CN116239603A - A kind of 2-aminopyrimidine heterocyclic compound and its application - Google Patents

Abstract

The invention belongs to the field of chemical drug synthesis, and in particular relates to a 2-aminopyrimidine heterocyclic compound and its application. The present invention proposes a series of 2-aminopyrimidine heterocyclic compounds with novel structures containing 4-amidophenoxy; they have significant inhibitory effects on lung cancer, cervical cancer and breast cancer, and have good market prospects.

Description

A 2-aminopyrimidine heterocyclic compound and its application

This application is a divisional application. The invention name of the original application is “Preparation and Application of 2-aminopyrimidine heterocyclic compounds containing 4-amidophenoxy group”, the application number is 202010568748.7, and the application date is 2020.06.20.

Technical Field

The invention belongs to the field of chemical drug synthesis, and specifically relates to a 2-aminopyrimidine heterocyclic compound and application thereof.

Background Art

Cancer, also known as malignant tumor, can cause the proliferation and differentiation of normal cells to lose control and undergo abnormal division. The tumor also has multiple biological pathological characteristics such as invasiveness and metastasis. It is a disease that seriously endangers human health.

Studies have found that EGFR is closely related to a series of life activities of tumor cells, such as proliferation, invasion, angiogenesis, tumor metastasis and inhibition of apoptosis. EGFR family members play a pivotal role and have become the primary and main target for cancer treatment, especially for the treatment of NSCLC. By inhibiting the kinase activity of EGFR tyrosine and blocking its signaling pathway, tumor growth can be effectively inhibited.

Summary of the invention

In order to develop a new type of highly effective anti-tumor drug, the inventors conducted extensive research on aminoheterocyclic pyrimidine compounds. On the basis of retaining active groups such as aminopyrimidine and Michael acceptor, the U-shaped structural scaffold of the third-generation EGFR inhibitor compound was maintained, and active groups such as small molecule alkyl side chains and halogens were introduced on the pyrimidine ring and acrylamide side chain to adjust the reactivity of the compound. The parent core structure was changed by molecular docking results, and a series of novel 2-aminopyrimidine heterocyclic compounds containing 4-amidophenoxy were designed and synthesized, whose structures are shown in the following general formula I or II:

Wherein, the condensed ring where the X ring is located is selected from:

_R1 is selected from a five-membered or six-membered heterocyclic ring, an aromatic ring or an aromatic heterocyclic ring, containing 1-3 substituents selected from hydrogen, halogen, trifluoromethyl, cyano, methoxy or _C1 - _C4 alkyl;

R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl or halogen;

_R3 is selected from hydrogen, _C1 - _C10 alkyl, _C3 - _C10 cycloalkyl, _C1 - _C4 alcohol hydroxyl,

_R4 and _R5 are the same or different and are independently selected from _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl, hydroxyethyl, and mercaptoethyl; or, _R4 and _R5 together with the nitrogen atom to which they are connected form a 5-10 membered saturated heterocyclic group, wherein the saturated heterocyclic group, in addition to the nitrogen atom connected to _R4 and _R5 , optionally contains 1-3 heteroatoms selected from O, N and S; and n is 0-3.

The compound can be used for preparing medicines for treating and/or preventing prostate cancer, lung cancer and cervical cancer.

Preferably, _R1 is selected from:

wherein R ₆ is selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, thiol, carboxyl, trifluoromethoxy, methyl, ethyl, propyl, butyl, cyclopropane, ethylene, propylene, acetylene, propyne, methoxy, ethoxy, propoxy, isopropoxy, butoxy or azido;

_R7 is selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, azido, cyano, mercapto, _C1 - _C4 alkyl, _C3 - _C6 cycloalkyl, _C1 - _C4 alkenyl, _C1 - _C4 alkynyl, _C1 - _C4 alkoxy.

More preferably, R ₁ is selected from a benzene ring or pyridine, and the benzene ring or pyridine contains a methoxy substituent.

Preferably, -R ₂ (CH) ₂ R ₃ is selected from:

More preferably, R ₂ is selected from H or F. _{R 3} is selected from methyl, ethyl, isopropyl, hydrogen or propyl.

Preferably, the compound of the general formula I and II is one selected from the following compounds:

N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide;

(E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)but-2-enamide;

N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-3-methyl-2-enamide;

(E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4-methylpent-2-enamide;

(E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)hexan-2-amide;

N-(3-((2-((3-methoxyphenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide;

2-Fluoro-N-(3-((2-((3-methoxyphenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide;

(E)-4-(dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-but-2-enamide;

(E)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4-(piperidin-1-yl)-but-2-enamide;

N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide;

(E)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)oxy)phenyl)-pent-2-enamide;

N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide;

2-Fluoro-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide;

(E)-4-(dimethylamino)-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-but-2-enamide;

(E)-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4-(piperidin-1-yl)-but-2-enamide.

The following synthetic routes describe the preparation of the general formula I and II of the present invention, and all starting materials are prepared by the methods described in the synthetic routes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final 4-amidophenoxy-containing 2-aminopyrimidine heterocyclic compounds of the present invention are prepared by the methods described in the synthetic routes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variables used in the synthetic routes are as defined below or as defined in the claims.

Taking N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide as an example, the synthesis method is as follows, and all raw materials are commercially available analytical grade.

Taking N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide as an example, the synthesis method is as follows, and all raw materials are commercially available analytical grade.

The present invention first synthesizes the intermediate VII, and then obtains the target compound through docking with different side chain amines and small molecule acyl chlorides with different substitutions or other methods.

According to some common methods in the field to which the present invention belongs, the quinazoline compounds of the above general formulas I and II in the present invention can be reacted with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and salts with the following acids are particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of the above general formula I, which may have weak activity or even no activity themselves, but after administration, they are converted into corresponding biologically active forms under physiological conditions (e.g., by metabolism, solvolysis or other means).

The present invention can contain the 2-aminopyrimidine heterocyclic compounds containing 4-amidephenoxy group of the above-mentioned general formula I and II, and their pharmaceutically acceptable salts, hydrates or solvates as active ingredients, mixed with pharmaceutically acceptable carriers or excipients to prepare a composition, and prepared into a clinically acceptable dosage form, wherein the above-mentioned pharmaceutically acceptable excipients refer to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The derivatives of the present invention can be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.

The clinical dosage of the 2-aminopyrimidine heterocyclic compounds containing 4-amidophenoxy groups of the above-mentioned general formulas I and II of the present invention for patients can be appropriately adjusted according to the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rates, and the age, gender, and disease stage of the patients, but the daily dosage for adults should generally be 10 to 500 mg, preferably 50 to 300 mg. According to the guidance of doctors or pharmacists, these preparations can be administered several times (preferably one to six times) at certain intervals.

The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some commonly used excipients in the pharmaceutical field. The above-mentioned several dosage forms can be injections, tablets, capsules, aerosols, suppositories, films, pills, external liniments, ointments and other dosage forms.

The carrier used in the pharmaceutical composition of the present invention is a common type available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizers, diluents, stabilizers, suspending agents, pigments, flavoring agents, preservatives, solubilizers and bases, etc. The pharmaceutical preparation can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically), and if some drugs are unstable under gastric conditions, they can be formulated into enteric-coated tablets.

The beneficial effects of the present invention are as follows: the present invention proposes a series of novel 2-aminopyrimidine heterocyclic compounds containing 4-amidophenoxy groups; the compounds have significant inhibitory effects on lung cancer, cervical cancer and breast cancer, and have good market prospects.

DETAILED DESCRIPTION

The following will be combined with the examples to clearly and completely describe the concept and technical effects of the present invention, so as to fully understand the purpose, scheme and effect of the present invention. In the examples, the nuclear magnetic resonance hydrogen spectrum was measured by Bruker ARX-400, and the mass spectrum was measured by Agilent 1100LC/TOF MSD; all reagents used were analytically pure or chemically pure.

2-aminopyrimidine heterocyclic compounds containing 4-amidophenoxy group of general formula Ⅰ and Ⅱ:

The structural formulas of Examples 1 to 28 of the present invention are shown in Table 1 below.

Table 1 Structural formula of Examples 1 to 28

Example 1 Preparation of 5N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide:

Step A: Preparation of methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (III1)

Add dimethyl 3,3'-thiodipropionate (II) (1130.0 g, 630.3 mmol) and NaH (60%, 22.7 g, 945.5 mmol) into a flask containing 500 mL of tetrahydrofuran. Stir the mixture at room temperature for 4 h. After the reaction, add the mixed solution into 1000 mL of water and extract with dichloromethane several times. Dry the obtained organic phase with anhydrous sodium sulfate, recover dichloromethane under reduced pressure to obtain III1, 104.3 g of yellow liquid, with a yield of 95.0%.

Step B: Preparation of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine-2,4-diol (IV1)

Compound III1 (50.0 g, 287.0 mmol) and urea (103.5 g, 1723.3 mmol) were dissolved in 500 mL of sodium methoxide solution. After stirring at 80°C for about 5 h, the reaction was completed. 500 mL of water was slowly added to the reaction solution. During the mixing process, fine particles visible to the naked eye precipitated. After vacuum filtration and drying, compound IV1 was obtained as a light yellow solid of 40.29 g with a yield of 76.2%.

Step C: Preparation of 2,4-dichloro-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (V1)

Compound IV1 (20.0 g, 108.5 mmol) was dissolved in 80 mL of phosphorus oxychloride solution and stirred at 120 °C for 3 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and then 500 mL of ice water was slowly added and stirred vigorously to precipitate solid. After vacuum filtration, the filter cake was washed with distilled water. After drying the filter cake, 19.8 g of light gray solid was obtained, and the yield was 82.6%.

Step D: Preparation of (22-chloro-4-(3-nitrophenoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine (VI1)

Compound V1 (19.0 g, 85.9 mmol), m-nitrophenol (12.0 g, 86.3 mmol), and cesium carbonate (31.0 g, 95.1 mmol) were placed in a flask containing 120 mL of 4-dioxane and stirred at room temperature for 6 h. A large amount of solid precipitated during the reaction. After the reaction was completed, the reaction mixture was poured into 250 mL of water and stirred for 30 min. After filtration and drying, 27.0 g of white solid was obtained, with a yield of 97.1%.

Step E: Preparation of N-(3-methoxyphenyl)-4-(3-nitrophenoxy)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (VII1a)

Compound VI1 (5 g, 15.4 mmol) was dissolved in 60 mL of acetonitrile, and then p-toluenesulfonic acid (5.6 g, 32.5 mmol) and amino side chain a (16.5 mmol) were added thereto in sequence. After stirring at 100 ° C for 3 h, the reaction was completed. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the acetonitrile was concentrated by about 50%. After adding twice the amount of water, a large amount of solid precipitated. The solid was filtered under reduced pressure and dried to obtain the key intermediate VII1a.

Step F: Preparation of 4-(3-aminophenoxy)-N-(3-methoxyphenyl)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-2-amine (VIII1a)

Compound Ⅶ1a (13.0 mmol) was dissolved in 60 mL of ethanol. Ferric chloride hexahydrate (15.6 mmol) and activated carbon (91.0 mmol) were added in sequence. After heating to 80 °C, hydrazine hydrate (130.0 mmol) was mixed with 10 mL of ethanol and added to the above solution. The mixture was refluxed and stirred for 4 h. After the reaction was completed, the solid in the reaction system was filtered out. The filter cake was then washed with 10 mL of anhydrous ethanol, the filtrate was collected, and the solvent was recovered by vacuum distillation. The residue was added to 60 mL of saturated sodium bicarbonate aqueous solution and stirred vigorously to precipitate the solid. The solid was filtered under reduced pressure and dried to obtain the key intermediate Ⅷ1a.

Step G: Preparation of N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide (IX1a)

Compound VIII 1a (1.5 mmol) was dissolved in 30 mL of dichloromethane, and DIPEA (3.0 mmol) was added. The solution was stirred in an ice bath for 5 minutes, and then the amide (3.0 mmol) diluted with an equal amount of dichloromethane was slowly dripped into the above solution. The reaction was completed within 2 hours. After the reaction was completed, the reaction mixture was filtered and the solvent was recovered by vacuum distillation. The residue was purified by silica gel column chromatography using dichloromethane/methanol = 70:1-30:1 as the eluent to obtain the target compound IX 1a with high purity.

Example 1 N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

mp:225.9–227.3℃; TOF MS ES+(m/z):(M+H)+:435.14; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.43(s,1H),9.40(s,1H),7.67(s,1H),7.54(d,J＝6.8Hz,1H),7.39(t,J＝7.5Hz,1H),7.19( s,1H),7.04(d,J＝6.0Hz,1H),6.93(s,2H),6.51–6.41(m,1H),6.38(d,J＝6.8Hz,1H),6.25(d,J =16.9Hz,1H),5.76(d,J=9.7Hz,1H),3.77(s,2H),3.54(s,3H),2.97(s,4H).

According to the method of Example 1, the intermediate VIII1a was reacted with different substituents _R2 to prepare the compounds of Examples 2 to 7.

Example 2 (E)-N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)but-2-enamide

mp:198.2–202.7℃; TOF MS ES+(m/z):(M+H)+:449.16; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.53(s,1H),9.37(s,1H),7.70(s,1H),7.57(d,J＝6.5Hz,1H),7.40–7.31(m,1H),7.19(s,1H ),7.03(s,1H),6.96–6.85(m,2H),6.76(s,1H),6.38(d,J＝5.0Hz,1H),6.25(d,J＝14.4Hz,1H),3.76 (s,2H),3.53(s,3H),2.96(s,4H),1.85(d,J=5.8Hz,3H).

Example 3 N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)-3-methyl-2-enamide

mp:199.7–201.6℃; TOF MS ES+(m/z):(M+H)+:463.18; ¹ H NMR(400MHz, DMSO-d ₆ )δ9.35(s,1H),7.27(s,1H ),7.13(d,J＝8.0Hz,1H),7.05(t,J＝8.0Hz,1H),6.96(t,J＝8.1Hz,1H),6.45(d,J＝8.1Hz,1H), 6.40(d,J＝8.0Hz,1H),6.35(s,1H),6.30(s,1H),5.25(s,2H),3.72(s,2H),3.55(s,3H),2.95(s ,4H),2.18(s,3H),1,84(s,3H).

Example 4 (E)-N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)pent-2-enamide

mp:200.7–202.4℃; TOF MS ES+(m/z):(M+H)+:463.18; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.31(s,1H),9.37(s,1H),7.63(s,1H),7.48(d,J＝8.6Hz,1H),7.35(t,J＝8.1Hz,1H),7.18( d,J＝9.2Hz,1H),7.02(d,J＝7.3Hz,1H),6.89(t,J＝8.1Hz,2H),6.36(d,J＝7.2Hz,1H),6.10(d, J＝15.3Hz,1H),5.95(d,J＝15.5Hz,1H),3.75(s,2H),3.51(s,3H),2.95(s,4H),2.06–1.89(m,2H), 1.22(d,J=10.0Hz,3H).

Example 5 (E)-N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)-4-methylpent-2-enamide

mp:230.5–234.5℃; TOF MS ES+(m/z):(M+H)+:477.19; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.41(s,1H),9.34(s,1H),7.27(s,1H),7.12(d,J＝8.1Hz,1H),7.04(t,J＝7.9Hz,1H),6.96( t,J＝8.1Hz,1H),6.45(d,J＝7.8Hz,1H),6.42–6.34(m,2H),6.30(d,J＝7.6Hz,1H),5.27(s,2H), 3.72(s,2H),3.55(s,3H),2.95(s,4H),1.98(s,1H),1.23(s,6H).

Example 6 (E)-N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)hex-2-enamide

mp:226.7–229.4℃; TOF MS ES+(m/z):(M+H)+:477.19; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.18(s,1H),9.20(s,1H),7.64(s,1H),7.51(s,1H),7.39(t,J＝8.0Hz,1H),7.31(d,J＝8.4 Hz,2H),6.89(d,J＝7.7Hz,1H),6.78(dd,J＝14.8,7.4Hz,1H),6.59(d,J＝7.6Hz,2H),6.11(d,J＝15.2 Hz,1H),3.76(s,2H),3.63(s,3H),2.99–2.89(m,4H),2.17(q,J＝6.7Hz,2H),1.44(dt,J＝14.4,7.3Hz ,2H),0.94–0.89(m,3H).

Example 7 2-Fluoro-N-(3-((2-((3-methoxyphenyl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

mp:215.2–217.4℃; TOF MS ES+(m/z):(M+H)+:453.14; ¹ H NMR(400MHz, DMSO-d ₆ )δ10.18(s,1H),9.36(s,1H ),7.27(s,1H),7.12(d,J＝8.0Hz,1H),7.05(t,J＝7.9Hz,1H),6.96(t,J＝8.1Hz,1H),6.45(d,J ＝7.9Hz,1H),6.40(d,J＝7.9Hz,1H),6.35(s,1H),6.31(d,J＝7.9Hz,1H),5.26(s,2H),3.72(s,2H ),3.55(s,3H),2.95(s,4H).

According to the method of Example 1, VI1 was synthesized and reacted with the amino side chain b to obtain VII1b, which was reduced to obtain VIII1b. The intermediate VIII1b was reacted with different substituents _R2 to obtain the compounds of Examples 8 to 13.

Example 8 N-(3-((2-((6-methoxypyridin-3-yl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

mp:189.2–190.7℃; TOF MS ES+(m/z):(M+H)+:436.14; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.24(s,1H),9.32(s,1H),8.21(s,1H),7.78(d,J＝8.7Hz,1H),7.65(s,1H),7.48(d,J＝9.1 Hz,1H),7.37(t,J＝8.1Hz,1H),6.89(dd,J＝8.0,2.2Hz,1H),6.78(dt,J＝14.3,7.0Hz,1H),6.48(d,J ＝8.2Hz,1H),6.12(d,J＝15.3Hz,1H),5.53(d,J＝14.3Hz,1H),3.76(s,2H),3.74(s,3H),2.95(s,4H ).

Example 9 (E)-N-(3-((2-((6-methoxypyridin-3-yl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)but-2-enamide

mp:187.6–190.1℃; TOF MS ES+(m/z):(M+H)+:450.16; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.14(s,1H),9.27(s,1H),8.17(s,1H),7.75(d,J＝8.6Hz,1H),7.45(d,J＝7.4Hz,1H),7.38( d,J＝9.1Hz,1H),6.89(d,J＝7.3Hz,1H),6.83–6.73(m,2H),6.45(s,1H),6.11(d,J＝14.8Hz,1H), 3.74(s,2H),3.72(s,3H),2.95–2.91(m,4H),1.85(d,J=6.7Hz,3H).

Example 10 N-(3-((2-((6-methoxypyridin-3-yl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)-3-methyl-2-enamide

mp:221.1–224.1℃; TOF MS ES+(m/z):(M+H)+:450.16; ¹ H NMR(400MHz, DMSO-d ₆ )δ10.08(s,1H),9.83(s,1H ),8.28(d,J＝5.4Hz,1H),8.05(s,1H),7.92(d,J＝8.4Hz,1H),7.39(s,1H),7.37–7.32(m,2H),7.29 (d,J＝6.5Hz,1H),6.53(d,J＝8.1Hz,1H),3.75–3.70(m,5H),2.96(d,J＝21.6Hz,4H),2.10(s,3H) ,1.84(s,3H).

Example 11 (E)-N-(3-((2-((6-methoxypyridin-3-yl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)pent-2-enamide

mp:214.3–216.4℃; TOF MS ES+(m/z):(M+H)+:464.17; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.14(s,1H),9.31(s,1H),8.21(s,1H),7.79(s,1H),7.65(s,1H),7.47(d,J＝7.6Hz,1H), 7.39(d,J＝7.6Hz,1H),6.93–6.81(m,2H),6.49(s,1H),6.09(d,J＝15.4Hz,1H),3.76(s,3H),3.74(s ,2H),2.95(s,4H),2.27–2.16(m,2H),1.03(t,J＝7.1Hz,3H).

Example 12 (E)-N-(3-((2-((6-methoxypyridin-3-yl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)-4-methylpent-2-enamide

mp:226.8–229.2℃; TOF MS ES+(m/z):(M+H)+:478.19; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.15(s,1H),9.30(s,1H),8.19(s,1H),7.76(d,J＝8.4Hz,1H),7.63(s,1H),7.45(d,J＝8.0 Hz,1H),7.37(d,J＝8.2Hz,1H),6.88(d,J＝7.8Hz,1H),6.81–6.73(m,1H),6.46(d,J＝6.5Hz,1H), 6.04(d,J＝15.4Hz,1H),3.74(s,2H),3.72(s,3H),2.94(d,J＝10.9Hz,4H),2.44(dd,J＝13.0,6.5Hz,1H ), 1.02 (d, J = 6.7Hz, 6H).

Example 13 (E)-N-(3-((2-((6-methoxypyridin-3-yl)amino)-7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidin-4-yl)oxy)phenyl)hex-2-enamide

mp:230.1–231.7℃; TOF MS ES+(m/z):(M+H)+:478.19; ¹ H NMR(400MHz, DMSO-d ₆ )δ10.24(s,1H),9.33(s,1H ),8.21(s,1H),7.77(d,J＝6.9Hz,1H),7.65(s,1H),7.48(d,J＝8.2Hz,1H),7.37(t,J＝7.5Hz,1H ),6.89(d,J＝7.9Hz,1H),6.78(dt,J＝14 .6,6.9Hz,1H),6.48(d,J＝8.3Hz,1H),6.12(d,J＝15.3Hz,1H),3.75(s,2H),3.73(s,3H),2.95(s ,4H),2.24–2.12(m,2H),1.49–1.42(m,2H),0.90(t,J=7.0Hz,3H).

Example 14 Preparation of N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide:

Step A: Preparation of 2,4-dichloro-6-(thiophen-2-yl)pyrimidine (V2)

A mixed liquid of 1,2-dimethoxyethane and water in a ratio of 5:1 was used as solvent, 2,4,6-trichloropyrimidine (70.0 g, 381.6 mmol), bis(triphenylphosphine)palladium dichloride and thiophene-2-ylboronic acid (25.2 g, 196.8 mmol) were placed in a 500 mL flask, and the compound was stirred at 90°C for about 1.5 hours using a one-pot method. The reaction was complete and the system was black and turbid. The solvent in the system was evaporated to dryness, and ethyl acetate/ether = 70:1-50:1 was used as an eluent. The residue was purified by silica gel column chromatography to obtain 21.0 g of the target compound V2 with a high purity, with a yield of 23.6%.

Step B: Preparation of 2-chloro-4-(3-nitrophenoxy)-6-(thiophen-2-yl)pyrimidine (VI2)

Compound V2 (19.0 g, 82.3 mmol) was dissolved in 120 mL of 1,4-dioxane, and m-nitrophenol (12.0 g, 86.3 mmol) and cesium carbonate (32.0 g, 99.5 mmol) were added to the solvent in sequence, and stirred at room temperature for 4 h. A large amount of solid was precipitated during the reaction. After the reaction was completed, the reaction solution was poured into 250 mL of water and stirred for 10 minutes. The solid was filtered out under reduced pressure and dried to obtain 24.0 g of yellow solid, with a yield of 87.4%.

Step D: Preparation of 3-((4-(3-nitrophenoxy)-6-(thiophen-2-yl)pyrimidin-2-yl)amino)benzonitrile (VII2c)

Dissolve compound VI2 (5.3 g, 16.0 mmol) in 60 mL of acetonitrile, then add p-toluenesulfonic acid (5.6 g, 32.5 mmol) and amino side chain c (16.0 mmol) to the solution in sequence. Stir at 100 °C and the reaction is completed after 4-5 hours. After cooling to room temperature, the reaction system is concentrated using a rotary evaporator. After the acetonitrile is concentrated to about 50%, add twice the amount of water to precipitate a large amount of solid. Filter out the solid under reduced pressure and dry to obtain the key intermediate VII2c.

Step E: Preparation of 3-((4-(3-aminophenoxy)-6-(thiophen-2-yl)pyrimidin-2-yl)amino)benzonitrile (VIII2c)

Compound Ⅶ2c (13.0 mmol) was dissolved in 60 mL of ethanol. Ferric chloride hexahydrate (15.6 mmol) and activated carbon (91.0 mmol) were added in sequence. After heating to 80°C, hydrazine hydrate (130.0 mmol) was mixed with 10 mL of ethanol and added to the above solution. The mixture was refluxed and stirred for 4 h. After the reaction was completed, the solid in the reaction system was filtered out. The filter cake was then washed with 10 mL of anhydrous ethanol and the filtrate was collected. Most of the solvent was removed by vacuum distillation. 60 mL of saturated sodium bicarbonate aqueous solution was added and stirred vigorously to precipitate the solid. Compound Ⅷ2c was obtained by filtration and filter cake drying.

Step F: Preparation of N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide (IX2c)

Compound VIII 2c (1.5 mmol) was dissolved in 30 mL of dichloromethane, and 3.0 mmol of N,N-diisopropylethylamine (DIPEA) was added. The solution was stirred in an ice bath for 5 min, and then the amide (3.0 mmol) diluted with an equal amount of dichloromethane was slowly dripped into the above solution. The reaction was completed within 2 h. After the reaction was completed, the solid in the reaction system was removed by vacuum filtration, and the filtrate was recovered by vacuum distillation. Using dichloromethane/methanol = 70:1-30:1 as the eluent, the residue was purified by silica gel column chromatography to obtain the target compound IX 2c with high purity.

Example 14 N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide

mp:207.2–208.4℃; TOF MS ES+(m/z):(M+H) ⁺ :440.11; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.34(s,1H),9.95(s,1H),8.08–8.05(m,1H),7.84(d,J＝5.2Hz,2H),7.71(d,J＝6.3Hz,1H), 7.52(d,J＝8.3Hz,1H),7.44(t,J＝8.1Hz,2H),7.33(s,2H),7.28–7.24(m,1H),7.16(s,1H),7.03–6.99 (m,1H),6.43(dd,J＝16.9,10.1Hz,1H),6.25(dd,J＝16.9,2.0Hz,1H),5.79–5.74(m,1H).

According to the method of Example 14, the intermediate VIII2c was reacted with different substituents _R2 to prepare the compounds of Examples 15 to 18.

Example 15 (E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)but-2-enamide

mp:209.9–211.1℃; TOF MS ES+(m/z):(M+H) ⁺ :454.13; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.13(s,1H),9.95(s,1H),8.07(d,J＝5.8Hz,2H),7.84(d,J＝5.1Hz,2H),7.69(d,J＝10.9Hz, 1H),7.49(d,J＝8.2Hz,1H),7.43(d,J＝7.9Hz,1H),7.34(s,2H),7.27–7.24(m,1H),7.16(s,1H), 6.98(d,J＝8.1Hz,1H), 6.79(dd,J＝15.3,7.6Hz,1H), 6.11(d,J＝15.3Hz,1H), 1.85(d,J＝7.0Hz,3H).

Example 16 N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-3-methyl-2-enamide

mp:197.2–199.2℃; TOF MS ES+(m/z):(M+H) ⁺ :468.15; ¹ H NMR(400MHz, DMSO-d ₆ )δ10.01(s,1H),9.95(s,1H ),8.06(d,J＝3.8Hz,1H),7.84(d,J＝4.9Hz,2H),7.67(s,1H),7.42(dt,J＝16.2,8.2Hz,3H),7.34(s ,2H),7.27–7.24(m,1H),7.15(s,1H),6.95(d,J＝8.1Hz,1H),5.86(s,1H),2.12(s,3H),1.85(s, 3H).

Example 17 (E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4-methylpent-2-enamide

mp:210.5.2–211.9℃; TOF MS ES+(m/z):(M+H) ⁺ :482.16; ¹ H NMR(400MHz, DMSO-d ₆ )δ10.19(s,1H),9.94(s ,1H),8.06(d,J＝3.8Hz,1H),7.84(d,J＝5.2Hz,2H),7.69(d,J＝4.5Hz,1H),7.49(d,J＝8.3Hz,1H ),7.42(t,J＝8.1Hz,1H),7.33(s,2H),7.25(t,J ＝4.4Hz,1H),7.15(s,1H),6.98(d,J＝8.0Hz,1H),6.81(d,J＝6.3Hz,1H),6.79–6.74(m,1H),6.06(d , J＝15.4Hz, 1H), 2.43 (dd, J＝13.1, 6.6Hz, 1H), 1.03 (d, J＝6.5Hz, 6H).

Example 18 (E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)hexane-2-amide

mp:222.3–223.5℃; TOF MS ES+(m/z):(M+H) ⁺ :482.16; ¹ H NMR (400MHz, DMSO-d ₆ )δ10.15(s,1H),9.95(s,1H),8.07(d,J＝3.7Hz,1H),7.85(d,J＝5.0Hz,2H),7.68(s,1H),7.49( d,J＝8.4Hz,1H),7.42(t,J＝8.0Hz,2H),7.33(s,2H),7.26(dd,J＝5.0,3.8Hz,1H),7.16(s,1H), 6.98(d,J＝7.9Hz,1H),6.82–6.76(m,1H),6.10(d,J＝15.4Hz,1H),2.18(d,J＝7.0Hz,2H),1.45(d,J =7.3Hz, 2H), 0.90 (d, J = 3.5Hz, 3H).

Example 19 N-(3-((2-((3-methoxyphenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide

TOF MS ES+(m/z):(M+H) ⁺ :445.13.

Example 20 2-Fluoro-N-(3-((2-((3-methoxyphenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide

TOF MS ES+(m/z):(M+H) ⁺ :463.12.

Example 21 (E)-4-(dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-but-2-enamide

TOF MS ES+(m/z):(M+H) ⁺ :476.18.

Example 22 (E)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4-(piperidin-1-yl)-but-2-enamide

TOF MS ES+(m/z):(M+H) ⁺ :516.21.

Example 23 N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

TOF MS ES+(m/z):(M+H) ⁺ :395.12.

Example 24 (E)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)oxy)phenyl)-pent-2-enamide

TOF MS ES+(m/z):(M+H) ⁺ :423.16.

Example 25 N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide

TOF MS ES+(m/z):(M+H) ⁺ :448.09.

Example 26 2-Fluoro-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide

TOF MS ES+(m/z):(M+H) ⁺ :466.08.

Example 27 (E)-4-(dimethylamino)-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-but-2-enamide

TOF MS ES+(m/z):(M+H) ⁺ :505.14.

Example 28 (E)-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4-(piperidin-1-yl)-but-2-enamide

TOF MS ES+(m/z):(M+H) ⁺ :545.17.

Pharmacological studies of the product of the present invention

In vitro cytotoxic activity

The pyrimidine- and pyridine-containing quinoline derivatives of general formula I and II of the present invention were screened for their in vitro inhibitory activities on lung cancer cells A549, breast cancer cells MCF-7, cervical cancer cells Hela and normal human cells LO2, with omotinib as the reference substance.

(1) After the cells are revived and passaged 2-3 times to stabilize, use trypsin solution (0.25%) to digest them from the bottom of the culture bottle. Pour the cell digestion solution into a centrifuge tube, and then add culture medium to stop digestion. Centrifuge the centrifuge tube at 800r/min for 10 minutes, discard the supernatant and add 5mL of culture medium, blow and mix the cells, aspirate 10μL of cell suspension and add it to the cell counting plate for counting, and adjust the cell concentration to ¹⁰⁴ /well. In the 96-well plate, except for A1 well which is a blank well without cells, add 100μL of cell suspension to the rest. Place the 96-well plate in an incubator and culture for 24 hours.

(2) Dissolve the test sample in 50 μL of dimethyl sulfoxide, then add an appropriate amount of culture medium to dissolve the sample into a 2 mg/mL solution. Then dilute the sample to 20, 4, 0.8, 0.16, and 0.032 μg/mL in a 24-well plate.

Each concentration was added to 3 wells, of which the growth of cells in the two rows and two columns around was greatly affected by the environment, and only the blank cell wells were used. The 96-well plate was placed in an incubator and cultured for 72 hours.

(3) The drug-containing culture medium in the 96-well plate was discarded, and the cells were rinsed twice with phosphate buffer solution (PBS). 100 μL of MTT (tetrazolium) (0.5 mg/mL) was added to each well and placed in an incubator for 4 hours. The MTT solution was discarded and 100 μL of dimethyl sulfoxide was added. The surviving cells and the MTT reaction product formazan were fully dissolved by shaking on a magnetic oscillator, and the result was measured in an ELISA instrument. The IC ₅₀ value of the drug can be obtained by the Bliss method.

The results of the compounds' inhibition of the activity of lung cancer cells A549, breast cancer cells MCF-7, cervical cancer cells Hela and human normal cells LO2 are shown in Table 2.

EGFR kinase activity assay

Using omatinib as a positive control, the HTRF technology was used to test the IC ₅₀ values of the newly synthesized compounds against various cancer cells, and the inhibitory effects of some compounds on EGFR were also tested.

Specific method: Prepare the working solution of ATP, TK Substrate-biotin (TK-substrate biotin), and Kinase buffer (kinase buffer) at the required concentration. ATP, TK Substrate-biotin, and Kinase buffer are mixed at a volume ratio of 2:2:2; dilute the drug with Kinase buffer to the required concentration; prepare EGFR enzyme working solution. In a white 384-well plate, add 6μL of mixed solution, 2μL of drug, and 2μL of kinase to each well, mix well, and place at 37℃ for reaction for 30min. Then add 5μL of streptokinase-labeled XL-665 and 5μL of Eu3+-bound cryptate antibody and mix well. After standing at room temperature for 30min, excite at 314nm on an ELISA reader, detect fluorescence at wavelengths of 665 and 620nm, calculate the kinase inhibition rate, and calculate the IC ₅₀ value of each drug by the Bliss method based on the absorbance.

Inhibition rate (%) = (Ratio 665/620 control well - Ratio 665/620 drug administration well) / Ratio 665/620 control well × 100%.

The experimental data were expressed as mean ± standard deviation. The significance test of the measurement data between groups was performed by one-way analysis of variance, and the pairwise comparison was performed by t-test. p < 0.05 was considered to be significantly different, and p < 0.01 was considered to be very significantly different.

Table 2 In vitro antitumor activity of some target compounds

Table 3 Enzyme activities of some target compounds

It can be clearly seen from the above test results that the compounds of general formula I and II to be protected by the present invention have good in vitro anti-cell proliferation activity and anti-EGFR kinase activity. The toxicity of all target compounds to normal human cells LO2 is lower than that of omotinib, and the inhibitory activity of some compounds to L858R/T790M double mutant lung cancer cells H1975 is better than that of omotinib. It can be seen from the data in the above table that, relative to the anti-EGFR wild-type kinase activity, the example compounds have a certain selectivity for EGFR double mutant kinases, which can also prove that the example compounds have good targeting and high selectivity, such as Examples 1 and 6. It can be concluded that the compounds of general formula I and II in the present invention may be potential EGFR inhibitors.

Although the present invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of the present invention.

Application example 1: Capsules

10 g of the compound of Example 9 was mixed with 20 g of auxiliary materials according to the requirements of pharmaceutical capsules, and then filled into hollow capsules. Each capsule weighed 300 mg.

Application Example 2: Tablets

10 g of the compound of Example 3 was added with 20 g of auxiliary materials according to the general tableting method in pharmacy, and mixed well, and then compressed into 100 tablets, each weighing 300 mg.

Application Example 3: Ointment

10 g of the compound of Example 4 is ground into powder and then mixed with 500 g of an oily base such as vaseline to obtain the compound.

Although the present invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be encompassed within the scope of the present invention.

Application example 4: Aerosol

10 g of the compound of Example 9 was dissolved in an appropriate amount of propylene glycol, and then distilled water and other materials were added to prepare 500 mL of a clear solution.

Application example 5: pills

10 g of the compound of Example 12 was heated and melted with 50 g of a matrix such as gelatin, and then dropped into low-temperature liquid paraffin to prepare 1000 pills.

Application Example 6: External Liniment

The compound of Example 16 (10 g) was mixed and ground with 2.5 g of auxiliary materials such as emulsifiers according to conventional pharmaceutical methods, and then distilled water was added to 200 mL to prepare the product.

Application example 7: Film

With 10 g of the compound of Example 19, polyvinyl alcohol, medicinal glycerin, water, etc. were stirred to expand, and then heated to dissolve. The mixture was filtered through an 80-mesh sieve, and the compound of Example 14 was added to the filtrate and stirred to dissolve. 100 films were made by a film coating machine.

Application Example 8: Suppository

10 g of the compound of Example 24 was ground into powder, and an appropriate amount of glycerin was added. After grinding evenly, melted glycerin gelatin was added, and the powder was ground evenly. The powder was poured into a mold coated with a lubricant to prepare 10 suppositories.

Claims (10)

1. A 2-aminopyrimidine heterocyclic compound, characterized in that the structure is as shown in the following general formula I or II:

Wherein, the fused ring where the X ring is located is selected from:

R ₁ is selected from a five-membered or six-membered heterocyclic ring, an aromatic ring or an aromatic heterocyclic ring, containing 1-3 selected from hydrogen, halogen, trifluoromethyl, cyano, methoxy or C ₁ to C ₄ alkyl substituents; R ₂ is selected from hydrogen, C ₁ -C ₄ alkyl or halogen; R ₃ is selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₄ alcoholic hydroxyl,

R ₄ and R ₅ are the same or different, and are independently selected from C ₁ to C ₆ alkyl, C ₃ to C ₆ cycloalkyl, hydroxyethyl, and mercaptoethyl; or, R ₄ and R ₅ and their respective The connected nitrogen atoms together form a 5-10 membered saturated heterocyclic group, which optionally contains 1 to 3 heterocyclic groups selected from O, N and S, except for the nitrogen atoms connected to _R4 and _R5 . atom; n is 0-3. 2. 2-aminopyrimidine heterocyclic compounds according to claim 1, characterized in that, _R1 is selected from:

wherein _R is selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxyl, amino, mercapto, carboxyl, trifluoromethoxy, methyl, ethyl, propyl, butyl, cyclopropane, ethylene , propylene, acetylene, propyne, methoxy, ethoxy, propoxy, isopropoxy, butoxy or azido; R ₇ is selected from halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, azido, cyano, mercapto, C ₁ ~C ₄ alkyl, C ₃ ~C ₆ cycloalkyl, C ₁ ~ C ₄ alkenyl, C ₁ -C ₄ alkynyl, C ₁ -C ₄ alkoxy. 3. The 2-aminopyrimidine heterocyclic compound according to claim 2, wherein _R is selected from benzene ring or pyridine, and said benzene ring or pyridine contains a methoxy substituent. 4. 2-aminopyrimidine heterocyclic compounds according to claim 1, characterized in that: -R ₂ (CH) ₂ R ₃ is selected from:

5. 2-aminopyrimidine heterocyclic compound according to claim 4, is characterized in that, R ₂ is selected from H or F. 6. The 2-aminopyrimidine heterocyclic compound according to claim 4, wherein _R is selected from methyl, ethyl, isopropyl, hydrogen or propyl. 7. The 2-aminopyrimidine heterocyclic compound according to claim 1, characterized in that: the compound of the general formula I and II is one selected from the following compounds: N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide; (E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thien-2-yl)pyrimidin-4-yl)oxy)phenyl)butan-2- enamide; N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-3-methyl-2- enamide; (E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4-methyl pent-2-enamide; (E)-N-(3-((2-((3-cyanophenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)hexa-2- amides; N-(3-((2-((3-methoxyphenyl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide; 2-fluoro-N-(3-((2-((3-methoxyphenyl)amino)-6-(thien-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide; (E)-4-(Dimethylamino)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6-(thiophen-2-yl)pyrimidine -4-yl)oxy)phenyl)-but-2-enamide; (E)-N-(3-((2-((1-Methyl-1H-pyrazol-3-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy) Phenyl)-4-(piperidin-1-yl)-but-2-enamide; N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidin-4-yl)oxy ) phenyl) acrylamide; (E)-N-(3-((2-((1-methyl-1H-pyrazol-3-yl)amino)-6,7-dihydrothiophene[3,2-d]pyrimidine-4- base)oxy)phenyl)-pent-2-enamide; N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thien-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide; 2-fluoro-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide ; (E)-4-(Dimethylamino)-N-(3-((2-((2-mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl) Oxy)phenyl)-but-2-enamide; (E)-N-(3-((2-((2-Mercaptopyridin-4-yl)amino)-6-(thiophen-2-yl)pyrimidin-4-yl)oxy)phenyl)-4 -(piperidin-1-yl)-but-2-enamide. 8. The use of a 2-aminopyrimidine heterocyclic compound as claimed in any one of claims 1-7 in the preparation of drugs for treating and/or preventing prostate cancer. 9. A use of the 2-aminopyrimidine heterocyclic compound according to any one of claims 1-7 in the preparation of drugs for treating and/or preventing lung cancer. 10. The use of a 2-aminopyrimidine heterocyclic compound as claimed in any one of claims 1-7 in the preparation of drugs for treating and/or preventing cervical cancer.