A gefitinib-linked triazole derivative, its preparation method and application

Abstract

The present invention discloses a gefitinib-linked triazole derivative, its preparation method and application, belonging to the technical field of pharmaceutical synthesis. The key points of the technical solution of the present invention are as follows: The gefitinib-linked triazole derivative molecule has the structure #imgabs0# where R is a benzyl-like structure. The present invention designs and synthesizes a gefitinib-linked triazole derivative with a novel structure. This type of compound has a good inhibitory effect on wild-type lung cancer tumor cells, can target MMP9 as an MMP9 inhibitor, and further inhibit the migration and metastasis of wild-type lung cancer tumors.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a gefitinib-linked triazole derivative, a preparation method thereof, and an application thereof. Background Art

[0002] Gefitinib belongs to the first-generation targeted therapeutic drug, which can bind to the epidermal growth factor receptor, thereby inhibiting the proliferation of tumor cells and the growth of new blood vessels1. Gefitinib (trade name: Iressa), the first epidermal growth factor receptor tyrosine kinase inhibitor developed by AstraZeneca, with its chemical name: 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy) quinazoline, was first launched in Japan in July 2002, mainly used for the treatment of non-small cell lung cancer. Its mechanism of action is mainly to inhibit the tyrosine kinase epidermal growth factor receptor (EGFR). By targeting EGFR, it competitively binds to the highly conserved ATP binding site of EGFR with ATP, inhibits the EGF receptor, promotes apoptosis, and can inhibit tumor angiogenesis, having a very broad clinical application prospect. However, with the market use of gefitinib, it has a good inhibitory effect on EGFR mutant lung cancer cells, but its inhibitory activity against wild-type lung cancer cells is weaker than that against mutant lung cancer cells. We want to improve the inhibitory activity against wild-type lung cancer cells by modifying the structure of EGFR-TKI.

[0003] The 1,2,3-triazole structure is a very important class of nitrogen-containing heterocyclic compounds, a five-membered heterocycle constructed by 3 nitrogen atoms and 2 carbon atoms, with the molecular formula C2N3H3. The 1,2,3-triazole has a special planar rigid structure, enabling it to have a strong ability to embed into DNA. At the same time, it has a large dipole moment and can form various non-covalent interaction forces such as hydrophobic, hydrogen bond, van der Waals force, and dipole-dipole bond with different biological targets. In addition, the structural characteristics of 1,2,3-triazole allow it to be used as an electronic equivalent substitute for amides, esters, carboxylic acids, olefin rigid analogs, etc. Therefore, it has broad biological activities and is often used as an important molecular building block for the synthesis of active compounds, such as the preparation of antibacterial, antimalarial, antifungal, antiviral, antituberculosis, and anticancer active compounds, etc., and has a wide application in the field of medicinal chemistry. There are a variety of clinical drugs whose original biological activities have been enhanced or new biological activities have been obtained after being modified by 1,2,3-triazole. For example, using the structural characteristics of the anti-HIV drug zidovudine with an azide group, a compound with 1,2,3-triazole is obtained through a click chemical reaction with a terminal alkyne compound, which has an inhibitory effect on Escherichia coli and Staphylococcus aureus.

[0004] To find compounds with good inhibitory effects on EGFR wild-type lung cancer cells, we modified gefitinib through click reaction and introduced 1,2,3-triazole groups into its structure, hoping that it could have inhibitory effects on wild-type lung cancer cells. Taking gefitinib as the positive control, we used the CCK-8 method to evaluate the in vitro anti-tumor activities against EGFR wild-type lung cancer cells H1299, A549, and H1437, and studied the effects on tumor cell colony formation, migration ability, and apoptosis. Summary of the Invention

[0005] The technical problem solved by the present invention is to provide a gefitinib-linked triazole derivative and its preparation method that are simple and easy to operate, have cheap and easily available raw materials, high reaction efficiency, and good inhibitory effects on tumor cells.

[0006] The present invention adopts the following technical solution to solve the above technical problem. The gefitinib-linked triazole derivative is characterized by having the following structure: Wherein R is a benzyl-like structure.

[0007] The preparation method of the gefitinib-linked triazole derivative of the present invention is characterized in that:

[0008] The preparation method of the gefitinib-linked triazole derivative of the present invention is characterized in that the specific steps in the preparation process are as follows:

[0009] (1): Dissolve a certain amount of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate in acetic acid solution. Cool the system to below 10 °C, and gradually add dropwise a certain amount of a mixed solution of nitric acid and sulfuric acid. After adding, gradually raise the temperature of the system to room temperature. React the system at a certain temperature for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Extract with ethyl acetate, dry with anhydrous sodium sulfate, and after evaporation, purify the crude product by column chromatography to obtain methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of the feed amount of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to nitric acid and sulfuric acid is 1:1 - 1.3:1 - 1.3; the reaction temperature is 20 - 50 °C.

[0010] (2) Dissolve a certain amount of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate in a nitromethane solution. Cool the system to below 10 °C, and dropwise add a certain amount of methyl nitrate. After addition, gradually raise the temperature of the system to room temperature. React the system at a certain temperature for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Extract with ethyl acetate, dry with anhydrous sodium sulfate, and after evaporation to dryness, purify the crude product by column chromatography to obtain methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of the input amount of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to methyl nitrate is 1:1 to 1.3; the reaction temperature is 0 to 40 °C.

[0011] (3) Dissolve a certain amount of methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate in an anhydrous methanol solution. At room temperature, add a certain amount of palladium-carbon in batches. After addition, react the system at the corresponding temperature for several hours. Monitor the reaction by TLC. After the reaction is completed, filter off the excess palladium-carbon from the system. After evaporation to dryness, purify the crude product by column chromatography to obtain methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of the input amount of methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to palladium-carbon is 1:0.02 to 0.2; the reaction temperature is 20 to 60 °C.

[0012] (4) Dissolve a certain amount of methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate and ammonium formate in a DMF solution. React the system at an elevated temperature for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Extract with ethyl acetate, dry with anhydrous sodium sulfate, and after evaporation to dryness, purify the crude product by column chromatography to obtain 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one; the molar ratio of the input amount of methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to ammonium formate is 1:3 to 1.6; the reaction temperature is 120 to 170 °C.

[0013] (5): Dissolve a certain amount of methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate and ammonium formate in a DMA or DMSO solution. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Extract with ethyl acetate, dry with anhydrous sodium sulfate, and after evaporation, purify the crude product by column chromatography to obtain 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one; the molar ratio of the input amount of methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to ammonium formate is 1:3 to 1.6; the reaction temperature is 60 to 100 °C, the microwave reaction gear is set to 6 - 8 gears, and the time is set: 15 min - 30 min.

[0014] (6): Dissolve a certain amount of 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one in phosphorus oxychloride solution. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Adjust the pH of the aqueous phase system to neutral with saturated sodium bicarbonate, extract with dichloromethane, separate the organic phase, then dry with anhydrous magnesium sulfate, filter and rotary evaporate under reduced pressure, and purify by column chromatography to obtain the product 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine; the reaction temperature is 60 to 100 °C, and the reaction time is 6 h - 18 h.

[0015] (7): Dissolve a certain amount of 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one in phosphorus oxychloride solution. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Adjust the pH of the aqueous phase system to neutral with saturated sodium bicarbonate, extract with dichloromethane, separate the organic phase, then dry with anhydrous magnesium sulfate, filter and rotary evaporate under reduced pressure, and purify by column chromatography to obtain the product 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine; set the microwave reaction gear to 6 - 8 gears, the temperature is set to 60 - 120 °C, and the time is set: 30 - 60 min.

[0016] (8): Dissolve a certain amount of 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine and meta-alkynylaniline in isopropanol solution. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, filter by suction to obtain the product N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine; the reaction temperature is 60 to 100 °C, the reaction time is 6 h - 18 h, and the molar ratio of the input amount of 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine to meta-alkynylaniline is 1:3 to 6.

[0017] (9): Dissolve a certain amount of 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine and meta-alkynylaniline in an isopropyl alcohol solution. React the system under heating for several hours, monitor the reaction by TLC. After the reaction is completed, filter to obtain the product N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine; set the microwave reaction power to: 300 - 400 watts, the temperature to 55 - 75 °C, and the time to: 30 - 60 min. The molar ratio of the feed amount of 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine to meta-alkynylaniline is 1:3 - 6.

[0018] (10): Dissolve a certain amount of N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine and 2-bromo-5-fluorobenzyl azide in a mixed solution of tert-butanol / water / tetrahydrofuran. React the system under heating for several hours, monitor the reaction by TLC. After the reaction is completed, purify by column chromatography to obtain the gefitinib triazole product; the reaction temperature is 60 - 100 °C, the reaction time is: 6 h - 18 h. The molar ratio of the feed amount of N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine to benzyl azide is 1:1.1 - 1.6.

[0019] The application of the gefitinib-linked triazole derivatives described in the present invention in the preparation of drugs for treating or preventing lung cancer.

[0020] Technical advantages of the present invention:

[0021] 1. A series of gefitinib-linked triazole derivatives with novel structures are obtained in the present invention.

[0022] 2. These compounds have good inhibitory effects on wild-type lung cancer tumor cells, can target MMP9 as an MMP9 inhibitor, and thus inhibit the migration and metastasis of wild-type lung cancer tumors; moreover, they can also induce DNA damage in hepG2 cells. Description of the drawings

[0023] Figure 1 1H NMR spectrum of compound 7a obtained in Example 13

[0024] Figure 2 1H NMR spectrum of compound 7j obtained in Example 15

[0025] Figure 3 1H NMR spectrum of compound 7q obtained in Example 15 Detailed implementation manners

[0026] The above content of the present invention will be further described in detail through the following examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0027] Example 1

[0028]

[0029] Dissolve methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (15 g) in acetic acid (100 mL) solution. Cool the system to below 10 °C, and gradually add dropwise a mixture of nitric acid (5.6 g) and sulfuric acid (5.7 g). After the addition, gradually raise the temperature of the system to room temperature. React the system at room temperature for 24 hours, monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system, extract with ethyl acetate, dry with anhydrous sodium sulfate, evaporate to dryness, and purify the crude product by column chromatography to obtain 10 g of methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate.

[0030] Example 2

[0031] Dissolve methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (15 g) in methanesulfonic acid (100 mL) solution. Cool the system to below 10 °C, and gradually add dropwise a mixture of nitric acid (5.6 g) and methanesulfonic acid (5.6 g). After the addition, gradually raise the temperature of the system to room temperature. React the system at room temperature for 8 hours, monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system, extract with ethyl acetate, dry with anhydrous sodium sulfate, evaporate to dryness, and purify the crude product by column chromatography to obtain 13 g of methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate.

[0032] Example 3

[0033] Dissolve methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (15 g) in nitromethane (100 mL) solution. Cool the system to 0 - 10 °C, saturate the system with boron trifluoride gas (until the reaction system can no longer dissolve boron trifluoride, as indicated by an obvious change in the pressure of the reaction system through the pressure valve), add methyl nitrate (6.7 g). After the addition, gradually raise the temperature of the system to room temperature. React the system at room temperature for 7.5 hours, monitor the completion of the reaction by TLC. Quench the reaction by adding 200 mL of water to the system, extract the reaction system 5 times with 100 mL of ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, evaporate to dryness to obtain 14.7 g of methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate.

[0034] Example 4

[0035] In a reaction flask, dissolve methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (1.5 g) in acetic acid (10 mL) solution to prepare solution A; then dissolve a mixture of nitric acid (0.6 g) and sulfuric acid (1.1 g) to prepare solution B (volume about 1 mL); simultaneously introduce A and B into a microchannel reactor at flow rates of 1 mL / min and 0.1 mL / min respectively, set the reactor temperature to 0 °C, after the reaction is completed, collect the reaction solution discharged from the reactor, pour it into ice water, a large amount of solid product appears, and obtain the product after recrystallization with isopropanol, obtaining 1.41 g of methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate. 1 1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.10 (s, 1H), 4.18 (t, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 3.73 (t, 4H), 2.55 - 2.47 (m, 6H), 2.06 (t, 2H).

[0036] Example 5

[0037]

[0038] Weigh the nitration product methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (1 g) obtained in the previous step, dissolve it in anhydrous methanol (10 mL), add Pd / C (10%, 0.1 g) for hydrogenation reaction, react the system overnight at room temperature, monitor the reaction by TLC, until the raw materials disappear, directly filter off the palladium carbon from the system, evaporate the excess solvent from the system and then purify it by column chromatography to obtain 0.7 g of solid product methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate.

[0039] Example 6

[0040] Weigh the nitration product methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (1.2 g) and dissolve it in acetone (20 mL). Dropwise add a solution of titanium trichloride (30%) in hydrochloric acid (50 mL) to the reaction system under an ice bath environment. After adding, gradually raise the temperature of the system to room temperature and react overnight. Monitor the reaction by TLC until the raw materials disappear. Pour the system into ice water (200 mL), extract with ethyl acetate (70 mL × 3), evaporate the excess solvent from the system and then purify it by column chromatography to obtain 0.76 g of solid product methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate.

[0041] Example 7

[0042] In a flow hydrogenation reaction apparatus (self-assembled), the hydrogenation flow system consists of a gas flow meter, a micromixer, a micro-packed bed, and a back pressure valve with a pressure resistance of 15 bar. A mixture containing methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (1 g) and methanol (20 mL) was pumped (flow rate 0.5 mL / min) through a pressure pump; hydrogen in the high-pressure cylinder entered the micro-reaction system through the gas flow meter at a flow rate of 1 mL / min. The liquid phase and the gas phase were combined through a T-tube and entered the micromixer, and the reaction temperature of the system was controlled at 25 °C; the reaction stream passed through the micro-packed bed (0.1 g of 10% Pd / C, 20.0 g of SiO2: 5 mL internal volume), and the residence time was 10.0 min; then the reaction stream was collected in a 50 mL conical flask, concentrated under vacuum, and the crude product was purified by column chromatography (DCM / MeOH = 100:1) to obtain 0.87 g of methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; 1 1H NMR (400 MHz, DMSO-d6): δ 7.54 (s, 1H), 7.14 (s, 1H), 6.43 (s, 2H), 4.28 (t, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 3.63 (t, 4H), 2.57 - 2.52 (m, 6H), 2.16 - 2.15 (m, 2H).

[0043] Example 8

[0044]

[0045] Methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (4.0 g) obtained in the previous step and ammonium formate (2.0 g) were dissolved in DMF (30 mL). The system was heated to 165 °C and reacted for 4 hours under a nitrogen atmosphere. The reaction was monitored by TLC. When the reaction was completely finished, the system was poured into ice water, extracted with ethyl acetate, the organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and finally purified by column chromatography to obtain 2.7 g of 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one.

[0046] Example 9

[0047] In a microwave chemical reactor (MCR-3), methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (4.0 g) obtained in the previous step and ammonium formate (2.0 g) were dissolved in DMA (30 mL). Turn on the power supply, insert the temperature sensor, and set the microwave reaction power to: 300 - 400 watts, the temperature to 80 °C, and the time to: 15 min. After the reaction is completely finished, the system was poured into ice water, and the system was slowly stirred. After the product precipitated, it was filtered by suction to obtain 2.95 g of the product 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one; 1 H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.44 (s, 1H), 7.12 (s, 1H), 4.11 (t, J = 6.5 Hz, 2H), 3.90 (s, 3H), 3.58 (t, J = 4.6 Hz, 4H), 2.44 (t, J = 7.0 Hz, 2H), 2.37 (s, 4H), 1.99 - 1.80 (m, 2H).

[0048] Example 10

[0049] In a microwave chemical reactor (MCR-3), methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate (4.0 g) obtained in the previous step and ammonium formate (2.0 g) were dissolved in DMSO (20 mL). Turn on the power supply, insert the temperature sensor, and set the microwave reaction power to: 300 - 400 watts, the temperature to 80 °C, and the time to: 15 min. After the reaction is completely finished, the system was poured into ice water, and the system was slowly stirred. After the product precipitated, it was filtered by suction to obtain 3.01 g of the product 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one.

[0050] Example 11

[0051]

[0052] Compound 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one (2.6 g) was dissolved in phosphorus oxychloride (10.0 mL). The system was heated to reflux. After reacting for 18 hours, TLC was continued to monitor the reaction. After the reaction was completely finished, the system was poured into ice water, and the pH of the aqueous phase system was adjusted to neutral with saturated sodium bicarbonate. It was extracted with dichloromethane, the organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography to obtain 2.1 g of the product 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine.

[0053] Example 12

[0054] In a microwave chemical reactor, dissolve 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one (2.6 g) in phosphorus oxychloride (10.0 mL); turn on the power supply, insert the temperature sensor, set the microwave reaction gear and set the temperature to 90 °C and the time to 45 min. After the reaction is completely finished, pour the system into ice water, adjust the pH of the aqueous phase system to neutral with saturated sodium bicarbonate, extract with dichloromethane, separate the organic phase, then dry with anhydrous magnesium sulfate, filter and rotary evaporate under reduced pressure to obtain 2.3 g of the product 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine. 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.43(s,1H),7.38(s,1H),4.23(t,2H),3.95(s,3H),3.57(t,4H),2.43(t,2H),2.37(s,4H),2.03-1.92(m,2H).

[0055] Example 13

[0056]

[0057] Dissolve 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine (1.5 g) in 40 mL of isopropanol, add m-ethynylaniline (1.58 g), heat the system to reflux, after reacting for 10 hours, monitor the reaction by TLC, after the reaction is completely finished, a large amount of solid product precipitates in the system, filter by suction to obtain 1.2 g of the product N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine.

[0058] Example 14

[0059] In a microwave chemical reactor, dissolve 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine (1.5 g) in 40 mL of isopropanol, add m-ethynylaniline (1.58 g). Turn on the power supply, insert the temperature sensor, set the microwave reaction power to 350 - 450 watts, set the temperature to 75 °C, and set the time to 30 min. After the reaction is completely finished, pour the system into ice water, slowly stir the system, wait for the product to precipitate, filter by suction to obtain 1.4 g of off-white solid product N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine.

[0060] Example 15

[0061]

[0062] Synthesis of the target product N-(3-(1-(2-bromo-5-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7a): In a reaction flask, N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (250 mg), 2-bromo-5-fluorobenzyl azide (160 mg), 10 mL of tert-butanol / 10 mL of water / 10 mL of tetrahydrofuran, copper sulfate pentahydrate (15 mg) and sodium ascorbate (12 mg) were added successively. The reaction was carried out at 90 °C for 12 h. After the raw materials were completely reacted and converted into the product, 30 mL of dichloromethane was added, and the reaction solution was filtered to obtain a yellow liquid. Then the organic phase was separated, and the aqueous phase was extracted twice with 15 mL of dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain a yellow solid. After column chromatography, 162 mg of pale yellow product 7a was obtained.

[0063] Example 16

[0064]

[0065] In a parallel reactor, N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (250 mg), 2-bromo-5-fluorobenzyl azide (160 mg), 10 mL of tert-butanol / 10 mL of water / 10 mL of tetrahydrofuran, copper sulfate pentahydrate (15 mg) and sodium ascorbate (23 mg) were added successively. The reaction was carried out at 90 °C for 12 h. After the raw materials were completely reacted and converted into the product, the excess tetrahydrofuran and tert-butanol in the system were evaporated. 50 mL of secondary water was added, and the mixture was placed in an ultrasonic instrument and ultrasonicated for 20 min, then allowed to stand for 1 h until a solid was formed. After centrifuging for 10 min, the supernatant was removed, and the product was recrystallized with a small amount of methanol and filtered to obtain 368 mg of pale yellow product 7a (due to the large polarity of the product and difficulty in purification, the purification method was improved and the yield was increased). 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 8.13 - 8.06 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.77 - 7.75 (m, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.45 (s, 1H), 7.30 - 7.15 (m, 2H), 5.75 (s, 2H), 4.25 - 4.15 (m, 2H), 3.98 (s, 3H), 3.61 - 3.53 (m, 4H), 2.44 - 2.37 (m, 3H), 2.09 - 1.92 (m, 2H).

[0066] Example 17

[0067]

[0068] In a parallel reactor, N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (250 mg), 2-fluoro-4-bromobenzyl azide (160 mg), 10 mL of tert-butanol / 10 mL of water / 10 mL of tetrahydrofuran, copper(II) sulfate pentahydrate (15 mg) and sodium ascorbate (23 mg) were added successively. The reaction was carried out at 90 °C for 12 h. After the raw materials were completely reacted and converted into products, the excess tetrahydrofuran and tert-butanol in the system were evaporated. 50 mL of secondary water was added, and the mixture was sonicated in an ultrasonic instrument for 20 min and then allowed to stand for 1 h. After the solid was formed, it was centrifuged for 10 min, and then the supernatant was removed. The product was recrystallized with a small amount of methanol and filtered to obtain 352 mg of N-(3-(1-(4-bromo-2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine. The yield was 91% (due to the large polarity of the product and difficulty in purification, the yield was improved after the purification method was improved). 1 H NMR (400 MHz, Chloroform-d) δ 9.60 (s, 1H), 8.64 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 9.6 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.54 - 7.31 (m, 3H), 5.71 (s, 2H), 4.21 (t, J = 6.3 Hz, 2H), 3.97 (s, 3H), 3.64 - 3.52 (m, 4H), 2.43 - 2.40 (m, 3H), 2.01 (t, J = 6.8 Hz, 2H).

[0069] The preparation methods of target compounds 7c - 7z are similar to those of 7a and 7b, except that the substituents of the active groups with azide structures are different. The structural characterization data are as follows:

[0070]

[0071] Target compound N-(3-(1-(3-chloro-4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7c): The yield was 89%.

[0072] Target compound N-(3-(1-(2-chloro-6-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7d): The yield was 95%.

[0073] Target compound 7-methoxy-6-(3-morpholinopropoxy)-N-(3-(1-(2-nitrobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)quinazolin-4-amine (7e): The yield was: 91%.

[0074] Target compound 7-methoxy-6-(3-morpholinopropoxy)-N-(3-(1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)quinazolin-4-amine (7f): The yield was: 75%.

[0075] Target compound N-(3-(1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7g): The yield was: 80%.

[0076] Target compound 7-methoxy-6-(3-morpholinopropoxy)-N-(3-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)phenyl)quinazolin-4-amine (7h): The yield was: 60%.

[0077] Target compound N-(3-(1-(4-iodobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7i): The yield was: 85%.

[0078] Target compound N-(3-(1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7j): The yield was: 87%.

[0079] Target compound N-(3-(1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7k): The yield was: 90%.

[0080] Target compound 7-methoxy-N-(3-(1-(2-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-(3-morpholinopropoxy)quinazolin-4-amine (7l): The yield was: 85%.

[0081] Target compound N-(3-(1-(3,5-dimethylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7m): The yield was: 84%.

[0082] Target compound 4-fluoro-2-((4-(3-((7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile (7n): Yield: 58%.

[0083] Target compound N-(3-(1-(3,5-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7o): Yield: 75%.

[0084] Target compound N-(3-(1-(3-iodobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7p): Yield: 92%.

[0085] Target compound N-(3-(1-(2-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7q), Yield: 84%.

[0086] Target compound N-(3-(1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7r): Yield: 91%.

[0087] Target compound 2-((4-(3-((7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-yl)amino)phenyl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile (7s): Yield: 87%.

[0088] Target compound N-(3-(1-(3,5-dibromobenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (7t): Yield: 95%.

[0089] Target compound 7-methoxy-N-(3-(1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-(3-morpholinopropoxy)quinazolin-4-amine (7u): Yield: 82%.

[0090] Target compound 7-methoxy-N-(3-(1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-(3-morpholinopropoxy)quinazolin-4-amine (7v): Yield: 87%.

[0091] Target compound 7-methoxy-N-(3-(1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-(3-morpholinopropoxy)quinazolin-4-amine (7w): The yield was: 89%.

[0092] Target compound 7-methoxy-N-(3-(1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-(3-morpholinopropoxy)quinazolin-4-amine (7x): The yield was: 85%.

[0093] Target compound 7-methoxy-N-(3-(1-(3-nitrophenyl)-1H-1,2,3-triazol-4-yl)phenyl)-6-(3-morpholinopropoxy)quinazolin-4-amine (7y): The yield was: 85%.

[0094] Target compound 7-methoxy-N-(3-(1-(lenalidomide)-1H-1,2,3-triazol-4-yl)phenyl)-6-(3-morpholinopropoxy)quinazolin-4-amine (7z): The yield was: 93%.

[0095] Example 16

[0096] Dissolve the obtained compound and gefitinib in DMSO to prepare stock solutions with a final concentration of 12800 μM. Dilute the compound with the corresponding cell culture medium to different concentrations for subsequent experiments (0, 2, 4, 8, 16, 32 μmol / L (where the final concentration of DMSO does not exceed 0.1% in the experiment)). Seed lung cancer cells in the logarithmic growth phase into a 96-well plate at a density of 5×103 cells per well and culture them in a 37°C, 5% CO2 cell incubator. After the cells adhere, divide the cells into a normal control group, a blank group, and different concentration drug groups (0, 2, 4, 8, 16, 32 μmol / L). Except for the normal control group without intervention, add the corresponding drugs to the other groups and culture them at 37°C and 5% CO2 for 48 h. Set 3 replicates for each group. Operate according to the method described in the CCK8 kit manual (No. C0039, Beyotime Biotechnology). Seed lung cancer cells in the logarithmic growth phase into a 96-well plate at a density of 5×10 3Cells were inoculated at a certain cell density in 96-well plates and cultured in a 37 °C, 5% CO2 cell incubator. After the cells adhered, the cells were divided into a normal control group, a blank group, and different concentration drug groups (0, 2, 4, 8, 16, 32 μmol / L). Except for the cells in the normal control group without intervention, the corresponding drugs were added to the remaining groups and cultured under the conditions of 37 °C and 5% CO2 for 48 h. Each group was set with 3 replicate wells. 10 μl of CCK8 reagent was added to each well, and after incubating in the 37 °C cell incubator in the dark for 1 - 4 h, the absorbance (optical density, OD) value was detected with an enzyme-linked immunosorbent assay (ELISA) reader (Bio-Tek) at a wavelength of 450 nm. Calculate the inhibition rate of cell growth in each group. Inhibition rate (%) = [(OD value of the experimental group - OD value of the blank group) / (OD value of the control group - OD value of the blank group)] × 100%, and further calculate the half inhibitory concentration (IC 50 50). The experiment was repeated 3 times. 10 μl of CCK8 reagent was added to each well, and after incubating in the 37 °C cell incubator in the dark for 1 - 4 h, the absorbance (optical density, OD) value was detected with an enzyme-linked immunosorbent assay (ELISA) reader (Bio-Tek) at a wavelength of 450 nm. Calculate the inhibition rate of cell growth in each group. Inhibition rate (%) = [(OD value of the experimental group - OD value of the blank group) / (OD value of the control group - OD value of the blank group)] × 100%, and further calculate the half inhibitory concentration (half inhibitory concentration, IC50). The experiment was repeated 3 times.

[0097]

[0098] Example 17

[0099] After treatment with compound 7a, the total apoptosis proportions of H1299 cells were 18.3% (2 μM), 28.3% (4 μM), and 47.9% (8 μM) ( Figure 3)。After treatment with compound 7j, the total apoptosis rates of H1299 cells were 13.2% (2 μM), 24.5% (4 μM), and 63.3% (8 μM), respectively. After treatment with compound 7q, the total apoptosis rates of H1299 cells were 20.43% (2 μM), 43.2% (4 μM), and 77.4% (8 μM), respectively. Compared with the control group, as the drug concentration increased, the apoptosis rate gradually increased (P<0.01, P<0.05). The above results suggest that 7a, 7j, and 7q can all significantly promote the apoptosis of H1299 lung cancer cell line and show concentration dependence. After treatment with compound 7a, the migration closure rates of H1299 cells were 73.8% (2 μM), 53.6% (4 μM), and 26.1% (8 μM), respectively. After treatment with compound 7j, the migration closure rates of H1299 cells were 76.5% (2 μM), 65.5% (4 μM), and 47.8% (8 μM), respectively. After treatment with compound 7q, the migration closure rates of H1299 cells were 72.59% (2 μM), 62.42% (4 μM), and 49.79% (8 μM), respectively. Compounds 7a, 7j, and 7q could inhibit the colony formation of H1299 cells at a concentration of 1 μM. Compounds 7a, 7j, and 7q could reduce the MMP9 protein in H1299 cells to about 50% at a concentration of 8 μM. Therefore, this type of compound can be used as an MMP9 inhibitor.

[0100] Example 18

[0101] We prepared compounds 7a - 7z at a concentration of 10 μM and detected their inhibitory activities against hepatocellular carcinoma cell line hepG2. It was found that most compounds showed better activities than gefitinib itself. The IC50 values of compounds 7i and 7p were 3.08 and 3.60 μM, respectively. At a concentration of 16 μM, the survival rates of these two compounds against L02 cells were 76.86% and 47.58%, respectively, showing safety. Compounds 7i and 7p at a concentration of 2 μM and acting for 24 h could reduce the migration and invasion abilities of hepG2 cells, and at a concentration of 2 μM, they could cause DNA damage in hepG2 cells, and compared with the blank control, they could increase the expression level of H2AX protein by about 42%.

[0102]

[0103] The above examples describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above examples. What is described in the above examples and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A gefitinib-linked triazole derivative, characterized in that, The structure of the gefitinib-linked triazole derivative is as follows: , where R is 2-bromo-5-fluorobenzyl, 2-fluoro-4-bromobenzyl, 3-chloro-4-fluorobenzyl, 2-fluoro-6-chlorobenzyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-fluorobenzyl, 4-trifluoromethylbenzyl, 4-iodobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-methylbenzyl, 3,5-dimethylbenzyl, 2-cyano-5-fluorobenzyl, 3,5-dimethoxybenzyl, 3-iodobenzyl, 2-bromobenzyl, 4-bromobenzyl, 2-cyano, 3,5-dibromobenzyl or 4-methylbenzyl.

2. The preparation method of a gefitinib-linked triazole derivative according to claim 1, wherein, Dissolve N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine and 2-bromo-5-fluorobenzyl azide in a mixed solution of tert-butanol / water / tetrahydrofuran. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, purify it by column chromatography to obtain the gefitinib triazole product; the reaction temperature is 60-100 °C, and the reaction time is 6 h - 18 h. The molar ratio of the feed amounts of N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine to benzyl azide is 1:1.1 - 1.

6.

3. The preparation method of a gefitinib-linked triazole derivative according to claim 2, characterized in that, Dissolve 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine and m-ethynylaniline in an isopropanol solution. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, filter by suction to obtain the product N-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine; the reaction temperature is 60-100 °C, and the reaction time is 6 h - 18 h. The molar ratio of the feed amounts of 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine to m-ethynylaniline is 1:3 - 6.

4. The preparation method of a gefitinib-linked triazole derivative according to claim 3, characterized in that, Dissolve 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one in phosphorus oxychloride solution. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Adjust the pH of the aqueous phase system to neutral with saturated sodium bicarbonate. Extract with dichloromethane, separate the organic phase, then dry it with anhydrous magnesium sulfate, filter and rotary evaporate under reduced pressure, and purify it by column chromatography to obtain the product 4-(3-((4-chloro-7-methoxyquinazolin-6-yl)oxy)propyl)morpholine; the reaction temperature is 60-100 °C, and the reaction time is 6 h - 18 h.

5. The preparation method of a gefitinib-linked triazole derivative according to claim 4, characterized in that, Dissolve methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate and ammonium formate in DMF solution. React the system under heating for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Extract with ethyl acetate, dry with anhydrous sodium sulfate, and after evaporation, purify the crude product by column chromatography to obtain 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one; the molar ratio of the feed amounts of methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to ammonium formate is 1:3 - 1.6; the reaction temperature is 120-170 °C; Alternatively, methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate and ammonium formate are dissolved in a DMA or DMSO solution, and the system is heated for several hours under reaction. The reaction is monitored by TLC. After the reaction is completed, the system is quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the crude product is purified by column chromatography to obtain 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one; the molar ratio of the feed amount of methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to ammonium formate is 1:3 to 1.6; the reaction temperature is 60 to 100 °C, and the microwave reaction time is set to 15 min - 30 min.

6. The preparation method of a gefitinib-linked triazole derivative according to claim 5, characterized in that, Methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate is dissolved in an anhydrous methanol solution. At room temperature, palladium carbon is added in batches. After addition, the system is reacted for several hours at the corresponding temperature. The reaction is monitored by TLC. After the reaction is completed, the excess palladium carbon is filtered off from the system, and the crude product is purified by column chromatography to obtain methyl 2-amino-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of the feed amount of methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to palladium carbon is 1:0.02 to 0.2; the reaction temperature is 20 to 60 °C.

7. The preparation method of a gefitinib-linked triazole derivative according to claim 6, characterized in that, Methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate is dissolved in an acetic acid solution to prepare solution A; then a mixed solution of nitric acid and sulfuric acid is dissolved and configured into solution B; A and B are simultaneously introduced into a microchannel reactor at a certain flow rate respectively. The reactor temperature is set to 0 °C. After the reaction is completed, the reaction solution discharged from the reactor is collected and poured into ice water. A large amount of solid product appears, and the product is obtained after recrystallization with isopropanol to obtain methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of the feed amount of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to nitric acid and sulfuric acid is 1:1 to 2:1 to 3.

8. The preparation method of a gefitinib-linked triazole derivative according to claim 6, characterized in that, Methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate is dissolved in a nitromethane solution. The system is cooled to below 10 °C, boron trifluoride gas is introduced into the system until saturation, and methyl nitrate is added. After addition, the system is gradually warmed to room temperature, and the system is reacted at room temperature. The reaction is monitored by TLC. After the reaction is completed, the system is quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the crude product is purified by column chromatography to obtain methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of the feed amount of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate to methyl nitrate is 1:1 to 3.

9. The preparation method of gefitinib-linked triazole derivatives according to claim 6, characterized in that, Dissolve methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate in acetic acid solution. Cool the system to below 10 °C and slowly add dropwise a mixed solution of nitric acid and sulfuric acid. After the addition, gradually warm the system to room temperature. React the system at a certain temperature for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate to dryness, and purify the crude product by column chromatography to obtain methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate, nitric acid, and sulfuric acid in the feed is 1:1 - 1.3:1 - 1.3; the reaction temperature is 20 - 50 °C; Or dissolve methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate in methanesulfonic acid solution. Cool the system to below 10 °C and slowly add dropwise a mixed solution of nitric acid and methanesulfonic acid. After the addition, gradually warm the system to room temperature. React the system at a certain temperature for several hours. Monitor the reaction by TLC. After the reaction is completed, quench the reaction by adding water to the system. Extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate to dryness, and purify the crude product by column chromatography to obtain methyl 2-nitro-4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate; the molar ratio of methyl 4-methoxy-3-(3-(morpholin-4-yl)propoxy)benzoate, nitric acid, and methanesulfonic acid in the feed is 1:1 - 1.3:1 - 1.3; the reaction temperature is 20 - 50 °C.

10. Use of the gefitinib-linked triazole derivative according to claim 1 in the preparation of an MMP9 inhibitor.

Images