A pyrimidine derivative containing a chiral pyrrolidinyl side chain, and a preparation method and application thereof

Abstract

The present application relates to the technical field of medicine, and provides a pyrimidine derivative containing chiral pyrrolidine in a side chain and a preparation method and application thereof.The pyrimidine derivative containing chiral pyrrolidine in a side chain provided by the present application has a structure shown in formula I.Compared with existing similar antitumor drugs, the pyrimidine derivative containing chiral pyrrolidine in a side chain provided by the present application has better in-vivo and in-vitro activity, small side effects, high safety, stronger blood-brain barrier penetration capacity, and the deuterated target object has better pharmacokinetic properties, and has a wide application prospect in the field of preparing anticancer drugs.Formula I.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a pyrimidine derivative with a chiral pyrrole alkyl side chain, its preparation method, and its application. Background Technology

[0002] c-Met kinase, encoded by the MET proto-oncogene, is a receptor tyrosine kinase and plays a crucial role in normal physiological processes as the only known receptor for hepatocyte growth factor (HGF). Abnormal activation of c-Met kinase disrupts the normal balance of cellular growth regulation, becoming a key factor driving tumor development, progression, and metastasis. Abnormal activation of c-Met kinase is primarily achieved through molecular mechanisms such as gene amplification, gene mutation, protein overexpression, and gene rearrangement. This abnormality is widespread in various malignant tumors, including non-small cell lung cancer (NSCLC), gastric cancer, ovarian cancer, pancreatic cancer, thyroid cancer, breast cancer, colorectal cancer, and renal cancer. Abnormal activation of c-Met kinase is also a significant mechanism by which tumors develop resistance to other targeted therapies. For example, in the treatment of NSCLC with EGFR inhibitors, when the EGFR signaling pathway is inhibited, tumor cells can achieve compensatory growth by activating the c-Met signaling pathway, leading to acquired drug resistance and treatment failure. Therefore, c-Met kinase is an important target for innovative drug development.

[0003] c-Met kinase inhibitors, as targeted therapies, work by blocking the activity of c-Met kinases, inhibiting the transduction of downstream abnormal signaling pathways, thereby suppressing tumor cell proliferation, invasion, and metastasis, and inducing tumor cell apoptosis. Currently, several c-Met kinase inhibitors, such as carmatinib and terpotinib, have been approved for clinical use worldwide for the treatment of metastatic NSCLC patients with MET exon 14 skipping mutations, significantly improving their survival prognosis. Furthermore, combination therapy regimens of c-Met kinase inhibitors with EGFR-TKIs have achieved breakthrough results in EGFR-TKI-resistant NSCLC patients. Examples include clinical trials of carmatinib combined with gefitinib and terpotinib combined with osimertinib, providing new treatment strategies for non-small cell lung cancer patients with acquired resistance.

[0004] Despite the promising prospects of c-Met kinase inhibitors in cancer treatment, several challenges remain, such as drug resistance in some patients, the need for high dosages of certain drugs, the need to improve efficacy, and high levels of side effects. Therefore, the search for novel c-Met kinase inhibitors with good anti-tumor activity and low side effects remains of great significance. Summary of the Invention

[0005] In view of this, the present invention provides a pyrimidine derivative with a chiral pyrrolidinium side chain, its preparation method, and its application. The pyrimidine derivative with a chiral pyrrolidinium side chain provided by the present invention has the characteristics of high activity and few side effects, and has broad application prospects in the field of anticancer drug preparation.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: A pyrimidine derivative with a chiral pyrrolidinium side chain, or a pharmaceutically acceptable salt or solvate thereof, wherein the pyrimidine derivative has the structure shown in Formula I: Formula I; In Formula I: R is hydrogen, alkyl, or substituted alkyl; the number of carbon atoms in the alkyl or substituted alkyl is 1 to 4; the substituent on the substituted alkyl is deuterium or a halogen atom; X is hydrogen or deuterium; R 1 It can be any of the following structures: .

[0007] Preferably, the pyrimidine derivative with a chiral pyrrolidinium side chain has any one of the following structures: .

[0008] Preferably, the anion of the pharmaceutically acceptable salt of the pyrimidine derivative with a chiral pyrroleyl side chain includes any one of chloride, acetate, and methanesulfonate ions.

[0009] Preferably, the solvate of the pyrimidine derivative with a chiral pyrrolidinyl side chain is a hydrate.

[0010] This invention also provides a method for preparing pyrimidine derivatives with chiral pyrroleyl side chains as described above. When R and X in Formula I are hydrogen, the preparation method includes the following steps: (1) 3-hydroxymethylphenylboronic acid, 2-iodo-5-bromopyrimidine, palladium catalyst, sodium carbonate and solvent were mixed and reacted to obtain intermediate 1; (2) The intermediate 1, thionyl chloride and dichloromethane are mixed and reacted to obtain intermediate 2; (3) The intermediate 2, 6-(3-cyanophenyl)-pyridazinone, potassium carbonate and solvent are mixed and reacted to obtain intermediate 3; (4) The intermediate 3, bis(pinacol)diboron, palladium catalyst, potassium acetate and solvent are mixed and reacted to obtain intermediate 4; (5) The intermediate 4, sodium perborate, tetrahydrofuran and water are mixed and reacted to obtain intermediate 5; (6) The intermediate 5, the compound with the structure shown in Formula A, triphenylphosphine, diisopropyl azodicarbonate and solvent are mixed and reacted to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain with the structure shown in Formula I. The structural formulas of intermediates 1 to 5 are shown in formulas 1 to 5: Formula 1; Formula 2; Formula 3; Equation 4; Equation 5; R 1 -OH Formula A; When R is an alkyl or substituted alkyl group and X is hydrogen in Formula I, the preparation method includes the following steps: (i) An acylphenylboronic acid derivative, 2-chloro-5-fluoropyrimidine, palladium catalyst and solvent were mixed and reacted to obtain intermediate 6; (ii) Intermediate 6, sodium formate, a chiral catalyst for asymmetric hydrogen transfer and solvent are mixed and reacted to obtain intermediate 7; (iii) Intermediate 7, 6-(3-cyanophenyl)-pyridazinone, cyanomethylenetri-n-butylphosphine and solvent are mixed and reacted to obtain intermediate 8; (iv) Intermediate 8, the compound with the structure shown in Formula A, sodium hydride and solvent are mixed and reacted to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain with the structure shown in Formula I. The structural formulas of intermediates 6 to 8 are shown in Formulas 6 to 8, and the structural formula of the acylphenylboronic acid derivative is shown in Formula 9. Formula 6; Formula 7; Formula 8; Formula 9.

[0011] The present invention also provides the use of the pyrimidine derivatives with chiral pyrrolidinyl side chains described above, or their pharmaceutically acceptable salts or solvates, in the preparation of c-Met kinase inhibitors.

[0012] The present invention also provides the use of the pyrimidine derivatives with chiral pyrrolidinyl side chains described above, or their pharmaceutically acceptable salts or solvates, in the preparation of anticancer drugs.

[0013] Preferably, the cancer is liver cancer or non-small cell lung cancer.

[0014] The present invention also provides a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable adjuvant; said active ingredient being a pyrimidine derivative with a chiral pyrrolidinium side chain as described in the above embodiments, or a pharmaceutically acceptable salt or solvate thereof.

[0015] Preferably, the dosage form of the pharmaceutical composition is any one of injection, tablet, capsule, pill, suspension, emulsion, microsphere and liposome.

[0016] This invention provides a pyrimidine derivative with a chiral pyrrolidinium side chain, or a pharmaceutically acceptable salt or solvate thereof, wherein the pyrimidine derivative has the structure shown in Formula I. The beneficial effects of this invention are: (1) Compared with existing antitumor drugs of the same kind, the pyrimidine derivatives with chiral pyrrole alkyl side chains provided by the present invention have better in vitro and in vivo activity, fewer side effects and higher safety.

[0017] (2) The deuterated target provided by the present invention has better pharmacokinetic properties.

[0018] (3) Brain metastasis of cancer is one of the main causes of death in cancer patients. The compound provided by the present invention (taking the target compound in Example 23 as an example) has a stronger ability to cross the blood-brain barrier than the existing drug terpoxtinib and has a strong potential to inhibit brain metastasis of cancer patients. Attached Figure Description

[0019] Figure 1 This is the synthetic route diagram for Method 1 (R is hydrogen, X is hydrogen); Figure 2 This is the synthetic route for Method 2 (R is an alkyl or substituted alkyl group, and X is hydrogen). Figure 3The results of the in vivo antitumor activity test in nude mice in Test Example 2 of the present invention are as follows: A is the growth curve of xenograft tumors in nude mice in different drug administration groups; B is the tumor volume and tumor growth inhibition rate of nude mice in each group after 16 days of drug administration; C is the weight change curve of mice in each group during the drug administration period; D is the actual image of the ex vivo tumor of nude mice in each group after 16 days of drug administration. Figure 4 This is a HE staining image of the main organ in Test Example 2 of the present invention. Detailed Implementation

[0020] This invention provides a pyrimidine derivative with a chiral pyrrolidinium side chain, or a pharmaceutically acceptable salt or solvate thereof, wherein the pyrimidine derivative has the structure shown in Formula I: Formula I; In Formula I: R is hydrogen, alkyl, or substituted alkyl; the number of carbon atoms in the alkyl or substituted alkyl is 1 to 4; the substituent on the substituted alkyl is deuterium or a halogen atom; X is hydrogen or deuterium; R 1 It can be any of the following structures: .

[0021] In this invention, the alkyl group or substituted alkyl group can specifically be methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl; the substituent on the substituted alkyl group specifically replaces the hydrogen atom on the saturated carbon element; when the substituent is a halogen atom, the halogen atom can be F, Cl, Br, or I.

[0022] In this invention, R and X in Formula I can be both hydrogen or not both hydrogen.

[0023] In this invention, the pyrimidine derivative with a chiral pyrrolidinium side chain preferably has any one of the following structures: .

[0024] In this invention, the anion of the pharmaceutically acceptable salt of the pyrimidine derivative with a chiral pyrroleyl side chain preferably includes any one of chloride ions, acetate ions, and methanesulfonate ions.

[0025] In this invention, the solvate of the pyrimidine derivative with a chiral pyrrolidinium side chain is preferably a hydrate.

[0026] The present invention does not have any special requirements for the preparation method of the pharmaceutically acceptable salt or solvate of the pyrimidine derivative containing chiral pyrroleyl group; any method well known to those skilled in the art can be used.

[0027] This invention also provides a method for preparing pyrimidine derivatives with chiral pyrroleyl side chains as described above. When R and X in Formula I are hydrogen, the preparation method (denoted as Method I) includes the following steps: (1) 3-hydroxymethylphenylboronic acid, 2-iodo-5-bromopyrimidine, palladium catalyst, sodium carbonate and solvent were mixed and reacted to obtain intermediate 1; (2) The intermediate 1, thionyl chloride and dichloromethane are mixed and reacted to obtain intermediate 2; (3) The intermediate 2, 6-(3-cyanophenyl)-pyridazinone, potassium carbonate and solvent are mixed and reacted to obtain intermediate 3; (4) The intermediate 3, bis(pinacol)diboron, palladium catalyst, potassium acetate and solvent are mixed and reacted to obtain intermediate 4; (5) The intermediate 4, sodium perborate, tetrahydrofuran and water are mixed and reacted to obtain intermediate 5; (6) The intermediate 5, the compound with the structure shown in Formula A, triphenylphosphine, diisopropyl azodicarbonate and solvent are mixed and reacted to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain with the structure shown in Formula I. The structural formulas of intermediates 1 to 5 are shown in formulas 1 to 5: Formula 1; Formula 2; Formula 3; Equation 4; Equation 5; R 1 -OH Formula A.

[0028] In this invention, the structures of 3-hydroxymethylphenylboronic acid (referred to as reagent 1), 2-iodo-5-bromopyrimidine (referred to as reagent 2), and 6-(3-cyanophenyl)-pyridazinone are shown in formulas B, C, and D, respectively; Formula B; Formula C; Formula D.

[0029] Figure 1 The following is a synthesis roadmap for Method 1, combined with... Figure 1 Please provide a detailed explanation.

[0030] This invention involves reacting 3-hydroxymethylphenylboronic acid, 2-iodo-5-bromopyrimidine, a palladium catalyst, sodium carbonate, and a solvent to obtain intermediate 1. In this invention, the molar ratio of 3-hydroxymethylphenylboronic acid to 2-iodo-5-bromopyrimidine is preferably 1-1.5:1; the palladium catalyst is preferably a palladium chloride diphenylphosphine complex; the molar ratio of 3-hydroxymethylphenylboronic acid to the palladium catalyst is preferably 1:0.1-0.2; the sodium carbonate is preferably anhydrous sodium carbonate, and the molar ratio of 3-hydroxymethylphenylboronic acid to sodium carbonate is preferably 1:1.5-2.5, specifically 1:2; the solvent is preferably anisole, water, and anhydrous ethanol, and the volume ratio of anisole, water, and anhydrous ethanol is preferably 1:1:2. Preferably, a solution of 3-hydroxymethylphenylboronic acid, anisole, and water is first added to a reaction flask, followed by the addition of sodium carbonate, palladium catalyst, 2-iodo-5-bromopyrimidine, and anhydrous ethanol. The preferred reaction temperature in step (1) is 85~95℃, specifically 89℃, and the preferred reaction time is 15~20h, specifically 18h. After the reaction is completed, the present invention preferably cools the obtained reaction solution and separates it into an organic phase and an aqueous phase. The aqueous phase is extracted with ethyl acetate, and the extracted organic phase and the separated organic phase are combined and washed with saturated brine, dried with anhydrous sodium sulfate, and desolventized under reduced pressure to obtain intermediate 1.

[0031] After obtaining intermediate 1, the present invention mixes intermediate 1, thionyl chloride, and dichloromethane to react and obtain intermediate 2. In the present invention, the molar ratio of intermediate 1 to thionyl chloride is preferably 1:2~3; the reaction temperature in step (2) is preferably 0℃~room temperature, and the reaction time is preferably 3~5h, specifically 4h; in a specific embodiment of the present invention, it is preferable to first dissolve intermediate 1 in dichloromethane, and then add thionyl chloride dropwise to the intermediate 1 solution under ice bath conditions, and after the addition is completed, the temperature is raised to room temperature for reaction. After the reaction is completed, the present invention preferably removes the solvent from the obtained reaction solution under reduced pressure, washes the residue with toluene to remove excess thionyl chloride, and then recrystallizes the obtained crude product to obtain intermediate 2. The solvent used for recrystallization is preferably toluene.

[0032] After obtaining intermediate 2, the present invention mixes intermediate 2, 6-(3-cyanophenyl)-pyridazinone, potassium carbonate and solvent to react and obtain intermediate 3; the molar ratio of intermediate 2 and 6-(3-cyanophenyl)-pyridazinone is preferably 1~1.5:1; the molar ratio of 6-(3-cyanophenyl)-pyridazinone and potassium carbonate is preferably 1:2~3, specifically 1:2.5, the potassium carbonate is preferably anhydrous potassium carbonate; the solvent is preferably NMP; the reaction temperature in step (3) is preferably 70~90℃, the reaction time is preferably 15~25h, specifically 20h; after the reaction is completed, the present invention adds water to the reaction system, stirs and separates the organic layer, extracts the obtained aqueous layer with dichloromethane, combines the extracted organic layer and the separated organic layer and washes it with saturated brine, dries it with anhydrous sodium sulfate and concentrates it to obtain crude product, and purifies the crude product by column chromatography to obtain intermediate 3.

[0033] After obtaining intermediate 3, the present invention mixes intermediate 3, bis(pinacol)diboron, palladium catalyst, potassium acetate and solvent to react and obtain intermediate 4. In the present invention, the molar ratio of intermediate 3 to bis(pinacol)diboron is preferably 1:1~1.5, specifically 1:1.2; the palladium catalyst is preferably PdCl2(PPh3)2; the molar ratio of intermediate 3 to palladium catalyst is preferably 1:0.02~0.05, specifically 1:0.03; the potassium acetate is preferably anhydrous potassium acetate; the molar ratio of intermediate 3 to potassium acetate is preferably 1:2.5~3.5, specifically 1:3; the solvent is preferably anhydrous DMF; the reaction temperature in step (4) is preferably 70~90℃, and the reaction time is preferably 15~20h, specifically 18h. After the reaction is complete, the present invention preferably cools the obtained reaction solution to room temperature, then adds water and dichloromethane (DCM), then filters it with diatomaceous earth to separate the organic layer, and then washes the obtained organic layer with saturated brine, dries it with anhydrous sodium sulfate and removes solvent under reduced pressure. The obtained residue is pulped in methyl tert-butyl ether to obtain a solid product, which is directly used in the next reaction step.

[0034] After obtaining intermediate 4, the present invention mixes intermediate 4, sodium perborate, tetrahydrofuran, and water to react and obtain intermediate 5. In the present invention, the sodium perborate is sodium perborate tetrahydrate; the molar ratio of intermediate 4 to sodium perborate is preferably 1.2~2:1, specifically 1.5:1; the reaction temperature in step (5) is preferably room temperature, and the reaction time is preferably 3~5h, specifically 4h; after the reaction is completed, the present invention preferably adds saturated ammonium chloride solution to the reaction system, stirs the resulting suspension at room temperature, filters it, washes the resulting precipitate with water, and then vacuum dries it to obtain intermediate 5; the stirring time at room temperature is preferably 15~18h, specifically 16h.

[0035] After obtaining intermediate 5, the present invention mixes intermediate 5, the compound with the structure shown in Formula A, triphenylphosphine (PPh3), diisopropyl azodicarbonate (DIAD), and a solvent to react and obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain of the structure shown in Formula I. The present invention does not have special requirements on the source of the compound with the structure shown in Formula A, and commercially available products or methods well known to those skilled in the art can be used. In the present invention, the molar ratio of the compound with the structure shown in Formula A to intermediate 5 is preferably 1~1.5:1, specifically 1.2:1; the molar ratio of triphenylphosphine to intermediate 5 is preferably 1~1.5:1, specifically 1.3:1; the molar ratio of DIAD to intermediate 5 is preferably 1~1.5:1, specifically 1.4:1; the solvent is preferably THF; the reaction temperature in step (6) is preferably 0℃~room temperature, and the reaction time is preferably 1~3h, specifically 2h. After the reaction is complete, the present invention preferably adds ice water to the reaction solution, and then performs dichloromethane extraction. The resulting organic layer is washed with brine, dried with anhydrous sodium sulfate and desolventized under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain as shown in Formula I.

[0036] In this invention, when R in Formula I is an alkyl or substituted alkyl group and X is hydrogen, the preparation method (denoted as Method II) includes the following steps: (i) An acylphenylboronic acid derivative (referred to as reagent 3), 2-chloro-5-fluoropyrimidine (referred to as reagent 4), palladium catalyst and solvent were mixed and reacted to obtain intermediate 6; (ii) Intermediate 6, sodium formate, a chiral catalyst for asymmetric hydrogen transfer and solvent are mixed and reacted to obtain intermediate 7; (iii) Intermediate 7, 6-(3-cyanophenyl)-pyridazinone, cyanomethylenetri-n-butylphosphine and solvent are mixed and reacted to obtain intermediate 8; (iv) Intermediate 8, the compound with the structure shown in Formula A, sodium hydride and solvent are mixed and reacted to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain with the structure shown in Formula I. The structural formulas of intermediates 6 to 8 are shown in Formulas 6 to 8, and the structural formula of the acylphenylboronic acid derivative is shown in Formula 9. Formula 6; Formula 7; Formula 8; Formula 9.

[0037] In this invention, the structural formula of the 2-chloro-5-fluoropyrimidine is shown in Formula E: Formula E.

[0038] In this invention, the synthetic route of method two is as follows: Figure 2 As shown below, in conjunction with Figure 2 Please provide a detailed explanation.

[0039] In this invention, an acylphenylboronic acid derivative, 2-chloro-5-fluoropyrimidine, a palladium catalyst, and a solvent are mixed and reacted to obtain intermediate 6. In this invention, the reaction conditions, post-treatment methods, and procedures in step (i) are the same as in step (1), except that the acylphenylboronic acid derivative is used instead of 3-hydroxymethylphenylboronic acid, and 2-chloro-5-fluoropyrimidine is used instead of 2-iodo-5-bromopyrimidine.

[0040] After obtaining intermediate 6, the present invention mixes intermediate 6, sodium formate, a chiral catalyst for asymmetric hydrogen transfer, and solvent to react and obtain intermediate 7. In this invention, the chiral catalyst for asymmetric hydrogen transfer is preferably prepared from a dichlororuthenium(II) dimer and a chiral ligand, wherein the molar ratio of the dichlororuthenium(II) dimer to the chiral ligand is preferably 1:2; the chiral ligand is N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide or N-((1R,2R)-2-amino-1,2-diphenylethyl)-1-((2R,4R)-camphorsulfonamide; in a specific embodiment of this invention, the dichlororuthenium(II) dimer, the chiral ligand, and water are preferably mixed and reacted at 50°C under nitrogen protection for 4 h to obtain the in-situ prepared chiral catalyst for asymmetric hydrogen transfer.

[0041] In this invention, the molar ratio of intermediate 6 to sodium formate is preferably 1:4 to 6, specifically 1:5; the solvent is preferably dichloromethane and water. In a specific embodiment of this invention, intermediate 6 is preferably dissolved in dichloromethane to obtain an intermediate 6 solution, and sodium formate is dissolved in water to obtain a sodium formate solution. Then, the intermediate 6 solution and the sodium formate solution are sequentially added to a chiral catalyst solution for asymmetric hydrogen transfer to carry out the reaction. The reaction temperature in step (ii) is preferably 40 to 60°C, and the reaction time is preferably 10 to 20 hours, specifically 12 hours. After the reaction is completed, this invention preferably separates the reaction solution into an organic phase and an aqueous phase. The aqueous phase is extracted with dichloromethane, and the extracted organic phase and the separated organic phase are combined and sequentially washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by silica gel column chromatography to obtain intermediate 7.

[0042] After obtaining intermediate 7, the present invention reacts intermediate 7, 6-(3-cyanophenyl)-pyridazinone, cyanomethylenetri-n-butylphosphine, and a solvent to obtain intermediate 8. In the present invention, the molar ratio of 6-(3-cyanophenyl)-pyridazinone to cyanomethylenetri-n-butylphosphine is preferably 1:2~3; the molar ratio of intermediate 7 to 6-(3-cyanophenyl)-pyridazinone is preferably 1~2:1, specifically 1.2:1; the solvent is preferably toluene; the reaction temperature in step (iii) is preferably 70~90℃, and the reaction time is preferably 20~30h, specifically 24h. After the reaction is complete, the present invention preferably pours the obtained reaction solution into water, then extracts it with ethyl acetate, and washes the obtained organic layer sequentially with saturated brine, dries it with anhydrous sodium sulfate, and removes the solvent under reduced pressure to obtain a crude product. The crude product is then purified by silica gel column chromatography to obtain intermediate 8.

[0043] After obtaining intermediate 8, the present invention mixes intermediate 8, the compound with the structure shown in Formula A, sodium hydride, and solvent to react and obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain of the structure shown in Formula I. In the present invention, the molar ratio of intermediate 8 to the compound with the structure shown in Formula A is preferably 1:1 to 1.5, specifically 1:1.2; the molar ratio of intermediate 8 to sodium hydride is preferably 1:2 to 3; the solvent is preferably DMF; the reaction temperature in step (iv) is preferably 0°C to room temperature, and the reaction time is preferably 2 to 4 hours, specifically 3 hours; in a specific embodiment of the present invention, it is preferable to first dissolve the compound with the structure shown in Formula A in a solvent, and then add NaH in batches to the solution of the compound with the structure shown in Formula A at 0°C. After stirring the mixture for 15 minutes, intermediate 8 is slowly added at 0°C, and then the reaction mixture is slowly raised to room temperature to carry out the reaction. After the reaction is completed, the reaction is preferably quenched with water. The resulting reaction solution is then extracted with ethyl acetate. The resulting organic phase is dried with anhydrous sodium sulfate and the solvent is removed under reduced pressure to obtain a crude product. The crude product is then purified by column chromatography to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain as shown in Formula I.

[0044] The present invention also provides the use of the pyrimidine derivatives with chiral pyrrolidinyl side chains described above, or their pharmaceutically acceptable salts or solvates, in the preparation of c-Met kinase inhibitors.

[0045] The present invention also provides the use of the pyrimidine derivatives with chiral pyrrolidinyl side chains or their pharmaceutically acceptable salts or solvates as described above in the preparation of anticancer drugs; in the present invention, the cancer is liver cancer or non-small cell lung cancer; the non-small cell lung cancer is specifically non-small cell lung cancer with abnormal c-Met kinase expression, which can be used to treat metastatic NSCLC patients carrying MET exon 14 skipping mutations; the liver cancer is specifically hepatocellular carcinoma with abnormal or mutated c-Met kinase expression.

[0046] The present invention also provides a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable adjuvant; said active ingredient is a pyrimidine derivative with a chiral pyrrolidinium side chain as described in the above-described embodiments, or a pharmaceutically acceptable salt or solvate thereof; said pharmaceutical composition is available in any one of the following dosage forms: injection, tablet, capsule, pill, suspension, emulsion, microsphere, and liposome. The route of administration of said pharmaceutical composition may be oral, spray, transdermal, intravenous, or intramuscular; said pharmaceutical composition is used to treat malignant tumors.

[0047] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0048] Example 1 Synthesis of target compound 1 (1) Synthesis of intermediate 1 A solution of anisole (40 mL) and water (40 mL) containing 11.4 g (40.0 mmol) of 2-iodo-5-bromopyrimidine was added to a reaction flask. Anhydrous sodium carbonate (8.43 g, 79.5 mmol), palladium chloride diphenylphosphine complex (0.28 g, 0.40 mmol), 3-(hydroxymethyl)phenylboronic acid (6.02 g, 39.6 mmol), and anhydrous ethanol (80 mL) were added sequentially at room temperature. The reaction system was stirred and heated to 89 °C for 18 hours, with thin-layer chromatography monitoring the reaction progress. After the reactants had largely disappeared, the mixture was cooled to room temperature, and the organic phase was separated. The aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude product was recrystallized from isopropanol to give a yellow solid. Yield: 75.6%. 1 H-NMR (400 MHz, d 6-DMSO) δ 9.07 (s, 2H), 8.41– 8.35 (m, 1H), 8.24 – 8.21 (m,1H), 7.63 – 7.39 (m, 2H), 5.33 (t, J = 5.8 Hz, 1H), 4.61 (dd, J = 5.9, 0.8Hz, 2H). 13 C-NMR (101 MHz, d 6 -DMSO) δ162.29, 158.61, 143.76, 136.40, 129.73,129.06, 126.54, 126.23, 118.89, 63.20. (2) Synthesis of intermediate 2 Intermediate 1 (7.66 g, 29.0 mmol) was added to a reaction flask and dissolved in dry dichloromethane (80 mL). Thionyl chloride (6.87 g, 58.0 mmol) was added dropwise under ice bath conditions. The reaction was stirred at room temperature for 4 hours, and then the solvent was removed under reduced pressure. The residue was washed three times with toluene to remove excess thionyl chloride. The crude product was recrystallized from toluene to give a white solid. Yield: 89.5%. ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.09 (s, 2H), 8.45 – 8.42 (m, 1H), 8.32 – 8.30 (m, 1H), 7.65 – 7.62 (m, 1H), 7.57 – 7.54 (m, 1H), 4.89 (s, 2H). ¹³C-NMR (101 MHz, d⁶-DMSO) δ 161.68, 158.72, 138.91, 136.97, 132.02, 129.75, 128.54, 128.01, 119.21, 46.35. (3) Synthesis of intermediate 3 6-(3-cyanophenyl)-pyridazinone (4.00 g, 20.0 mmol) was added to a reaction flask and dissolved in NMP (75 mL). Then, intermediate 2 (6.54 g, 23.2 mmol) and anhydrous potassium carbonate (6.91 g, 50.0 mmol) were added. The reaction mixture was stirred at 80 °C for 20 hours. Water was then added to the reaction mixture, and the mixture was stirred and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography to give intermediate 3. Yield: 94.2%. 1H-NMR (400 MHz, d 6 -DMSO) δ 9.08 (s, 2H), 8.45 – 8.37 (m,2H), 8.28 – 8.23 ​​(m, 2H), 8.17 (d, J = 9.8 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.62 – 7.48 (m, 2H), 7.16 (d, J = 9.8 Hz, 1H), 5.46 (s,2H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 161.84, 159.26, 158.74, 142.53, 137.69,136.87, 135.91, 133.35, 131.63, 131.34, 130.88, 130.74, 130.63, 129.95,129.70, 128.12, 127.59, 119.13, 118.98, 112.64, 46.15. (4) Synthesis of intermediate 4 Intermediate 3 (7.97 g, 18.0 mmol) was dissolved in anhydrous DMF (45 mL) at room temperature, followed by the addition of bis(pinacol)diboron (5.47 g, 21.6 mmol), anhydrous potassium acetate (5.29 g, 53.9 mmol), and PdCl2(PPh3)2 (0.36 g, 0.54 mmol). The reaction mixture was stirred at 80 °C for 18 hours. After cooling to room temperature, water and dichloromethane (DCM) were added to the mixture, followed by filtration through diatomaceous earth. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the residue was prepared into a slurry in methyl tert-butyl ether (90 mL) to give a pale yellow solid, which was used directly in the next step. Yield: 70.9%.

[0049] (5) Synthesis of intermediate 5 Sodium perborate tetrahydrate (2.73 g, 17.9 mmol) was added in portions to a suspension of intermediate 4 (5.88 g, 12.0 mmol) in THF (30 mL) and water (60 mL), and the mixture was stirred at room temperature for 4 hours. A saturated ammonium chloride solution (22 mL) was added to the reaction mixture, and the resulting suspension was stirred at room temperature for 16 hours. The mixture was filtered, the precipitate was washed with water, and then dried under vacuum to obtain a grayish-white powdery key intermediate 5. Yield: 85.3%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 10.57 (s, 1H), 8.44 (s,2H), 8.37 – 8.35 (m, 2H), 8.26 – 8.22 (m, 1H), 8.21 – 8.18 (m, 1H), 8.17 (d,J = 9.8 Hz, 1H), 7.96 – 7.88 (m, 1H), 7.74 – 7.89 (m, 1H), 7.49 – 7.42 (m,2H), 7.16 (d, J = 9.8 Hz, 1H), 5.44 (s, 2H). 13 C1-NMR (101 MHz, d 6 -DMSO) δ159.25, 155.17, 151.15, 145.04, 142.44, 138.14, 137.34, 135.94, 133.32,131.28, 130.86, 130.71, 130.60, 129.93, 129.77, 129.35, 127.21, 126.65,118.96, 112.64, 55.38, 55.13. (6) Synthesis of the target compound in Example 1 (R)N-methylprolyl (1.2 equivalents, 1.20 mmol) and PPh3 (1.3 equivalents, 1.30 mmol) were successively added to a 10 mL solution of THF containing intermediate 5 (1.0 equivalents, 1.00 mmol). Then, a 10 mL solution of THF containing DIAD (1.4 equivalents, 1.40 mmol) was slowly added dropwise under ice bath conditions. The reaction was stirred at room temperature for 2 hours. After TLC detection of complete reaction, ice water was added, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the product. Yield: 66.1%. HRMS (ESI) (m / z) [M+H] +calcdfor C 28 H 27 N6O2, 479.21955; found, 479.22801 and HPLC purity: 98.8090%. 1 H-NMR (400MHz, d 6 -DMSO) δ 8.65 (d, J = 1.3 Hz, 2H), 8.41 – 8.36 (m, 2H), 8.26 – 8.21 (m,2H), 8.17 (d, J = 9.8 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.9 Hz,1H), 7.51 – 7.47 (m, 2H), 7.16 (d, J = 9.8 Hz, 1H), 5.45 (s, 2H), 4.23 – 4.03(m, 2H), 3.00 – 2.93 (m, 1H), 2.70 – 2.59 (m, 1H), 2.38 (s, 3H), 2.20 (d, J =7.2 Hz, 1H), 2.01 – 1.93 (m, 1H), 1.76 – 1.62 (m, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 159.25, 156.32, 152.14, 145.76, 144.66, 142.46, 137.83, 137.43,135.93, 133.33, 131.30, 130.86, 130.72, 130.61, 130.14, 129.92, 129.44,127.43, 126.87, 118.98, 112.64, 71.88, 64.01, 57.47, 55.09, 41.76, 28.69,23.16. Example 2 Synthesis of target compound 2 The same method as in Example 1 was used, except that in the final step of synthesizing target compound 2, (S)N-methylprolyl was used instead of (R)N-methylprolyl in Example 1. Yield: 60.7%. HRMS (ESI) (m / z) [M+H] + calcdfor C 28 H 27N6O2, 479.21955; found, 479.28878 and HPLC purity: 98.7780%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.65 (d, J = 1.5 Hz, 2H), 8.41 – 8.37 (m, 2H), 8.27 –8.21 (m, 2H), 8.17 (d, J = 9.8 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.71 (t, J= 7.9 Hz, 1H), 7.50 – 7.46 (m, 2H), 7.16 (d, J = 9.7 Hz, 1H), 5.45 (s, 2H), 4.27 – 4.03 (m, 2H), 2.98 – 2.94 (m, 1H), 2.63 – 2.57 (m, 1H), 2.37 (s, 3H), 2.19 (d, J = 2.9 Hz, 1H), 2.01 – 1.93 (m, 1H), 1.72 – 1.60 (m, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 159.24, 156.30, 152.15, 145.74, 144.64, 142.45, 137.83,137.42, 135.92, 133.32, 131.28, 130.85, 130.71, 130.60, 130.12, 129.91,129.43, 127.43, 126.87, 118.98, 112.64, 71.95, 63.95, 57.48, 55.08, 41.78,28.73, 23.16. Example 3 Synthesis of target compound 3 The same method as in Example 1 was used, except that in the final step of synthesizing target compound 3, (S)N-ethylprolyl was used instead of (R)N-methylprolyl in Example 1. Yield: 63.9%. HRMS (ESI) (m / z) [M+H] + calcdfor C 29 H 29N6O2, 493.23520; found, 493.24632 and HPLC purity: 96.6516%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.65 (s, 2H), 8.38 (d, J = 9.5 Hz, 2H), 8.21 (d, J = 19.3Hz, 2H), 8.03 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.74 – 7.70 (m, 1H), 7.49(s, 2H), 7.16 (d, J = 9.8 Hz, 1H), 5.45 (s, 2H), 4.13 (d, J = 48.3 Hz, 2H), 3.16 – 3.06 (m, 1H), 3.01 – 2.93 (m, 1H), 2.06 – 1.92 (s, 1H), 1.79 – 1.69(m, 2H), 1.56 – 1.52 (m, 2H), 1.40 – 1.33 (m, 2H), 1.12 – 0.98 (m, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 159.25, 158.34, 156.38, 152.09, 144.72, 142.45, 137.82,137.42, 135.92, 133.32, 131.29, 130.86, 130.72, 130.61, 130.14, 129.91,129.44, 127.44, 126.88, 118.98, 112.64, 55.09, 53.61, 44.88, 25.83, 24.63,23.18. Example 4 Synthesis of target compound 4 Using the same method as in Example 1, in the final step of the synthesis of target compound 4, 2-(2-(N-methylpyrrolyl)ethanol was used instead of (R)N-ethylproline alcohol in Example 1. Yield: 58.4%. HRMS (ESI) (m / z)[M+H] + calcd for C 29 H 29N6O2, 493.23520; found, 493.24632 and HPLC purity:99.5284%. 1H-NMR (400 MHz, d6-DMSO) δ 8.65 (d, J = 1.5 Hz, 2H), 8.44 – 8.37(m, 2H), 8.26 – 8.22 (m, 2H), 8.17 (d, J = 9.8 Hz, 1H), 7.93 (d, J = 7.7 Hz,1H), 7.73 – 7.70 (m, 1H), 7.53 – 7.46 (m, 2H), 7.16 (d, J = 9.7 Hz, 1H), 5.45(s, 2H), 4.24 – 4.15 (m, 1H), 4.05 (dd, J = 9.7, 5.9 Hz, 1H), 3.05 – 2.89 (m,1H), 2.60 (dq, J = 11.0, 5.9 Hz, 1H), 2.37 (s, 3H), 2.19 (d, J = 2.9 Hz, 1H), 2.01 – 1.94 (m, 1H), 1.74 – 1.62 (m, 3H), 1.43 – 1.33 (m, 2H). 13C-NMR (101MHz, d6-DMSO) δ 159.24, 156.31, 152.15, 144.64, 142.45, 137.83, 137.42,135.92, 133.32, 131.28, 130.85, 130.71, 130.60, 130.13, 129.91, 129.43, 127.43, 126.87, 118.98, 112.64, 71.95, 63.95, 57.48, 55.08, 41.78, 28.93, 28.73, 23.16. Example 5 Synthesis of target compound 5 The same method as in Example 1 was used, except that in the final step of synthesizing target compound 5, (S)N-acetylprolyl was used instead of (R)N-methylprolyl in Example 1. Yield: 73.5%. HRMS (ESI) (m / z) [M+Na] + calcd for C 29 H 26N6O3Na, 529.19641; found, 529.19675 and HPLC purity: 98.0406%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.68 (d, J = 6.4 Hz, 2H), 8.38 (dd, J = 4.9, 3.3Hz, 2H), 8.24 (ddt, J = 8.8, 5.2, 1.6 Hz, 2H), 8.17 (d, J = 9.8 Hz, 1H), 7.93(d, J = 7.8 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.48 (dt, J = 5.2, 1.6 Hz,2H), 7.16 (d, J = 9.7 Hz, 1H), 5.45 (s, 2H), 4.36 – 4.19 (m, 2H), 4.11 (td, J= 10.7, 7.7 Hz, 1H), 3.55 – 3.37 (m, 2H), 2.12 – 1.99 (m, 2H), 1.97 (s, 3H), 1.95 – 1.84 (m, 2H). 13 C-NMR (101 MHz, CDCl3) δ 170.06, 159.42, 157.41, 151.49,143.96, 142.14, 137.95, 136.14, 135.99, 132.54, 130.78, 130.26, 129.97,129.81, 129.63, 129.38, 128.96, 128.28, 127.37, 118.43, 113.33, 68.14, 55.76,55.45, 48.25, 27.70, 24.30, 22.95. Example 6 Synthesis of target compound 6 (1) Synthesis of intermediate 6 The same method was used to prepare intermediate 1 in Example 1, except that 3-acetylphenylboronic acid and 2-iodo-5-bromopyrimidine were used instead of 3-acetylphenylboronic acid and 2-chloro-5-fluoropyrimidine in Example 1. Yield: 72.6%. ESI-MS m / z 217.04 ([M+H]) + ). 1H-NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.69 (s, 2H), 8.63 –8.57 (m, 1H), 8.10 – 8.07 (m, 1H), 7.62 – 7.54 (m, 1H), 2.70 (s, 3H). (2) Synthesis of intermediate 7 Step 1: In a 500 mL reaction flask, add ruthenium(II) dichloro(p-cymene)dimer (0.15 g, 0.25 mmol), chiral ligand N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide (0.22 g, 0.50 mmol), and water (125 mL). React at 50 °C under nitrogen protection for 4 hours to obtain the in-situ prepared chiral catalyst for asymmetric hydrogen transfer.

[0050] Step 2: Dissolve intermediate 6 (5.40 g, 25.0 mmol) in dichloromethane (DCM, 200 mL) and sodium formate (HCOONa, 8.51 g, 125 mmol) in water (75 mL).

[0051] Step 3: The dichloromethane solution and sodium formate solution of intermediate 6 were sequentially added to the chiral catalyst solution. The reaction mixture was stirred continuously at 50°C for 12 hours. After the reaction was completed as monitored by TLC, the organic phase was separated, and the aqueous phase was extracted with dichloromethane M. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain intermediate 7. Yield: 85.9%. ESI-MS m / z 219.04 ([M+H]) + ). (3) Synthesis of intermediate 8 Toluene (200 mL) was added to a reaction flask containing 6-(3-cyanophenyl)-pyridazinone (1.0 equivalent, 15.0 mmol) and CMBP (2.0 equivalent, 30.0 mmol). The mixture was stirred at 80 °C for 10 min under nitrogen protection, followed by the addition of intermediate 7 (1.2 equivalent, 18.0 mmol). After stirring at 80 °C for 24 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the crude product. This crude product was then purified by silica gel column chromatography to give intermediate 8. Yield: 43.7%. 1H-NMR (400 MHz, CDCl3) δ 8.73 – 8.67 (m, 3H), 8.34 –8.31 (m, 1H), 8.19 (t, J = 1.7 Hz, 1H), 8.02 – 7.96 (m, 1H), 7.72 – 7.67 (m,1H), 7.63 – 7.54 (m, 3H), 7.46 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 9.7 Hz, 1H), 6.55 (q, J = 7.1 Hz, 1H), 1.93 (d, J = 7.1 Hz, 3H). (4) Synthesis of target compound 6 At 0 °C, NaH (2.0 equivalent) was added in portions to a solution of (R)N-methylprolyl (1.2 equivalent, 1.20 mmol DMF (6.0 mL)). After stirring the mixture for 15 minutes, intermediate 8 (1.0 equivalent, 1.00 mmol) was slowly added at 0 °C. The reaction mixture was slowly brought to room temperature and reacted for 3 hours. The reaction was quenched with water, and the product was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give target compound 6. Yield: 48.2%. HRMS (ESI) (m / z) [M+H] + calcd for C29H29N6O2, 493.23520; found, 493.24914 and HPLC purity: 98.6208%. 1H-NMR (400 MHz, d6-DMSO) δ 8.68 (s, 2H), 8.49 (d, J =1.6 Hz, 1H), 8.39 (d, J = 1.8 Hz, 1H), 8.32 – 7.26 (m, 1H), 8.23 ​​(dd, J =7.6, 1.6 Hz, 1H), 8.15 (d, J = 9.8 Hz, 1H), 7.97 – 7.88 (m, 1H), 7.73 (t, J =7.9 Hz, 1H), 7.57 – 7.41 (m, 2H), 7.12 (d, J = 9.7 Hz, 1H), 6.39 (q, J = 7.0Hz, 1H), 4.25 (ddd, J = 43.2, 10.1, 5.4 Hz, 2H), 3.04 (t, J = 7.3 Hz, 2H),2.98 – 2.85 (m, 1H), 2.46 (s, 3H), 2.14 – 1.97 (m, 1H), 1.85 (d, J = 7.1 Hz,3H), 1.80 – 1.64 (m, 3H). 13C-NMR (101 MHz, d6-DMSO) δ 158.99, 156.55,151.90, 144.76, 142.02, 141.88, 137.69, 136.24, 133.29, 130.81, 130.76,130.57, 130.15, 129.77, 129.35, 129.13, 126.85, 126.49, 119.05, 112.67, 70.78, 64.56, 57.26, 56.13, 41.41, 28.22, 22.96, 20.32. Example 7. Synthesis of target compound 7 Following the same method as in Example 6, in the synthesis of chiral intermediate 7, the chiral ligand N-((1R,2R)-2-amino-1,2-diphenylethyl)-1-((2R,4R)-camphorsulfonamide was substituted for the N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide chiral ligand in Example 6. Yield: 39.6%. HRMS (ESI) (m / z) [M+H] + calcd for C 29 H 29 N6O2, 493.23520; found, 493.24632 and HPLC purity: 99.0681%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.66 (s, 2H), 8.44 (d, J = 38.3 Hz, 2H), 8.32 –8.10 (m, 3H), 7.93 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.58 – 7.43(m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.23 – 4.05 (m,2H), 3.07 – 2.96 (m, 1H), 2.68 (s, 1H), 2.40 (s, 3H), 2.32 – 2.20 (m, 1H), 1.99 (dd, J = 11.4, 7.3 Hz, 1H), 1.84 (d, J = 7.0 Hz, 3H), 1.78 – 1.60 (m,3H). 13 C-NMR (101 MHz, d 6-DMSO) δ 158.99, 156.41, 152.08, 144.69, 142.03,141.88, 137.71, 136.24, 133.30, 130.82, 130.76, 130.58, 130.16, 129.78,129.36, 129.10, 126.83, 126.47, 119.06, 112.68, 71.67, 64.10, 57.44, 56.12,41.71, 28.61, 23.13, 20.33. Example 8 Synthesis of target compound 8 The same method as in Example 6 was used, except that in the final step of synthesizing target compound 8, (S)N-methylprolyl was used instead of (R)N-methylprolyl in Example 6. Yield: 45.0%. HRMS (ESI) (m / z) [M+H] + calcdfor C 29 H 29 N6O2, 493.23520; found, 493.25196 and HPLC purity: 98.9829%. 1 H-NMR (400 MHz, d 6-DMSO) δ 8.66 (s, 2H), 8.49 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 1.8Hz, 1H), 8.31 – 8.26 (m, 1H), 8.23 ​​(dd, J = 7.5, 1.8 Hz, 1H), 8.14 (d, J =9.8 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.58 – 7.42(m, 2H), 7.12 (d, J = 9.7 Hz, 1H), 6.39 (q, J = 7.0 Hz, 1H), 4.20 (dd, J =9.8, 5.3 Hz, 1H), 4.08 (dd, J = 9.7, 5.7 Hz, 1H), 3.00 (dt, J = 9.2, 4.4 Hz, 1H), 2.68 (t, J = 7.3 Hz, 1H), 2.40 (s, 3H), 2.30 – 2.19 (m, 1H), 2.06 – 1.94(m, 1H), 1.85 (d, J = 7.0 Hz, 3H), 1.76 – 1.62 (m, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 158.99, 156.42, 152.08, 144.67, 142.02, 141.86, 137.71, 136.24,133.28, 130.81, 130.74, 130.56, 130.15, 129.77, 129.34, 129.10, 126.83,126.47, 119.05, 112.68, 71.68, 64.10, 57.44, 56.12, 41.70, 28.61, 23.12,20.32. Example 9 Synthesis of target compound 9 Following the same method as in Example 6, in the synthesis of chiral intermediate 7, the chiral ligand N-((1R,2R)-2-amino-1,2-diphenylethyl)-1-((2R,4R)-camphorsulfonamide was used instead of the N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide chiral ligand in Example 6. In the final step of the synthesis of target compound 9, (S)N-methylprolyl was used instead of (R)N-methylprolyl in Example 6. Yield: 41.6%. HRMS (ESI) (m / z) [M+H] + calcd for C 29 H 29 N6O2, 493.23520; found, 493.24349 and HPLC purity: 99.2252%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.66 (s, 2H), 8.49 (d, J = 1.8 Hz, 1H), 8.41 – 8.36(m, 1H), 8.32 – 8.26 (m, 1H), 8.24 – 8.21 (m, 1H), 8.14 (d, J = 9.7 Hz, 1H),7.95 – 7.89 (m, 1H), 7.75 – 7.71 (m, 1H), 7.56 – 7.44 (m, 2H), 7.11 (d, J =9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.14 (ddd, J = 42.3, 9.8, 5.5 Hz, 2H),3.00 (dt, J = 9.2, 4.3 Hz, 1H), 2.68 (d, J = 8.8 Hz, 1H), 2.40 (s, 3H), 2.31– 2.20 (m, 1H), 2.04 – 1.93 (m, 1H), 1.84 (d, J = 7.0 Hz, 3H), 1.76 – 1.61(m, 3H). 13 C-NMR (101 MHz, d 6-DMSO) δ 163.75, 161.16, 156.84, 149.44, 146.78,146.62, 142.46, 141.00, 138.05, 135.57, 135.51, 135.32, 134.91, 134.53,134.11, 133.86, 131.58, 131.22, 123.81, 117.43, 76.43, 68.85, 62.20, 60.87,46.46, 45.38, 45.17, 44.96, 44.75, 44.54, 44.33, 44.13, 33.36, 27.88, 25.08. Example 10 Synthesis of target compound 10 The same method as in Example 6 was used in the synthesis of target compound 10, except that (S)-N-ethylprolyl was used instead of (R)-N-methylprolyl in Example 6. Yield: 46.6%. HRMS (ESI) (m / z) [M+H] + calcd forC 30 H 31 N6O2, 507.25085; found, 507.31134 and HPLC purity: 97.8511%. 1 H-NMR (400MHz, d 6-DMSO) δ 8.66 (s, 2H), 8.48 (s, 1H), 8.39 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.57 – 7.43 (m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.23 – 4.01 (m, 2H), 3.13 – 3.05 (m, 1H), 3.01 –2.82 (m, 2H), 2.40 (brs, 1H), 2.25 (brs, 1H), 1.96 (t, J = 9.1 Hz, 1H), 1.84(d, J = 7.0 Hz, 3H), 1.76 – 1.65 (m, 3H), 1.04 (t, J = 7.1 Hz, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 159.00, 156.40, 152.13, 144.73, 142.04, 141.88, 137.72,136.24, 133.30, 130.82, 130.76, 130.58, 130.16, 129.78, 129.36, 129.10,126.83, 126.46, 119.06, 112.68, 62.64, 56.12, 53.61, 49.10, 28.44, 23.22,20.33. Example 11 Synthesis of target compound 11 Following the same method as in Example 6, in the synthesis of chiral intermediate 11, the chiral ligand N-((1R,2R)-2-amino-1,2-diphenylethyl)-1-((2R,4R)-camphorsulfonamide was used instead of the N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide chiral ligand in Example 6, and (S)-N-ethylprolyl was used instead of (R)-N-methylprolyl in Example 6. Yield: 45.1%. HRMS (ESI) (m / z) [M+H] + calcd for C30 H 31 N6O2,507.25085; found, 507.30561 and HPLC purity: 97.1277%. 1 H-NMR (400 MHz, d 6 -DMSO)δ 8.66 (s, 2H), 8.48 (s, 1H), 8.39 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.22(d, J = 7.6 Hz, 1H), 8.14 (d, J = 9.8 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.73(t, J = 7.9 Hz, 1H), 7.78 – 7.69 (dt, J = 15.3, 7.6 Hz, 2H), 7.11 (d, J = 9.7Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.22 – 4.01 (m, 2H), 3.09 (s, 1H), 3.01 –2.81 (m, 2H), 2.33 (d, J = 60.3 Hz, 2H), 2.00 – 1.91 (m, 1H), 1.84 (d, J =7.0 Hz, 3H), 1.78 – 1.64 (m, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 158.99, 156.40,152.12, 144.72, 142.03, 141.87, 137.72, 136.24, 133.29, 130.82, 130.76,130.57, 130.15, 129.78, 129.35, 129.10, 126.83, 126.47, 119.06, 112.68,62.65, 56.12, 53.61, 49.10, 28.43, 23.22, 20.33. Example 12 Synthesis of target compound 12 The same method as in Example 6 was used in the synthesis of target compound 12, except that 2-(2-(N-methylpyrrolyl)ethanol was used instead of (R)-N-methylprolyl in Example 6. Yield: 50.5%. HRMS (ESI) (m / z) [M+H] +calcd for C 30 H 31 N6O2, 507.25085; found, 507.31420 and HPLC purity: 99.0972%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.65 (s, 2H), 8.48 (d, J = 1.8 Hz, 1H), 8.41 – 8.37(m, 1H), 8.31 – 8.26 (m, 1H), 8.24 – 8.19 (m, 1H), 8.14 (d, J = 9.8 Hz, 1H),7.93 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.55 – 7.43 (m, 2H), 7.11(d, J = 9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.22 (t, J = 6.8 Hz, 2H), 2.98(ddd, J = 9.7, 6.9, 3.4 Hz, 1H), 2.32 – 2.20 (m, 4H), 2.17 – 2.07 (m, 2H), 2.00 – 1.90 (m, 1H), 1.84 (d, J = 7.0 Hz, 3H), 1.73 – 1.60 (m, 3H), 1.55 –1.47 (m, 1H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 158.99, 156.35, 151.97, 144.62,142.03, 141.87, 137.72, 136.25, 133.29, 130.82, 130.76, 130.58, 130.16,129.78, 129.35, 129.11, 126.81, 126.44, 119.06, 112.68, 67.06, 63.31, 56.97,56.11, 32.79, 30.70, 22.16, 20.33. Example 13 Synthesis of target compound 13 Following the same method as in Example 6, in the synthesis of chiral intermediate 7, the chiral ligand N-((1R,2R)-2-amino-1,2-diphenylethyl)-1-((2R,4R)-camphorsulfonamide was used instead of the N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide chiral ligand in Example 6, and 2-(2-(N-methylpyrrolyl)ethanol was used instead of (R)-N-methylprolyl in Example 6. Yield: 48.1%. HRMS (ESI) (m / z) [M+H] + calcd forC 30 H 31 N6O2, 507.25085; found, 507.33501 and HPLC purity: 99.5886%. 1 H-NMR (400MHz, d 6 -DMSO) δ 8.65 (s, 2H), 8.47 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 1.8 Hz,1H), 8.31 – 8.26 (m, 1H), 8.24 – 8.19 (m, 1H), 8.14 (d, J = 9.8 Hz, 1H), 7.98– 7.86 (m, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.59 – 7.40 (m, 2H), 7.11 (d, J =9.8 Hz, 1H), 6.37 (q, J = 6.9 Hz, 1H), 4.22 (t, J = 5.8, 2H), 2.97 (ddd, J =9.7, 6.7, 3.4 Hz, 1H), 2.34 – 2.18 (m, 4H), 2.16 – 2.06 (m, 2H), 1.94 (dt, J= 13.5, 7.4 Hz, 1H), 1.83 (d, J = 7.0 Hz, 3H), 1.72 – 1.60 (m, 3H), 1.55 –1.47 (m, 1H). 13 C-NMR (101 MHz, d 6-DMSO) δ 159.00, 156.35, 151.99, 144.64,142.05, 141.89, 137.72, 136.26, 133.32, 130.84, 130.78, 130.60, 130.17,129.80, 129.37, 129.12, 126.81, 126.44, 119.07, 112.68, 67.09, 63.28, 57.02, 56.11, 40.72, 32.86, 30.73, 22.18, 20.34.

[0052] Example 14 Synthesis of target compound 14 The same method as in Example 6 was used in the synthesis of target compound 14, except that (R)-N-methylprolyl was replaced with (3-(N-methylpyrrolyl))methanol in Example 6. Yield: 47.7%. HRMS (ESI) (m / z) [M+H] + calcd for C 29 H 29 N6O2, 493.23520; found, 493.31406 and HPLC purity: 96.2682%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.65 (s, 2H), 8.48 (d, J = 1.9 Hz, 1H), 8.39 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H),7.93 (d, J = 7.7 Hz, 1H), 7.79 – 7.70 (m, 1H), 7.59 – 7.40 (m, 2H), 7.11 (d,J = 9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.14 – 3.95 (m, 2H), 2.71 – 2.54(m, 3H), 2.47 – 2.43 (m, 2H), 2.30 (s, 3H), 2.02 – 1.95 (m, 1H), 1.84 (d, J =7.0 Hz, 3H), 1.59 – 1.51 (m, 1H). 13 C-NMR (101 MHz,d 6 -DMSO) δ 159.00, 156.42,152.04, 144.64, 142.03, 141.87, 137.71, 136.24, 133.30, 130.82, 130.76,130.58, 130.16, 129.78, 129.36, 129.11, 126.83, 126.47, 119.06, 112.68,72.21, 59.06, 56.12, 55.71, 42.04, 37.36, 27.81, 20.32. Example 15 Synthesis of target compound 15 Following the same method as in Example 6, in the synthesis of chiral intermediate 7, the chiral ligand N-((1R,2R)-2-amino-1,2-diphenylethyl)-1-((2R,4R)-camphorsulfonamide was used instead of the N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide chiral ligand in Example 6; in the synthesis of target compound 15, (R)-N-methylprolyl was used instead of (3-(N-methylpyrrolyl))methanol. Yield: 40.5%. HRMS (ESI) (m / z) [M+H] + calcd for C 29 H 29 N6O2, 493.23520; found, 493.31689 and HPLC purity: 96.8385%. 1 H-NMR (400 MHz, d 6-DMSO) δ 8.65 (s, 2H), 8.48 (d, J = 2.0 Hz, 1H), 8.38 (d, J= 1.8 Hz, 1H), 8.32 – 8.27 (m, 1H), 8.22 (d, J = 7.6, 1.6 Hz, 1H), 8.14 (d, J= 9.8 Hz, 1H), 7.93 (d, J = 7.7, 1.4 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.55– 7.44 (m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.16 –4.04 (m, 2H), 2.69 – 2.57 (m, 3H), 2.47 (t, J = 6.2 Hz, 2H), 2.31 (s, 3H), 2.05 – 1.94 (m, 1H), 1.84 (d, J = 7.0 Hz, 3H), 1.61 – 1.51 (m, 1H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 159.00, 156.43, 152.03, 144.64, 142.03, 141.87, 137.70,136.24, 133.29, 130.82, 130.76, 130.57, 130.15, 129.78, 129.35, 129.11,126.83, 126.47, 119.06, 112.67, 72.15, 58.99, 56.12, 55.69, 41.99, 37.34,27.77, 20.32.

[0053] Example 16 Synthesis of target compound 16 The same method as in Example 6 was used in the synthesis of target compound 16, except that 3-(pyrrolidone-1-yl)propanol was used instead of (R)-N-methylprolyl in Example 6. Yield: 55.0%. HRMS (ESI) (m / z) [M+H] + calcdfor C 30 H 31N6O2, 507.25085; found, 507.33501 and HPLC purity: 98.0267%. 93.6% eewas determined by HPLC analysis on a Daicel Chiralpak AD-H column. 1 H-NMR (400MHz, d 6 -DMSO) δ 8.64 (s, 2H), 8.48 (s, 1H), 8.39 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.56 – 7.44 (m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 2.57 (t, J = 7.2 Hz, 2H), 2.48 – 2.51 (m, 4H), 1.98 – 1.89 (m, 2H), 1.84 (d, J = 7.0 Hz, 3H), 1.72 –1.64 (m, 4H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 158.99, 156.33, 152.02, 144.62,142.02, 141.86, 137.72, 136.24, 133.29, 130.81, 130.75, 130.56, 130.15,129.78, 129.34, 129.08, 126.81, 126.45, 119.05, 112.67, 67.44, 56.12, 54.04,52.38, 28.39, 23.55, 20.32. Example 17 Synthesis of target compound 17 Following the same method as in Example 6, in the synthesis of chiral intermediate 7, the chiral ligand N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2R,4R)-camphorsulfonamide was replaced with the chiral ligand N-((1S,2S)-2-amino-1,2-diphenylethyl)-1-((2S,4S)-camphorsulfonamide) in Example 1; in the synthesis of target compound 17, 3-(pyrrolidone-1-yl)propanol was replaced with (R)-N-methylprolyl in Example 6. Yield: 51.3%. HRMS (ESI) (m / z) [M+H] + calcd for C 30 H 31 N6O2, 507.25085; found, 507.33215 and HPLC purity: 99.6246%.84.5% ee was determined by HPLC analysis on a Daicel Chiralpak AD-Hcolumn. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.64 (s, 2H), 8.48 (s, 1H), 8.39 (s, 1H),8.29 (d, J = 8.1 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 9.8 Hz, 1H),7.93 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.58 – 7.42 (m, 2H), 7.11(d, J = 9.7 Hz, 1H), 6.38 (q, J = 7.0 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 2.56(t, J = 7.1 Hz, 2H), 2.49 – 2.38 (m, 4H), 1.97 – 1.88 (m, 2H), 1.84 (d, J =7.0 Hz, 3H), 1.72 – 1.61 (m, 4H). 13 C-NMR (101 MHz, d 6-DMSO) δ 158.99, 156.33,152.03, 144.61, 142.02, 141.86, 137.72, 136.24, 133.29, 130.81, 130.75,130.56, 130.15, 129.78, 129.34, 129.08, 126.81, 126.45, 119.05, 112.67,67.47, 56.12, 54.05, 52.40, 28.46, 23.56, 20.32.

[0054] Example 18 Synthesis of target compound 18 The same method as in Example 6 was used in the synthesis of target compound 18, except that (R)-N-methylprolyl was replaced with (R)-N-ethylprolyl in Example 6. Yield: 45.9%. HRMS (ESI) (m / z) [M+H] + calcd forC 30 H 31 N6O2, 507.25085; found, 507.25289 and HPLC purity: 99.69%. 1H-NMR (400MHz, CDCl3) δ 8.66 (d, J = 1.9 Hz, 1H), 8.52 (s, 2H), 8.28 (dt, J = 7.8, 1.5Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.99 (dt, J = 8.0, 1.6 Hz, 1H), 7.69 (dt,J = 7.8, 1.4 Hz, 1H), 7.62 – 7.51 (m, 3H), 7.43 (t, J = 7.7 Hz, 1H), 7.03 (d,J = 9.7 Hz, 1H), 6.55 (q, J = 7.0 Hz, 1H), 4.15 (dd, J = 9.3, 5.0 Hz, 1H),4.01 (dd, J = 9.3, 6.3 Hz, 1H), 3.30 – 3.20 (m, 1H), 2.98 (tdd, J = 14.9,11.7, 6.5 Hz, 2H), 2.53 – 2.46 (m, 1H), 2.36 – 2.30 (m, 1H), 2.09 – 2.01 (m,1H), 1.92 (d, J = 7.0 Hz, 3H), 1.86 – 1.80 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H). 13 C-NMR (101 MHz, CDCl3) δ 159.24, 157.41, 151.66, 144.03, 141.76, 140.66,137.88, 136.37, 132.43, 130.30, 129.86, 129.75, 129.60, 129.37, 128.75,128.64, 127.24, 126.99, 118.56, 113.39, 71.68, 62.72, 56.34, 53.96, 49.59,29.70, 28.43, 23.12, 20.03, 13.69. Example 19 Synthesis of target compound 19 The same method as in Example 6 was used in the synthesis of target compound 19, except that furan-methanol was used instead of (R)-N-methylprolyl in Example 6. Yield: 49.4%. HRMS (ESI) (m / z) [M+H] + calcd for C 28 H26 N5O3,480.20356; found, 480.25201 and HPLC purity: 95.3705%. 1 H-NMR (400 MHz, d 6 -DMSO)δ 8.66 (s, 2H), 8.48 (s, 1H), 8.38 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 8.22(d, J = 7.5 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.61 – 7.40 (m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 6.38 (q,J = 7.0 Hz, 1H), 4.23 – 4.05 (m, 2H), 3.80 (dt, J = 13.1, 7.5 Hz, 2H), 3.71 –3.64 (m, 1H), 3.57 (dd, J = 8.8, 5.4 Hz, 1H), 2.74 – 2.67 (m, 1H), 2.10 –1.99 (m, 1H), 1.84 (d, J = 7.1 Hz, 3H), 1.69 (dt, J = 12.7, 6.7 Hz, 1H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 158.99, 156.48, 151.98, 144.67, 142.02, 141.88,137.69, 136.24, 133.29, 130.81, 130.76, 130.57, 130.15, 129.78, 129.35,129.12, 126.84, 126.48, 119.06, 112.67, 70.88, 70.11, 67.37, 56.12, 38.56,28.89, 20.32. Example 20 Synthesis of target compound 20 (1) Synthesis of deuterated N-methylprolyl intermediate 9 Under ice bath conditions, lithium aluminum hydride (LiAlD4, 4.5 mmol) was added to an anhydrous tetrahydrofuran (THF, 10 mL) solution of SN-methylproline (3.00 mmol). The ice bath was removed, and the mixture was stirred under reflux under nitrogen protection and monitored by TLC. After the reaction was complete, the reaction mixture was cooled to room temperature, and then ice water and 5% NaOH aqueous solution were added sequentially. The resulting mixture was filtered through diatomaceous earth. The filtrate was extracted with ethyl acetate; the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain deuterated N-methylproline intermediate 9, which was directly used in the next step.

[0055] (2) Target compound 20 was prepared using the same method as in Example 6, except that deuterated N-methylprolyl intermediate 9 was used instead of (R)-N-methylprolyl in Example 6. Yield: 46.1%. HRMS (ESI) (m / z) [M+H] + calcdfor C 29 H 27 D2N6O2, 495.24775; found, 495.30844 and HPLC purity: 99.0815%. 1 H-NMR (400 MHz, d 6 -DMSO) δ 8.66 (s, 2H), 8.47 (s, 1H), 8.39 (s, 1H), 8.29 (d, J =8.2 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.93 (d, J =7.7 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.60 – 7.43 (m, 2H), 7.11 (d, J = 9.7Hz, 1H), 6.37 (q, J = 7.0 Hz, 1H), 3.04 – 2.95 (m, 1H), 2.66 (brs, 1H), 2.40(s, 3H), 2.30 – 2.20 (m, 1H), 2.04 – 1.95 (m, 1H), 1.84 (d, J = 7.1 Hz, 3H), 1.75 – 1.62 (m, 3H). 13 C-NMR (101 MHz, d 6-DMSO) δ 159.00, 156.39, 152.11,144.71, 142.04, 141.89, 137.71, 136.25, 133.31, 130.84, 130.78, 130.61,130.17, 129.80, 129.38, 129.11, 126.82, 126.46, 119.06, 112.68, 63.95, 57.46,56.12, 41.72, 28.56, 23.14, 20.34. Example 21 Synthesis of target compound 21 (1) Synthesis of deuterated intermediate 10 Using the same synthesis method as in Example 20, in the synthesis of deuterated intermediate 10, S-proline protected by N-Boc can be used instead of SN-methylproline.

[0056] (2) Target compound 21 was prepared using the same method as in Example 6, except that deuterated alcohol intermediate 10 was used instead of (R)-N-methylprolyl in Example 6. Yield: 47.4%. HRMS (ESI) (m / z) [M+H] + calcd forC 29 H 24 D5N6O2, 498.26658; found, 498.32265 and HPLC purity: 96.9984%. 1 H-NMR (400MHz, d 6-DMSO) δ 8.67 (s, 2H), 8.47 (d, J = 8.0 Hz, 1H), 8.41 – 8.35 (m, 1H), 8.29 (d, J = 8.1 Hz, 1H), 8.23 ​​(d, J = 7.6 Hz, 1H), 8.13 (t, J = 8.9 Hz, 1H),7.93 (d, J = 7.8 Hz, 1H), 7.79 – 7.64 (m, 1H), 7.58 – 7.43 (m, 2H), 7.12 (d,J = 9.7 Hz, 1H), 6.38 (q, J = 7.1 Hz, 1H), 3.10 – 2.97 (m, 1H), 2.79 – 2.65(m, 1H), 2.30 (d, J = 10.6 Hz, 1H), 2.08 – 1.95 (m, 1H), 1.83 (d, J = 7.5 Hz, 3H), 1.77 – 1.61 (m, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 159.00, 156.43, 152.05,144.70, 142.03, 137.71, 136.24, 133.29, 130.82, 130.76, 130.58, 130.16,129.78, 129.36, 129.11, 126.83, 126.47, 119.06, 112.68, 64.00, 57.31, 56.12,28.44, 23.10, 20.33. Example 22 Synthesis of target compound 22 (1) Synthesis of deuterated intermediate 11 Using the same synthesis method as in Example 20, in the synthesis of deuterated intermediate 11, SN-methylproline can be replaced with N-Boc-protected SN-methylproline.

[0057] (2) Target compound 22 was prepared using the same method as in Example 6, except that (R)-N-methylprolyl was replaced with deuterated intermediate 11. Yield: 52.7%. HRMS (ESI) (m / z) [M+H] + calcd for C 29 H 26D3N6O2,496.25403; found, 496.32160 and HPLC purity: 98.0587%. 1 H-NMR (400 MHz, d 6 -DMSO)δ 8.67 (s, 2H), 8.48 (s, 1H), 8.39 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.22(d, J = 7.6 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.58 – 7.44 (m, 2H), 7.11 (d, J = 9.7 Hz, 1H), 6.38 (q,J = 7.0 Hz, 1H), 4.25 – 4.05 (m, 2H), 3.07 – 2.98 (m, 1H), 2.72 (brs, 1H), 2.29 (d, J = 9.1 Hz, 1H), 2.06 – 1.97 (m, 1H), 1.84 (d, J = 7.0 Hz, 3H), 1.77– 1.58 (m, 3H). 13 C-NMR (101 MHz, d 6 -DMSO) δ 159.00, 156.43, 152.06, 144.70,142.03, 141.88, 137.70, 136.24, 133.30, 130.82, 130.76, 130.58, 130.16,129.78, 129.36, 129.11, 126.83, 126.47, 119.06, 112.68, 64.12, 57.33, 56.12,28.54, 23.11, 20.33. Example 23 Synthesis of target compound 23 The same synthetic method as in Example 1 was used, except that deuterated intermediate 11 was substituted for SN-methylproline. Yield: 66.8%. HRMS (ESI) (m / z) [M+H] + calcd for C 28 H 24D3N6O2, 482.23838; found,482.22550 and HPLC purity: 99.69%. 1 H-NMR (400 MHz, CDCl3) δ 8.57 (d, J = 1.8Hz, 1H), 8.54 – 8.51 (m, 2H), 8.29 (d, J = 7.8Hz, 1H), 8.16 – 8.13 (m, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.69 (d, J = 7.8Hz, 1H), 7.63 (d, J = 9.7 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.44 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 9.7 Hz, 1H), 5.50 (s, 2H), 4.14 (dd, J = 9.3, 5.3 Hz, 1H), 4.06 (dd, J = 9.4, 5.3 Hz, 1H), 3.16 (ddd, J = 9.1, 6.9, 2.2 Hz, 1H), 2.81 – 2.71 (m, 1H), 2.41 – 2.31 (m,1H), 2.13 – 2.00 (m, 1H), 1.93 – 1.73 (m, 3H). 13 C-NMR (101 MHz, CDCl3) δ159.41, 157.37, 151.65, 143.96, 142.14, 137.93, 136.14, 136.00, 132.52,130.78, 130.31, 129.92, 129.78, 129.68, 129.37, 128.99, 128.35, 127.35,118.44, 113.36, 71.28, 64.16, 57.60, 55.44, 28.41, 23.11. Test Example 1: Inhibitory activity of the target compound against hepatocellular carcinoma cells MHCC97H and non-small cell lung cancer cells EBC-1. This invention tested the antiproliferative activity of the provided target compound against human hepatocellular carcinoma cells MHCC97H and human non-small cell lung cancer cells EBC-1 using the MTT assay, with terpoxtinib as a positive control. The specific experimental steps are as follows: MHCC-97H cells were cultured in high-glucose DMEM medium containing 10% fetal bovine serum (FBS), and EBC-1 cells were cultured in a medium prepared with FBS, penicillin, and DMEM at a ratio of 10:1:89. Both cell lines were cultured at 37°C in a 5% CO2 incubator. The antiproliferative activity of the compound was assessed using the MTT assay. Cells were first digested with trypsin and resuspended into a single-cell suspension. Cell counting was performed using a hemocytometer, and 5,000 cells were seeded into each well of a 96-well plate. After incubation for 24 hours, drug solutions with preset concentration gradients were added, and the cells were cultured for another 72 hours. After culture was terminated, 10 μL of MTT solution (5 mg / mL) prepared in PBS was added to each well. After 4 hours of incubation, remove the supernatant and add 150 μL of DMSO to each well. Shake the wells to ensure complete dissolution of the crystals. Measure the absorbance at 570 nm using a microplate reader and calculate the inhibition rate using the following formula: Inhibition rate (%) = 1 - (Experimental group OD - Blank control OD) / (Negative control OD - Blank control OD). Finally, calculate the IC50 value using GraphPad Prism software. Perform at least three independent replicates.

[0058] Table 1. Effects of the compounds in the examples on hepatocellular carcinoma cells MHCC97H and non-small cell lung cancer cells EBC-1. Inhibitory activity (IC) 50 ,nM)

[0059] The data in Table 1 show that the target compounds provided by this invention exhibit excellent anti-proliferative activity against human liver cancer cells MHCC97H and non-small cell lung cancer cells EBC-1, with some target compounds showing better performance than the positive control drug terpoxtinib.

[0060] Test Example 2: In vivo antitumor activity test of representative compounds (compounds of Examples 18 and 23, test codes (R)-21m, 11g, respectively) in nude mice. To further investigate the antitumor effects of the compounds of this invention, in vivo antitumor activity studies were conducted in animals. The experimental procedures are as follows: BALB / c nude mice (3-5 weeks old, 18-20 g) were used. Human non-small cell lung cancer cells (EBC-1) cultured to the 3rd-5th generation in logarithmic growth phase were digested with trypsin and then prepared into 1.0 × 10⁻⁶ m² / g medium. 7A cell suspension with a concentration of [number] cells / ml was prepared. Cells were subcutaneously injected into the right axilla of nude mice to establish a tumor growth model. The tumor was cultured until its average volume reached 250 mm². 3 Mice were randomly divided into 5 groups: a model control group, a positive control group (terpollinib, 4 mg / kg), a compound from Example 18 (4 mg / kg), a compound from Example 18 (8 mg / kg), and a compound from Example 23 (4 mg / kg), with 8 mice in each group. Each experimental group received the prescribed dose via gavage (20 mL / kg), while the model control group received the solvent via gavage. Administered once daily for 16 consecutive days. Tumor diameter and body weight were measured two days after administration to each group. After the last administration, mice were sacrificed using carbon dioxide inhalation, tumor tissue was dissected, and the tumor weight was measured and photographed. The tumor inhibition rate (TGI) was calculated (based on mouse tumor weight). The experimental results are as follows: Figure 3 As shown, Figure 3 In the figures: A shows the growth curves of xenografted tumors in nude mice in different drug administration groups; B shows the final tumor volume and tumor growth inhibition rate of nude mice in each group after 16 days of drug administration; C shows the weight change curves of mice in each group during the drug administration period; and D shows the actual images of ex vivo tumors of nude mice in each group after 16 days of drug administration.

[0061] Figure 3 The results showed that, at the same dosage, both compound 18 (R)-21m, TGI: 58.6%) and compound 23 (11g, TGI: 64.9%) exhibited better in vivo antitumor activity than the positive control drug terpoltinib group (TGI: 33.5%). Increasing the dose of compound 18 to 8 mg / kg resulted in a tumor growth inhibition rate of 77.3%, demonstrating a clear dose-dependent relationship. No weight loss was observed in any group throughout the trial.

[0062] To assess the safety of the test compounds, we randomly selected major organs (liver, heart, spleen, lung, kidney, etc.) from 3-4 mice in each group for HE staining to determine the toxic side effects of the test compounds on normal mouse organs. The histopathological examination results of the major organs are as follows: Figure 4 As shown, Figure 4 The results showed that mild to slight mononuclear cell infiltration was observed in the perivascular area and sinusoids of the liver in some animals in the terpotentiib group and the compound group of Example 18 (code (R)-21m, 8mg / kg), while no such phenomenon was observed in the compound group of Example 23 (code 11g), indicating that the target compound of Example 23 has higher safety and lower toxicity.

[0063] Test Example 3: Liver microsomal stability analysis of representative compounds (Examples 2 and 23) The metabolic stability of a drug has a significant impact on its bioavailability, which in turn affects its in vivo safety and therapeutic efficacy. To preliminarily explore the metabolic stability of the target compound in this invention, a rat liver microsomal stability test was conducted on the deuterated target compound of Example 23 and the corresponding non-deuterated compound (target compound of Example 2), using terpoxtinib as a reference. The results are shown in Table 2.

[0064] Table 2. Liver microsomal stability tests of representative compounds

[0065] The results in Table 2 show that the target compound of Example 2 had a slightly longer half-life (T1 / 2) than terpoxtinib (13.58 and 11.14 minutes, respectively) and a lower clearance rate (102.06 and 124.41 ml / min / g, respectively), indicating that the target compound of Example 2 has good metabolic stability. Compared with the target compound of Example 2, the target compound of Example 23 had a longer half-life and a lower clearance rate (T1 / 2 = 18.78 minutes, Clint = 73.80 ml / min / g), indicating that deuterium substitution at specific sites of the drug molecule helps to improve its stability.

[0066] Test Example 4: Test of the blood-brain barrier crossing of a representative compound (Example 23) Statistics show that up to 30% to 50% of non-small cell lung cancer (NSCLC) patients develop brain metastases during the course of their disease. As one of the key driver gene variants closely related to brain metastases in NSCLC, c-Met gene abnormalities have a crucial impact on treatment strategies and prognosis. They are also one of the main causes of patient death and a key biological basis for acquired treatment resistance. To evaluate the blood-brain barrier penetration ability of the compounds provided in this invention, the target compound in Example 23 was used as a representative. First, the lipophilicity parameter LogP was predicted using the SwissADM online tool and compared with the reference drug terpoltinib. The results showed that the LogP value of the target compound in Example 23 was 3.71, slightly higher than that of terpoltinib (3.61), indicating that the former has stronger lipophilicity and is theoretically more likely to cross the blood-brain barrier. Furthermore, the blood-brain barrier penetration ability of the target compound in Example 23 in BALB / c-nu mice was evaluated by measuring the drug concentration in brain tissue homogenate and plasma at different time points after administration and calculating the brain / plasma ratio (B / P). The results are shown in Table 3.

[0067] Table 3. Example 23 Compound and Terpotinib Blood-Brain Barrier Crossing Test in Mice

[0068] The results in Table 3 show that, 4 hours after administration, the brain / plasma ratio of the target compound in Example 23 reached 78.14%, while that of terpoxtinib was only 37.52%. This indicates that the brain penetration ability of the target compound in Example 23 is significantly better than that of terpoxtinib, demonstrating its excellent potential in inhibiting brain metastases in patients with non-small cell lung cancer.

[0069] 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 with a chiral pyrrolidinium side chain, or a pharmaceutically acceptable salt or solvate thereof, characterized in that, The pyrimidine derivative with a chiral pyrrolidinium side chain has the structure shown in Formula I: Equation I; In Formula I: R is hydrogen, alkyl, or substituted alkyl; the number of carbon atoms in the alkyl or substituted alkyl is 1 to 4; the substituent on the substituted alkyl is deuterium or a halogen atom; X is hydrogen or deuterium; R 1 It can be any of the following structures: 。 2. The pyrimidine derivative with a chiral pyrrolidinium side chain according to claim 1, or its pharmaceutically acceptable salt or solvate, is characterized in that, The pyrimidine derivative with a chiral pyrrolidinium side chain has any one of the following structures: 。 3. The pyrimidine derivative with a chiral pyrrolidinium side chain according to claim 1, or its pharmaceutically acceptable salt or solvate, is characterized in that... The pharmaceutically acceptable salts of the pyrimidine derivatives with chiral pyrroleyl groups in the side chains include any one of chloride, acetate, and methanesulfonate ions as anions.

4. The pyrimidine derivative with a chiral pyrrolidinium side chain according to claim 1, or its pharmaceutically acceptable salt or solvate, characterized in that, The solvate of the pyrimidine derivative with a chiral pyrrolidinium side chain is a hydrate.

5. The method for preparing the pyrimidine derivative with a chiral pyrrolidinium side chain according to any one of claims 1 to 4, characterized in that, When R and X are hydrogen in Formula I, the preparation method includes the following steps: (1) 3-hydroxymethylphenylboronic acid, 2-iodo-5-bromopyrimidine, palladium catalyst, sodium carbonate and solvent were mixed and reacted to obtain intermediate 1; (2) The intermediate 1, thionyl chloride and dichloromethane are mixed and reacted to obtain intermediate 2; (3) The intermediate 2, 6-(3-cyanophenyl)-pyridazinone, potassium carbonate and solvent are mixed and reacted to obtain intermediate 3; (4) The intermediate 3, bis(pinacol)diboron, palladium catalyst, potassium acetate and solvent are mixed and reacted to obtain intermediate 4; (5) The intermediate 4, sodium perborate, tetrahydrofuran and water are mixed and reacted to obtain intermediate 5; (6) The intermediate 5, the compound with the structure shown in Formula A, triphenylphosphine, diisopropyl azodicarbonate and solvent are mixed and reacted to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain with the structure shown in Formula I. The structural formulas of intermediates 1 to 5 are shown in formulas 1 to 5: Formula 1; Formula 2; Formula 3; Equation 4; Equation 5; R 1 -OH Formula A; When R is an alkyl or substituted alkyl group and X is hydrogen in Formula I, the preparation method includes the following steps: (i) An acylphenylboronic acid derivative, 2-chloro-5-fluoropyrimidine, palladium catalyst and solvent were mixed and reacted to obtain intermediate 6; (ii) Intermediate 6, sodium formate, a chiral catalyst for asymmetric hydrogen transfer and solvent are mixed and reacted to obtain intermediate 7; (iii) Intermediate 7, 6-(3-cyanophenyl)-pyridazinone, cyanomethylenetri-n-butylphosphine and solvent are mixed and reacted to obtain intermediate 8; (iv) Intermediate 8, the compound with the structure shown in Formula A, sodium hydride and solvent are mixed and reacted to obtain a pyrimidine derivative with a chiral pyrrolidinyl side chain with the structure shown in Formula I. The structural formulas of intermediates 6 to 8 are shown in Formulas 6 to 8, and the structural formula of the acylphenylboronic acid derivative is shown in Formula 9. Formula 6; Formula 7; Formula 8; Formula 9.

6. The use of the pyrimidine derivative with a chiral pyrrolidinium side chain as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of c-Met kinase inhibitors.

7. The use of the pyrimidine derivative with a chiral pyrrolidinium side chain as described in any one of claims 1 to 4, or its pharmaceutically acceptable salt or solvate, in the preparation of an anticancer drug.

8. The application according to claim 7, characterized in that, The cancer in question is either liver cancer or non-small cell lung cancer.

9. A pharmaceutical composition, characterized in that, It includes an active ingredient and a pharmaceutically acceptable adjuvant; the active ingredient is a pyrimidine derivative with a chiral pyrrolidinium side chain as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt or solvate thereof.

10. The pharmaceutical composition according to claim 9, characterized in that, The dosage form of the pharmaceutical composition is any one of injection, tablet, capsule, pill, suspension, emulsion, microsphere, and liposome.

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