3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives and their preparation and application

Abstract

The present invention discloses 3-(1,2,3-triazole-4-yl)tetrahydroquinazoline-2,4-dione derivatives and their preparation methods and applications. The 3-(1,2,3-triazole-4-yl)tetrahydroquinazoline-2,4-dione derivatives have a compound of formula (I) or a pharmaceutically acceptable salt thereof. The compounds are inhibitors of NQO1 enzymes and can be used in combination with a variety of clinical anti-tumor drugs to treat pancreatic cancer and non-small cell lung cancer, thereby reducing the dosage of anti-tumor drugs and improving drug safety. #imgabs0#

Description

Technical Field

[0001] The invention relates to a class of compounds and a preparation method and application thereof, and in particular to 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives and a preparation method and application thereof. Background Art

[0002] The NQO1 enzyme is also known as D-lipoamide dehydrogenase. It uses flavin adenine dinucleotide (FAD) as a cofactor and reduced nicotinamide adenine dinucleotide NAD(P)H as a coenzyme. It can reduce quinone compounds to hydroquinone compounds through a two-electron reduction process. The two-electron reduction process of the NQO1 enzyme can effectively prevent the generation of toxic reactive oxygen species (ROS) and other free radicals by quinone compounds in the body through a single-electron reduction process, thereby protecting cells.

[0003] The expression of NQO1 enzyme is low in normal tissues, but affected by the higher level of oxidative stress in tumor cells, NQO1 enzyme will be transcribed in large quantities under the regulation of nuclear transcription factor NRF2. Studies have shown that NQO1 protein is closely related to the occurrence and development of tumors, so it is considered to be an effective tumor marker and has also been developed as a drug target for the treatment of various tumors. NQO1 protein is highly expressed in many solid tumors such as lung cancer and pancreatic cancer, and patients with high expression of NQO1 have significantly worse prognosis; there are also reports that the increase in NQO1 protein activity may be related to the increased resistance of tumor cells to anti-tumor drugs.

[0004] The current method for treating advanced pancreatic cancer and non-small cell lung cancer is chemotherapy using drugs such as gemcitabine, cisplatin and 5-fluorouracil. When using these anti-tumor drugs, patients often experience adverse reactions such as bone marrow suppression and organ damage.

[0005] Purpose of the Invention

[0006] Purpose of the invention: The purpose of the present invention is to provide 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives, which can be used as inhibitors of NQO1 enzymes and can be used in combination with anti-tumor drugs to treat pancreatic cancer and non-small cell lung cancer, while reducing the dosage of anti-tumor drugs, reducing side effects, and ensuring drug safety. Another purpose of the present invention is to provide a preparation method of the 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives and their use in the preparation of drugs used in combination with anti-tumor drugs to treat pancreatic cancer and non-small cell lung cancer.

[0007] Technical solution: The 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives of the present invention are compounds having the structure of formula (I) or pharmaceutically acceptable salts thereof:

[0008]

[0009] Among them, Ar 1 represents a 5- to 6-membered aromatic ring containing carbon and nitrogen atoms;

[0010] Ar 2 represents an aryl group containing 5 to 6 atoms, or an 8-10-membered bicyclic aryl or heteroaryl group, wherein the heteroaryl group refers to an aryl group containing 1 to 2 identical or different heteroatoms selected from nitrogen and oxygen in the ring members;

[0011] R 1 Representatives are located in Ar 1 One or more substituents at any position on the ring, the substituents being selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, halogen, acyl, hydroxyl;

[0012] R 2 represents one or more substituents located at any position on Ar, the substituents being selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 haloalkyl, halogen, phenyl, trifluoromethoxy, cyano, hydroxyl, amino, carboxyl, sulfamoyl, C1-C4 alkylsulfonyl, C1-C4 acylamino, C1-C4 alkylaminoacyl;

[0013] X can represent an imino group, an oxygen atom or a chemical bond; m is 1 or 2; and n is 0 or 1.

[0014] The 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives, wherein:

[0015] Ar 1 Selected from

[0016] Ar 2 Selected from

[0017] m is 1 and n is 1.

[0018] The 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives are selected from the following compounds:

[0019]

[0020]

[0021]

[0022]

[0023]

[0024] The pharmaceutically acceptable salt of the 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivative is a salt formed by the compound and an acid or a base, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid; and the base is an inorganic base containing an alkaline metal cation, an alkaline earth metal cation or an ammonium cation salt, choline, diethanolamine or morpholine.

[0025] The preparation method of the 3-(1,2,3-triazole-4-yl)tetrahydroquinazoline-2,4-dione derivatives comprises the following steps:

[0026] Compound (II) is subjected to a copper-catalyzed 1,3-dipolar cycloaddition reaction of azide and terminal alkyne to obtain compound (I);

[0027]

[0028] A pharmaceutical composition comprising the 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivative and a pharmaceutically acceptable carrier; the 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivative can be added with a pharmaceutically acceptable carrier to prepare a pharmaceutical preparation.

[0029] The application of the 3-(1,2,3-triazole-4-yl)tetrahydroquinazoline-2,4-dione derivatives in the preparation of NQO1 enzyme inhibitor drugs.

[0030] The application of the pharmaceutical composition in the preparation of NQO1 enzyme inhibitor drugs.

[0031] The application is that the drug is used in combination with an anti-tumor drug to treat tumor diseases.

[0032] In the application, the tumor disease is selected from pancreatic cancer and non-small cell lung cancer.

[0033] Beneficial effects: Compared with the prior art, the present invention has the following advantages: the compound of the present invention or its pharmaceutically acceptable salt can be used in combination with a variety of clinical anti-tumor drugs to treat pancreatic cancer, non-small cell lung cancer and other cancers, thereby reducing the dosage of anti-tumor drugs. The compound of the present invention is an NQO1 inhibitor, which can be used in combination with anti-tumor drugs to promote tumor cell apoptosis, and can effectively reduce the dosage of anti-tumor drugs while improving the efficacy, reduce side effects, and ensure drug safety, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The figure shows that the representative compounds enhance the killing of cancer cells when used in combination with gemcitabine;

[0035] Figure 2 The figure shows that representative compounds enhance the killing of cancer cells when used in combination with cisplatin. DETAILED DESCRIPTION

[0036] The following examples are provided to illustrate the present invention in detail. In the present invention, the following examples are provided to better illustrate the present invention and are not intended to limit the scope of the present invention.

[0037] Example 1 3-({1-[(4-fluorophenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-8-hydroxy-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0038] 8-Hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione (40 mg, 0.19 mmol), 1-azidomethyl-4-fluorobenzene (0.25 mmol, 43 μL), copper sulfate pentahydrate (5% equiv, 2.4 mg), and sodium ascorbate (5% equiv, 1.9 mg) were dissolved in 1 mL of anhydrous N,N-dimethylformamide. The reaction mixture was heated at 80 ℃ for 8 hours. After the reaction, excess water was added to the reaction solution, and the solid was collected by filtration. The residue was separated by silica gel column chromatography using petroleum ether: ethyl acetate = 1:1 as the developing solvent to obtain the target compound 3-({1-[(4-fluorophenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-8-hydroxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 48 mg, with a yield of 68.4%, as a white solid. mp>300℃, the compound 1 H-NMR (400 MHz, DMSO-d 6)δ10.57(s,2H),8.04(s,1H),7.44–7.34(m,3H),7.19(t,J=8.7Hz,2H),7.10(d,J= 7.7Hz,1H),7.03(t,J=7.8Hz,1H),5.52(s,2H),5.13(s,2H).HRMS(ESI):calcd.For C 18 H 14 FN 5 O 3 [M+H] + 368.1153, found 368.1150.

[0039] Example 2 3-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-8-hydroxy-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0040] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 1-azidomethyl-4-chlorobenzene is used to replace 1-azidomethyl-4-fluorobenzene (0.25mmol, 44μL) to obtain the target compound 3-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-8-hydroxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 52mg, yield 71.2%, white solid. mp>300℃, the compound 1 H-NMR (400 MHz, DMSO-d 6 )δ10.60(s,2H),8.06(s,1H),7.46–7.38(m,3H),7.36–7.28(m,2H),7.11(dd,J=7.9 ,1.4Hz,1H),7.03(t,J=7.8Hz,1H),5.54(s,2H),5.14(s,2H).HRMS(ESI):calcd.For C 18 H 14 C1N 5 O 3 [M+H] + 384.0858, found 384.0862.

[0041] Example 3 3-({1-[(4-bromophenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-8-hydroxy-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0042] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 1-azidomethyl-4-bromobenzene (48 μL, 0.25 mmol) is used to replace 1-azidomethyl-4-fluorobenzene to obtain 57 mg of the target compound 3-({1-[(4-bromophenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-8-hydroxy-1,2,3,4-tetrahydroquinazoline-2,4-dione as a white solid with a yield of 69.8%. mp>300°C, the compound 1 H-NMR (400 MHz, DMSO-d 6 )δ10.66(s,1H),10.47(s,1H),8.05(s,1H),7.56(d,J=8.0Hz,2H),7.40(d,J=7.8Hz,1H),7.25(d,J=8. 0Hz,2H),7.11(d,J=7.8Hz,1H),7.04(t,J=7.9Hz,1H),5.52(s,2H),5.14(s,2H).HRMS(ESI):calcd.For C 18 H 14 Bn 5 O 3 [M+H] + 428.0353, found 428.0355.

[0043] Example 4 8-Hydroxy-3-[(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentan-4-yl)methyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0044] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 1-(azidomethyl)-4-(trifluoromethyl)benzene (43 μL, 0.25 mmol) is used to replace 1-azidomethyl-4-fluorobenzene to obtain the target compound 8-hydroxy-3-[(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentane-4-yl)methyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione 52 mg, with a yield of 65.1%, as a white solid. mp>300°C, the compound has 1 H-NMR (400 MHz, DMSO-d 6)δ10.70(s,1H),10.47(s,1H),8.11(s,1H),7.74(d,J=7.8Hz,2H),7.48(d,J=7.9Hz,2H),7.40( d,J=7.8Hz,1H),7.08(dd,J=24.6,7.8Hz,2H),5.66(s,2H),5.15(s,2H).HRMS(ESI):calcd.For C 19 H 14 F 3 N 5 O 3 [M+H] + 418.1122, found 418.1127.

[0045] Example 5 8-Hydroxy-3-[(1-{[4-(methyldioxy-λ6-thio)phenyl]methyl}-1,2,3-triazacyclopentan-4-yl)methyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0046] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. [4-(azidomethyl)phenyl](methyl)dioxy-λ6-sulfane (53 mg, 0.25 mmol) is used to replace 1-azidomethyl-4-fluorobenzene to obtain the target compound 8-hydroxy-3-[(1-{[4-(methyldioxy-λ6-sulfanyl)phenyl]methyl}-1,2,3-triazacyclopentane-4-yl)methyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione 50 mg, with a yield of 61.0%, as a white solid. mp>300°C, the compound has 1 H-NMR (400 MHz, DMSO-d 6 )δ10.62(s,2H),8.12(s,1H),7.92(d,J=7.9Hz,2H),7.53(d,J=7.9Hz,2H),7.40(d,J=7.9Hz,1H),7.11 (d,J=7.8Hz,1H),7.04(t,J=7.8Hz,1H),5.68(s,2H),5.15(s,2H),3.19(s,3H).HRMS(ESI):calcd.For C 19 H 17 N 5 O 5 S[M+H] + 428.1023, found 428.1018.

[0047] Example 6 4-({4-[(8-hydroxy-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)benzene-1-sulfonamide

[0048] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 4-(azidomethyl)benzene-1-sulfonamide (53 mg, 0.25 mmol) is used to replace 1-azidomethyl-4-fluorobenzene to obtain 44 mg of the target compound 4-({4-[(8-hydroxy-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)benzene-1-sulfonamide, with a yield of 54.6%, as a white solid. mp>300°C, the compound has 1 H NMR (300MHz, DMSO-d6) δ10.95(s,1H),8.09(s,1H),7.80(d,J=7.9Hz,2H),7.48(dd,J=17.6,8.0Hz,3H ),7.35(s,1H),7.17(t,J=8.1Hz,1H),5.63(s,2H),5.14(s,2H),3.89(s,3H)..HRMS(ESI):calcd.For C 18 H 16 N 6 O 5 S[M+H] + 429.0976, found 429.0974.

[0049] Example 7 8-Hydroxy-3-{[1-({4-[(trifluoromethyl)oxy]phenyl}methyl)-1,2,3-triazacyclopentan-4-yl]methyl}-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0050] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 1-(azidomethyl)-4-[(trifluoromethyl)oxy]benzene (50 μL, 0.25 mmol) is used to replace 1-azidomethyl-4-fluorobenzene to obtain the target compound 8-hydroxy-3-{[1-({4-[(trifluoromethyl)oxy]phenyl}methyl)-1,2,3-triazacyclopentane-4-yl]methyl}-1,2,3,4-tetrahydroquinazoline-2,4-dione 51 mg, with a yield of 61.7%, as a white solid. mp>300°C, the compound has 1 H-NMR (300 MHz, DMSO-d 6)δ8.11(s,1H),7.42(q,J=8.9Hz,5H),7.10(dd,J=17.3,7.7Hz,2H),5.60(s,2H),5.16(s,2H).HRMS(ESI):calcd.For C 19 H 14 F 3 N 5 O 4 [M+H] + 434.1071, found 434.1066.

[0051] Example 8 4-({4-[(8-hydroxy-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)benzene-1-carbonitrile

[0052] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 4-(azidomethyl)benzene-1-carbonitrile (0.25mmol, 39.5mg) is used to replace 1-azidomethyl-4-fluorobenzene to obtain 47mg of the target compound 4-({4-[(8-hydroxy-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)benzene-1-carbonitrile, with a yield of 66.2%, as a white solid. mp>300℃, the compound has 1 H-NMR (400 MHz, DMSO-d 6 )δ10.62(s,2H),8.11(s,1H),7.84(d,J=8.0Hz,2H),7.42(dd,J=14.4,7.9Hz,3H),7.11( d,J=7.6Hz,1H),7.03(t,J=7.9Hz,1H),5.66(s,2H),5.15(s,2H).HRMS(ESI):calcd.ForC 19 H 14 N 6 O 3 [M+H] + 375.1200, found 375.1194.

[0053] Example 9 8-Hydroxy-3-({1-[(4-methylphenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0054] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 4-(azidomethyl)-1-methylbenzene (0.25mmol, 48μL) is used to replace 1-azidomethyl-4-fluorobenzene to obtain the target compound 3-({1-[(4-methylphenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione 43mg, yield 62.3%, white solid. mp>300℃. The compound 1 HNMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.46(t,J=7.5Hz,1H),7.15(dt,J=7.8,1 .0Hz,2H),7.12–7.08(m,2H),6.90(dd,J=7.5,2.0Hz,1H),5.29(t,J=1.0Hz,2H),5.01(s,2H),2.34(d,J=1.9Hz,3H).HRMS(ESI):calcd.For C 19 H 17 N 5 O 3 [M+H] + 364.1404, found 364.1407.

[0055] Example 10 4-({4-[(8-hydroxy-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)benzoic acid

[0056] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 4-(azidomethyl)benzoic acid (0.25mmol, 44.3mg) is used to replace 1-azidomethyl-4-fluorobenzene to obtain 38mg of the target compound 4-({4-[(2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)benzoic acid, with a yield of 50.9%, as a white solid. mp>300℃. The compound 1H NMR(500MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.94–7.88(m,3H),7.80(s,1H),7.50–7.39(m,2H),7.34(d dt,J=7.3,2.4,1.2Hz,2H),6.90(dd,J=7.5,2.0Hz,1H),5.30(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C 19 H 15 N 5 O 5 [M+H] - 392.1000, found 392.0993.

[0057] Example 11 8-Hydroxy-3-({1-[(4-nitrophenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0058] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 4-(azidomethyl)-1-nitrobenzene (0.25mmol, 44.54mg) is used to replace 1-azidomethyl-4-fluorobenzene to obtain 40mg of the target compound 8-hydroxy-3-({1-[(4-nitrophenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, with a yield of 53.4%, as a white solid. mp>300℃. The compound 1 H NMR 400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),8.22–8.12(m,2H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.64–7. 56(m,2H),7.46(t,J=7.5Hz,1H),6.90(dd,J=7.5,2.0Hz,1H),5.32(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C 18 H 14 N 6 O 5 [M+H] + 395.1098, found 395.1101.

[0059] Example 12 8-Hydroxy-3-({1-[(4-hydroxyphenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0060] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged. 4-(azidomethyl)phenol (0.25mmol, 37.29mg) is used to replace 1-azidomethyl-4-fluorobenzene to obtain 36mg of the target compound 8-hydroxy-3-({1-[(4-hydroxyphenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, with a yield of 51.9%, as a white solid. mp>300℃. The compound 1 H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.46(t,J=7.5Hz,1H),7.22(s, 1H),7.11–7.04(m,2H),6.90(dd,J=7.5,2.0Hz,1H),6.80–6.74(m,2H),5.30(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C 18 H 15 N 5 O 4 [M+H] + 366.1197, found 366.1203.

[0061] Example 13 8-Hydroxy-3-{[1-(pyridin-2-ylmethyl)-1,2,3-triazacyclopentan-4-yl]methyl}-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0062] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged, and 2-(azidomethyl)pyridine (0.25mmol, 54μL) is used to replace 1-azidomethyl-4-fluorobenzene. The target compound 8-hydroxy-3-{[1-(pyridin-2-ylmethyl)-1,2,3-triazacyclopentane-4-yl]methyl}-1,2,3,4-tetrahydroquinazoline-2,4-dione is obtained in an amount of 44mg, with a yield of 66.1%, as a white solid. mp>300℃. The 1HNMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),8.51(dd,J=5.0,1.2Hz ,1H),7.97(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.73(td,J=8.0,1.2Hz,1H),7.4 6(t,J=7.5Hz,1H),7.32(dd,J=8.0,1.0Hz,1H),7.26(ddd,J=8.0,5.1,1.1Hz,1H ),6.90(dd,J=7.5,2.0Hz,1H),5.61(s,2H),5.01(s,2H).HRMS(ESI):calcd.For C 17 H 14 N 6 O 3 [M+H] + 351.1200, found 351.1201.

[0063] Example 14 8-Hydroxy-3-({1-[(4-phenylphenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0064] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged, and 1-(azidomethyl)-4-phenylbenzene (0.25mmol, 53μL) is used to replace 1-azidomethyl-4-fluorobenzene. 42mg of the target compound 8-hydroxy-3-({1-[(4-phenylphenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione is obtained with a yield of 52.0%. 1 H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.62–7.58(m,2H),7.57–7.53(m ,2H),7.48–7.35(m,4H),7.24–7.20(m,2H),6.90(dd,J=7.5,2.0Hz,1H),5.30(t,J=1.0Hz,2H),5.01(s,2H).HRMS(ESI):calcd.For C 24 H 19 N 5 O 3 [M+H] +426.1591,found426.1596

[0065] Example 15 8-Hydroxy-3-({1-[(3-methoxyphenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0066] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged, and 1-(azidomethyl)-3-methoxybenzene (0.25mmol, 41μL) is used to replace 1-azidomethyl-4-fluorobenzene. The target compound 8-hydroxy-3-({1-[(3-methoxyphenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione is obtained in an amount of 47 mg with a yield of 65.2%. 1 H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.67(s,1H),7.90(dd,J=7.5,2.0Hz,1H),7.80(s,1H),7.46(t,J=7.5Hz,1H),7.19(t,J=7.5Hz,1H),7.07(dtt ,J=7.5,2.0,1.0Hz,1H),6.90(dd,J=7.5,2.0Hz,1H),6.84(dq,J=5.1,2.0Hz ,2H),5.34(t,J=1.0Hz,2H),5.01(s,2H),3.82(s,3H).HRMS(ESI):calcd.For C 19 H 17 N 5 O 4 [M+H] + 380.1353, found 380.1355.

[0067] Example 16 8-Hydroxy-3-[(1-{[3-(methylamino)phenyl]methyl}-1,2,3-triazacyclopentan-4-yl)methyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0068] The preparation method is the same as that in Example 1. The raw material of 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione remains unchanged, and [2-(azidomethyl)phenyl](methyl)amine (0.25mmol, 48μL) is used to replace 1-azidomethyl-4-fluorobenzene. The target compound 8-hydroxy-3-({1-[(3-methoxyphenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione is obtained in the form of a white solid with a yield of 59.7%. 1 H-NMR(400MHz,Chloroform-d)δ7.94(dd,J=7.5,2.0Hz,1H),7.79(s,1H),7.44(td,J=7.5,2.0Hz,1H),7.29(dd,J=7.5,2.0Hz,1H),7.21–7.1 4(m,2H),7.13–7.07(m,2H),6.94(dd,J=7.4,1.8Hz,1H),6.64(s,1H),5.37(d,J=0.9Hz,2H),5.01(s,2H),3.13(s,3H).HRMS(ESI):calcd.For C 19 H 18 N 6 O 3 [M+H] + 379.1513, found 379.1510.

[0069] Example 17 2-{[1-(4-chlorophenyl)-1,2,3-triazacyclopentyl-4-yl]methyl}isoindole-1,3-dione

[0070] The preparation method was the same as that in Example 1, except that 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione was replaced with 2-(prop-2-ynyl)isoindole-1,3-dione (0.19 mmol, 35.2 mg), and 1-azidomethyl-4-fluorobenzene was replaced with 4-azido-1-chlorobenzene (0.25 mmol, 46 μL) to obtain 51 mg of the target compound 2-{[1-(4-chlorophenyl)-1,2,3-triazacyclopentane-4-yl]methyl}isoindole-1,3-dione with a yield of 78.9%. The compound was a white solid. 1H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.89(dd,J=5.4,3.0Hz,2H),7.75(dd,J=5.5 ,3.0Hz,2H),7.70–7.65(m,2H),7.52–7.47(m,2H),5.10(s,2H).HRMS(ESI):calcd.For C 17 H 11 C1N 4 O 2 [M+H] + 339.0643, found 339.0645.

[0071] Example 18 2-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentyl-4-yl}methyl)isoindole-1,3-dione

[0072] The preparation method is the same as that of Example 1. 2-(prop-2-ynyl)isoindole-1,3-dione (0.19mmol, 35.2mg) was used to replace 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, and 4-(azidomethyl)-1-chlorobenzene (0.25mmol, 44μL) was used to replace 1-azidomethyl-4-fluorobenzene. 49.4mg of the target compound 2-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)isoindole-1,3-dione was obtained with a yield of 74.1%. The compound was a white solid. 1 HNMR(400MHz,Chloroform-d)δ7.87(dd,J=5.5,3.0Hz,2H),7.74(dd,J=5.5,3.0Hz,2H),7.53( s,1H),7.38–7.33(m,2H),7.24–7.18(m,2H),5.47(s,2H),4.99(s,2H).HRMS(ESI):calcd.For C 18 H 13 C1N 4 O 2 [M+H] + 353.0800, found 353.0809.

[0073] Example 19 2-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentyl-4-yl}methyl)isoindole-1,3-dione

[0074] The preparation method was the same as that in Example 1, except that 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione was replaced with 3-(prop-2-ynyl)-3,4-dihydro-2H-benzo[2,1-e][1,3]oxazacyclohexane-2,4-dione (0.19 mmol, 38.2 mg), and 1-azidomethyl-4-fluorobenzene was replaced with 4-azido-1-chlorobenzene (0.25 mmol, 46 μL) to obtain 48.6 mg of the target compound 2-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)isoindole-1,3-dione with a yield of 72.1%. The compound was a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.14(dd,J=7.9,1.6Hz,1H),8.12(s,1H),7.78–7.71(m,1H),7.71–7.67(m,2H ),7.53–7.48(m,2H),7.41(ddd,J=8.2,7.4,1.0Hz,1H),7.31(dd,J=8.3,1.0Hz,1H).HRMS(ESI):calcd.For C 18 H 13 C1N 4 O 3 [M+H] + 355.0592, found 369.0751.

[0075] Example 20 3-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentan-4-yl}methyl)-3,4-dihydro-2H-benzo[2,1-e][1,3]oxazepine-2,4-dione

[0076] The preparation method is the same as that of Example 1. 3-(prop-2-ynyl)-3,4-dihydro-2H-benzo[2,1-e][1,3]oxazepine-2,4-dione (0.19mmol, 38.2mg) was used to replace 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, and 4-(azidomethyl)-1-chlorobenzene (0.25mmol, 44μL) was used to replace 1-azidomethyl-4-fluorobenzene. The target compound 3-({1-[(4-chlorophenyl)methyl]-1,2,3-triazacyclopentane-4-yl}methyl)-3,4-dihydro-2H-benzo[2,1-e][1,3]oxazepine-2,4-dione was obtained in an amount of 49.5mg with a yield of 70.1%. The compound was a white solid. 1H-NMR(400MHz,Chloroform-d)δ8.00(dd,J=7.5,2.0Hz,1H),7.78(s,1H),7.46(td,J=7.5 ,2.0Hz,1H),7.36–7.23(m,6H),5.31(d,J=1.1Hz,2H),5.09(s,2H).HRMS(ESI):calcd.ForC 18 H 13 C1N 4 O 3 [M+H] + 369.0749, found 369.0744.

[0077] Example 21 3-[2-(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentan-4-yl)ethyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0078] The preparation method was the same as that in Example 1, except that 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione was replaced by 3-(but-3-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione (40 mg, 0.19 mmol), and 1-(azidomethyl)-4-(trifluoromethyl)benzene (0.25 mmol, 44 μL) was replaced by 1-azidomethyl-4-fluorobenzene to obtain 44 mg of the target compound 3-[2-(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentane-4-yl)ethyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione, with a yield of 56.7%. HRMS (ESI) of the compound: calcd.For C 20 H 16 F 3 N 5 O 2 [M+H] +416.1329, found 416.1325.

[0079] Example 22 3-[2-(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentan-4-yl)ethyl]-3,4-dihydro-2H-benzo[2,1-e][1,3]oxazepine-2,4-dione

[0080] The preparation method was the same as that of Example 1, except that 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione was replaced with 3-(but-3-ynyl)-3,4-dihydro-2H-benzo[2,1-e][1,3]oxazacyclohexane-2,4-dione (41 mg, 0.19 mmol), and 1-(azidomethyl)-4-(trifluoromethyl)benzene (0 .25mmol, 44μL) to replace 1-azidomethyl-4-fluorobenzene, to obtain 57mg of white solid 3-[2-(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentane-4-yl)ethyl]-3,4-dihydro-2H-benzo[2,1-e][1,3]oxazacyclohexane-2,4-dione, with a yield of 72.1%, as a white solid. HRMS (ESI) of the compound: calcd.For C 20 H 15 F 3 N 4 O 3 [M+H] + 417.1169, found 417.1171.

[0081] Example 23 2-[2-(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentyl-4-yl)ethyl]isoindole-1,3-dione

[0082] The preparation method is the same as that of Example 1, except that 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione is replaced by 2-(but-3-ynyl)isoindole-1,3-dione (38 mg, 0.19 mmol), and 1-(azidomethyl)-4-(trifluoromethyl)benzene (0.25 mmol, 44 μL) is replaced by 1-azidomethyl-4-fluorobenzene to obtain 52 mg of the target compound 2-[2-(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentane-4-yl)ethyl]isoindole-1,3-dione, with a yield of 68.4%, as a white solid. HRMS (ESI) of the compound: calcd.For C 20 H 15 F 3 N 4 O 2[M+H]+401.1220,found 401.1228.

[0083] Example 24 3-[(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentan-4-yl)methyl]-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-2,4-dione

[0084] The preparation method was the same as that in Example 1, except that 8-methoxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-2,4-dione (38 mg, 0.19 mmol) was used instead of 8-methoxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1-(azidomethyl)-4-(trifluoromethyl)benzene (0.25 mmol, 44 μL) was used instead of 1-azidomethyl-4-fluorobenzene to obtain 48 mg of the target compound 3-[(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentane-4-yl)methyl]-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidine-2,4-dione, with a yield of 62.4%. HRMS (ESI) of the compound: calcd.For C 18 H 13 F 3 N 6 O 2 [M+H] + 403.1125, found 403.1127.

[0085] Example 25 3-{[1-(1H-indol-3-ylmethyl)-1,2,3-triazacyclopentan-4-yl]methyl}-7-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0086] The preparation method is the same as that in Example 1, except that 8-hydroxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione is replaced with 7-methoxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione (44 mg, 0.19 mmol), and 1-azidomethyl-4-fluorobenzene is replaced with 3-(azidomethyl)-1H-indole (0.25 mmol, 44 μL), to obtain the target compound 3-{[1-(1H-indol-3-ylmethyl)-1,2,3-triazacyclopentane-4-yl]methyl}-7-methoxy-1,2,3,4-tetrahydroquinazoline-2,4-dione 44 mg, with a yield of 54.1%, as a white solid. HRMS (ESI) of the compound: calcd.For C 21 H 18 N 6 O 3 [M+H] +403.1513, found 403.1508.

[0087] Example 26 4-({4-[(5-chloro-2,4-dioxyidene-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentan-1-yl}methyl)benzene-1-carboxamide

[0088] The preparation method is the same as that of Example 1, except that 8-methoxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione is replaced with 5-chloro-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1-azidomethyl-4-fluorobenzene is replaced with 4-(azidomethyl)benzene-1-carboxamide (0.25 mmol, 44 mg) to obtain the target compound 4-({4-[(5-chloro-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)benzene-1-carboxamide as a white solid. HRMS (ESI) of the compound: calcd.For C 21 H 16 F 3 N 5 O 3 [M+H] + 444.1278, found 444.1274.

[0089] Example 27 N-[4-({4-[(6-methyl-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)phenyl]acetamide

[0090] The preparation method was the same as that in Example 1, except that 6-methyl-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione (41 mg, 0.19 mmol) was used to replace 8-methoxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, and N-[4-(azidomethyl)phenyl]acetamide (0.25 mmol, 44 μL) was used to replace 1-azidomethyl-4-fluorobenzene to obtain the target compound N-[4-({4-[(6-methyl-2,4-dioxy-1H-quinazolin-3-yl)methyl]-1,2,3-triazacyclopentane-1-yl}methyl)phenyl]acetamide 50 mg, with a yield of 63.3%, as a white solid. HRMS (ESI) of the compound: calcd.For C 21 H 20 N 6 O 3 [M+H] + 405.1670, found 405.1677.

[0091] Example 28 6-Acetyl-3-[(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentan-4-yl)methyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione

[0092] The preparation method is the same as that of Example 1. 6-acetyl-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione (46 mg, 0.19 mmol) was used to replace 8-methoxy-3-(prop-2-ynyl)-1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1-(azidomethyl)-4-(trifluoromethyl)benzene (0.25 mmol, 44 μL) was used to replace 1-azidomethyl-4-fluorobenzene to obtain the target compound 6-acetyl-3-[(1-{[4-(trifluoromethyl)phenyl]methyl}-1,2,3-triazacyclopentane-4-yl)methyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione 51 mg, with a yield of 61.1%, as a white solid. HRMS (ESI) of the compound: calcd.ForC 18 H 14 C1N 5 O 3 [M+H] + 384.0858, found 384.0862.

[0093] Embodiment 29

[0094] Pharmacological experiments and results of some compounds of the present invention:

[0095] 1. The inhibitory effect of the compounds of the present invention on NQO1 protein was tested by spectrophotometry.

[0096] In order to evaluate the inhibitory effect of the series of inventive compounds on NQO1 protein, the present invention uses spectrophotometry to test the inhibitory effect of the series of compounds on the binding of NQO1 protein and its substrate β-lapachone. The test method is as follows: the test equipment is a 96-well white plate, the test volume is 200 μL, the mother solution of the tested series of compounds is diluted with a buffer solution to obtain three different concentrations, and then 2 μL of compound, 2 μL of NQO1 protein, 2 μL of β-lapachone, and 190 μL of buffer solution are added to each well. After incubation at 37°C for 5 minutes, 4 μL of NADPH is added to each well, and then the absorbance at 340nm is immediately detected using a Spectra Max i3x multifunctional microplate reader. The test results are analyzed using Graphpad Prism 8. The blank control used in the test is 192 μL of buffer solution, 2 μL of NQO1 protein, 2 μL of β-lapachone, and 4 μL of NADPH, and the positive control is an equal concentration of natural NQO1 inhibitor dicoumarol. The buffer solution is prepared as follows: 0.2M Na2 HPO 4 , 0.2M NaH 2 PO 4 ,0.9% NaCl.

[0097] Table 1 Inhibitory activity of NAD(P)H:quinone oxidoreductase 1 of the example compounds

[0098]

[0099]

[0100] As shown in Table 1, the 3-alkyl substituted 1,2,3-triazole-2,4-quinazolinedione compounds of the present invention have strong NAD(P)H:quinone oxidoreductase 1 inhibitory activity. The activity of most of the example compounds is better than that of the natural NAD(P)H:quinone oxidoreductase 1 inhibitor dicoumarol. Among the example compounds, the NQO1 protein inhibitory activity of Example-4 is the best.

[0101] 2. MTT assay was used to test the cytotoxicity of some compounds of the present invention in combination with gemcitabine on human pancreatic cancer cell line MIAPaCa-2 and in combination with cisplatin or 5-fluorouracil on human lung cancer cell line A549

[0102] The experimental method is as follows: Different tumor cells are inoculated in a 96-well plate and then placed in an incubator to wait for the cells to adhere. All compounds are prepared into 100mM stock solutions, and the compounds are diluted to 200μM with buffer solution, and then three times diluted to obtain six concentrations in succession. Take 100μL of compound solution and 100μL of buffer solution and add them to each well of the 96-well plate. Incubate the 96-well plate at 37°C for 72 hours, then add 20μL of 5mg / ml MTT solution to each well and incubate in the incubator for 4 hours. After the incubation is over, aspirate and remove the solution in each well, add 150μL of DMSO solution to each well, shake on a shaker for 10 minutes, detect the absorbance at 570nm, and analyze the test results using Graphpad Prism 8.

[0103] Table 2 Cytotoxicity of some Example compounds combined with gemcitabine

[0104]

[0105]

[0106] Table 3 Cytotoxicity of some Example compounds combined with cisplatin

[0107]

[0108]

[0109] Table 4 Effects of Example Compounds and Antitumor Drugs

[0110]

[0111] As can be seen from Tables 2 and 3, the results of the combined drug experiments of the representative compounds of the present invention show that the representative compounds can enhance the efficacy of killing cancer cells when used in combination with gemcitabine, cisplatin or 5-fluorouracil. Furthermore, the optimal compound 4 in the embodiment of the present invention exhibits better cytotoxicity when used in combination with gemcitabine or cisplatin at a higher concentration ( Figure 1 , 2 ).

Claims

1. A 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivative, characterized in that: Selected from the following compounds or pharmaceutically acceptable salts thereof:

2. The 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivative according to claim 1, characterized in that: The pharmaceutically acceptable salt is a salt formed by the compound and an acid or a base, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid; and the base is an inorganic base containing an alkaline metal cation, an alkaline earth metal cation or an ammonium cation salt, choline, diethanolamine or morpholine.

3. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivative according to any one of claims 1 to 2 and a pharmaceutically acceptable carrier; the above-mentioned 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivative can be added with a pharmaceutically acceptable carrier to prepare a pharmaceutical preparation.

4. Use of the 3-(1,2,3-triazol-4-yl)tetrahydroquinazoline-2,4-dione derivatives according to any one of claims 1 to 2 in the preparation of NQO1 enzyme inhibitor drugs.

5. Use of the pharmaceutical composition according to claim 3 in the preparation of NQO1 enzyme inhibitor drugs.

6. The use according to claim 4 or 5, characterized in that: The drug is used in combination with an anti-tumor drug to treat tumor diseases, and the tumor diseases are selected from pancreatic cancer and non-small cell lung cancer.

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