Chromene[4,3-b]indoline derivatives, methods for their synthesis and use

Abstract

The application discloses a series of chrysen [4, 3-b] indoline derivatives, a synthesis method and application thereof. The chrysen [4, 3-b] indoline derivative is obtained by placing 2, 3-fused ring indoline derivatives in a polar solvent, adding a reducing agent to perform a reduction reaction, placing the obtained intermediate product in an organic solvent, and performing a ring closure reaction in the presence of an acid catalyst. The test results of the applicant show that the target compounds have good inhibition effect on a plurality of tumor cell strains, and are expected to be used for preparing antitumor drugs.

Description

Technical Field

[0001] This invention relates to chromene[4,3-b]indoline derivatives, their synthesis methods, and applications, belonging to the field of pharmaceutical technology. Background Technology

[0002] Tinones, also known as benzopyrans, have skeletons widely found in natural products, such as vitamin E, flavonoids, and isoflavones. Tinone derivatives possess a wide range of biological and pharmacological activities. Anti-allergic and anticancer activities have been reported.

[0003] Indole alkaloids are an important class of natural products. Due to their large number and complex structure, they often have significant physiological activities and have therefore been favored by synthetic chemists and medicinal chemists.

[0004] Chromenoindole structures are widely found in various alkaloids and important therapeutic molecules with different biological activities. Introducing a ring onto chromenoindole may further affect the biological activity of this type of skeleton. Therefore, the efficient construction of chromenoindole skeletons is one of the hot topics and challenges in organic synthesis. The main strategies for constructing such skeletons include cycloaddition of functionalized indoles to 1,3-dipolar molecules, intramolecular nucleophilic cyclization of functionalized indoles, ring-closure metathesis of indoles, and other related cascade reactions. However, these methods have drawbacks such as cumbersome steps, complex starting materials, limited substrates, and poor functional group compatibility. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a series of novel chromene[4,3-b]indoline derivatives, their synthesis methods and applications.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] The chromene[4,3-b]indoline derivatives described in this invention are compounds having the structure shown in Formula 2 below, or pharmaceutically acceptable salts thereof:

[0008]

[0009] in:

[0010] R 1 Represents hydrogen, halogen atoms, and C 1～4 alkyl, C 1～4 alkoxy or C 1～4 Perfluoroalkyl groups;

[0011] R 2 Represents hydrogen, halogen atoms, and C 1～4 alkyl, C 1～4 alkoxy or C 1～4 Perfluoroalkyl groups;

[0012] R 3 Represents hydrogen, halogen atoms, and C 1～4 alkyl, C 1～4 alkoxy or C 1～4 Perfluoroalkyl groups;

[0013] X represents an oxygen atom or an N-methyl atom.

[0014] In some preferred embodiments, the chromene[4,3-b]indoline derivative of the present invention may specifically be any one of the following compounds 2a to 2u:

[0015] 2a:R 1 =H,R 2 =H,R 3 =H,X=O;

[0016] 2b:R 1 =4-Me,R 2 =H,R 3 =H,X=O;

[0017] 2c:R 1 =4-CF3,R 2 =H,R 3 =H,X=O;

[0018] 2d:R 1 =4-F,R 2 =H,R 3 =H,X=O;

[0019] 2e:R 1 =4-Br,R 2 =H,R 3 =H,X=O;

[0020] 2f:R 1 =3-OMe,R 2 =H,R 3 =H,X=O;

[0021] 2g:R 1 =2-Br,R 2 =H,R 3 =H,X=O;

[0022] 2h:R 1 =H,R 2 =7-Me,R 3 =H,X=O;

[0023] 2i:R 1 =H,R 2 =5-OMe,R 3=H,X=O;

[0024] 2j:R 1 =H,R 2 =5-CF3,R 3 =H,X=O;

[0025] 2k:R 1 =H,R 2 =5-Cl,R 3 =H,X=O;

[0026] 2l:R 1 =H,R 2 =4,6-Me,R 3 =H,X=O;

[0027] 2m:R 1 =H,R 2 =H,R 3 =4-OMe,X=O;

[0028] 2n:R 1 =H,R 2 =H,R 3 =4-F,X=O;

[0029] 2o:R 1 =H,R 2 =H,R 3 =5-Br,X=O;

[0030] 2p:R 1 =H,R 2 =H,R 3 =4,5-Me,X=O;

[0031] 2q:R 1 =H,R 2 =H,R 3 =H,X=N-Me;

[0032] 2r:R 1 =H,R 2 =5-Br,R 3 =4-Br,X=O;

[0033] 2s:R 1 =H,R 2 =6-Br,R 3 =4-Br,X=O;

[0034] 2t:R 1 =4-Me,R 2 =5-Cl,R 3 =4-Br,X=O;

[0035] 2u:R 1 =3-Br,R 2 =5-Cl,R 3 =4-Br,X=O.

[0036] The method for synthesizing the chromene [4,3-b]indoline derivative of the present invention mainly includes the following steps: taking the compound shown in Formula 1 and placing it in a polar solvent, adding a reducing agent to carry out a reduction reaction, and obtaining the intermediate product shown in Formula 3; then placing the intermediate product shown in Formula 3 in an organic solvent and carrying out a cyclization reaction in the presence of an acid catalyst to obtain the crude product of the target compound.

[0037]

[0038] in:

[0039] R 1 Represents hydrogen, halogen atoms, and C 1～4 alkyl, C 1～4 alkoxy or C 1～4 Perfluoroalkyl groups;

[0040] R 2 Represents hydrogen, halogen atoms, and C 1～4 alkyl, C 1～4 alkoxy or C 1～4 Perfluoroalkyl groups;

[0041] R 3 Represents hydrogen, halogen atoms, and C 1～4 alkyl, C 1～4 alkoxy or C 1～4 Perfluoroalkyl groups;

[0042] X represents an oxygen atom or an N-methyl group;

[0043] The acid catalyst is trifluoromethanesulfonic acid or sulfuric acid, or a mixture of the two.

[0044] The applicant discovered in experiments that using trifluoromethanesulfonic acid and / or sulfuric acid as acid catalysts in the ring-closing reaction is crucial for synthesizing the target compound of this invention. When other acid catalysts (such as benzoic acid, p-toluenesulfonic acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, acetic acid, etc.) are used instead of trifluoromethanesulfonic acid or sulfuric acid, the target compound of this invention is not formed. In the synthesis method described in this invention, the amount of the acid catalyst is preferably 1 to 2 times the molar amount of the compound shown in Formula 1.

[0045] In the above synthesis method, the organic solvent is selected from one or more combinations of toluene, tetrahydrofuran, acetonitrile, dichloromethane, trichloromethane, 1,2-dichloroethane, and dioxane. The amount of organic solvent used is preferably sufficient to dissolve the reactants. Generally, based on 1 mmol of the compound shown in Formula 1, all reactants are usually dissolved in 1 to 10 mL of organic solvent.

[0046] In the above synthetic method, the ring-closing reaction is typically carried out under air conditions. The specific temperature for the ring-closing reaction can be an ice bath, under heating, or without heating; preferably, the reaction is carried out at or below 40°C, and more preferably at 0°C to room temperature (25°C). The reaction is monitored by TLC until complete. Based on the applicant's experience, when the reaction is carried out at room temperature, a reaction time of 5–36 hours is suitable.

[0047] In the above synthesis method, the compound shown in Formula 1 can be reduced to the intermediate product shown in Formula 3 using conventional reducing agents and polar solvents. Preferred reducing agents include lithium aluminum hydride or sodium borohydride. When lithium aluminum hydride is used as the reducing agent, the corresponding polar solvent is preferably tetrahydrofuran and / or diethyl ether. When sodium borohydride is used as the reducing agent, the corresponding polar solvent is preferably methanol. The crude product obtained after extraction (with water and dichloromethane), washing (with saturated sodium chloride aqueous solution), and drying (with anhydrous sodium sulfate) does not require purification and can be directly used in the next reaction step.

[0048] The compound represented by Formula 1 involved in the synthetic method described in this invention is a 2,3-fused-ring indoline derivative, which can be synthesized with reference to existing literature (Xiao-Pan Ma, Kun Li, Si-Yi Wu, Cui Liang, Gui-Fa Su* and Dong-Liang Mo*, Green Chem. 2017, 19, 5761-5766), or a self-designed synthetic route can be used, which will not be detailed here. The crude product of Formula 2 obtained by the above method is usually required for practical applications. Therefore, this invention also includes a step of purifying the obtained crude target compound. Specifically, conventional purification methods can be used to purify the crude product of Formula 2, such as silica gel thin-layer chromatography or silica gel column chromatography, or recrystallization. The eluent used in chromatography is the same as the solvent used in recrystallization. It can be a mixed solvent composed of petroleum ether and ethyl acetate in a volume ratio of 50:1 to 5:1, or a mixed solvent composed of n-hexane and ethyl acetate in a volume ratio of 50:1 to 5:1.

[0049] The applicant discovered through experiments that some of the target compounds of this invention have good antitumor activity. Based on this, this invention also provides the use of the above-mentioned chromene[4,3-b]indoline derivatives or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs.

[0050] Furthermore, the present invention also includes a pharmaceutical composition comprising a therapeutically effective dose of the above-mentioned chromene[4,3-b]indoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

[0051] Compared with existing technologies, this invention provides a series of novel chromene[4,3-b]indoline derivatives and their synthetic methods. The applicant's experimental results show that some of the target compounds of this invention have good inhibitory effects on various tumor cell lines and are expected to be used in the preparation of antitumor drugs. Detailed Implementation

[0052] To better explain the technical solution of the present invention, the present invention will be further described in detail below with reference to the embodiments, but the implementation of the present invention is not limited thereto.

[0053] The 2,3-fused-ring indoline derivatives (i.e., the compounds shown in Formula 1) involved in the following embodiments were synthesized according to the following synthetic route:

[0054]

[0055] 1a:R 1 =H,R 2 =H,R 3 =H,X=O 1b:R 1 =4-Me,R 2 =H,R 3 =H,X=O

[0056] 1c:R 1 =4-CF3,R 2 =H,R 3 =H,X=O 1d:R 1 =4-F,R 2 =H,R 3 =H,X=O

[0057] 1e:R 1 =4-Br,R 2 =H,R 3 =H,X=O 1f:R 1 =3-OMe,R 2 =H,R 3 =H,X=O

[0058] 1g:R 1 =2-Br,R2 =H,R 3 =H,X=O 1h:R 1 =H,R 2 =7-Me,R 3 =H,X=O

[0059] 1i:R 1 =H,R 2 =5-OMe,R 3 =H,X=O 1j:R 1 =H,R 2 =5-CF3,R 3 =H,X=O

[0060] 1k:R 1 =H,R 2 =5-Cl,R 3 =H,X=O 1l:R 1 =H,R 2 =4,6-Me,R 3 =H,X=O

[0061] 1m:R 1 =H,R 2 =H,R 3 =4-OMe,X=O 1n:R 1 =H,R 2 =H,R 3 =4-F,X=O

[0062] 1o:R 1 =H,R 2 =H,R 3 =5-Br,X=O 1p:R 1 =H,R 2 =H,R 3 =4,5-Me,X=O

[0063] 1q:R 1 =H,R 2 =H,R 3 =H,X=N-Me 1r:R 1 =H,R 2 =5-Br,R 3 =4-Br,X=O

[0064] 1s:R 1 =H,R 2 =6-Br,R 3 =4-Br,X=O 1t:R 1 =4-Me,R 2 =5-Cl,R 3 =4-Br,X=O

[0065] 1u:R 1 =3-Br,R 2 =5-Cl,R 3 =4-Br,X=O

[0066] The specific synthesis method is as follows: Oxime S1 (0.5 mmol), diaryl iodide S2 (1 mmol, 2.0 equiv), KOH (0.6 mmol, 1.2 equiv), and CCl4 (5.0 mL) were added to a 25 mL sealed tube. The mixture was stirred at room temperature for 2–12 h until the oxime S1 completely disappeared (TLC monitoring). Then, the temperature was increased to 80 °C and the mixture was stirred for 3–6 h to eliminate the intermediate nitrone (TLC monitoring). The solvent was removed from the obtained material under reduced pressure, and the mixture was separated by column chromatography (petroleum ether / ethyl acetate = 50:1–10:1, volume ratio) to obtain the compound shown in Formula 1. Due to space limitations, only the characterization data of compound 1a are listed here:

[0067]

[0068] 1a: Pale yellow solid, 127 mg, 72% yield; MP: 161–162 °C. 1 H NMR (400MHz, CDCl3): δ9.50(s,1H),7.29(d,J=7.2Hz,2H),7.24(t,J=7.2Hz,2H),7.19–7.15(m,1H),7.11(d,J=7.6Hz,1H),7.07–7.03(m,J=6.8Hz,3H ),6.90–6.86(m,2H),6.76–6.73(m,2H),6.63(d,J=8.0Hz,1H),6.40(d,J=1 6.0Hz,1H),4.66(d,J=12.8Hz,1H),4.30(brs,1H),4.27(d,J=12.4Hz,1H); 13 CNMR (100MHz, CDCl3): δ197.0,154.2,149.9,135.7,132.7,130.1,129.1,129.0,128.6,128. 2,127.4,126.9,126.8,124.6,122.7,122.1,120.3,117.6,110.8,69.9,63.0,61.6;IR(thin film)3367,2925,2848,1709,1602,1482,1214,1059,755cm -1 HRMS(ESI)m / z calcd for C 24 H 20 NO2[M+H]+ :354.1494,found:354.1495.

[0069] Example 1

[0070] The chromene [4,3-b]indoline derivative (i.e., the compound shown in Formula 2) of this invention was synthesized according to the following synthetic route.

[0071]

[0072] 2a:R 1 =H,R 2 =H,R 3 =H,X=O 2b:R 1 =4-Me,R 2 =H,R 3 =H,X=O

[0073] 2c:R 1 =4-CF3,R 2 =H,R 3 =H,X=O 2d:R 1 =4-F,R 2 =H,R 3 =H,X=O

[0074] 2e:R 1 =4-Br,R 2 =H,R 3 =H,X=O 2f:R 1 =3-OMe,R 2 =H,R 3 =H,X=O

[0075] 2g:R 1 =2-Br,R 2 =H,R 3 =H,X=O 2h:R 1 =H,R 2 =7-Me,R 3 =H,X=O

[0076] 2i:R 1 =H,R 2 =5-OMe,R 3 =H,X=O 2j:R 1 =H,R 2 =5-CF3,R 3 =H,X=O

[0077] 2k:R 1 =H,R 2 =5-Cl,R 3 =H,X=O 2l:R1 =H,R 2 =4,6-Me,R 3 =H,X=O

[0078] 2m:R 1 =H,R 2 =H,R 3 =4-OMe,X=O 2n:R 1 =H,R 2 =H,R 3 =4-F,X=O

[0079] 2o:R 1 =H,R 2 =H,R 3 =5-Br,X=O 2p:R 1 =H,R 2 =H,R 3 =4,5-Me,X=O

[0080] 2q:R 1 =H,R 2 =H,R 3 =H,X=N-Me

[0081] Compound 1 was dissolved in methanol (2 mL), and NaBH4 (0.4 mmol, 2.0 equiv) was added. The mixture was reacted at room temperature for 0.5–1 h until compound 1 was completely reacted (TLC monitoring). The reaction mixture was extracted with H2O (10 mL) and CH2Cl2 (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate to obtain the intermediate product shown in Formula 3, which was directly used in the next step. The intermediate product shown in Formula 3 was placed in a reaction tube equipped with a stir bar, and 2 mL of organic solvent was added (the organic solvent used for target products 2a–2e was dichloromethane, the organic solvent used for target products 2f–2j was dichloroethane, tetrahydrofuran, acetonitrile, dioxane, and trichloromethane, respectively, and the organic solvent used for the remaining target products was toluene). Trifluoromethanesulfonic acid (1.0 equiv., 0.2 mmol) was added under ice bath conditions. After stirring for 10 min, the mixture was transferred to room temperature and reacted for 5–36 h until the intermediate product shown in Formula 3 was completely consumed (TLC monitoring). The solvent was removed from the obtained reactants under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1–10:1, volume ratio) to obtain target product 2. Different target products and their characterization are as follows:

[0082]

[0083] 2a: Yellow solid, 58 mg, 82% yield; MP: 87-88℃; 11H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.2 Hz, 1H), 7.30 - 7.18 (m, 5H), 7.15 - 7.11 (m, 3H), 7.08 - 7.04 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.90 - 6.86 (m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 4.13 (d, J = 12.4 Hz, 2H), 3.90 (d, J = 11.2 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H), 3.73 (d, J = 11.2 Hz, 1H), 2.48 (d, J = 13.2 Hz, 1H), 2.18 (t, J = 12.4 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.3, 148.8, 141.3, 129.5, 129.3, 128.7, 128.2, 127.5, 127.1, 125.7, 123.6, 123.4, 121.8, 119.8, 118.0, 111.0, 75.7, 66.9, 66.1, 62.2, 44.4, 42.3; IR (thin film): 3343, 3029, 2922, 2858, 1608, 1488, 1221, 1089, 759, 698 cm -1 ; HRMS (ESI) m / z calcd for C 24 1H 22 NO2 [M + H] + 356.1645, found 356.1639.

[0084]

[0085] 2b: Yellow solid, 13 mg, 18% yield; Mp: 90 - 91 °C; 1 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.6 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.16 - 7.05 (m, 6H), 6.98 (d, J = 8.0 Hz, 1H), 6.91 - 6.87 (m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.16 (d, J = 12.4 Hz, 1H), 4.14 (d, J = 12.4 Hz, 2H), 3.87 (d, J = 5.2 Hz, 1H), 3.85 (d, J = 5.2 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 2.48 (d, J = 13.2 Hz, 1H), 3.27 (s, 3H), 2.20 (t, J = 12.0 Hz, 1H);13 C NMR (100 MHz, CDCl3): δ 154.2, 148.9, 138.3, 137.2, 129.5, 129.3, 128.9, 128.7, 127.1, 125.7, 123.6, 123.4, 121.8, 119.8, 118.0, 111.0, 75.6, 66.9, 66.1, 62.2, 44.4, 42.3, 21.1; IR (thin film): 3349, 2959, 1609, 1488, 1220, 1099, 754, 627 cm -1 ; HRMS (ESI) m / z calcd for C 25 H 24 NO2 [M + H] + 370.1802, found 370.1812.

[0086]

[0087] 2c: Colorless oil, 35 mg, 41% yield (dr = 7:1); Major isomer: 1 H NMR (400 MHz, CDCl3): δ 7.50 - 7.48 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.33 - 7.25 (m, 4H), 7.19 - 7.08 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.92 - 6.88 (m, 1H), 6.71 (d, J = 7.6 Hz, 1H), 4.66 - 4.58 (m, 1H), 4.29 (s, 1H), 4.15 (d, J = 12.8 Hz, 1H), 3.97 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.75 (d, J = 11.6 Hz, 1H), 2.49 (d, J = 13.2 Hz, 1H), 2.14 (t, J = 12.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): δ 154.3, 148.7, 145.3, 129.7 (q, J = 35.0 Hz), 129.5, 129.3, 128.9, 128.1 (q, J = 237.0 Hz), 127.0, 126.0, 125.2 (q, J = 3.6 Hz), 123.4, 123.3, 122.0, 120.0, 118.1, 111.2, 75.1, 66.9, 66.1, 62.2, 44.4, 42.6; 19 F NMR (376 MHz, CDCl3): δ -180.9; minor isomer:1 1H NMR (400 MHz, CDCl3): δ 7.61 - 7.59 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.33 - 7.25 (m, 4H), 7.19 - 7.08 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.82 - 6.78 (m, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.66 - 4.58 (m, 1H), 3.97 (d, J = 11.6 Hz, 1H), 3.91 (s, 1H), 3.87 (d, J = 11.6 Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H), 2.31 (d, J = 13.2 Hz, 1H), 2.22 (t, J = 12.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 153.5, 148.2, 145.6, 129.8, 129.7 (q, J = 35.0 Hz), 129.2, 128.6, 128.1 (q, J = 237.0 Hz), 126.1, 125.5 (q, J = 3.7 Hz), 124.7, 122.7, 122.6, 121.6, 119.9, 117.3, 111.1, 76.2, 72.1, 64.9, 63.5, 45.0, 41.8; IR (thin film): 3415, 3029, 2921, 2865, 1618, 1489, 1224, 1067, 759, 675 cm -1 ; HRMS (ESI) m / z calcd for C 25 H 21 F3NO2 [M + H] + 424.1519, found 424.1515.

[0088]

[0089] 2d: White solid, 64 mg, 86% yield; Mp: 108 - 109 °C; 11H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 7.6 Hz, 1H), 7.24 - 7.17 (m, 2H), 7.08 - 7.03 (m, 3H), 7.01 - 6.97 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.86 - 6.80 (m, 3H), 6.63 (d, J = 7.6 Hz, 1H), 4.53 (d, J = 12.4 Hz, 1H), 4.09 (s, 1H), 4.06 (d, J = 12.4 Hz, 1H), 3.81 - 3.75 (m, 2H), 3.66 (d, J = 11.2 Hz, 1H), 2.38 (d, J = 13.2 Hz, 1H), 2.08 (t, J = 12.4 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 163.3 (d, J = 243.5 Hz), 154.3, 148.8, 137.1 (d, J = 2.9 Hz), 129.4, 129.3, 128.8, 127.5 (d, J = 8.0 Hz), 127.1, 123.4, 123.3, 121.9, 119.9, 118.0, 115.2 (d, J = 21.1 Hz), 111.1, 75.1, 66.9, 66.2, 62.2, 44.4, 42.4; 19 19F NMR (376 MHz, CDCl3): δ -233.2; IR (thin film): 3343, 3029, 2922, 1608, 1488, 1221, 1089, 759, 698 cm -1 ; HRMS (ESI) m / z calcd for C 24 H 21 19FNO2 [M + H] + : 374.1551, found 374.1545.

[0090]

[0091] 2e: White solid, 75 mg, 87% yield (dr = 14:1); Mp: 87 - 88 °C; 11H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 7.6 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.29 - 7.23 (m, 2H), 7.15 - 7.11 (m, 1H), 7.08 - 7.04 (m, 1H), 7.02 - 6.97 (m, 3H), 6.90 - 6.86 (m, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.60 (d, J = 12.4 Hz, 1H), 4.15 (s, 1H), 4.11 (d, J = 12.4 Hz, 1H), 3.85 - 3.80 (m, 2H), 3.72 (d, J = 11.2 Hz, 1H), 2.42 (d, J = 13.2 Hz, 1H), 2.10 (t, J = 12.4 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.2, 148.7, 140.3, 131.2, 129.3, 129.2, 128.7, 127.4, 127.0, 123.3, 121.9, 121.2, 119.8, 118.0, 111.0, 75.0, 66.8, 66.0, 62.1, 44.3, 42.4; IR (thin film): 3332, 3025, 2921, 1610, 1488, 1221, 1089, 759, 675 cm -1 ; HRMS (ESI) m / z calcd for C 24 18 21 11 + BrNO2 [M + H]+ 434.0750, found 434.0751.

[0092]

[0093] 2f: Yellow oil, 60 mg, 78% yield (dr = 11:1); 1 1H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.6 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.17 - 7.11 (m, 2H), 7.07 - 7.04 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.89 - 6.86 (m, 1H), 6.73 - 6.72 (m, 3H), 6.69 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 12.8 Hz, 1H), 4.15 (s, 1H), 4.13 (d, J = 12.8 Hz, 1H), 3.88 - 3.79 (m, 2H), 3.72 - 3.70 (m, 4H), 2.47 (d, J = 13.2 Hz, 1H), 2.17 (t, J = 12.4 Hz, 1H);13 13C NMR (100 MHz, CDCl3): δ 159.5, 154.3, 148.8, 142.9, 129.4, 129.3, 128.7, 127.1, 123.5, 123.4, 121.9, 119.8, 118.0, 117.9, 112.9, 111.5, 111.0, 75.6, 66.9, 66.1, 62.2, 55.2, 44.4, 42.3; IR (thin film): 3415, 3030, 2921, 1613, 1488, 1221, 1086, 757, 699 cm -1 ; HRMS (ESI) m / z calcd for C 25 H 24 NO3 [M + H] + 386.1751, found 386.1746.

[0094]

[0095] 2g: Colorless oil, 61 mg, 71% yield; 1 1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 7.6 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.29 - 7.24 (m, 2H), 7.22 - 7.18 (m, 1H), 7.15 - 7.11 (m, 1H), 7.08 - 7.02 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.91 - 6.87 (m, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.64 (d, J = 12.4 Hz, 1H), 4.18 - 4.13 (m, 3H), 3.88 (d, J = 11.2 Hz, 1H), 3.74 (d, J = 11.2 Hz, 1H), 2.68 (d, J = 13.2 Hz, 1H), 1.89 (t, J = 12.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.1, 148.9, 140.8, 132.3, 129.4, 129.3, 128.7, 128.6, 128.0, 127.5, 127.2, 123.3, 122.7, 121.6, 121.0, 119.7, 117.8, 111.0, 74.9, 66.8, 66.0, 62.2, 44.4, 40.7; IR (thin film): 3416, 3025, 2924, 2863, 1618, 1487, 1261, 1097, 801, 688 cm -1 ; HRMS (ESI) m / z calcd for C24 H 21 BrNO2[M+H] + 434.0750, found 434.0750.

[0096]

[0097] 2h: White solid, 69mg, 93% yield; MP: 87-88℃; 1 H NMR (400MHz, CDCl3): δ7.50 (d, J = 7.6Hz, 1H), 7.32-7.28 (m, 1H), 7.25-7.19 ( m,3H),7.17-7.13(m,3H),7.10-7.07(m,1H),7.00-6.97(m,2H),6.85-6.82( m,1H),4.61(d,J=12.4Hz,1H),4.14(d,J=12.4Hz,1H),3.97(s,1H),3.92-3. 84(m,2H),3.74(d,J=11.2Hz,1H),2.51(d,J=13.2Hz,1H),2.15-2.09(m,4H); 13 CNMR (100MHz, CDCl3): δ154.3,147.4,141.4,129.7,129.3,128.8,128.2,127.5,127.1,125.7 ,123.7,121.9,120.8,120.4,120.0,118.0,75.8,67.0,66.3,62.1,44.6,42.8,16.7; IR(thin film):3373,3028,2932,1606,1486,1216,1095,760,699cm -1 HRMS(ESI)m / z calcd for C 25 H 24 NO2[M+H] + 370.1802, found 370.1798.

[0098]

[0099] 2i: Colorless oil, 67mg, 87% yield (dr = 6:1); Major isomer: 1H NMR(400MHz,CDCl3):δ7.44(d,J=7.6Hz,1H),7.37-7.30(m,1H),7.28-7.26(m,1H),7.23-7.18(m,2H),7.17-7.15(m,2H),7.07-7.03(m,1H),6.99(d,J=8.0Hz,1H),6.87-6.86(m,1H),6.71-6.63(m,2H),4.57(d,J=12.8Hz,1H),4.12(d,J=12.4Hz,1H),3.91(d,J=12.0Hz,1H),3.84(d,J=11.6Hz,1H),3.79(s,3H),3.74-3.72(m,2H),2.47(d,J=13.6Hz,1H),2.20(t,J=12.0Hz,1H); 13 C NMR(100MHz,CDCl3):δ154.4,154.2,142.5,141.3,131.8,129.2,128.4,128.2,127.5,127.2,125.7,121.9,117.9,113.6,112.4,110.1,75.9,66.8,66.2,62.3,55.8,45.1,42.2;minor isomer: 1 H NMR(400MHz,CDCl3):δ7.37-7.30(m,2H),7.28-7.26(m,1H),7.23-7.18(m,2H),7.17-7.15(m,2H),7.07-7.03(m,1H),6.99(d,J=8.0Hz,1H),6.77-6.76(m,1H),6.58-6.55(m,2H),4.91(d,J=10.4Hz,1H),4.59(s,3H),4.12(d,J=12.4Hz,1H),3.91(d,J=12.0Hz,1H),3.84(d,J=11.6Hz,1H),3.65-3.62(m,2H),2.40(s,1H),2.30(t,J=12.8Hz,1H); 1313C NMR (100 MHz, CDCl3): δ 153.9, 153.4, 141.9, 141.5, 130.6, 130.2, 128.4, 127.7, 125.9, 124.7, 123.7, 121.4, 117.1, 113.4, 111.4, 109.5, 72.1, 64.9, 63.8, 60.3, 55.7, 45.3, 41.8; IR (thin film): 3415, 3030, 2920, 2863, 1617, 1490, 1225, 1032, 761, 698 cm -1 ; HRMS (ESI) m / z calcd for C 25 H 24 NO3 [M + H] + 386.1751, found 386.1751.

[0100]

[0101] 2j: Colorless oil, 70 mg, 83% yield (dr = 11:1); 1 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.43 - 7.38 (m, 2H), 7.33 - 7.30 (m, 1H), 7.26 - 7.20 (m, 3H), 7.16 - 7.14 (m, 2H), 7.10 - 7.06 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 4.45 (s, 1H), 4.15 (d, J = 12.8 Hz, 1H), 3.90 - 3.80 (m, 2H), 3.73 (d, J = 11.2 Hz, 1H), 2.52 (d, J = 13.2 Hz, 1H), 2.14 (t, J = 12.4 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.2, 151.6, 140.9, 129.6, 129.4, 128.8 (q, J = 269.1 Hz), 128.3, 127.7, 126.9, 126.8 (q, J = 3.7 Hz), 125.7, 122.6, 122.0, 121.9 (q, J = 32.1 Hz), 120.8 (q, J = 3.6 Hz), 118.1, 109.7, 75.6, 66.6, 65.9, 62.9, 44.1, 42.5; 1919F NMR (376 MHz, CDCl3): δ -179.1; IR (thin film): 3415, 3034, 2923, 2867, 1622, 1496, 1222, 1065, 761, 698 cm -1 ; HRMS (ESI) m / z calcd for C 25 H 21 F3NO2 [M + H] + 424.1519, found 424.1520.

[0102]

[0103] 2k: White solid, 62 mg, 80% yield (dr = 2.5:1); Mp: 87 - 88 °C; major isomer: 1 1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 7.6 Hz, 1H), 7.35 - 7.34 (m, 1H), 7.25 - 7.23 (m, 2H), 7.22 - 7.20 (m, 2H), 7.17 - 7.15 (m, 2H), 7.09 - 7.05 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.54 (d, J = 12.8 Hz, 1H), 4.16 (s, 1H), 4.11 (d, J = 12.8 Hz, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.72 (d, J = 11.6 Hz, 1H), 2.49 (d, J = 13.6 Hz, 1H), 2.15 (t, J = 11.6 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.2, 147.5, 141.2, 131.5, 129.6, 128.7, 128.4, 127.8, 127.1, 125.8, 124.5, 124.0, 122.1, 118.2, 111.9, 75.8, 66.7, 66.1, 62.9, 44.8, 42.4; minor isomer: 11H NMR (400 MHz, CDCl3): δ 7.35 - 7.34 (m, 1H), 7.32 - 7.30 (m, 2H), 7.28 - 7.27 (m, 2H), 7.13 - 7.11 (m, 2H), 7.09 - 7.05 (m, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.90 - 6.86 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 4.89 (d, J = 10.4 Hz, 1H), 4.58 - 4.57 (m, 2H), 4.34 (s, 1H), 4.11 (d, J = 12.8 Hz, 1H), 3.63 (d, J = 12.4 Hz, 1H), 2.41 - 2.40 (m, 1H), 2.09 (t, J = 12.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 153.5, 147.0, 141.4, 131.1, 129.6, 128.6, 127.9, 126.0, 124.8, 124.4, 123.2, 123.1, 121.7, 117.4, 111.9, 77.1, 72.0, 64.8, 64.2, 45.4, 41.6; IR (thin film): 3362, 3032, 2931, 2862, 1609, 1488, 1223, 1091, 755, 680 cm -1 ; HRMS (ESI) m / z calcd for C 24 H 21 ClNO2 [M + H] + 390.1255, found 390.1251.

[0104]

[0105] 21: Colorless oil, 31 mg, 41% yield; 1 1H NMR (400 MHz, CDCl3): δ 7.44 (d, J = 7.6 Hz, 1H), 7.31 - 7.23 (m, 3H), 7.20 - 7.19 (m, 3H), 7.08 - 7.04 (m, 1H), 6.99 (d, J = 8.0 Hz, 1H),​13C NMR (100 MHz, CDCl3): δ 154.1, 149.6, 141.5, 138.5, 135.3, 129.2, 128.2, 127.5, 127.0, 125.8, 123.6, 123.5, 121.7, 118.0, 109.9, 76.1, 66.4, 65.7, 61.9, 46.0, 41.7, 21.3, 19.4; IR (thin film): 3416, 3029, 2919, 2864, 1616, 1488, 1222, 1087, 759, 672 cm -1 ; HRMS (ESI) m / z calcd for C 26 H 26 NO2 [M + H] + 384.1958, found 384.1956.

[0106] [[ID=*13]]

[0107] 2m: yellow oil, 25 mg, 33% yield (dr = 14:1); 1 1H NMR (400 MHz, CDCl3): δ 7.28 - 7.20 (m, 4H), 7.18 - 7.12 (m, 3H), 6.97 - 6.93 (m, 2H), 6.91 - 6.88 (m, 2H), 6.72 (d, J = 8.0 Hz, 1H), 4.62 (d, J = 12.4 Hz, 1H), 4.15 (d, J = 12.8 Hz, 2H), 3.94 (d, J = 11.6 Hz, 1H), 3.82 - 3.79 (m, 4H), 3.71 (d, J = 11.6 Hz, 1H), 2.46 (d, J = 13.2 Hz, 1H), 2.20 (t, J = 12.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.4, 148.8, 148.2, 141.3, 129.6, 128.7, 128.3, 127.6, 125.8, 124.3, 123.4, 119.9, 118.7, 115.0, 112.2, 111.2, 75.8, 67.1, 66.3, 62.5, 55.8, 44.6, 42.5; IR (thin film): 3415, 3030, 2920, 2861, 1610, 1496, 1261, 1024, 806, 700 cm -1 ; HRMS (ESI) m / z calcd for C 25 H 24 NO3 [M + H] + Please note that in the original text, there is a potential error in line break formatting in the "13C NMR" and "IR" data parts. The translated text preserves the original structure as much as possible while following the translation rules. If this is a formatting issue in the source document, it might need to be corrected for better readability in the context of the overall patent text. Also, the "7-digit tags" -1 - + are preserved exactly as they are in the original.386.1751, found 386.1748.

[0108]

[0109] 2n: Colorless oil, 64mg, 86% yield (dr=13:1); 1 H NMR (400MHz, CDCl3): δ7.28-7.20(m,4H),7.17-7.11(m,4H),7.03-6.98(m,1 H),6.96-6.93(m,1H),6.91-6.88(m,1H),6.70(d,J=7.6Hz,1H),4.61(d,J=12 .4Hz,1H),4.11(d,J=12.4Hz,2H),3.90(d,J=11.2Hz,1H),3.82(d,J=11.6Hz ,1H),3.73(d,J=11.6Hz,1H),2.37(d,J=13.2Hz,1H),2.19(t,J=12.0Hz,1H); 13 C NMR (100MHz, CDCl3): δ158.8 (d, J = 238.5Hz), 150.3 (d, J = 1.5Hz), 148.6, 141.0, 129.2, 128.8, 128.3, 127.7, 125.7, 124.8 (d, J = 6.6Hz),123.5,120.0,119.3(d,J=8.0Hz),116.5(d,J=22.6Hz),113.3(d,J=22.6Hz),111.1,75.7,67.1,66.1,62.4,44.2,42.4; 19 F NMR (376MHz, CDCl3): δ-232.1; IR (thin film): 3344, 3031, 2921, 2863, 1607, 1494, 1258, 1090, 754, 683cm -1 HRMS(ESI)m / z calcd for C 24 H 21 FNO2[M+H] + 374.1551, found 374.1546.

[0110]

[0111] 2o: Colorless oil, 74mg, 86% yield (dr=11:1); 11H NMR (400 MHz, CDCl3): δ 7.30 - 7.28 (m, 2H), 7.25 - 7.19 (m, 4H), 7.17 - 7.15 (m, 4H), 6.91 - 6.82 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.60 (d, J = 12.8 Hz, 1H), 4.12 (s, 1H), 4.07 (d, J = 12.4 Hz, 1H), 3.88 - 3.81 (m, 2H), 3.74 (d, J = 11.6 Hz, 1H), 2.41 (d, J = 13.2 Hz, 1H), 2.18 (t, J = 12.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 155.1, 148.6, 141.1, 129.0, 128.9, 128.5, 128.3, 127.7, 125.7, 125.0, 123.5, 122.8, 122.3, 121.1, 120.0, 111.1, 75.8, 67.0, 66.0, 62.1, 44.2, 42.2; IR (thin film): 3416, 3029, 2920, 2861, 1599, 1484, 1261, 1091, 757, 699 cm -1 ; HRMS (ESI) m / z calcd for C 24 H 21 BrNO2 [M + H] + 434.0750, found 434.0749.

[0112]

[0113] 2p: White solid, 54 mg, 70% yield (dr = 12:1); Mp: 87 - 88 °C; 1 1H NMR (400 MHz, CDCl3): δ 7.26 - 7.21 (m, 4H), 7.18 - 7.16 (m, 3H), 7.12 (d, J = 7.6 Hz, 1H), 6.89 - 6.85 (m, 1H), 6.78 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 4.59 (d, J = 12.4 Hz, 1H), 4.13 (d, J = 12.8 Hz, 2H), 3.94 (d, J = 11.2 Hz, 1H), 3.81 (d, J = 11.2 Hz, 1H), 3.69 (d, J = 11.2 Hz, 1H), 2.47 (d, J = 13.2 Hz, 1H), 2.25 (s, 3H), 2.24 (s, 3H), 2.17 (t, J = 12.4 Hz, 1H); 1313C NMR (100 MHz, CDCl3): δ 152.1, 149.0, 141.4, 138.0, 130.0, 129.7, 128.6, 128.2, 127.7, 127.5, 125.9, 123.4, 120.6, 119.7, 118.6, 111.0, 75.8, 66.9, 66.2, 62.1, 44.5, 42.1, 19.6, 19.2; IR (thin film): 3416, 3029, 2926, 2862, 1616, 1494, 1260, 1091, 754, 700 cm -1 ; HRMS (ESI) m / z calcd for C 26 H 26 NO2 [M + H] + 384.1958, found 384.1953.

[0114]

[0115] 2q: Colorless oil, 66 mg, 89% yield (dr = 1:1); one isomer: 1 1H NMR (400 MHz, CDCl3): δ 7.40 - 7.38 (m, 2H), 7.31 - 7.30 (m, 2H), 7.27 - 7.19 (m, 2H), 7.12 - 7.06 (m, 3H), 6.88 - 6.81 (m, 2H), 6.67 - 6.60 (m, 2H), 4.60 (d, J = 12.4 Hz, 1H), 4.16 (d, J = 12.4 Hz, 1H), 3.99 (t, J = 12.4 Hz, 1H), 3.65 (d, J = 12.0 Hz, 1H), 3.15 (d, J = 11.6 Hz, 1H), 2.91 (s, 3H), 2.51 (d, J = 13.2 Hz, 1H), 2.16 (d, J = 13.2 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 148.6, 146.4, 141.8, 132.4, 130.7, 128.4, 128.2, 128.0, 127.4, 126.0, 124.6, 122.7, 119.5, 117.5, 112.4, 111.1, 77.4, 73.6, 65.2, 54.8, 45.5, 42.8, 39.4; another isomer: 1H NMR (400MHz, CDCl3): δ7.36-7.33(m,2H),7.27-7.19(m,2H),7.17-7.15(m,2H),7.0 3-6.99(m,3H),6.77-6.72(m,2H),6.67-6.60(m,1H),6.49(d,J=8.4Hz,1H),4.93(d ,J=10.8Hz,1H),3.99(t,J=12.4Hz,1H),3.82(d,J=12.4Hz,1H),3.51(d,J=12.0Hz, 1H),2.88(s,3H),2.62(d,J=12.0Hz,1H),2.35(d,J=13.6Hz,1H),2.10-2.06(m,1H); 13 CNMR (100MHz, CDCl3): δ148.4,145.6,141.6,131.2,128.9 128.2,128.1,127.6,127.2,125.8,123.4,122.0,119.3,117.0,111.7,110.8,76.0,67.4,63.7,51.4,44.6,42.6,39.4;IR(thin film):3356,3029,2917,2860,1605,1480,1252,1090,748,699cm -1 HRMS(ESI)m / z calcd for C 25 H 25 N₂O[M+H] + 369.1961, found 369.1956.

[0116] Comparative Example 1-1

[0117] Example 1 was repeated, except that in the ring-closing reaction, methanol, dimethyl sulfoxide, or N,N-dimethylformamide was used instead of dichloromethane as the reaction solvent to prepare the target product 2a. The results showed that the target product 2a was not obtained in any of them.

[0118] Example 2

[0119] The chromene [4,3-b]indoline derivatives of this invention were synthesized according to the following synthetic route.

[0120]

[0121] 2r:R 1 =H,R 2 =5-Br,R 3 =4-Br,X=O 2s:R 1 =H,R2 =6-Br,R 3 =4-Br,X=O

[0122] 2t:R 1 =4-Me,R 2 =5-Cl,R 3 =4-Br,X=O 2u:R 1 =3-Br,R 2 =5-Cl,R 3 =4-Br,X=O

[0123] Compound 1 was dissolved in diethyl ether (2 mL), and LiAlH4 (0.4 mmol, 2.0 equiv) was added. The mixture was reacted at room temperature for 0.5–1 h until compound 1 was completely reacted (TLC monitoring). The reaction mixture was extracted with H2O (10 mL) and CH2Cl2 (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate to obtain the intermediate product shown in Formula 3, which was directly used in the next step. The intermediate product shown in Formula 3 was placed in a reaction tube equipped with a stir bar, and 2 mL of organic solvent was added (the organic solvents used for target products 2r–2t were dichloromethane, acetonitrile, and toluene, respectively, and the organic solvent used for target product 2u was a mixed solvent composed of dichloromethane and tetrahydrofuran in a 1:1 volume ratio). Sulfuric acid (1.0 equiv., 0.2 mmol) was added at room temperature, and the mixture was reacted for 5–36 h until the intermediate product shown in Formula 3 was completely consumed (TLC monitoring). The solvent was removed from the obtained reactants under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate = 50:1–10:1, volume ratio) to obtain target product 2. Different target products and their characterization are as follows:

[0124]

[0125] 2r: Yellow solid, 77 mg, 75% yield; MP: 94-95℃; 11H NMR (400 MHz, CDCl3): δ 7.43 (d, J = 7.6 Hz, 1H), 7.34 - 7.33 (m, 1H), 7.25 - 7.23 (m, 2H), 7.22 - 7.20 (m, 2H), 7.17 - 7.15 (m, H), 7.09 - 7.05 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.53 (d, J = 12.8 Hz, 1H), 4.16 (s, 1H), 4.10 (d, J = 12.8 Hz, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.71 (d, J = 11.6 Hz, 1H), 2.49 (d, J = 13.6 Hz, 1H), 2.14 (t, J = 11.6 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.2, 147.3, 141.2, 131.5, 129.5, 128.7, 128.2, 127.7, 127.1, 125.7, 124.5, 124.0, 122.0, 118.2, 111.7, 75.8, 66.7, 66.0, 62.7, 44.6, 42.4. IR (thin film): 3360, 3031, 2931, 2861, 1605, 1487, 1221, 1090, 759, 680 cm -1 ; HRMS (ESI) m / z calcd for C 24 H 20 Br2NO2 [M + H] + 511.9855, found 511.9856.

[0126]

[0127] 2s: Yellow solid, 80 mg, 78% yield; Mp: 97 - 98 °C; 11H NMR (400 MHz, CDCl3): δ 7.46 (d, J = 7.6 Hz, 1H), 7.35 - 7.33 (m, 1H), 7.27 - 7.23 (m, 2H), 7.22 - 7.20 (m, 2H), 7.18 - 7.15 (m, H), 7.09 - 7.04 (m, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 4.54 (d, J = 12.8 Hz, 1H), 4.15 (s, 1H), 4.10 (d, J = 12.8 Hz, 1H), 3.89 (d, J = 10.8 Hz, 1H), 3.85 (d, J = 11.2 Hz, 1H), 3.70 (d, J = 11.6 Hz, 1H), 2.46 (d, J = 13.6 Hz, 1H), 2.15 (t, J = 11.6 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.3, 147.3, 141.5, 131.4, 129.3, 128.7, 128.1, 127.7, 127.0, 125.5, 124.4, 124.0, 122.2, 118.2, 111.6, 75.4, 66.3, 66.0, 62.5, 44.5, 42.2. IR (thin film): 3361, 3032, 2930, 2863, 1602, 1486, 1223, 1091, 758, 681 cm -1 ; HRMS (ESI) m / z calcd for C 24 H 20 Br2NO2 [M + H] + 511.9855, found 511.9856.

[0128]

[0129] 2t: Yellow solid, 77 mg, 80% yield; Mp: 103 - 104 °C; 11H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 7.6 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.25 - 7.23 (m, 2H), 7.21 - 7.20 (m, 2H), 7.19 - 7.16 (m, 1H), 7.08 - 7.05 (m, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.53 (d, J = 12.8 Hz, 1H), 4.13 (s, 1H), 4.10 (d, J = 12.8 Hz, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.71 (d, J = 11.6 Hz, 1H), 2.45 (d, J = 13.6 Hz, 1H), 2.18 (s, 3H)), 2.13 (t, J = 11.6 Hz, 1H); 13 13C NMR (100 MHz, CDCl3): δ 154.4, 147.2, 141.3, 131.2, 129.3, 128.5, 128.0, 127.8, 127.1, 125.4, 124.5, 124.1, 122.0, 118.1, 111.5, 75.3, 66.2, 66.1, 62.4, 44.4, 42.1. IR (thin film): 3359, 3031, 2932, 2861, 1600, 1487, 1221, 1092, 757, 680 cm -1 ; HRMS (ESI) m / z calcd for C 25 H 22 BrClNO2 [M + H] + 482.0517, found 482.0519.

[0130]

[0131] 2u: Yellow solid, 75 mg, 69% yield; Mp: 110 - 111 °C; 1H NMR (400MHz, CDCl3): δ7.47 (d, J = 7.6Hz, 1H), 7.35-7.32 (m, 1H), 7.26-7.24 (m, 2H), 7.23-7 .20(m,2H),7.18-7.13(m,H),7.08-7.05(m,1H),7.01(d,J=8.0Hz,1H),6.58(d,J=8.0Hz,1H ),4.55(d,J=12.8Hz,1H),4.16(s,1H),4.13(d,J=12.8Hz,1H),3.88(d,J=10.8Hz,1H),3.8 4(d,J=11.2Hz,1H),3.71(d,J=11.6Hz,1H),2.44(d,J=13.6Hz,1H),2.14(t,J=11.6Hz,1H); 13 C NMR (100MHz, CDCl3): δ153.5,146.8,140.5,131.7,129.2,128.5,128.0,127.7,127.2, 125.4,124.4,124.2,122.1,118.3,111.6,75.5,66.2,66.1,62.4,44.3,42.1.IR(thin film):3362,3034,2932,2864,1600,1485,1221,1092,757,681cm -1 ;HRMS(ESI)m / zcalcd forC 24 H 19 Br2ClNO2[M+H] + 545.9466, found 545.9464.

[0132] Comparative Example 2-1

[0133] Example 2 was repeated, except that benzoic acid, p-toluenesulfonic acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, or acetic acid were used instead of sulfuric acid as acid catalysts in the ring-closing reaction in order to prepare the target product 2r-2u, but the result was that the corresponding target product was not obtained.

[0134] Experimental Example 1: In vitro inhibitory activity experiment of the target compound of the present invention against multiple human tumor lines.

[0135] (1) Cell culture: T24, MGC-803, HepG2, NCI-H460, SKOV3, and 7702 cells were cultured in DMEM medium containing 10% (v / v) fetal bovine serum and 1% (v / v) penicillin and streptomycin antibiotics. The culture was carried out in an incubator at 37°C, 5% CO2, and 95% air, with the medium changed every other day. After the cells reached confluence, they were passaged and cryopreserved.

[0136] (2) Seeding: Take cells in the logarithmic growth phase, remove the old culture medium, wash twice with PBS, digest the cells with trypsin, and after the cells become rounded, add fresh culture medium to stop cell digestion and pipette the suspended cells to prepare a single-cell suspension. Take an appropriate amount of cell suspension, add a certain amount of culture medium to dilute it, and seed it into 96-well plates, 180 μL per well, with 20,000 to 40,000 cells per well.

[0137] (3) Drug addition: Add 20 μL of the test sample to each well of a 96-well plate containing tumor cells to achieve a final concentration of 10 μM for initial screening. Based on the results of the initial screening, different concentration gradients of compounds were set for further screening, with 5 replicates per group. After adding the compounds, the plates were incubated in a CO2 incubator for 48 h. Then, 10 μL of prepared MTT solution was added to each well, and the plates were incubated in a CO2 incubator for another 4–6 h.

[0138] (4) Test: Take culture medium from the 96-well plate, add 100 μL of DMSO, and shake on a shaker for 5–10 min to completely dissolve the crystallized formazan. Measure the absorbance (OD) value using a microplate reader at a dual wavelength of 570 nm and a reference wavelength of 630 nm, and calculate the inhibition rate. Inhibition rate = (1 - OD value of sample group / OD value of blank group) × 100%. Calculate the IC50 value of each compound against different tumor cell lines using SPSS software. The test results are shown in Table 1 below:

[0139] Table 1:

[0140]

Claims

1. Use of chromene [4, 3-b] indoline derivatives of the structure shown in the following formula 2 or pharmaceutically acceptable salts thereof in the preparation of antitumor drugs; wherein: R1 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 haloalkylthio, C1-6 alkyl ； ​ R 1 = 4-F, R 2 = H, R 3 = H, X = O; or is R 1 =H, R 2 =5-CF3, R 3 =H, X=O; or is R 1 =H, R 2 =H, R 3 =4-OMe, X=O.

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