A macrocyclic polyamine-derived quinazoline compound and its preparation method and application

Abstract

The present invention discloses a quinazoline compound derived from a macrocyclic polyamine, a preparation method and an application thereof, and belongs to the technical field of quinazoline compounds. The general structural formula of the quinazoline compound derived from a macrocyclic polyamine is as follows: in response to the problem of limited inhibitory activity coverage caused by different mutation types of epidermal growth factor receptor (EGFR) in different patients in the prior art, the present invention strives to provide a broader and more effective activity spectrum, especially against complex EGFR variants, through innovative design and chemical structure adjustment; at the same time, through innovative design and chemical structure adjustment, the problem of drug resistance that may be generated during the treatment of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is targetedly addressed, and the anti-cancer cell proliferation activity of the drug in drug-resistant cells is improved; by introducing cyclic polyamines into the quinazoline skeleton, the potential sites of the chemical structure are more fully utilized to improve the activity of the inhibitor against EGFR containing the C797S triple mutation, filling this gap in the prior art.

Description

Technical Field

[0001] The present invention belongs to the technical field of compounds, and in particular relates to a quinazoline compound derived from a macrocyclic polyamine, and a preparation method and application thereof. Background Art

[0002] Quinazoline derivatives, a key class of EGFR inhibitors, have achieved remarkable success in the targeted treatment of non-small cell lung cancer (NSCLC), with examples such as gefitinib, erlotinib, and icotinib. These inhibitors, by specifically blocking the EGFR signaling pathway, have become important drugs in the treatment of NSCLC. Gefitinib, a first-generation EGFR inhibitor, has demonstrated clinical success, inhibiting the growth of NSCLC by inhibiting EGFR activity. As EGFR tyrosine kinase inhibitors, erlotinib and icotinib have distinguished themselves in clinical practice with their excellent safety profile and low side effects, providing NSCLC patients with more advanced treatment options. Despite the success of marketed EGFR inhibitors, they still have several limitations, including insufficient inhibition of triple-mutated EGFR and drug resistance in some patients.

[0003] Currently, EGFR inhibitors have the following main technical problems: (1) Limited activity spectrum coverage: Current EGFR inhibitors have limited activity spectrum coverage in combating the complexity of EGFR mutants, especially the effectiveness against EGFR triple mutants (EGFR19del / T790M / C797S) needs to be improved. (2) Drug resistance: EGFR-TK inhibitors are prone to drug resistance during long-term treatment, especially against common EGFR mutants such as the d746-750 / T790M / C797S triple mutation. (3) Inadequate use of chemical structure: Some existing EGFR inhibitors do not fully utilize the structural characteristics of the target and the common growth characteristics of cancer cells, such as high energy dependence. The vast majority of inhibitor development relies on screening rather than active design, so that the designed chemical structure is insufficiently active against specific variants. Summary of the Invention

[0004] In order to solve the above technical problems, the present invention provides a quinazoline compound derived from a macrocyclic polyamine, and a preparation method and application thereof.

[0005] To achieve the above objectives, the present invention provides the following technical solutions:

[0006] The present invention provides a quinazoline compound derived from a macrocyclic polyamine, the general structural formula of which is shown in formula (I):

[0007]

[0008] In formula (I), R is selected from aryl or heteroaryl, wherein the aryl or heteroaryl group is substituted by one or more alkyl, halogen, aryl, cyano, methoxy or halobenzyl groups.

[0009] Furthermore, the macrocyclic polyamine-derived quinazoline compound has the following structural formula:

[0010]

[0011] The present invention provides a salt of a quinazoline compound derived from a macrocyclic polyamine, including a hydrochloride, sulfate, maleate, succinate, adipate, glycolate, malate, fumarate, benzenesulfonate, benzoate, hippurate or oxalate of the quinazoline compound derived from a macrocyclic polyamine; and a solvate, hydrate or polymorph of the salt.

[0012] The present invention also provides a method for preparing the macrocyclic polyamine-derived quinazoline compound, comprising the following steps:

[0013] 7-Fluoro-6-nitroquinazolin-4(3H)-one is used as a raw material, thionyl chloride is added to carry out a chlorination reaction on the carbonyl group at position 4; then, a substituted aniline is added to carry out a nucleophilic substitution reaction (i.e., a substituted aniline is attached to the 4-Cl of quinazoline); then, ammonia is added to replace the fluorine atom at position 7 with an amino group (i.e., the addition of ammonia will ammoniate the fluorine atom at position 7 of quinazoline); palladium on carbon is added to catalytically reduce the nitro group at position 6 to an amino group; the resulting product is reacted with ethylenediaminetetraacetic dianhydride under reflux to alkylate the amino groups at positions 6 and 7, thereby obtaining the macrocyclic polyamine-derived quinazoline compound (ak);

[0014] The synthetic route of the macrocyclic polyamine-derived quinazoline compound is as follows:

[0015]

[0016] In the above route, (i) SOCl2, DMF, 90°C; (ii) substituted aniline, Et3N, i-PrOH, 15°C; (iii) ammonia, EtOH, 50°C; (iv) Pd / C, THF, 35°C; (v) ethylenediaminetetraacetic dianhydride, THF, 60°C.

[0017] R1 in compound ak is shown in Table 1.

[0018] Table 1 R1 in compound ak

[0019]

[0020] As a comparison, the present invention also synthesized compound The synthesis method is as follows: 4-(3-Chloro-4-fluorophenyl)quinazoline-4,6,7-triamine undergoes a nucleophilic substitution reaction under chloroacetyl chloride catalysis to generate N,N'-(4-((3-chloro-4-fluorophenyl)amino)quinazoline-6,7-diyl)bis(2-chloroacetamide), which is then condensed with ethylenediamine to obtain the target compound, namely 4-((3-chloro-4-fluorophenyl)amino)-6,8,9,10,11,12,13,15-octahydro-[1,4,7,10]tetraazadodecyl[2,3-g]quinazoline-7,14-dione.

[0021] The present invention provides a pharmaceutical composition comprising the macrocyclic polyamine-derived quinazoline compound or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

[0022] The present invention also provides a kit for treating cancer, comprising the macrocyclic polyamine-derived quinazoline compound or a pharmaceutically acceptable salt thereof.

[0023] The present invention also provides the use of the macrocyclic polyamine-derived quinazoline compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer.

[0024] Compared with the prior art, the present invention has the following advantages and technical effects:

[0025] To address the limited inhibitory activity coverage of existing technologies for different EGFR mutation types, this invention, through innovative design and chemical structure adjustments, strives to provide a broader and more effective spectrum of activity, especially against complex EGFR variants. Furthermore, through innovative design and chemical structure adjustments, starting from the 4-aminoquinazoline structure, additional hydrogen donors (NH / OH) are introduced at positions 6 and 7 of the side chain, which helps improve the potency of the inhibitor against the target. Furthermore, the synthetic method does not use a linker, but directly incorporates the cyclic polyamine into the quinazoline ring, making the molecular structure more compact and reducing the flexibility of the compound. This specifically addresses the drug resistance that may arise during treatment with EGFR-TK inhibitors, enhancing the drug's anti-cancer activity in drug-resistant cells. By introducing the cyclic polyamine into the quinazoline backbone, the potential sites of the chemical structure are more fully utilized to enhance the inhibitor's activity against EGFR triple mutants, filling this gap in the prior art. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The accompanying drawings, which constitute part of this application, are intended to provide a further understanding of this application. The exemplary embodiments and descriptions of this application are intended to explain this application and do not constitute an improper limitation on this application. In the accompanying drawings:

[0027] Figure 1 For compound a 1H NMR spectrum;

[0028] Figure 2 For compound a 13 C NMR spectrum;

[0029] Figure 3 is the HRMS spectrum of compound b;

[0030] Figure 4 is the HRMS spectrum of compound c;

[0031] Figure 5 is the HRMS spectrum of compound d;

[0032] Figure 6 is the HRMS spectrum of compound e;

[0033] Figure 7 is the HRMS spectrum of compound f;

[0034] Figure 8 is the HRMS spectrum of compound g;

[0035] Figure 9 For compound h 1 H NMR spectrum;

[0036] Figure 10 For compound h 13 C NMR spectrum;

[0037] Figure 11 For compound i 1 H NMR spectrum;

[0038] Figure 12 For compound i 13 C NMR spectrum;

[0039] Figure 13 is the HRMS spectrum of compound i;

[0040] Figure 14 For compound j 1 H NMR spectrum;

[0041] Figure 15 For compound j 13 C NMR spectrum;

[0042] Figure 16 is the HRMS spectrum of compound j;

[0043] Figure 17 For compound k 1 H NMR spectrum;

[0044] Figure 18 For compound k13 C NMR spectrum;

[0045] Figure 19 is the HRMS spectrum of compound k;

[0046] Figure 20 For compound 1 1 H NMR spectrum;

[0047] Figure 21 For compound 1 13 C NMR spectrum;

[0048] Figure 22 is the HRMS spectrum of compound 1;

[0049] Figure 23 Osimertinib and compounds b, i, and k target EGFR del19 / T790M / C797S proliferation inhibition. DETAILED DESCRIPTION

[0050] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0051] It should be understood that the terms described herein are intended only to describe particular embodiments and are not intended to limit the present invention. In addition, for numerical ranges herein, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Each smaller range between any intermediate value within a stated value or stated range and any other stated value or intermediate value within the stated range is also encompassed by the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded within the scope.

[0052] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of any conflict with any incorporated document, the contents of this specification shall prevail.

[0053] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments described herein without departing from the scope or spirit of the invention. Other embodiments will be apparent to those skilled in the art from the description of the invention. The description and examples are intended to be illustrative only.

[0054] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.

[0055] All starting materials and solvents were commercially available. All reactions were monitored by thin-layer chromatography (TLC) and visualized by ultraviolet light (254 or 365 nm) or iodine fumigation. All reaction systems were purified. NMR measurements were performed using a Bruker AVANCE III NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the solvents, with tetramethylsilane (TMS) as the internal standard. All chemical shifts are reported in parts per million (ppm), and the following abbreviations are used to describe peak splitting patterns when necessary: ​​s (singlet), d (doublet), t (triplet), m (multiplet), dd (doublet of doublets). Coupling constants (J) are expressed in Hertz (Hz). MS measurements were performed using an Agilent 1260 Infinity LC / MS G6125B mass spectrometer (manufacturer: Agilent). High-resolution mass spectrometry (HRMS) was performed using a liquid chromatography-tandem mass spectrometer (Xevo G2 Qtof).

[0056] The technical solution of the present invention is further illustrated by the following examples.

[0057] Example 1 Synthesis of 4-chloro-7-fluoro-6-nitro-3,4-dihydroquinazoline (2)

[0058] In a 250 ml round-bottom flask, 15.0 g (71.8 mmol) of 7-fluoro-6-nitro-4-hydroxyquinazoline, 98.3 g (826.1 mmol) of thionyl chloride (SOCl2) and 5 mL of DMF (dimethylformamide) were added and the system was heated to 90°C and refluxed for 3.5 hours. After the reaction was completed, the system was naturally cooled to below 50°C. The thionyl chloride was removed by concentration under reduced pressure to obtain a white solid. 100 ml of dichloromethane was added to the system and the temperature was lowered to below 10°C. The system was slowly poured into a 100 ml ice-water mixture and stirred for 0.5 hours before separation, the aqueous phase was discarded, and the organic phase was retained. The organic phase was washed with 100 ml of saturated sodium chloride solution and the aqueous phase was discarded. The organic phase was dried over anhydrous sodium sulfate for 2 hours. After filtration, the filtrate was evaporated to obtain 14.4 g of solid, i.e., compound 2, with a yield of 88.3%.

[0059] Synthesis of N-(4-bromo-2-fluorophenyl)-7-fluoro-6-nitro-3,4-dihydroquinazolin-4-amine (3i)

[0060] Weigh 4.0 g (18.8 mmol) of compound 2 obtained in Example 1, and weigh 3.8 g (19.8 mmol) of 2-fluoro-4-bromoaniline to measure 40 ml of isopropanol, add them to a 100 ml round-bottom flask, control the temperature to stir at 10-15 ° C, and slowly add 7.8 mL (56.4 mmol) of triethylamine to the system over a period of about 15 minutes. Maintain the temperature at 25-35 ° C and continue stirring for 8 hours. Monitor the reaction by thin layer chromatography to see that it is basically complete. Stop the reaction and add 40 ml of water to the system. Stir for 30 minutes and filter. The resulting solid is dried at 45 ° C for 12 hours to obtain 3.4 g of white solid 3i in a yield of 50.8%.

[0061] Synthetic N 4 -(4-Bromo-2-fluorophenyl)-6-nitro-3,4-dihydroquinazoline-4,7-diamine (4i)

[0062] Weigh 3.4 g of compound 3i and add it to a 250 ml round-bottom flask. Measure 60 ml of aqueous ammonia solution and 120 ml of ethanol and add them to the flask. Stirring is initiated and the reaction is heated to 50°C for 48 hours. Thin layer chromatography (TLC) analysis reveals a small amount of residual starting material, so the reaction is stopped. The solvent is removed by concentration under reduced pressure, 100 ml of water is added, and the mixture is stirred for 30 minutes before filtering. The resulting solid is dried at 45°C for approximately 12 hours to obtain 2.1 g of yellow solid 4i, with a yield of 62.5%. LC-MS: m / z 378 [M+H] + .

[0063] Synthetic N 4 -(4-Bromo-2-fluorophenyl)-3,4-dihydroquinazoline-4,6,7-triamine (5i)

[0064] 2.1 g of compound 4i and 0.4 g of Pd / C were weighed and added to a 250 ml round-bottom flask. Then, 100 ml of tetrahydrofuran was added to the system, and the air was evacuated under reduced pressure. The reaction was carried out under hydrogen pressure at 30-35°C for 4 hours. The reaction was stopped after completion of the reaction as monitored by thin-layer chromatography. The Pd / C catalyst was removed by filtration, and the solvent was concentrated under reduced pressure to obtain 1.9 g of 5i as a yellow solid, with a yield of 98.4%. LC-MS: m / z 348 [M+H] + .

[0065] Synthesis of 2,2'-(4-((4-bromo-2-fluorophenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (i)

[0066] Weigh 2.1 g of ethylenediaminetetraacetic acid dianhydride (8.2 mmol), add it to a 250 ml round-bottom flask, and add 50 ml of tetrahydrofuran. Start stirring and heat to 60 ° C reflux. Weigh 1.9 g of compound 5i (8.2 mmol), dissolve it in 50 ml of tetrahydrofuran, and slowly add it dropwise to the above system. After about 1 hour of addition, the reaction temperature is maintained at 60 ° C and the reaction is continued for 3 hours. The reaction solution is concentrated, dissolved in DMF, and subjected to reverse phase column chromatography to obtain 1 gram of crude product with a crude yield of 30.3%. The crude product is then subjected to preparative liquid purification and subsequently freeze-dried to obtain 300 mg of yellow solid i product with a total yield of 9.1%. High-resolution mass spectrometry: Chemical formula: C 24 H 23 BrFN7O6.[M+H]+=604.0950; measured: 604.0947. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),10.13(s,1H),9.81(d,J=61.8Hz,1H),8.46(d,J=8.4Hz,2H),8.17(d,J=13.1Hz,1H) ,7.66(d,J=9.9Hz,1H),7.49(dd,J=20.7,8.3Hz,2H),3.61(d,J=25.0Hz,4H),3.45(d,J=5.1Hz,4H),2.86(q,J=6.6Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ173.51,173.21,172.20,170.73,158.25,155.88,155.22,138.25,130.09,1 28.89,128.01,121.47,119.94,119.71,118.96,111.64,61.51,60.84,56.60,55.99,54.47,54.01.

[0067] Compound i 1 H NMR spectrum see Figure 11 , 13 C NMR spectrum see Figure 12 , HRMS spectrum see Figure 13 .

[0068] Example 2 2,2'-(4-((3-chlorophenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (a)

[0069] The synthesis method of compound a is similar to that of compound i, and the product is a white solid with a yield of 15%.1 H NMR (400MHz, Methanol-d4) δ8.42(s,1H),8.25(s,1H),8.03(s,1H),7.89(s,1H),7.59(d,J=7 .5Hz,1H),7.25(t,J=7.8Hz,1H),7.06(d,J=7.4Hz,1H),3.48(t,J=15.0Hz,8H),2.92(s,4H). 13 C NMR(101MHz,Methanol-d4)δ192.84,188.32,171.67,157.80,157.62,155.03,154.26,147.94,140.07,137.37 ,133.72,129.51,123.74,121.90,120.25,119.92,108.15,104.57,98.66,97.46,95.07,83.71,60.74,56.42.

[0070] Compound a 1 H NMR spectrum see Figure 1 , 13 C NMR spectrum see Figure 2 .

[0071] Example 3 2,2'-(4-((3-fluorophenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (b)

[0072] The synthesis method of b is similar to that of i. It is a white solid with a yield of 15%. Chemical formula: C 24 H 24 FN7O6[M+H] + =526.1845, high-resolution mass spectrum: 526.1840. 1 H NMR (400MHz, Methanol-d4) δ10.40(s,1H),10.13(s,1H),9.89(s,1H),8.64(s,1H),8.55(s,1H),8.23(s,1H),7.96(d,J=11.9Hz,1H),7.70(dd,J= 8.1,2.0Hz,1H),7.41(dd,J=8.4,7.1Hz,1H),6.92(td,J=8.4,2.6Hz,1H) ,3.64(s,2H),3.57(s,2H),3.45(d,J=5.2Hz,4H),2.86(d,J=10.0Hz,4H). 13C NMR (101MHz, DMSO-d6) δ173.57,173.18,172.39,170.64,163.64,161.25,157.44,155.04,149.61,141.70,141.59,138.41,130. 41,130.32,128.73,121.75,118.84,117.90,111.87,110.30,110.10,109.15,108.89,61.57,60.76,56.68,55.94,54.50,53.95.

[0073] The HRMS spectrum of compound b is shown in Figure 3 .

[0074] Example 4 2,2'-(4-((3-bromophenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (c)

[0075] The synthesis method of c is similar to that of i. It is a white solid with a yield of 15%. Chemical formula: C 24 H 24 BrN7O6[M+H] + =586.1044, high-resolution mass spectrum: 586.1045. 1 H NMR (400MHz, DMSO-d6) δ10.67(s,2H),9.91(s,1H),8.58(d,J=28.4Hz,2H),8.24(d,J=15.9Hz,2H),7.92(d, J=8.1Hz,1H),7.33(d,J=8.0Hz,1H),7.27(d,J=8.0Hz,1H),3.46(dd,J=41.1,15.6Hz,8H),2.87-2.74(m,4H) .13CNMR(101MHz,DMSO)δ173.12,172.77,171.82,170.28,163.18,154.50,148.84,137.83,135.89,131.97, 130.57,129.24,128.42,127.82,121.10,118.40,111.12,61.12,60.40,59.82,56.29,55.51,54.05,53.56. 13C NMR(101MHz,DMSO-d6)δ188.90,188.33,172.74,172.24,157.15,155.09,149.61,143.63,138.15,130.38,1 25.69,124.05,121.21,120.56,113.66,113.11,111.71,106.88,61.77,60.63,58.51,57.76,56.14,54.73.

[0076] The HRMS spectrum of compound c is shown in Figure 4 .

[0077] Example 5 2,2'-(4-((3-methoxyphenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (d)

[0078] The synthesis method of d is similar to that of i, and it is a white solid with a yield of 25%. Chemical formula: C 24 H 24 FN7O6[M+H] + =538.2045, high-resolution mass spectrum: 538.2057. 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),10.12(s,1H),9.72(s,1H),8.57(d,J=17.8Hz,2H),8.18(d,J=21.0Hz,1H),7.63-7.44(m,2H),7 .29(t,J=8.1Hz,1H),6.71(dd,J=8.3,2.5Hz,1H),3.78(s,3H),3.64(s,2H),3.57(s,2H),3.44(d,J=6.7Hz,4H),2.85(d,J=9.6Hz,4H). 13 C NMR (101MHz, DMSO-d6) δ173.20,172.80,172.00,170.23,163.22,159.41,154.81,149.14,140.51,137.88,129. 23,128.16,121.43,118.38,114.41,111.49,108.96,108.01,61.18,60.36,56.34,55.55,55.11,54.11,53.54.

[0079] The HRMS spectrum of compound d is shown in Figure 5 .

[0080] Example 6 2,2'-(4-((4-ethylphenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (e)

[0081] The synthesis method of e is similar to that of i. It is a white solid with a yield of 13%. Chemical formula: C 26 H 29 N7O6[M+H] + =536.2252, high-resolution mass spectrum: 536.2255. 1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=13.4Hz,1H),8.47(d,J=65.8Hz,1H),7.89(t,J=28.8Hz,2H),7.56-7.32(m,2H),7.14(dd,J=23.8 ,6.8Hz,1H),5.96(s,2H),4.23(q,J=7.1Hz,1H),3.90-3.52(m,6H),2.89-2.77(m,2H),2.71(s,2H),2.19(s,1H),1.50-1.13(m,5H). 13 C NMR(101MHz,DMSO-d6)δ186.99,170.90,167.88,149.92,149.81,144.68,129.37,128.68,124.98,122.5 5,119.88,101.98,100.32,92.88,85.26,69.82,60.23,58.09,55.38,28.74,22.50,21.22,16.02,14.55.

[0082] The HRMS spectrum of compound e is shown in Figure 6 .

[0083] Example 7 2,2'-(7,14-dioxo-4-(phenylamino)-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (f)

[0084] The synthesis method of f is similar to i. White solid, yield 23%. Chemical formula: C 24 H 25 N7O6[M+H] + =508.1939, high-resolution mass spectrum: 508.1938. 1H NMR (400MHz, DMSO-d6) δ10.37(s,1H),10.11(s,1H),9.90-9.68(m,1H),8.55(d,J=6.8Hz,2H),8.17(d,J=19.5Hz,2H),7.86(d,J =8.0Hz,2H),7.39(t,J=7.7Hz,2H),7.12(t,J=7.4Hz,1H),3.60(d,J=29.6Hz,4H),3.44(d,J=6.5Hz,4H),2.85(d,J=8.9Hz,4H). 13 C NMR (101MHz, DMSO-d6) δ173.58,155.27,128.89,124.09,122.76,118.80,61.58,60.76,55.94,54.49,53.93,49.06,39.93.

[0085] The HRMS spectrum of compound f is shown in Figure 7 .

[0086] Example 8 2,2'-(4-((3-chloro-4-fluorophenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (g)

[0087] The synthesis method of g is similar to that of i. White solid, yield 13%. Chemical formula: C 24 H 23 ClFN7O6[M+H] + =560.1455, high-resolution mass spectrum: 560.1538. 1 H NMR (400MHz, Methanol-d4) δ8.48(d,J=3.7Hz,1H),8.35(s,1H),8.12(d,J=5.2Hz,1H),8.07- 7.99(m,1H),7.70-7.60(m,1H),7.25-7.18(m,1H),3.59-3.48(m,8H),2.97(d,J=9.5Hz,4H). 13C NMR(101MHz,Methanol-d4)δ176.11,175.72,173.22,171.81,154.29,148.11,137.45,135.70,128.98,124.2 7,122.51,119.89,119.46,116.08,115.86,112.17,110.20,98.45,61.26,60.79,59.05,57.95,55.55,54.62.

[0088] The HRMS spectrum of compound g is shown in Figure 8 .

[0089] Example 9 2,2'-(4-((2,4-dichlorophenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (h)

[0090] The synthesis method of h is similar to i. White solid, yield 15%. 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),10.12(s,1H),9.94(s,1H),8.43(s,2H),8.16(d,J=9.6Hz,1H),7.72 (d,J=2.3Hz,1H),7.63-7.43(m,2H),3.60(d,J=26.7Hz,4H),3.44(d,J=6.0Hz,4H),2.85(d,J=5.1Hz,4H). 13 C NMR(101MHz,DMSO-d6)δ173.53,173.18,172.23,170.69,164.41,159.43,155.11,139.70,132.80,129.65 ,128.83,128.23,121.51,116.66,110.01,61.53,60.81,60.23,56.70,55.92,54.46,53.97,21.22,14.54.

[0091] Compound h 1 H NMR spectrum see Figure 9 , 13 C NMR spectrum see Figure 10 .

[0092] Example 10 2,2'-(4-((4-bromo-2-ethylphenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (j)

[0093] The synthesis method of j is similar to that of i. White solid, yield 15%. Chemical formula: C 26 H 28 BrN7O6[M+H] + =614.1357, high-resolution mass spectrum: 614.1361. 1 H NMR (400MHz, Methanol-d4) δ8.30(s,1H),8.24(s,1H),8.10(s,1H),7.40(d,J=2.2Hz,1H),7.30(dd,J=8.3,2.2Hz,1H),7.10(d ,J=8.4Hz,1H),3.47(d,J=3.7Hz,5H),3.39(s,4H),2.80(dd,J=20.4,6.2Hz,4H),2.48(q,J=7.6Hz,2H),1.02(t,J=7.5Hz,3H). 13 C NMR(101MHz,Methanol-d4)δ190.44,182.29,173.85,171.77,153.71,143.72,133.44,131.79,129.93,1 29.54,121.21,120.71,117.70,115.06,61.11,60.66,56.71,56.26,54.99,54.49,53.77,24.03,13.12.

[0094] Compound j 1 H NMR spectrum see Figure 14 , 13 C NMR spectrum see Figure 15 , HRMS spectrum see Figure 16 .

[0095] Example 11 2,2'-(4-((3-chloro-4-((3-fluorobenzyloxy)phenyl)amino)-7,14-dioxo-6,7,8,10,11,13,14,15-octaoxa-[[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-9,12-diyl)diacetic acid (k)

[0096] The synthesis method of k is similar to i. White solid, yield 15%. Chemical formula: C 31 H 29ClFN7O7[M+H] + =666.1874, high-resolution mass spectrum: 666.1863. 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),10.17(s,1H),9.79(s,1H),8.53(d,J=29.5Hz,2H),8. 12(d,J=52.1Hz,2H),7.75(s,1H),7.46–7.15(m,5H),5.25(s,2H),3.56(s,8H),2.84(s,4H). 13 C NMR(151MHz,DMSO-d6)δ173.61,173.21,172.37,170.64,163.48,161.87, 157.47,155.22,150.01,149.51,140.18,138.26,133.81,131.06,128.60, 124.31,123.79,122.49,121.63,121.47,118.87,115.23,115.09,114.78, 114.57,114.42,111.73,69.86,61.59,60.78,56.80,56.01,54.52,53.94.

[0097] Compound K 1 H NMR spectrum see Figure 17 , 13 C NMR spectrum see Figure 18 , HRMS spectrum see Figure 19 .

[0098] Comparative Example 1 4-((3-chloro-4-fluorophenyl)amino)-6,8,9,10,11,12,13,15-octahydro-[1,4,7,10]tetraazacyclododecan-2,3-g]quinazoline-7,14-dione (1)

[0099] White solid, yield 15%. Chemical formula: C 20 H 19 ClFN7O2[M+H] + =444.1346, high-resolution mass spectrum: 444.1205. 1H NMR (400MHz, Methanol-d4) δ8.32 (s, 1H), 8.11 (d, J = 3.8Hz, 1H), 7.83 (dd, J = 6.7, 2.7Hz, 1H), 7.49 (dd, J = 8. 1,4.4Hz,1H),7.17(t,J=8.8Hz,1H),6.81(s,1H),4.34(s,2H),3.62(d,J=8.6Hz,4H),3.25(d,J=5.3Hz,2H). 13 C NMR(101MHz,Methanol-d4)δ169.10,157.70,156.08,153.64,152.43,150.20,145.80,135.22,1 24.63,124.06,122.70,121.15,120.03,119.85,116.06,115.84,104.99,103.89,50.66,41.44.

[0100] Comparative Example 1: 1 H NMR spectrum see Figure 20 , 13 C NMR spectrum see Figure 21 , HRMS spectrum see Figure 22 .

[0101] Cell culture

[0102] Cell source: PC-9 cell line carrying triple EGFR mutation (EGFR del19 / T790M / C797S ) was purchased from Nanjing Kebai Company. PC-9 (EGFR del19 / T790M / C797S ) cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) at 37° C. in a humidified atmosphere containing 5% CO 2 .

[0103] Prepare a cell suspension of active cells in the logarithmic growth phase and count them. Inoculate the cell suspension (12,000 per well) into a 96-well plate. Incubate the plate at 37°C, 5% CO2 for 12-24 hours. Then remove the residual culture medium and add the drug-containing culture medium. After 48 hours, remove the old culture medium and add 10% CCK-8 culture medium (prepared just before use). Shake the plate gently. Monitor color development at 0.5, 1.0, and 2.0 hours. Measure the absorbance at 450nm using a microplate reader. Repeat the experiment three times and calculate the average value to obtain the final result. Blank group setup: Add the same volume of CCK-8 as the experimental wells to the 96-well plate, incubate for the same time as the experimental wells, and then measure the absorbance at 450nm.

[0104] Data were analyzed using GraphPad Prism 10.0. 50 The concentration that results in 50% inhibition of cell growth, ie, the half-inhibitory concentration of antiproliferation, was calculated by a nonlinear regression analysis protocol, ie, "log (inhibitor) vs normalized response—Variable slop."

[0105] Figure 23 Osimertinib and compounds b, i, and k target EGFR del19 / T790M / C797S proliferation inhibition.

[0106] The half-inhibitory concentration (IC50) of icotinib, osimertinib and compound a to compound 1 of the present invention 50 , μM) see Table 2.

[0107] Table 2

[0108] Compound number <![CDATA[PC-9 del19 / T790M / C797S ]]> Compound number <![CDATA[PC-9 del19 / T790M / C797S ]]> a 0.528 h 0.889 b 0.063 i 0.076 c 0.351 j 0.332 d 0.669 k 0.102 e 0.157 l 8.404 f 1.423 Icotinib 2.357 g 1.308 Osimertinib 1.888

[0109] As shown in Table 2, the quinazoline compounds derived from macrocyclic polyamines of the present invention have a more effective activity spectrum and enhance the activity of the inhibitor against EGFR triple mutants.

[0110] The above are merely preferred embodiments of the present application, but the scope of protection of the present application is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in this application should be included in the scope of protection of the present application. Therefore, the scope of protection of the present application should be based on the scope of protection of the claims.

Claims

1. A quinazoline compound derived from a macrocyclic polyamine, characterized in that The structural formula is as follows: 、 、 、 、 、 、 、 、 、 or .

2. A salt of a quinazoline compound derived from a macrocyclic polyamine, characterized in that: The invention relates to a quinazoline compound derived from a macrocyclic polyamine according to claim 1, wherein the quinazoline compound comprises a hydrochloride, a sulfate, a maleate, a succinate, an adipate, a glycolate, a malate, a fumarate, a benzenesulfonate, a benzoate, a hippurate or an oxalate.

3. A pharmaceutical composition, characterized in that The invention comprises the macrocyclic polyamine-derived quinazoline compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

4. A kit for treating cancer, characterized in that: The invention relates to a quinazoline compound derived from a macrocyclic polyamine according to claim 1 or a pharmaceutically acceptable salt thereof.

5. Use of the macrocyclic polyamine-derived quinazoline compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a drug for treating cancer.

6. A method for preparing a quinazoline compound derived from a macrocyclic polyamine according to claim 1, characterized in that: The following steps are involved: 7-Fluoro-6-nitroquinazolin-4(3H)-one is used as a raw material, thionyl chloride is added to carry out a chlorination reaction on the carbonyl group at the 4th position; then, a substituted aniline is added to carry out a nucleophilic substitution reaction, and then ammonia water is added to replace the fluorine atom at the 7th position with an amino group, and palladium carbon is added to catalytically reduce and aminize the nitro group at the 6th position to an amino group, and the obtained product is refluxed with ethylenediaminetetraacetic dianhydride to obtain the macrocyclic polyamine-derived quinazoline compound.

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