2-phenylpyrimidine platelet aggregation inhibitors and processes and uses thereof

Abstract

This invention relates to 2-phenylpyrimidine platelet aggregation inhibitors, their preparation methods, and their application in the preparation of drugs for treating thrombotic diseases, belonging to the field of pharmaceutical technology. The compounds of this invention, their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates have the structures shown in Formula I, wherein R1-R5 and A are as described in the claims and specification. The compounds of this invention, their pharmaceutically usable salts, tautomers, pharmaceutically usable solvates, and their pharmaceutical compositions have platelet aggregation inhibitory activity and can be used to prepare drugs for the prevention and treatment of thrombotic diseases.

Description

Technical Field

[0001] This invention relates to 2-phenylpyrimidine platelet aggregation inhibitors, their preparation methods, and their application in the preparation of drugs for treating thromboembolic diseases, belonging to the field of pharmaceutical technology. Background Technology

[0002] Thromboembolic diseases, such as acute myocardial infarction and stroke, remain the most common causes of death and morbidity in developing countries. It is a pathological process caused by various intrinsic and extrinsic factors leading to the formation of thrombi or embolisms within arteries and veins, further resulting in damage to tissue and organ function. It is one of the most common cardiovascular and cerebrovascular diseases clinically, and is also a cause and complication of many other cardiovascular and cerebrovascular diseases. Once a thrombus forms, it often causes irreversible and serious consequences.

[0003] The formation of a stable platelet embolus involves three distinct stages: platelet adhesion, platelet activation and expansion, and platelet aggregation. Numerous strategies have been developed to reduce the risk of pathological thrombosis by interfering with platelet adhesion, activation, or aggregation. Platelet activation plays a crucial role in thrombotic complications. Therefore, antiplatelet therapy remains an important means of preventing and treating thrombotic diseases in clinical practice.

[0004] Currently available drugs that inhibit platelet aggregation include clopidogrel and ticagrelor, but the variety is very limited and they all have certain bleeding side effects. Therefore, the development of highly effective platelet aggregation inhibitors with low bleeding side effects has good application prospects. Summary of the Invention

[0005] The purpose of this invention is to provide a compound represented by general formula I, which has platelet aggregation inhibition activity and can be used to prepare a drug for the prevention and treatment of thrombotic diseases.

[0006] Compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0007]

[0008] R1 is a cyano group and a hydrogen atom;

[0009] R2 is a cyano group and a hydrogen atom;

[0010] R3 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy group;

[0011] R4 is a substituted or unsubstituted 5-6 aryl or heteroaryl group, wherein the substituent is cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 sulfonamide, or C1-C4 acylamino.

[0012] R5 is a hydroxyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group;

[0013] A represents O and NH;

[0014] n = 0 - 3.

[0015] The present invention preferably includes compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0016] R1 is a cyano group and a hydrogen atom;

[0017] R2 is a cyano group and a hydrogen atom;

[0018] R1 and R2 are not simultaneously hydrogen atoms and cyano groups;

[0019] R3 is a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group;

[0020] R4 is a substituted or unsubstituted phenyl, pyrimidinyl, or pyrazolyl group, wherein the substituent is a cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 sulfonamide, or C1-C4 acylamino group.

[0021] R5 is hydroxyl, C1-C4 alkyl, or C1-C4 alkoxy;

[0022] A represents O and NH;

[0023] n = 0 - 1.

[0024] The present invention preferably includes compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0025] R1 is a cyano group and a hydrogen atom;

[0026] R2 is a cyano group and a hydrogen atom;

[0027] R1 and R2 are not simultaneously hydrogen atoms and cyano groups;

[0028] R3 is a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group;

[0029] R4 is a substituted or unsubstituted phenyl, pyrimidinyl, or pyrazolyl group, wherein the substituent is a cyano, C1-C4 alkyl, C1-C4 alkoxy, methanesulfonylamino, or acetylamino group;

[0030] R5 is hydroxyl, C1-C4 alkyl, or C1-C4 alkoxy;

[0031] A represents O and NH;

[0032] n = 0 - 1.

[0033] The present invention preferably includes compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0034] R1 is a cyano group and a hydrogen atom;

[0035] R2 is a cyano group and a hydrogen atom;

[0036] R1 and R2 are not simultaneously hydrogen atoms and cyano groups;

[0037] R3 represents a hydrogen atom or a methyl group;

[0038] R4 is p-cyanophenyl, m-cyanophenyl, o-cyanophenyl, 3-methanesulfonylaminophenyl, 3-acetamidophenyl, pyrimidin-3-yl, 1H-pyrazol-5-yl;

[0039] R5 represents hydroxyl or ethoxy groups;

[0040] Specifically, the present invention provides compounds of general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates, which are any one of the following compounds (1) to (31):

[0041] (1). Ethyl 2-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy]-6-methylpyrimidine-5-carboxylate (4)

[0042] (2). Ethyl 2-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy]pyrimidine-5-carboxylate (5a)

[0043] (3). Ethyl 2-(3-cyanophenyl)-4-[(3-cyanobenzyl)oxy]pyrimidine-5-carboxylate (5b)

[0044] (4). Ethyl 2-(3-cyanophenyl)-4-[(2-cyanobenzyl)oxy]pyrimidine-5-carboxylate (5c)

[0045] (5). Ethyl 2-(4-cyanophenyl)-4-[(4-cyanobenzyl)oxy]pyrimidine-5-carboxylate (6a)

[0046] (6). Ethyl 2-(4-cyanophenyl)-4-[(3-cyanobenzyl)oxy]pyrimidine-5-carboxylate (6b)

[0047] (7). Ethyl 2-(4-cyanophenyl)-4-[(2-cyanobenzyl)oxy]pyrimidine-5-carboxylate (6c)

[0048] (8). 2-(3-Cyanophynyl)-4-[(4-Cyanobenzyl)oxy]-6-methylpyrimidin-5-carboxylic acid (7)

[0049] (9). 2-(3-Cyanophynyl)-4-[(4-Cyanobenzyl)oxy]pyrimidine-5-carboxylic acid (8a)

[0050] (10). 2-(3-Cyanophynyl)-4-[(3-Cyanobenzyl)oxy]pyrimidine-5-carboxylic acid (8b)

[0051] (11). 2-(3-Cyanophynyl)-4-[(2-Cyanobenzyl)oxy]pyrimidine-5-carboxylic acid (8c)

[0052] (12). 2-(4-Cyanophynyl)-4-[(4-Cyanobenzyl)oxy]pyrimidine-5-carboxylic acid (9a)

[0053] (13). 2-(4-Cyanophynyl)-4-[(3-Cyanobenzyl)oxy]pyrimidine-5-carboxylic acid (9b)

[0054] (14). 2-(4-Cyanophynyl)-4-[(2-Cyanobenzyl)oxy]pyrimidine-5-carboxylic acid (9c)

[0055] (15). 2-(3-cyanophenyl)-4-[3-(methanesulfonamide)phenoxy]pyrimidine-5-carboxylic acid (13)

[0056] (16). 2-(3-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylic acid (18a)

[0057] (17). 2-(3-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylic acid (18b)

[0058] (18). 2-(3-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylic acid (18c)

[0059] (19). 2-(3-cyanophenyl)-4-(pyridin-3-yloxy)pyrimidine-5-carboxylic acid (18d)

[0060] (20). 2-(3-cyanophenyl)-4-(3-acetaminophenoxy)pyrimidine-5-carboxylic acid (18e)

[0061] (21). 2-(4-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylic acid (19a)

[0062] (22). 2-(4-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylic acid (19b)

[0063] (23). 2-(4-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylic acid (19c)

[0064] (24). 2-(3-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylic acid (20a)

[0065] (25). 2-(3-Cyanophenyl)-4-[(3-Cyanophenyl)amino]pyrimidine-5-carboxylic acid (20b)

[0066] (26). 2-(3-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylic acid (20c)

[0067] (27). 2-(3-cyanophenyl)-4-(pyridin-3-ylamino)pyrimidine-5-carboxylic acid (20d)

[0068] (28). 2-(3-cyanophenyl)-4-[(1H-pyrazol-5-yl)amino]pyrimidine-5-carboxylic acid (20e)

[0069] (29). 2-(4-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylic acid (21a)

[0070] (30). 2-(4-cyanophenyl)-4-[(3-cyanophenyl)amino]pyrimidine-5-carboxylic acid (21b)

[0071] (31). 2-(4-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylic acid (21c)

[0072]

[0073]

[0074] Furthermore, the present invention provides intermediates for preparing compounds of general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

[0075]

[0076] The present invention also provides a method for preparing the compound represented by general formula I and its pharmaceutically usable salt, comprising the following steps:

[0077] Using m-cyanobenzonitrile 1a as a raw material, an imine ester was generated in methanol via sodium methoxide catalysis. Subsequently, it was ammonolyzed with ammonium chloride to obtain m-cyanoformamidine hydrochloride 2a. Intermediate 2a was cyclized with diethyl 2-(1-methoxyethylidene)malonate in an ethanol-sodium ethoxide system to obtain key intermediate 3a. Intermediate 3a was alkylated with p-cyanobenzyl chloride in N,N-dimethylformamide, potassium carbonate, and potassium iodide to obtain compound 4. Finally, compound 4 was hydrolyzed with lithium hydroxide to obtain compound 7.

[0078] The synthesis of compounds 8a-8c and 9a-9c is similar to that of compound 7. Terephthalonitrile 1b is catalyzed by sodium methoxide in methanol to generate an imine ester, which is then ammonolyzed with ammonium chloride to give p-cyanoformamidine hydrochloride 2b. Then, 3-cyanoformamidine hydrochloride 2a or 4-cyanoformamidine hydrochloride 2b is reacted with ethoxymethylene in an ethanol-sodium ethoxide system to construct a pyrimidine ring to give intermediates 3b and 3c. Intermediates 3b and 3c are alkylated with cyano-substituted benzyl chloride derivatives in N,N-dimethylformamide, potassium carbonate, and potassium iodide to give compounds 5a-5c and 6a-6c. Subsequently, compounds 5a-5c and 6a-6c are hydrolyzed in a saturated lithium hydroxide solution and tetrahydrofuran to give compounds 8a-8c and 9a-9c.

[0079] Intermediates 3b and 3c were chlorinated with thionyl chloride in N,N-dimethylformamide solution to give intermediates 10a and 10b. Intermediates 10a and 10b were reacted with cyano-substituted phenols in potassium carbonate and N,N-dimethylformamide solution to give compounds 14a-14e and 15a-15c. Hydrolysis of these compounds gave compounds 18a-18e and 19a-19c.

[0080] Using intermediate 10a as a starting material, intermediate 11 was obtained by substitution reaction with m-aminophenol in N,N-dimethylformamide and potassium carbonate. Intermediate 11 was then sulfonated with p-toluenesulfonylchlorosulfonate in the presence of pyridine to obtain intermediate 12. Subsequently, intermediate 21 was hydrolyzed to obtain compound 13.

[0081] Using intermediates 10a and 10b as raw materials, compounds 16a-16e and 17a-17c were reacted with cyano-substituted aniline in acetone with concentrated hydrochloric acid as a catalyst. Then, compounds 16a-16e and 17a-17c were hydrolyzed to give compounds 20a-20e and 21a-21c.

[0082]

[0084] Reagents and conditions: (a) i: Sodium methoxide, methanol, room temperature; ii: Ammonium chloride, methanol, 50°C; (b) Diethyl 2-(1-ethoxyethylene)malonate or diethyl ethoxymethylenemalonate, sodium hydride, ethanol, 80°C; (c) Benzyl chloride derivative, potassium carbonate, potassium iodide, N,N-dimethylformamide, room temperature; (d) Lithium hydroxide, tetrahydrofuran, water, 35°C; (e) Thionyl chloride, N,N-dimethylformamide, 0°C; (f) 3-aminophenol, potassium carbonate, N,N-dimethylformamide, room temperature; (g) Methanesulfonyl chloride, triethylamine, anhydrous tetrahydrofuran, 0°C–25°C; (h) Phenol derivative or 3-hydroxypyridine, potassium carbonate, N,N-dimethylformamide, room temperature; (i) Aniline derivative or 3-aminopyridine or 5-aminopyrazole, concentrated hydrochloric acid, acetone, 60°C.

[0085] The present invention provides a pharmaceutical composition comprising the aforementioned compound or pharmaceutically acceptable salt having platelet aggregation inhibitory activity, and its isomers, polymorphs, pharmaceutically acceptable solvates as active ingredients, as well as pharmaceutically acceptable excipients, carriers, diluents, etc.

[0086] Pharmaceutical compositions containing the compounds of the present invention can be prepared by conventional methods, for example, as described in Remington: The Science and Practice of Pharmacy, 19th ED., 1995. The compositions can be in conventional dosage forms such as capsules, tablets, powders, solutions, suspensions, syrups, aerosols, or topical administration. They can contain suitable solid or liquid carriers, or form an injectable solution or suspension in a suitable sterile medium. The compositions can contain 5%-20%, preferably 0.5%-10% by weight of the active compound, with the balance being pharmaceutically acceptable carriers, excipients, diluents, solvents, etc.

[0087] Typical compositions contain a compound of Formula I or a pharmaceutically acceptable salt, isomer, polymorph, pharmaceutically acceptable solvate, and a pharmaceutically acceptable excipient, which may be a carrier or diluent, or diluted by a carrier, or packaged in a carrier, which may be in the form of capsules, sachets, paper, or other solvents. When the carrier is used as a diluent, it may be a solid, semi-solid, or liquid substance, which may serve as a carrier, excipient, or medium for the active compound. The active compound may be absorbed in the form of a particulate solid in a container such as a sachet. Some suitable carriers are water, salt solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, gypsum powder, sucrose, cyclodextrin, amylose, magnesium stearate, talc, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty amides, fatty acid monoglycerides or diglycerides, quaternary tetraethanolamine fatty acid esters, polyoxyethylene, hydroxymethyl cellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent may comprise any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, used alone or mixed with waxes. Formulations of the present invention can be formulated by methods inhibited in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient.

[0088] The pharmaceutical composition may be sterile and may be mixed with excipients, emulsifiers, buffers and / or colorants if desired, provided that it does not react with the active compound.

[0089] It can be administered via any route, as long as it effectively delivers the active compound to the appropriate or desired site of activity, such as oral, nasal, transdermal, pulmonary, or parenteral administration, such as rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular, intranasal, ophthalmic solution, or ointment, with oral administration being preferred.

[0090] If a solid carrier is used for oral administration, the formulation can be compressed into tablets, or encapsulated as powder or pellets, or formulated as lozenges or sugar tablets. If a liquid carrier is used, the formulation can be a syrup, emulsion, soft gelatin capsule, or sterile injection, such as an aqueous or non-aqueous liquid suspension or solution.

[0091] For intranasal administration, the formulation may contain a compound of formula I dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol delivery. This carrier may contain additives including solubilizers such as propylene glycol, surfactants, and absorption enhancers such as lecithin or cyclodextrin, or preservatives such as parabens. For parenteral administration, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions of the active compound dissolved in polyhydroxylated castor oil.

[0092] Tablets, sugar-coated pills, or capsules containing talc and / or carbohydrate carriers or binders are particularly suitable for oral administration. Preferably, the carrier of the tablets, sugar-coated pills, or capsules includes lactose, corn starch, and / or potato starch. When a sweetened carrier is available, a syrup can be used.

[0093] The present invention also provides the use of compounds of general formula I or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of platelet aggregation inhibitors.

[0094] The present invention also provides the use of compounds of general formula I or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof in the preparation of medicaments for treating thromboembolic diseases. Attached Figure Description

[0095] Figure 1 The rate of carrageenan-induced tail vein thrombosis in mice.

[0096] Figure 2 To investigate the efficacy of drugs in rats with acute cerebral infarction.

[0097] Figure 3 This represents the volume of bleeding. Detailed Implementation

[0098] The following embodiments further illustrate the present invention, but do not limit the invention thereon.

[0099] The compounds of the present invention were prepared according to the above procedure.

[0100] Example 1.3-Cyanobenzamide Hydrochloride (2a)

[0101] 10 g (78.1 mmol) of m-cyanobenzene and sodium methoxide were added to 250 mL of methanol and stirred overnight at room temperature. After the reaction of m-cyanobenzene was complete, NH4Cl was added, and the mixture was transferred to 60 °C for further reaction. After the reaction was completed, the solvent was concentrated under vacuum, and ethyl acetate was added and stirred. A large amount of white solid precipitated out. The solid was filtered, dried, and yielded 12.83 g of white solid, with a yield of 91%. Mp 226.4-227.1 °C, ESI-MS (m / z) = 146.1 [M+H] + .

[0102] Example 2.4-Cyanobenzamide Hydrochloride (2b)

[0103] 10 g (78.1 mmol) of p-cyanobenzonitrile and sodium methoxide were added to 250 mL of methanol and stirred overnight at room temperature. After the reaction of p-cyanobenzonitrile was complete, NH4Cl was added, and the mixture was transferred to 60 °C for further reaction. After the reaction was completed, the solvent was concentrated under vacuum, and ethyl acetate was added and stirred. A large amount of white solid precipitated out. The solid was filtered, dried, and 10.43 g of white solid was obtained, with a yield of 65%. Mp 218.2-219.1 °C, ESI-MS (m / z) = 146.1 [M+H] + .

[0104] Example 3.2-(3-cyanophenyl)-4-hydroxy-6-methylpyrimidine-5-carboxylic acid ethyl ester (3a)

[0105] 3-Cyanobenzamide hydrochloride 2a (3.08 g, 17 mmol) and diethyl 2-(1-methoxyethylidene)malonate (3.68 g, 17 mmol) were dissolved in 80 mL of anhydrous ethanol. NaH (0.85 g, 43 mmol) was added in portions at -5 °C. After the addition was complete, the mixture was stirred for 30 minutes, then transferred to room temperature and stirred for 1 h. The reaction was then carried out at 80 °C and monitored by TLC. After the reaction was complete, a portion of the solvent was concentrated under vacuum, and 100 mL of water was added. The pH was adjusted to 5-6 with 1 mol / L dilute hydrochloric acid, resulting in the precipitation of a white solid. The mixture was stirred for 30 minutes and then filtered. The filter cake was washed with 100 mL of water and dried to obtain 2.34 g of a pale yellow solid, yield 48%, Mp 200.3-200.9 °C, ESI-MS (m / z) = 284.04 [M+H]. + .

[0106] Example 4.2-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy]-6-methylpyrimidine-5-carboxylic acid ethyl ester (4)

[0107] Ethyl 2-(3-cyanophenyl)-4-hydroxy-6-methylpyrimidin-5-carboxylate 3a (1 g, 3.5 mmol), p-cyanobenzyl chloride (0.589 g, 3.88 mmol), potassium carbonate (0.967 g, 7 mmol), and potassium iodide (0.0581 g, 0.35 mmol) were dissolved in 10 mL of LDM. The mixture was stirred at 40 °C and monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, 50 mL of water was added, and the mixture was stirred for 30 minutes. The mixture was then filtered to give 782.3 mg of a pale yellow solid (55% yield). 500 mg of the crude product was purified by column chromatography (PE:EA = 3:1) to give 389.3 mg of pure product, Mp 143.2-143.9 °C, ESI-MS (m / z) = 399.1 [M+H]. + . 1 H NMR (400MHz, DMSO-d6) δ8.70–8.67(m,1H),8.65(dt,J=8.0,1.4Hz,1H),8.03(dt,J=8.0,1.4Hz,1H),7.89(d,J=8.4Hz, 2H),7.78–7.72(m,1H),7.68(d,J=8.4Hz,2H),5.75(s,2H),4.39(q,J=7.1Hz,2H),2.54(s,3H),1.31(t,J=7.1Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ166.6,166.0,165.11,161.2,142.5,137.5,135.3,133.0, 132.8,132.0,130.56,128.3,119.1,118.8,112.5,111.1,67.7,62.1,22.7,14.4.

[0108] Example 5. Ethyl 6-(3-cyanophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (3b)

[0109] 10 g (68.5 mmol) of 3-cyanobenzoamide hydrochloride 2a and 14.8 g (68.5 mmol) of diethyl ethoxymethylene malonate were added to 250 mL of anhydrous ethanol. NaH (4.9 g, 204 mmol) was added in portions at -5 °C, and the mixture was stirred for 10 minutes. The mixture was then transferred to room temperature and stirred for 1 hour, followed by overnight reaction at 80 °C. After the reaction was completed by TLC monitoring, the solution was concentrated under vacuum until the volume was halved. The pH was adjusted to 5-6 with 1 mol / L dilute HCl, and a large amount of water was added. A white solid precipitated. After stirring for 30 minutes, the mixture was filtered, and the filter cake was washed with 100 mL of water and dried to obtain a white solid with a yield of 73%. Mp 209.6-210.3 °C, ESI-MS (m / z) = 292 [M+Na].+ . 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.56(s,1H),8.46(d,J=8.1Hz,1H),8.10(d, J=7.8Hz,1H),7.78(t,J=7.8Hz,1H),4.27(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).

[0110] Example 6. Ethyl 6-(4-cyanophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (3c)

[0111] Using 4-cyanobenzoamide hydrochloride 2b as a raw material, the preparation method was the same as 3b, yielding a white solid with a yield of 65%, Mp 214.6-215.8℃, and ESI-MS (m / z) = 292 [M+Na]. + .

[0112] Example 7.2-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid ethyl ester (5a)

[0113] Ethyl 6-(3-cyanophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 3b (1 g, 3.7 mmol), p-cyanobenzyl chloride (0.56 g, 3.7 mmol), potassium carbonate (1.03 g, 7.4 mmol), and potassium iodide (0.061 g, 0.37 mmol) were added to 10 mL of DMF and stirred at room temperature for 2 h. The reaction was monitored by TLC. After the reaction was complete, 100 mL of water was added, resulting in the precipitation of a large amount of white solid. The mixture was stirred for 30 minutes and then filtered. The filter cake was washed with 30 mL of water and dried to obtain 1.38 g of white solid, yield 97%. Mp 167.6–168.2 °C, ESI-MS (m / z) 407 [M + Na] + , 1 H NMR (400MHz, DMSO-d6) δ9.06(s,1H),8.70(s,1H),8.67(d,J=8.1Hz,1H),8.04(d,J=7.7Hz,1H),7.92(d,J=7.9Hz,1H),7.8 3(d,J=7.9Hz,1H),7.76(q,J=7.7Hz,2H),7.58(t,J=7.1Hz,1H),5.84(s,2H),4.29(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H). 13C NMR(100MHz,DMSO-d6)δ166.7,163.8,161.2,139.7,135.7,133.9,133.6, 133.2,132.3,130.7,129.7,129.6,118.7,117.5,112.6,66.8,61.6,14.3.

[0114] Example 8. Ethyl 2-(3-cyanophenyl)-4-[(3-cyanobenzyl)oxy)pyrimidine-5-carboxylate (5b)

[0115] Using m-cyanobenzyl chloride as a raw material, the preparation method was the same as 5a, yielding 1.32 g of a white solid, with a yield of 93%. Mp 201.9-210.5℃, ESI-MS (m / z) = 407 [M+Na]. + , 1 H NMR(400MHz,Chloroform-d)δ9.17(s,1H),8.76(t,J=1.5Hz,1H),8.70(dt,J=8.0,1.4Hz,1H),7.90(s,1H),7.82(dd,J=7.7,1. 5Hz,2H),7.64(t,J=7.7Hz,2H),7.56(t,J=7.7Hz,1H),5.72(s,2H),4.45(q,J=7.1Hz,2H),1.44(t,J=7.1Hz,3H),1.25(s,1H). 13 C NMR(100MHz,Chloroform-d)δ164.2,161.4,137.5,137.5,134.7,132.8,132.5,131. 8,131.3,130.5,129.6,129.5,118.5,118.5,113.1,112.9,111.1,67.4,61.8,14.3.

[0116] Example 9. Ethyl 2-(3-cyanophenyl)-4-[(2-cyanobenzyl)oxy)pyrimidine-5-carboxylate (5c)

[0117] Using o-cyanobenzyl chloride as a raw material, the preparation method was the same as in 5a, yielding 1.3 g of a white solid, with a yield of 91%. Mp 187.1-188.5℃, ESI-MS (m / z) = 385.1 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ9.17(s,1H),8.75(s,1H),8.69(d,J=8.3Hz,1H),7.81(d,J=7.7Hz,1H),7.73(d,J=8 .3Hz,2H),7.70(d,J=8.3Hz,2H),7.63(t,J=7.7Hz,1H),5.75(s,2H),4.44(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H). 13 C NMR(100MHz,Chloroform-d)δ166.9,164.2,162.9,161.3,141.2,137.5,134. 8,132.8,132.5,132.5,129.6,127.5,113.1,112.0,111.0,67.6,61.6,14.3.

[0118] Example 10. Ethyl 2-(4-cyanophenyl)-4-[(4-cyanobenzyl)oxy)pyrimidine-5-carboxylate (6a)

[0119] Ethyl 6-(4-cyanophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 3c (1 g, 3.7 mmol), p-cyanobenzyl chloride (0.56 g, 3.7 mmol), potassium carbonate (1.03 g, 7.4 mmol), and potassium iodide (0.061 g, 0.37 mmol) were added to 10 mL of DMF and stirred at room temperature for 2 h. The reaction was monitored by TLC. After the reaction was complete, 100 mL of water was added, resulting in the precipitation of a large amount of white solid. The mixture was stirred for 30 minutes and then filtered. The filter cake was washed with 30 mL of water and dried to obtain 1.04 g of white solid, yield 74%. Mp 193.0–194.5 °C, ESI-MS (m / z) = 385 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.55(d,J=8.5Hz,2H),8.02(d,J=8.5Hz,2H),7.94(d,J=7.7Hz,1H),7.85(d,J= 7.7Hz,1H),7.79(t,J=7.6Hz,1H),7.60(t,J=7.6Hz,1H),5.85(s,2H),4.31(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H).

[0120] Example 11.2-(4-cyanophenyl)-4-[(3-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid ethyl ester (6b)

[0121] Using m-cyanobenzyl chloride as a raw material, the preparation method was the same as 6a, yielding 1.21 g of a white solid, with a yield of 85%. Mp 176.6-177.4℃, ESI-MS (m / z) = 385 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.53(d,J=8.2Hz,2H),7.99(d,J=8.2Hz,3H),7.90(d,J=7.8Hz,1H) ,7.83(d,J=7.8Hz,1H),7.65(t,J=7.8Hz,1H),5.71(s,2H),4.34(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0122] Example 12. Ethyl 2-(4-cyanophenyl)-4-[(2-cyanobenzyl)oxy)pyrimidine-5-carboxylate (6c)

[0123] Using o-cyanobenzyl chloride as a raw material, the preparation method was the same as 6a, yielding 1.13 g of a white solid, 79% yield, Mp 220.5-221.1℃, ESI-MS (m / z) = 385 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.57(d,J=8.5Hz,2H),8.03(d,J=8.5Hz,2H),7.91(d,J= 8.3Hz,2H),7.77(d,J=8.3Hz,2H),5.80(s,2H),4.35(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).

[0124] Example 13. 2-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy]-6-methylpyrimidin-5-carboxylic acid (7)

[0125] 4-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy]-6-methylpyrimidin-5-carboxylic acid ethyl ester (300 mg, 0.75 mmol) was dissolved in 5 mL tetrahydrofuran, 5 mL saturated lithium hydroxide solution, and 1 mL water. The reaction was carried out at 35 °C and monitored by TLC. After the reaction was completed, the tetrahydrofuran and lithium hydroxide solutions separated into layers in a single-necked flask. The organic layer was collected, and 1 mol / L dilute hydrochloric acid was added. A large amount of white solid precipitated out. The solid was filtered, and the filter cake was washed with 10 mL of water and dried to obtain 217 mg of white solid, with a yield of 77%. 200 mg of the solid was purified by column chromatography (DCM:MeOH:AcOH = 50:1:1) to obtain 134 mg of pure product. Mp 229.4-229.9 °C, ESI-MS (m / z) = 371.08 [M+H]+ , 1 H NMR(400MHz, DMSO-d6)δ8.67–8.65(m,1H),8.63(dt,J=7.9,1.4Hz,1H),8.01(dt,J=7.9,1.4Hz, 1H),7.91–7.87(m,2H),7.74(t,J=7.8Hz,1H),7.69(d,J=8.6Hz,2H),5.75(s,2H),2.54(s,3H). 13 C NMR(100MHz,DMSO-d6)δ166.6,165.6,165.6,160.6,142.7,137.7,135.1,1 32.8,131.8,130.5,128.3,119.1,118.9,114.5,112.4,111.1,67.6,22.6.

[0126] Example 14. 2-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid (8a)

[0127] Using ethyl 2-(3-cyanophenyl)-4-[(4-cyanobenzyl)oxy)pyrimidine-5-carboxylate 5a as a starting material, the preparation method was the same as in section 7, yielding 315.6 mg of a white solid, with a yield of 85%, Mp 217.4-217.8℃, and ESI-MS (m / z) = 379.06 [M+Na]. + . 1 H NMR (400MHz, DMSO-d6) δ13.45(s,1H),9.09(s,1H),8.71(s,1H),8.69(d,J=7.8Hz,1H),8.05(d,J=7.8Hz,1H),7.94(d, J=7.8Hz,1H),7.84(d,J=6.6Hz,1H),7.79(d,J=6.6Hz,1H),7.76(d,J=7.8Hz,1H),7.59(t,J=7.8Hz,1H),5.89(s,2H). 13 C NMR(100MHz,DMSO-d6)δ166.8,164.4,163.5,161.3,140.1,137.4,135.6,133.9,13 3.6,133.5,132.2,130.6,129.6,129.5,118.8,117.6,112.62,112.1,111.4,66.6.

[0128] Example 15. 2-(3-cyanophenyl)-4-[(3-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid (8b)

[0129] Using ethyl 2-(3-cyanophenyl)-4-[(3-cyanobenzyl)oxy)pyrimidine-5-carboxylate 5b as a starting material, the preparation method was the same as in 7, yielding 270.8 mg of a white solid, with a yield of 73%, Mp 204.3-204.9℃, and ESI-MS (m / z) = 357.09 [M+H]. + . 1 HNMR (400MHz, DMSO-d6) δ13.42(s,1H),9.10(s,1H),8.73–8.71(m,1H),8.69(dt,J=7.7,1.4Hz,1H),8.05(dt,J=7.7, 1.4Hz,1H),7.94(d,J=7.7Hz,1H),7.84(d,J=7.6Hz,1H),7.81–7.75(m,2H),7.59(td,J=7.6,1.4Hz,1H),5.89(s,2H). 13 C NMR(100MHz,DMSO-d6)δ166.9,164.4,163.6,161.4,140.1,137.4,135.6,133.9,1 33.6,133.2,132.2,130.6,129.6,129.5,118.7,117.5,112.6,112.1,111.4,66.6.

[0130] Example 16. 2-(3-cyanophenyl)-4-[(2-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid (8c)

[0131] Using ethyl 2-(3-cyanophenyl)-4-[(2-cyanobenzyl)oxy)pyrimidine-5-carboxylate 5c as a starting material, the preparation method was the same as in section 7, yielding 134 mg of a white solid, with a molecular weight (Mp) of 234.4-235.1℃ and an ESI-MS (m / z) of 357.09 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ8.98(s,1H),8.58(d,J=7.6Hz,2H),7.95(d,J=7.6Hz,1H),7.84(d,J=8.1Hz,2H),7.69(dd,J=8.1,8.5Hz,3H),5.71(s,2H). 13 C NMR(100MHz,DMSO-d6)δ166.8,164.6,163.4,161.1,142.5,137.4,135.4,1 33.1,132.8,132.1,130.5,128.2,119.2,118.8,112.5,112.3,110.9,67.6.

[0132] Example 17. 2-(4-cyanophenyl)-4-[(4-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid (9a)

[0133] Using ethyl 2-(4-cyanophenyl)-4-[(4-cyanobenzyl)oxy)pyrimidine-5-carboxylate 6a as a starting material, the preparation method was the same as in 7, yielding a white solid with a yield of 67%, Mp 251.9-252.7℃, and ESI-MS (m / z) = 357.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.53(d,J=8.5Hz,2H),8.00(d,J=8.5Hz,2H),7.90(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H),5.78(s,2H). 13 C NMR (101MHz, DMSO-d6) δ164.5,163.9,161.3,142.6,140.4,133.3,132.9,129.5,128.3,119.21,118.9,114.4,112.2,111.0,67.7.

[0134] Example 18. 2-(4-cyanophenyl)-4-[(3-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid (9b)

[0135] Using ethyl 2-(4-cyanophenyl)-4-[(3-cyanobenzyl)oxy)pyrimidine-5-carboxylate 6b as a starting material, the preparation method was the same as in 7, yielding a white solid with a yield of 71%, Mp 242.1-243.4℃, and ESI-MS (m / z) = 357.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ13.50(s,1H),9.10(s,1H),8.57(d,J=8.5Hz,2H),8.03(d,J=8.5 Hz,3H),7.90(d,J=7.8Hz,1H),7.82(d,J=7.8Hz,1H),7.64(t,J=7.8Hz,1H),5.76(s,2H). 13 CNMR(100MHz,DMSO-d6)δ167.0,164.6,163.9,161.2,140.4,138.6,133.2,1 32.6,132.1,131.3,130.2,129.5,119.2,119.0,114.5,112.3,111.9,67.4.

[0136] Example 19. 2-(4-cyanophenyl)-4-[(2-cyanobenzyl)oxy)pyrimidine-5-carboxylic acid (9c)

[0137] Using ethyl 2-(4-cyanophenyl)-4-[(2-cyanobenzyl)oxy)pyrimidine-5-carboxylate 6c as a starting material, the preparation method was the same as in 7, yielding a white solid with a yield of 53%, Mp 249.7-250.0℃, and ESI-MS (m / z) = 357.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.11(s,1H),8.55(d,J=8.6Hz,2H),8.02(d,J=8.6Hz,2H),7.97(s,1H),7. 94(d,J=6.5Hz,1H),7.84(d,J=6.5Hz,1H),7.81–7.75(m,1H),7.58(t,J=7.6Hz,1H),5.87(s,2H). 13 C NMR (100MHz, DMSO-d6) δ166.9,164.5,163.9,161.4,140.4,140.0,134.0,133.7,133.3,129.6,129.6,129.5,118.9,114.5,112.2,111.4,66.6.

[0138] Example 20. Ethyl 4-chloro-2-(3-cyanophenyl)pyrimidine-5-carboxylate (10a)

[0139] Ethyl 2-(3-cyanophenyl)-6-oxo-1,2-dihydropyridine-5-carboxylate 3b (10 g, 37.3 mmol) was dissolved in 20 mL of DMF. Thionyl chloride (5.74 g, 48 mmol) was added dropwise using a dropping funnel at a rate of one drop per second under ice-conditioning. After the addition was complete, the reaction was allowed to proceed for 2 h, monitored by TLC. Once the reaction was complete, the solution was slowly added dropwise to 200 mL of 10% potassium carbonate solution at 0 °C. A large amount of pale yellow solid precipitated. The solution was transferred to room temperature and stirred for 30 minutes, then filtered. The filter cake was washed with 30 mL of water and dried in a vacuum oven to obtain 7.7 g of pale yellow solid, yield 76%, Mp 214.4–215.6 °C, ESI-MS (m / z) = 288 [M+H]. + ,

[0140] Example 21. Ethyl 4-chloro-2-(4-cyanophenyl)pyrimidine-5-carboxylate (10b)

[0141] Using ethyl 2-(4-cyanophenyl)-6-oxo-1,2-dihydropyridine-5-carboxylate 3c as a starting material, the preparation method was the same as in 10a, yielding a pale yellow solid with a yield of 67%, Mp 219.7-220.6℃, and ESI-MS (m / z) = 288 [M+H]. + .

[0142] Example 22.2-(3-cyanophenyl)-4-(3-aminophenoxy)pyrimidine-5-carboxylic acid ethyl ester (11)

[0143] m-Aminophenol (208.72 mg, 1.914 mmol) and potassium carbonate (480.97 mg, 3.48 mmol) were dissolved in 10 mL of DMF and stirred at room temperature for 15 minutes. Ethyl 4-chloro-2-(3-cyanophenyl)pyrimidin-5-carboxylate 10a (500 mg, 1.74 mmol) was dissolved in 10 mL of DMF and slowly added dropwise to the m-aminophenol. After the addition was complete, the mixture was stirred at room temperature for 10 minutes. The mixture was then transferred to 60 °C and heated for TLC monitoring. After the reaction was complete, the mixture was cooled to room temperature, and 20 mL of saturated sodium bicarbonate aqueous solution and 30 mL of water were added. A large amount of pale yellow solid precipitated. After stirring for 30 minutes, the mixture was filtered. The filter cake was washed twice with 20 mL of water and dried to obtain 543.2 mg of pale yellow solid (86% yield). 300 mg of the purified product was purified by column chromatography (PE:EA = 4:1) to obtain 200 mg of the pure pale yellow solid. 212.3-212.9℃,ESI-MS(m / z)=361.1[M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.18(s,1H),8.39(d,J=9.4Hz,2H),8.02(d,J=7.7Hz,1H),7.72(t,J=7.7Hz,1H),7.14(t,J=8.1Hz,1H),6.54 (dd,J=8.1,1.2Hz,1H),6.45(t,J=7.4Hz,1H),6.41(dd,J=7.6,1.9Hz,1H),5.35(s,2H),4.38(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,3H).

[0144] Example 23. Synthesis of ethyl 2-(3-cyanophenyl)-4-[3-(methanesulfonamide)phenoxy]pyrimidine-5-carboxylate (12)

[0145] A mixture of ethyl 4-(3-aminophenoxy)-2-(3-cyanophenyl)pyrimidine-5-carboxylate 11 (150 mg, 0.416 mmol) and pyridine (49.41 mg, 0.625 mmol) was stirred in an ice bath for 10 minutes, and p-toluenesulfonyl chloride (52.48 mg, 0.458 mmol) was added. After the reaction was complete, the reaction solution was concentrated under vacuum to give a yellow oil. Then, 5 mL of 1 M HCl solution was added to the mixture, and the mixture was extracted three times with 30 mL of dichloromethane, washed twice with 20 mL of saturated salt solution, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure to give a solid, which was directly used for the next step without purification. ESI-MS (m / z) = 436.3 [MH] + .

[0146] Example 24. 2-(3-cyanophenyl)-4-[3-(methylsulfonamido)phenoxy]pyrimidine-5-carboxylic acid (13)

[0147] Using ethyl 2-(3-cyanophenyl)-4-[3-(methylsulfonamido)phenoxy]pyrimidine-5-carboxylate 12 as the starting material, the preparation method was the same as in section 7, yielding a white solid with a yield of 67%, Mp 228.6-229.2℃, and ESI-MS (m / z) = 411 [M+H]. + , 1 H NMR(400MHz,DMSO-d6)δ10.00(s,1H),9.21(s,1H),8.43–8.32(m,2H),8.00(dt,J=7.7,1.4Hz,1H),7 .74–7.65(m,1H),7.50(t,J=8.1Hz,1H),7.25–7.18(m,2H),7.09(dd,J=8.1,1.8Hz,1H),3.06(s,3H). 13 C NMR (100MHz, DMSO-d6) δ167.1,164.4,163.5,162.2,152.9,140.1,137.3,135.6,133.0,132.0,130.8,130.7,118.7,117.5,117.4,113.5,112.5.

[0148] Example 25. Ethyl 2-(3-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylate (14a)

[0149] p-Cyanophenol (207.13 mg, 1.74 mmol) and potassium carbonate (481 mg, 3.48 mmol) were dissolved in 10 mL of DMF and stirred at room temperature for 20 minutes. Ethyl 4-chloro-2-(3-cyanophenyl)pyrimidin-5-carboxylate 10a (500 mg, 1.74 mmol) was dissolved in 5 mL of DMF, and this solution was added dropwise to the p-cyanophenol. The mixture was stirred at room temperature for 10 minutes, then transferred to 60 °C for reaction. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and 30 mL of water was added. A large amount of white solid precipitated. After stirring for 30 minutes, the mixture was filtered, the filter cake was washed with 20 mL of water, and dried to obtain 543.46 mg of white solid (yield 84%), Mp 245.3–245.9 °C, ESI-MS (m / z) = 393.1 [M+Na]. + , 1 H NMR(400MHz, DMSO-d6)δ9.25(s,1H),8.36(t,J=8.1Hz,1H),8.33–8.28(m,1H),8.06–7.97(m ,3H),7.71(t,J=8.1Hz,1H),7.62–7.55(m,2H),4.39(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0150] Example 26. Ethyl 2-(3-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylate (14b)

[0151] Using m-cyanophenol as a raw material, the preparation method was the same as in 14a, yielding 517.2 mg of a white solid, with a yield of 80%, Mp 240.2-240.8℃, and ESI-MS (m / z) =393.0 [M+Na]. + , 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.33(s,1H),8.30(d,J=8.0Hz,1H),8.01(dt,J=7.7,1.5Hz,1H),7.94(s,1H), 7.90–7.85(m,1H),7.76(dd,J=7.8,2.1Hz,2H),7.71(t,J=7.8Hz,1H),4.40(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0152] Example 27. Ethyl 2-(3-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylate (14c)

[0153] Using o-cyanophenol as a raw material, the preparation method was the same as in 14a, yielding 483.6 mg of a white solid, with a yield of 75%, Mp 247.7-248.7℃, and ESI-MS (m / z) =393.1 [M+Na]. + , 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.36–8.33(m,1H),8.31(dt,J=8.0,Hz,1H),8.08(dd,J=7.8,1.7Hz,1H),8.03(dt,J=7.7 ,1.4Hz,1H),7.96–7.89(m,1H),7.75–7.67(m,2H),7.62(td,J=7.7,1.1Hz,1H),4.43(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H).

[0154] Example 28. Ethyl 2-3-(cyanophenyl)-4-(pyridine-3-oxy)pyrimidine-5-carboxylate (14d)

[0155] Using 3-hydroxypyridine as a starting material, the preparation method was the same as in 14a, yielding a white solid with a yield of 91%, Mp 214.2-214.8℃, and ESI-MS (m / z) = 347.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.65(d,J=2.7Hz,1H),8.61(dd,J=1.4Hz,1H),8.34(t,J=1.4Hz,1H),8.31(dt,J=7.9,1.4Hz,1H),8.02(dt,J= 7.7,1.4Hz,1H),7.88(ddd,J=8.4,2.8,1.4Hz,1H),7.71(t,J=7.8Hz,1H), 7.62(dd,J=8.3,4.7Hz,1H), 4.41(q,J=7.1Hz,2H), 1.37(t,J=7.1Hz,3H).

[0156] Example 29. Synthesis of ethyl 2-(3-cyanophenyl)-4-(3-acetamidophenoxy)pyrimidine-5-carboxylate (14e)

[0157] Using 3-acetaminophenol as a raw material, the preparation method was the same as in 14a, yielding a white solid in 83% yield. Mp 231.2-231.8℃. ESI-MS (m / z) = 403.0 [M+H] + 425.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ10.15(s,1H),9.22(s,1H),8.41(s,1H),8.38(d,J=8.0Hz,1H),8.01(dt,J=7.7,1.5Hz,1H),7.80(s,1H),7.71(t,J =7.8Hz,1H),7.44(t,J=7.9Hz,1H),7.40(d,J=8.3Hz,1H),7.01(d,J=8.2Hz,1H),4.39(q,J=7.1Hz,2H),2.07(s,3H),1.36(t,J=7.1Hz,3H).

[0158] Example 30. Ethyl 2-(4-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylate (15a)

[0159] p-Cyanophenol (207.13 mg, 1.74 mmol) and potassium carbonate (481 mg, 3.48 mmol) were dissolved in 10 mL of DMF and stirred at room temperature for 20 minutes. Ethyl 4-chloro-2-(4-cyanophenyl)pyrimidin-5-carboxylate 10b (500 mg, 1.74 mmol) was dissolved in 5 mL of DMF, and this solution was added dropwise to the p-cyanophenol. The mixture was stirred at room temperature for 10 minutes, then transferred to 60 °C for reaction. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, and 30 mL of water was added. A large amount of white solid precipitated. After stirring for 30 minutes, the mixture was filtered, the filter cake was washed with 20 mL of water, and dried to obtain 543.46 mg of white solid (yield 84%). Mp 239.2-239.8 °C. ESI-MS (m / z) = 371.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ9.30 (s, 1H), 8.23 ​​(d, J = 8.6Hz, 2H), 8.03 (d, J = 8.7Hz, 2H), 7.9 7(d,J=8.6Hz,2H), 7.59(d,J=8.8Hz,2H), 4.39(q,J=7.1Hz,2H), 1.35(t,J=7.1Hz,3H).

[0160] Example 31. Ethyl 2-(4-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylate (15b)

[0161] Using m-cyanophenol as a raw material, the preparation method was the same as in 15a, yielding a white solid with a yield of 73%, Mp 234.5-235.4℃, and ESI-MS (m / z) = 371.1 [M+H]. + , 1H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 8.20 (d, J = 8.5Hz, 2H), 7.97 (d, J = 8.5Hz, 2H), 7.94 (q, J = 5. 9Hz,1H),7.90–7.84(m,1H),7.75(d,J=5.9Hz,2H),4.40(q,J=7.1Hz,2H),1.36(t,J=7.1Hz,3H).

[0162] Example 32. Ethyl 2-(4-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylate (15c)

[0163] Using o-cyanophenol as a raw material, the preparation method was the same as in 15a, yielding a white solid with a yield of 78%, Mp 236.3-237.1℃, and ESI-MS (m / z) = 371.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.34(s,1H),8.20(d,J=8.5Hz,2H),8.06(dd,J=7.8Hz,1H),7.97(d,J=8.5Hz,2H),7 .94–7.86(m,1H),7.67(d,J=8.5Hz,1H),7.60(t,J=7.8Hz,1H),4.42(q,J=7.1Hz,2H),1.37(t,J=7.1Hz,3H).

[0164] Example 33. Ethyl 2-(3-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylate (16a)

[0165] Ethyl 4-chloro-2-(3-cyanophenyl)pyrimidin-5-carboxylate 10a (500 mg, 1.74 mmol) and p-aminobenzonitrile (411.56 mg, 3.48 mmol) were dissolved in 25 mL of acetone and stirred for 3 minutes. After the solid was dispersed, 20 drops of concentrated hydrochloric acid were added, and the reaction was heated at 60 °C. TLC monitoring was performed. After the reaction was complete, the mixture was cooled to room temperature, and excess acid and aniline were neutralized by adding a saturated sodium carbonate solution. 50 mL of water was added, and a large amount of white solid precipitated. After stirring for 30 minutes, the mixture was filtered, the filter cake was washed with 20 mL of water, and dried to obtain 574.6 mg of a pale yellow solid, yield 89%, Mp 233.4-234.6 °C, ESI-MS (m / z) = 367.9 [MH]. + , 1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.07(s,1H),8.57(s,2H),8.04(s,1H),7 .96(s,2H),7.87(s,2H),7.76(s,1H),4.47–4.33(m,2H),1.39(t,J=7.1Hz,3H).

[0166] Example 34. Ethyl 2-(3-cyanophenyl)-4-[(3-cyanophenyl)amino]pyrimidine-5-carboxylate (16b)

[0167] Using m-aminobenzonitrile as a raw material, the preparation method was the same as in 16a, yielding a white solid with a yield of 84%, Mp 237.8-238.6℃, and ESI-MS (m / z) = 370.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ10.23(s,1H),8.99(s,1H),8.48(d,J=7.8Hz,2H),8.22(s,1H),8.04–7.94 (m,2H),7.71(t,J=7.8Hz,1H),7.62(d,J=7.1Hz,2H),4.40(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0168] Example 35. Ethyl 2-(3-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylate (16c)

[0169] Using o-aminobenzonitrile as a raw material, the preparation method was the same as in 16a, yielding a gray solid with a yield of 73%, Mp 331.2-232.2℃, and ESI-MS (m / z) = 370.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),9.06(s,1H),8.51–8.43(m,2H),8.20(d,J=8.5Hz,1H),8.01(dt,J=7.7,1.4Hz,1H),7.92(dd, J=7.7,1.5Hz,1H),7.84–7.77(m,1H),7.74–7.70(m,1H),7.42(td,J=7.7,1.1Hz,1H),4.43(q,J=7.1Hz,2H),1.40(t,J=7.1Hz,3H).

[0170] Example 36. Ethyl 2-(3-cyanophenyl)-4-(pyridine-3-amino)pyrimidine-5-carboxylate (16d)

[0171] Using 3-aminopyridine as a starting material, the preparation method was the same as in 16a, yielding a brown solid with a yield of 67%, Mp 227.3-228.9℃, and ESI-MS (m / z) = 346.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.00(s,1H),8.90(t,J=4.7Hz,1H),8.53–8.47(m,2H),8.40(d,J=4.7Hz,1H),8.16(d,J=8. 2Hz, 1H), 8.02 (d, J = 7.7Hz, 1H), 7.73 (t, J = 8.2Hz, 1H), 7.48 (dd, J = 8.2, 4.7Hz, 1H), 4.41 (q, J = 7.1Hz, 2H), 1.39 (t, J = 7.1Hz, 3H).

[0172] Example 37. Ethyl 2-(3-cyanophenyl)-4-[(1H-pyrazole)amino]pyrimidine-5-carboxylate (16e)

[0173] Using 3-aminopyrazole as a raw material, the preparation method was the same as in 16a, yielding a pale yellow solid with a yield of 43%, Mp 213.2-213.9℃, and ESI-MS (m / z) = 335.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),9.01(s,1H),8.64(d,J=7.8Hz,2H),8.05(dt,J=7.8,1.5Hz,1H),7.89 (d,J=2.4Hz,1H),7.78(t,J=8.2Hz,1H),6.81(d,J=2.4Hz,1H),4.40(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H).

[0174] Example 38. Ethyl 2-(4-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylate (17a)

[0175] Ethyl 4-chloro-2-(4-cyanophenyl)pyrimidin-5-carboxylate 10b (500 mg, 1.74 mmol) and p-aminobenzonitrile (411.56 mg, 3.48 mmol) were dissolved in 25 mL of acetone and stirred for 3 minutes. After the solid was dispersed, 20 drops of concentrated hydrochloric acid were added, and the reaction was heated at 60 °C. TLC monitoring was performed. After the reaction was complete, the mixture was cooled to room temperature, and excess acid and aniline were neutralized by adding saturated sodium carbonate solution. 50 mL of water was added, and a large amount of white solid precipitated. After stirring for 30 minutes, the mixture was filtered, the filter cake was washed with 20 mL of water, and dried to obtain 542 mg of white solid (yield 84%). Mp 239.1–239.7 °C, ESI-MS (m / z) = 370.1 [M+H] + , 1 HNMR(400MHz,DMSO-d6)δ10.44(s,1H),9.32(s,1H),9.13(s,1H),8.50(dd,J=8.4Hz,2 H),8.11–7.94(m,3H),7.90(d,J=8.4Hz,1H),4.41(q,J=7.6Hz,2H),1.42–1.33(m,3H).

[0176] Example 39. Ethyl 2-(4-cyanophenyl)-4-[(3-cyanophenyl)amino]pyrimidine-5-carboxylate (17b)

[0177] Using m-aminobenzonitrile as a raw material, the preparation method was the same as in 17a, yielding a white solid with a yield of 82%, Mp 234.5-234.9℃, and ESI-MS (m / z) = 370.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.10(s,1H),8.42(d,J=8.4Hz,2H),8.22(s,1H),8.09(s, 1H), 8.00 (d, J = 8.4Hz, 2H), 7.66 (d, J = 5.5Hz, 2H), 4.43 (q, J = 7.1Hz, 2H), 1.39 (t, J = 7.1Hz, 3H).

[0178] Example 40. Ethyl 2-(4-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylate (17c)

[0179] Using o-aminobenzonitrile as a raw material, the preparation method was the same as in 17a, yielding a white solid with a yield of 71%, Mp 230.8-231.7℃, and ESI-MS (m / z) = 370.1 [M+H]. + , 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),9.11(s,1H),8.36(d,J=8.3Hz,2H),8.20(d,J=8.3Hz,1H),7.97(d,J=8.0Hz,2 H),7.93(d,J=7.6Hz,1H),7.82(t,J=8.0Hz,1H),7.43(t,J=7.6Hz,1H),4.44(q,J=7.1Hz,2H),1.40(t,J=7.1Hz,3H).

[0180] Example 41.2-(3-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylic acid (18a)

[0181] Using ethyl 2-(3-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylate 14a as a starting material, the preparation method was the same as in section 7, yielding a white solid with a yield of 54%, Mp 239.1-239.7℃, and ESI-MS (m / z) = 340.8 [MH]. + , 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.36(t,J=1.5Hz,1H),8.31(dt,J=1.4Hz,1H),8.07–7.98(m,3H),7.74–7.67(m,1H),7.62–7.56(m,2H). 13 C NMR (100MHz, DMSO-d6) δ166.7,164.1,163.5,162.4,156.1,137.1,135.7,134.7,132.9,131.9,130.8,123.5,118.9,118.7,112.9,112.6,109.0.

[0182] Example 42. 2-(3-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylic acid (18b)

[0183] Using ethyl 2-(3-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylate 14b as a starting material, the preparation method was the same as in section 7, with a yield of 58%, Mp 223.4-224.1℃, and ESI-MS (m / z) = 343.1 [M+H]. + , 1H NMR (400MHz, DMSO-d6) δ9.13 (s, 1H), 8.33 (s, 1H), 8.30 (d, J = 8.0Hz, 1H), 7. 98(dt,J=7.7Hz,1H),7.90(s,1H),7.83(t,J=7.7Hz,1H),7.74–7.66(m,3H). 13 C NMR(100MHz,DMSO-d6)δ166.9,163.7,162.7,162.3,152.5,137.0,135.9,133.0 ,132.0,131.7,130.9,130.5,127.8,126.1,118.7,118.4,113.0,112.6,111.8.

[0184] Example 43. 2-(3-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylic acid (18c)

[0185] Using ethyl 2-(3-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylate 14c as the starting material, the preparation method was the same as in section 7, with a yield of 45%, Mp 218.5-219.1℃, and ESI-MS (m / z) = 343.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.34(q,J=8.3Hz,1H),8.31(dt,J=7.9,1.4Hz,1H),8.08(dd,J=7.7,1.6Hz,1 H),8.02(dt,J=7.8,1.4Hz,1H),7.93(ddd,J=8.3,7.5,1.7Hz,1H),7.74–7.65(m,2H),7.61(td,J=7.7,1.1Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ166.7,163.9,163.6,162.8,153.9,136.9,135.8,135.7 ,134.3,132.9,131.9,130.9,127.4,123.9,118.6,115.7,112.7,112.4,106.6.

[0186] Example 44.2-(3-cyanophenyl)-4-(pyridin-3-oxy)pyrimidine-5-carboxylic acid (18d)

[0187] Using ethyl 2-(3-cyanophenyl)-4-(pyridin-3-oxy)pyrimidine-5-carboxylate 14d as the starting material, the preparation method was the same as in section 7, yielding a white solid with a yield of 79%, Mp 226.1-227.4℃, and ESI-MS (m / z) = 319.1 [M+H]. + , 1 H NMR(400MHz,DMSO-d6)δ13.72(s,1H),9.24(s,1H),8.69–8.53(m,2H),8.32(d,J=8.4Hz,2H),8 .01(d,J=7.7Hz,1H),7.88(d,J=5.6Hz,1H),7.70(t,J=7.8Hz,1H),7.62(dd,J=8.3,4.7Hz,1H). 13 C NMR (101MHz, DMSO-d6) δ167.2,164.2,163.5,162.4,149.2,147.5,144.0,137.1,135.7,132.9,131.9,130.8,130.3,125.0,112.6,112.5.

[0188] Example 45. Ethyl 2-(3-cyanophenyl)-4-(3-acetaminophenoxy)pyrimidine-5-carboxylate (18e)

[0189] Using ethyl 2-(3-cyanophenyl)-4-(3-acetamidophenoxy)pyrimidine-5-carboxylate (14e) as a starting material, the preparation method was the same as in section 7, yielding a white solid in 75% yield. Mp 264.9-265.9℃, ESI-MS (m / z) =375.0 [M+H] + 397.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),9.20(s,1H),8.40(t,J=2.1Hz,1H),8.38(dt,J=7.9,1.4Hz,1H),8.00(dt,J=7.7,1.5Hz ,1H),7.78(t,J=2.1Hz,1H),7.70(t,J=7.8Hz,1H),7.47–7.42(m,1H),7.41(d,J=8.2Hz,1H),7.04–6.97(m,1H),2.07(s,3H). 13CNMR(100MHz,DMSO-d6)δ169.1,167.2,164.4,163.5,162.1,152.5,141.0,1 37.3,135.6,132.9,132.1,130.7,130.0,118.7,116.6,116.5,112.7,112.5.

[0190] Example 33.2-(4-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylic acid (19a)

[0191] Using ethyl 2-(4-cyanophenyl)-4-(4-cyanophenoxy)pyrimidine-5-carboxylate 15a as a starting material, the preparation method was the same as 7a, yielding a white solid with a yield of 55%, Mp 265.4-266.3℃, ESI-MS (m / z) = 343.0 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.24 (s, 1H), 8.20 (d, J = 8.4Hz, 2H), 8.01 (d, J = 8.7Hz, 2H), 7.94 (d, J = 8.4Hz, 2H), 7.57 (d, J = 8.7Hz, 2H). 13 C NMR (100MHz, DMSO-d6) δ166.7,164.2,163.7,162.3,156.1,140.0,134.7,133.4,129.2,123.5,118.9,114.5,109.0.

[0192] Example 34. 2-(4-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylic acid (19b)

[0193] Using ethyl 2-(4-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylate 15b as a starting material, the preparation method was the same as in section 7, yielding a white solid in 43% yield, with a molecular weight (Mp) of 257.4-257.9℃ and an ESI-MS (m / z) of 343.0 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.25 (s, 1H), 8.19 (d, J = 8.4Hz, 2H), 7.95 (d, J = 8.4Hz, 2H), 7.92 (s, 1H), 7.85 (t, J = 5.5Hz, 1H), 7.73 (d, J = 5.5Hz, 2H). 13C NMR (100MHz, DMSO-d6) δ167.0,164.2,163.8,162.3,152.7,140.1,133.4,131.6,130.4,129.1,127.9,126.0,118.8,118.5,114.5,113.0.

[0194] Example 35. 2-(4-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylic acid (19c)

[0195] Using ethyl 2-(4-cyanophenyl)-4-(2-cyanophenoxy)pyrimidine-5-carboxylate 15c as a starting material, the preparation method was the same as in section 7, yielding a white solid with a yield of 56%, Mp 244.9-245.3℃, and ESI-MS (m / z) = 343.0 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.17(d,J=8.5Hz,2H),8.05(dd,J=7.8,1.6Hz,1H),7. 94(d,J=8.5Hz,2H),7.92–7.86(m,1H),7.63(d,J=8.5Hz,1H),7.59(td,J=7.8,1.1Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ166.7,164.0,163.9,162.8,153.9,139.8,135.8,134.4,133.4,129.1,127.5,123.9,118.8,115.7,114.7,112.5,106.6.

[0196] Example 46. 2-(3-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylic acid (20a)

[0197] Ethyl 2-(3-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylate 16a (300 mg, 0.75 mmol) was dissolved in 5 mL of tetrahydrofuran, 5 mL of saturated lithium hydroxide solution, and 1 mL of water. The reaction was carried out at 35 °C and monitored by TLC. After the reaction was completed, the tetrahydrofuran and lithium hydroxide solutions separated into layers in a single-necked flask. The organic layer was collected, and 1 mol / L dilute hydrochloric acid was added. A large amount of white solid precipitated out. The mixture was filtered, and the filter cake was washed with 10 mL of water and dried to give 213 mg of white solid, yield 75%, Mp 276.5-277.8 °C, ESI-MS (m / z) = 342.1 [M+H] + , 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),9.04(s,1H),8.60–8.55(m,2H),8.03(dt,J=7 .7,1.4Hz,1H),7.96(d,J=8.7Hz,2H),7.86(d,J=8.7Hz,2H),7.75(t,J=7.7Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ168.1,163.6,160.3,159.4,142.6,138.1,135.4,133.7,133.2,132.1,130.7,121.9,119.4,118.9,112.5,106.6,106.0.

[0198] Example 47. 2-(3-cyanophenyl)-4-[(3-cyanophenyl)amino]pyrimidine-5-carboxylic acid (20b)

[0199] Using ethyl 2-(3-cyanophenyl)-4-[(3-cyanophenyl)amino]pyrimidine-5-carboxylate 16b as a starting material, the preparation method was the same as that for 20a, yielding a white solid with a yield of 78%, Mp 263.2-264.2℃, and ESI-MS (m / z) = 342.1 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),9.03(s,1H),8.59–8.52(m,2H),8.27(s,1H),8.07–7.98(m,2H),7.78–7.70(m,1H),7.63(d,J=5.9Hz,2H). 13 C NMR(100MHz,DMSO-d6)δ168.1,163.5,160.2,159.5,139.1,138.3,135.3,13 3.0,132.0,130.6,128.0,127.1,125.4,119.0,118.8,112.5,112.2,106.4.

[0200] Example 48. 2-(3-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylic acid (20c)

[0201] Using ethyl 2-(3-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylate 16c as the starting material, the preparation method was the same as that for 20a, yielding a white solid in 70% yield, with a molecular weight (Mp) of 281.2-281.8℃ and an ESI-MS (m / z) of 342.1 [M+H]. + , 1H NMR (400MHz, DMSO-d6) δ14.18(s,1H),10.95(s,1H),9.07(s,1H),8.51(d,J=8.3Hz,2H),8.31(d,J=8.3Hz,1H),8. 01(d,J=7.7Hz,1H),7.90(dd,J=7.8,1.5Hz,1H),7.84–7.77(m,1H),7.72(t,J=8.0Hz,1H),7.39(t,J=7.6Hz,1H). 13 C NMR(100MHz,DMSO-d6)δ168.1,163.6,160.4,159.7,140.9,138.0,135.3,134.4 ,133.6,133.1,132.1,130.6,125.5,124.5,118.8,117.1,112.4,106.2,105.9.

[0202] Example 49. 2-(3-cyanophenyl)-4-(pyridine-3-amino)pyrimidine-5-carboxylic acid (20d)

[0203] Using ethyl 2-(3-cyanophenyl)-4-(pyridin-3-amino)pyrimidine-5-carboxylate 16d as the starting material, the preparation method was the same as that for 20a, yielding a white solid with a yield of 74%, Mp 283.6-284.9℃, ESI-MS (m / z) = 318.1 [M+H]. + , 1 H NMR(400MHz,DMSO-d6)δ14.05(s,1H),10.73(s,1H),9.00(s,1H),8.72–8.60(m,2H),8. 05(dt,J=7.7,Hz,1H),7.88(d,J=2.4Hz,1H),7.82–7.74(m,1H),6.84(d,J=2.4Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ206.6,168.5,164.1,159.9,158.5,145.7,138.5,135.3,133.2,132.1,130.7,128.8,119.0,112.4,105.0,97.5,59.5.

[0204] Example 50. 2-(3-cyanophenyl)-4-[(1H-pyrazole)amino]pyrimidine-5-carboxylic acid (20e)

[0205] Using ethyl 2-(3-cyanophenyl)-4-[(1H-pyrazole)amino]pyrimidine-5-carboxylate 16e as the starting material, the preparation method was the same as 20a, yielding a white solid in 65% yield, Mp 267.3-267.9℃, ESI-MS (m / z) =307.1 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),9.03(s,1H),8.95(d,J=2.6Hz,1H),8.55(t,J=2.6Hz,2H),8.41(d, J=4.7Hz,1H),8.21(d,J=7.7Hz,1H),8.03(d,J=7.7Hz,1H),7.75(t,J=8.1Hz,1H),7.51(dd,J=4.7Hz,1H). 13 C NMR (101MHz, DMSO-d6) δ168.1,163.7,160.3,159.8,145.2,143.7,138.2,135.4,135.1,133.1,132.1,130.7,124.2,118.9,112.4,105.9.

[0206] Example 51. 2-(4-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylic acid (21a)

[0207] Using ethyl 2-(4-cyanophenyl)-4-[(4-cyanophenyl)amino]pyrimidine-5-carboxylate 17a as a starting material, the preparation method was the same as that for 20a, yielding a white solid in 70% yield, with a molecular weight (Mp) of 287.4-288.9℃ and an ESI-MS (m / z) of 342 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ10.74(s,1H),8.99(s,1H),8.37(d,J=8.5Hz,2H),7.94(s,1H),7.91(d,J=8.5Hz,2H),7.89(s,1H),7.82(d,J=8.5Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ168.1,164.0,160.3,159.3,142.5,140.9,133.7,133.2,129.4,121.8,119.4,119.0,114.2,106.3,106.0.

[0208] Example 52. 2-(4-cyanophenyl)-4-[(3-cyanophenyl)amino]pyrimidine-5-carboxylic acid (21b)

[0209] Using ethyl 2-(4-cyanophenyl)-4-[(3-cyanophenyl)amino]pyrimidine-5-carboxylate 17b as a starting material, the preparation method was the same as that for 20a, yielding a white solid in 55% yield, with a molecular weight (Mp) of 279.8-280.5℃ and an ESI-MS (m / z) of 342 [M+H]. + , 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),9.03(s,1H),8.40(d,J=8.1Hz,2H),8 .22(s,1H),8.05(d,J=8.1Hz,1H),7.96(d,J=8.2Hz,2H),7.66–7.55(m,2H). 13 CNMR(100MHz,DMSO-d6)δ168.1,163.3,159.9,159.6,141.4,139.5,133.1,130.6,129.1,127.5,126.4,124.8,119.1,119.0,114.0,112.2.

[0210] Example 53. 2-(4-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylic acid (21c)

[0211] Using ethyl 2-(4-cyanophenyl)-4-[(2-cyanophenyl)amino]pyrimidine-5-carboxylate 17c as the starting material, the preparation method was the same as that for 20a, yielding a white solid in 63% yield, Mp 274.1-274.9℃, ESI-MS (m / z) = 342 [M+H]. + , 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),9.10(s,1H),8.40(d,J=8.2Hz,2H),8.31(d,J=8.2Hz, 1H),7.98(d,J=8.2Hz,2H),7.91(d,J=7.8Hz,1H),7.85–7.76(m,1H),7.39(t,J=7.8Hz,1H). 13 C NMR (100MHz, DMSO-d6) δ168.1,163.3,159.9,159.6,141.4,139.5,133.1,130.6,129.1,127.5,126.4,124.8,119.1,119.0,114.0,112.2.

[0212] Example 54. Preparation of tablets containing compound 2-(3-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylic acid (18b)

[0213] Prescription composition and content:

[0214]

[0215] Coating solution prescription:

[0216] Opadai (03B26796) 21g 95% ethanol (appropriate amount)

[0217] Makes approximately 430ml

[0218] Process:

[0219] The excipients that have passed through a 100-mesh sieve are mixed with the active pharmaceutical ingredient that has passed through a 60-mesh sieve. The mixture is then prepared into a soft mass with 95% ethanol, granulated with an 18-mesh sieve, dried in a ventilated environment at 60°C, granulated again with a 16-mesh sieve, and then mixed evenly with magnesium stearate. Finally, it is tableted using a shallow concave punch with a diameter of 6mm.

[0220] Preparation of coating solution: Add an appropriate amount of 95% ethanol to a container, turn on the stirrer, and evenly add the prescribed amount of Opadry (03B26796) solid powder into the vortex, while trying to avoid any powder floating on the liquid surface. If necessary, the speed can be increased to maintain a proper vortex. After all the Opadry has been added, reduce the stirring speed until the vortex disappears, and continue stirring for 45 minutes to obtain the coating solution.

[0221] Preparation of film-coated tablets: Place the tablet core in a coating pan and maintain the temperature at 60℃±5℃ for coating to obtain the final product.

[0222] Example 55. Preparation of capsules containing compound 2-(3-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylic acid (18b): Formulation composition and content:

[0223]

[0224] Process:

[0225] Take the prescribed amount of 2-(3-cyanophenyl)-4-(3-cyanophenoxy)pyrimidine-5-carboxylic acid (18b), add PEG-400, 1,2-propanediol and Tween-80, stir at about 40°C to completely dissolve the drug, and process into soft capsules after cooling to room temperature.

[0226] Example 56. ADP-induced inhibition of rabbit platelet aggregation

[0227] 1. Plasma preparation

[0228] Blood was collected from the marginal ear vein of healthy male rabbits and anticoagulated with 3.8% sodium citrate. Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were prepared by centrifugation (800 rpm, 10 minutes) (3000 rpm, 10 minutes). The prepared plasma was used within 0.5-3 hours after preparation.

[0229] 2. Determination of platelet aggregation using the microplate assay

[0230] Weigh the test drug and add an appropriate amount of DMSO to prepare a 10mM stock solution, then dilute with physiological saline to prepare a 10× stock solution. Add 135 μL of PRP to each well of the ELISA plate, followed by 15 μL of each concentration of 10× drug stock solution. For the solvent control group, add 15 μL of physiological saline to the PRP solution; for the blank control group, add 15 μL of physiological saline to the 135 μL PPP solution. All experimental groups are replicates. After vortexing, incubate the ELISA plate at 37°C for 5 minutes and measure the A0 value at 655 nm. Add 15 μL of the inducer bisphosphononucleotide (ADP) working solution (25 μmol / L) to each well and incubate with vortexing at 37°C. Measure the A1 value at 655 nm based on the maximum aggregation time determined in the preliminary experiment. Calculate the platelet aggregation rate (AR) and platelet aggregation inhibition rate (AIR) using the following formulas.

[0231] AR = (A0 – A1) / (A0 – Appp)

[0232] AIR = (1 – AR sample / AR control)

[0233] Calculate IC based on AIR values ​​at different concentrations. 50 value.

[0234] Example 57. Evaluation of the neuroprotective activity of hydrogen peroxide-induced hippocampal neurons (HT22)

[0235] Experimental procedure: 5000 HT22 cells in logarithmic growth phase were seeded into 96-well plates, 100 μL per well, and incubated in a CO2 incubator for 24 h. Then, 10 μL of the compound (final concentration 10 μM) was added to the 96-well plates and incubated for 2 h. Then, 10 μL of hydrogen peroxide (final concentration 500 μM) was added and incubated for 24 h. Cell viability was then measured by MTT assay. The results are shown in Table 1.

[0236] Table 1. IC50 of the target compound 50 Value (Mean + SD)

[0237]

[0238] a The inhibition rate of the target compound on platelet aggregation at 20 μM;

[0239] b Cell viability of HT22 cells in the blank control group after injury induced by 500 μM H2O2: 65.8% ± 5.1%.

[0240] Example 58. Effect of gavage administration of compound 18b on tail vein thrombosis in male KM mice

[0241] 1. Experimental animals: Kunming mice, male, 25-28g (n=8)

[0242] 2. Main reagents: physiological saline, carrageenan, 0.5% CMC-Na.

[0243] 3. Experimental Procedure: Mice of uniform weight were randomly divided into a control group, a model group, and groups receiving different doses of 18b (dose of 2.5 mg / kg, 5 mg / kg, 10 mg / kg, and 20 mg / kg, respectively), and a positive control group (dose of clopidogrel 15 mg / kg). The administration volume was 0.1 mL / 10 g. Except for the control and model groups, which received CMC-Na, the other groups received different doses of the drug for 7 consecutive days. One hour after administration on the 7th day, all groups were intraperitoneally injected with 50 mg / kg carrageenan solution (the control group received physiological saline) at a volume of 0.1 mL / 10 g. The length from tail root to tail tip (total tail length) of each group was measured simultaneously. Forty-eight hours after the intraperitoneal injection of carrageenan, the length of the tail that turned black was measured for each group.

[0244] Evaluation index: Degree of thrombosis in mice = length of black tail of mouse / total tail length of mouse.

[0245] 4. Experimental Results

[0246] The results showed that gavage administration of compound 18b significantly reduced the length of venous thrombi in mice, thereby decreasing the thrombus formation rate.

[0247] Example 59. Evaluation of drug efficacy in acute cerebral infarction

[0248] 1. Reagents

[0249] 20% urethane, positive control: edaravone and BPTU, test compound 18b, triphenyltetrazolium chloride (TTC)

[0250] 2. Instruments

[0251] Curved needle holder, micro forceps, artery clamp, 7-0 needle-supported suture, etc.

[0252] 3. Laboratory animals

[0253] Fifty-six male SD rats were used in the experiment, which included a model group, a blank control group, a positive control group (6 mg / kg: edaravone, 10 mg / kg: BPTU), and compound 18b groups at low, medium, and high doses (2.5 mg / kg, 5 mg / kg, and 10 mg / kg respectively). Animals were acclimatized for 7 days before the experiment until they reached a suitable weight (250-280 g). The animal room temperature was maintained at 22±3℃, and the humidity at 45%±10%.

[0254] 4. Experimental Procedure

[0255] Rats were anesthetized by intraperitoneal injection of 20% urethane. The rats were then placed gently on a warming pad and maintained at 37°C. The right common carotid artery, external carotid artery, and internal carotid artery were exposed using ophthalmic scissors and forceps. The right middle cerebral artery was then permanently occluded using silicone-coated fishing line in the model group, positive control group, and compound group. Immediately afterward, the positive control group and compound group received tail vein injection; the model group and control group received tail vein injection of saline. Neurological function scores were assessed for all rats 24 hours later.

[0256] 5. TTC staining - infarct area assessment

[0257] After assessment of neurological dysfunction, rats were euthanized, and the brain, with the cerebellum and olfactory bulb removed, was coronally sectioned into 2.0 mm thick sections. All sections were immersed in 2% TTC at 37°C for 20 minutes; infarcted brain tissue appeared white, while non-infarcted areas appeared red. Coronal sections were photographed with a mobile phone and analyzed using image processing software (ImageJ). The infarct volume of the entire brain was calculated using the following formula: Corrected infarct area = (contralateral area × 2 + ipsilateral non-infarcted area - total brain area) / 2 × contralateral area × 100%.

[0258] The results are as follows Figure 2 As shown, the results indicate that compound 18b can significantly improve the infarct area of ​​brain tissue caused by acute cerebral infarction in rats in a dose-dependent manner.

[0259] Example 60. Bleeding Risk Assessment

[0260] 1. Reagents

[0261] 20% urethane, physiological saline, positive control: edaravone and BPTU, test compound 18b.

[0262] 2. Instruments

[0263] Scalpel, 15mL syringe, timer, water bath, vernier caliper.

[0264] 3. Laboratory animals

[0265] Twenty-four male SD rats were used: a control group, a positive control group (6 mg / kg: edaravone, 10 mg / kg: BPTU), and a compound 18b group (10 mg / kg). Animals were acclimatized for 7 days before the experiment until they reached a suitable weight (250-280 g). The animal room temperature was maintained at 22±3℃, and the humidity at 45%±10%.

[0266] 4. Experimental Procedure

[0267] Rats were anesthetized by intraperitoneal injection of 20% urethane. The rats were then placed stably on a warming mat and maintained at 37°C. The treated group and the control group were administered the drug via tail vein injection, while the control group received saline. Immediately afterward, the tail was cut 3 mm from the tip, and the severed tail was placed in a centrifuge tube containing 8 mL of saline. A 15-minute timer was started. The centrifuge tube readings were taken after 15 minutes to calculate the blood loss volume.

[0268] The results are as follows Figure 3 As shown, the results indicate that the bleeding volume of compound 18b was lower than that of the positive control drugs ticagrelor and BPTU, suggesting that compound 18b has a correspondingly lower bleeding risk.

[0269] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. Compounds represented by general formula I and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates: in, R1 is a cyano group and a hydrogen atom; R2 is a cyano group and a hydrogen atom; R3 is a hydrogen atom, a C1-C6 alkyl group, or a C1-C6 alkoxy group; R4 is a substituted or unsubstituted 5-6 aryl or heteroaryl group, wherein the substituent is cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 sulfonamide, or C1-C4 acylamino. R5 is a hydroxyl group, a C1-C6 alkyl group, or a C1-C6 alkoxy group; A represents O and NH; n = 0-3, preferably 0-1.

2. The compound of general formula I according to claim 1, and its pharmaceutically usable salt, tautomer, and pharmaceutically usable solvate: wherein, R4 is a substituted or unsubstituted phenyl, pyrimidinyl, or pyrazolyl group, wherein the substituent is a cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 sulfonamide, or C1-C4 acylamino.

3. The compound of general formula I according to claim 1 or 2, and its pharmaceutically usable salt, tautomer, or pharmaceutically usable solvate: in, R4 is a substituted or unsubstituted phenyl, pyrimidinyl, or pyrazolyl group, wherein the substituent is a cyano, C1-C4 alkyl, C1-C4 alkoxy, methanesulfonylamino, or acetylamino group; Preferably, R4 is p-cyanophenyl, m-cyanophenyl, o-cyanophenyl, 3-methanesulfonylaminophenyl, 3-acetaminophenyl, pyrimidin-3-yl, or 1H-pyrazol-5-yl.

4. Compounds with the following structures and their pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

5. A pharmaceutical composition comprising any one of the compounds of claims 1-4 and their pharmaceutically acceptable salts, tautomers, or pharmaceutically acceptable solvates.

6. The use of the compound of any one of claims 1-4, its pharmaceutically usable salt, tautomer, pharmaceutically usable solvate, or the pharmaceutical composition of claim 5 in the preparation of a platelet aggregation inhibitor.

7. The use of the compound of any one of claims 1-4, its pharmaceutically usable salt, tautomer, pharmaceutically usable solvate, or the pharmaceutical composition of claim 5 in the preparation of a medicament for treating thromboembolic diseases.

8. The use of the compound of any one of claims 1-4, its pharmaceutically usable salt, tautomer, pharmaceutically usable solvate, or the pharmaceutical composition of claim 5 in the preparation of a neuroprotective medicament.

9. Intermediates for preparing the compound of claim 4 and its pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates:

10. Use of the intermediate of claim 9 in the preparation of the compound of general formula I of claim 1 and its pharmaceutically usable salts, tautomers, and pharmaceutically usable solvates.

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