Cyclic ether modified 3-cyano-4-arylaminoquinoline derivative as well as preparation method and application thereof

Abstract

The invention relates to a cyclic ether modified 3-cyano-4-arylaminoquinoline derivative and a preparation method and application thereof, the cyclic ether modified 3-cyano-4-arylaminoquinoline derivative is a compound as shown in a formula I or pharmaceutically acceptable salt thereof, tests prove that the cyclic ether modified 3-cyano-4-arylaminoquinoline derivative has good in-vitro antitumor activity, and a basis is provided for further research and development of antitumor drugs. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a cyclic ether-modified 3-cyano-4-arylaminoquinoline derivative, a preparation method and an application thereof. Background Art

[0002] Malignant tumors are usually referred to as "cancer". In the 21st century, cancer is still a difficult problem for scientists to overcome. With the continuous development of life sciences, the main treatment methods for cancer are conventional surgical resection, chemotherapy, radiotherapy and biological immunotherapy. Chemotherapy is also called drug therapy, which is a method of treating malignant tumors by using chemical drugs, orally or intramuscularly, intravenously, intraarterially, and locally, to destroy cancer cells or inhibit their proliferation to achieve therapeutic effects.

[0003] Compared with traditional cytotoxic drugs, targeted drugs can precisely act on cancer-related targets such as kinases, proteins, and signal transduction pathways, specifically killing cancer cells without affecting normal cells, and have the advantages of strong specificity and few adverse reactions. This type of drug also plays a pivotal role in cancer treatment. Targeted drugs are often used clinically to treat early cancer or in combination with traditional chemotherapy drugs to treat advanced cancer.

[0004] At present, microtubule-targeting agents (MTAs) represented by paclitaxel, vinblastine, and docetaxel are the basic first-line anti-tumor drugs, which are widely used in the treatment of solid tumors and hematological malignancies. However, most patients always develop resistance to chemotherapy drugs including paclitaxel after long-term treatment, and the medication process is accompanied by various toxic and side effects such as allergic reactions, bone marrow suppression, and neurotoxicity, and the 5-year survival rate is only 20-30%. Most of the MTAs on the market are natural products extracted from plants, with large molecular weights and complex structures, and face problems such as poor physical and chemical properties and low bioavailability. These shortcomings and deficiencies have severely restricted the clinical use of MTAs.

[0005] The present application obtains a series of cyclic ether-modified 3-cyano-4-arylaminoquinoline derivatives by analyzing and studying microtubule protein inhibitors, etc. Experiments have verified that the cyclic ether-modified 3-cyano-4-arylaminoquinoline derivatives have good in vitro antitumor activity. Summary of the invention

[0006] The purpose of the present invention is to provide a cyclic ether-modified 3-cyano-4-arylaminoquinoline derivative and a preparation method and application thereof for the treatment of anti-tumor diseases.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] The first aspect of the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Among them, R 1 for

[0011] R 2 is H, C1-C8 straight or branched alkoxy;

[0012] R 3 is H, nitro, C1-C8 straight chain or branched alkyl, C1-C8 straight chain or branched alkoxy, C1-C8 straight chain or branched alkanethio, NR x R y , saturated or unsaturated C3-C8 cycloalkyl,

[0013] R x , R y are independently H, C1-C8 straight or branched chain alkyl;

[0014] R 4 is H, halogen, hydroxyl, C1-C8 straight or branched alkyl, C1-C8 straight or branched alkoxy, C1-C8 straight or branched alkanethio, C2-C8 alkynyl, C2-C8 alkenyl, C2-C8 acyl, C1-C8 carboxyl, saturated or unsaturated C3-C8 cycloalkyl, 5-6 membered heterocyclic group containing 1-3 independently selected from N, O, S, 5-6 membered heteroaryl containing 1-3 independently selected from N, O, S,

[0015] L 1 For -O-, -(CH 2 ) n C(O)—, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, —C(O)NH—, —NHC(O)—, —CHCHC(O)—;

[0016] Ring A is

[0017] R 5 is H, halogen, C1-C8 straight or branched alkyl, C1-C8 straight or branched alkoxy, C1-C8 carboxyl, C1-C8 ester;

[0018] R 6 is H, halogen, C1-C8 straight or branched alkyl, halogenated C1-C8 straight or branched alkyl, C1-C8 ester group;

[0019] n is 0, 1, 2, 3, 4 or 5.

[0020] As some preferred embodiments of the present invention, the R 1 for

[0021] R 2 is H, C1-C5 straight or branched alkoxy;

[0022] R 3 is H, nitro, C1-C5 straight chain or branched alkyl, C1-C5 straight chain or branched alkoxy, C1-C5 straight chain or branched alkanethio, NR x R y , saturated or unsaturated C3-C6 cycloalkyl,

[0023] R x , R y are independently H, C1-C5 straight or branched chain alkyl;

[0024] R 4 is H, halogen, hydroxyl, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkoxy, C1-C5 straight or branched alkanethio, C2-C5 alkynyl, C2-C5 alkenyl, C2-C5 acyl, C1-C5 carboxyl, saturated or unsaturated C3-C6 cycloalkyl, 5-6 membered heterocyclic group containing 1-3 independently selected from N, O, S, 5-6 membered heteroaryl containing 1-3 independently selected from N, O, S,

[0025] L 1 For -O-, -(CH 2 ) n C(O)—, C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, —C(O)NH—, —NHC(O)—, —CHCHC(O)—;

[0026] Ring A is

[0027] R 5 is H, halogen, C1-C5 straight chain or branched alkyl; C1-C5 straight chain or branched alkoxy, C1-C5 carboxyl, C1-C5 straight chain or branched alkoxycarbonyl;

[0028] R 6 is H, halogen, C1-C5 straight or branched alkyl, 1-3 halogenated C1-C5 straight or branched alkyl, C1-C5 straight or branched alkoxycarbonyl;

[0029] n is 0, 1, 2 or 3.

[0030] As some preferred embodiments of the present invention, the C1-C5 straight or branched alkyl group is selected from -CH 3 , —CH 2 CH 3 ,—CH(CH 3 ) 2 ,—(CH 2 ) 2 CH 3 ,—(CH 2 ) 3 CH 3 , —CH 2 CH(CH 3 ) 2 ,—C(CH 3 ) 3 ,—CH(CH 3 )CH 2 CH 3 ,—(CH 2 ) 4 CH 3 ,—CH(CH 3 )(CH 2 ) 2 CH 3 ,—CH(CH 2 CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —CH 2 CH(CH 3 )CH 2 CH 3 ,—C(CH 3 ) 2 CH 2 CH 3 ,—CH(CH 3 )CH(CH 3 ) 2 ,—(CH 2 ) 2 CH(CH 3 ) 2 ;

[0031] The C1-C5 straight or branched alkoxy group is selected from -OCH 3 , —OCH 2 CH 3 ,—OCH(CH 3 ) 2 ,—O(CH 2 ) 2 CH3 , —O(CH 2 ) 3 CH 3 , —OCH 2 CH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OCH(CH 3 )CH 2 CH 3 , —O(CH 2 ) 4 CH 3 , —OCH(CH 3 )(CH 2 ) 2 CH 3 , —OCH(CH 2 CH 3 ) 2 , —OCH 2 C(CH 3 ) 3 , —OCH 2 CH(CH 3 )CH 2 CH 3 , —OC(CH 3 ) 2 CH 2 CH 3 , —OCH(CH 3 )CH(CH 3 ) 2 , —O(CH 2 ) 2 CH(CH 3 ) 2 ;

[0032] The C1-C5 straight-chain or branched-chain alkylthio group is selected from —SCH 3 , —SCH 2 CH 3 , —SCH(CH 3 ) 2 , —S(CH 2 ) 2 CH 3 , —S(CH 2 ) 3 CH 3 , —SCH 2 CH(CH 3 ) 2 , —SC(CH 3 ) 3 , —SCH(CH 3 )CH2 CH 3 ,—S(CH 2 ) 4 CH 3 ,—SCH(CH 3 )(CH 2 ) 2 CH 3 ,—SCH(CH 2 CH 3 ) 2 ,—SCH 2 C(CH 3 ) 3 ,—SCH 2 CH(CH 3 )CH 2 CH 3 ,—SC(CH 3 ) 2 CH 2 CH 3 ,—SCH(CH 3 )CH(CH 3 ) 2 ,—S(CH 2 ) 2 CH(CH 3 ) 2 ;

[0033] The halogen is selected from F, Cl, Br, I;

[0034] The C2-C5 alkenyl group is selected from vinyl, isopropenyl, n-propenyl, n-butenyl, isobutenyl, sec-butenyl, n-pentenyl and isopentenyl;

[0035] The C2-C5 alkynyl group is selected from ethynyl, propynyl, butynyl, and pentynyl;

[0036] The C2-C5 acyl group is selected from —COCH 3 , —COCH 2 CH 3 , —COCH(CH 3 ) 2 ,—CO(CH 2 ) 2 CH 3 ,—CO(CH 2 ) 3 CH 3 , —COCH 2 CH(CH 3 ) 2 ,—COC(CH 3 ) 3 , —COCH(CH 3 )CH2 CH 3 ;

[0037] The C1-C5 carboxyl group is selected from —COOH, —CH 2 COOH, —(CH 2 ) 2 COOH, —(CH 2 ) 3 COOH, —(CH 2 ) 4 COOH, —CH 2 CH(CH 3 ) 2 COOH;

[0038] The C1-C5 alkoxycarbonyl group is selected from —COOCH 3 , —COOCH 2 CH 3 , —COOCH(CH 3 ) 2 , —COO(CH 2 ) 2 CH 3 , —COO(CH 2 ) 3 CH 3 , —COOCH 2 CH(CH 3 ) 2 , —COOC(CH 3 ) 3 , —COOCH(CH 3 )CH 2 CH 3 , —COO(CH 2 ) 4 CH 3 , —COOCH(CH 3 )(CH 2 ) 2 CH 3 , —COOCH(CH 2 CH 3 ) 2 , —COOCH 2 C(CH 3 ) 3 , —COOCH 2 CH(CH 3 )CH 2 CH 3 , —COOC(CH 3 ) 2 CH 2 CH 3 , —COOCH3 )CH(CH 3 ) 2 , —COO(CH 2 ) 2 CH(CH 3 ) 2 ;

[0039] The saturated or unsaturated C3-C6 cycloalkyl is selected from cyclopropane, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl containing 1 unsaturated bond, cyclobutyl containing 1 unsaturated bond, cyclopentyl containing 1 or 2 unsaturated bonds, and cyclohexyl containing 1 or 2 unsaturated bonds;

[0040] The 5-6 membered heteroaryl group containing 1-3 independently selected from N, O, and S is selected from pyrrole, furan, thiophene, oxazole, thiazole, and pyridine;

[0041] The 5-6 membered heterocyclic group containing 1-3 selected from N, O, and S is selected from piperazinyl, morpholinyl, piperidine, and tetrahydropyrrolyl;

[0042] The 1-3 halogenated C1-C5 alkyl group is selected from CF 3 , CH 2 CF 3 , (CH 2 ) 2 CF 3 , (CH 2 ) 3 CF 3 , (CH 2 ) 4 CF 3 .

[0043] As some preferred embodiments of the present invention, the R 2 is selected from hydrogen, methoxy;

[0044] The R 3 is selected from hydrogen, methoxy, methyl, methylmercapto, nitro, dimethylamino, cyclopropyl,

[0045]

[0046] The R 4 is selected from hydrogen, methoxy, hydroxy, bromine, methylmercapto, fluorine, ethynyl, vinyl, isopropyl, acetyl, carboxyl, cyclopropyl,

[0047] The ring A is selected from

[0048] The R 5 is selected from hydrogen, methoxycarbonyl, carboxyl, methyl, methoxy, and fluorine;

[0049] The R 6 Selected from hydrogen, methyl, trifluoromethyl, fluorine, chlorine, bromine, methoxyl.

[0050] As some preferred embodiments of the present invention, the compound structure is as follows:

[0051]

[0052]

[0053] The second aspect of the present invention provides a method for preparing the compound represented by the above formula I, and the specific route is as follows:

[0054]

[0055] Wherein, step i is to add 3,4-dihydroxybenzoic acid and MeOH to the reaction container in sequence, and then add SOCl to the reaction bottle at -5-5°C. 2 After the addition is complete, move to an oil bath, heat to reflux, and react for 6-10 hours;

[0056] Step ii is to sequentially add intermediate TE-1, 1,2-dibromoethane, K 2 CO 3 , DMF, heat to 70-90℃ and react for 4-8h;

[0057] Step iii is to add 70% H 2 SO 4 , AcOH was stirred in an ice-water bath, and 65% HNO was slowly added dropwise 3 , stir for 5-15 min. Add intermediate TE-2 and stir at room temperature for 2-4 h;

[0058] Step iv is to sequentially add intermediate TE-3, MeOH, H 2 O, Fe, AcOH, raise the temperature to reflux reaction for 0.5-2h, cool to room temperature after the reaction is completed, concentrate part of the solvent under reduced pressure, add saturated sodium bicarbonate to adjust the pH to 7-8, add EA and purified water, raise the temperature to 60-80℃, and stir for 5-15min;

[0059] Step V is to sequentially add DMF, intermediate TE-4, and DMF-DMA into a reaction vessel, and heat to 140-160° C. to react for 4-6 hours;

[0060] Step ⅵ is to add THF to the reaction vessel, replace nitrogen 2-4 times, move to a -85--70°C cold trap and stir for 3-10 minutes, add n-BuLi, stir for 3-10 minutes, slowly add MeCN, keep the temperature for 15-25 minutes, dissolve the intermediate TE-5 with THF, slowly add it to the three-necked flask, and react at -85--70°C for 1.5-2.5 hours;

[0061] Step ⅶ Add intermediate TE-6 and SOCl to the reaction vessel. 2 , 1,2-dichloroethane, DMF, reflux reaction for 3-5h;

[0062] Step VIII: When the aromatic amine is a biaryl, the intermediate TE-7, aromatic amine, and MeCN are sequentially added to the reaction vessel, and the temperature is raised to 70-90°C for reaction for 1-3h;

[0063] When the aromatic amine is the remaining aromatic amine, the intermediate TE-7, aromatic amine and i-PrOH are sequentially added into the reaction vessel and the temperature is raised to 75-95° C. for reaction for 2-4 hours.

[0064] As a further improvement of the present invention, the dosage relationship is as follows:

[0065] In step ⅰ, 3,4-dihydroxybenzoic acid, SOCl 2 The dosage relationship is 5-10mmol:1ml;

[0066] In step ii, the molar ratio of the intermediate TE-1 to 1,2-dibromoethane is 1:1.8-2.2;

[0067] 65% HNO in step iii 3 , the molar ratio of the intermediate TE-2 is 1-1.3:1;

[0068] In step ⅳ, the amount of intermediate TE-3, Fe, and AcOH is 1 mmol: 3.8-4.2 mmol: 0.3-0.8 ml;

[0069] In step V, the mass ratio of intermediate TE-4 and DMF-DMA is 1:1.0-1.2;

[0070] In step ⅶ, intermediate TE-6, SOCl 2 The dosage relationship is 1g: 18-22ml;

[0071] In step VIII, the molar ratio of the intermediate TE-7 to the aromatic amine is 1:1-1.5.

[0072] As some preferred embodiments of the present invention, the post-treatment steps are as follows: Step i: After the reaction is completed, the temperature is cooled to room temperature, the solvent is removed by concentration under reduced pressure, a white solid is precipitated, the product is dragged with DCM, and the residual SOCl is removed.2 , and finally drying to obtain the intermediate TE-1;

[0073] After the reaction in step ii is completed, the temperature is lowered to room temperature, and the reaction solution is slowly poured into purified water containing ice cubes, extracted with EA, and the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by column chromatography using PE-EA eluent to obtain TE-2;

[0074] After the reaction in step iii is completed, the reaction solution is slowly added into ice water to gradually precipitate a white solid, which is filtered by suction, the filter cake is rinsed with purified water, and air-dried to obtain the intermediate TE-3;

[0075] Step iv After the reaction is completed, filter while hot, separate the liquids, extract with EA, combine the organic phases, wash the organic phases with saturated brine, and remove anhydrous Na 2 SO 4 The organic phase was dried and concentrated under reduced pressure to obtain a crude product, which was recrystallized from PE-EA to obtain intermediate TE-4;

[0076] After the reaction in step ⅴ is completed, the temperature is cooled to room temperature, and the solvent is removed by concentration under reduced pressure, and toluene is dragged 4-5 times to obtain intermediate TE-5;

[0077] Step ⅵ After the reaction is completed, move the three-necked flask indoors and wait for the three-necked flask to warm to room temperature. Add saturated ammonium chloride solution to the reaction flask and stir for 5-10 minutes to gradually precipitate solids. Filter under reduced pressure and rinse the filter cake with purified water. Beat the filter cake with MeCN at room temperature for 0.5-2 hours, filter under reduced pressure and dry the filter cake with air blast to constant weight to obtain intermediate TE-6;

[0078] After the reaction in step ⅶ is completed, the temperature is lowered to 45-55°C, and the filter is filtered under reduced pressure, and the filter cake is washed with PE, and the filter cake is air-dried to a constant weight to obtain the intermediate TE-7;

[0079] After the reaction in step VIII is completed, the filter is filtered under reduced pressure, and the filter cake is washed with a corresponding solvent, and the filter cake is air-dried to a constant weight to obtain the target compound.

[0080] The third aspect of the present invention provides a composition containing the compound represented by formula I or a pharmaceutically acceptable salt thereof.

[0081] The fourth aspect of the present invention provides the use of the compound represented by the above formula I or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

[0082] The beneficial effects of adopting the above technical solution are:

[0083] The compounds provided by the present invention have been verified by experiments to exhibit good in vitro anti-tumor activity, laying a foundation for later drug development. DETAILED DESCRIPTION

[0084] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially.

[0085] Example 1

[0086]

[0087] Add 3,4-dihydroxybenzoic acid (50 g, 0.325 mol) and 300 ml MeOH to a 500 ml single-necked bottle, and add 50 ml SOCl to the reaction bottle at 0 °C in a cold trap. 2 After the addition was complete, the mixture was moved to an oil bath and heated to reflux. After 8 hours of reaction, TLC detected that the reaction of the raw material was complete, cooled to room temperature, concentrated under reduced pressure to remove the solvent, and a white solid was precipitated. The product was dragged with 50 ml of DCM in two batches to remove the residual SOCl 2 Finally, 53.6 g of off-white solid was obtained by drying, with a yield of 98.3%.

[0088]

[0089] To a 500 ml eggplant-shaped flask, add the intermediate TE-1 (10 g, 0.060 mol), 1,2-dibromoethane (22.1 g, 0.119 mol), K 2 CO 3 (24.7g, 0.179mol), 100ml DMF, heated to 80℃ for 6h. After TLC detection, the reaction was complete, and then cooled to room temperature. After post-treatment, the reaction solution was slowly poured into 600ml purified water containing ice cubes, extracted with 300ml EA, extracted three times, washed the organic phase once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate TE-2 crude product, which was purified by column chromatography (PE:EA=5:1) to obtain 7.8g of brown solid with a yield of 67.7%.

[0090]

[0091] Add 70% H 2 SO 4 (6.5 g, 0.046 mol) and AcOH (10 ml) were stirred in an ice-water bath, and 65% HNO was slowly added dropwise 3(3.6 g, 0.037 mol), stirred for 10 min. Add intermediate TE-2 (6.0 g, 0.031 mol), stirred at room temperature for 3 h. TLC detected that the reaction was complete, post-treatment, the reaction solution was slowly added into 200 ml of ice water, white solid gradually precipitated, filtered, purified water was used to rinse the filter cake, and air-dried to obtain 4.2 g of intermediate TE-3, with a yield of 57.4%.

[0092]

[0093] In a 250 ml eggplant-shaped flask, intermediate TE-3 (2.4 g, 0.010 mol), MeOH (25 ml), H 2 O (25 ml), Fe (2.2 g, 0.040 mol), AcOH (5 ml), heated to reflux for 1 h. TLC detected that the reaction was complete, cooled to room temperature, and concentrated under reduced pressure until the solvent remained about 20 ml, added saturated sodium bicarbonate to adjust the pH to 7-8, added 50 ml EA and 30 ml purified water, heated to 70 ° C, and stirred for 10 min. Filtered while hot, separated, extracted with EA (50 ml × 3), combined the organic phase, washed the organic phase twice with saturated brine, and anhydrous NaSO 4 The organic phase was dried and concentrated under reduced pressure to obtain the crude intermediate TE-4, which was recrystallized from PE / EA to obtain 1.4 g of the pure intermediate TE-4 with a yield of 69.2%.

[0094]

[0095] Add DMF (20 ml), intermediate TE-4 (2.0 g, 0.0096 mol), and DMF-DMA (2.28 g, 0.0191 mol) to a 250 ml eggplant-shaped bottle, and heat to 150 ° C for 5 hours. TLC detection shows that the reaction is relatively complete, and some TE-4 is not completely reacted. After post-treatment, cool to room temperature, concentrate under reduced pressure to remove the solvent, and drag with toluene 4 to 5 times to obtain intermediate TE-5. Since intermediate TE-5 is a Schiff base structure and is very active, the product of this step does not need to be purified and is directly used in the next step.

[0096]

[0097] Add THF (30.0 ml) to a 250 ml three-necked flask, replace nitrogen three times, move to a -78 ° C cold trap and stir for 5 min, add 1.6 mol / L n-BuLi (14.9 ml, 0.0239 mol), and stir for 5 min. Slowly add MeCN (0.982 g, 0.0239 mol) and keep the temperature for 20 min. Dissolve the intermediate TE-5 obtained above in THF (20.0 ml), slowly add it to the three-necked flask, and react at -78 ° C for 2 h. TLC detection reaction is complete, post-processing, and the three-necked flask is moved to room temperature. Add 100.0 ml of saturated ammonium chloride solution to the reaction flask, stir for 10 min, gradually precipitate solids, reduce pressure and filter, and rinse the filter cake with purified water. The filter cake is slurried with 20.0 ml MeCN at room temperature for 1 h, reduced pressure and filter, and the filter cake is air-dried to constant weight to obtain 0.60 g of intermediate TE-6, with a two-step yield of 27.6%.

[0098]

[0099] In a 100 ml eggplant-shaped bottle, add intermediate TE-6 (0.20 g, 0.00087 mol), SOCl 2 (4ml), 1,2-dichloroethane (6ml), 3 drops of DMF, reflux reaction for 4h. TLC detection of complete reaction, post-treatment, cool to 50℃, vacuum filter, PE elution filter cake, air drying to constant weight, 0.118g intermediate TE-7, yield 54.7%.

[0100] Example 2

[0101]

[0102] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-methoxyaniline (0.030 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0.0456 g TE008, with a yield of 68.4% and a purity of 99.86%. MS-ESI (m / z): 334.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6): δ11.22(s,1H),8.97(s,1H),8.39(s,1H),7.57(s,1H),7.39(t,J=8.1Hz,1H),7 .04(d,J=2.1Hz,1H),7.00(dt,J=7.0,2.9Hz,2H),4.53–4.42(m,4H),3.78(s,3H).

[0103] Experimental Example 3

[0104]

[0105] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 4-methoxyaniline (0.030 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0275 g TE009, with a yield of 41.2% and a purity of 98.65%. MS-ESI (m / z): 334.1 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ): δ11.28(s,1H),8.91(s,1H),8.45(s,1H),7.59(s,1H),7.37(d,J=8.8Hz, 2H), 7.03 (d, J=8.9Hz, 2H), 4.47 (ddd, J=22.6, 6.3, 3.2Hz, 4H), 3.81 (s, 3H).

[0106] Experimental Example 4

[0107]

[0108] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3,4-dimethoxyaniline (0.037 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 °C for 3 h. TLC detected that the reaction was complete, and after post-treatment, the temperature was lowered to 50 °C and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound TE010, with a yield of 42.5% and a purity of 97.09%. MS-ESI (m / z): 364.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6): δ11.13(s,1H),8.94(s,1H),8.35(s,1H),7.53(s,1H),7.09(d,J=2.3Hz,1H),7.04(d,J=8.5Hz ,1H),6.99(dd,J=8.5,2.3Hz,1H),4.48(ddd,J=22.0,6.3,3.1Hz,4H),3.81(s,3H),3.75(s,3H).

[0109] Experimental Example 5

[0110]

[0111] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3,5-dimethoxyaniline (0.037 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0364 g TE011, with a yield of 50.1% and a purity of 98.06%. MS-ESI (m / z): 364.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.27(s,1H),8.97(s,1H),8.42(s,1H),7.60(s,1H),6.63(d,J=2.2Hz, 2H), 6.54 (t, J=2.2Hz, 1H), 4.47 (ddd, J=23.0, 6.2, 3.1Hz, 4H), 3.76 (s, 6H).

[0112] Experimental Example 6

[0113]

[0114] Add intermediate TE-7 (0.050 g, 0.00020 mol), 5-amino-2-methoxyphenol (0.033 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. The reaction was complete by TLC detection, and the reaction was post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0242 g TE012, with a yield of 34.7% and a purity of 99.12%. MS-ESI (m / z): 350.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ11.00(s,1H),9.47(s,1H),8.91(s,1H),8.31(s,1H),7.50(s,1H),6.99(d,J=8 .2Hz,1H),6.83(d,J=8.1Hz,2H),4.47(ddd,J=22.0,6.3,3.1Hz,4H),3.81(s,3H).

[0115] Experimental Example 7

[0116]

[0117] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-bromo-4-methoxyaniline (0.048 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. The reaction is complete by TLC detection, and the reaction is post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake is washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0255 g TE013, with a yield of 30.9% and a purity of 97.77%. MS-ESI (m / z): 412.0 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.10(s,1H),8.96(s,1H),8.33(s,1H),7.73(d,J=2.5Hz,1H),7.51(s,1H),7 .46(dd,J=8.8,2.6Hz,1H),7.22(d,J=8.9Hz,1H),4.52–4.43(m,4H),3.91(s,3H).

[0118] Experimental Example 8

[0119]

[0120] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), p-methylaniline (0.026 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0257 g TE014, with a yield of 40.5% and a purity of 99.45%. MS-ESI (m / z): 318.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ11.33(s,1H),9.07(s,1H),8.53(s,1H),7.69(s,1H),7.47–7.41(m,4H),4.60(ddd,J=22.4,6.3,3.1Hz,4H),2.50(s,3H).

[0121] Experimental Example 9

[0122]

[0123] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-aminophenol (0.026 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 °C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 °C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0285 g TE015, with a yield of 44.6% and a purity of 99.63%. MS-ESI (m / z): 320.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.03(s,1H),9.88(s,1H),8.95(s,1H),8.30(s,1H),7.50(s,1H),7.2 6(t,J=8.0Hz,1H),6.86–6.80(m,3H),4.47(ddd,J=22.2,6.4,3.2Hz,4H).

[0124] Experimental Example 10

[0125]

[0126] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 4-(methylthio)aniline (0.033 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0267 g TE016, with a yield of 38.2% and a purity of 97.88%. MS-ESI (m / z): 350.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ11.03(s,1H),8.95(s,1H),8.31(s,1H),7.49(s,1H),7.37(d,J=1.3Hz,4H),4.47(ddd,J=21.7,6.3,3.2Hz,4H),2.52(s,3H).

[0127] Experimental Example 11

[0128]

[0129] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-(methylthio)aniline (0.033 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0265 g TE017, with a yield of 37.9% and a purity of 99.08%. MS-ESI (m / z): 350.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.14(s,1H),8.97(s,1H),8.35(s,1H),7.54(s,1H),7.42(t,J=7.9Hz,1H),7.34(d, J=1.9Hz,1H),7.32–7.26(m,1H),7.23–7.16(m,1H),4.48(ddd,J=21.8,6.4,3.2Hz,4H).

[0130] Experimental Example 12

[0131]

[0132] Add intermediate TE-7 (0.050 g, 0.00020 mol), N, N-dimethylbenzene-1,4-diamine (0.033 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0335 g TE018, with a yield of 48.3% and a purity of 97.30%. MS-ESI (m / z): 347.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ10.96(s,1H),8.88(s,1H),8.32(s,1H),7.50(q,J=2.1Hz,1H),7.26–7.19( m,2H),6.80(d,J=8.4Hz,2H),4.46(ddd,J=21.7,6.3,3.1Hz,4H),2.97(s,6H).

[0133] Experimental Example 13

[0134]

[0135] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 4-nitroaniline (0.033 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0231 g TE019, with a yield of 33.2% and a purity of 97.30%. MS-ESI (m / z): 349.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.35(s,1H),9.06(s,1H),8.30(d,J=2.1Hz,1H),8.28(d,J=5.2Hz,2H),7.60(s,1H),7.58–7.53(m,2H),4.48(ddd,J=22.3,6.4,3.2Hz,4H).

[0136] Experimental Example 14

[0137]

[0138] Add intermediate TE-7 (0.050 g, 0.00020 mol), m-bromoaniline (0.041 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 °C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 °C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0271 g TE020, with a yield of 35.4% and a purity of 99.25%. MS-ESI (m / z): 382.0 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ11.23(s,1H),9.00(s,1H),8.36(s,1H),7.70(d,J=2.3Hz,1H),7.63–7.5 7(m,1H),7.55(s,1H),7.47–7.42(m,2H),4.48(ddd,J=21.8,6.4,3.2Hz,4H).

[0139] Experimental Example 15

[0140]

[0141] Add intermediate TE-7 (0.050 g, 0.00020 mol), m-fluoroaniline (0.027 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 °C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 °C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0242 g TE021, with a yield of 37.7% and a purity of 98.63%. MS-ESI (m / z): 322.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.37(s,1H),9.01(s,1H),8.42(s,1H),7.59(s,1H),7.53(td,J=8.2,6.5Hz,1H) ,7.37(dt,J=10.0,2.3Hz,1H),7.32–7.24(m,2H),4.48(ddd,J=22.5,6.4,3.2Hz,4H).

[0142] Experimental Example 16

[0143]

[0144] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-ethynylaniline (0.028 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0421 g TE022, with a yield of 64.3% and a purity of 99.60%. MS-ESI (m / z): 328.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ11.23(s,1H),8.99(s,1H),8.38(s,1H),7.55(d,J=3.4Hz,2H),7.53–7.47(m,3H),4.48(ddd,J=22.0,6.3,3.1Hz,4H),4.32(s,1H).

[0145] Experimental Example 17

[0146]

[0147] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-vinylaniline (0.029 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0294 g TE023, with a yield of 44.6% and a purity of 98.80%. MS-ESI (m / z): 330.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.32(s,1H),8.97(s,1H),8.44(s,1H),7.60–7.55(m,2H),7.52(dt,J=7.8,1.5Hz,1H),7.46(t,J=7.7Hz,1H),7.35(dt,J=8. 0,1.5Hz,1H),6.78(dd,J=17.6,11.0Hz,1H),5.91(d,J=17.6Hz,1H),5.34(d,J=11.0Hz,1H),4.48(ddd,J=22.6,6.4,3.2Hz,4H).

[0148] Experimental Example 18

[0149]

[0150] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-isopropylaniline (0.032 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0327 g TE024, with a yield of 47.4% and a purity of 98.68%. MS-ESI (m / z): 346.2 (M+H) + , 1H NMR (400 MHz, DMSO-d 6 ): δ11.31(s,1H),8.95(s,1H),8.43(s,1H),7.59(s,1H),7.40(t,J=7.7Hz,1H),7.36–7.27(m,2H), 7.27–7.20(m,1H),4.47(ddd,J=22.5,6.3,3.2Hz,4H),2.93(p,J=6.9Hz,1H),1.22(d,J=6.9Hz,6H).

[0151] Experimental Example 19

[0152]

[0153] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-acetylaniline (0.032 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0347 g TE025, with a yield of 50.2% and a purity of 98.35%. MS-ESI (m / z): 345.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.42(s,1H),8.99(s,1H),8.46(s,1H),8.02–7.98(m,2H),7.72(dt,J=8.1, 1.5Hz,1H),7.65(t,J=7.8Hz,1H),7.59(s,1H),4.52–4.44(m,4H),2.61(s,3H).

[0154] Experimental Example 20

[0155]

[0156] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-aminobenzoic acid (0.033 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0342 g TE026, with a yield of 49.3% and a purity of 98.60%. MS-ESI (m / z): 348.1 (M+H) + ,1 H NMR (400 MHz, DMSO-d 6 ): δ11.37(s,1H),8.99(s,1H),8.43(s,1H),7.99–7.93(m,2H),7.70(dt,J=7.9,1 .6Hz,1H),7.62(t,J=8.0Hz,1H),7.57(s,1H),4.48(ddd,J=22.2,6.4,3.2Hz,4H).

[0157] Experimental Example 21

[0158]

[0159] Add intermediate TE-7 (0.050 g, 0.00020 mol), 4-cyclopropylaniline (0.032 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0344 g TE027, with a yield of 50.1% and a purity of 98.13%. MS-ESI (m / z): 344.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.15(s,1H),8.94(s,1H),8.37(s,1H),7.54(s,1H),7.30(d,J=8.3Hz,2H),7.18(d,J=8.3Hz, 2H),4.52–4.42(m,4H),1.99(ddd,J=13.4,8.5,5.0Hz,1H),1.04–0.98(m,2H),0.75–0.67(m,2H).

[0160] Experimental Example 22

[0161]

[0162] Add intermediate TE-7 (0.050 g, 0.00020 mol), 2-naphthylamine (0.034 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection. After post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0264 g TE028, with a yield of 37.3% and a purity of 98.13%. MS-ESI (m / z): 354.1 (M+H) + ,1 H NMR (400 MHz, DMSO-d 6 ): δ11.24(s,1H),8.97(s,1H),8.38(s,1H),8.05(d,J=8.7Hz,1H),8.02–7.94(m,3H) ,7.57(ddd,J=9.0,4.5,2.1Hz,3H),7.53(s,1H),4.49(ddd,J=21.8,6.3,3.2Hz,4H).

[0163] Experimental Example 23

[0164]

[0165] Add intermediate TE-7 (0.050 g, 0.00020 mol), 1H-indole-5-amine (0.032 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0318 g TE029, with a yield of 46.5% and a purity of 97.36%. MS-ESI (m / z): 343.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.41(s,1H),11.21(s,1H),8.87(s,1H),8.38(s,1H),7.60(d,J=2.0Hz,1H),7.53(s,1H),7.49(d,J=8.5Hz,1 H),7.46(t,J=2.8Hz,1H),7.12(dd,J=8.5,2.1Hz,1H),6.51(t,J=2.6Hz,1H),4.47(ddd,J=21.9,6.3,3.2Hz,4H).

[0166] Experimental Example 24

[0167]

[0168] Add intermediate TE-7 (0.050 g, 0.00020 mol), 1H-indole-6-amine (0.032 g, 0.00024 mol), i-PrOH (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0296 g TE030, with a yield of 43.3% and a purity of 98.96%. MS-ESI (m / z): 343.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.42(d,J=2.3Hz,1H),11.30(s,1H),8.90(s,1H),8.41(s,1H),7.62(d,J=8.3Hz,1H),7.55( s,1H),7.49–7.44(m,2H),7.03(dd,J=8.3,1.9Hz,1H),6.51(t,J=2.5Hz,1H),4.52–4.42(m,4H).

[0169] Experimental Example 25

[0170]

[0171] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), benzofuran-5-amine (0.032 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH, and the filter cake was air-dried to constant weight to obtain the target compound 0.0268 g TE031, with a yield of 39.0% and a purity of 97.28%. MS-ESI (m / z): 344.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.48(s,1H),8.93(s,1H),8.49(s,1H),8.11(d,J=2.2Hz,1H),7.76(d,J=2.2Hz,1H),7.72(d,J=8.7Hz ,1H),7.59(s,1H),7.39(dd,J=8.7,2.2Hz,1H),7.05(d,J=2.1Hz,1H),4.48(ddd,J=22.2,6.4,3.2Hz,4H).

[0172] Experimental Example 26

[0173]

[0174] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 5-aminoisobenzofuran-1(3H)-one (0.036 g, 0.00024 mol), i-PrOH (10 ml), and heat to 85 ° C for 3 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0198 g TE032, with a yield of 27.6% and a purity of 96.08%. MS-ESI (m / z): 360.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.42(s,1H),9.05(s,1H),8.37(s,1H),7.91(d,J=8.2Hz,1H),7.67(d,J=1. 8Hz,1H),7.58(d,J=9.2Hz,2H),5.44(s,2H),4.48(ddd,J=22.5,6.4,3.2Hz,4H).

[0175] Experimental Example 27

[0176]

[0177] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-cyclopropylaniline (0.032 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH and air-dried to constant weight to obtain the target compound 0.0227 g TE033, with a yield of 33.0% and a purity of 98.70%. MS-ESI (m / z): 344.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ10.96(s,1H),8.93(s,1H),8.27(s,1H),7.47(s,1H),7.35(t,J=7.8Hz,1H),7.17(dt,J=7.8,2.1Hz,2H), 7.10(d,J=1.9Hz,1H),4.51–4.43(m,4H),1.98(td,J=8.4,4.3Hz,1H),1.01–0.94(m,2H),0.73–0.68(m,2H).

[0178] Experimental Example 28

[0179]

[0180] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-(thiophen-2-yl)aniline (0.042 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0271 g TE034, with a yield of 35.2% and a purity of 96.73%. MS-ESI (m / z): 386.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.36(s,1H),8.99(s,1H),8.45(s,1H),7.76(t,J=1.9Hz,1H),7.71(dt,J=7.9,1.3Hz,1H),7.60(q,J=2.9,2.2Hz,3 H),7.53(t,J=7.9Hz,1H),7.38(dd,J=7.1,2.0Hz,1H),7.16(dd,J=5.0,3.7Hz,1H),4.48(ddd,J=22.6,6.3,3.1Hz,4H).

[0181] Experimental Example 29

[0182]

[0183] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-(furan-2-yl)aniline (0.038 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0312 g TE035, with a yield of 42.3% and a purity of 95.90%. MS-ESI (m / z): 370.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ11.36(s,1H),8.99(s,1H),8.44(s,1H),7.77(ddd,J=11.2,7.7,1.6Hz,3H),7.59(s,1H),7.54(t,J=7.8 Hz,1H),7.36(dt,J=8.2,1.3Hz,1H),7.05(d,J=3.4Hz,1H),6.63(dd,J=3.4,1.8Hz,1H),4.53–4.44(m,4H).

[0184] Experimental Example 30

[0185]

[0186] The intermediate TE-7 (0.050 g, 0.00020 mol), 3-(1H-pyrrol-2-yl)aniline (0.038 g, 0.00024 mol), and MeCN (10 ml) were added to a 100 ml eggplant-shaped bottle in sequence, and the temperature was raised to 80°C for 2 h. The reaction was complete by TLC detection, and the mixture was post-treated, cooled to 50°C, and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0332 g TE036, with a yield of 45.1% and a purity of 98.80%. MS-ESI (m / z): 369.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.44(s,1H),11.22(s,1H),8.98(s,1H),8.39(s,1H),7.69(dt,J=4.1,1.8Hz,2H),7.57(s,1H),7.45(t,J=8.1Hz,1H), 7.23–7.16(m,1H),6.88(q,J=2.3Hz,1H),6.59(p,J=1.7Hz,1H),6.13(q,J=2.7Hz,1H),4.49(ddd,J=22.1,6.3,3.1Hz,4H).

[0187] Experimental Example 31

[0188]

[0189] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-(oxazol-5-yl)aniline (0.038 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0290 g TE037 with a yield of 39.2% and a purity of 96.37%. MS-ESI (m / z): 371.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.24(s,1H),8.98(s,1H),8.50(s,1H),8.38(d,J=2.0Hz,1H),7.81(t,J=1.9Hz,1H),7.79–7.76(m, 2H), 7.60 (t, J=7.9Hz, 1H), 7.55 (d, J=1.2Hz, 1H), 7.45 (ddd, J=7.9, 2.2, 1.0Hz, 1H), 4.53–4.45 (m, 4H).

[0190] Experimental Example 32

[0191]

[0192] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-(thiazol-5-yl)aniline (0.042 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0324 g TE038, with a yield of 41.9% and a purity of 96.13%. MS-ESI (m / z): 387.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.32(s,1H),9.13(s,1H),9.00(s,1H),8.42(s,2H),7.85–7.79(m, 2H),7.57(s,1H),7.53–7.49(m,2H),4.48(ddd,J=22.2,6.3,3.1Hz,4H).

[0193] Experimental Example 33

[0194]

[0195] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-(pyridin-2-yl)aniline (0.041 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0276 g TE039, with a yield of 36.3% and a purity of 99.35%. MS-ESI (m / z): 381.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.35(s,1H),8.99(s,1H),8.70(dd,J=4.8,1.8Hz,1H),8.43(s,1H),8.23–8.13(m,2H),8.07(d,J=8.0Hz,1H),7.97(td, J=7.7,1.9Hz,1H),7.63(t,J=7.9Hz,1H),7.59–7.50(m,2H),7.44(dd,J=7.5,4.9Hz,1H),4.49(ddd,J=22.1,6.3,3.2Hz,4H).

[0196] Experimental Example 34

[0197]

[0198] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-(pyridin-3-yl)aniline (0.041 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0300 g TE040, with a yield of 39.5% and a purity of 97.28%. MS-ESI (m / z): 381.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ10.98(s,1H),9.02(d,J=2.4Hz,1H),8.89(s,1H),8.70–8.64(m,1H),8.35–8.28(m,2H),7.8 6(d,J=2.0Hz,1H),7.79(d,J=7.8Hz,1H),7.75–7.59(m,2H),7.53–7.45(m,2H),4.48(ddd,4H).

[0199] Experimental Example 35

[0200]

[0201] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 2', 3', 4', 5'-tetrahydro-[1,1'-biphenyl]-3-amine (0.041 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. The reaction was complete by TLC detection, and the reaction was post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH, and the filter cake was air-dried to constant weight to obtain the target compound 0.0285 g TE041, with a yield of 37.2% and a purity of 93.10%. MS-ESI (m / z): 384.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.08(s,1H),8.95(s,1H),8.32(s,1H),7.50(s,1H),7.48–7.39(m,3H),7.28(dt,J=7.1,1.9Hz,1H),6.24(td,J=4. 1,2.0Hz,1H),4.52–4.44(m,4H),2.41–2.33(m,2H),2.18(tt,J=6.0,3.1Hz,2H),1.78–1.67(m,2H),1.65–1.56(m,2H).

[0202] Experimental Example 36

[0203]

[0204] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-(4-morpholinyl)aniline (0.043 g, 0.00024 mol), i-PrOH (10 ml) in sequence, and heat to 85 ° C for 3 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with i-PrOH, and the filter cake was air-dried to constant weight to obtain the target compound 0.0326 g TE042, with a yield of 42.0% and a purity of 93.10%. MS-ESI (m / z): 389.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ11.16(s,1H),8.94(s,1H),8.37(s,1H),7.56(s,1H),7.32(t,J=8.4Hz,1H),7.04–6.97(m,2H), 6.88–6.82(m,1H),4.47(ddd,J=22.2,6.3,3.2Hz,4H),3.74(t,J=4.8Hz,4H),3.15(t,J=4.8Hz,4H).

[0205] Experimental Example 37

[0206]

[0207] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-phenoxyaniline (0.044 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction is complete by TLC detection. After post-treatment, cool to 50 ° C, and filter under reduced pressure. Wash the filter cake with MeCN, and air dry the filter cake to constant weight to obtain the target compound 0.0250 g TE043, with a yield of 31.6% and a purity of 97.54%. MS-ESI (m / z): 396.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.16(s,1H),8.97(s,1H),8.31(s,1H),7.55–7.46(m,2H),7.44–7.35(m,2H),7.23(dd,J=8.0,2.0Hz ,1H),7.16(d,J=7.4Hz,1H),7.13(t,J=2.2Hz,1H),7.11–7.05(m,3H),4.47(ddd,J=21.7,6.3,3.2Hz,4H).

[0208] Experimental Example 38

[0209]

[0210] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-aminobenzophenone (0.047 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0327 g TE044, with a yield of 40.2% and a purity of 98.65%. MS-ESI (m / z): 408.2 (M+H) + ,1 H NMR (400 MHz, DMSO-d 6 ): δ11.23(s,1H),8.99(s,1H),8.33(s,1H),7.81–7.76(m,3H),7.75–7.72(m,2H),7.69( d,J=7.4Hz,2H),7.58(t,J=7.6Hz,2H),7.51(s,1H),4.48(ddd,J=21.2,6.3,3.1Hz,4H).

[0211] Experimental Example 39

[0212]

[0213] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 3-(phenylethynyl)aniline (0.046 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0373 g TE045, with a yield of 46.3% and a purity of 99.35%. MS-ESI (m / z): 404.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.47(s,1H),8.99(s,1H),8.50(s,1H),7.65(d,J=1.9Hz,1H),7.60(s,1H),7.57(dd,J =6.6,2.7Hz,3H),7.55–7.47(m,2H),7.45–7.41(m,3H),4.48(ddd,J=22.3,6.3,3.2Hz,4H).

[0214] Experimental Example 40

[0215]

[0216] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-aminobenzanilide (0.051 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. TLC detected that the reaction was complete, post-processed, cooled to 50 ° C, and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0384 g TE046, with a yield of 45.5% and a purity of 97.45%. MS-ESI (m / z): 423.1 (M+H) +, 1 H NMR (400 MHz, DMSO-d 6 ): δ11.26(s,1H),10.38(s,2H),9.01(s,2H),8.38(s,2H),8.06(d,J=4.0Hz,4H),7.83–7.76(m,4H),7.71 –7.64(m,4H),7.54(s,2H),7.41–7.32(m,4H),7.12(t,J=7.3Hz,2H),4.49(ddd,J=21.6,6.5,3.2Hz,8H).

[0217] Experimental Example 41

[0218]

[0219] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), N-(3-aminophenyl)benzamide (0.051 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0335 g TE047, with a yield of 39.7% and a purity of 98.80%. MS-ESI (m / z): 423.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.09(s,1H),10.51(s,1H),8.97(s,1H),8.33(s,1H),8.07(t,J=2.1Hz,1H),7.99–7.96(m,2H),7.75(dd,J=8.2,2.0Hz,1H),7.64–7.5 9(m,1H),7.55(dd,J=8.2,6.5Hz,2H),7.50(s,1H),7.46(t,J=8.1Hz,1H),7.17(dd,J=7.7,2.1Hz,1H),4.48(ddd,J=21.2,6.4,3.2Hz,4H).

[0220] Experimental Example 42

[0221]

[0222] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), (E)-3-(3-aminophenyl)-1-phenyl-2-propene-1-one (0.054 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0384 g TE048, with a yield of 44.3% and a purity of 98.66%. MS-ESI (m / z): 434.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.39(s,1H),9.00(s,1H),8.47(s,1H),8.15(d,J=7.0Hz,2H),8.07–7.98(m,2H),7.95(d,J=7.5Hz,1 H),7.78(d,J=15.6Hz,1H),7.68(t,J=7.3Hz,1H),7.62–7.52(m,5H),4.49(ddd,J=22.3,6.4,3.2Hz,4H).

[0223] Experimental Example 43

[0224]

[0225] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), (E)-3-(4-aminophenyl)-1-phenyl-2-propene-1-one (0.054 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0409 g TE049, with a yield of 47.2% and a purity of 92.21%. MS-ESI (m / z): 434.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.30(s,1H),9.02(s,1H),8.39(s,1H),8.18(dd,J=7.2,1.7Hz,2H),8.06–7.97(m,3H),7.80(d,J=15. 6Hz,1H),7.71–7.65(m,1H),7.61–7.56(m,3H),7.51(d,J=8.3Hz,2H),4.48(ddd,J=22.4,6.4,3.2Hz,4H).

[0226] Experimental Example 44

[0227]

[0228] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), (E)-1-(4-aminophenyl)-3-(3,4,5-trimethoxyphenyl)-2-propene-1-one (0.075 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete after TLC detection, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake was washed with MeCN, and the filter cake was air-dried to constant weight to obtain the target compound 0.0533 g TE050, with a yield of 50.9% and a purity of 96.02%. MS-ESI (m / z): 524.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.46(s,1H),9.06(s,1H),8.43(s,1H),8.32–8.26(m,2H),7.97(d,J=15.5Hz,1H),7.73(d,J=15.5 Hz,1H),7.64–7.57(m,3H),7.26(s,2H),4.49(ddd,J=22.8,6.3,3.2Hz,4H),3.87(s,6H),3.72(s,3H).

[0229] Experimental Example 45

[0230]

[0231] Add intermediate TE-7 (0.050 g, 0.00020 mol), 6-methyl-(1,1'-biphenyl)-3-amine (0.044 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0321 g TE051, with a yield of 40.8% and a purity of 94.57%. MS-ESI (m / z): 394.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6): δ10.95(s,1H),8.94(s,1H),8.27(s,1H),7.50–7.43(m,3H),7.42(s,1H),7.3 9–7.35(m,3H),7.34–7.31(m,1H),7.27(s,1H),4.50–4.43(m,4H),2.27(s,3H).

[0232] Experimental Example 46

[0233]

[0234] Add intermediate TE-7 (0.050 g, 0.00020 mol), 6-trifluoromethyl-(1,1'-biphenyl)-3-amine (0.057 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. TLC detection shows that the reaction is complete, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake is washed with MeCN and air-dried to constant weight to obtain the target compound 0.0421 g TE052, with a yield of 47.1% and a purity of 98.73%. MS-ESI (m / z): 448.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.21(s,1H),9.02(s,1H),8.31(s,1H),7.92(d,J=8.6Hz,1H),7.59(dd,J=8.4,2.3Hz, 1H),7.52(s,1H),7.49–7.41(m,4H),7.37–7.31(m,2H),4.48(ddd,J=20.5,6.3,3.1Hz,4H).

[0235] Experimental Example 47

[0236]

[0237] Add intermediate TE-7 (0.050 g, 0.00020 mol), 6-fluoro-(1,1'-biphenyl)-3-amine (0.045 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0190 g TE053, with a yield of 23.9% and a purity of 98.71%. MS-ESI (m / z): 398.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d6 )δ11.95(s,1H),8.84(s,1H),8.36(s,1H),7.50–7.44(m,3H),7.43(s,1H),7.37– 7.33(m,3H),7.54–7.51(m,1H),7.26(s,1H),4.48(ddd,J=22.0,6.4,3.2Hz,4H).

[0238] Experimental Example 48

[0239]

[0240] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 6-chloro-(1,1'-biphenyl)-3-amine (0.049 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete after TLC detection, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake was washed with MeCN, and the filter cake was air-dried to constant weight to obtain the target compound 0.0361 g TE054, with a yield of 43.6% and a purity of 98.60%. MS-ESI (m / z): 414.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.37(s,1H),9.01(s,1H),8.43(s,1H),7.70(d,J=8.5Hz,1H),7.57–7.52(m,2H),7.4 8(dd,J=8.3,2.6Hz,3H), 7.45(dt,J=7.9,2.0Hz,3H), 4.48(ddd,J=21.8,6.2,3.1Hz,4H).

[0241] Experimental Example 49

[0242]

[0243] Add intermediate TE-7 (0.050 g, 0.00020 mol), 6-bromo-(1,1'-biphenyl)-3-amine (0.060 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete after TLC detection, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0309 g TE055, with a yield of 33.7% and a purity of 97.60%. MS-ESI (m / z): 458.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d6 ): δ11.35(s,1H),9.01(s,1H),8.43(s,1H),7.85(d,J=8.5Hz,1H),7.55(s,1H),7.49(dt ,J=4.3,2.1Hz,2H),7.47(s,1H),7.44–7.38(m,4H),4.48(ddd,J=22.0,6.4,3.2Hz,4H).

[0244] Experimental Example 50

[0245]

[0246] Add intermediate TE-7 (0.050 g, 0.00020 mol), 5-amino-(1,1'-biphenyl)-2-carboxylic acid methyl ester (0.054 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete after TLC detection, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0261 g TE056, with a yield of 29.8% and a purity of 98.56%. MS-ESI (m / z): 438.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.39(s,1H),9.03(s,1H),8.42(s,1H),7.87(d,J=8.3Hz,1H),7.57(d,J=1.5Hz,1H),7.52(dd,J=8.3,2.1Hz, 1H),7.47(d,J=2.2Hz,1H),7.45–7.37(m,3H),7.32–7.28(m,2H),4.48(ddd,J=22.4,6.3,3.2Hz,4H),3.60(s,3H).

[0247] Experimental Example 51

[0248]

[0249] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-amino-(1,1'-biphenyl)-4-carboxylic acid methyl ester (0.054 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete after TLC detection, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0288 g TE057, with a yield of 32.9% and a purity of 99.35%. MS-ESI (m / z): 438.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 )δ11.35(s,1H),9.01(s,1H),8.43(s,1H),7.85(d,J=8.5Hz,1H),7.55(s,1H),7.49(dt ,J=4.3,2.1Hz,2H),7.47(s,1H),7.44–7.38(m,4H),4.48(ddd,J=22.0,6.4,3.2Hz,4H).

[0250] Experimental Example 52

[0251]

[0252] Add intermediate TE-7 (0.050 g, 0.00020 mol), 3-amino-(1,1'-biphenyl)-4-carboxylic acid (0.051 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete after TLC detection, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0266 g TE058, with a yield of 31.4% and a purity of 98.85%. MS-ESI (m / z): 424.1 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ8.58(s,1H),8.05(d,J=8.2Hz,1H),7.76(s,1H),7.74–7.66(m,2H),7.55–7.36(m,6H),4.46–4.36(m,4H).

[0253] Experimental Example 53

[0254]

[0255] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 4-methyl-(1,1'-biphenyl)-3-amine (0.044 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0241 g TE059, with a yield of 30.7% and a purity of 98.85%. MS-ESI (m / z): 394.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.08(s,1H),8.94(s,1H),8.44(s,1H),7.76–7.68(m,4H),7.52(s,1H),7.50–7 .44(m,3H),7.37(t,J=7.3Hz,1H),4.49(ddd,J=20.4,6.3,3.2Hz,4H),2.29(s,3H).

[0256] Experimental Example 54

[0257]

[0258] To a 100 ml eggplant-shaped bottle, add the intermediate TE-7 (0.050 g, 0.00020 mol), 4-methoxy-(1,1'-biphenyl)-3-amine (0.048 g, 0.00024 mol), and MeCN (10 ml) in sequence, and heat to 80 ° C for 2 h. The reaction was complete by TLC detection, and after post-treatment, the temperature was lowered to 50 ° C and filtered under reduced pressure. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0185 g TE060, with a yield of 22.6% and a purity of 99.13%. MS-ESI (m / z): 410.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.23(s,1H),8.96(s,1H),8.51(s,1H),7.79(dq,J=4.9,2.4Hz,2H),7.70–7.65(m,2H),7.61(s,1H),7.4 5(t,J=7.6Hz,2H),7.37–7.31(m,1H),7.27(d,J=9.3Hz,1H),4.47(ddd,J=23.2,6.3,3.2Hz,4H),3.83(s,3H).

[0259] Experimental Example 55

[0260]

[0261] Add intermediate TE-7 (0.050 g, 0.00020 mol), 4-fluoro-(1,1'-biphenyl)-3-amine (0.045 g, 0.00024 mol), and MeCN (10 ml) to a 100 ml eggplant-shaped bottle, and heat to 80 ° C for 2 h. The reaction was complete after TLC detection, post-treatment, cooling to 50 ° C, and vacuum filtration. The filter cake was washed with MeCN and air-dried to constant weight to obtain the target compound 0.0327 g TE061, with a yield of 41.2% and a purity of 96.42%. MS-ESI (m / z): 398.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d 6 ): δ11.21(s,1H),9.03(s,1H),8.46(s,1H),7.93(dd,J=7.5,2.4Hz,1H),7.82(ddd,J=8.6,4.7,2.4Hz,1H) ,7.73–7.68(m,2H),7.57(s,1H),7.54–7.46(m,3H),7.43–7.37(m,1H),4.49(ddd,J=21.7,6.3,3.1Hz,4H).

[0262] Embodiment 56

[0263] Some targets were screened for their in vitro tumor cell proliferation inhibition activity against non-small cell lung cancer A549. The experiment used double-wells, with microtubule inhibitors colchicine and paclitaxel, and EGFR inhibitor gefitinib as positive control groups, and 0.1% DMSO as blank group. 5μM and 0.5μM were the initial screening drug concentrations. The experimental results are shown in Table 1.

[0264] Table 1: Preliminary screening results of some target compounds on the inhibition of A549 cell proliferation

[0265]

[0266]

[0267] Embodiment 57

[0268] In the tumor cell proliferation inhibition experiment, the present invention selected solid tumors (including non-small cell lung cancer A549, breast cancer MCF-7 and cervical cancer Hela) for compound activity screening. The above three cell lines were purchased from the cell bank of the Chinese Academy of Sciences. The CCK-8 method was selected as the anti-proliferation experimental detection method.

[0269] S1 Preparation

[0270] First, the biosafety cabinet needs to be sterilized by ultraviolet light for 30 minutes. Afterwards, wipe your hands and the surface of the biosafety cabinet with 75% alcohol cotton balls. Place the culture medium, fetal bovine serum, phosphate buffered saline (PBS) solution, and trypsin used in the experiment into the biosafety cabinet.

[0271] S2 cell recovery

[0272] Adjust the constant temperature water bath to 37.0℃, take out the cells from the liquid nitrogen tank, quickly move them to a 37℃ water bath, shake them at a constant speed until the cryopreservation solution melts, quickly move them to a biosafety cabinet that has been sterilized with UV light in advance, mix the cell cryopreservation solution with 4ml of complete culture medium into a 10ml EP tube, and then centrifuge at 800r / min for 5min. After centrifugation, discard the supernatant, add 6ml of complete culture medium, and pipette evenly. Add 6ml of cell suspension to a T25 cell culture flask and place the culture flask in a 5% CO 2 , cultured in a 37°C cell culture incubator.

[0273] S3 cell medium replacement

[0274] Discard the culture medium in the cell culture flask, rinse with phosphate-buffered saline (PBS) three times, and add 6 ml of complete culture medium. Move the culture flask to 37°C, 5% CO 2 Culture in an incubator.

[0275] S4 cell passaging

[0276] Discard the medium in the cell culture flask, rinse with PBS three times, and add 1 ml of trypsin to digest the cells. Move the culture flask to 37°C, CO 2 Culture in the incubator for 1-2 minutes. Under the microscope, most of the cells become oval and fall off from the bottom of the culture bottle. Add 2 ml of complete culture medium to stop digestion, gently blow the bottom of the culture bottle, transfer the cell suspension to the EP tube, and then use a centrifuge to centrifuge at 800r / min for 5 minutes. After centrifugation, discard the supernatant, add 2 ml of complete culture medium, and blow evenly. Take an appropriate volume of cell suspension into the culture bottle, and add complete culture medium to each culture bottle to 6 ml. Then, move the culture bottle to 37°C, 5% CO 2 Culture in an incubator.

[0277] S5 Cell Cryopreservation

[0278] Select cells that are in logarithmic growth and have good morphology for cryopreservation. First, discard the cell culture medium, rinse with PBS three times, add 1ml of trypsin for digestion, and 2ml of complete culture medium to terminate digestion. Move the cell suspension to an EP tube and centrifuge it at 800r / min for 5min. After centrifugation, discard the supernatant. Add 1ml of freezing solution with a ratio of FBS:DMSO = 9:1, gently blow it evenly, transfer it to a sterile cryopreservation tube, and seal it with a sealing film. Place the cryopreservation tube in a 4°C refrigerator for 10min, then in a -20°C refrigerator for 30min, and finally in a -80 refrigerator overnight. The next day, place the cryopreservation tube in a liquid nitrogen tank for long-term storage, and register the placement location.

[0279] In vitro anti-tumor cell proliferation experimental procedures

[0280] Collect cells in the logarithmic growth phase and in good condition for inoculation. Use a cell counting plate to count and adjust the cell density of the cell suspension to 5×10 4 / mL, add 100μl cell suspension (5000 / well) to each well of a 96-well plate. Adhere to the wall overnight in a cell culture incubator. The next day, discard the culture medium, add 100μl of drug-containing culture medium with different concentration gradients to each well, and continue to culture in the cell culture incubator for 48h. After 48h, add 10μl CCK-8 solution to each well and incubate in a cell culture incubator for 1 to 3h. Use an enzyme-labeled instrument to measure the OD value of each well of the 96-well plate at 450nm and control it between 0.8-1.2.

[0281] The calculation formula is as follows:

[0282]

[0283] The concentration-effect curves and half inhibitory concentration (IC) of some of the experimental targets on tumor cells 50 ) values ​​were calculated using GraphPad Prism9 software.

[0284] The results of the in vitro anti-A549 tumor cell proliferation activity of some target compounds are shown in Table 2;

[0285] The results of the in vitro anti-MCF-7 tumor cell proliferation activity of some target compounds are shown in Table 3;

[0286] The results of the in vitro anti-Hela tumor cell proliferation activity of some target compounds are shown in Table 4;

[0287] Table 2 Anti-A549 tumor cell proliferation activity

[0288]

[0289] Table 3 Anti-MCF-7 tumor cell proliferation activity

[0290]

[0291] Table 4 Anti-Hela tumor cell proliferation activity

[0292]

[0293] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art may still modify the technical solutions described in the aforementioned embodiments, or make equivalent substitutions for some of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound represented by formula I or a pharmaceutically acceptable salt thereof: in, R1 is R2 is H, C1-C8 straight or branched alkoxy; R3 is H, nitro, C1-C8 straight chain or branched alkyl, C1-C8 straight chain or branched alkoxy, C1-C8 straight chain or branched alkanethio, NR x R y , saturated or unsaturated C3-C8 cycloalkyl, R x , R y are independently H, C1-C8 straight or branched chain alkyl; R4 is H, halogen, hydroxyl, C1-C8 straight or branched alkyl, C1-C8 straight or branched alkoxy, C1-C8 straight or branched alkanethio, C2-C8 alkynyl, C2-C8 alkenyl, C2-C8 acyl, C1-C8 carboxyl, saturated or unsaturated C3-C8 cycloalkyl, 5-6 membered heterocyclic group containing 1-3 independently selected from N, O, S, 5-6 membered heteroaryl containing 1-3 independently selected from N, O, S, L1 is -O-, -(CH2) n C(O)—, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, —C(O)NH—, —NHC(O)—, —CHCHC(O)—; Ring A is R5 is H, halogen, C1-C8 straight or branched alkyl, C1-C8 straight or branched alkoxy, C1-C8 carboxyl, C1-C8 ester; R6 is H, halogen, C1-C8 straight or branched alkyl, halogenated C1-C8 straight or branched alkyl, C1-C8 ester group; n is 0, 1, 2, 3, 4 or 5.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The R1 is R2 is H, C1-C5 straight or branched alkoxy; R3 is H, nitro, C1-C5 straight chain or branched alkyl, C1-C5 straight chain or branched alkoxy, C1-C5 straight chain or branched alkanethio, NR x R y , saturated or unsaturated C3-C6 cycloalkyl, R x , R y are independently H, C1-C5 straight or branched chain alkyl; R4 is H, halogen, hydroxyl, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkoxy, C1-C5 straight or branched alkanethio, C2-C5 alkynyl, C2-C5 alkenyl, C2-C5 acyl, C1-C5 carboxyl, saturated or unsaturated C3-C6 cycloalkyl, 5-6 membered heterocyclic group containing 1-3 independently selected from N, O, S, 5-6 membered heteroaryl containing 1-3 independently selected from N, O, S, L1 is -O-, -(CH2) n C(O)—, C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene, —C(O)NH—, —NHC(O)—, —CHCHC(O)—; Ring A is R5 is H, halogen, C1-C5 straight chain or branched alkyl; C1-C5 straight chain or branched alkoxy, C1-C5 carboxyl, C1-C5 straight chain or branched alkoxycarbonyl; R6 is H, halogen, C1-C5 straight or branched alkyl, 1-3 halogenated C1-C5 straight or branched alkyl, C1-C5 straight or branched alkoxycarbonyl; n is 0, 1, 2 or 3.

3. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The C1-C5 straight or branched alkyl group is selected from —CH3, —CH2CH3, —CH(CH3)2, —(CH2)2CH3, —(CH2)3CH3, —CH2CH(CH3)2, —C(CH3)3, —CH(CH3)CH2CH3, —(CH2)4CH3, —CH(CH3)(CH2)2CH3, —CH(CH2CH3)2, —CH2C(CH3)3, —CH2CH(CH3)CH2CH3, —C(CH3)2CH2CH3, —CH(CH3)CH(CH3)2, —(CH2)2CH(CH3)2; The C1-C5 straight or branched alkoxy group is selected from —OCH3, —OCH2CH3, —OCH(CH3)2, —O(CH2)2CH3, —O(CH2)3CH3, —OCH2CH(CH3)2, —OC(CH3)3, —OCH(CH3)CH2CH3, —O(CH2)4CH3, —OCH(CH3)(CH2)2CH3, —OCH(CH2CH3)2, —OCH2C(CH3)3, —OCH2CH(CH3)CH2CH3, —OC(CH3)2CH2CH3, —OCH(CH3)CH(CH3)2, —O(CH2)2CH(CH3)2; The C1-C5 straight or branched alkanethiol group is selected from —SCH3, —SCH2CH3, —SCH(CH3)2, —S(CH2)2CH3, —S(CH2)3CH3, —SCH2CH(CH3)2, —SC(CH3)3, —SCH(CH3)CH2CH3, —S(CH2)4CH3, —SCH(CH3)(CH2)2CH3, —SCH(CH2CH3)2, —SCH2C(CH3)3, —SCH2CH(CH3)CH2CH3, —SC(CH3)2CH2CH3, —SCH(CH3)CH(CH3)2, —S(CH2)2CH(CH3)2; The halogen is selected from F, Cl, Br, I; The C2-C5 alkenyl group is selected from vinyl, isopropenyl, n-propenyl, n-butenyl, isobutenyl, sec-butenyl, n-pentenyl and isopentenyl; The C2-C5 alkynyl group is selected from ethynyl, propynyl, butynyl, and pentynyl; The C2-C5 acyl group is selected from —COCH3, —COCH2CH3, —COCH(CH3)2, —CO(CH2)2CH3, —CO(CH2)3CH3, —COCH2CH(CH3)2, —COC(CH3)3, —COCH(CH3)CH2CH3; The C1-C5 carboxyl group is selected from —COOH, —CH2COOH, —(CH2)2COOH, —(CH2)3COOH, —(CH2)4COOH, —CH2CH(CH3)2COOH; The C1-C5 alkoxycarbonyl group is selected from -COOCH3, -COOCH2CH3, -COOCH(CH3)2, -COO(CH2)2CH3, -COO(CH2)3CH3, -COOCH2CH(CH3)2, -COOC(CH3)3, -COOCH(CH3)CH2CH3, -COO(CH2)4CH 3. —COOCH(CH3)(CH2)2CH3, —COOCH(CH2CH3)2, —COOCH2C(CH3)3, —COOCH2CH(CH3)CH2CH3, —COOC(CH3)2CH2CH3, —COOCH(CH3)CH(CH3)2, —COO(CH2)2CH(CH3)2; The saturated or unsaturated C3-C6 cycloalkyl is selected from cyclopropane, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl containing 1 unsaturated bond, cyclobutyl containing 1 unsaturated bond, cyclopentyl containing 1 or 2 unsaturated bonds, and cyclohexyl containing 1 or 2 unsaturated bonds; The 5-6 membered heteroaryl group containing 1-3 independently selected from N, O, and S is selected from pyrrole, furan, thiophene, oxazole, thiazole, and pyridine; The 5-6 membered heterocyclic group containing 1-3 selected from N, O, and S is selected from piperazinyl, morpholinyl, piperidine, and tetrahydropyrrolyl; The 1-3 halogenated C1-C5 alkyl group is selected from CF3, CH2CF3, (CH2)2CF3, (CH2)3CF3, (CH2)4CF3.

4. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Said R2 is selected from hydrogen and methoxy; The R3 is selected from hydrogen, methoxy, methyl, methylthio, nitro, dimethylamino, cyclopropyl, The R4 is selected from hydrogen, methoxy, hydroxyl, bromine, methylmercapto, fluorine, ethynyl, vinyl, isopropyl, acetyl, carboxyl, cyclopropyl, The ring A is selected from The R5 is selected from hydrogen, methoxycarbonyl, carboxyl, methyl, methoxy, and fluorine; The R6 is selected from hydrogen, methyl, trifluoromethyl, fluorine, chlorine, bromine, and methoxyl.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound structure is as follows:

6. A method for preparing a compound of formula I or a salt thereof as claimed in any one of claims 1 to 5, characterized in that: The route is as follows: Wherein, step i is to sequentially add 3,4-dihydroxybenzoic acid and MeOH to the reaction vessel, and then dropwise add SOCl2 to the reaction bottle at -5-5°C. After the dropwise addition is complete, move to an oil bath, heat to reflux, and react for 6-10 hours; Step ii is to sequentially add intermediate TE-1, 1,2-dibromoethane, K2CO3, and DMF into a reaction vessel, raise the temperature to 70-90°C, and react for 4-8 hours; Step iii is to add 70% H2SO4 and AcOH to the reaction vessel and stir in an ice-water bath, slowly add 65% HNO3 dropwise, stir for 5-15 minutes, add intermediate TE-2, and stir at room temperature for 2-4 hours; Step iv is to sequentially add intermediate TE-3, MeOH, H2O, Fe, and AcOH to a reaction vessel, raise the temperature to reflux for reaction for 0.5-2h, cool to room temperature after the reaction is completed, concentrate part of the solvent under reduced pressure, add saturated sodium bicarbonate to adjust the pH to 7-8, add EA and purified water, raise the temperature to 60-80°C, and stir for 5-15min; Step V is to sequentially add DMF, intermediate TE-4, and DMF-DMA into a reaction vessel, and heat to 140-160° C. to react for 4-6 hours; Step ⅵ is to add THF to the reaction vessel, replace nitrogen 2-4 times, move to a -85--70°C cold trap and stir for 3-10 minutes, add n-BuLi, stir for 3-10 minutes, slowly add MeCN, keep the temperature for 15-25 minutes, dissolve the intermediate TE-5 with THF, slowly add it to the three-necked flask, and react at -85--70°C for 1.5-2.5 hours; Step ⅶ Add intermediate TE-6, SOCl2, 1,2-dichloroethane and DMF into a reaction vessel and reflux for 3-5h; Step VIII: When the aromatic amine is a biaryl, the intermediate TE-7, aromatic amine, and MeCN are sequentially added to the reaction vessel, and the temperature is raised to 70-90°C for reaction for 1-3h; When the aromatic amine is the remaining aromatic amine, the intermediate TE-7, aromatic amine and i-PrOH are sequentially added into the reaction vessel and the temperature is raised to 75-95° C. for reaction for 2-4 hours.

7. The method for preparing the compound of formula I or a salt thereof according to claim 6, characterized in that: The dosage relationship is as follows: In step i, the dosage of 3,4-dihydroxybenzoic acid and SOCl2 is 5-10mmol:1ml; In step ii, the molar ratio of the intermediate TE-1 to 1,2-dibromoethane is 1:1.8-2.2; In step iii, the molar ratio of 65% HNO3 to intermediate TE-2 is 1-1.3:1; In step ⅳ, the amount of intermediate TE-3, Fe, and AcOH is 1mmol: 3.8-42mmol: 0.3-0.8ml; In step V, the mass ratio of intermediate TE-4 and DMF-DMA is 1:1.0-1.2; In step ⅶ, the amount of intermediate TE-6 and SOCl2 is 1g: 18-22ml; In step VIII, the molar ratio of the intermediate TE-7 to the aromatic amine is 1:1-1.

5.

8. The method for preparing the compound of formula I or a salt thereof according to claim 6, characterized in that: After the reaction of steps i-viii, post-treatment is required. After the reaction of step i is completed, the temperature is cooled to room temperature, and the solvent is removed by concentration under reduced pressure to precipitate a white solid. The product is carried out with DCM to remove the residual SOCl2, and finally dried to obtain the intermediate TE-1; After the reaction in step ii is completed, the temperature is lowered to room temperature, and the reaction solution is slowly poured into purified water containing ice cubes, extracted with EA, and the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which is purified by column chromatography using PE-EA eluent to obtain TE-2; After the reaction in step iii is completed, the reaction solution is slowly added into ice water to gradually precipitate a white solid, which is filtered by suction, the filter cake is rinsed with purified water, and air-dried to obtain the intermediate TE-3; Step ⅳ After the reaction is completed, filter while hot, separate the liquids, extract with EA, combine the organic phases, wash the organic phases with saturated brine, dry the organic phases with anhydrous Na2SO4, and concentrate under reduced pressure to obtain a crude product, which is recrystallized with PE-EA to obtain intermediate TE-4; After the reaction in step ⅴ is completed, the temperature is cooled to room temperature, and the solvent is removed by concentration under reduced pressure, and toluene is dragged 4-5 times to obtain intermediate TE-5; Step ⅵ After the reaction is completed, move the three-necked flask indoors and wait for the three-necked flask to warm to room temperature. Add saturated ammonium chloride solution to the reaction flask and stir for 5-10 minutes to gradually precipitate solids. Filter under reduced pressure and rinse the filter cake with purified water. Beat the filter cake with MeCN at room temperature for 0.5-2 hours, filter under reduced pressure and dry the filter cake with air blast to constant weight to obtain intermediate TE-6; After the reaction in step ⅶ is completed, the temperature is lowered to 45-55°C, and the filter is filtered under reduced pressure, and the filter cake is washed with PE, and the filter cake is air-dried to a constant weight to obtain the intermediate TE-7; After the reaction in step VIII is completed, the filter is filtered under reduced pressure, and the filter cake is washed with a corresponding solvent, and the filter cake is air-dried to a constant weight to obtain the target compound.

9. A composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5.

10. Use of the compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5 in the preparation of anti-tumor drugs.

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