1,4-Benzodiazepines and their uses in the preparation of antitumor drugs

Abstract

This invention belongs to the fields of medicinal chemistry and pharmaceutical technology, and relates to 1,4-benzodiazepines and their use in the preparation of antitumor drugs, specifically the use of 1,4-benzodiazepines in the preparation of annexin A3 (ANXA3) degrading agents and in the preparation of drugs for treating cancer. In particular, it discloses the use of 1,4-benzodiazepines, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or compositions of drugs with these as active ingredients, in the preparation of drugs for the prevention and treatment of tumors. These compounds can bind to the ANXA3 protein, induce ANXA3 protein degradation, inhibit the proliferation, cloning, migration, and invasion of tumor cells, and exert antitumor therapeutic effects in vivo. They can be used to treat solid tumors and hematological malignancies, including breast cancer, cervical cancer, ovarian cancer, colorectal cancer, gastric cancer, pancreatic cancer, lung cancer, esophageal cancer, liver cancer, leukemia, and melanoma.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and pharmaceutical technology, and relates to 1,4-benzodiazepines. Class of compounds and their uses in the preparation of antitumor drugs, specifically involving 1,4-benzodiazepines Use of class compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutical compositions thereof with medically acceptable carriers in the preparation of ANXA3 degrading agents and in the preparation of medicaments for the prevention and / or treatment of cancer. Background Technology

[0002] Cancer is a common malignant tumor disease in clinical practice, characterized by rapid disease progression and high mortality. The latest report from the World Health Organization shows that in 2020, there were 19.3 million new cancer cases and 10 million deaths from cancer globally (CA: Acancer Journal for Clinicians, 2021, 71(3):209-249). It is projected that by 2040, the number of new cancer cases worldwide will reach 28.4 million, an increase of 47% compared to 2020. Therefore, cancer has become one of the major diseases seriously endangering global human health.

[0003] Currently, there are three main methods for treating tumors: surgical treatment, radiotherapy, and drug therapy. Among them, drug therapy has undergone breakthrough progress from chemotherapy to targeted therapy and then to immunotherapy, which has significantly improved the survival of tumor patients. Targeted drugs, because they can specifically act on abnormally expressed proteins in tumor cells, thereby inducing tumor cell-specific death without affecting surrounding normal cells, have become a hot area of ​​anti-tumor drug research and development in recent years. According to the different properties and mechanisms of action of drugs, targeted drugs can be mainly divided into several types, such as macromolecular antibodies, small molecule inhibitors, small molecule agonists, and small molecule degraders. To date, small molecule inhibitors are one of the important types of targeted therapy, but they still have obvious shortcomings and limitations, such as the inability to completely block the biological function of proteins, the inability to efficiently act on the active binding pocket of protein targets, and the lack of selectivity, which easily leads to off-target effects and drug resistance. In recent years, small molecule degraders have overturned the previous concept that targets are "difficult to drug". These small molecule degraders not only require small amounts and have high selectivity, but also greatly reduce off-target effects (Cell Chemical Biology. 2017, 24(9): 1181-1190). Furthermore, small molecule degrading agents possess unique catalytic mechanisms, particularly their ability to target traditionally "difficult-to-drug" targets and address pain points such as drug resistance. Consequently, research on small molecule degrading agents has become a hot topic and cutting-edge field in new drug development, and has achieved rapid progress. From the clinical development pipelines already underway, small molecule degrading agents have demonstrated excellent efficacy and safety, especially in the treatment of malignant tumors, where they possess broad application value. Therefore, developing small molecule degrading agents with novel targets has become an important research direction in anti-tumor drug development, potentially meeting the urgent unmet clinical needs of cancer patients.

[0004] According to literature research, Annexin A3 (ANXA3) is a member of the Annexin (ANX) family and can utilize Ca2+ as a protein. 2+ In a dependent manner, it binds to acidic phospholipids and participates in a series of Ca2+ processes on the cell membrane surface. 2+ The physiological activities involved include vesicle transport, membrane fusion during exocytosis, signal transduction, and Ca2+. 2+The formation of channels and the interaction between cytoskeletal proteins (Nature reviews Molecular cell biology, 2005, 6(6):449-461.) are well understood, but the biochemical function of ANXA3 protein remains largely unknown. Under normal circumstances, ANXA3 protein is expressed in differentiated cells of the myeloid cell line. However, recent clinical and biomedical basic research has found scientific evidence of abnormal expression of ANXA3 protein in various cancers such as breast cancer, ovarian cancer, lung adenocarcinoma, prostate cancer, kidney cancer, colon cancer, pancreatic cancer, and liver cancer, and the abnormal expression of ANXA3 protein is closely related to the progression of these cancers (Clinical and Translational Oncology, 2013, 15(2):106-110). For example, several studies have been dedicated to revealing the important role of ANXA3 in the development and progression of breast cancer. ANXA3 is highly expressed in breast tumor samples, especially in many triple-negative breast cancer (TNBC) tumor samples, with a positive expression rate of 79.66%, which is significantly higher than that of other types of breast cancer patients. Moreover, the high expression level of ANXA3 is closely related to poor prognosis (BioMed Research International, 2017, 2017: 1-7). Silencing ANXA3 expression based on RNA interference technology significantly inhibited the proliferation, migration, and invasion activities of TNBC at the cellular level and induced apoptosis (Oncology reports, 2017, 37(1): 388-398; Clinical breast cancer, 2018, 18(4): 713-719). Importantly, silencing ANXA3 expression not only significantly inhibited the growth of TNBC xenografts in vivo at the animal level, but also effectively suppressed lung metastasis of orthotopic TNBC xenografts, while reducing the resistance of TNBC cells to the chemotherapeutic drug doxorubicin (Pathology-Research and Practice, 2018, 214(10):1719-1725; CellDeath&Disease, 2018, 9(2):1-11). Therefore, it is speculated that developing selective degraders targeting ANXA3 to induce ANXA3 protein degradation may be a promising new strategy for antitumor therapy. However, regarding ANXA3 as a novel drug target, no small chemical molecules that can target and degrade ANXA3 and exhibit antitumor pharmacological activity have been reported to date. Summary of the Invention

[0005] Due to the shortcomings of existing technologies, this application provides 1,4-benzodiazepine Class of compounds and their uses in the preparation of antitumor drugs, specifically involving 1,4-benzodiazepines Use of class compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutical compositions thereof with medically acceptable carriers in the preparation of ANXA3 degrading agents and in the preparation of medicaments for the prevention and / or treatment of cancer.

[0006] This application, through structure-activity relationship screening of a self-built small molecule compound library targeting ANXA3 binding and degradation activities, and studies on anti-tumor cell activities, discovered an original 1,4-benzodiazepine. These compounds can target and degrade ANXA3 and exhibit antitumor pharmacological activity.

[0007] The first objective of this invention is to provide 1,4-benzodiazepine 1,4-benzodiazepine, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; These compounds are compounds or salts having the structure shown in formula (I).

[0008]

[0009]

[0010] In formula (I),

[0011] R1 is selected from a hydrogen atom or a methyl group;

[0012] X is a linking group, selected from: R2 is selected from:

[0013] 1) Substituted benzene, its structure is:

[0014] in,

[0015] R3-R7 are each independently selected from hydrogen, halogen, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, dimethylamino, nitro, cyano, or acetyl.

[0016] 2) Aromatic six-membered heterocyclic rings, with the following structure:

[0017] in,

[0018] R8-R 11 Each is independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, or methoxy;

[0019] R'8-R' 11 Each is independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, or methoxy;

[0020] R 12 -R14 Each is independently selected from hydrogen or halogen;

[0021] R' 12 -R' 14 Each is independently selected from hydrogen or trifluoromethyl;

[0022] R” 12 -R” 14 Each is independently selected from hydrogen;

[0023] 3) Aromatic five-membered heterocyclic rings, with the following structure:

[0024] in,

[0025] A is selected from nitrogen, oxygen, or sulfur;

[0026] B is selected from carbon or nitrogen;

[0027] C is selected from carbon or nitrogen;

[0028] D is selected from carbon or nitrogen;

[0029] E is selected from nitrogen or oxygen;

[0030] F is selected from carbon or nitrogen;

[0031] R 15 -R 18 Each is independently selected from hydrogen, methyl, or trifluoromethyl;

[0032] R' 15 -R' 17 Each is independently selected from hydrogen or methyl;

[0033] 4) Aliphatic heterocyclic or adamantane, with the following structure:

[0034] in,

[0035] G is selected from carbon or nitrogen;

[0036] R 19 Selected from methoxy or ethylene glycol.

[0037] In this invention, some 1,4-benzodiazepines represented by formula (I) are further provided. The specific structure of the compound:

[0038]

[0039]

[0040]

[0041] In this invention, pharmaceutically acceptable salts refer to compounds that, within the scope of reliable pharmaceutical evaluation, are suitable for contact with human or lower animal tissues without undue toxicity, irritation, or allergic reactions, have a reasonably reasonable benefit-risk ratio, are typically water- or oil-soluble or dispersible, and can be effectively used for their intended purpose.

[0042] Some compounds or stereoisomers of this invention contain basic groups such as amino groups that can form salts with acids, and can form acidic salts with inorganic and / or organic acids. These also include zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkyl ammonium salts. These salts can be obtained directly during the final separation and purification of the compound or its stereoisomers. Alternatively, they can be obtained by mixing the compound or its stereoisomers with an appropriate amount (e.g., an equimolar amount) of acid. These salts may precipitate in solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after reaction in an aqueous medium.

[0043] The pharmaceutically acceptable salts described in this invention include organic acid salts such as citrate, benzenesulfonate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate; inorganic acid salts such as hydrochloride, sulfate, hydrobromide, hydrofluoric acid, hydroiodide, hydrochloride, phosphate, etc.; or salts that can form glutamate or aspartate salts with amino acids such as glutamic acid or aspartic acid.

[0044] This invention relates to 1,4-benzodiazepines. Solvents of the same type of compound are also within the scope of protection of this invention, and the solvents are preferably water, alcohol or alcohol-water mixtures, where alcohol refers to methanol or ethanol.

[0045] A second object of the present invention is to provide 1,4-benzodiazepine as shown in formula (I). Use of a class of compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutical compositions thereof with a medically acceptable carrier, in the preparation of ANXA3 degrading agents.

[0046] Binding activity tests based on surface plasmon resonance showed that the 1,4-phenylenediamine represented by formula (I) The compounds exhibit sub-micromolar ANXA3 binding activity, as shown in Table 1. Western blot assays demonstrated that these compounds can induce ANXA3 protein degradation in TNBC cells, with activity at the micromolar level, as shown in Table 1. The degradation activity of representative isomers I-9a19, (R)-I-9a19, or (S)-I-9a19 is shown in Table 1. Figure 1 As shown.

[0047] A further object of the present invention is to provide 1,4-benzodiazepine as shown in formula (I). The use of the compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition thereof with a medically acceptable carrier, in the preparation of an antitumor drug, wherein the antitumor drug is a drug for the prevention and / or treatment of cancer. In vitro antitumor activity tests on various tumor cell lines showed that the compound possesses micromolar-level antitumor activity, as shown in Table 1. In particular, compound I-9a19 significantly inhibited the cloning, migration, and invasion functions of TNBC cells, as shown in Table 1. Figure 2 As shown. In particular, compound I-9a19 demonstrated effective therapeutic effects and induced ANXA3 protein degradation in tumor tissue in an in vivo TNBC xenograft model, with activity results as shown in... Figure 3 As shown.

[0048] The aforementioned drugs may also contain one or more pharmaceutically acceptable carriers, including conventional pharmaceutical diluents, excipients, fillers, binders, humectants, disintegrants, absorption promoters, surfactants, adsorbents, lubricants, etc., and flavoring agents, sweeteners, etc. may be added if necessary.

[0049] The present invention also provides an antitumor drug composition that exerts its antitumor effect by acting as a degrader of annexin ANXA3, wherein the antitumor drug composition is a tablet, capsule, pill, injection, sustained-release formulation, spray or nano-drug delivery system.

[0050] The beneficial effect of the present invention lies in the 1,4-benzodiazepine provided. These compounds are a novel class of ANXA3 small-molecule degraders, exhibiting not only sub-micromolar ANXA3 binding activity but also significant ANXA3-degrading activity in TNBC cells and at the animal level. Furthermore, they significantly inhibit the proliferation, cloning, migration, and invasion of TNBC cells in vitro. Using a female BALB / c nude mouse orthotopic xenograft model of human MDA-MB-231 cells, their in vivo anti-TNBC therapeutic effect has been confirmed, demonstrating good potential and application prospects. They can be further developed into drugs for treating cancers including breast cancer, cervical cancer, ovarian cancer, colorectal cancer, gastric cancer, pancreatic cancer, lung cancer, esophageal cancer, liver cancer, leukemia, and melanoma. Preferably, the antitumor drug is an anti-triple-negative breast cancer drug.

[0051] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0052] The 1,4-benzodiazepine provided by this invention These compounds, along with their pharmaceutically acceptable salts, represent a novel class of ANXA3 small molecule degraders, none of which have been reported in Scifinder. These compounds exert antitumor therapeutic effects in vitro and in vivo by directly binding to ANXA3 and inducing its degradation, addressing the current lack of small molecule drugs that can directly bind to ANXA3 and exhibit antitumor activity. This provides a new treatment option and medication regimen for clinical use in cancer treatment. Attached Figure Description

[0053] Figure 1 Detection of the effects of compounds I-9a19, (R)-I-9a19 and (S)-I-9a19 on ANXA3 protein levels;

[0054] Figure 2 Detection of the effects of compound I-9a19 on TNBC cell cloning, migration, and invasion;

[0055] Figure 3 In vivo efficacy study of compound I-9a19 against TNBC and detection of its ability to induce ANXA3 degradation in tumor tissue. Detailed Implementation

[0056] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. However, these embodiments are only used to further illustrate the present invention and do not change the scope of protection of the present invention.

[0057] Example 1

[0058] 2-O-2-(3-phenylurea)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a1).

[0059] 1.1 Preparation of intermediate compound 7

[0060]

[0061] Weigh 5.00 g (66.6 mmol) of benzyl carbamate (7.93 g, 52.5 mmol) into a 100 mL round-bottom flask, add 80 mL of toluene and stir to dissolve. Add 7.5 mL (66.6 mmol) of glyoxylic acid hydrate dropwise, stir for 20 min, then heat the system to 80 °C and react for 2 h. Filter to obtain compound 1, a white solid of 16.01 g, yield 97%; ESI-MS: m / z 349.0 [M+Na] + C 16 H 14 N4O4.

[0062] Under ice bath conditions, 5.00 g (15 mmol) of compound 1 was dissolved in 30 mL of tetrahydrofuran and cooled to 0 °C. 2 mL (23.6 mmol) of oxaloyl chloride was slowly added dropwise to this solution, followed by 2-3 drops of DMF. After reacting for 2 h, 3.02 g (15.3 mmol) of 2-aminophenylbenzophenone and 3.67 mL (33.7 mmol) of N-methylmorpholine were dissolved in 20 mL of tetrahydrofuran. At 0 °C, this solution was slowly added dropwise to compound 2 over approximately 20-30 min using a constant pressure dropping funnel. The temperature was then raised to room temperature, and the reaction was allowed to proceed for 2-4 h. The system was filtered through diatomaceous earth, washed with 20 mL of tetrahydrofuran, and the organic phase was concentrated under vacuum. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to give compound 3, a yellow oil, 3.8 g, yield 49%; ESI-MS: m / z 506.0 [M+H] + C 29 H 23 N5O4.

[0063] Compound 3, 5 g (9.9 mmol), was dissolved in 10 mL of methanol and placed at 0 °C. 15 mL of ammonia in methanol was added. The mixture was slowly heated to room temperature and reacted for 16 h. The solid was filtered off, and the organic phase was concentrated under vacuum. The solution was dissolved in ethyl acetate, washed twice with 1 N sodium hydroxide aqueous solution, extracted with NaCl, dried over Na₂SO₄, concentrated, and then 60 mL of acetic acid and 3.8 g (49.3 mmol) of ammonium acetate were added. The reaction was carried out overnight at room temperature under nitrogen protection. After vacuum concentration of the reaction solution, ethyl acetate:ether = 1:3 was added, followed by 1 N sodium hydroxide aqueous solution until the pH reached above 8. The suspension was placed at 0 °C, and the solid was filtered off. The solid was washed continuously with water and ether to obtain 51.1 g of a gray solid, yielding 30%. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.47(d,J=7.6Hz,1H),7.62(s,1H),7.54-7.15(m,13H), 5.03(d,J=16.1Hz,3H).ESI-MS: m / z 386.0[M+H] + C 24 H 20 N2O3.

[0064] Compound 5 (13.0 mmol) was placed in a round-bottom reaction flask, and 3.0 g (21.7 mmol) of anhydrous potassium carbonate and 2.5 g (17.6 mmol) of iodomethane were added. The mixture was dissolved in 30 mL of ultra-dry DMF, and the reaction was carried out under nitrogen balloon protection with three purgings. The reaction was carried out at room temperature for 5 h. The reaction was quenched with ice water and EA at 0 °C. The organic phase was washed with saturated brine and dried with Na2SO4. The crude product was purified by silica gel column chromatography under reduced pressure (ethyl acetate / petroleum ether = 1 / 3) to give 6.3 g of gray solid, with a yield of 58%. 1 H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.71(s, 1H),7.64(d,J=8.0Hz,1H),7.51(s,3H),7.45(d,J=7.2Hz,2H),7.33(d,J=19.3Hz,7H),5.04(s,2H),3.35(d,J=3.7Hz,3H).ESI-MS:m / z400.2[M+H] + C 24 H 21 N3O3.

[0065] Compound 6 was dissolved in 10 mL of acetic acid in a round-bottom reaction flask, and 30 mL of 33% hydrobromic acid solution was added. The reaction was carried out at room temperature for 2-4 h. A solid was produced. The solution was adjusted to neutral with sodium bicarbonate solution, extracted with ethyl acetate and water, and the organic layer was dried with Na2SO4. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give 7 1.4 g of brown oil, with a yield of 70%. 1 H NMR (400MHz, DMSO-d6) δ7.65(t,J=6.0Hz,1H),7.59(t,J=6.7Hz,1H),7.46(ddd,J=20.8,14.2, 7.5Hz, 5H), 7.27 (d, J = 5.2Hz, 2H), 4.26 (d, J = 6.0Hz, 1H), 3.34 (s, 3H). 13 C NMR (151MHz, DMSO-d6)δ169.89,164.23,142.76,137.83,131.59,130.18,129.16,129.03, 128.21,128.15,123.91,121.74,70.19,34.45.ESI-MS:m / z 266.0[M+H] + C 16 H 15 N3O.

[0066] 1.2 Preparation of intermediate compound 8a1

[0067]

[0068] Weigh 1.70 g (18.2 mmol) of chloroacetamide into a 25 mL round-bottom flask, add 20 mL of 1,2-dichloroethane and stir to dissolve. At 0 °C, add 2 mL (23.4 mmol) of oxalyl chloride dropwise, stirring for 1 h. Then, heat the system to 90 °C and reflux for 5 h. Cool the system to rt, and slowly add 1.69 g (18.2 mmol) of aniline to the above system. Stir for 6–8 h, and filter to obtain 2.83 g of white solid, yield 73%. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.17(s,1H),7.52(d,2H),7.34(t,2H),7.10(t,1H),4.40(s,2H); 13 C NMR (151MHz, DMSO-d6) δ168.6,150.2,137.4,128.9,123.8,119.7,43.2; HR-MS(ESI):m / z[M+H] + calcd for C9H9ClN2O2:213.0425,found:213.0425.

[0069] 1.3 Preparation of final product I-9a1

[0070]

[0071] Take a 25 mL round-bottom flask, add 200 mg (0.75 mmol) of compound 7, 210 μL of triethylamine and 110 μL of CS2, and stir at room temperature for 2 h. Then add 6 mL of acetonitrile to dissolve the system, and then add 160 mg (0.75 mmol) of compound 8a1. After reacting at room temperature for 6 h, monitor the reaction on a TLC plate (take a small amount of reaction solution, add saturated sodium chloride solution and ethyl acetate, and spot the ethyl acetate layer on the plate). When the starting material spot basically disappears, stop the reaction, evaporate the system to dryness, extract with ethyl acetate and water, dry the organic phase with anhydrous sodium sulfate and then evaporate the solvent. Purify the crude product by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 3) to give 130 mg of yellow solid, yield 33%. 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),10.96(s,1H),10.33(s,1H),7.92-6.95(m,14H), 5.97(s,1H),4.25(s,2H),3.39(s,3H); 13C NMR(150MHz,DMSO-d6)δ196.47,170.13,166.95,165.92,150.27,142.53,137.32,137.23,132.29,130.75 ,129.59,129.34,128.79,128.24,127.87,124.41,123.55,122.07,119.47,75.31,38.58,34.73; ESI-MS: m / z 517.8[M+H] + C 26 H 23 N5O3S2,HRMS calcd.518.1315[M+H] + ,found 518.1319.

[0072] Example 2

[0073] 2-O-2-(3-(4-trifluoromethyl)phenyl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a2)

[0074] 2.1 Preparation of intermediate 2-chloro-N-(4-(trifluoromethyl)phenyl)carbamoyl)acetamide (8a2)

[0075] Intermediate 8a2 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.14-10.96(m,1H),10.41(s,1H),7.81-7.68(m,4H),4.43(s,2H).

[0076] 2.2 Preparation of final product I-9a2

[0077] Compound I-9a2 was synthesized by replacing the raw material with the same equivalent of 8a2 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),11.04(s,1H),10.54(s,1H), 7.60(dd,J=71.2,29.4Hz,13H),5.95(s,1H),4.24(s,2H),3.36(s,3H) .

[0078] Example 3

[0079] 2-O-2-(3-(2-(trifluoromethyl)phenyl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a3)

[0080] 3.1 Preparation of intermediate 2-chloro-N-(2-(trifluoromethyl)phenyl)carbamoyl)acetamide (8a3)

[0081] Intermediate 8a3 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.60(s,1H),8.07(d,J=8.2Hz,1H),7.77-7.64(m,2H),7.35(d,J=7.5Hz,1H),4.39(d,J=7.3Hz,2H).

[0082] 3.2 Preparation of final product 9a3

[0083] Compound I-9a3 was synthesized by replacing the raw material with the same equivalent of 8a3 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.53(s,1H),11.20(s,1H),10.73(s,1H), 8.09(s,1H),7.68(s,5H),7.59-7.43(m,5H),7.30(s,2H),5.94(s,1H),4.25(s,2H), 3.37(s,3H) .

[0084] Example 4

[0085] 2-(3-(4-(dimethylamino)phenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a4)

[0086] 4.1 Preparation of intermediate 2-chloro-N-(4-(dimethylamino)phenyl)carbamoyl)acetamide (8a4)

[0087] Intermediate 8a4 was synthesized according to the method in step 1.2 of Example 1. 1H NMR (400MHz, DMSO-d6) δ10.87-10.73(m,1H),9.96-9.80(m,1H),7.29(s,2H),6.68(s,2H),4.33(s,2H),2.83(d,J=3.3Hz,6H).

[0088] 4.2 Preparation of final product I-9a4

[0089] Compound I-9a4 was synthesized by replacing the raw material with the same equivalent of 8a4 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.46 (d, J=6.3Hz, 1H), 10.75 (s, 1H), 9.99(s,1H),7.66(s,2H),7.53(s,3H),7.44(d,J=7.2Hz,2H),7.25(d,J=9 .8Hz,4H),6.64(s,2H),5.92(s,1H),4.17(s,2H),3.33(s,3H),2.79(s,6H) .

[0090] Example 5

[0091] 2-O-2-(3-(4-(trifluoromethoxy)phenyl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a5)

[0092] 5.1 Preparation of intermediate 2-chloro-N-((4-(trifluoromethoxy)phenyl)carbamoyl)acetamide (8a5)

[0093] Intermediate 8a5 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.24(s,1H),7.66(td,J=6.1,3.0Hz,2H),7.35(t,J=6.8Hz,2H),4.47-4.35(m,2H).

[0094] 5.2 Preparation of the final product I-9a5

[0095] Compound I-9a5 was synthesized by replacing the raw material with the same equivalent of 8a5 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.50 (d, J=6.7Hz, 1H), 10.97 (s, 1H), 10.39(s,1H),7.75-7.68(m,2H),7.65-7.61(m,2H),7.60-7.57(m,2H),7.55-7.52 (m,1H),7.47(t,J=7.5Hz,2H),7.31(dp,J=7.8,2.0Hz,4H),5.96(d,J=6.7Hz,1H), 4.25(s,2H),3.38(d,J=1.6Hz,3H) .

[0096] Example 6

[0097] 2-(3-(3-fluorophenyl)ureo)-2-oxoethyl(1-methyl-2-oxy-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a6)

[0098] 6.1 Preparation of intermediate 2-chloro-N-((3-fluorophenyl)carbamoyl)acetamide (8a6)

[0099] Intermediate 8a6 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),10.27(s,1H),7.63-7.52(m,1H),7.44-7.33(m,1H),7.33-7.26(m,1H),7.04-6.89(m,1H),4.39(s,2H).

[0100] 6.2 Preparation of final product I-9a6

[0101] Compound I-9a6 was synthesized by replacing the raw material with the same equivalent of 8a6 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.49 (s, 1H), 10.92 (d, J = 54.2Hz, 1H), 10.45(s,1H),7.71(d,J=10.2Hz,2H),7.64-7.56(m,2H),7.51(dd,J=22.4,6.1Hz,4 H),7.37-7.29(m,3H),7.23(d,J=8.5Hz,1H),6.90(s,1H),5.96(s,1H),4.26(s,2H), 3.35(s,3H) .

[0102] Example 7

[0103] 2-(3-(3-chlorophenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a7)

[0104] 7.1 Preparation of intermediate 2-chloro-N-((3-chlorophenyl)carbamoyl)acetamide (8a7)

[0105] Intermediate 8a7 was synthesized according to step 1.2 of Example 1. ESI-MS: m / z 247.0 [M+H] + .

[0106] 7.2 Preparation of final product I-9a7

[0107] Compound I-9a7 was synthesized by replacing the raw material with the same equivalent of 8a7 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),11.00(s,1H),10.41(s,1H), 7.72(dd,J=22.1,11.6Hz,3H),7.63-7.52(m,3H),7.48(t,J=7.4Hz,2H),7.35( d,J=16.8Hz,4H),7.14(d,J=7.5Hz,1H),5.97(s,1H),4.26(s,2H),3.39(s,3H) .

[0108] Example 8

[0109] 2-(3-(4-bromophenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a8)

[0110] 8.1 Preparation of intermediate N-((4-bromophenyl)carbamoyl)-2-chloroacetamide (8a8)

[0111] Intermediate 8a8 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.99(d,J=28.7Hz,1H),10.19(s,1H),7.54-7.49(m,4H),4.39(d,J=4.5Hz,2H).

[0112] 8.2 Preparation of the final product I-9a8

[0113] Compound I-9a8 was synthesized by replacing the raw materials with the same equivalent of 8a8 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.49(d,J=8.8Hz,1H),10.96(s,1H), 10.34(s,1H),7.76-7.67(m,2H),7.59(d,J=8.0Hz,2H),7.50(d,J=7.7Hz,7H), 7.37-7.29(m,2H),5.96(d,J=7.8Hz,1H),4.24(s,2H),3.38(s,3H) .

[0114] Example 9

[0115] 2-(3-(3-bromophenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a9)

[0116] 9.1 Preparation of intermediate N-((3-bromophenyl)carbamoyl)-2-chloroacetamide (8a9)

[0117] Intermediate 8a9 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.23(s,1H),7.92(s,1H),7.45(d,J=6.0Hz,1H),7.30(d,J=4.6Hz,2H),4.43-4.39(m,2H).

[0118] 9.2 Preparation of the final product I-9a9

[0119] Compound I-9a9 was synthesized by replacing the raw materials with the same equivalent of 8a9 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.56-11.47(m,1H),11.01(s,1H),10.39(s,1H),7.91(s,1H),7.73(dd,J=14.2,6.6Hz,3H),7.60(d,J=7.9Hz,2H),7.55(d,J =7.0Hz,1H),7.50(d,J=7.4Hz,2H),7.41(s,1H),7.34(d,J=7.5Hz,2H),7.27(d,J=4.5Hz,2H),5.98(d,J=6.6Hz,1H),4.26(s,2H) .

[0120] Example 10

[0121] 2-(3-(2-cyanophenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a10)

[0122] 10.1 Preparation of intermediate 2-chloro-N-((2-cyanophenyl)carbamoyl)acetamide (8a10)

[0123] Intermediate 8a10 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ11.30(s,1H),10.81(s,1H),8.24-8.12(m,1H),7.86(t,J=6.1Hz,1H),7.73(q,J=6.9Hz,1H),7.32(q,J=7.3,6.6Hz,1H),4.43(d,J=4.7Hz,2H).

[0124] 10.2 Preparation of the final product I-9a10

[0125] Compound I-9a10 was synthesized by replacing the raw materials with the same equivalent of 8a10 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.57 (d, J=6.8Hz, 1H), 11.28 (s, 1H), 10.97(s,1H),8.19(d,J=8.5Hz,1H),7.83(d,J=8.0Hz,1H),7.72(s,3H),7.61(d ,J=7.2Hz,2H),7.56(d,J=6.1Hz,1H),7.50(d,J=7.4Hz,2H),7.33(t,J=13.8Hz, 3H), 5.98 (d, J = 6.5Hz, 1H), 4.29 (s, 2H), 3.40 (s, 3H).

[0126] Example 11

[0127] 2-(3-(2-acetylphenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a11)

[0128] 11.1 Preparation of intermediate N-((2-acetylphenyl)carbamoyl)-2-chloroacetamide (8a11)

[0129] Intermediate 8a11 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ12.13(s,1H),10.93(s,1H),8.38(d,J=8.5Hz,1H),8.04(d,J=7.9Hz,1H ),7.61(t,J=8.0Hz,1H),7.24(t,J=7.6Hz,1H),4.37(s,2H),2.63(s,3H).

[0130] 11.2 Preparation of the final product I-9a11

[0131] Compound I-9a11 was synthesized by replacing the raw materials with the same equivalent of 8a11 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ 12.16 (s, 1H), 11.54 (d, J = 6.3Hz, 1H), 10.88 (s, 1H), 8.38 (d, J = 8.5Hz, 1H), 8.00 (d, J = 8.1Hz, 1H), 7.72 (d, J = 10.1Hz, 2H),7.61(d,J=7.7Hz,2H),7.57(d,J=8.0Hz,2H),7.48(t,J=7.5Hz,2H),7.34(d, J=8.1Hz,2H),7.22(d,J=8.0Hz,1H),6.00-5.96(m,1H),4.23(d,J=3.9Hz,2H),3.40(s,3H),2.60(s,3H).

[0132] Example 12

[0133] 2-(3-(3-ethylphenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a12)

[0134] 12.1 Preparation of intermediate 2-chloro-N-((3-ethylphenyl)carbamoyl)acetamide (8a12)

[0135] Intermediate 8a12 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ10.89(s,1H),10.13(s,1H),7.35(d,J=7.3Hz,2H),7.24(t,J=7.9Hz,1H),6. 96(d,J=7.5Hz,1H),4.40(s,2H),2.59(q,J=7.6Hz,2H),1.18(t,J=7.6Hz,3H).

[0136] 12.2 Preparation of the final product I-9a12

[0137] The compound I-9a12 was synthesized by replacing the raw material with the same equivalent of 8a12 according to step 1.3 in Example 1. 1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),10.96(s,1H),10.34(s, 1H),7.74(d,J=10.6Hz,2H),7.62(d,J=7.6Hz,2H),7.57(d,J=6.6Hz,1H),7.51 (d,J=7.2Hz,2H),7.35(s,4H),7.24(s,1H),6.95(d,J=7.3Hz,1H),5.99(s,1H), 4.27(s,2H),3.62(s,3H),1.78(s,2H),1.19(d,J=7.8Hz,3H).

[0138] Example 13

[0139] 2-(3-(5-chloro-2-(trifluoromethyl)phenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a13)

[0140] 13.1 Preparation of intermediate 2-chloro-N-((5-chloro-2-(trifluoromethyl)phenyl)carbamoyl)acetamide (8a13)

[0141] Intermediate 8a13 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),10.80(s,1H),8.26(s,1H),7.77(d,J=8.5Hz,1H),7.43(d,J=8.6Hz,1H),4.40(d,J=1.9Hz,2H).

[0142] 13.2 Preparation of the final product I-9a13

[0143] The compound I-9a13 was synthesized by replacing the raw material with the same equivalent of 8a13 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.52(s,1H),11.32(s,1H),10.91(s,1H),8.25(s,1H),7.71(d,J=9.4Hz,2H),7.59-7.51(m,3H),7.45(d,J=7.5Hz,2H), 7.37(d,J=8.4Hz,1H),7.29(d,J=8.7Hz,2H),5.92(s,1H),4.23(s,2H),3.35(s,3H) .

[0144] Example 14

[0145] 2-(3-(3-chloro-5-nitrophenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a14)

[0146] 14.1 Preparation of intermediate 2-chloro-N-((3-chloro-5-nitrophenyl)carbamoyl)acetamide (8a14)

[0147] Intermediate 8a14 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.49(s,1H),8.54(q,J=1.9Hz,1H),8.10(d,J=2.1Hz,1H),7.99(q,J=1.8Hz,1H),4.42(d,J=1.6Hz,2H).

[0148] 14.2 Preparation of the final product I-9a14

[0149] Compound I-9a14 was synthesized by replacing the raw material with the same equivalent of 8a14 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),11.15(s,1H),10.66(s, 1H),8.54(s,1H),8.10(s,1H),7.95(s,1H),7.74-7.67(m,2H),7.59(d,J=6.4Hz,2H ),7.54(d,J=8.1Hz,1H),7.52-7.45(m,2H),7.33(d,J=6.3Hz,2H),5.97(d,J=8.0Hz, 1H),4.27(s,2H),3.38(s,3H) .

[0150] Example 15

[0151] 2-(3-(5-fluoro-2-nitrophenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a15)

[0152] 15.1 Preparation of intermediate 2-chloro-N-((5-fluoro-2-nitrophenyl)carbamoyl)acetamide (8a15)

[0153] Intermediate 8a15 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.07(s,1H),11.35(s,1H),8.33(ddd,J=15.1,10.6,4.4Hz,2H),7.21(td,J=6.9,3.6Hz,1H),4.39(d,J=5.5Hz,2H).

[0154] 15.2 Preparation of the final product I-9a15

[0155] Compound I-9a15 was synthesized by replacing the raw material with the same equivalent of 8a15 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.16 (s, 1H), 11.52 (d, J = 5.5Hz, 1H), 11.29(s,1H),8.42-8.24(m,2H),7.76-7.65(m,2H),7.59(d,J=6.3Hz,2H),7.53(d, J=8.2Hz,1H),7.52-7.45(m,2H),7.32(d,J=5.6Hz,2H),7.17(t,J=8.3Hz,1H),5.96 (d,J=5.8Hz,1H),4.26(s,2H),3.38(s,3H) .

[0156] Example 16

[0157] 2-(3-(3-chloro-4-nitrophenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a16)

[0158] 16.1 Preparation of intermediate 2-chloro-N-((3-chloro-4-nitrophenyl)carbamoyl)acetamide (8a16)

[0159] Intermediate 8a16 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),10.53(s,1H),8.12(dd,J=8.9,4.1Hz,1H),8.04(d,J=3.5Hz,1H), 7.71(d,J=9.0Hz,1H), 4.43(d,J=4.0Hz,2H).

[0160] 16.2 Preparation of the final product I-9a16

[0161] Compound I-9a16 was synthesized by replacing the raw material with the same equivalent of 8a16 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.51 (d, J = 7.2Hz, 1H), 11.17 (s, 1H), 10.69(s,1H),8.09(d,J=9.2Hz,1H),8.03(s,1H),7.70(q,J=6.7Hz,3H),7.58(d ,J=8.2Hz,2H),7.54(d,J=5.6Hz,1H),7.47(t,J=8.2Hz,2H),7.38-7.27(m,3H), 5.96(d,J=8.6Hz,1H),4.27(s,2H),3.38(s,3H) .

[0162] Example 17

[0163] 2-(3-(5-chloro-2-methoxyphenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a17)

[0164] 17.1 Preparation of intermediate 2-chloro-N-((5-chloro-2-methoxyphenyl)carbamoyl)acetamide (8a17)

[0165] Intermediate 8a17 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ11.18(d,J=14.0Hz,1H),10.74(s,1H),8.33-8.13(m,1H),7.25-7.08(m,2H),4.45-4.34(m,2H),3.91(dd,J=13.7,3.4Hz,3H).

[0166] 17.2 Preparation of the final product I-9a17

[0167] Compound I-9a17 was synthesized by replacing the raw material with the same equivalent of 8a17 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.56(d,J=6.7Hz,1H),11.14(s,1H), 10.85(s,1H),8.22(s,1H),7.76-7.68(m,2H),7.60(d,J=7.8Hz,2H),7.55(d,J=7.0 Hz,1H),7.49(t,J=7.5Hz,2H),7.34(d,J=8.3Hz,2H),7.09(d,J=3.5Hz,2H),5.97(d,J=6.5Hz,1H),4.24(s,2H),3.87(s,3H).

[0168] Example 18

[0169] 2-(3-(5-fluoro-2-methoxyphenyl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a18)

[0170] 18.1 Preparation of intermediate 2-chloro-N-((5-fluoro-2-methoxyphenyl)carbamoyl)acetamide (8a18)

[0171] Intermediate 8a18 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ11.14(s,1H),10.75(s,1H),8.00(d,J=10.8Hz,1H),7.15-7.04(m,1H),6.90(t,J=8.4Hz,1H),4.39(s,2H),3.93-3.86(m,3H).

[0172] 18.2 Preparation of the final product I-9a18

[0173] Compound I-9a18 was synthesized by replacing the raw materials with the same equivalent of 8a18 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.57 (d, J = 7.1Hz, 1H), 11.13 (s, 1H), 10.87(s,1H),8.01(dd,J=10.7,3.2Hz,1H),7.75-7.68(m,2H),7.61(d,J=7.7Hz,2H),7.56(d,J=7.7Hz,1H),7.49(t,J=7. 5Hz,2H),7.36-7.31(m,2H),7.06(dd,J=9.2,5.2Hz,1H),6.88(td,J=8.5,3.2Hz,1H),5.98(d,J=7.0Hz,1H),4.24(d,J=7.5 Hz, 2H), 3.85 (d, J = 7.7Hz, 3H), 3.40 (s, 3H).

[0174] Example 19

[0175] 2-(3-(5-chloro-2-nitrophenyl)ureo)-2-oxoethyl-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a19)

[0176] 19.1 Preparation of intermediate 2-chloro-N-((5-chloro-2-nitrophenyl)carbamoyl)acetamide (8a19)

[0177] Intermediate 8a19 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.97(s,1H),11.36(s,1H),8.57(s,1H),8.21(d,1H),7.39(d,1H),4.41(s,2H); 13C NMR (150MHz, DMSO-d6) δ168.5, 150.4, 139.6, 136.6, 134.3, 127.5, 123.7, 122.1, 43.1; HR-MS (ESI): m / z[MH]-calcd for C9H7Cl2N3O4: 289.9741, found: 289.9740.

[0178] 19.2 Preparation of the final product I-9a19

[0179] Compound I-9a19 was synthesized by replacing the raw material with the same equivalent of 8a19 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ12.09 (s, 1H), 11.57 (d, J = 6.5Hz, 1H), 11.33(s,1H),8.60(s,1H),8.19(d,J=9.0Hz,1H),7.79-7.66(m,2H),7.64-7. 44(m,5H),7.41-7.27(m,3H),5.97(d,J=6.3Hz,1H),4.27(s,2H),3.39(s,3H); 13 C NMR (150MHz, DMSO-d6)δ196.38,169.91,166.98,165.91,150.43,142.53,139.46,137.24, 136.37,134.30,132.28,130.75,129.61,129.37,128.23,127.88,127.39,124.40,123.34, 122.06,121.84,75.37,38.58,34.73; ESI-MS:m / z 596.6[M+H] + C 26 H 21 ClN6O5S2, HRMS calcd.597.0776[M+H] + ,found 597.0780.

[0180] Example 20

[0181] 2-(3-(5-chloro-2-nitrophenyl)ureo)-2R-oxoethyl-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio((R)-I-9a19)

[0182] Synthesized according to the method in Example 19. Given the seven-membered nitrogen in the structure of compound I-9a19. The ring contains one chiral C atom, and it is a mixture with a pair of enantiomers. We performed chiral column separation of I-9a19 to obtain the optically pure compound (R)-I-9a19, as follows:

[0183] Column: CHIRALPAK IG (IG00CE-UC011, Column size: 0.46cm ID×25cm L,

[0184] Injection: 2μL, Mobile phase: DCM / MeOH=80 / 20(V / V), Flow rate: 1.0 mL / min,

[0185] Wavelength: UV 254nm, Temperature: 35℃, HPLC equipment: Shimadzu LC-20AT.

[0186] Compound (R)-I-9a19 was prepared. 1 H NMR(400MHz,DMSO-d6)δ12.09(s,1H),11.57(d, J=6.5Hz,1H),11.33(s,1H),8.60(s,1H),8.19(d,J=9.0Hz,1H),7.79-7.66(m,2H) ,7.64-7.44(m,5H),7.41-7.27(m,3H),5.97(d,J=6.3Hz,1H),4.27(s,2H),3.39(s, 3H); 13 C NMR(150MHz,DMSO-d6)δ196.38,169.91,166.98,165.91,150.43,142.53, 139.46,137.24,136.37,134.30,132.28,130.75,129.61,129.37,128.23,127 .88,127.39,124.40,123.34,122.06,121.84,75.37,38.58,34.73; ESI-MS:m / z 596.6[M+H] + C 26 H 21 ClN6O5S2,HRMScalcd.597.0776[M+H] + , found 597.0780.l; HPLC column: t (R) = 4.187min, ee = 99.08%, [a] 20 D = +73.0 (c = 0.1, CHCl3)

[0187] Example 21

[0188] 2-(3-(5-chloro-2-nitrophenyl)ureo)-2S-oxoethyl-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio((S)-I-9a19)

[0189] Following the steps of Example 20, compound (S)-I-9a19 was prepared and resolved. 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),11.57(d,J=6.5Hz,1H),11.33(s,1H),8.60(s,1H),8.19(d, J=9.0Hz,1H),7.79-7.66(m,2H),7.64-7.44(m,5H),7.41-7.27(m,3H),5.97(d,J=6.3Hz,1H),4.27(s,2H),3.39(s,3H); 13 C NMR(150MHz,DMSO-d6)δ196.38, 169.91,166.98,165.91,150.43,142.53,139.46,137.24,136.37,134.30,132.28,130.75 ,129.61,129.37,128.23,127.88,127.39,124.40,123.34,122.06,121.84,75.37,38.58, 34.73; ESI-MS:m / z 596.6[M+H] + C 26 H 21 ClN6O5S2,HRMS calcd.597.0776[M+H] + , found 597.0780; HPLCcolumn:t(S)=3.419min,ee=99.68%,[a] 20 D = -68.0 (c = 0.1, CHCl3).

[0190] Example 22

[0191] 2-(3-(2,4-dimethoxybenzyl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) Preparation of -3-yl)carbodithio(I-9a20)

[0192] 22.1 Preparation of intermediate 2-chloro-N-((2,4-dimethoxybenzyl)carbamoyl)acetamide (8a20)

[0193] Intermediate 8a20 was synthesized according to the method in step 1.2 of Example 1. 1H NMR(400MHz,DMSO-d6) δ10.67(s,1H),10.00(s,1H),7.63-7.42(m,3H),4.88(s,2H),4.38(s,2H),3.79(s,3H),3.73(s,3H); HR-MS(ESI):m / z[MH]-calcd for C12H15ClN2O4:285.0648,found:285.0645.

[0194] 22.2 Preparation of the final product I-9a20

[0195] The compound I-9a20 was synthesized by replacing the raw material with the same equivalent of 8a20 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.48(s,1H),10.58(s,1H),8.47(s,1H), 7.81-7.28(m,9H),7.06(d,J=7.8Hz,1H),6.62-6.41(m,2H),5.98-5.95( m,1H),4.22(s,2H),4.14(s,2H),3.78(s,3H),3.72(s,3H),3.38(s,3H); 13 C NMR(150MHz, DMSO-d6)δ196.52,169.36,166.93,165.92,159.87,157.82,152.49,142.53,137.24, 132.28,130.74,129.59,129.34,129.08,128.23,127.87,124.40,122.07,1 18.33,104.26,98.27,75.24,55.33,55.04,38.46,37.90,34.72; ESI-MS:m / z 591.8[M+H] + C 29 H 29 N5O5S2,HRMS calcd.592.1683[M+H] + ,found 592.1685 .

[0196] Example 23

[0197] 2-O-2-(3-(pyridin-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b1)

[0198] 23.1 Preparation of intermediate 2-chloro-N-(pyridin-2-ylcarbamoyl)acetamide (8b1)

[0199] Intermediate 8b1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),10.61(s,1H),8.31(s,1H),7.96-7.81(m,2H),7.15(d,J=5.2Hz,1H),4.43(s,2H).

[0200] 23.2 Preparation of final product I-9b1

[0201] Compound I-9b1 was synthesized by replacing the starting material with the same equivalent of 8b1 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H),11.14(s,1H),10.69(s,1H), 8.28(s,2H),7.92(s,2H),7.79(s,2H),7.68(s,3H),7.51(m,8H),7.30(s,3H),7.11(s,1H),5.94(s,1H),4.24(s,3H),3.37(s,4H) .

[0202] Example 24

[0203] 2-(3-(5-fluoropyridin-2-yl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b2)

[0204] 24.1 Preparation of intermediate 2-chloro-N-(5-fluoropyridin-2-yl)carbamoyl)acetamide (8b2)

[0205] Intermediate 8b2 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.61(s,1H),8.33(d,J=3.0Hz,1H),7.99(dd,J=9.5,4.1Hz,1H),7.79(td,J=8.6,2.9Hz,1H),4.41(s,2H).

[0206] 24.2 Preparation of final product I-9b2

[0207] Compound I-9b2 was synthesized by replacing the starting material with the same equivalent of 8b2 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),11.12(s,1H),10.74(s, 1H),8.28(s,1H),7.97(s,1H),7.81-7.61(m,4H),7.60-7.40(m,5H),7.28(s,1H),5.92(s,1H),4.22(s,2H),3.35(s,3H).

[0208] Example 25

[0209] 2-(3-(6-chloropyridin-2-yl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b3)

[0210] 25.1 Preparation of intermediate 2-chloro-N-((6-chloropyridin-2-yl)carbamoyl)acetamide (8b3)

[0211] Intermediate 8b3 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.60(s,1H),7.91(dd,J=18.9,8.0Hz,2H),7.25(d,J=7.5Hz,1H),4.42(s,2H).

[0212] 23.2 Preparation of final product I-9b3

[0213] Compound I-9b3 was synthesized by replacing the starting material with the same equivalent of 8b3 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.51(s,1H),11.15(s,1H),10.74(s,1H), 7.90(d,J=8.0Hz,1H),7.84(d,J=7.9Hz,1H),7.66(s,2H),7.55(d,J=7.5Hz,3H),7 .45(d,J=7.3Hz,2H),7.28(s,2H),7.20(d,J=7.9Hz,1H),5.92(s,1H),4.23(s,2H), 3.35(s,3H) .

[0214] Example 26

[0215] 2-O-2-(3-(5-(trifluoromethyl)pyridin-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b4)

[0216] 26.1 Preparation of intermediate 2-chloro-N-((5-(trifluoromethyl)pyridin-2-yl)carbamoyl)acetamide (8b4)

[0217] Intermediate 8b4 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),10.85(s,1H),8.74(s,1H),8.20(d,J=31.3Hz,2H),4.46(s,2H).

[0218] 26.2 Preparation of final product I-9b4

[0219] Compound I-9b4 was synthesized by replacing the starting material with the same equivalent of 8b4 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.53(s,1H),11.27(s,1H),10.98(s,1H), 8.66(s,1H),8.19(d,J=8.5Hz,1H),8.11(d,J=6.7Hz,1H),7.70-7.64(m,2H),7.5 3(dd,J=18.1,7.5Hz,3H),7.48-7.41(m,2H),7.28(t,J=7.4Hz,2H),5.92(d,J=8.2 Hz,1H),4.24(s,2H),3.35(s,3H) .

[0220] Example 27

[0221] 2-(3-(3-cyanopyridin-2-yl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b5)

[0222] 27.1 Preparation of intermediate 2-chloro-N-((3-cyanopyridin-2-yl)carbamoyl)acetamide (8b5)

[0223] Intermediate 8b5 was synthesized according to the method in step 1.2 of Example 1. 1H NMR(400MHz,DMSO-d6) δ11.29(d,J=8.0Hz,1H),10.61(s,1H),8.72(d,J=5.3Hz,1H),8.40(d,J=8.0Hz,1H),7.49(t,J=6.5Hz,1H),4.46(d,J=7.5Hz,2H).

[0224] 27.2 Preparation of the final product I-9b5

[0225] Compound I-9b5 was synthesized by replacing the starting material with the same equivalent of 8b5 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),11.30(d,J=6.2Hz,1H), 10.72(s,1H),8.69(s,1H),8.39(d,J=8.2Hz,1H),7.74(dd,J=13.3,6.9Hz,2H), 7.61(t,J=7.2Hz,2H),7.56(s,1H),7.50(q,J=7.5,7.0Hz,3H),7.42-7.29 (m,2H),5.99(t,J=6.7Hz,1H),4.31(d,J=6.5Hz,2H),3.41(d,J=6.5Hz,3H) .

[0226] Example 28

[0227] 2-(3-(6-fluoropyridin-2-yl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b6)

[0228] 28.1 Preparation of intermediate 2-chloro-N-((6-fluoropyridin-2-yl)carbamoyl)acetamide (8b6)

[0229] Intermediate 8b6 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),10.54(s,1H),8.04-7.97(m,1H),7.88(dd,J=8.0,2.3Hz,1H),6.92(dd,J=8.0,2.3Hz,1H),4.44(s,2H).

[0230] 28.2 Preparation of the final product I-9b6

[0231] Compound I-9b6 was synthesized by replacing the starting material with an equivalent amount of 8b6 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.55(d,J=6.7Hz,1H),11.19(s,1H), 10.71(s,1H),8.00(d,J=8.3Hz,1H),7.89(d,J=8.2Hz,1H),7.72(d,J=10.7Hz, 2H),7.60(d,J=7.2Hz,2H),7.56(d,J=6.3Hz,1H),7.50(d,J=7.3Hz,2H),7.34(d, J=6.9Hz,2H),6.90(d,J=8.0Hz,1H),5.97(d,J=6.5Hz,1H),4.28(s,2H),3.40(s, 3H) .

[0232] Example 29

[0233] 2-O-2-(3-(trifluoromethyl)pyridin-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b7)

[0234] 29.1 Preparation of intermediate 2-chloro-N-((3-(trifluoromethyl)pyridin-2-yl)carbamoyl)acetamide (8b7)

[0235] Intermediate 8b7 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.59(s,1H),8.75(s,1H),8.26(d,J=7.3Hz,1H),7.53(s,1H),4.45(s,2H).

[0236] 29.2 Preparation of final product I-9b7

[0237] Compound I-9b7 was synthesized by replacing the starting material with an equivalent amount of 8b7 according to step 1.3 in Example 1. 1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),11.20(s,1H),10.72(s,1H), 8.72(s,1H),8.24(d,J=8.2Hz,1H),7.72(s,3H),7.60(s,2H),7.49(s,2H),7.34(s,2H),5.98(d,J=6.5Hz,1H),4.28(s,2H),3.40(s,3H) .

[0238] Example 30

[0239] 2-O-2-(3-(6-(trifluoromethyl)pyridin-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b8)

[0240] 30.1 Preparation of intermediate 2-chloro-N-((6-(trifluoromethyl)pyridin-2-yl)carbamoyl)acetamide (8b8)

[0241] Intermediate 8b8 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ11.13(s,1H),10.76(d,J=5.5Hz,1H),8.25(d,J=7.8Hz,1H),8.12(t,J=7.9Hz,1H),7.66(t,J=6.3Hz,1H),4.46(d,J=4.9Hz,2H).

[0242] 30.2 Preparation of final product I-9b8

[0243] Compound I-9b8 was synthesized by replacing the starting material with the same equivalent of 8b8 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),11.23(s,1H),10.93(d,J=11.2Hz,1H),8.27(d,J=8.7Hz,1H),8.12(s,1H),7.72(s,3H),7.64-7.59(m,3H), 7.50(s,2H),7.34(s,2H),5.98(s,1H),4.30(s,2H),3.41(s,3H) .

[0244] Example 31

[0245] 2-O-2-(3-(4-(trifluoromethyl)pyridin-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b9)

[0246] 31.1 Preparation of intermediate 2-chloro-N-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)acetamide (8b9)

[0247] Intermediate 8b9 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),10.85(s,1H),8.63(d,J=5.4Hz,1H),8.25(d,J=5.4Hz,1H),7.55(d,J=5.7Hz,1H),4.46(d,J=5.5Hz,2H).

[0248] 31.2 Preparation of final product I-9b9

[0249] Compound I-9b9 was synthesized by replacing the starting material with the same equivalent of 8b9 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),11.27(s,1H),11.00(s,1H), 8.59(d,J=4.8Hz,1H),8.26(s,1H),7.71(d,J=10.9Hz,2H),7.60(d,J=7.3Hz,2H ),7.55(d,J=6.4Hz,1H),7.49(d,J=8.8Hz,3H),7.33(d,J=7.2Hz,2H),5.97(d,J= 6.4Hz,1H),4.29(s,2H),3.39(s,3H) .

[0250] Example 32

[0251] 2-(3-(3-fluoropyridin-2-yl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b10)

[0252] 32.1 Preparation of intermediate 2-chloro-N-((3-fluoropyridin-2-yl)carbamoyl)acetamide (8b10)

[0253] Intermediate 8b10 was synthesized according to the method in step 1.2 of Example 1.1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.23(s,1H),8.26(d,J=4.7Hz,1H),7.82(t,J=9.3Hz,1H),7.36(dt,J=8.6,4.4Hz,1H),4.45(s,2H).

[0254] 32.2 Preparation of the final product I-9b10

[0255] Compound I-9b10 was synthesized by replacing the starting material with the same equivalent of 8b10 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),11.22(s,1H),10.35(s, 1H),8.25(d,J=4.3Hz,1H),7.84-7.69(m,4H),7.63-7.58(m,2H),7.56(d,J=3.4Hz ,1H),7.50(dd,J=7.5,4.1Hz,2H),7.37-7.33(m,2H),5.99(dt,J=6.7,3.7Hz,1H), 4.36-4.25(m,2H),3.40(s,3H).

[0256] Example 33

[0257] 2-(3-(3-nitropyridin-2-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b11)

[0258] 33.1 Preparation of intermediate 2-chloro-N-((3-nitropyridin-2-yl)carbamoyl)acetamide (8b11)

[0259] Intermediate 8b11 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ11.27(d,J=7.3Hz,1H),11.08(d,J=6.8Hz,1H),8.73(d,J=5.1Hz,1H),8.51(d,J=8.1Hz,1H),7.51(dd,J=8.3,4.7Hz,1H),4.44(d,J=8.0Hz,2H).

[0260] 33.2 Preparation of the final product I-9b11

[0261] Compound I-9b11 was synthesized by replacing the starting material with the same equivalent of 8b11 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.59(s,1H),11.31(s,1H),11.20(s, 1H),8.70(s,1H),8.49(s,1H),7.72(s,2H),7.60(s,2H),7.57(s,1H),7.52–7.4 8(m,3H),7.34(s,2H),5.99(d,J=5.6Hz,1H),4.30(s,2H),3.41(d,J=6.4Hz,3H).

[0262] Example 34

[0263] 2-(3-(6-chloro-3-nitropyridin-2-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9b12)

[0264] 34.1 Preparation of intermediate 2-chloro-N-((6-chloro-3-nitropyridin-2-yl)carbamoyl)acetamide (8b12)

[0265] Intermediate 8b12 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H),11.28(s,1H),8.56(dd,J=8.5,1.4Hz,1H),7.59-7.52(m,1H),4.43(d,J=1.4Hz,2H).

[0266] 34.2 Preparation of the final product I-9b12

[0267] Compound I-9b12 was synthesized by replacing the starting material with the same equivalent of 8b12 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.54 (d, J=20.4Hz, 1H), 11.29 (s, 1H),9.81(s,1H),8.53(d,J=7.9Hz,1H),8.45(d,J=10.9Hz,1H),7.70(s,2H),7. 59(d,J=7.5Hz,1H),7.53(d,J=11.7Hz,2H),7.48(d,J=8.1Hz,2H),7.33(d,J=7.7 Hz,2H),5.97(d,J=6.3Hz,1H),4.28(s,2H),3.39(s,3H) .

[0268] Example 35

[0269] 2-O-2-(3-(pyridin-3-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9c1)

[0270] 35.1 Preparation of intermediate 2-chloro-N-(pyridin-3-ylcarbamoyl)acetamide (8c1)

[0271] Intermediate 8c1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ11.01(s,1H),10.19(s,1H),8.70(d,J=2.6Hz,1H),8.30(dd,J=4.7,1.5Hz,1H ), 8.00 (ddd, J=8.1, 2.6, 1.4Hz, 1H), 7.36 (dd, J=8.4, 4.7Hz, 1H), 4.40 (s, 2H).

[0272] 35.2 Preparation of final product I-9c1

[0273] The compound I-9c1 was synthesized by replacing the starting material with the same equivalent of 8c1 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.52 (d, J = 5.7Hz, 1H), 11.05 (s, 1H), 10.34(s,1H),8.68(d,J=8.9Hz,1H),8.28(d,J=3.4Hz,1H),7.98(d,J=4.8Hz,1H), 7.76-7.67(m,2H),7.59(d,J=6.7Hz,2H),7.54(d,J=6.8Hz,1H),7.52-7.45(m,2H), 7.37-7.30(m,3H),5.97(d,J=6.3Hz,1H),4.26(s,2H),3.39(s,3H) .

[0274] Example 36

[0275] 2-(3-(2-methoxypyridin-3-yl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9c2)

[0276] 36.1 Preparation of intermediate 2-chloro-N-((2-methoxypyridin-3-yl)carbamoyl)acetamide (8c2)

[0277] Intermediate 8c2 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.55(s,1H),8.38(d,J=7.7Hz,1H),7.86(d,J=4.8Hz,1H),7.04–6.96(m,1H),4.38(s,2H),3.95(s,3H).

[0278] 36.2 Preparation of final product I-9c2

[0279] The compound I-9c2 was synthesized by replacing the starting material with the same equivalent of 8c2 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.53 (d, J=8.0Hz, 1H), 11.11 (s, 1H), 10.68(s,1H),8.39(d,J=7.7Hz,1H),7.83(d,J=6.8Hz,1H),7.74-7.66(m,2H),7.5 9(d,J=8.6Hz,2H),7.54(d,J=7.9Hz,1H),7.47(t,J=8.1Hz,2H),7.34-7.28(m,2H), 7.02-6.91(m,1H),6.01-5.93(m,1H),4.23(s,2H),3.93(s,3H),3.38(s,3H) .

[0280] Example 37

[0281] 2-O-2-(3-(4-(trifluoromethyl)pyridin-3-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9c3)

[0282] 37.1 Preparation of intermediate 2-chloro-N-((4-(trifluoromethyl)pyridin-3-yl)carbamoyl)acetamide (8c3)

[0283] Intermediate 8c3 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),10.63(s,1H),9.28(s,1H),8.64(d,J=5.1Hz,1H),7.80(d,J=5.0Hz,1H),4.44(s,2H).

[0284] 37.2 Preparation of the final product I-9c3

[0285] The compound I-9c3 was synthesized by replacing the starting material with the same equivalent of 8c3 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.59 (d, J=6.5Hz, 1H), 11.39 (s, 1H), 10.79(s,1H),9.31(d,J=8.7Hz,1H),8.67-8.59(m,1H),7.8-7.72(m,3H),7.62(d, J=7.4Hz,2H),7.58(s,1H),7.51(t,J=7.3Hz,2H),7.36(d,J=9.0Hz,2H),5.99(d,J= 6.7Hz,1H),4.32(s,2H),3.42(s,3H).

[0286] Example 38

[0287] 2-(3-((2-methoxypyridin-3-yl)methyl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9c4)

[0288] 38.1 Preparation of intermediate 2-chloro-N-(((2-methoxypyridin-3-yl)methyl)carbamoyl)acetamide (8c4)

[0289] Intermediate 8c4 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR(400MHz,DMSO-d6) δ10.69(s,1H),8.55(s,1H),8.12–8.02(m,1H),7.53(d,J=7.3Hz,1H),6.97(dd,J=7.2,5.1Hz,1H),4.30(d,J=7.6Hz,4H),3.90(s,3H).

[0290] 38.2 Preparation of the final product I-9c4

[0291] Compound I-9c4 was synthesized according to step 1.3 of Example 1, with the starting material replaced by an equivalent amount of 8c4. ESI-MS: m / z 563.2 [M+H] + .

[0292] Example 39

[0293] 2-(3-(6-chloropyrimidin-4-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9d1)

[0294] 39.1 Preparation of intermediate 2-chloro-N-((6-chloropyrimidin-4-yl)carbamoyl)acetamide (8d1)

[0295] Intermediate 8d1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.30(s,1H),10.85(s,1H),8.77(s,1H),7.97(d,J=2.7Hz,1H),4.46(d,J=2.4Hz, 2H).

[0296] 39.2 Preparation of final product I-9d1

[0297] Compound I-9d1 was synthesized by replacing the starting material with the same equivalent of 8d1 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),11.38(s,1H),10.99(s,1H), 8.71(s,1H),7.94(s,1H),7.70-7.63(m,2H),7.57-7.50(m,3H),7.45(d,J =8.0Hz,2H),7.28(s,2H),5.91(s,1H),4.24(s,2H),3.34(d,J=3.2Hz,3H) .

[0298] Example 40

[0299] 2-O-2-(3-(2-(trifluoromethyl)pyrimidin-5-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9e1)

[0300] 40.1 Preparation of intermediate 2-chloro-N-((2-(trifluoromethyl)pyrimidin-5-yl)carbamoyl)acetamide (8e1)

[0301] Intermediate 8e1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.26(s,1H),10.55(s,1H),9.26(s,2H),4.45(s,2H).

[0302] 40.2 Preparation of the final product I-9e1

[0303] The compound I-9e1 was synthesized by replacing the raw material with the same equivalent of 8e1 according to step 1.3 in Example 1.1 H NMR(400MHz,DMSO-d6)δ11.53(s,1H),11.28(s,1H),10.66(s,1H), 9.21(s,2H),7.68(s,2H),7.57(s,2H),7.45(s,2H),7.29(s,2H),5.93(s,1H),4.26(s,2H),3.35(s,3H) .

[0304] Example 41

[0305] 2-O-2-(3-(pyrazin-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9f1)

[0306] 41.1 Preparation of intermediate 2-chloro-N-(pyrazin-2-ylcarbamoyl)acetamide (8f1)

[0307] Intermediate 8f1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.21(s,1H),10.62(s,1H),9.21(s,1H),8.40(d,J=2.1Hz,2H),4.43(d,J=2.1Hz, 2H).

[0308] 41.2 Preparation of the final product I-9f1

[0309] The compound I-9f1 was synthesized by replacing the raw material with the same equivalent of 8f1 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),9.22(s,1H),8.38(d,J= 10.8Hz,2H),7.73-7.65(m,2H),7.57(d,J=6.0Hz,2H),7.52(d,J=6.4Hz,1H),7 .48-7.43(m,3H),7.30(q,J=8.2Hz,3H),5.93(s,1H),4.25(s,2H),3.36(s,3H) .

[0310] Example 42

[0311] 2-(3-(1H-pyrazol-5-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g1)

[0312] 42.1 Preparation of intermediate N-((1H-pyrazol-5-yl)carbamoyl)-2-chloroacetamide (8g1)

[0313] The intermediate 8g1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ12.42(s,1H),10.89(s,1H),10.27(s,1H),7.657.54(m,1H),6.42-6.29(m,1H),4.35(d,J=7.8Hz,2H).

[0314] 42.2 Preparation of final product I-9g1

[0315] The compound I-9g1 was synthesized by replacing the raw material with the same equivalent amount of 8g1 in step 1.3 of Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),11.14(s,1H),10.65(s,1H), 8.16(s,1H),7.71(d,J=8.0Hz,3H),7.59-7.51(m,3H),7.48(d,J=5.2Hz,2H),7.30(s,2H),6.67(s,1H),5.95(s,1H),4.21(s,2H),3.37(s,3H) .

[0316] Example 43

[0317] 2-O-2-(3-(thiazo-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g2)

[0318] 43.1 Preparation of intermediate 2-chloro-N-(thiazolyl-2-carbamoyl)acetamide (8 g 2)

[0319] Intermediate 8g2 was synthesized according to step 1.2 of Example 1. ESI-MS: m / z 219.9 [M+H] +

[0320] 43.2 Preparation of final product I-9g2

[0321] The compound I-9g2 was synthesized by replacing the raw material with the same equivalent amount of 8g2 in step 1.3 of Example 1. 1H NMR (400MHz, DMSO-d6) δ11.53 (d, J=6.9Hz, 1H), 11.40 (s, 2H), 7.69(d,J=10.1Hz,2H),7.56(dd,J=13.5,7.2Hz,3H),7.46(dq,J=12.6,5.8,3.4H z,3H),7.29(t,J=13.3Hz,3H),6.00–5.88(m,1H),4.28(d,J=9.4Hz,2H),3.36(s, 3H) .

[0322] Example 44

[0323] 2-(3-methyl-1,2,4-thiadiazol-5-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g3)

[0324] 44.1 Preparation of intermediate 2-chloro-N-((3-methyl-1,2,4-thiadiazol-5-yl)carbamoyl)acetamide (8g3)

[0325] Intermediate 8g3 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.62(s,1H),11.45(s,1H),4.52(s,2H),2.45(s,3H).

[0326] 44.2 Preparation of final product I-9g3

[0327] The compound I-9g3 was synthesized by replacing the raw material with the same equivalent amount of 8g3 in step 1.3 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H),11.59(s,1H),11.53(d,J=3.9Hz,1H),7.71(d,J=7.6Hz,2H),7.58(d,J=8.2Hz,3H),7.48(d,J=7.3Hz,3H), 7.32(s,2H),5.95(d,J=5.5Hz,1H),4.32(s,2H),3.38(s,3H),2.42(s,3H) .

[0328] Example 45

[0329] 2-(3-(oxazol-2-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g4)

[0330] 45.1 Preparation of intermediate 2-chloro-N-(oxazol-2-ylcarbamoyl)acetamide (8g / 4)

[0331] The intermediate 8g4 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),10.93(s,1H),7.92(s,1H),7.15(s,1H),4.52(s,2H).

[0332] 45.2 Preparation of final product I-9g4

[0333] The compound I-9g4 was synthesized according to step 1.3 of Example 1, with the starting material replaced by an equivalent amount of 8g4. ESI-MS: m / z 509.1 [M+H] + .

[0334] Example 46

[0335] 2-(3-(5-methyl-1,3,4-oxadiazol-2-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g5)

[0336] 46.1 Preparation of intermediate 2-chloro-N-((5-methyl-1,3,4-oxadiazol-2-yl)carbamoyl)acetamide (8g / 5)

[0337] Intermediate 8g5 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.87(s,1H),4.47(s,2H),3.34(s,3H).

[0338] 46.2 Preparation of final product I-9g5

[0339] The compound I-9g5 was synthesized by replacing the raw material with the same equivalent amount of 8g5 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.52 (d, J=7.8Hz, 1H), 11.27 (s, 1H), 10.90(s,1H),7.76-7.67(m,2H),7.58(d,J=7.6Hz,2H),7.53(d,J=6.9Hz,1H),7.4 7(t,J=7.3Hz,2H),7.32(q,J=8.0,7.1Hz,2H),6.02–5.91(m,1H),4.28(s,2H),3.38 (s,3H),2.44(s,3H) .

[0340] Example 47

[0341] 2-(3-(4-methyloxazolyl-2-yl)ureido)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g6)

[0342] 47.1 Preparation of intermediate 2-chloro-N-((4-methyloxazol-2-yl)carbamoyl)acetamide (8g6)

[0343] Intermediate 8g6 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.28(s,1H),10.95(s,1H),7.43(s,1H),4.56(d,J=9.3Hz,2H),2.07(d,J=9.7Hz, 3H).

[0344] 47.2 Preparation of final product I-9g6

[0345] The compound I-9g6 was synthesized by replacing the raw material with the same equivalent amount of 8g6 in step 1.3 of Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),11.26(s,1H),10.88(s,1H), 7.72(d,J=9.6Hz,2H),7.62-7.57(m,3H),7.55(s,1H),7.49(q,J=7.9,5.9Hz,2H), 7.34(d,J=7.4Hz,2H),5.96(d,J=6.7Hz,1H),4.32(s,2H),3.39(s,3H),2.04(d,J= 3.6Hz,3H) .

[0346] Example 48

[0347] 2-Oxo-2-(3-(4-(trifluoromethyl)oxazol-2-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g7)

[0348] 48.1 Preparation of intermediate 2-chloro-N-((4-(trifluoromethyl)oxazol-2-yl)carbamoyl)acetamide (8g7)

[0349] Intermediate 8g7 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),11.08(s,1H),8.73(s,1H),4.48(s,2H).

[0350] 48.2 Preparation of final product I-9g7

[0351] The compound I-9g7 was synthesized by replacing the raw material with the same equivalent amount of 8g7 in step 1.3 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.55 (s, 1H), 11.25 (d, J = 45.6Hz, 2H), 9.66(s,1H),8.91-8.60(m,2H),7.76(s,2H),7.70-7.47(m,4H),7.37(d,J=11.3Hz ,1H),6.00(d,J=10.6Hz,1H),4.53(d,J=11.7Hz,1H),4.35(d,J=11.5Hz,1H),3.11 (s,3H).

[0352] Example 49

[0353] 2-(3-(1,3-dimethyl-1H-pyrazol-5-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g8)

[0354] 49.1 Preparation of intermediate 2-chloro-N-((1,3-dimethyl-1H-pyrazol-5-yl)carbamoyl)acetamide (8g)

[0355] Intermediate 8g8 was synthesized according to the method in step 1.2 of Example 1. 1H NMR (400MHz, DMSO-d6) δ11.19(s,1H),10.36(s,1H),6.16(s,1H),4.47(s,2H),2.16(s,3H).

[0356] 49.2 Preparation of final product I-9g8

[0357] The compound I-9g8 was synthesized according to step 1.3 of Example 1, with the starting material replaced by an equivalent amount of 8g8. ESI-MS: m / z 536.2 [M+H] + .

[0358] Example 50

[0359] 2-(3-(1-methyl-1H-pyrazol-5-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9g9)

[0360] Preparation of intermediate 2-chloro-N-((1-methyl-1H-pyrazol-5-yl)carbamoyl)acetamide (8g / 9g)

[0361] Intermediate I-8g9 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.13(s,1H),7.36(s,1H),6.23(s,1H),4.44(s,2H),3.68(s,3H).

[0362] 50.2 Preparation of final product I-9g9

[0363] The compound I-9g9 was synthesized according to step 1.3 of Example 1, with the starting material replaced by an equivalent amount of 8g9. ESI-MS: m / z 522.1 [M+H] + .

[0364] Example 51

[0365] 2-(3-(5-methylisoxazo-3-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9h1)

[0366] 51.1 Preparation of intermediate 2-chloro-N-((5-methylisoxazol-3-yl)carbamoyl)acetamide (8h1)

[0367] Intermediate 8h1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),10.50(s,1H),6.58(d,J=1.2Hz,1H),4.41(s,2H),2.38(d,J=1.0Hz, 3H).

[0368] 51.2 Preparation of final product I-9h1

[0369] The compound I-9h1 was synthesized by replacing the raw material with the same equivalent of 8h1 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.52 (d, J=6.4Hz, 1H), 11.19 (s, 1H), 10.66(s,1H),7.77-7.66(m,2H),7.62-7.57(m,2H),7.55(d,J=7.0Hz,1H),7.51-7. 45(m,2H),7.37-7.29(m,2H),6.58(d,J=4.2Hz,1H),5.97(d,J=6.5Hz,1H),4.27(s, 2H),3.40(s,3H),2.38(s,3H) .

[0370] Example 52

[0371] 2-(3-(1-methyl-1H-1,2,4-triazol-3-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9h2)

[0372] 52.1 Preparation of intermediate 2-chloro-N-((1-methyl-1H-1,2,4-triazol-3-yl)carbamoyl)acetamide (8h2)

[0373] Intermediate 8h2 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.30(s,1H),8.37(s,1H),4.45(s,2H),3.80(s,3H).

[0374] 52.2 Preparation of final product I-9h2

[0375] The compound I-9h2 was synthesized by replacing the raw material with the same equivalent of 8h2 according to step 1.3 in Example 1.1 H NMR(400MHz,DMSO-d6)δ11.46(s,1H),11.05(s,1H),10.38(s,1H), 8.33(s,1H),7.75-7.66(m,2H),7.59(d,J=7.7Hz,2H),7.54(d,J=5.7Hz,1H),7.4 8(t,J=6.8Hz,2H),7.33(d,J=8.3Hz,2H),6.00-5.91(m,1H),4.27(s,2H),3.79(s, 3H),3.39(s,3H) .

[0376] Example 53

[0377] 2-(morpholino-4-carbamate)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9i1)

[0378] 53.1 Preparation of intermediate N-(2-chloroacetyl)morpholine-4-carboxamide (8i1)

[0379] Intermediate 8i1 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.25(s,1H),4.54-4.42(m,2H),3.54(dq,J=8.0,3.3,2.7Hz,4H),3.36(dd,J=5.3,2.9Hz,4H).

[0380] 53.2 Preparation of final product I-9i1

[0381] The compound I-9i1 was synthesized by replacing the raw material with the same equivalent of 8i1 according to step 1.3 in Example 1. 1 H NMR(400MHz,DMSO-d6)δ11.41(s,1H),10.16(s,1H),7.76-7.68(m, 2H),7.59(d,J=8.8Hz,2H),7.54(d,J=5.3Hz,1H),7.51-7.44(m,2H),7.37-7.30(m, 2H),5.96(s,1H),4.26(s,2H),3.54(s,4H),3.38(s,3H),3.35-3.34(m,4H) .

[0382] Example 54

[0383] 2-(4-methoxypiperidin-1-carbamate)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9i2)

[0384] 54.1 Preparation of intermediate N-(2-chloroacetyl)-4-methoxypiperidine-1-carboxamide (8i2)

[0385] Intermediate 8i2 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.20(s,1H),4.47(s,2H),3.62(d,J=5.7Hz,2H),3.41(d,J=23.7Hz,2H),3.16(s,3H),1.79(s,2H),1.42(s,2H).

[0386] 54.2 Preparation of the final product I-9i2

[0387] The compound I-9i2 was synthesized by replacing the raw material with the same equivalent of 8i2 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.36 (d, J=6.3Hz, 1H), 10.07 (s, 1H), 7.76-7.67(m,2H),7.58(d,J=7.9Hz,2H),7.54(d,J=6.3Hz,1H),7.47(t,J=7.2Hz,2 H),7.33(q,J=7.6Hz,2H),5.96(d,J=6.7Hz,1H),4.25(s,2H),3.38(s,3H),3.24(d, J=1.2Hz,1H),3.22(s,3H),1.78(d,J=6.6Hz,4H),1.44-1.30(m,4H) .

[0388] Example 55

[0389] 2-Oxo-2-(1,4-dioxa-8-azaspirocyclic[4,5]decane-8-carboxamido)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9i3)

[0390] 55.1 Preparation of intermediate N-(2-chloroacetyl)-1,4-dioxa-8-azaspirocyclic[4.5]decane-8-carboxamide (8i3)

[0391] Intermediate 8i3 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),4.47(s,2H),3.90(d,J=6.0Hz,4H),3.49-3.36(m,4H),1.67-1.58(m,4H).

[0392] 55.2 Preparation of the final product I-9i3

[0393] The compound I-9i3 was synthesized by replacing the raw material with the same equivalent of 8i3 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.36 (d, J=6.5Hz, 1H), 10.14 (s, 1H), 7.75-7.67(m,2H),7.58(d,J=8.0Hz,2H),7.53(d,J=7.0Hz,1H),7.47(t,J=7.3Hz,2 H),7.32(t,J=8.3Hz,2H),5.96(d,J=6.4Hz,1H),4.25(s,2H),3.87(s,4H),3.42(d, J=4.4Hz,4H),3.38(s,3H),1.61-1.56(m,4H) .

[0394] Example 56

[0395] 2-O-2-(3-(tetrahydro-2H-pyran-4-yl)ureo)ethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9i4)

[0396] 56.1 Preparation of intermediate 2-chloro-N-((tetrahydro-2H-pyran-4-yl)carbamoyl)acetamide (8i4)

[0397] Intermediate 8i4 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.05(s,1H),4.27(s,2H),3.79(d,J=12.7Hz,4H),1.77(d,J=12.6Hz, 2H), 1.62 (d, J = 21.1Hz, 1H), 1.45 (tt, J = 11.0, 5.8Hz, 2H).

[0398] 56.2 Preparation of the final product I-9i4

[0399] The compound I-9i4 was synthesized by replacing the raw material with the same equivalent of 8i4 according to step 1.3 in Example 1. 1 H NMR (400MHz, DMSO-d6) δ11.45 (d, J=6.1Hz, 1H), 10.54 (s, 1H), 8.14(s,1H),7.76-7.68(m,2H),7.62-7.53(m,3H),7.52-7.45(m,2H),7.37-7.29(m, 2H),5.97(d,J=8.2Hz,1H),4.15(s,2H),3.85-3.74(m,4H),3.39(s,3H),1.98(d,J=8.1Hz,1H),1.76(d,J=4.7Hz,2H),1.61(s,2H) .

[0400] Example 57

[0401] 2-(3-((3s,5s,7s)-adamantane-1-yl)ureo)-2-oxoethyl(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-9i5)

[0402] 57.1 Preparation of intermediate N-(((3s,5s,7s)-adamantane-1-yl)carbamoyl)-2-chloroacetamide (8i5)

[0403] Intermediate 8i5 was synthesized according to the method in step 1.2 of Example 1. 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.01(s,1H),4.25(q,J=6.4,5.0Hz,2H),2.04(s,3H),1.97-1.91(m,6H),1.63(d,J=8.7Hz,6H).

[0404] 57.2 Preparation of the final product I-9i5

[0405] The compound I-9i5 was synthesized by replacing the raw material with the same equivalent of 8i5 according to step 1.3 in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.43 (d, J=19.5Hz, 1H), 10.35 (s, 1H), 8.11(s,1H),7.77-7.67(m,2H),7.63-7.53(m,3H),7.48(t,J=7.4Hz,2H),7.38-7.29 (m,2H),5.97(d,J=6.3Hz,1H),4.13(s,2H),3.40(s,3H),2.02(s,3H),1.92(d,J=9.3 Hz,6H),1.62(s,6H) .

[0406] Example 58

[0407] 2-O-2-(3-(4-(trifluoromethoxy)phenyl)ureo)ethyl(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-10a1)

[0408] 58.1 Preparation of final product I-10a1

[0409] Compound I-10a1 was synthesized according to the method in step 1.3 of Example 1. 1 H NMR(400MHz, DMSO-d6)δ11.49(s,1H),11.00(s,2H),10.42(s,1H),7.65(dd,J=8.8,3.4Hz,3H), 7.57-7.51(m,3H),7.48(d,J=7.3Hz,2H),7.36-7.29(m,4H),7.26(d,J=6.9Hz,1H),5.91(d,J=5.5Hz,1H),4.28(s,2H) .

[0410] Example 59

[0411] 2-(3-(4-(dimethylamino)phenyl)ureo)-2-oxoethyl(2-oxy-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-10a2)

[0412] 59.1 Preparation of final product I-10a2

[0413] Compound I-10a2 was synthesized according to step 1.3 of Example 1. 1H NMR (400MHz, DMSO-d6) δ11.45(s,1H),10.99(s,1H),10.80(s,1H),10.04(s,1H),7.65(t,J=7.7 Hz,1H),7.54(d,J=7.8Hz,3H),7.49(d,J=7.2Hz,2H),7.30(td,J=14.6,14.1,8.5 Hz,5H),6.69(d,J=8.5Hz,2H),5.92(d,J=6.4Hz,1H),4.25(s,2H),2.85(d,J=4.0Hz,6H) .

[0414] Example 60

[0415] 2-O-2-(3-(2-(trifluoromethyl)phenyl)ureo)ethyl(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-10a3)

[0416] 60.1 Preparation of final product I-10a3

[0417] Compound I-10a3 was synthesized according to step 1.3 of Example 1. 1 H NMR(400MHz, DMSO-d6)δ11.46(s,1H),11.20(s,1H),10.98(s,1H),10.75(s,1H),8.12(d,J=8 .1Hz,1H),7.69(dq,J=20.2,7.6Hz,3H),7.54(d,J=7.3Hz,3H),7.48(t,J=7.7Hz, 2H),7.31(td,J=19.1,18.1,8.1Hz,4H),5.91(d,J=6.6Hz,1H),4.30(d,J=5.1Hz, 2H) .

[0418] Example 61

[0419] 2-(3-(5-chloro-2-nitrophenyl)ureo)-2-oxoethyl(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-10a4)

[0420] 61.1 Preparation of the final product I-10a4

[0421] Compound I-10a4 was synthesized according to step 1.3 of Example 1. 1H NMR(400MHz, DMSO-d6)δ12.06(s,1H),11.48(d,J=6.6Hz,1H),11.30(s,1H),10.96(s,1H),8.57 (d,J=2.3Hz,1H),8.16(d,J=8.9Hz,1H),7.60(t,J=7.5Hz,1H),7.49(d,J=7.4Hz, 3H),7.46-7.40(m,2H),7.34(dd,J=8.9,2.3Hz,1H),7.31-7.24(m,2H),7.20(t,J= 7.6Hz,1H),5.86(d,J=6.7Hz,1H),4.24(d,J=4.6Hz,2H) .

[0422] Example 62

[0423] 2-O-2-(3-(pyridin-2-yl)ureo)ethyl(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-10a5)

[0424] 62.1 Preparation of the final product I-10a5

[0425] Compound I-10a5 was synthesized according to step 1.3 of Example 1. 1 H NMR(400MHz, DMSO-d6)δ11.49(s,1H),11.16(s,1H),11.04-10.96(m,1H),10.71(s,1H),8.31(s, 1H),7.96(s,1H),7.82(s,1H),7.66(s,1H),7.58-7.45(m,5H),7.36-7.22(m,3H),7.14(s,1H),5.92(s,1H),4.30(s,2H) .

[0426] Example 63

[0427] 2-(morpholino-4-carbamate)-2-oxoethyl(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)carbodithio(I-10a6)

[0428] 63.1 Preparation of the final product I-10a6

[0429] Compound I-10a6 was synthesized according to the method in step 1.3 of Example 1. 1H NMR(400MHz, DMSO-d6)δ11.33(s,1H),10.97(s,1H),10.14(s,1H),7.64(s,1H),7.49(s,3H),7.45 (d,J=7.5Hz,2H),7.31(s,2H),7.22(t,J=7.6Hz,1H),5.83(s,1H),4.27(s,2H),3.53(s,4H),3.35(s,4H) .

[0430] Example 64

[0431] 2-(3-(3-chloro-5-(trifluoromethyl)phenyl)ureo)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)oxazol-5-carboxamide (I-11a1)

[0432] 64.1 Preparation of intermediate 2-(3-(3-chloro-5-(trifluoromethyl)phenyl)ureo)oxazol-5-carboxylic acid (8j1)

[0433] The operation is the same as that for the synthesis of 8j2. 1 H NMR (400MHz, DMSO-d6) δ13.44(s,1H),11.44(s,1H),10.29(s,1H),8.08(s,1H),7.82(s,1H),7.73(s,1H),7.65(s,1H).

[0434] 64.2 Preparation of final product I-11a1

[0435]

[0436] 0.132 g (0.38 mmol) of compound 8j1, 0.07 g (0.38 mmol) of EDCI, and 0.06 g (0.45 mmol) of HOBT were weighed and placed in a 100 mL round-bottom flask. 1 mL of N-methylmorpholine and 20 mL of dichloromethane were added. The mixture was stirred at room temperature for 30 min. Then, 0.1 g (0.38 mmol) of compound 7 was added to the reaction system, and the reaction was allowed to proceed overnight at room temperature. The reaction system was concentrated under vacuum and then purified by column chromatography to obtain the final product I-11a1, with a yield of 50%. 1H NMR(400MHz, DMSO-d6)δ10.39(s,1H),9.41(s,1H),8.11(s,2H),7.72(dq,J=25.7,9.3Hz,5H), 7.57(d,J=7.6Hz,2H),7.52(d,J=6.4Hz,1H),7.46(d,J=7.4Hz,2H),7.34(s,2H),5.45(d,J=7.7Hz,1H),3.39(s,3H) .

[0437] Example 65

[0438] 3-(3-(3-chloro-5-(trifluoromethyl)phenyl)ureo)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)benzamide (I-11a2)

[0439] Preparation of intermediate 8j2 (65.1)

[0440]

[0441] 0.5 g (3 mmol) of ethyl 3-aminobenzoate and 0.7 mL (4.5 mmol) of triethylamine were dissolved in a 100 mL round-bottom flask. Dichloromethane was added to dissolve the compound, and 0.45 g (2 mmol) of phenyl 4-chloro-3-trifluoromethyl isocyanate was added at room temperature. The reaction was allowed to proceed overnight. A solid precipitated during the reaction. The obtained compound was filtered and 20 mL of a 1:1 mixture of 2N NaOH and methanol was added. The mixture was reacted at room temperature for 3 h. The pH was adjusted to acidic by adding excess hydrochloric acid. The organic solvent was evaporated under vacuum, and the mixture was extracted three times with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography to obtain 8j2, a white solid, in 50% yield. 1 H NMR (400MHz, DMSO-d6) δ12.93 (s,1H),9.19(s,1H),9.06(s,1H),8.16-8.05(m,2H),7.70-7.51(m,4H),7.40(d,J=7.7 Hz,1H).

[0442] 65.2 Preparation of final product I-11a2

[0443] The procedure is the same as that for the synthesis of 11a1. 1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),9.47(d, J=7.9Hz,1H),9.36(s,1H),8.11(s,1H),7.94(s,1H),7.68(dt,J=20.0,9.7Hz,5H), 7.62-7.56(m,3H),7.51(d,J=7.0Hz,1H),7.49-7.33(m,5H),5.52(d,J=7.7Hz,1H), 3.40(s,3H) .

[0444] Example 66

[0445] 5-Chloro-N-(4-((1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diaza) -3-yl)amino)-4-oxobutyl)-2-nitrobenzamide (I-11a3)

[0446] Preparation of intermediate 8j3 (66.1)

[0447]

[0448] Weigh 0.3 g (1.5 mmol) of 3-chloro-2-nitrobenzoic acid, 0.38 g (3.0 mmol) of EDCI, and 0.85 g (2.2 mmol) of HOBT into a 100 mL round-bottom flask. Add 1 mL of N-methylmorpholine and 20 mL of dichloromethane. Stir at room temperature for 30 min, then add 0.25 g (1.5 mmol) of ethyl 4-aminobutyrate to the reaction system and react overnight at room temperature. Concentrate the reaction system under vacuum to obtain the amide condensation product. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 8.77 (d, J = 5.7Hz, 1H), 8.08 (dd, J = 8.6, 1.8Hz, 1H), 7.81–7.71 (m, 2H), 4.07 (tt, J = 8.0, 4.1Hz, 2H), 3.23 (t, J = 6.6Hz, 2H), 2.39 (t, J = 7.5Hz, 2H), 1.76 (p, J = 7.1Hz, 2H), 1.19 (td, J = 7.1, 1.7Hz, 3H). The product was added to 20 mL of a 1:1 aqueous solution of methanol and NaOH (2N), reacted at room temperature for 2 h, neutralized with 2N HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under vacuum, and column chromatography to give compound 8j3 as a white solid, yield 48%. 1H NMR (400MHz, DMSO-d6) δ12.11(s,1H),8.77(s,1H),8.08(s,1H),7.75(s,2H),3.22(s,2H),2.31(s,2H),1.72(s,2H).

[0449] 66.2 Preparation of the final product I-11a3

[0450] The procedure is the same as that for the synthesis of I-11a1. 1 H NMR(400MHz,DMSO-d6)δ9.14(d,J=12.3Hz, 1H),8.74(s,1H),8.06(d,J=9.1Hz,1H),7.80-7.63(m,4H),7.51(d,J=10.2Hz,3H), 7.48-7.41(m,2H),7.36-7.27(m,2H),5.31(d,J=8.3Hz,1H),3.36(s,3H),3.24(d,J= 10.8Hz,2H),2.35(t,J=7.3Hz,2H),1.81-1.69(m,2H) .

[0451] Example 67

[0452] The 1,4-benzodiazepine described in this invention Tests on the binding activity of similar compounds to ANXA3 protein.

[0453] Experimental method: The binding activity of compound I to ANXA3 protein was determined by surface plasmon resonance method.

[0454] Main reagents used in the experiment: recombinant ANXA3 protein (expressed and purified by E. coli system), ethanolamine (Cytiva, USA), CM5 chip (Cytiva, USA), amino-coupling kit (Cytiva, USA), Biacore T200 biomacromolecule interaction instrument (GE, USA).

[0455] Experimental Procedure: The Biacore T200 instrument was used for testing. ANXA3 protein was coupled to a CM5 sensor chip. PBS was used as the mobile phase. Compound I solution was flowed through the chip surface at a flow rate of 30 μL / min. The binding time was 30 s, and the dissociation time was 45 s. Signal changes were recorded. The data were fitted and analyzed using Biacore T200 software to calculate the affinity (K0.05) between compound I and ANXA3 protein. D ).

[0456] Example 68

[0457] The 1,4-benzodiazepine described in this invention Tests on the degradation activity of similar compounds on ANXA3 protein.

[0458] Experimental methods: The degradation activity of compound I on ANXA3 protein was determined by Western blotting.

[0459] Cell culture: Human TNBC cells MDA-MB-231, which highly express ANXA3, were cultured in DMEM medium containing 10% serum and 100 U / mL penicillin-streptomycin. Culture conditions: 37℃, 5% CO2.

[0460] Main reagents used in the experiment: protease inhibitor (Roche, Switzerland), BCA protein quantification kit (Thermo Fisher Scientific, USA), ECL chromogenic solution (WBKLS0500, Milipore, USA), Tubulin antibody (HC101-02, TransGen Biotech, Beijing), ANXA3 antibody (11804-1-AP, Proteineach, USA), secondary antibody (HS201-01, HS101-01, TransGen Biotech, Beijing).

[0461] Experimental steps: 1.5*10 4 Cells were seeded in 6cm culture dishes. After 24 hours, the cells were treated with a solution of compound I as the experimental group. A culture medium containing 0.1% DMSO was added as the control group. After 24 hours of incubation, cells were collected, lysed on ice for 30 minutes with RIAP solution, and then centrifuged at 12000 rpm for 15 minutes at 4°C. The supernatant was collected. Total protein concentration was determined using a BCA kit. The total protein loading was 50 μg. Stacking gel electrophoresis was performed at 80V, separating gel electrophoresis at 120V, followed by constant voltage transfer at 110V for 90 minutes. The membrane was blocked with 5% skim milk at room temperature for 1 hour, incubated overnight at 4°C with primary antibody, washed with TBST, and incubated with horseradish peroxidase-labeled IgG secondary antibody at room temperature for 1 hour. After washing with TBST, ECL chromogenic buffer was evenly dropped onto a PVDF membrane for development. Protein bands were analyzed using ImageJ software, and the half-maximal concentration (DC) was calculated. 50 ).

[0462] Example 69

[0463] The 1,4-benzodiazepine described in this invention In vitro experiments on the inhibition of tumor cell viability by similar compounds.

[0464] Cell culture: Same as in Example 68.

[0465] Main reagents used in the experiment: MTT (Sigma-Aldrich, USA), fetal bovine serum (Ausbian, Australia), and DMEM culture medium (Gibco, USA).

[0466] Experimental Procedure: 5000 cells were seeded into 96-well plates. After 24 hours, compound I was added as the experimental group. Medium containing 0.1% DMSO was used as the control group. Unseeded wells served as the blank group. After 72 hours of incubation, 100 μL of MTT / PBS solution was added to each well, and incubation continued for 4 hours. The supernatant was removed, and 150 μL of DMSO was added. The absorbance (OD) of the 96-well plate at 490 nm was measured. The half-maximal inhibitory concentration (IC50) of compound I was calculated using GraphPad Prism 6 software. 50 The methods for measuring the activity of other tumor cells (human cervical cancer cells HeLa, human ovarian cancer cells A2780, and human colon cancer cells HCT116) are similar to those for MDA-MB-231.

[0467] Example 70

[0468] The compound I-9a19 described in this invention was used in an in vitro experiment to inhibit the formation of tumor cell clones.

[0469] Cell culture: Same as in Example 68.

[0470] Main reagents used in the experiment: paraformaldehyde (Sinopharm Chemical Reagent Co., Ltd.), crystal violet (Bailingwei Technology Co., Ltd.).

[0471] Experimental Procedure: 2000 cells were introduced into 6-well plates. After 24 hours, 2.5 μM I-9a19 solution was added to the cells as the experimental group. Culture medium containing 0.1% DMSO was added to the cells as the control group. The culture medium containing the compound was changed every 3 days. After 2–3 weeks of culture, when visible clones appeared in the control group, the culture was stopped, and paraformaldehyde was added for fixation for 15 min. Then, crystal violet staining was added for 30 min, followed by washing, air drying, and photographing. The colony formation rate was calculated. Colony formation rate = (number of clones / number of seeded cells) × 100%

[0472] Example 71

[0473] Experimental results on the in vitro inhibitory effect of compound I-9a19 on tumor cell migration described in this invention.

[0474] Cell culture: Same as in Example 68.

[0475] Main reagents used in the experiment: Transwell chambers (Corning Incorporated, USA).

[0476] Experimental procedure: Add 680 μL of serum-containing culture medium to the lower chamber of the Transwell, and add 2*10 μL of serum-containing culture medium to the upper chamber.4 Cells were resuspended in 300 μL of serum-free culture medium containing I-9a19 as the experimental group. Cells were also resuspended in 300 μL of serum-free culture medium containing 0.1% DMSO as the control group, and incubated for 24 h. Subsequently, the chambers were removed, the upper chamber was cleaned with cotton swabs, and fixed in paraformaldehyde for 30 min. Then, crystal violet staining was performed for 30 min. After cleaning, the chambers were air-dried. 3-5 fields of view were randomly selected under a microscope for photographing and cell counting.

[0477] Example 72

[0478] Experimental results on the in vitro inhibitory effect of compound I-9a19 on tumor cell invasion described in this invention.

[0479] Cell culture: Same as in Example 68.

[0480] The main reagents used in the experiment were the same as those in Example 71.

[0481] Experimental procedure: Except for changing the pre-laying of Matrigel in the upper chamber of the Transwell to 36 hours instead of 24 hours, the rest of the operation was the same as in Example 71.

[0482] Example 73

[0483] In vivo pharmacodynamic studies of compound I-9a19 against TNBC.

[0484] Cell culture: Same as in Example 68.

[0485] Main reagents used in the experiment: Matrigel (BD Biosciences, USA), RIPA lysis buffer (Thermo Fisher Scientific, USA).

[0486] Experimental steps: 1×10 6 One cell was injected into the fourth pair of mammary pads of female BALB / c nude mice, and the tumor volume was increased to approximately 100 mm². 3 Subsequently, nude mice were randomly divided into a blank solvent group, a control drug docetaxel (DTX) group, and a compound I-9a19 treatment group. Drug administration began on day 1 and continued for 19 days. Afterward, the mice were sacrificed, tumor tissue was obtained, weighed, and the total glycated protein (TGI) was calculated. Then, 10 mg of tumor tissue was added to RIPA lysis buffer, centrifuged, and the supernatant was collected. Protein quantification was performed using the BCA method, and subsequent procedures were performed according to the Western blot assay.

[0487] In summary, the binding activity test based on surface plasmon resonance indicates that the 1,4-phenylenediamine represented by formula (I) is effective. The compounds exhibit sub-micromolar ANXA3 binding activity, as shown in Table 1. Western blot assays demonstrated that these compounds can induce ANXA3 protein degradation in TNBC cells, with activity at the micromolar level, as shown in Table 1. The degradation activity of representative isomers I-9a19, (R)-I-9a19, or (S)-I-9a19 is shown in Table 1. Figure 1 As shown.

[0488] In vitro antitumor activity assays on various tumor cell lines showed that the compounds possessed micromolar-level antitumor activity, as shown in Table 1. In particular, compound I-9a19 significantly inhibited the cloning, migration, and invasion of TNBC cells, as shown in the activity results. Figure 2 As shown. In particular, compound I-9a19 demonstrated effective therapeutic effects and induced ANXA3 protein degradation in tumor tissue in an in vivo TNBC xenograft model, with activity results as shown in... Figure 3 As shown.

[0489] Table 1. Affinity, degradation activity, and inhibitory activity of compound I against ANXA3 and different tumor cell lines.

[0490]

[0491]

[0492]

[0493] Affinity K D , Degradation of active DC 50 and half-maximal inhibitory concentration (IC50) 50 : *: >100μM, **: 10-100μM, ***: 1-10μM, ****: <1μM.

Claims

1. A 1,4-benzodiazepine compound of formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, （I） In formula (I), R1 is selected from a hydrogen atom or a methyl group; X-R2 is selected from: , , , or ,in, R2 is selected from: 1) Substituted benzene, its structure is: ,in, R3-R7 are each independently selected from hydrogen, halogen, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, dimethylamino, nitro, cyano, or acetyl. 2) An aromatic six-membered heterocyclic ring, the structure of which is: , , , or ,in, R8-R 11 are each independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl or methoxy; R'8-R' 11 are each independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl or methoxy; R 12 -R 14 Each is independently selected from hydrogen or halogen; R' 12 -R' 14 Each is independently selected from hydrogen or trifluoromethyl; R'' 12 -R'' 14 Each is independently selected from hydrogen; 3) Aromatic five-membered heterocyclic rings, with the following structure: or ,in, A is selected from nitrogen, oxygen, or sulfur; B is selected from carbon or nitrogen; C is selected from carbon or nitrogen; D is selected from carbon or nitrogen; E is selected from nitrogen or oxygen; F is selected from carbon or nitrogen; R 15 -R 18 Each is independently selected from hydrogen, methyl, or trifluoromethyl; R' 15 -R' 17 Each is independently selected from hydrogen or methyl; 4) Aliphatic heterocycles, with the following structure: or ,in, G is selected from carbon or nitrogen; R 19 Selected from methoxy groups. 2.1, 4-benzodiazepine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, characterized in that, The 1,4-benzodiazepines are specifically selected from compounds with the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

3. The 1,4-benzodiazepine compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to claim 1 or 2, characterized in that, When selected as a stereoisomer, it is either the R or S configuration in the C3 position stereo configuration, specifically selected from ( R )-I-9a19 or ( S Compound )-I-9a19: or .

4. A pharmaceutical composition comprising the 1,4-benzodiazepine compound of claim 1, 2 or 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a medically acceptable carrier.

5. Use of a pharmaceutical composition comprising the 1,4-benzodiazepine compound of claim 1, 2 or 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition comprising the 1,4-benzodiazepine compound of formula (I) of claim 1, 2 or 3, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a medically acceptable carrier, in the preparation of a medicament as an ANXA3 degrader.

6. Use in the preparation of an antitumor drug of a 1,4-benzodiazepine compound of formula (I) as claimed in claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutical composition comprising a 1,4-benzodiazepine compound of formula (I) as claimed in claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a medically acceptable carrier; wherein the tumor is selected from cervical cancer, ovarian cancer, colon cancer or triple-negative breast cancer.

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