CN103333119A - 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compound and its preparation method and use - Google Patents

Abstract

The present invention relates to a class of 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid compounds represented by the following general formula (I) and pharmaceutically acceptable salts or pharmaceutically acceptable salts thereof Acceptable solvent mixtures, preparation methods thereof, pharmaceutical compositions containing the compounds, and the preparation of these compounds for the prevention or treatment of diseases related to abnormal cell proliferation and morphological changes, especially for the treatment or prevention of tumor growth and metastasis use in medicines.

Description

1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid compound and its preparation method and use

Technical field:

The invention relates to the field of medical technology, in particular to a class of 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acid compounds with antitumor activity and pharmaceutically acceptable salts or pharmaceutically acceptable salts thereof. acceptable solvates, their preparation methods, pharmaceutical compositions containing the compounds, and the preparation of these compounds for the prevention or treatment of abnormal cell proliferation, morphological changes and other related diseases, especially for the treatment or prevention of tumor growth Uses with Diverted Drugs. the

Background technique:

Tumor is a disease that seriously threatens human health. It is mainly induced by unreasonable diet, genetic factors, and environmental factors. The mechanism of action of anti-tumor drugs and the targets of drugs are various, and the multi-drug resistance of tumor cells often leads to the failure of treatment. Finding effective and safe anti-tumor drugs with low toxicity and side effects has always been the goal pursued by researchers in the research and development of cancer drugs. the

Pyrimidine is a very important class of six-membered heterocyclic compounds. It is favored by people in the fields of medicine and pesticides because of its wide range of biological activities. As a basic building block for the design and synthesis of drug molecules, it has attracted great attention from medicinal chemists. Most of the chemical structures of this class of drugs are similar to the metabolite pyrimidine bases necessary for cell growth and reproduction, so they can compete for the binding site of enzymes and interfere with the metabolism of pyrimidine and its precursors in nucleotides in the form of pseudo-metabolites . On the other hand, they can also combine with nucleic acids to replace the corresponding normal nucleotides, thereby interfering with the normal biosynthesis of DNA and preventing the division and reproduction of tumor cells. Especially in recent years, a large number of pyrimidine compounds with anti-tumor activity have been reported. In addition to the marketed drugs, some new pyrimidine compounds have entered the stage of clinical trials. the

Pyrimidine compounds have become important lead compounds in the discovery and development of antitumor drugs, and are a time-honored field of drug research. Existing research results have shown that the diversity of substitution sites and substituents on the pyrimidine ring enables anti-tumor active pyrimidine compounds to have diverse targets, such as inhibiting cyclin-dependent kinases, tyrosine protein kinases, Carbonic anhydrase, dihydrofolate reductase and interference with tubulin polymerization, etc. Therefore, the synthesis of pyrimidine compounds with novel structures has potential anti-tumor biological activity and application value, and has important theoretical and practical significance. the

In 1983, Polish scientists Dlugosz, Machon et al. reported in a document that the following route 1 represented a class of 6-[(substituted phenyl)amino]-1,2-dihydro-4-methyl-2 -Oxy-5-pyrimidine carboxylic acid compound, after preliminary pharmacological research tests, this type of compound has a good anti-leukemia therapeutic effect, but the reported synthetic route is difficult to prepare raw materials, and the yield is extremely low. (Dlugosz A, Machon Z. et al Synthesis and biological properties of amides of 4-arylamino-2-hydroxy-6-methyl-5-pyrimidinecarboxylic acids Acta Poloniae Pharmaceutical1983, 40: 1-6)

Recently, the inventors designed a set of 1,2-dihydro-6-methyl-4-substituted amino- 5-pyrimidine carboxylic acid compound, the structure shown in general formula (I), is expected to influence its combination with the receptor binding site by synthesizing this type of novel chemical entity, improve bioavailability and biological activity, and reduce drug toxicity. Adverse reactions. And based on this assumption, the inventors have invented a class of novel multi-component reactions using isocyanates as key raw materials, and have easily synthesized the designed 1,2-dihydro-6-methyl-4- Substituted amino-5-pyrimidine carboxylic acid compounds and their derivatives (structure shown in general formula (I)), this reaction route has the advantages of easy availability of raw materials, fewer steps and high yield. According to preliminary in vitro anti-tumor activity tests, compounds with this type of structure have good tumor inhibitory activity, and the in vitro activity of some compounds is significantly better than that of known compounds (5-fluorouracil and cytarabine). Many anti-tumor compounds with pyrimidine as the core have opened up new fields. the

Invention content:

One object of the present invention is to provide 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structural compound or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, The compound has a structure as shown in the following general formula (I), and it has good inhibitory effect on various tumor cells. the

Meanwhile, another object of the present invention also provides a three-component Biginelli-like reaction using isocyanate as a raw material. The reaction can efficiently synthesize 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structural compounds and derivatives thereof. In this reaction, the active carbonyl compound (aldehyde or ketone) in the reaction is replaced by isocyanate. This is the first time that isocyanate, urea and its derivatives, and 1,3 dicarbonyl compound are used for multi-component reaction. The reaction is simple and the product yield is high. , inspired people to use isocyanates as raw materials to synthesize new compounds with structural diversity through more multi-component reactions. the

The compound represented by the general formula (I) of the present invention, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate exerts a good effect of inhibiting the growth of tumor cells. Therefore another object of the present invention is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate used for preventing or treating abnormal cell proliferation and morphology in vivo. The application in medicines related to diseases such as changes, especially in the preparation of medicines for treating or preventing tumor growth and metastasis. the

Another object of the present invention is to provide a pharmaceutical composition comprising the compound represented by the general formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or a mixture thereof as an active ingredient. the

Another object of the present invention is to provide the application of the above-mentioned pharmaceutical composition in medicines for the prevention or treatment of diseases related to abnormal cell proliferation and morphological changes in organisms, especially in the preparation of drugs for the treatment or prevention of tumor growth and metastasis. application of the drug. the

Another object of the present invention is to provide a method for treating diseases related to abnormal cell proliferation, morphological changes or tumor growth and metastasis in a living body, said method comprising administering to a patient a therapeutically effective amount of a compound comprising the general formula (I ) compound, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, or its mixture as the active ingredient of the pharmaceutical composition

The general structural formula of the pyrimidine compound of the present invention is as shown in the following general formula (I):

in:

^R is any substituted or unsubstituted phenyl, heterocyclyl, benzoheterocyclyl, lower alkyl or cycloalkyl, lower haloalkyl, lower nitroalkyl, lower cyanoalkyl, lower alkyl- Cycloalkyl, cycloalkyl-lower alkyl, lower alkyl-cycloalkyl-lower alkyl;

Preferably R represents the ^following groups, substituted or unsubstituted phenyl, heterocyclyl, benzoheterocyclyl, lower alkyl;

X is oxygen, sulfur or NR ³ ; wherein, R ³ is hydrogen, optionally substituted phenyl, C1-C4 alkyl, C3-C6 cycloalkyl;

Preferably X is oxygen, sulfur or NH;

^R is hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted lower alkyl or cycloalkyl, lower alkyl-cycloalkyl, cycloalkyl-lower alkyl, lower alkyl-cycloalkyl- Lower alkyl groups, protected and unprotected sugar groups;

Preferably R represents the ^following groups: hydrogen, substituted or unsubstituted phenyl, lower alkyl or cycloalkyl, lower haloalkyl, lower nitroalkyl, lower cyanoalkyl, protected and unprotected ribose, protected and unprotected deoxyribose, protected and unprotected arabinose, protected and unprotected xylose, protected and unprotected glucose;

Wherein, the heterocyclic group has aromaticity or non-aromaticity, is a 5-7 membered heterocyclic ring, and contains 1-3 heteroatoms selected from N, O and S;

The term "lower" related to alkyl herein refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing 1-6 carbon atoms; the term "lower" related to alkenyl or alkynyl refers to a group containing 2-6 carbon atoms and one or more double bonds or triple bonds; cycloalkyl refers to rings containing 3-7 carbons; aryl refers to mono-, bi-, or tricyclic hydrocarbon compounds, wherein at least one ring is Aromatic rings, each containing up to 7 carbon atoms. the

The phenyl, heterocyclyl or benzoheterocyclyl is optionally replaced by 1-3 members selected from C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, polyhalogenated-C1- C4-Alkyl, Polyhalo-C1-C4-Alkoxy, C1-C4-Alkoxy-C1-C4-Alkyl, C1-C4-Alkoxy-C1-C4-Alkoxy-C1- C4-alkyl, C3-C8cycloalkoxy-C1-C4-alkyl, halogen, nitro, trifluoromethyl, carbamoyl, hydroxyl, cyano, substituted; 

The halogen is fluorine, chlorine, bromine or iodine;

The pharmaceutically acceptable acid addition salts thereof of the present invention include compounds of general formula (I), addition salts formed with the following acids: sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, formic acid , acetic acid, propionic acid, butyric acid, malonic acid, adipic acid, maleic acid, citric acid, tartaric acid, lactic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, nadisulfonic acid , oxalic acid, benzoic acid, succinic acid, camphorsulfonic acid, glutamic acid, aspartic acid, malic acid, salicylic acid, ascorbic acid, isonicotinic acid, mandelic acid, pyruvic acid, or fumaric acid. the

The pharmaceutically acceptable solvates of the compound represented by the general formula (I) of the present invention include without limitation the solvates of the compound represented by the general formula (I) with water, ethanol, isopropanol, ether or acetone . the

The structure of the pyrimidine compound of general formula (I) described in the present invention is a class of 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid compound represented by one of the following general formulas and derivatives, as shown in the following formula:

Wherein, R ¹ and R ² are the same as defined in the general formula (1).

In some preferred embodiments of the present invention, the compound of the general formula (I) and its pharmaceutically acceptable salt or pharmaceutically acceptable solvate is a compound selected from the following compounds:

1,2-Dihydro-1-phenyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA1) 

1,2-Dihydro-1-ethyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA2) 

1,2-Dihydro-1-methyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA3) 

1,2-Dihydro-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA4)

1,2-Dihydro-1-isobutyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA5)

1,2-Dihydro-1-phenyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB1)

1,2-Dihydro-1-ethyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB2)

1,2-Dihydro-1-methyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB3)

1,2-Dihydro-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB4)

1,2-Dihydro-1-isobutyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB5)

1,2-Dihydro-1-phenyl-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC1) 

1,2-Dihydro-1-ethyl-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC2)

1,2-Dihydro-1-methyl-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC3) 

1,2-Dihydro-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC4)

1,2-Dihydro-1-isobutyl-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC5)

1,2-Dihydro-6-methyl-2-thio-4-(m-toluidyl)-5-pyrimidinecarboxylic acid (ID1) 

1,2-Dihydro-6-methyl-2-thio-4-(p-chloroanilino)-5-pyrimidinecarboxylic acid (ID2) 

1,2-Dihydro-6-methyl-2-thio-4-(anilino)-5-pyrimidinecarboxylic acid (ID3)

1,2-Dihydro-1-phenyl-6-methyl-2-thio-4-(m-toluidine)-5-pyrimidinecarboxylic acid (ID4)

1,2-Dihydro-1-ethyl-6-methyl-2-thio-4-(m-toluidyl)-5-pyrimidinecarboxylic acid (ID5)

1,2-Dihydro-1-phenyl-6-methyl-2-thio-4-(p-chloroanilino)-5-pyrimidinecarboxylic acid (ID6) 

1,2-Dihydro-1-phenyl-6-methyl-2-thio-4-(anilino)-5-pyrimidinecarboxylic acid (ID7) 

1,2-Dihydro-6-methyl-2-imino-4-(m-toluidyl)-5-pyrimidinecarboxylic acid (IE1) 

1,2-Dihydro-6-methyl-2-imino-4-(p-chloroanilino)-5-pyrimidinecarboxylic acid (IE2) 

1,2-Dihydro-6-methyl-2-imino-4-(anilino)-5-pyrimidinecarboxylic acid (IE3) 

The compound structural formula in the partial preferred embodiment of the present invention is as follows:

The pharmaceutical composition of the present invention, which contains an effective amount of the compound of the present invention, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate, the dosage form can be tablet, capsule, powder, granule, pill, Common pharmaceutical dosage forms such as suppositories, oral liquids, suspensions, and injections. Tablets and capsules for oral administration contain traditional excipients such as fillers, diluents, lubricants, dispersants and binders, and can be prepared according to methods well known in the art. the

The dosage of the drug treatment containing the compound of the present invention, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate varies with the disease, age and body weight, the dosage range is 0.001-100mg/kg per day, the preferred dosage The range is 0.1-50mg/kg per day, and it can deviate from this dosage range according to the degree of disease and the different dosage forms. the

Another object of the present invention is to provide a preparation method of the compound represented by the above general formula (I) or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof. This is also the first time that isocyanate, urea and its derivatives, and 1,3 dicarbonyl compounds are used to synthesize compounds with a cytosine core. The preparation method has strong novelty and high application value, as shown in the following reaction scheme;

Wherein, R ₁ , R ₂ and X are the same as defined in general formula (I);

The method includes the following steps;

(1) raw material 1 reacts with raw material 2 to generate intermediate 1 in the presence of alkali;

(2) intermediate 1 reacts with raw material 3 in the presence of alkali to generate compound 1;

Wherein, the base used in step (1) is triethylamine, morpholine, piperidine, piperazine, methylpiperazine, NaH, pyridine, imidazole, N-methylimidazole, 1,8-diazabicyclo[ 5.4.0] Undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP) or 1,4 - Diazabicyclo[2.2.2]octane (DABCO), or N,N-diisopropylethylamine (DIPEA); the reaction solvent is 1,2-dichloroethane, toluene, benzene, cyclohexane alkane, methyl tert-butyl ether, carbon tetrachloride, n-hexane or a mixed solvent optionally composed of these solvents, preferably 1,2-dichloroethane, toluene, tetrahydrofuran or acetonitrile; the reaction temperature is from 0°C to 150 °C, preferably between 20 °C and 70 °C;

The base used in step (2) is triethylamine, pyridine, imidazole, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5 -diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP), or N,N-diisopropylethylamine (DIPEA); the reaction solvent is 1,2 - Dichloroethane, toluene, benzene, cyclohexane, methyl tert-butyl ether, carbon tetrachloride, n-hexane or a mixed solvent of these solvents, preferably 1,2-dichloroethane, toluene , tetrahydrofuran or acetonitrile; the reaction temperature is from 0°C to 150°C, preferably from 40°C to 100°C;

)

Detailed ways:

The present invention will be further elaborated below in conjunction with specific examples. These examples are for illustrative purposes only, and do not limit the scope and spirit of the present invention. the

Preparation Example

¹ H-NMR and ¹³ C-NMR are determined by Bruker AVANCE300 instrument: aniline, p-chloroaniline, 3-methylaniline, solid phosgene, ethyl acetoacetate, toluene, 1,2-dichloroethane, cyclohexane Alkane, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, thiourea, hydrochloric acid Guanidine, guanidine nitrate, urea, phenyl urea, ethyl urea, and isobutyl urea are all produced by China Pharmaceutical Reagent Co., Ltd. All solvents were re-distilled before use, and the anhydrous solvents used were obtained by drying according to standard methods; except for the instructions, all reactions were carried out under nitrogen protection and tracked by thin-layer chromatography. After washing with saturated sodium chloride aqueous solution and drying with anhydrous sodium sulfate; the purification of the product uses silica gel (200-300 mesh) column chromatography except recrystallization; wherein column chromatography silica gel (200-300 mesh) and GF- 254 TLC silica gel plates were produced by Qingdao Ocean Chemical Factory.

1. Preparation of Compound IA1 of Preparation Example 1

1,2-Dihydro-1-phenyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA1) 

The preparation route is as follows:

1.1 Preparation of m-tolyl isocyanate

Add 5.94g (20mmol) of triphosgene and 200mL of toluene solvent in the there-necked flask equipped with stirrer, thermometer and constant pressure dropping funnel, after stirring and dissolving, mix 2.15g (20mmol) m-toluidine with 0.51g (5mmol) of The triethylamine mixture was slowly and uniformly added dropwise to the reaction system through a constant-pressure dropping funnel, and the dropwise addition was completed in 30 minutes. During the dropwise addition, the temperature of the reaction system was kept at 0-5° C. in an ice bath. After the dropwise addition, the ice bath was removed, and heated to reflux for 4-6h. The solution was distilled under reduced pressure (12mmHg), and the fraction at 74-76°C was collected to obtain 1.83g of m-tolyl isocyanate, with a yield of 83%. the

1.2 Preparation of ethyl 3-oxo-2-[(3-methylaniline)carbonyl]butanoate

Dissolve 1.30 g (10 mmol) of ethyl acetoacetate and 0.24 g (10 mmol) of sodium hydride in 100 mL of toluene. After stirring for 30 min, slowly add 1.33 g (10 mmol) of m-tolylisocyanate and stir for 3 hours. Pour the reaction solution into 100 mL of water, separate the organic layer, wash with saturated brine, extract with toluene (30 mL×3), combine the organic layers, dry over anhydrous sodium sulfate, spin off the solvent, and perform column chromatography (petroleum ether: ethyl acetate = 4:1) 2.50 g of the intermediate ethyl 3-oxo-2-[(3-methylaniline)carbonyl]butyrate was obtained with a yield of 95%. the

1.3 Preparation of Compound IA1

Dissolve the intermediate 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid ethyl ester 1.32g (5mmol), phenylurea 0.68g (5mmol) in 50mL toluene, add dropwise 0.07g (0.5mmol ) DBU, reflux at 80° C. for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.39 g of pure product with a yield of 83%. the

White solid; melting point: 219-221°C; ¹ H-NMR (300MHz, DMSO) δ: 11.78 (1H, s), 10.42 (1H, s), 7.6-6.8 (9H, m), 2.29 (3H, s) , 1.93 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 162.1, 161.5, 154.0, 150.2, 138.8, 137.9, 136.5, 129.5, 129.1, 128.9, 128.6, 124.2, 119.7, 116.4, 110.6, 21.1 , 18.7; HRMS (ESI) for (M+Na) ⁺ : calcd358.1168, found358.1179

2. Preparation of Preparation Example 2 Compound IA2

1,2-Dihydro-1-ethyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA2) 

2.1 Preparation of compound IA2

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; the intermediate 3-oxo-2-[(3-methylaniline) carbonyl] butyric acid ethyl ester 1.32g (5mmol), ethyl urea 0.44g (5mmol) was dissolved in 50mL toluene, and 0.07g was added dropwise (0.5 mmol) DBU, reflux at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.12 g of pure product with a yield of 78%. the

White solid; melting point: 207-210°C; ¹ H-NMR (300MHz, DMSO) δ: 11.59 (1H, s), 10.50 (1H, s), 7.5-6.8 (4H, m), 3.81 (2H, q, J = 7.13), 2.37 (3H, s), 2.28 (3H, s), 1.16 (3H, t, J = 7.13) ¹³ C-NMR (75MHz, DMSO) δ: 162.5, 160.9, 150.2, 149.5, 138.7, 138.0, 128.5, 124.1, 119.7, 116.4, 105.5, 35.1, 21.1, 18.1, 16.6; HRMS (ESI) for (M+Na) ⁺ : calcd310.1168, found310.1173

3. Preparation of Preparation Example 3 Compound IA3

1,2-Dihydro-1-methyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA3) 

3.1 Preparation of compound IA3

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; the intermediate 3-oxo-2-[(3-methylaniline) carbonyl] butyric acid ethyl ester 1.32g (5mmol), methyl urea 0.37g (5mmol) was dissolved in 50mL toluene, and 0.07g was added dropwise (0.5 mmol) DBU, reflux at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 2) to obtain 1.05 g of pure product with a yield of 71%. the

White solid; melting point: 203-205oC; ¹ H-NMR (300MHz, DMSO) δ: 11.59 (1H, s), 10.31 (1H, s), 7.5-6.8 (4H, m), 3.34 (3H, s), 2.38 (3H, s), 2.29 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 162.4, 161.1, 155.1, 150.6, 138.9, 137.9, 128.5, 124.2, 119.7, 116.4, 110.6, 30.6, 21.1 , 17.5; HRMS (ESI) for (M+Na)+: calcd296.1011, found296.1018

4. Preparation of Preparation Example 4 Compound IA4

1,2-Dihydro-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA4)

4.1 Preparation of compound IA4

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; intermediate 3-oxygen-2-[(3-methylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), urea 0.31g (5mmol) was dissolved in 50mL toluene, and 0.07g (0.5 mmol) DBU, reflux at 80° C. for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 4) to obtain 0.88 g of pure product with a yield of 68%. the

White solid; melting point: 190-192°C; ¹ H-NMR (300MHz, DMSO) δ: 11.56 (1H, s), 11.43 (1H, s), 10.89 (1H, s), 7.5-6.8 (4H, m) , 2.42(3H, s), 2.28(3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 164.0, 161.9, 158.6, 149.5, 138.7, 138.0, 128.6, 124.0, 119.9, 116.5, 104.7, 21.1, 18.6; HRMS(ESI) for (M+Na)+: calcd282.0855, found282.0861

5. Preparation of Preparation Example 5 Compound IA5

1,2-Dihydro-1-isobutyl-6-methyl-2-oxo-4-(m-toluidine)-5-pyrimidinecarboxylic acid (IA5)

5.1 Preparation of compound IA5

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; intermediate 3-oxo-2-[(3-methylaniline) carbonyl] butyric acid ethyl ester 1.32g (5mmol), isobutyl urea 0.59g (5mmol) was dissolved in 50mL toluene, added dropwise 0.07 g (0.5 mmol) DBU, reflux at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain a crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.23 g of pure product with a yield of 78%. the

White powdery solid; melting point 197-199°C; ¹ H-NMR (300MHz, DMSO) δ: 11.13 (1H, s), 10.34 (1H, s), 7.7-7.3 (4H, m), 3.38 (2H, d , J=6.9Hz), 2.43(3H, s), 2.29(3H, s), 2.03(1H, m), 1.02(6H, d, J=7.0Hz); ¹³ C-NMR (75MHz, DMSO)δ : 166.7, 162.7, 158.5, 143.7, 137.8, 137.7, 129.0, 128.9, 118.9, 115.2, 106.7, 30.2, 24.4, 23.6, 21.8, 18.6; HRMS(ESI) for (M+Na) ⁺ : calcd316.1161, found316 .1169

6. Preparation of Example 6 Compound IB1

1,2-Dihydro-1-phenyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB1)

6.1 Preparation of p-chlorophenylisocyanate

Add 5.94g (20mmol) triphosgene and 200mL toluene solvent in the there-necked flask equipped with stirrer, thermometer and constant pressure dropping funnel, after stirring and dissolving, mix p-chloroaniline 2.55g (20mmol) with triethylamine 0.51g ( 5 mmol) of the mixed solution was slowly and uniformly added dropwise to the reaction system through a constant pressure dropping funnel, and the dropwise addition was completed in 30 minutes. During the dropwise addition, the temperature of the reaction system was kept at 0-5° C. in an ice bath. After the dropwise addition, the ice bath was removed, and heated to reflux for 4-6h. This solution was subjected to vacuum distillation (30mmHg), and the fraction at 129-133°C was collected to obtain 2.49 g of p-chlorophenyl isocyanate. Yield 81%. the

6.2 Preparation of ethyl 3-oxo-2-[(4-chloroaniline)carbonyl]butyrate

Dissolve 1.30 g (10 mmol) of ethyl acetoacetate and 0.24 g (10 mmol) of sodium hydride in 100 mL of toluene. After stirring for 30 min, slowly add 1.54 g (10 mmol) of p-chlorophenylisocyanate and stir for 3 hours. Pour the reaction solution into 100 mL of water, separate the organic layer, wash with saturated brine, extract with toluene (30 mL×3), combine the organic layers, dry over anhydrous sodium sulfate, spin off the solvent, and perform column chromatography (petroleum ether: ethyl acetate = 4:1) 2.69 g of the intermediate ethyl 3-oxo-2-[(4-chloroaniline)carbonyl]butyrate was obtained, with a yield of 95%. the

6.3 Preparation of Compound IB1

Dissolve the intermediate 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid ethyl ester 1.42g (5mmol), phenylurea 0.68g (5mmol) in 50mL toluene, add dropwise 0.07g (0.5mmol) DBU, reflux at 80°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.57 g of pure product with a yield of 91%. the

White solid; melting point: 209-211°C; ¹ H-NMR (300MHz, DMSO) δ: 11.82 (1H, s), 10.63 (1H, s), 7.8-7.3 (9H, m), 1.93 (3H, s) ; ¹³ C-NMR (75MHz, DMSO) δ: 162.3, 161.4, 154.2, 150.2, 137.8, 136.4, 129.5, 129.1, 128.9, 128.6, 127.1, 120.8, 110.4, 18.7; HRMS (ESI) for (M+Na) ⁺ : calcd378.0621, found378.0639

7. Preparation of Preparation Example 7 Compound IB2

1,2-Dihydro-1-ethyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB2)

7.1 Preparation of Compound IB2

Using the same preparation steps as in Preparation Example 6.1, p-chlorophenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 6.2, 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid was synthesized Ethyl ester; Intermediate 3-oxo-2-[(4-chloroaniline) carbonyl] butyric acid ethyl ester 1.42g (5mmol), ethyl urea 0.44g (5mmol) was dissolved in 50mL toluene, and 0.07g ( 0.5 mmol) DBU, reflux at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.29 g of pure product with a yield of 84%. the

White solid; melting point: 221-223°C; ¹ H-NMR (300MHz, DMSO) δ: 11.13 (1H, s), 10.34 (1H, s), 7.7-7.3 (4H, m), 3.87 (2H, q, J=6.9Hz), 2.43 (3H, s), 1.22 (3H, t, J=6.9Hz); ¹³ C-NMR (75MHz, DMSO) δ: 166.7, 162.7, 158.5, 143.7, 137.8, 137.7, 129.0, 128.9, 118.9, 115.2, 106.7, 30.2, 24.4, 21.8; HRMS (ESI) for (M+Na) ⁺ : calcd330.0621, found330.0627

8. Preparation of Example 8 Compound IB3

1,2-Dihydro-1-methyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB3)

8.1 Preparation of Compound IB3

Using the same preparation steps as in Preparation Example 6.1, p-chlorophenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 6.2, 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid was synthesized Ethyl ester; intermediate 3-oxo-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), methylurea 0.37g (5mmol) were dissolved in 50mL toluene, and 0.07g ( 0.5 mmol) DBU, reflux at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 2) to obtain 1.10 g of pure product with a yield of 75%. the

White solid; melting point: 206-209°C; ¹ H-NMR (300MHz, DMSO) δ: 11.09 (1H, s), 9.63 (1H, s), 7.5-7.3 (4H, m), 3.09 (3H, s) , 2.37 (3H, s) ¹³ C-NMR (75MHz, DMSO) δ: 167.6, 164.5, 154.0, 148.3, 137.1, 136.8, 130.1, 123.0, 116.0, 110.3, 29.5, 16.3. HRMS (ESI) for (M+ Na) ⁺ : calcd316.0465, found316.0469

9. Preparation of Preparation Example 9 Compound IB4

1,2-Dihydro-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB4)

9.1 Preparation of Compound IB4

Using the same preparation steps as in Preparation Example 6.1, p-chlorophenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 6.2, 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid was synthesized Ethyl ester; intermediate 3-oxo-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), urea 0.31g (5mmol) was dissolved in 50mL toluene, and 0.07g (0.5mmol) was added dropwise ) DBU, reflux at 80° C. for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 4) to obtain 0.94 g of pure product with a yield of 67%. the

White solid; melting point: 195-197°C; ¹ H-NMR (300MHz, DMSO) δ: 11.55 (2H, s), 11.02 (1H, s), 7.7-7.3 (4H, m), 2.40 (3H, s) ; ¹³ C-NMR (75MHz, DMSO) δ: 162.4, 161.1, 155.0, 150.6, 138.9, 137.9, 128.5, 124.2, 119.7, 110.6, 17.5; HRMS (ESI) for (M+Na) ⁺ : calcd302.0308, found302.0314

10. Preparation of Preparation Example 10 Compound IB5

1,2-Dihydro-1-isobutyl-6-methyl-2-oxo-4-(4-chloroanilino)-5-pyrimidinecarboxylic acid (IB5)

10.1 Preparation of Compound IB5

Using the same preparation steps as in Preparation Example 6.1, p-chlorophenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 6.2, 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid was synthesized Ethyl ester; the intermediate 3-oxo-2-[(4-chloroaniline) carbonyl] butyric acid ethyl ester 1.42g (5mmol), isobutyl urea 0.59g (5mmol) was dissolved in 50mL toluene, and 0.07g was added dropwise (0.5 mmol) DBU, reflux at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.40 g of pure product with a yield of 84%. the

White powdery solid; melting point 193-195°C; ¹ H-NMR (300MHz, DMSO) δ: 11.83 (1H, s), 10.23 (1H, s), 7.7-7.3 (4H, m), 3.26 (2H, d , J=7.5Hz), 2.41(3H, s), 2.18(3H, s), 1.98(1H, m), 0.92(6H, d, J=6.9Hz); ¹³ C-NMR (75MHz, DMSO)δ : 166.5, 162.6, 158.3, 144.1, 138.4, 137.7, 129.1, 129.0, 119.0, 115.1, 106.4, 30.1, 24.5, 23.3, 21.4, 19.1; HRMS(ESI) for (M+Na) ⁺ : calcd358.0934, found358 .0969

11. Preparation of Compound IC1 of Preparation Example 11

1,2-Dihydro-1-phenyl-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC1) 

11.1 Preparation of phenylisocyanate

Add 5.94g (20mmol) of triphosgene and 200mL of toluene solvent into the three-necked flask equipped with a stirrer, thermometer and constant pressure dropping funnel. After stirring and dissolving, add 1.86g (20mmol) of aniline and 0.50g (5mmol) The mixed solution was slowly and uniformly added dropwise to the reaction system through a constant pressure dropping funnel, and the dropwise addition was completed in 30 minutes. During the dropwise addition, the temperature of the reaction system was kept at 0-5°C in an ice bath. After the dropwise addition, the ice bath was removed, and heated to reflux for 4-6h. The solution was subjected to fractional distillation, and the fraction at 159-168°C was collected to obtain 1.91 g of phenylisocyanate with a yield of 81%. the

11.2 Preparation of ethyl 3-oxo-2-[(aniline)carbonyl]butanoate

Dissolve 1.30 g (10 mmol) of ethyl acetoacetate and 0.24 g (10 mmol) of sodium hydride in 100 mL of toluene. After stirring for 30 min, slowly add 1.19 g (10 mmol) of phenylisocyanate and stir for 3 hours. Pour the reaction solution into 100 mL of water, separate the organic layer, wash with saturated brine, extract with toluene (30 mL×3), combine the organic layers, dry over anhydrous sodium sulfate, spin off the solvent, and perform column chromatography (petroleum ether: ethyl acetate = 4:1) 2.31 g of the intermediate ethyl 3-oxo-2-[(aniline)carbonyl]butyrate was obtained with a yield of 93%. the

11.3 Preparation of compound IC1

Dissolve the intermediate 3-oxo-2-[(aniline)carbonyl]butanoic acid ethyl ester 1.25g (5mmol), phenylurea 0.68g (5mmol) in 50mL toluene, add 0.07g (0.5mmol) DBU dropwise, 80 °C for 2 hours at reflux. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product (ethanol: water = 1: 1) was recrystallized to obtain 1.24 g of pure product with a yield of 77%. the

White powdery solid; melting point 215-217°C; ¹ H-NMR (300MHz, DMSO) δ: 11.47 (1H, s), 10.80 (1H, s), 7.89-7.20 (10H, m), 2.30 (3H, s ); ¹³ C-NMR (75MHz, DMSO) δ: 162.4, 161.7, 154.6, 150.3, 137.9, 135.1, 130.5, 129.1, 128.3, 127.4, 120.2, 109.8, 19.2; HRMS (ESI) for (M+Na) ⁺ : calcd344.1011, found344.1027

12. Preparation of Compound IC2 of Preparation Example 12

1,2-Dihydro-1-ethyl-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC2)

12.1 Preparation of Compound IC2

Use the same preparation steps as in Preparation Example 11.1 to synthesize phenyl isocyanate; use the same preparation steps as in Preparation Example 11.2 to synthesize ethyl 3-oxo-2-[(aniline)carbonyl]butanoate; Dissolve 1.25g (5mmol) of ethyl 3-oxo-2-[(aniline)carbonyl]butanoate, 0.44g (5mmol) of ethyl urea in 50mL of toluene, add 0.07g (0.5mmol) of DBU dropwise, and reflux at 80°C 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.17 g of pure product with a yield of 86%. the

White powdery solid; melting point 222-224°C; ¹ H-NMR (300MHz, DMSO) δ: 11.03 (1H, s), 10.14 (1H, s), 7.81-7.28 (5H, m), 3.79 (2H, q , J=7.5Hz), 2.47 (3H, s), 1.42 (3H, t, J=7.5Hz); ¹³ C-NMR (75MHz, DMSO) δ: 166.7, 162.7, 158.5, 143.7, 137.8, 137.7, 129.0 , 128.9, 118.9, 115.2, 106.7, 29.6, 23.3, 20.5; HRMS (ESI) for (M+Na) ⁺ : calcd296.1011, found296.1027

13. Preparation of Example 13 Compound IC3

1,2-Dihydro-1-methyl-6-methyl-2-oxo 4-(anilino)-5-pyrimidinecarboxylic acid (IC3)

13.1 Preparation of compound IC3

Use the same preparation steps as in Preparation Example 11.1 to synthesize phenyl isocyanate; use the same preparation steps as in Preparation Example 11.2 to synthesize ethyl 3-oxo-2-[(aniline)carbonyl]butanoate; Dissolve 5 mmol of ethyl 3-oxo-2-[(aniline) carbonyl] butyrate, 0.37 g (5 mmol) of methylurea in 50 mL of toluene, add 0.07 g (0.5 mmol) of DBU dropwise, and reflux at 80°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 2) to obtain 0.99 g of pure product with a yield of 77%. the

White powdery solid; melting point 202-204°C; ¹ H-NMR (300MHz, DMSO) δ: 11.49 (1H, s), 9.68 (1H, s), 7.51-7.20 (5H, m), 3.19 (3H, s ), 2.41 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 168.7, 162.3, 153.9, 148.3, 136.8, 135.3, 134.1, 121.0, 118.1, 109.3, 29.7, 16.3. HRMS (ESI) for ( M+Na) ⁺ : calcd282.0855, found282.0863

14. Preparation of Compound IC4 of Preparation Example 14

1,2-Dihydro-6-methyl-2-oxo 4-(anilino)-5-pyrimidinecarboxylic acid (IC4)

14.1 Preparation of Compound IC4

Use the same preparation steps as in Preparation Example 11.1 to synthesize phenyl isocyanate; use the same preparation steps as in Preparation Example 11.2 to synthesize ethyl 3-oxo-2-[(aniline)carbonyl]butanoate; Dissolve 1.25g (5mmol) of ethyl 3-oxo-2-[(aniline)carbonyl]butanoate, 0.31g (5mmol) of urea in 50mL of toluene, add 0.07g (0.5mmol) of DBU dropwise, and reflux at 80°C for 3 hours . The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 4) to obtain 0.73 g of pure product with a yield of 59%. the

White solid; melting point: 206-208°C; ¹ H-NMR (300MHz, DMSO) δ: 11.15 (1H, s), 9.9 (2H, s), 8.1-7.0 (5H, m), 2.21 (3H, s) ; ¹³ C-NMR (75MHz, DMSO) δ: 166.7, 158.5, 155.1, 154.6, 137.8, 137.7, 129.0, 128.9, 122.5, 118.8, 106.7, 24.4; HRMS (ESI) for (M+Na) ⁺ : calcd268. 0698,found268.0706

15. Preparation of Compound IC5 of Preparation Example 15

1,2-Dihydro-1-isobutyl-6-methyl-2-oxo-4-(anilino)-5-pyrimidinecarboxylic acid (IC5)

15.1 Preparation of Compound IC5

Use the same preparation steps as in Preparation Example 11.1 to synthesize phenyl isocyanate; use the same preparation steps as in Preparation Example 11.2 to synthesize ethyl 3-oxo-2-[(aniline)carbonyl]butanoate; 1.25 g (5 mmol) of ethyl 3-oxo-2-[(aniline) carbonyl] butyrate, 0.59 g (5 mmol) of isobutylurea were dissolved in 50 mL of toluene, 0.07 g (0.5 mmol) of DBU was added dropwise, at 80°C Reflux for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.22 g of pure product with a yield of 81%. the

White powdery solid; melting point 201-203°C; 1H-NMR (300MHz, DMSO) δ: 11.64 (1H, s), 10.38 (1H, s), 7.80-7.03 (5H, m), 3.56 (2H, d, J=7.2Hz), 2.43(3H, s), 2.09(3H, s), 1.96(1H, m), 0.91(6H, d, J=7.0Hz); 13C-NMR (75MHz, DMSO) δ: 167.1 , 161.8, 159.0, 145.8, 138.7, 136.3, 128.7, 128.0, 120.1, 115.8, 106.7, 31.2, 23.8, 22.7, 21.1, 19.6; HRMS(ESI) for (M+Na) ⁺ : calcd324.1324, found324.1339

16. Preparation of Compound ID1 in Preparation Example 16

1,2-Dihydro-6-methyl-2-thio-4-(m-toluidyl)-5-pyrimidinecarboxylic acid (ID1) 

16.1 Preparation of compound ID1

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; Intermediate 3-oxygen-2-[(3-methylaniline) carbonyl] ethyl butyrate 1.32g (5mmol), thiourea 0.38g (5mmol) were dissolved in 50mL toluene, and 0.07g ( 0.5mmol) DBU, N ₂ protection, reflux at 70°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain a crude product. The crude product was recrystallized (ethanol: water = 1: 4) to obtain 1.01 g of pure product with a yield of 73%.

White solid; melting point: 164-166°C; ¹ H-NMR (300MHz, DMSO) δ: 11.58 (1H, s), 11.47 (1H, s), 10.89 (1H, s), 7.5-6.8 (4H, m) , 2.41(3H, s), 2.28(3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 164.0, 161.9, 158.6, 149.5, 138.7, 138.0, 128.6, 124.0, 119.9, 116.6, 107.5, 23.1, 15.9; HRMS (ESI) for (M+Na) ⁺ : calcd275.3262, found275.3278

17. Preparation of Compound ID2 in Preparation Example 17

1,2-Dihydro-6-methyl-2-thio-4-(p-chloroanilino)-5-pyrimidinecarboxylic acid (ID2) 

17.1 Preparation of Compound ID2

Using the same preparation steps as in Preparation Example 6.1, p-chlorophenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 6.2, 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid was synthesized Ethyl ester; intermediate 3-oxygen-2-[(4-chloroaniline) carbonyl] ethyl butyrate 1.42g (5mmol), thiourea 0.38g (5mmol) were dissolved in 50mL toluene, and 0.07g (0.5 mmol) DBU, N ₂ protection, reflux at 70°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 4) to obtain 0.98 g of pure product with a yield of 66%.

Off-white solid; melting point: 166-168°C; ¹ H-NMR (300MHz, DMSO) δ: 12.90 (1H, s), 12.65 (1H, s), 10.79 (1H, s), 7.7-7.3 (4H, m) , 2.37 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 166.5, 159.3, 154.2, 150.7, 142.9, 138.3, 129.3, 123.1, 121.1, 117.7, 106.7, 24.5; HRMS (ESI) for (M +Na) ⁺ : calcd318.0080, found318.0086

18. Preparation of Compound ID3 in Preparation Example 18

1,2-Dihydro-6-methyl-2-sulfur 4-(anilino)-5-pyrimidinecarboxylic acid (ID3)

18.1 Preparation of Compound ID3

Use the same preparation steps as in Preparation Example 11.1 to synthesize phenyl isocyanate; use the same preparation steps as in Preparation Example 11.2 to synthesize ethyl 3-oxo-2-[(aniline)carbonyl]butanoate; Dissolve 5mmol of ethyl 3-oxo-2-[(aniline)carbonyl]butanoate, 0.38g (5mmol) of thiourea in 50mL of toluene, add 0.07g (0.5mmol) of DBU dropwise, protect under _N2 , and reflux at 70°C 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 4) to obtain 0.95 g of pure product with a yield of 73%.

White powdery solid; melting point 156-158°C; ¹ H-NMR (300MHz, DMSO) δ: 11.15 (1H, s), 9.90 (2H, s), 8.12-7.01 (5H, m), 2.21 (3H, s ); ¹³ C-NMR (75MHz, DMSO) δ: 166.7, 158.5, 155.1, 154.6, 137.8, 137.7, 129.0, 128.9, 122.5, 118.8, 106.7, 24.4; HRMS (ESI) for (M+Na) ⁺ : calcd268 .0698, found 268.0706

19. Preparation of Compound ID4 in Preparation Example 19

1,2-Dihydro-1-phenyl-6-methyl-2-sulfur 4-(m-toluidine)-5-pyrimidinecarboxylic acid (ID4)

19.1 Preparation of Compound ID4

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; intermediate 3-oxo-2-[(3-methylaniline) carbonyl] butyric acid ethyl ester 1.32g (5mmol), phenylthiourea 0.76g (5mmol) were dissolved in 50mL toluene, added dropwise 0.07 g (0.5 mmol) DBU, N ₂ protection, reflux at 75°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain a crude product. The crude product was recrystallized (ethanol: water = 1: 4) to obtain 1.49 g of pure product with a yield of 85%.

White powdery solid; melting point 219-221oC; ¹ H-NMR (300MHz, DMSO) δ: 11.78 (1H, s), 10.42 (1H, s), 7.6-6.8 (9H, m), 2.29 (3H, s) , 1.93 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 162.1, 161.5, 154.0, 150.2, 138.8, 137.9, 136.5, 129.5, 129.1, 128.9, 128.6, 124.2, 119.7, 116.4, 110.6, 21.1 , 18.7; HRMS (ESI) for (M+Na)+: calcd358.1168, found358.1179

20. Preparation of Compound ID5 in Preparation Example 20

1,2-Dihydro-1-ethyl-6-methyl-2-thio-4-(m-toluidyl)-5-pyrimidinecarboxylic acid (ID5)

20.1 Preparation of Compound ID5

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; intermediate 3-oxo-2-[(3-methylaniline) carbonyl] butyric acid ethyl ester 1.32g (5mmol), ethylthiourea 0.52g (5mmol) were dissolved in 50mL toluene, added dropwise 0.07 g (0.5 mmol) DBU, N ₂ protection, reflux at 75°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain a crude product. The crude product was recrystallized (ethanol: water = 1: 2) to obtain 1.18 g of pure product with a yield of 78%.

White powdery solid; melting point 187-189°C; ¹ H-NMR (300MHz, DMSO) δ: 11.29 (1H, s), 9.85 (1H, s), 7.5-6.8 (4H, m), 3.81 (2H, q , J=7.70), 2.47 (3H, s), 2.38 (3H, s), 1.46 (3H, t, J=7.70); ¹³ C-NMR (75MHz, DMSO) δ: 162.5, 160.9, 150.2, 149.2, 139.4, 137.4, 129.6, 125.2, 120.6, 117.3, 106.4, 36.0, 22.2, 19.0, 17.5; HRMS (ESI) for (M+Na) ⁺ : calcd326.0939, found326.0947;

21. Preparation of Compound ID6 in Preparation Example 21

1,2-Dihydro-1-phenyl-6-methyl-2-thio-4-(p-chloroanilino)-5-pyrimidinecarboxylic acid (ID6) 

21.1 Preparation of compound ID6

Using the same preparation steps as in Preparation Example 6.1, p-chlorophenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 6.2, 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid was synthesized Ethyl ester; the intermediate 3-oxo-2-[(4-chloroaniline) carbonyl] butyric acid ethyl ester 1.42g (5mmol), phenylthiourea 0.76g (5mmol) were dissolved in 50mL toluene, and 0.07g was added dropwise (0.5mmol) DBU, N ₂ protection, reflux at 70°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.60 g of pure product with a yield of 86%.

White powdery solid; melting point 219-221°C; ¹ H-NMR (300MHz, DMSO) δ: 11.61 (1H, s), 10.48 (1H, s), 7.80-7.21 (9H, m), 2.11 (3H, s ); ¹³ C-NMR (75MHz, DMSO) δ: 161.7, 160.1, 153.2, 151.2, 138.8, 136.9, 129.4, 128.9, 128.3, 127.0, 120.8, 109.6, 19.7; HRMS (ESI) for (M+Na) ⁺ : calcd394.0393, found394.0401

22. Preparation of Compound ID7 in Preparation Example 22

1,2-Dihydro-1-phenyl-6-methyl-2-thio-4-(anilino)-5-pyrimidinecarboxylic acid (ID7) 

22.1 Preparation of compound ID7

Use the same preparation steps as in Preparation Example 11.1 to synthesize phenyl isocyanate; use the same preparation steps as in Preparation Example 11.2 to synthesize ethyl 3-oxo-2-[(aniline)carbonyl]butanoate; 1.25 g (5 mmol) of ethyl 3-oxo-2-[(aniline) carbonyl] butyrate, 0.76 g (5 mmol) of phenylthiourea were dissolved in 50 mL of toluene, 0.07 g (0.5 mmol) of DBU was added dropwise, N ₂ Protection, reflux at 80°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the white solid was filtered to obtain the crude product. The crude product was recrystallized (ethanol: water = 1: 1) to obtain 1.19 g of pure product with a yield of 71%.

White powdery solid; melting point 203-205°C; 1H-NMR (300MHz, DMSO) δ: 11.78 (1H, s), 10.42 (1H, s), 7.70-6.81 (10H, m), 2.29 (3H, s) ; ¹³ C-NMR (75MHz, DMSO) δ: 162.7, 161.4, 154.1, 150.4, 138.3, 137.2, 136.1, 129.7, 128.4, 124.2, 119.7, 116.4, 110.6, 23.1; HRMS (ESI) for (M+Na) ⁺ : calcd360.0783, found360.0776

23. Preparation of Compound IE1 of Preparation Example 23

1,2-Dihydro-6-methyl-2-imino 4-(m-toluidine)-5-pyrimidinecarboxylic acid (IE1) 

23.1 Preparation of compound IE1

Using the same preparation steps as in Preparation Example 1.1, m-tolyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 1.2, 3-oxo-2-[(3-methylaniline)carbonyl]butanoic acid was synthesized Ethyl ester; add 0.48g (5mmol) of guanidine hydrochloride and 0.41g (4mmol) of triethylamine to 50mL of toluene, until the mixture is completely clarified, add the intermediate 3-oxo-2-[(3-methylaniline)carbonyl] Ethyl butyrate 1.32g (5mmol), while adding 0.07g (0.5mmol) DBU dropwise, _N2 protection, reflux at 75°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the tan solid was filtered to obtain a crude product. The crude product was recrystallized (acetone: water = 1: 1) to obtain 0.50 g of pure product with a yield of 39%.

Brown-yellow solid; melting point: 178-181°C; ¹ H-NMR (300MHz, DMSO) δ: 11.47 (2H, s), 10.91 (1H, s), 9.97 (1H, s), 7.53-6.80 (4H, m ), 2.28 (3H, s), 2.07 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 165.8, 162.7, 159.4, 149.3, 136.3, 135.0, 128.0, 118.1, 117.6, 115.0, 110.4, 26.7 , 20.8; HRMS (ESI) for (M+Na) ⁺ : calcd281.1014, found281.1021

24. Preparation of Compound IE2 of Preparation Example 24

1,2-Dihydro-6-methyl-2-imino-4-(p-chloroanilino)-5-pyrimidinecarboxylic acid (IE2) 

24.1 Preparation of compound IE2

Using the same preparation steps as in Preparation Example 6.1, p-chlorophenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 6.2, 3-oxo-2-[(4-chloroaniline)carbonyl]butanoic acid was synthesized Ethyl ester; add 0.48g (5mmol) of guanidine hydrochloride and 0.41g (4mmol) of triethylamine to 50mL of toluene, until the mixed solution is completely clarified, add the intermediate 3-oxo-2-[(4-chloroaniline)carbonyl]butyl Ethyl acetate 1.42g (5mmol), while 0.07g (0.5mmol) DBU was added dropwise, N ₂ protection, reflux at 75°C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the tan solid was filtered to obtain a crude product. The crude product was recrystallized (acetone: water = 1: 1) to obtain 0.61 g of pure product with a yield of 44%.

Brown-yellow solid; melting point: 171-173°C; ¹ H-NMR (300MHz, DMSO) δ: 11.51 (2H, m), 10.91 (1H, s), 9.49 (1H, m), 7.50-7.17 (4H, m ), 2.33 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 166.7, 162.7, 153.5, 143.7, 137.9, 137.8, 129.0, 118.8, 115.2, 106.7, 21.8; HRMS (ESI) for (M+ Na) ⁺ : calcd301.0468, found301.0476

25. Preparation of Compound IE3 in Preparation Example 25

1,2-Dihydro-6-methyl-2-imino-4-(anilino)-5-pyrimidinecarboxylic acid (IE3) 

25.1 Preparation of compound IE3

Using the same preparation steps as in Preparation Example 11.1, phenyl isocyanate was synthesized; using the same preparation steps as in Preparation Example 11.2, 3-oxo-2-[(aniline)carbonyl] ethyl butyrate was synthesized; hydrochloric acid Add 0.48g (5mmol) of guanidine and 0.41g (4mmol) of triethylamine into 50mL of toluene. After the mixture is completely clarified, add 1.25g (5mmol) of the intermediate 3-oxo-2-[(aniline)carbonyl]butyric acid ethyl ester , while adding 0.07g (0.5mmol) DBU dropwise, N ₂ protection, reflux at 75°C for 3 hours. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was concentrated, poured into 50 mL of ice water, and the tan solid was filtered to obtain a crude product. The crude product was recrystallized (acetone: water = 1: 1) to obtain 0.57 g of pure product with a yield of 47%.

Brown-yellow solid; melting point: 176-178oC; ¹ H-NMR (300MHz, DMSO) δ: 11.31 (1H, s), 10.63 (1H, s), 9.90 (1H, s), 8.11-7.03 (5H, m) , 2.21 (3H, s); ¹³ C-NMR (75MHz, DMSO) δ: 166.7, 158.5, 154.5, 144.4, 137.1, 136.7, 129.0, 128.9, 122.5, 119.2, 106.4, 25.4; HRMS (ESI) for (M +Na) ⁺ : calcd267.0858, found267.0846

26. Experimental example: Antitumor activity test of the compound of the present invention

The compound of the present invention has been carried out tumor cell proliferation inhibition test, and test method adopts conventional MTT method (such as Lv Qiujun editor-in-chief " new drug pharmacology research method ", 2007: 242-243)

The cell lines are human liver cancer cells (HepG2), cervical cancer cells (Hela), esophageal cancer cells (Eca109), non-small cell lung cancer cells (A549),

Human lung cancer cells (A549), human colon cancer cells (HT-29), human liver cancer cells (SMMC-7721), human glioma cells (U251), human gastric adenocarcinoma cells (SGC-7901), human breast cancer cells ( MCF-7). The culture medium is DMEM+15%NBS+double antibody. the

Preparation of sample solution: After dissolving in DMSO (Merck), add PBS (-) to make a 100 μmol/L solution or a uniform suspension, then dilute with DMSO in PBS (-), the final concentrations are 0.1, 1 , 10, 20, 40, 60, 80, 100 μmol/L. the

The marketed antineoplastic drugs cytarabine (Ara-C) and 5-fluorouracil (5-FU) were formulated into a reference solution under the same conditions. the

Cell culture: adherent growth tumor cells were cultured in 1640 culture medium containing 10% inactivated newborn bovine serum, penicillin and streptomycin (each 1 million U/L), placed at 37°C, 5% CO ₂ , saturated Cultivated in a humidified carbon dioxide incubator. Cells adhere to the wall and grow once every 2-3 days. When passing, first pour out the culture medium, wash with PBS twice, trypsinize, add fresh culture medium and pipette evenly, adjust the cells to an appropriate concentration and transfer to a new culture bottle , add culture medium to an appropriate amount. Cells in logarithmic growth phase were used for experiments.

MTT assay for cell viability and determination of IC ₅₀ ;

Experimental principle: The dehydrogenase in the mitochondria of living cells can reduce the yellow MTT to formazan (MTT formazan), an insoluble blue-purple product, and deposit it in the cells. The amount produced is proportional to the number of living cells, while dead cells There is no such function. DMSO can dissolve blue-purple crystals, and the color depth is proportional to the amount contained, so the light absorption value measured by a microplate reader can reflect the cell survival rate. the

Experimental method: cells in the logarithmic growth phase were collected, digested, counted, and inoculated in a 96-well culture plate at a density of 2×104/mL, 100 μl per well. After culturing for 24 hours, the cells were treated with the compound to be tested at concentrations of 0.1, 1, 10, 20, 40, 60, 80, and 100 μmol/L. Five replicate wells were set up for each concentration in the experimental group, and the culture solution containing 0.4% DMSO was used as the control. After 48 hours of drug action, the supernatant was removed, and 100 μl MTT (2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium hydrobromide) was added to each well (1mg/mL), continue to cultivate for 4 hours, discard the supernatant, add 100μl DMSO to each well, shake and mix well, measure the absorbance value at 570nm with a microplate reader, and use the _IC50 calculation software (China Pharmaceutical University) to calculate half of the Inhibitory concentration ( _IC50 ).

The test results are shown in the table, wherein, the sample refers to the 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid compound prepared in the corresponding embodiment, and the sample number corresponds to the compound described in the preparation example. The specific number of the compound obtained. the

Table 1 The half inhibitory concentration IC ₅₀ (unit: μmol/L) of the compounds on different tumor cells

The above experimental results show that the compounds of the present invention have good antitumor activity, and the in vitro antitumor activity of compounds IA1, IB1, IB2, IB5, IC5, ID1, ID4, ID6, and IE3 is significantly better than that of cytarabine and 5-fluorouracil , the antitumor activity of the rest of the compounds in some cell lines was better than the positive control drug cytarabine and 5-fluorouracil, and the antitumor activity of the compound with a substituent at the ^N1 position was significantly better than that of the compound without a substituent (IA1, IB4, IC4). Therefore, the 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid compounds and their pharmaceutically acceptable salts or pharmaceutically acceptable solvates or mixtures thereof of the present invention are used as active ingredients The pharmaceutical composition can be used to prepare antitumor drugs.

Claims (8)

1. The present invention relates to a 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structural compound or a pharmaceutically acceptable salt or hydrate or a mixture thereof as a pharmaceutical combination of active ingredients The general structural formula of the compound is shown in the following formula (I): in: ^R is any substituted or unsubstituted phenyl, heterocyclyl, benzoheterocyclyl, lower alkyl or cycloalkyl, lower haloalkyl, lower nitroalkyl, lower cyanoalkyl, lower alkyl- Cycloalkyl, cycloalkyl-lower alkyl, lower alkyl-cycloalkyl-lower alkyl; X is oxygen, sulfur or NR ³ ; wherein, R ³ is hydrogen, optionally substituted phenyl, C1-C4 alkyl, C3-C6 cycloalkyl; ^R is hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted lower alkyl or cycloalkyl, lower alkyl-cycloalkyl, cycloalkyl-lower alkyl, lower alkyl-cycloalkyl- Lower alkyl groups, protected and unprotected sugar groups; Wherein, the heterocyclic group has aromaticity or non-aromaticity, is a 5-7 membered heterocyclic ring, and contains 1-3 heteroatoms selected from N, O and S; The term "lower" related to alkyl herein refers to a straight-chain or branched saturated aliphatic hydrocarbon group containing 1-6 carbon atoms; the term "lower" related to alkenyl or alkynyl refers to a group containing 2-6 A group of carbon atoms and one or more double bonds or triple bonds; cycloalkyl refers to a ring containing 3-7 carbons; aryl refers to a mono-, bi-, or tricyclic hydrocarbon compound in which at least one ring is aromatic rings, each containing up to 7 carbon atoms. the The phenyl, heterocyclyl or benzoheterocyclyl is optionally replaced by 1-3 members selected from C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, polyhalogenated-C1- C4-Alkyl, Polyhalo-C1-C4-Alkoxy, C1-C4-Alkoxy-C1-C4-Alkyl, C1-C4-Alkoxy-C1-C4-Alkoxy-C1- C4-alkyl, C3-C8cycloalkoxy-C1-C4-alkyl, halogen, nitro, trifluoromethyl, carbamoyl, hydroxyl, cyano; The halogen is fluorine, chlorine, bromine or iodine. 2. The 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structural compound or its pharmaceutically acceptable salt or hydrate or its mixture according to claim 1 as an active A pharmaceutical composition of ingredients, characterized in that: ^R represents the following groups, substituted or unsubstituted phenyl, heterocyclyl, benzoheterocyclyl, lower alkyl; X is oxygen, sulfur or NH; R ² represents the following groups: hydrogen, substituted or unsubstituted phenyl, lower alkyl or cycloalkyl, lower haloalkyl, lower nitroalkyl, lower cyanoalkyl, protected and unprotected ribose, protected and Unprotected deoxyribose, protected and unprotected arabinose, protected and unprotected xylose, protected and unprotected glucose; The substituted phenyl includes without limitation: 2, 3 or 4-methoxyphenyl, 2, 3 or 4-ethoxyphenyl, 2, 3 or 4-methylphenyl, 2, 3 or 4-ethylphenyl, 2, 3 or 4-chlorophenyl, 2, 3 or 4-bromophenyl, 2, 3 or 4-fluorophenyl, 2, 3 or 4-nitrophenyl, 2, 3 or 4-trifluoromethylphenyl, 2, 3 or 4-cyanophenyl, 2,3 or 2,4-dichlorophenyl, 2,3 or 2,4-dimethoxybenzene Base, 2,3 or 2,4-dinitrophenyl, 2,3 or 2,4-dimethylphenyl, 2,3 or 2,4-diethylphenyl, 2,3 or 2, 4-Ditrifluoromethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triethylphenyl, 2,4,6-trimethoxyphenyl, 2,4, 6-Trichlorophenyl The heterocyclic group and substituted heterocyclic group include without limitation: furan-2 or 3-yl, 2, 3 or 4-methylfuran-2-yl, 2, 3 or 4-fluorofuran-2 -yl, 2, 3 or 4-chlorofuran-2-yl, 2, 3 or 4-bromofuran-2-yl, 2, 4 or 5-methylfuran-3-yl, 2, 4 or 5-fluorofuran -3 base, 2, 4 or 5-chlorofuran-3 base, 2, 4 or 5-bromofuran-3 base, thiophene-2 or 3 base, 2, 3 or 4-methylthiophen-2-yl, 2 , 3 or 4-fluorothiophen-2-yl, 2, 3 or 4-chlorothiophen-2-yl, 2, 3 or 4-bromothiophen-2-yl, 2, 4 or 5-methylthiophen-3-yl , 2, 4 or 5-fluorothiophen-3 base, 2, 4 or 5-chlorothiophen-3 base, 2, 4 or 5-bromothiophen-3 base, 1H-pyrrol-2 or 3 base and pyridine-2, 3 or 4-base; The benzoheterocyclic group and substituted benzoheterocyclic group include without limitation: benzo[c][1,2,5]oxadiazolin-4 or 5-yl, 1H-indole- 2, 3, 4, 5, 6 or 7-yl, 1,3-dihydro-benzo[d]imidazol-2-one or 5-yl, 1H-indol-one-4, 5, 6 or 7 -yl and 1-methylindol-2-one-4, 5, 6 or 7-yl. the 3. The 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structure compound or its pharmaceutically acceptable salt or pharmaceutically acceptable solvate according to claim 1 or a mixture thereof as the pharmaceutical composition of the active ingredient, characterized in that: the structure of the pyrimidine compound of the general formula (I) is a class of 1,2-dihydro-6- Methyl-4-substituted amino-5-pyrimidine carboxylic acid compounds and derivatives:

Wherein, R ¹ and R ² are the same as defined in the general formula (1) in claim 1. 4. 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structural compounds or pharmaceutically acceptable salts thereof according to claim 1 include compounds of general formula (I), Addition salts with the following acids: sulfuric acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, malonic acid, adipic acid, maleic acid, citric acid, Tartaric acid, lactic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, nadisulfonic acid, oxalic acid, benzoic acid, succinic acid, camphorsulfonic acid, glutamic acid, aspartic acid, malic acid , salicylic acid, ascorbic acid, isonicotinic acid, mandelic acid, pyruvic acid, or fumaric acid. the Pharmaceutically acceptable solvates include, but are not limited to, solvates of the compound represented by general formula (I) with water, ethanol, isopropanol, diethyl ether or acetone. the 5. Any 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structural compound or its pharmaceutically acceptable salt or pharmaceutically acceptable salt according to any one of claims 1-4. The pharmaceutical composition that accepts the solvate or its mixture as the active ingredient is characterized in that: the pharmaceutical composition of the general formula (I), which contains an effective amount of the compound of the present invention, its pharmaceutically acceptable salt or pharmaceutical Acceptable solvate, dosage form can be pharmaceutically commonly used dosage forms such as tablet, capsule, powder, granule, pill, suppository, oral liquid, suspension, injection. Tablets and capsules for oral administration contain traditional excipients such as fillers, diluents, lubricants, dispersants and binders, and can be prepared according to methods well known in the art. the The dosage of the drug treatment containing the compound of the present invention, its pharmaceutically acceptable salt or pharmaceutically acceptable solvate varies with the disease, age and body weight, the dosage range is 0.001-100mg/kg per day, the preferred dosage The range is 0.1-50mg/kg per day, and it can deviate from this dosage range according to the degree of disease and the different dosage forms. the 6. According to claims 1-5, preparing any one of the 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidine carboxylic acid structural compounds or pharmaceutically acceptable salts or pharmaceutically acceptable salts thereof A method of pharmaceutical composition with acceptable solvates or mixtures thereof as active ingredients, said method utilizing isocyanate, urea and its derivatives or thiourea and its derivatives or guanidine and its derivatives, 1,3 dicarbonyl Compound synthesis has a cytosine core compound, as shown in the following reaction scheme;

Wherein, R ¹ , R ² and X are the same as defined in general formula (I); The method includes the following steps; (1) raw material 1 reacts with raw material 2 to generate intermediate 1 in the presence of alkali; (2) intermediate 1 reacts with raw material 3 in the presence of alkali to generate compound 1; Wherein, the base used in step (1) is triethylamine, morpholine, piperidine, piperazine, methylpiperazine, NaH, pyridine, imidazole, N-methylimidazole, 1,8-diazabicyclo[ 5.4.0] Undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP) or 1,4 - Diazabicyclo[2.2.2]octane (DABCO), or N,N-diisopropylethylamine (DIPEA); the reaction solvent is 1,2-dichloroethane, toluene, benzene, cyclohexane alkane, methyl tert-butyl ether, carbon tetrachloride, n-hexane or a mixed solvent optionally composed of these solvents, preferably 1,2-dichloroethane, toluene, tetrahydrofuran or acetonitrile; the reaction temperature is from 0°C to 150 °C, preferably between 20 °C and 70 °C; The base used in step (2) is triethylamine, pyridine, imidazole, N-methylimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5 -diazabicyclo[4.3.0]non-5-ene (DBN), 4-dimethylaminopyridine (DMAP), or N,N-diisopropylethylamine (DIPEA); the reaction solvent is 1,2 -dichloroethane, toluene, benzene, cyclohexane, methyl tert-butyl ether, carbon tetrachloride, normal hexane or the mixed solvent of optional composition with these solvents, preferably 1,2-dichloroethane, toluene , tetrahydrofuran or acetonitrile; the reaction temperature is from 0°C to 150°C, preferably from 40°C to 100°C. the 7. Any 1,2-dihydro-6-methyl-4-substituted amino-5-pyrimidinecarboxylic acids and pharmaceutically acceptable salts thereof or pharmaceutically acceptable salts thereof according to any one of claims 1-6. The application of solvent mixture or its mixture as active ingredient in the preparation of medicines for preventing or treating diseases related to abnormal proliferation and morphological changes of cells in vivo, especially in the preparation of medicines for treating or preventing tumor growth and metastasis application of the drug. the 8. The application according to claim 7, which is to provide a method for treating diseases related to abnormal cell proliferation, morphological changes or tumor growth and metastasis in a living body, said method comprising administering a therapeutically effective amount of A pharmaceutical composition comprising a compound represented by the general formula (I), a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, or a mixture thereof as an active ingredient. the