Benzochromone derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of compound synthesis, and particularly relates to a benzochromone derivative as well as a preparation method and application thereof, and the benzochromone derivative has high ROS (reactive oxygen species) production efficiency and excellent anti-tumor activity. According to the benzochromone derivative, a benzochromone tricyclic compound serves as a parent, a photosensitive group is conjugated and modified on the parent to synthesize a small molecule compound, ROS generation can be effectively improved under the illumination condition, the killing effect of the benzochromone derivative on tumor cells is promoted, meanwhile, the advantages of low toxicity, good targeting performance, minimally invasive performance and the like of the benzochromone derivative are combined, and the novel benzochromone derivative is obtained. The compound can specifically kill tumor cells, ensures that normal tissues are not damaged, and further shows excellent anti-tumor activity and high safety.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology, specifically relating to a benzochrome ketone derivative, its preparation method, and its application. Background Technology

[0002] Photosensitizers are widely used in medicine, industry, biomedicine, and the environment. Their advantages, such as light absorption, energy transfer, and chemical reactivity, make them highly valuable and promising for applications in photodynamic therapy, photopolymerization, photolithography, photosensitive drugs, photosensitive sensors, and photocatalytic degradation. For example, Chinese patent CN109280051A discloses the preparation of a chromone compound and its application in dye-sensitized solar cells.

[0003] In the medical field, photodynamic therapy (PDT) is a minimally invasive treatment method that uses photosensitizers, light, and oxygen to generate reactive oxygen species (ROS) to selectively kill tumor cells. It has attracted considerable attention in cancer treatment due to its minimal damage to healthy tissues. Its selectivity stems from the preferential accumulation of photosensitizers in tumor cells, benefiting from the enhanced penetration and retention effects of tumors and their acidic microenvironment. With its advantages of low toxicity, good targeting, and minimal invasiveness, it can specifically kill tumor cells while ensuring that normal tissues remain undamaged, and is gradually becoming a research hotspot in cancer treatment, showing great potential in treating various types of tumors. PDT has become a promising treatment method for treating various diseases, including cancer. Traditional photosensitizers mainly include porphyrins and their derivatives, phthalocyanines, and phenothiazine compounds, with porphyrin systems being the most extensively studied. However, although porphyrins and phthalocyanine photosensitizers have achieved clinical application, their planar conjugated structures easily lead to aggregation-induced quenching effects, significantly reducing the efficiency of reactive oxygen species (ROS) generation. Furthermore, the complex molecular structure and poor bioavailability of phototherapy (PDT) have limited its application in the treatment of deep tumors. Therefore, developing novel photosensitizers with high ROS quantum yield and excellent biodistribution properties has become a key research direction for promoting the development of PDT technology.

[0004] Developing novel and highly efficient photosensitizers will enrich the structural types of PDT therapeutic molecules, provide theoretical references for innovative PDT-based drug research, and offer more possibilities and options for better adapting to clinical applications, thereby improving tumor selectivity and photochemical efficiency. Therefore, developing novel and highly efficient photosensitizers and their preparation methods is of great significance for promoting the application of PDT in tumor treatment, skin disease treatment (such as actinic keratosis and psoriasis), and infectious disease treatment (such as drug-resistant bacterial infections and oral infections). Summary of the Invention

[0005] This invention aims to overcome the limitations of existing PDT photosensitizers and explore their photophysical properties and ROS generation efficiency to improve the efficacy and safety of tumor treatment. Therefore, a benzochrome ketone derivative, its preparation method, and its application are proposed.

[0006] Specifically, this is achieved through the following technical solutions:

[0007] The first objective of this invention is to provide a benzochrome ketone derivative, comprising compounds, stereoisomers, hydrates, or pharmaceutically acceptable salts of general formula (I), the structure of which is as follows:

[0008]

[0009] Where Y is selected from O, N, Any one of the following; X is selected from hydrogen, tritium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted C1-C6 alkoxyacyl, substituted or unsubstituted C1-C6 alkylsulfonyl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C3-C6 heterocyclic, substituted or unsubstituted C3-C6 heterocyclic acyl, substituted or unsubstituted C4-C 10 Fused heterobicyclic groups, substituted or unsubstituted C4-C 10 Fused heterobicyclic acyl, substituted or unsubstituted C4-C 10 Fused heterobicyclic amino; R 1 The group is selected from hydrogen, tritium, fluorine, chlorine, bromine, iodine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted amino; the substitution refers to substitution by any one or more of fluorine, chlorine, bromine, iodine, hydroxyl, nitro, amino, carboxylic acid, carboxylic acid ester, cyano, and acyl.

[0010] Furthermore, R 1 Selected from hydrogen, tritium, fluorine, chlorine, bromine, iodine, methyl, methoxy; R 2 Selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, ethylamino, unsubstituted C1-C6 alkoxy groups, Middle; R 3 Selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl.

[0011] Furthermore, the substituted C4-C 10 Fused heterobicyclic acyl group is Z is selected from nitrogen, oxygen, sulfur, and amino atoms; M is selected from hydrogen, tritium, and amino atoms.

[0012] The benzochrome ketone derivatives include at least one of the following compounds:

[0013] Target compound 1: 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one;

[0014] Target compound 2: 2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one;

[0015] Target compound 3: 2-(2-(diethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one;

[0016] Target compound 4: 2-(2-aminobenzo[d]thiazolyl)-4H-benzo[g]chromene-4-one;

[0017] Target compound 5: 2-(2-(dimethylamino)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-one;

[0018] Target compound 6: 2-(2-aminobenzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-one;

[0019] Target compound 7: 2-(2-(diethylamino)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-one;

[0020] Target compound 8: 2-(2-(piperazin-1-yl)benzo[d]thiazo-6-yl)-4H-benzo[g]chromen-4-one;

[0021] Target compound 9: 7-bromo-2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one;

[0022] Target compound 10: 2-(2-(diethylamino)-1H-benzo[d]imidazol-6-yl)-8-methoxy-4H-benzo[g]chromene-4-one;

[0023] Target compound 11: 2-(2-aminobenzo[d]imidazol-6-yl)-8-bromo-4H-benzo[g]chromen-4-one;

[0024] Target compound 12: 8-methoxy-2-(2-(piperazin-1-yl)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromen-4-one;

[0025] Target compound 13: 8-bromo-2-(2-(diethylamino)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-one;

[0026] Target compound 14: 2-(2-aminobenzo[d]thiazolyl)-8-bromo-4H-benzo[g]chromen-4-one;

[0027] Target compound 15: 8-iodo-2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one;

[0028] Target compound 16: (E)-6-(4-((4-methoxyphenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine;

[0029] Target compound 17: (E)-3-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate;

[0030] Target compound 18: (E)-6-(7-bromo-4-((3-(imidazolidine-1-yl)phenyl)imino)-4H-benzo[g]chromen-2-yl)-1H-benzo[d]imidazol-2-amine;

[0031] Target compound 19: (E)-4-((8-methoxy-2-(2-(piperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenylmethylcarbamate;

[0032] Target compound 20: (E)-3-((8-chloro-2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenol

[0033] Target compound 21: (E)-N,N-diethyl-4-((8-methyl-2-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide;

[0034] Target compound 22: (E)-4-((2-(2-aminobenzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)-N,N-diethylbenzamide;

[0035] Target compound 23: (E)-6-(7-bromo-4-((3-(imidazolidine)-1-yl)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]thiazol-2-amine;

[0036] Target compound 24: (E)-3-((7-methoxy-2-(2-(piperazin-1-yl)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate;

[0037] Target compound 25: (E)-4-bromo-N-phenyl-N-(4-((2-(2-(piperazin-1-yl)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)aniline;

[0038] Target compound 26: (E)-6-(4-((4-(imidazolidine-1-yl)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)-N,N-dimethylbenzo[d]thiazol-2-amine;

[0039] Target compound 27: (E)-N,N-diethyl-3-((2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide;

[0040] Target compound 28: (E)-4-((7-methoxy-2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate;

[0041] Target compound 29: (E)-4-bromo-N-phenyl-N-(4-((2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)aniline;

[0042] Target compound 30: (E)-6-(4-((4-(imidazolidine-1-yl)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)-N,N-dimethyl-1H-benzo[d]imidazol-2-amine;

[0043] Target compound 31: (E)-3-amino-N-(2-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide;

[0044] Target compound 32: (E)-6-(4-((2-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine;

[0045] Target compound 33: (E)-6-(4-((4-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine;

[0046] Target compound 34: (E)-6-(4-((3-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine;

[0047] Target compound 35: (E)-3-amino-N-(3-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide:

[0048] Target compound 36: (E)-6-(4-((4-(ethylamino)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine;

[0049] Target compound 37: (E)-3-amino-N-(4-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide;

[0050] Target compound 38: (E)-N-(2-((2-(2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)-3-(piperazin-1-yl)propionamide;

[0051] Target compound 39: (E)-N-(4-((2-(2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)-3-(piperazin-1-yl)propionamide;

[0052] Target compound 40: (E)-N-ethyl-3-((2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide.

[0053] The second objective of this invention is to provide a method for preparing benzochrome ketone derivatives, using 3-hydroxy-2-acetylnaphthalene 1 as a starting material, which undergoes an aldol condensation reaction with 3-hydroxy-4-nitrobenzaldehyde to obtain intermediate 2, followed by I2-catalyzed free radical cyclization to obtain a fused ring structure 3; reducing 3 to obtain intermediate 4, which then reacts with cyanogen bromide to form a cyclization ring to obtain a key intermediate 5; intermediate 5 undergoes imine condensation, side-chain amide condensation, and deprotection to obtain the target compound 7.

[0054] Furthermore, the specific steps for preparing the benzochrome ketone derivatives are as follows:

[0055] Step a: Using 3-hydroxy-4-nitrobenzaldehyde as a raw material, dissolve it in methanol, add 3 equivalents of sodium hydroxide, and heat the mixture in an oil bath at 55°C for 24 hours to obtain intermediate 2;

[0056] Step b: Dissolve intermediate 2 in dimethyl sulfoxide, add 0.3 equivalents of elemental iodine, and react at 150°C for 8 hours to obtain cyclic structure 3;

[0057] Step c: Dissolve the cyclic structure 3 in a methanol / water mixed solvent, add 6.5 equivalents of iron powder and 6.5 equivalents of ammonium chloride, and reflux at 80°C for 5 hours to obtain intermediate 4; the volume ratio of the methanol / water mixed solvent is 1:1.

[0058] Step d: Intermediate 4 is dissolved in a methanol / dichloromethane mixed solvent, and 3.0 equivalents of cyanogen bromide are added. The reaction is carried out at 35°C for 24 hours to obtain intermediate 5. The methanol / dichloromethane mixed solvent has a volume ratio of methanol:dichloromethane = 2:1.

[0059] Step e: Intermediate 4 is dissolved in toluene, and 2.0 equivalents of o-phenylenediamine and 3.0 equivalents of ethyl titanate are added. The mixture is reacted at 120°C under nitrogen protection for 36 hours to obtain intermediate 6.

[0060] Step f: Intermediate 6 was dissolved in N,N-dimethylformamide solvent, and N-tert-butoxycarbonyl-protected aminocarboxylic acid, 1.3 equivalents of HATU condensing agent, and 3.0 equivalents of N,N-diisopropylethylamine were added. After reacting at room temperature for 8 hours under nitrogen atmosphere, it was immediately dissolved in dichloromethane, and then 10.0 equivalents of trifluoroacetic acid were added. The deprotection reaction was carried out at room temperature for 6 hours to obtain target compound 7.

[0061] The third objective of this invention is to provide another method for preparing benzo[a]chromone derivatives, using 3-hydroxy-2-acetylnaphthalene as the starting material, undergoing an aldol condensation reaction with 3-hydroxy-4-nitrobenzaldehyde to obtain intermediate 2, followed by I2-catalyzed free radical cyclization to obtain a fused ring structure 3; reducing 3 to obtain intermediate 4, followed by trimethyl orthoformate condensation to obtain a ring-closed intermediate 8, which then reacts with dimethylamine or diethylamine under TBAI / TBHP to obtain intermediate 9; intermediate 9 undergoes imine condensation with substituted aniline to obtain 10, which is then condensed with an aminocarboxylic acid side chain, and finally deprotected to obtain the target compound 11.

[0062] Furthermore, the specific steps for preparing the benzochrome ketone derivatives are as follows:

[0063] Step 1: Using 3-hydroxy-4-nitrobenzaldehyde as a raw material, dissolve it in methanol, add 3 equivalents of sodium hydroxide, and heat the mixture in an oil bath at 55°C for 24 hours to obtain intermediate 2;

[0064] Step 2: Dissolve intermediate 2 in dimethyl sulfoxide, add 0.3 equivalents of elemental iodine, and react at 150°C for 8 hours to obtain cyclic structure 3;

[0065] Step 3: Dissolve the cyclic structure 3 in a methanol / water mixed solvent, add 6.5 equivalents of iron powder and 6.5 equivalents of ammonium chloride, and reflux at 80°C for 5 hours to obtain intermediate 4; the volume ratio of the methanol / water mixed solvent is 1:1.

[0066] Step 4: Intermediate 4 is dissolved in toluene, and 2.0 equivalents of triethoxymethane are added. The mixture is reacted at 150°C for 3 hours to obtain intermediate 8.

[0067] Step 5: Dissolve intermediate 8 in acetonitrile, add 1.2 equivalents of tetrabutylammonium iodide (TBAI), 2.0 equivalents of tert-butylhydrogen peroxide (TBHP), and 3.0 equivalents of dimethylamine / triethylamine mixed base, and react at 100°C for 3-6 hours to obtain intermediate 9;

[0068] Step 6: Dissolve intermediate 9 in toluene, add 2.0 equivalents of o-phenylenediamine and 3.0 equivalents of ethyl titanate, and react at 120°C under nitrogen protection for 36 hours to obtain intermediate 10;

[0069] Step 7: Dissolve intermediate 10 in DMF, add N-Boc protected aminocarboxylic acid, 1.3 equivalents of HATU, and 3.0 equivalents of DIPEA. Stir at room temperature for 8 hours under nitrogen protection. Immediately dissolve in dichloromethane, add 10.0 equivalents of trifluoroacetic acid (TFA), react at room temperature for 6 hours, remove TFA / DCM by vacuum distillation, neutralize with saturated NaHCO3 to pH=7, and back-extract the aqueous phase with DCM 3 times to ensure product recovery.

[0070] The fourth objective of this invention is to provide the application of the aforementioned benzochrome ketone derivatives in the preparation of photosensitizers.

[0071] The fifth objective of this invention is to provide the application of the aforementioned benzochrome ketone derivatives in the preparation of photodynamic therapy drugs.

[0072] The sixth objective of this invention is to provide the application of the aforementioned benzochrome ketone derivatives in the preparation of antitumor drugs.

[0073] Furthermore, the antitumor drug refers to a drug for proliferative diseases induced by mTOR kinase, including colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumor, cervical cancer, esophageal cancer, gallbladder cancer, CNS cancer, malignant glioma, myeloproliferative disease, leukemia, and lymphoma.

[0074] The seventh objective of this invention is to provide the application of the aforementioned benzochrome ketone derivatives in the preparation of cell-targeted drugs.

[0075] The cells include colorectal cancer cells, gastric cancer cells, breast cancer cells, lung cancer cells, liver cancer cells, prostate cancer cells, pancreatic cancer cells, thyroid cancer cells, bladder cancer cells, kidney cancer cells, brain tumor cells, cervical cancer cells, esophageal cancer cells, gallbladder cancer cells, malignant glioma cells, leukemia cells, and lymphoma cells.

[0076] Beneficial effects:

[0077] The benzo[a]chromone derivatives of this invention exhibit high ROS production efficiency, excellent antitumor activity, high safety, and good biocompatibility and solubility. Among them, tricyclic benzo[a]chromone has high ROS production efficiency, which can increase the ROS concentration in tumor cells, while also possessing good biological activity and water solubility, which can improve its biocompatibility and make it easier to be taken up.

[0078] The benzochrome ketone derivatives of this invention use benzochrome ketone tricyclic compounds as the parent compound and conjugate photosensitive groups on the parent compound to synthesize small molecule compounds. Under light irradiation, they can effectively enhance the production of ROS and promote its killing effect on tumor cells. At the same time, combined with its many advantages such as low toxicity, good targeting, and minimal invasiveness, it can specifically kill tumor cells while ensuring that normal tissues are not damaged, thus exhibiting excellent anti-tumor activity and high safety. Attached Figure Description

[0079] Figure 1 Singlet oxygen yield diagrams under continuous laser irradiation at 460 nm for mixed solutions prepared with 9,10-anthratridiyl-bis(methylene)dicarboxylic acid (ABDA) in all examples;

[0080] Figure 2 This is one of the synthetic routes used in all embodiments;

[0081] Figure 3 This is the second synthetic route for preparing all embodiments and derivatives;

[0082] Figure 4 The maximum absorption spectrum of the preferred compound in the examples is shown. Detailed Implementation

[0083] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0084] Please see Figure 2 as well as Figure 3The technical solution provided by the embodiments of the present invention is: a method for preparing and applying benzochrome ketone derivatives. The following embodiments describe the raw materials used:

[0085] Unless otherwise stated, all temperatures in the examples described below are in degrees Celsius. Reagents were purchased from commercial suppliers such as AlfaAesar Chemical Company, Bailingwei Technology Co., Ltd., Aladdin Reagent Co., Ltd., Beijing Coupling Technology Co., Ltd., etc., and were used without further purification unless otherwise stated. Common reagents were purchased from Shantou Xilong Chemical Plant, Guangzhou Chemical Reagent Factory, Tianjin Zhiyuan Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant, etc.

[0086] In the examples described below, silica gel columns were used. The silica gel (200-300 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy was performed using CDCl3 or DMSO-d6 as solvents (in ppm), with TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are observed, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in Hertz (Hz).

[0087] In the embodiments described below, low-resolution mass spectrometry (MS) data were determined using an Agilent 6120 series LC-MS spectrometer equipped with a G1311B quaternary pump and a G1316BTCC (column temperature maintained at 30°C). A G1329B autosampler and a G1315CDAD detector were used for analysis, and an ESI source was used in the LC-MS spectrometer.

[0088] In the examples described below, the injection volume was determined by the sample concentration; the flow rate was 0.5 mL / min; and the HPLC peak values ​​were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was isopropanol / n-hexane (40:60).

[0089] For ease of description, some raw materials will be described using their abbreviations in the examples described below. These abbreviations are explained in comparison with their full names as follows: DCM is CH2Cl2, i.e., dichloromethane; CDCl3 is deuterated chloroform; PE is petroleum ether; EtOAc and EA are both ethyl acetate; MeOH and CH3OH are both methanol; NaOH is sodium hydroxide; DMSO-d6 is hexadeuterated dimethyl sulfoxide; DIPEA is N,N-diisopropylethylamine; HATU is N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea.

[0090] The target compound can be synthesized via the following route: a synthetic route for C-4 aniline-substituted derivatives. Starting with 3-hydroxy-2-acetylnaphthalene 1, it undergoes an aldol condensation reaction with 3-hydroxy-4-nitrobenzaldehyde to give intermediate 2, followed by I2-catalyzed radical cyclization to obtain a fused ring structure 3. Reduction of 3 yields intermediate 4, which is then cyclized with cyanogen bromide to give the key intermediate 5. 5 undergoes imine condensation, side-chain amide condensation, and deprotection to obtain the target compound 7. Imine condensation is the key step in the entire route, but the yield is relatively low.

[0091]

[0092] Derivative Synthesis Route 1

[0093] Reagents and conditions: (a) 3-hydroxy-4-nitrobenzaldehyde, sodium hydroxide (3.0 equivalents), methanol solvent, oil bath heating at 55°C, reaction for 24 hours; (b) iodine (0.3 equivalents), dimethyl sulfoxide solvent, reaction at 150°C, maintained for 8 hours; (c) iron powder (6.5 equivalents), ammonium chloride (6.5 equivalents), methanol / water mixed solvent (volume ratio 1:1), reflux at 80°C, reaction for 5 hours; (d) cyanogen bromide (3.0 equivalents), methanol / dichloromethane mixed solvent (volume ratio 2:1). 1) React at 35℃ for 24 hours; (e) o-phenylenediamine (2.0 equivalents), ethyl titanate (3.0 equivalents), toluene solvent, react at 120℃ under nitrogen protection for 36 hours; (f) N-tert-butoxycarbonyl-protected aminocarboxylic acid, HATU condensing agent (1.3 equivalents), N,N-diisopropylethylamine (3.0 equivalents), N,N-dimethylformamide solvent, nitrogen atmosphere, react at room temperature for 8 hours; (g) trifluoroacetic acid (10.0 equivalents), dichloromethane solvent, deprotection reaction at room temperature for 6 hours.

[0094] The alkylamino-substituted derivatives of oxazolamide can be synthesized via route two. Intermediate 4 is condensed with trimethyl orthoformate to give cyclic intermediate 8, which then reacts with dimethylamine or diethylamine under TBAI / TBHP to give the corresponding key intermediate 9. 9 undergoes an imine condensation with substituted aniline to give 10, which is subsequently condensed with an aminocarboxylic acid side chain, and finally deprotected to give the target compound 11.

[0095]

[0096] Derivative Synthesis Route 2

[0097] Reagents and conditions: (a) Triethoxymethane condensation reaction: Triethoxymethane (2.0 equivalents), toluene as solvent, reaction at 150℃ for 3 hours; (b) Oxidative amination reaction: Tetrabutylammonium iodide (TBAI, 1.2 equivalents), tert-butyl hydroperoxide (TBHP, 2.0 equivalents), dimethylamine / triethylamine mixed base (3.0 equivalents), acetonitrile as solvent, reaction at 100℃ for 3-6 hours, TBHP / TBAI constitutes the oxidative catalytic system, and amines must be strictly anhydrous; (c) Titanium-catalyzed quinoline cyclization: o-phenylenediamine (2.0 equivalents), ethyl titanate ( (d) HATU-mediated amide coupling: N-Boc protected aminocarboxylic acid, HATU (1.3 equivalents), DIPEA (3.0 equivalents), DMF as solvent, nitrogen protection, stirred at room temperature for 8 hours; (e) Acidic deprotection reaction: trifluoroacetic acid (TFA, 10.0 equivalents), dichloromethane as solvent, reacted at room temperature for 6 hours, TFA / DCM removed under reduced pressure, neutralized to pH 7 with saturated NaHCO3, aqueous phase back-extracted with DCM 3 times to ensure product recovery. Heterocyclic intermediates involved in the route were synthesized according to relevant literature. The preparation of other target compounds can be based on the above route and further route design according to actual conditions.

[0098] Synthesis of 1-(3-hydroxynaphth-2-yl)ethyl-1-one (intermediate 1):

[0099] 1.5 g (7.97 mmol) of 2-hydroxy-3-naphthoic acid was weighed and placed in a 250 mL double-necked flask. Tetrahydrofuran was added to dissolve the acid, and argon gas was used to replace the precipitate. The mixture was stirred at -78 °C for 15 minutes, and then 0.526 g (23.91 mmol) of lithium methyl was slowly added dropwise. The mixture was then reacted at 0 °C for 3 hours. The reaction was monitored by TLC until completion. Dilute hydrochloric acid solution was added to the reaction mixture to adjust the pH to approximately 6–7. The mixture was extracted with ethyl acetate and water. The upper organic phase was dried, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 40:1) to obtain a golden-yellow solid. Yield: 54.6%. 1 H NMR (400MHz, DMSO-d6) δ8.21(s,1H),8.13(s,1H),7.75(s,1H),7.51(d,J=1.0Hz,2H),7.28(s,1H). 13C NMR(100MHz,DMSO-d6)δ204.62,161.48,137.39,131.24,130.68,130.32,130. 30,128.51,127.24,120.66,112.95,29.94.HRMS(ESI):m / z[M+H]+calcd.for[C 12 H 10 O2]+:187.0759,found:187.0734.

[0100] Synthesis of (E)-3-(3-hydroxy-4-nitrophenyl)-1-(3-hydroxynaphth-2-yl)propen-2-en-1-one (intermediate 2):

[0101] 1-(3-hydroxynaphth-2-yl)ethyl-1-one (0.4 g, 2.15 mmol) was dissolved in 150 mL of ethanol, and a 20% sodium hydroxide aqueous solution was slowly added under ice bath conditions. After stirring for 10 minutes, 3-hydroxy-4-nitrobenzaldehyde (0.36 g, 2.15 mmol) was added, and nitrogen was used to displace the nitrogen atmosphere. The reaction was carried out at room temperature for 12 hours, and the reaction was monitored by TLC until completion. The pH of the reaction mixture was adjusted to approximately 1–2 with dilute hydrochloric acid. A yellow solid precipitated was filtered, and the upper layer was slurried with ethanol and ethyl acetate and dried under reduced pressure to obtain a pale yellow solid. Yield: 69.3%. 1 HNMR(400MHz,DMSO-d6)δ9.78(s,1H),8.47(s,1H),8.06(s,1H),7.88(d,J=7.5Hz,1H),7.80–7.73(m,2H),7.73– 7.65(m,2H),7.51(d,J=1.1Hz,1H),7.40(dd,J=2.0,1.0Hz,1H),7.32(s,1H).HRMS(ESI):m / z[M+H]+calcd.for[C 19 H 13 NO5]+:336.0872,found:336.0893.

[0102] Synthesis of 2-(3-hydroxy-4-nitrophenyl)-4H-benzo[g]chromen-4-one (intermediate 3):

[0103] (E)-3-(3-hydroxy-4-nitrophenyl)-1-(3-hydroxynaphth-2-yl)propen-2-en-1-one (0.67 g, 1.99 mmol) was dissolved in DMSO, and elemental iodine was added. The reaction was carried out at 150 °C for 8 hours. After the reaction was completed by TLC, the reaction mixture was cooled to room temperature, and the iodine was quenched with sodium thiosulfate solution. A suitable amount of water was added, and a solid precipitated. The solid was filtered, and the upper layer was washed with ethyl acetate and ethanol and dried under reduced pressure to obtain a yellow solid. Yield: 52.9%. 1 H NMR(400MHz,DMSO-d6)δ9.89(s,2H),8.43(s,2H),8.25(s,2H),7.93(d,J=7.5Hz,2H),7.86(s,2H), 7.76(s,2H),7.70(dd,J=7.5,2.0Hz,2H),7.51(d,J=1.1Hz,3H),7.47(d,J=2.0Hz,2H),6.79(s,2H). 13 C NMR(100MHz,DMSO-d6)δ180.24,166.06,159.19,150.70,137.24,137.10,132.67,130.94,130.31,130.24,1 29.72,129.14,127.03,126.66,123.91,120.53,120.37,109.62,109.37.HRMS(ESI):m / z[M+H]+calcd.for[C 19 H 11 NO5]+:334.0715,found:334.0695.

[0104] Synthesis of 2-(4-amino-3-hydroxyphenyl)-4H-benzo[g]chromen-4-one (intermediate 4):

[0105] Weigh out 0.35 g (1.05 mmol) of 2-(3-hydroxy-4-nitrophenyl)-4H-benzo[g]chromen-4-one, 0.39 g (6.83 mmol) of reduced iron, and 0.37 g (6.83 mmol) of ammonium chloride into a 250 mL flask. Dissolve the mixture in ethanol / water (1.5 / 1), purge with nitrogen, reflux, and react at 80 °C for 4 hours. Monitor the reaction by TLC until complete. Filter while hot, evaporate the lower layer to dryness, wash with water and ethyl acetate respectively, concentrate under reduced pressure, and precipitate by silica gel column chromatography (dichloromethane / methanol = 60 / 1) to give a yellow solid. Yield: 62.8%. 1H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.43(s,1H),8.25(s,1H),7.86(s,1H),7.76(s,1H),7.71(dd,J=7.5,2.0Hz,1H) ,7.51(d,J=1.0Hz,2H),7.26–7.18(m,2H),6.79(s,1H),4.15(s,1H),4.02(s,1H).HRMS(ESI):m / z[M+H]+calcd.for[C 19 H 13 NO3]+:304.0974,found:304.0952.

[0106] Synthesis of 2-benzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (intermediate 8):

[0107] 2-(4-amino-3-hydroxyphenyl)4H-benzo[g]chromene-4-one (0.3 g, 1.98 mmol) and gallium trifluoromethanesulfonate (52 mg, 0.198 mmol) were added sequentially to a 100 ml round-bottom flask and dissolved in toluene. Triethyl orthoformate (0.18 g, 23.76 mmol) was added under stirring and the reaction was carried out at room temperature for 1 h. The reaction was completed by TLC. The reaction solution was concentrated under reduced vacuum and purified by silica gel column chromatography (dichloromethane / methanol = 60 / 1) to give a yellow solid. Yield: 9.7%. 1 H NMR (400MHz, DMSO-d6) δ180.27,165.86,159.19,152.46,150.73,137.41,137.10,132.67,130. 94,130.31,130.24,129.14,127.79,127.60,126.66,120.53,116.71,109.62,109.06,108.24. 13 C NMR(100MHz,DMSO-d6)δ180.27,165.86,159.19,152.46,150.73,137.41,137.10,132.67,130.94,130.31, 130.24,129.14,127.79,127.60,126.66,120.53,116.71,109.62,109.06,108.24.HRMS(ESI)calcd.for:C 20 H 11 NO3[M+H]+:314.0817, found:314.0843.

[0108] Example 1

[0109] Synthesis of 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one:

[0110] 0.36 g (1.65 mmol) of 2-(4-amino-3-hydroxyphenyl)-4H-benzo[g]chromen-4-one was dissolved in methanol, and 0.38 g (4.95 mmol) of cyanogen bromide was added. The reaction was carried out at 35 °C for 36 hours. The reaction was monitored by TLC until completion. Saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to approximately 7–8. A solid precipitated and was filtered. The lower layer was extracted with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 60 / 1) to obtain a yellow solid. Yield: 60.3%. 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.25(s,1H),7.86(s,1H),7.81–7.74(m,3H),7.63(s,1H),7.51(d,J=1.0Hz,2H),6.79(s,1H),5.96(s,2H). 13 C NMR(100MHz,DMSO-d6)δ180.27,166.01,165.60,159.19,149.56,142.89,137.10,132.67,130.94,130.67,130.3 1,130.24,129.14,126.66,126.05,120.53,115.69,110.88,109.62,109.06.HRMS(ESI):m / z[M+H]+calcd.for[C 20 H 12 N2O3]+:329.0926,found:329.0957.

[0111] Example 2

[0112] Synthesis of 2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one:

[0113] 2-Benzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.29 g, 0.448 mmol) and TBAI (3.4 mg, 0.0448 mmol) were added sequentially to a 100 ml round-bottom flask and dissolved in acetonitrile. Dimethylamine (0.12 g, 1.344 mmol), TBHP (0.16 g, 0.896 mmol), and glacial acetic acid (0.12 g, 0.896 mmol) were then added under stirring. The mixture was refluxed at 100 °C for 1 h. TLC was used to determine the complete reaction of the starting material. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the product, a pale yellow solid, with a yield of 21.12%. 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),8.25(s,1H),7.86(s,1H),7.79(s,1H),7.75(d,J=4.0 Hz,2H),7.63(s,1H),7.51(d,J=1.0Hz,2H),6.79(s,1H),3.13(s,5H).HRMS(ESI)calcd.for C 22 H 16 N2O3[M+H]+:357.1239, found:357.1222;

[0114] Example 3

[0115] Synthesis of 2-(2-(diethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one:

[0116] 2-Benzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.14 g, 0.52 mmol) and TBAI (17 mg, 0.052 mmol) were added sequentially to a 100 ml round-bottom flask and dissolved in acetonitrile. Triethylamine (0.14 g, 1.56 mmol), TBHP (81 mg, 1.04 mmol), and glacial acetic acid (54 mg, 1.04 mmol) were added under stirring. The mixture was refluxed at 100 °C for 1 h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced vacuum, and the product was obtained by silica gel column chromatography. The product was a pale yellow solid with a yield of 19.12%. 1 H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.25(s,1H),7.86(s,1H),7.79(s,1H),7.75(d,J= 4.0Hz,2H),7.63(s,1H),7.51(d,J=1.0Hz,2H),6.79(s,1H),3.59(s,3H),1.20(s,5H). 13C NMR(100MHz,DMSO-d6)δ180.27,166.01,163.27,159.19,148.26,141.81,137.10,132.67,130.94,130.31,130.24 ,129.14,128.96,126.66,125.83,120.53,115.58,110.88,109.62,109.06,43.12,14.01.HRMS(ESI)calcd.for:C 24 H 20 N2O3[M+H]+:358.1552, found:358.1564;

[0117] Example 4

[0118] Synthesis of 2-(2-aminobenzo[d]thiazolyl-6-yl)-4H-benzo[g]chromen-4-one:

[0119] A 15 mL solution of 2 mmol of 2-(4-aminophenyl)-4H-benzo[g]chromen-4-one in acetonitrile was added to a 15 mL solution of 8 mmol of KSCN in acetonitrile. Then, 0.06 g (30 mol% BF3) of nano-BF3 / SiO2 was added. The mixture was placed in a mixture of ice and salt and stirred for 30 min. At 0 °C, a 3 mL solution of 4 mmol of bromine in acetonitrile was added dropwise at a constant rate using a dropping funnel. After the addition was complete, the mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC to indicate the reaction was complete. The reaction mixture was poured into water and stirred. The mixture was heated to 70 °C in a steam bath. The catalyst was removed by hot filtration. The filtrate was neutralized with 10% NaOH solution. The upper precipitate was dried with 10 mL of ethanol and recrystallized to give a yellow solid with a yield of 45%. 1 HNMR (400MHz, DMSO-d6) δ8.43(s,1H),8.25(s,1H),8.16(s,1H),7.86(s,1H),7.76(d,J=1.1Hz,3H),7.51(d,J=1.0Hz,1H),6.79(d,J=1.6Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ180.27,170.14,164.93,158.89,150.28,137.10,132.77,132.67,130.94,130.31,130.2 4,129.14,129.11,127.82,126.66,121.60,120.46,119.84,109.62,109.27.HRMS(ESI):m / z[M+H]+calcd.for[C 20 H12 N2O3]+:345.0698,found:345.0682.

[0120] Example 5

[0121] Synthesis of 2-(2-(dimethylamino)benzo[d]thiazo-6-yl)-4H-benzo[g]chromen-4-one:

[0122] 2-Benzo[d]thiazolyl)-4H-benzo[g]chromen-4-one (150 mg, 0.448 mmol) and TBAI (17 mg, 0.0448 mmol) were added sequentially to a 100 ml round-bottom flask and dissolved in acetonitrile. Dimethylamine (61 mg, 1.344 mmol), TBHP (81 mg, 0.896 mmol), and glacial acetic acid (54 mg, 0.896 mmol) were added under stirring. The mixture was refluxed at 100 °C for 1 h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced vacuum, and the product was obtained by silica gel column chromatography. The product was a pale yellow solid with a yield of 24.23%. 1 HNMR(400MHz,DMSO-d6)δ8.43(s,1H),8.25(s,1H),8.18(s,1H),7.86(s,1H),7.78–7.73( m,3H),7.51(d,J=1.0Hz,2H),6.79(s,1H),3.10(s,5H).HRMS(ESI)m / z[M+H]+calcd.for[C 22 H 16 N2O2S]+:373.1011, found:373.1024;

[0123] Example 6

[0124] Synthesis of 2-(2-aminobenzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one:

[0125] 0.5 g (1.65 mmol) of 2-(3,4-diaminophenyl)-4H-benzo[g]chromen-4-one was dissolved in methanol, and 0.38 g (4.95 mmol) of cyanogen bromide was added. The reaction was carried out at 35 °C for 36 hours. The reaction was monitored by TLC until completion. Saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to approximately 7–8. A solid precipitated and was filtered. The lower layer was extracted with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 60 / 1) to give a yellow solid. Yield: 43.5%. 1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.25(s,1H),7.93(s,1H),7.85(d,J=6.8Hz,2H), 7.75(d,J=11.8Hz,2H),7.51(d,J=1.0Hz,2H),6.79(s,1H),6.48(s,1H),6.32(s,1H). 13 C NMR(100MHz,DMSO-d6)δ180.27,165.66,158.89,157.58,139.29,139.09,137.10,132.67,130.94,130.31,130.2 4,129.29,129.14,128.95,126.66,120.46,118.41,111.17,109.62,109.24.HRMS(ESI):m / z[M+H]+calcd.for[C 20 H 13 N3O2]+:328.1086,found:328.1094.

[0126] Example 7

[0127] Synthesis of 2-(2-(diethylamino)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one:

[0128] 2-Benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one (0.18 g, 0.52 mmol) and TBAI (17 mg, 0.052 mmol) were added sequentially to a 100 ml round-bottom flask and dissolved in acetonitrile. Triethylamine (0.14 g, 1.56 mmol), TBHP (81 mg, 1.04 mmol), and glacial acetic acid (54 mg, 1.04 mmol) were added under stirring. The mixture was refluxed at 100 °C for 1 h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced vacuum, and the product was obtained by silica gel column chromatography. The product was a pale yellow solid with a yield of 23.32%. 1 HNMR (400MHz, DMSO-d6) δ8.43(s,1H),8.25(s,1H),7.94(s,1H),7.86(d,J=4.5Hz,2H),7.75(d,J=11.8Hz,2 H),7.51(d,J=1.0Hz,2H),6.79(s,1H),3.55–3.43(m,4H),1.20(s,5H).HRMS(ESI): m / z[M+H]+calcd.for[C 24 H 21N3O2]+:384.1712, found:384.1725;

[0129] Example 8

[0130] Synthesis of 2-(2-(piperazin-1-yl)benzo[d]thiazo-6-yl)-4H-benzo[g]chromen-4-one:

[0131] The starting material, tert-butyl 4-(6-(4-oxo-4H-benzo[g]chromen-2-yl)benzo[d]thiazo-2-yl)piperazine-1-carboxylate (207 mg, 0.5 mmol), was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC analysis confirmed the reaction was complete. The pH was adjusted to approximately 7–8 with saturated sodium bicarbonate solution. The reaction mixture was concentrated under reduced pressure and extracted 2–3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 56.2%. 1 HNMR(400MHz,DMSO-d6)δ8.43(s,1H),8.25(s,1H),8.18(s,1H),7.86(s,1H),7.76(d,J=1.9Hz ,3H),7.51(d,J=1.0Hz,2H),6.79(s,1H),3.61(s,2H),3.55(s,2H),2.88(s,5H),2.10(s,1H). 13 C NMR (100MHz, DMSO-d6) δ180.27,169.14,164.93,158.89,150.32,137.10,132.81,132.67,130.94,130.31,130.24,129. 14,129.11,128.68,126.66,123.58,121.07,120.46,109.62,109.27,55.66,48.88.HRMS(ESI):m / z[M+H]+calcd.for[C 24 H 19 N3O2S]+:414.1276,found:414.1283.

[0132] Example 9

[0133] Synthesis of 7-bromo-2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one:

[0134] In Example 7, triethylamine was replaced with N-methylpiperazine, and other steps and operations were similar to those in Example 7, yielding a yellow solid with a yield of 48.7%. 1 HNMR(400MHz,DMSO-d6)δ8.43(s,1H),8.25(s,1H),7.93(d,J=16.6Hz,2H),7.86(s,1H), 7.71(d,J=3.4Hz,2H),7.56(s,1H),6.89(s,1H),3.60(s,2H),3.49(s,2H),2.58(s,4H). 13 C NMR(100MHz,DMSO-d6)δ180.27,165.66,159.19,158.14,138.16,137.70,136.81,133.92,132.89,129.59,129.34,128.89, 127.49,126.18,123.09,121.26,118.41,111.27,109.48,109.24,54.34,48.65,45.49.HRMS(ESI):m / z[M+H]+calcd.for[C 25 H 21 BrN4O2]+:489.0926,found:489.0933.

[0135] Example 10

[0136] Synthesis of 2-(2-(diethylamino)-1H-benzo[d]imidazol-6-yl)-8-methoxy-4H-benzo[g]chromen-4-one:

[0137] The raw material 1-(3-hydroxynaphth-2-yl)ethyl-1-one in Example 7 was replaced with 1-(3-hydroxy-6-methoxynaphth-2-yl)ethyl-1-one. Other steps and operations were similar to those in Example 7, yielding a yellow solid with a yield of 37.4%. 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),7.94(s,1H),7.86(d,J=1.6Hz,2H),7.80(s,1H),7.75(s,1H),7.27(s ,1H),7.03(s,1H),6.79(s,1H),3.83(s,3H),3.52(d,J=12.3Hz,2H),3.46(d,J=12.5Hz,2H),1.20(s,6H). 13C NMR(100MHz,DMSO-d6)δ180.27,165.66,160.84,159.67,159.46,140.72,136.34,136.30,132.92,130.33,129.34,128.89, 126.50,121.12,118.41,117.00,111.27,110.47,109.24,108.16,55.97,43.47,13.85.HRMS(ESI):m / z[M+H]+calcd.for[C 25 H 23 N3O3]+:414.1818,found:414.1824.

[0138] Example 11

[0139] Synthesis of 2-(2-aminobenzo[d]imidazol-6-yl)-8-bromo-4H-benzo[g]chromen-4-one:

[0140] The raw material 1-(3-hydroxynaphth-2-yl)ethyl-1-one in Example 6 was replaced with 1-(6-bromo-3-hydroxynaphth-2-yl)ethyl-1-one. Other steps and operations were similar to those in Example 6, yielding a yellow solid with a yield of 43.5%. 1 H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.08(s,1H),8.03(s,1H),7.93(s,1H),7.84(s ,1H),7.78(s,1H),7.73(s,1H),7.58(s,1H),6.79(s,1H),6.48(s,1H),6.32(s,1H). 13 C NMR(100MHz,DMSO-d6)δ180.27,165.66,159.03,157.58,139.29,139.09,137.42,132.80,132.01,130.22,129.2 9,128.95,127.83,126.50,123.99,120.92,118.41,111.17,109.64,109.24.HRMS(ESI):m / z[M+H]+calcd.for[C 20 H 12 BrN3O2]+:406.0191,found:406.0187.

[0141] Example 12

[0142] Synthesis of 8-methoxy-2-(2-(piperazin-1-yl)benzo[d]thiazo-6-yl)-4H-benzo[g]chromen-4-one:

[0143] The raw material 1-(3-hydroxynaphth-2-yl)ethyl-1-one in Example 8 was replaced with 1-(3-hydroxy-6-methoxynaphth-2-yl)ethyl-1-one. Other steps and operations were similar to those in Example 8, yielding a yellow solid with a yield of 47.2%. 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.18(s,1H),7.86(s,1H),7.80(s,1H),7.76(d,J=2.0Hz,2 H),7.27(s,1H),7.03(s,1H),6.79(s,1H),3.83(s,3H),3.61(s,2H),3.55(s,2H),2.88(s,4H). 13 CNMR(100MHz,DMSO-d6)δ180.27,169.14,165.01,160.84,159.46,150.32,136.30,132.92,132.81,130.33,129.11,128.68 ,126.50,123.58,121.12,121.07,117.00,110.47,109.27,108.16,55.97,55.66,48.88.HRMS(ESI):m / z[M+H]+calcd.for[C 25 H 21 N3O3S]+:444.1382,found:444.1377.

[0144] Example 13

[0145] Synthesis of 8-bromo-2-(2-(diethylamino)benzo[d]thiazo-6-yl)-4H-benzo[g]chromen-4-one:

[0146] The raw materials 1-(3-hydroxynaphth-2-yl)ethyl-1-one and dimethylamine in Example 5 were replaced with 1-(6-bromo-3-hydroxynaphth-2-yl)ethyl-1-one and triethylamine, respectively. The other steps and operations were similar to those in Example 5, yielding a yellow solid with a yield of 51.3%. 1 H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.24(s,1H),8.19(s,1H),8.03(s,1H ),7.80–7.74(m,3H),7.58(s,1H),6.79(s,1H),3.66(s,3H),1.25(s,5H). 13C NMR (100MHz, DMSO-d6) δ180.27,169.26,165.01,159.09,150.32,137.42,132.95,132.80,132.01,130.22,129.11,128. 68,127.83,126.50,123.99,123.58,121.07,120.92,109.64,109.27,43.86,13.62.HRMS(ESI):m / z[M+H]+calcd.for[C 24 H 19 BrN2O2S]+:479.0429,found:479.0433.

[0147] Example 14

[0148] Synthesis of 2-(2-aminobenzo[d]thiazolyl)-8-bromo-4H-benzo[g]chromen-4-one:

[0149] The raw material 1-(3-hydroxynaphth-2-yl)ethyl-1-one in Example 4 was replaced with 1-(6-bromo-3-hydroxynaphth-2-yl)ethyl-1-one. Other steps and operations were similar to those in Example 4, yielding a yellow solid with a yield of 43.3%. 1 H NMR (400MHz, DMSO-d6) δ8.47(s,1H),8.16(s,1H),8.08(s,1H),8.03(s,1H),7.77(d,J=10.2Hz,3H),7.58(s,1H),6.79(d,J=1.6Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ180.27,170.14,164.93,159.09,150.28,137.42,132.80,132.77,132.01,130.22,129.1 1,127.83,127.82,126.50,123.99,121.60,120.92,119.84,109.64,109.27.HRMS(ESI):m / z[M+H]+calcd.for[C 20 H 11 BrN2O2S]+:422.9803,found:422.9811.

[0150] Example 15

[0151] Synthesis of 8-iodo-2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one:

[0152] The starting material 2-(benzo[d]thiazol-6-yl)-4H-benzo[g]chromen-4-one in Example 8 was replaced with 2-(1H-benzo[d]imidazol-6-yl)-8-iodo-4H-benzo[g]chromen-4-one, and the other steps and operations were similar to those in Example 8, yielding a yellow solid with a yield of 62.1%. 1 H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.31(s,1H),7.89(s,1H),7.94(s,1H),7.86(s ,1H),7.81(s,1H),7.73(s,1H),7.69(s,1H),6.79(s,1H),3.62(s,3H),2.88(s,4H). 13 C NMR(100MHz,DMSO-d6)δ180.27,165.66,159.03,157.83,138.11,138.07,137.23,136.81,133.47,131.54,129.71, 129.34,128.89,126.50,120.92,118.41,111.27,110.89,109.24,96.78,49.59,HRMS(ESI):m / z[M+H]+calcd.for[C 24 H 19 IN4O2]+:523.0631,found:523.0638.

[0153] Example 16

[0154] Synthesis of (E)-6-(4-((4-methoxyphenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine:

[0155] In a 100 ml round-bottom flask, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.3 g, 0.915 mmol) and 4-methoxyaniline (0.23 g, 1.83 mmol) were added sequentially, with a suitable amount of toluene as solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added under stirring, and the atmosphere was purged with nitrogen. The mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. After dissolving the solid in dichloromethane and methanol, the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 36.3%. 1H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.23(s,1H),7.83(d,J=7.2Hz,2H),7.79(s,1H),7.71(s,1H),7.64(s ,1H),7.51(d,J=1.0Hz,2H),7.33–7.27(m,2H),6.97–6.91(m,2H),6.55(s,1H),5.96(s,2H),3.82(s,3H); 13 C NMR(100MHz,DMSO-d6)δ165.60,159.98,159.92,158.74,157.08,149.56,147.14,142.89,136.32,132.40,130.32,130.24,129.77,1 29.08,128.39,125.77,123.96,123.79,117.95,115.97,115.57,113.78,109.19,108.28,55.86.HRMS(ESI):m / z[M+H]+calcd.for[C 27 H 19 N3O3]+:434.1505,found:434.1512.

[0156] Example 17

[0157] Synthesis of (E)-3-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate:

[0158] In a 100 ml round-bottom flask, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one (0.3 g, 0.915 mmol) and 3-aminophenyl diethylcarbamate (0.39 g, 1.83 mmol) were added sequentially, with a suitable amount of toluene as solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added under stirring, and the atmosphere was purged with nitrogen. The mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. After dissolving the solid in dichloromethane and methanol, the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 32.2%. 1H NMR(400MHz, DMSO-d6),7.79(s,1H),7.71(s,1H),7.64(s,1H),7.51(d,J=1.0Hz,2H),7.37–7.2 9(m,2H),7.15(dt,J=12.5,7.5,2.0Hz,2H),6.55(s,1H),5.96(s,2H),3.31(s,3H),1.18(s,5H); 13 C NMR(100MHz,DMSO-d6)δ165.60,159.98,157.34,156.78,156.27,152.41, 149.56,147.34,142.89,136.32,132.40,132.11,130.32,130.24,129.77, 129.08,128.39,125.77,123.96,121.72,119.11,118.62,115.57,113.58, 112.54,109.19,108.28,43.84,14.11.HRMS(ESI):m / z[M+H]+calcd.for[C 31 H 26 N4O4]+:519.2032,found:519.2041.

[0159] Example 18

[0160] (E)-6-(7-bromo-4-((3-(imidazolidine-1-yl)phenyl)imino)-4H-benzo[g]chromen-2-yl)-1H-benzo[d]imidazol-2-amine:

[0161] In a 100 ml round-bottom flask, 2-(2-amino-1H-benzo[d]imidazol-6-yl)-7-bromo-4H-benzo[g]chromen-4-one (0.37 g, 0.915 mmol) and 3-(imidazolidine-1-yl)aniline (0.3 g, 1.83 mmol) were added sequentially, with a suitable amount of toluene as solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added under stirring, and the atmosphere was purged with nitrogen. The mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. After dissolving the solid in dichloromethane and methanol, the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 26.4%. 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.13(s,1H),7.91(s,2H),7.84(s,1H),7.7 3(s,1H),7.65(s,1H),7.56(s,1H),7.29(dt,J=7.5,2.0Hz,1H),7.16(t,J=7.5H z,1H),6.92(t,J=2.0Hz,1H),6.81(dt,J=7.3,2.0Hz,1H),6.54(s,1H),6.48(s, 1H), 6.32 (s, 1H), 4.20 (s, 2H), 3.53 (s, 2H), 3.43 (d, J = 0.8Hz, 1H), 3.01 (s, 2H); 13 C NMR(100MHz,DMSO-d6)δ160.65,157.73,157.58,151.58,149.96,139.29,139.09,136.38,133.07,132.89,132.24,129.05,128.53,127.89,127 .35,123.10,122.94,120.13,119.77,118.41,117.74,112.88,110.46,110.16,109.22,95.52,51.51,47.93.HRMS(ESI):m / z[M+H]+calcd.for[C 29 H 23 BrN6O]+:551.1195,found:551.1219.

[0162] Example 19

[0163] Synthesis of (E)-4-((8-methoxy-2-(2-(piperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenylmethylcarbamate:

[0164] In a 100 ml round-bottom flask, 8-methoxy-2-(2-(piperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.39 g, 0.915 mmol) and 4-aminophenylmethylcarbamate (0.31 g, 1.83 mmol) were added sequentially. Toluene was used as a solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added with stirring. Nitrogen gas was purged, and the mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. The solution was dissolved in dichloromethane and methanol, filtered, and the lower layer was evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 31.2%.1 H NMR (400MHz, DMSO-d6) δ8.35(s,1H),7.86(s,1H),7.80(d,J=7.4Hz,1H),7.65(d,J=9.9Hz,1H),7.45–7.3 9(m,1H),7.27(d,J=10.3Hz,1H),7.20–7.14(m,1H),3.83(s,1H),3.62(s,2H),2.87(s,2H),2.74(s,1H). 13 C NMR(100MHz,DMSO-d6)δ163.08,160.83,159.98,158.74,157.43,156.30, 150.78,148.26,147.97,141.84,135.68,129.78,128.69,127.75,125.77 ,124.29,123.79,122.47,118.38,117.00,115.58,113.78,109.48,108.8 8,106.31,55.97,52.61,48.60,27.27.HRMS(ESI):m / z[M+H]+calcd.for[C 33 H 29 N5O5]+:576.2247,found:576.2252.

[0165] Example 20

[0166] Synthesis of (E)-3-((8-chloro-2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenol:

[0167] In Example 2, 2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromone-4-one was replaced with 8-chloro-2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromone-4-one and reacted with 3-aminophenol. The other steps and operations were similar to those in Example 16, yielding a yellow solid with a yield of 43.2%. 1H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.30(s,1H),7.92(s,1H),7.80(d,J=7.5Hz,2H),7.76(s,1H),7.64(d,J=0.8Hz,2H),7.44(s,1 H),7.19(t,J=7.5Hz,1H),7.11(dt,J=7.5,2.0Hz,1H),6.71(t,J=2.0Hz,1H),6.67(dt,J=7.3,2.1Hz,1H),6.55(s,1H),3.13(s,5H). 13 C NMR(100MHz,DMSO-d6)δ162.07,160.57,159.98,156.56,156.16,149.38,147.53,142.07,136.56,135.71,133.62,131.64,130.72,128.60, 127.75,125.86,125.77,123.97,119.60,118.52,116.74,115.58,113.48,108.90,108.50,106.71,38.12HRMS(ESI):m / z[M+H]+calcd.for[C 28 H 20 ClN3O3]+:482.1271,found:482.1268.

[0168] Example 21

[0169] Synthesis of (E)-N,N-diethyl-4-((8-methyl-2-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide:

[0170] In Example 17, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one and 3-aminophenyl diethylcarbamate were replaced with 8-methyl-2-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one and 4-amino-N,N-diethylbenzamide, respectively. The other steps and operations were similar to those in Example 17, yielding a yellow solid with a yield of 33.1%. 1H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.89(s,1H),7.80(d,J=7.6Hz,1H),7.66–7.57(m,2H),7.55(d,J=4.0Hz,1H),7.48–7.42 (m,1H),7.31(s,1H),6.55(s,0H),3.65(s,1H),3.58(s,1H),3.39(s,2H),2.61(s,1H),2.54(s,1H),2.46(s,1H),1.20(s,3H). 13 C NMR(100MHz,DMSO-d6)δ171.49,164.34,159.98,156.22,155.88,150.52,148 .26,141.84,141.64,135.48,134.83,132.64,131.05,129.83,128.09,127.7 5,127.36,125.77,123.88,121.91,117.95,115.58,113.78,108.88,108.74, 54.60,54.15,45.49,43.53,22.07,13.76.HRMS(ESI):m / z[M+H]+calcd.for[C 37 H 37 N5O3]+:600.2975,found:600.2978.

[0171] Example 22

[0172] Synthesis of (E)-4-((2-(2-aminobenzo[d]thiazolyl)-4H-benzo[g]chromene-4-ylidene)amino)-N,N-diethylbenzamide:

[0173] In Example 17, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one and 3-aminophenyl diethylcarbamate were replaced with 2-(2-aminobenzo[d]thiazolyl)-4H-benzo[g]chromene-4-one and 4-amino-N,N-diethylbenzamide, respectively. The other steps and operations were similar to those in Example 17, yielding a yellow solid with a yield of 33.6%. 1H NMR(400MHz,DMSO-d6)δ8.36(s,1H),8.23(s,1H),8.17(s,1H),7.84(s,1H),7.76(s,2H),7.71(s,1H),7.63 –7.57(m,2H),7.51(d,J=1.0Hz,2H),7.48–7.42(m,2H),6.79(s,2H),6.48(s,1H),3.39(s,3H),1.20(s,5H). 13 C NMR(100MHz,DMSO-d6)δ171.49,170.14,160.13,157.08,156.20,150.52,150.28,136.32,134.83,133.15,132.64,132.40,130.32,130.24, 129.77,129.08,128.28,126.18,123.96,121.91,121.87,119.79,117.83,112.19,109.19,43.53,13.76.HRMS(ESI):m / z[M+H]+calcd.for[C 31 H 26 N4O2S]+:519.1855,found:519.1843.

[0174] Example 23

[0175] Synthesis of (E)-6-(7-bromo-4-((3-(imidazolidine)-1-yl)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]thiazol-2-amine:

[0176] In Example 22, 2-(2-aminobenzo[d]thiazol-6-yl)-4H-benzo[g]chromen-4-one and 4-amino-N,N-diethylbenzamide were replaced with 2-(2-aminobenzo[d]thiazol-6-yl)-7-bromo-4H-benzo[g]chromen-4-one, respectively.

[0177] The same steps and operations were performed similarly to those in Example 22, with the addition of 3-(imidazolidine-1-yl)aniline, to yield a yellow solid in a yield of 29.8%. 1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.17(s,1H),8.13(s,1H),7.91(s,1H), 7.76(s,2H),7.65(s,1H),7.56(s,1H),7.29(dt,J=7.5,2.0Hz,1H),7.16(t, J=7.5Hz,1H),6.92(t,J=2.0Hz,1H),6.81(dt,J=7.3,2.0Hz,1H),6.79(s,2H ),6.47(s,1H),4.20(s,2H),3.53(s,2H),3.43(d,J=0.9Hz,1H),3.01(s,2H). 13 C NMR(100MHz,DMSO-d6)δ170.14,160.13,157.73,157.08,151.58,150.28, 149.96,136.38,133.15,133.07,132.89,132.24,128.53,128.28,127.89, 126.18,123.10,122.94,121.87,120.13,119.79,119.77,117.74,112.19 ,110.16,109.22,95.52,51.51,47.93.HRMS(ESI):m / z[M+H]+calcd.for[C 29 H 22 BrN5OS]+:568.0807,found:568.0813.

[0178] Example 24

[0179] Synthesis of (E)-3-((7-methoxy-2-(2-(piperazin-1-yl)benzo[d]thiazo-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate:

[0180] The starting material (E)-4-(6-(4-((3-((diethylcarbamoyl)oxy)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)benzo[d]thiazolyl)piperazine-1-carboxylic acid tert-butyl ester (367 mg, 0.5 mmol) was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC showed that the reaction was complete. The pH was adjusted to approximately 7-8 with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and extracted 2-3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 48.9%. 1H NMR(400MHz, DMSO-d6)δ8.23(s,1H),8.18(s,1H),7.78–7.71(m,3H),7.69(s,1H),7.43(s,1H),7.37–7.29(m,2H),7.15(ddt,J= 12.5,7.5,2.0Hz,2H),7.03(s,1H),6.47(s,1H),3.83(s,2H),3.61(s,2H),3.55(s,2H),3.31(s,3H),2.88(s,4H),1.18(s,5H). 13 C NMR(100MHz,DMSO-d6)δ169.14,160.28,160.13,157.60,156.78,156.27,152.4 1,150.32,147.34,132.95,132.47,132.11,132.04,128.30,128.08,125.77,12 3.48,121.72,121.41,121.01,119.11,117.92,117.17,112.54,112.19,111.35 ,109.56,55.97,55.66,48.88,43.84,14.11.HRMS(ESI):m / z[M+H]+calcd.for[C 36 H 35 N5O4S]+:634.2488,found:634.2495.

[0181] Example 25

[0182] Synthesis of (E)-4-bromo-N-phenyl-N-(4-((2-(2-(piperazin-1-yl)benzo[d]thiazo-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)aniline:

[0183] The starting material (E)-4-(6-(4-((4-(((4-bromophenyl)(phenyl)amino)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]thiazo-2-yl)piperazine-1-carboxylic acid tert-butyl ester (417 mg, 0.5 mmol) was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC was used to determine the complete reaction of the starting material. The pH was adjusted to approximately 7-8 with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and extracted 2-3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 54.3%. 1HNMR(400MHz,DMSO-d6)δ8.36(s,1H),8.23(s,1H),8.18(s,1H),7.84(s,1H),7.76(d,J=1.5Hz,2H),7.71(s,1H),7.56–7.49(m,4H), 7.35–7.24(m,7H),7.28–7.16(m,4H),7.09(tt,J=7.4,2.0Hz,1H),6.48(s,1H),3.61(s,2H),3.55(s,2H),2.88(s,4H),2.10(s,1H). 13 C NMR(100MHz,DMSO-d6)δ169.14,160.13,157.08,156.22,150.32,149.65,148.51,14 7.88,146.89,136.32,133.04,132.95,132.40,130.74,130.32,130.24,129.77,129. 08,128.30,126.92,125.77,124.88,124.53,123.97,123.96,123.48,122.84,121.0 1,119.13,117.83,112.19,109.19,55.66,48.88.HRMS(ESI):m / z[M+H]+calcd.for[C 42 H 32 BrN5OS]+:734.1589,found:734.1576.

[0184] Example 26

[0185] Synthesis of (E)-6-(4-((4-(imidazolidine-1-yl)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)-N,N-dimethylbenzo[d]thiazol-2-amine:

[0186] In Example 23, 2-(2-aminobenzo[d]thiazolyl)-7-bromo-4H-benzo[g]chromen-4-one and 3-(imidazolidine-1-yl)aniline were replaced with 2-(2-(dimethylamino)benzo[d]thiazolyl)-7-methoxy-4H-benzo[g]chromen-4-one and 4-(imidazolidine-1-yl)aniline, respectively. The other steps and operations were similar to those in Example 23, yielding a yellow solid with a yield of 28.6%. 1H NMR(400MHz,DMSO-d6)δ8.23(s,1H),8.18(s,1H),7.77–7.71(m,3H),7.69(s,1H),7.43(s,1H),7.23–7.17(m,2H),7.03(s,1 H),6.98–6.91(m,2H),6.48(s,1H),4.19(s,2H),3.83(s,2H),3.53(s,2H),3.40(d,J=0.8Hz,1H),3.10(s,5H),3.01(s,2H). 13 C NMR(100MHz,DMSO-d6)δ168.76,160.28,160.13,157.60,156.22,152.14, 149.45,147.54,133.08,132.47,132.04,128.30,128.08,125.77,123.46 ,121.89,121.24,121.01,119.06,117.92,117.17,112.19,111.35,109.5 6,95.93,55.97,51.85,47.88,39.57.HRMS(ESI):m / z[M+H]+calcd.for[C 32 H 29 N5O2S]+:548.2120,found:548.2128.

[0187] Example 27

[0188] Synthesis of (E)-N,N-diethyl-3-((2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide:

[0189] In Example 21, 8-methyl-2-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one and 4-amino-N,N-diethylbenzamide were replaced with 2-(2-(4-methylpiperazin-1-yl)benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one and 3-amino-N,N-diethylbenzamide, respectively. The other steps and operations were similar to those in Example 21, yielding a yellow solid with a yield of 33.1%. 1H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.23(s,1H),7.96(s,1H),7.85(d,J=11.5Hz,1H),7.72(d,J=10.1Hz,1H),7. 58–7.43(m,3H),7.37–7.31(m,1H),6.54(s,0H),3.60(s,1H),3.49(s,1H),3.39(s,2H),2.58(s,2H),1.20(s,3H). 13 C NMR(100MHz,DMSO-d6)δ170.71,160.65,158.14,157.73,157.08,149.13,137 .93,137.45,136.76,136.32,132.40,130.32,130.24,129.77,129.26,129.08 ,128.38,126.95,123.96,123.08,121.25,118.41,117.95,112.88,111.45,1 09.19,54.34,48.65,45.49,43.53,13.76.HRMS(ESI):m / z[M+H]+calcd.for[C 36 H 36 N6O2]+:585.2978,found:585.2983.

[0190] Example 28

[0191] Synthesis of (E)-4-((7-methoxy-2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate:

[0192] In Example 25, (E)-4-(6-(4-((4-((4-bromophenyl)(phenyl)amino)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]thiazo-2-yl)piperazine-1-carboxylate tert-butyl ester was replaced with (E)-4-(6-(4-((4-((diethylcarbamoyl)oxy)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)-1H-benzo[d]imidazo-2-yl)piperazine-1-carboxylate tert-butyl ester. The other steps and operations were similar to those in Example 25, yielding a yellow solid with a yield of 65.7%. 1HNMR(400MHz, DMSO-d6)δ8.23(s,1H),7.96(s,1H),7.86(s,1H),7.73(d,J=1.4Hz,2H),7.69(s,1H),7.45–7.39(m, 3H),7.25–7.20(m,2H),7.03(s,1H),6.54(s,1H),3.83(s,2H),3.62(s,3H),3.30(s,3H),2.88(s,4H),1.18(s,5H). 13 C NMR(100MHz,DMSO-d6)δ160.65,160.28,158.80,157.83,157.60,156.16,1 49.91,147.97,137.93,136.76,132.47,132.04,129.26,128.08,126.95,12 3.79,122.49,121.24,118.41,117.92,117.17,112.88,111.45,111.35,109 .56,55.97,49.59,48.04,43.84,14.11.HRMS(ESI):m / z[M+H]+calcd.for[C 36 H 36 N6O4]+:617.2876,found:617.2866.

[0193] Example 29

[0194] Synthesis of (E)-4-bromo-N-phenyl-N-(4-((2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)aniline:

[0195] In Example 25, (E)-4-(6-(4-((4-((4-bromophenyl)(phenyl)amino)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]thiazolyl-2-yl)piperazine-1-carboxylate tert-butyl ester was replaced with (E)-4-(6-(4-((4-((4-bromophenyl)(phenyl)amino)phenyl)imino)-4H-benzo[g]chromen-2-yl)-1H-benzo[d]imidazolyl-2-yl)piperazine-1-carboxylate tert-butyl ester. The other steps and operations were similar to those in Example 25, yielding a yellow solid in 58.5% yield. 1H NMR (400MHz, DMSO-d6) δ8.36(s,1H),8.23(s,1H),7.96(s,1H),7.85(d,J=11.5Hz,1H),7.72(d,J=10.3Hz,1H ),7.56–7.49(m,3H),7.35–7.16(m,8H),7.09(tt,J=7.4,2.0Hz,1H),6.54(s,1H),3.62(s,2H),2.88(s,3H). 13 C NMR(100MHz,DMSO-d6)δ160.65,160.28,158.80,157.83,157.60,156.16,1 49.91,147.97,137.93,136.76,132.47,132.04,129.26,128.08,126.95,12 3.79,122.49,121.24,118.41,117.92,117.17,112.88,111.45,111.35,109 .56,55.97,49.59,48.04,43.84,14.11.HRMS(ESI):m / z[M+H]+calcd.for[C 42 H 33 BrN6O]+:717.1977,found:717.1981.

[0196] Example 30

[0197] Synthesis of (E)-6-(4-((4-(imidazolidine-1-yl)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)-N,N-dimethyl-1H-benzo[d]imidazol-2-amine:

[0198] In Example 26, 2-(2-(dimethylamino)benzo[d]thiazolyl-6-yl)-7-methoxy-4H-benzo[g]chromen-4-one was replaced with 2-(2-(dimethylamino)-1H-benzo[d]imidazolyl-6-yl)-7-methoxy-4H-benzo[g]chromen-4-one, and the other steps and operations were similar to those in Example 26, yielding a yellow solid with a yield of 31.4%. 1H NMR(400MHz, DMSO-d6)δ8.23(s,1H),7.96(s,1H),7.86(s,1H),7.73(d,J=1.4Hz,2H),7.69(s,1H),7.43(s,1H),7.23–7.17(m,2H),7 .03(s,1H),6.98–6.91(m,2H),6.54(s,1H),4.19(s,2H),3.83(s,3H),3.53(s,2H),3.40(d,J=0.7Hz,1H),3.11(s,5H),3.01(s,2H). 13 C NMR(100MHz,DMSO-d6)δ160.65,160.28,158.12,157.60,156.23,149.45, 147.54,140.22,137.04,132.47,132.04,129.24,128.08,126.95,121.89 ,121.24,119.06,118.41,117.92,117.17,112.88,111.36,111.35,109.5 6,95.93,55.97,51.85,47.88,37.55.HRMS(ESI):m / z[M+H]+calcd.for[C 32 H 30 N6O2]+:531.2508,found:531.2521.

[0199] Example 31

[0200] Synthesis of (E)-3-amino-N-(2-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide:

[0201] The starting material (E)-(3-((2-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)amino)3-oxopropyl)carbamate tert-butyl ester (295 mg, 0.5 mmol) was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC analysis confirmed the reaction was complete. The pH was adjusted to approximately 7–8 with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and extracted 2–3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 49.5%. 1H NMR (400MHz, DMSO-d6) δ9.36(s,1H),8.36(s,1H),8.23(s,1H),7.83(d,J=7.2Hz,2H),7.79(s,1H),7.73–7.62(m,3H),7.51(d,J=1.0Hz,2H),7.4 1(dd,J=7.2,2.3Hz,1H),7.32–7.21(m,2H),6.63(s,1H),5.96(s,2H),4 .14(s,1H),4.03(s,1H),2.89(d,J=12.2Hz,1H),2.84(d,J=12.4Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ172.06,165.60,160.03,157.49,153.41,149.56, 143.45,142.89,137.21,136.32,132.40,131.06,130.32,130.24,129.77, 129.08,129.06,128.39,125.77,124.02,123.96,123.23,117.74,115.57, 113.47,109.19,108.28,43.20,35.98.HRMS(ESI):m / z[M+H]+calcd.for[C 29 H 23 N5O3]+:490.1879,found:490.1874.

[0202] Example 32

[0203] Synthesis of (E)-6-(4-((2-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine:

[0204] In a 100 ml round-bottom flask, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.3 g, 0.915 mmol) and 1,2-phenylenediamine (0.19 g, 1.83 mmol) were added sequentially, with a suitable amount of toluene as solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added under stirring, and the atmosphere was purged with nitrogen. The mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. After dissolving the solid in dichloromethane and methanol, the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 39.2%. 1HNMR(400MHz,DMSO-d6)δ8.25(d,J=1.9Hz,1H),7.89(dt,J=7.9,1.7Hz,1H),7.7 6–7.67(m,4H),7.63(d,J=8.1Hz,1H),7.55–7.45(m,2H),7.41(dd,J=7.9,1.3Hz ,1H),7.28–7.21(m,1H),7.14(ddd,J=8.4,7.0,1.5Hz,1H),6.85(dd,J=7.2,1.5 Hz,1H),6.78(s,1H),5.65(s,2H),4.35(d,J=6.8Hz,1H),4.24(d,J=6.8Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ165.06,159.09,154.22,153.16,151.69,143.28,142.67,134.63,133.62,129.73,129.21,128.45,127.92,127.7 2,127.25,126.40,126.00,124.71,121.26,120.80,120.18,115.47,114.64,112.21,107.97,104.71.HRMS(ESI):m / z[M+H]+calcd.for[C 26 H 18 N4O2]+:419.2644,found:419.2631.

[0205] Example 33

[0206] Synthesis of (E)-6-(4-((4-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine:

[0207] In a 100 ml round-bottom flask, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.3 g, 0.915 mmol) and 1,4-phenylenediamine (0.19 g, 1.83 mmol) were added sequentially, with a suitable amount of toluene as solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added under stirring, and the atmosphere was purged with nitrogen. The mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. After dissolving the solid in dichloromethane and methanol, the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 35.2%. 1HNMR(400MHz, DMSO-d6)δ8.27(d,J=2.3Hz,1H),7.89(dt,J=7.9,1.7Hz,1H),7.76–7.67(m,4H),7.63(d,J=8 .1Hz,1H),7.55–7.45(m,2H),7.17–7.11(m,2H),6.70(s,1H),6.68–6.62(m,2H),5.66(s,2H),4.25(s,2H). 13 C NMR(100MHz,DMSO-d6)δ165.06,159.16,155.85,154.53,154.11,151.69,143.28,139.83,134.63,129.73,129.21,127.92,127.7 2,127.25,126.40,125.85,124.98,120.92,120.80,116.72,114.64,112.21,107.97,104.91.HRMS(ESI):m / z[M+H]+calcd.for[C 26 H 18 N4O2]+:419.2644,found:419.2636.

[0208] Example 34

[0209] Synthesis of (E)-6-(4-((3-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine:

[0210] In a 100 ml round-bottom flask, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.3 g, 0.915 mmol) and 1,3-phenylenediamine (0.19 g, 1.83 mmol) were added sequentially, with a suitable amount of toluene as solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added under stirring, and the atmosphere was purged with nitrogen. The mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. After dissolving the solid in dichloromethane and methanol, the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 28.9%. 1HNMR(400MHz, DMSO-d6)δ8.27(d,J=1.8Hz,1H),7.89(dt,J=8.1,1.8Hz,1H),7.76–7.67(m,4H),7.63(d,J=8.1Hz,1H),7.55–7.45(m, 2H),7.29–7.21(m,2H),6.87–6.83(m,1H),6.70(s,1H),6.58–6.52(m,1H),5.66(s,2H),4.51(d,J=5.5Hz,1H),4.46(d,J=5.5Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ165.06,159.16,154.49,154.14,151.69,150.28,150.14,143.28,134.63,129.73,129.21,128.54,127.92,127.7 2,127.25,126.40,125.85,120.92,120.80,115.74,114.64,113.77,112.21,107.97,106.11,104.67.HRMS(ESI):m / z[M+H]+calcd.for[C 26 H 18 N4O2]+:419.2644,found:419.2657.

[0211] Example 35

[0212] Synthesis of (E)-3-amino-N-(3-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide:

[0213] The starting material (E)-(3-((3-(((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)amino)3-oxopropyl)carbamate tert-butyl ester (295 mg, 0.5 mmol) was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC analysis confirmed the reaction was complete. The pH was adjusted to approximately 7–8 with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and extracted 2–3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 58.2%. 1H NMR(400MHz, DMSO-d6)δ9.08(s,1H),8.29–8.25(m,1H),7.89(dt,J=7.9,1.7Hz,1H),7.76–7.67(m,4H),7.66–7.61(m,2H),7.55–7.45(m,2H ),7.42–7.34(m,2H),7.13–7.07(m,1H),6.70(s,1H),5.66(s,2H),3.22(t,J=6.6Hz,2H),2.96(tt,J=6.6,4.9Hz,2H),2.52(t,J=4.9Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ172.64,165.06,159.16,154.41,154.14,151.69, 149.21,143.28,140.42,134.63,129.73,129.40,129.21,127.92,127.72, 127.25,126.40,125.85,120.92,120.80,119.87,117.51,114.64,112.21, 111.53,107.97,104.67,37.72,37.62.HRMS(ESI):m / z[M+H]+calcd.for[C 29 H 23 N5O3]+:490.1879,found:490.1885.

[0214] Example 36

[0215] Synthesis of (E)-6-(4-((4-(ethylamino)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine:

[0216] In a 100 ml round-bottom flask, 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromen-4-one (0.3 g, 0.915 mmol) and N-ethyl-1,4-phenylenediamine (24.9 mg, 1.83 mmol) were added sequentially, with a suitable amount of toluene as solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added under stirring, and the atmosphere was purged with nitrogen. The mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. After dissolving the solid in dichloromethane and methanol, the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 35.7%. 1H NMR(400MHz, DMSO-d6)δ8.27(d,J=2.3Hz,1H),7.89(dt,J=7.9,1.7Hz,1H),7.76–7.67(m,4H),7.63(d,J=8.1Hz,1H),7.55–7.45(m,2H),7 .25–7.19(m,2H),6.70(s,1H),6.49–6.43(m,2H),5.72(t,J=3.8Hz,1H),5.66(s,2H),3.24(qd,J=6.2,3.9Hz,2H),1.23(t,J=6.1Hz,3H). 13 C NMR (100MHz, DMSO-d6) δ165.06,159.16,154.53,154.11,151.69,147.37,143.28,142.15,134.63,129.73,129.21,127.92,127.72,127. 25,126.40,125.85,125.06,120.92,120.80,114.83,114.64,112.21,107.97,104.91,37.78,14.14.HRMS(ESI):m / z[M+H]+calcd.for[C 28 H 22 N4O2]+:447.1734,found:447.1724.

[0217] Example 37

[0218] Synthesis of (E)-3-amino-N-(4-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide:

[0219] The starting material (E)-(3-((4-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)amino)3-oxopropyl)carbamate tert-butyl ester (295 mg, 0.5 mmol) was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC analysis confirmed the reaction was complete. The pH was adjusted to approximately 7–8 with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and extracted 2–3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 44.7%. 1H NMR (400MHz, DMSO-d6) δ9.21 (s, 1H), 8.27 (d, J = 2.3Hz, 1H), 7.89 (dt, J = 7.9 ,1.7Hz,1H),7.76–7.67(m,4H),7.63(d,J=8.1Hz,1H),7.61–7.56(m,2H),7 .55–7.45(m,2H),7.29(dd,J=8.7,1.5Hz,2H),6.70(s,1H),5.66(s,2H),3. 22(t,J=6.6Hz,2H),2.96(tt,J=6.6,4.9Hz,2H),2.52(t,J=4.9Hz,2H).13C NMR(100MHz,DMSO-d6)δ172.74,165.06,159.16,154.53,154.11,151.69,143.28,142.48,137.55,134.63,129.73,129.21,127.92,127.72, 127.25,126.40,125.85,124.85,121.19,120.92,120.80,114.64,112.21,107.97,104.91,37.72,37.62.HRMS(ESI):m / z[M+H]+calcd.for[C 29 H 23 N5O3]+:490.1879,found:490.1888.

[0220] Example 38

[0221] Synthesis of (E)-N-(2-((2-(2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)-3-(piperazin-1-yl)propionamide:

[0222] The starting material (E)-4-(3-((2-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)amino)3-oxopropyl)piperazine-1-carboxylic acid tert-butyl ester (329 mg, 0.5 mmol) was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC was used to determine the complete reaction of the starting material. The pH was adjusted to approximately 7-8 with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and extracted 2-3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 51.3%. 1H NMR (400MHz, DMSO-d6) δ9.29 (s, 1H), 8.29–8.25 (m, 1H), 7.90 (ddd, J = 7.9, 2.8, 1.5Hz, 2H), 7.76–7.67(m,4H),7.63(d,J=8.1Hz,1H),7.56(dd,J=8.2,1.5Hz,1H),7.54–7.45(m,2H),7. 37(td,J=7.3,1.6Hz,1H),7.27(ddd,J=8.6,7.2,1.5Hz,1H),6.78(s,1H),5.66(s,2H),2.7 5(t,J=5.8Hz,2H),2.70(ddd,J=6.2,5.3,2.6Hz,4H),2.62–2.54(m,6H),1.94–1.88(m,1H). 13 C NMR(100MHz,DMSO-d6)δ170.90,165.06,159.09,154.22,153.42,151.69,143 .28,139.49,134.63,133.81,129.73,129.21,127.92,127.86,127.72,127.25 ,126.40,126.00,125.52,122.50,121.14,120.80,119.42,114.64,112.21,10 7.97,105.47,54.23,51.79,44.80,42.00.HRMS(ESI):m / z[M+H]+calcd.for[C 29 H 23 N5O3]+:559.2413,found:559.2433.

[0223] Example 39

[0224] Synthesis of (E)-N-(4-((2-(2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)-3-(piperazin-1-yl)propionamide:

[0225] The starting material (E)-4-(3-((4-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)amino)3-oxopropyl)piperazine-1-carboxylic acid tert-butyl ester (329 mg, 0.5 mmol) was dissolved in dry dichloromethane. Trifluoroacetic acid (1.2 g, 5 mmol) was slowly added dropwise with stirring. The reaction was carried out at room temperature for 4 hours. TLC showed that the reaction was complete. The pH was adjusted to approximately 7-8 with saturated sodium bicarbonate solution. The reaction solution was concentrated under reduced pressure and extracted 2-3 times with ethyl acetate and water. The combined organic phases were dried, concentrated under reduced pressure, and subjected to neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) to give a yellow solid. Yield: 45.8%. 1 H NMR(400MHz, DMSO-d6)δ7.89(dt,J=8.1,1.8Hz,0H),7.76–7.67(m,2H),7.66–7.56(m,2H),7.55–7.45(m,1H ),7.29(dd,J=8.7,1.5Hz,1H),5.66(s,1H),2.75(t,J=5.8Hz,1H),2.70(ddd,J=6.2,5.3,2.6Hz,2H),2.58(m J=7.9,5.5,3.4,2.6Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ170.86,165.06,159.16,154.53,154.11,151.69, 143.28,142.48,137.55,134.63,129.73,129.21,127.92,127.72,127.25 ,126.40,125.85,124.85,121.19,120.92,120.80,114.64,112.21,107.9 7,104.91,54.23,51.79,44.80,42.04.HRMS(ESI):m / z[M+H]+calcd.for[C 29 H 23 N5O3]+:559.2413,found:559.2426.

[0226] Example 40

[0227] Synthesis of (E)-N-ethyl-3-((2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide:

[0228] In a 100 ml round-bottom flask, 2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one (205 mg, 0.915 mmol) and 3-amino-N-ethylbenzamide (300 mg, 1.83 mmol) were added sequentially. Toluene was used as a solvent. Tetraethyl titanate (0.63 g, 2.75 mmol) was added with stirring. Nitrogen gas was purged, and the mixture was refluxed at 120 °C for 24 hours. The reaction was monitored by TLC until completion. A suitable amount of water was added to the reaction mixture, and the mixture was evaporated to dryness. The solution was dissolved in dichloromethane and methanol, and the lower layer was filtered and evaporated to dryness. Neutral alumina column chromatography (dichloromethane / methanol = 150 / 1) yielded a yellow solid. Yield: 33.2%. 1 H NMR(400MHz, DMSO-d6)δ8.29–8.25(m,1H),8.08(t,J=4.2Hz,1H),7.89(dt,J=7.9,1.7Hz,1H), 7.85–7.76(m,4H),7.76–7.70(m,2H),7.69(d,J=2.0Hz,1H),7.57–7.45(m,3H),7.26(ddd,J=8 .2,1.9,1.2Hz,1H),6.69(s,1H),3.67(dd,J=6.4,3.7Hz,2H),3.62(dd,J=6.4,3.7Hz,2H),3.5 3(ddd,J=12.3,6.4,3.7Hz,2H), 3.40(m,J=32.3,12.5,6.4,4.0Hz,4H), 1.25(t,J=6.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ167.96,158.56,154.50,154.46,154.11,147.57,141.9 7,139.39,134.63,134.61,130.58,129.21,128.99,127.92,127.72,127.59,12 7.25,126.40,125.85,124.74,122.82,121.77,120.97,115.80,112.21,109.87 ,104.19,54.16,48.05,45.30,34.91,14.71.HRMS(ESI):m / z[M+H]+calcd.for[C 28 H 22 N4O2]+:557.2433,found:557.2445.

[0229] The successful preparation of benzochrome ketone derivatives can be demonstrated by structural characterization using proton NMR, carbon NMR, and mass spectrometry.

[0230] Table 1 Chemical structural formulas of intermediates and derivatives of each example

[0231]

[0232]

[0233]

[0234]

[0235] UV-Vis absorption spectra of benzo[a]chromone derivatives

[0236] First, the UV-Vis absorption spectra of benzo[a]chromone derivatives in pure aqueous solution were measured. A 1 cm double-pass cuvette was used, and 3 mL of a solution with a final concentration of 5 μM of the compound was added. The UV-Vis absorption spectra were obtained by measuring with a UV-Vis spectrophotometer.

[0237] Singlet oxygen ( 1 O2) is a key factor in the effectiveness of PDT. Therefore, it can be determined based on the in vitro solution activity of benzo[a]chromone derivatives. 1 A preliminary assessment of O2 generation efficiency was conducted to determine the potential application of benzo[a]chromone derivatives in photosensitive dyeing (PDT). Benzo[a]chromone derivatives were compared with the commercial photosensitizer methylene blue, using 9,10-anthratridimyl-bis(methylene)dicarboxylic acid (ABDA) as the singlet oxygen source. 1 O2) detection reagents.

[0238] When ABDA captures 1 When exposed to O2, the absorption intensity at its maximum absorption wavelength of 400 nm decreases. Therefore, we can determine the formation of the compound by evaluating the degree of photobleaching of ABDA. 1 The ability of O2.

[0239] The specific experimental procedure was as follows: Using a 1cm double-pass cuvette, 3mL of a pure aqueous solution containing 5μM of the compound was first added, followed by the addition of ABDA solution to ensure a final working concentration of 50μM. The solution was then continuously irradiated with an LED lamp (460nm), and the UV-Vis absorption spectrum was measured every 60s for 5 minutes, recording the change in absorbance at 400nm. Figure 1The results shown in Table 2 indicate that within a 5-minute illumination period, Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 15, 16, 17, 21, 22, 23, 25, 27, 28, 29, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, and Methylene Blue (MB) all produced singlet oxygen yields of 50% or higher. Among them, Examples 1, 3, 6, 10, 11, 13, 16, 27, 28, 31, 34, 35, 36, 37, 39, and 40 all achieved yields of over 70%, which were significantly better than the positive control, Methylene Blue.

[0240] Table 2 Singlet oxygen in the target compound ( 1 O2) Yield Activity

[0241] Example <![CDATA[ 1 O2 yield (%) Example <![CDATA[ 1 O2 yield (%) Example 1 77.16±2.1 Example 22 66.01±3.1 Example 2 68.45±0.9 Example 23 51.33±2.1 Example 3 75.29±1.9 Example 24 23.44±0.3 Example 4 54.22±1.7 Example 25 60.87±3.7 Example 5 56.17±0.8 Example 26 20.73±2.2 Example 6 76.19±1.2 Example 27 72.17±1.6 Example 7 60.61±3.5 Example 28 76.24±4.6 Example 8 50.08±4.9 Example 29 65.52±1.5 Example 9 65.87±2.1 Example 30 10.73±2.2 Example 10 67.11±3.7 Example 31 79.78±3.6 Example 11 79.63±2.6 Example 32 69.23±8.3 Example 12 35.75±2.5 Example 33 69.75±5.6 Example 13 74.61±1.2 Example 34 77.34±7.5 Example 14 13.71±0.6 Example 35 81.56±4.9 Example 15 56.58±1.5 Example 36 70.19±6.7 Example 16 81.32±1.1 Example 37 83.73±3.1 Example 17 61.19±0.4 Example 38 66.53±5.5 Example 18 14.73±3.1 Example 39 79.58±8.6 Example 19 6.22±2.5 Example 40 89.17±3.3 Example 20 5.56±3.3 MB 50.59±1.1 Example 21 69.29±6.1 - -

[0242] Cell viability test:

[0243] The CCK-8 colorimetric assay assesses the cytotoxicity of compounds by quantifying mitochondrial dehydrogenase activity. The procedure involves a standardized process: WST-8 is reduced to water-soluble formazan (λmax = 450 nm) by live-cell mitochondrial dehydrogenases in a 1-Methoxy PMS electron transport system. The absorbance of WST-8 is linearly correlated with the number of live cells (R0). 2 >0.995). Cell seeding: Prepare single-cell suspensions using medium containing 10% FBS, and seed at a rate of 5 × 10⁶ cells / cells. 4 cells / mL (adherent system) or 9×10 4 Cells / mL (suspension) were seeded into 96-well plates (90 μL / well) and pre-cultured at 37℃ / 5% CO2 for 24 h. Drug treatment: serially diluted sample solution (10 μL / well), settings: primary screening group: single concentration (n=3 replicates); IC50... 50 Group: 6 concentration gradients (including blank control, n=3 replicates), treated at 37℃ for 48 h. Colorimetric detection: After removing the culture medium (direct detection of suspension cells), add 10% CCK-8 working solution (100 μL) to each well and incubate in the dark for 2 h (dynamic monitoring of the colorimetric curve). Data analysis: OD450 values ​​were measured using a microplate reader, and the inhibition rate was calculated using the formula: Inhibition rate = (OD450 + OD450) / (OD450 + OD450) * ... Control -OD Drug ) / (OD Control -OD Blank )×100%, using GraphPad 9.0 Four-parameter model fitting of dose-response curve (95% confidence interval).

[0244] Cell viability assays were performed on Examples 1, 3, 6, 11, 16, 28, 31, 34, 35, 37, 39, and 40, which showed singlet oxygen production greater than 75%, along with methylene blue. First, the inhibitory activity of the selected compounds against the proliferation of four cell lines was measured. The results are shown in Table 3. The examples exhibited high inhibitory activity against 4T1, HCT-116, A549, and A375 cells, effectively inhibiting the proliferation of various tumor cells under 10 μM treatment. These results indicate that the benzo[a]chromone derivatives of this invention can effectively generate singlet oxygen with higher efficiency than MB, and can be used for anti-tumor research.

[0245] Table 3 shows the phototoxic antitumor activity of the selected compounds against some tumor cells.

[0246]

[0247] Example a: The compound and MB were administered at a concentration of 10 μM;

[0248] b. Standard deviation of the three measurements;

[0249] After 8 hours of drug treatment, all cells were irradiated with 460nm light for 5 minutes.

[0250] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A benzochromone derivative, characterized in that, This includes compounds, stereoisomers, hydrates, or pharmaceutically acceptable salts of general formula (I), the structure of which is as follows: Where Y is selected from O, N, Any one of the following; X is selected from hydrogen, tritium, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted C1-C6 alkoxyacyl, substituted or unsubstituted C1-C6 alkylsulfonyl, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C3-C6 heterocyclic, substituted or unsubstituted C3-C6 heterocyclic acyl, substituted or unsubstituted C4-C 10 Fused heterobicyclic groups, substituted or unsubstituted C4-C 10 Fused heterobicyclic acyl, substituted or unsubstituted C4-C 10 Fused heterobicyclic amino; R 1 The group is selected from hydrogen, tritium, fluorine, chlorine, bromine, iodine, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted amino; the substitution refers to substitution by any one or more of fluorine, chlorine, bromine, iodine, hydroxyl, nitro, amino, carboxylic acid, carboxylic acid ester, cyano, and acyl.

2. A benzochromene derivative as described in claim 1, characterized in that, R 1 Selected from hydrogen, tritium, fluorine, chlorine, bromine, iodine, methyl, methoxy; R 2 Selected from fluorine, chlorine, bromine, iodine, hydroxyl, amino, ethylamino, unsubstituted C1-C6 alkoxy groups, R 3 Selected from fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, and cyclopropyl.

3. A benzochromene derivative as described in claim 1, characterized in that, The substituted C4-C 10 Fused heterobicyclic acyl group is Z is selected from nitrogen, oxygen, sulfur, and amino; M is selected from hydrogen, tritium, and amino.

4. A benzochrome ketone derivative, characterized in that, Includes at least one of the following compounds: Target compound 1: 2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one; Target compound 2: 2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one; Target compound 3: 2-(2-(diethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-one; Target compound 4: 2-(2-aminobenzo[d]thiazolyl)-4H-benzo[g]chromene-4-one; Target compound 5: 2-(2-(dimethylamino)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-one; Target compound 6: 2-(2-aminobenzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-one; Target compound 7: 2-(2-(diethylamino)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-one; Target compound 8: 2-(2-(piperazin-1-yl)benzo[d]thiazo-6-yl)-4H-benzo[g]chromen-4-one; Target compound 9: 7-bromo-2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one; Target compound 10: 2-(2-(diethylamino)-1H-benzo[d]imidazol-6-yl)-8-methoxy-4H-benzo[g]chromene-4-one; Target compound 11: 2-(2-aminobenzo[d]imidazol-6-yl)-8-bromo-4H-benzo[g]chromen-4-one; Target compound 12: 8-methoxy-2-(2-(piperazin-1-yl)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromen-4-one; Target compound 13: 8-bromo-2-(2-(diethylamino)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-one; Target compound 14: 2-(2-aminobenzo[d]thiazolyl)-8-bromo-4H-benzo[g]chromen-4-one; Target compound 15: 8-iodo-2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromen-4-one; Target compound 16: (E)-6-(4-((4-methoxyphenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine; Target compound 17: (E)-3-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate; Target compound 18: (E)-6-(7-bromo-4-((3-(imidazolidine-1-yl)phenyl)imino)-4H-benzo[g]chromen-2-yl)-1H-benzo[d]imidazol-2-amine; Target compound 19: (E)-4-((8-methoxy-2-(2-(piperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenylmethylcarbamate; Target compound 20: (E)-3-((8-chloro-2-(2-(dimethylamino)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenol Target compound 21: (E)-N,N-diethyl-4-((8-methyl-2-(2-(4-methylpiperazin-1-yl)benzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide; Target compound 22: (E)-4-((2-(2-aminobenzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)-N,N-diethylbenzamide; Target compound 23: (E)-6-(7-bromo-4-((3-(imidazolidine)-1-yl)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]thiazol-2-amine; Target compound 24: (E)-3-((7-methoxy-2-(2-(piperazin-1-yl)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate; Target compound 25: (E)-4-bromo-N-phenyl-N-(4-((2-(2-(piperazin-1-yl)benzo[d]thiazolyl-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)aniline; Target compound 26: (E)-6-(4-((4-(imidazolidine-1-yl)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)-N,N-dimethylbenzo[d]thiazol-2-amine; Target compound 27: (E)-N,N-diethyl-3-((2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide; Target compound 28: (E)-4-((7-methoxy-2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl diethylcarbamate; Target compound 29: (E)-4-bromo-N-phenyl-N-(4-((2-(2-(piperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)aniline; Target compound 30: (E)-6-(4-((4-(imidazolidine-1-yl)phenyl)imino)-7-methoxy-4H-benzo[g]chromen-2-yl)-N,N-dimethyl-1H-benzo[d]imidazol-2-amine; Target compound 31: (E)-3-amino-N-(2-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide; Target compound 32: (E)-6-(4-((2-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine; Target compound 33: (E)-6-(4-((4-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine; Target compound 34: (E)-6-(4-((3-aminophenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine; Target compound 35: (E)-3-amino-N-(3-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide: Target compound 36: (E)-6-(4-((4-(ethylamino)phenyl)imino)-4H-benzo[g]chromen-2-yl)benzo[d]oxazol-2-amine; Target compound 37: (E)-3-amino-N-(4-((2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)propionamide; Target compound 38: (E)-N-(2-((2-(2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)-3-(piperazin-1-yl)propionamide; Target compound 39: (E)-N-(4-((2-(2-(2-aminobenzo[d]oxazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)phenyl)-3-(piperazin-1-yl)propionamide; Target compound 40: (E)-N-ethyl-3-((2-(2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-6-yl)-4H-benzo[g]chromene-4-ylidene)amino)benzamide.

5. A method for preparing a benzochrome ketone derivative as described in any one of claims 1-4, characterized in that, Starting with 3-hydroxy-2-acetylnaphthalene 1, intermediate 2 was obtained by aldol condensation reaction with 3-hydroxy-4-nitrobenzaldehyde, followed by I2-catalyzed free radical cyclization to obtain fused ring structure 3; Reduction 3 yields intermediate 4, which is then cyclized with cyanogen bromide to give key intermediate 5; intermediate 5 undergoes imine condensation, side-chain amide condensation, and deprotection to give target compound 7.

6. A method for preparing a benzochrome ketone derivative as described in any one of claims 1-4, characterized in that, Starting from 3-hydroxy-2-acetylnaphthalene, intermediate 2 was obtained by aldol condensation with 3-hydroxy-4-nitrobenzaldehyde, and then cyclically cyclized by I2 catalytic free radical to obtain fused ring structure 3. Reduction 3 yields intermediate 4, which is then condensed with trimethyl orthoformate to give cyclized intermediate 8. Intermediate 8 is then reacted with dimethylamine or diethylamine under the action of TBAI / TBHP to give intermediate 9. Intermediate 9 undergoes imine condensation with substituted aniline to give 10. Intermediate 10 is then condensed with the side chain of aminocarboxylic acid, and finally deprotected to give target compound 11.

7. The use of a benzochrome ketone derivative as described in any one of claims 1-4 in the preparation of a photosensitizer.

8. The use of a benzochrome ketone derivative as described in any one of claims 1-4 in the preparation of photodynamic therapy drugs.

9. The use of a benzochrome ketone derivative as described in any one of claims 1-4 in the preparation of an antitumor drug.

10. The use of a benzochrome ketone derivative as described in any one of claims 1-4 in the preparation of cell-targeted drugs.

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