Pyrimidine ring-containing hydrazone compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a pyrimidine ring-containing hydrazone compound as well as a preparation method and application thereof. The compound is specifically a compound as shown in a formula I and any one or more of pharmaceutically acceptable salts, stereoisomers, tautomers, homologues, solvates, prodrugs or polymorphic substances thereof. Researches prove that the compound has a good anti-tumor effect, particularly has a relatively strong killing effect on cervical cancer cells, has low toxicity to normal cells, and is a safe, effective and low-toxicity candidate anti-tumor drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a hydrazone compound containing a pyrimidine ring and a preparation method and application thereof. BACKGROUND

[0002] Malignant tumor is one of the major diseases threatening the human beings all over the world, and seriously threatens the safety of human life. At present, the treatment methods of malignant tumor mainly include surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, gene therapy, etc. Among them, chemotherapy is one of the most important means for treating malignant tumor in the clinic, however, the chemotherapy drugs have problems such as large side effects and easy drug resistance. Therefore, it is necessary to develop new antitumor drugs to reduce the side effects of chemotherapy and improve the curative effect.

[0003] Hydrazone compounds have diverse chemical reactivity and biological activity, and therefore have attracted extensive attention of researchers in the field of drug discovery and development. They have a wide range of applications in the medical field, mainly in the aspects of anticonvulsant, antifungal, antidepressant, anticancer, analgesic, anti-inflammatory, antiviral, antiplatelet, antimalarial, antibacterial, cardioprotective / vasodilatory, anti-HIV, antiparasitic, antidiabetic, antiprotozoal, antitrypanosomal, and antischistosomal, etc. Pyrimidine compounds have been widely studied due to their anticancer, antimicrobial, anti-inflammatory, antihypertensive, antimalarial, and antiviral activities, and have important biological and pharmacological significance. Based on this, some researchers have explored hydrazone compounds containing pyrimidine rings. For example, the patent with the publication number CN107698565A discloses a class of hydrazone compounds containing indole pyrimidine rings, which uses indole, cyanoacetic acid and DMF-DMA as raw materials, synthesizes the intermediate 3-(dimethylamino)-2-(1H-indole-3-carbonyl)-acrylonitrile through two-step reaction, and then reacts with nitroguanidine to obtain the key intermediate 2-hydrazino-4-(1H-indole-3-carbonyl)-pyrimidine-5-carbonitrile through ring formation and nitro reduction, and then reacts with different aromatic aldehydes to obtain the target product. The compound contains both indole pyrimidine ring and acyl hydrazone active structures.

[0004] Therefore, it is of great significance to explore new hydrazone compounds containing pyrimidine rings for tumor treatment. SUMMARY

[0005] In view of this, one of the purposes of the present application is to provide a hydrazone compound containing a pyrimidine ring, which has the ability to kill cervical cancer cells, and provides a new direction and idea for the research and development of new antitumor drugs.

[0006] To achieve the above-mentioned purposes, the present application adopts the following technical solutions:

[0007] Hydrazones containing pyrimidine rings, the compounds being any one or more of compounds of formula I and pharmaceutically acceptable salts, stereoisomers, tautomers, homologues, solvates, prodrugs or polymorphs thereof;

[0008]

[0009] wherein R 1 are independently selected from:

[0010] R 2 , R 3 , R 4 are independently selected from: R 1 , R 2 , R 3 , R 4 are the same or different;

[0011] R 5 are independently selected from: R 1 , R 2 , R 3 , R 4 , R 5 are the same or different;

[0012] are independently selected from:

[0013] A, B, C, D, E are independently selected from carbon or nitrogen, A, B, C, D, E are the same or different.

[0014] Further, the compounds are any one or more of Compound 1-Compound 57 and pharmaceutically acceptable salts, stereoisomers, tautomers, homologs, solvates, prodrugs, or polymorphs thereof; Compound 1 is (E)-6-(2-((1H-indol-3-yl)methyl)hydrazino)-N,N-diethylpyrimidin-4-amine; Compound 2 is (E)-N,N-diethyl-6-(2-(2-methyl-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 3 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-2- carboxylic acid; Compound 4 is (E)-methyl 3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-2- carboxylate; Compound 5 is (E)-N,N-diethyl-6-(2-((4-methyl-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4- amine; Compound 6 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-4- carbonitrile; Compound 7 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-4- carboxylic acid; Compound 8 is methyl (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-4- carboxylate; Compound 9 is (E)-N,N-diethyl-6-(2-((4-(trifluoromethyl)-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4- amine; Compound 10 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indol-4-ol; Compound 11 is (E)-N,N-diethyl-6-(2-((4-methoxy-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4- amine; Compound 12 is (E)-N,N-diethyl-6-(2-((4-nitro-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4- amine; Compound 13 is (E)-N,N-diethyl-6-(2-((4-fluoro-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4- amine; Compound 14 is (E)-N,N-diethyl-6-(2-((5-methyl-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4- amine; Compound 15 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-5- carbonitrile; Compound 16 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-5- carboxylic acid; Compound 17 is methyl (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-5- carboxylate;The compound 18 is (E)-N,N-diethyl-6-(2-((5-(trifluoromethyl)-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 19 is (E)-3-((2-(6- (diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)-1H-indol-5-ol; the compound 20 is (E)-N,N-diethyl-6-(2-((5-methoxy-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin- 4-amine; the compound 21 is (E)-N,N-diethyl-6-(2-((5-nitro-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 22 is (E)-N,N-diethyl-6-(2- ((5-fluoro-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 23 is (E)-N,N-diethyl-6-(2-((6-methyl-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin- 4-amine; the compound 24 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)- 1H-indole-6-carbonitrile; the compound 25 is (E)-3-((2-(6-(diethylamino)pyrimidin-4- yl)hydrazonoyl)methyl)-1H-indole-6-carboxylic acid; the compound 26 is methyl (E)-3- ((2-(6-(diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)-1H-indole-6-carboxylic acid; the compound 27 is (E)-N,N-diethyl-6-(2-((6-(trifluoromethyl)-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 28 is (E)-3-((2-(6- (diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)-1H-indol-6-ol; the compound 29 is (E)-N,N-diethyl-6-(2-((6-methoxy-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin- 4-amine; the compound 30 is (E)-N,N-diethyl-6-(2-((6-nitro-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 31 is (E)-N,N-diethyl-6-(2- ((6-fluoro-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 32 is (E)-N,N-diethyl-6-(2-((7-methyl-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin- 4-amine; the compound 33 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)- 1H-indole-7-carboxylic acid; the compound 34 is methyl (E)-3-((2-(6-(diethylamino)pyrimidin- 4-yl)hydrazonoyl)methyl)-1H-indole-7-carboxylic acid; the compound 35 is (E)-N,N- diethyl-6-(2-((7-(trifluoromethyl)-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4- amine;The compound 36 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indol-7-ol; the compound 37 is (E)-N,N-diethyl-6-(2-((7-methoxy-1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-amine; the compound 38 is (E)-N,N-diethyl-6-(2-((7-nitro-1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-amine; the compound 39 is (E)-N,N-diethyl-6-(2-((7-fluoro-1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-amine; the compound 40 is (E)-6-(2-((1H-indazol-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 41 is (E)-6-(2-((1H-pyrrolo[3,2-b]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 42 is (E)-6-(2-((1H-pyrrolo[3,2-c]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 43 is (E)-6-(2-((1H-pyrrolo[2,3-c]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 44 is (E)-6-(2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 45 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N,N-dimethylpyrimidin-4-amine; the compound 46 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N-ethyl-N-methylpyrimidin-4-amine; the compound 47 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N-ethyl-N-propylpyrimidin-4-amine; the compound 48 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N,N-dipropylpyrimidin-4-amine; the compound 49 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N-ethyl-N-heptylpyrimidin-4-amine; the compound 50 is (E)-3-((2-(6-(piperidin-1-yl)pyrimidin-4-yl)hydrazono)methyl)-1H-indole; the compound 51 is (E)-3-((2-(6-(azocin-1-yl)pyrimidin-4-yl)hydrazono)methyl)-1H-indole; the compound 52 is (E)-3-(6-(2-((1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine; the compound 53 is (E)-4-(6-(2-((1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-yl)morpholine;The compound 54 is (E)-4-(6-(2-((1H-indol-3-yl)methyl)hydrazono)pyrimidin-4-yl)-3,5-dimethylmorpholine; the compound 55 is (E)-4-(6-(2-((1H-indol-3-yl)methyl)hydrazono)pyrimidin-4-yl)-2,6-dimethylmorpholine; the compound 56 is (E)-3-((2-(6-(4-methylpiperazin-1-yl)pyrimidin-4-yl)hydrazono)methyl)-1H-indole; and the compound 57 is (E)-3-((2-(6-(4-ethylpiperazin-1-yl)pyrimidin-4-yl)hydrazono)methyl)-1H-indole.

[0015] Further, the compound is any one or more of the compound 1, the compound 2, the compound 4, the compound 5, the compound 7, the compound 10, the compound 12 to the compound 15, the compound 18 to the compound 23, the compound 26, the compound 27, the compound 29, the compound 31, the compound 32, the compound 36, the compound 38 to the compound 42, the compound 44 to the compound 48, the compound 51, the compound 53, and the compound 54.

[0016] The second object of the present application is to provide a preparation method of the aforementioned hydrazone compound containing a pyrimidine ring.

[0017] To achieve the above object, the present application adopts the following technical solution:

[0018] The preparation method of the aforementioned hydrazone compound containing a pyrimidine ring comprises the following steps:

[0019] (1) taking 4,6-dichloropyrimidine and the compound III as raw materials, adding EtOH and Et3N, and reacting to obtain the compound IV;

[0020] (2) adding hydrazine hydrate to the compound IV obtained in step (1), and reacting to obtain the compound V;

[0021] (3) mixing the compound V obtained in step (2) with the compound VI, MeOH and CH3COOH, and refluxing to react to obtain the hydrazone compound containing a pyrimidine ring;

[0022] The structural formula of the compound III is shown in formula III, the structural formula of the compound IV is shown in formula IV, the structural formula of the compound V is shown in formula V, and the structural formula of the compound VI is shown in formula VI;

[0023]

[0024]

[0025] In formula III to formula VI, R 1 is arbitrarily selected from:

[0026] R 2 , R 3 , R 4 independently and arbitrarily selected from: R 1 , R 2 , R 3 , R 4 are the same or different;

[0027] R 5 are arbitrarily selected from: R 1 , R 2 , R 3 , R 4 , R 5 are the same or different;

[0028] are arbitrarily selected from:

[0029] A, B, C, D, E are independently and arbitrarily selected from carbon or nitrogen, and A, B, C, D, E are the same or different.

[0030] The preparation method provided by the present application is to synthesize the target product compound I from compound II, compound III and compound VI. The nitrogen atom in compound III has a lone pair of electrons, has nucleophilicity, attacks the chlorine atom with partial positive charge in compound II, and generates a nucleophilic substitution reaction to generate compound IV; the nitrogen atom in hydrazine hydrate has a lone pair of electrons, has nucleophilicity, attacks the chlorine atom with partial positive charge in compound IV, and generates a nucleophilic substitution reaction to generate compound V; the carbonyl group in compound VI has electrophilicity, the nitrogen atom in compound V has nucleophilicity, the nitrogen atom attacks the carbonyl carbon atom to generate rearrangement, and dehydration occurs to generate condensation reaction to generate the target product compound I.

[0031] Further, in step (1), the reaction temperature is -5°C to 5°C, and more preferably 0°C.

[0032] Further, in step (2), the reaction time is 8h-15h; and in step (3), the reaction time is 4h-8h.

[0033] As a preference, in step (2), the reaction time is 10h.

[0034] As a preference, in step (3), the reaction time is 5h.

[0035] Further, the molar ratio of the 4,6-dichloropyrimidine, the compound III and the Et3N is 1:1-1.5:1-1.5, preferably 1:1.1:1.1; the molar ratio of the compound IV and the hydrazine hydrate is 1:15-30, preferably 1:20; the molar ratio of the compound VI and the compound V is 1:1-1.5, preferably 1:1.1.

[0036] Further, in the step (1), the concentration of the 4,6-dichloropyrimidine in the EtOH is 0.5M.

[0037] Further, in the step (3), the concentration of the compound VI in the MeOH is 0.05M; the concentration of the compound VI in the CH3COOH is 10M, and the volume ratio of the MeOH and the CH3COOH is 200:1.

[0038] As a preferred technical scheme, the method comprises the following steps:

[0039] (1) mixing the compound II and the compound III, then adding the EtOH and the Et3N, stirring at 0℃ overnight; after the reaction is completed, vacuum concentration under reduced pressure, and then purified by silica gel column chromatography to obtain the compound IV;

[0040] (2) mixing the compound IV and the hydrazine hydrate, then refluxing and stirring for 10h; after the reaction is completed, quenching by adding water, extracting with ethyl acetate; washing the organic phase with saturated sodium chloride, drying the organic phase with anhydrous sodium sulfate, vacuum concentration under reduced pressure, and then purified by silica gel column chromatography to obtain the compound V.

[0041] (3) mixing the compound VI, the compound V, the MeOH and the CH3COOH, then refluxing and stirring for 5h; after the reaction is completed, cooling to room temperature, vacuum concentration under reduced pressure, and then purified by silica gel column chromatography to obtain the target product compound I.

[0042] The third object of the present application is to provide a pharmaceutical composition.

[0043] To achieve the above object, the present application adopts the following technical scheme:

[0044] The pharmaceutical composition contains the aforementioned hydra containing pyrimidine ring compound.

[0045] Further, the pharmaceutical composition further contains a pharmaceutically acceptable carrier or excipient.

[0046] The fourth object of the present application is to provide the use of the aforementioned hydra containing pyrimidine ring compound in the preparation of an antitumor drug.

[0047] To achieve the above object, the present application adopts the following technical scheme:

[0048] The use of the aforementioned hydra containing pyrimidine ring compound in the preparation of an antitumor drug.

[0049] Further, the tumor includes cervical cancer.

[0050] The present application has the advantages of:

[0051] 1. The hydrazone compound containing a pyrimidine ring has good anti-tumor effect, strong killing ability to cervical cancer cells, low toxicity to normal cells, safety, effectiveness and low toxicity. The hydrazone compound containing a pyrimidine ring has important significance for the research and development of new anti-tumor drugs. BRIEF DESCRIPTION OF DRAWINGS

[0052] Figure 1 The preparation process flow chart of the hydrazone compound containing a pyrimidine ring. DETAILED DESCRIPTION

[0053] The technical solutions of the present application will be further clearly and completely described below in combination with specific examples. Obviously, the described examples are only some of the embodiments of the present application, not all the embodiments. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments in the present application without creative labor are within the protection scope of the present application.

[0054] In the embodiments of the present application, the raw material compounds 1, 2 and 5 involved in the experiment are purchased from Shanghai Bide Pharmaceutical, Meril, Aladdin, Shin and the like; the rest of the reagents are purchased from Chengdu Kolon Chemical Co., Ltd., with purity of AR or CP grade; the glass instruments used in the experiment are purchased from Beijing Lianhua and Xingwei Glass Instrument Co., Ltd., and are used after washing and drying.

[0055] In the embodiments of the present application, the preparation method of compound I is as follows:

[0056] (1) Preparation of compound IV

[0057] Compound II (1 mmol, 1 eq) and compound III (1.1 mmol, 1.1 eq) were weighed and placed in a two-neck reaction bottle, a stirring rod was added, 2 mL of EtOH was added, the reaction bottle was placed at 0℃, and then Et3N (1.1 mmol, 1.1 eq) was added, and the reaction was carried out at 0℃ overnight, and the reaction progress was monitored by TLC; after the reaction was completed, vacuum concentration was carried out, and the crude product was purified by silica gel column chromatography to obtain compound IV.

[0058] (2) Preparation of compound V

[0059] Compound IV (1 eq) was weighed into a two-necked reaction flask, a stirring bar was added, a condenser was mounted, hydrazine hydrate (20 eq) was added, and the mixture was stirred under reflux for 10 h. After the reaction was completed, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The crude product was concentrated under vacuum and reduced pressure, and the target product Compound V was obtained by column chromatography on silica gel.

[0060] (3) Preparation of Compound I

[0061] Compound VI (0.5 mmol, 1 eq) and Compound V (0.55 mol, 1.1 eq) were weighed into a two-necked reaction flask, a stirring bar was added, a condenser was mounted, 10 mL of MeOH was added, and then 0.05 mL of CH3COOH was added. The mixture was stirred under reflux for 5 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was cooled to room temperature, concentrated under vacuum and reduced pressure, and the target product Compound I was obtained by column chromatography on silica gel.

[0062] wherein Compound II is 4,6-dichloropyrimidine, the structural formula of which is shown in Formula II; the general structural formula of Compound III is shown in Formula III; the general structural formula of Compound IV is shown in Formula IV; the general structural formula of Compound V is shown in Formula V; the general structural formula of Compound VI is shown in Formula VI; and the general structural formula of Compound I is shown in Formula I;

[0063]

[0064] In Compounds I-Compound VI, R 1 is independently selected from:

[0065] R 2 , R 3 , R 4 is independently selected from: R 1 , R 2 , R 3 , R 4 are the same or different;

[0066] R 5 is independently selected from:

[0067] R 1 , R 2 , R 3 , R 4 , R 5 are the same or different;

[0068] is independently selected from:

[0069]

[0070] A, B, C, D, E are independently selected from carbon or nitrogen, and A, B, C, D, E are the same or different.

[0071] In the embodiments of the present application, the structural formulae of some of the compounds are shown in Table 1.

[0072] Table 1. Compound information table

[0073]

[0074]

[0075] In the embodiments of the present application, the compound I is specifically compound 1-compound 57, and the basic information of the target compounds 1-compound 57 is shown in Table 2.

[0076] Table 2. Basic information table of target compounds 1-compound 57

[0077]

[0078]

[0079]

[0080]

[0081]

[0082]

[0083]

[0084]

[0085] Example 1. Preparation of compound 1

[0086] (1) Preparation of compound IV

[0087] Weigh 4,6-dichloropyrimidine (2 mmol, 296 mg, 1 eq) and diethylamine (2.2 mmol, 160 mg, 1.1 eq) into a two-neck reaction bottle, add a stirring rod, add 4 mL of EtOH, place the reaction bottle at 0°C, then add Et3N (2.2 mmol, 222 mg, 1.1 eq), and react overnight at 0°C. Monitor the reaction progress by TLC. After the reaction is completed, concentrate under vacuum and reduce pressure, and purify the crude product by silica gel column chromatography to obtain 6-chloro-N,N-diethylpyrimidin-4-amine, with a yield of 215 mg and a yield of 58%.

[0088] (2) Preparation of compound V

[0089] Step (1) prepared 6-chloro-N,N-diethylpyrimidin-4-amine (1 mmol, 185 mg, 1 eq) was weighed into a two-necked reaction flask, a stirring bar was added, a condensation reflux tube was placed, hydrazine hydrate (20 mmol, 641 mg, 20 eq) was added, and stirring was performed under reflux for 10 h. After the reaction was completed, water was added for quenching, and extraction was performed with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under vacuum and reduced pressure. The crude product was purified by silica gel column chromatography to obtain N,N-diethyl-6-hydrazinylpyrimidin-4-amine (Compound V) in a yield of 157 mg and a yield of 87%.

[0090] (3) Preparation of Compound I

[0091] Compound VI is

[0092] Compound VI (0.5 mmol, 72 mg, 1 eq) and Compound V prepared in step (2) (0.55 mmol, 99 mg, 1.1 eq) were weighed into a two-necked reaction flask, a stirring bar was added, a condensation reflux tube was placed, 10 mL of MeOH was added, and then 0.05 mL of CH3COOH was added. Stirring was performed under reflux for 5 h, and the progress of the reaction was monitored by TLC. After the reaction was completed, cooling was performed to room temperature, and concentration was performed under vacuum and reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target product Compound 1 in a yield of 119 mg and a yield of 77% and a HPLC purity of 99.17%.

[0093] 1 H-NMR results: δ 11.41 (s, 1H), 10.52 (s, 1H), 8.24 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.05 (s, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.3 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.20 (s, 1H), 3.49 (q, J = 6.7 Hz, 4H), 1.15 (t, J = 6.9 Hz, 6H).

[0094] Example 2. Preparation of Compounds 2-44

[0095] Compounds 2-44 were prepared according to the method of Example 1, with the exception that the starting compound VI was different. Compound VI was selected from indoles substituted with different position substituents, and the compound VI and the corresponding final product are shown in Table 3. The yield, HPLC purity, and 1 H-NMR results are shown in Table 4.

[0096] Table 3. Starting compound VI for Compounds 2-44

[0097]

[0098]

[0099]

[0100] Table 4

[0101]

[0102]

[0103]

[0104]

[0105] Example 3. Preparation of compound 45

[0106] (1) Preparation of compound IV

[0107] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and dimethylamine (99 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction bottle, add a stirring rod, add 4 mL of EtOH, place the reaction bottle at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), react at 0°C overnight, monitor the reaction progress by TLC, after the reaction is completed, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 6-chloro-N,N-dimethylpyrimidin-4-amine, with a yield of 154 mg and a yield of 49%.

[0108] (2) Preparation of compound V

[0109] Take 6-chloro-N,N-dimethylpyrimidin-4-amine (142 mg, 0.9 mmol, 1 eq) into a two-necked reaction bottle, add a stirring rod, mount a condenser reflux tube, add hydrazine hydrate (577 mg, 18 mmol, 20 eq), stir for 10 h under reflux, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain N,N-dimethyl-6-hydrazinylpyrimidin-4-amine, with a yield of 123 mg and a yield of 80%.

[0110] (3) Preparation of compound I

[0111] The target product compound 45 was prepared from 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and N,N-dimethyl-6-hydrazinylpyrimidin-4-amine (0.55 mmol, 84 mg, 1.1 eq) prepared in step (2) according to the method of step (3) "Preparation of compound I" in Example 1, with a yield of 56 mg, a yield of 40%, and an HPLC purity of 98.34%.

[0112] 1 H-NMR results: δ 11.46 (s, 1H), 10.54 (s, 1H), 8.26 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.05 (s, 1H), 7.69 (d, J = 2.6 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.20-7.09 (m, 2H), 6.17 (s, 1H), 3.06 (s, 6H).

[0113] Example 4. Preparation of compound 46

[0114] (1) Preparation of compound IV

[0115] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and methyl ethylamine (130 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction bottle, add a stirring rod, add 4 mL of EtOH, place the reaction bottle at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react at 0°C overnight. Monitor the progress of the reaction by TLC. After the reaction is completed, concentrate under vacuum and reduce the pressure. Purify the crude product by silica gel column chromatography to obtain 6-chloro-N-ethyl-N-methylpyrimidin-4-amine, with a yield of 188 mg and a yield of 55%.

[0116] (2) Preparation of compound V

[0117] Take 6-chloro-N-ethyl-N-methylpyrimidin-4-amine (171 mg, 1 mmol, 1 eq) into a two-necked reaction bottle, add a stirring rod, mount a condensation reflux tube, add hydrazine hydrate (641 mg, 20 mmol, 20 eq), and stir at reflux for 10 h. After the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase over anhydrous sodium sulfate, concentrate under vacuum and reduce the pressure. Purify the crude product by silica gel column chromatography to obtain N-ethyl-6-hydrazinyl-N-methylpyrimidin-4-amine, with a yield of 104 mg and a yield of 62%.

[0118] (3) Preparation of compound I

[0119] The target product compound 46 was prepared from 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and N-ethyl-6-hydrazinyl-N-methylpyrimidine-4-amine (0.55 mmol, 83 mg, 1.1 eq) prepared in step (2) according to the method of step (3) "Preparation of compound I" in Example 1, in a yield of 79 mg, 54% in yield, and 95.91% in HPLC purity.

[0120] 1 H-NMR results: δ 11.40 (s, 1H), 10.51 (s, 1H), 8.25 (s, 1H), 8.19 (d, J = 7.7 Hz, 1H), 8.04 (s, 1H), 7.68 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 7.9 Hz, 1H), 7.17 (t, J = 7.0 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 6.17 (s, 1H), 3.56 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.11 (t, J = 7.0 Hz, 3H).

[0121] Example 5. Preparation of compound 47

[0122] (1) Preparation of compound IV

[0123] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and N-ethyl-n-propylamine (192 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction bottle, add a stirring rod, add 4 mL of EtOH, place the reaction bottle at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), react overnight at 0°C, monitor the reaction progress by TLC, after the reaction is completed, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 6-chloro-N-ethyl-N-propylpyrimidine-4-amine in a yield of 207 mg, 52% in yield.

[0124] (2) Preparation of compound V

[0125] Take 6-chloro-N-ethyl-N-propylpyrimidine-4-amine (199 mg, 1 mmol, 1 eq) into a two-necked reaction bottle, add a stirring rod, install a condenser reflux tube, add hydrazine hydrate (496 mg, 20 mmol, 20 eq), stir for 10 h under reflux, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain N-ethyl-6-hydrazinyl-N-propylpyrimidine-4-amine in a yield of 144 mg, 74% in yield.

[0126] (3) Preparation of compound I

[0127] Using 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and N-ethyl-6-hydrazino-N-propylpyrimidin-4-amine (0.55 mmol, 107 mg, 1.1 eq) obtained in step (2) as raw materials, the target product, compound 47, was prepared according to the method of step (3) "Preparation of Compound Ⅰ" in Example 1. The yield was 130 mg, the yield was 81%, and the HPLC purity was 95.95%.

[0128] 1 H-NMR results: δ11.44(s,1H),10.55(s,1H),8.30–8.16(m,2H),8.04(s,1H),7.70(d,J=2.2Hz,1H),7.43(d,J=8.0Hz,1H),7.19(t,J=7.5Hz,1H),7.09 (t,J=7.4Hz,1H),6.17(s,1H),3.54(q,J=6.7Hz,2H),3.37(q,J=7.0Hz,2H),1.63(q,J=7.2Hz,2H),1.15(t,J=6.6Hz,3H),0.96(t,J=7.0Hz,3H).

[0129] Example 6. Preparation of Compound 48

[0130] (1) Preparation of Compound IV

[0131] 4,6-Dichloropyrimidine (296 mg, 2 mmol, 1 eq) and di-n-propylamine (223 mg, 2.2 mmol, 1.1 eq) were weighed and placed in a two-necked reaction flask. A stirrer was added, 4 mL of EtOH was added, and the reaction flask was placed at 0°C. Et3N (222 mg, 2.2 mmol, 1.1 eq) was added and reacted at 0°C overnight. The reaction progress was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure in vacuo. The crude product was purified by silica gel column chromatography to obtain 6-chloro-N,N-dipropylpyrimidin-4-amine in a yield of 201 mg (47%).

[0132] (2) Preparation of Compound V

[0133] 6-Chloro-N, N-dipropylpyrimidin-4-amine (192 mg, 0.9 mmol, 1 eq) was weighed and placed in a two-necked reaction flask. A stirrer was added and a reflux tube was placed. Hydrazine hydrate (577 mg, 18 mmol, 20 eq) was added and stirred at reflux for 10 h. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The organic phase was concentrated under vacuum. The crude product was purified by silica gel column chromatography to obtain 6-hydrazino-N, N-dipropylpyrimidin-4-amine in a yield of 147 mg and a yield of 78%.

[0134] (3) Preparation of Compound I

[0135] Using 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 6-hydrazinyl-N,N-dipropylpyrimidin-4-amine (0.55 mmol, 115 mg, 1.1 eq) prepared in step (2) as starting materials, the target product Compound 48 was prepared in accordance with the method of step (3) “Preparation of Compound I” in Example 1, with a yield of 104 mg, a yield of 62%, and an HPLC purity of 99.02%.

[0136] 1 H-NMR results: δ 11.40 (s, 1H), 10.48 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.13 (s, 1H), 3.56 - 3.29 (m, 4H), 1.66 - 1.53 (m, 4H), 0.92 (t, J = 7.2 Hz, 6H).

[0137] Example 7. Preparation of Compound 49

[0138] (1) Preparation of Compound IV

[0139] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and N-ethyl-N-heptanamine (346 mg, 2.2 mmol, 1.1 eq) into a two-neck reaction bottle, add a stirrer, add 4 mL of EtOH, place the reaction bottle at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), react at 0°C overnight, monitor the reaction progress by TLC, after the reaction is completed, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 6-chloro-N-heptyl-N-propylpyrimidin-4-amine, with a yield of 243 mg, a yield of 45%.

[0140] (2) Preparation of Compound V

[0141] Take 6-chloro-N-heptyl-N-propylpyrimidin-4-amine (242 mg, 0.9 mmol, 1 eq) into a two-necked reaction flask, add a stirring rod, install a condenser reflux tube, add hydrazine hydrate (577 mg, 18 mmol, 20 eq), stir at reflux for 10 h, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain N-heptyl-6-hydrazinyl-N-propylpyrimidin-4-amine, with a yield of 160 mg and a yield of 67%.

[0142] (3) Preparation of Compound I

[0143] Take 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and N-heptyl-6-hydrazinyl-N-propylpyrimidin-4-amine (0.55 mmol, 132 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product Compound 49 according to the method of step (3) "Preparation of Compound I" in Example 1, with a yield of 98 mg, a yield of 50%, and an HPLC purity of 96.53%.

[0144] 1 H-NMR results: δ 11.47 (s, 1H), 10.54 (s, 1H), 8.25 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.17 (s, 1H), 3.67-3.36 (m, 4H), 1.65-1.53 (m, 2H), 1.51-0.97 (m, 11H), 0.81 (t, J = 6.4 Hz, 3H).

[0145] Example 8. Preparation of Compound 50

[0146] (1) Preparation of Compound IV

[0147] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and piperidine (170 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction flask, add a stirring rod, add 4 mL of EtOH, place the reaction flask at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react at 0°C overnight. Monitor the reaction progress by TLC. After the reaction is completed, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 4-chloro-6-(piperidin-1-yl)pyrimidine, with a yield of 292 mg and a yield of 69%.

[0148] (2) Preparation of Compound V

[0149] Take 4-chloro-6-(piperidin-1-yl)pyrimidine (211 mg, 1 mmol, 1 eq) into a two-necked reaction flask, add a stirring bar, install a condenser reflux tube, add hydrazine hydrate (641 mg, 20 mmol, 20 eq), stir at reflux for 10 h, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase over anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 4-hydrazinyl-6-(piperidin-1-yl)pyrimidine, with a yield of 164 mg and a yield of 85%.

[0150] (3) Preparation of Compound I

[0151] Take 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 4-hydrazinyl-6-(piperidin-1-yl)pyrimidine (0.55 mmol, 106 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product Compound 50 according to the method of step (3) "Preparation of Compound I" in Example 1, with a yield of 88 mg, a yield of 55%, and an HPLC purity of 96.17%.

[0152] 1 H-NMR results: δ 11.48 (s, 1H), 10.54 (s, 1H), 8.25 (s, 1H), 8.15 (d, J = 7.4 Hz, 1H), 8.04 (s, 1H), 7.69 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.20-7.08 (m, 2H), 6.27 (s, 1H), 3.64-3.51 (m, 4H), 1.68-1.46 (m, 6H).

[0153] Example 9. Preparation of Compound 51

[0154] (1) Preparation of Compound IV

[0155] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and heptamethylimine (226 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction flask, add a stirring bar, add 4 mL of EtOH, place the reaction flask at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react at 0°C overnight. Monitor the progress of the reaction by TLC, and after the reaction is completed, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 1-(6-chloropyrimidin-4-yl) azokon, with a yield of 216 mg and a yield of 48%.

[0156] (2) Preparation of Compound V

[0157] Take 1-(6-chloropyrimidin-4-yl)azocon (203 mg, 0.9 mmol, 1 eq) into a two-necked reaction flask, add a stirring rod, install a condenser reflux tube, add hydrazine hydrate (557 mg, 18 mmol, 20 eq), stir at reflux for 10 h, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 1-(6-hydrazinylpyrimidin-4-yl)azocon, with a yield of 157 mg and a yield of 79%.

[0158] (3) Preparation of Compound I

[0159] Take 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 1-(6-hydrazinylpyrimidin-4-yl)azocon (0.55 mmol, 121 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product Compound 51 according to the method of step (3) "Preparation of Compound I" in Example 1, with a yield of 101 mg, a yield of 58%, and an HPLC purity of 97.66%.

[0160] 1 H-NMR results: δ 11.39 (s, 1H), 10.50 (s, 1H), 8.23 (s, 1H), 8.20 (d, J = 7.8 Hz, 1H), 8.04 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 6.20 (s, 1H), 3.71-3.55 (m, 4H), 1.83-1.68 (m, 4H), 1.58-1.47 (m, 4H), 1.47-1.37 (m, 2H).

[0161] Example 10. Preparation of Compound 52

[0162] (1) Preparation of Compound IV

[0163] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and 2,3,4,5-tetrahydro-1H- benzo[D]azepine (324 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction flask, add a stirring rod, add 4 mL of EtOH, place the reaction flask at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react at 0°C overnight. Monitor the reaction progress by TLC, and after the reaction is completed, concentrate under vacuum and reduced pressure. Purify the crude product by silica gel column chromatography to obtain 3-(6-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine, with a yield of 265 mg and a yield of 51%.

[0164] (2) Preparation of compound V

[0165] Take 3-(6-chloropyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (260 mg, 1 mmol, 1 eq) into a two-necked reaction flask, add a stirring rod, install a condenser reflux tube, add hydrazine hydrate (641 mg, 20 mmol, 20 eq), stir and reflux for 10 h, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 3-(6-hydrazinylpyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine, with a yield of 140 mg and a yield of 55%.

[0166] (3) Preparation of compound I

[0167] Take 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 3-(6-hydrazinylpyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.55 mmol, 140 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product compound 52 according to the method of step (3) “Preparation of compound I” in Example 1, with a yield of 111 mg, a yield of 58%, and an HPLC purity of 96.97%.

[0168] 1 H-NMR results: δ 11.44 (s, 1H), 10.61 (s, 1H), 8.33-8.19 (m, 2H), 8.11 (s, 1H), 7.70 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.28-7.03 (m, 6H), 6.36 (s, 1H), 3.90-3.75 (m, 4H), 3.02-2.89 (m, 4H).

[0169] Example 11. Preparation of compound 53

[0170] (1) Preparation of compound IV

[0171] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and morpholine (191 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction flask, add a stirring rod, add 4 mL of EtOH, place the reaction flask at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react overnight at 0°C. Monitor the reaction progress by TLC, and after the reaction is completed, concentrate under vacuum and reduced pressure. Purify the crude product by silica gel column chromatography to obtain 4-(6-chloropyrimidin-4-yl)morpholine, with a yield of 386 mg and a yield of 88%.

[0172] (2) Preparation of compound V

[0173] Take 4-(6-chloropyrimidin-4-yl)morpholine (200 mg, 2 mmol, 1 eq) into a two-necked reaction bottle, add a stirring rod, install a condenser reflux tube, add hydrazine hydrate (641 mg, 18 mmol, 20 eq), stir at reflux for 10 h, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase with anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 4-(6-hydrazinylpyrimidin-4-yl)morpholine, with a yield of 176 mg and a yield of 90%.

[0174] (3) Preparation of compound I

[0175] Take 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 4-(6-hydrazinylpyrimidin-4-yl)morpholine (0.55 mmol, 107 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product compound 53 according to the method of step (3) “Preparation of compound I” in Example 1, with a yield of 142 mg, a yield of 44%, and an HPLC purity of 98.63%.

[0176] 1 H-NMR results: δ 11.46 (s, 1H), 10.66 (s, 1H), 8.27 (s, 1H), 8.17 (d, J = 6.8 Hz, 1H), 8.09 (s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.41 (d, J = 7.0 Hz, 1H), 7.21-7.12 (m, 2H), 6.28 (s, 1H), 3.69 (t, J = 4.4 Hz, 4H), 3.54 (t, J = 4.4 Hz, 4H).

[0177] Example 12. Preparation of compound 54

[0178] (1) Preparation of compound IV

[0179] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and 3,5-dimethylmorpholine (253 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction bottle, add a stirring rod, add 4 mL of EtOH, place the reaction bottle at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react at 0°C overnight. Monitor the reaction progress by TLC, and after the reaction is completed, concentrate under vacuum and reduced pressure. Purify the crude product by silica gel column chromatography to obtain 4-(6-chloropyrimidin-4-yl)-3,5-dimethylmorpholine, with a yield of 360 mg and a yield of 79%.

[0180] (2) Preparation of compound V

[0181] Take 4-(6-chloropyrimidin-4-yl)-3,5-dimethylmorpholine (227 mg, 1 mmol, 1 eq) into a two-necked reaction flask, add a stirring rod, install a condenser reflux tube, add hydrazine hydrate (641 mg, 20 mmol, 20 eq), stir at reflux for 10 h, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase over anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 4-(6-hydrazinylpyrimidin-4-yl)-3,5-dimethylmorpholine, with a yield of 167 mg and a yield of 75%.

[0182] (3) Preparation of compound I

[0183] Take 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 4-(6-hydrazinylpyrimidin-4-yl)-3,5-dimethylmorpholine (0.55 mmol, 111 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product compound 54 according to the method of step (3) “Preparation of compound I” in Example 1, with a yield of 210 mg, a yield of 67%, and an HPLC purity of 98.42%.

[0184] 1 H-NMR results: δ 11.40 (s, 1H), 10.62 (s, 1H), 8.25 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.12 (s, 1H), 7.69 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.22-7.07 (m, 2H), 6.27 (s, 1H), 4.14-4.04 (m, 4H), 3.68-3.61 (m, 2H), 1.29 (d, J = 6.2 Hz, 6H).

[0185] Example 13. Preparation of compound 55

[0186] (1) Preparation of compound IV

[0187] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and 2,6-dimethylmorpholine (253 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction flask, add a stirring rod, add 4 mL of EtOH, place the reaction flask at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react at 0°C overnight. Monitor the reaction progress by TLC, and after the reaction is completed, concentrate under vacuum and reduced pressure. Purify the crude product by silica gel column chromatography to obtain 4-(6-chloropyrimidin-4-yl)-2,6-dimethylmorpholine, with a yield of 150 mg and a yield of 66%.

[0188] (2) Preparation of compound V

[0189] Weigh 4-(6-chloropyrimidin-4-yl)-2,6-dimethylmorpholine (114 mg, 1 mmol, 1 eq) into a two-necked reaction flask, add a stirring rod, mount a condenser reflux tube, add hydrazine hydrate (641 mg, 18 mmol, 20 eq), stir under reflux for 10 h, after the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase over anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 4-(6-hydrazinylpyrimidin-4-yl)-2,6-dimethylmorpholine, with a yield of 161 mg and a yield of 72%.

[0190] (3) Preparation of compound I

[0191] Use 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 4-(6-hydrazinylpyrimidin-4-yl)-2,6-dimethylmorpholine (0.55 mmol, 111 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product compound 55 according to the method of step (3) “Preparation of compound I” in Example 1, with a yield of 117 mg, a yield of 67%, and an HPLC purity of 98.42%.

[0192] 1 H-NMR results: δ 11.43 (s, 1H), 10.65 (s, 1H), 8.24 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.06 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 6.29 (s, 1H), 4.15 (d, J = 12.5 Hz, 2H), 3.67-3.52 (m, 2H), 2.55-2.45 (m, 2H), 1.17 (d, J = 6.4 Hz, 6H).

[0193] Example 14. Preparation of compound 56

[0194] (1) Preparation of compound IV

[0195] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and N-methylpiperazine (220 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction flask, add a stirring rod, add 4 mL of EtOH, place the reaction flask at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react overnight at 0°C. Monitor the reaction progress by TLC. After the reaction is completed, concentrate under vacuum and reduced pressure. Purify the crude product by silica gel column chromatography to obtain 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidine, with a yield of 247 mg and a yield of 58%.

[0196] (2) Preparation of compound V

[0197] Take 4-chloro-6-(4-methylpiperazin-1-yl)pyrimidine (212 mg, 1 mmol, 1 eq) into a two-necked reaction flask, add a stirring rod, mount a condenser reflux tube, add hydrazine hydrate (641 mg, 20 mmol, 20 eq), and stir for 10 h under reflux. After the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase over anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 4-hydrazinyl-6-(4-methylpiperazin-1-yl)pyrimidine, with a yield of 112 mg and a yield of 54%.

[0198] (3) Preparation of compound I

[0199] Take 3-indolecarboxaldehyde (0.5 mmol, 72 mg, 1 eq) and 4-hydrazinyl-6-(4-methylpiperazin-1-yl)pyrimidine (0.55 mmol, 114 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product compound 56 according to the method of step (3) “Preparation of compound I” in Example 1, with a yield of 70 mg, a yield of 42%, and an HPLC purity of 98.24%.

[0200] 1 H-NMR results: δ 11.47 (s, 1H), 10.63 (s, 1H), 8.25 (s, 1H), 8.16 (d, J = 7.0 Hz, 1H), 8.06 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.21-7.10 (m, 2H), 6.27 (s, 1H), 3.60-3.51 (m, 4H), 2.42-2.32 (m, 4H), 2.19 (s, 3H).

[0201] Example 15. Preparation of compound 57

[0202] (1) Preparation of compound IV

[0203] Take 4,6-dichloropyrimidine (296 mg, 2 mmol, 1 eq) and N-ethylpiperazine (251 mg, 2.2 mmol, 1.1 eq) into a two-necked reaction flask, add a stirring rod, add 4 mL of EtOH, place the reaction flask at 0°C, then add Et3N (222 mg, 2.2 mmol, 1.1 eq), and react overnight at 0°C. Monitor the progress of the reaction by TLC. After the reaction is completed, concentrate under vacuum and reduced pressure. Purify the crude product by silica gel column chromatography to obtain 4-chloro-6-(4-ethylpiperazin-1-yl)pyrimidine, with a yield of 213 mg and a yield of 47%.

[0204] (2) Preparation of compound V

[0205] Take 4-chloro-6-(4-ethylpiperazin-1-yl)pyrimidine (203 mg, 0.9 mmol, 1 eq) into a two-necked reaction flask, add a stirring rod, mount a condenser reflux tube, add hydrazine hydrate (577 mg, 18 mmol, 20 eq), and stir for 10 h under reflux. After the reaction is completed, quench with water, extract with ethyl acetate, wash the organic phase with saturated sodium chloride, dry the organic phase over anhydrous sodium sulfate, concentrate under vacuum and reduced pressure, and purify the crude product by silica gel column chromatography to obtain 4-(4-ethylpiperazin-1-yl)-6-hydrazinylpyrimidine, with a yield of 100 mg and a yield of 50%.

[0206] (3) Preparation of compound I

[0207] Take 3-indolecarboxaldehyde (0.4 mmol, 58 mg, 1 eq) and 4-(4-ethylpiperazin-1-yl)-6-hydrazinylpyrimidine (0.44 mmol, 98 mg, 1.1 eq) prepared in step (2) as raw materials, and prepare the target product compound 57 according to the method of step (3) “Preparation of compound I” in Example 1; the yield is 60 mg, the yield is 43%, and the HPLC purity is 98.97%.

[0208] 1 H-NMR results: δ 11.63 (s, 1H), 10.62 (s, 1H), 8.27 (s, 1H), 8.16 (d, J = 6.8 Hz, 1H), 8.06 (s, 1H), 7.69 (s, 1H), 7.42 (d, J = 7.0 Hz, 1H), 7.24-7.03 (m, 2H), 6.27 (s, 1H), 3.58-3.50 (m, 4H), 2.45-2.36 (m, 4H), 2.32 (q, J = 6.7 Hz, 2H), 1.00 (t, J = 7.0 Hz, 3H).

[0209] Example 16. In vitro anti-tumor activity and cytotoxicity assay of compound I

[0210] The MTT [3-(4,5)-dimethyl-2-thiazole-(2,5)-phenyl bromide tetrazolium blue] method was used to determine the drug concentration at which the inhibition rate of the compounds I (compounds 1-57) prepared in Examples 1-15 reached 50% on human cervical cancer cell line (Hela), the half maximal inhibitory concentration (IC 50 ) of each compound was used to represent the cytotoxicity of the compounds on human normal lung bronchial epithelial cells (BEAS-2B), the concentration CC 50 at which the survival rate of BEAS-2B cells was inhibited to 50% was used to represent the cytotoxicity of each compound. The specific steps are as follows:

[0211] (1) Preparation of culture solution: DMEM (basic culture medium) 89%, fetal bovine serum 10%, penicillin-streptomycin solution (10000 IU / mL, 10000 μg / mL) 1%;

[0212] (2) Cultivation of two kinds of cells: using the culture solution prepared in step (1) (the volume of the culture solution is about 1 / 10 of the capacity of the culture bottle), cultivate human cervical cancer cell line and human normal lung bronchial epithelial cells in a 37°C, 5% CO2 incubator, and determine the subculture time according to the growth state of the cells;

[0213] (3) Preparation of different concentrations of drugs: using DMEM (a small amount of DMSO is used to help dissolve) to prepare the stock solution, the final concentration of DMSO in each well of the cell suspension after adding the drug is generally not more than 0.05%-0.1%; dilute the stock solution with DMEM to six concentration gradients (50 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM and 0.001 μM), and store in a -20°C refrigerator for standby;

[0214] (4) Cell incubation: take the tumor cells in the logarithmic growth phase, adjust the concentration of the cell suspension to 5×10 4 / mL, mix well, and then add to a 96-well culture plate (100 μL / well), and cultivate in a 37°C, 5% CO2 incubator for 24 h;

[0215] (5) Drug addition: add the diluted drugs of different concentration gradients to the 96-well culture plate, set 3 replicate wells for each concentration gradient, and continue to cultivate for 72 h; the experiment is divided into an experimental group (culture solution, cells and compound I), a control group (culture solution and cells) and a blank group (only culture solution);

[0216] (6) Surviving cell detection: 20 μL of MTT (5 mg / mL) was added to each well of the 96-well plate after 72 h of culture; after 4 h of incubation at 37 °C, the supernatant was removed, 200 μL of DMSO was added to each well, and the mixture was shaken until the formazan crystals were completely dissolved; the optical density (OD value) of each well was detected at 570 nm using an automatic microplate reader.

[0217] (7) Inhibition rate calculation: the killing ability of compounds 1-57 on cancer cells (Hela) and the toxicity on normal cells (BEAS-2B) were calculated using the following formula, respectively.

[0218] Growth inhibition rate = (1 - survival rate) x 100% = [1 - (OD experiment - OD blank) / (OD control - OD blank)] x 100%, wherein OD experiment is the average optical density of the experimental group, OD control is the average optical density of the control group, and OD blank is the average optical density of the blank group.

[0219] (8) According to the compound I concentration-cancer cell (Hela) growth inhibition rate, the IC 50 , unit: μM; according to the compound I concentration-normal cell (BEAS-2B) growth inhibition rate, the CC 50 , unit: μM.

[0220] Results: As shown in Table 5, the results show that the compounds I (compounds 1-57) prepared in Examples 1-15 all have anti-tumor effect and low toxicity on normal cells.

[0221] Table 5. Cancer cell killing ability and normal cell toxicity data of compounds 1-57

[0222]

[0223]

[0224] Note: In Table 5, IC 50 : half inhibition concentration, the killing ability of the compound on cancer cells; CC 50 : half toxicity concentration, the toxicity of the compound on normal cells.

Claims

1. Hydrazones containing a pyrimidine ring, characterized in that, The compound is any one or more of the compounds shown in Formula I and pharmaceutically acceptable salts, stereoisomers, tautomers, homologues, solvates, prodrugs or polymorphs thereof. wherein R 1 optionally selected from: R 2 , R 3 , R 4 are independently arbitrarily selected from: R 1 , R 2 , R 3 , R 4 are the same or different; R 5 optionally selected from: R 3 , R 4 , R 5 are identical or different; optionally selected from: A, B, C, D, E are independently selected from carbon or nitrogen, and A, B, C, D, E are the same or different.

2. The compound of claim 1, wherein The compounds are any one or more of Compound 1-Compound 57 and pharmaceutically acceptable salts, stereoisomers, tautomers, homologs, solvates, prodrugs, or polymorphs thereof; Compound 1 is (E)-6-(2-((1H-indol-3-yl)methyl)hydrazino)-N,N-diethylpyrimidin-4-amine; Compound 2 is (E)-N,N-diethyl-6-(2-(2-methyl-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 3 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-2-carboxylic acid; Compound 4 is (E)-methyl 3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-2-carboxylate; Compound 5 is (E)-N,N-diethyl-6-(2-((4-methyl-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 6 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-4-carbonitrile; Compound 7 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-4-carboxylic acid; Compound 8 is methyl (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-4-carboxylate; Compound 9 is (E)-N,N-diethyl-6-(2-((4-(trifluoromethyl)-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 10 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indol-4-ol; Compound 11 is (E)-N,N-diethyl-6-(2-((4-methoxy-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 12 is (E)-N,N-diethyl-6-(2-((4-nitro-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 13 is (E)-N,N-diethyl-6-(2-((4-fluoro-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 14 is (E)-N,N-diethyl-6-(2-((5-methyl-1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-amine; Compound 15 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-5-carbonitrile; Compound 16 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-5-carboxylic acid; Compound 17 is methyl (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indole-5-carboxylate;The compound 18 is (E)-N,N-diethyl-6-(2-((5-(trifluoromethyl)-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 19 is (E)-3-((2-(6- (diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)-1H-indol-5-ol; the compound 20 is (E)-N,N-diethyl-6-(2-((5-methoxy-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4- amine; the compound 21 is (E)-N,N-diethyl-6-(2-((5-nitro-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 22 is (E)-N,N-diethyl-6-(2- ((5-fluoro-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 23 is (E)-N,N-diethyl-6-(2-((6-methyl-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4- amine; the compound 24 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)- 1H-indole-6-carbonitrile; the compound 25 is (E)-3-((2-(6-(diethylamino)pyrimidin-4- yl)hydrazonoyl)methyl)-1H-indole-6-carboxylic acid; the compound 26 is methyl (E)-3- ((2-(6-(diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)-1H-indole-6-carboxylic acid; the compound 27 is (E)-N,N-diethyl-6-(2-((6-(trifluoromethyl)-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 28 is (E)-3-((2-(6- (diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)-1H-indol-6-ol; the compound 29 is (E)-N,N-diethyl-6-(2-((6-methoxy-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4- amine; the compound 30 is (E)-N,N-diethyl-6-(2-((6-nitro-1H-indol-3- yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 31 is (E)-N,N-diethyl-6-(2- ((6-fluoro-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4-amine; the compound 32 is (E)-N,N-diethyl-6-(2-((7-methyl-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4- amine; the compound 33 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazonoyl)methyl)- 1H-indole-7-carboxylic acid; the compound 34 is methyl (E)-3-((2-(6-(diethylamino)pyrimidin-4- yl)hydrazonoyl)methyl)-1H-indole-7-carboxylic acid; the compound 35 is (E)-N,N- diethyl-6-(2-((7-(trifluoromethyl)-1H-indol-3-yl)methylidene)hydrazinyl)pyrimidin-4- amine;The compound 36 is (E)-3-((2-(6-(diethylamino)pyrimidin-4-yl)hydrazono)methyl)-1H-indol-7-ol; the compound 37 is (E)-N,N-diethyl-6-(2-((7-methoxy-1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-amine; the compound 38 is (E)-N,N-diethyl-6-(2-((7-nitro-1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-amine; the compound 39 is (E)-N,N-diethyl-6-(2-((7-fluoro-1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-amine; the compound 40 is (E)-6-(2-((1H-indazol-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 41 is (E)-6-(2-((1H-pyrrolo[3,2-b]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 42 is (E)-6-(2-((1H-pyrrolo[3,2-c]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 43 is (E)-6-(2-((1H-pyrrolo[2,3-c]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 44 is (E)-6-(2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methylidene)hydrazino)-N,N-diethylpyrimidin-4-amine; the compound 45 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N,N-dimethylpyrimidin-4-amine; the compound 46 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N-ethyl-N-methylpyrimidin-4-amine; the compound 47 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N-ethyl-N-propylpyrimidin-4-amine; the compound 48 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N,N-dipropylpyrimidin-4-amine; the compound 49 is (E)-6-(2-((1H-indol-3-yl)methylidene)hydrazino)-N-ethyl-N-heptylpyrimidin-4-amine; the compound 50 is (E)-3-((2-(6-(piperidin-1-yl)pyrimidin-4-yl)hydrazono)methyl)-1H-indole; the compound 51 is (E)-3-((2-(6-(azocin-1-yl)pyrimidin-4-yl)hydrazono)methyl)-1H-indole; the compound 52 is (E)-3-(6-(2-((1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine; the compound 53 is (E)-4-(6-(2-((1H-indol-3-yl)methylidene)hydrazino)pyrimidin-4-yl)morpholine;The compound 54 is (E)-4-(6-(2-((1H-indol-3-yl)methyl)hydrazino)pyrimidin-4-yl)-3,5- dimethylmorpholine; the compound 55 is (E)-4-(6-(2-((1H-indol-3-yl)methyl)hydrazino)pyrimidin-4- yl)-2,6-dimethylmorpholine; the compound 56 is (E)-3-((2-(6-(4-methylpiperazin-1-yl)pyrimidin-4- yl)hydrazono)methyl)-1H-indole; the compound 57 is (E)-3-((2-(6-(4-ethylpiperazin-1-yl)pyrimidin-4- yl)hydrazono)methyl)-1H-indole.

3. The compound of claim 2, wherein The compound is any one or more of Compound 1, Compound 2, Compound 4, Compound 5, Compound 7, Compound 10, Compound 12-Compound 15, Compound 18-Compound 23, Compound 26, Compound 27, Compound 29, Compound 31, Compound 32, Compound 36, Compound 38-Compound 42, Compound 44-Compound 48, Compound 51, Compound 53, Compound 54.

4. The method of producing the hydrazone compound containing a pyrimidine ring according to any one of claims 1 to 3, characterized by, The method comprises the following steps: (1) using 4,6-dichloropyrimidine and compound III as raw materials, adding EtOH and Et3N to obtain compound IV by reaction; (2) adding hydrazine hydrate to the compound IV obtained in step (1) to obtain compound V by reaction; (3) mixing compound V obtained in step (2) with compound VI, MeOH and CH3COOH, and heating to reflux to obtain the hydrazone compound containing a pyrimidine ring; The compound III has a structural formula shown in Formula III, the compound IV has a structural formula shown in Formula IV, the compound V has a structural formula shown in Formula V, and the compound VI has a structural formula shown in Formula VI; In the formulae III to VI, R 1 is optionally selected from: R 2 , R 3 , R 4 are independently and arbitrarily selected from: R 1 , R 2 , R 3 , R 4 are the same or different; R 5 is optionally selected from: R 1 , R 2 , R 3 , R 4 , R 5 are the same or different; optionally selected from: A, B, C, D, E are independently selected from carbon or nitrogen, and A, B, C, D, E are the same or different.

5. The preparation method according to claim 4, characterized in that In step (1), the reaction temperature is-5℃-5℃.

6. The preparation method according to claim 4, characterized in that In step (2), the reaction time is 8h-15h; in step (3), the reaction time is 4h-8h.

7. The preparation method according to claim 4, characterized in that The molar ratio of 4,6-dichloropyrimidine, compound III and Et3N is 1:1-1.5:1-1.5; the molar ratio of compound IV and hydrazine hydrate is 1:15-30; the molar ratio of compound VI and compound V is 1:1-1.

5.

8. A pharmaceutical composition, characterized by, The pharmaceutical composition contains the hydrazone compound containing a pyrimidine ring according to any one of claims 1-3.

9. Use of the hydrazone compound containing a pyrimidine ring according to any one of claims 1-3 in the preparation of an antitumor drug.

10. Use according to claim 9, characterized in that, The tumor includes cervical cancer.

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