Synthesis and application of 4-amine-2, 7-disubstituted quinazoline derivative

Abstract

The invention discloses synthesis and application of 4-amine-2, 7-disubstituted quinazoline derivatives, and the structural general formula of the 4-amine-2, 7-disubstituted quinazoline derivatives is I, the 4-amine-2, 7-disubstituted quinazoline derivative disclosed by the invention shows a certain histone demethylase inhibitory activity, and can be used for preparing a histone demethylase inhibitor. The compound can be used as a histone demethylase inhibitor and is used for preparing medicines for treating various diseases mediated by histone demethylase.

Description

Technical Field

[0001] This application relates to 4-amine-2,7-disubstituted quinazoline derivatives, synthesis methods, applications, and drugs, belonging to the fields of chemistry and pharmaceuticals. Background Art

[0002] Among the histone modifications before transcription, lysine methylation has been the most widely studied. Histone lysine methylation modification is one of the causes of epigenetic changes. Enzymes that regulate lysine methylation are mainly divided into two categories: histone lysine methyltransferases (HKMTs) and histone lysine demethylases (HKDMs). HKMTs are responsible for transferring methyl groups from methyl donors to histone lysines to complete methylation modification. The function of HKDMs is mainly to remove methyl groups from histone lysines to complete the demethylation process. Their biological functions are opposite, and they jointly regulate the methylation state of histone lysines. The misregulation of histone lysine demethylases (HKDMs) is closely related to the occurrence and development of many diseases, such as senile diseases, tumors, etc. HKDMs are also related to the drug resistance of tumor drugs. Therefore, HKDMs have become an important target for the development of new anti-tumor drugs and have attracted more and more attention.

[0003] So far, two types of histone lysine demethylases (HKDMs) have been discovered: one is lysine specific demethylases (LSDs), also known as FAD (flavin adenine dinucleotide)-dependent amine oxidases, including LSD1 and LSD2. The other is JmjC (Jumonji domain-containing protein) histone demethylases, which are a family of proteins containing a Jumonji domain in the molecule. Different from LSD1, it can catalyze the demethylation of trimethylated lysine. The N-terminal and C-terminal of its family members both contain a small characteristic domain of Jumonji, called JmjN and JmjC respectively. Among them, the JmjN domain is related to transcriptional regulation, and JmjC is a component of the enzyme active center of the JmjC family. Some JmjCs containing the JmjC domain that have been discovered so far show different substrate specificities, and their demethylation catalytic process depends on the participation of Fe(II) and α-ketoglutaric acid (2-OG).

[0004] Histone demethylase is an emerging drug target. It has been less than 20 years since the discovery of the first class of histone demethylase, the LSD family. The discovery of the second class, the JmjC family, is even later. Currently, the research on the JmjC family is still in the development stage. Although various types of JmjC inhibitors have been discovered successively in recent years, most of them are derived from other targets, and inevitably have problems of selectivity and clinical efficacy. JmjC histone demethylase has gradually become an important target for studying epigenetics and has received increasing attention. Developing new JmjC inhibitors is expected to provide new ideas for anti-tumor treatment. A series of 4-amine-2,7-disubstituted quinazoline derivatives designed and synthesized in this invention have structures different from those of the JmjC histone demethylase inhibitors reported in previous studies and belong to a new type of inhibitor structure. Conducting structural modification and in-depth pharmacological research on the compounds of this invention is expected to develop new histone demethylase inhibitors. Summary of the Invention

[0005] In view of the deficiencies of the prior art, this invention provides a 4-amine-2,7-disubstituted quinazoline histone demethylase inhibitor, and this invention also provides a preparation method and application of this compound.

[0006] The technical solution of this invention is as follows:

[0007] I. 4-amine-2,7-disubstituted quinazoline histone demethylase inhibitor

[0008] A 4-amine-2,7-disubstituted quinazoline histone demethylase inhibitor, or a pharmaceutically acceptable salt, ester or prodrug thereof, has the following general structural formula I:

[0009]

[0010] Wherein, R is a straight-chain alkyl or alkoxy group with 1-9 carbons, a branched-chain alkyl or alkoxy group with 1-9 carbons, an alkyl group with 1-9 carbons containing a double bond, a triple bond, a sulfur-, oxygen- or nitrogen-containing substituent on the carbon chain, a carbocyclic alkyl or a substituted carbocyclic alkyl, a carbocyclic alkyl or a substituted carbocyclic alkyl containing N and O heteroatoms, a phenyl or a substituted phenyl, a heteroaryl or a substituted heteroaryl, a benzyl or a substituted benzyl;

[0011] Ar1 and Ar2 are benzene rings, monosubstituted or polysubstituted benzene rings, fused benzene ring - unsaturated or saturated 5- or 6-membered carbocyclic rings, fused benzene ring - 5- or 6-arylheterocyclic rings, fused benzene ring - 5- or 6-membered carbocyclic heterocyclic rings.

[0012] Preferably, the compound of the above general formula I is one of the following.

[0013]

[0014]

[0015]

[0016] II. Preparation method of 4-amino-2,7-disubstituted quinazoline histone demethylase inhibitors

[0017] A preparation method of a 4-amino-2,7-disubstituted quinazoline derivative. Using 2-amino-4-bromobenzoic acid (1a) as a raw material, it is cyclized with urea under high temperature conditions to obtain compound 1b, and then reacted with phosphorus oxychloride at high temperature to obtain an important intermediate 1c. Due to the high activity of the chlorine at the top of compound 1c, it will preferentially react with amines containing different substituents under high temperature and alkaline conditions to obtain a 4-substituted quinazoline intermediate (1d). 1d is coupled with boric acids with different substituents at the 7th position of quinazoline through the Suzuki reaction to obtain intermediate (1e). 1e is further subjected to a Suzuki coupling reaction to couple various groups at the 2nd position of quinazoline, or reacted with amines containing different substituents under alkaline conditions to obtain intermediate 1f. Finally, 1f is hydrolyzed with sodium hydroxide to remove the ester group to obtain a 4-amino-2,7-disubstituted quinazoline derivative I.

[0018] The synthesis route is as Figure 1 shown.

[0019] Reagents and conditions: (a) urea, 200 °C; (b) phosphorus oxychloride, reflux; (c) substituted amine, N-ethyldiisopropylamine, tetrahydrofuran, reflux; (d) substituted boric acid, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, potassium phosphate, N,N-dimethylformamide, 90 °C; (e) substituted boric acid, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, potassium phosphate, N,N-dimethylformamide, 90 °C; (f) 30% sodium hydroxide aqueous solution by mass fraction, a mixed solvent of methanol and tetrahydrofuran (1:1), reflux;

[0020] Among them, R1`, R2, and R3 are as shown in general formula I.

[0021] According to the preference of the present invention, the preparation method of the 4-amino-2,7-disubstituted quinazoline derivative is specifically as follows:

[0022] (1) Place 1 mmol of commercially available 2-amino-4-bromobenzoic acid (1a) in a 25 mL round-bottom flask, add 10 mmol of urea, and react at 200 °C for 2 h. After monitoring the reaction by TLC and completion, cool to 90 °C, add 10 mL of water to the reaction solution, stir for 20 min, then cool to room temperature, filter by suction, wash with water, and dry. Recrystallize with methanol to obtain a white powdery intermediate compound 1b.

[0023] (2) Place 1 mmol of intermediate compound 1b in a 25 mL round-bottom flask, add 5 mL of POCl3, and reflux at 110 °C for 2 - 3 h. After monitoring the reaction by TLC and completion, cool to room temperature. Slowly add the reaction solution dropwise to a large amount of ice water, extract the aqueous phase three times with dichloromethane (30 mL × 3), combine the organic phases, wash the organic phase three times with saturated brine (30 mL × 3), and finally dry with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1c as a white powder.

[0024] (3) Place 1 mmol of intermediate compound 1c in a 25 mL round-bottom flask, dissolve it with 5 mL of tetrahydrofuran, then add 1.5 mmol of the corresponding amine and 2.5 mmol of N,N-diisopropylethylamine (DIPEA), and reflux at 65 °C for 4 - 5 h. After monitoring the reaction by TLC and completion, cool to room temperature. Add 50 mL of ethyl acetate to the reaction solution for dilution, wash it three times with water (30 mL × 3), wash it three times with saturated brine (30 mL × 3), and dry the organic phase with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1d.

[0025] (4) Place 1 mmol of intermediate compound 1d in a 25 mL round-bottom flask, completely dissolve it with 5 mL of 1,4-dioxane, add 1.2 mmol of the corresponding boric acid and 0.15 mmol of Pd(dppf)Cl2, then dissolve 2.5 mmol of K2CO3 in 1 mL of water and add it to the round-bottom flask. Under nitrogen protection, react at 90 °C for 8 h. After monitoring the reaction by TLC and completion, cool to room temperature. Add 50 mL of ethyl acetate to the reaction solution for dilution, wash it three times with water (30 mL × 3), wash it three times with saturated brine (30 mL × 3), and dry the organic phase with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1e.

[0026] (5) Place 1 mmol of intermediate compound 1e in a 25 mL round-bottom flask, completely dissolve it with 5 mL of DMF, add 1.2 mmol of the corresponding boric acid, 0.15 mmol of Pd(dppf)Cl2, and 2.5 mmol of tripotassium phosphate. Under nitrogen protection, react at 90 °C for 8 h. After monitoring the reaction by TLC and completion, cool to room temperature. Add 50 mL of ethyl acetate to the reaction solution for dilution, wash it three times with water (30 mL × 3), wash it three times with saturated brine (30 mL × 3), and dry the organic phase with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1f.

[0027] (6) Place 1 mmol of intermediate compound 1f in a 50 mL round-bottom flask, dissolve it in 5 mL of methanol, add 1 mL of 2N NaOH aqueous solution, and stir at room temperature for 4 h. After monitoring the completion of the reaction by TLC, adjust the pH to weakly acidic with 1N hydrochloric acid. A precipitate will form. Filter to obtain the precipitate and wash it with a large amount of water. Recrystallize from ethanol to obtain the target compound of 4-amine-2,7-disubstituted quinazoline.

[0028] The room temperature mentioned in the present invention refers to 20 - 30 °C.

[0029] III. Histone Demethylase Inhibitory Activity of 4-Amine-2,7-Disubstituted Quinazoline Derivatives

[0030] The in vitro histone demethylase inhibitory activity levels of some 4-amine-2,7-disubstituted quinazoline derivatives synthesized according to the above method were tested. The results showed that most compounds had significant inhibitory activity against histone demethylase. Therefore, 4-amine-2,7-disubstituted quinazoline derivatives have the value of further research and development and can be used as histone demethylase inhibitors for the preparation of drugs for treating various diseases mediated by histone demethylase. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is a synthetic route diagram of the derivatives of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0032] The following examples are helpful for understanding the present invention, but cannot limit the content of the present invention.

[0033] Example 1: Preparation of 4-(((2-(Furan-2-yl)-7-(pyridin-4-yl)quinazolin-4-yl)amino)methyl)benzoic Acid (A01)

[0034] (1) Place 1 mmol of commercially available 2-amino-4-bromobenzoic acid (1a) in a 25 mL round-bottom flask, add 10 mmol of urea, and react at 200 °C for 2 h. After monitoring the completion of the reaction by TLC, cool to 90 °C, add 10 mL of water to the reaction solution, stir for 20 min, then cool to room temperature, filter by suction, wash with water, and dry. Recrystallize from methanol to obtain the intermediate compound 1b as a white powder.

[0035] (2) Place 1 mmol of intermediate compound 1b in a 25 mL round-bottom flask, add 5 mL of POCl3, and reflux at 110 °C for 2 - 3 h. After monitoring the reaction by TLC and completion, cool to room temperature. Slowly add the reaction solution dropwise to a large amount of ice water, extract the aqueous phase with dichloromethane three times (30 mL × 3), combine the organic phases, wash the organic phase with saturated brine three times (30 mL × 3), and finally dry with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1c as a white powder.

[0036] (3) Place 1 mmol of intermediate compound 1c in a 25 mL round-bottom flask, dissolve it with 5 mL of tetrahydrofuran, then add 1.5 mmol of the corresponding amine and 2.5 mmol of N,N-diisopropylethylamine (DIPEA), reflux at 65 °C for 4 - 5 h. After monitoring the reaction by TLC and completion, cool to room temperature. Add 50 mL of ethyl acetate to the reaction solution for dilution, wash with water three times (30 mL × 3), wash with saturated brine three times (30 mL × 3), and dry the organic phase with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1d.

[0037] (4) Place 1 mmol of intermediate compound 1d in a 25 mL round-bottom flask, completely dissolve it with 5 mL of 1,4-dioxane, add 1.2 mmol of the corresponding boric acid and 0.15 mmol of Pd(dppf)Cl2. Then dissolve 2.5 mmol of K2CO3 in 1 mL of water and add it to the round-bottom flask. Under nitrogen protection, react at 90 °C for 8 h. After monitoring the reaction by TLC and completion, cool to room temperature. Add 50 mL of ethyl acetate to the reaction solution for dilution, wash with water three times (30 mL × 3), wash with saturated brine three times (30 mL × 3), and dry the organic phase with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1e.

[0038] (5) Place 1 mmol of intermediate compound 1e in a 25 mL round-bottom flask, completely dissolve it with 5 mL of DMF, add 1.2 mmol of the corresponding boric acid, 0.15 mmol of Pd(dppf)Cl2, and 2.5 mmol of tripotassium phosphate. Under nitrogen protection, react at 90 °C for 8 h. After monitoring the reaction by TLC and completion, cool to room temperature. Add 50 mL of ethyl acetate to the reaction solution for dilution, wash with water three times (30 mL × 3), wash with saturated brine three times (30 mL × 3), and dry the organic phase with anhydrous Na2SO4. After rotary evaporation of the solvent under reduced pressure, purify by column chromatography (DCM:EA = 40:1) to obtain intermediate compound 1f.

[0039] (6) Place 1 mmol of intermediate compound 1f in a 50 mL round-bottom flask, dissolve it in 5 mL of methanol, add 1 mL of 2N aqueous NaOH solution, and stir at room temperature for 4 h. After monitoring the completion of the reaction by TLC, adjust the pH to weakly acidic with 1N hydrochloric acid, and a precipitate will form. Filter to obtain the precipitate and wash it with a large amount of water. After recrystallization from ethanol, the target compound A01 of 4-amino-2,7-disubstituted quinazoline is obtained. White solid; yield 67%; m.p. 311 - 313 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 9.58 (s, 1H), 8.69 (s, 2H), 8.63 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H), 7.94–7.85 (m, 6H), 7.58 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 2.9 Hz, 1H), 6.64 (s, 1H), 4.87 (d, J = 4.7 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6, ppm) δ: 159.4, 153.8, 153.0, 150.5, 150.3, 146.0, 145.2, 141.4, 129.4, 127.7, 125.4, 124.6, 123.8, 121.8, 114.2, 113.1, 112.2, 43.7. HRMS-ESI: m / z calced for C 25 H 18 N4O3 [M + H] + 423.1452, found 423.1450.

[0040] Example 2: Preparation of N-benzyl-2-(furan-2-yl)-7-(4-methoxyphenyl)quinazolin-4-amine (A02)

[0041] The preparation method of A02 is the same as that of A01. White solid; yield 87%; m.p. 159 - 161 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 8.92 (t, J = 5.9 Hz, 1H), 8.33 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.86–7.85 (m, 1H), 7.82–7.78 (m, 3H), 7.47 (d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.25–7.21 (m, 2H), 7.08–7.06 (m, 2H), 6.65 (dd, J = 3.3, 1.7 Hz, 1H), 4.87 (d, J = 5.8 Hz, 2H), 3.81 (s, 3H). 13CNMR(100MHz, DMSO-d6, ppm) δ: 159.7, 159.3, 153.6, 153.2, 150.3, 144.9, 144.0, 139.8, 131.2, 128.3, 128.3, 127.6, 126.8, 123.9, 123.8, 123.4, 114.5, 112.7, 112.4, 112.0, 55.2, 43.7. HRMS-ESI: m / z calced for C 26 H 21 N3O2[M + H] + 408.1707, found 408.1705.

[0042] Example 3: Preparation of 2-(furan-2-yl)-7-(4-methoxyphenyl)-N-(4-methylbenzyl)quinazolin-4-amine (A03)

[0043] The preparation method of A03 is the same as that of A01. White solid; yield 90%; m.p. 181 - 183 °C; 1 H NMR(400MHz, DMSO-d6, ppm) δ: 8.88(t, J = 5.9Hz, 1H), 8.32(d, J = 8.7Hz, 1H), 7.93(d, J = 1.8Hz, 1H), 7.86(dd, J = 1.5, 0.8Hz, 1H), 7.82 - 7.77(m, 3H), 7.35(d, J = 8.0Hz, 2H), 7.24(dd, J = 3.3, 0.7Hz, 1H), 7.12(d, J = 7.9Hz, 2H), 7.07(d, J = 8.8Hz, 2H), 6.65(dd, J = 3.3, 1.7Hz, 1H), 4.81(d, J = 5.8Hz, 2H), 3.81(s, 3H), 2.25(s, 3H). 13 C NMR(100MHz, DMSO-d6, ppm) δ: 159.6, 159.3, 153.6, 153.2, 150.3, 144.9, 143.9, 136.7, 135.8, 131.2, 128.8, 128.3, 127.6, 123.8, 123.8, 123.4, 114.5, 112.7, 112.4, 112.0, 55.2, 43.5, 20.7. HRMS-ESI: m / z calced for C 27 H 23 N3O2[M + H] + 422.1863, found 422.1861.

[0044] Example 4: Preparation of 2-(furan-2-yl)-N-(4-methoxybenzyl)-7-(4-ethoxyphenyl)quinazolin-4-amine (A04)

[0045] The preparation method of A04 is the same as that of A01. White solid; yield 85%; m.p. 135 - 137 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 8.85 (t, J = 5.9 Hz, 1H), 8.31 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.87 (d, J = 0.7 Hz, 1H), 7.82 - 7.76 (m, 3H), 7.41 (d, J = 8.7 Hz, 2H), 7.27 (dd, J = 3.3, 0.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.66 (dd, J = 3.3, 1.7 Hz, 1H), 4.78 (d, J = 5.7 Hz, 2H), 3.81 (s, 3H), 3.70 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, ppm) δ: 159.6, 159.2, 158.3, 153.6, 153.2, 150.3, 144.9, 143.9, 131.7, 131.2, 129.0, 128.3, 123.8, 123.7, 123.4, 114.5, 113.7, 112.7, 112.4, 112.0, 55.2, 55.0, 43.2. HRMS-ESI: m / z calced for C 27 H 23 N3O3 [M + H] + 438.1812, found 438.1809.

[0046] Example 5: Preparation of 4-(((2-(furan-2-yl)-7-(4-methoxyphenyl)quinazolin-4-yl)amino)methyl)phenol (A05)

[0047] The preparation method of A05 is the same as that of A01. White solid; yield 62%; m.p. 244 - 246 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 9.30 (s, 1H), 8.80 (t, J = 5.8 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 0.7 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.76 (dd, J = 8.6, 1.8 Hz, 1H), 7.29–7.25 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 6.72–6.70 (m, 2H), 6.66 (dd, J = 3.3, 1.7 Hz, 1H), 4.74 (d, J = 5.7 Hz, 2H), 3.82 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 159.7, 159.2, 156.3, 153.6, 153.2, 150.3, 144.9, 143.9, 131.2, 129.9, 129.1, 128.4, 123.8, 123.7, 123.5, 115.0, 114.6, 112.7, 112.4, 112.1, 55.3, 43.3. HRMS-ESI: m / z calced for C 26 H 21 N3O3 [M + H] + 424.1656, found 424.1658.

[0048] Example 6: Preparation of methyl 4-(((2-(furan-2-yl)-7-(4-methoxyphenyl)quinazolin-4-yl)amino)methyl)benzoate (A06)

[0049] The preparation method of A06 is the same as that of A01. White solid; yield 69%; m.p. 122 - 124 °C; 1 1H NMR (400 MHz, CDCl3, ppm) δ: 8.12 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.79 (d, J = 8.6 Hz, 1H), 7.62 - 7.58 (overlap, 4H), 7.46 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 5.6 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 6.53 (dd, J = 3.1, 1.6 Hz, 1H), 6.44 (t, J = 5.4 Hz, 1H), 4.96 (d, J = 5.6 Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H). 1313C NMR (100 MHz, CDCl3, ppm) δ: 167.0, 160.0, 159.4, 154.2, 153.3, 150.7, 145.2, 144.8, 144.1, 132.0, 130.1, 129.4, 128.5, 127.9, 125.5, 124.7, 121.3, 114.6, 113.3, 112.3, 112.0, 55.5, 52.2, 44.9. HRMS-ESI: m / z calcd for C 28 H 23 N3O4 [M+H] + 466.1761, found 466.1765.

[0050] Example 7: Preparation of Methyl 4-(((2-(Furan-2-yl)-7-(pyridin-4-yl)quinazolin-4-yl)amino)methyl)benzoate (A07)

[0051] The preparation method of A07 is the same as that of A01. White solid; yield 67%; m.p. 128 - 130 °C; 1 1H NMR (400 MHz, CDCl3, ppm) δ: 8.66 (d, J = 5.1 Hz, 2H), 8.19 (s, 1H), 7.95 (d, J = 8.0 Hz, 3H), 7.61 - 7.59 (overlap, 2H), 7.54 (d, J = 5.3 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.27 (s, 1H), 6.91 (s, 1H), 6.53 (dd, J = 3.3, 1.7 Hz, 1H), 4.97 (d, J = 5.1 Hz, 2H), 3.87 (s, 3H); 13 13C NMR (100 MHz, CDCl3, ppm) δ: 66.9, 159.5, 154.5, 153.1, 150.7, 150.5, 147.1, 145.0, 143.9, 142.3, 130.1, 129.4, 127.9, 126.9, 124.1, 122.2, 121.8, 113.9, 113.7, 112.1, 52.2, 45.0. HRMS-ESI: m / z calcd for C 26 H 20 N4O3 [M+H] + 437.1608, found 437.1605.

[0052] Example 8: Preparation of 2-(Furan-2-yl)-N-(4-nitrobenzyl)-7-(pyridin-4-yl)quinazolin-4-amine (A08)

[0053] The preparation method of A08 is the same as that of A01. Pale yellow solid; yield 78%; m.p. 120 - 122 °C; 1 H NMR (400 MHz, DMSO - d6, ppm) δ: 9.18 (t, J = 5.2 Hz, 1H), 8.71 (d, J = 4.7 Hz, 2H), 8.42 (d, J = 8.6 Hz, 1H), 8.21 (d, J = 8.0 Hz, 2H), 8.17 (s, 1H), 7.96 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 4.7 Hz, 2H), 7.86 (s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.19 (s, 1H), 6.64 (d, J = 1.5 Hz, 1H), 4.97 (d, J = 5.3 Hz, 2H). 13 C NMR (100 MHz, DMSO - d6, ppm) δ: 159.3, 153.6, 152.8, 150.4, 150.2, 147.8, 146.5, 145.8, 145.2, 141.5, 128.5, 125.5, 124.0, 123.9, 123.5, 121.6, 113.9, 113.1, 112.1, 43.5. HRMS - ESI: m / z calced for C 24 H 17 N5O3 [M + H] + 424.1404, found 424.1402.

[0054] Example 9: Preparation of 2 - (furan - 2 - yl) - 7 - (6 - methoxypyridin - 3 - yl) - N - (4 - nitrobenzyl) quinazolin - 4 - amine (A09).

[0055] The preparation method of A09 is the same as that of A01. Pale yellow solid; yield 79%; m.p. 203 - 205 °C; 1 H NMR (400 MHz, CDCl3, ppm) δ: 8.48 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.10 (s, 1H), 7.88 - 785 (m, 2H), 7.60 – 7.55 (m, 4H), 7.20 (s, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.56 - 6.53 (m, 2H), 5.03 (d, J = 5.3 Hz, 2H), 3.99 (s, 3H). 1313C NMR(100MHz, CDCl3, ppm) δ: 164.4, 159.4, 154.2, 153.0, 150.8, 147.4, 146.4, 145.5, 145.0, 142.7, 137.5, 128.5, 125.8, 124.5, 124.0, 121.7, 113.6, 112.5, 112.1, 111.4, 53.9, 44.6. HRMS-ESI: m / z calced for C 25 H 19 N5O4[M + H] + 454.1510, found 454.1508.

[0056] Example 10: Preparation of 1-(4-hydroxyphenyl)-2-(4-(4-methoxyphenyl)-6-(3-nitrophenyl)pyrimidin-2-yl)guanidine hydrochloride (A10)

[0057] The preparation method of A10 is the same as that of A01. Pale yellow solid; yield 72%; m.p. 212 - 214 °C; 1 1H NMR(400MHz, DMSO-d6, ppm) δ: 9.19(s, 1H), 8.41(d, J = 8.5Hz, 1H), 8.33(d, J = 7.9Hz, 2H), 8.20(d, J = 7.9Hz, 2H), 8.15–8.12(m, 3H), 7.92(d, J = 8.4Hz, 1H), 7.86(s, 1H), 7.72(d, J = 8.0Hz, 2H), 7.19(s, 1H), 6.64(d, J = 1.5Hz, 1H), 4.96(d, J = 5.1Hz, 2H). 13 13C NMR(100MHz, DMSO-d6, ppm) δ: 159.3, 153.7, 152.8, 150.2, 147.8, 147.2, 146.5, 145.3, 145.1, 142.0, 128.5, 128.5, 125.9, 124.3, 124.1, 123.9, 123.5, 113.7, 113.1, 112.1, 43.5. HRMS-ESI: m / z calced for C 25 H 17 N5O5[M + H] + 468.1302, found 468.1300.

[0058] Example 11: Preparation of 4-(2-(furan-2-yl)-4-((4-nitrobenzyl)amino)quinazolin-7-yl)benzoic acid (A11)

[0059] The preparation method of A11 is the same as that of A01. White solid; yield 48%; m.p. 305 - 307 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 11.01 (s, 1H), 8.73 (d, J = 8.6 Hz, 1H), 8.40 (s, 1H), 8.27–8.22 (m, 3H), 8.13 (d, J = 8.2 Hz, 3H), 7.94 (d, J = 8.0 Hz, 2H), 7.89 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 6.91 (s, 1H), 5.12 (d, J = 5.0 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6, ppm) δ: 167.1, 163.1, 159.3, 153.5, 152.7, 147.9, 146.5, 145.2, 143.4, 143.0, 130.1, 128.6, 127.4, 125.2, 124.4, 123.7, 123.5, 113.3, 113.2, 112.1, 43.5. HRMS-ESI: m / z calced for C 26 H 18 N4O5 [M + H] + 467.1350, found 467.1348.

[0060] Example 12: Preparation of Ethyl 4-(2-(4-(4-methoxyphenyl))-6-(3-nitrophenyl)pyrimidin-2-yl)guanidino)piperidine-1-carboxylate hydrochloride (A12)

[0061] The preparation method of A12 is the same as that of A01. White solid; yield 65%; m.p. 237 - 239 °C; 1 H NMR (600 MHz, DMSO-d6, ppm) δ: 12.29 (s, 1H), 8.70 (d, J = 5.7 Hz, 2H), 8.51 (t, J = 5.1 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.13 (s, 1H), 7.91–7.89 (m, 4H), 7.27 (d, J = 3.2 Hz, 1H), 6.68–6.67 (m, 1H), 3.82 (dd, J = 12.3, 6.6 Hz, 2H), 2.74 (t, J = 6.9 Hz, 2H). 1313C NMR(150MHz, DMSO-d6, ppm) δ: 173.1, 159.3, 153.8, 153.0, 150.4, 150.1, 145.9, 145.1, 141.2, 125.4, 123.9, 123.7, 121.6, 114.0, 112.9, 112.1, 37.0, 33.2. HRMS-ESI: m / z calcd for C 20 H 16 N4O3 [M+H] + 361.1295, found 361.1297.

[0062] Example 13: Preparation of 3-((2-(furan-2-yl)-7-(4-nitrophenyl)quinazolin-4-yl)amino)propanoic acid (A13)

[0063] The preparation method of A13 is the same as that of A01. White solid; yield 62%; m.p. 216 - 218 °C; 1 1H NMR(600MHz, DMSO-d6, ppm) δ: 12.22(s, 1H), 8.52(s, 1H), 8.33 - 8.30(overlap, 3H), 8.11(d, J = 8.5Hz, 2H), 8.07(s, 1H), 7.89(s, 1H), 7.85(d, J = 8.5Hz, 1H), 7.27(d, J = 2.9Hz, 1H), 6.67(d, J = 1.2Hz, 1H), 3.82(dd, J = 12.1, 6.4Hz, 2H), 2.74(t, J = 6.8Hz, 2H). 13 13C NMR(150MHz, DMSO-d6, ppm) δ: 173.1, 159.3, 153.7, 152.9, 149.8, 147.2, 145.3, 145.2, 141.8, 128.4, 125.6, 124.1, 123.9, 113.7, 113.1, 112.1, 37.0, 33.2. HRMS-ESI: m / z calcd for C 21 H 16 N4O5 [M+H] + 405.1193, found 405.1191.

[0064] Example 14: Preparation of 4-(((2-(furan-2-yl)-7-(4-methoxyphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A14)

[0065] The preparation method of A14 is the same as that of A01. White solid; yield 87%; m.p. 302 - 304 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 12.89 (s, 1H), 9.00 (t, J = 5.8 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 7.94 - 7.91 (m, 3H), 7.85–7.80 (m, 4H), 7.57 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 3.3 Hz, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.63 (dd, J = 3.1, 1.6 Hz, 1H), 4.92 (d, J = 5.5 Hz, 2H), 3.82 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.2, 159.7, 159.3, 153.5, 153.1, 150.3, 145.0, 144.9, 144.1, 131.2, 129.4, 129.3, 128.4, 127.5, 124.0, 123.8, 123.4, 114.6, 112.8, 112.4, 112.0, 55.3, 43.6. HRMS-ESI: m / z calced for C 27 H 21 N3O4 [M+H] + 452.1605, found 452.1603.

[0066] Example 15: Preparation of 4-(((7-(4-aminophenyl)-2-(furan-2-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A15)

[0067] The preparation method of A15 is the same as that of A01. White solid; white solid; yield 46%; m.p. 307 - 309 °C; 1 1H NMR (600 MHz, DMSO-d6, ppm) δ: 12.85 (s, 1H), 9.07 (t, J = 5.8 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H), 8.06 (d, J = 1.2 Hz, 1H), 8.03 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.92 - 7.89 (m, 3H), 7.85 (s, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H), 7.20 (d, J = 3.2 Hz, 1H), 6.65 - 6.64 (m, 1H), 4.92 (d, J = 5.6 Hz, 2H). 1313C NMR (150 MHz, DMSO-d6, ppm) δ: 167.5, 167.2, 159.3, 153.6, 153.0, 150.2, 145.0, 144.9, 143.5, 141.5, 133.9, 129.4, 128.3, 127.5, 127.0, 125.1, 124.3, 123.7, 113.2, 112.9, 112.1, 107.0, 43.6. HRMS-ESI: m / z calced for C 27 H 20 N4O4 [M+H] + 465.1557, found 465.1552.

[0068] Example 16: Preparation of (1r,4r)-4-(2-(4-(4-methoxyphenyl))-6-(3-nitrophenyl)pyrimidin-2-yl)guanidino)cyclohexane-1-carboxylic acid hydrochloride (A16)

[0069] The preparation method of A16 is the same as that of A01. White solid; yield 71%; m.p. 325 - 327 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.88 (s, 1H), 9.02 (t, J = 5.7 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.92 - 7.90 (overlap, 3H), 7.85 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 1.2 Hz, 1H), 7.37 (dd, J = 8.1, 1.3 Hz, 1H), 7.18 (d, J = 3.1 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.63 (dd, J = 3.0, 1.6 Hz, 1H), 6.10 (s, 2H), 4.91 (d, J = 5.4 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.3, 153.5, 153.0, 150.3, 148.2, 147.7, 145.1, 145.0, 144.1, 133.1, 129.5, 129.3, 127.6, 124.3, 124.2, 123.4, 121.1, 112.8, 112.5, 112.1, 108.9, 107.5, 101.4, 43.6. HRMS-ESI: m / z calced for C 27 H 19 N3O5 [M+H] +466.1397, found 466.1393.

[0070] Example 17: Preparation of 4-((7-(4-(dimethylamino)phenyl)-2-(furan-2-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A17)

[0071] The preparation method of A17 is the same as that of A01. White solid; yield 74%; m.p. 301 - 303 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 12.93 (s, 1H), 8.97 (t, J = 5.7 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.93–7.90 (m, 3H), 7.85 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 3.3 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.64–6.63 (m, 1H), 4.92 (d, J = 5.5 Hz, 2H), 2.96 (s, 6H). 13 C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.3, 153.4, 153.2, 150.5, 150.4, 145.1, 144.9, 144.5, 129.5, 129.4, 127.7, 127.5, 125.9, 123.5, 123.3, 122.5, 112.7, 112.6, 112.0, 111.8, 43.6, 39.9. HRMS-ESI: m / z calced for C 28 H 24 N4O3 [M + H] + 465.1921, found 465.1924.

[0072] Example 18: Preparation of 4-(((7-(4-chlorophenyl)-2-(furan-2-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A18)

[0073] The preparation method of A18 is the same as that of A01. White solid; yield 85%; m.p. 307 - 309 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 12.88 (s, 1H), 9.07 (t, J = 5.8 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.92 - 7.89 (m, 4H), 7.85–7.82 (m, 2H), 7.58 - 7.56 (m, 4H), 7.20 (d, J = 3.2 Hz, 1H), 6.64 (dd, J = 3.2, 1.7 Hz, 1H), 4.92 (d, J = 5.6 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.4, 153.6, 153.0, 150.3, 145.1, 145.0, 143.1, 137.8, 133.4, 129.5, 129.4, 129.1, 129.0, 127.6, 124.8, 124.2, 123.7, 113.1, 113.0, 112.1, 43.7. HRMS-ESI: m / z calced for C 26 H 18 ClN3O3 [M + H] + 456.1109, found 456.1112.

[0074] Example 19: Preparation of 4 - ((((2-(furan-2-yl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A19)

[0075] The preparation method of A19 is the same as that of A01. White solid; yield 84%; m.p. 184 - 186 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 12.76 (s, 1H), 9.06 (t, J = 5.5 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 8.02 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.88 - 7.86 (overlap, 4H), 7.63 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 3.0 Hz, 1H), 6.82 (dd, J = 17.6, 11.0 Hz, 1H), 6.65 (s, 1H), 5.95 (d, J = 17.7 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 4.93 (d, J = 5.3 Hz, 2H). 1313C NMR (100 MHz, DMSO-d6, ppm) δ: 167.2, 159.3, 153.5, 153.0, 150.2, 145.0, 145.0, 143.9, 138.2, 137.2, 136.1, 129.5, 129.3, 127.5, 127.4, 126.9, 124.5, 124.1, 123.6, 115.0, 112.9, 112.9, 112.1, 43.7. HRMS-ESI: m / z calcd for C 28 H 21 N3O3 [M+H] + 448.1656, found 448.1652.

[0076] Example 20: Preparation of 4-(4-((4-carboxybenzyl)amino)-2-(furan-2-yl)quinazolin-7-yl)benzoic acid (A20)

[0077] The preparation method of A20 is the same as that of A01. White solid; yield 42%; m.p. 349 - 351 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 11.22 (s, 1H), 8.78 (d, J = 8.6 Hz, 1H), 8.47 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 7.8 Hz, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.94–7.89 (m, 4H), 7.66 (d, J = 7.8 Hz, 2H), 6.92 (s, 1H), 5.06 (d, J = 4.1 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.1, 166.9, 159.9, 149.3, 148.3, 145.6, 145.5, 142.7, 141.6, 131.3, 130.3, 129.9, 129.5, 128.2, 127.4, 126.5, 125.4, 120.1, 117.1, 113.9, 111.8, 44.6. HRMS-ESI: m / z calcd for C 27 H 19 N3O5 [M+H] + 466.1397, found 466.1395.

[0078] Example 21: Preparation of 4-(((7-(3,5-dimethylphenyl)-2-(furan-2-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A21)

[0079] The preparation method of A21 is the same as that of A01. White solid; yield 84%; m.p. 353 - 355 °C; 1 H NMR(400 MHz, DMSO-d6, ppm) δ: 9.02 (t, J = 5.9 Hz, 1H), 8.36 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.86–7.85 (m, 1H), 7.82 (dd, J = 8.6, 1.7 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.46 (s, 2H), 7.21–7.20 (m, 1H), 7.05 (s, 1H), 6.64 (dd, J = 3.3, 1.7 Hz, 1H), 4.92 (d, J = 5.6 Hz, 2H), 2.35 (s, 6H). 13 C NMR(100 MHz, DMSO-d6, ppm) δ: 167.2, 159.4, 153.5, 153.1, 150.3, 145.0, 144.9, 144.6, 138.8, 138.2, 129.8, 129.5, 129.4, 127.6, 124.9, 124.6, 124.3, 123.4, 112.8, 112.0, 43.6, 21.0. HRMS-ESI: m / z calced for C 28 H 23 N3O3 [M + H] + 450.1812, found 450.1811.

[0080] Example 22: Preparation of 4-(((2-(furan-2-yl)-7-(quinolin-3-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A22)

[0081] The preparation method of A22 is the same as that of A01. White solid; yield 76%; m.p. 346 - 348 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 9.43 (d, J = 2.2 Hz, 1H), 9.13 (t, J = 5.3 Hz, 1H), 8.88 (d, J = 1.9 Hz, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.26 (d, J = 1.4 Hz, 1H), 8.10 - 8.05 (m, 3H), 7.93 (d, J = 8.2 Hz, 2H), 7.88 (s, 1H), 7.83 - 7.79 (m, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 3.2 Hz, 1H), 6.65 (dd, J = 3.2, 1.6 Hz, 1H), 4.94 (d, J = 5.3 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.4, 153.6, 152.9, 150.2, 149.4, 147.2, 145.2, 144.9, 141.4, 133.9, 131.6, 130.1, 129.5, 129.4, 128.7, 127.6, 127.6, 127.2, 125.3, 124.4, 123.9, 113.3, 113.1, 112.1, 43.7. HRMS-ESI: m / z calced for C 29 H 20 N4O3 [M + H] + 473.1608, found 473.1605.

[0082] Example 23: Preparation of 4-((2,7-bis(furan-2-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A23) The preparation method of A23 is the same as that of A01. White solid; yield 81%; m.p. 357 - 359 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 9.02 (t, J = 5.9 Hz, 1H), 8.32 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 1.6 Hz, 1H), 7.92 - 7.84 (m, 5H), 7.56 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 3.4 Hz, 1H), 7.19 (d, J = 3.1 Hz, 1H), 6.69 (dd, J = 3.4, 1.8 Hz, 1H), 6.64 (dd, J = 3.3, 1.7 Hz, 1H), 4.90 (d, J = 5.7 Hz, 2H). 1313C NMR(100MHz,DMSO-d6,ppm)δ:167.3,159.2,153.7,152.9,152.0,150.3,145.0,144.9,144.2,134.2,129.4,127.6,123.7,121.0,120.8,112.9,112.6,112.6,112.1,108.7,43.6.HRMS-ESI:m / z calced for C 24 H 17 N3O4[M+H] + 412.1292,found 412.1296.

[0083] Example 24: Preparation of 4-(((2-(furan-2-yl)-7-(6-methoxypyridin-3-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A24)

[0084] The preparation method of A24 is the same as that of A01. White solid; yield 73%; m.p. 312 - 314 °C; 1 1H NMR(600MHz,DMSO-d6,ppm)δ:12.51(s,1H),9.25(s,1H),8.69(d,J = 2.0Hz,1H),8.38(d,J = 8.6Hz,1H),8.21(dd,J = 8.6,2.2Hz,1H),8.02(s,1H),7.92 - 7.87(m,4H),7.57(d,J = 8.1Hz,2H),7.27(s,1H),6.97(d,J = 8.6Hz,1H),6.67(s,1H),4.94(d,J = 5.5Hz,2H),3.93(s,3H). 13 13C NMR(150MHz,DMSO-d6,ppm)δ:167.2,163.7,159.4,152.8,151.9,145.6,145.5,144.6,141.7,137.9,129.5,129.4,127.9,127.6,124.2,123.8,112.5,112.3,110.9,53.5,43.8.HRMS-ESI:m / z calced for C 26 H 20 N4O4[M+H] + 453.1557,found 453.1554.

[0085] Example 25: Preparation of 4-(((7-(3-acetamidophenyl)-2-(furan-2-yl)quinazolin-4-yl)amino)methyl)benzoic acid (A25)

[0086] The preparation method of A25 is the same as that of A01. White solid; yield 62%; m.p. 299 - 301 °C; 1 H NMR (400 MHz, DMSO - d6, ppm) δ: 11.13 (s, 1H), 10.39 (s, 1H), 8.74 (d, J = 8.8 Hz, 1H), 8.33 (d, J = 1.2 Hz, 1H), 8.25–8.21 (m, 2H), 7.93–7.91 (m, 4H), 7.66 - 7.60 (m, 3H), 7.48–7.41 (m, 2H), 6.90 (dd, J = 3.6, 1.7 Hz, 1H), 5.03 (d, J = 5.6 Hz, 2H), 2.10 (s, 3H). 13 C NMR (100 MHz, DMSO - d6, ppm) δ: 168.7, 167.1, 159.9, 149.1, 148.3, 146.9, 145.8, 142.8, 140.4, 138.1, 129.8, 129.7, 129.5, 129.3, 128.1, 126.2, 125.2, 121.8, 119.8, 117.5, 113.9, 111.3, 44.6, 24.1. HRMS - ESI: m / z calced for C 28 H 22 N4O4 [M + H] + 479.1714, found 479.1711.

[0087] Example 26: Preparation of 4 - (((2 - (furan - 2 - yl) - 7 - (4 - phenoxyphenyl) quinazolin - 4 - yl) amino) methyl) benzoic acid (A26)

[0088] The preparation method of A26 is the same as that of A01. White solid; yield 89%; m.p. 229 - 231 °C; 1 H NMR (400 MHz, DMSO - d6, ppm) δ: 9.03 (t, J = 5.6 Hz, 1H), 8.36 (d, J = 8.6 Hz, 1H), 7.97–7.85 (m, 7H), 7.57 (d, J = 8.1 Hz, 2H), 7.46 - 7.42 (m, 2H), 7.20–7.11 (m, 6H), 6.63 (d, J = 1.4 Hz, 1H), 4.92 (d, J = 5.3 Hz, 2H). 1313C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.3, 157.4, 156.2, 153.6, 153.0, 150.3, 145.0, 143.7, 133.8, 130.2, 129.5, 129.3, 128.9, 127.6, 124.3, 124.1, 124.0, 123.6, 119.3, 118.7, 112.9, 112.7, 112.1, 43.6. HRMS-ESI: m / z calced for C 32 H 23 N3O4[M + H] + 514.1761, found 514.1763.

[0089] Example 27: Preparation of 4 - ((((2 - (furan - 2 - yl)-7-(3-(methylthio)phenyl)quinazolin - 4 - yl)amino)methyl)benzoic acid (A27)

[0090] The preparation method of A27 is the same as that of A01. White solid; yield 84%; m.p. 319 - 321 °C; 1 1H NMR (600 MHz, DMSO - d6, ppm) δ: 12.66 (s, 1H), 9.08 (s, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.86 - 7.85 (overlap, 2H), 7.67 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 2.9 Hz, 1H), 6.65 (s, 1H), 4.92 (d, J = 5.5 Hz, 2H). 13 13C NMR (150 MHz, DMSO - d6, ppm) δ: 167.2, 159.3, 153.4, 152.8, 149.9, 145.1, 144.9, 144.1, 139.7, 139.3, 129.6, 129.4, 129.3, 127.5, 125.8, 124.7, 124.5, 124.2, 123.7, 123.5, 113.0, 113.0, 112.1, 43.7, 14.6. HRMS - ESI: m / z calced for C 27 H 21 N3O3S[M + H] + 468.1376, found 468.1374.

[0091] Preparation of 4-(((2-(Furan-2-yl)-7-(4-nitrophenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A28)

[0092] The preparation method of A28 is the same as that of A01. Pale yellow solid; yield 64%; m.p. 325 - 327 °C; 1 H NMR (600 MHz, DMSO-d6, ppm) δ: 12.71 (s, 1H), 9.19 (s, 1H), 8.42 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 8.6 Hz, 2H), 8.13–8.11 (m, 3H), 7.93 - 7.88 (m, 4H), 7.58 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 2.9 Hz, 1H), 6.65 (s, 1H), 4.93 (d, J = 5.5 Hz, 2H). 13 C NMR (150 MHz, DMSO-d6, ppm) δ: 167.2, 159.3, 153.5, 152.5, 149.6, 147.2, 145.3, 145.2, 144.7, 142.1, 129.5, 129.4, 128.5, 127.6, 125.5, 124.4, 124.1, 123.9, 113.7, 113.4, 112.2, 43.8. HRMS-ESI: m / z calced for C 26 H 18 N4O5[M + H] + 467.1350, found 467.1352.

[0093] Example 29: Preparation of 4-(((2-(Furan-2-yl)-7-phenylquinazolin-4-yl)amino)methyl)benzoic acid (A29)

[0094] The preparation method of A29 is the same as that of A01. White solid; yield 89%; m.p. 347 - 349 °C; 1 H NMR (600 MHz, DMSO-d6, ppm) δ: 12.87 (s, 1H), 9.03 (t, J = 5.8 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.85 (m, 4H), 7.58 (d, J = 8.1 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 6.64 (dd, J = 3.0, 1.5 Hz, 1H), 4.93 (d, J = 5.7 Hz, 2H).13 C NMR(150MHz, DMSO-d6, ppm) δ: 167.2, 159.4, 153.6, 153.0, 150.3, 145.0, 144.4, 139.0, 129.4, 129.4, 129.1, 128.4, 127.5, 127.2, 124.7, 124.3, 123.5, 112.9, 112.0, 43.6. HRMS-ESI: m / z calced for C 26 H 19 N3O3 [M + H] + 422.1499, found 422.1497.

[0095] Example 30: Preparation of 4 - ((2 - chloro - 7-(4 - vinylphenyl)quinazolin - 4 - yl)amino)methyl)benzoic acid (A30)

[0096] The preparation method of A30 is the same as that of A01. White solid; yield 91%; m.p. 431 - 433 °C; 1 H NMR(400MHz, DMSO-d6, ppm) δ: 9.40(t, J = 5.7Hz, 1H), 8.40(d, J = 9.1Hz, 1H), 7.94 - 7.92(overlap, 4H), 7.85(d, J = 8.2Hz, 2H), 7.62(d, J = 8.2Hz, 2H), 7.49(d, J = 8.1Hz, 2H), 6.81(dd, J = 17.6, 11.0Hz, 1H), 5.94(d, J = 17.7Hz, 1H), 5.34(d, J = 11.0Hz, 1H), 4.85(d, J = 5.5Hz, 2H). 13 C NMR(100MHz, DMSO-d6, ppm) δ: 161.0, 157.3, 151.0, 144.6, 143.6, 137.7, 137.4, 136.0, 129.5, 127.5, 127.3, 126.9, 125.0, 123.9, 123.6, 115.2, 112.5, 43.8. HRMS-ESI: m / z calced for C 24 H 18 ClN3O2 [M + H] + 416.1160, found 416.1163.

[0097] Example 31: Preparation of 4 - ((2 - methoxy - 7-(4 - vinylphenyl)quinazolin - 4 - yl)amino)methyl)benzoic acid (A31)

[0098] The preparation method of A31 is the same as that of A01. White solid; yield 72%; m.p. 200 - 202 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 12.84 (s, 1H), 9.03 (t, J = 5.0 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 7.7 Hz, 2H), 7.83–7.78 (m, 3H), 7.70 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 2H), 7.47 (d, J = 7.8 Hz, 2H), 6.80 (dd, J = 17.6, 11.0 Hz, 1H), 5.92 (d, J = 17.7 Hz, 1H), 5.32 (d, J = 10.9 Hz, 1H), 4.82 (d, J = 5.1 Hz, 2H), 3.85 (s, 3H). 13 C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 162.9, 161.6, 151.5, 144.6, 144.0, 138.4, 137.1, 136.1, 129.5, 129.3, 127.3, 127.2, 126.9, 123.7, 123.0, 122.0, 115.0, 111.5, 53.7, 43.5. HRMS-ESI: m / z calced for C 25 H 21 N3O3 [M + H] + 412.1656, found 412.1658.

[0099] Example 32: Preparation of 4-(((2-phenyl-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A32)

[0100] The preparation method of A32 is the same as that of A01. White solid; yield 82%; m.p. 309 - 311 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 9.09 (t, J = 5.7 Hz, 1H), 8.45–8.41 (m, 3H), 8.07 (d, J = 1.5 Hz, 1H), 7.94–7.87 (m, 5H), 7.61 (dd, J = 19.0, 8.2 Hz, 4H), 7.47–7.46 (m, 3H), 6.81 (dd, J = 17.6, 11.0 Hz, 1H), 5.94 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 11.0 Hz, 1H), 5.00 (d, J = 5.4 Hz, 2H). 1313C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.7, 159.5, 150.6, 145.1, 143.8, 138.5, 138.3, 137.2, 136.1, 130.2, 129.5, 129.4, 128.3, 127.9, 127.4, 127.3, 126.9, 124.8, 124.3, 123.6, 115.0, 112.9, 43.8. HRMS-ESI: m / z calcd for C 30 H 23 N3O2 [M+H] + 458.1863, found 458.1861.

[0101] Example 33: Preparation of 4-(((2-(pyridin-3-yl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A33).

[0102] The preparation method of A33 is the same as that of A01. White solid; yield 75%; m.p. 305 - 307 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 9.51 (s, 1H), 9.22 (s, 1H), 8.68 (d, J = 8.5 Hz, 2H), 8.44 (d, J = 8.6 Hz, 1H), 8.08 (s, 1H), 7.93 - 7.87 (m, 5H), 7.63 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H), 7.51 (m, 1H), 6.82 (dd, J = 17.6, 10.9 Hz, 1H), 5.94 (d, J = 17.7 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 5.00 (d, J = 5.3 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.2, 159.6, 158.1, 150.8, 150.1, 149.2, 145.0, 144.0, 138.2, 137.3, 136.1, 135.2, 133.7, 129.5, 129.3, 127.4, 127.3, 126.9, 124.7, 124.7, 123.7, 123.6, 115.1, 113.0, 43.9. HRMS-ESI: m / z calcd for C 29 H 22 N4O2 [M+H] + 459.1816, found 459.1814.

[0103] Example 34: Preparation of 4-(((2-(pyridin-4-yl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A34)

[0104] The preparation method of A34 is the same as that of A01. White solid; yield 74%; m.p. 344 - 346 °C; 1 H NMR (400 MHz, DMSO-d6, ppm) δ: 12.87 (s, 1H), 9.24 (t, J = 5.7 Hz, 1H), 8.71 (d, J = 5.7 Hz, 2H), 8.45 (d, J = 8.7 Hz, 1H), 8.28 (d, J = 5.8 Hz, 2H), 8.10 (d, J = 1.2 Hz, 1H), 7.97–7.88 (m, 5H), 7.61 (dd, J = 17.6, 8.2 Hz, 4H), 6.2 (dd, J = 17.6, 11.0 Hz, 1H), 5.94 (d, J = 17.7 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 5.00 (d, J = 5.5 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.8, 157.9, 150.2, 150.1, 145.8, 144.9, 144.1, 138.1, 137.3, 136.1, 129.6, 129.4, 127.5, 127.4, 127.0, 125.2, 125.0, 123.7, 121.9, 115.2, 113.3, 43.8. HRMS-ESI: m / z calced for C 29 H 22 N4O2 [M + H] + 459.1816, found 459.1814.

[0105] Example 35: Preparation of 4-(((2-(4-chlorophenyl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A35)

[0106] The preparation method of A35 is the same as that of A01. White solid; yield 78%; m.p. 304 - 306 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 9.12 (t, J = 5.8 Hz, 1H), 8.42 (t, J = 8.4 Hz, 3H), 8.05 (d, J = 1.5 Hz, 1H), 7.94–7.86 (m, 5H), 7.62 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 6.81 (dd, J = 17.6, 11.0 Hz, 1H), 5.93 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 11.1 Hz, 1H), 4.98 (d, J = 5.5 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.5, 158.7, 150.4, 144.9, 143.9, 138.2, 137.4, 137.2, 136.1, 135.0, 129.6, 129.6, 129.5, 128.3, 127.4, 127.3, 126.9, 124.8, 124.5, 123.6, 115.0, 112.9, 43.8. HRMS-ESI: m / z calced for C 30 H 22 ClN3O2 [M+H] + 492.1473, found 492.1475.

[0107] Example 36: Preparation of 4-(((2-(4-methoxyphenyl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A36)

[0108] The preparation method of A36 is the same as that of A01. White solid; yield 86%; m.p. 406 - 408 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 9.02 (t, J = 5.8 Hz, 1H), 8.39 - 8.37 (m, 3H), 8.01 (d, J = 1.5 Hz, 1H), 7.93–7.84 (m, 5H), 7.63 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 8.9 Hz, 2H), 6.82 (dd, J = 17.6, 11.0 Hz, 1H), 5.94 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 11.1 Hz, 1H), 4.98 (d, J = 5.5 Hz, 2H), 3.81 (s, 3H). 1313C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 161.1, 159.5, 159.4, 150.7, 145.2, 143.7, 138.4, 137.1, 136.1, 131.0, 129.6, 129.5, 129.3, 127.4, 127.3, 126.9, 124.6, 123.8, 123.5, 115.0, 113.6, 112.7, 55.3, 43.7. HRMS-ESI: m / z calcd for C 31 H 25 N3O3 [M+H] + 488.1969, found 488.1967.

[0109] Example 37: Preparation of 4-(((2,7-bis(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A37)

[0110] The preparation method of A37 is the same as that of A01. White solid; yield 87%; m.p. 405 - 407 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 9.09 (t, J = 5.6 Hz, 1H), 8.41 (d, J = 8.2 Hz, 3H), 8.06 (d, J = 1.2 Hz, 1H), 7.94 - 7.87 (m, 5H), 7.63 (d, J = 8.2 Hz, 2H), 7.59 - 7.56 (m, 4H), 6.85–6.76 (m, 2H), 5.96 (d, J = 5.9 Hz, 1H), 5.91 (d, J = 5.8 Hz, 1H), 5.35 (s, 1H), 5.32 (s, 1H), 4.99 (d, J = 5.4 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 161.2, 153.8, 153.7, 145.3, 140.1, 138.9, 134.1, 133.6, 133.3, 132.5, 131.8, 131.5, 125.2, 125.0, 124.0, 123.2, 123.2, 122.8, 122.0, 120.8, 120.2, 119.6, 111.7, 111.5, 109.4, 43.6. HRMS-ESI: m / z calcd for C 32 H 25 N3O2 [M+H] + 484.2020, found 484.2023.

[0111] Example 38: Preparation of 4-(((2-(4-hydroxyphenyl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A38)

[0112] The preparation method of A38 is the same as that of A01. White solid; yield 72%; m.p. 298 - 300 °C; 1 H NMR (600 MHz, DMSO-d6, ppm) δ: 12.90 (s, 1H), 9.82 (s, 1H), 8.95 (t, J = 5.3 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.28 (d, J = 8.2 Hz, 2H), 7.98 (s, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.86 (d, J = 7.8 Hz, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 6.84 - 6.79 (m, 3H), 5.93 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 10.9 Hz, 1H), 4.98 (d, J = 5.2 Hz, 2H). 13 C NMR (150 MHz, DMSO-d6, ppm) δ: 167.3, 159.8, 159.6, 159.3, 150.7, 145.2, 143.6, 138.5, 137.1, 136.1, 129.7, 129.5, 129.4, 127.4, 127.3, 127.0, 126.9, 124.6, 123.6, 123.5, 115.6, 115.0, 112.6, 43.7. HRMS-ESI: m / z calced for C 30 H 23 N3O3 [M + H] + 474.1812, found 474.1815.

[0113] Example 39: Preparation of 4-(((2-(propylamino)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A39)

[0114] The preparation method of A39 is the same as that of A01. White solid; yield 89%; m.p. 314 - 316 °C; 11H NMR (600 MHz, DMSO-d6, ppm) δ: 12.74 (s, 1H), 10.48 (s, 1H), 8.49 (t, J = 15.9 Hz, 1H), 8.28 (d, J = 21.6 Hz, 1H), 7.91 (d, J = 8.1 Hz, 2H), 7.74 - 7.73 (overlap, 3H), 7.65–7.51 (m, 5H), 6.80 (dd, J = 17.6, 11.0 Hz, 1H), 5.93 (d, J = 17.7 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 4.85 (s, 2H), 3.27 (d, J = 5.5 Hz, 2H), 1.38 (dd, J = 13.7, 6.8 Hz, 2H), 0.78 (t, J = 7.0 Hz, 3H). 13 13C NMR (150 MHz, DMSO-d6, ppm) δ: 167.2, 159.7, 153.1, 145.8, 143.3, 139.7, 137.8, 137.2, 135.9, 129.6, 129.5, 127.4, 127.3, 127.0, 125.2, 122.6, 115.5, 113.6, 108.6, 44.5, 42.3, 22.1, 11.1. HRMS-ESI: m / z calced for C 27 H 26 N4O2 [M + H] + 439.2129, found 439.2126.

[0115] Example 40: Preparation of 4 - ((((2 - ((2 - hydroxyethyl)amino)-7-(4 - vinylphenyl)quinazolin - 4 - yl)amino)methyl)benzoic acid (A40)

[0116] The preparation method of A40 is the same as that of A01. White solid; yield 84%; m.p. 280 - 282 °C; 1 1H NMR (600 MHz, DMSO-d6, ppm) δ: 12.44 (s, 1H), 10.42 (s, 1H), 8.48–8.12 (m, 3H), 7.92 (d, J = 5.1 Hz, 2H), 7.75 - 7.54 (m, 9H), 6.82–6.78 (m, 1H), 5.94 (d, J = 17.5 Hz, 1H), 5.35 (d, J = 9.9 Hz, 1H), 4.86 (s, 3H), 3.83 - 3.61 (m, 2H), 3.54–3.45 (m, 2H). 1313C NMR(150MHz,DMSO-d6,ppm)δ:167.2,159.7,159.3,153.3,145.8,143.2,140.0,137.8,137.3,136.0,129.7,129.5,127.7,127.3,127.0,125.1,122.6,115.5,113.8,108.6,59.2,44.4,43.4.HRMS-ESI:m / z calcedfor C 26 H 24 N4O3[M+H] + 441.1921,found441.1919.

[0117] Example 41: Preparation of (E)-4-((2-(prop-1-en-1-yl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A41)

[0118] The preparation method of A41 is the same as that of A01. White solid; yield 87%; m.p. 205 - 207 °C; 1 1H NMR(400MHz,DMSO-d6,ppm)δ:8.88(t,J = 5.7Hz,1H),8.33(d,J = 8.6Hz,1H),7.91(overlap,3H),7.82(overlap,3H),7.61(d,J = 8.1Hz,2H),7.51(d,J = 8.0Hz,2H),7.02(dd,J = 15.1,7.1Hz,1H),6.80(dd,J = 17.6,11.0Hz,1H),6.36(d,J = 15.3Hz,1H),5.92(d,J = 17.7Hz,1H),5.32(d,J = 11.0Hz,1H),4.89(d,J = 5.4Hz,2H),1.89(d,J = 6.8Hz,3H). 13 13C NMR(100MHz,DMSO-d6,ppm)δ:167.3,160.2,158.9,150.5,145.1,143.6,138.4,137.1,136.1,135.1,132.3,129.5,129.4,127.3,126.9,124.4,123.8,123.4,115.0,112.9,43.4,18.0.HRMS-ESI:m / zcalced for C 27 H 23 N3O2[M+H] + 422.1863,found 422.1861.

[0119] Example 42: Preparation of 4-(((2-(3,5-dimethylphenyl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A42)

[0120] The preparation method of A42 is the same as that of A01. White solid; yield 85%; m.p. 297 - 299 °C; 1 H NMR (600 MHz, DMSO-d6, ppm) δ: 12.88 (s, 1H), 9.04 (t, J = 5.6 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.05 (s, 1H), 7.99 (s, 2H), 7.93 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 3H), 7.63 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 6.82 (dd, J = 17.6, 10.9 Hz, 1H), 5.94 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 11.0 Hz, 1H), 4.96 (d, J = 5.3 Hz, 2H), 2.33 (s, 6H). 13 C NMR (150 MHz, DMSO-d6, ppm) δ: 167.3, 159.9, 159.3, 150.6, 145.2, 143.7, 138.4, 138.3, 137.1, 137.0, 136.1, 131.5, 129.4, 129.4, 127.4, 127.3, 126.9, 125.8, 124.8, 124.1, 123.5, 115.0, 112.9, 44.0, 21.1. HRMS-ESI: m / z calced for C 32 H 27 N3O2 [M + H] + 486.2176, found 486.2174.

[0121] Example 43: Preparation of 4-((2-amino-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A43)

[0122] The preparation method of A43 is the same as that of A01. White solid; yield 47%; m.p. 405 - 407 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 10.19 (t, J = 5.8 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.4 Hz, 3H), 7.71 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 6.80 (dd, J = 17.6, 11.0 Hz, 1H), 5.94 (d, J = 18.0 Hz, 1H), 5.35 (d, J = 11.4 Hz, 1H), 4.88 (d, J = 5.6 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 160.3, 154.9, 145.7, 142.9, 139.9, 137.9, 137.3, 136.0, 129.9, 129.5, 127.7, 127.4, 127.0, 125.0, 122.7, 115.5, 114.1, 108.9, 43.9. HRMS-ESI: m / z calced for C 24 H 20 N4O2 [M+H] + 397.1659, found 397.1656.

[0123] Example 44: Preparation of 4-(((2-(pyrimidin-2-ylamino)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A44)

[0124] The preparation method of A44 is the same as that of A01. White solid; yield 42%; m.p. 345 - 347 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 10.66 (s, 1H), 8.82 (d, J = 4.8 Hz, 2H), 8.59 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.84 - 7.79 (m, 3H), 7.72 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 4.8 Hz, 1H), 6.78 (dd, J = 17.6, 11.0 Hz, 1H), 5.93 (d, J = 17.7 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 4.94 (s, 2H). 1313C NMR (100 MHz, DMSO-d6, ppm) δ: 167.2, 160.0, 158.5, 157.7, 145.5, 143.0, 137.9, 136.9, 136.0, 129.8, 129.4, 128.6, 127.4, 126.9, 124.9, 124.1, 116.8, 115.6, 110.4, 44.2. HRMS-ESI: m / z calcd for C 28 H 22 N6O2 [M+H] + 475.1877, found 475.1873.

[0125] Example 45: Preparation of 4-(4-((4-Carboxybenzyl)amino)-7-(4-vinylphenyl)quinazolin-2-yl)benzoic acid (A45)

[0126] The preparation method of A45 is the same as that of A01. White solid; yield 44%; m.p. 451 - 453 °C; 1 1H NMR (400 MHz, DMSO-d6, ppm) δ: 9.14 (t, J = 5.8 Hz, 1H), 8.52 (d, J = 8.5 Hz, 2H), 8.43 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H), 7.94 - 7.92 (overlap, 3H), 7.88 (d, J = 8.4 Hz, 2H), 7.60 (dd, J = 14.6, 8.3 Hz, 4H), 6.81 (dd, J = 17.6, 11.0 Hz, 1H), 5.93 (d, J = 17.9 Hz, 1H), 5.33 (d, J = 11.3 Hz, 1H), 5.00 (d, J = 5.4 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.7, 167.6, 159.6, 159.0, 150.4, 144.8, 143.9, 142.2, 138.2, 137.2, 136.1, 132.8, 130.0, 129.5, 129.3, 127.9, 127.4, 127.4, 126.9, 124.9, 124.7, 123.6, 115.1, 113.0, 43.9. HRMS-ESI: m / z calcd for C 31 H 23 N3O4 [M+H] + 502.1761, found 502.1758.

[0127] Example 46: Preparation of 4-((2-(4-(trifluoromethyl)phenyl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A46)

[0128] The preparation method of A46 is the same as that of A01. White solid; yield 79%; m.p. 249 - 251 °C; 1 H NMR (600 MHz, DMSO-d6, ppm) δ: 12.88 (s, 1H), 9.16 (t, J = 6.0 Hz, 1H), 8.61 (d, J = 8.1 Hz, 2H), 8.43 (d, J = 8.7 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.95–7.90 (m, 3H), 7.87 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.60 (dd, J = 16.2, 8.1 Hz, 4H), 6.81 (dd, J = 17.6, 10.9 Hz, 1H), 5.93 (d, J = 17.7 Hz, 1H), 5.33 (d, J = 11.0 Hz, 1H), 5.00 (d, J = 5.7 Hz, 2H). 13 C NMR (150 MHz, DMSO-d6, ppm) δ: 167.3, 159.6, 158.3, 150.3, 144.9, 144.0, 142.3, 138.2, 137.2, 136.1, 130.2, 129.9, 129.5, 128.5, 127.4, 127.4, 126.9, 125.2, 125.2, 124.9, 124.8, 123.6, 123.4, 115.0, 113.1, 43.8. HRMS-ESI: m / z calced for C 31 H 22 F3N3O2[M + H] + 526.1737, found 526.1734.

[0129] Example 47: Preparation of 4-((2-(benzo[d][1,3]dioxol-5-yl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A47)

[0130] The preparation method of A47 is the same as that of A01. White solid; yield 75%; m.p. 391 - 393 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 9.03 (t, J = 5.8 Hz, 1H), 8.38 (d, J = 8.7 Hz, 1H), 8.04 (dd, J = 8.2, 1.6 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.88–7.84 (m, 4H), 7.63 (d, J = 8.3 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 6.99 (d, J = 8.2 Hz, 1H), 6.82 (dd, J = 17.6, 11.0 Hz, 1H), 6.08 (s, 2H), 5.94 (d, J = 18.1 Hz, 1H), 5.34 (d, J = 11.4 Hz, 1H), 4.97 (d, J = 5.6 Hz, 2H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.3, 159.2, 150.5, 149.1, 147.4, 145.0, 143.8, 138.3, 137.1, 136.1, 132.9, 129.5, 129.5, 127.4, 127.2, 126.9, 124.7, 123.9, 123.5, 122.6, 115.0, 112.7, 108.0, 107.7, 101.4, 43.8. HRMS-ESI: m / z calcd for C 31 H 23 N3O4 [M+H] + 502.1761, found 502.1758.

[0131] Example 48: Preparation of 4-(((2-(3-(methylthio)phenyl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A48)

[0132] The preparation method of A48 is the same as that of A01. White solid; yield 71%; m.p. 307 - 309 °C; 11H NMR (400 MHz, DMSO-d6, ppm) δ: 9.14 (t, J = 5.8 Hz, 1H), 8.44 (d, J = 8.7 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 7.7 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.96–7.89 (m, 5H), 7.62 (dd, J = 16.5, 8.3 Hz, 4H), 7.44 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 6.83 (dd, J = 17.6, 11.0 Hz, 1H), 5.95 (d, J = 17.7 Hz, 1H), 5.35 (d, J = 11.1 Hz, 1H), 4.99 (d, J = 5.5 Hz, 2H), 2.52 (s, 3H). 13 13C NMR (100 MHz, DMSO-d6, ppm) δ: 167.3, 159.5, 159.1, 150.5, 145.0, 143.8, 139.1, 138.3, 138.1, 137.2, 136.1, 129.6, 129.5, 128.9, 127.5, 127.4, 127.2, 126.9, 125.2, 124.9, 124.5, 124.4, 123.6, 115.0, 113.0, 43.9, 14.8. HRMS-ESI: m / z calced for C 31 H 25 N3O2S [M+H] + 504.1740, found 504.1744.

[0133] Example 49: Preparation of 4-(((2-(1H-pyrazol-5-yl)-7-(4-vinylphenyl)quinazolin-4-yl)amino)methyl)benzoic acid (A49)

[0134] The preparation method of A49 is the same as that of A01. White solid; yield 62%; m.p. 323 - 325 °C; 11H NMR (400 MHz, CDCl3, ppm) δ: 12.13 (t, J = 8.5 Hz, 1H), 11.01 (d, J = 3.6 Hz, 1H), 10.74 (d, J = 12.8 Hz, 1H), 10.11 (d, J = 2.4 Hz, 1H), 10.00 (d, J = 12.1 Hz, 2H), 9.95–9.89 (m, 3H), 9.80 (s, 1H), 9.57 (d, J = 12.3 Hz, 2H), 9.50 (d, J = 12.1 Hz, 2H), 8.37 (dd, J = 26.0, 16.2 Hz, 1H), 7.95–7.91 (m, 1H), 7.08 (d, J = 26.2 Hz, 1H), 6.19 (d, J = 16.5 Hz, 1H), 5.63 (d, J = 8.2 Hz, 2H). 13 13C NMR (100 MHz, CDCl3, ppm) δ: 167.3, 160.8, 152.6, 150.7, 144.4, 144.4, 142.4, 138.1, 137.3, 136.1, 129.6, 129.5, 129.4, 127.5, 127.4, 126.9, 124.2, 123.9, 115.1, 112.8, 107.8, 43.9. HRMS-ESI: m / z calcd for C 27 H 21 N5O2 [M+H] + 448.1768, found 448.1766.

[0135] Example 50: Preparation of Methyl 4 - ((((2 - ((2 - hydroxyethyl)amino)-7-(4 - vinylphenyl)quinazolin - 4 - yl)amino)methyl)benzoate (A50)

[0136] The preparation method of A50 is the same as that of A01. White solid; yield 88%; m.p. 122 - 124 °C; 11H NMR (400 MHz, CDCl3, ppm) δ: 7.97 (d, J = 8.2 Hz, 2H), 7.64–7.57 (m, 4H), 7.45 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.32 (dd, J = 8.4, 1.6 Hz, 1H), 6.73 (dd, J = 17.6, 10.9 Hz, 1H), 6.32 (s, 1H), 5.79 (d, J = 17.6 Hz, 1H), 5.45 (s, 1H), 5.29 (d, J = 10.9 Hz, 1H), 4.81 (d, J = 5.4 Hz, 2H), 3.89 (s, 3H), 3.84–3.82 (m, 2H), 3.59 (d, J = 2.2 Hz, 2H). 13 13C NMR (100 MHz, CDCl3, ppm) δ: 167.0, 160.6, 160.1, 151.2, 145.3, 143.9, 139.3, 137.5, 136.4, 130.1, 129.4, 127.6, 127.5, 126.8, 122.7, 121.6, 121.0, 114.5, 110.0, 64.8, 52.3, 45.4, 44.7. HRMS-ESI: m / z calced for C 27 H 26 N4O3 [M+H] + 455.2078, found 455.2075.

[0137] Example 51: Determination of Histone Demethylase Inhibitory Activity

[0138] 1. The determination procedure is as follows:

[0139] In the JMJD3 enzyme inhibitory activity test, GSK-J1 was used as the reference compound; in the inhibitory activity tests of other JMJD subfamily enzymes, pyridine-2,4-dicarboxylic acid (2,4-PDCA) was used as the reference compound. The primary screening was to test the repeated inhibition rates at a single compound concentration (50 μM). For IC 50For the calculation, 5 concentrations were tested for each compound, with the starting concentration being 50 μM and a 5-fold dilution gradient. The substrate solution was prepared by adding the peptide, ascorbic acid, 2-OG, and Fe(II) to 1x experimental buffer. 5 μL of the enzyme solution was transferred to the assay plate of the compound mixture and incubated at room temperature for 15 minutes. 5 μL of the substrate solution was added to each well and incubated at room temperature for 60 minutes. 15 μL of the acceptor solution and the donor solution were added to 1x Alphalisa buffer and incubated at room temperature in weak light for 60 minutes, and the endpoint was read using an EnSpire in Alpha mode. Curve fitting calculation was performed using formula (1): Inh% = (Max - Signal) / (Max - Min)*100 to calculate the inhibition rate. Using formula (2): Y = Bottom + (Top - Bottom) / (1 + 10 ∧ ((LogIC 50 -X)*HillSlope)) to fit the data in GraphPad to obtain the IC 50 value. (Where Y is the inhibition rate %, and X is the compound concentration)

[0140] 2. Results of the activity test

[0141] Table 1. Inhibitory activities of some compounds against JMJD3 enzyme

[0142]

[0143]

[0144] 38 of these compounds were selected for the KDM6B enzyme inhibitory activity test. The results in Table 1 show that 30 compounds have a certain degree of inhibitory activity against the KDM6B enzyme, and among them, 3 compounds, A31, A38, and A40, have significant inhibitory activity (IC 50 values are in the range of 1.8 - 4.0 μM).

[0145] Table 2. Inhibitory activities of some compounds against other KDM subfamilies

[0146]

[0147] Some compounds with better activities were selected to test their inhibitory activities against other subtypes of the JMJD enzyme, and the results are shown in Table 2. Some compounds also have a certain degree of inhibitory effect on other JMJD subfamilies. Among them, compounds A31 and A40 show good enzyme-selective inhibition against JMJD3, showing better selectivity than GSK-J1. This type of compound shows good development prospects.

[0148] The above are only some specific implementation cases of the present invention, and the specific content or common knowledge known in the solution is not described in detail here. It should be noted that the above embodiments do not limit the present invention in any way. For those skilled in the art, all technical solutions obtained by means of equivalent replacement or equivalent transformation fall within the protection scope of the present invention. The protection scope claimed in this application shall be subject to the content of its claims, and the specific implementation manners described in the specification can be used to interpret the content of the claims.

Claims

1. A 4 - amine - 2,7 - disubstituted quinazoline derivative, characterized in that, The general structural formula of the derivative is I, In general formula I, R is independently selected from: straight-chain alkyl or alkoxy with 1-9 carbons, branched-chain alkyl or alkoxy with 1-9 carbons, alkyl with double bond, triple bond, sulfur-containing, oxygen-containing or nitrogen-containing substituent on the carbon chain of 1-9 carbons, cycloalkyl or substituted cycloalkyl, cycloalkyl or substituted cycloalkyl containing N and O heteroatoms, phenyl or substituted phenyl, heteroaryl or substituted heteroaryl, benzyl or substituted benzyl; Ar1 is independently selected from: benzene ring, mono-substituted or multi-substituted benzene ring, fused benzene ring-unsaturated or saturated 5- or 6-membered carbon ring, fused benzene ring-5- or 6-aryl heterocycle, fused benzene ring-5- or 6-membered carbon heterocycle; Ar2 is independently selected from: benzene ring, mono-substituted or multi-substituted benzene ring, fused benzene ring-unsaturated or saturated 5- or 6-membered carbon ring, fused benzene ring-5- or 6-aryl heterocycle, fused benzene ring-5- or 6-membered carbon heterocycle.

2. The 4-amino-2,7-disubstituted quinazoline derivative according to claim 1, wherein The derivative is A01 or A02 or A03 or A04 or A05 or A06 or A07 or A08 or A09 or A10 or A11 or A12 or A13 or A14 or A15 or A16 or A17 or A18 or A19 or A20 or A21 or A22 or A23 or A24 or A25 or A26 or A27 or A28 or A29 or A30 or A31 or A32 or A33 or A34 or A35 or A36 or A37 or A38 or A39 or A40 or A41 or A42 or A43 or A44 or A45 or A46 or A47 or A48 or A49 or A50.

3. The preparation method of 4-amino-2,7-disubstituted quinazoline derivatives as claimed in claim 1, characterized in that: The preparation method includes the following steps: Using 2-amino-4-bromobenzoic acid as the starting material, cyclizing with urea at a certain temperature, and then reacting with phosphorus oxychloride to obtain a 2,4,7-trisubstituted quinazoline intermediate; the chlorine at the 4th position reacts with different amines under alkaline conditions to obtain a 4-amine-2,7-disubstituted quinazoline intermediate; the halogens at the 2nd and 7th positions react with different boric acids respectively, and finally through hydrolysis to obtain the 4-amine-2,7-disubstituted quinazoline derivative I.

4. The preparation method of the 4-amino-2,7-disubstituted quinazoline derivatives according to claim 3, characterized in that: The certain temperature is 200 °C.

5. Use of the 4-amine-2,7-disubstituted quinazoline derivative according to claim 1 as a histone demethylase inhibitor.

6. Use of the 4-amine-2,7-disubstituted quinazoline derivative according to claim 1 in the preparation of a medicament for treating diseases mediated by histone demethylase.

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