A pyrimidine derivative containing a cyclopropane sulfonamide group, and pharmaceutically acceptable salts thereof, and a method for preparing and use thereof

Abstract

The application belongs to the technical field of medicines, and provides a pyrimidine derivative containing a cyclopropane sulfonamide group, a pharmaceutically acceptable salt thereof, a preparation method and application thereof. The pyrimidine derivative containing a cyclopropane sulfonamide group has a structure shown in formula I. The pyrimidine derivative containing a cyclopropane sulfonamide group has a cyclopropane sulfonamide group substituted in the A ring and no alkoxy group substituted in the C ring. The active molecules can not only effectively inhibit the drug resistance of the third generation targeted drug Osimertinib after EGFR C797S mutation, but also can significantly inhibit EGFR single mutation or double mutation (L858R, del 19, T790M). The preparation method of the pyrimidine derivative containing a cyclopropane sulfonamide group and the pharmaceutically acceptable salt thereof has the advantages of simple synthesis process and low cost.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more particularly to a pyrimidine derivative containing cyclopropanesulfonylamino, its pharmaceutically acceptable salt, its preparation method, and its application. Background Technology

[0002] Malignant tumors, commonly known as cancer, are major diseases that seriously threaten human health and life. Among all common cancers, lung cancer has the highest mortality rate, and lung cancer and breast cancer rank first in incidence among male and female malignant tumors, respectively. Epidermal growth factor receptor (EGFR) is a type of receptor tyrosine kinase. EGFR is widely distributed in the epithelial cell membrane except for vascular tissue. In normal cells, EGFR tyrosine kinase is regulated by its ligands, playing a role in regulating the growth and proliferation of normal cells. When the regulatory gene of this pathway is mutated or amplified, it can abnormally activate the downstream pathway mediated by it, thereby inducing various cancers. Gefitinib is a first-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) and has good efficacy in patients with non-small cell lung cancer with EGFR gene-sensitive mutations. However, patients usually develop varying degrees of acquired resistance after 1 to 2 years of treatment. Osimertinib (AZD9291) is a third-generation EGFR-TKI targeted drug with a high response rate against resistance caused by the EGFR L858R / T790M mutation. Clinical studies have shown that nearly half of patients resistant to first-generation EGFR-TKIs such as gefitinib experienced local tumor shrinkage after using osimertinib, demonstrating excellent anti-tumor efficacy. However, after a period of use, patients may develop resistance, with the EGFR C797S mutation being one of the main mechanisms of resistance, accounting for approximately 40%. Given this situation, the search for and development of novel drugs capable of overcoming resistance to third-generation EGFR-TKI targeted drugs is of great significance. A 2017 article, "Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer. Ken Uchibori et al., Nature Communications, 2017, 8:1-16. DOI:10.1038 / ncomms14768.," reported that the combination of brigatinib (AP26113), a drug effective in treating anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer, and EGFR monoclonal antibodies (such as cetuximab) effectively overcame resistance to the third-generation targeted drug osimertinib caused by EGFR C797S mutations, showing good efficacy in mouse pharmacodynamic models. Since then, various novel active compounds capable of inhibiting resistance to the third-generation targeted drug osimertinib have been discovered.

[0003]

[0004] For example, WO2018 / 230934KO and Chinese patent CN110740999A1 disclose pyrimidine derivatives containing methanesulfonylamino, the optimal compound of which shows an IC50 of 0.027 μM against murine Baf3-EGFR 19del / T790M / C797S tumor cells. 50 Value. The general structural formula of the compound in this patent is as follows, in which R1 is CH3 or NH2, R2 is hydrogen, halogen, methoxy or one or more halogens unsubstituted or substituted methyl groups; R3 is hydrogen, halogen or straight-chain or branched C1-6 alkyl; R4 is straight-chain or branched C1-6 alkyl, etc.

[0005]

[0006] The activity of pyrimidine derivatives containing methanesulfonylamino with the above structure against tumor cells needs to be further improved. Summary of the Invention

[0007] In view of this, the object of the present invention is to provide a pyrimidine derivative containing cyclopropanesulfonylamino, a pharmaceutically acceptable salt thereof, a method for its preparation, and its application. The pyrimidine derivative containing cyclopropanesulfonylamino and its pharmaceutically acceptable salt provided by the present invention have better activity and fewer side effects.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] This invention provides a pyrimidine derivative containing cyclopropanesulfonylamino and a pharmaceutically acceptable salt thereof, wherein the pyrimidine derivative containing cyclopropanesulfonylamino has the structure shown in Formula I:

[0010]

[0011] In Formula I, R1 is hydrogen, halogen atom, alkyl, substituted alkyl, alkoxycarbonyl or substituted alkoxycarbonyl; the number of carbon atoms of the alkyl and substituted alkyl is 1 to 4; the substituted alkyl or substituted alkoxycarbonyl is in which the hydrogen atom on the saturated carbon atom is replaced by a deuterium or halogen atom;

[0012] R2 is a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, an amino group, a substituted amino group, an alkylamide group, or a substituted alkylamide group; the alkyl group and the substituted alkyl group have 1 to 4 carbon atoms; the alkylamide group or the substituted alkylamide group has 1 to 4 carbon atoms; the substituted alkyl group, the substituted amino group, and the substituted alkylamide group are saturated carbon atoms in which hydrogen atoms are replaced by deuterium.

[0013] R3 is a chain alkyl, chain heteroalkyl, substituted chain heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl; the number of atoms of the chain alkyl, chain heteroalkyl, and substituted chain heteroalkyl is 2 to 4, and the number of atoms of the cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl is 3 to 7; the heteroatom of the chain heteroalkyl, substituted chain heteroalkyl, heterocycloalkyl, and substituted heterocycloalkyl is nitrogen, oxygen, or sulfur; the substituted chain heteroalkyl is a group in which the hydrogen atom on the carbon or nitrogen atom is replaced by an alkyl, substituted alkyl, unsaturated hydrocarbon group, or substituted unsaturated hydrocarbon group. The saturated hydrocarbon group is substituted, wherein the substituted cycloalkyl and substituted heterocycloalkyl are in which the hydrogen atom on the carbon atom or nitrogen atom of the ring skeleton is replaced by an alkyl, substituted alkyl, unsaturated hydrocarbon group or substituted unsaturated hydrocarbon group; the number of carbon atoms of the alkyl, substituted alkyl, unsaturated hydrocarbon group or substituted unsaturated hydrocarbon group is 1 to 4; the hydrogen atom of the substituted alkyl and substituted unsaturated hydrocarbon group is replaced by deuterium; the hydrogen atom on the carbon atom of the substituted cycloalkyl and substituted heterocycloalkyl are in which the hydrogen atom of the carbon atom of the ring skeleton is replaced by an amino, substituted amino, mercapto or substituted mercapto; the hydrogen atom of the substituted amino and substituted mercapto is replaced by an alkyl or deuterated alkyl group.

[0014] Preferably, R1 is a halogen atom, wherein the halogen atom is fluorine, chlorine or bromine.

[0015] Preferably, R2 is hydrogen, a halogen atom, methyl, substituted methyl, ethyl, substituted ethyl, amino, acetamino, or substituted acetamino; wherein the substituted methyl, substituted ethyl, and substituted acetamino are hydrogen atoms on saturated carbon atoms that are replaced by deuterium.

[0016] Preferably, R3 is a substituted chain heteroalkyl or a substituted heterocyclic alkyl, wherein the number of atoms of the substituted heterocyclic alkyl is 6 to 7, and the heteroatom of the substituted chain heteroalkyl or the substituted heterocyclic alkyl is nitrogen; wherein the hydrogen atom on the nitrogen atom of the substituted heterocyclic alkyl is replaced by methyl, ethyl, deuterated methyl, deuterated ethyl or -N(CH3)2; wherein the hydrogen atom on the nitrogen atom of the substituted chain heteroalkyl is replaced by methyl, ethyl, deuterated methyl or deuterated ethyl.

[0017] Preferably, the pyrimidine derivative containing cyclopropanesulfonylamino has the following structure:

[0018]

[0019]

[0020] This invention also provides a method for preparing the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts as described above. The method for preparing the pyrimidine derivatives containing cyclopropanesulfonylamino includes the following steps:

[0021] The pyrimidine compound shown in Formula 1 and the compound shown in Formula 2 undergo a first reaction under the action of an acid-binding agent to obtain the compound shown in Formula 3.

[0022] The compound shown in Formula 3 and cyclopropylsulfonyl chloride undergo a second reaction under the action of an acid-binding agent to obtain the compound shown in Formula 4.

[0023] The compounds shown in Formula 4 and Formula 5 undergo a third reaction under the action of an adjuvant to obtain the pyrimidine derivative containing cyclopropanesulfonylamino.

[0024]

[0025] Preferably, in the first reaction, the molar ratio of the pyrimidine compound shown in Formula 1 to the compound shown in Formula 2 is 1 to 1.5:1; the molar ratio of the pyrimidine compound shown in Formula 1 to the acid-binding agent is 1:1 to 3; the acid-binding agent includes one or more of diisopropylethylamine, triethylamine, and sodium hydride; the temperature of the first reaction is 80 to 90°C, and the time is 2 to 6 hours.

[0026] In the second reaction, the molar ratio of the compound shown in Formula 3 to cyclopropylsulfonyl chloride is 1:1 to 1.2, the molar ratio of the compound shown in Formula 3 to the acid-binding agent is 1:1 to 3, the acid-binding agent is pyridine, the temperature of the second reaction is 15 to 40°C, and the time is 10 to 24 h.

[0027] In the third reaction, the molar ratio of the compound shown in Formula 4 to the compound shown in Formula 5 is 1-1.5:1-1.5, the molar ratio of the compound shown in Formula 4 to the auxiliary agent is 1:3-5, the auxiliary agent is one or more of trifluoroacetic acid, hydrochloric acid, sulfonic acid and methanesulfonic acid, the temperature of the third reaction is 80-90°C, and the time is 24-48h.

[0028] The present invention also provides the application of the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts as described in the above technical solutions, or the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts prepared by the preparation method described in the above technical solutions, in the preparation of antitumor drugs.

[0029] Preferably, the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts are used in the form of solvates.

[0030] Preferably, the dosage form of the antitumor drug includes injections, tablets, capsules, pills, suspensions, or emulsions.

[0031] This invention provides a pyrimidine derivative containing cyclopropanesulfonylamino and its pharmaceutically acceptable salt, wherein the pyrimidine derivative containing cyclopropanesulfonylamino has the structure shown in Formula I. The pyrimidine derivative of this invention is a pyrimidine derivative with cyclopropanesulfonylamino substitution on ring A and no alkoxy substitution on ring C. These active molecules can more effectively inhibit EGFR after resistance to the third-generation targeted drug osimertinib. C797S Mutations can also significantly inhibit EGFR single or double mutations (L858R, del 19, T790M, etc.). Data from the examples show that the pyrimidine derivatives containing cyclopropanesulfonylamino groups in this invention inhibit EGFR triple mutations, such as EGFR... L858R / T790M / C797S and EGFR double mutation EGFR L858R / T790M Anti-tumor experiments at the tumor cell and animal levels have demonstrated that it has excellent anti-tumor growth effects.

[0032] The present invention also provides a method for preparing the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts as described in the above technical solution. The preparation method provided by the present invention has the advantages of simple synthesis process and low cost. Attached Figure Description

[0033] Figure 1 The graph shows the growth of tumors in nude mice in each treatment group and the control group. Detailed Implementation

[0034] This invention provides a pyrimidine derivative containing cyclopropanesulfonylamino and a pharmaceutically acceptable salt thereof, wherein the pyrimidine derivative containing cyclopropanesulfonylamino has the structure shown in Formula I:

[0035]

[0036] In Formula I, R1 is hydrogen, halogen atom, alkyl, substituted alkyl, alkoxycarbonyl or substituted alkoxycarbonyl; the number of carbon atoms of the alkyl and substituted alkyl is 1 to 4; the substituted alkyl or substituted alkoxycarbonyl is in which the hydrogen atom on the saturated carbon atom is replaced by a deuterium or halogen atom;

[0037] R2 is a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, an amino group, a substituted amino group, an alkylamide group, or a substituted alkylamide group; the alkyl group and the substituted alkyl group have 1 to 4 carbon atoms; the alkylamide group or the substituted alkylamide group has 1 to 4 carbon atoms; the substituted alkyl group, the substituted amino group, and the substituted alkylamide group are saturated carbon atoms in which hydrogen atoms are replaced by deuterium.

[0038] R3 is a chain alkyl, chain heteroalkyl, substituted chain heteroalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl; the number of atoms of the chain alkyl, chain heteroalkyl, and substituted chain heteroalkyl is 2 to 4, and the number of atoms of the cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl is 3 to 7; the heteroatom of the chain heteroalkyl, substituted chain heteroalkyl, heterocycloalkyl, and substituted heterocycloalkyl is nitrogen, oxygen, or sulfur; the substituted chain heteroalkyl is a group in which the hydrogen atom on the carbon or nitrogen atom is replaced by an alkyl, substituted alkyl, unsaturated hydrocarbon group, or substituted unsaturated hydrocarbon group. The saturated hydrocarbon group is substituted, wherein the substituted cycloalkyl and substituted heterocycloalkyl are in which the hydrogen atom on the carbon atom or nitrogen atom of the ring skeleton is replaced by an alkyl, substituted alkyl, unsaturated hydrocarbon group or substituted unsaturated hydrocarbon group; the number of carbon atoms of the alkyl, substituted alkyl, unsaturated hydrocarbon group or substituted unsaturated hydrocarbon group is 1 to 4; the hydrogen atom of the substituted alkyl and substituted unsaturated hydrocarbon group is replaced by deuterium; the hydrogen atom on the carbon atom of the substituted cycloalkyl and substituted heterocycloalkyl are in which the hydrogen atom of the carbon atom of the ring skeleton is replaced by an amino, substituted amino, mercapto or substituted mercapto; the hydrogen atom of the substituted amino and substituted mercapto is replaced by an alkyl or deuterated alkyl group.

[0039] In this invention, R1 is preferably a halogen atom, which is preferably fluorine, chlorine or bromine, and more preferably chlorine or bromine.

[0040] In this invention, R2 is preferably hydrogen, a halogen atom, methyl, substituted methyl, ethyl, substituted ethyl, amino, acetamino, or substituted acetamino; the substituted methyl, substituted ethyl, and substituted acetamino are hydrogen atoms on saturated carbon atoms that are substituted with deuterium; the halogen is preferably fluorine, chlorine, or bromine, and more preferably chlorine; R2 is more preferably hydrogen, chlorine, methyl, or -CD3.

[0041] In this invention, R3 is preferably a substituted chain heteroalkyl or a substituted heterocyclic alkyl, wherein the number of atoms of the substituted heterocyclic alkyl is preferably 6 to 7, and the heteroatom of the substituted chain heteroalkyl and the substituted heterocyclic alkyl is preferably nitrogen; wherein the hydrogen atom on the nitrogen atom of the substituted heterocyclic alkyl is preferably replaced by methyl, ethyl, deuterated methyl, deuterated ethyl or -N(CH3)2; wherein the hydrogen atom on the nitrogen atom of the substituted chain heteroalkyl is preferably replaced by methyl, ethyl, deuterated methyl or deuterated ethyl.

[0042] In this invention, the pharmaceutically acceptable salt of the pyrimidine derivative containing cyclopropanesulfonylamino is preferably a salt formed by the pyrimidine derivative containing cyclopropanesulfonylamino with chloride ions, methanesulfonate ions or organic acid ions.

[0043] In this invention, the pyrimidine derivative containing cyclopropanesulfonylamino has the following structure:

[0044]

[0045]

[0046] The pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts provided by this invention are effective against EGFR triple-mutated tumor cells such as Baf3-EGFR. L858R / T790M / C797S It has excellent inhibitory effects on cell proliferation, and is also effective against human EGFR double-mutant tumor cells such as H1975. L858R / T790M It also has good inhibitory activity.

[0047] This invention also provides a method for preparing the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts as described above. The method for preparing the pyrimidine derivatives containing cyclopropanesulfonylamino includes the following steps:

[0048] The pyrimidine compound shown in Formula 1 and the compound shown in Formula 2 undergo a first reaction under the action of an acid-binding agent to obtain the compound shown in Formula 3.

[0049] The compound shown in Formula 3 and cyclopropylsulfonyl chloride undergo a second reaction under the action of an acid-binding agent to obtain the compound shown in Formula 4.

[0050] The compounds shown in Formula 4 and Formula 5 undergo a third reaction under the action of an adjuvant to obtain the pyrimidine derivative containing cyclopropanesulfonylamino.

[0051]

[0052] The pyrimidine compound shown in Formula 1 and the compound shown in Formula 2 undergo a first reaction under the action of an acid-binding agent to obtain the compound shown in Formula 3.

[0053] In this invention, the acid-binding agent preferably includes one or more of diisopropylethylamine, triethylamine, and sodium hydride, and more preferably diisopropylethylamine. In this invention, the reagent for the first reaction is preferably an alcohol solvent, which preferably includes one or more of ethanol, isopropanol, and butanol, and more preferably isopropanol.

[0054] In this invention, the molar ratio of the pyrimidine compound shown in Formula 1 to the compound shown in Formula 2 is preferably 1 to 1.5:1. In this invention, the molar ratio of the pyrimidine compound shown in Formula 1 to the acid-binding agent is preferably 1:1 to 3. The temperature of the first reaction is 80 to 90°C, and the time is 2 to 6 hours.

[0055] In this invention, the temperature of the first reaction is preferably 80–90°C, and the time is preferably 3–5 hours. In this invention, the first reaction is preferably carried out under nitrogen protection.

[0056] After the first reaction, the present invention preferably further includes: cooling the obtained first reaction solution to room temperature, performing vacuum filtration, and washing the filter cake with isopropanol.

[0057] After obtaining the compound shown in Formula 3, the compound shown in Formula 3 of the present invention and cyclopropylsulfonyl chloride undergo a second reaction under the action of an acid-binding agent to obtain the compound shown in Formula 4.

[0058] In this invention, the acid-binding agent is preferably pyridine. In this invention, the solvent for the second reaction preferably includes dichloromethane and / or chloroform, more preferably dichloromethane.

[0059] In this invention, the molar ratio of the compound shown in Formula 3 to cyclopropylsulfonyl chloride is preferably 1:1 to 1.2. In this invention, the molar ratio of the compound shown in Formula 3 to the acid-binding agent is preferably 1:1 to 3.

[0060] In this invention, the temperature of the second reaction is preferably 15–40°C, more preferably 20–35°C; the time is preferably 10–24 h, more preferably 12–16 h. In this invention, the second reaction is preferably carried out under nitrogen protection.

[0061] After the second reaction, the present invention preferably further includes: cooling the obtained second reaction solution to room temperature, filtering by suction, and washing the obtained filter cake with water.

[0062] After obtaining the compound shown in Formula 4, the compound shown in Formula 4 and the compound shown in Formula 5 of the present invention undergo a third reaction under the action of an adjuvant to obtain the pyrimidine derivative containing cyclopropanesulfonylamino.

[0063] In this invention, the auxiliary agent is preferably one or more selected from trifluoroacetic acid, hydrochloric acid, sulfonic acid, and methanesulfonic acid, and more preferably trifluoroacetic acid. In this invention, the third solvent is preferably an alcohol solvent, which preferably includes one or more selected from ethanol, isopropanol, and butanol, and more preferably isopropanol. In this invention, the compound of formula 5 is preferably prepared by a method well known in the art, specifically according to the following preparation formula:

[0064]

[0065] In this invention, the molar ratio of the compound shown in Formula 4 to the compound described in Formula 5 is preferably 1 to 1.5:1 to 1.5. In this invention, the molar ratio of the compound shown in Formula 4 to the auxiliary is preferably 1:3 to 5.

[0066] In this invention, the temperature of the third reaction is preferably 80–90°C, and the time is preferably 24–48 hours. During the third reaction, TLC monitoring is preferably used until the reaction is complete.

[0067] After the third reaction, the present invention preferably further includes: cooling the obtained third reaction solution to room temperature, and then performing concentration and column chromatography purification in sequence.

[0068] In this invention, the preparation reaction formula for the pyrimidine derivative containing cyclopropanesulfonylamino group is as follows:

[0069]

[0070] The present invention also provides the application of the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts as described in the above technical solutions, or the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts prepared by the preparation method described in the above technical solutions, in the preparation of antitumor drugs.

[0071] In this invention, the pyrimidine derivatives containing cyclopropanesulfonylamino and their pharmaceutically acceptable salts are preferably used in the form of solvates, which preferably include hydrates.

[0072] In this invention, the dosage form of the antitumor drug preferably includes injections, tablets, capsules, pills, suspensions, or emulsions. In this invention, the route of administration of the antitumor drug preferably includes oral, spray, transdermal, intravenous, or intramuscular injection.

[0073] In this invention, the antitumor drug preferably also includes pharmaceutically acceptable adjuvants. This invention does not specifically limit the types and amounts of the acceptable adjuvants; those skilled in the art can set them according to actual needs.

[0074] The following detailed description, in conjunction with embodiments, illustrates the pyrimidine derivatives containing cyclopropanesulfonylamino groups provided by the present invention, their preparation methods, and their applications. However, these descriptions should not be construed as limiting the scope of protection of the present invention.

[0075] Example 1. Synthesis of target compound 1

[0076]

[0077] (1) Synthesis of intermediate 3

[0078]

[0079] 2,4-Dichloro-5-bromopyrimidine (6.83 g, 30 mmol), o-phenylenediamine (3.24 g, 30 mmol), and DIPEA (diisopropylethylamine, 8.52 g, 66 mmol) were placed in 60 mL of isopropanol under nitrogen protection and reacted at 85 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with isopropanol to give 8 g of white solid, with a yield of 89.1%. 1HNMR (600MHz, DMSO-d6) δ8.79(s,1H),8.34(s,1H),7.05-6.97(m,2H),6.76(dd,J=8.1,1.4Hz,1H),6.57(td,J=7.5,1.4Hz,1H),5.06-4.82(m,2H).

[0080] (2) Synthesis of intermediate 4

[0081]

[0082] Intermediate 3 (7.48 g, 25 mmol), cyclopropylsulfonyl chloride (3.86 g, 27.5 mmol), and pyridine (5.93 g, 75 mmol) were placed in 15 mL of dichloromethane under nitrogen protection and reacted at room temperature for 16 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with water to give 9.3 g of white solid, with a yield of 92%. 1 H NMR(600MHz,Chloroform-d)δ8.53(s,1H),8.33(s,1H),8.13(dd,J=8.3,1.4Hz,1H),7.47-7.37(m,2H),7.23(td, J=7.7,1.4Hz,1H),6.29(s,1H),2.53(tt,J=8.0,4.8Hz,1H),1.15(ddd,J=5.8,4.7,1.8Hz,2H),1.09-0.99(m,2H).

[0083] (3) Synthesis of aniline derivative intermediate 5

[0084] a. Synthesis of intermediate 5a

[0085]

[0086] Pinaryl 2-fluoro-5-nitrophenylboronic acid (8.01 g, 30 mmol), deuterated iodomethane (10.0 g, 30 mmol), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine(II) (0.63 g, 0.9 mmol) were placed in 60 mL of DMF. 11 mL of an aqueous solution containing cesium fluoride (11.32 g, 75 mmol) was added. The mixture was reacted under nitrogen protection at 45 °C for 24 h. After cooling to room temperature, the mixture was extracted three times with 100 mL of ethyl acetate. The organic phase was concentrated and purified by column chromatography to give 3.7 g of a white solid, yield 78.03%. MS (ESI): 159.1 [M+H] + .

[0087] b. Synthesis of intermediate 5b

[0088]

[0089] Intermediate 5a (3.16 g, 20 mmol) and anhydrous piperazine (4.30 g, 50 mmol) were placed in 50 mL of acetonitrile under nitrogen protection and reacted at 85 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and purified by column chromatography to give 3.7 g of a yellow solid, yield 82.5%. MS (ESI): 226.59.

[0090] c. Synthesis of intermediate 5c

[0091]

[0092] Intermediate 5b (3.25 g, 14.5 mmol), deuterated methanol p-toluenesulfonate (3.6 g, 19 mmol), and cesium carbonate (9.1 g, 28 mmol) were placed in 30 mL of DMF under nitrogen protection and reacted at 90 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, extracted three times with 100 mL of dichloromethane, and purified by column chromatography to give 1.8 g of a yellow solid, yield 51.44%. MS (ESI): 243.65.

[0093] d. Synthesis of intermediate 5d

[0094]

[0095] Intermediate 5c (1.68 g, 7 mmol) and palladium / carbon (0.33 g, 0.2 wt) were placed in 50 mL of methanol, purged with hydrogen, and reacted at room temperature for 10 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the reaction solution was concentrated to give 1.4 g of white solid, yield 94.7%. MS (ESI): 213.52.

[0096] (4) Synthesis of target compound 1

[0097]

[0098] Intermediate 4 (0.40 g, 1 mmol), intermediate 5d (0.21 g, 1 mmol), and 0.5 mL of trifluoroacetic acid were placed in 30 mL of isopropanol under nitrogen protection and reacted at 85 °C for 24 h. The reaction was monitored by TLC until completion. After cooling to room temperature, the reaction solution was concentrated and purified by column chromatography to give 0.37 g of a white solid, with a yield of 70.83%. 1H NMR(600MHz,Chloroform-d)δ8.04(s,1H),7.82(dd,J=8.0,1.5Hz,1H),7.75(s,1H),7.47(d d,J=7.9,1.5Hz,1H),7.30(td,J=7.7,1.6Hz,1H),7.23(td,J=7.7,1.5Hz,2H),7.18(d,J=2. 7Hz,1H),7.13(dd,J=8.5,2.7Hz,1H),7.08-7.05(m,1H),6.83(d,J=8.6Hz,1H),2.83(t,J=4 .8Hz,4H),2.51(d,J=50.8Hz,4H),2.46-2.40(m,1H),1.12-1.03(m,2H),0.95-0.89(m,2H). MS(ESI)m / z:577.1.

[0099] Example 2. Synthesis of target compound 2

[0100]

[0101] The same method as in Example 1 was used, except that 2,4,5-trichloropyrimidine was used instead of 2,4-dichloro-5-bromopyrimidine in the preparation of intermediate 3; and p-nitrofluorobenzene was used instead of intermediate 5a in the preparation of intermediate 5d. 1 HNMR(600MHz,DMSO-d6)δ9.41-9.29(m,1H),9.14(s,1H),8.51(s,1H),8.13(s,1H),8.10-8.04(m,1H),7.46-7.38(m,3H),7.33(td,J=7.8,1.6 Hz,1H),7.21(td,J=7.6,1.5Hz,1H),6.78(d,J=8.6Hz,2H),3.04(t,J=5.0Hz,4H),2.56-2.51(m,1H),2.47(t,J=5.0Hz,4H),0.91-0.81(m,4H). MS(ESI)m / z:516.7.

[0102] Example 3. Synthesis of target compound 3

[0103]

[0104] The target compound was obtained by using the same method as in Example 2, but by replacing the deuterated methyl p-toluenesulfonate with deuterated ethyl p-toluenesulfonate, thus obtaining target compound 3. 1H NMR (600MHz, DMSO-d6) δ9.42(s,1H),9.14(s,1H),8.51(s,1H),8.13(s,1H),8.10-7.99(m,1H),7.41(dt,J=8.7,2.6Hz,3H),7.33(td,J=7.7,1. 6Hz,1H),7.21(td,J=7.6,1.5Hz,1H),6.78(d,J=8.7Hz,2H),3.06(t,J= 5.0Hz, 4H), 2.57 (t, J = 4.8Hz, 4H), 2.54-2.51 (m, 1H), 0.91-0.81 (m, 4H). MS(ESI)m / z:532.7.

[0105] Example 4. Synthesis of target compound 4

[0106]

[0107] The same method as in Example 1 was used. The target compound 4 was obtained by replacing intermediate 5a in Example 1 with p-nitrofluorobenzene. 1 H NMR (600MHz, DMSO-d6) δ9.37(d,J=4.1Hz,1H),9.28(s,1H),8.47(s,1H),8.23(d,J=3.9 Hz,1H),8.06(s,1H),7.49-7.40(m,3H),7.36(td,J=7.7,1.6Hz,1H),7.22(td,J=7.7,1 .6Hz,1H),6.85(d,J=8.5Hz,2H),3.70(d,J=13.1Hz,2H),3.50(d,J=12.1Hz,2H),3.14( d,J=9.5Hz,2H),2.94-2.87(m,2H),2.54(dq,J=8.0,4.8,4.1Hz,1H),0.95-0.82(m,4H). MS(ESI)m / z:560.15.

[0108] Example 5. Synthesis of target compound 5

[0109]

[0110] The same method as in Example 2 was used. In the preparation of intermediate 5, 3-chloro-4-fluoronitrobenzene was used instead of p-nitrofluorobenzene, which was then reacted with N-methylpiperazine and the nitro group was reduced. 1H NMR(600MHz,Chloroform-d)δ8.05(s,1H),7.87(s,1H),7.82(dd,J=8.1,1.4Hz,1H), 7.58(d,J=2.6Hz,1H),7.47(dd,J=7.9,1.5Hz,1H),7.44-7.31(m,2H),7.24(dd,J=7.6 ,1.5Hz,2H),7.09(dd,J=8.7,2.6Hz,1H),6.79(d,J=8.6Hz,1H),3.06(m,4H),2.88(m ,4H),2.57(s,3H),2.53-2.42(m,1H),1.12(dt,J=7.2,3.6Hz,2H),1.04-0.91(m,2H).

[0111] Example 6. Synthesis of target compound 6

[0112]

[0113] Using the same method as in Example 5, 2,4-dichloro-5-bromopyrimidine was used instead of 2,4,5-trichloropyrimidine in the preparation of intermediate 3 to obtain target compound 6. 1 H NMR(600MHz,Chloroform-d)δ8.10(s,1H),8.00(s,1H),7.76(dd,J=8.0,1.5Hz,1H),7.49(dd,J= 7.9,1.6Hz,1H),7.46-7.42(m,1H),7.34(td,J=7.8,1.6Hz,1H),7.28(dd,J=7.7,1.5Hz,2H),7.2 6(d,J=1.5Hz,1H),7.20(dd,J=8.7,2.6Hz,1H),6.76(d,J=8.7Hz,1H),3.35-2.98(m,8H),2.86(s ,3H), 2.54(tt,J=8.0,4.8Hz,1H), 1.12(qd,J=5.7,1.0Hz,2H), 1.00(ddd,J=7.7,4.4,3.2Hz,2H).

[0114] Example 7. Synthesis of target compound 7

[0115]

[0116] The target compound 7 was prepared using the same method as in Example 1, except that 3-methyl-4-fluoro-nitrobenzene was used to replace intermediate 5a in the preparation of intermediate 5. 5a was directly reacted with 4-(N,N-dimethyl)aminopiperidine and then the nitro group was reduced. 1H NMR(500MHz,DMSO-d6)δ11.20(s,1H),10.30(s,1H),9.41(s,1H),9.26(s,1H),8.42(s,1H ),7.77(s,1H),7.52-7.48(m,1H),7.36-7.31(m,2H),7.17(d,J=6.9Hz,1H),6.97(s,1H),3 .30(s,1H),3.19(d,J=6.1Hz,2H),2.81(d,J=35.2Hz,2H),2.73(d,J=4.6Hz,6H),2.57-2. 52(m,1H),2.51(s,3H),2.21-2.17(m,2H),2.02-1.90(m,2H),0.87-0.84(m,J=4.4Hz,4H). 13 C NMR (126MHz, DMSO) δ158.59,154.29,150.95,133.37,132.71,131.42,131.31,127.78,127.7 6,127.25,127.04,122.97,119.96,118.92,93.24,61.93,51.40,29.88,25.96,18.31,5.66.

[0117] Example 8. Synthesis of target compound 8

[0118]

[0119] The synthesis of target compound 8 can be performed using the same method as in Example 7, except that 2,4-dichloro-5-bromopyrimidine can be replaced with 2,4,5-trichloropyrimidine. 1 H NMR(400MHz,DMSO-d6)δ10.58(s,1H),9.78(s,1H),9.35(s,1H),8.26(s,1H),7.84(d,J =8.3Hz,1H),7.47(dd,J=7.6,1.7Hz,1H),7.36-7.26(m,2H),7.21(d,J=9.9Hz,1H),6.91 (s,1H),3.44(q,J=7.0Hz,1H),3.32-3.20(m,2H),3.19-3.08(m,2H),2.75(d,J=5.0Hz, 6H),2.68-2.67(m,2H),2.13(s,3H),2.10(s,1H),1.92-1.76(m,2H),0.86-0.84(m,4H). 13C NMR (101MHz, DMSO) δ181.46,158.15,132.70,131.72,127.55,127.39,127.25,127.0 6,122.80,119.92,118.75,104.96,61.87,51.43,39.46,29.96,26.12,18.33,5.62.

[0120] Example 9. Synthesis of target compound 9

[0121]

[0122] Using the same method as in Example 5, 3-chloro-4-fluoronitrobenzene was replaced with p-nitrofluorobenzene. 1 HNMR(400MHz,DMSO-d6)δ9.22(s,1H),8.53(s,1H),8.16(s,1H),8.03(d,J=8.1Hz,1H),7.46-7.38(m,2H),7.31 (dtd,J=16.5,8.7,8.1,2.1Hz,2H),7.22(td,J=7.6,1.5Hz,1H),6.92(d,J=8.7Hz,1H),3.32-3.25(m,2H),3.22

[0123] -3.17(m,3H),3.01(t,J=6.1Hz,2H),2.76(s,6H),2.57-2.51(m,1H),2.01(dt,J=11.3,4.6Hz,2H),0.91-0.81(m,J=14.9,4.9,2.3Hz,4H). 13 C NMR (101MHz, DMSO) δ158.27,156.08,155.07,147.29,136.25,135.11,132.83,129.32,128.46,127.58,125. 53,125.13,121.85,121.47,118.12,104.25,58.01,55.31,53.95,51.50,44.83,29.60,25.68,18.88,5.61.

[0124] Example 10. Synthesis of target compound 10

[0125]

[0126] Intermediate 5 can be prepared by replacing 3-chloro-4-fluoronitrobenzene with p-nitrofluorobenzene, following the same method as in Example 1 and referring to the method in Example 5. 1H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.44(s,1H),8.16(s,2H),7.39(d,J=7.2Hz,1H),7.29(dd,J=15.8,7.5Hz,3H),7.14(t,J=6.9Hz,1H),6.57(d,J= 7.8Hz,2H),3.50(d,J=9.9Hz,4H),2.66(s,2H),2.50(s,6H),1.99(d,J=21. 1Hz,1H),1.91(d,J=4.9Hz,2H),1.16(d,J=11.7Hz,1H),0.92-0.85(m,4H). 13 C NMR (101MHz, DMSO) δ159.14,159.04,157.72,156.34,145.02,135.62,129.30,128.09,128.04,127. 00,124.36,122.52,122.40,111.66,70.26,57.55,56.75,48.46,48.30,46.33,29.61,27.21,5.65.

[0127] Example 11. Synthesis of target compound 11

[0128]

[0129] The target compound 11 was synthesized using the same method as in Example 1, but with N-methylperiperazine used as the starting material instead of N-methylperiperazine. 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.44(s,1H),9.39(s,1H),8.68(s,1H),8.2 4(s,1H),8.04(s,1H),7.43(d,J=7.7Hz,1H),7.36-7.30(m,2H),7.24(t,J=7.5Hz, 1H),6.63(d,J=8.4Hz,2H),3.68-3.63(m,2H),3.49-3.38(m,4H),3.19-3.05(m,2H ),2.79(d,J=3.6Hz,3H),2.58-2.54(m,1H),2.33-2.14(m,2H),0.99-0.80(m,4H). 13CNMR(101MHz,DMSO)δ158.88,157.65,156.47,146.79,135.28,132.62,129.79,127.69, 126.58,124.61,121.25,116.71,93.07,70.26,62.01,49.33,41.70,29.71,28.12,5.61.

[0130] Example 12. Synthesis of target compound 12

[0131]

[0132] The synthesis of target compound 12 was carried out using the same method as in Example 11, except that 2,4,5-trichloropyrimidine was used to replace 2,4-dichloro-5-bromopyrimidine to prepare intermediate 4. 1 H NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.48(s,1H),8.12(s,2H),7.47-7.26( m,4H),7.20(td,J=7.6,1.5Hz,1H),6.63(d,J=8.7Hz,2H),3.65(t,J=4.6Hz ,2H),3.40(t,J=6.2Hz,2H),3.32-3.26(m,2H),3.23(d,J=5.6Hz,2H),2.80 (s,3H),2.55(dt,J=9.3,4.6Hz,1H),2.18-2.07(m,2H),0.96-0.82(m,4H). 13 C NMR(101MHz,DMSO)δ158.51,155.88,155.04,144.32,135.43,130.64,128.70,128.61,127.68,1 25.21,124.82,121.91,112.32,103.71,56.98,55.80,47.50,45.01,44.14,29.55,24.64,5.65.

[0133] Example 13. Synthesis of target compound 13

[0134]

[0135] The synthesis of target compound 13 can be carried out using the same method as in Example 1, except that intermediate 5a is replaced by 3-methyl-4-fluoronitrobenzene and N-methylperiperazine is used as the starting material to replace N-methylperiperazine. 1H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.96(s,1H),7.85(d,J=7.9Hz,1H),7.48(d,J=7.7Hz ,1H),7.39(s,1H),7.31(t,J=7.1Hz,1H),7.24(dd,J=13.1,5.4Hz,2H),7.15(d,J=8.5Hz,2H),6 .81(d,J=8.2Hz,1H),3.21(t,J=5.1Hz,4H),3.10(t,J=4.4Hz,2H),3.00(t,J=6.2Hz,2H),2.71( s,3H),2.50(tt,J=8.1,4.6Hz,1H),2.13(d,J=4.0Hz,3H),2.11-2.02(m,2H),1.11-0.92(m,4H). 13 C NMR (101MHz, CDCl3) δ158.11,156.97,156.91,147.58,135.26,135.20,133.54,129.25,128.49,127.86,125 .84,125.67,121.96,121.90,118.23,93.63,58.98,55.64,53.91,51.78,45.23,29.63,25.62,18.52,5.70.

[0136] Example 14. Synthesis of target compound 14

[0137]

[0138] The target compound 14 was synthesized using the same method as in Example 2, with N,N,N-trimethylethylenediamine used as the starting material instead of N-methylpiperazine. 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.82(s,1H),9.39(s,1H),9.12(s,1H),8.25( s,1H),7.88(d,J=7.8Hz,1H),7.47(dd,J=7.9,1.6Hz,1H),7.38(td,J=7.7,1.6Hz,1H ),7.32-7.28(m,2H),6.72(d,J=8.5Hz,2H),3.68(t,J=7.5Hz,2H),3.17(t,J=7.5Hz ,2H),2.87(s,3H),2.80(s,6H),2.56-2.52(m,J=4.8,2.7Hz,1H),0.90-0.84(m,4H). 13CNMR(101MHz,DMSO)δ159.25,158.90,157.27,145.03,133.66,130.76,130.47,129.55,127.88,1 27.36,126.61,126.35,122.42,117.88,113.54,104.28,52.83,47.53,42.86,38.94,29.77,5.65.

[0139] Example 15. Synthesis of target compound 15

[0140]

[0141] The synthesis of target compound 15 was carried out using the same method as in Example 1, except that intermediate 5a was replaced with 4-fluoro-nitrobenzene and piperazine was replaced with N,N,N-trimethylethylenediamine as the starting material. 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),9.86(s,1H),9.40(s,1H),8.96(s,1H ),8.31(s,1H),7.91(s,1H),7.46(dd,J=7.9,1.4Hz,1H),7.38(td,J=7.8,1. 5Hz,1H),7.30(d,J=6.4Hz,2H),6.72(d,J=8.1Hz,2H),3.74-3.63(m,2H),3 .17(s,2H),2.88(s,3H),2.80(s,6H),2.59-2.54(m,1H),0.95-0.81(m,4H). 13 CNMR(101MHz,DMSO)δ159.26,158.91,157.77,155.58,145.08,134.21,129.46,128.15,127.52,1 26.22,126.18,122.55,117.89,114.98,113.51,92.77,52.82,47.51,42.86,38.93,29.71,5.69.

[0142] Example 16. Synthesis of target compound 16

[0143]

[0144] The synthesis of target compound 16 was carried out using the same method as in Example 2, except that 3-methyl-4-fluoronitrobenzene was used as the starting material instead of 4-fluoronitrobenzene, and N,N,N-trimethylethylenediamine was used as the reagent to introduce the R3 group. 1H NMR(400MHz,Chloroform-d)δ7.90(dt,J=9.1,3.7Hz,3H),7.52-7.41(m,1H),7.34-7.17(m,5H),7.13(td,J=8.8,2.6Hz,1H),6.89(t,J=8.7Hz,1H),2.9 6(q,J=7.9Hz,2H),2.60(s,3H),2.48-2.43(m,2H),2.42(d,J=8.7Hz,1H),2 .24(s,6H),2.15(s,3H),1.07(dt,J=8.6,3.3Hz,2H),0.90(t,J=6.7Hz,2H). 13 C NMR (101MHz, CDCl3) δ157.82,156.21,154.29,147.22,134.93,134.50,133.91,129.01,128.40,127. 92,125.51,125.36,122.46,120.33,118.15,104.84,57.40,54.54,45.75,42.84,29.85,18.29,5.74.

[0145] Example 17. Synthesis of target compound 17

[0146]

[0147] The synthesis of target compound 17 was carried out using the same method as in Example 16, except that 2,4,5-trichloropyrimidine 4 was replaced with 2,4-dichloro-5-bromopyrimidine in the synthesis of intermediate 4. 1 HNMR(400MHz,Chloroform-d)δ7.99(s,1H),7.87-7.79(m,2H),7.47(d,J=7.7Hz,1H),7.31(t,J=7.6Hz,1H),7.27-7.19(m,3H),7.13(d,J=8. 2Hz,1H),6.90(d,J=8.4Hz,1H),3.02-2.88(m,2H),2.62(s,3H),2.48- 2.42(m,2H),2.27(s,6H),2.17(s,3H),2.10(s,1H),1.09-0.89(m,4H). 13C NMR (101MHz, CDCl3) δ158.30,157.10,156.89,147.24,134.97,134.43,133.92,129.23,128.32,127. 90,125.66,125.55,122.50,120.33,118.20,93.53,57.38,54.52,45.74,42.85,29.93,18.28,5.75.

[0148] Example 18. Synthesis of target compound 18

[0149]

[0150] Using the same method as in Example 1, N-methylperiperazine was substituted for N-deuterated methylperiperazine to obtain target compound 18. 1 H NMR(400MHz,Chloroform-d)δ8.05(s,1H),7.93(s,1H),7.83(d,J=7.9Hz,1H),7.49(d,J=7.7Hz, 1H),7.38(s,1H),7.31(t,J=7.1Hz,1H),7.23(dd,J=13.1,5.4Hz,2H),7.14(d,J=8.5Hz,2H),6.8 0(d,J=8.2Hz,1H),3.22(t,J=5.1Hz,4H),3.11(t,J=4.4Hz,2H),3.01(t,J=6.2Hz,2H),2.71(s,3 H), 2.49 (tt, J = 8.1, 4.6Hz, 1H), 2.11-2.02 (m, 2H), 1.51-1.15 (m, 4H). HRMS (ESI) m / z: 588.1769.

[0151] Example 19. Synthesis of target compound 19

[0152]

[0153] Using the same method as in Example 1, N-deuterated methylpiperazine was substituted for N-deuterated methylpiperazine to obtain target compound 19. 1H NMR(400MHz,Chloroform-d)δ8.09(s,1H),7.91(s,1H),7.82(d,J=7.9Hz,1H),7.46(d,J= 7.7Hz,1H),7.41(s,1H),7.30(t,J=7.1Hz,1H),7.27(dd,J=13.1,5.4Hz,2H),7.13(d,J=8. 5Hz,2H),6.79(d,J=8.2Hz,1H),3.18(t,J=5.1Hz,4H),3.11(t,J=4.4Hz,2H),3.02(t,J=6 .2Hz,2H),2.52(tt,J=8.1,4.6Hz,1H),2.12(s,3H),2.17-2.05(m,2H),1.16-1.06(m,4H). HRMS(ESI)m / z:588.1763.

[0154] Example 20. Synthesis of target compound 20

[0155]

[0156] Using the same method as in Example 18, 2,4-dichloro-5-bromopyrimidine was substituted with 2,4,5-trichloropyrimidine to obtain target compound 20. 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.41(s,1H),8.15(s,2H),7.49-7.21( m,4H),7.22(td,J=7.6,1.5Hz,1H),6.60(d,J=8.7Hz,2H),3.62(t,J=4.6Hz ,2H),3.41(t,J=6.2Hz,2H),3.30-3.21(m,2H),3.21(d,J=5.6Hz,2H),2.79 (s,3H),2.53(dt,J=9.3,4.6Hz,1H),2.16-2.05(m,2H),1.15-0.92(m,4H). HRMS(ESI)m / z:544.2215.

[0157] Example 21. Synthesis of target compound 21

[0158]

[0159] Using the same method as in Example 1, the target compound was obtained by replacing intermediate 5a with 4-nitrofluorobenzene and replacing N-deuterated methylpiperazine with N-deuterated methylpiperazine. 1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.92(s,1H),7.79(d,J=7.9Hz,1H),7.45(d ,J=7.7Hz,1H),7.38(s,1H),7.32(t,J=7.1Hz,1H),7.26(dd,J=13.1,5.4Hz,2H),7.11( d,J=8.5Hz,2H),6.77(d,J=8.2Hz,1H),3.16(t,J=5.1Hz,4H),3.13(t,J=4.4Hz,2H),3. 01(t,J=6.2Hz,2H),2.52(tt,J=8.1,4.6Hz,1H),2.17-2.05(m,2H),1.13-1.03(m,4H). HRMS(ESI)m / z:574.1562.

[0160] Synthesis of the control compound

[0161]

[0162] The preferred compound for comparison was synthesized according to the method disclosed in Chinese Patent Publication No. CN110740999A.

[0163] Example of tumor cell proliferation inhibition experiment

[0164] This experiment used the MTT assay to test the inhibitory activity of the target compounds on cell proliferation in the Ba / F3 Del19 / T790M / C797SEGFR triple mutant cell lines, the Ba / F3 L858R / T790M / C797S EGFR triple mutant cell line, the H1975 L858R / T790M double mutant cell line, and the PC9 single mutant cell line. The Ba / F3 Del19 / T790M / C797S EGFR triple mutant cells were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.; the double mutant human cancer cell lines (H1975, PC9) were purchased from Genio Biotechnology Co., Ltd. (Guangzhou, China) and identified by cell gene sequencing.

[0165] The tumor cells used were cultured in RPMI 1640 medium containing 10% FBS, 100 units / mL penicillin, and 100 μg / mL streptomycin. All cells were incubated at 37°C in a 5% CO2 atmosphere. Mycoplasma contamination tests were negative.

[0166] Tumor cells (5×10) 3Cells per well were seeded into 96-well sterile culture plates and incubated overnight. The plates were then treated with different concentrations of the drug (10, 1, 0.1, 0.05, 0.01, and 0.001 μM). After 48 hours of culture, MTT was added to each well, and the plates were incubated for 40 minutes. Chemiluminescence signals were detected using a PerkinElmer microplate reader. Data analysis was performed using GraphPad Prism 8 software to determine the half-maximal inhibitory concentration (IC50) of the compound and the positive control. 50 Value. The target compound's effect on triple-mutated tumor cells Ba / F3 (EGFR) Ba / F3Del19 / T790M / C797S ) and Ba / F3 (EGFR L858R / T790M / C797S The inhibitory activity against tumor cells is shown in Table 1.

[0167] Table 1. Inhibitory activity of compounds against EGFR triple-mutant tumor cells.

[0168]

[0169]

[0170] As can be seen from Table 1, the antitumor compound provided by the present invention, due to the replacement of the methylsulfonyl group in the control example with a cyclopropanesulfonyl group in the A ring, the removal of the alkoxy group in the C ring, and the deuteration strategy, has significantly improved the antitumor cell proliferation activity compared with the control example, producing unexpected effects.

[0171] Some of the target compounds are effective against double-mutant tumor cells H1975 (EGFR). L858R / T790M The inhibitory activity of EGFR single-mutant tumor cells PC3 on PC3 is shown in Table 2.

[0172] Table 2 shows the inhibitory activity of some compounds on the proliferation of EGFR double-mutant and single-mutant tumor cells.

[0173]

[0174]

[0175] *NT indicates that it has not been tested.

[0176] As shown in Table 2, the antitumor active compound provided by this invention not only exhibits excellent antiproliferative effects against EGFR triple-mutated tumor cells, but also shows good efficacy against EGFR double-mutated human tumor cells such as H1975 and EGFR single-mutated tumor cells PC9. Since the occurrence of EGFR mutations in tumor cells is a gradual process, meaning that EGFR double and triple mutations may coexist within a certain timeframe, the antitumor active molecule provided by this invention, which inhibits both EGFR triple and double mutations, has promising application prospects.

[0177] Example of tumor suppression in animals:

[0178] To test the antitumor activity of the target compound in animals, Ba / F3 (EGFR) was used. Ba / F3Del19 / T790M / C797S A tumor model was established subcutaneously in nude mice using tumor cells, and preliminary experiments were conducted using compound 1. The experiment was divided into three groups: a saline group, a compound 1 (40 mg / kg) group, and a brigatinib (25 mg / kg) group. Tumors were classified as tumors when their volume reached 150–200 mm². 3 Mice in each group were administered the drug or saline solution once daily via gavage. Tumor volume and body weight were measured every other day. After 7 days of administration, the experiment was terminated, and the mice were euthanized. Tumor masses were removed, weighed, and the tumor inhibition rate (TGI) was calculated. The experimental results are as follows: Figure 1 As shown. Figure 1 The graph shows the growth of tumors in nude mice in each treatment group and the control group. Figure 1 It can be seen that compound 1, at a dose of 40 mg per kilogram of nude mice, exhibited a tumor inhibition rate (TGI) of 75.1%. The positive control drug brigatinib, at a dose of 25 mg per kilogram of nude mice, showed a tumor inhibition rate (TGI) of 38.9%, which is similar to the results in the literature.

[0179] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pyrimidine derivative containing cyclopropanesulfonylamino and a pharmaceutically acceptable salt thereof, characterized in that, The pyrimidine derivative containing cyclopropanesulfonylamino has the structure shown in Formula I: Equation I; In Equation I, R1 is a halogen atom; R2 is a hydrogen atom, a halogen atom, an alkyl group, or a substituted alkyl group; the number of carbon atoms in the alkyl group and the substituted alkyl group is 1 to 4; the substituted alkyl group is a saturated carbon atom in which hydrogen atoms are replaced by deuterium; R3 is a substituted chain heteroalkyl or a substituted heterocyclic alkyl; the number of atoms of the substituted chain heteroalkyl is 2 to 4, and the number of atoms of the substituted heterocyclic alkyl is 3 to 7; the heteroatom of the substituted chain heteroalkyl and the substituted heterocyclic alkyl is nitrogen; the hydrogen on the carbon atom or nitrogen atom of the substituted chain heteroalkyl is replaced by an alkyl or substituted alkyl, and the hydrogen on the carbon atom or nitrogen atom of the substituted heterocyclic alkyl is replaced by an alkyl or substituted alkyl; the number of carbon atoms of the alkyl and the substituted alkyl is 1 to 4; the hydrogen on the substituted alkyl is replaced by deuterium; the hydrogen on the carbon atom of the substituted heterocyclic alkyl is replaced by an amino or a substituted amino; the hydrogen on the substituted amino is replaced by an alkyl or a deuterated alkyl.

2. The pyrimidine derivative containing cyclopropanesulfonylamino and its pharmaceutically acceptable salt according to claim 1, characterized in that, In R1, the halogen atom is fluorine, chlorine, or bromine.

3. The pyrimidine derivative containing cyclopropanesulfonylamino and its pharmaceutically acceptable salt according to claim 1, characterized in that, R2 is hydrogen, a halogen atom, methyl, substituted methyl, ethyl, or substituted ethyl; wherein the substituted methyl or substituted ethyl is a hydrogen atom on a saturated carbon atom that is replaced by deuterium.

4. The pyrimidine derivative containing cyclopropanesulfonylamino and its pharmaceutically acceptable salt according to claim 1, characterized in that, In R3, the number of atoms of the substituted heterocyclic alkyl group is 6 to 7, and the substituted heterocyclic alkyl group is in which the hydrogen atom on the nitrogen atom of the ring skeleton is replaced by methyl, ethyl, deuterated methyl, deuterated ethyl or -N(CH3)2; the substituted chain heteroalkyl group is in which the hydrogen atom on the nitrogen atom is replaced by methyl, ethyl, deuterated methyl or deuterated ethyl.

5. The pyrimidine derivative containing cyclopropanesulfonylamino and its pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that, The pyrimidine derivative containing cyclopropanesulfonylamino has the following structure: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 6. A method for preparing the pyrimidine derivative containing cyclopropanesulfonylamino and its pharmaceutically acceptable salt as described in any one of claims 1 to 5, characterized in that, The method for preparing the pyrimidine derivative containing cyclopropanesulfonylamino includes the following steps: The pyrimidine compound shown in Formula 1 and the compound shown in Formula 2 undergo a first reaction under the action of an acid-binding agent to obtain the compound shown in Formula 3. The compound shown in Formula 3 and cyclopropylsulfonyl chloride undergo a second reaction under the action of an acid-binding agent to obtain the compound shown in Formula 4. The compounds shown in Formula 4 and Formula 5 undergo a third reaction under the action of an adjuvant to obtain the pyrimidine derivative containing cyclopropanesulfonylamino. Formula 1, Equation 2, Formula 3, Equation 4, Formula 5.

7. The preparation method according to claim 6, characterized in that, In the first reaction, the molar ratio of the pyrimidine compound shown in Formula 1 to the compound shown in Formula 2 is 1~1.5:1; the molar ratio of the pyrimidine compound shown in Formula 1 to the acid-binding agent is 1:1~3; the acid-binding agent includes one or more of diisopropylethylamine, triethylamine and sodium hydride; the temperature of the first reaction is 80~90℃, and the time is 2~6h. In the second reaction, the molar ratio of the compound shown in Formula 3 to cyclopropylsulfonyl chloride is 1:1 to 1.2, the molar ratio of the compound shown in Formula 3 to the acid-binding agent is 1:1 to 3, the acid-binding agent is pyridine, the temperature of the second reaction is 15 to 40°C, and the time is 10 to 24 h. In the third reaction, the molar ratio of the compound shown in Formula 4 to the compound shown in Formula 5 is 1~1.5:1~1.5, the molar ratio of the compound shown in Formula 4 to the auxiliary agent is 1:3~5, the auxiliary agent is one or more of trifluoroacetic acid, hydrochloric acid and methanesulfonic acid, the temperature of the third reaction is 80~90℃, and the time is 24~48h.

8. The use of the pyrimidine derivatives containing cyclopropanesulfonylamino groups as described in any one of claims 1 to 5 and their pharmaceutically acceptable salts in the preparation of antitumor drugs.

9. The application according to claim 8, characterized in that, The dosage forms of the antitumor drugs include injections, tablets, capsules, pills, suspensions, or emulsions.

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