Rutaecarpin derivative as well as synthesis method and application thereof

Abstract

The invention provides a rutaecarpin derivative as well as a synthesis method and application thereof, and particularly, the rutaecarpin derivative has remarkable biological activity and good selectivity when being used as a CAMK II kinase inhibitor. By optimizing the chemical structure of the compound, the pharmacological efficacy of the compound is remarkably enhanced, and particularly, the compound shows a good application prospect in treating diseases (such as neurodegenerative diseases and cardiovascular diseases) related to abnormal activity of CAMKII.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, specifically to the synthesis and application of a class of rutaecarpine derivatives, especially their application as calcium / calmodulin-dependent kinase II (CaMKII) kinase inhibitors. Background Art

[0002] With the acceleration of the social aging process, neurodegenerative diseases have posed a major challenge in the global public health field. Diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) not only seriously damage the quality of life of patients, but also cause a huge socio-economic burden. Data from the World Health Organization shows that there are already 50 million AD patients, PD affects more than 10 million people, although the incidence of ALS is relatively low, its five-year fatality rate is as high as 90%, and HD, as a rare autosomal dominant genetic disease, also shows explosive progression characteristics in people aged 40-50. These diseases are commonly characterized by irreversible degeneration of neurons - the deposition of amyloid-β protein in AD causes synaptic dysfunction, the apoptosis of dopaminergic neurons in the substantia nigra in PD leads to motor control disorders, the synchronous degeneration of upper / lower motor neurons in ALS causes progressive muscle atrophy, and mutant huntingtin in HD destroys the basal ganglia neural circuit through toxic aggregation. It is worth noting that the core pathological processes of the above diseases are all closely related to abnormal calcium ion signal regulation. Among them, calcium / calmodulin-dependent protein kinase II (CaMKII), as the core hub of neuron plasticity regulation, has been found that abnormal phosphorylation modification thereof can simultaneously drive multiple pathological phenotypes such as synaptic loss in AD, mitochondrial autophagy disorder in PD, and glutamate excitotoxicity in ALS. Based on the pivotal position of CaMKII in neurodegeneration, this study focuses on the discovery and functional verification of novel CaMKII inhibitors, aiming to provide lead compounds for disease-modifying therapies targeting this kinase.

[0003] Calcium / calmodulin-dependent kinase II (CaMKII) is a class of widely expressed serine / threonine kinases that regulate core physiological processes such as neuronal synaptic plasticity, myocardial contraction, and immune response by sensing calcium signals. Its family consists of four subtypes (α / β / γ / δ), and the catalytic domains of each subtype are highly homologous (sequence similarity > 95%). Currently reported CaMKII inhibitors can be divided into three categories, but they all have significant defects. Ca 2+ / CaM competitive inhibitors such as KN-62 and KN-93 bind to the calmodulin-binding domain of CaMKII and block Ca 2+ / CaM-dependent activation;

[0004] At present, some CAMKⅡ inhibitors have been reported, but most of them have problems such as poor selectivity and large side effects. Therefore, it is necessary to develop CAMKⅡ kinase inhibitors with high selectivity and low toxicity. SUMMARY OF THE INVENTION

[0005] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a class of rutaecarpine derivatives with selective inhibitory activity against CaMKII.

[0006] In order to achieve the above purpose, the technical scheme adopted by the present invention is as follows:

[0007] The first aspect of the present invention provides a rutaecarpine derivative having CaMKⅡ inhibitory activity, which is characterized in that the compound is a compound of formula (Ⅰ), or a pharmaceutically acceptable salt, stereoisomer, deuterated compound or prodrug thereof.

[0008]

[0009] Wherein; X is N, C;

[0010] R1 is selected from the group consisting of: H, halogen, C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, C 6-8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, wherein the C 6-8 aryl, 5-8 membered heteroaryl is optionally mono- or polysubstituted by m R3s;

[0011] R2 is selected from the group consisting of: H, CF3, COOMe;

[0012] L (linker) is selected from the group consisting of: single bond, -NH-C(O)-, -NH-, -NH-S(O)-NH-, -NH-SO2-;

[0013] Each R3 is independently selected from the group consisting of: hydrogen, halogen, -CN, -OH, -NO2, -NH2, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, C containing 1-4 heteroatoms selected from N, 0 or S 1-6 heteroalkyl, halo C1-6 heteroalkyl containing 1-4 heteroatoms selected from N, 0 or S; or, two R3s together with the atoms to which they are attached form C 3-6 cycloalkyl, C 6-10Aryl, 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O or S, wherein the C 3-6 Cycloalkyl, C 6-10 Aryl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl are optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, ═O, -CN, -OH, -NR4R5, ═NR4, -C(O)R4, -C(O)OR4, -SR4, C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1 to 4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, halo C containing 1 to 4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O or S;

[0014] Each R4 and R5 are each independently selected from the group consisting of: H, C 1-6 Alkyl, C 1-6 Alkoxy, C containing 1 to 4 heteroatoms selected from N, O or S 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O or S; or, R4 and R5 together with the heteroatom to which they are attached form a 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O or S;

[0015] m is selected from: 0, 1, 2, 3; is a single bond or a double bond.

[0016] In certain preferred embodiments of the compound of formula I, the parent nucleus can be further defined to obtain a more preferred subclass as follows:

[0017]

[0018] Formula IA, based on formula I, X is C, L is a single bond, R2 is H, R1 is C 6-8 Aryl, 5- to 8-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O or S, wherein the C 6-8 Aryl, 5- to 8-membered heteroaryl are optionally mono- or polysubstituted with m R3;

[0019] Formula IB, based on formula I, X is N, L is a single bond, R2 is H, R1 is a benzene ring, a nitrogen heterocycle, an unsaturated alkyl ring; R3 is methoxy, methoxycarbonyl, [1,3]dioxy;

[0020] General formula IC, based on general formula I, where X is C, L is -NH-C(O)-, R2 is H, CF3, and R1 is C1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, C 6-8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, where the C 6-8 aryl, 5-8 membered heteroaryl is optionally mono- or polysubstituted by m R3 groups; R3 is H, halogen, C 1-6 heteroalkyl;

[0021] General formula ID, based on general formula I, where X is C, L is selected from -NH-C(S)-NH- or -NH-C(O)-NH-, R2 is H, and R1 is C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, C 6-8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, where the C 6-8 aryl, 5-8 membered heteroaryl is optionally mono- or polysubstituted by m R3 groups; R3 is H, halogen, C 1-6 heteroalkyl;

[0022] General formula IE, based on general formula I, where X is C, L is -NH-SO2-, R2 is H, and R1 is C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, C 6-8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, where the C 6-8 aryl, 5-8 membered heteroaryl is optionally mono- or polysubstituted by m R3 groups; R3 is H, halogen, C 1-6 heteroalkyl;

[0023] General formula IF, based on general formula I, where X is C, L is -NH-, R2 is H, and R1 is C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, C 6-8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S, where the C 6-8An aryl or 5- to 8-membered heteroaryl is optionally mono- or polysubstituted by m R3; R3 is H, halogen, a C containing 1 to 4 heteroatoms selected from N, O or S 1-6 heteroalkyl;

[0024] Preferably, the compounds of the above general formulas IA-IF are one of the following

[0025] Table 1. Structures of Preferred Compounds

[0026]

[0027]

[0028]

[0029] II. Preparation Method of Rutaecarpine Derivative Calcium / Calmodulin-Dependent Protein Kinase II Inhibitor

[0030] A preparation method of a CaMKII inhibitory activity rutaecarpine derivative as

[0031] When synthesizing the preferred skeleton IA of the parent nucleus I: Using commercially available 5-bromoindoxyl anhydride as the starting material, first reacting with tryptamine in a basic environment under reflux to carry out a condensation reaction to obtain intermediate 2. Intermediate 2 undergoes formylation and dehydration to obtain intermediate 3. The intermediate reacts with boric acid / boronic acid pinacol ester substituted with different R3 through Suzuki coupling to obtain a series of different rutaecarpine derivatives IA01-IA46. Among them, IA43-IA46 are generated by the condensation reaction of the coupling product IA10 of 4-carboxyphenylboronic acid with different H2NR4 or HNR4R5 under the action of EDCI.

[0032] The synthetic route is as Figure 1 .

[0033] Reagents and conditions: (a) tryptamine, dioxane, reflux; (b) triethyl orthoformate, reflux; (c) phosphorus pentoxide, dichloromethane, reflux; (d) substituted boric acid / boronic ester, cesium carbonate, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, dioxane, reflux; (e) substituted amine, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, triethylamine, dichloromethane, tetrahydrofuran, room temperature.

[0034] When synthesizing the preferred skeleton IB of the parent nucleus I: Using commercially available 2-amino-5-bromonicotinic acid as the starting material, first reacting with tryptamine in a basic environment to carry out a condensation reaction to obtain intermediate 5. Intermediate 5 undergoes formylation and dehydration to obtain intermediate 6. The intermediate reacts with boric acid / boronic acid pinacol ester substituted with different R3 through Suzuki coupling to obtain a series of different rutaecarpine derivatives IB.

[0035] The synthetic route is as follows Figure 2 .

[0036] Reagents and conditions: (a) tryptamine, dioxane, reflux; (b) triethyl orthoformate, reflux; (c) phosphorus pentoxide, dichloromethane, reflux; (d) substituted boronic acid / boronic ester, cesium carbonate, 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride, dioxane, reflux.

[0037] When synthesizing the preferred skeletons IC (R2 = H), ID - IF of the parent nucleus I: Starting from commercially available 5-nitroisatoic anhydride, first a condensation reaction occurs with tryptamine in a basic environment to obtain intermediate 8. Intermediate 8 undergoes cyclization to obtain intermediate 9. The nitro group of intermediate 9 undergoes a reduction reaction with iron powder to generate an amino group to obtain intermediate 10. Intermediate 10 reacts with different R1-substituted acyl chlorides in a basic environment to obtain the preferred skeleton IC; intermediate 10 reacts with different R1-substituted isocyanates / isothiocyanates in a basic environment to obtain the preferred skeleton ID; intermediate 10 reacts with different R1-substituted sulfonyl chlorides in a basic environment to obtain the preferred skeleton IE; intermediate 10 undergoes a Buchwald–Hartwig coupling reaction with different R1-substituted bromides under palladium catalysis to obtain the preferred skeleton IF.

[0038] The synthetic route is as follows Figure 3 .

[0039] Reagents and conditions: (a) tryptamine, ethanol, reflux; (b) triethyl orthoformate, p-toluenesulfonic acid, reflux; (c) iron powder, ammonium chloride, ethanol, reflux; (d) substituted acyl chloride, N-diisopropylethylamine, dichloromethane, room temperature; (e) substituted acyl chloride, N-diisopropylethylamine, dichloromethane, room temperature; (f) substituted sulfonyl chloride, N-diisopropylethylamine, dichloromethane, room temperature; (g) substituted aryl bromide, sodium tert-butoxide, palladium acetate, 1,1'-binaphthalene-2,2'-bis(diphenylphosphine), dioxane, reflux.

[0040] When synthesizing the preferred skeleton IC (R2 = CF3) of the parent nucleus I: Starting from commercially available 5-nitroisatoic anhydride, first a three-component reaction occurs with trifluoroacetic anhydride and tryptamine in a basic environment to obtain intermediate 11. Intermediate 11 undergoes a reduction reaction with iron powder to obtain intermediate 10. Intermediate 10 reacts with different R1-substituted acyl chlorides in a basic environment to obtain the preferred skeleton IC.

[0041] The synthetic route is as follows Figure 4 .

[0042] Reagents and conditions: (a) Tryptamine, trifluoroacetic anhydride, pyridine, reflux; (b) Iron powder, ammonium chloride, ethanol, reflux; (c) Substituted acyl chloride, N - diisopropylethylamine, dichloromethane, room temperature; (e) Substituted acyl chloride, N - diisopropylethylamine, dichloromethane, room temperature;

[0043] Among them, R1 - R5 and X are as shown in General Formula I of Claim 1.

[0044] The room temperature mentioned in the present invention refers to 20 - 30°C.

[0045] III. CaMKⅡα kinase inhibitory activity of rutaecarpine derivatives

[0046] The inhibitory activity levels of some rutaecarpine derivatives synthesized according to the above method against calcium / calmodulin - dependent kinase II were tested. The results showed that most compounds had significant inhibitory activity against calcium / calmodulin - dependent kinase II. Especially for the preferred skeleton IA, multiple compounds showed activity at the nanomolar level. Therefore, this type of derivative has the value of further research and development and can be used as a calcium / calmodulin - dependent kinase II inhibitor for the treatment of various diseases mediated by calcium / calmodulin - dependent kinase II.

[0047] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments. Description of the Drawings

[0048] Figure 1 It is the synthetic route diagram of derivative IA of the present invention.

[0049] Figure 2 It is the synthetic route diagram of derivative IB of the present invention.

[0050] Figure 3 It is the synthetic route diagram of derivatives IC, ID, IE, and IF of the present invention.

[0051] Figure 4 It is another synthetic route diagram of derivative IC of the present invention. Specific Embodiments

[0052] The following examples are helpful for understanding the present invention, but cannot limit the content of the present invention.

[0053] Example 1: Preparation of methyl 4 - [3 - [2 - (1H - indol - 3 - yl)ethyl] - 4 - oxo - 3,4 - dihydroquinazolin - 6 - yl]benzoate (IA01)

[0054] 5-Bromo-isatoic anhydride (Compound 1, 0.05 mol, 12.1 g) and tryptamine (0.05 mol, 8 g) were added to 1,4-dioxane and reacted at 80 °C overnight. After the reaction, the reaction solution was evaporated to dryness to obtain 15 g of white solid intermediate Compound 2 without further purification. The above Compound 2 (10 mmol, 3.5 g) was dissolved in 50 ml of triethyl orthoformate and reacted at 95 °C for 2 h. The solvent was distilled off, and it was added to 10 ml of DCM. Phosphorus pentoxide (15 mmol, 2.1 g) was added under ice bath, and the reaction was carried out at room temperature for 30 min. After the reaction, the organic phase was washed successively with saturated sodium bicarbonate and saturated brine, and then distilled under reduced pressure. Crystallization was carried out bidirectionally with methanol and dichloromethane, and 2.5 g of white intermediate Compound 3 was obtained by filtration with a yield of 62%.

[0055] The intermediate 3 (0.5 mmol, 184 mg) was placed in a 25 ml round-bottom flask, and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.75 mmol, 196 mg), 1,4-dioxane (5 ml) were added. 1.5 ml of 1 M cesium carbonate solution was added, and the catalyst 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (0.05 mmol, 36 mg) was added under nitrogen protection. The reaction was carried out at 90 °C overnight. After the reaction, the reaction solution was evaporated to dryness, dissolved in a mixed solution of dichloromethane and methanol (v / v = 10:1, 100 ml), and the organic phase was washed with saturated brine. The organic phase was collected, distilled under reduced pressure, and then separated and purified by column chromatography (dichloromethane:methanol = 60:1) to obtain 200 mg of white solid Compound IA01 with a yield of 64%. M.p.: 189 - 190 °C. 1 H NMR (DMSO, 400 MHz) δ 10.91 (1H, s), 8.47 (1H, d, J = 2.2 Hz), 8.18 (1H, dd, J = 8.5, 2.3 Hz), 8.13 (1H, s), 8.07 (1H, d, J = 8.6 Hz), 7.93 (1H, d, J = 8.6 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 8.2 Hz), 7.15 (1H, d, J = 2.4 Hz), 7.08 (0H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.5 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.89 (3H, s), 3.16 (2H, t, J = 7.2 Hz). 1313C NMR (DMSO, 100 MHz) δ 166.4, 160.6, 148.8, 148.3, 143.6, 137.5, 136.7, 133.2, 130.4, 129.3, 128.5, 127.6, 127.5, 124.4, 123.9, 122.4, 121.6, 118.9, 118.7, 112.0, 110.6, 52.7, 47.3, 24.9. HRMS-ESI: m / z calced for C 26 H 21 N3O3 [M+H] + 424.1656, found 424.1658.

[0056] Example 2: Preparation of methyl 2-[4-[3-[2-(1H-indol-3-yl)ethyl]-4-oxo-3,4-dihydroquinazolin-6-yl]phenyl]acetate (IA02): The preparation method was the same as that of IA01, except that 4-(2-methoxy-2-oxoethyl)phenylboronic acid was used instead of methyl 4-methoxycarbonylphenylboronate. White solid; yield 66%; M.p.: 173 - 174 °C; 1 1H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.41 (1H, d, J = 2.3 Hz), 8.12 (1H, dd, J = 8.6, 2.2 Hz), 8.10 (1H, s), 7.75 (2H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.11–7.05 (1H, m), 7.02–6.94 (1H, m), 4.27 (2H, t, J = 7.3 Hz), 3.76 (2H, s), 3.76 (4H, s), 3.15 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 171.6, 160.3, 147.9, 147.3, 138.3, 137.4, 136.3, 134.3, 132.7, 130.3, 127.9, 127.0, 126.9, 123.5, 123.2, 122.0, 121.2, 118.5, 118.4, 111.6, 110.2, 51.8, 46.9, 24.5. HRMS-ESI: m / z calced for C 27 H 23 N3O3 [M+H] + 438.1812, found 438.1818.

[0057] Example 3: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-aminophenyl)quinazolin-4(3H)-one (IA03): The preparation method was the same as that of IA02, except that 4-aminophenylboronic acid pinacol ester was used instead of 4-(2-methoxy-2-oxoethyl)phenylboronic acid. White solid; yield 67%; M.p.: 213-215 °C; 1 H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.29 (1H, d, J = 2.3 Hz), 8.03 (1H, s), 8.00 (1H, dd, J = 8.6, 2.4 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.62 (1H, d, J = 8.5 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.13 (1H, d, J = 2.5 Hz), 7.09 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.5 Hz), 6.70 (2H, d, J = 8.6 Hz), 5.39 (2H, s), 4.26 (2H, t, J = 7.3 Hz), 3.15 (2H, t, J = 7.4 Hz); 13 C NMR (DMSO, 100 MHz) δ 160.8, 149.5, 147.5, 146.4, 139.7, 136.8, 132.0, 128.1, 127.9, 127.5, 126.2, 123.9, 122.4, 121.6, 119.0, 118.8, 114.8, 112.0, 110.7, 47.2, 25.0. HRMS-ESI: m / z calced for C 24 H 20 N4O [M+H] + 381.1710, found 381.1715.

[0058] Example 4: Preparation of 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzaldehyde (IA04): The preparation method was the same as that of IA03, except that 4-formylphenylboronic acid pinacol ester was used instead of 4-aminophenylboronic acid pinacol ester. White solid, yield 62%; M.p.: 275 - 276 °C; 1H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 10.08 (2H, s), 8.51 (2H, d, J = 2.3 Hz), 8.21 (2H, dd, J = 8.5, 2.3 Hz), 8.14 (2H, s), 8.03 (5H, s), 7.75 (2H, d, J = 8.6 Hz), 7.65 (2H, d, J = 7.9 Hz), 7.37 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 2.5 Hz), 7.10 (1H, t, J = 7.5 Hz), 7.03–6.93 (1H, m), 4.29 (3H, t, J = 7.3 Hz), 3.17 (3H, t, J = 7.3 Hz); 13C NMR (100 MHz, DMSO) δ 193.2, 160.6, 148.9, 148.4, 144.8, 137.5, 136.8, 135.8, 133.3, 130.8, 128.5, 128.0, 127.5, 124.7, 123.9, 122.5, 121.6, 118.9, 118.8, 112.0, 110.6, 47.3, 24.9. HRMS-ESI: m / z calced for C 25 H 19 N3O2[M+H] + 393.1477, found 393.1483.

[0059] Example 5: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-fluorophenyl)quinazolin-4(3H)-one (IA05): The preparation method was the same as that of IA04, except that 4-fluorophenylboronic acid pinacol ester was used instead of 4-formylphenylboronic acid pinacol ester. White solid, yield 65%, 11H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.40 (1H, d, J = 2.3 Hz), 8.16–8.09 (2H, m), 7.85 (2H, dd, J = 8.9, 5.3 Hz), 7.72 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.41–7.31 (3H, m), 7.14 (1H, d, J = 2.4 Hz), 7.09 (1H, t, J = 7.0 Hz), 6.98 (1H, t, J = 8.0 Hz), 4.28 (2H, t, J = 7.2 Hz), 3.16 (2H, t, J = 7.2 Hz); 13 13C NMR (DMSO, 100 MHz) δ 163.9, 161.4, 160.7, 148.4, 147.7, 138.1, 136.7, 135.8, 133.2, 129.5, 129.4, 128.4, 127.5, 123.9, 123.8, 122.4, 121.6, 118.9, 118.8, 116.6, 116.4, 112.0, 110.6, 47.3, 24.9. HRMS-ESI: m / z calced for C 24 H 18 FN3O [M+H] + 384.1507, found 384.1503.

[0060] Example 6: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-methoxyphenyl)quinazolin-4(3H)-one (IA06): The preparation method was the same as that of IA05, except that 4-methoxyphenylboronic acid pinacol ester was used instead of 4-fluorophenylboronic acid pinacol ester. White solid, yield 68%, 1 1H NMR (DMSO, 400 MHz) δ 10.88 (1H, s), 8.36 (1H, d, J = 2.3 Hz), 8.12–8.04 (2H, m), 7.73 (2H, d, J = 8.9 Hz), 7.68 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.13 (1H, d, J = 2.5 Hz), 7.12–7.04 (3H, m), 6.98 (1H, t, J = 7.5 Hz), 4.27 (2H, t, J = 7.4 Hz), 3.82 (3H, s), 3.15 (1H, t, J = 7.2 Hz). 13¹³C NMR (DMSO, 100 MHz) δ 160.7, 159.8, 148.1, 147.2, 138.8, 136.8, 132.8, 131.6, 128.5, 128.3, 127.5, 123.9, 122.9, 122.4, 121.6, 118.9, 118.8, 115.1, 112.0, 110.6, 55.7, 47.3, 24.9. HRMS-ESI: m / z calcd for C 25 H 21 N3O2 [M+H] + 396.1707, found 396.1711

[0061] Example 7: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-propylphenyl)quinazolin-4(3H)-one (IA07): The preparation method was the same as that of IA06, except that 4-propylphenylboronic acid pinacol ester was used instead of 4-methoxyphenylboronic acid pinacol ester. White solid, yield 72%, 1 ¹H NMR (DMSO, 400 MHz) δ 10.88 (1H, s), 8.39 (1H, d, J = 2.2 Hz), 8.12 (1H, d, J = 2.3 Hz), 8.10 (1H, s), 7.69 (3H, d, J = 8.4 Hz), 7.64 (1H, d, J = 8.4 Hz), 7.34 (3H, t, J = 8.9 Hz), 7.14 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.97 (1H, t, J = 6.9 Hz), 4.27 (2H, t, J = 7.3 Hz), 3.15 (2H, t, J = 7.2 Hz), 2.61 (2H, t, J = 7.6 Hz), 1.62 (2H, dt, J = 14.7, 7.4 Hz), 0.92 (3H, t, J = 7.3 Hz), 13 ¹³C NMR (DMSO, 100 MHz) δ 160.3, 147.8, 147.1, 142.1, 138.6, 136.3, 136.2, 134.2, 132.6, 129.2, 129.1, 127.9, 127.5, 127.0, 126.7, 123.4, 123.0, 122.0, 121.2, 118.5, 118.3, 115.0, 111.5, 110.2, 46.9, 36.9, 24.5, 24.1, 13.7. HRMS-ESI: m / z calcd for C 27 H 25 N3O [M+H] + 408.2071, found 408.2067

[0062] Example 8: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-(tert-butyl)phenyl)quinazolin-4(3H)-one (IA08): The preparation method was the same as that of IA07, except that 4-(tert-butyl)phenylboronic acid pinacol ester was used instead of 4-propylphenylboronic acid pinacol ester. White solid, yield 76%, 1 H NMR (DMSO, 600 MHz) δ 10.90 (1H, s), 8.40 (1H, d, J = 2.4 Hz), 8.12–8.09 (2H, m), 7.70 (3H, dd, J = 8.4, 4.2 Hz), 7.65 (1H, d, J = 7.9 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.14 (1H, s), 7.08 (1H, t, J = 6.9 Hz), 6.98 (2H, t, J = 7.4 Hz), 4.27 (2H, t, J = 7.4 Hz), 3.15 (2H, t, J = 7.4 Hz), 1.32 (9H, s); 13 C NMR (DMSO, 151 MHz) δ 160.7, 151.0, 148.2, 147.5, 138.9, 136.8, 136.4, 133.0, 128.3, 127.5, 127.0, 126.5, 123.9, 123.4, 122.4, 121.6, 118.9, 118.8, 112.0, 110.6, 47.3, 34.8, 31.5, 25.0. HRMS-ESI: m / z calced for C 28 H 27 N3O [M + H] + 422.2227, found 422.2234.

[0063] Example 9: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (IA09): The preparation method was the same as that of IA08, except that 4-(trifluoromethyl)phenylboronic acid was used instead of 4-(tert-butyl)phenylboronic acid pinacol ester. White solid, yield 80%, 11H NMR (DMSO, 400 MHz) δ 10.88 (1H, s), 8.48 (1H, d, J = 2.2 Hz), 8.23–8.15 (1H, m), 8.12 (1H, s), 8.01 (2H, d, J = 8.9 Hz), 7.85 (2H, d, J = 8.6 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.13 (1H, d, J = 2.5 Hz), 7.07 (1H, t, J = 6.9 Hz), 6.97 (1H, t, J = 6.9 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.15 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.6, 148.9, 148.3, 143.2, 137.4, 136.7, 133.4, 128.6, 128.2, 127.5, 126.5, 126.4, 124.5, 123.9, 122.5, 121.6, 118.9, 118.7, 112.0, 110.6, 47.3, 24.9. HRMS-ESI: m / z calcd for C 25 H 18 F3N3O [M+H] + 434.1475, found 434.1469.

[0064] Example 10: Preparation of 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzoic acid (IA10): The preparation method was the same as that of IA9, except that 4-carboxyphenylboronic acid was used instead of 4-trifluoromethylphenylboronic acid. A white solid was obtained with a yield of 76%. 1 1H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.49 (1H, d, J = 2.3 Hz), 8.19 (1H, dd, J = 8.5, 2.3 Hz), 8.12 (1H, s), 8.07 (2H, d, J = 8.3 Hz), 7.92 (2H, d, J = 8.4 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 8.0 Hz), 7.15 (1H, d, J = 2.3 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.3 Hz), 4.29 (2H, t, J = 7.2 Hz), 3.42 (1H, s), 3.16 (2H, t, J = 7.3 Hz); 13¹³C NMR (DMSO, 100 MHz) δ 167.6, 160.7, 148.7, 148.2, 143.2, 137.8, 136.7, 133.3, 130.6, 128.5, 127.5, 124.4, 123.9, 122.4, 121.6, 118.9, 118.7, 112.0, 110.6, 47.3, 24.9. HRMS-ESI: m / z calcd for C 25 H 19 N3O3 [M+H] + 410.1500, found 410.1507.

[0065] Example 11: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one (IA11): The preparation method was the same as that of IA10, except that 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1-carbonitrile was used instead of 4-carboxyphenylboronic acid. White solid, yield 68%, 1 ¹H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.43 (1H, d, J = 2.3 Hz), 8.16–8.09 (2H, m), 7.92 (2H, d, J = 8.0 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.3 Hz), 7.09 (1H, t, J = 6.9 Hz), 6.98 (1H, t, J = 6.9 Hz), 4.29 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz); 13 ¹³C NMR (DMSO, 100 MHz) δ 160.7, 148.6, 148.0, 138.6, 137.5, 136.8, 133.2, 132.0, 131.9, 129.3, 129.3, 129.2, 128.5, 127.5, 124.1, 123.9, 122.4, 122.1, 121.6, 118.9, 118.8, 112.0, 110.6, 47.3, 24.9. HRMS-ESI: m / z calcd for C 25 H 18 F3N3O2 [M+H] + 450.1424, found 450.1428.

[0066] Example 12: Preparation of 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzamide (IA12): The preparation method was the same as that of IA11, except that 4-carbamoylphenylboronic acid was used instead of 4-trifluoromethoxyphenylboronic acid pinacol ester. White solid, yield 42%, 1 H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.6, 2.3 Hz, 1H), 8.12 (s, 1H), 8.11 (s, 2H), 8.03 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.08 (t, J = 7.0 Hz, 1H), 6.98 (t, J = 6.9 Hz, 1H), 4.28 (t, J = 7.3 Hz, 2H), 3.16 (t, J = 7.2 Hz, 2H), 13 C NMR (DMSO, 100 MHz) δ 167.6, 160.3, 148.3, 147.7, 141.4, 137.7, 136.4, 133.6, 132.9, 128.5, 128.1, 127.1, 126.8, 123.8, 123.5, 122.0, 121.2, 118.6, 118.4, 111.6, 110.2, 47.0, 24.5. HRMS-ESI: m / z calced for C 25 H 20 N4O2 [M + H] + 409.1659, found 409.1654.

[0067] Example 13: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(3-aminophenyl)quinazolin-4(3H)-one (IA13): The preparation method was the same as that of IA12, except that 3-aminophenylboronic acid was used instead of 4-carbamoylphenylboronic acid. Pale yellow solid, yield 47%, 11H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.35 (1H, d, J = 2.2 Hz), 8.09 (1H, s), 8.03 (1H, dd, J = 8.5, 2.3 Hz), 7.69 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.19–7.13 (2H, m), 7.09 (1H, t, J = 6.9 Hz), 7.01–6.95 (2H, m), 6.90 (1H, d, J = 6.7 Hz), 6.62 (1H, dd, J = 8.0, 2.9 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.57 (2H, s), 3.16 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.8, 149.9, 148.2, 147.5, 139.9, 136.7, 132.9, 130.2, 128.2, 127.5, 123.9, 123.3, 122.3, 121.6, 118.9, 118.8, 114.7, 114.1, 112.5, 112.0, 110.6, 47.3, 24.9. HRMS-ESI: m / z calcd for C 24 H 20 N4O [M+H] + 381.1710, found 381.1716.

[0068] Example 14: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(3-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (IA14): The preparation method was the same as that of IA13, except that 3-trifluoromethylphenylboronic acid was used instead of 3-aminophenylboronic acid. White solid, yield 67%, 1 1H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.47 (1H, d, J = 2.4 Hz), 8.20 (1H, dd, J = 8.5, 2.3 Hz), 8.06 - 8.15 (3H, m), 7.81–7.70 (3H, m), 7.64 (1H, d, J = 6.9 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.97 (1H, t, J = 7.5 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.16 (3H, t, J = 7.3 Hz); 1313C NMR (DMSO, 100 MHz) δ 160.7, 148.8, 148.2, 140.3, 137.4, 136.7, 133.4, 131.5, 130.8, 130.6, 130.3, 130.0, 128.5, 127.5, 126.0, 125.0, 124.5, 123.9, 123.8, 123.8, 123.3, 122.4, 121.6, 118.9, 118.7, 112.0, 110.6, 47.4, 24.9. HRMS-ESI: m / z calcd for C 25 H 18 F3N3O2 [M+H] + 434.1475, found 434.1470

[0069] Example 15: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(3-(methylthio)phenyl)quinazolin-4(3H)-one (IA15): The preparation method was the same as that of IA14, except that 3-(methylthio)phenylboronic acid was used instead of 3-(trifluoromethyl)phenylboronic acid. White solid, yield 67%, 1 1H NMR (DMSO, 400 MHz) δ 10.91 (1H, s), 8.39 (1H, d, J = 2.3 Hz), 8.05 - 8.13 (2H, m), 7.67 (2H, t, J = 9.0 Hz), 7.58 (1H, s), 7.49 (2H, d, J = 6.5 Hz), 7.42 (1H, t, J = 7.8 Hz), 7.38 (1H, d, J = 8.2 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.15 (1H, d, J = 2.6 Hz), 7.09 (1H, t, J = 7.2 Hz), 6.99 (1H, t, J = 7.4 Hz), 4.27 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.3, 148.0, 147.4, 139.6, 139.4, 138.2, 136.4, 132.8, 129.7, 127.9, 127.1, 125.3, 124.0, 123.6, 123.5, 123.4, 121.9, 121.2, 118.5, 118.4, 111.6, 110.2, 46.9, 24.5, 14.6. HRMS-ESI: m / z calcd for C 25 H 21 N3O S [M+H] + 412.1479, found 412.1479

[0070] Example 16: Preparation of N-(3-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)phenyl)acetamide (IA16): The preparation method was the same as that of IA15, except that 3-acetamidophenylboronic acid was used instead of 3-methylthiophenylboronic acid. White solid, yield 57%, 1 H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 10.13 (1H, s), 8.39 (1H, s), 8.12–8.02 (3H, m), 7.74 (1H, s), 7.64 (2H, d, J = 8.3 Hz), 7.49–7.40 (2H, m), 7.36 (1H, d, J = 8.2 Hz), 7.15 (1H, d, J = 2.4 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.5 Hz), 4.29 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz), 2.09 (3H, s); 13 C NMR (DMSO, 100 MHz) δ 169.0, 160.7, 151.1, 147.8, 140.6, 139.6, 138.9, 136.7, 133.0, 130.1, 128.4, 127.5, 126.6, 123.9, 123.7, 121.9, 121.6, 118.9, 118.7, 117.6, 112.0, 110.6, 109.6, 47.3, 40.6, 40.3, 40.1, 39.9, 39.7, 39.5, 39.3, 24.9, 24.6. HRMS-ESI: m / z calced for C 26 H 22 N4O2 [M + H] + 423.1816, found 423.1821.

[0071] Example 17: Preparation of 2-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzonitrile (IA17): The preparation method was the same as that of IA16, except that 2-cyanophenylboronic acid was used instead of 3-acetamidophenylboronic acid. White solid, yield 48%, 11H NMR (DMSO, 600 MHz) δ 8.24 (1H, d, J = 2.2 Hz), 8.15 (1H, s), 7.86–7.80 (2H, m), 7.67 (2H, dd, J = 8.2, 4.5 Hz), 7.57–7.51 (2H, m), 7.49–7.45 (2H, m), 7.42 (1H, s), 7.36 (1H, d, J = 8.1 Hz), 7.16 (1H, d, J = 2.4 Hz), 7.09 (1H, t, J = 7.5 Hz), 7.00 (1H, t, J = 7.4 Hz), 4.28 (2H, t, J = 7.5 Hz), 3.15 (2H, t, J = 7.5 Hz); 13 13C NMR (DMSO, 150 MHz) δ 171.4, 160.7, 148.4, 147.5, 139.6, 138.3, 137.8, 136.8, 135.0, 130.5, 130.0, 128.2, 128.0, 127.4, 127.4, 125.8, 123.8, 121.8, 121.6, 118.9, 118.8, 112.0, 110.6, 47.2, 25.0. HRMS-ESI: m / z calced for C 25 H 18 N4O [M + H] + 291.1554, found 391.1561.

[0072] Example 18: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2-isopropoxyphenyl)quinazolin-4(3H)-one (IA18): The preparation method was the same as that of IA17, except that 2-isopropoxyphenylboronic acid pinacol ester was used instead of 2-cyanophenylboronic acid. White solid, yield 65%, 1 1H NMR (DMSO, 600 MHz) δ 10.90 (1H, s), 8.37 (1H, d, J = 2.4 Hz), 8.10 (1H, s), 7.96 (1H, dd, J = 8.4, 2.4 Hz), 7.65 (2H, dd, J = 8.3, 5.3 Hz), 7.43–7.32 (3H, m), 7.16 (1H, s), 7.13 (1H, d, J = 8.4 Hz), 7.09 (1H, t, J = 7.5 Hz), 7.05 (1H, t, J = 7.4 Hz), 6.98 (1H, t, J = 7.4 Hz), 4.59 (1H, p, J = 6.0 Hz), 4.29 (2H, t, J = 7.4 Hz), 3.17 (2H, t, J = 7.4 Hz), 1.22 (3H, s), 1.21 (3H, s); 1313C NMR (DMSO, 150 MHz) δ 160.8, 154.8, 148.2, 147.2, 137.4, 136.8, 135.8, 131.1, 129.8, 129.8, 127.5, 127.0, 126.6, 123.8, 121.8, 121.6, 121.5, 118.9, 118.8, 115.2, 112.0, 110.7, 70.5, 47.3, 25.0, 22.2. HRMS-ESI: m / z calced for C 27 H 25 N3O2 [M+H] + 424.2020, found 424.2016.

[0073] Example 19; Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2-chlorophenyl)quinazolin-4(3H)-one (IA19): The preparation method was the same as that of IA18, except that 2-chlorophenylboronic acid was used instead of 2-isopropoxyphenylboronic acid pinacol ester. White solid, yield 70%, 1 1H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 8.40 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.67–7.60 (m, 2H), 7.53 (dd, J = 7.2, 2.1 Hz, 1H), 7.52–7.44 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 4.29 (t, J = 7.4 Hz, 2H), 3.16 (t, J = 7.4 Hz, 2H), 13 13C NMR (DMSO, 150 MHz) δ 160.3, 149.2, 146.2, 138.8, 137.9, 136.7, 136.1, 132.1, 131.7, 130.5, 130.3, 128.3, 127.4, 127.0, 126.5, 123.9, 121.6, 121.6, 118.9, 118.8, 112.0, 110.5, 47.6, 24.9. HRMS-ESI:

[0074] m / z calced for C 24 H 18 ClN3O [M+H] + 400.1211, found 400.1208.

[0075] Example 20; Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2-nitrophenyl)quinazolin-4(3H)-one (IA20): The preparation method was the same as that of IA19, except that 2-nitrophenylboronic acid pinacol ester was used instead of 2-chlorophenylboronic acid. White solid, yield 70%, 1 1H NMR (DMSO, 600 MHz) δ 10.89 (1H, s), 8.15 (1H, s), 8.11 (1H, s), 8.07 (1H, d, J = 8.1 Hz), 7.83 (1H, t, J = 7.6 Hz), 7.78 (1H, d, J = 8.4 Hz), 7.71 (1H, d, J = 8.4 Hz), 7.69–7.65 (1H, m), 7.62 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.15 (1H, s), 7.08 (1H, t, J = 7.5 Hz), 6.97 (1H, t, J = 7.5 Hz), 4.27 (2H, t, J = 7.4 Hz), 3.15 (2H, t, J = 7.4 Hz); 13 13C NMR (DMSO, 150 MHz) δ 160.5, 149.1, 149.0, 148.1, 136.7, 136.1, 134.5, 134.4, 133.9, 132.6, 129.9, 128.1, 127.4, 125.4, 124.9, 123.9, 122.1, 121.6, 118.9, 118.7, 112.0, 110.6, 47.4, 24.9. HRMS-ESI: m / z calcd for C 24 19 18 H + 4N4O3 [M + H]

[0076] Example 21: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one (IA21): The preparation method was the same as that of IA20, except that benzo-1,4-dioxane-6-boronic acid was used instead of 2-nitrophenylboronic acid pinacol ester. White solid, yield 66%. 11H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.32 (1H, d, J = 2.2 Hz), 8.08 (1H, s), 8.05 (1H, dd, J = 8.5, 2.4 Hz), 7.70–7.62 (2H, m), 7.36 (1H, dd, J = 8.2, 1.0 Hz), 7.28–7.23 (2H, m), 7.14 (1H, d, J = 2.3 Hz), 7.09 (1H, ddd, J = 8.1, 6.9, 1.2 Hz), 7.01–6.95 (2H, m), 4.30 (4H, d, J = 1.1 Hz), 4.27 (2H, t, J = 7.2 Hz), 3.15 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.7, 148.1, 147.3, 144.3, 144.1, 138.5, 136.7, 132.9, 132.5, 128.2, 127.5, 123.9, 123.1, 122.3, 121.6, 120.2, 118.9, 118.8, 118.2, 115.8, 112.0, 110.6, 64.7, 64.6, 47.3, 25.0. HRMS-ESI: m / z calced for C 26 H 21 N3O3 [M + H] + 424.1656, found 424.1651.

[0077] Example 22: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-(dimethylamino)-3-methoxyphenyl)quinazolin-4(3H)-one (IA22): The preparation method was the same as that of IA21, except that 4-(dimethylamino)-3-methoxyphenylboronic acid pinacol ester was used instead of benzo-1,4-dioxane-6-boronic acid. White solid, yield 52%, 1 1H NMR (400 MHz, DMSO) δ 10.90 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 12.2 Hz, 2H), 7.66 (dd, J = 8.2, 4.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.0 Hz, 2H), 7.14 (d, J = 2.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.03–6.91 (m, 2H), 4.27 (t, J = 7.3 Hz, 2H), 3.91 (s, 3H), 3.16 (t, J = 7.4 Hz, 2H), 2.74 (s, 6H), 1313C NMR (DMSO, 100 MHz) δ 160.8, 152.5, 147.9, 147.2, 142.5, 139.2, 136.8, 132.9, 132.4, 128.1, 127.5, 123.9, 122.9, 122.3, 121.6, 119.7, 118.9, 118.8, 118.4, 112.0, 110.7, 110.6, 55.9, 47.3, 43.0, 25.0. HRMS-ESI: m / z calcd for C 27 H 26 N4O2 [M+H] + 439.2129, found 439.2130.

[0078] Example 23: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(benzo[d][1,3]dioxol-5-yl)quinazolin-4(3H)-one (IA23): The preparation method was the same as that of IA22, except that 3,4-(methylenedioxy)phenylboronic acid was used instead of 4-(dimethylamino)-3-methoxyphenylboronic acid pinacol ester. White solid, yield 70%, 1 1H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.33 (1H, d, J = 2.3 Hz), 8.08 (1H, s), 8.05 (1H, dd, J = 8.6, 2.3 Hz), 7.65 (2H, dd, J = 8.2, 5.1 Hz), 7.40–7.33 (2H, m), 7.25 (1H, dd, J = 8.1, 1.9 Hz), 7.14 (1H, s), 7.09 (1H, t, J = 7.0 Hz), 7.04 (1H, d, J = 8.1 Hz), 6.99 (1H, t, J = 7.0 Hz), 6.10 (2H, s), 4.27 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.7, 148.7, 148.1, 147.8, 147.3, 138.8, 136.7, 133.5, 133.0, 128.2, 127.5, 123.9, 123.4, 122.3, 121.6, 121.2, 118.9, 118.8, 112.0, 110.6, 109.3, 107.7, 101.8, 47.3, 24.9. HRMS-ESI: m / z calcd for C 25 H 19 N3O3 [M+H] + 410.1500, found 410.1507.

[0079] Example 24: Preparation of methyl 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxybenzoate (IA24): The preparation method was the same as that of IA23, except that 3-methoxy-4-methoxycarbonylphenylboronic acid was used instead of 3,4-(methylenedioxy)phenylboronic acid. White solid, yield 72%, 1 1H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.21 (1H, dd, J = 8.5, 2.3 Hz), 8.13 (1H, s), 7.79 (1H, d, J = 8.1 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.6 Hz), 7.47 (1H, d, J = 1.7 Hz), 7.41 (1H, dd, J = 8.1, 1.7 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.5 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.97 (3H, s), 3.81 (3H, s), 3.16 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 166.4, 160.7, 159.3, 148.8, 148.3, 144.4, 137.9, 136.8, 133.5, 132.1, 128.4, 127.5, 124.5, 123.9, 122.4, 121.6, 119.5, 119.1, 118.9, 118.7, 112.0, 111.4, 110.6, 56.5, 52.4, 47.3, 24.9. HRMS-ESI: m / z calcd for C 27 H 23 N3O4 [M + H] + 454.1762, found 454.1765.

[0080] Example 25: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)quinazolin-4(3H)-one (IA25): The preparation method was the same as that of IA24, except that 2-(4-methylpiperazin-1-yl)pyrimidine-5-boronic acid pinacol ester was used instead of 3-methoxy-4-methoxycarbonylphenylboronic acid. White solid, yield 63%, 11H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.81 (2H, s), 8.37 (1H, d, J = 2.3 Hz), 8.13–8.05 (2H, m), 7.68 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.13 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.0 Hz), 6.98 (1H, t, J = 7.2 Hz), 4.27 (2H, t, J = 7.3 Hz), 3.80 (4H, t, J = 4.9 Hz), 3.15 (2H, t, J = 7.3 Hz), 2.39 (4H, t, J = 5.0 Hz), 2.23 (3H, s); 13 13C NMR (DMSO, 100 MHz) δ 161.0, 160.6, 156.5, 148.2, 147.4, 136.7, 134.1, 132.0, 128.4, 127.5, 123.9, 122.5, 122.3, 121.6, 121.2, 118.9, 118.8, 112.0, 110.6, 54.8, 47.3, 46.3, 43.8, 25.0. HRMS-ESI: m / z calcd for C 27 H 27 N7O [M+H] + 466.2350, found 466.2343.

[0081] Example 26: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)quinazolin-4(3H)-one (IA26): The preparation method was the same as that of IA25, except that 4-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenylboronic acid pinacol ester was used instead of 3-methoxy-4-chlorophenylboronic acid. White solid, yield 60%, 11H NMR (600 MHz, DMSO) δ 10.87 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.04–8.00 (m, 2H), 7.65–7.58 (t, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.22 (dd, J = 8.4, 2.3 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 7.11–7.04 (m, 2H), 6.97 (t, J = 7.9 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 4.29–4.22 (m, 4H), 3.31–3.25 (t, 2H), 3.14 (t, J = 7.3 Hz, 2H), 2.88 (s, 3H), 13 13C NMR (DMSO, 150 MHz) δ 160.4, 147.3, 146.4, 144.3, 138.7, 136.9, 136.4, 132.0, 127.9, 127.8, 127.1, 123.5, 122.0, 121.7, 121.2, 119.8, 118.6, 118.4, 113.4, 113.0, 111.6, 110.3, 64.6, 48.4, 46.9, 38.2, 24.6. HRMS-ESI: m / z calcd for C 27 H 24 N4O2 [M + H] + 437.1973, found 437.1979.

[0082] Example 27: Preparation of 3-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-5-nitrobenzoic acid (IA27): The preparation method was the same as that of IA26, except that 3-nitro-5-carboxyphenylboronic acid was used instead of 4-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)phenylboronic acid pinacol ester. Yellow solid, yield 40%, 1 1H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 8.71 (1H, t, J = 2.0 Hz), 8.59 (1H, s), 8.47 (1H, d, J = 2.4 Hz), 8.28–8.21 (1H, m), 8.14 (1H, s), 7.74 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.6 Hz), 6.97 (1H, t, J = 7.4 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz);13 C NMR (DMSO, 100 MHz) δ 165.8, 160.6, 149.1, 149.1, 148.6, 141.3, 136.7, 135.8, 133.8, 133.5, 133.3, 128.7, 127.5, 125.6, 124.9, 123.9, 123.2, 122.4, 121.6, 118.9, 118.7, 112.0, 110.6, 47.4, 24.9. HRMS-ESI: m / z calced for C 25 H 18 N4O5 [M+H] + 455.1350, found 455.1346.

[0083] Example 28: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(benzo[d][1,3]dioxol-4-yl)quinazolin-4(3H)-one (IA28): The preparation method was the same as that of IA27, except that 2,3-(methylenedioxy)phenylboronic acid was used instead of 3-nitro-5-carboxyphenylboronic acid. White solid, yield 70%, 1 H NMR (600 MHz, DMSO) δ 10.89 (s, 1H), 8.59 (s, 1H), 8.17 (d, J = 10.6 Hz, 1H), 8.11 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 7.1 Hz, 1H), 7.14 (s, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.99 (s, 1H), 6.98 (s, 1H), 6.97 (s, 1H), 6.15 (s, 2H), 4.27 (t, J = 7.4 Hz, 2H), 3.15 (t, J = 7.4 Hz, 2H), 13 C NMR (DMSO, 150 MHz) δ 160.2, 148.2, 147.9, 147.3, 144.6, 136.3, 133.7, 133.2, 127.7, 127.1, 124.7, 123.5, 122.5, 121.8, 121.2, 120.7, 120.7, 118.5, 118.4, 111.6, 110.2, 108.4, 101.0, 46.9, 24.5. HRMS-ESI: m / z calced for C 25 H 19 N3O3 [M+H] + 410.1500, found 410.1503.

[0084] Example 29: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2-chloro-5-(trifluoromethyl)phenyl)quinazolin-4(3H)-one (IA29): The preparation method was the same as that of IA28, except that 2,3-(methylenedioxy)phenylboronic acid was used instead. White solid, yield 62%, 1 1H NMR (DMSO, 400 MHz) δ 10.95 (1H, s), 8.43 (1H, s), 8.28 (1H, d, J = 2.2 Hz), 7.97 (1H, d, J = 8.5 Hz), 7.91–7.75 (4H, m), 7.63 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.16 (1H, d, J = 2.4 Hz), 7.07 (1H, t, J = 7.0 Hz), 6.97 (1H, t, J = 7.3 Hz), 4.29 (2H, t, J = 7.4 Hz), 3.16 (2H, t, J = 7.4 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.2, 149.5, 146.5, 139.9, 136.7, 136.4, 136.3, 136.1, 131.6, 129.0, 128.7, 127.4, 127.0, 126.5, 125.5, 123.9, 122.8, 121.6, 121.6, 118.9, 118.7, 112.0, 110.5, 47.7, 24.8. HRMS-ESI: m / z calcd for C 25 H 17 ClF3N3O [M + H] +

[0085] 468.1085, found 468.1080.

[0086] Example 30: Preparation of dimethyl 2-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)terephthalate (IA30): The preparation method was the same as that of IA29, except that 2,5-bis(methoxycarbonyl)phenylboronic acid pinacol ester was used instead of 2-chloro-5-(trifluoromethyl)phenylboronic acid pinacol ester. White solid, yield 50%, 11H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.16 (1H, s), 8.10 (2H, dd, J = 8.1, 1.8 Hz), 8.02 (1H, d, J = 1.7 Hz), 7.97 (1H, d, J = 8.1 Hz), 7.78 (1H, dd, J = 8.4, 2.2 Hz), 7.69 (1H, d, J = 8.4 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 6.2 Hz), 7.16 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.0 Hz), 6.98 (1H, t, J = 8.0 Hz), 4.29 (2H, t, J = 7.3 Hz), 3.92 (3H, s), 3.65 (3H, s), 3.16 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 101 MHz) δ

[0087] 168.0, 165.7, 160.6, 148.8, 147.9, 140.7, 138.4, 136.7, 135.1, 134.8, 132.8, 131.5, 130.7, 129.0, 127.7, 127.5, 125.6, 123.9, 121.9, 121.6, 118.9, 118.7, 112.0, 110.6, 53.1, 52.9, 47.3, 24.9. HRMS-ESI: m / z calcd for C 28 H 23 N3O5 [M+H] + 482.1711, found 482.1708.

[0088] Example 31: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(benzo[c][1,2,5]thiadiazol-5-yl)quinazolin-4(3H)-one (IA31): The preparation method was the same as that of IA30, except that benzo[c][1,2,5]thiadiazol-5-ylboronic acid was used instead of 2,5-bis(methoxycarbonyl)phenylboronic acid pinacol ester. White solid, yield 71%, 11H NMR (DMSO, 400 MHz) δ 10.89 (0H, s), 8.54 (1H, d, J = 2.4 Hz), 8.42 (0H, s), 8.28 (1H, dd, J = 8.6, 2.4 Hz), 8.22–8.08 (3H, m), 7.73 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, s), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.4 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.17 (2H, t, J = 7.2 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.6, 155.3, 154.3, 148.8, 148.3, 140.6, 137.4, 136.7, 133.7, 130.3, 128.5, 127.5, 124.9, 123.9, 122.4, 122.2, 121.6, 119.0, 118.9, 118.7, 112.0, 110.6, 47.4, 24.9. HRMS-ESI: m / z calced for C 24 H 17 N5OS [M+H] + 424.1227, found 424.1230.

[0089] Example 32: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-4

[0090] (3H)-one (IA32): Prepared in the same manner as IA31, except that 6-(piperazin-1-yl)pyridine-3-boronic acid pinacol ester was used instead of benzo[c][1,2,5]thiadiazol-5-ylboronic acid. White solid, yield 52%, 1 1H NMR (DMSO, 400 MHz) δ 10.92 (1H, s), 9.03 (2H, s), 8.62 (1H, d, J = 2.5 Hz), 8.38 (1H, d, J = 2.2 Hz), 8.16–8.05 (3H, m), 7.70 (1H, d, J = 8.5 Hz), 7.64 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.12–7.04 (2H, m), 6.98 (1H, t, J = 6.8 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.85–3.78 (4H, m), 3.24 (4H, s), 3.15 (2H, t, J = 7.6 Hz);13 13C NMR (DMSO, 100 MHz) δ 160.7, 158.0, 148.1, 147.3, 146.2, 136.8, 136.4, 132.4, 128.4, 127.5, 125.1, 123.9, 122.6, 122.5, 121.6, 118.9, 118.7, 112.0, 110.6, 108.1, 47.3, 42.9, 42.2, 25.0. HRMS-ESI: m / z calcd for C 27 H 26 N6O [M+H] + 451.2241, found 451.2247.

[0092] Example 33: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(thiazol-5-yl)quinazolin-4(3H)-one (IA33): The preparation method was the same as that of IA32, except that 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole was used instead of 2-formyl-4,5-(methylenedioxy)phenylboronic acid. White solid, yield 59%, 1 1H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 9.17 (1H, s), 8.50 (1H, s), 8.37 (1H, d, J = 2.2 Hz), 8.17 (1H, dd, J = 8.5, 2.3 Hz), 8.12 (1H, s), 7.69 (1H, d, J = 8.6 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.4 Hz), 7.09 (1H, t, J = 8.2 Hz), 6.98 (1H, t, J = 7.5 Hz), 4.28 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 101 MHz) δ 160.4, 154.8, 148.7, 148.1, 140.8, 137.9, 136.7, 132.7, 129.8, 128.7, 127.5, 123.9, 123.8, 122.6, 121.6, 118.9, 118.7, 112.0, 110.6, 47.4, 24.9. HRMS-ESI: m / z calcd for C 21 H 16 N4OS [M+H] + 373.1118, found 373.1115.

[0093] Example 34: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(quinolin-7-yl)quinazolin-4(3H)-one (IA34): The preparation method was the same as that of IA33, except that quinoline-3-boronic acid was used instead of thiazole-5-boronic acid pinacol ester. White solid, yield 52%. 1 H NMR (DMSO, 600 MHz) δ 10.90 (1H, s), 9.37 (1H, d, J = 2.4 Hz), 8.85 (1H, d, J = 2.4 Hz), 8.66 (1H, d, J = 2.2 Hz), 8.37 (1H, dd, J = 8.4, 2.4 Hz), 8.15 (1H, s), 8.14 (1H, d, J = 8.2 Hz), 8.09 (1H, d, J = 8.4 Hz), 7.85–7.78 (2H, m), 7.69 (1H, ddd, J = 8.1, 6.8, 1.2 Hz), 7.65 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.3 Hz), 7.09 (1H, t, J = 8.0 Hz), 6.99 (1H, t, J = 7.9 Hz), 4.31 (2H, t, J = 7.3 Hz), 3.18 (2H, t, J = 7.3 Hz); 13 C NMR (DMSO, 150 MHz) δ 160.7, 149.8, 148.8, 148.2, 147.4, 136.7, 136.0, 133.9, 133.5, 132.0, 130.4, 129.1, 129.1, 128.7, 128.1, 127.7, 127.5, 124.6, 123.9, 122.6, 121.6, 118.9, 118.8, 112.0, 110.6, 47.4, 24.9. HRMS-ESI: m / z calced for C 27 H 20 N4O [M + H] + 417.1710, found 417.1713.

[0094] Example 35: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(furan-3-yl)quinazolin-4(3H)-one (IA35): The preparation method was the same as that of IA34, except that furan-3-boronic acid was used instead of quinoline-3-boronic acid. White solid, yield 52%, 11H NMR (600 MHz, DMSO) δ 10.87 (s, 1H), 8.37 (d, J = 15.3 Hz, 2H), 8.07 (d, J = 6.2 Hz, 2H), 7.80 (s, 1H), 7.63 (dd, J = 8.3, 4.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 11.4 Hz, 2H), 7.07 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 4.26 (t, J = 7.4 Hz, 2H), 3.14 (t, J = 7.4 Hz, 2H), 13 13C NMR (DMSO, 150 MHz) δ 160.2, 147.6, 146.9, 144.8, 140.3, 136.3, 131.8, 130.8, 127.8, 127.1, 125.0, 123.4, 122.0, 121.9, 121.1, 118.5, 118.3, 111.5, 110.2, 108.7, 46.8, 24.5. HRMS-ESI: m / z calcd for C 22 H 17 N3O2 [M + H] + 356.1394, found 356.1398.

[0095] Example 36: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(3,5-dimethylisoxazol-4-yl)quinazolin-4(3H)-one (IA36): The preparation method was the same as that of IA35, except that 3,5-dimethylisoxazole-4-boronic acid was used instead of furan-3-boronic acid. White solid, yield 62%, 1 1H NMR (DMSO, 600 MHz) δ 10.89 (1H, s), 8.17 (1H, s), 8.13 (1H, d, J = 2.2 Hz), 7.84 (1H, dd, J = 8.4, 2.1 Hz), 7.73 (1H, d, J = 8.4 Hz), 7.65 (1H, d, J = 7.7 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 8.1 Hz), 6.98 (1H, t, J = 6.9 Hz), 4.27 (2H, t, J = 7.4 Hz), 3.15 (2H, t, J = 7.4 Hz), 2.46 (3H, s), 2.28 (3H, s); 13CNMR (DMSO, 150 MHz) δ 166.2, 160.5, 158.6, 148.7, 147.5, 136.7, 135.3, 129.0, 128.3, 127.5, 126.3, 123.9, 122.3, 121.6, 118.9, 118.8, 115.6, 112.0, 110.6, 47.3, 24.9, 11.9, 11.0. HRMS-ESI: m / z calced for C 23 H 20 N4O2 [M+H] + 385.1660, found 85.1653.

[0096] Example 37: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(benzofuran-3-yl)quinazolin-4(3H)-one (IA37): The preparation method was the same as that of IA36, except that benzofuran-3-boronic acid was used instead of 3,5-dimethylisoxazole-4-boronic acid. White solid, yield 71%, 1 H NMR (DMSO, 400 MHz) δ 10.91 (1H, s), 8.60 (1H, s), 8.53 (1H, d, J = 2.2 Hz), 8.20 (1H, dd, J = 8.5, 2.2 Hz), 8.14 (1H, s), 7.99 (1H, dd, J = 7.4, 1.9 Hz), 7.77 (1H, d, J = 8.5 Hz), 7.73 (1H, dd, J = 5.9, 1.9 Hz), 7.67 (1H, d, J = 7.8 Hz), 7.49–7.41 (2H, m), 7.37 (1H, d, J = 7.1 Hz), 7.16 (1H, d, J = 2.5 Hz), 7.10 (1H, t, J = 7.5 Hz), 7.00 (1H, t, J = 6.9 Hz), 4.30 (2H, t, J = 7.4 Hz), 3.18 (2H, t, J = 7.3 Hz) 13 C NMR (DMSO, 100 MHz) δ 160.6, 155.7, 148.4, 147.6, 144.2, 136.8, 133.4, 130.7, 128.5, 127.5, 125.7, 125.5, 124.1, 123.9, 123.8, 122.6, 121.6, 120.6, 118.9, 118.8, 112.5, 112.0, 110.6, 47.4, 24.9. HRMS-ESI: m / z calced for C 26 H 19 N3O2 [M+H] + 406.1551, found 406.1551.

[0097] Example 38: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2-fluoropyridin-4-yl)quinazolin-4(3H)-one (IA38): The preparation method was the same as that of IA37, except that 2-fluoropyridine-4-boronic acid pinacol ester was used instead of benzofuran-3-boronic acid. White solid, yield 66%, 1 H NMR (DMSO, 400 MHz) δ 10.92 (1H, s), 8.51 (1H, d, J = 2.3 Hz), 8.29 (1H, d, J = 5.3 Hz), 8.16 (1H, dd, J = 8.6, 2.3 Hz), 8.14 (1H, s), 7.71 (1H, d, J = 5.3 Hz), 7.68 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.57 (1H, s), 7.38 (1H, d, J = 8.1 Hz), 7.16 (1H, d, J = 2.4 Hz), 7.09 (1H, t, J = 7.0 Hz), 6.98 (1H, t, J = 7.0 Hz), 4.27 (2H, t, J = 7.3 Hz), 3.17 (2H, t, J = 7.5 Hz); 13 C NMR (DMSO, 100 MHz) δ 165.7, 163.4, 160.5, 152.2, 152.1, 149.2, 149.2, 148.8, 148.6, 136.8, 134.6, 134.5, 133.0, 128.5, 127.5, 125.0, 123.8, 122.4, 121.6, 120.1, 120.0, 118.9, 118.7, 112.0, 110.6, 107.4, 107.0, 47.4, 24.9. HRMS-ESI: m / z calced for C 27 H 17 FN4O [M + H] + 385.1460, found 385.1457.

[0098] Example 39: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(2-methoxynaphthalen-1-yl)quinazolin-4(3H)-one (IA39): The preparation method was the same as that of IA38, except that 2-methoxynaphthalene-1-boronic acid pinacol ester was used instead of 2-fluoropyridine-4-boronic acid pinacol ester. White solid, yield 62%, 11H NMR (DMSO, 400 MHz) δ 10.86 (1H, s), 8.07 (1H, d, J = 13.6 Hz), 7.94 (1H, d, J = 9.2 Hz), 7.84 (1H, d, J = 6.3 Hz), 7.67 (2H, q, J = 7.3 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 9.2 Hz), 7.32 (1H, d, J = 8.1 Hz), 7.28 (3H, d, J = 3.2 Hz), 7.11 (1H, s), 7.02 (1H, t, J = 7.6 Hz), 6.91 (1H, t, J = 7.5 Hz), 4.22 (2H, t, J = 7.3 Hz), 3.73 (3H, s), 3.10 (2H, t, J = 7.4 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.7, 154.2, 148.4, 147.5, 137.6, 136.8, 135.2, 133.1, 130.3, 129.0, 128.6, 128.3, 127.6, 127.5, 127.3, 124.5, 124.0, 123.9, 123.1, 122.0, 121.6, 119.0, 118.8, 114.3, 112.0, 110.7, 56.8, 47.3, 25.1. HRMS-ESI: m / z calced for C 29 H 23 N3O2 [M + H] + 446.1864, found 446.1870.

[0099] Example 40: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(1H-pyrazol-3-yl)quinazolin-4(3H)-one (IA40): The preparation method was the same as that of IA39, except that 1H-pyrazole-3-boronic acid pinacol ester was used instead of 2-methoxynaphthalene-1-boronic acid pinacol ester. White solid, yield 33%, 1 1H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.61 (1H, d, J = 2.1 Hz), 8.28 (1H, d, J = 8.0 Hz), 8.07 (1H, s), 7.86 (1H, s), 7.66 (1H, d, J = 8.3 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.5 Hz), 6.89 (1H, s), 4.28 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz);13 13C NMR (DMSO, 100 MHz) δ 160.8, 149.5, 148.0, 147.6, 136.7, 132.9, 131.7, 130.8, 128.0, 127.5, 123.9, 122.3, 122.1, 121.6, 118.9, 118.7, 112.0, 110.7, 102.7, 47.3, 24.9. HRMS-ESI: m / z calced for C 21 H 17 N5O [M+H] + 356.1506, found 356.1499.

[0100] Example 41: Preparation of 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)cyclohex-3-ene-1-carboxylate (IA41): The preparation method was the same as that of IA40, except that 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was used instead of 1H-pyrazole-3-boronic acid pinacol ester. White solid, yield 70%, 1 1H NMR (DMSO, 600 MHz) δ 10.88 (1H, s), 8.11 (1H, s), 8.05 (1H, s), 7.91 (1H, d, J = 8.5 Hz), 7.61 (1H, d, J = 7.9 Hz), 7.56 (1H, d, J = 8.5 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.12 (1H, s), 7.07 (1H, t, J = 8.1 Hz), 6.96 (1H, t, J = 7.4 Hz), 6.34 (1H, s), 4.24 (2H, t, J = 7.4 Hz), 3.65 (3H, s), 3.12 (2H, t, J = 7.4 Hz), 2.65 (1H, d, J = 11.3 Hz), 2.53 (2H, d, J = 5.6 Hz), 2.47 (1H, s), 2.43–2.31 (1H, m), 2.16–2.09 (1H, m), 1.82–1.69 (1H, m); 13 13C NMR (DMSO, 150 MHz) δ 175.6, 160.7, 148.0, 147.3, 139.7, 136.7, 134.7, 131.2, 127.6, 127.5, 124.6, 123.8, 121.8, 121.6, 121.4, 118.9, 118.7, 112.0, 110.6, 52.0, 47.2, 38.3, 28.3, 26.2, 25.6, 24.9. HRMS-ESI: m / z calced for C 26 H 25N3O3[M+H] + 428.1969, found 428.1965.

[0101] Example 42: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)quinazolin-4(3H)-one (IA42): The preparation method was the same as that of IA41, except that 3,6-dihydro-2H-thiopyran-4-ylboronic acid pinacol ester was used instead of 1-methyl-1,2,3,6-tetrahydropyridin-4-ylboronic acid pinacol ester. White solid, yield 68%, 1 1H NMR (DMSO, 600 MHz) δ 10.87 (1H, s), 8.15 (1H, d, J = 2.4 Hz), 8.06 (1H, s), 7.96 (1H, s), 7.63 (1H, d, J = 7.8 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.36 (1H, s), 7.13 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.0 Hz), 6.97 (1H, t, J = 7.4 Hz), 6.46 (1H, s), 4.29–4.23 (4H, m), 3.86 (2H, t, J = 5.4 Hz), 3.14 (2H, t, J = 7.3 Hz), 2.54 (2H, dq, J = 5.4, 2.6 Hz); 13 13C NMR (DMSO, 150 MHz) δ 160.7, 148.1, 147.6, 138.4, 136.7, 132.5, 130.9, 127.7, 127.5, 124.9, 123.8, 122.0, 121.6, 121.3, 118.9, 118.7, 112.0, 110.6, 65.6, 64.1, 47.3, 26.7, 24.9. HRMS-ESI: m / z calced for C 23 H 21 N3O2[M+H] + 372.1707, found 372.1707.

[0102] Example 43: Preparation of 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N-(3-hydroxypropyl)-N-methylbenzamide (IA43)

[0103] Weigh compound IA10 (204 mg, 0.5 mmol) into a reaction flask, add 4 mL of DCM, and successively add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (143 mg, 0.75 mmol), triethylamine (174 μL, 1.25 mmol), and 3-(methylamino)-1-propanol (66.8 mg, 0.75 mmol); react overnight at room temperature; after detecting the completion of the reaction by TLC, dilute the reaction solution with dichloromethane / methanol (10:1) and wash it with saturated brine; evaporate the solvent under reduced pressure, and perform column separation using a dichloromethane / methanol system to obtain compound IA43, a white solid, with a yield of 61%. 1 H NMR (DMSO, 600 MHz) δ 8.45 (1H, d, J = 2.3 Hz), 8.16 (1H, dd, J = 8.5, 2.3 Hz), 8.12 (1H, s), 7.84 (2H, d, J = 7.8 Hz), 7.73 (1H, d, J = 8.5 Hz), 7.65 (1H, d, J = 7.9 Hz), 7.56–7.49 (2H, m), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.3 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.4 Hz), 4.49 (1H, s), 4.28 (2H, t, J = 7.3 Hz), 3.58–3.49 (2H, m), 3.32 (2H, d, J = 6.9 Hz), 3.16 (2H, t, J = 7.3 Hz), 2.97 (3H, d, J = 22.1 Hz), 1.73 (2H, dt, J = 44.9, 7.1 Hz); 13 C NMR (DMSO, 150 MHz) δ 170.7, 170.1, 160.7, 148.6, 147.9, 140.0, 139.8, 138.2, 136.7, 136.6, 133.2, 128.4, 128.2, 128.0, 127.5, 127.2, 124.0, 123.9, 122.4, 121.6, 118.9, 118.8, 112.0, 110.6, 59.0, 58.5, 55.4, 48.6, 44.8, 37.7, 32.8, 31.5, 30.4. HRMS-ESI: m / z calced for C 23 H 21 N3O2 [M + H] + 372.1707, found 372.1707.

[0104] Example 44: Preparation of 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-N,N-dimethylbenzamide (IA44): The preparation method was the same as that of IA43, except that dimethylamine hydrochloride was used instead of 3-(methylamino)-1-propanol. White solid, yield 30%, 1 H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.46 (1H, d, J = 2.2 Hz), 8.16 (1H, dd, J = 8.5, 2.3 Hz), 8.12 (1H, s), 7.85 (2H, d, J = 8.4 Hz), 7.73 (1H, d, J = 8.6 Hz), 7.65 (1H, d, J = 7.8 Hz), 7.55 (2H, d, J = 8.4 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.5 Hz), 7.09 (1H, t, J = 6.9 Hz), 6.98 (1H, t, J = 6.9 Hz), 4.29 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz), 3.02 (3H, s), 2.97 (3H, s); 13 C NMR (DMSO, 100 MHz) δ 170.2, 160.7, 148.6, 148.0, 140.1, 138.2, 136.8, 136.3, 133.2, 128.4, 128.4, 127.5, 127.2, 124.0, 123.9, 122.4, 121.6, 118.9, 118.8, 112.0, 110.6, 47.3, 39.5, 35.3, 24.9. HRMS-ESI: m / z calcedfor C 27 H 24 N4O2 [M + H] + 437.1973, found 437.1978.

[0105] Example 45: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-azepane-1-carbonyl)phenyl)quinazolin-4(3H)-one (IA45): The preparation method was the same as that of IA44, except that cyclohexylamine was used instead of dimethylamine hydrochloride. White solid, yield 70%, 11H NMR (DMSO, 600 MHz) δ 10.90 (1H, s), 8.46 (1H, d, J = 2.2 Hz), 8.18 (1H, dt, J = 8.5, 2.0 Hz), 8.13 (1H, s), 7.88–7.83 (2H, m), 7.74–7.70 (1H, m), 7.68 (1H, dt, J = 5.4, 3.4 Hz), 7.53–7.47 (2H, m), 7.35 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.4 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.4 Hz), 4.29 (2H, t, J = 7.3 Hz), 4.18–4.09 (4H, m), 3.16 (2H, t, J = 7.3 Hz), 1.62 (4H, q, J = 6.2 Hz), 1.35 (4H, td, J = 7.2, 3.3 Hz); 13 13C NMR (DMSO, 150 MHz) δ 170.3, 167.5, 160.7, 148.6, 147.9, 139.6, 138.2, 137.3, 136.7, 133.2, 132.2, 132.1, 129.1, 128.5, 127.7, 127.5, 127.3, 124.0, 123.9, 122.4, 121.6, 118.9, 118.8, 112.0, 110.6, 49.6, 47.3, 45.9, 30.2, 29.3, 28.8, 27.7, 27.3, 26.3, 24.9, 23.7, 22.9. HRMS-ESI: m / z calced for C 31 H 30 N4O2 [M+H] + 491.2442, found 491.2447.

[0106] Example 46: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(4-(4-methylpiperazine-1-carbonyl)phenyl)quinazolin-4(3H)-one (IA46): The preparation method was the same as that of IA45, except that N-methylpiperazine was used instead of cyclohexylimine. White solid, yield 32%, 11H NMR (DMSO, 400 MHz) δ 10.90 (1H, s), 8.45 (1H, s), 8.16 (1H, dd, J = 8.6, 2.3 Hz), 8.13 (1H, s), 7.86 (2H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.4 Hz), 7.65 (1H, d, J = 7.9 Hz), 7.53 (2H, d, J = 8.2 Hz), 7.35 (1H, s), 7.15 (1H, s), 7.09 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.4 Hz), 4.29 (2H, t, J = 7.3 Hz), 3.64 (4H, d, J = 27.0 Hz), 3.16 (2H, t, J = 7.4 Hz), 2.34 (4H, d, J = 27.0 Hz), 2.21 (3H, s); 13 13C NMR (DMSO, 100 MHz) δ 169.1, 160.7, 148.6, 148.0, 140.2, 138.2, 136.7, 135.8, 133.2, 128.5, 128.3, 127.5, 127.3, 124.1, 123.9, 122.4, 121.6, 118.9, 118.8, 112.0, 110.6, 47.3, 46.1, 24.9. HRMS-ESI: m / z calcd for C 30 H 29 N5O2 [M + H] + 492.2395, found 492.2392.

[0107] Example 47: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(benzo[d][1,3]dioxol-5-yl)pyrimido[2,3-d]pyrimidin-4(3H)-one (IB01):

[0108] Weigh 2-amino-5-bromonicotinic acid 4 (2.1 g, 10 mmol) into a reaction flask, add 20 mL of DCM to dissolve it, and successively add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g, 15 mmol) and tryptamine (1.6 g, 10 mmol); react overnight at room temperature; after the reaction is completed, pour the reaction solution into water; filter the precipitate and wash it with a large amount of water to obtain intermediate 5; dissolve intermediate 5 (1.8 g, 0.5 mmol) in triethyl orthoformate, stir at 90 °C for about 0.5 h, and detect the completion of the reaction by TLC; remove triethyl orthoformate under reduced pressure, add anhydrous dichloromethane to the evaporated fraction, slowly add phosphorus pentoxide (2.1 g, 15 mmol), reflux at 50 °C for 20 minutes, after the reaction is completed, dilute it with a solution of dichloromethane / methanol (10:1), wash it successively with saturated sodium bicarbonate solution and saturated brine, evaporate the organic phase under reduced pressure, and dry it to obtain intermediate 6 without further purification 1 H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 9.05 (1H, d, J = 2.6 Hz), 8.71 (1H, d, J = 2.6 Hz), 8.31 (1H, s), 7.58 (1H, d, J = 7.7 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.07 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 6.96 (1H, ddd, J = 8.0, 7.0, 1.0 Hz), 4.26 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.2 Hz); 13 C NMR (DMSO, 100 MHz) δ 160.3, 156.9, 151.9, 137.9, 136.7, 127.4, 124.0, 121.6, 118.9, 118.6, 118.5, 117.9, 112.0, 110.3, 47.6, 24.6.

[0109] (7) Place intermediate 6 (184 mg, 0.5 mmol) in a 25 ml round-bottom flask, add 3,4-(methylenedioxy)phenylboronic acid (123 mg, 0.75 mmol), dioxane (5 mL), add 1.5 mL of 1 M cesium carbonate solution, and add the catalyst 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (0.05 mmol, 36 mg) under nitrogen protection, and react at 90 °C overnight. After the reaction, evaporate the reaction solution to dryness, dissolve it with a mixed solution of dichloromethane and methanol (v / v = 10:1, 100 mL), filter off the insoluble salts with a suction funnel, and separate and purify it by column chromatography (dichloromethane:methanol = 60:1) to obtain compound IB01. White solid, yield 70%, 11H NMR (DMSO, 400 MHz) δ 10.91 (1H, s), 9.22 (1H, dd, J = 2.7, 1.4 Hz), 8.66 (1H, dd, J = 2.8, 1.4 Hz), 8.27 (1H, d, J = 1.4 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.49 (1H, s), 7.39–7.31 (2H, m), 7.15 (1H, s), 7.13–7.04 (2H, m), 6.97 (1H, t, J = 7.5 Hz), 6.11 (2H, s), 4.28 (2H, t, J = 7.3 Hz), 3.16 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 161.3, 157.1, 154.3, 151.0, 148.8, 148.3, 136.7, 134.4, 132.4, 130.3, 127.4, 123.9, 121.6, 121.6, 118.9, 118.7, 116.9, 112.0, 110.5, 109.5, 107.8, 101.9, 47.4, 24.8. HRMS-ESI: m / z calcd for C 24 H 18 N4O3 [M+H] + 411.1452, found 411.1448.

[0110] Example 48: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(6-methoxypyridin-3-yl)pyrimido[2,3-d]pyrimidin-4(3H)-one (IB02): The preparation method was the same as that of IB01, except that 6-methoxypyridine-3-boronic acid pinacol ester was used instead of 3,4-(methylenedioxy)phenylboronic acid. White solid, yield 73%, 1 1H NMR (DMSO, 600 MHz) δ 10.89 (1H, s), 9.29 (1H, d, J = 2.6 Hz), 8.76 (1H, s), 8.69 (1H, s), 8.30 (1H, s), 8.24 (1H, d, J = 8.6 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.15 (1H, d, J = 2.5 Hz), 7.08 (1H, t, J = 7.5 Hz), 6.98 (2H, dd, J = 8.0, 4.0 Hz), 4.29 (2H, t, J = 7.3 Hz), 3.93 (3H, s), 3.16 (2H, t, J = 7.4 Hz); 13CNMR (DMSO, 150 MHz) δ 164.2, 161.3, 157.4, 154.2, 151.3, 145.9, 138.4, 136.8, 132.6, 131.8, 127.5, 125.8, 123.9, 121.6, 118.9, 118.7, 117.1, 112.0, 111.4, 110.5, 53.9, 47.5, 24.8. HRMS-ESI: m / z calced for C 23 H 19 N5O2 [M+H] + 398.1612, found 398.1616.

[0111] Example 49: Preparation of 4-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl)cyclohex-3-ene-1-carboxylate (IB03): The preparation method was the same as that of IB02, except that 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was used instead of 6-methoxypyridine-3-boronic acid pinacol, and the yield was 66%. 1 H NMR (DMSO, 600 MHz) δ 10.90 (1H, s), 9.08 (2H, d, J = 2.7 Hz), 8.41 (2H, d, J = 2.6 Hz), 8.24 (2H, s), 7.60 (2H, d, J = 7.9 Hz), 7.35 (2H, dt, J = 8.1, 0.9 Hz), 7.14 (2H, d, J = 2.4 Hz), 7.07 (2H, ddd, J = 8.0, 6.9, 1.1 Hz), 6.96 (2H, ddd, J = 7.9, 7.0, 1.0 Hz), 6.49 (2H, ddt, J = 5.1, 3.3, 1.6 Hz), 4.26 (4H, t, J = 7.3 Hz), 3.66 (6H, s), 3.14 (5H, t, J = 7.3 Hz), 2.68 (2H, dtt, J = 12.5, 5.4, 3.2 Hz), 2.55 (5H, tt, J = 5.8, 2.7 Hz), 2.40 (2H, ddq, J = 18.4, 9.3, 3.0 Hz), 2.17–2.10 (2H, m), 1.76 (2H, ddt, J = 12.8, 10.9, 7.8 Hz); 1313C NMR (DMSO, 150 MHz) δ 175.5, 161.3, 157.0, 153.1, 150.8, 136.7, 135.2, 132.4, 130.3, 127.4, 126.1, 123.9, 121.6, 118.9, 118.7, 116.5, 112.0, 110.5, 74.0, 52.1, 47.4, 38.1, 28.2, 25.8, 25.4, 25.4, 24.7. HRMS-ESI: m / z calced for C 25 H 24 N4O3 [M+H] + 429.1922, found 429.1918.

[0112] Example 50: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzamide (IC01)

[0113] Take nitroisatoic anhydride 7 (6.24 g, 30 mmol) and tryptamine (4.8 g, 30 mmol) in 150 mL of ethanol, and reflux at heating for 3 h. Monitor the reaction progress by TLC, concentrate after cooling, and recrystallize in ethanol to obtain 9 g of a yellow solid compound 8. Add 150 mL of triethyl orthoformate, reflux at 115 °C for 4 h. After complete reaction, distill off the solvent, and perform flash column purification using a silica gel column, eluting the product with PE:EA = 1:2 to obtain 5 g of a beige compound 9.

[0114] Take compound 9 (3.34 g, 10 mmol) in a 250 mL single-necked round-bottom flask, add 80 mL of ethanol and 20 mL of water. Then slowly add Fe powder (2.79 g, 50 mmol) and NH4Cl (5.35 g, 100 mmol) and reflux for 3 h. Monitor the reaction progress by TLC, filter the supernatant after cooling, extract the supernatant with DCM (3 × 50 mL), wash with 100 mL of saturated brine, dry over anhydrous Na2SO4, spin-dry and column-chromatograph, DCM:EA = 5:1, to obtain 2.5 g of a light brown solid compound 10, with a yield of 72%.

[0115] Compound 10 (200 mg, 0.66 mmol) was taken in a 25 mL single-necked round-bottom flask, and 10 mL of DCM was added and stirred. Then, N,N-diisopropylethylamine (300 μL, 1.65 mmol) was added dropwise to the solution, and benzoyl chloride (91 μL, 0.79 mmol) was slowly added dropwise under an ice bath until the solution became clear. The solution was stirred overnight until it became turbid. After detecting the completion of the reaction by TLC, at 25 °C, 20 mL of DCM was added, and the mixture was washed successively with 0.1 M HCl, 10% NaHCO3 and water, dried over anhydrous Na2SO4, and then an impure crude product was obtained from the organic phase. It was purified using a silica gel column, and the product was eluted with DCM:EA:MeOH = 25:5:1 to obtain a pale yellow solid compound with a yield of 78%. 1 H NMR (DMSO, 400 MHz) δ 10.86 (1H, s), 10.60 (1H, s), 8.73 (1H, s), 8.25–8.16 (1H, m), 8.02 (3H, d, J = 6.7 Hz), 7.59 (5H, dt, J = 25.4, 8.4 Hz), 7.35 (1H, dd, J = 7.7, 3.1 Hz), 7.13 (1H, s), 7.08 (1H, t, J = 7.4 Hz), 6.97 (1H, t, J = 7.4 Hz), 4.27 (2H, t, J = 6.8 Hz), 3.15 (2H, t, J = 6.7 Hz); 13 C NMR (DMSO, 100 MHz) δ 165.8, 160.1, 146.6, 144.1, 137.9, 136.3, 134.6, 131.8, 128.5, 127.8, 127.6, 127.0, 126.9, 123.4, 121.8, 121.1, 118.4, 118.3, 115.7, 111.5, 110.2, 46.8, 24.4. HRMS-ESI: m / z calced for C25H20N4O2 [M+H] + 409.1660, found 409.1654.

[0116] Example 51: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-phenylacetamide (IC02): The preparation method was the same as that of IC01, except that phenylacetyl chloride was used instead of benzoyl chloride, and the yield was 74%. 11H NMR (DMSO, 400 MHz) δ 10.86 (s, 1H), 10.56 (s, 1H), 8.52 (s, 1H), 7.97 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 3.0 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H), 7.34 (q, J = 7.5 Hz, 6H), 7.28–7.22 (m, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 6.95 (t, J = 7.3 Hz, 1H), 4.23 (t, J = 7.2 Hz, 2H), 3.69 (s, 2H), 3.11 (t, J = 7.2 Hz, 3H). 13 13C NMR (DMSO, 100 MHz) δ 169.5, 160.1, 146.5, 143.8, 137.9, 136.3, 135.8, 129.2, 128.4, 127.8, 127.0, 126.7, 125.8, 123.4, 121.9, 121.1, 118.5, 118.3, 114.4, 111.5, 110.2, 46.8, 43.4, 40.1, 24.4. HRMS-ESI: m / z calced for C 26 H 22 N4O2 [M + H] + 423.1816, found 423.1821.

[0117] Example 52: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)cinnamamide (IC03): The preparation method was the same as that of IC02, except that cinnamoyl chloride was used instead of phenylacetyl chloride, and the yield was 80%. 1 1H NMR (DMSO, 400 MHz) δ 10.88 (1H, s), 10.64 (1H, s), 8.66 (1H, s), 8.04 (1H, dd, J = 8.8, 2.4 Hz), 8.01 (1H, s), 7.69–7.59 (5H, m), 7.50–7.41 (3H, m), 7.34 (1H, d, J = 8.1 Hz), 7.13 (1H, d, J = 1.9 Hz), 7.07 (1H, t, J = 7.4 Hz), 6.97 (1H, t, J = 7.4 Hz), 6.87 (1H, d, J = 15.8 Hz), 4.25 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.1 Hz); 1313C NMR (DMSO, 100 MHz) δ 163.8, 160.1, 146.6, 144.0, 140.7, 138.0, 136.3, 134.6, 130.0, 129.1, 127.9, 127.9, 127.0, 125.9, 123.4, 122.0, 121.9, 121.1, 118.5, 118.3, 114.6, 111.5, 110.2, 46.8, 24.5. HRMS-ESI: m / z calced for C 27 H 22 N4O2 [M+H] + 435.1816, found 435.1820.

[0118] Example 53: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)cyclohexanecarboxamide (IC04): The preparation method was the same as that of IC03, except that cyclohexanecarbonyl chloride was used instead of cinnamoyl chloride, and the yield was 62%. 1 1H NMR (DMSO, 500 MHz) δ 10.73 (s, 1H), 10.07 (s, 1H), 8.41 (s, 1H), 7.82 (s, 2H), 7.79 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 6.97 (s, 1H), 6.93 (t, J = 7.6 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 4.09 (t, J = 7.3 Hz, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.23 (t, J = 11.5 Hz, 2H), 1.66 (dd, J = 31.9, 12.5 Hz, 5H), 1.52 (d, J = 12.0 Hz, 1H), 1.35–1.24 (m, 2H), 1.12 (dq, J = 25.3, 12.1 Hz, 5H). 13 13C NMR (DMSO, 125 MHz) δ 174.8, 160.2, 146.4, 143.7, 138.2, 136.3, 127.7, 127.1, 126.0, 123.4, 121.9, 121.2, 118.5, 118.3, 114.4, 111.6, 110.3, 46.8, 45.0, 29.2, 25.5, 24.5. HRMS-ESI: m / z calced for C 25 H 26 N4O2 [M+H] + 415.2129, found 415.2124.

[0119] Example 54: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pivalamide (IC05): The preparation method was the same as that of IC04, except that pivaloyl chloride was used instead of cyclohexanecarbonyl chloride, and the yield was 74%. 1 H NMR (DMSO, 400 MHz) δ 10.86 (1H, s), 9.56 (1H, s), 8.56 (1H, d, J = 1.9 Hz), 8.10 (1H, dd, J = 8.8, 2.0 Hz), 7.97 (1H, s), 7.64–7.50 (2H, m), 7.35 (1H, d, J = 8.0 Hz), 7.12 (1H, s), 7.07 (1H, t, J = 7.5 Hz), 6.96 (1H, t, J = 7.4 Hz), 4.26 (2H, t, J = 7.0 Hz), 3.14 (2H, t, J = 7.0 Hz), 1.27 (9H, s) 13 C NMR (DMSO, 100 MHz) δ 176.8, 160.1, 146.4, 143.8, 138.1, 136.3, 127.3, 127.0, 126.8, 123.3, 121.7, 121.1, 118.4, 118.2, 115.5, 111.5, 110.2, 46.7, 27.1, 24.4. HRMS-ESI: m / z calcd for C 23 H 24 N4O2 [M+H] + 389.1973, found 389.1979.

[0120] Example 55: Preparation of (E)-N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methylbut-2-enamide (IC06): The preparation method was the same as that of IC05, except that (E)-2-methyl-2-butenoyl chloride was used instead of pivaloyl chloride, and the yield was 72% 1. 1H NMR (DMSO, 500 MHz) δ 10.87 (s, 1H), 10.01 (s, 1H), 8.60 (d, J = 2.7 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.98 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.07 (t, J = 7.4 Hz, 2H), 6.96 (t, J = 7.3 Hz, 2H), 6.52 (q, J = 6.1 Hz, 1H), 4.24 (t, J = 6.9 Hz, 3H), 3.13 (t, J = 6.8 Hz, 3H), 1.87 (s, 3H), 1.80 (d, J = 6.6 Hz, 3H). 13 13C NMR (DMSO, 125 MHz) δ 167.9, 160.1, 146.4, 143.8, 138.1, 136.3, 132.4, 131.0, 127.4, 127.0, 126.7, 123.3, 121.8, 121.1, 118.4, 118.2, 115.3, 111.5, 110.2, 46.7, 24.4, 13.9, 12.5. HRMS-ESI: m / z calced for C 23 H 22 N4O2 [M+H] + 387.1816, found 387.1820.

[0121] Example 56: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)methacrylamide (IC07): The preparation method was the same as that of IC06, except that methacryloyl chloride was used instead of OR(E)-2-methyl-2-butenoyl chloride, and the yield was 58%. 1 1H NMR (DMSO, 600 MHz) δ 10.88 (1H, s), 10.16 (1H, s), 8.10 (1H, dd, J = 8.8, 2.5 Hz), 8.00 (1H, s), 7.60 (2H, t, J = 8.0 Hz), 7.35 (1H, dt, J = 8.3, 0.9 Hz), 7.13 (1H, d, J = 2.3 Hz), 7.08 (1H, ddd, J = 8.1, 7.0, 1.2 Hz), 6.97 (1H, ddd, J = 7.9, 7.0, 1.0 Hz), 5.89 (1H, s), 5.58 (1H, s), 4.25 (2H, t, J = 7.3 Hz), 3.14 (2H, t, J = 7.3 Hz), 1.99 (3H, s); 13CNMR (DMSO, 150 MHz) δ 167.4, 160.6, 147.0, 144.4, 140.6, 138.2, 136.7, 128.0, 127.5, 127.2, 123.8, 122.2, 121.6, 121.0, 118.9, 118.7, 115.9, 111.9, 110.7, 47.2, 24.9, 19.2. HRMS-ESI: m / z calced for C 22 H 20 N4O2[M + H] + 373.1660, found 373.1658.

[0122] Example 57: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)butanamide (IC08): The preparation method was the same as that of IC07, except that n-butyryl chloride was used instead of methacryloyl chloride, and the yield was 64%. 1 H NMR (DMSO, 400 MHz) δ 10.88 (1H, s), 10.28 (1H, s), 8.55 (1H, d, J = 2.5 Hz), 7.97 (1H, s), 7.94 (1H, dd, J = 8.9, 2.5 Hz), 7.60 (1H, d, J = 7.5 Hz), 7.58 (1H, d, J = 8.8 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.12 (1H, d, J = 2.5 Hz), 7.07 (1H, t, J = 7.5 Hz), 6.96 (1H, t, J = 7.5 Hz), 4.24 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.2 Hz), 2.34 (2H, t, J = 7.3 Hz), 1.65 (2H, h, J = 7.4 Hz), 0.94 (3H, t, J = 7.4 Hz); 13 C NMR (DMSO, 100 MHz) δ 172.0, 160.6, 146.8, 144.1, 138.4, 136.7, 128.2, 127.5, 126.3, 123.8, 122.3, 121.6, 118.9, 118.7, 114.7, 111.9, 110.7, 47.2, 38.8, 24.9, 19.0, 14.1. HRMS-ESI: m / z calced for C 22 H 22 N4O2[M + H] + 375.1816, found 375.1811.

[0123] Example 58: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzofuran-2-carboxamide (IC09): The preparation method was the same as that of IC08, except that 1-benzofuran-2-carbonyl chloride was used instead of n-butyryl chloride, and the yield was 69%. 1 H NMR (DMSO, 400 MHz) δ 10.94 (1H, s), 10.91 (1H, s), 8.79 (1H, d, J = 2.5 Hz), 8.24 (1H, dd, J = 8.9, 2.5 Hz), 8.04 (1H, s), 7.88 (1H, s), 7.86 (1H, d, J = 7.6 Hz), 7.76 (1H, d, J = 8.3 Hz), 7.67 (1H, d, J = 8.9 Hz), 7.63 (1H, d, J = 7.9 Hz), 7.54 (1H, ddd, J = 8.5, 7.2, 1.3 Hz), 7.44–7.33 (2H, m), 7.15 (1H, d, J = 2.3 Hz), 7.09 (1H, ddd, J = 8.1, 7.0, 1.2 Hz), 6.99 (1H, ddd, J = 8.0, 7.0, 1.1 Hz), 4.28 (3H, t, J = 7.3 Hz), 3.16 (3H, t, J = 7.2 Hz); 13 C NMR (DMSO, 100 MHz) δ 160.5, 157.3, 155.0, 148.9, 147.3, 144.8, 137.6, 136.7, 128.2, 127.8, 127.6, 127.5, 127.5, 124.4, 123.8, 123.5, 122.3, 121.6, 118.9, 118.7, 116.5, 112.5, 112.0, 111.6, 110.7, 47.3, 24.9. HRMS-ESI: m / z calced for C 27 H 20 N4O3[M + H] + 449.1609, found 449.1614.

[0124] Example 59: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methylbutyramide (IC10): The preparation method was the same as that of IC09, except that 2-methylbutyryl chloride was used instead of 1-benzofuran-2-carbonyl chloride, and the yield was 77%. 11H NMR (DMSO, 600 MHz) δ 10.87 (1H, s), 10.25 (1H, s), 8.57 (1H, d, J = 2.5 Hz), 8.00–7.95 (2H, m), 7.60 (1H, d, J = 7.9 Hz), 7.58 (1H, d, J = 8.8 Hz), 7.35 (1H, dt, J = 8.1, 1.0 Hz), 7.12 (1H, d, J = 2.3 Hz), 7.07 (1H, ddd, J = 8.1, 7.0, 1.2 Hz), 6.97 (1H, ddd, J = 7.9, 6.9, 1.0 Hz), 4.25 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 1.70–1.60 (1H, m), 1.49–1.39 (1H, m), 1.12 (3H, d, J = 6.8 Hz), 0.89 (3H, t, J = 7.4 Hz); 13 13C NMR (DMSO, 150 MHz) δ 175.5, 160.5, 146.8, 144.1, 138.5, 136.7, 128.1, 127.5, 126.4, 123.8, 122.3, 121.5, 118.9, 118.7, 114.9, 111.9, 110.7, 46.0, 42.7, 27.3, 24.9, 17.9, 12.2. HRMS-ESI: m / z calcd for 23 C 24 19H24N4O2 [M + H]+ + 389.1973, found 389.1972.

[0125] Example 60: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)tetrahydro-2H-pyran-4-carboxamide (IC11): The preparation method was the same as that of IC10, except that tetrahydro-2H-pyran-4-carbonyl chloride was used instead of 2-methylbutanoyl chloride, and the yield was 81%. 11H NMR (DMSO, 400 MHz) δ 10.88 (1H, s), 10.29 (1H, s), 8.55 (1H, s), 7.98 (1H, s), 7.96 (1H, d, J = 8.8 Hz), 7.58 (2H, t, J = 8.9 Hz), 7.34 (1H, d, J = 8.2 Hz), 7.12 (1H, d, J = 2.6 Hz), 7.07 (1H, t, J = 7.0 Hz), 6.96 (1H, t, J = 7.5 Hz), 4.24 (2H, t, J = 7.2 Hz), 3.92 (2H, dt, J = 11.5, 2.6 Hz), 3.42–3.31 (2H, m), 3.12 (2H, t, J = 7.2 Hz), 2.64 (1H, tt, J = 10.3, 4.7 Hz), 1.78–1.61 (4H, m); 13 13C NMR (DMSO, 100 MHz) δ 173.5, 160.3, 146.7, 143.9, 138.2, 136.5, 127.9, 127.2, 126.1, 123.6, 122.1, 121.3, 118.7, 118.5, 114.6, 111.7, 110.4, 66.6, 47.0, 42.0, 29.0, 24.7. HRMS-ESI: m / z calced for C 24 H 24 N4O3 [M + H] + 417.1922, found 417.1926.

[0126] Example 61: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-4-methoxybenzamide (IC12): The preparation method was the same as that of IC11, except that 4-methoxybenzoyl chloride was used instead of tetrahydropyran-4-carbonyl chloride, and the yield was 59%. 1 1H NMR (DMSO, 400 MHz) δ 10.89 (1H, d, J = 2.4 Hz), 10.47 (1H, s), 8.71 (1H, d, J = 2.4 Hz), 8.21 (1H, dd, J = 8.9, 2.5 Hz), 8.07–7.97 (3H, m), 7.63 (2H, dd, J = 8.4, 3.7 Hz), 7.36 (1H, dt, J = 8.2, 0.9 Hz), 7.16–7.05 (4H, m), 6.98 (1H, ddd, J = 7.9, 7.0, 1.1 Hz), 4.27 (2H, t, J = 7.2 Hz), 3.86 (3H, s), 3.15 (2H, t, J = 7.2 Hz); 1313C NMR (DMSO, 100 MHz) δ 165.6, 162.6, 160.6, 147.0, 144.4, 138.6, 136.7, 130.2, 128.0, 127.5, 127.4, 127.0, 123.8, 122.3, 121.6, 118.9, 118.7, 116.1, 114.2, 112.0, 110.7, 55.9, 47.2, 24.9. HRMS-ESI: m / z calcd for C 26 H 22 N4O3 [M+H] + 439.1765, found 439.1769.

[0127] Example 62: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3,4,5-trimethoxybenzamide (IC13): The preparation method was the same as that of IC12, except that 4-methoxybenzoyl chloride was used instead of 3,4,5-trimethoxybenzoyl chloride, and the yield was 65%. 1 1H NMR (DMSO, 400 MHz) δ 10.91 (1H, s), 10.53 (1H, s), 8.66 (1H, d, J = 2.5 Hz), 8.24 (1H, dd, J = 8.9, 2.5 Hz), 8.03 (1H, s), 7.65 (1H, d, J = 8.8 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.35 (3H, d, J = 8.4 Hz), 7.15 (1H, s), 7.08 (1H, t, J = 7.5 Hz), 6.97 (1H, t, J = 7.4 Hz), 4.27 (2H, t, J = 7.3 Hz), 3.90 (6H, s), 3.75 (3H, s), 3.15 (2H, t, J = 7.2 Hz); 13 13C NMR (DMSO, 100 MHz) δ 165.5, 160.6, 153.1, 147.2, 144.6, 140.9, 138.3, 136.7, 130.1, 128.0, 127.6, 127.5, 123.8, 122.3, 121.6, 118.9, 118.7, 116.4, 112.0, 110.7, 105.9, 60.6, 56.6, 47.2, 24.9. HRMS-ESI: m / z calcd for C 28 H 26 N4O5 [M+H] + 499.1976, found 499.1971.

[0128] Example 63: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-methylbenzamide (IC14): The preparation method was the same as that of IC13, except that 3-methylbenzoyl chloride was used instead of 4-methoxybenzoyl chloride, and the yield was 74%. 1 H NMR (DMSO, 400 MHz) δ 10.86 (1H, d, J = 2.3 Hz), 10.55 (1H, s), 8.72 (1H, d, J = 2.5 Hz), 8.20 (1H, dd, J = 8.9, 2.5 Hz), 8.01 (1H, s), 7.86–7.77 (2H, m), 7.63 (2H, dd, J = 8.4, 6.4 Hz), 7.47–7.40 (2H, m), 7.35 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 2.3 Hz), 7.08 (1H, t, J = 7.3 Hz), 6.97 (1H, t, J = 7.4 Hz), 4.27 (2H, t, J = 7.2 Hz), 3.15 (2H, t, J = 7.2 Hz), 2.42 (3H, s); 13 C NMR (DMSO, 100 MHz) δ 165.8, 160.1, 146.6, 144.1, 137.9, 137.8, 136.3, 134.6, 132.4, 128.3, 128.2, 127.6, 127.0, 126.9, 124.9, 123.3, 121.8, 121.1, 118.4, 118.3, 115.7, 111.5, 110.2, 46.8, 24.4, 21.0. HRMS-ESI: m / z calced for C 26 H 22 N4O2[M + H] + 423.1816, found 423.1812.

[0129] Example 64: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)nicotinamide (IC15): The preparation method was the same as that of IC14, except that nicotinoyl chloride hydrochloride was used instead of 3-methylbenzoyl chloride, and the yield was 71%. 11H NMR (DMSO, 500 MHz) δ 10.87 (s, 1H), 10.80 (s, 1H), 9.15 (s, 1H), 8.79–8.75 (m, 1H), 8.71 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.59 (t, J = 6.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 4.26 (t, J = 6.8 Hz, 2H), 3.14 (t, J = 7.2 Hz, 2H). 13 13C NMR (DMSO, 125 MHz) δ 164.4, 160.2, 152.4, 148.8, 146.9, 144.4, 137.6, 136.4, 135.7, 130.4, 127.8, 127.1, 127.1, 123.7, 123.5, 122.0, 121.2, 118.6, 118.3, 116.0, 111.6, 110.3, 47.0, 24.5. HRMS-ESI: m / z calced for C 24 H 19 N5O2 [M+H] + 410.1612, found 410.1614.

[0130] Example 65: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)furan-2-carboxamide (IC16): The preparation method was the same as that of IC15, except that 2-furoyl chloride was used instead of nicotinic acid hydrochloride, and the yield was 66%. 1 1H NMR (DMSO, 500 MHz) δ 10.88 (1H, d, J = 2.4 Hz), 10.57 (1H, s), 8.69 (1H, s), 8.17 (1H, d, J = 11.2 Hz), 7.99 (2H, d, J = 13.5 Hz), 7.62 (2H, dd, J = 8.3, 4.5 Hz), 7.42 (1H, d, J = 3.4 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.13 (1H, s), 7.07 (1H, t, J = 7.5 Hz), 6.97 (1H, t, J = 7.4 Hz), 6.74 (1H, s), 4.26 (2H, t, J = 7.2 Hz), 3.14 (2H, t, J = 7.2 Hz). 1313C NMR (DMSO, 125 MHz) δ 160.1, 156.4, 147.2, 146.7, 146.0, 144.2, 137.3, 136.3, 127.7, 127.0, 126.9, 123.4, 121.9, 121.1, 118.5, 118.3, 115.7, 115.2, 112.3, 111.5, 110.2, 46.8, 24.5. HRMS-ESI: m / z calcd for C 23 H 18 N4O3 [M+H] + 399.1452, found 399.1457.

[0131] Example 66: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-methoxybenzamide (IC17): The preparation method was the same as that of IC16, except that 2-methoxybenzoyl chloride was used instead of 2-furoyl chloride, and the yield was 74%. 1 1H NMR (DMSO, 400 MHz) δ 10.88 (1H, s), 10.48 (1H, s), 8.72 (1H, s), 8.06 (1H, d, J = 9.1 Hz), 8.01 (1H, s), 7.63 (3H, dd, J = 14.8, 7.9 Hz), 7.52 (1H, t, J = 7.9 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.19 (1H, d, J = 8.4 Hz), 7.13 (1H, s), 7.08 (2H, td, J = 7.7, 3.6 Hz), 6.97 (1H, t, J = 7.5 Hz), 4.26 (2H, t, J = 7.2 Hz), 3.91 (3H, s), 3.14 (2H, t, J = 7.2 Hz); 13 13C NMR (DMSO, 101 MHz) δ 164.9, 160.1, 156.5, 146.6, 144.1, 137.7, 136.3, 132.2, 129.7, 127.7, 127.1, 126.5, 124.9, 123.4, 121.9, 121.1, 120.5, 118.5, 118.3, 115.1, 112.0, 111.5, 110.2, 55.9, 46.8, 24.5. HRMS-ESI: m / z calcd for C 26 H 22 N4O3 [M+H] + 439.1765, found 439.1759.

[0132] Example 67: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-2-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)-3,5-dimethylbenzamide (IC18)

[0133] Weigh 7 (5.2 g, 24.98 mmol) of the initial compound 5-nitroisatoic anhydride and dissolve it in anhydrous pyridine solution (100 mL). At room temperature, slowly add trifluoroacetic anhydride solution (3.7 mL, 37.47 mmol) diluted with anhydrous pyridine (4 mL) to the solution. Stir the reaction at room temperature for 1 hour, then heat it under reflux for 1 hour. Add tryptamine (4.0 g, 24.98 mmol) and reflux for 1 hour. Monitor the reaction progress by TLC. After the reaction is completed, cool the solution to room temperature and pour it into 500 mL of ice water. Let it stand for 1 hour to form a precipitate, filter and dry it to obtain the target compound 11.

[0134] Accurately weigh the intermediate compound 11 (3.3 g, 10 mmol) into a 250 mL round-bottom flask, and add 80 mL of a mixed solvent (ethanol: water = 4:1). Add ammonium chloride (5.3 g, 100 mmol) and iron powder (2.8 g, 50 mmol) in sequence, and reflux the reaction at 80 °C for 3 h. After the reaction is complete, dilute it with 150 mL of dichloromethane / methanol solution (10:1), filter off the insoluble matter with diatomaceous earth, wash the filtrate with saturated brine, collect the organic phase, dry it with anhydrous sodium sulfate, and separate and purify it by column chromatography (dichloromethane: methanol = 30:1) to obtain the intermediate 12. 1 H NMR (DMSO, 400 MHz) δ 10.97 (1H, s), 7.68 (1H, d, J = 7.8 Hz), 7.56 (1H, d, J = 8.6 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.32 (1H, d, J = 2.6 Hz), 7.25 (1H, s), 7.18 (1H, dd, J = 8.7, 2.7 Hz), 7.10 (1H, t, J = 7.5 Hz), 7.03 (1H, t, J = 7.4 Hz), 4.34–4.17 (1H, m), 3.18–2.99 (2H, m); 13 C NMR (DMSO, 100 MHz) δ 160.6, 150.6, 136.3, 136.0, 134.9, 129.5, 127.0, 123.2, 123.1, 122.5, 121.2, 120.1, 118.6, 118.2, 117.4, 111.6, 110.3, 106.2, 45.5, 24.3.

[0135] Compound 10 (245 mg, 0.66 mmol) was taken and stirred in 5 mL of DCM. Then, N,N-diisopropylethylamine (300 μL, 1.65 mmol) was added dropwise to the solution, and 3,5-dimethylbenzoyl chloride (116 μL, 0.79 mmol) was slowly added dropwise to the solution under an ice bath until the solution became clear. The solution was stirred overnight until it became turbid. After the reaction was detected to be complete by TLC, at 25 °C, 20 mL of DCM was added, and the mixture was washed successively with 0.1 M HCl, 10% NaHCO3, and water, dried over anhydrous Na2SO4, and then the organic phase gave an impure crude product. Purification using a silica gel column, eluting the product with DCM:EA:MeOH = 25:5:1, gave a pale yellow solid compound with a yield of 71%. 1 H NMR (DMSO, 400 MHz) δ 11.02 (1H, s), 10.72 (1H, s), 8.85 (1H, s), 8.33 (1H, d, J = 8.8 Hz), 7.85 (1H, d, J = 8.7 Hz), 7.69 (1H, d, J = 7.7 Hz), 7.63 (2H, s), 7.39 (1H, d, J = 8.0 Hz), 7.25 (2H, d, J = 15.0 Hz), 7.10 (1H, t, J = 7.3 Hz), 7.04 (1H, t, J = 7.3 Hz), 4.27 (2H, t, J = 8.3 Hz), 3.12 (2H, t, J = 8.3 Hz), 2.37 (6H, s); 13 C NMR (DMSO, 100 MHz) δ 166.2, 160.7, 140.4, 137.7, 136.4, 134.4, 133.3, 128.8, 127.3, 127.0, 125.6, 123.2, 122.1, 121.2, 118.6, 118.1, 115.6, 111.7, 110.1, 45.8, 24.1, 20.9. HRMS-ESI: m / z calced for C 26 H 22 N4O3 [M + H] + 439.1765, found 439.1759.

[0136] Example 68: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-2-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)-3-bromobenzamide (IC19): The preparation method was the same as that of IC18, except that 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester was used instead of 6-methoxypyridine-3-boronic acid pinacol, and the yield was 64%. 11H NMR (DMSO, 400 MHz) δ 10.99 (1H, s), 10.82 (1H, s), 8.81 (1H, s), 8.29 (1H, d, J = 11.2 Hz), 8.20 (1H, s), 8.00 (1H, d, J = 7.5 Hz), 7.84 (2H, dt, J = 15.2, 8.2 Hz), 7.69 (1H, d, J = 7.7 Hz), 7.58–7.47 (1H, m), 7.38 (1H, d, J = 8.0 Hz), 7.27 (1H, s), 7.10 (1H, t, J = 7.5 Hz), 7.04 (1H, t, J = 7.4 Hz), 4.26 (2H, t, J = 8.4 Hz), 3.12 (2H, t, J = 8.5 Hz); 13 13C NMR (DMSO, 100 MHz) δ 164.4, 160.7, 140.6, 140.0, 136.6, 136.5, 136.4, 134.8, 130.9, 130.8, 130.4, 128.9, 127.4, 127.1, 127.0, 123.3, 122.2, 121.8, 121.3, 119.8, 118.7, 118.2, 117.0, 115.9, 111.7, 110.1, 45.9, 24.1. HRMS-ESI: m / z calcd for C 26 H 22 N4O3 [M+H] + 439.1765, found 439.1759.

[0137] Example 69: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-2-(trifluoromethyl)-3,4-dihydroquinazolin-6-yl)-2,3-dimethoxybenzamide (IC20): The preparation method was the same as that of IC19, except that 2,3-dimethoxybenzoyl chloride was used instead of 3-bromobenzoyl chloride, and the yield was 74%. 11H NMR (DMSO, 600 MHz) δ 10.98 (1H, s), 10.82 (1H, s), 8.86 (1H, d, J = 2.3 Hz), 8.16 (1H, dd, J = 8.9, 2.4 Hz), 7.87 (1H, d, J = 8.7 Hz), 7.69 (1H, d, J = 7.9 Hz), 7.27 (1H, s), 7.24 (1H, d, J = 8.3 Hz), 7.21 (1H, t, J = 7.9 Hz), 7.15 (1H, dd, J = 7.4, 1.8 Hz), 7.11 (1H, t, J = 7.5 Hz), 7.05 (1H, t, J = 7.4 Hz), 4.27 (2H, t, J = 8.4 Hz), 3.88 (3H, s), 3.83 (3H, s), 3.12 (2H, t, J = 8.4 Hz); 13 13C NMR (DMSO, 150 MHz) δ 166.1, 161.2, 153.1, 146.3, 140.9, 140.8, 140.5, 140.5, 136.7, 131.7, 129.5, 127.4, 127.3, 124.9, 123.7, 122.7, 121.7, 120.4, 119.7, 119.1, 118.5, 117.9, 115.5, 115.3, 112.1, 110.5, 61.7, 56.5, 46.3, 24.5.

[0138] Example 70: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)morpholine-4-carboxamide (ID01)

[0139] Weigh compound 10 (200 mg, 0.66 mmol), add 10 mL of THF and stir until completely dissolved. Under ice bath and nitrogen, slowly add triethylamine (274 μL, 1.97 mmol) and thiophosgene CSCl2 (75 μL, 0.98 mmol) to the solution in sequence. Stir the resulting mixture at 60 °C for 3 h, then cool to room temperature. Concentrate, dissolve the residue in ethyl acetate, wash with saturated brine, dry and filter. Concentrate the filtrate to obtain the isothiocyanate of compound 10. Without further purification, add 5 mL of DCM. Add dropwise Et3N (1.65 mmol, 2.5 equiv), and slowly add morpholine (63 μL, 0.72 mmol). Reflux at 60 °C for 8 h. After detecting the completion of the reaction by TLC, quench with water, extract with DCM, wash with saturated brine, and dry. Purify using a silica gel column, elute the product with DCM:EA:MeOH = 25:5:1 to obtain the light yellow solid compound ID01 with a yield of 58%. 11H NMR (CDCl3, 400 MHz) δ 8.42 (1H, d, J = 8.1 Hz), 8.10 (1H, dd, J = 12.6, 4.3 Hz), 7.93 (1H, d, J = 2.5 Hz), 7.80 (1H, dd, J = 8.7, 2.5 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.53 (1H, dd, J = 8.8, 1.4 Hz), 7.44 (1H, s), 7.31 (1H, d, J = 8.1 Hz), 7.17 (1H, t, J = 7.6 Hz), 7.09 (1H, t, J = 7.5 Hz), 6.77 (1H, d, J = 2.7 Hz), 4.24 (2H, t, J = 6.7 Hz), 3.89 (4H, t, J = 4.8 Hz), 3.72 (4H, t, J = 4.7 Hz), 3.19 (2H, t, J = 6.6 Hz); 13 13C NMR (CDCl3, 100 MHz) δ 183.0, 160.9, 146.3, 145.6, 139.2, 136.6, 131.7, 127.8, 126.9, 123.1, 122.4, 122.3, 119.8, 119.6, 118.3, 111.7, 111.0, 66.3, 49.2, 47.5, 25.1. HRMS-ESI: m / z calcd for C 22 H 23 N5O2S [M+H] + 434.1646, found 434.1648.

[0140] Example 71: Preparation of 1-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-phenylthiourea (ID02)

[0141] Weigh intermediate 10 (304 mg, 1 mmol), add 6 mL of dichloromethane, add Et3N (348 μL, 2.5 mmol) and phenyl isothiocyanate (179 μL, 1.5 mmol); react overnight at room temperature; after the reaction is completed, dilute the reaction solution with dichloromethane-methanol (10:1), wash with saturated brine, dry over anhydrous Na2SO4, filter, and evaporate the solvent. Purify using a silica gel column, elute the product with DCM:EA:MeOH = 25:5:1 to obtain a pale yellow solid compound ID02 with a yield of 61%. 11H NMR (DMSO, 400 MHz) δ 10.86 (1H, s), 10.11 (2H, s), 10.01 (2H, s), 8.33 (2H, d, J = 2.5 Hz), 8.01 (2H, s), 7.92 (2H, dd, J = 8.8, 2.6 Hz), 7.60 (4H, t, J = 8.3 Hz), 7.48 (4H, d, J = 7.8 Hz), 7.36 (6H, t, J = 8.0 Hz), 7.16 (2H, t, J = 7.4 Hz), 7.12 (2H, d, J = 2.3 Hz), 7.08 (2H, t, J = 7.5 Hz), 6.97 (2H, t, J = 7.4 Hz), 4.25 (4H, t, J = 7.2 Hz), 3.13 (4H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 180.3, 160.5, 147.4, 145.1, 139.6, 138.8, 136.7, 130.8, 129.1, 127.6, 127.4, 125.3, 124.3, 123.8, 122.0, 121.6, 119.5, 119.0, 118.7, 112.0, 110.6, 47.3, 24.9. HRMS-ESI: m / z calcd for C 25 H 21 N5OS [M+H] + 440.1540, found 440.1543.

[0142] Example 72: Preparation of 1-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)thiourea (ID03): The preparation method was the same as that of ID02, except that 3-(tert-butyl)-5-isothiocyanato-1-(p-tolyl)-1H-pyrazole was used instead of phenyl isothiocyanate, and the yield was 54%. 1HNMR (DMSO, 400 MHz) δ 10.88 (1H, d, J = 2.4 Hz), 10.22 (1H, s), 9.68 (1H, s), 8.21 (1H, s), 8.04 (1H, s), 7.62 (1H, d, J = 7.9 Hz), 7.56 (1H, d, J = 8.7 Hz), 7.48 (2H, d, J = 8.1 Hz), 7.37–7.31 (1H, m), 7.29 (1H, s), 7.13 (1H, d, J = 2.3 Hz), 7.08 (1H, t, J = 7.6 Hz), 6.98 (1H, t, J = 7.4 Hz), 6.37 (1H, s), 4.25 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 2.36 (3H, s), 1.30 (9H, s); 13 C NMR (DMSO, 100 MHz) δ 181.2, 170.4, 160.4, 159.9, 147.2, 145.1, 137.9, 136.7, 136.3, 130.9, 129.8, 129.4, 127.2, 127.0, 123.4, 123.2, 121.5, 121.1, 120.0, 118.5, 118.3, 111.5, 110.2, 101.5, 46.8, 32.2, 30.2, 24.5, 20.6. HRMS-ESI: m / z calced for C 33 H 33 N7OS [M + H] + 576.2541, found 576.2548.

[0143] Example 73: Preparation of 1-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-(3,4-dimethoxyphenyl)thiourea (ID04): The preparation method was the same as that of IC03, except that 3,4-dimethoxyphenyl isothiocyanate was used instead of 3-(tert-butyl)-5-isothiocyanato-1-(p-tolyl)-1H-pyrazole, and the yield was 64%. 11H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 9.92 (1H, s), 9.88 (1H, s), 8.31 (1H, d, J = 2.5 Hz), 8.04 (1H, s), 7.93 (1H, dd, J = 8.8, 2.5 Hz), 7.63 (1H, d, J = 8.0 Hz), 7.58 (1H, dd, J = 8.8, 1.9 Hz), 7.35 (1H, d, J = 8.1 Hz), 7.16–7.11 (2H, m), 7.08 (1H, t, J = 7.4 Hz), 7.01–6.96 (2H, m), 6.94 (1H, s), 4.25 (2H, t, J = 7.3 Hz), 3.76 (3H, s), 3.75 (3H, s), 3.13 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 180.2, 170.8, 160.4, 148.9, 147.4, 146.9, 145.1, 138.9, 136.7, 132.5, 130.9, 127.5, 127.5, 123.8, 122.0, 121.6, 119.6, 118.9, 118.8, 117.0, 112.2, 112.0, 110.7, 109.8, 56.2, 56.0, 47.2, 25.0. HRMS-ESI: m / z calcd for C 27 H 25 N5O3S [M+H] + 500.1751, found 500.1754.

[0144] Example 74: Preparation of 1-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-(3-(trifluoromethyl)phenyl)thiourea (ID05): The preparation method was the same as that of ID04, except that 3-(trifluoromethyl)phenyl isothiocyanate was used instead of 3,4-dimethoxyphenyl isothiocyanate, and the yield was 53%. 11H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 10.38 (1H, s), 10.25 (1H, s), 8.33 (1H, d, J = 2.3 Hz), 8.07 (1H, s), 7.97 (1H, s), 7.95 (1H, d, J = 8.8 Hz), 7.80 (1H, d, J = 8.2 Hz), 7.63 (2H, dd, J = 8.3, 4.0 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.49 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 2.5 Hz), 7.09 (1H, t, J = 7.6 Hz), 6.99 (1H, t, J = 7.5 Hz), 4.27 (2H, t, J = 7.3 Hz), 3.15 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 180.5, 160.4, 147.6, 145.3, 140.7, 138.4, 136.8, 130.8, 130.1, 129.7, 129.4, 127.9, 127.5, 125.9, 123.8, 123.2, 122.1, 121.6, 121.3, 120.4, 120.3, 119.7, 118.9, 118.8, 112.0, 110.6, 47.2, 25.0. HRMS-ESI: m / z calcd for C 26 H 20 F3N5O3S [M+H] + 508.1414, found 508.1421.

[0145] Example 75: Preparation of 1-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-(4-fluorophenyl)thiourea (ID06): The preparation method was the same as that of ID05, except that 4-fluorophenyl isothiocyanate was used instead of 3-trifluoromethylphenyl isothiocyanate, and the yield was 71%. 11H NMR (DMSO, 400 MHz) δ 10.89 (1H, d, J = 2.4 Hz), 10.13 (1H, s), 9.99 (1H, s), 8.33 (1H, d, J = 2.5 Hz), 8.05 (1H, s), 7.94 (1H, dd, J = 8.8, 2.6 Hz), 7.63 (1H, d, J = 7.4 Hz), 7.60 (1H, d, J = 8.8 Hz), 7.50 (1H, dd, J = 9.0, 5.0 Hz), 7.36 (1H, d, J = 8.1 Hz), 7.21 (2H, t, J = 8.9 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.08 (1H, ddd, J = 8.2, 6.9, 1.2 Hz), 6.98 (1H, ddd, J = 8.0, 7.0, 1.1 Hz), 4.25 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 180.2, 160.5, 160.0, 158.1, 147.0, 144.7, 138.3, 136.3, 135.6, 135.5, 130.3, 127.3, 127.0, 126.4, 126.3, 123.4, 121.6, 121.1, 119.0, 118.5, 118.3, 115.4, 115.1, 111.5, 110.2, 46.8, 24.5. HRMS-ESI: m / z calced for C 25 H 20 FN5OS [M+H] + 458.1446, found 458.1442.

[0146] Example 76: Preparation of 1-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-(p-tolyl)thiourea (ID07): The preparation method was the same as that of ID06, except that p-tolyl isothiocyanate was used instead of 4-fluorophenyl isothiocyanate, and the yield was 61%. 11H NMR (DMSO, 400 MHz) δ 10.87 (1H, s), 10.02 (1H, s), 9.93 (1H, s), 8.34 (1H, d, J = 2.5 Hz), 8.02 (1H, s), 7.93 (1H, dd, J = 8.8, 2.6 Hz), 7.60 (2H, dd, J = 15.2, 8.4 Hz), 7.35 (2H, d, J = 7.9 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.08 (1H, t, J = 7.4 Hz), 6.97 (1H, t, J = 7.4 Hz), 4.25 (2H, t, J = 7.3 Hz), 3.13 (2H, t, J = 7.2 Hz), 2.29 (3H, s); 13 13C NMR (DMSO, 100 MHz) δ 179.8, 160.1, 147.0, 144.6, 138.5, 136.6, 136.3, 134.1, 130.4, 129.1, 127.2, 127.1, 124.1, 123.4, 121.6, 121.2, 119.0, 118.6, 118.4, 111.6, 110.3, 46.8, 24.6, 20.6. HRMS-ESI: m / z calced for C 26 H 23 N5OS [M + H] + 454.1697, found 454.1693.

[0147] Example 77: Preparation of 1-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-benzylurea (ID08): The preparation method was the same as that of ID07, except that benzyl isocyanate was used instead of p-toluenethiocyanate, and the yield was 66%. 1 1H NMR (DMSO, 400 MHz) δ 10.89 (1H, s), 9.04 (1H, s), 8.36 (1H, s), 7.80 (1H, dd, J = 8.8, 2.6 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.53 (1H, d, J = 8.8 Hz), 7.38–7.31 (5H, m), 7.25 (1H, d, J = 4.3 Hz), 7.13 (1H, s), 7.08 (1H, t, J = 7.5 Hz), 6.98 (1H, t, J = 7.4 Hz), 6.78 (1H, t, J = 5.8 Hz), 4.36 (2H, d, J = 5.8 Hz), 4.24 (2H, t, J = 7.2 Hz), 3.13 (2H, t, J = 7.0 Hz); 1313C NMR (DMSO, 100 MHz) δ 160.4, 155.4, 145.8, 142.7, 140.5, 139.6, 136.5, 128.6, 127.9, 127.4, 127.2, 127.0, 125.1, 123.6, 122.3, 121.3, 118.7, 118.5, 112.5, 111.7, 110.5, 46.9, 43.2, 24.7. HRMS-ESI: m / z calced for C 26 H 23 N5O2 [M+H] + 438.1925, found 438.1920.

[0148] Example 78: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)morpholine-4-carboxamide (ID09): The preparation method was the same as that of ID01, except that triphosgene was used instead of thiophosgene, and the yield was 62%. 1 1H NMR (DMSO, 400 MHz) δ 10.86 (1H, s), 8.94 (1H, s), 8.33 (1H, d, J = 2.4 Hz), 7.99–7.91 (2H, m), 7.60 (1H, d, J = 7.9 Hz), 7.53 (1H, d, J = 8.9 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.13 (1H, s), 7.07 (1H, t, J = 7.5 Hz), 6.96 (1H, t, J = 7.5 Hz), 4.24 (2H, t, J = 7.3 Hz), 3.63 (4H, t, J = 4.7 Hz), 3.47 (4H, t, J = 4.8 Hz), 3.12 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.6, 155.4, 146.4, 143.3, 139.8, 136.7, 127.7, 127.5, 126.8, 123.8, 122.2, 121.5, 118.9, 118.7, 114.7, 111.9, 110.7, 66.5, 47.1, 44.6, 24.9. HRMS-ESI: m / z calced for C 23 H 23 N5O3 [M+H] + 418.1874, found 418.1878.

[0149] Example 79: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-nitrobenzenesulfonamide (IE01)

[0150] Weigh compound 10 (200 mg, 0.66 mmol), and add 5 mL of DCM. Under ice bath, successively add N,N-diisopropylethylamine (300 μL, 1.65 mmol) and o-nitrobenzenesulfonyl chloride (265 mg, 1.2 mmol). Reflux at 60 °C for 8 h. After the reaction is complete, quench with saturated Na2S2O3, extract with DCM, wash with saturated brine, dry over anhydrous Na2SO4, filter, and evaporate the solvent. Purify using a silica gel column, elute the product with DCM:MeOH = 25:1 to obtain a pale yellow solid compound 12 with a yield of 55 - 70%. 1 H NMR (DMSO, 400 MHz) δ 11.20 (1H, s), 10.89 (1H, s), 8.06–7.99 (3H, m), 7.94–7.81 (3H, m), 7.60 (3H, d, J = 9.1 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.14 (1H, s), 7.08 (1H, t, J = 7.5 Hz), 6.95 (1H, t, J = 7.4 Hz), 4.22 (2H, t, J = 7.2 Hz), 3.09 (2H, t, J = 7.2 Hz); 13 C NMR (DMSO, 101 MHz) δ 160.2, 148.3, 147.7, 145.3, 136.7, 135.7, 135.4, 133.2, 131.6, 130.3, 129.1, 127.4, 125.3, 123.8, 122.5, 121.6, 118.9, 118.7, 116.4, 111.9, 110.6, 47.3, 24.8. HRMS-ESI: m / z calced for C 24 H 19 N5O5S [M + H] + 490.1180, found 490.1180.

[0151] Example 80: N-(3-(2-(1H-Indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-4-methoxybenzenesulfonamide (IE02): The preparation method is the same as that of IE01, except that 4-methoxybenzenesulfonyl chloride is used instead of o-nitrobenzenesulfonyl chloride, and the yield is 64%. 11H NMR (DMSO, 400 MHz) δ 10.87 (1H, s), 10.64 (1H, s), 8.00 (1H, s), 7.88 (1H, s), 7.73 (2H, d, J = 8.5 Hz), 7.56 (3H, dd, J = 11.3, 5.8 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.15–6.99 (4H, m), 6.93 (1H, t, J = 7.4 Hz), 4.20 (2H, t, J = 7.3 Hz), 3.78 (3H, s), 3.09 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 163.0, 160.3, 147.3, 144.7, 137.1, 136.7, 131.2, 129.4, 128.9, 127.4, 126.8, 123.8, 122.5, 121.5, 118.9, 118.7, 115.3, 115.0, 111.9, 110.6, 56.1, 47.3, 24.9. HRMS-ESI: m / z calcd for C 25 H 22 N4O4S [M+H] + 475.1435, found 475.1431.

[0152] Example 81: Preparation of N-(3-(2-(1H-indol-3-yl)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-2-chlorobenzenesulfonamide (IE03): The preparation method was the same as that of IE02, except that 2-chlorobenzenesulfonyl chloride was used instead of 4-methoxybenzenesulfonyl chloride, and the yield was 68%. 1 1H NMR (DMSO, 400 MHz) δ 11.12 (1H, s), 10.87 (1H, s), 8.11 (1H, d, J = 7.8 Hz), 8.00 (1H, s), 7.88 (1H, s), 7.65 (2H, d, J = 5.6 Hz), 7.56 (5H, t, J = 6.5 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.12 (1H, s), 7.06 (1H, t, J = 7.5 Hz), 6.93 (1H, t, J = 7.4 Hz), 4.19 (2H, t, J = 7.2 Hz), 3.08 (2H, t, J = 7.1 Hz); 1313C NMR (DMSO, 100 MHz) δ 160.2, 147.4, 144.7, 136.7, 136.2, 135.4, 132.5, 132.1, 131.2, 129.0, 128.4, 127.4, 126.1, 123.8, 122.6, 121.5, 118.7, 114.6, 111.9, 110.6, 60.2, 55.4, 47.3, 24.8, 14.6. HRMS-ESI: m / z calcd for C 24 H 19 ClN4O3S [M+H] + 479.0940, found 4798.0935.

[0153] Example 82: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-(benzylamino)quinazolin-4(3H)-one (IF01):

[0154] Weighed 10 (304 mg, 1 mmol) of intermediate 10 into 6 mL of dioxane. Under nitrogen protection, benzylamine (128.4 mg, 1.2 mmol), sodium tert-butoxide (144 mg, 1.5 mmol), palladium acetate (11 mg, 0.05 mmol), and 1,1'-binaphthalene-2,2'-bis(diphenylphosphine) (62 mg, 0.1 mmol) were added successively, and the reaction was carried out at 90 °C overnight. After the reaction, the reaction solution was evaporated to dryness, dissolved in a mixed solution of dichloromethane and methanol (v / v = 10:1, 100 mL), the filtrate was washed with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, and separated and purified by column chromatography (dichloromethane:methanol = 60:1) to obtain compound IF01 with a yield of 80%. 1 1H NMR (DMSO, 400 MHz) δ 10.83 (1H, s), 7.78 (1H, d, J = 7.7 Hz), 7.62–7.55 (1H, m), 7.35 (5H, dd, J = 15.1, 6.9 Hz), 7.25–7.15 (2H, m), 7.10 (3H, d, J = 10.8 Hz), 6.96 (1H, d, J = 7.0 Hz), 6.89–6.82 (1H, m), 4.37 (2H, t, J = 6.3 Hz), 4.17 (2H, d, J = 6.8 Hz), 3.08 (2H, t, J = 6.3 Hz); 1313C NMR (DMSO, 101 MHz) δ 160.2, 147.8, 143.3, 139.6, 139.6, 139.3, 136.4, 128.5, 128.5, 128.0, 127.2, 127.1, 126.9, 123.3, 122.7, 121.8, 121.2, 118.5, 118.4, 111.6, 110.4, 103.4, 46.6, 46.5, 24.7. HRMS-ESI: m / z calced for C 25 H 22 N4O [M+H] + 395.1867, found 395.1873.

[0155] Example 83: Preparation of 3-(2-(1H-indol-3-yl)ethyl)-6-((3-methoxy-4-nitrophenyl)amino)quinazolin-4(3H)-one (IF02): The preparation method was the same as that of IF01, except that 3-methoxy-4-nitroaniline was used instead of benzylamine, and the yield was 54%. 1 1H NMR (DMSO, 400 MHz) δ 10.93 (1H, s), 9.61 (1H, s), 8.08 (1H, s), 8.04 (1H, d, J = 9.1 Hz), 8.01 (1H, d, J = 2.7 Hz), 7.75 (1H, dd, J = 8.9, 2.6 Hz), 7.69 (1H, d, J = 5.4 Hz), 7.67 (1H, d, J = 4.9 Hz), 7.40 (1H, d, J = 8.1 Hz), 7.19 (1H, d, J = 2.5 Hz), 7.13 (1H, t, J = 7.5 Hz), 7.02 (1H, t, J = 7.5 Hz), 6.85 (1H, d, J = 2.4 Hz), 6.81 (1H, dd, J = 9.1, 2.3 Hz), 4.30 (2H, t, J = 7.3 Hz), 3.94 (3H, s), 3.18 (2H, t, J = 7.3 Hz); 13 13C NMR (DMSO, 100 MHz) δ 160.3, 156.3, 150.6, 146.8, 143.9, 139.8, 136.7, 132.0, 131.9, 130.3, 129.3, 129.2, 129.2, 127.5, 127.3, 123.8, 123.0, 121.6, 118.9, 118.7, 114.5, 112.0, 110.7, 106.8, 99.1, 56.6, 47.2, 24.9. HRMS-ESI: m / z calced for C 25 H 21 N5O4 [M+H] +456.1667, found 456.1661.

[0156] Example 84: Determination of the inhibitory activity of calcium / calmodulin-dependent kinase II

[0157] Using the compounds IA01 - IF02 provided in Examples 1 - 83, their inhibitory activities against calcium / calmodulin-dependent kinase II were tested. The test method is as follows: In the CaMKII enzyme inhibition assay, the reference compound was the broad-spectrum kinase inhibitor Staurosporine. The primary screening was to test the repeated inhibition rates at a single compound concentration (50 μM). For the calculation of IC 50 , five concentrations of each compound were tested, with the starting concentration of 50 μM and a 5-fold dilution gradient. Prepare the kinase reaction buffer, the components of which include 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM CaCl2, 1 μg / ml Calmodulin, 2 mM DTT, 0.01% Triton X-100, and 0.01% BSA. All compounds were dissolved in DMSO at a concentration of 10 mM. The compounds were diluted 100-fold to the required final concentration and transferred to the well plate. 10 μl of 2-fold concentrated kinase solution was added to each well, and 10 μl of 1-fold kinase buffer was added to the enzyme-free control well. After shaking well, it was incubated for 10 minutes. 10 μl of 2-fold concentrated substrate solution (containing ULight-CREBtide (Ser133) peptide and ATP) was added, and after shaking well, it was incubated at room temperature for 30 minutes. 20 μl of the detection solution was added to each well to stop the reaction, and after mixing well, it was incubated at room temperature for 60 minutes. Data at the excitation wavelength of 340 nm, emission wavelengths of 665 nm and 615 nm were read using an Envision detector. The signal ratio (665 nm / 615 nm) was exported, converted to the percentage inhibition value, and curve fitting and IC 50 calculation were performed in MS Excel. The inhibition rate was calculated by formula (1): Inh%=(Max - Signal) / (Max - Min)*100. The IC 50 value was obtained by fitting the data in GraphPad using formula (2): Y = Bottom+(Top - Bottom) / (1 + 10∧((LogIC 50 - X)*Hill Slope)). (where Y is the inhibition rate %, and X is the compound concentration), and the test results are shown in Table 2.

[0158] Table 2. Inhibitory activities of some compounds against CaMKⅡα kinase

[0159]

[0160]

[0161] Among these, some compounds of 66 rutaecarpine derivatives were selected for the CaMKⅡα enzyme inhibition activity test. The results in Table 2 show that 30 compounds have a certain degree of inhibitory activity against the CaMKⅡα enzyme (IC 50 <20 μM), and 8 compounds, namely IA01, IA03, IA23, IA24, IA25, IA32, IC06, and ID03, have significant inhibitory activity (IC 50 <3 μM).

[0162] Table 3. Inhibitory activity of some compounds against CaMKⅡβ kinase

[0163]

[0164] Among these, some compounds of 23 rutaecarpine derivatives were selected for the CaMKⅡβ enzyme inhibition activity test. The results in Table 2 show that 11 compounds have a certain degree of inhibitory activity against the CaMKⅡβ enzyme (IC 50 <20 μM), and 3 compounds, namely IA01, IA23, and IC06, have significant inhibitory activity (IC 50 <3 μM).

[0165] In summary, the embodiments of the present invention provide a class of rutaecarpine derivatives, their preparation methods and applications. The structures of these compounds are novel and have a certain inhibitory effect on CaMKⅡα kinase, belonging to a new type of inhibitor structure. In addition, the preparation method of the compound is simple, easy to operate, has low requirements for equipment, and is suitable for large-scale industrial production in the later stage. Through structural modification and in-depth pharmacological research of the compound, it has good application prospects in the preparation of CaMKⅡα kinase inhibitors and for neurodegenerative diseases, and has strong development potential.

[0166] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A rutaecarpine derivative, characterized in that, The general structural formula of the derivative is In general formula I: X is independently selected from N, C; R1 is independently selected from the group consisting of: H, halogen, C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4-8 membered heterocycloalkyl containing 1-4 heteroatoms selected from N, O or S, C 6-8 aryl, 5-8 membered heteroaryl containing 1-4 heteroatoms selected from N, O or S; R2 is independently selected from the group consisting of: H, CF3, COOMe; L (linker) is independently selected from the following group: single bond, -NH-C(O)-, -NH-, -NH-S(O)-NH-, -NH-SO2-.

2. The rutaecarpine derivative according to claim 1, wherein The C described in R1 6-8 aryl, 5- to 8-membered heteroaryl is optionally mono- or polysubstituted by m R3s; Each R3 is independently selected from the group consisting of: hydrogen, halogen, -CN, -OH, -NO2, -NH2, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C having 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halo-C having 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl; Alternatively, two R3 together with the atoms to which they are attached form a C 3-6 cycloalkyl, C 6-10 aryl, 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O or S, wherein said C 3-6 cycloalkyl, C 6-10 aryl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl is optionally substituted with 0 to 6 substituents selected from the group consisting of deuterium, halogen, ═O, -CN, -OH, -NR4R5, ═NR4, -C(O)R4, -C(O)OR4, -SR4, C 1-6 alkyl, C 1-6 alkoxy, C containing 1 to 4 heteroatoms selected from N, O or S 1-6 heteroalkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C containing 1 to 4 heteroatoms selected from N, O or S 1-6 heteroalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O or S; R4 and R5 are each independently selected from the group consisting of: H, C 1-6 alkyl, C 1-6 alkoxy, C containing 1-4 heteroatoms selected from N, O or S 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 membered hetero cycloalkyl containing 1-4 heteroatoms selected from N, O or S; Alternatively, R4 and R5 together with the heteroatom to which they are attached form a 3- to 6-membered heteroalkyl ring containing 1 to 4 heteroatoms selected from N, O or S; m is selected from: 0, 1, 2, 3.

3. The rutaecarpine derivative according to claim 1, characterized in that, The derivative is General formula IA, based on general formula I, where X is C, L is a single bond, R2 is H, and R1 is C 6-8 aryl, 5- to 8-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, or S, where the C 6-8 aryl, 5- to 8-membered heteroaryl is optionally mono- or polysubstituted by m R3 groups; including IA01 or IA02 or IA03 or IA04 or IA05 or IA06 or IA07 or IA08 or IA09 or IA10 or IA11 or IA12 or IA13 or IA14 or IA15 or IA16 or IA17 or IA18 or IA19 or IA20 or IA21 or IA22 or IA23 or IA24 or IA25 or IA26 or IA27 or IA28 or IA29 or IA30 or IA31 or IA32 or IA33 or IA34 or IA35 or IA36 or IA37 or IA38 or IA39 or IA40 or IA41 or IA42 or IA43 or IA44 or IA45 or IA46.

4. The rutaecarpine derivative according to claim 1, wherein The derivative is general formula IB. On the basis of general formula I, X is N, L is a single bond, R2 is H, R1 is a benzene ring, a nitrogen heterocycle, an unsaturated alkyl ring; R3 is methoxy, methoxycarbonyl, [1,3]dioxy; including IB01 or IB02 or IB03.

5. The rutaecarpine derivative according to claim 1, wherein, The derivative is General formula IC, based on general formula I, where X is C, L is -NH-C(O)-, R2 is H, CF3, and R1 is C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4- to 8-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, or S, C 6-8 aryl, 5- to 8-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, or S, where the C 6-8 aryl, 5- to 8-membered heteroaryl is optionally mono- or polysubstituted by m R3; R3 is H, halogen, C containing 1 to 4 heteroatoms selected from N, 0, or S 1-6 heteroalkyl; including IC01 or IC02 or IC03 or IC04 or IC05 or IC06 or IC07 or IC08 or IC09 or IC10 or IC11 or IC12 or IC13 or IC14 or IC15 or IC16 or IC17 or IC18 or IC19 or IC20.

6. The rutaecarpine derivative according to claim 1, wherein The derivative is General formula ID, based on general formula I, where X is C, L is selected from -NH-C(S)-NH- or -NH-C(O)-NH-, R2 is H, and R1 is C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4- to 8-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, or S, C 6-8 aryl, 5- to 8-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, or S, wherein the C 6-8 aryl, 5- to 8-membered heteroaryl is optionally mono- or polysubstituted by m R3 groups; R3 is H, halogen, C containing 1 to 4 heteroatoms selected from N, 0, or S 1-6 heteroalkyl; including ID01 or ID02 or ID03 or ID04 or ID05 or ID06 or ID07 or ID08 or ID09.

7. The rutaecarpine derivative according to claim 1, wherein The derivative is General formula IE, based on general formula I, X is C, L is -NH-SO2-, R2 is H, and R1 is C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4- to 8-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, or S, C 6-8 aryl, 5- to 8-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, or S, wherein the C 6-8 aryl, 5- to 8-membered heteroaryl is optionally mono- or polysubstituted by m R3 groups; R3 is H, halogen, C containing 1 to 4 heteroatoms selected from N, 0, or S 1-6 heteroalkyl; including IE01 or IE02 or IE03.

8. The rutaecarpine derivative according to claim 1, wherein The derivative is General formula IF, based on general formula I, X is C, L is -NH-, R2 is H, and R1 is C 1-6 alkyl, saturated or partially saturated C 3-8 cycloalkyl, saturated or partially saturated 4- to 8-membered heterocycloalkyl containing 1 to 4 heteroatoms selected from N, O, or S, C 6-8 aryl, 5- to 8-membered heteroaryl containing 1 to 4 heteroatoms selected from N, O, or S, wherein the C6-8 aryl and 5- to 8-membered heteroaryl are optionally mono- or polysubstituted by m R3 groups; R3 is H, halogen, C containing 1 to 4 heteroatoms selected from N, 0, or S 1-6 heteroalkyl; including IF01 or IF02.

9. Use of the rutaecarpine derivative according to claim 1 as a calcium / calmodulin-dependent kinase II (CaMKⅡ) kinase inhibitor.

10. Use of the rutaecarpine derivative according to claim 1 in the development of a drug for treating CaMKⅡ-mediated diseases.

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