Tricyclic heterocyclic derivative as well as preparation method and application thereof

Abstract

The invention provides a tricyclic heterocyclic derivative as well as a preparation method and application thereof, the structural general formula of the tricyclic heterocyclic derivative is as shown in (I): # imgabs0. The invention provides application of a medicine formed by the tricyclic heterocyclic derivative and a pharmaceutically acceptable excipient thereof in preparation of an anti-tumor medicine, and the anti-tumor medicine is intervened by targeting BRAFV600E. The result of a CCK-8 experiment shows that the tricyclic heterocyclic derivative disclosed by the invention has relatively strong anti-tumor activity and can be used for preparing anti-tumor drugs. Kinase activity detection experiments show that the synthesized compounds have remarkable kinase inhibition activity and have the prospect of clinically developing anti-tumor drugs.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a tricyclic heterocyclic derivative and a preparation method and application thereof. Background Art

[0002] Highly invasive, metastatic and recurrent malignant tumors are common and frequently occurring diseases that seriously threaten human life and health. According to WHO statistics, there are 30 million new cases of malignant tumors each year, making it a major disease threatening human health. According to research, RAF kinase and the RAS-RAF-MEK-ERK (MAPK) pathway mediated by it play a significant role in the occurrence, development and metastasis of malignant tumors. The MAPK pathway signal transduction in malignant tumor cells is excessively upregulated, and the signal is transmitted from the extracellular space to the cell nucleus through the specific cascade phosphorylation of RAS, RAF, MEK and ERK, triggering the malignant proliferation and differentiation of cells. As a key kinase in the MAPK pathway, RAF is divided into three subtypes: ARAF, BRAF and CRAF. It can transmit signals such as cell proliferation and differentiation in a RAS-dependent or RAS-independent manner and participate in the completion of mature cell functions.

[0003] The BRAF gene is located on chromosome 7q34 and is closely related to the growth, differentiation and apoptosis of tumor cells. BRAF gene mutations usually occur in the protein kinase activation region, mainly including point mutations, small fragment deletions, amplifications, gene fusions, etc. The most common mutation type is BRAF V600E (Amino acid at position 600 mutates from valine to glutamate). After the BRAF gene mutates, the functional activity of the BRAF-MAPK pathway signal mediated by it increases hundreds of times in the cell. The above pathway is overactivated, and the acceleration of cell proliferation and the extension of cell survival can lead to the formation and development of tumors.

[0004] Currently, drugs targeting BRAF are an effective method for tumor intervention and treatment, such as vemurafenib and dabrafenib. However, the therapeutic effect of vemurafenib is poor. After 5-12 months of medication, 50%-70% of BRAF V600E Patients will develop mutations and acquire drug resistance. Although the combination of dabrafenib and trametinib can temporarily relieve symptoms, half of the patients still acquire drug resistance after 7-14 months, and the combination therapy will produce a variety of adverse reactions. In addition, the clinical trial of neoadjuvant therapy with the immunosuppressant pembrolizumab was not significantly different from that of small molecule targeted drugs. Therefore, it is urgent to develop a new BRAF inhibitor with a nucleus structure to address the above clinical problems. Summary of the invention

[0005] In view of this, the present invention proposes a tricyclic heterocyclic derivative and a preparation method and application thereof to solve the above problems.

[0006] The technical solution of the present invention is achieved in this way:

[0007] A tricyclic heterocyclic derivative, the general structural formula of the tricyclic heterocyclic derivative is shown as (I):

[0008]

[0009] in:

[0010] Ring A, Ring B and Ring C include:

[0011] 1. represents any aromatic ring selected from the group consisting of a substituted benzene ring, an indane ring, a tetralin ring, a piperidine ring, a furan ring, a thiophene ring, a pyrazole ring, an isoxazole ring, a thiazole ring and a tetrahydroquinoline ring;

[0012] 2. Represents substituted C 1 -C 6 A four- to seven-membered monocyclic non-aromatic heterocyclic group consisting of a cycloalkyl group, a pyrrolidinyl group, an oxacycloalkyl group and a tetrahydropyranyl group;

[0013] X 1 , X 4 are different and are each independently selected from a carbon atom or a nitrogen atom;

[0014] X 2 , X 3 are the same or different and are each independently selected from a carbon atom or a nitrogen atom;

[0015] X 5 is selected from a sulfur atom or -CH=CH-;

[0016] R 1 is selected from a hydrogen atom or an alkyl group which may be substituted;

[0017] Z 1 is selected from CH or a nitrogen atom;

[0018] Z 2 Selected from oxygen atoms, -C(R 2 )(R 3 )-,-NH-,-C(R 2 )(R 3 )-NH-, -NH-C(R 2 )(R 3 )-,-C(R 2 )(R 3 )-O-、-OC(R 2 )(R 3 )-,alkyl;

[0019] The R 2 , R 3Each is independently selected from a hydrogen atom, an alkyl group which may be substituted or a cycloalkyl group which may be substituted;

[0020] Alternatively, the R 2 , R 3 They bond with each other and with adjacent carbon atoms to form cycloalkanes which may be substituted.

[0021] Furthermore, the tricyclic heterocyclic derivatives include:

[0022]

[0023]

[0024]

[0025]

[0026] A method for preparing a tricyclic heterocyclic derivative comprises the following steps:

[0027]

[0028] Specifically:

[0029] (1) mixing compound i, compound ii and an acidic substance for reflux reaction, collecting and treating the reaction solution to obtain compound iii;

[0030] (2) Under an inert atmosphere, compound iv, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and 1-hydroxybenzotriazole are added to an organic solvent and stirred, an amine / alcohol compound is added, the reaction is continued, and the reaction solution is collected and treated to obtain compound v;

[0031] (3) Compound v is added to an organic solvent, hydrogen chloride is added, and the mixture is stirred at low temperature. The mixture is heated to room temperature and stirred to react. The reaction solution is collected and treated to obtain compound vi.

[0032] (4) Adding compound iii, compound vi and a basic substance into an organic solvent for reaction, collecting and treating the reaction solution to obtain the corresponding target tricyclic heterocyclic derivative.

[0033] Furthermore, in step (1), the acidic substance is any one of formic acid, acetic acid and acetic anhydride; the molar ratio of compound i, compound ii and the acidic substance is 1.3:1:5; the temperature of the reflux reaction is 100-120°C, and the time is 4-8h; the treatment of the reaction liquid is specifically: cooling the reaction liquid to room temperature, adding a sodium hydroxide solution with a concentration of 4 mol / L, adjusting the pH to 6-7, extracting with ethyl acetate, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, and performing silica gel column chromatography.

[0034] Further, in step (2), the inert atmosphere is argon or nitrogen; the molar ratio of the compound iv, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and 1-hydroxybenzotriazole is 1:1-3:1-3; the organic solvent is at least one of dichloromethane, acetone, methanol, ethanol, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide and N,N-dimethylacetamide; the molar ratio of the organic solvent to the compound iv is 5:1; the amine / alcohol compound includes benzylamine, aniline, 2-ethylhexane, The invention relates to a method for treating a reaction liquid comprising: washing the reaction liquid with water, drying the reaction liquid with anhydrous sodium sulfate, and performing silica gel column chromatography.

[0035] Furthermore, in step (3), the organic solvent is at least one of ethyl acetate, acetone, methanol, ethanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N,N-dimethylformamide and N,N-dimethylacetamide; the molar ratio of the compound v to the organic solvent is 10:1; the low-temperature stirring is stirring at -10 to 0°C for 30-60 minutes; the stirring reaction time is 2-16 hours; and the treatment of the reaction liquid is specifically: the reaction liquid is subjected to reduced pressure distillation to remove the solvent, and recrystallized through a mixed solvent of ethanol and ether in a volume ratio of 1:5-10.

[0036] Furthermore, in step (4), the alkaline substance is at least one of sodium hydroxide, potassium carbonate, potassium hydroxide, sodium carbonate and sodium bicarbonate; the molar ratio of compound iii, compound vi to the alkaline substance and the organic solvent is 1:1-2:1-2:2; the organic solvent is at least one of acetonitrile, acetone, ethanol, methanol, dichloromethane, ethyl acetate, chloroform, carbon tetrachloride, toluene, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide; the reaction time is 3-8h, and the temperature is 60-80°C; the treatment of the reaction liquid is specifically: adding water to the reaction liquid, extracting with ethyl acetate, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and performing silica gel column chromatography.

[0037] The invention discloses an application of a tricyclic heterocyclic derivative in the preparation of an anti-tumor drug.

[0038] Furthermore, the drug comprises the tricyclic heterocyclic derivative and a pharmaceutically acceptable excipient thereof.

[0039] Furthermore, the anti-tumor drug is a drug that targets BRAF V600E to intervene.

[0040] In addition, the present invention also includes prodrugs of the tricyclic heterocyclic derivatives of the present invention, which are derivatives of general formula (I) that may have weak activity or even no activity themselves, but after administration, they are converted into corresponding biologically active forms under physiological conditions (e.g., by metabolism, solvent decomposition or other pathways). The present invention includes pharmaceutical compositions, which contain tricyclic heterocyclic derivatives of general formula (I) as active ingredients, and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients refer to any diluent, adjuvant and / or carrier that can be used in the pharmaceutical field. The tricyclic heterocyclic derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions. The pharmaceutical compositions of the present invention can be formulated into several dosage forms, which contain excipients commonly used in the pharmaceutical field: oral preparations (such as tablets, capsules, solutions or suspensions), injectable preparations (such as injectable solutions or suspensions, or injectable dry powders (which can be used immediately by adding injection water before injection)) and topical preparations (such as ointments, gels or solutions). The carriers of the pharmaceutical composition of the present invention are common types available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers, etc. for injection preparations; bases, diluents, lubricants, preservatives, etc. for local preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically), and if some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

[0041] Terminology

[0042] The term "aromatic ring" refers to a 5-11-membered monocyclic or bicyclic aromatic ring that contains, in addition to carbon atoms, 1-4 oxygen atoms, sulfur atoms and nitrogen atoms, and other heteroatoms, such as benzene, pyridine and other monocyclic aromatic hydrocarbons, naphthalene, tetralin, indene, indane and other partially saturated aromatic hydrocarbons with 9-11 carbon atoms (C 9 -C 11 The term "alkyl" refers to a bicyclic aromatic hydrocarbon having 1 to 6 carbon atoms (C 1 -C 6 ) of a straight or branched saturated hydrocarbon group, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl and their various branched isomers. The term "cycloalkyl" refers to a 4-6 membered (C 4 -C 6 ) is a monocyclic alicyclic saturated hydrocarbon group, such as cyclobutyl, cyclopentyl, and cyclohexyl.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] The results of CCK-8 experiments show that the tricyclic heterocyclic derivatives of the present invention have strong anti-tumor activity and can be used to prepare anti-tumor drugs. Kinase activity detection experiments show that the compounds synthesized by the present invention have significant kinase inhibitory activity and have the prospect of clinical development of anti-tumor drugs. DETAILED DESCRIPTION

[0045] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0046] Abbreviation

[0047]

[0048]

[0049] Example 1-Compound I-1

[0050] N-(4-methylbenzyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0051] (1) Under nitrogen protection, 5-bromo-1,3,4-thiadiazole-2-amine (9.00 g, 50.0 mmol), tert-butyl nitrite (7.22 g, 70 mmol) and copper bromide (13.40 g, 60 mmol) were dissolved in 100 mL of anhydrous acetonitrile and reacted at room temperature. The reaction progress was monitored by TLC during the reaction. After 20 h of reaction, ammonium chloride solution was added to quench the reaction. The mixture was extracted with dichloromethane (20 mL×3), dried over anhydrous sodium sulfate for 3 h, filtered, and the filtrate was distilled under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1 gradient elution). The eluate containing the target product was collected, concentrated under reduced pressure, and dried in vacuo to obtain white crystals (10.85 g) with a yield of 89%, i.e., 2,5-dibromo-1,3,4-thiadiazole;

[0052] (2) 2,5-dibromo-1,3,4-thiadiazole (3.17 g, 13 mmol), anthranilic acid (1.37 g, 10 mmol) and acetic acid (3 mL) were added to a 250 mL round-bottom flask and refluxed at 120°C for 5 h. The reaction progress was monitored by TLC. After the reaction, 4 mol / L sodium hydroxide solution was added to adjust the pH to 6, and the mixture was extracted with ethyl acetate (25 mL×4). The organic layers were combined and washed with saturated sodium chloride solution (25 mL×3), dried over anhydrous sodium sulfate for 3.5 h, filtered to remove the solid, concentrated the organic layer under reduced pressure, and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate in a volume ratio of 4:1, gradient elution). The eluate containing the target product was collected, distilled under reduced pressure, and dried in vacuo to obtain a yellow solid (0.28 g) with a yield of 20%, i.e., 2-bromo-5H-[1,3,4]thiadiazole[2,3-b]quinazolin-5-one;

[0053] 1 H NMR (500MHz, Chloroform-d) δ8.20(dd,J=8.0,1.0Hz,1H),7.75(ddd,J=8.5,7.0,1.5Hz,1H),7.67(dd,J=8.5,1.5Hz,1H),7.51(ddd,J=8.0,7.0,1.5Hz,1H).

[0054] (3) Under nitrogen protection, 3-aminobenzoic acid (6.86 g, 50 mmol), di-tert-butyl dicarbonate (32.74 g, 150 mmol), and triethylamine (15.18 g, 150 mmol) were dissolved in 120 mL of a mixed solvent of 1,4-dioxane and water (volume ratio 2:1), and stirred at room temperature for 24 h. After the reaction was completed, the mixture was distilled under reduced pressure, the pH was adjusted to 5 with 1 M hydrochloric acid, filtered, and the filter residue was dried under vacuum to obtain a white solid (9.50 g) with a yield of 80%, namely Boc-protected 3-aminobenzoic acid;

[0055] 1 H NMR(500MHz,Chloroform-d)δ8.22(t,J=2.0Hz,1H),7.81(ddd,J=8.0,2.0,1.0Hz,1H ),7.68(ddd,J=8.0,2.0,1.0Hz,1H),7.44(t,J=8.0Hz,1H),7.41(s,1H),1.46(s,9H).

[0056] (4) Under nitrogen protection, Boc-protected 3-aminobenzoic acid (1.19 g, 5 mmol), EDC (1.55 g, 10 mmol) and HOBt (1.01 g, 7.5 mmol) were dissolved in dichloromethane (20 mL) and stirred at room temperature for 30 min. During this period, dichloromethane (5 mL) containing benzylamine (1.07 g, 10 mmol) was gradually added dropwise, and the reaction solution was stirred for 12 h at room temperature. During this period, the reaction process was monitored by TLC. After the reaction was completed, the reaction system was washed with water (20 mL), dried over anhydrous sodium sulfate for 3 h, filtered, and the organic layer was concentrated under reduced pressure. Purification was performed by silica gel column chromatography (eluent was dichloromethane:ethyl acetate in a volume ratio of 50:1, gradient elution), the eluent was collected, concentrated under reduced pressure, and dried in vacuo to obtain a slightly yellow solid product (1.19 g) with a yield of 70%, namely (3-(benzylcarbamoyl)phenyl)carbamic acid tert-butyl ester;

[0057] 1 H NMR(500MHz,Chloroform-d)δ8.25(t,J=5.5Hz,1H),7.99(t,J=2.0Hz,1H),7.67-7.64(m ,2H),7.45(t,J=8.0Hz,1H),7.33-7.27(m,6H),4.59(dt,J=5.5,1.0Hz,2H),1.46(s,9H).

[0058] (5) Under nitrogen protection, tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate (1.63 g, 5 mmol) and anhydrous ethyl acetate (10 mL) were added to a 25 mL round-bottom flask, and an ethyl acetate solution (1 mL) containing anhydrous hydrogen chloride (4 mol / L) was drawn into a disposable syringe and slowly injected into the reaction bottle at 0°C. After the addition was completed, stirring was continued for 30 min, and then the reaction system was moved to room temperature and continued to react for 18 h. The reaction progress was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure, and recrystallized from an ethanol and ether system with a volume ratio of 1:8 to obtain a white solid (0.72 g) with a yield of 52%, namely 3-amino-N-benzylbenzamide;

[0059] 1 H NMR(500MHz,Chloroform-d)δ8.29(t,J=6.0Hz,1H),7.50(ddd,J=8.0,2.0,1.0Hz,1H),7.3 6-7.25(m,8H),6.88(ddd,J=8.0,2.0,1.5Hz,1H),4.59(dt,J=6.0,1.0Hz,2H),4.29(s,2H).

[0060] (6) 2-Bromo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one (0.56 g, 2 mmol), sodium hydroxide (0.10 g, 2.4 mmol), 3-amino-N-benzylbenzamide (0.66 g, 2.4 mmol) and acetonitrile (10 mL) were added into a 100 mL round-bottom flask and reacted at 80 °C for 3 h. The reaction progress was monitored by TLC. After the reaction, water (30 mL) was added to the system, extracted with ethyl acetate (15 mL×4), the organic layers were combined, washed with saturated sodium chloride solution (10 mL×3), filtered, concentrated under reduced pressure, and purified and separated by silica gel column chromatography (the eluent was ethyl acetate:methanol in a volume ratio of 20:1, gradient elution), and the eluate containing the target product was collected, concentrated under reduced pressure, and dried in vacuo to obtain a white solid compound (0.79 g) with a yield of 75%, namely N-(4-methylbenzyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0061] mp=213.2-213.8℃. 1 H NMR(500MHz,Chloroform-d)δ8.76(t,J=6.0Hz,1H),8.19(dd,J=8.0,2.0Hz,

[0062] 1H),7.94(t,J=2.0Hz,1H),7.72(ddd,J=9.0,7.0,2.0Hz,1H),7.66-7.59(m,2H),7.50-7.47(m,1H),7.40(dt,J=8.0,1 .5Hz,1H),7.33(t,J=8.0Hz,1H),7.21-7.19(m,2H),7.10-7.08(m,2H),4.54(dt,J=6.0,1.0Hz,2H),2.34-2.33(m,3H). 13 C NMR(125MHz,Chloroform-d)δ167.85,157.88,156.80,151.48,144.12,140.39,137.44,136.45,135.08,134.92, 129.73,128.82,127.78,126.64,124.82,122.78,122.76,119.70,118.61,44.75,21.04.MS(ESI)m / z:442.51[M+H + ].

[0063] Example 2-Compound I-2

[0064] 3-((5-Oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-phenylbenzamide

[0065] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with aniline (0.93 g, 10 mmol) to finally obtain a slightly yellow solid product (1.17 g) with a yield of 75%, namely, tert-butyl (3-(phenylcarbamoyl)phenyl)carbamate;

[0066] 1 H NMR(500MHz,Chloroform-d)δ8.78(s,1H),8.09(t,J=2.0Hz,1H),7.71-7.63(m,5 H),7.47(dd,J=8.5,7.5Hz,1H),7.34-729(m,3H),7.16-7.12(m,1H),1.46(s,9H).

[0067] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-(phenylcarbamoyl)phenyl)carbamate (1.56 g, 5 mmol), and a white solid (0.75 g) was obtained with a yield of 60%, i.e., 3-amino-N-phenylbenzamide;

[0068] 1 H NMR(500MHz,Chloroform-d)δ8.78(s,1H),7.71-7.65(m,3H),7.52-7.48(m,1H),7. 37-7.29(m,5H),7.15-7.13(m,1H),6.88(ddd,J=8.0,2.0,1.0Hz,1H),4.29(s,2H).

[0069] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-phenylbenzamide (0.6 g, 2.4 mmol), and a white solid compound (0.64 g) was finally obtained with a yield of 64%, namely 3-((5-oxo-5H-[1,3,4]thiadiazo[2,3-b]quinazolin-2-yl)amino)-N-phenylbenzamide.

[0070] mp=205.8-206.4℃. 1 H NMR (500MHz, Chloroform-d) δ8.96 (s, 2H), 8.19 (dd, J = 8.0, 2.0Hz, 2H), 8.02

[0071] (t,J=2.0Hz,2H),7.75-7.70(m,3H),7.70-7.67(m,5H),7.62(dd,J=8.5,1.5Hz,2H),7.4 9(ddd,J=8.0,7.0,1.5Hz,2H),7.42-7.36(m,4H),7.34-7.29(m,4H),7.11-7.04(m,2H). 13 C NMR(125MHz,Chloroform-d)δ166.16,157.88,156.80,151.48,144.12,140.67,139.07,135.08,134.25,128.9 5,128.81,127.78,126.64,124.86,124.27,123.23,122.76,120.52,120.45,118.61.MS(ESI)m / z:414.46[M+H + ].

[0072] Example 3-Compound I-3

[0073] 2-((2-ethyl-6-methylphenyl)amino)-7-methyl-5H-[1,3,4]thiadiazo[2,3-b]quinazolin-5-one

[0074] Compared with the synthesis method of Example 1: step (1) is the same as that of Example 1; in step (2), o-aminobenzoic acid is replaced with 4-methyl-2-aminobenzoic acid (1.51 g, 10 mmol), and finally a yellow solid (0.3 g) is obtained with a yield of 25%, namely 2-bromo-7-methyl-5H-[1,3,4]thiadiazo[2,3-b]quinazolin-5-one;

[0075] 1 H NMR (500MHz, Chloroform-d) δ7.99-7.95 (m, 1H), 7.49 (d, J = 8.5Hz, 1H), 7.44-7.39 (m, 1H), 2.38 (s, 3H).

[0076] Steps (3)-(5) are missing; in step (6), 3-amino-N-benzylbenzamide is replaced by 2-ethyl-6-methylaniline (0.32 g, 2.4 mmol), and a white solid compound (0.46 g) is finally obtained with a yield of 55%, namely 2-((2-ethyl-6-methylphenyl)amino)-7-methyl-5H-[1,3,4]thiadiazo[2,3-b]quinazolin-5-one.

[0077] mp=194.7-195.2℃. 1H NMR(500MHz,Chloroform-d)δ8.47(s,1H),7.89-7.86(m,1H),7.41(d,J=

[0078] 1.0Hz,2H),7.12(t,J=8.0Hz,1H),7.03-6.95(m,2H),2.58-2.53(m,2H),2.38(s,3H),2.22(d,J=1.0Hz,3H),1.20(t,J=7.0Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ158.69,156.63,151.85,141.97,139.80,135.81,135.73,135.36,131.54 ,128.50,127.48,126.89,123.61,123.51,119.86,24.33,20.71,17.58,15.06.MS(ESI)m / z:351.44[M+H + ].

[0079] Example 4-Compound I-4

[0080] N-(4-Fluorophenyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0081] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 4-fluoroaniline (1.11 g, 10 mmol), and finally a yellow solid product (1.07 g) is obtained with a yield of 65%, namely tert-butyl (3-((4-fluorophenyl)carbamoyl)phenyl)carbamate;

[0082] 1 H NMR (500MHz, Chloroform-d) δ8.58(s,1H),8.09(t,J=2.0Hz,1H),7.67(d,J=2.0Hz,1H),7.65(d,J=2. 0Hz,1H),7.47(dd,J=8.0,7.5Hz,1H),7.44-7.38(m,3H),7.29(s,1H),7.16-7.08(m,3H),1.46(s,9H).

[0083] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-((4-fluorophenyl)carbamoyl)phenyl)carbamate (1.65 g, 5 mmol), and a white solid (0.77 g) was finally obtained with a yield of 55%, i.e., 3-amino-N-(4-fluorophenyl)benzamide;

[0084] 1 H NMR(500MHz,Chloroform-d)δ8.58(s,1H),7.50-7.48(m,1H),7.45-7.38(m,3H),7. 37-7.28(m,3H),7.16-7.08(m,3H),6.88(ddd,J=8.0,2.0,1.0Hz,1H),4.29(s,2H).

[0085] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(4-fluorophenyl)benzamide (0.64 g, 2.4 mmol) to finally obtain a white solid compound (0.75 g) with a yield of 72%, namely N-(4-fluorophenyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0086] mp=214.8-215.3℃. 1 H NMR (500MHz, Chloroform-d) δ8.54 (s, 1H), 8.19 (dd, J = 8.0, 2.0Hz, 1H), 8.02

[0087] (t,J=2.0Hz,1H),7.75-7.67(m,2H),7.65-7.56(m,3H),7.49(ddd,J=8.0,7.0,1.5Hz,1H),7.43-7.34(m,2H),7.14-7.07(m,2H). 13 C NMR(125MHz,Chloroform-d)δ166.15,158.02(d, 1 J C-F =253.0Hz),157.88,156.80,151.48,144.12,140.67,136.26(d, 4 J C-F =4.0Hz),135.08,134.25,128.81,127.78,126.64,124.86,123.23,122.76,122.65(d, 3 J C-F=9.0Hz),120.45,118.61,116.10(d, 2 J C-F =20.0Hz).MS(ESI)m / z:432.45[M+H + ].

[0088] Example 5-Compound I-5

[0089] N-(4-Fluorobenzyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0090] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced with 4-aminobenzoic acid, and finally Boc-protected 4-aminobenzoic acid is obtained;

[0091] 1 H NMR (500MHz, Chloroform-d) δ8.01-7.95(m,2H),7.93(s,1H),7.56-7.50(m,2H),1.46(s,9H).

[0092] In step (4), Boc-protected 3-aminobenzoic acid was replaced with Boc-protected 4-aminobenzoic acid, and benzylamine was replaced with 4-fluorobenzylamine (1.25 g, 10 mmol), to finally obtain a white solid compound (2.68 g) with a yield of 78%, i.e., tert-butyl (4-((4-fluorobenzyl)carbamoyl)phenyl)carbamate;

[0093] 1 H NMR(500MHz,Chloroform-d)δ7.91(s,1H),7.89-7.81(m,4H),7.52-7.46(m,3H),7.42-7.35(m,2H),7.16-7.08(m,3H),4.56-4.52(m,3H),1.46(s,9H).

[0094] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-((4-fluorobenzyl)carbamoyl)phenyl)carbamate (1.72 g, 5 mmol), and a white solid (1.10 g) was obtained with a yield of 91%, i.e., 4-amino-N-(4-fluorobenzyl)benzamide;

[0095] 1H NMR(500MHz,Chloroform-d)δ7.84(t,J=6.0Hz,1H),7.72-7.66(m,2H),7.30-7.26(m ,2H),7.16-7.08(m,2H),6.50-6.44(m,2H),4.54(s,2H),4.54(dd,J=5.5,1.0Hz,2H).

[0096] In step (6), 3-amino-N-benzylbenzamide was replaced with 4-amino-N-(4-fluorobenzyl)benzamide (0.59 g, 2.4 mmol) to finally obtain a white solid compound (0.69 g) with a yield of 65%, namely N-(4-fluorobenzyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0097] mp=212.4-212.9℃. 1 H NMR(500MHz,Chloroform-d)δ8.67(t,J=6.0Hz,1H),8.19(dd,J=8.0,2.0

[0098] Hz,1H),7.85-7.79(m,2H),7.72(ddd,J=8.0,7.0,1.5Hz,1H),7.62(dd,J=8.5,1.5Hz,1H),7. 60-7.57(m,2H),7.50-7.47(m,1H),7.38-7.34(m,2H),7.11-7.03(m,2H),4.53-4.52(m,2H). 13 C NMR(125MHz,Chloroform-d)δ168.30,162.00(d, 1 J C-F =253.0Hz),157.88,156.80,151.56,144.12,142.34,136.39(d, 4 J C-F =3.0Hz),135.08,129.77(d, 3 J C-F =8.0Hz),129.30,127.78,126.64,124.63,122.76,121.35,118.61,115.29(d, 2 J C-F =20.0Hz),44.75.MS(ESI)m / z:446.47[M+H + ].

[0099] Example 6-Compound I-6

[0100] N-(2-Fluorobenzyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0101] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced with 4-aminobenzoic acid, and finally Boc-protected 4-aminobenzoic acid is obtained;

[0102] In step (4), Boc-protected 3-aminobenzoic acid was replaced with Boc-protected 4-aminobenzoic acid, and benzylamine was replaced with 2-fluorobenzylamine (1.25 g, 10 mmol), to finally obtain a white solid compound (2.98 g) with a yield of 87%, i.e., tert-butyl (4-((2-fluorobenzyl)carbamoyl)phenyl)carbamate;

[0103] 1 H NMR(500MHz,Chloroform-d)δ8.02(t,J=7.0Hz,1H),7.91(s,1H),7.89-7.83(m,2H),7.52-7.46(m,3H),7. 42-7.38(m,1H),7.34-7.26(m,1H),7.25-7.17(m,1H),7.16-7.10(m,1H),4.68-4.62(m,3H),1.46(s,9H).

[0104] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-((2-fluorobenzyl)carbamoyl)phenyl)carbamate (1.74 g, 5 mmol) to finally obtain a white solid (1.03 g) with a yield of 84%, i.e., 4-amino-N-(2-fluorobenzyl)benzamide;

[0105] 1 H NMR(500MHz,Chloroform-d)δ8.09(t,J=7.0Hz,1H),7.72-7.66(m,2H),7.42-7.39(m,1H),7.32- 7.28(m,1H),7.25-7.21(m,1H),7.11(m,1H),6.50-6.44(m,2H),4.66-4.60(m,2H),4.54(s,2H).

[0106] In step (6), 3-amino-N-benzylbenzamide was replaced with 4-amino-N-(2-fluorobenzyl)benzamide (0.56 g, 2.4 mmol) to finally obtain a white solid compound (0.59 g) with a yield of 55%, namely N-(2-fluorobenzyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0107] mp=214.5-215.1℃. 1 H NMR(500MHz,Chloroform-d)δ8.53(t,J=7.0Hz,1H),8.19(dd,J=8.0,2.0

[0108] Hz,1H),7.85-7.79(m,2H),7.72(ddd,J=9.0,7.0,2.0Hz,1H),7.62(dd,J=8.5,1.5Hz,1H),7.60-7.56(m,2H),7.49 (ddd,J=8.0,7.0,1.5Hz,1H),7.40-7.36(m,1H),7.31-7.27(m,1H),7.17-7.07(m,2H),4.60(dd,J=7.0,1.0Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ168.11,160.68(d, 1 J C-F =253.0Hz),157.88,156.80,151.56,144.12,142.34,135.08,130.41(d, 3 J C-F =8.0Hz),129.36(d, 3 J C-F =8.0Hz),129.30,127.78,127.36(d, 2 J C-F =20.0Hz),126.64,124.81(d, 4 J C-F =3.0Hz),124.77,122.76,121.35,118.61,115.33(d, 2 J C-F =20.0Hz),37.87(d, 3 J C-F =5.0Hz),MS(ESI)m / z:446.47[M+H + ].

[0109] Example 7-Compound I-7

[0110] 3-((5-Oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(thiophen-2-ylmethyl)benzamide

[0111] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 2-thiophenemethylamine (1.13 g, 10 mmol), and finally a yellow solid product (1.99 g) is obtained with a yield of 60%, namely tert-butyl (3-((thiophen-2-ylmethyl)carbamoyl)phenyl)carbamate;

[0112] 1 H NMR(500MHz,Chloroform-d)δ8.16(t,J=2.0Hz,1H),8.07(t,J=5.0Hz,1H),7.68-7.64(m,3H) ,7.48-7.41(m,3H),7.29(s,1H),7.05-6.95(m,3H),4.71(dd,J=5.0,1.0Hz,3H),1.46(s,9H).

[0113] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-((thiophen-2-ylmethyl)carbamoyl)phenyl)carbamate (1.66 g, 5 mmol) to finally obtain a white solid (1.01 g) with a yield of 87%, i.e., 3-amino-N-(thiophen-2-ylmethyl)benzamide;

[0114] 1 H NMR(500MHz,Chloroform-d)δ8.13(t,J=5.0Hz,1H),7.52-7.42(m,3H),7.37-7.27(m ,3H),7.05-6.95(m,3H),6.90-6.86(m,1H),4.71(dd,J=4.5,1.0Hz,3H),4.29(s,2H).

[0115] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(thiophen-2-ylmethyl)benzamide (0.56 g, 2.4 mmol) to finally obtain a white solid compound (0.47 g) with a yield of 45%, namely N-(4-fluorophenyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0116] mp=198.7-199.5℃. 1H NMR(500MHz,Chloroform-d)δ8.65(t,J=5.0Hz,1H),8.19(dd,J=8.0,2.0

[0117] Hz,1H),7.94(t,J=2.0Hz,1H),7.72(dddJ=9.0,7.0,2.0Hz,1H),7.66-7.59(m,2H),7.49(ddd,J=8. 0,7.0,1.5Hz,1H),7.41-7.37(m,1H),7.37-7.29(m,2H),7.01-6.92(m,2H),4.68(d,J=5.0Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ167.50,157.88,156.80,151.48,144.12,141.78,140.39,135.08,134.98,128. 79,127.78,127.06,126.64,125.84,125.77,124.82,122.76,119.70,118.61,38.49.MS(ESI)m / z:434.50[M+H + ].

[0118] Example 8-Compound I-8

[0119] N-(sec-butyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0120] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 2-butylamine (0.73 g, 10 mmol), and finally a yellow solid product (1.05 g) is obtained with a yield of 72%, namely tert-butyl (3-(sec-butylcarbamoyl)phenyl)carbamate;

[0121] 1 H NMR(500MHz,Chloroform-d)δ7.98(t,J=2.0Hz,1H),7.66(m,3H),7.45(t,J=8.0Hz,1H),7.29(s,1H),6.87(d ,J=8.5Hz,1H),3.99-3.88(m,1H),1.74-1.70(m,1H),1.46(s,13H),1.23(d,J=6.5Hz,4H),1.02-0.94(m,4H).

[0122] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-(sec-butylcarbamoyl)phenyl)carbamate (1.46 g, 5 mmol) to finally obtain a white solid (0.48 g) with a yield of 42%, i.e., 3-amino-N-(sec-butyl)benzamide;

[0123] 1 H NMR(500MHz,Chloroform-d)δ7.48(ddd,J=8.0,2.0,1.0Hz,1H),7.33(t,J=8.0Hz,1H),7.26(d,J=2.0Hz,1H),6.93(d,J=8 .5Hz,1H),6.92-6.88(m,1H),4.29(s,2H),3.99-3.88(m,1H),1.48-1.42(m,1H),1.23(d,J=6.5Hz,3H),0.94-0.90(m,3H).

[0124] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(sec-butyl)benzamide (0.55 g, 2.4 mmol) to finally obtain a white solid compound (0.55 g) with a yield of 58%, namely N-(sec-butyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0125] mp=189.5-190.2℃. 1 H NMR (500MHz, Chloroform-d) δ8.19 (dd, J=8.0, 2.0Hz, 1H), 7.92 (t, J=2.0

[0126] Hz,1H),7.72(ddd,J=9.0,7.0,2.0Hz,1H),7.65-7.57(m,2H),7.53-7.45(m,2H),7.40(dt,J=8.0,1.5Hz,1H),7.3 6-7.29(m,1H),4.05-3.94(m,1H),1.547-1.51(m,J=7.5,5.0Hz,2H),1.21(d,J=6.5Hz,3H),0.94(t,J=7.5Hz,3H). 13C NMR(125MHz,Chloroform-d)δ167.50,157.88,156.80,151.48,144.12,141.78,140.39,135.08,134.98,128. 79,127.78,127.06,126.64,125.84,125.77,124.82,122.76,119.70,118.61,38.49.MS(ESI)m / z:394.47[M+H + ].

[0127] Example 9-Compound I-9

[0128] 4-((5-Oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(4-phenylbutan-2-yl)benzamide

[0129] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced by 4-aminobenzoic acid to finally obtain Boc-protected 4-aminobenzoic acid; in step (4), Boc-protected 3-aminobenzoic acid is replaced by Boc-protected 4-aminobenzoic acid, and benzylamine is replaced by 2-thiopheneethylamine (1.27 g, 10 mmol), to finally obtain a white solid compound (2.70 g) with a yield of 78%, i.e., tert-butyl (4-((2-(thiophen-2-yl)ethyl)carbamoyl)phenyl)carbamate;

[0130] 1 H NMR(500MHz,Chloroform-d)δ8.15(t,J=5.0Hz,1H),7.91(s,1H),7.88-7.82(m,3H),7.52-7.46(m,3H),7.19(dd,J=5. 0,2.0Hz,1H),6.93(dd,J=6.0,5.0Hz,1H),6.68-6.64(mm,1H),3.45(q,J=5.0Hz,3H),3.05-3.01(m,3H),1.46(s,9H).

[0131] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-((2-(thiophen-2-yl)ethyl)carbamoyl)phenyl)carbamate (1.73 g, 5 mmol) to finally obtain a white solid (1.14 g) with a yield of 85%, i.e., 4-amino-N-(2-(thiophen-2-yl)ethyl)benzamide;

[0132] 1H NMR(500MHz,Chloroform-d)δ8.25(t,J=4.7Hz,1H),7.71-7.65(m,2H),7.19(dd,J=5.5,2.0Hz,1H),6.93(dd,J =6.0,5.5Hz,1H),6.66-6.60(m,1H),6.50-6.44(m,2H),4.54(s,2H),3.45(q,J=5.0Hz,2H),3.04-3.00(m,2H).

[0133] In step (6), 3-amino-N-benzylbenzamide was replaced with 4-amino-N-(2-(thiophen-2-yl)ethyl)benzamide (0.61 g, 2.4 mmol) to finally obtain a white solid compound (0.53 g) with a yield of 54%, namely 3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(4-phenylbutan-2-yl)benzamide.

[0134] mp=201.3-201.9℃. 1 H NMR (500MHz, Chloroform-d) δ8.19 (dd, J=8.0, 2.0Hz, 1H), 8.11 (t, J=5.0

[0135] Hz,1H),7.85-7.79(m,2H),7.72(ddd,J=9.0,7.0,2.0Hz,1H),7.62(dd,J=8.5,1.5Hz,1H),7.60-7.56(m,2H),7.49(ddd,J=8.0,7.0,1.5H z,1H),7.19(dd,J=5.5,1.5Hz,1H),6.93(dd,J=6.0,5.5Hz,1H),6.66(dd,J=6.0,1.5Hz,1H),3.46(q,J=5.0Hz,2H),3.07(t,J=5.0Hz,2H). 13 C NMR(125MHz,Chloroform-d)δ168.38,157.88,156.80,151.56,144.12,142.34,141.76,135.08,129.30,127. 78,127.16,126.64,125.57,125.51,125.44,122.76,121.35,118.61,41.33,30.56.MS(ESI)m / z:448.53[M+H + ].

[0136] Example 10-Compound I-10

[0137] 4-((5-Oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(4-phenylbutan-2-yl)benzamide

[0138] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced by 4-aminobenzoic acid to finally obtain Boc-protected 4-aminobenzoic acid; in step (4), Boc-protected 3-aminobenzoic acid is replaced by Boc-protected 4-aminobenzoic acid, and benzylamine is replaced by 4-phenyl-2-butylamine (1.49 g, 10 mmol), to finally obtain a white solid compound (2.06 g) with a yield of 56%, i.e., tert-butyl (4-((4-phenylbutan-2-yl)carbamoyl)phenyl)carbamate;

[0139] 1 H NMR(500MHz,Chloroform-d)δ7.93-7.84(m,3H),7.52-7.46(m,2H),7.30-7.17(m,5H),6.81(d,J=8.0Hz,1H),3 .95-3.92(m,1H),2.77-2.58(m,2H),1.96-1.92(m,1H),1.82-1.78(m,1H),1.46(s,9H),1.23(d,J=6.0Hz,3H).

[0140] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-((4-phenylbutan-2-yl)carbamoyl)phenyl)carbamate (1.84 g, 5 mmol) to finally obtain a white solid (1.14 g) with a yield of 85%, i.e., 4-amino-N-(4-phenylbutan-2-yl)benzamide;

[0141] 1 H NMR(500MHz,Chloroform-d)δ7.57-7.51(m,2H),7.30-7.17(m,5H),6.93(d,J=8.0Hz,1H),6.50-6.44(m,2H), 4.54(s,2H),3.083.94(m,1H),2.77-2.58(m,2H),1.96-1.92(m,1H),1.83-1.72(m,1H),1.23(d,J=6.0Hz,3H).

[0142] In step (6), 3-amino-N-benzylbenzamide was replaced with 4-amino-N-(4-phenylbutan-2-yl)benzamide (0.64 g, 2.4 mmol) to finally obtain a white solid compound (0.61 g) with a yield of 54%, namely 4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(4-phenylbutan-2-yl)benzamide.

[0143] mp=207.8-208.5℃. 1 H NMR(500MHz,Chloroform-d)δ8.19(dd,J=8.0,2.0Hz,1H),7.83-7.77(m,

[0144] 2H),7.77-7.75(m,1H),7.62(dd,J=8.5,1.5Hz,1H),7.60-7.56(m,2H),7.50-7.47(m,1H),7.42(d,J=8.0H z,1H),7.29-7.17(m,6H),4.00-3.03(m,1H),2.66-2.62(m,2H),1.87-1.69(m,2H),1.23(d,J=6.0Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ167.28,157.57,155.92,153.28,144.11,143.03,141.58,135.08,129.38,128.88,128 .65,128.52,127.78,126.64,126.57,122.77,121.33,118.50,46.35,36.94,32.44,20.87.MS(ESI)m / z:470.56[M+H + ].

[0145] Example 11-Compound I-11

[0146] N-((5-methylfuran-2-yl)methyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0147] Compared with the synthesis method of Example 1: steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced by 4-aminobenzoic acid to finally obtain Boc-protected 4-aminobenzoic acid; in step (4), Boc-protected 3-aminobenzoic acid is replaced by Boc-protected 4-aminobenzoic acid, and benzylamine is replaced by 5-methylfurfurylamine (1.11 g, 10 mmol), to finally obtain a white solid compound (2.28 g) with a yield of 69%, i.e., tert-butyl (4-(((5-methylfuran-2-yl)methyl)carbamoyl)phenyl)carbamate;

[0148] 1 H NMR(500MHz,Chloroform-d)δ7.91(s,1H),7.87(d,J=1.00Hz,1H),7.85(d,J=1.5Hz,1H),7.72(t,J=5.0Hz,1H),7.49(d,J=1.5Hz, 1H),7.48(d,J=1.5Hz,1H),6.50-6.46(m,1H),6.06-6.03(m,1H),4.61(dd,J=5.0,1.0Hz,2H),2.17(d,J=1.0Hz,3H),1.46(s,9H).

[0149] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-(((5-methylfuran-2-yl)methyl)carbamoyl)phenyl)carbamate (1.65 g, 5 mmol) to finally give a white solid (0.75 g) with a yield of 75%, i.e., 4-amino-N-((5-methylfuran-2-yl)methyl)benzamide;

[0150] 1 H NMR(500MHz,Chloroform-d)δ7.81(t,J=5.0Hz,1H),7.72-7.66(m,2H),6.50-6.44(m,3 H),6.07-6.02(m,1H),4.61(dd,J=5.0,1.0Hz,2H),4.54(s,2H),2.17(d,J=1.0Hz,3H).

[0151] In step (6), 3-amino-N-benzylbenzamide was replaced with 4-amino-N-((5-methylfuran-2-yl)methyl)benzamide (0.55 g, 2.4 mmol) to finally obtain a white solid compound (0.40 g) with a yield of 39%, namely N-((5-methylfuran-2-yl)methyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0152] mp=199.8-200.4℃. 1 H NMR(500MHz,Chloroform-d)δ8.56(t,J=5.0Hz,1H),8.19(dd,J=8.0,2.0

[0153] Hz,1H),7.83-7.80(m,2H),7.72(ddd,J=9.0,7.0,2.0Hz,1H),7.62(dd,J=8.5,1.5Hz,1H),7.60-7.57(m,2H),7.49( ddd,J=8.0,7.0,1.5Hz,1H),6.33(d,J=5.0Hz,1H),6.02-6.01(m,1H),4.51(d,J=5.0Hz,2H),2.25(d,J=1.0Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ168.13,157.88,156.80,152.97,152.19,151.56,144.12,142.34,135.08,129. 30,127.78,126.64,125.38,122.76,121.35,118.61,108.53,108.18,37.23,12.80.MS(ESI)m / z:432.47[M+H + ].

[0154] Example 12-Compound I-12

[0155] 3-((5-Oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(4-phenylbutan-2-yl)benzamide

[0156] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 4-phenyl-2-butylamine (1.49 g, 10 mmol), and finally a yellow solid product (0.85 g) is obtained with a yield of 46%, namely tert-butyl (3-((4-phenyl-2-butyl)carbamoyl)phenyl)carbamate;

[0157] 1H NMR(500MHz,Chloroform-d)δ7.98(t,J=2.0Hz,1H),7.71-7.65(m,2H),7.45(t,J=8.0Hz,1H),7.29(s,1H),7.28-7.22(m,3H),7.21-7.18(m,2H ),6.86(d,J=8.0Hz,1H),3.99-3.95(m,1H),2.75-2.79(m,1H),2.61-2. 57(m,1H),1.95-1.93(m,1H),1.79-1.76(m,1H),1.23(d,J=6.0Hz,3H).

[0158] In step (5), tert-butyl (3-(phenylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-((4-phenylbutan-2-yl)carbamoyl)phenyl)carbamate (1.84 g, 5 mmol) to finally obtain a white solid (1.00 g) with a yield of 66%, i.e., 3-amino-N-(4-phenyl-2-butyl)benzamide;

[0159] 1 H NMR(500MHz,Chloroform-d)δ7.98(t,J=2.0Hz,1H),7.68-7.63(m,3H),7.45(t,J=8.0Hz,1H),7.29(s,1H),7.28-7.17(m,7H),6.86(d,J=8. 0Hz,1H),3.95-3.90(m,1H),2.75-2.71(m,1H),2.67-2.63(m,1H),1.9 5-1.92(m,1H),1.81-1.77(m,1H),1.46(s,9H),1.23(d,J=6.0Hz,4H).

[0160] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(4-phenyl-2-butyl)benzamide (0.73 g, 2.4 mmol) to finally obtain a white solid compound (0.59 g) with a yield of 52%, namely 3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(4-phenylbutan-2-yl)benzamide.

[0161] mp=210.1-210.7℃. 1 H NMR (500MHz, Chloroform-d) δ8.19 (dd, J=8.0, 2.0Hz, 1H), 7.92 (t, J=2.0Hz,

[0162] 1H),7.72(ddd,J=9.,7.0,2.0Hz,1H),7.65-7.57(m,3H),7.49(m,J=8.0,7.0,1.5Hz,1H),7.40(dt,J=8.0,1.5Hz,1H), 7.35-7.30(m,1H),7.28-7.17(m,5H),4.00-3.93(m,1H),2.66-2.62(m,2H),1.87-1.69(m,2H),1.23(d,J=6.0Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ167.36,157.57,155.92,153.24,144.11,141.58,140.65,135.08,134.73,128.80,128.65,128 .52,127.78,126.64,126.57,124.83,122.77,122.24,119.65,118.50,46.36,36.94,32.44,20.87.MS(ESI)m / z:470.56[M+H + ].

[0163] Example 13-Compound I-13

[0164] N-(Furan-2-ylmethyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0165] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 2-furylmethylamine (1.49 g, 10 mmol), and finally a yellow solid product (3.16 g) is obtained with a yield of 86%, namely tert-butyl (3-(furan-2-ylmethyl)carbamoyl)phenyl)carbamate;

[0166] 1 H NMR(500MHz,Chloroform-d)δ7.99(t,J=2.0Hz,1H),7.69-7.61(m,3H),7.53(t,J=1.55Hz,1H),7.45(t, J=8.0Hz,1H),6.39(dd,J=5.0,1.5Hz,1H),6.25-6.18(m,1H),4.66(dd,J=5.0,1.0Hz,2H),1.46(s,9H).

[0167] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-(furan-2-ylmethyl)carbamoyl)phenyl)carbamate (1.84 g, 5 mmol) to finally obtain a white solid (0.92 g) with a yield of 69%, i.e., 3-amino-N-(furan-2-ylmethyl)benzamide;

[0168] 1 H NMR(500MHz,Chloroform-d)δ7.70(t,J=5.0Hz,1H),7.55-7.47(m,2H),7.37-7.28(m,2H),6.88(ddd,J=8.0 ,2.0,1.0Hz,1H),6.39(dd,J=5.0,1.5Hz,1H),6.30-6.28(m,1H),4.66(dd,J=5.0,1.0Hz,2H),4.29(s,2H).

[0169] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(furan-2-ylmethyl)benzamide (0.64 g, 2.4 mmol) to finally obtain a white solid compound (0.50 g) with a yield of 44%, namely N-(furan-2-ylmethyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0170] mp=202.0-202.6℃. 1 H NMR(500MHz,Chloroform-d)δ8.56(t,J=5.0Hz,1H),8.19(dd,J=8.0,2.0

[0171] Hz,1H),7.94(t,J=2.5Hz,1H),7.72(ddd,J=9.0,7.0,2.0Hz,1H),7.66-7.59(m,2H),7.49(ddd,J=8 .0,7.0,1.5Hz,1H),7.41-7.39(m,1H),7.36-7.29(m,2H),6.30-6.24(m,2H),4.50(d,J=5.0Hz,2H). 13C NMR(125MHz,Chloroform-d)δ167.73,157.88,156.80,151.85,151.48,144.12,142.29,140.39,135.08,134. 99,128.80,127.78,126.64,124.82,122.76,119.70,118.61,110.56,107.45,36.41.MS(ESI)m / z:418.44[M+H + ].

[0172] Example 14-Compound I-14

[0173] N-(4-methylcyclohexyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0174] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 4-methyl-1-cyclohexylamine (1.23 g, 10 mmol), and finally a yellow solid product (2.63 g) is obtained with a yield of 85%, namely tert-butyl (3-((4-methylcyclohexyl)carbamoyl)phenyl)carbamate;

[0175] 1 H NMR (500MHz, Chloroform-d) δ7.98 (t, J = 2.0 Hz, 1H), 7.67-7.60 (m, 2H), 7.48-7.41 (m, 1H), 7.29 (s, 1H), 6.92 (d, J = 7. 5Hz,1H),3.77-3.72(m,1H),1.76-1.71(m,2H),1.59-1.45(m,4H),1.46(s,9H),1.33-1.22(m,3H),0.95-0.87(m,3H).

[0176] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-((4-methylcyclohexyl)carbamoyl)phenyl)carbamate (1.66 g, 5 mmol) to finally obtain a white solid (0.77 g) with a yield of 66%, i.e., 3-amino-N-(4-methylcyclohexyl)benzamide;

[0177] 1H NMR(500MHz,Chloroform-d)δ7.53-7.47(m,1H),7.33(t,J=8.0Hz,1H),7.26(t,J=2.0Hz,1H),6.96(d,J=8.0Hz,1H),6.91-6.86(m, 1H),4.29(s,1H),3.70-3.70(m,1H),1.79-1.75(m,2H),1.61-1.50(m,2H),1.47-1.42(m,2H),1.34-1.22(m,3H),0.95-0.87(m,3H).

[0178] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(4-methylcyclohexyl)benzamide (0.56 g, 2.4 mmol), and a white solid compound (0.35 g) was finally obtained with a yield of 34%, namely N-(4-methylcyclohexyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0179] mp=213.5-214.1℃. 1 H NMR (500MHz, Chloroform-d) δ8.19 (dd, J=8.0, 1.8Hz, 1H), 7.92 (t, J=2.0

[0180] Hz,1H),7.72(ddd,J=9.0,7.0,2.0Hz,1H),7.65-7.57(m,3H),7.49(ddd,J=7.9,7.0,1.5Hz,1H),7.41-7.39(m,1H),7.33(t,J= 8.01H),3.68-3.62(m,1H),1.73-1.64(m,4H),1.59-1.53(m,2H),1.34-1.28(m,1H),1.23-1.16(m,2H),0.91(d,J=7.5Hz,3H). 13 CNMR(125MHz,Chloroform-d)δ167.59,157.57,155.92,153.24,144.11,140.65,135.08,134.67,128.80,127.7 8,126.64,124.83,122.77,122.24,119.65,118.50,49.17,31.87,31.78,31.23,20.32.MS(ESI)m / z:434.53[M+H + ].

[0181] Example 15-Compound I-15

[0182] N-(4-ethoxyphenyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0183] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced by 4-aminobenzoic acid to finally obtain Boc-protected 4-aminobenzoic acid; in step (4), Boc-protected 3-aminobenzoic acid is replaced by Boc-protected 4-aminobenzoic acid, and benzylamine is replaced by 4-ethoxyaniline (1.37 g, 10 mmol), to finally obtain a white solid compound (2.24 g) with a yield of 63%, namely (4-((4-ethoxyphenyl)carbamoyl)phenyl)carbamate tert-butylcarbamate;

[0184] 1 H NMR(500MHz,Chloroform-d)δ9.14(s,1H),7.98-7.89(m,4H),7.60-7.54(m,3H),7.54-7 .49(m,3H),6.92-6.86(m,3H),4.03(q,J=6.5Hz,3H),1.46(s,9H),1.43(t,J=6.5Hz,4H).

[0185] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-((4-ethoxyphenyl)carbamoyl)phenyl)carbamate tert-butyl carbamate (1.78 g, 5 mmol) to finally obtain a white solid (0.74 g) with a yield of 58%, i.e., 4-amino-N-(4-ethoxyphenyl)benzamide;

[0186] 1 H NMR(500MHz,Chloroform-d)δ9.14(s,1H),7.81-7.75(m,3H),7.60-7.54(m,3H),6.92-6 .86(m,3H),6.62-6.56(m,3H),4.54(s,2H),4.03(q,J=7.0Hz,3H),1.43(t,J=7.0Hz,4H).

[0187] In step (6), 3-amino-N-benzylbenzamide was replaced with 4-amino-N-(4-ethoxyphenyl)benzamide (0.61 g, 2.4 mmol) to finally obtain a white solid compound (0.59 g) with a yield of 54%, namely N-(4-ethoxyphenyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0188] mp=195.6-196.2℃. 1 H NMR (500MHz, Chloroform-d) δ9.01 (s, 1H), 8.19 (dd, J = 8.0, 1.8Hz, 1H), 7.85

[0189] -7.79(m,2H),7.72(m,J=9.0,7.0,2.0Hz,1H),7.70-7.65(m,2H),7.62(dd,J=8.5,1.5Hz,1H),7.60-7.55 (m,2H),7.49(m,J=8.0,7.0,1.5Hz,1H),6.91-6.85(m,2H),4.03(q,J=7.0Hz,2H),1.42(t,J=7.0Hz,3H). 13 CNMR(125MHz,Chloroform-d)δ165.81,157.88,156.80,155.40,151.56,144.12,143.10,135.08,132.86,130 .23,127.78,126.64,123.93,123.15,122.76,121.43,118.61,115.54,63.44,14.67.MS(ESI)m / z:458.51[M+H + ].

[0190] Example 16-Compound I-16

[0191] N-(3-methoxybenzyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0192] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced by 4-aminobenzoic acid to finally obtain Boc-protected 4-aminobenzoic acid; in step (4), Boc-protected 3-aminobenzoic acid is replaced by Boc-protected 4-aminobenzoic acid, and benzylamine is replaced by 3-methoxybenzylamine (1.37 g, 10 mmol), to finally obtain a white solid compound (2.60 g) with a yield of 73%, i.e., tert-butyl (4-((3-methoxybenzyl)carbamoyl)phenyl)carbamate;

[0193] 1 H NMR(500MHz,Chloroform-d)δ8.28(t,J=6.0Hz,1H),7.91(s,1H),7.89-7.83(m,3H),7.52-7.46(m,3H),7. 23(s,1H),7.16(m,1H),6.92-6.84(m,1H),6.83-6.79(m,1H),4.48-4.42(m,3H),3.78(s,3H),1.46(s,9H).

[0194] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-((3-methoxybenzyl)carbamoyl)phenyl)carbamate (1.78 g, 5 mmol) to finally obtain a white solid (0.70 g) with a yield of 55%, i.e., 4-amino-N-(3-methoxybenzyl)benzamide;

[0195] 1 H NMR(500MHz,Chloroform-d)δ8.36(t,J=6.0Hz,1H),7.72-7.66(m,3H),7.26-7.20(m,1H),7.19-7.13(m,1 H),6.89-6.87(m,1H),6.84-6.76(m,1H),6.50-6.44(m,3H),4.54(s,2H),4.48-4.42(m,2H),3.78(s,3H).

[0196] In step (6), 3-amino-N-benzylbenzamide was replaced with 4-amino-N-(3-methoxybenzyl)benzamide (0.61 g, 2.4 mmol) to finally obtain a white solid compound (0.71 g) with a yield of 65%, namely N-(3-methoxybenzyl)-4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0197] mp=200.4-200.9℃.1 H NMR(500MHz,Chloroform-d)δ8.78(t,J=6.0Hz,1H),8.19(dd,J=8.0,2.0

[0198] Hz,1H),7.85-7.79(m,2H),7.77-7.72(m,1H),7.65-7.55(m,3H),7.49(ddd,J=8.0,7.0,1.5Hz,1H),7.20( t,J=8.0Hz,1H),7.08-7.06(m,1H),6.90-6.89(m,1H),6.81-6.79(m,1H),4.47-4.46(m,2H),3.81(s,2H). 13 C NMR(125MHz,Chloroform-d)δ168.30,159.94,157.88,156.80,151.56,144.12,142.34,140.55,135.08,129.71, 129.30,127.78,126.64,124.63,122.76,121.35,118.61,112.97,112.95,55.14,44.16.MS(ESI)m / z:458.51[M+H + ].

[0199] Example 17-Compound I-17

[0200] N-(2,4-dimethoxyphenyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide

[0201] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 2,4-dimethoxyaniline (1.53 g, 10 mmol), and finally a yellow solid product (2.46 g) is obtained with a yield of 66%, namely tert-butyl (3-((2,4-dimethoxyphenyl)carbamoyl)phenyl)carbamate;

[0202] 1H NMR(500MHz,Chloroform-d)δ8.35-8.29(m,3H),8.09(t,J=2.0Hz,1H),7.66(dd,J=8.0,2.0Hz,3H),7.47(dd,J=8.5 ,7.5Hz,1H),7.29(s,1H),7.22(dd,J=8.5,2.5Hz,1H),6.61(d,J=2.5Hz,1H),3.90(s,3H),3.81(s,3H),1.46(s,9H).

[0203] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (3-((2,4-dimethoxyphenyl)carbamoyl)phenyl)carbamate (1.86 g, 5 mmol) to finally obtain a white solid (0.75 g) with a yield of 55%, i.e., 3-amino-N-(2,4-dimethoxyphenyl)benzamide;

[0204] 1 H NMR(500MHz,Chloroform-d)δ8.36-8.29(m,2H),7.51-7.45(m,1H),7.38-7.27(m,3H),7.22(dd,J =9.0,2.5Hz,1H),6.90-6.84(m,1H),6.61(d,J=2.5Hz,1H),4.29(s,2H),3.90(s,3H),3.81(s,3H).

[0205] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(2,4-dimethoxyphenyl)benzamide (0.65 g, 2.4 mmol) to finally obtain a white solid compound (0.54 g) with a yield of 47%, namely N-(2,4-dimethoxyphenyl)-3-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzamide.

[0206] mp=211.2-211.8℃. 1 H NMR (500MHz, Chloroform-d) δ8.95 (s, 1H), 8.19 (dd, J = 8.0, 1.7Hz, 1H), 8.13

[0207] (d,J=9.0Hz,1H),8.01(t,J=2.0Hz,1H),7.75-7.66(m,3H),7.62(dd,J=8.5,1.5Hz,1H),7.51-7.49(m ,1H),7.43-7.33(m,3H),6.61(d,J=2.5Hz,1H),6.55(dd,J=8.5,2.5Hz,1H),3.89(s,3H),3.82(s,3H). 13 CNMR(125MHz,Chloroform-d)δ165.87,160.18,157.88,156.80,152.35,151.48,144.12,140.67,135.08,134.29,128.81,127 .78,127.29,126.64,124.86,123.16,122.76,122.61,120.45,118.61,108.86,99.24,55.64,55.46.MS(ESI)m / z:474.51[M+H + ].

[0208] Example 18-Compound I-18

[0209] 3-((5-Oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)-N-(pyridin-2-ylmethyl)benzamide

[0210] Compared with the synthesis method of Example 1: Steps (1) to (3) are the same as those of Example 1; in step (4), benzylamine is replaced with 2-aminomethylpyridine (1.08 g, 10 mmol), and finally a slightly yellow solid product (1.41 g) is obtained with a yield of 86%, namely, tert-butyl ((3-(pyridin-2-ylmethyl)carbamoyl)phenyl)carbamate;

[0211] 1 H NMR(500MHz,Chloroform-d)δ8.46(dd,J=4.0,2.0Hz,1H),8.22(t,J=5.5Hz,1H),8.16(t,J=2.0Hz,1H),7.6 9-7.62(m,4H),7.51-7.41(m,3H),7.37-7.32(m,1H),7.29(s,1H),4.63(dd,J=5.5,1.0Hz,3H),1.46(s,9H).

[0212] In step (5), tert-butyl (3-(phenylcarbamoyl)phenyl)carbamate was replaced with tert-butyl ((3-(pyridin-2-ylmethyl)carbamoyl)phenyl)carbamate (1.64 g, 5 mmol) to finally obtain a white solid (0.95 g) with a yield of 72%, i.e., 3-amino-N-(pyridin-2-ylmethyl)benzamide;

[0213] 1 H NMR(500MHz,Chloroform-d)δ8.46(dd,J=4.0,2.0Hz,1H),8.25(t,J=5.5Hz,1H),7.66(td,J=7.5,1.5Hz,1H),7. 52-7.44(m,3H),7.36-7.28(m,4H),6.88(ddd,J=8.0,2.0,1.5Hz,1H),4.63(dd,J=5.5,1.0Hz,3H),4.29(s,2H).

[0214] In step (6), 3-amino-N-benzylbenzamide was replaced with 3-amino-N-(pyridin-2-ylmethyl)benzamide (0.63 g, 2.4 mmol) to finally obtain a white solid compound (0.79 g) with a yield of 75%, namely 3-((5-oxo-5H-[1,3,4]thiadiazo[2,3-b]quinazolin-2-yl)amino)-N-(pyridin-2-ylmethyl)benzamide.

[0215] mp=199.4-200.2℃. 1 H NMR(500MHz,Chloroform-d)δ8.60(t,J=5.5Hz,1H),8.48(dd,J=4.0,2.0

[0216] Hz,1H),8.19(dd,J=8.0,2.0Hz,1H),7.94(t,J=2.0Hz,1H),7.75-7.68(m,2H),7.65-7.60(m, 2H),7.53-7.46(m,2H),7.40(dt,J=8.0,1.5Hz,1H),7.37-7.30(m,2H),4.61(d,J=5.5Hz,2H). 13C NMR(125MHz,Chloroform-d)δ167.67,158.52,157.88,156.80,151.48,149.47,144.12,140.39,136.84,135.08,1 34.98,128.79,127.78,126.64,124.82,122.76,122.33,122.14,119.70,118.61,45.24.MS(ESI)m / z:429.47[M+H + ].

[0217] Example 19-Compound I-19

[0218] 2-((4-(1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)phenyl)amino)-5H-[1,3,4]thiadiazo[2,3-b]quinazolin-5-one

[0219] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced by 4-aminobenzoic acid to finally obtain Boc-protected 4-aminobenzoic acid; in step (4), Boc-protected 3-aminobenzoic acid is replaced by Boc-protected 4-aminobenzoic acid, and benzylamine is replaced by 1,2,3,4-tetrahydroisoquinoline (1.33 g, 10 mmol), to finally obtain a white solid compound (3.10 g) with a yield of 88%, namely tert-butyl (4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)carbamate;

[0220] 1 H NMR(500MHz,Chloroform-d)δ7.65-7.59(m,3H),7.52-7.46(m,3H),7.18-7.11(m, 4H), 4.63 (d, J = 1.0Hz, 2H), 3.83 (t, J = 5.0Hz, 3H), 2.96-2.84 (m, 3H), 1.46 (s, 9H).

[0221] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl (4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)carbamate (1.76 g, 5 mmol) to finally obtain a white solid (0.82 g) with a yield of 65%, i.e., (4-aminophenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone;

[0222] 1H NMR(500MHz,Chloroform-d)δ7.53-7.47(m,3H),7.26-7.20(m,1H),7.19-7.10(m,4H),6.71 -6.65(m,3H),4.63(d,J=1.0Hz,2H),4.51(s,2H),3.83(t,J=5.0Hz,3H),2.96-2.84(m,3H).

[0223] In step (6), 3-amino-N-benzylbenzamide was replaced with (4-aminophenyl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone (0.60 g, 2.4 mmol) to finally obtain a white solid compound (0.70 g) with a yield of 64%, namely 2-((4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)amino)-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one.

[0224] mp=192.7-193.1℃. 1 H NMR (500MHz, Chloroform-d) δ8.19 (dd, J=8.0, 1.8Hz, 1H), 7.72 (ddd, J=

[0225] 9.0,7.0,2.0Hz,1H),7.62(dd,J=8.5,1.5Hz,1H),7.56-7.51(m,2H),7.49(ddd,J=8.0,7.0,1.5Hz,1H),7.31-7.21(m,3H ),7.19-7.11(m,3H),4.67(d,J=1.0Hz,2H),3.80(dd,J=5.5,4.5Hz,1H),3.72(dd,J=5.5,4.5Hz,1H),2.94-2.92(m,2H). 13 C NMR(125MHz,Chloroform-d)δ169.16,157.88,156.80,151.56,144.12,142.51,135.90,135.08,132.53,131.18,129.90, 128.51,127.78,127.29,127.21,126.71,126.64,122.76,121.72,118.61,50.94,44.41,28.90.MS(ESI)m / z:454.52[M+H + ].

[0226] Example 20-Compound I-20

[0227] Ethyl 4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzoate

[0228] Compared with the synthesis method of Example 1: step (1) is the same as Example 1; steps (2)-(5) are missing; in step (6), 3-amino-N-benzylbenzamide is replaced with ethyl 4-aminobenzoate (0.40 g, 2.4 mmol), and finally a white solid compound (0.51 g) is obtained with a yield of 58%, namely ethyl 4-((5-oxo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-2-yl)amino)benzoate.

[0229] mp=182.3-182.7℃. 1 H NMR(500MHz,Chloroform-d)δ8.19(dd,J=8.0,1.8Hz,1H),7.91-7.85(m,2H),7.72

[0230] (ddd,J=9.0,7.0,2.0Hz,1H),7.65-7.58(m,3H),7.49(ddd,J=8.0,7.0,1.5Hz,1H),4.35(q,J=6.5Hz,2H),1.38(t,J=6.5Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ166.45,157.88,156.80,151.57,144.12,143.10,135.08,131. 56,127.78,126.64,124.41,122.76,120.57,118.61,60.99,14.30.MS(ESI)m / z:367.39[M+H + ].

[0231] Example 21-Compound I-21

[0232] 2-((4-Phenoxyphenyl)amino)-5H-[1,3,4]thiadiazo[2,3-b]quinazolin-5-one

[0233] Compared with the synthesis method of Example 1: step (1) is the same as Example 1; steps (2)-(5) are missing; in step (6), 3-amino-N-benzylbenzamide is replaced by 4-phenoxyaniline (0.44 g, 2.4 mmol), and finally a white solid compound (0.69 g) is obtained with a yield of 75%, namely 2-((4-phenoxyphenyl)amino)-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one.

[0234] mp=194.3-195.1℃. 1 H NMR (500MHz, Chloroform-d) δ8.19 (dd, J=8.0, 2.0Hz, 1H), 7.72 (ddd, J=

[0235] 9.0,7.0,2.0Hz,1H),7.62(dd,J=8.5,1.5Hz,1H),7.55-7.51(m,2H),7.49(ddd,J=8.0,7. 0,1.5Hz,1H),7.39-7.32(m,2H),7.12-7.09(m,1H),7.02-6.96(m,2H),6.87-6.81(m,2H). 13 C NMR(125MHz,Chloroform-d)δ157.88,157.32,156.80,151.60,151.28,144.12,136.72,135.08,1 29.85,127.78,126.64,124.45,123.89,122.76,120.26,119.09,118.61.MS(ESI)m / z:387.43[M+H + ].

[0236] Example 22-Compound I-22

[0237] 4-Methylcyclohexyl-3-((9-oxo-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)oxy)benzoate

[0238] Step (1) is the same as step (1) of Example 1; Step (2): replace o-aminobenzoic acid with 2-aminonicotinic acid (1.38 g, 10 mmol) to finally obtain 2-bromo-9H-pyrido[2,3-d][1,3,4]thiadiazo[3,2-a]pyrimidin-9-one (0.76 g) with a yield of 27%;

[0239] 1 H NMR (500MHz, Chloroform-d) δ8.76 (dd, J=4.0, 2.5Hz, 1H), 8.66 (dd, J=7.5, 2.0Hz, 1H), 7.49 (dd, J=7.5, 4.0Hz, 1H).

[0240] Step (3): 4-methylcyclohexyl-3-hydroxybenzoate (2.06 g) was synthesized from p-hydroxybenzoic acid (1.38 g, 10 mmol) and 4-methylcyclohexanol (1.14 g, 10 mmol) using the method of step (4) of Example 1, with a yield of 88%;

[0241] 1 H NMR(500MHz,Chloroform-d)δ7.72-7.70(m,1H),7.37(t,J=2.0Hz,1H),7.31(dd,J=8.5,7.5Hz,1H),6.96-6.94(m,1H), 4.93(p,J=5.0Hz,1H),,1.87-1.80(m,2H),1.78-1.71(m,2H),1.69-1.59(m,2H),1.45-1.32(m,3H),0.95-0.86(m,3H).

[0242] Step (4): 2-bromo-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-9-one (0.57 g, 2 mmol) and potassium carbonate (0.39 g, 3 mmol) were dissolved in 10 mL of N,N-dimethylformamide, 4-methylcyclohexyl-3-hydroxybenzoate (0.56 g, 2.4 mmol) was added, and the mixture was reacted at 100° C. for 1.5 h. After the reaction, 50 mL of water was added to the system, and the mixture was extracted with ethyl acetate, dried and filtered, and purified and separated by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain 4-methylcyclohexyl-3-((9-oxo-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)oxy)benzoate (0.75 g) with a yield of 72%.

[0243] 1 H NMR(500MHz,Chloroform-d)δ8.76(dd,J=3.8,2.2Hz,1H),8.66(dd,J=7.6,2.1Hz, 1H),7.70(ddd,J=8.0,2.0,1.0Hz,1H),7.52-7.46(m,2H),7.34(d,J=8.0Hz,1H),7. 13(ddd,J=8.0,1.5,1.0Hz,1H),4.95-4.93(m,1H),1.87-1.81(m,2H),1.76-1.70( m,2H),1.69-1.59(m,2H),1.45-1.36(m,2H),1.40-1.32(m,1H),0.95-0.86(m,3H). 13C NMR(125MHz,Chloroform-d)δ166.44,160.38,157.64,156.78,154.82,154.07,153.78,134.64,132.05,13 0.16,125.90,124.94,121.74,120.47,111.53,72.48,32.23,31.59,30.27,21.12.MS(ESI)m / z:437.49[M+H + ].

[0244] Example 23-Compound I-23

[0245] 7-Methyl-2-((4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)thio)-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-9-one Step (1) is the same as Step (1) of Example 1; Step (2): replacing o-aminobenzoic acid with 2-amino-5-methylpyridine-3-carboxylic acid (1.38 g, 10 mmol) to finally obtain 2-bromo-7-methyl-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-9-one (1.01 g) with a yield of 34%;

[0246] 1 H NMR (500MHz, Chloroform-d) δ8.79 (d, J=1.5Hz, 1H), 8.35 (dd, J=2.0, 1.0Hz, 1H), 2.45 (s, 3H).

[0247] Steps (3)-(5) are missing; in step (6), 2-bromo-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-9-one (0.59 g, 2 mmol) and potassium carbonate (0.39 g, 3 mmol) are dissolved in 10 mL of N,N-dimethylformamide, (3,4-dihydroisoquinolin-2(1H)-yl)(4-mercaptophenyl)methanone (0.65 g, 2.4 mmol) is added, and the mixture is reacted at 100° C. for 1.5 h. After the reaction, 50 mL of water was added to the system, extracted with ethyl acetate, dried and filtered, and purified and separated by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain 2-(4-phenoxy)phenoxy-9H-pyrido[2,3-d][1,3,4]thiadiazo[3,2-a]pyrimidin-9-one (0.70 g) with a yield of 72%.

[0248] 1H NMR(500MHz,Chloroform-d)δ8.35(dd,J=1.5,1.0Hz,1H),8.01(d,J=2.5Hz,1H),7.84-7.78(m,2H),7.67-7.61(m,2H),7. 22-7.13(m,2H),7.16-7.10(m,2H),4.63(d,J=1.0Hz,2H),3.83(t,J=5.0Hz,2H),2.96-2.84(m,2H),2.45(d,J=1.0Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ169.23,159.99,157.15,155.50,154.33,154.07,136.15,135.57,134.13,133.12,132.16 ,131.96,129.50,128.76,128.43,127.55,126.97,126.54,110.08,50.98,44.89,29.01,18.05.MS(ESI)m / z:486.58[M+H + ].

[0249] Example 24-Compound I-24

[0250] 2-(4-Phenoxy)phenoxy-9H-pyrido[2,3-d][1,3,4]thiadiazo[3,2-a]pyrimidin-9-one

[0251] Step (1) is the same as step (1) of Example 1; Step (2): replace (3,4-dihydroisoquinolin-2(1H)-yl)(4-mercaptophenyl)methanone with 4-phenoxyphenol (0.45 g, 2.4 mmol) to finally obtain 2-(4-phenoxy)phenoxy-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-9-one (0.26 g) with a yield of 35%.

[0252] 1 H NMR(500MHz,Chloroform-d)δ8.76(dd,J=4.0,2.5Hz,1H),8.66(dd,J=7.5,2.0Hz,1H) ,7.49(dd,J=7.5,4.0Hz,1H),7.39-7.31(m,1H),7.13-7.09(m,1H),7.05-6.96(m,5H). 13C NMR(125MHz,Chloroform-d)δ160.63,158.81,157.29,157.05,155.16,154.75,151.66,148.8 9,134.63,129.75,124.52,122.15,121.73,120.58,118.94,112.44.MS(ESI)m / z:389.40[M+H + ].

[0253] Example 25-Compound I-25

[0254] 2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-7-methyl-9H-pyrido[2,3-d][1,3,4]thiadiazo[3,2-a]pyrimidin-9-one

[0255] Step (1) is the same as step (1) of Example 1; step (2): replacing o-aminobenzoic acid with 2-amino-5-methylpyridine-3-carboxylic acid (1.38 g, 10 mmol) to finally obtain 2-bromo-7-methyl-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-9-one (1.01 g) with a yield of 34%; step (3): replacing (3,4-dihydroisoquinolin-2(1H)-yl)(4-mercaptophenyl)methanone with 4-phenoxyphenol (0.45 g, 2.4 mmol) to finally obtain 2-((4-methoxy-2-(trifluoromethyl)phenyl)amino)-7-methyl-9H-pyrido[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-9-one (0.41 g) with a yield of 50%.

[0256] 1 H NMR(500MHz,Chloroform-d)δ9.89(s,1H),8.35(dd,J=1.5,1.0Hz,1H),8.03-7.99(m,1H),7.57(d,J=7 .5Hz,1H),7.22(dt,J=2.0,1.0Hz,1H),6.88(dd,J=8.0,2.0Hz,1H),3.78(s,3H),2.45(d,J=1.0Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ159.43,157.70,154.46(q, 4 J C-F =2.5Hz),154.41,154.07,151.79,134.80,134.73(q, 3 J C-F=5.0Hz),134.66,132.19,129.50,128.58,126.39,125.30(q, 1 J C-F =273.5Hz),124.36(q, 4 J C-F =3.5Hz),122.01,120.43,120.04(q, 2 J C-F =32.5Hz),119.65,114.52,112.79,112.75(q, 3 J C-F =4.0Hz),112.70,110.38,55.61,18.05.MS(ESI)m / z:408.37[M+H + ].

[0257] Example 26-Compound I-26

[0258] 3-Fluoro-4-((5-oxo-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)amino)benzoic acid naphthyl-2-yl

[0259] Compared with the synthesis method of Example 1: step (1) is the same; step (2): replacing o-aminobenzoic acid with 3-aminopyridine-2-carboxylic acid (1.38 g, 10 mmol), finally obtaining 2-bromo-5H-pyrido[3,2-d][1,3,4]thiadiazo[3,2-a]pyrimidin-5-one (0.85 g), with a yield of 30%;

[0260] 1 H NMR (500MHz, Chloroform-d) δ8.65 (dd, J=4.0, 2.0Hz, 1H), 7.91 (dd, J=8.0, 2.0Hz, 1H), 7.57 (dd, J=8.0, 4.0Hz, 1H).

[0261] Step (3): 3-aminobenzoic acid was replaced with 4-amino-3-fluorobenzoic acid (0.77 g, 50 mmol) to finally obtain Boc-protected 4-amino-3-fluorobenzoic acid (1.15 g) with a yield of 90%;

[0262] 1 H NMR (500MHz, Chloroform-d) δ7.96-7.85 (m, 3H), 7.80 (dd, J=9.5, 2.0Hz, 1H), 7.25 (d, J=3.0Hz, 1H), 1.46 (s, 9H).

[0263] Step (4): replace Boc-protected 3-aminobenzoic acid with Boc-protected 4-amino-3-fluorobenzoic acid (1.28 g, 5 mmol), and replace benzylamine with 2-naphthol (1.43 g, 10 mmol), to finally obtain 2-naphthyl-4-((tert-butoxycarbonyl)amino)-3-fluorobenzoate (1.56 g), with a yield of 28%;

[0264] 1 H NMR(500MHz,Chloroform-d)δ7.98-7.91(m,2H),7.88-7.79(m,2H),7.76-7.68(m,2H),7. 53-7.46(m,2H),7.45-7.38(m,1H),7.24(dd,J=8.5,2.5Hz,1H),7.18(s,1H),1.46(s,9H).

[0265] Step (5): replacing tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate with 2-naphthyl-4-((tert-butyloxycarbonyl)amino)-3-fluorobenzoate (1.91 g, 5 mmol) to finally obtain 2-naphthyl-4-amino-3-fluorobenzoate (1.12 g) with a yield of 80%;

[0266] 1 H NMR(500MHz,Chloroform-d)δ7.88-7.79(m,2H),7.76-7.66(m,3H),7.53-7.46(m,2H),7.45- 7.38(m,1H),7.24(dd,J=8.5,2.5Hz,1H),7.08(dd,J=9.5,5.0Hz,1H),3.89(d,J=3.5Hz,2H).

[0267] Step (6): Replace 2-bromo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one with 2-bromo-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (0.56 g, 2 mmol), and replace 3-amino-N-benzylbenzamide with 2-naphthyl-4-amino-3-fluorobenzoate (0.67 g, 2.4 mmol) to finally obtain 3-fluoro-4-((5-oxo-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)amino)benzoic acid naphthyl-2-yl (0.42 g) with a yield of 43%.

[0268] 1H NMR(500MHz,Chloroform-d)δ9.88(d,J=3.5Hz,1H),8.65(dd,J=3.5,2.0Hz,1H),7.91(dd,J=8.0,2.0Hz,1H),7.89-7 .82(m,2H),7.76-7.68(m,3H),7.57(dd,J=8.0,4.0Hz,1H),7.53-7.46(m,2H),7.46-7.35(m,2H),7.26-7.21(m,1H). 13 C NMR(125MHz,Chloroform-d)δ164.77(d, 4 J C-F =5.0Hz),157.65,156.05,152.29(d, 1 J C-F =255.0Hz),151.36(d, 4 J C-F =2.5Hz),150.25,146.10,141.32,137.59,134.34,132.28(d, 2 J C-F =13.5Hz),131.40,129.23,128.42(d, 4 J C-F =4.0Hz),127.71,127.42,126.94,126.64,126.17,126.07,122.40(d, 3 J C-F =7.5Hz),122.06(d, 3 J C-F =7.5Hz),121.89,118.32(d, 2 J C-F =21.5Hz),117.01.MS(ESI)m / z:484.48[M+H + ].

[0269] Example 27-Compound I-27

[0270] 2-((4-(Piperazine-1-carbonyl)phenyl)amino)-5H-pyrido[3,2-d][1,3,4]thiadiazo[3,2-a]pyrimidin-5-one

[0271] Compared with the synthesis method of Example 1: Steps (1)-(2) are the same as those of Example 1; in step (3), 3-aminobenzoic acid is replaced by 4-aminobenzoic acid to finally obtain Boc-protected 4-aminobenzoic acid; in step (4), Boc-protected 3-aminobenzoic acid is replaced by Boc-protected 4-aminobenzoic acid, and benzylamine is replaced by N-BOC-piperazine (1.85 g, 10 mmol), to finally obtain a white solid compound (3.24 g) with a yield of 80%, i.e., tert-butyl 4-(4-((tert-butyloxycarbonyl)amino)benzoyl)piperazine-1-carboxylate;

[0272] 1 H NMR (500MHz, Chloroform-d) δ7.67(s,1H),7.64-7.59(m,2H),7.53-7.47(m,2H),3.72-3.67(m,4H),3.55-3.49(m,4H),1.46(s,18H).

[0273] In step (5), tert-butyl (3-(benzylcarbamoyl)phenyl)carbamate was replaced with tert-butyl 4-(4-((tert-butyloxycarbonyl)amino)benzoyl)piperazine-1-carboxylate (0.81 g, 5 mmol) to finally obtain a white solid (0.61 g) with a yield of 40%, i.e. (4-aminophenyl)(piperazin-1-yl)methanone;

[0274] 1 H NMR (500MHz, Chloroform-d) δ7.53-7.47(m,2H),6.71-6.65(m,2H),4.51(s,2H),3.68-3.62(m,4H),3.02-2.96(m,4H),2.23(p,J=3.5Hz,1H).

[0275] In step (6), 2-bromo-5H-[1,3,4]thiadiazolo[2,3-b]quinazolin-5-one was replaced with 2-bromo-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (0.56 g, 2 mmol), and 3-amino-N-benzylbenzamide was replaced with (4-aminophenyl)(piperazin-1-yl)methanone (0.73 g, 2.4 mmol) to finally obtain a white solid compound (0.43 g) with a yield of 50%, namely 2-((4-(piperazine-1-carbonyl)phenyl)amino)-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one.

[0276] 1H NMR(500MHz,Chloroform-d)δ9.35(s,1H),8.65(dd,J=4.0,2.0Hz,1H),7.91(dd,J=8.0,2.0Hz,1H),7.78-7.72(m ,2H),7.65-7.59(m,2H),7.57(dd,J=8.0,4.0Hz,1H),3.68-3.62(m,4H),3.02-2.96(m,4H),2.23(p,J=3.5Hz,1H). 13 C NMR(125MHz,Chloroform-d)δ170.14,157.55,156.05,151.86,146.10,142.33,141.33, 137.54,131.42,129.59,126.94,126.07,121.58,48.33,45.67.MS(ESI)m / z:408.45[M+H + ].

[0277] Example 28-Compound I-28

[0278] 3-Fluorophenyl 4-((5-oxo-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)oxy)benzoate

[0279] Step (1): 3-Fluorophenyl-4-hydroxybenzoate (0.40 g) was synthesized from p-hydroxybenzoic acid (0.69 g, 5 mmol) and 3-fluorophenol (1.12 g, 10 mmol) by the method of step (4) of Example 1, with a yield of 87%;

[0280] 1 H NMR(500MHz,Chloroform-d)δ7.98-7.92(m,2H),7.46(s,1H),7.30(td,J=7.5, 5.0Hz,1H),7.05-7.11(m,1H),6.97-6.90(m,3H),6.85(dt,J=12.0,2.0Hz,1H).

[0281] Step (2): 3-Fluorophenyl 4-((5-oxo-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)oxy)benzoate (0.36 g) was synthesized from 2-bromo-5H-pyrido[3,2-d][1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (0.56 g, 2 mmol) and 3-fluorophenyl-4-hydroxybenzoate (0.56 g, 2.4 mmol) using the method of step (6) of Example 1 in a yield of 41%.

[0282] 1 H NMR(500MHz,Chloroform-d)δ8.65(dd,J=3.5,2.0Hz,1H),8.02-7.96(m,2H),7.91(dd,J=8.0,2.0Hz,1H),7.57(dd,J=8 .0,4.0Hz,1H),7.30(td,J=7.5,5.0Hz,1H),7.20-7.14(m,2H),7.10-7.08(m,1H),6.97-6.89(m,1H),6.89-6.81(m,1H). 13 C NMR(125MHz,Chloroform-d)δ164.88,163.26(d, 1 J C-F =246.0Hz),160.66,157.71,157.34,156.04,153.00(d, 3 J C-F =6.5Hz),146.10,141.00,137.60,132.53,130.28(d, 3 J C-F =10Hz),126.92,126.07,122.96,121.16,118.25(d, 4 J C-F =5.0Hz),112.56(d, 2 J C-F =22.5Hz),109.62(d,J C-F =25.0Hz).MS(ESI)m / z:435.40[M+H + ].

[0283] Example 29-Compound I-29

[0284] 3-Methyl-5-((5-oxo-5H-[1,3,4]thiadiazo[3,2-a]thiazo[5,4-d]pyridin-2-yl)amino)-N-(1-phenylpropan-2-yl)benzamide

[0285] Compared with the synthesis method of Example 1: step (1) is the same as Example 1; steps (2)-(5) are missing; in step (6), 3-amino-N-benzylbenzamide is replaced by 3-amino-5-methyl-N-(1-phenylpropan-2-yl)benzamide (0.64 g, 2.4 mmol), and finally a white solid compound (0.35 g) is obtained with a yield of 36%, namely 3-methyl-5-((5-oxo-5H-[1,3,4]thiadiazo[3,2-a]thiazolo[5,4-d]pyridin-2-yl)amino)-N-(1-phenylpropane-2-yl)benzamide.

[0286] 1 H NMR(500MHz,Chloroform-d)δ9.32(s,1H),8.75(s,1H),7.84(t,J=2.0Hz,1H),7.59-7.53(m,2H),7.33-7.26(m,2H),7.23(td,J=7 .0,1.5Hz,3H),6.98(d,J=8.0Hz,1H),4.26-4.14(m,1H),3.00-2.92(m,1H),2.75-2.67(m,1H),2.36(s,3H),1.15(d,J=6.5Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ167.14,156.66,152.84,151.34,142.15,139.89,139.57,139.43,138.69,135.02,133 .06,129.15,128.76,127.15,124.16,123.69,117.32,108.38,47.77,42.38,21.15,20.06.MS(ESI)m / z:476.59[M+H + ].

[0287] Example 30-Compound I-30

[0288] Methyl 4-(3-methyl-5-((5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]thiazolo[5,4-d]pyridin-2-yl)oxy)benzamido)benzoate

[0289] Compared with the synthesis method of Example 1: step (1) is the same as Example 1; steps (2)-(5) are missing; in step (6), 3-amino-N-benzylbenzamide is replaced by 4-(3-hydroxy-5-methylbenzamido)benzoic acid methyl ester (0.68 g, 2.4 mmol), and finally a white solid compound (0.49 g) is obtained with a yield of 42%, namely 4-(3-methyl-5-((5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]thiazolo[5,4-d]pyridin-2-yl)oxy)benzamido)benzoic acid methyl ester.

[0290] 1 H NMR(500MHz,Chloroform-d)δ9.04(s,1H),8.75(s,1H),7.98-7.90(m,4H),7.54(t,J =2.5Hz,1H),7.32(t,J=2.0Hz,1H),6.85(t,J=2.0Hz,1H),3.87(s,3H),2.38(s,3H). 13 C NMR(125MHz,Chloroform-d)δ166.92,166.49,159.93,156.67,153.65,153.21,143.27,140.76,139.97,139.20, 132.97,132.89,131.72,124.43,123.82,123.25,119.58,117.82,105.51,52.10,21.13.MS(ESI)m / z:493.52[M+H + ].

[0291] Example 31-Compound I-31

[0292] 3-((5-oxo-6,8-dihydro-5H-furo[3,4-d][1,3,4]thiadiazolo[3,2-a]pyridin-2-yl)amino)-N-(thiophen-2-ylmethyl)benzamide

[0293] Compared with the synthesis method of Example 1: step (1) is the same as Example 1; steps (2)-(5) are missing; in step (6), 3-amino-N-benzylbenzamide is replaced by 3-amino-N-(thiophen-2-ylmethyl)benzamide (0.57 g, 2.4 mmol), and finally a white solid compound (0.58 g) is obtained with a yield of 57%, namely 3-((5-oxo-6,8-dihydro-5H-furo[3,4-d][1,3,4]thiadiazolo[3,2-a]pyridin-2-yl)amino)-N-(thiophen-2-ylmethyl)benzamide.

[0294] 1 H NMR(500MHz,Chloroform-d)δ9.24(s,1H),8.07(t,J=5.0Hz,1H),7.94(t,J=2.0Hz,1H),7.58-7.54(m,1H),7.53-7.50(m,1H),7.44(dd,J=5.0, 2.0Hz,1H),7.33(t,J=8.0Hz,1H),7.04-7.00(m,2H),6.99-6.96(m,1H),4.74(d,J=1.0Hz,2H),4.71(dd,J=5.0,1.0Hz,2H),4.55-4.51(m,2H). 13 C NMR(125MHz,Chloroform-d)δ166.99,156.85,151.64,150.69,150.12,141.87,140.08,135.30,128.90,126 .80,126.09,125.70,125.03,122.47,119.54,115.95,108.88,75.99,74.75,38.49.MS(ESI)m / z:425.49[M+H + ].

[0295] Pharmacological experiments

[0296] 1. CCK-8 detection experiment

[0297] Experimental subjects: Human malignant melanoma A375 cells (BRAF WT type cells), thyroid cancer cell 8505C cells (BRAF V600E mutant cells) and p61-BRAF V600E Tumor cell 8505C cells (using lentiviral transfection to construct overexpression of spliceosome p61-BRAF V600E System, used to construct Vemurafenib-resistant cell model).

[0298] Experimental method: 100 μL cell suspension (5.0×10 4 / well) were distributed in a 96-well plate and placed in a 5% CO 2 , pre-cultured in a 37°C incubator for 24 hours, added different concentrations (0-30 μM) of the drug to be tested to the designated wells, the control drug was the positive drug Vemurafenib, and 5 replicate wells were set for each concentration. After 24 hours of drug action, 100 μL of 10% CCK-8 reagent was added to each well, and cultured for 3 hours. The absorbance at 450 nm was measured using an enzyme reader, IC 50 Refers to the concentration of inhibitor at which cell growth is inhibited by half.

[0299] Cell survival rate = [(As-Ab) / (Ac-Ab)] × 100%, As is the drug administration group (culture medium containing cells, CCK-8, and the drug to be tested); Ac is the control group (culture medium containing cells, CCK-8, and no drug to be tested); Ab is the blank group (culture medium without cells and the drug to be tested, CCK-8). The experimental results are shown in Table 1.

[0300] Table 1

[0301]

[0302] manual

[0303]

[0304] The compounds synthesized in Examples 1-31 of the present invention all showed significant activity in inhibiting cell proliferation against three types of cancer cells, among which the compounds synthesized in Examples 1-21 in Table 1 were preferred.

[0305] 2. Kinase activity detection experiment

[0306] Experimental principle: ADP-GloTM Kinase Assay measures the activity of ADP-generating enzyme by quantifying the ADP produced during the kinase reaction. The detection process is divided into two steps: first, after the kinase reaction, add ADP-Glo ​​in an equal volume to the kinase reaction. TM The reagent is used to terminate the kinase reaction and consume the remaining ATP, and then the kinase detection reagent is added to convert ADP into ATP, and the newly synthesized ATP is detected by the luciferase / luciferin reaction. The light signal generated is detected using a luminescence detector. The relationship between the luminescence signal and the ADP concentration is determined by the ATP-ADP conversion curve. The luminescence signal generated is proportional to the ADP concentration generated and is correlated with the enzyme activity.

[0307] Experimental method: Based on 384-well plates, preferred kinase: ADP-Glo TM Regent: Kinase DetectionRegent = 10:10:20. Use 1× kinase reaction buffer to dilute the drug in a gradient, take 1μL of the drug to be tested in the gradient concentration and add it to the designated wells. Select Vemurafenib as the positive drug, take 2.5× optimal concentration enzyme and add it to all wells, incubate at 37°C for 15 minutes; add 2× optimal concentration ATP and 2× optimal concentration substrate and incubate for 60 minutes; after the kinase or ATP is fully reacted, add ADP-Glo TMRegent was incubated for 60 min to terminate the kinase reaction and consume the remaining ATP; 20 μL Kinase Detection Regent was added and incubated for 60 min to convert ADP into ATP; the RU luminescence value was detected by an enzyme-labeled instrument.

[0308] Kinase inhibition rate = [1-(As-Ab) / (Ac-Ab)] × 100%, As is the drug group (containing ATP, substrate, kinase, kinase reaction buffer and the drug to be tested); Ac is the control group (containing ATP, substrate, kinase, kinase reaction buffer, but not the drug to be tested); Ab is the blank group (containing only ATP, substrate, and kinase reaction buffer). Kinase IC 50 The results are shown in Table 2.

[0309] Table 2

[0310]

[0311] The compounds synthesized in Examples 1-31 of the present invention all have significant kinase inhibitory activity, among which the compounds synthesized in Examples 1-21 in Table 2 are preferred.

[0312] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A tricyclic heterocyclic derivative, characterized in that: The general structural formula of the tricyclic heterocyclic derivative is shown in (I): in: Ring A, Ring B and Ring C include:

1. represents any aromatic ring selected from the group consisting of a substituted benzene ring, an indane ring, a tetralin ring, a piperidine ring, a furan ring, a thiophene ring, a pyrazole ring, an isoxazole ring, a thiazole ring and a tetrahydroquinoline ring; 2. A four- to seven-membered monocyclic non-aromatic heterocyclic group consisting of a substituted C1-C6 cycloalkyl, pyrrolidinyl, oxacycloalkyl and tetrahydropyranyl group; X 1 , X 4 are different and are each independently selected from a carbon atom or a nitrogen atom; X 2 , X 3 are the same or different and are each independently selected from a carbon atom or a nitrogen atom; X 5 is selected from a sulfur atom or -CH=CH-; R 1 is selected from a hydrogen atom or an alkyl group which may be substituted; Z 1 is selected from CH or a nitrogen atom; Z 2 Selected from oxygen atoms, -C(R 2 )(R 3 )-,-NH-,-C(R 2 )(R 3 )-NH-, -NH-C(R 2 )(R 3 )-,-C(R 2 )(R 3 )-O-、-OC(R 2 )(R 3 )-,alkyl; The R 2 , R 3 Each is independently selected from a hydrogen atom, an alkyl group which may be substituted or a cycloalkyl group which may be substituted; Alternatively, the R 2 , R 3 They bond with each other and with adjacent carbon atoms to form cycloalkanes which may be substituted.

2. A tricyclic heterocyclic derivative according to claim 1, characterized in that: The tricyclic heterocyclic derivatives include:

3. The method for preparing a tricyclic heterocyclic derivative according to claim 2, characterized in that: The specific steps include: (1) mixing compound i, compound ii and an acidic substance for reflux reaction, collecting and treating the reaction solution to obtain compound iii; (2) Under an inert atmosphere, compound iv, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and 1-hydroxybenzotriazole are added to an organic solvent and stirred, an amine / alcohol compound is added, the reaction is continued, and the reaction solution is collected and treated to obtain compound v; (3) Compound v is added to an organic solvent, hydrogen chloride is added, and the mixture is stirred at low temperature. The mixture is heated to room temperature and stirred to react. The reaction solution is collected and treated to obtain compound vi. (4) adding compound iii, compound vi and a basic substance to an organic solvent for reaction, collecting and treating the reaction solution to obtain the corresponding target tricyclic heterocyclic derivative; Among them, the structural formulas of compound i to compound vi are:

4. The method for preparing a tricyclic heterocyclic derivative according to claim 3, characterized in that: In step (1), the acidic substance is any one of formic acid, acetic acid and acetic anhydride; The molar ratio of the compound i, the compound ii and the acidic substance is 1.3:1:5; The reflux reaction temperature is 100-120°C and the time is 4-8h; The treatment of the reaction liquid is specifically as follows: cooling the reaction liquid to room temperature, adding a sodium hydroxide solution with a concentration of 4 mol / L, adjusting the pH to 6-7, extracting with ethyl acetate, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, and performing silica gel column chromatography.

5. The method for preparing a tricyclic heterocyclic derivative according to claim 3, characterized in that: In step (2), the inert atmosphere is argon or nitrogen; The molar ratio of the compound iv, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole is 1:1-3:1-3; The organic solvent is at least one of dichloromethane, acetone, methanol, ethanol, acetonitrile, dimethyl sulfoxide, 1,4-dioxane, N,N-dimethylformamide and N,N-dimethylacetamide; The molar ratio of the organic solvent to compound iv is 5:1; The amine / alcohol compounds include benzylamine, aniline, 2-ethyl-6-methylaniline, 4-fluorobenzylamine, 4-fluoroaniline, 2-butylamine, 2-thiopheneethylamine, 4-phenyl-2-butylamine, 5-methylfurfurylamine, 2-furylmethylamine, 4-methyl-1-cyclohexylamine, 2-aminomethylpyridine, and 4-ethoxyaniline; The molar ratio of the amine / alcohol compound to compound iv is 1-2:1; The stirring is performed at 10-60° C. for 30-60 min; The time of the continued reaction is 6-24h; The specific steps of treating the reaction liquid are: washing the reaction liquid with water, drying with anhydrous sodium sulfate, and performing silica gel column chromatography.

6. The method for preparing a tricyclic heterocyclic derivative according to claim 3, characterized in that: In step (3), the organic solvent is at least one of ethyl acetate, acetone, methanol, ethanol, dichloromethane, chloroform, carbon tetrachloride, toluene, acetonitrile, dimethyl sulfoxide, dioxane, N,N-dimethylformamide and N,N-dimethylacetamide; The molar ratio of the compound v to the organic solvent is 10:1; The low temperature stirring is stirring at -10 to 0°C for 30 to 60 minutes; The stirring reaction time is 2-16 hours; The treatment of the reaction liquid specifically comprises: performing reduced pressure distillation on the reaction liquid to remove the solvent, and performing recrystallization through a mixed solvent of ethanol and ether in a volume ratio of 1:5-10.

7. The method for preparing a tricyclic heterocyclic derivative according to claim 3, characterized in that: In step (4), the alkaline substance is at least one of sodium hydroxide, potassium carbonate, potassium hydroxide, sodium carbonate and sodium bicarbonate; The molar ratio of the compound iii, the compound vi, the alkaline substance and the organic solvent is 1:1-2:1-2:2; The organic solvent is at least one of acetonitrile, acetone, ethanol, methanol, dichloromethane, ethyl acetate, chloroform, carbon tetrachloride, toluene, dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide; The reaction time is 3-8h and the temperature is 60-80°C; The specific steps of treating the reaction liquid are: adding water to the reaction liquid, extracting with ethyl acetate, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, and performing silica gel column chromatography.

8. Use of the tricyclic heterocyclic derivative according to any one of claims 1 or 2 in the preparation of antitumor drugs.

9. The use according to claim 8, characterized in that The medicine comprises the tricyclic heterocyclic derivative and a pharmaceutically acceptable excipient thereof.

10. The use according to claim 8, characterized in that The anti-tumor drug is by targeting BRAF V600E to intervene.

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