Chromone biindole derivative as well as preparation method and application thereof

Abstract

The invention discloses a chromone biindole derivative and a preparation method and application thereof, the chromone biindole derivative has a general formula I and a chemical structure of the general formula I. The preparation method of the chromone biindole derivative takes chromone 3-formaldehyde, an amine compound and an indole compound as raw materials and adopts a one-pot method for preparation, and the method is simple and easy for industrial production. Meanwhile, the chromone biindole derivative has anti-tumor activity.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a chromone biindole derivative and a preparation method and application thereof. Background Art

[0002] Chromones are plant-derived metabolites that exhibit a wide range of biological activities, such as antioxidant, anticancer, antiviral, and anti-inflammatory effects. Many chemists have been actively seeking methods to quickly and efficiently synthesize structurally diverse chromones. The traditional synthesis method is to condense 2'-hydroxyacetophenone with aromatic aldehydes to form α-hydroxyketones through Claisen-Schmidt reaction / Michael addition, but it is limited by substrate limitations. At the same time, the synthesis of chromone analogs through transition metal catalysis can avoid substrate limitations, but usually requires expensive noble metals or highly active reagents that are sensitive to air and water. Although these strategies have significantly advanced the research on the synthesis of structurally diverse chromones, they encounter limitations when applied to complex molecules due to substrate limitations and the need for noble metals.

[0003] Indole is a key heterocyclic framework present in many biologically active compounds and is closely related to the development of anticancer drugs in medicinal chemistry. Directly introducing indole into the chromone skeleton structure is an effective method to construct the chromone-indole skeleton. However, due to the electron donor effect of oxygen atoms, this transformation is difficult, which hinders the direct connection of chromone and indole.

[0004] In view of the universality and importance of chromone and indole analogs, especially in medicinal chemistry, there is an urgent need for a method that operates under mild conditions (e.g., room temperature), has broad functional group tolerance, mild reaction conditions, does not use transition metals during the reaction, and avoids complex post-reaction treatment. For this purpose, the present invention is completed and provides chromone-indole derivatives with antitumor activity. Summary of the invention

[0005] In view of this, the purpose of the present invention is to provide a chromone biindole derivative and a preparation method and application thereof, wherein the chromone biindole derivative has anti-tumor activity. At the same time, the preparation method avoids the use of noble metal catalysts, but adopts a multi-component reaction, and then under the condition of hexafluoroisopropanol as a solvent, only needs to react at room temperature, and synthesizes the chromone biindole derivative by a one-pot method, or under the condition of 1,2-dichloroethane as a solvent, through a traditional oil bath heating method, synthesizes the chromone biindole derivative by a one-pot method.

[0006] The following embodiments are provided to accomplish the purpose of the present invention.

[0007] In one embodiment, the present invention provides a chromone biindole derivative or a pharmaceutically acceptable salt or a solvate thereof, wherein the chromone biindole derivative is a compound represented by general formula I or general formula II:

[0008]

[0009] in,

[0010] R 1 is one or more of hydrogen, alkyl and halogen,

[0011] R 2 is C1-C4 alkyl, cyclobutyl, substituted or unsubstituted phenyl,

[0012] R 3 is one or more of a substituted or unsubstituted alkyl group, an alkoxy group, a chlorine-substituted aryl group and a halogen atom,

[0013] Ar is a substituted or unsubstituted phenyl group or an aromatic hetero group.

[0014] In some embodiments, the above-mentioned chromone biindole derivatives or pharmaceutically acceptable salts or solvates thereof,

[0015] The R 1 is one or more of hydrogen, C1-C4 alkyl and halogen;

[0016] The R 2 is C1-C4 alkyl, cyclobutyl or alkoxyphenyl;

[0017] The R 3 is one or more of hydrogen, substituted or unsubstituted C1-C4 alkyl, C1-C3 alkoxy, substituted or unsubstituted aryl and halogen;

[0018] Preferably, Ar is phenyl, 5-chlorophenyl, 6-bromophenyl, 5-iodophenyl, 5-methoxyphenyl or pyridyl.

[0019] In some embodiments, the above-mentioned chromone biindole derivatives or pharmaceutically acceptable salts or solvates thereof,

[0020] The R 1 is one or more of hydrogen, isopropyl, ethyl, methyl and halogen, wherein the halogen is F, Cl and Br;

[0021] The R 2 is tert-butyl, cyclobutyl or methoxyphenyl;

[0022] The R 3It is one or more of hydrogen, substituted or unsubstituted C1-C4 alkyl, methoxy, substituted or unsubstituted phenyl and halogen, wherein the substituted C1-C4 alkyl is substituted by Cl(CH2)3OC(O)CH2-, halogen or hydroxyl, and the substituted phenyl is substituted by halogen, and the halogen is F, Cl, Br or I.

[0023] In some embodiments, the above-mentioned chromone biindole derivatives or pharmaceutically acceptable salts or solvates thereof are selected from the following compounds:

[0024] (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one;

[0025] (Z)-3-((tert-Butylamino)methylene)-2-(5-chloro-1H-indol-3-yl)chroman-4-one;

[0026] (Z)-2-(6-bromo-1H-indol-3-yl)-3-(tert-butylamino)methylene)chroman-4-one;

[0027] (Z)-3-((tert-Butylamino)methylene)-2-(5-iodo-1H-indol-3-yl)chroman-4-one;

[0028] (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)chroman-4-one;

[0029] (Z)-3-((tert-Butylamino)methylene)-2-(2-methyl-1H-indol-3-yl)chroman-4-one;

[0030] (Z)-3-((tert-butylamino)methylene)-2-(5-methoxy-2-methyl-1H-indol-3-yl)chroman-4-one;

[0031] (Z)-3-((tert-butylamino)methylene)-2-(2-phenyl-1H-indol-3-yl)chroman-4-one;

[0032] (Z)-2-(5-bromo-2-phenyl-1H-indol-3-yl)-3-((tert-butylamino)methylene)chroman-4-one;

[0033] (Z)-3-((tert-butylamino)methylene)-2-(2-(4-chlorophenyl)-1H-indol-3-yl)chroman-4-one;

[0034] (Z)-3-((tert-butylamino)methylene)-2-(1-(2-chloroethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)chroman-4-one;

[0035] 2-Chloroethyl (Z)-2-(3-((tert-butylamino)methylene)-4-oxochromon-2-yl)-1H-indol-1-yl)acetate;

[0036] (Z)-3-((tert-Butylamino)methylene)-2-(1-ethyl-2-methyl-1H-indol-3-yl)chroman-4-one;

[0037] (Z)-3-((tert-butylamino)methylene)-2-(1,2-dimethyl-1H-indol-3-yl)chroman-4-one;

[0038] (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-3-yl)-6-methylchroman-4-one;

[0039] (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-3-yl)-6-isopropylchroman-4-one;

[0040] (Z)-3-((tert-Butylamino)methylene)-6-fluoro-2-(1H-indol-3-yl)chroman-4-one;

[0041] (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)chroman-4-one;

[0042] (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one;

[0043] (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)-7-methylchroman-4-one;

[0044] (Z)-3-((tert-butylamino)methylene)-6-methyl-2-(1-methyl-1H-indol-3-yl)chroman-4-one;

[0045] (Z)-3-((cyclobutylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one;

[0046] (Z)-2-(1H-indol-3-yl)-3-(((4-methoxyphenyl)amino)methylene)chroman-4-one;

[0047] (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-1-yl)chroman-4-one;

[0048] (Z)-3-((tert-Butylamino)methylene)-2-(5-chloro-1H-indol-1-yl)chroman-4-one;

[0049] (Z)-2-(5-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)chroman-4-one;

[0050] (Z)-3-((tert-butylamino)methylene)-2-(5-iodo-1H-indol-1-yl)chroman-4-one;

[0051] (Z)-2-(6-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)chroman-4-one;

[0052] (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)chroman-4-one;

[0053] (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)chroman-4-one;

[0054] (Z)-3-((tert-butylamino)methylene)-2-(3-methyl-1H-indol-1-yl)chroman-4-one;

[0055] (Z)-3-((tert-butylamino)methylene)-2-(3-(2-hydroxyethyl)-1H-indol-1-yl)chroman-4-one;

[0056] (Z)-3-((tert-butylamino)methylene)-6-fluoro-2-(1H-indol-1-yl)chroman-4-one;

[0057] (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)chroman-4-one;

[0058] (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-1-yl)-6-isopropylchroman-4-one;

[0059] (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)-7-methylchroman-4-one.

[0060] In another embodiment, the present invention provides a method for synthesizing the chromone biindole derivatives of the present invention, characterized in that it comprises the following reaction:

[0061]

[0062] In the formula, the R 1 , R 2 , R 3 and Ar are defined as in the previous embodiment,

[0063] 1) reacting the compound of formula 1, the compound of formula 2 and the compound of formula 3 in one pot to obtain the compound of general formula I, or

[0064] 2) The compound of formula 1, the compound of formula 2 and the compound of formula 3 are reacted in one pot to prepare the compound of general formula II.

[0065] Preferably, in the above-mentioned preparation method of the present invention, the reaction in reaction 1) is carried out in a solvent of hexafluoroisopropanol and a microwave reaction tube.

[0066] Preferably, in the above preparation method of the present invention, the reaction in reaction 2) is carried out in a solvent of 1,2-dichloroethane and a microwave reaction tube.

[0067] Preferably, in the above-mentioned preparation method of the present invention, compound 1 is chromone-3-carboxaldehyde, compound 2 is an amine compound, and compound 3 is an indole compound, and the molar ratio of compound 1, compound 2, and compound 3 is 1:1.5:1.

[0068] In a specific embodiment, a method for preparing a chromone biindole derivative of the present invention is as follows:

[0069]

[0070] In the formula, the R 1 , R 2 , R 3 The definitions of and Ar are the same as those in the aforementioned embodiment, compound 4 is a compound of formula I, and compound 5 is a compound of formula II.

[0071] Preferably, the synthesis method is as follows:

[0072] Compound 1, Compound 2 and Compound 3 were dissolved in hexafluoroisopropanol in a microwave reaction tube, reacted at room temperature for 4 hours, the solution was spin-dried, and purified by silica gel column to obtain target compound 4 (i.e., compound of formula I); Compound 1, Compound 2 and Compound 3 were dissolved in 1,2-dichloroethane in a microwave reaction tube, reacted at 100° C. in an oil bath for 2 hours, the solution was spin-dried, and purified by silica gel column to obtain target compound 5 (i.e., compound of formula II);

[0073] The compound 1 is chromone-3-carboxaldehyde, the compound 2 is an amine compound, and the compound 3 is an indole compound.

[0074] Preferably, the molar ratio of compound 1, compound 2 and compound 3 is 1:1.5:1.

[0075] In another aspect, the present invention provides the use of the chromone biindole derivatives or pharmaceutically acceptable salts or solvates thereof in the preparation of anti-tumor drugs. Preferably, the tumor is lung cancer or colon cancer.

[0076] The present invention has the following beneficial effects:

[0077] 1) The present invention uses substituted chromone, amine compounds and indole compounds as raw materials, and obtains chromone-indole derivatives through multi-component reaction at room temperature or under oil bath heating conditions.

[0078] 2) The synthetic route of the present invention has the advantages of simple operation process, short reaction time, avoidance of the use of precious metal catalysts, simple post-treatment, and low cost.

[0079] 3) The chromone biindole derivatives prepared by the preparation method of the present invention have anti-tumor activity, especially colon cancer and lung cancer. DETAILED DESCRIPTION

[0080] The technical scheme of the present invention will be described clearly and completely in conjunction with specific embodiments. Obviously, the described embodiments are only some representative embodiments of the present invention, rather than all embodiments. Based on the spirit and essence of the present invention, simple modifications and alternative implementation schemes obtained by ordinary technicians in the field without creative work are all within the scope of protection of the present invention.

[0081] The preparation reaction formula of the chromone biindole derivatives in the following examples is as follows:

[0082]

[0083] In the formula, R 1 is a hydrogen atom, a methyl group, an isopropyl group, a chlorine atom, a bromine atom, or a fluorine atom; 2is tert-butyl, cyclobutyl, 4-methoxyphenyl; said R 3 is methyl, aryl, ethyl, ester; Ar is phenyl, 5-chlorophenyl, 6-bromophenyl, 5-iodophenyl, 5-methoxyphenyl, pyridyl, wherein the molar ratio of compound 1, compound 2, and compound 3 is 1:1.5:1. Compound 4 is the compound of general formula I, and compound 5 is the compound of general formula II.

[0084] Example 1 Preparation of Chromone Biindole Derivatives

[0085] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0086]

[0087] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole were dissolved in 2 mL of hexafluoroisopropanol (HFIP), reacted at room temperature for 4 hours, then the solvent was spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one with a yield of 89%.

[0088] 1 H-NMR (400MHz, CDCl3) δ10.41 (d, J = 13.3Hz, 1H), 8.53 (s, 1H), 7.84 (dd, J = 7. 7,1.3Hz,1H),7.75(d,J=7.7Hz,1H),7.20(d,J=7.8Hz,1H),7.15(d,J=7.3Hz ,1H),7.07(dd,J=11.1,4.0Hz,1H),7.03(t,J=7.2Hz,1H),6.96(d,J=2.2Hz, 1H), 6.86 (t, J = 7.5Hz, 1H), 6.75 (t, J = 10.4Hz, 2H), 6.20 (s, 1H), 1.06 (s, 9H). 13C-NMR (100MHz, CDCl3) δ182.02,158.62,147.89,136.89,133.55,126.04,125.33,124.36,122.46 ,121.25,120.58,120.00,117.69,115.59,111.55,100.26,75.78,52.39,29.99.HRMS(ESI)calcd forC 22 H 23 N2O2 + [M+H] + :347.1755,found:347.1753.

[0089] Example 2 Preparation of Chromone Biindole Derivatives

[0090] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a 5-chlorophenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0091]

[0092] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 5-chloroindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-1H-indol-3-yl)chroman-4-one with a yield of 91%.

[0093] 1 H-NMR (400MHz, CDCl3) δ10.40(d,J=13.2Hz,1H),8.23(s,1H),7.83(dd,J=7.8,1.5Hz,1H),7.70(d,J=8.5Hz,1H),7.26(d,J=1.6Hz,1H),7.2 4–7.19(m,1H),7.04(td,J=4.0,1.8Hz,2H),6.90(t,J=7.5Hz,1H),6.78(d,J=8.1Hz,1H),6.74(d,J=13.4Hz,1H),6.18(s,1H),1.14(s,9H). 13C-NMR (100MHz, CDCl3) δ181.84,158.27,147.42,137.13,133.54,128.50,126.01,125.68,124.53,12 4.26,121.57,121.33,120.85,117.58,116.45,111.29,99.93,75.42,52.39,30.03.HRMS(ESI)calcd for C 22 H 22 ClN2O2 + [M+H] + :381.1365,found:381.1365.

[0094] Example 3 Preparation of Chromone Biindole Derivatives

[0095] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a 6-bromophenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-2-(6-bromo-1H-indol-3-yl)-3-(tert-butylamino)methylene)chroman-4-one, and its structural formula is as follows:

[0096]

[0097] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 6-bromoindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-2-(6-bromo-1H-indol-3-yl)-3-(tert-butylamino)methylene)chroman-4-one with a yield of 90%.

[0098] 1 H-NMR (400MHz, CDCl3) δ10.50(d,J=13.2Hz,1H),8.32(s,1H),8.02(d,J=1.6Hz,1H),7.93(dd,J=7.8,1.7Hz,1H),7.34–7.29(m,2H),7. 23(d,J=8.6Hz,1H),7.15(d,J=2.5Hz,1H),7.02–6.98(m,1H),6.90(d,J=8.0Hz,1H),6.85(d,J=13.3Hz,1H),6.26(s,1H),1.25(s,9H). 13C-NMR (100MHz, CDCl3) δ181.85,158.26,147.46,135.38,133.55,127.64,126.18,126.03,125.49,12 4.25,123.26,121.33,117.65,115.98,113.43,112.81,99.75,75.34,52.41,30.02.HRMS(ESI)calcd for C 22 H 22 BrN2O2 + [M+H] + :425.0860,found:425.0855.

[0099] Example 4 Preparation of Chromone Biindole Derivatives

[0100] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a 5-iodophenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(5-iodo-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0101]

[0102] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 5-iodoindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(5-iodo-1H-indol-3-yl)chroman-4-one with a yield of 94%.

[0103] 1 H-NMR (400MHz, CDCl3) δ10.40(d,J=13.3Hz,1H),8.52(s,1H),8.11(d,J=1.3Hz,1H),7.83(dd,J=7.8,1.6Hz,1H),7.34(dd,J=8.5,1.6Hz,1H),7.23–7 .19(m,1H),7.00(d,J=8.5Hz,1H),6.97(d,J=2.3Hz,1H),6.92–6.87(m,1H ),6.80(d,J=7.7Hz,1H),6.74(d,J=13.3Hz,1H),6.14(s,1H),1.12(s,9H). 13C-NMR (100MHz, CDCl3) δ181.89,158.35,147.71,135.90,133.63,130.85,129.45,128.39,126.03,1 25.98,124.26,121.38,117.68,115.28,113.47,99.79,83.68,75.42,52.48,30.03.HRMS(ESI)calcd for C 22 H 22 IN2O2 + [M+H] + :473.0721,found:473.0721.

[0104] Example 5 Preparation of Chromone Biindole Derivatives

[0105] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a pyridyl group, that is, the chromone biindole derivative of this embodiment is a synthesis of (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)chroman-4-one, and its structural formula is as follows:

[0106]

[0107] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 5-azaindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound ((Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)benzodihydropyran-4-one with a yield of 83%.

[0108] 1 H-NMR (400MHz, CDCl3) δ10.39(d,J=13.2Hz,1H),9.13(s,1H),8.21(s,1H),7.81(dd,J=7.8,1.6Hz,1H),7.23–7.14(m ,3H),7.07(d,J=0.5Hz,1H),6.91–6.86(m,1H),6.84(d,J=13.3Hz,1H),6.81–6.77(m,1H),6.24(s,1H),1.19(s,9H). 13C-NMR (100MHz, CDCl3) δ181.61,157.77,147.10,143.21,140.94,140.60,133.66,126.28,12 5.99,124.13,121.43,117.67,117.53,107.00,99.73,75.02,52.50,30.05.HRMS(ESI)calcd for C 21 H 22 N3O2 + [M+H] + :348.1707,found:348.1704.

[0109] Example 6 Preparation of Chromone Biindole Derivatives

[0110] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 2-methyl, Ar is phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(2-methyl-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0111]

[0112] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 2-methylindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(2-methyl-1H-indol-3-yl)chroman-4-one with a yield of 89%.

[0113] 1 H-NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.42(d,J=13.3Hz,1H),7.78(dd,J=7.7,1.6Hz,1H),7.43(d,J=7.9Hz,1H),7.38–7.33(m,1H),7.30(d,J= 8.0Hz,1H),7.04–6.98(m,2H),6.91(dd,J=11.0,4.0Hz,1H),6.84(d,J=7 .7Hz,1H),6.80(d,J=13.2Hz,1H),6.35(s,1H),2.38(s,3H),1.09(s,9H). 13C-NMR (100MHz, DMSO-d6) δ181.45,159.64,148.20,135.93,135.74,133.85,127.44,126.32,124.48,121. 32,120.89,119.80,119.17,117.74,111.20,108.57,100.13,75.53,52.32,29.93,12.37.HRMS(ESI)calcd forC 23 H 25 N2O2 + [M+H] + :361.1911,found:361.1910.

[0114] Example 7 Preparation of Chromone Biindole Derivatives

[0115] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 2-methyl, Ar is 5-methoxyphenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(5-methoxy-2-methyl-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0116]

[0117] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 2-methyl-5-methoxyindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(5-methoxy-2-methyl-1H-indol-3-yl)benzodihydropyran-4-one with a yield of 87%.

[0118] 1H-NMR (400MHz, CDCl3) δ10.58(d,J=13.4Hz,1H),8.31(s,1H),8.02(dd,J=7.8,1.6Hz,1H),7.41–7.35(m,1H),7.20(d,J=8.7Hz,1H),7.12–7 .05(m,2H),6.97(d,J=8.1Hz,1H),6.80(dd,J=8.8,2.4Hz,1H),6.70(d,J=13.4Hz,1H),6.32(s,1H),3.77(s,3H),2.43(s,3H),1.13(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.84,160.11,154.13,148.40,135.63,133.47,130.60,127.45,126.34,124.56,1 21.32,117.57,111.75,111.40,108.02,102.10,99.92,75.54,55.91,52.21,29.99,12.31.HRMS(ESI)calcd for C 24 H 27 N2O3 + [M+H] + :391.2017,found:391.2016.

[0119] Example 8 Preparation of Chromone Biindole Derivatives

[0120] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 2-phenyl, Ar phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(2-phenyl-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0121]

[0122] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 2-phenylindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(2-phenyl-1H-indol-3-yl)chroman-4-one with a yield of 92%.

[0123] 1H-NMR (400MHz, DMSO-d6) δ11.66 (s, 1H), 10.43 (d, J = 13.3Hz, 1H), 7.80 (dd, J = 7.7 ,1.6Hz,1H),7.63–7.58(m,2H),7.57(d,J=8.0Hz,1H),7.52(t,J=7.6Hz,2H),7.47 (d,J=8.1Hz,1H),7.40(ddd,J=13.4,9.9,4.6Hz,2H),7.20-7.13(m,1H),7.08–6.9 8(m,2H),6.88(d,J=7.7Hz,1H),6.73(d,J=13.1Hz,1H),6.35(s,1H),1.02(s,9H). 13 C-NMR(100MHz,DMSO-d6)δ181.49,159.69,148.29,138.65,136.74,134.01,132.33,129.34,128.96,128.74,127.30,1 26.49,124.47,122.36,121.66,121.20,119.76,117.68,112.12,108.33,99.78,75.99,52.33,29.80.HRMS(ESI)calcd for C 28 H 27 N2O2 + [M+H] + :423.2068,found:423.2068.

[0124] Example 9 Preparation of Chromone Biindole Derivatives

[0125] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 2-phenyl, Ar is 5-bromophenyl, that is, the chromone biindole derivative of this embodiment is (Z)-2-(5-bromo-2-phenyl-1H-indol-3-yl)-3-((tert-butylamino)methylene)chroman-4-one, and its structural formula is as follows:

[0126]

[0127] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 2-phenyl-5-bromoindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 1 hour. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-2-(5-bromo-2-phenyl-1H-indol-3-yl)-3-((tert-butylamino)methylene)chroman-4-one with a yield of 90%.

[0128] 1 H-NMR (400MHz, CDCl3) δ10.43(d,J=13.4Hz,1H),8.49(d,J=11.3Hz,1H),7.92–7.85(m,2H),7.44(d,J=7.0Hz,2H),7.40–7.3 2(m,3H),7.30-7.23(m,3H),6.97(t,J=7.5Hz,1H),6.86(d,J=8.2Hz,1H),6.60(d,J=13.4Hz,1H),6.31(s,1H),1.01(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.67,159.75,148.16,139.43,134.88,133.55,131.37,129.16,128.96,128.34,126.4 2,125.77,124.47,124.36,121.51,117.48,113.68,112.66,108.61,99.70,75.52,52.28,29.92.HRMS(ESI)calcd for C 28 H 26 BrN2O2 + [M+H] + :501.1173,found:501.1172.

[0129] Example 10 Preparation of Chromone Biindole Derivatives

[0130] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 2-(4-chlorophenyl), Ar is phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(2-(4-chlorophenyl)-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0131]

[0132] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 2-(4-chlorophenyl)indole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(2-(4-chlorophenyl)-1H-indol-3-yl)chroman-4-one with a yield of 87%.

[0133] 1 H-NMR (400MHz, CDCl3) δ10.42(d,J=13.3Hz,1H),8.42(s,1H),7.89(dd,J=7 .8,1.5Hz,1H),7.72(d,J=8.0Hz,1H),7.41–7.32(m,5H),7.28(dd,J=11.0,4 .4Hz,1H),7.15(d,J=7.2Hz,1H),7.06(d,J=7.3Hz,1H),6.96(t,J=7.2Hz,1 H),6.85(d,J=8.1Hz,1H),6.61(d,J=13.3Hz,1H),6.31(s,1H),0.98(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.67,159.80,148.21,136.86,136.34,134.67,133.53,130.40,129.61,129.28,127.13,12 6.41,124.47,123.14,121.87,121.46,120.59,117.45,111.20,109.41,99.90,75.65,52.21,29.89.HRMS(ESI)calcd for C 28 H 26 ClN2O2 + [M+H] + :457.1678,found:457.1677.

[0134] Example 11 Preparation of Chromone Biindole Derivatives

[0135] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 1-(2-chloroethyl), Ar is pyridyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1-(2-chloroethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)chroman-4-one, and its structural formula is as follows:

[0136]

[0137] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 1-(2-chloroethyl)-1H-pyrrolo[2,3-c]pyridine were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(1-(2-chloroethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)benzodihydropyran-4-one with a yield of 89%.

[0138] 1 H-NMR (400MHz, CDCl3) δ10.49(d,J=13.3Hz,1H),9.76(s,1H),8.19(d,J=6.8Hz,1H),8.06(d,J=6.7Hz,1H),7.89(s,1H),7.80(dd,J=7.8, 1.6Hz,1H),7.24–7.17(m,1H),6.94–6.85(m,2H),6.75(d,J=7.9Hz,1H),6.26(s,1H),5.20–4.98(m,2H),4.17–4.01(m,2H),1.25(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.86,157.10,147.29,139.19,134.34,133.81,132.94,131.66,131.57,126. 16,123.93,121.84,118.87,117.36,116.85,98.78,74.14,61.45,52.73,44.34,30.02.HRMS(ESI)calcd for C 23 H 25 ClN3O2 + [M+H] + :410.1630,found:410.1633.

[0139] Example 12 Preparation of Chromone Biindole Derivatives

[0140] R in chromone biindole derivatives 1 is a hydrogen atom, R 2is tert-butyl, R3 is 1-(2-chloroethyl-acetate), Ar is phenyl, that is, the chromone biindole derivative of this embodiment is 2-chloroethyl (Z)-2-(3-((tert-butylamino)methylene)-4-oxochromone-2-yl)-1H-indol-1-yl) acetate, and its structural formula is as follows:

[0141]

[0142] In a 10mL microwave reaction tube, 0.3mmol of chromone-3-carboxaldehyde, 0.45mmol of tert-butylamine and 0.3mmol of 2-chloroethyl 2-(1H-indol-1-yl) acetate were dissolved in 2mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target 2-chloroethyl (Z)-2-(3-((tert-butylamino)methylene)-4-oxochromone-2-yl)-1H-indol-1-yl) acetate with a yield of 82%.

[0143] 1 H-NMR (400MHz, CDCl3) δ10.39(d,J=13.2Hz,1H),7.86–7.75(m,2H),7.21–7.15(m,2H),7.14(d,J=5.9Hz,1H),7.10(d,J=8.0Hz,1H),6.95 (s,1H),6.89(t,J=7.3Hz,1H),6.81–6.74(m,2H),6.21(s,1H),4.73(d,J=1.5Hz,2H),4.31–4.25(m,2H),3.54–3.48(m,2H),1.14(s,9H). 13 C-NMR (100MHz, CDCl3) δ181.83,168.04,158.36,147.63,137.37,133.43,129.21,126.73,126.01,124.32,122.75,1 21.18,121.02,120.33,117.64,116.26,109.14,100.03,75.41,64.87,52.39,47.52,41.17,30.01.HRMS(ESI)calcd forC 26 H 28 ClN2O4 + [M+H] + :467.1733,found:467.1732.

[0144] Example 13 Preparation of Chromone Biindole Derivatives

[0145] R in chromone biindole derivatives1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 1-ethyl-2-methyl, Ar is phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1-ethyl-2-methyl-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0146]

[0147] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 1-ethyl-2-methylindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1-ethyl-2-methyl-1H-indol-3-yl)chroman-4-one with a yield of 90%.

[0148] 1 H-NMR (400MHz, CDCl3) δ10.58 (d, J=13.3Hz, 1H), 8.04 (dd, J=7.8, 1.7Hz, 1H), 7. 69(d,J=7.9Hz,1H),7.41–7.34(m,2H),7.23–7.17(m,1H),7.12–7.06(m,2H),6.9 8(dd,J=8.2,0.6Hz,1H),6.65(dd,J=13.3,0.7Hz,1H),6.42(d,J=0.6Hz,1H),4.2 1(ddd,J=14.5,7.3,3.7Hz,2H),2.49(s,3H),1.40(t,J=7.2Hz,3H),1.12(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.72,160.15,148.29,136.04,135.61,133.40,126.59,126.39,124.58,121.23,121. 19,120.38,119.57,117.51,109.02,107.71,100.39,75.82,52.13,37.93,29.96,15.31,10.71.HRMS(ESI)calcd for C 25 H 29 N2O2 + [M+H] + :389.2224,found:389.2222.

[0149] Example 14 Preparation of Chromone Biindole Derivatives

[0150] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is 1,2-dimethyl, Ar is phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1,2-dimethyl-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0151]

[0152] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 1,2-dimethylindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1,2-dimethyl-1H-indol-3-yl)benzodihydropyran-4-one with a yield of 85%.

[0153] 1 H-NMR (400MHz, CDCl3) δ10.63(d,J=13.3Hz,1H),8.04(dd,J=7.8,1.5Hz,1H),7.69(d,J=7.9Hz,1H),7.41–7.35(m,1H),7.33(d,J=8.2Hz,1H),7.21 (t,J=7.6Hz,1H),7.09(dd,J=14.6,7.2Hz,2H),6.96(d,J=8.2Hz,1H),6. 71(d,J=13.3Hz,1H),6.42(s,1H),3.72(s,3H),2.49(s,3H),1.13(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.74,160.12,148.38,137.18,136.60,133.40,126.44,126.29,124.57,121.25,1 21.23,120.41,119.64,117.50,108.99,107.56,100.26,75.81,52.16,30.01,29.67,10.94.HRMS(ESI)calcd forC 24 H 27 N2O2 + [M+H] + :375.2068,found:375.2066.

[0154] Example 15 Preparation of Chromone Biindole Derivatives

[0155] R in chromone biindole derivatives 1 is 6-methyl, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)-6-methylchroman-4-one, and its structural formula is as follows:

[0156]

[0157] In a 10 mL microwave reaction tube, 0.3 mmol of 6-methyl-chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)-6-methylchroman-4-one with a yield of 86%.

[0158] 1 H-NMR (400MHz, CDCl3) δ10.39(d,J=13.0Hz,1H),8.05(s,1H),7.77(d,J=7.8Hz,1H),7.63(d,J=1.8Hz,1H),7.29–7.26(m,1H),7.12(dd,J=11.1, 4.1Hz,1H),7.09–7.04(m,2H),7.01(dd,J=8.4,2.3Hz,1H),6.75(d,J=13 .2Hz,1H),6.69(d,J=8.3Hz,1H),6.19(s,1H),2.21(s,3H),1.13(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.16,156.40,147.37,136.74,134.32,130.41,126.01,125.93,124.89,123.9 3,122.55,120.67,120.08,117.38,116.34,111.24,100.36,75.52,52.23,30.02,20.60.HRMS(ESI)calcd for C 23 H 25 N2O2 + [M+H] + :361.1911,found:361.1910.

[0159] Example 16 Preparation of Chromone Biindole Derivatives

[0160] R in chromone biindole derivatives 1 is 6-isopropyl, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)-6-isopropylchroman-4-one, and its structural formula is as follows:

[0161]

[0162] In a 10 mL microwave reaction tube, 0.3 mmol of 6-isopropyl-chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)-6-isopropylchroman-4-one with a yield of 89%.

[0163] 1 H-NMR (400MHz, CDCl3) δ10.44(d,J=13.2Hz,1H),8.28(s,1H),7.74(dd,J=13.4,4.9Hz,2H),7.23(d,J=8.0Hz,1H),7.06(ddd ,J=18.9,13.2,4.6Hz,4H),6.78–6.66(m,2H),6.19(s,1H),2.76(dq,J=13.4,6.7Hz,1H),1.13(d,J=6.9Hz,6H),1.09(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.30,156.75,147.63,141.59,136.81,132.12,125.97,125.08,123.87,123.19,122. 47,120.66,120.01,117.38,115.90,111.38,100.37,75.60,52.26,33.44,30.00,24.05,24.02.HRMS(ESI)calcd for C 25 H 29 N2O2 + [M+H] + :389.2224,found:389.2225.

[0164] Example 17 Preparation of Chromone Biindole Derivatives

[0165] R in chromone biindole derivatives 1 is 6-fluoro, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-6-fluoro-2-(1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0166]

[0167] In a 10 mL microwave reaction tube, 0.3 mmol of 6-fluorochromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-fluoro-2-(1H-indol-3-yl)chroman-4-one with a yield of 87%.

[0168] 1 H-NMR (400MHz, CDCl3) δ10.53(d,J=13.2Hz,1H),8.28(s,1H),7.86(d,J=7.8Hz,1H),7.59(dd,J=8.7,3.1Hz,1H),7.37(d,J=8.1Hz,1H),7.23( t,J=7.5Hz,1H),7.20–7.12(m,2H),6.98(td,J=8.4,3.1Hz,1H),6.89(d,J=13.4Hz,1H),6.84(dd,J=8.9,4.3Hz,1H),6.30(s,1H),1.23(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.81,158.68,156.30,154.43,147.98,136.78,125.89,125.13,122.6 4,120.55,120.21,120.16,118.97,118.90,115.95,111.56,111.38,99.94,75.71,52.51,29.98. 19 F-NMR(376MHz,CDCl3)δ-122.27.HRMS(ESI)calcd for C 22 H 22 FN2O2 + [M+H] +:365.1660,found:365.1663.

[0169] Example 18 Preparation of Chromone Biindole Derivatives

[0170] R in chromone biindole derivatives 1 is 6-chloro, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0171]

[0172] In a 10 mL microwave reaction tube, 0.3 mmol of 6-chlorochromone-3-carboxaldehyde, 0.45 mmol of cyclopentylamine and 0.3 mmol of indole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)chroman-4-one with a yield of 88%.

[0173] 1 H-NMR (400MHz, DMSO-d6) δ11.00(d,J=1.5Hz,1H),10.43(d,J=13.4Hz,1H),7.72(d,J=7.8Hz,1H),7.63(d,J=2.7Hz,1H),7.36(dd,J=1 2.4,10.9Hz,2H),7.28(dd,J=8.7,2.8Hz,1H),7.12–7.07(m,1H),7.05–6.99(m,2H),6.83(d,J=8.7Hz,1H),6.41(s,1H),1.25(s,9H). 13 C-NMR(100MHz,DMSO-d6)δ178.81,156.60,149.28,137.20,133.18,126.35,126.15,125.89,125.26,1 25.07,122.01,120.13,120.08,119.58,116.35,112.21,99.69,75.52,52.80,29.99.HRMS(ESI)calcd for C 22 H 22 ClN2O2 + [M+H] + :381.1365,found:381.1366.

[0174] Example 19 Preparation of Chromone Biindole Derivatives

[0175] R in chromone biindole derivatives 1 is 6-bromo, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0176]

[0177] In a 10 mL microwave reaction tube, 0.3 mmol 6-bromochromone-3-carboxaldehyde, 0.45 mmol tert-butylamine and 0.3 mmol indole were dissolved in 2 mL hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one with a yield of 90%.

[0178] 1 H-NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.44(d,J=13.4Hz,1H),7.78(t,J=3.8Hz,1H),7.74(d,J=7.8Hz,1H),7.39(ddd,J= 14.2,6.0,3.1Hz,3H),7.11(t,J=7.6Hz,1H),7.04(dd,J=12.3,4.7Hz,2H),6.79(d,J=8.7Hz,1H),6.43(s,1H),1.26(s,9H). 13 C-NMR(100MHz,DMSO-d6)δ178.73,157.02,149.29,137.21,135.97,128.11,126.38,126.36,126.16,1 22.02,120.49,120.13,119.59,116.36,112.91,112.22,99.65,75.53,52.80,29.99.HRMS(ESI)calcd for C 22 H 22 BrN2O2 + [M+H] + :425.0860,found:425.0860.

[0179] Example 20 Preparation of Chromone Biindole Derivatives

[0180] R in chromone biindole derivatives 1 is 6-chloro-7-methyl, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)-7-methylchroman-4-one, and its structural formula is as follows:

[0181]

[0182] In a 10 mL microwave reaction tube, 0.3 mmol 6-chloro-7-methylchromone-3-carboxaldehyde, 0.45 mmol tert-butylamine and 0.3 mmol indole were dissolved in 2 mL hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)-7-methylchroman-4-one with a yield of 86%.

[0183] 1 H-NMR (400MHz, CDCl3) δ10.46(d,J=13.2Hz,1H),8.32(s,1H),7.86(t,J=3.5Hz,2H),7.37(d,J=8.0Hz,1H),7.20(ddd,J=1 4.9,14.0,7.0Hz,2H),7.11(d,J=2.2Hz,1H),6.88(d,J=13.3Hz,1H),6.75(s,1H),6.29(s,1H),2.27(s,3H),1.24(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.64,156.61,147.67,141.78,136.77,126.97,125.93,125.12,123.41,1 22.60,120.46,120.14,119.87,116.26,111.39,99.65,75.74,52.45,30.00,20.49.HRMS(ESI)calcd for C 23 H 24 ClN2O2 + [M+H] + :395.1521,found:395.1521.

[0184] Example 21 Preparation of Chromone Biindole Derivatives

[0185] R in chromone biindole derivatives 1 is 6-methyl, R 2 is tert-butyl, R 3 is 1-methyl, Ar is phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-6-methyl-2-(1-methyl-1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0186]

[0187] In a 10 mL microwave reaction tube, 0.3 mmol of 6-methylchromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of N-methylindole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-methyl-2-(1-methyl-1H-indol-3-yl)chroman-4-one with a yield of 94%.

[0188] 1 H-NMR (400MHz, CDCl3) δ10.51(d,J=13.0Hz,1H),7.86(d,J=7.9Hz,1H),7.73(d,J=1.8Hz,1H),7.31–7.23(m,2H),7.19–7.13(m,1H),7.1 0(dd,J=8.3,2.1Hz,1H),7.01(s,1H),6.88(d,J=13.2Hz,1H),6.78(d,J=8.3Hz,1H),6.27(s,1H),3.74(s,3H),2.31(s,3H),1.25(s,9H). 13 C-NMR (100MHz, CDCl3) δ182.18,156.39,147.36,137.59,134.31,130.31,129.62,126.50,125.93,123.90,1 22.06,120.70,119.60,117.41,114.63,109.39,100.39,75.46,52.24,32.82,30.06,20.61.HRMS(ESI)calcd for C 24 H 27 N2O2 + [M+H] + :375.2068,found:375.2086.

[0189] Example 22 Preparation of Chromone Biindole Derivatives

[0190] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is cyclobutyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((cyclobutylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one, and its structural formula is as follows:

[0191]

[0192] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of cyclobutylamine and 0.3 mmol of indole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((cyclobutylamino)methylene)-2-(1H-indol-3-yl)benzodihydropyran-4-one with a yield of 87%.

[0193] 1 H-NMR (400MHz, CDCl3) δ10.20(dd,J=12.3,8.0Hz,1H),8.38(s,1H),7.85(dd,J=7.7,1 .5Hz,1H),7.75(d,J=7.8Hz,1H),7.27–7.17(m,2H),7.10(dd,J=11.1,4.0Hz,1H),7.0 7–6.99(m,2H),6.88(t,J=7.2Hz,1H),6.78(d,J=8.1Hz,1H),6.62(d,J=12.9Hz,1H),6 .19(s,1H),2.91–2.78(m,1H),1.62(s,2H),1.27–1.19(m,2H),1.09(d,J=23.5Hz,2H). 13 C-NMR (100MHz, CDCl3) δ182.11,158.69,150.04,136.83,133.48,126.07,125.97,125.14,124.31,122.48,1 21.22,120.61,120.05,117.62,115.62,111.44,100.40,75.60,57.31,34.05,25.16,24.39.HRMS(ESI)calcd for C 22 H 21 N2O2 + [M+H] + :345.1598,found:345.1599.

[0194] Example 23 Preparation of Chromone Biindole Derivatives

[0195] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is 4-methoxyphenyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-2-(1H-indol-3-yl)-3-(((4-methoxyphenyl)amino)methylene)chroman-4-one, and its structural formula is as follows:

[0196]

[0197] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of 4-methoxyaniline and 0.3 mmol of indole were dissolved in 2 mL of hexafluoroisopropanol and reacted at room temperature for 4 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-2-(1H-indol-3-yl)-3-(((4-methoxyphenyl)amino)methylene)chroman-4-one with a yield of 76%.

[0198] 1 H-NMR (400MHz, CDCl3) δ11.90(d,J=12.4Hz,1H),8.29(s,1H),7.88(dd,J=7.8,1.6Hz,1H),7.77(d,J=7.7Hz,1H),7.25–7.18(m,2H),7.14–7.05(m,2H ),7.03(d,J=2.4Hz,1H),6.99(d,J=12.4Hz,1H),6.90(t,J=7.5Hz,1H),6. 80(d,J=8.1Hz,1H),6.68(td,J=9.1,2.4Hz,4H),6.27(s,1H),3.62(s,3H). 13 C-NMR (100MHz, CDCl3) δ183.24,159.05,156.32,143.03,136.78,134.19,133.66,126.29,125.88,125.07,123 .84,122.73,121.44,120.60,120.29,117.87,115.31,114.97,111.46,103.60,75.58,55.57.HRMS(ESI)calcd for C 25 H 21 N2O3 + [M+H] + :397.1547,found:397.1545.

[0199] Example 24 Preparation of Chromone Biindole Derivatives

[0200] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-1-yl)chroman-4-one, and its structural formula is as follows:

[0201]

[0202] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole were dissolved in 2 mL of 1,2-dichloroethane (DCE), and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-1-yl)chroman-4-one with a yield of 42%.

[0203] 1 H-NMR (400MHz, CDCl3) δ10.87(d,J=13.0Hz,1H),7.86(d,J=7.7Hz,1H),7.69(d,J=8.2Hz,1H),7.50(d,J=7.8Hz,1H),7.22(d,J=7.6 Hz,1H),7.17(d,J=7.2Hz,1H),7.08(t,J=7.5Hz,1H),7.01–6.90(m,4H),6.70(d,J=8.2Hz,1H),6.28(d,J=2.9Hz,1H),1.24(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.31,155.60,149.27,135.90,133.87,129.54,126.03,125.86,123.00,12 2.18,122.15,120.97,120.59,117.86,110.91,102.35,96.57,83.81,53.19,29.99.HRMS(ESI)calcd for C 22 H 23 N2O2 + [M+H] + :347.1755,found:347.1759.

[0204] Example 25 Preparation of Chromone Biindole Derivatives

[0205] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a 5-chlorophenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-1H-indol-1-yl)chroman-4-one, and its structural formula is as follows:

[0206]

[0207] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 5-chloroindole were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-1H-indol-1-yl)benzodihydropyran-4-one with a yield of 37%.

[0208] 1 H-NMR (400MHz, CDCl3) δ10.96(d,J=13.3Hz,1H),7.96(dd,J=7.8,1.4Hz,1H),7.81(s,1H),7.49(d,J=8.4Hz,1H),7.34–7.29( m,1H),7.15(dd,J=8.4,1.7Hz,1H),7.09–7.03(m,3H),6.95(s,1H),6.84(d,J=8.2Hz,1H),6.34(d,J=3.4Hz,1H),1.37(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.19,155.31,149.25,136.22,133.97,128.11,128.04,126.73,125.87,12 2.93,122.36,121.74,121.25,117.85,111.12,102.27,96.11,83.95,53.28,29.99.HRMS(ESI)calcd for C 22 H 22 ClN2O2 + [M+H] + :381.1365,found:381.1366.

[0209] Example 26 Preparation of Chromone Biindole Derivatives

[0210] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a 5-bromophenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-2-(5-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)chroman-4-one, and its structural formula is as follows:

[0211]

[0212] In a 10mL microwave reaction tube, 0.3mmol of chromone-3-carboxaldehyde, 0.45mmol of tert-butylamine and 0.3mmol of 5-bromoindole were dissolved in 2mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-2-(5-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)benzodihydropyran-4-one with a yield of 39%.

[0213] 1 H-NMR (400MHz, CDCl3) δ10.87(d,J=13.1Hz,1H),7.86(dd,J=7.8,1.6Hz,1H),7.59(dd,J=14.9,5.2Hz,2H),7.29(dd,J=8.7,1.8 Hz,1H),7.20(dt,J=7.3,2.1Hz,2H),7.00–6.93(m,3H),6.87(s,1H),6.69(d,J=8.2Hz,1H),6.21(d,J=3.4Hz,1H),1.27(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.19,155.28,149.22,134.50,133.95,131.27,127.21,125.89,124.96,12 3.42,122.95,122.37,117.75,113.84,112.50,101.72,96.16,84.05,53.27,29.99.HRMS(ESI)calcd for C 22 H 22 BrN2O2 + [M+H] + :425.0860,found:425.0859.

[0214] Example 27 Preparation of Chromone Biindole Derivatives

[0215] R in chromone biindole derivatives1 is a hydrogen atom, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a 5-iodophenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(5-iodo-1H-indol-1-yl)chroman-4-one, and its structural formula is as follows:

[0216]

[0217] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 5-iodoindole were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(5-iodo-1H-indol-1-yl)benzodihydropyran-4-one with a yield of 33%.

[0218] 1 H-NMR (400MHz, CDCl3) δ10.87(d,J=13.3Hz,1H),7.88–7.78(m,2H),7.50–7.43(m,2H),7.22–7.16(m, 1H), 6.98–6.92 (m, 3H), 6.87 (s, 1H), 6.69 (dd, J=8.2, 0.6Hz, 1H), 6.19 (d, J=3.4Hz, 1H), 1.26 (s, 9H). 13 C-NMR (100MHz, CDCl3) δ180.18,155.28,149.23,134.96,133.96,132.07,130.44,129.74,126.8 4,125.89,122.94,122.37,117.76,113.01,101.46,96.15,83.98,53.28,29.99.HRMS(ESI)calcd for C 22 H 22 IN2O2 + [M+H] + :437.0721,found:437.0720.

[0219] Example 28 Preparation of Chromone Biindole Derivatives

[0220] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3is a hydrogen atom, Ar is a 6-bromophenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-2-(6-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)chroman-4-one, and its structural formula is as follows:

[0221]

[0222] In a 10mL microwave reaction tube, 0.3mmol of chromone-3-carboxaldehyde, 0.45mmol of tert-butylamine and 0.3mmol of 6-bromoindole were dissolved in 2mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-2-(6-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)benzodihydropyran-4-one with a yield of 37%.

[0223] 1 H-NMR (400MHz, CDCl3) δ10.87(d,J=13.1Hz,1H),7.89–7.85(m,2H),7.35(d,J=8.4Hz,1H),7.23(dd,J=11.2,4.3Hz,1 H),7.17(d,J=1.7Hz,1H),6.99–6.94(m,3H),6.85(s,1H),6.74(d,J=8.0Hz,1H),6.24(d,J=3.3Hz,1H),1.27(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.18,155.32,149.23,136.63,133.96,128.37,126.63,125.87,123.83,12 2.93,122.36,122.12,117.85,115.76,114.06,102.33,96.12,83.92,53.28,29.98.HRMS(ESI)calcd for C 22 H 22 BrN2O2 + [M+H] + :425.0860,found:425.0859.

[0224] Example 29 Preparation of Chromone Biindole Derivatives

[0225] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3is a hydrogen atom, Ar is a pyridyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)chroman-4-one, and its structural formula is as follows:

[0226]

[0227] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 7-azaindole were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)benzodihydropyran-4-one with a yield of 43%.

[0228] 1 H-NMR (400MHz, CDCl3) δ10.43(d,J=13.3Hz,1H),8.25(dd,J=4.7,1.3Hz,1H),8.12(dd,J=7.9,1.4Hz,1H),7.83(dd,J=7.8,1.6Hz ,1H),7.30–7.16(m,3H),7.05(dd,J=7.9,4.8Hz,1H),6.94–6.87(m,1H),6.77(dd,J=10.7,7.6Hz,2H),6.19(s,1H),1.16(s,9H). 13 C-NMR (100MHz, CDCl3) δ181.80,158.17,149.20,147.24,143.22,133.53,129.40,126.08,125.6 3,124.25,121.40,118.79,117.49,116.16,114.89,99.79,75.66,52.38,30.05.HRMS(ESI)calcd for C 21 H 22 N3O2 + [M+H] + :348.1707,found:348.1706.

[0229] Example 30 Preparation of Chromone Biindole Derivatives

[0230] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3is a hydrogen atom, Ar is a pyridyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)chroman-4-one, and its structural formula is as follows:

[0231]

[0232] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 6-azaindole were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)benzodihydropyran-4-one with a yield of 23%.

[0233] 1 H-NMR (400MHz, CDCl3) δ10.42(d,J=13.3Hz,1H),8.74(s,1H),8.19(d,J=5.6Hz,1H),7.83(dd,J=7.8,1.6Hz,1H),7.72( dd,J=5.6,0.7Hz,1H),7.30(s,1H),7.24–7.16(m,2H),6.92–6.86(m,1H),6.81–6.73(m,2H),6.22(s,1H),1.15(s,9H). 13 C-NMR (100MHz, CDCl3) δ181.76,158.11,147.27,137.88,134.17,134.07,133.64,131.22,129.6 0,126.07,124.19,121.44,117.57,116.10,115.32,99.81,75.13,52.46,30.03.HRMS(ESI)calcd forC 21 H 22 N3O2 + [M+H] + :348.1707,found:348.1705.

[0234] Example 31 Preparation of Chromone Biindole Derivatives

[0235] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3is 3-methyl, Ar is phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(3-methyl-1H-indol-1-yl)chroman-4-one, and its structural formula is as follows:

[0236]

[0237] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of 3-methylindole were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(3-methyl-1H-indol-1-yl)chroman-4-one with a yield of 90%.

[0238] 1 H-NMR (400MHz, CDCl3) δ11.01(d,J=13.2Hz,1H),8.02(dd,J=7.7,1.4Hz,1H),7.77(d,J=8.2Hz,1H),7.57(d,J=7.8Hz,1H), 7.37–7.28(m,2H),7.22(t,J=7.5Hz,1H),7.11–6.98(m,3H),6.89(s,1H),6.83(d,J=8.2Hz,1H),2.23(s,3H),1.37(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.39,155.84,149.29,136.26,133.86,129.98,125.89,123.48,122.97,122. 15,122.06,120.02,119.08,117.88,111.53,110.69,96.82,83.65,53.17,30.01,9.70.HRMS(ESI)calcd for C 23 H 25 N2O2 + [M+H] + :361.1911,found:361.1910.

[0239] Example 32 Preparation of Chromone Biindole Derivatives

[0240] R in chromone biindole derivatives 1 is a hydrogen atom, R 2 is tert-butyl, R 3is 3-(2-hydroxyethyl), Ar is phenyl, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(3-(2-hydroxyethyl)-1H-indol-1-yl)chroman-4-one, and its structural formula is as follows:

[0241]

[0242] In a 10 mL microwave reaction tube, 0.3 mmol of chromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole-3-ethanol were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(3-(2-hydroxyethyl)-1H-indol-1-yl)chroman-4-one with a yield of 89%.

[0243] 1 H-NMR (400MHz, CDCl3) δ10.98(d,J=13.3Hz,1H),7.98(dd,J=7.8,1.5Hz,1H),7.78(d,J=8.2Hz,1H),7.59(d,J=7.9Hz,1H),7.36–7.28(m,2 H),7.20(t,J=7.5Hz,1H),7.08–7.01(m,3H),6.97(s,1H),6.80(d,J=8.2Hz,1H),3.79(t,J=6.4Hz,2H),2.90(t,J=6.4Hz,2H),1.35(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.31,155.63,149.30,136.46,133.89,129.16,125.90,124.26,122.96,122.47,1 22.20,120.35,119.13,117.81,112.12,111.04,96.59,83.76,62.48,53.22,29.99,28.69.HRMS(ESI)calcd for C 24 H 27 N2O3 + [M+H] + :391.2017,found:391.2014.

[0244] Example 33 Preparation of Chromone Biindole Derivatives

[0245] R in chromone biindole derivatives 1 is 6-fluoro, R 2is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-6-fluoro-2-(1H-indol-1-yl)chroman-4-one, and its structural formula is as follows:

[0246]

[0247] In a 10 mL microwave reaction tube, 0.3 mmol 6-fluorochromone-3-carboxaldehyde, 0.45 mmol tert-butylamine and 0.5 mmol indole were dissolved in 2 mL 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-fluoro-2-(1H-indol-1-yl)chroman-4-one with a yield of 34%.

[0248] 1 H-NMR (400MHz, CDCl3) δ10.88(d,J=13.1Hz,1H),7.68(d,J=8.2Hz,1H),7.55–7.49(m,2H),7.22(t,J=7.6Hz,1H),7.09(t,J= 7.5Hz,1H),6.97(dd,J=8.4,5.0Hz,2H),6.93–6.86(m,2H),6.67(dd,J=8.9,4.3Hz,1H),6.30(d,J=3.4Hz,1H),1.26(s,9H). 13 C-NMR (100MHz, CDCl3) δ180.31,155.63,149.30,136.46,133.89,129.16,125.90,124.26,122.96,1 22.47,122.20,120.35,119.13,117.81,112.12,111.04,96.59,83.76,62.48,53.22,29.99,28.69. 19 F NMR(376MHz,CDCl3)δ-120.75.HRMS(ESI)calcd for C 22 H 22 FN2O2 + [M+H] + :365.1660,found:365.1659.

[0249] Example 34 Preparation of Chromone Biindole Derivatives

[0250] R in chromone biindole derivatives 1is 6-chloro, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)chroman-4-one, and its structural formula is as follows:

[0251]

[0252] In a 10 mL microwave reaction tube, 0.3 mmol of 6-chlorochromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)chroman-4-one with a yield of 38%.

[0253] 1 H-NMR (400MHz, CDCl3) δ10.89(d,J=13.2Hz,1H),7.82(d,J=2.6Hz,1H),7.66(d,J=8.2Hz,1H),7.51(d,J=7.9Hz,1H),7.22(t,J=7 .6Hz,1H),7.13–7.07(m,2H),6.96(dd,J=8.4,5.0Hz,2H),6.93(s,1H),6.64(d,J=8.7Hz,1H),6.30(d,J=3.3Hz,1H),1.26(s,9H). 13 C-NMR (100MHz, CDCl3) δ178.85,153.97,149.65,135.84,133.54,129.57,127.55,125.85,125.52,12 4.06,122.26,121.05,120.73,119.43,110.79,102.62,96.18,83.83,53.43,29.95.HRMS(ESI)calcd for C 22 H 22 ClN2O2 + [M+H] + :381.1365,found:381.1363.

[0254] Example 35 Preparation of Chromone Biindole Derivatives

[0255] R in chromone biindole derivatives 1 is 6-isopropyl, R 2 is tert-butyl, R3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-1-yl)-6-isopropylchroman-4-one, and its structural formula is as follows:

[0256]

[0257] In a 10 mL microwave reaction tube, 0.3 mmol of 6-isopropylchromone-3-carboxaldehyde, 0.45 mmol of tert-butylamine and 0.3 mmol of indole were dissolved in 2 mL of 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(1H-indol-1-yl)-6-isopropylchroman-4-one with a yield of 35%.

[0258] 1 H-NMR (400MHz, CDCl3) δ10.90(d,J=13.0Hz,1H),7.73(d,J=2.2Hz,1H),7.69(d,J =8.2Hz,1H),7.50(d,J=7.9Hz,1H),7.21(t,J=7.7Hz,1H),7.07(dd,J=11.7,4.9H z,2H),7.00(d,J=3.4Hz,1H),6.92(t,J=6.6Hz,2H),6.64(d,J=8.4Hz,1H),6.29( d,J=3.3Hz,1H),2.78(dt,J=13.8,6.9Hz,1H),1.24(s,9H),1.14(d,J=6.9Hz,6H). 13 C-NMR (100MHz, CDCl3) δ180.65,153.72,149.18,142.63,135.93,132.54,129.52,126.11,123.01,122.52,1 22.10,120.92,120.54,117.58,110.97,102.22,96.68,83.82,53.10,33.43,29.98,23.97.HRMS(ESI)calcd for C 25 H 29 N2O2 + [M+H] + :389.2224,found:389.2223.

[0259] Example 36 Preparation of Chromone Biindole Derivatives

[0260] R in chromone biindole derivatives 1 is 6-chloro-7-methyl, R 2 is tert-butyl, R 3 is a hydrogen atom, Ar is a phenyl group, that is, the chromone biindole derivative of this embodiment is (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)-7-methylchroman-4-one, and its structural formula is as follows:

[0261]

[0262] In a 10 mL microwave reaction tube, 0.3 mmol 6-chloro-7-methyl-chromone-3-carboxaldehyde, 0.45 mmol tert-butylamine and 0.3 mmol indole were dissolved in 2 mL 1,2-dichloroethane, and reacted for 2 hours in an oil bath at 100° C., then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)-7-methylchroman-4-one with a yield of 34%.

[0263] 1 H-NMR (400MHz, CDCl3) δ10.83(d,J=13.1Hz,1H),7.80(s,1H),7.67(d,J=8.2Hz,1H),7.51(d,J=7.9Hz,1H),7.22(t,J =7.3Hz,1H),7.09(t,J=7.4Hz,1H),6.99–6.88(m,3H),6.58(s,1H),6.29(d,J=3.3Hz,1H),2.15(s,3H),1.26(s,9H). 13 C-NMR (100MHz, CDCl3) δ179.06,153.79,149.36,142.41,135.83,129.54,128.09,125.91,125.84,122.2 0,122.07,121.01,120.66,120.07,110.78,102.42,96.07,83.87,53.29,29.97,20.47.HRMS(ESI)calcd for C 23 H 24 ClN2O2 + [M+H] + :395.1521,found:395.1520.

[0264] Biological activity test experiment

[0265] Human tumor cells A549 and HCT116 are from the American Type Culture Collection (ATCC, Manassas, VA, USA). Human non-small cell lung cancer cell A549 was cultured with Ham's F-12K (Kaighn's) medium (GIBCO, 21127022, USA) and supplemented with 10% fetal bovine serum (FBS, Gibco, 10099, Australia). Human colon cancer cell HCT116 cells were cultured with high glucose DMEM (Hyclone, SH30022.01, USA) medium supplemented with 10% fetal bovine serum (FBS, Gibco, 10099, Australia). Cells were cultured in a humidified incubator at 37°C and 5% CO2.

[0266] The MTT method was used to detect the anticancer activity of the compounds on tumor cell proliferation. The counted tumor cells were inoculated in a 96-well plate containing 100 μL complete medium, with A549 and HCT116 cells at 4×10 per well. 3 Inoculate each well. After incubation for 24 hours, 100 μL of complete medium containing 10 μM compound was added to each well and incubated for another 48 hours. After discarding the medium, 200 μL of dimethyl sulfoxide (DMSO) was added to each well to dissolve the generated formazan product. The absorbance value was measured at a wavelength of 570 nm using an ELISA reader from Bio-Tek, USA, and the compound inhibition rate was finally calculated using GraphPad Prism 8 software. All MTT assays were repeated at least three times, and the results are shown in Table 1.

[0267] Table 1. Bioactivity data of compounds

[0268]

[0269]

[0270] The data in Table 1 show that the chromone biindole derivatives of the present invention have inhibitory activity on the cell activity of human non-small cell lung cancer cells A549 and human colon cancer cells HCT116. Therefore, the chromone biindole derivatives of the present invention can be used to prepare anti-tumor drugs, especially for preparing drugs for treating lung cancer and colon cancer. Among them, the anti-tumor drug comprises a chromone biindole derivative or a pharmaceutically acceptable salt, hydrate or a combination thereof and an excipient, and the anti-tumor drug can be any one of granules, tablets, pills, capsules, injections or dispersants.

[0271] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the purpose and scope of the technical solutions of the present invention, which should be included in the scope of the claims of the present invention. The techniques, shapes, and structural parts not described in detail in the present invention are all well-known technologies.

Claims

1. A chromone biindole derivative or a pharmaceutically acceptable salt or a solvate thereof, characterized in that: The chromone biindole derivatives are compounds represented by general formula I or general formula II: in, R 1 is one or more of hydrogen, alkyl and halogen, R 2 is C1-C4 alkyl, cyclobutyl, substituted or unsubstituted phenyl, R 3 is one or more of a substituted or unsubstituted alkyl group, an alkoxy group, a chlorine-substituted aryl group and a halogen atom, Ar is a substituted or unsubstituted phenyl group or an aromatic hetero group.

2. The chromone biindole derivative or pharmaceutically acceptable salt or solvate thereof according to claim 1, The R 1 is one or more of hydrogen, C1-C4 alkyl and halogen; The R 2 is C1-C4 alkyl, cyclobutyl or alkoxyphenyl; The R 3 is one or more of hydrogen, substituted or unsubstituted C1-C4 alkyl, C1-C3 alkoxy, substituted or unsubstituted aryl and halogen; The Ar is phenyl, 5-chlorophenyl, 6-bromophenyl, 5-iodophenyl, 5-methoxyphenyl or pyridyl.

3. The chromone biindole derivative or pharmaceutically acceptable salt or solvate thereof according to claim 1, The R 1 is one or more of hydrogen, isopropyl, ethyl, methyl and halogen, wherein the halogen is F, Cl and Br; The R 2 is tert-butyl, cyclobutyl or methoxyphenyl; The R 3 is one or more of hydrogen, substituted or unsubstituted C1-C4 alkyl, methoxy, substituted or unsubstituted phenyl and halogen, wherein, The substituted C1-C4 alkyl group has a substituent of Cl(CH2)3OC(O)CH2-, halogen or hydroxyl; the substituted phenyl group has a substituent of halogen, and the halogen is F, Cl, Br or I.

4. The chromone biindole derivative or its pharmaceutically acceptable salt or solvate according to claim 1, selected from the following compounds: (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-1H-indol-3-yl)chroman-4-one; (Z)-2-(6-bromo-1H-indol-3-yl)-3-(tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-2-(5-iodo-1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[3,2-c]pyridin-3-yl)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-2-(2-methyl-1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(5-methoxy-2-methyl-1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-phenyl-1H-indol-3-yl)chroman-4-one; (Z)-2-(5-bromo-2-phenyl-1H-indol-3-yl)-3-((tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-(4-chlorophenyl)-1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(1-(2-chloroethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)chroman-4-one; 2-Chloroethyl (Z)-2-(3-((tert-butylamino)methylene)-4-oxochromon-2-yl)-1H-indol-1-yl)acetate; (Z)-3-((tert-Butylamino)methylene)-2-(1-ethyl-2-methyl-1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(1,2-dimethyl-1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-3-yl)-6-methylchroman-4-one; (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-3-yl)-6-isopropylchroman-4-one; (Z)-3-((tert-Butylamino)methylene)-6-fluoro-2-(1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)chroman-4-one; (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-3-yl)-7-methylchroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-methyl-2-(1-methyl-1H-indol-3-yl)chroman-4-one; (Z)-3-((cyclobutylamino)methylene)-2-(1H-indol-3-yl)chroman-4-one; (Z)-2-(1H-indol-3-yl)-3-(((4-methoxyphenyl)amino)methylene)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-1-yl)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-2-(5-chloro-1H-indol-1-yl)chroman-4-one; (Z)-2-(5-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(5-iodo-1H-indol-1-yl)chroman-4-one; (Z)-2-(6-bromo-1H-indol-1-yl)-3-(tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-b]pyridin-1-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(1H-pyrrolo[2,3-c]pyridin-1-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(3-methyl-1H-indol-1-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(3-(2-hydroxyethyl)-1H-indol-1-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-fluoro-2-(1H-indol-1-yl)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)chroman-4-one; (Z)-3-((tert-Butylamino)methylene)-2-(1H-indol-1-yl)-6-isopropylchroman-4-one; (Z)-3-((tert-Butylamino)methylene)-6-chloro-2-(1H-indol-1-yl)-7-methylchroman-4-one.

5. A method for synthesizing the chromone biindole derivatives according to any one of claims 1 to 4, characterized in that: The following reactions are included: 1) reacting the compound of formula 1, the compound of formula 2 and the compound of formula 3 in one pot to obtain the compound of general formula I, or 2) The compound of formula 1, the compound of formula 2 and the compound of formula 3 are reacted in one pot to prepare the compound of general formula II.

6. The preparation method according to claim 5, characterized in that: Reaction 1) is completed in a solvent of hexafluoroisopropanol and a microwave reaction tube.

7. The preparation method according to claim 5, characterized in that: Reaction 2) is completed in a solvent of 1,2-dichloroethane and a microwave reaction tube.

8. The preparation method according to claim 5, wherein compound 1 is chromone-3-carboxaldehyde, compound 2 is an amine compound, and compound 3 is an indole compound, and the molar ratio of compound 1, compound 2, and compound 3 is 1:1.5:

1.

9. Use of the chromone biindole derivative or the pharmaceutically acceptable salt or the solvate thereof according to any one of claims 1 to 4 in the preparation of antitumor drugs.

10. The use according to claim 9, wherein the tumor is lung cancer or colon cancer.

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