,28.1.

[0444] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 31 H 27 NNaO5) + :516.1787, molecular weight captured by high-resolution mass spectrometry: 516.1783.

[0445] HPLC: 98% ee, Daicel chiral chromatographic column model: IC-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=9.5min,t R (major) = 15.0min.

[0446] Embodiment 45

[0447] The difference between Example 45 and Example 32 is that: in the step, 2-oxo-3-phenylindole-1-carboxylic acid tert-butyl ester b-1 is replaced with 3-(4-fluorobenzyl)-2-oxoindoline-1-carboxylic acid tert-butyl ester b-14 (34.1 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 45 is obtained - 3-(4-fluorobenzyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxoindoline-1-carboxylic acid tert-butyl ester (41.2 mg) with a yield of 85%.

[0448] The structural formula of compound 45 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 14, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0449] Data characterization of chiral 3,3-disubstituted indolone compound 45: [α] D 20= +153.33 (c = 0.46, CHCl3)

[0450] 1 H NMR (600MHz, CDCl3) δ7.45 (dd, J=8.3, 2.6Hz, 1H), 7.24–7.22 (m, 1H), 7.16 (t, J=7.6Hz, 1H),7.07(dd,J=11.4,7.9Hz,4H),6.91–6.86(m,1H),6.73(d,J=9.7Hz,1H),6.71–6.62 (m,4H),6.34–6.30(m,1H),4.34(t,J=8.2Hz,1H),3.47–3.43(m,1H),3.30(dd,J=12.8, 2.7Hz, 1H), 3.20 (dd, J=12.6, 2.6Hz, 1H), 1.85 (d, J=8.8Hz, 1H), 1.52 (d, J=2.8Hz, 9H).

[0451] 13 C NMR (151MHz, CDCl3) δ177.7, 162.6, 160.9, 148.4, 139.7, 137.0, 131.9, 131.3 (d, J = 7.9Hz), 130.2, 130.1 (d, J = 3.2Hz), 128. 3,128.1,128.0,127.5,126.2,125.4,124.6,124.5,123.6,114.6,114.3(d,J=21.3Hz),83.8,70.6,55.8,49.4,42.2,27.9.

[0452] 19 F NMR(376MHz,CDCl3)δ-116.23.HRMS(ESI)m / z(M+Na) + : Calculated molecular weight (C 39 H 28 FNNaO4) + :508.1900, molecular weight captured by high-resolution mass spectrometry: 508.1901.

[0453] HPLC: 99% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=13.5min,t R (major) = 10.3min.

[0454] Embodiment 46

[0455] The difference between Example 46 and Example 32 is that: in the step, tert-butyl 2-oxo-3-phenylindolone-1-carboxylate b-1 is replaced with tert-butyl 2-oxo-3-(p-tolylthio)indoline-1-carboxylate b-15 (35.5 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 46 is obtained - tert-butyl 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(p-tolylthio)indoline-1-carboxylate (45.3 mg) with a yield of 91%.

[0456] The structural formula of compound 46 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 15, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0457] Data characterization of chiral 3,3-disubstituted indolone compound 46: [α] D 20 = +130.10 (c = 0.10, CHCl3)

[0458] 1 H NMR(400MHz, CDCl3) δ7.60(d,J=8.2Hz,1H),7.46(dd,J=7.6,1.4Hz,1H),7.26–7.00(m,8H),6.95(d,J=8.0Hz,2H),6.81(dd,J=9.9,2.7Hz ,1H),6.73(dd,J=9.9,2.7Hz,1H),4.48(t,J=11.0Hz,1H),3.47(dt,J=11.8,2.7Hz,1H),2.26(s,3H),1.66(d,J=10.6Hz,1H),1.57(s,9H). 1

[0459] 3 C NMR (101MHz, CDCl3) δ174.6,148.7,140.1,139.5,137.8,137.0,132.4,129.7,129.3,129.0,128.1, 127.7,126.3,126.1,125.9,125.7,124.4,124.1,123.8,114.9,83.9,71.5,60.3,47.1,28.0,21.2.

[0460] HRMS (ESI) m / z (M+Na) +: Calculated molecular weight (C 30 H 29 NNaO4S) + :522.1715, molecular weight captured by high-resolution mass spectrometry: 522.1704

[0461] HPLC: 98% ee, Daicel chiral chromatographic column model: ID, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=21.6min,t R (major) = 15.1min.

[0462] Embodiment 47

[0463] The difference between Example 47 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-methyl-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-16 (32.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 47 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-5-methyl-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (41.6 mg) with a yield of 89%.

[0464] The structural formula of compound 47 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 16, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0465] Data characterization of chiral 3,3-disubstituted indolone compound 47: [α] D 20 = +53.42 (c = 0.71, CHCl3)

[0466] 1H NMR(600MHz, CDCl3) δ7.82(d,J=8.4Hz,1H),7.37–7.26(m,5H),7.26–7.22(m,1H),7.20–7.10(m,3H),7.08(d,J=1.9Hz,1H),7.02(dd,J=7.1,1.6Hz,1 H),6.49(dd,J=9.9,2.7Hz,1H),5.67(dd,J=9.9,2.9Hz,1H),4.47–4.43(m ,1H),3.97(dt,J=11.3,2.8Hz,1H),2.27(s,3H),1.71(s,1H),1.60(s,9H).

[0467] 13 C NMR (151MHz, CDCl3) δ177.3,149.4,138.1,138.1,137.8,133.4,132.5,129.6,129.2,128.7,128.1, 128.0,127.7,127.7,127.6,127.1,126.9,125.9,124.0,115.2,84.0,71.6,57.7,50.9,28.1,21.1.

[0468] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO4) + :490.1994, molecular weight captured by high-resolution mass spectrometry: 490.1989.

[0469] HPLC: 98% ee, Daicel chiral chromatographic column model: IJ-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=15.0min,t R (major) = 10.9min.

[0470] Embodiment 48

[0471] The difference between Example 48 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-17 (33.9 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those of Example 32, and finally a white solid compound 48 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-5-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (44.5 mg) with a yield of 92%.

[0472] The structural formula of compound 48 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 17, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0473] Data characterization of chiral 3,3-disubstituted indolone compound 17: [α] D 20 = +64.13 (c = 0.23, CHCl3)

[0474] 1 H NMR (600MHz, CDCl3) δ7.88(d,J=9.5Hz,1H),7.38–7.25(m,6H),7.21–7.14(m,2H),7.04–7.00(m,1H),6.86(d,J=8.1Hz,2H),6.49(d d,J=9.9,2.7Hz,1H),5.67(dd,J=9.9,2.8Hz,1H),4.48(t,J=10.8Hz,1H),4.01–3.96(m,1H),3.73(s,3H),1.63(s,1H),1.61(s,9H).

[0475] 13 C NMR (101MHz, CDCl3) δ177.3,156.2,138.0,137.8,134.0,132.4,129.8,128.8,128.5,128.1,128 .0,127.8,127.7,126.7,126.0,123.9,116.4,113.4,113.3,84.1,71.7,57.9,55.6,51.0,28.1.

[0476] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5) +:506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1939

[0477] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=9.6min,t R (major) = 6.3min.

[0478] Embodiment 49

[0479] The difference between Example 49 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-chloro-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-18 (34.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those of Example 32, and finally white solid Compound 49 is obtained - 5-chloro-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (36.0 mg) with a yield of 74%.

[0480] The structural formula of compound 49 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 18, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0481] Data characterization of chiral 3,3-disubstituted indolinone compound 18: [α] D 20 = +50.59 (c = 1.18, CHCl3)

[0482] 1 H NMR(600MHz, CDCl3)δ7.91(d,J=8.7Hz,1H),7.34–7.27(m,7H),7.24–7.12(m,3H),7.09–7.01(m,1H),6.50(dd,J=9.9,2.6 Hz,1H),5.60(dd,J=9.9,3.0Hz,1H),4.43(t,J=10.5Hz,1H),3.95(dt,J=11.1,2.9Hz,1H),2.03–1.98(m,1H),1.59(s,9H).

[0483] 13C NMR (151MHz, CDCl3) δ176.4,149.1,139.0,137.4,137.3,132.2,130.2,129.3,129.0,128.9,128 .7,128.2,128.0,127.9,127.7,127.0,126.1,126.0,124.0,116.7,84.6,71.5,57.6,50.9,28.0.

[0484] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 ClNNaO4) + :510.1448, molecular weight captured by high-resolution mass spectrometry: 510.1446.

[0485] HPLC: 99% ee, Daicel chiral chromatographic column model: IF-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=34.7min,t R (major) = 31.3min.

[0486] Embodiment 50

[0487] The difference between Example 50 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-fluoro-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-19 (32.7 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 50 is obtained - 5-fluoro-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (41.0 mg) with a yield of 90%.

[0488] The structural formula of compound 50 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 19, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0489] Data characterization of chiral 3,3-disubstituted indolone compound 50: [α] D 20 = +122.54 (c = 0.28, CHCl3)

[0490] 1 H NMR (400MHz, CDCl3) δ7.95 (dd, J=9.8, 4.7Hz, 1H), 7.37–7.12 (m, 8H), 7.03 (dtd, J=7.1, 3.9, 1.8Hz, 3H), 6.50 (dd, J=9.9, 2.7H z,1H),5.62(dd,J=9.9,2.9Hz,1H),4.44(t,J=10.7Hz,1H),3.97(dt,J=11.4,2.8Hz,1H),1.88(d,J=10.2Hz,1H),1.60(s,9H).

[0491] 13 C NMR (101MHz, CDCl3) δ176.7, 160.4, 158.0, 149.3, 137.52, 137.45, 136.5 (d, J = 2.4Hz), 132.3, 130.2, 129.0 (d, J = 8.1Hz), 128.9, 128.2, 128. 0,127.8,127.8,126.11,126.08,123.9,116.8(d,J=7.9Hz),115.3(d, J=22.7Hz),114.3(d,J=24.5Hz),84.4,71.6,57.79,57.77,51.0,28.1.

[0492] 19 F NMR (376MHz,CDCl3)δ-117.95.

[0493] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1739.

[0494] HPLC:>99%ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 35°C, detector wavelength: 254 nm, retention time: t R (minor)=11.4min,t R (major) = 9.1min.

[0495] Embodiment 51

[0496] The difference between Example 51 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 6-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-20 (33.9 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 51 is obtained - 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-6-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (41.0 mg) with a yield of 85%.

[0497] The structural formula of compound 51 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 20, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0498] Characterization data of chiral 3,3-disubstituted indolone compound 51: [α] D 20 = +94.34 (c = 0.53, CHCl3)

[0499] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=2.4Hz,1H),7.36–7.27(m,6H),7.22–7.14(m,3H),7.04–6.98(m,1H),6.68(dd,J=8.6,2.4Hz,1H),6.45(dd,J=10. 0,2.8Hz,1H),5.63(dd,J=9.9,2.7Hz,1H),4.45(t,J=11.2Hz,1H),3.94( dt,J=12.0,2.9Hz,1H),3.83(s,3H),1.78(d,J=10.8Hz,1H),1.61(s,9H).

[0500] 13 C NMR (101MHz, CDCl3) δ177.8,160.0,149.3,141.5,138.5,138.1,132.4,129.6,128.7,128.0,128.0, 127.7,127.6,127.6,126.9,125.9,123.6,118.7,109.9,102.0,84.2,71.9,57.2,55.5,51.2,28.1.

[0501] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 30 H 29 NNaO5)+ :506.1943, molecular weight captured by high-resolution mass spectrometry: 506.1937

[0502] HPLC: 99% ee, Daicel chiral chromatographic column model: IA-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=45.1min,t R (major) = 29.3min.

[0503] Embodiment 52

[0504] The difference between Example 52 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 6-bromo-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-21 (38.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those of Example 32, and finally a white solid compound 52 is obtained - 6-bromo-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (47.3 mg) with a yield of 89%.

[0505] The structural formula of compound 52 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 21, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0506] Data characterization of chiral 3,3-disubstituted indolone compound 52: [α] D 20 = +140.10 (c = 0.23, CHCl3)

[0507] 1 H NMR(400MHz, CDCl3)δ8.20(d,J=1.7Hz,1H),7.32–7.25(m,7H),7.23–7.13(m,3H),7.05–6.98(m,1H),6.47(dd,J=9.9, 2.7Hz,1H),5.61(dd,J=9.8,2.7Hz,1H),4.41(t,J=9.8Hz,1H),3.98–3.91(m,1H),1.85(d,J=10.2Hz,1H),1.61(s,9H).

[0508] 13C NMR (101MHz, CDCl3) δ176.6,149.1,141.5,137.7,137.4,132.8,130.0,128.9,128.21,128.19,128. 0,127.80,127.75,126.8,126.3,126.13,126.05,123.7,122.5,119.1,84.8,71.7,57.4,51.0,28.0.

[0509] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 BrNNaO4) + :554.0943, molecular weight captured by high-resolution mass spectrometry: 554.0942.

[0510] HPLC: 96% ee, Daicel chiral chromatographic column model: IC, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=8.4min,t R (major) = 7.0min.

[0511] Embodiment 53

[0512] The difference between Example 53 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 6-fluoro-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-22 (32.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those of Example 32, and finally a white solid compound 53 is obtained - 6-fluoro-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (44.7 mg) with a yield of 95%.

[0513] The structural formula of compound 53 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 22, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0514] Data characterization of chiral 3,3-disubstituted indolone compound 22: [α] D 20 = +118.81 (c = 0.21, CHCl3)

[0515] 1 H NMR (400MHz, CDCl3) δ7.75(dd,J=10.4,2.5Hz,1H),7.30(s,3H),7.29–7.21(m,4H),7.17(dt,J=5.9,2.4Hz,2H),7.03–6.99(m,1H),6.47(dd ,J=9.9,2.7Hz,1H),5.62(dd,J=9.8,2.8Hz,1H),4.41(t,J=10.8Hz,1H),3.95(dt,J=11.6,2.8Hz,1H),1.93(d,J=10.4Hz,1H),1.61(s,9H).

[0516] 13 C NMR (101MHz, CDCl3) δ177.0,163.9,161.5,149.1,141.6(d,J=12.4Hz),137.8,137.7,132.3,129.9,128.9,128.8,128.2,128.04,127.95, 127.9,127.8,127.72,127.68,126.4,126.0,123.8,122.5,122.5,110.5(d,J=22.5Hz),104.2(d,J=29.5Hz),84.7,71.7,57.3,51.0,28.0.

[0517] 19 F NMR (376MHz,CDCl3)δ-110.59.

[0518] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 FNNaO4) + :494.1744, molecular weight captured by high-resolution mass spectrometry: 494.1741.

[0519] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=10.5min,t R (major) = 7.0min.

[0520] Embodiment 54

[0521] The difference between Example 54 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 7-bromo-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-23 (38.7 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as those of Example 32, and finally white solid Compound 54 is obtained - 7-bromo-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (48.3 mg) with a yield of 91%.

[0522] The structural formula of compound 54 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 23, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0523] Data characterization of chiral 3,3-disubstituted indolone compound 54: [α] D 20 = +100.56 (c = 0.97, CHCl3)

[0524] 1 H NMR(600MHz, CDCl3) δ7.96(d,J=8.2Hz,1H),7.36–7.23(m,7H),7.19–7.08(m,3H),7.00(d,J=6.1Hz,1H),6.46(dd,J=9.9,2.7H z,1H),5.65(dd,J=9.9,2.7Hz,1H),4.43(t,J=11.1Hz,1H),3.96(dt,J=11.9,2.9Hz,1H),1.89(d,J=10.3Hz,1H),1.60(s,9H).

[0525] 13 C NMR (151MHz, CDCl3) δ177.2,149.3,140.5,138.1,137.9,132.4,129.6,128.69,128.65,128.0,12 7.9,127.7,127.6,127.2,127.1,126.8,125.9,123.8,123.7,115.5,84.1,71.7,57.6,51.0,28.0.

[0526] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 26 BrNNaO4) +:554.0943, Molecular weight captured by high-resolution mass spectrometry: 554.0943.

[0527] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=9.4min,t R (major) = 7.1min.

[0528] Embodiment 55

[0529] The difference between Example 55 and Example 32 is that: in the step, 2-oxo-3-phenylindolone-1-carboxylic acid tert-butyl ester b-1 is replaced with 5-(2-chloroethyl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester b-24 (37.1 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally white solid Compound 55 is obtained - 5-(2-chloroethyl)-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (43.7 mg) with a yield of 85%.

[0530] The structural formula of compound 55 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 24, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0531] Data characterization of chiral 3,3-disubstituted indolone compound 24: [α] D 20 = +27.00 (c = 0.15, CHCl3)

[0532] 1 H NMR(600MHz, CDCl3)δ7.89(d,J=8.4Hz,1H),7.37–7.27(m,5H),7.23–7.12(m ,5H),7.03(d,J=7.2Hz,1H),6.51(dd,J=9.8,2.6Hz,1H),5.68(ddd,J=9.8,3 .1,1.2Hz,1H),4.41(t,J=10.2Hz,1H),3.98(dt,J=10.8,2.9Hz,1H),3.62–3 .54(m,2H),2.96(dh,J=14.3,7.3Hz,2H),1.72(d,J=9.9Hz,1H),1.61(s,9H).

[0533] 13 C NMR (126MHz, CDCl3) δ177.1,149.3,139.2,137.8,137.6,133.7,132.4,129.7,129.1,128.8,128.1,127. 91,127.86,127.82,127.5,127.4,126.7,126.1,124.2,115.6,84.3,71.5,57.6,51.0,45.1,38.6,28.1.

[0534] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 31 H 30 ClNNaO4) + :538.1761, molecular weight captured by high-resolution mass spectrometry: 538.1753

[0535] HPLC: 98% ee, Daicel chiral chromatographic column model: IF-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=18.2min,t R (major) = 11.1min.

[0536] Embodiment 56

[0537] The difference between Example 56 and Example 32 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 1,4-dihydro-1,4-epoxyanthracene a-2 (38.8 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 56 is obtained - 3-(1-hydroxy-1,2-dihydroanthracene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (47.8 mg) with a yield of 95%.

[0538] The structural formula of compound 56 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 25, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0539] Data characterization of chiral 3,3-disubstituted indolone compound 56: [α] D 20 = +68.79 (c = 1.24, CHCl3)

[0540] 1 H NMR(500MHz, CDCl3)δ8.00(d,J=8.7Hz,1H),7.75–7.69(m,2H),7.67(s,1H ),7.44(s,1H),7.43–7.39(m,2H),7.37–7.28(m,7H),7.13(td,J=7.6,0.9H z,1H),6.63(dd,J=9.9,2.7Hz,1H),5.73(dd,J=9.9,2.6Hz,1H),4.56–4.48 (m,1H),4.02(dt,J=11.4,2.7Hz,1H),1.87(d,J=10.6Hz,1H),1.63(s,9H).

[0541] 13 C NMR (151MHz, CDCl3) δ177.3,149.5,140.7,138.2,136.6,133.2,133.0,131.0,129.9,128.81,128.78,128.0,127.91,127. 88,127.82,127.67,127.64,127.47,127.2,126.8,126.1,126.0,124.8,123.9,122.5,115.6,84.2,72.1,57.7,51.4,28.1.

[0542] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 33 H 29 NNaO4) + :526.1994, molecular weight captured by high-resolution mass spectrometry: 526.1989.

[0543] HPLC: 98% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 80 / 20, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=9.4min,t R (major) = 7.5min.

[0544] Embodiment 57

[0545] The difference between Example 57 and Example 32 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 6,7-dimethoxy-1,4-dihydro-1,4-epoxynaphthalene a-3 (40.8 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally the white solid compound 57 is obtained - 3-(1-hydroxy-6,7-dimethoxy-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (48.7 mg) with a yield of 95%.

[0546] The structural formula of compound 57 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 26, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0547] Characterization data of chiral 3,3-disubstituted indolone compound 57: [α] D 20 = +73.16 (c = 0.56, CHCl3)

[0548] 1 H NMR(600MHz, CDCl3)δ7.96(d,J=8.2Hz,1H),7.37–7.28(m,7H),7.14(td,J=7.5,0.8Hz,1H),6.86(s,1H),6.58(s,1H),6.39(dd,J=9.9,2.7Hz,1H) ,5.58(dd,J=9.8,2.8Hz,1H),4.39(t,J=11.3Hz,1H),3.95(dt,J=12.0,2 .8Hz,1H),3.85(s,3H),3.80(s,3H),1.69(d,J=10.8Hz,1H),1.61(s,9H).

[0549] 13 C NMR (151MHz, CDCl3) δ177.4,149.4,148.8,148.2,140.5,138.1,130.8,129.2,128.8,128.7,128.0,127.8,127 .3,127.2,125.2,124.8,123.9,115.5,109.8,107.89,107.86,84.2,71.8,57.8,56.1,56.0,51.4,28.2,28.1.

[0550] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 31 H31 NNaO6) + :536.2049, molecular weight captured by high-resolution mass spectrometry: 536.2046.

[0551] HPLC: 98% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=10.5min,t R (major) = 11.2min.

[0552] Embodiment 58

[0553] The difference between Example 58 and Example 32 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 6,7-difluoro-1,4-dihydro-1,4-epoxynaphthalene a-4 (36.0 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 58 is obtained - 3-(6,7-difluoro-1-hydroxy-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (43.5 mg) with a yield of 89%.

[0554] The structural formula of compound 58 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 27, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0555] Data characterization of chiral 3,3-disubstituted indolone compound 27: [α] D 20 = +106.72 (c = 0.39, CHCl3)

[0556] 1 H NMR(400MHz, CDCl3)δ7.96(d,J=8.2Hz,1H),7.38(td,J=7.9,1.4Hz,2H),7.33–7.27(m,6H),7.21–7.07(m,2H),6.83(dd,J=10.4,7.6Hz,1H),6.3 7(dd,J=9.9,2.8Hz,1H),5.70(dd,J=9.9,2.7Hz,1H),4.37(t,J=11.3Hz,1H),3.96(dt,J=12.1,2.9Hz,1H),2.00(d,J=10.4Hz,1H),1.61(s,9H).

[0557] 13 C NMR (101MHz, CDCl3) δ177.2,149.3,140.5,137.8,128.93,128.85,128.0,127.93,127.90,127.82,127. 79,127.0,126.9,124.0,115.7,114.7(d,J=18.0Hz),113.8(d,J=19.5Hz),84.5,71.1,57.5,50.6,28.1.

[0558] 19 F NMR (376MHz, CDCl3) δ-137.89 (d, J = 20.9Hz), -140.48 (d, J = 20.8Hz).

[0559] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 25 F2NNaO4) + :512.1649, Molecular weight captured by high-resolution mass spectrometry: 512.1649.

[0560] HPLC: 98% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=5.8min,t R (major) = 5.2min.

[0561] Embodiment 59

[0562] The difference between Example 59 and Example 32 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 6,7-dibromo-1,4-dihydro-1,4-epoxynaphthalene a-5 (60.0 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally the white solid compound 59 is obtained - 3-(6,7-dibromo-1-hydroxy-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (52.4 mg) with a yield of 86%.

[0563] The structural formula of compound 59 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 28, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0564] Data characterization of chiral 3,3-disubstituted indolone compound 28: [α] D 20 = +365.72 (c = 0.18, CHCl3)

[0565] 1 H NMR (600MHz, CDCl3) δ7.97(d,J=8.3Hz,1H),7.49(s,1H),7.37(t,J=8.0Hz,1H),7.28(s,4H),7.27–7.21(m,3H),7.15(t,J=7.6Hz,1H),6 .36(dd,J=9.8,2.6Hz,1H),5.74(dt,J=10.0,2.1Hz,1H),4.34(d,J=12.0Hz,1H),3.93(dd,J=12.0,2.6Hz,1H),1.65(s,1H),1.61(s,9H).

[0566] 13 C NMR (151MHz, CDCl3) δ177.0,149.3,140.6,138.8,137.6,133.2,130.4,129.5,129.1,128.9,128.8 ,128.0,127.82,127.75,126.89,126.85,124.0,123.6,123.5,115.7,84.4,70.8,57.5,50.5,28.1.

[0567] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 29 H 25 Br2NNaO4) + :632.0048, Molecular weight captured by high-resolution mass spectrometry: 632.0043

[0568] HPLC: 97% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 92 / 8, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=9.3min,t R (major) = 8.0min.

[0569] Embodiment 60

[0570] The difference between Example 60 and Example 32 is that: in the step, 1,4-dihydro-1,4-epoxynaphthalene a-1 is replaced with 5,6,7,8-tetramethyl-1,4-dihydro-1,4-epoxynaphthalene a-6 (40.0 mg, 0.2 mmol, 2.0 eq), and the other preparation steps and conditions are the same as Example 32, and finally a white solid compound 60 is obtained - 3-(1-hydroxy-5,6,7,8-tetramethyl-1,2-dihydronaphthalene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (39.1 mg) with a yield of 77%.

[0571] The structural formula of compound 60 is: The absolute configuration is: (R, S, S), which is a diastereomer with inverted configuration of the quaternary carbon center compared with Example 29, that is, the "stereodivergent synthesis" of diastereomers is achieved.

[0572] Data characterization of chiral 3,3-disubstituted indolone compound 29: [α] D 20 = +75.40 (c = 0.27, CHCl3)

[0573] 1 H NMR (500MHz, CDCl3) δ7.69 (d, J=8.1Hz, 1H), 7.49 (dd, J=7.1, 1.6Hz, 2H), 7.36 –7.27(m,3H),6.97–6.90(m,3H),6.46(td,J=7.6,1.1Hz,1H),5.76(ddd,J=10 .1,5.6,1.7Hz,1H),4.76(dt,J=6.3,1.5Hz,1H),3.99(dd,J=5.6,1.3Hz,1H), 2.19(s,3H),2.12(s,3H),2.00(s,3H),1.92(s,3H),1.62(s,9H),1.59(s,1H).

[0574] 13 C NMR (126MHz, CDCl3) δ175.6,149.1,138.9,136.9,135.2,134.7,131.1,130.5,129.4,128.6,128.2,127. 8,127.6,127.0,126.8,126.1,122.7,122.4,114.0,84.4,65.5,57.6,50.1,28.0,16.6,16.6,15.0,14.1.

[0575] HRMS (ESI) m / z (M+Na) + : Calculated molecular weight (C 33 H 35 NNaO4) + :532.2464, molecular weight captured by high-resolution mass spectrometry: 532.2456.

[0576] HPLC:>99%ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 94 / 6, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=16.5min,t R (major) = 9.0min.

[0577] Embodiment 61

[0578] Compound 1 tert-butyl 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindolin-1-carboxylate (45.3 mg, 0.1 mmol, 1.0 equiv) and zinc chloride (13.6 mg, 0.1 mmol, 1.0 equiv) were added to a 10 ml test tube equipped with a magnetic stirrer. Chloroform (1.0 ml) was then added as a solvent, and the mixture was stirred at 40°C for 24 hours. After the reaction was completed, the reaction mixture was quenched with water (2 ml) and extracted twice with ethyl acetate (10 ml). The combined organic phase was dried over anhydrous sodium sulfate, and the volatiles were removed to obtain a crude product. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain the desired compound 61 - (R)-3-(naphthalen-2-yl)-3-phenylindolin-2-one (33.5 mg, yield 93%, ee>99%).

[0579] The reaction formula of Example 61 is:

[0580]

[0581] The structural formula of compound 61 is: The absolute configuration is: (R)

[0582] Data characterization of chiral 3,3-diaryl substituted indolinone compound 61: [α] D 20 = +8.04 (c = 0.26, CHCl3)

[0583] 1H NMR(400MHz, CDCl3)δ8.79(s,1H),7.82–7.75(m,2H),7.75–7.67(m,2H),7.53–7.40 (m,3H),7.33–7.19(m,7H),7.06(td,J=7.6,1.0Hz,1H),6.98(dd,J=7.8,1.0Hz,1H).

[0584] 13 C NMR (101MHz, CDCl3) δ179.8,141.5,140.2,138.8,133.4,133.0,132.5,128.6,128.5, 128.3,128.2,127.48,127.45,127.0,126.7,126.4,126.2,126.1,122.9,110.4,63.1.

[0585] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 24 H 18 NO) + :336.1388, Molecular weight captured by high-resolution mass spectrometry: 336.1385

[0586] HPLC:>99%ee, Daicel chiral chromatographic column model: AS-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=17.1min,t R (major) = 21.3min.

[0587] Embodiment 62

[0588] The difference between Example 62 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 17 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-5-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (48.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 61, and finally Compound 62 is obtained as a white solid - (R)-5-methoxy-3-(naphthalen-2-yl)-3-phenylindolin-2-one (36.5 mg) with a yield of 99%.

[0589] The structural formula of compound 62 is: The absolute configuration is: (R).

[0590] Data characterization of chiral 3,3-diaryl substituted indolinone compound 62: [α] D 20 = +15.60 (c = 0.10, CHCl3)

[0591] 1 H NMR (600MHz, CDCl3) δ9.51 (s, 1H), 7.76–7.63 (m, 4H), 7.39–7.24 (m, 8H), 6.84 (d, J = 8.8Hz, 2H), 6.74–6.69 (m, 1H), 3.71 (s, 3H).

[0592] 13 C NMR (151MHz, CDCl3) δ181.6,156.4,140.7,138.1,134.8,133.0,132.9,132.5,128.6,12 8.4,128.2,127.6,127.4,127.0,126.4,126.3,126.2,113.3,112.9,111.7,64.2,55.7.

[0593] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 25 H 20 NO2) + :366.1494, Molecular weight captured by high-resolution mass spectrometry: 366.1491

[0594] HPLC: 98% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=9.4min,t R (major) = 11.3min.

[0595] Embodiment 63

[0596] The difference between Example 63 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 19 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-5-fluoro-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (48.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 61, and finally Compound 63, (R)-5-fluoro-3-(naphthalen-2-yl)-3-phenylindolin-2-one (35.0 mg) is obtained as a white solid with a yield of 99%.

[0597] The structural formula of compound 63 is: The absolute configuration is: (R).

[0598] Data characterization of chiral 3,3-diaryl substituted indolinone compound 63: [α] D 20 = +4.81 (c = 0.26, CHCl3)

[0599] 1 H NMR(400MHz, CDCl3)δ9.26(s,1H),7.82–7.76(m,2H),7.75–7.67(m,2H),7.49– 7.39(m,3H),7.35–7.27(m,5H),7.00(dd,J=8.1,2.3Hz,1H),6.94–6.85(m,2H).

[0600] 13 C NMR (101MHz, CDCl3) δ180.1, 159.2 (d, J = 241.1Hz), 141.0, 138.2, 136.2 (d, J = 2.3Hz), 135.0 (d, J = 7.9Hz), 132.8 (d, J = 42.1Hz), 128.7, 128.5, 128.4, 128.2, 127.7, 127.5, 127.0, 126.42, 126.38, 126.3, 114.9 (d, J = 23.5Hz), 114.0 (d, J = 24.9Hz), 111.2 (d, J = 8.2Hz), 63.6 (d, J = 1.7Hz).

[0601] 19 F NMR (376MHz,CDCl3)δ-119.60.

[0602] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 24 H 17 FNO)+ :354.1294, molecular weight captured by high-resolution mass spectrometry: 354.1288

[0603] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=10.2min,t R (major) = 12.3min.

[0604] Embodiment 64

[0605] The difference between Example 64 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 25 3-(1-hydroxy-1,2-dihydroanthracene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (50.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 61, and finally Compound 64, (R)-3-(anthracen-2-yl)-3-phenylindolin-2-one (37.7 mg) is obtained as a white solid with a yield of 98%.

[0606] The structural formula of compound 64 is: The absolute configuration is: (R).

[0607] Data characterization of chiral 3,3-diaryl substituted indolinone compound 63: [α] D 20 = +12.60 (c = 0.17, CHCl3)

[0608] 1 H NMR(600MHz, CDCl3)δ8.87(s,1H),8.31(dd,J=38.4,4.0Hz,2H),7.98–7.88(m,3H),7.82 (d,J=3.8Hz,1H),7.49–7.16(m,10H),7.09(t,J=6.3Hz,1H),7.00(dd,J=7.7,4.1Hz,1H).

[0609] 13C NMR (151MHz, CDCl3) δ179.7,141.2,140.3,138.0,133.2,131.90,131.86,131.1,130.7,128.7,12 8.6,128.5,128.4,128.1,127.5,126.9,126.7,126.4,125.9,125.43,125.40,122.9,110.5,63.2.

[0610] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 28 H 20 NO) + :386.1545, molecular weight captured by high-resolution mass spectrometry: 386.1550.

[0611] HPLC:>99%ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=12.2min,t R (major) = 15.7min.

[0612] Embodiment 65

[0613] The difference between Example 65 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 11 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(1H-pyrrol-1-yl)indoline-1-carboxylic acid tert-butyl ester (44.2 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 61, and finally Compound 65 - (R)-3-(phenyl)-3-(N-pyrrolyl)indolin-2-one (32.0 mg) is obtained as a white solid with a yield of 99%.

[0614] The structural formula of compound 65 is: The absolute configuration is: (R).

[0615] Characterization data of chiral 3,3-diaryl substituted indolone compound 65: [α] D 20 = +6.02 (c = 0.30, CHCl3)

[0616] 1H NMR (500MHz, CDCl3) δ8.62(s,1H),7.86–7.79(m,2H),7.76(dd,J=7.7,1.7Hz,1H),7.68(d,J=2.0Hz,1H),7.54–7.44(m,3H),7.36(dd,J=7.7,1 .3Hz,1H),7.30(td,J=7.8,1.2Hz,1H),7.09(td,J=7.6,1.1Hz,1H),6.99(dt,J=7.8,0.8Hz,1H),6.81(t,J=2.2Hz,2H),6.25(t,J=2.3Hz,2H).

[0617] 13 C NMR (126MHz, CDCl3) δ176.1,140.1,135.8,133.1,132.9,130.0,129.9,128.9 ,128.4,127.6,126.8,126.5,126.2,124.5,123.3,120.7,110.9,109.1,70.4.

[0618] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 22 H 17 N2O) + :325.1341, molecular weight captured by high-resolution mass spectrometry: 325.1349.

[0619] HPLC: 99% ee, Daicel chiral chromatographic column model: IA-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=12.6min,t R (major) = 11.7min.

[0620] Embodiment 66

[0621] The difference between Example 66 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 32 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (44.2 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 61, and finally Compound 66 - (S)-3-(phenyl)-3-(N-pyrrolyl)indolin-2-one (33.0 mg) is obtained as a white solid with a yield of 99%.

[0622] The structural formula of compound 66 is: The absolute configuration is: (S).

[0623] Characterization data of chiral 3,3-diaryl substituted indolone compound 65: [α] D 20 =-6.97 (c = 0.66, CHCl3)

[0624] 1 H NMR(400MHz, CDCl3)δ8.79(s,1H),7.82–7.75(m,2H),7.75–7.67(m,2H),7.53–7.40 (m,3H),7.33–7.19(m,7H),7.06(td,J=7.6,1.0Hz,1H),6.98(dd,J=7.8,1.0Hz,1H).

[0625] 13 C NMR (101MHz, CDCl3) δ179.8,141.5,140.2,138.8,133.4,133.0,132.5,128.6,128.5, 128.3,128.2,127.48,127.45,127.0,126.7,126.4,126.2,126.1,122.9,110.4,63.1.

[0626] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 24 H 18 NO) + :336.1388, Molecular weight captured by high-resolution mass spectrometry: 336.1385

[0627] HPLC: 97% ee, Daicel chiral chromatographic column model: AS-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=22.0min,t R (major) = 17.1min.

[0628] Embodiment 67

[0629] The difference between Example 67 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 48 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-5-methoxy-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (48.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 61, and finally Compound 67, (S)-5-methoxy-3-(naphthalen-2-yl)-3-phenylindolin-2-one (36.5 mg) is obtained as a white solid with a yield of 99%.

[0630] The structural formula of compound 67 is: The absolute configuration is: (S).

[0631] Data characterization of chiral 3,3-diaryl substituted indolone compound 67: [α] D 20 =-22.10 (c = 0.22, CHCl3)

[0632] 1 H NMR (600MHz, CDCl3) δ9.51 (s, 1H), 7.76–7.63 (m, 4H), 7.39–7.24 (m, 8H), 6.84 (d, J = 8.8Hz, 2H), 6.74–6.69 (m, 1H), 3.71 (s, 3H).

[0633] 13 C NMR (151MHz, CDCl3) δ181.6,156.4,140.7,138.1,134.8,133.0,132.9,132.5,128.6,12 8.4,128.2,127.6,127.4,127.0,126.4,126.3,126.2,113.3,112.9,111.7,64.2,55.7.

[0634] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 25 H20 NO2) + :366.1494, Molecular weight captured by high-resolution mass spectrometry: 366.1491

[0635] HPLC: 99% ee, Daicel chiral chromatographic column model: IB-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: t R (minor)=11.5min,t R (major) = 9.5min.

[0636] Embodiment 68

[0637] The difference between Example 68 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 50 5-fluoro-3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (48.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 61, and finally Compound 68 - (S)-5-fluoro-3-(naphthalen-2-yl)-3-phenylindolin-2-one (35.0 mg) is obtained as a white solid with a yield of 99%.

[0638] The structural formula of compound 68 is: The absolute configuration is: (S).

[0639] Data characterization of chiral 3,3-diaryl substituted indolone compound 68: [α] D 20 =-12.07 (c = 0.60, CHCl3)

[0640] 1 H NMR(400MHz, CDCl3)δ9.26(s,1H),7.82–7.76(m,2H),7.75–7.67(m,2H),7.49– 7.39(m,3H),7.35–7.27(m,5H),7.00(dd,J=8.1,2.3Hz,1H),6.94–6.85(m,2H).

[0641] 13C NMR (101MHz, CDCl3) δ180.1, 159.2 (d, J = 241.1Hz), 141.0, 138.2, 136.2 (d, J = 2.3Hz), 135.0 (d, J = 7.9Hz), 132.8 (d, J = 42.1Hz), 128.7, 128.5, 128.4, 128.2, 127.7, 127.5, 127.0, 126.42, 126.38, 126.3, 114.9 (d, J = 23.5Hz), 114.0 (d, J = 24.9Hz), 111.2 (d, J = 8.2Hz), 63.6 (d, J = 1.7Hz).

[0642] 19 F NMR (376MHz,CDCl3)δ-119.60.

[0643] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 24 H 17 FNO) + :354.1294, molecular weight captured by high-resolution mass spectrometry: 354.1288

[0644] HPLC: 99% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25°C, detector wavelength: 254 nm, retention time: tR (minor) = 12.4 min, tR (major) = 10.1 min.

[0645] Embodiment 69

[0646] The difference between Example 69 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 56 3-(1-hydroxy-1,2-dihydroanthracene-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester (50.3 mg, 0.1 mmol, 1.0 eq), and the other preparation steps and conditions are the same as Example 61, and finally a white solid compound 69 is obtained, namely (S)-3-(anthracen-2-yl)-3-phenylindolin-2-one 69 (37.7 mg), with a yield of 98%.

[0647] The structural formula of compound 69 is: The absolute configuration is: (S).

[0648] Characterization data of chiral 3,3-diaryl substituted indolone compound 69: [α] D 20 =-20.00 (c = 0.63, CHCl3)

[0649] 1 H NMR(600MHz, CDCl3)δ8.87(s,1H),8.31(dd,J=38.4,4.0Hz,2H),7.98–7.88(m,3H),7.82 (d,J=3.8Hz,1H),7.49–7.16(m,10H),7.09(t,J=6.3Hz,1H),7.00(dd,J=7.7,4.1Hz,1H).

[0650] 13 C NMR (151MHz, CDCl3) δ179.7,141.2,140.3,138.0,133.2,131.90,131.86,131.1,130.7,128.7,12 8.6,128.5,128.4,128.1,127.5,126.9,126.7,126.4,125.9,125.43,125.40,122.9,110.5,63.2.

[0651] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 28 H 20 NO) + :386.1545, molecular weight captured by high-resolution mass spectrometry: 386.1550.

[0652] HPLC: 97% ee, Daicel chiral chromatographic column model: OD-H, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 85 / 15, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=16.1min,t R (major) = 12.0min.

[0653] Embodiment 70

[0654] The difference between Example 70 and Example 61 is that in the step, Compound 1 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-phenylindoline-1-carboxylic acid tert-butyl ester is replaced with Compound 42 3-(1-hydroxy-1,2-dihydronaphthalen-2-yl)-2-oxo-3-(1H-pyrrol-1-yl)indoline-1-carboxylic acid tert-butyl ester (44.2 mg, 0.1 mmol, 1.0 equiv), and the other preparation steps and conditions are the same as Example 61, and finally Compound 70 - (S)-3-(phenyl)-3-(N-pyrrolyl)indolin-2-one (32.0 mg) is obtained as a white solid with a yield of 99%.

[0655] The structural formula of compound 70 is: The absolute configuration is: (S).

[0656] Characterization data of chiral 3,3-diaryl substituted indolone compound 70: [α] D 20 =-5.09 (c = 0.12, CHCl3)

[0657] 1 H NMR (500MHz, CDCl3) δ8.62(s,1H),7.86–7.79(m,2H),7.76(dd,J=7.7,1.7Hz,1H),7.68(d,J=2.0Hz,1H),7.54–7.44(m,3H),7.36(dd,J=7.7,1 .3Hz,1H),7.30(td,J=7.8,1.2Hz,1H),7.09(td,J=7.6,1.1Hz,1H),6.99(dt,J=7.8,0.8Hz,1H),6.81(t,J=2.2Hz,2H),6.25(t,J=2.3Hz,2H).

[0658] 13 C NMR (126MHz, CDCl3) δ176.1,140.1,135.8,133.1,132.9,130.0,129.9,128.9 ,128.4,127.6,126.8,126.5,126.2,124.5,123.3,120.7,110.9,109.1,70.4.

[0659] HRMS (ESI) m / z (M+H) + : Calculated molecular weight (C 22 H 17 N2O) + :325.1341, molecular weight captured by high-resolution mass spectrometry: 325.1349.

[0660] HPLC: 97% ee, Daicel chiral chromatographic column model: IA-3, mobile phase polarity: n-hexane (volume) / isopropanol (volume) = 90 / 10, mobile phase flow rate: 1.0 mL / min, column oven temperature: T = 25 °C, detector wavelength: 254 nm, retention time: t R (minor)=11.6min,t R (major) = 12.3min.

[0661] Embodiment 71

[0662] The preparation method of chiral 3,3-disubstituted indole ketone compounds comprises the following steps:

[0663] Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I);

[0664] Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

[0665] The 3-substituted indole one compound represented by formula (IV) is compound b-1;

[0666] The benzoxanorbornene compound represented by formula (III) is compound a-1;

[0667] In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indole ketone compound represented by formula (IV) is 1.95:1;

[0668] The reaction temperature was 40°C and the reaction time was 30 minutes;

[0669] The rhodium catalyst is 1,5-cyclooctadiene acetylacetonate rhodium, and the molar ratio of 1,5-cyclooctadiene acetylacetonate rhodium to the 3-substituted indolone compound represented by formula (IV) is 0.045:1;

[0670] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine, (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.045:1;

[0671] Zinc chloride is used as a co-catalyst, and the molar ratio of zinc chloride to the 3-substituted indole ketone compound represented by formula (IV) is 0.2:1;

[0672] The reaction solvent is toluene.

[0673] In step (2), chloroform is used as the solvent, the reaction temperature is 40° C., and the reaction time is 10 hours;

[0674] Zinc chloride is used as a dehydrating agent and a deprotecting agent at the same time; the molar ratio of zinc chloride to the chiral 3,3-disubstituted indole ketone compound shown in formula (I) is 1.0:1.

[0675] Embodiment 72

[0676] The preparation method of chiral 3,3-disubstituted indole ketone compounds comprises the following steps:

[0677] Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I);

[0678] Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

[0679] The 3-substituted indole one compound represented by formula (IV) is compound b-1;

[0680] The benzoxanorbornene compound represented by formula (III) is compound a-1;

[0681] In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indolone compound represented by formula (IV) is 2.05:1;

[0682] The reaction temperature was 60°C and the reaction time was 2 hours;

[0683] The rhodium catalyst is 1,5-cyclooctadiene acetylacetonate rhodium, and the molar ratio of 1,5-cyclooctadiene acetylacetonate rhodium to the 3-substituted indolone compound represented by formula (IV) is 0.060:1;

[0684] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine, (R)-(-)-1-(SP The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.060:1;

[0685] Zinc chloride is used as a co-catalyst, and the molar ratio of zinc chloride to the 3-substituted indole ketone compound represented by formula (IV) is 2.0:1;

[0686] The reaction solvent is toluene.

[0687] In step (2), chloroform is used as the solvent, the reaction temperature is 60° C., and the reaction time is 20 hours;

[0688] Zinc chloride is used as a dehydrating agent and a deprotecting agent at the same time; the molar ratio of zinc chloride to the chiral 3,3-disubstituted indole ketone compound shown in formula (I) is 2.0:1.

[0689] Embodiment 73

[0690] The preparation method of chiral 3,3-disubstituted indole ketone compounds comprises the following steps:

[0691] Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I);

[0692] Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

[0693] The 3-substituted indole one compound represented by formula (IV) is compound b-1;

[0694] The benzoxanorbornene compound represented by formula (III) is compound a-1;

[0695] In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indole ketone compound represented by formula (IV) is 2:1;

[0696] The reaction temperature was 50°C and the reaction time was 1 hour;

[0697] The rhodium catalyst is 1,5-cyclooctadiene acetylacetonate rhodium, and the molar ratio of 1,5-cyclooctadiene acetylacetonate rhodium to the 3-substituted indole ketone compound represented by formula (IV) is 0.05:1;

[0698] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine, (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.05:1;

[0699] Zinc chloride is used as a co-catalyst, and the molar ratio of zinc chloride to the 3-substituted indole ketone compound represented by formula (IV) is 1:1;

[0700] The reaction solvent is toluene.

[0701] In step (2), chloroform is used as the solvent, the reaction temperature is 50° C., and the reaction time is 15 hours;

[0702] Zinc chloride is used as a dehydrating agent and a deprotecting agent at the same time; the molar ratio of zinc chloride to the chiral 3,3-disubstituted indole ketone compound shown in formula (I) is 1.5:1.

[0703] Embodiment 74

[0704] The preparation method of chiral 3,3-disubstituted indole ketone compounds comprises the following steps:

[0705] Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I);

[0706] Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

[0707] The 3-substituted indole one compound represented by formula (IV) is compound b-17;

[0708] The benzoxanorbornene compound represented by formula (III) is compound a-1;

[0709] In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indole ketone compound represented by formula (IV) is 1.95:1;

[0710] The reaction temperature was 40°C and the reaction time was 30 minutes;

[0711] The rhodium catalyst is di(1,5-cyclooctadiene) rhodium tetrafluoroborate, and the molar ratio of di(1,5-cyclooctadiene) rhodium tetrafluoroborate to the 3-substituted indole ketone compound represented by formula (IV) is 0.045:1;

[0712] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine; (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.045:1;

[0713] Dysprosium chloride is used as a co-catalyst, and the molar ratio of dysprosium chloride to the 3-substituted indolone compound represented by formula (IV) is 0.2:1;

[0714] The reaction solvent was 1,2-dichloroethane.

[0715] In step (2), chloroform is used as the solvent, the reaction temperature is 40° C., and the reaction time is 10 hours;

[0716] Zinc chloride is used as a dehydrating agent and a deprotecting agent at the same time; the molar ratio of zinc chloride to the chiral 3,3-disubstituted indole ketone compound shown in formula (I) is 1.0:1.

[0717] Embodiment 75

[0718] The preparation method of chiral 3,3-disubstituted indole ketone compounds comprises the following steps:

[0719] Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I);

[0720] Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

[0721] The 3-substituted indole one compound represented by formula (IV) is compound b-17;

[0722] The benzoxanorbornene compound represented by formula (III) is compound a-1;

[0723] In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indolone compound represented by formula (IV) is 2.05:1;

[0724] The reaction temperature was 60°C and the reaction time was 2 hours;

[0725] The rhodium catalyst is di(1,5-cyclooctadiene) rhodium tetrafluoroborate, and the molar ratio of di(1,5-cyclooctadiene) rhodium tetrafluoroborate to the 3-substituted indolone compound represented by formula (IV) is 0.060:1;

[0726] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine; (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.060:1;

[0727] Dysprosium chloride is used as a co-catalyst, and the molar ratio of dysprosium chloride to the 3-substituted indolone compound represented by formula (IV) is 2.0:1;

[0728] The reaction solvent was 1,2-dichloroethane.

[0729] In step (2), chloroform is used as the solvent, the reaction temperature is 60° C., and the reaction time is 20 hours;

[0730] Zinc chloride is used as a dehydrating agent and a deprotecting agent at the same time; the molar ratio of zinc chloride to the chiral 3,3-disubstituted indole ketone compound shown in formula (I) is 2.0:1.

[0731] Embodiment 76

[0732] The preparation method of chiral 3,3-disubstituted indole ketone compounds comprises the following steps:

[0733] Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I);

[0734] Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

[0735] The 3-substituted indole one compound represented by formula (IV) is compound b-17;

[0736] The benzoxanorbornene compound represented by formula (III) is compound a-1;

[0737] In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indole ketone compound represented by formula (IV) is 2:1;

[0738] The reaction temperature is 40-60°C and the reaction time is 1 hour;

[0739] The rhodium catalyst is di(1,5-cyclooctadiene) rhodium tetrafluoroborate, and the molar ratio of di(1,5-cyclooctadiene) rhodium tetrafluoroborate to the 3-substituted indole ketone compound represented by formula (IV) is 0.05:1;

[0740] The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine; (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.05:1;

[0741] Dysprosium chloride is used as a co-catalyst, and the molar ratio of dysprosium chloride to the 3-substituted indolone compound represented by formula (IV) is 1:1;

[0742] The reaction solvent was 1,2-dichloroethane.

[0743] In step (2), chloroform is used as the solvent, the reaction temperature is 50° C., and the reaction time is 10 to 20 hours;

[0744] Zinc chloride is used as a dehydrating agent and a deprotecting agent at the same time; the molar ratio of zinc chloride to the chiral 3,3-disubstituted indole ketone compound shown in formula (I) is 1.5:1.

[0745] Performance Testing

[0746] The compounds of Examples 1 to 70 and commercially available drugs 5-fluorouracil (5-Fu, 5-Fluorouracil), irinotecan, vorinostar, and oxaliplatin were used as positive controls to experiment on the anticancer activity of the human colorectal cancer cell line HCT116.

[0747] The human colorectal cancer cell line HCT116 (derived from the cell bank of Shanghai Institute of Cell Biology (SIBS) of the Chinese Academy of Sciences) was selected as the test cell line and cultured in a 37°C incubator containing 5% CO2 using McCoy's 5AMedium (Gibco) medium supplemented with 10% (v / v) fetal bovine serum (FBS, Yisheng Biotechnology (Shanghai) Co., Ltd.) and 1% (v / v) penicillin / streptomycin (Meilun Biotechnology).

[0748] Compounds 1-70, 5-fluorouracil (5-Fu, 5-Fluorouracil), irinotecan, vorinostar, and oxaliplatin were screened for their anticancer activity against colorectal cancer cells (HCT116) using the MTT method.

[0749] Cell viability assay: Cancer cells in the logarithmic growth phase were inoculated into 96-well plates. Overnight, McCoy's 5AMedium (Gibco) medium supplemented with 10% (v / v) fetal bovine serum (FBS, Yisheng Biotechnology (Shanghai) Co., Ltd.) and 1% (v / v) penicillin / streptomycin (Meilun Biotechnology) was used to prepare compounds without compounds (blank control group) and other compounds with different concentrations (30μM, 3μM, 0.3μM) (70 compounds in total from 1 to 70, three concentration gradients for each compound), mixed and added 100μL to each well, and treated in an incubator containing 5% CO2 at 37°C for 24h. After 24h, the state of the cells after administration was observed under a microscope. Use basal culture medium (McCoy's 5AMedium (Gibco) culture medium without fetal bovine serum, penicillin and streptomycin) to prepare 10% (v / v) concentration of CCK-8 reagent (Meilun Biotechnology), discard the original solution in each well, add 100 μL of the above-prepared CCK-8 reagent under light-proof conditions, put it in a cell culture incubator containing 5% CO2 at 37°C for 2 hours, and then use an enzyme reader to detect the absorbance value (OD) of each well at 450nm, and calculate the cell survival rate. Use Graphpad Prism to calculate IC 50 Each experiment was repeated three times.

[0750] IC 50 Value: The concentration of compound required to kill half of the colorectal cancer cells

[0751] IC values ​​of some compounds against colorectal cancer cell lines 50 The values ​​are compared with those in Table 1. The test results show that some compounds have high inhibitory activity against colorectal cancer cells HCT116.

[0752] Table 1 Experimental results of the effects of the compounds of Examples 1 to 70 and commercially available drugs 5-fluorouracil (5-Fu, 5-Fluorouracil), irinotecan, vorinostar, and oxaliplatin on the anticancer activity of colorectal cancer cells (HCT116)

[0753]

[0754]

[0755]

[0756] Note: ND means no relevant determination was performed

[0757] The above data show that under the same experimental conditions, compounds 15, 16, 17, 18, 21, 25, 28, 29, 32, 33, 35, 37, 38, 39, 40, 44, 46, 47, 49, 50, 52, 55, 52, 55, 60, 62, 63, 64, 67, 68, and 69 have better anti-colorectal cancer activity than the commercial drug oxaliplatin (IC 50 =28.79 μM). Furthermore, the anti-colorectal cancer drug activity of compounds 16, 17, 18, 21, 25, 28, 29, 32, 33, 35, 38, 39, 44, 46, 47, 49, 52, 55, 60, 62, 63, 64, 67, 68, and 69 is superior to that of the commercially available drug 5-fluorouracil (5-Fu, 5-Fluorouracil, IC 50 =18.32 μM). Furthermore, the anti-colorectal cancer drug activity of compounds 16, 17, 18, 21, 25, 28, 29, 32, 35, 38, 39, 44, 46, 49, 52, 55, 52, 55, 60, 62, 63, 64, 67, 68, and 69 is superior to that of the commercially available drug irinotecan (IC 50 =12.87 μM). Furthermore, the anti-colorectal cancer drug activity of compounds 17 and 39 is superior to that of the commercially available drug Vorinostar (IC 50 =4.99 μM), showing the powerful anti-tumor drug activity of 3,3-disubstituted indolone compounds.

[0758] The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A chiral 3,3-disubstituted indole ketone compound, characterized in that: The structural formula is shown in formula (I) or formula (II): In formula (I), the carbon atom marked with "*" is a chiral center; R 1 is tert-butoxy, ethoxy or benzyloxy; R 2 is methyl, methoxy, chlorine, fluorine, β-chloroethyl or hydrogen; R 3 is bromine, fluorine, methoxy or hydrogen; R 4 is bromine or hydrogen; R 5 is methyl or hydrogen; R 6 is methoxy, fluorine, bromine, methyl or hydrogen, or simultaneously in both R 6 The position of a phenyl group; R 7 is methyl or hydrogen; R 8 is p-methylphenyl, p-tert-butylphenyl, p-methoxyphenyl, p-fluorophenyl, m-methoxyphenyl, m-fluorophenyl, 2-naphthyl, N-pyrrolyl, 2-thienyl, 6-benzofuranyl, p-fluorobenzyl, p-methylphenylmercapto or phenyl; In formula (II), the carbon atom marked with "*" is the chiral center; R 1’ is N-pyrrolyl or phenyl; R 2’ is methoxy, fluorine or hydrogen; R 3’ for hydrogen, or simultaneously in both R 3’ There is a phenyl group in the position.

2. The method for preparing the chiral 3,3-disubstituted indole ketone compound according to claim 1, characterized in that: The general reaction formula is as follows: The steps include: Step (1), asymmetric ring-opening reaction: reacting the 3-substituted indole one compound represented by formula (IV) with the benzoxanorbornene compound represented by formula (III) in the presence of a rhodium catalyst, a chiral ligand and a co-catalyst under an inert atmosphere to obtain a chiral 3,3-disubstituted indole one compound represented by formula (I); Step (2), dehydration and removal of N-protecting group reaction: Under an inert gas atmosphere, the chiral 3,3-disubstituted indole one compound represented by formula (I) is treated with zinc chloride to obtain a chiral 3,3-diaryl indole one compound represented by formula (II).

3. The method for preparing a chiral 3,3-disubstituted indole ketone compound according to claim 2, characterized in that: In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indolone compound represented by formula (IV) is 1.95-2.05:1; The reaction temperature is 40-60°C and the reaction time is 30 minutes to 2 hours; The rhodium catalyst is 1,5-cyclooctadiene acetylacetonate rhodium, and the molar ratio of 1,5-cyclooctadiene acetylacetonate rhodium to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1; The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine, (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1; Zinc chloride is used as a co-catalyst, and the molar ratio of zinc chloride to the 3-substituted indole ketone compound represented by formula (IV) is 0.2-2.0:1; The reaction solvent is toluene.

4. The method for preparing a chiral 3,3-disubstituted indole ketone compound according to claim 2, characterized in that: In step (1), the molar ratio of the benzoxanorbornene compound represented by formula (III) to the 3-substituted indolone compound represented by formula (IV) is 1.95-2.05:1; The reaction temperature is 40-60°C and the reaction time is 30 minutes to 2 hours; The rhodium catalyst is di(1,5-cyclooctadiene) rhodium tetrafluoroborate, and the molar ratio of di(1,5-cyclooctadiene) rhodium tetrafluoroborate to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1; The chiral ligand used is (R)-(-)-1-(S P )-2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine; (R)-(-)-1-(S P The molar ratio of 2-diphenylphosphinoferrocenylethyl-di-tert-butylphosphine to the 3-substituted indolone compound represented by formula (IV) is 0.045-0.060:1; Dysprosium chloride is used as a co-catalyst, and the molar ratio of dysprosium chloride to the 3-substituted indolone compound represented by formula (IV) is 0.2-2.0:1; The reaction solvent was 1,2-dichloroethane.

5. The method for preparing a chiral 3,3-disubstituted indole ketone compound according to claim 2, characterized in that: In step (2), chloroform is used as the solvent, the reaction temperature is 40 to 60° C., and the reaction time is 10 to 20 hours; Zinc chloride is used as a dehydrating agent and a deprotecting agent at the same time; the molar ratio of zinc chloride to the chiral 3,3-disubstituted indole ketone compound shown in formula (I) is 1.0-2.0:

1.

6. Use of the chiral 3,3-disubstituted indolone compounds according to claim 1 in the preparation of drugs for treating colorectal cancer.

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