Hydroxyl flavanone derivative as well as preparation method and application thereof

Abstract

The invention discloses a hydroxyl flavanone derivative as well as a preparation method and application thereof, the hydroxyl flavanone derivative is a compound as shown in a formula I or a formula II, and a synthesis method is provided and comprises the following steps: dissolving chromone 3-formaldehyde, an amine compound and a phenol compound in hexafluoroisopropanol or chlorobenzene; and carrying out microwave reaction at 130 DEG C or reaction in an oil bath at 100 DEG C, and purifying through a silica gel column to obtain a target compound. According to the method, one-pot synthesis is adopted, use of a noble metal catalyst is avoided, and the synthesized hydroxyflavanone derivative has antitumor activity and is used for preparing antitumor drugs.

Description

Technical Field

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

[0002] Many flavonoid derivatives and phenolic derivatives have very wide biological and pharmaceutical activities, especially good performance in anti-tumor. Similarly, some hydroxyflavanone derivatives also have a wide range of biological activities, such as anti-tumor, anti-microbial, anti-histamine activities, etc. These compounds include: eriodictyol, naringenin, hesperidin, (+)-anastatin A and (+)-anastatin B. The synthesis of this type of compound can be synthesized by the intramolecular oxa-Michael addition reaction of 2'-hydroxychalcone to synthesize hydroxyflavanone derivatives. There are also reports that such compounds are obtained by transition metal-catalyzed conjugate addition reactions of chromone electrophilic reaction sites.

[0003] With the extensive exploration of the biological activities of hydroxyflavanone compounds, more and more research has been conducted on this type of compounds, and the synthesis and biological activities of related compounds have also been reported. However, the current synthesis methods of this type of compounds still have certain limitations, such as substrate restrictions during the reaction process, compatibility of functional groups, use of expensive transition metals, and complex post-reaction treatment. Summary of the invention

[0004] In view of the defects of the prior art, the purpose of the present invention is to provide a hydroxyflavanone derivative and a preparation method and application thereof. The hydroxyflavanone derivative has anti-tumor activity and can be used to prepare anti-tumor drugs. At the same time, the synthesis method avoids the use of precious metal catalysts, but adopts a multi-component reaction, and then uses hexafluoroisopropanol as a solvent and microwave radiation heating to synthesize the hydroxyflavanone derivative in a one-pot method, or uses chlorobenzene as a solvent and a traditional oil bath heating method to synthesize the hydroxyflavanone derivative in a one-pot method.

[0005] In order to achieve the purpose of the present invention, the following technical solutions are provided:

[0006] In one embodiment, a hydroxyflavanone derivative of the present invention is a compound represented by Formula I or Formula II or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R 1 Selected from C 1 -C 4 one or more of an alkyl group, a hydroxyl group, a halogen atom and a hydrogen atom,

[0010] R 2 C 1 -C 4 an alkyl group, a substituted or unsubstituted aryl group, or a cycloalkyl group,

[0011] Ar is indolyl, or unsubstituted or substituted phenyl.

[0012] In a preferred embodiment, the hydroxyflavanone derivatives of the present invention are

[0013] The R 1 One or more selected from methyl, ethyl, propyl, isopropyl, hydroxyl, chlorine, bromine and hydrogen atoms;

[0014] The R 2 is ethyl, isopropyl, tert-butyl, cyclopentyl or p-chlorophenyl;

[0015] Ar is phenyl or substituted phenyl, wherein the substituted phenyl is selected from C 1 -C 4 Alkyl, halogen, hydroxyl, alkoxy, and hydroxyethyl, one or both, more preferably, the C 1 -C 4 The alkyl group is methyl, ethyl, propyl, isopropyl, sec-butyl or tert-butyl; the alkoxy group is methoxy or ethoxy.

[0016] Preferably, the hydroxyflavanone derivatives of the present invention, R 1 is a hydrogen atom, a hydroxyl group, a methyl group, an isopropyl group, a chlorine atom, or a bromine atom; 2 is tert-butyl, isopropyl, cyclopentyl, 4-chlorophenyl; Ar is phenyl, 3-tert-butylphenyl, 3-sec-butylphenyl, 2-methyl-5-isopropylphenyl, 3-ethylphenyl, 3-phenylphenyl, 2-chlorophenyl, 3-bromophenyl, 3,5-dimethylphenyl, 2-hydroxyphenyl, 4,5-dimethoxyphenyl, 5-(2-hydroxyethyl)phenyl, 5-methoxyphenyl, 5-chlorophenyl, benzo[d][1,3]dioxol-5-yl, 1H-indol-4-yl, 1H-indol-7-yl.

[0017] Preferably, the hydroxyflavanone derivatives of the present invention are selected from the following compounds or their pharmaceutically acceptable salts or hydrates:

[0018] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)chroman-4-one;

[0019] (Z)-2-(3-(tert-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one;

[0020] (Z)-2-(3-(sec-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one;

[0021] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-5-isopropyl-2-methylphenyl)chroman-4-one;

[0022] (Z)-3-((tert-butylamino)methylene)-2-(3-ethyl-4-hydroxyphenyl)chroman-4-one;

[0023] (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one;

[0024] (Z)-3-((tert-butylamino)methylene)-2-(2-chloro-4-hydroxyphenyl)chroman-4-one;

[0025] (Z)-2-(3-bromo-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one;

[0026] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-3,5-dimethylphenyl)chroman-4-one;

[0027] (Z)-3-((tert-butylamino)methylene)-2-(2,4-dihydroxyphenyl)chroman-4-one;

[0028] (3Z,3'Z)-2,2'-(4,6-dihydroxy-1,3-phenylene)bis(3-((tert-butylamino)methylene)chroman-4-one);

[0029] (Z)-3-((tert-butylamino)methylene)-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one;

[0030] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-methylchroman-4-one;

[0031] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-isopropylchroman-4-one;

[0032] (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(4-hydroxyphenyl)chroman-4-one;

[0033] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(4-hydroxyphenyl)-7-methylchroman-4-one;

[0034] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(4-hydroxyphenyl)chroman-4-one;

[0035] (Z)-6-chloro-3-((cyclopentylamino)methylene)-2-(4-hydroxyphenyl)-7-methylchroman-4-one;

[0036] (Z)-3-(((4-chlorophenyl)amino)methylene)-2-(4-hydroxyphenyl)chroman-4-one;

[0037] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)chroman-4-one;

[0038] (Z)-2-(3-(tert-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one;

[0039] (Z)-2-(3-(sec-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one;

[0040] (Z)-3-((tert-butylamino)methylene)-2-(3-ethyl-2-hydroxyphenyl)chroman-4-one;

[0041] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one;

[0042] (Z)-2-(3-bromo-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one;

[0043] (Z)-3-((tert-butylamino)methylene)-2-(4-chloro-2-hydroxyphenyl)chroman-4-one;

[0044] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-3-isopropyl-6-methylphenyl)chroman-4-one;

[0045] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one;

[0046] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-(2-hydroxyethyl)phenyl)chroman-4-one;

[0047] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-methoxyphenyl)chroman-4-one;

[0048] (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one;

[0049] (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)chroman-4-one;

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

[0051] (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxy-1H-indol-7-yl)chroman-4-one;

[0052] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)-6-methylchroman-4-one;

[0053] (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(2-hydroxyphenyl)chroman-4-one;

[0054] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(2-hydroxyphenyl)chroman-4-one;

[0055] (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one;

[0056] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(5-chloro-2-hydroxyphenyl)chroman-4-one;

[0057] (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)-6-isopropylchroman-4-one;

[0058] (Z)-2-(2-hydroxy-4,5-dimethoxyphenyl)-3-((isopropylamino)methylene)chroman-4-one;

[0059] (Z)-3-((cyclopentylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one.

[0060] In another embodiment, the present invention provides a method for preparing a hydroxyflavanone derivative, wherein the hydroxyflavanone derivative is compound 4 (i.e., the compound shown in formula I) and compound 5 (i.e., the compound shown in formula II), comprising the following reaction:

[0061]

[0062] in,

[0063] R1 is selected from one or more of a C1-C4 alkyl group, a hydroxyl group, a halogen atom and a hydrogen atom,

[0064] R2 is a C1-C4 alkyl group, a substituted or unsubstituted aryl group, or a cycloalkyl group,

[0065] Ar is indolyl, or unsubstituted or substituted phenyl.

[0066] Reaction 1) Compound 1, Compound 2 and Compound 3 react to obtain Compound 4; or

[0067] Reaction 2) Compound 1, Compound 2 and Compound 3 are reacted to obtain Compound 5,

[0068] In the above-mentioned preparation method of the present invention, the reaction 1) comprises dissolving compound 1, compound 2 and compound 3 in an organic solvent A, heating to 80-130° C. for reaction, and obtaining compound 4.

[0069] In the above-mentioned preparation method of the present invention, the reaction 1), the heating is microwave heating, the reaction temperature is 130° C., and after the reaction is completed, the target compound 4 is purified by column.

[0070] In the above-mentioned preparation method of the present invention, in the reaction 1), the organic solvent A is hexafluoroisopropanol;

[0071] In the above-mentioned preparation method of the present invention, the reaction 2) comprises dissolving compound 1, compound 2 and compound 3 in an organic solvent B, and reacting at 80-130° C. to obtain compound 5.

[0072] In the above preparation method of the present invention, the reaction 2) is heated by oil bath heating, and the reaction temperature is 100°C.

[0073] In the above preparation method of the present invention, in the reaction 2), the organic solvent B is chlorobenzene.

[0074] In the above preparation method of the present invention, the molar ratio of compound 1, compound 2 and compound 3 is 1:1.1:1.

[0075] The present invention also provides a pharmaceutical composition comprising the above-mentioned hydroxyflavanone derivatives or pharmaceutically acceptable salts or hydrates thereof and pharmaceutical excipients. The pharmaceutical composition is in the form of granules, tablets, pills, capsules, injections or dispersants. The pharmaceutical excipients are selected from pharmaceutical excipients well known in the art, including but not limited to fillers, disintegrants, binders, lubricants, injection solvents, etc.

[0076] The present invention also provides the use of the hydroxyflavanone derivatives of the present invention in the preparation of anti-tumor drugs. Preferably, the tumor is lung cancer, colon cancer, prostate cancer or pancreatic cancer.

[0077] The present invention has the following beneficial effects:

[0078] (1) The present invention uses substituted chromones, amine compounds and phenol compounds as raw materials, and obtains hydroxyflavanone derivatives through multi-component reaction under microwave radiation or oil bath heating. For the first time, hydroxyflavanone derivatives with anti-tumor activity were synthesized by multi-component reaction without using expensive transition metal catalysts, and showed strong inhibitory effects on human non-small cell lung cancer cells A549, human colon cancer cells HCT116, human prostate cancer cells PC-3 and human pancreatic cancer cells PANC-1, and can be used to prepare anti-tumor drugs.

[0079] (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. DETAILED DESCRIPTION

[0080] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only a representative part of the embodiments of the present invention, rather than all the embodiments. Based on the following embodiments, the technical solutions obtained by ordinary technicians in this field by simply modifying and adapting the technical solution of the present invention without making creative work also fall within the scope of protection of the present invention.

[0081] The following example is a method for preparing hydroxyflavanone derivatives represented by the compound represented by Formula I (ie, Compound 4) and the compound represented by Formula II (ie, Compound 5), and the reaction formula is as follows:

[0082]

[0083] Compound 1 is chromone-3-carboxaldehyde, compound 2 is an amine compound, and compound 3 is indole, substituted or unsubstituted phenol.

[0084] Among them, R 1 is an alkyl group, a halogen atom or a hydrogen atom; 2is an alkyl or aryl group; Ar is a phenyl or indolyl group; more specifically, R 1 is a hydrogen atom, a hydroxyl group, a methyl group, an isopropyl group, a chlorine atom, or a bromine atom; 2 is tert-butyl, isopropyl, cyclopentyl, 4-chlorophenyl; Ar is phenyl, 3-tert-butylphenyl, 3-sec-butylphenyl, 2-methyl-5-isopropylphenyl, 3-ethylphenyl, 3-phenylphenyl, 2-chlorophenyl, 3-bromophenyl, 3,5-dimethylphenyl, 2-hydroxyphenyl, 4,5-dimethoxyphenyl, 5-(2-hydroxyethyl)phenyl, 5-methoxyphenyl, 5-chlorophenyl, benzo[d][1,3]dioxol-5-yl, 1H-indol-4-yl, 1H-indol-7-yl.

[0085] Example 1

[0086] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0087]

[0088] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol were dissolved in 2mL of hexafluoroisopropanol, and the mixture was reacted for 3 hours under microwave conditions of 80°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)chroman-4-one with a yield of 78%.

[0089] 1 H-NMR (400MHz, CDCl 3 )δ10.48(d,J=13.4Hz,1H),7.88(d,J=7.8Hz,1H),7.33(t,J=8.1Hz,3H),6.99(t,J=7.5Hz,1H),6.89( d,J=8.2Hz,1H),6.84(d,J=8.2Hz,2H),6.56(d,J=13.2Hz,1H),5.92(s,1H),5.59(s,1H),1.23(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.65,158.37,155.96,147.91,133.71,131.98,129.41,126.22,124. 10,121.43,117.50,115.38,101.26,80.97,52.46,29.99.HRMS(ESI)calcd for C 20H 22 NO 3 + [M+H] + :324.1594,found:324.1592.

[0090] Example 2

[0091] (Z)-2-(3-(tert-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one, the structural formula of which is as follows:

[0092]

[0093] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-tert-butylphenol were dissolved in 2mL of hexafluoroisopropanol, and the mixture was reacted for 2 hours under microwave conditions of 110°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-2-(3-(tert-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one with a yield of 75%.

[0094] 1 H-NMR (400MHz, CDCl 3 )δ10.38(d,J=13.0Hz,1H),7.86(dd,J=7.7,1.4Hz,1H),7.33-7.28(m,1H),7.25(d,J=7.8Hz,1H),7.02(t,J=7.5Hz,1H) ,6.95(s,1H),6.92-6.86(m,2H),6.77(t,J=7.6Hz,1H),6.39(d,J=13.4Hz,1H),6.00(s,1H),1.36(s,9H),1.12(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.57,157.77,154.5,147.63,138.0,133.55,127.88,127.59,126.51,124.84,122 .96,122.60,119.57,117.43,98.88,82.78,52.51,34.9,29.88,29.5.HRMS(ESI)calcd for C 24 H 30 NO 3 + [M+H] + :380.2220,found:380.2225.

[0095] Example 3

[0096] (Z)-2-(3-(sec-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one, the structural formula of which is as follows:

[0097]

[0098] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-sec-butylphenol were dissolved in 2mL of hexafluoroisopropanol, and the mixture was reacted for 1 hour under microwave conditions of 130°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound ((Z)-2-(3-(sec-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one with a yield of 79%.

[0099] 1 H-NMR (400 MHz, DMSO-d 6 )δ10.38(dd,J=13.2,5.8Hz,1H),9.29(s,1H),7.70(d,J=7.4Hz,1H),7.39 -7.33(m,1H),7.10(dd,J=4.5,2.2Hz,1H),7.01-6.96(m,2H),6.95-6.88(m ,2H),6.73(dd,J=8.2,3.0Hz,1H),5.99(s,1H),3.00-2.93(m,1H),1.57-1. 45(m,2H),1.23(d,J=1.3Hz,9H),1.08(d,J=6.9Hz,3H),0.75-0.70(m,3H). 13 C-NMR (100 MHz, DMSO-d 6 )δ180.31,158.27,154.93,148.69,134.01,133.09,131.55,126.33,126.09,125.90,124.36 ,121.43,117.94,114.94,80.35,52.49,33.51,30.06,29.52,20.95,12.41.HRMS(ESI)calcd for C 24 H 30 NO 3 + [M+H] + :380.2220,found:3380.2221.

[0100] Example 4

[0101] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-5-isopropyl-2-methylphenyl)chroman-4-one, the structural formula of which is as follows:

[0102]

[0103] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-isopropyl-5-methylphenol were dissolved in 2mL of hexafluoroisopropanol, and the mixture was reacted for 1 hour under microwave conditions of 130°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-5-isopropyl-2-methylphenyl)chroman-4-one with a yield of 77%.

[0104] 1 H-NMR (400MHz, CDCl 3 )δ10.32(d,J=13.4Hz,1H),7.88(dd,J=7.8,1.6Hz,1H),7.31-7.25(m,1H),7.23(s,1H),6.98-6.91(m,1H),6.86(d,J=8.1Hz,1 H),6.59(s,1H),6.26(d,J=13.4Hz,1H),6.05(s,1H),3.19-3.12(m,1H),2.19(s,3H),1.15(dd,J=6.9,3.5Hz,6H),1.09(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ182.39,159.42,153.1,147.83,134.92,133.6,132.59,128.51,126.74,126.44,124 .27,121.37,117.44,101.35,79.45,52.30,29.9,26.91,22.84,18.87.HRMS(ESI)calcd for C 24 H 30 NO 3 + [M+H] + :380.2220,found:380.2227.

[0105] Example 5

[0106] Synthesis of (Z)-3-((tert-butylamino)methylene)-2-(3-ethyl-4-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0107]

[0108] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-ethylphenol were dissolved in 2mL of hexafluoroisopropanol, and the reaction was carried out at 100°C in a microwave for 2 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-(3-ethyl-4-hydroxyphenyl)chroman-4-one with a yield of 79%.

[0109] 1 H-NMR (400MHz, CDCl 3 )δ10.40(d,J=13.2Hz,1H),7.82(d,J=7.7Hz,1H),7.26(dd,J=8.1,7.3Hz,1H),7.18(s,1H),7.05(d,J=8.1Hz,1H),6.92(t,J=7.4Hz,1H), 6.82(d,J=8.2Hz,1H),6.72(d,J=8.2Hz,1H),6.47(d,J=13.3Hz,1H),5.92(s,1H),5.84(s,1H),2.61-2.55(m,2H),1.14(d,J=3.5Hz,12H). 13 C-NMR (100 MHz, CDCl 3 )δ181.76,158.59,154.01,148.17,133.70,131.54,130.45,129.07,126.74,126.27,124 .14,121.39,117.50,115.10,101.54,81.38,52.45,29.9,23.06,14.13.HRMS(ESI)calcd for C 22 H 26 NO 3 + [M+H] + :352.1907,found:352.1904.

[0110] Example 6

[0111] It is (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one, and its structural formula is as follows:

[0112]

[0113] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-phenylphenol were dissolved in 2mL of hexafluoroisopropanol, and the reaction was carried out under microwave conditions of 100°C for 1 hour. Then the solvent was spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one with a yield of 65%.

[0114] 1 H-NMR (400MHz, CDCl 3 )δ10.41(d,J=13.2Hz,1H),7.81(dd,J=7.7,1.5Hz,1H),7.41-7.36(m,4H),7.33-7.28(m,2H),7.28 (s,2H),6.94-6.89(m,2H),6.83(d,J=8.2Hz,1H),6.55(d,J=13.3Hz,1H),5.88(s,1H),1.16(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.62,158.41,152.82,147.8,136.95,133.72,132.20,130.08,129.23,129.09,128.74,128.2 6,127.96,126.27,124.17,121.46,117.52,116.00,101.23,81.06,52.46,30.03.HRMS(ESI)calcd for C 26 H 26 NO 3 + [M+H] + :400.1907,found:400.1903.

[0115] Example 7

[0116] (Z)-3-((tert-butylamino)methylene)-2-(2-chloro-4-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0117]

[0118] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 3-chlorophenol were dissolved in 2mL of hexafluoroisopropanol, and the mixture was reacted for 1 hour under microwave conditions of 130°C. 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-chloro-4-hydroxyphenyl)chroman-4-one with a yield of 70%.

[0119] 1 H-NMR (400MHz, CDCl 3 )δ10.42(d,J=13.5Hz,1H),7.84(dd,J=7.8,1.6Hz,1H),7.37(d,J=8.5Hz,1H),7.30-7.26(m,1H),6.98-6.93(m,1H),6.8 9(d,J=2.5Hz,1H),6.83(d,J=8.2Hz,1H),6.73(dd,J=8.5,2.4Hz,1H),6.41(d,J=13.3Hz,1H),6.24(s,1H),1.14(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.80,158.63,156.65,147.87,133.74,130.35,129.09,126.30,124.03 ,121.59,117.40,116.33,114.70,77.55,52.55,29.95.HRMS(ESI)calcdfor C 20 H 21 ClNO 3 + [M+H] + :358.1204,found:358.1200.

[0120] Example 8

[0121] (Z)-2-(3-bromo-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one, the structural formula of which is as follows:

[0122]

[0123] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-bromophenol were dissolved in 2mL of hexafluoroisopropanol, and the reaction was carried out under microwave conditions of 100°C for 2 hours. The solvent was then spin-dried and separated by a silica gel column to obtain the target compound (Z)-2-(3-bromo-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one with a yield of 74%.

[0124] 1 H NMR (400 MHz, CDCl 3 )δ10.44(d,J=12.7Hz,1H),7.81(t,J=7.7Hz,1H),7.52-7.46(m,1H),7.26(dd,J=11.3,4.1Hz,1H),7.22(dd,J =8.4,1.9Hz,1H),6.98-6.88(m,2H),6.82(d,J=8.2Hz,1H),6.54(d,J=13.2Hz,1H),5.81(s,1H),1.20(s,9H). 13 C{ 1 H}NMR (100MHz, CDCl 3 )δ181.35,157.89,152.38,147.62,134.03,133.77,131.60,128.76,126.24,124. 03,121.59,117.50,115.98,110.27,100.43,80.09,52.53,30.01.HRMS(ESI)calcd for C 20 H 21 BrNO 3 + [M+H] + :402.0699,found:402.0693.

[0125] Example 9

[0126] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-3,5-dimethylphenyl)chroman-4-one, the structural formula of which is as follows:

[0127]

[0128] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 1,6-dimethylphenol were dissolved in 2mL of hexafluoroisopropanol, and the reaction was carried out under microwave conditions of 130°C for 1 hour. Then the solvent was spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-3,5-dimethylphenyl)chroman-4-one with a yield of 88%.

[0129] 1 H-NMR (400MHz, CDCl 3 )δ10.43(d,J=12.9Hz,1H),7.82(dd,J=7.7,1.6Hz,1H),7.27-7.23(m,1H),7.00(s,2H),6.94-6. 89(m,1H),6.82(d,J=8.2Hz,1H),6.50(d,J=13.3Hz,1H),5.79(s,1H),2.17(s,6H),1.16(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.69,158.51,152.42,147.99,133.61,131.26,128.42,126.23,124.18, 123.19,121.32,117.4,101.31,81.39,52.37,30.03,16.05.HRMS(ESI)calcd for C 22 H 26 NO 3 + [M+H] + :352.1907,found:352.1903.

[0130] Example 10

[0131] (Z)-3-((tert-butylamino)methylene)-2-(2,4-dihydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0132]

[0133] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of resorcinol were dissolved in 2mL of hexafluoroisopropanol, and the reaction was carried out under microwave conditions of 130°C for 1 hour. Then the solvent was spin-dried and separated by a silica gel column to obtain the target compound (Z)-3-((tert-butylamino)methylene)-2-(2,4-dihydroxyphenyl)chroman-4-one with a yield of 69%.

[0134] 1 H-NMR (400 MHz, DMSO-d 6 )δ10.40(d,J=13.2Hz,1H),9.53(s,1H),9.31(s,1H),7.75-7.71(m,1H),7.34(dd,J=7.3,0.9Hz,1H),6.98(t,J=7.5Hz,1H),6.91(d,J= 8.4Hz,1H),6.84(d,J=7.9Hz,1H),6.32(d,J=1.9Hz,1H),6.20(s,1H),6.16(dd,J=8.4,2.0Hz,1H),5.76(d,J=0.7Hz,1H),1.20(s,9H). 13 C-NMR (100 MHz, DMSO-d 6 )δ180.71,158.73,156.40,148.50,133.95,129.52,126.17,124.1,121.23,117.70,106.62,102.74,100.13,75.46,52.47,29.99.HRMS(ESI)calcd for C 20 H 22 NO 4 + [M+H] + :340.1543,found:340.1544.

[0135] Embodiment 11

[0136] (3Z,3'Z)-2,2'-(4,6-dihydroxy-1,3-phenylene)bis(3-((tert-butylamino)methylene)chroman-4-one), the structural formula of which is as follows:

[0137]

[0138] Synthesis method: In a 10mL microwave reaction tube, 1.0mmol of chromone-3-carboxaldehyde, 1.1mmol of tert-butylamine and 0.5mmol of resorcinol were dissolved in 2mL of hexafluoroisopropanol, and the reaction was carried out under microwave conditions of 130°C for 1 hour. Then the solvent was spin-dried and separated by silica gel column to obtain the target compound (3Z,3'Z)-2,2'-(4,6-dihydroxy-1,3-phenylene)bis(3-((tert-butylamino)methylene)chroman-4-one) with a yield of 64%.

[0139] 1 H-NMR (400MHz, CDCl 3 )δ10.55(d,J=13.3Hz,1H),10.43(d,J=13.4Hz,1H),7.88-7.85(m,2H),7.37-7.31(m,2H),7.07-7.02(m,2H),6.92(dd,J=7.5,6.1Hz ,2H),6.77(s,1H),6.65(t,J=8.4Hz,1H),6.61-6.56(m,1H),6.46(d,J=13.4Hz,1H),6.01(d,J=3.2Hz,2H),1.28(s,9H),1.14(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.13,157.36,157.17,147.54,133.62,133.54,129.97,126.38,124.59,122.57,117.32 ,116.24,115.82,105.97,98.49,98.25,80.71,80.39,52.67,29.98,29.86.HRMS(ESI)calcd for C 34 H 37 N 2 O 6 + [M+H] + :569.2646,found:569.2644.

[0140] Example 12

[0141] (Z)-3-((tert-butylamino)methylene)-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0142]

[0143] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 5-hydroxy-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol are dissolved in 2mL of hexafluoroisopropanol, and the reaction is carried out under microwave conditions of 130°C for 1 hour, and then the solvent is spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one with a yield of 70%.

[0144] 1 H-NMR (400MHz, CDCl 3 )δ12.82(s,1H),9.96(d,J=13.5Hz,1H),7.30(d,J=8.4Hz,2H),7.17(t,J=8.2Hz,1H),6.84(d,J=8.3Hz,2H), 6.55(d,J=13.6Hz,1H),6.45(d,J=8.3Hz,1H),6.34(d,J=8.1Hz,1H),5.87(s,1H),5.71(s,1H),1.23(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ185.32,161.64,158.42,156.05,148.21,135.36,131.68,129.34,115.50,109.53,109.07,107.41,99.54,80.58,52.88,29.94.HRMS(ESI)calcd for C 20 H 22 NO 4 + [M+H] + :340.1543,found:340.1539.

[0145] Embodiment 13

[0146] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-methylchroman-4-one, the structural formula of which is as follows:

[0147]

[0148] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-methyl-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol are dissolved in 2mL of hexafluoroisopropanol, and the reaction is carried out under microwave conditions of 130°C for 1 hour, and then the solvent is spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-methylchroman-4-one with a yield of 79%.

[0149] 1 H-NMR (400MHz, CDCl 3 )δ10.46(d,J=13.2Hz,1H),7.67(s,1H),7.29(d,J=8.4Hz,2H),7.13(dd,J=8.3,1.7Hz,1H),6.85(d, J=8.4Hz,2H),6.79(d,J=8.3Hz,1H),6.58(d,J=13.3Hz,1H),5.88(s,1H),2.27(s,3H),1.21(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.88,156.28,147.91,134.67,131.94,130.70,129.33,126.13,123.68,117.27,115.39,101.39,80.83,52.44,29.97,20.61.HRMS(ESI)calcd for C 21 H 24 NO 3 + [M+H] + :338.1751,found:338.1755.

[0150] Embodiment 14

[0151] (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-isopropylchroman-4-one, the structural formula of which is as follows:

[0152]

[0153] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-isopropyl-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol are dissolved in 2mL of hexafluoroisopropanol, and the mixture is reacted for 1 hour under microwave conditions of 130°C, and then the solvent is spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-isopropylchroman-4-one with a yield of 80%.

[0154] 1 H-NMR (400MHz, CDCl 3 )δ10.50(d,J=13.3Hz,1H),7.76(d,J=2.3Hz,1H),7.29(d,J=8.5Hz,2H),7.20(dd,J=8.4,2.3Hz,1H),6.87(d,J=8.5Hz ,2H),6.82(d,J=8.4Hz,1H),6.57(d,J=13.3Hz,1H),5.89(s,1H),2.84(dt,J=13.8,6.9Hz,1H),1.19(d,J=6.6Hz,15H). 13 C-NMR (100 MHz, CDCl 3 )δ182.04,156.58,156.49,148.26,141.87,132.46,131.54,129.33,123.53, 117.27,115.51,101.48,80.89,52.52,33.40,29.94,23.99.HRMS(ESI)calcd for C 23 H 28 NO 3 + [M+H] + :366.2064,found:366.2060.

[0155] Embodiment 15

[0156] (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(4-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0157]

[0158] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-hydroxy-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol are dissolved in 2mL of hexafluoroisopropanol, and the reaction is carried out under microwave conditions of 130°C for 1 hour, and then the solvent is spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(4-hydroxyphenyl)chroman-4-one with a yield of 68%.

[0159] 1 H-NMR (400 MHz, DMSO-d 6 )δ10.33(d,J=13.2Hz,1H),9.42(s,1H),9.14(s,1H),7.10(dd,J=15.5,7.8Hz,3H),7.05(d,J= 2.9Hz, 1H), 6.77 (dd, J=8.7, 3.0Hz, 1H), 6.70 (dd, J=8.6, 6.9Hz, 3H), 5.88 (s, 1H), 1.25 (s, 9H). 13 C-NMR (100 MHz, DMSO-d 6 ))δ180.44,157.40,151.78,150.77,148.64,132.24,129.00,124.76,121. 64,118.78,115.32,110.80,100.83,79.39,52.50,30.04.HRMS(ESI)calcd for C 20 H 22 NO 4 + [M+H] + :340.1543,found:340.1544.

[0160] Example 16

[0161] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(4-hydroxyphenyl)-7-methylchroman-4-one, the structural formula of which is as follows:

[0162]

[0163] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-chloro-7-methyl-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol are dissolved in 2mL of hexafluoroisopropanol, and the reaction is carried out under microwave conditions of 110°C for 1.5 hours. Then the solvent is dried by spin drying and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(4-hydroxyphenyl)-7-methylchroman-4-one with a yield of 73%.

[0164] 1 H-NMR (400MHz, CDCl 3 )δ10.44(d,J=13.3Hz,1H),7.80(s,1H),7.30-7.24(m,2H),6.84(d,J=8.5Hz,2 H), 6.76 (s, 1H), 6.61 (d, J = 13.4Hz, 1H), 5.88 (s, 1H), 2.30 (s, 3H), 1.22 (s, 9H). 13 C-NMR (100 MHz, CDCl 3 )δ180.38,156.54,156.20,148.18,142.19,131.76,129.34,127.23,126.14, 123.13,119.73,115.43,100.58,81.02,52.62,29.95,20.58.HRMS(ESI)calcd for C 21 H 23 ClNO 3 + [M+H] + :372.1361,found:372.1358.

[0165] Embodiment 17

[0166] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(4-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0167]

[0168] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-chloro-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol were dissolved in 2mL of hexafluoroisopropanol, and the mixture was reacted for 2 hours under microwave conditions at 90°C. 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-(4-hydroxyphenyl)chroman-4-one with a yield of 74%.

[0169] 1 H-NMR (400MHz, CDCl 3 )δ10.51(d,J=12.9Hz,1H),7.83(s,1H),7.27(dd,J=17.9,8.1Hz,4H),6.88-6.77(m,3H),6.59(d,J=13.3Hz,1H),5.91(s,1H),1.24(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ180.14,156.72,156.02,148.28,133.35,131.72,129.40,126.66,125. 79,125.17,119.09,115.43,100.71,81.11,52.65,29.96.HRMS(ESI)calcd forC 20 H 21 ClNO 3 + [M+H] + :358.1204,found:358.1200.

[0170] Embodiment 18

[0171] (Z)-6-chloro-3-((cyclopentylamino)methylene)-2-(4-hydroxyphenyl)-7-methylchroman-4-one, the structural formula of which is as follows:

[0172]

[0173] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-chloro-7-methyl-chromone-3-carboxaldehyde, 0.55mmol of cyclopentylamine and 0.5mmol of phenol are dissolved in 2mL of hexafluoroisopropanol, and the mixture is reacted for 1 hour under microwave conditions of 130°C. The solvent is then spin-dried and separated by a silica gel column to obtain the target (Z)-6-chloro-3-((cyclopentylamino)methylene)-2-(4-hydroxyphenyl)-7-methylchroman-4-one with a yield of 60%.

[0174] 1 H-NMR (400MHz, CDCl 3 )δ10.44(d,J=13.3Hz,1H),7.80(s,1H),7.30-7.24(m,2H),6.84(d,J=8.5Hz,2 H), 6.76 (s, 1H), 6.61 (d, J = 13.4Hz, 1H), 5.88 (s, 1H), 2.30 (s, 3H), 1.22 (s, 9H).13 C-NMR (100 MHz, CDCl 3 )δ180.38,156.54,156.20,148.18,142.19,131.76,129.34,127.23,126.14, 123.13,119.73,115.43,100.58,81.02,52.62,29.95,20.58.HRMS(ESI)calcd for C 22 H 23 ClNO 3 + [M+H] + :384.1361,found:384.1358.

[0175] Embodiment 19

[0176] (Z)-3-(((4-chlorophenyl)amino)methylene)-2-(4-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0177]

[0178] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of 4-chloroaniline and 0.5mmol of phenol were dissolved in 2mL of hexafluoroisopropanol, and the reaction was carried out under microwave conditions of 130°C for 1 hour. Then the solvent was spin-dried and separated by a silica gel column to obtain the target (Z)-3-(((4-chlorophenyl)amino)methylene)-2-(4-hydroxyphenyl)chroman-4-one with a yield of 74%.

[0179] 1 H-NMR (400 MHz, DMSO-d 6 )δ11.67(d,J=12.4Hz,1H),9.47(d,J=14.5Hz,1H),7.77(dd,J=7.8,1.6Hz,1H),7.69(d,J=12.3Hz,1H),7.39(dd,J =11.1,5.4Hz,3H),7.32-7.28(m,2H),7.19(d,J=8.5Hz,2H),7.01-6.95(m,2H),6.71(d,J=8.6Hz,2H),6.16(s,1H). 13 C-NMR (100 MHz, DMSO-d 6)δ182.15,158.41,157.65,142.74,140.70,139.57,135.31,131.45,129.95,129.02,128.7 3,127.55,126.42,123.50,121.84,118.54,118.15,115.53,104.98,79.42.HRMS(ESI)calcd for C 22 H 17 ClNO 3 + [M+H] + :378.0891,found:378.0888.

[0180] Embodiment 20

[0181] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0182]

[0183] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours at an oil bath temperature of 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)chroman-4-one with a yield of 74%.

[0184] 1 H-NMR (400MHz, CDCl 3 )δ10.50(d,J=13.1Hz,1H),7.92(d,J=7.1Hz,1H),7.39-7.35(m,1H),7.29(d,J=7.4Hz,1H),7.09(d,J=7.8Hz,2 H),6.97(t,J=7.9Hz,2H),6.90(t,J=7.5Hz,1H),6.83(s,1H),6.56(d,J=13.4Hz,1H),6.11(s,1H),1.23(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.42,157.49,155.43,147.55,133.67,130.47,129.31,126.47,124.62,123 .35,122.57,120.1,117.38,117.28,98.78,81.41,52.64,29.91.HRMS(ESI)calcd for C 20 H 22 NO 3 + [M+H] + :324.1594,found:324.1592.

[0185] Embodiment 21

[0186] (Z)-2-(3-(tert-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one, the structural formula of which is as follows:

[0187]

[0188] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-tert-butylphenol are dissolved in 2mL of chlorobenzene, and reacted for 2 hours in an oil bath at 130°C. The solvent is then spin-dried and separated by a silica gel column to obtain the target (Z)-2-(3-(tert-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one with a yield of 70%.

[0189] 1 H-NMR (400MHz, CDCl 3 )δ10.51(d,J=13.3Hz,1H),7.98(dd,J=7.7,1.5Hz,1H),7.45-7.39(m,1H),7.38-7.34(m,1H),7.14(t,J=7.5Hz,1H), 7.08(s,1H),7.04-6.97(m,2H),6.89(t,J=7.6Hz,1H),6.51(d,J=13.4Hz,1H),6.12(s,1H),1.48(s,9H),1.24(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.57,157.77,154.59,147.68,138.00,133.58,127.90,127.61,126.52,124.84,12 2.97,122.63,119.60,117.45,98.88,82.76,52.53,34.92,30.0,29.60.HRMS(ESI)calcd for C 24 H 30 NO 3 + [M+H] + :380.2220,found:380.2226.

[0190] Embodiment 22

[0191] (Z)-2-(3-(sec-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one, the structural formula of which is as follows:

[0192]

[0193] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-sec-butylphenol are dissolved in 2mL of chlorobenzene, and reacted for 6 hours in an oil bath at 80°C. The solvent is then spin-dried and separated by a silica gel column to obtain the target (Z)-2-(3-(sec-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one with a yield of 72%.

[0194] 1 H-NMR (400MHz, CDCl 3 )δ10.40(t,J=12.1Hz,1H),7.85(dd,J=7.8,1.7Hz,1H),7.32-7.26(m,1H),7.12 -7.09(m,1H),7.03-6.98(m,1H),6.89(d,J=8.2Hz,1H),6.85(d,J=7.4Hz,1H),6 .79(d,J=6.5Hz,1H),6.40(d,J=13.4Hz,1H),6.00(d,J=3.9Hz,1H),3.16-3.01( m,1H),1.65-1.50(m,2H),1.18-1.13(m,3H),1.11(d,J=4.3Hz,9H),0.78(m,3H). 13 C-NMR (100 MHz, CDCl 3)δ181.57,157.82,153.07,147.60,135.50,133.58,128.12,126.82,126.51,124.79,122.2 5,119.95,117.43,82.53,82.26,52.53,34.08,33.22,29.86,20.77,12.38.HRMS(ESI)calcd for C 24 H 30 NO 3 + [M+H] + :380.2220,found:380.2222.

[0195] Embodiment 23

[0196] (Z)-3-((tert-butylamino)methylene)-2-(3-ethyl-2-hydroxyphenyl)chroman-4-one, the structural formula is as follows:

[0197]

[0198] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-ethylphenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 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)-3-((tert-butylamino)methylene)-2-(3-ethyl-2-hydroxyphenyl)chroman-4-one with a yield of 69%.

[0199] 1 H-NMR (400MHz, CDCl 3 )δ10.51(d,J=13.0Hz,1H),8.01-7.92(m,1H),7.43-7.37(m,1H),7.21(dd,J=7.4,1.5Hz,1H),7.15-7.09(m,1H),6.98(dd,J =13.0,5.2Hz,2H),6.88(dd,J=8.5,6.5Hz,2H),6.56(d,J=13.4Hz,1H),6.13(s,1H),2.81-2.68(m,2H),1.27-1.25(m,12H). 13 C-NMR (100 MHz, CDCl 3)δ181.50,157.64,153.25,147.67,133.64,132.45,130.2,127.06,126.50,124.73 ,122.67,119.90,117.4,98.8,81.98,52.58,29.91,23.17,14.35.HRMS(ESI)calcd for C 22 H 26 NO 3 + [M+H] + :352.1907,found:352.1903.

[0200] Embodiment 24

[0201] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one, the structural formula of which is as follows:

[0202]

[0203] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-phenylphenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 2 hours in an oil bath at 130°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one with a yield of 60%.

[0204] 1 H-NMR (400MHz, CDCl 3 )δ10.44(m,1H),7.86(m,1H),7.46(m,2H),7.38(m,2H),7.29(m,2H),7.24(m,1H),7.11 (m,1H),7.00(m,1H),6.89(m,2H),6.69(s,1H),6.60(m,1H),6.17(s,1H),1.18(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.42,157.58,151.7,147.61,137.64,133.67,131.34,129.83,129.39,128.61,127. 46,126.45,124.70,122.37,120.33,117.38,98.96,80.28,52.61,29.99.HRMS(ESI)calcd for C 26 H 26 NO 3 + [M+H] + :400.1907,found:400.1903.

[0205] Embodiment 25

[0206] (Z)-2-(3-bromo-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one, the structural formula of which is as follows:

[0207]

[0208] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-bromophenol are dissolved in 2mL of chlorobenzene, and the mixture is reacted for 4 hours in an oil bath at 100°C. The solvent is then spin-dried and separated by a silica gel column to obtain the target (Z)-2-(3-bromo-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one with a yield of 77%.

[0209] 1 H-NMR (400MHz, CDCl 3 )δ10.45(d,J=12.9Hz,1H),7.84(dd,J=7.8,1.5Hz,1H),7.40(dd,J=8.0,1.4Hz,1H),7.31-7.26(m,1H),7.12(dd ,J=7.6,1.0Hz,1H),6.98(m,1H),6.85(m,1H),6.71(m,1H),6.66(s,1H),6.56(m,1H),6.17(s,1H),1.18(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.24,157.5,150.89,147.55,133.74,132.85,128.39,126.69,126.40,124. 21,122.19,121.34,117.29,111.01,98.75,78.51,52.63,29.95.HRMS(ESI)calcd forC 20 H 21 BrNO 3 + [M+H] + :402.0699,found:402.0698.

[0210] Embodiment 26

[0211] (Z)-3-((tert-butylamino)methylene)-2-(4-chloro-2-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0212]

[0213] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 3-chlorophenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 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)-3-((tert-butylamino)methylene)-2-(4-chloro-2-hydroxyphenyl)chroman-4-one with a yield of 78%.

[0214] 1 H-NMR (400MHz, CDCl 3 )δ10.52(d,J=13.2Hz,1H),7.91(dd,J=7.8,1.6Hz,1H),7.39-7.34(m,1H),7.20(s,1H),7.10-7.06(m,1H),7.04(d,J=8.2Hz,1H), 6.99(d,J=2.0Hz,1H),6.93(dd,J=8.2,0.6Hz,1H),6.86(dd,J=8.2,2.0Hz,1H),6.63(d,J=13.4Hz,1H),6.10(s,1H),1.25(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.32,157.21,156.14,147.55,135.62,133.81,130.15,126.51,124.45,122.72,120.36,117.49,98.40,80.27,52.77,29.96.HRMS(ESI)calcd for C 20 H 21 ClNO 3 + [M+H] + :358.1204,found:358.1200.

[0215] Embodiment 27

[0216] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-3-isopropyl-6-methylphenyl)chroman-4-one, the structural formula of which is as follows:

[0217]

[0218] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 2-isopropyl-5-methylphenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 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)-3-((tert-butylamino)methylene)-2-(2-hydroxy-3-isopropyl-6-methylphenyl)chroman-4-one with a yield of 74%.

[0219] 1 H-NMR (400MHz, CDCl 3 )δ10.23(d,J=13.3Hz,1H),7.90(dd,J=7.8,1.6Hz,1H),7.37-7.33(m,1H),7.12-7.03(m,3H),6.95(dd,J=8.2,0.6Hz,1H),6.68(d,J=7.8Hz ,1H),6.28(s,1H),6.21(dd,J=13.5,0.6Hz,1H),3.31-3.24(m,1H),2.14(s,3H),1.20(d,J=6.9Hz,3H),1.13(d,J=6.9Hz,3H),1.06(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ182.20,158.49,153.35 147.0,135.04,133.67,126.72,125.17,122.78,121.8,119.20,117.64,98.37,79.74,52.42,29.81,26.72,23.09,22.16,19.13.HRMS(ESI)calcd for C 24 H 30 NO 3 + [M+H] + :380.2220,found:380.2217.

[0220] Embodiment 28

[0221] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0222]

[0223] Synthesis method: In a 10mL microwave reaction tube, 0.55mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 3,4-dimethoxyphenol were dissolved in 2mL of chlorobenzene, and reacted for 4 hours in an oil bath at 110°C. The solvent was then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one with a yield of 74%.

[0224] 1 H-NMR (400MHz, CDCl 3 )δ10.52(d,J=13.3Hz,1H),7.92(dd,J=7.7,1.3Hz,1H),7.40-7.35(m,1H),7.09(t,J=7.5Hz,1H),6.9 6(d,J=8.2Hz,1H),6.61(dd,J=13.1,4.7Hz,3H),6.04(s,1H),3.87(s,3H),3.80(s,3H),1.24(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.59,157.8,150.59,149.77,147.66,142.52,133.67,126.48,124.59,122.49,117 .40,113.68,112.63,101.79,98.95,81.30,56.68,55.98,52.63,29.95.HRMS(ESI)calcd forC 22 H 26 NO 5 + [M+H] + :384.1805,found:384.1802.

[0225] Embodiment 29

[0226] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-(2-hydroxyethyl)phenyl)chroman-4-one, the structural formula of which is as follows:

[0227]

[0228] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 4-hydroxyphenylethanol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 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)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-(2-hydroxyethyl)phenyl)chroman-4-one with a yield of 76%.

[0229] 1 H-NMR (400MHz, CDCl 3 )δ10.42(d,J=13.4Hz,1H),7.85(dd,J=7.7,1.5Hz,1H),7.32-7.28(m,1H),7.06(dd,J=8.2,2.1Hz,1H),7.01(t,J=7. 5Hz,1H),6.87(dd,J=11.9,5.3Hz,3H),6.67(s,1H),6.49(m,1H),6.02(s,1H),3.71(s,2H),2.71(s,2H),1.15(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.41,157.57,154.02,147.56,133.68,130.89,130.08,129.73,126.48,124.60 ,123.46,122.54,117.36,98.76,81.26,63.80,52.6,38.25,29.90.HRMS(ESI)calcd for C 22 H 26 NO 4 + [M+H] + :368.1856,found:368.1855.

[0230] Embodiment 30

[0231] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-methoxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0232]

[0233] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 4-methoxyphenol are dissolved in 2mL of chlorobenzene, and the mixture is reacted for 4 hours in an oil bath at 100°C. The solvent is then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-methoxyphenyl)chroman-4-one with a yield of 80%.

[0234] 1 H-NMR (400MHz, CDCl 3 )δ10.44(d,J=13.2Hz,1H),7.85(dd,J=7.8,1.6Hz,1H),7.32-7.27(m,1H),7.03-6.98(m,1H),6.86(dd,J=16.0,8.5Hz,2 H),6.76(dd,J=8.8,3.0Hz,1H),6.61(d,J=3.0Hz,1H),6.54(m,1H),6.35(s,1H),6.00(s,1H),3.67(s,3H),1.17(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.35,157.51,153.20,149.15,147.58,133.64,126.48,124.59,124.29,122.50, 117.89,117.33,115.48,114.81,98.54,81.11,55.82,52.63,29.93.HRMS(ESI)calcd for C 21 H 24 NO 4 + [M+H] + :354.1700,found:354.1705.

[0235] Embodiment 31

[0236] (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0237]

[0238] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 4-chlorophenol are dissolved in 2mL of chlorobenzene, and the mixture is reacted for 4 hours in an oil bath at 100°C. The solvent is then spin-dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one with a yield of 80%.

[0239] 1 H-NMR (400MHz, CDCl 3 )δ10.55(d,J=13.1Hz,1H),7.91(dd,J=7.8,1.6Hz,1H),7.39-7.34(m,1H),7.21(dd,J=8.6,2.6Hz,1H),7.10(dd,J =5.7,1.8Hz,2H),6.99(s,1H),6.94(d,J=8.2Hz,1H),6.90(d,J=8.6Hz,1H),6.65(m,1H),6.07(s,1H),1.27(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.13,157.01,154.01,147.58,133.78,130.19,128.90,126.54,125.68,125 .03,124.43,122.73,118.48,117.25,97.94,80.21,52.8,29.94.HRMS(ESI)calcd for C 20 H 21 ClNO 3 + [M+H] + :358.1204,found:358.1202.

[0240] Embodiment 32

[0241] (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)chroman-4-one, the structural formula of which is as follows:

[0242]

[0243] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 3,4-methylenedioxyphenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 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)-3-((tert-butylamino)methylene)-2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)chroman-4-one with a yield of 82%.

[0244] 1 H-NMR (400MHz, CDCl 3 )δ10.54(d,J=13.2Hz,1H),7.90(m,1H),7.38-7.33(m,1H),7.09-7.04(m,1H),6.95-6.91(m, 1H), 6.70 (d, J = 13.3Hz, 1H), 6.59 (s, 1H), 6.53 (s, 1H), 6.02 (s, 1H), 5.90 (s, 2H), 1.27 (s, 9H). 13 C-NMR (100 MHz, CDCl 3)δ181.43,157.38,150.72,148.80,147.68,141.05,133.68,126.46,124.51,122.48, 117.36,115.67,108.48,101.32,99.39,98.57,80.67,52.71,29.98.HRMS(ESI)calcd for C 21 H 22 NO 5 + [M+H] + :368.1492,found:368.1489.

[0245] Embodiment 33

[0246] (Z)-3-((tert-butylamino)methylene)-2-(5-hydroxy-1H-indol-4-yl)chroman-4-one, the structural formula of which is as follows:

[0247]

[0248] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 5-hydroxyindole were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours in an oil bath at 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(5-hydroxy-1H-indol-4-yl)benzodihydropyran-4-one with a yield of 67%.

[0249] 1 H-NMR (400MHz, CDCl 3 )δ10.46(d,J=13.6Hz,1H),8.19(s,1H),8.02(dd,J=7.8,1.5Hz,1H),7.46-7.42(m,1H),7.36(d,J=8.7Hz,1H),7.22(t,J= 2.8Hz,1H),7.16(t,J=7.5Hz,1H),7.05(d,J=8.1Hz,1H),6.96(m,1H),6.65(s,1H),6.60(s,1H),6.40(m,2H),1.10(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ182.07,158.66,149.41,147.86,133.51,130.41,127.26,126.58,125.29,125.06,122. 53,117.61,113.71,112.55,110.71,100.09,98.97,79.80,52.42,29.78.HRMS(ESI)calcd for C 22 H 23 N 2 O 3 + [M+H] + :363.1703,found:363.1700.

[0250] Embodiment 34

[0251] (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxy-1H-indol-7-yl)chroman-4-one, the structural formula of which is as follows:

[0252]

[0253] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 6-hydroxyindole were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 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)-3-((tert-butylamino)methylene)-2-(6-hydroxy-1H-indol-7-yl)benzodihydropyran-4-one with a yield of 63%.

[0254] 1 H-NMR (400MHz, CDCl 3 )δ10.33(d,J=13.5Hz,1H),8.61(s,1H),7.86(dd,J=7.8,1.3Hz,1H),7.44(m,1H),7.33-7.27(m,1H),7.04-7.02(m,1H),6.9 9(t,J=7.5Hz,1H),6.90(m,1H),6.71(d,J=8.5Hz,1H),6.60(s,1H),6.44-6.38(m,1H),6.31(d,J=13.5Hz,1H),0.93(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ182.31,159.20,150.07,147.92,134.67,133.62,126.59,124.76,123.46,122.93,122. 24,121.99,117.50,110.48,105.17,102.36,98.55,76.59,52.50,29.69.HRMS(ESI)calcd for C 22 H 23 N 2 O 3 + [M+H] + :363.1703,found:363.1705.

[0255] Embodiment 35

[0256] (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)-6-methylchroman-4-one, the structural formula of which is as follows:

[0257]

[0258] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-methylchromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours at an oil bath temperature of 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)-6-methylchroman-4-one with a yield of 76%.

[0259] 1 H-NMR (400MHz, CDCl 3 )δ10.49(d,J=13.0Hz,1H),7.71(s,1H),7.29(s,1H),7.17(d,J=8.2Hz,1H),7.08(d,J=7.4Hz,1H),6.97(d, J=8.1Hz,1H),6.87(dd,J=13.8,6.4Hz,3H),6.55(d,J=13.4Hz,1H),6.07(s,1H),2.32(s,3H),1.23(s,9H). 13 C-NMR (100 MHz, CDCl 3)δ181.63,155.50,147.42,134.49,132.00,130.39,129.26,126.41,124.23,123 .48,120.10,117.26,117.10,98.92,81.40,52.56,29.91,20.66.HRMS(ESI)calcd for C 21 H 24 NO 3 + [M+H] + :338.1751,found:338.1748.

[0260] Embodiment 36

[0261] (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(2-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0262]

[0263] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-hydroxy-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of phenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours at an oil bath temperature of 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(2-hydroxyphenyl)chroman-4-one with a yield of 65%.

[0264] 1 H-NMR (400MHz, CDCl 3 )δ10.42(d,J=9.9Hz,1H),7.47-7.44(m,1H),7.30-7.22(m,2H),7.09-7.05(m,1H),7.00-6.92(m, 2H),6.91-6.82(m,3H),6.55(dd,J=13.4,6.2Hz,1H),6.04(d,J=6.2Hz,1H),1.21(d,J=6.6Hz,9H). 13 C-NMR (100 MHz, CDCl 3 )δ181.38,155.45,151.52,148.04,130.44,129.24,124.96,123.28,121.66, 120.16,118.47,117.31,111.69,99.18,81.29,52.84,29.85.HRMS(ESI)calcd for C 20H 22 NO 4 + [M+H] + :340.1543,found:340.1540.

[0265] Embodiment 37

[0266] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(2-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0267]

[0268] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol 6-chloro-chromone-3-carboxaldehyde, 0.55mmol tert-butylamine and 0.5mmol phenol were dissolved in 2mL chlorobenzene, and reacted for 4 hours under an oil bath of 100°C. 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-(2-hydroxyphenyl)chroman-4-one with a yield of 63%.

[0269] 1 H-NMR (400MHz, CDCl 3 )δ10.52(d,J=13.2Hz,1H),7.86(d,J=1.8Hz,1H),7.32-7.24(m,2H),7.10(d,J=7.5Hz,1H),6.97(d, J=8.1Hz,1H),6.90(t,J=7.5Hz,2H),6.71(s,1H),6.60(d,J=13.5Hz,1H),6.12(s,1H),1.23(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ179.97,155.97,155.20,148.05,133.32,130.57,129.26,127.81,126.11,125. 66,123.34,120.32,118.94,117.20,98.41,81.06,52.84,29.87.HRMS(ESI)calcd for C 20 H 21 ClNO 3 + [M+H] + :358.1204,found:358.1205.

[0270] Embodiment 38

[0271] (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0272]

[0273] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-bromo-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 4-chlorophenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours at an oil bath temperature of 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one with a yield of 78%.

[0274] 1 H-NMR (400MHz, CDCl 3 )δ10.57(d,J=13.1Hz,1H),8.01(s,1H),7.44(d,J=8.6Hz,1H),7.22(d,J=8.7Hz,1H),7.07( s,1H),6.89(d,J=8.6Hz,1H),6.83(d,J=8.6Hz,1H),6.67(m,2H),6.05(s,1H),1.28(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ179.54,155.85,153.84,147.99,136.30,130.41,129.28,128.93,125.93,125. 40,125.22,119.20,118.55,115.41,97.36,80.28,53.03,29.91.HRMS(ESI)calcd for C 20 H 20 BrClNO 3 + [M+H] + :436.0310,found:436.0308.

[0275] Embodiment 39

[0276] (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(5-chloro-2-hydroxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0277]

[0278] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-chloro-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 4-chlorophenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours in an oil bath at 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(5-chloro-2-hydroxyphenyl)chroman-4-one with a yield of 77%.

[0279] 1 H-NMR (400MHz, CDCl 3 )δ10.57(d,J=12.5Hz,1H),7.87(s,1H),7.31(dd,J=8.5,2.8Hz,1H),7.25-7.21(m,1H),7.07( s,1H),6.92-6.87(m,2H),6.67(dd,J=13.5,2.6Hz,1H),6.05(s,1H),5.35(s,1H),1.28(s,9H). 13 C-NMR (100 MHz, CDCl 3 )δ179.69,155.36,153.86,147.97,133.45,130.41,128.94,128.13,126.22, 125.53,125.21,118.82,118.56,97.43,80.36,53.02,29.91.HRMS(ESI)calcd for C 20 H 20 Cl 2 NO 3 + [M+H] + :392.0815,found:392.0817.

[0280] Embodiment 40

[0281] (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)-6-isopropylchroman-4-one, the structural formula of which is as follows:

[0282]

[0283] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of 6-isopropyl-chromone-3-carboxaldehyde, 0.55mmol of tert-butylamine and 0.5mmol of 4-chlorophenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours at an oil bath temperature of 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)-6-isopropylchroman-4-one with a yield of 80%.

[0284] 1 H-NMR (400MHz, CDCl 3 )δ10.59(d,J=13.1Hz,1H),7.78(d,J=2.1Hz,1H),7.25-7.19(m,2H),7.08(t,J=3.6Hz,2H),6.88(dd,J=12 .4,8.5Hz,2H),6.63(d,J=13.3Hz,1H),6.04(s,1H),2.93-2.86(m,1H),1.26(s,9H),1.24(d,J=6.9Hz,6H). 13 C-NMR (100 MHz, CDCl 3 )δ181.44,155.08,154.13,147.52,143.31,132.35,130.14,128.90,125.72,124.96,124 .02,123.77,118.51,117.01,98.04,80.27,52.73,33.49,29.93,23.94.HRMS(ESI)calcd for C 23 H 27 ClNO 3 + [M+H] + :400.1674,found:400.1672.

[0285] Embodiment 41

[0286] (Z)-2-(2-hydroxy-4,5-dimethoxyphenyl)-3-((isopropylamino)methylene)chroman-4-one, the structural formula of which is as follows:

[0287]

[0288] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of isopropylamine and 0.5mmol of 3,4-dimethoxyphenol were dissolved in 2mL of chlorobenzene, and the mixture was reacted for 4 hours in an oil bath at 100°C. The solvent was then dried and separated by a silica gel column to obtain the target (Z)-2-(2-hydroxy-4,5-dimethoxyphenyl)-3-((isopropylamino)methylene)benzodihydropyran-4-one with a yield of 82%.

[0289] 1 H-NMR (400MHz, CDCl 3 )δ10.26-10.07(m,1H),7.93(dd,J=7.7,1.5Hz,1H),7.41-7.35(m,1H),7.12-7.06(m,1H),6.96(d,J=7.9Hz,1H),6.63(s,1H) ,6.59(s,1H),6.46(d,J=13.0Hz,1H),6.03(s,1H),3.87(s,3H),3.81(s,3H),3.40-3.32(m,1H),1.21(dd,J=6.4,4.4Hz,6H). 13 C-NMR (100 MHz, CDCl 3 )δ181.86,158.03,150.56,149.87,142.56,133.71,126.52,124.54,117.43,113.45 ,112.62,101.92,99.25,81.09,56.67,55.96,50.69,23.86,23.71.HRMS(ESI)calcd for C 21 H 24 NO 5 + [M+H] + :370.1649,found:370.1650.

[0290] Embodiment 42

[0291] (Z)-3-((cyclopentylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one, the structural formula of which is as follows:

[0292]

[0293] Synthesis method: In a 10mL microwave reaction tube, 0.5mmol of chromone-3-carboxaldehyde, 0.55mmol of cyclopentylamine and 0.5mmol of 3,4-dimethoxyphenol were dissolved in 2mL of chlorobenzene, and reacted for 4 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)-3-((cyclopentylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one with a yield of 80%.

[0294] 1 H-NMR (400MHz, CDCl 3 )δ10.30(m,1H),7.92(d,J=7.6Hz,1H),7.38(m,1H),7.09(m,1H),6.97(d,J=8.2Hz,1H),6.60(m,2H),6.46(m,1H),6.01(s ,1H),3.88(s,3H),3.81(s,3H),3.57(dd,J=13.1,6.5Hz,1H),1.97-1.85(m,2H),1.73(d,J=3.5Hz,2H),1.62-1.51(m,4H). 13 C-NMR (100 MHz, CDCl 3 )δ181.75,157.98,150.63,150.44,149.76,142.57,133.65,126.51,124.59,122.48,117.41,11 3.37,112.78,102.01,99.24,81.34,60.49,56.72,55.97,34.05,23.48,23.45.HRMS(ESI)calcd for C 23 H 26 NO 5 + [M+H] + :396.1805,found:396.1803.

[0295] Biological activity test experiment

[0296] Human tumor cells A549, HCT116, PC-3 and PANC-1 are all from the American Type Culture Collection (ATCC, Manassas, VA, USA). 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). Human non-small cell lung cancer cells A549 and human prostate cancer cells PC cells were cultured with Ham's F-12K (Kaighn's) medium (GIBCO, 21127022, USA) and supplemented with 10% fetal bovine serum (FBS, Gibco, 10099, Australia). Human pancreatic cancer cell PANC-1 cells were cultured in RPMI 1640 medium (GIBCO, 61870044, USA) supplemented with 10% fetal bovine serum (FBS, Gibco, 10099, Australia). The cells were incubated at 37°C and 5% CO 2 Culture in a humidified incubator.

[0297] The anticancer activity of the compounds on the viability of human tumor cells was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT, Bio-Tek, ST316, Shanghai, China). Tumor cells were counted and seeded into 96-well plates containing 100 μL of complete medium. The seeding density of human non-small cell lung cancer cells A549, human colon cancer cells HCT116 and human prostate cancer cells PC-3 was 4000 per well, and the seeding density of human pancreatic cancer cells PANC-1 was 2000 per well. The absorbance was measured at a wavelength of 570 nm (Bio-Tek, Winooski, VT, USA), and the inhibition rate of the compounds and the IC of Example 15 and Example 36 were analyzed using GraphPad Prism 8. 50 All MTT assays were repeated at least three times, and the results are shown in Table 1:

[0298] Table 1. Bioactivity data of compounds

[0299]

[0300] The data in Table 1 show that the hydroxyflavanone derivatives of the present invention have a certain inhibitory effect on the cell activity of human non-small cell lung cancer cells A549, human colon cancer cells HCT116, human prostate cancer cells PC-3 and human pancreatic cancer cells PANC-1. Therefore, the hydroxyflavanone derivatives of the present invention can be used to prepare anti-tumor drugs, especially for preparing drugs for treating lung cancer, colon cancer, prostate cancer or pancreatic cancer. Among them, the anti-tumor drug comprises a hydroxyflavanone 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.

[0301] 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 known technologies.

Claims

1. A hydroxyflavanone derivative, which is a compound represented by formula I or formula II or a pharmaceutically acceptable salt thereof: in, R 1 One or more selected from C1-C4 alkyl, hydroxyl, halogen atom and hydrogen atom, R 2 is a C1-C4 alkyl group, a substituted or unsubstituted aryl group, or a cycloalkyl group, Ar is indolyl, or unsubstituted or substituted phenyl.

2. The hydroxyflavanone derivative according to claim 1, The R 1 One or more selected from methyl, ethyl, propyl, isopropyl, hydroxyl, chlorine, bromine and hydrogen atoms; The R 2 It is ethyl, isopropyl, tert-butyl, cyclopentyl or p-chlorophenyl.

3. The hydroxyflavanone derivative according to claim 1, wherein Ar is phenyl or substituted phenyl, and the substituted phenyl is selected from C1-C4 alkyl, halogen, hydroxyl, alkoxy, One or more of hydroxyethyl and phenyl.

4. The hydroxyflavanone derivative according to claim 3, wherein the C1-C4 alkyl group is methyl, ethyl, propyl, isopropyl, sec-butyl or tert-butyl; and the alkoxy group is methoxy, ethoxy or methylenedioxy.

5. The hydroxyflavanone derivative according to claim 1, wherein R 1 is a hydrogen atom, a hydroxyl group, a methyl group, an isopropyl group, a chlorine atom, or a bromine atom; 2 is tert-butyl, isopropyl, cyclopentyl, 4-chlorophenyl; Ar is phenyl, 3-tert-butylphenyl, 3-sec-butylphenyl, 2-methyl-5-isopropylphenyl, 3-ethylphenyl, 3-phenylphenyl, 2-chlorophenyl, 3-bromophenyl, 3,5-dimethylphenyl, 2-hydroxyphenyl, 4,5-dimethoxyphenyl, 5-(2-hydroxyethyl)phenyl, 5-methoxyphenyl, 5-chlorophenyl, benzo[d][1,3]dioxol-5-yl, 1H-indol-4-yl, 1H-indol-7-yl.

6. The hydroxyflavanone derivative according to claim 1, selected from the following compounds or pharmaceutically acceptable salts thereof: (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)chroman-4-one; (Z)-2-(3-(tert-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one; (Z)-2-(3-(sec-butyl)-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-5-isopropyl-2-methylphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(3-ethyl-4-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-chloro-4-hydroxyphenyl)chroman-4-one; (Z)-2-(3-bromo-4-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxy-3,5-dimethylphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2,4-dihydroxyphenyl)chroman-4-one; (3Z,3'Z)-2,2'-(4,6-dihydroxy-1,3-phenylene)bis(3-((tert-butylamino)methylene)chroman-4-one); (Z)-3-((tert-butylamino)methylene)-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-methylchroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(4-hydroxyphenyl)-6-isopropylchroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(4-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(4-hydroxyphenyl)-7-methylchroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(4-hydroxyphenyl)chroman-4-one; (Z)-6-chloro-3-((cyclopentylamino)methylene)-2-(4-hydroxyphenyl)-7-methylchroman-4-one; (Z)-3-(((4-chlorophenyl)amino)methylene)-2-(4-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)chroman-4-one; (Z)-2-(3-(tert-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one; (Z)-2-(3-(sec-butyl)-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(3-ethyl-2-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-[1,1'-biphenyl]-3-yl)chroman-4-one; (Z)-2-(3-bromo-2-hydroxyphenyl)-3-((tert-butylamino)methylene)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(4-chloro-2-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-3-isopropyl-6-methylphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-(2-hydroxyethyl)phenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxy-5-methoxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(5-hydroxy-1H-indol-4-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(6-hydroxy-1H-indol-7-yl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(2-hydroxyphenyl)-6-methylchroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-hydroxy-2-(2-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(2-hydroxyphenyl)chroman-4-one; (Z)-6-bromo-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-6-chloro-2-(5-chloro-2-hydroxyphenyl)chroman-4-one; (Z)-3-((tert-butylamino)methylene)-2-(5-chloro-2-hydroxyphenyl)-6-isopropylchroman-4-one; (Z)-2-(2-hydroxy-4,5-dimethoxyphenyl)-3-((isopropylamino)methylene)chroman-4-one; (Z)-3-((cyclopentylamino)methylene)-2-(2-hydroxy-4,5-dimethoxyphenyl)chroman-4-one.

7. A method for preparing the hydroxyflavanone derivatives according to any one of claims 1 to 6, characterized in that: The following reactions are included: in, R 1 One or more selected from C1-C4 alkyl, hydroxyl, halogen atom and hydrogen atom, R 2 is a C1-C4 alkyl group, a substituted or unsubstituted aryl group, or a cycloalkyl group, Ar is indolyl, or unsubstituted or substituted phenyl; Reaction 1) Compound 1, Compound 2 and Compound 3 react to obtain Compound 4; or Reaction 2) Compound 1, Compound 2 and Compound 3 are reacted to obtain Compound 5.

8. The preparation method according to claim 7, wherein the reaction 1) comprises dissolving compound 1, compound 2 and compound 3 in an organic solvent A, heating to 80-130° C. to react, to obtain compound 4 (compound shown in formula I); and the reaction 2) comprises dissolving compound 1, compound 2 and compound 3 in an organic solvent B, reacting at 80-130° C. to obtain compound 5 (compound shown in formula II).

9. The preparation method according to claim 8, wherein the heating in reaction 1) is microwave heating, the reaction temperature is 130°C, and after the reaction is completed, the target compound 4 is purified by column; the heating in reaction 2) is oil bath heating, the reaction temperature is 100°C.

10. The preparation method according to claim 8, wherein in the reaction 1), the organic solvent A is hexafluoroisopropanol; and in the reaction 2), the organic solvent B is chlorobenzene.

11. The preparation method according to claim 7, wherein the molar ratio of compound 1, compound 2 and compound 3 is 1:1.1:

1.

12. A pharmaceutical composition comprising the hydroxyflavanone derivative or pharmaceutically acceptable salt or hydrate thereof according to any one of claims 1 to 6 and a pharmaceutically acceptable excipient.

13. Use of the hydroxyflavanone derivative according to any one of claims 1 to 6 in the preparation of anti-tumor drugs.

14. The use according to claim 13, wherein the tumor is lung cancer, colon cancer, prostate cancer or pancreatic cancer.

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