1-(4 / 5-cyano-6-substituted pyrimidine-2-yl)-1H-pyrazole-4-formic acid compound as well as preparation method and application thereof

Abstract

The invention discloses a 1-(4 / 5-cyano-6-substituted pyrimidine-2-yl)-1H-pyrazole-4-formic acid compound as well as a preparation method and application thereof, and belongs to the technical field of medicines. According to the invention, the 1-(4 / 5-cyano-6-substituted pyrimidine-2-yl)-1H-pyrazole-4-formic acid compound is innovatively designed and synthesized, the synthesized target compound is subjected to in-vitro xanthine oxidase inhibitory activity test, and the result proves that the compound has the advantages that the activity of the compound is obviously improved; the 1-(4 / 5-cyano-6-substituted pyrimidine-2-yl)-1H-pyrazole-4-formic acid compound prepared by the invention has an effect of inhibiting xanthine oxidase (XO), and meanwhile, the preparation method disclosed by the invention is simple and feasible, and can be used for preparing medicines for treating and / or preventing hyperuricemia and gout diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more specifically, to a 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound and a preparation method and application thereof. Background Art

[0002] Gout is a metabolic disease caused by purine metabolism disorder or reduced uric acid excretion, which leads to excessively high serum uric acid concentration, crystallization of urate, and deposition in soft tissues or joints, causing an inflammatory response and subsequently inducing gout.

[0003] The main cause of gout is that when the production of uric acid in the body increases or its excretion decreases, it can lead to an increase in uric acid levels. When it exceeds its solubility limit, uric acid will be deposited in joints and soft tissues, causing an inflammatory response. Uric acid is the final product of purine metabolism in the human body. Xanthine oxidase (XO), as a key enzyme in the purine metabolism process, first oxidizes hypoxanthine to xanthine, and then further oxidizes it to uric acid. Xanthine oxidase inhibitors generally bind to the catalytic active site at the center of the molybdenum atom, reversibly or irreversibly inhibiting the activity of xanthine oxidase, preventing the substrate from undergoing hydroxylation reactions, reducing uric acid production, and reducing the concentration of uric acid in serum, thereby achieving the effect of treating hyperuricemia.

[0004] Currently, xanthine oxidase inhibitors on the market include allopurinol, febuxostat, etc., but the types are very limited and have certain toxic side effects. Therefore, the development of highly effective and low-toxic xanthine oxidase inhibitors has good application prospects. Summary of the invention

[0005] The purpose of the present invention is to overcome the above-mentioned defects of the prior art and provide a 1-(4 / 5-cyano-6-substituted pyrimidine-2-yl)-1H-pyrazole-4-carboxylic acid compound and its preparation method and application, which has the effect of inhibiting xanthine oxidase (XO) and can be used to prepare drugs for treating and (or) preventing hyperuricemia and gout.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds and pharmaceutically acceptable salts, isomers, polymorphs or solvates thereof, wherein the structure of the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds is shown in the general formula I:

[0008]

[0009] Among them, R 1is methoxy, dimethylamino, isobutylamino, pyrrolidinyl, piperidinyl, morpholinyl, trifluoroethylamino, phenylamino, benzylamino, 4-methoxybenzylamino, 4-trifluoromethylbenzylamino, 2-methoxyphenylamino, 3-methoxyphenylamino, 4-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino, 4-methylphenylamino, 2-fluorophenylamino, 4-fluorophenylamino, 2-chlorophenylamino, 3-chlorophenylamino, 4-chlorophenylamino, 2-bromophenylamino, 3-bromophenylamino, 4-bromophenylamino, 2,3-dimethylphenylamino, 2,6-dimethylphenylamino, 3,5-dimethylphenylamino One of phenylamino, 3,4-dimethoxyphenylamino, 3,5-dimethoxyphenylamino, 2,6-dimethoxyphenylamino, 2,3-dimethoxyphenylamino, 2,4-dimethoxyphenylamino, 2,4,6-trimethylphenylamino, benzo[d][1,3]dioxol-5-amino, 2,2-difluorobenzo[d][1,3]dioxol-5-amino, 3-cyanophenylamino, and 4,5-dimethylisoxazole-3-amino; R2 is a hydrogen atom or a cyano group; R3 is a hydrogen atom or a cyano group; R4 is a hydrogen atom or an amino group; R5 is a hydrogen atom or a methyl group.

[0010] The pharmaceutically acceptable salt refers to organic and inorganic salts of the compounds of the present invention, including but not limited to: salts of carboxylic acid moieties, which may be alkali metal salts such as Li, Na and K salts; alkaline earth metal salts such as Ca salts and Mg salts; organic base salts such as various amino acids, guanidine, diethanolamine, choline, etc.; ammonium salts or substituted ammonium salts and aluminum salts. The salt may be an acid addition salt, including but not limited to hydrochloride, sulfate, nitrate, phosphate, perchlorate, borate, tartrate, maleate, citrate, succinate, palmitate, methanesulfonate, benzoate, benzenesulfonate, salicylate, glycerophosphate, ketoglutarate, ascorbate, etc.

[0011] The solvates include, but are not limited to, hydrates or other crystallization solvents such as alcohol.

[0012] Optionally, the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound is any one of the following compounds A7-1 to D7-30:

[0013] A7-1: 1-(4-cyano-6-methoxypyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid;

[0014] A7-2: 1-[4-cyano-6-(dimethylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid;

[0015] A7-4: 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid;

[0016] A7-7: 1-{4-cyano-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid;

[0017] A7-8: 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid;

[0018] A7-9: 1-[4-(Benzylamino)-6-cyanopyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid;

[0019] A7-10: 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid;

[0020] A7-11: 1-{4-cyano-6-{[4(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid;

[0021] B7-1: 1-[4-cyano-6-methoxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0022] B7-2: 1-[4-cyano-6-(dimethylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0023] B7-3: 1-[4-cyano-6-(isobutylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0024] B7-4; 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0025] B7-6: 1-(4-cyano-6-morpholinopyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid;

[0026] B7-8: 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0027] B7-10: 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0028] B7-12: 1-(4-cyano-6-hydroxypyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid;

[0029] B7-13: 1-{4-cyano-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0030] B7-14: 1-{4-cyano-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0031] B7-15: 1-{4-cyano-6-[(4-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0032] B7-16: 1-{4-cyano-6-[(4-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0033] B7-17: 1-{4-cyano-6-[(4-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0034] B7-18: 1-{4-cyano-6-[(2-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0035] B7-19: 1-{4-cyano-6-[(3-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0036] B7-20: 1-{4-cyano-6-[(2-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0037] B7-21: 1-{4-cyano-6-[(3-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0038] B7-22: 1-{4-cyano-6-[(2-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0039] B7-23: 1-{4-cyano-6-[(2-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0040] B7-24: 1-{4-cyano-6-[(3-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0041] B7-25: 1-{4-cyano-6-[(2-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0042] B7-26: 1-{4-cyano-6-[(3-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0043] B7-27: 1-{4-cyano-6-[(2,3-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0044] B7-28: 1-{4-cyano-6-[(2,6-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0045] B7-29: 1-{4-cyano-6-[(3,5-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0046] B7-30: 1-{4-cyano-6-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0047] B7-31: 1-{4-cyano-6-[(3,5-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0048] B7-32: 1-[4-Cyano-6-(benzo[d][1,3]dioxol-5-ylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0049] B7-33: 1-[4-Cyano-6-(naphthalen-2-ylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0050] B7-34: 1-{4-cyano-6-[(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0051] B7-35: 1-{4-cyano-6-[(2,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0052] B7-36: 1-{4-cyano-6-[(2,6-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0053] B7-37: 1-{4-cyano-6-[(2,3-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0054] B7-38: 1-{4-cyano-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0055] B7-39: 1-{4-cyano-6-[(3-cyanophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0056] B7-40: 1-{4-cyano-6-{[(4,5-dimethyl)isoxazol-3-yl]amino}pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0057] C7-1: 1-(4-cyano-6-methoxypyrimidin-2-yl)-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid;

[0058] C7-4: 1-[4-Cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid;

[0059] C7-5: 1-[4-Cyano-6-(piperidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid;

[0060] C7-6: 1-[(4-cyano-6-morpholinyl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid;

[0061] C7-8: 1-[4-Cyano-6-(phenylamino)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid;

[0062] D7-30: 1-{5-cyano-6-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid;

[0063]

[0064]

[0065] The present invention also discloses a method for preparing the above-mentioned 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound and its pharmaceutically acceptable salt, isomer, polymorph or solvate, comprising the following steps:

[0066] Route 1: Preparation of compounds A7-1, A7-2, A7-4, A7-7 to A7-11, B7-1 to B7-4, B7-6, B7-8, B7-10, B7-12 to B7-40, C7-1, C7-4 to C7-6, C7-8;

[0067] Orotic acid is used as a starting material and dissolved in tetrahydrofuran, and reacted with N,N'-carbonyldiimidazole to prepare a mixed anhydride, and then ammonia water is added for condensation reaction to obtain the intermediate 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 2;

[0068] The intermediate 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 2 is subjected to a two-step chlorination and dehydration reaction in one pot to obtain the key intermediate 2,6-dichloropyrimidine-4-carbonitrile 3;

[0069] The key intermediate 2,6-dichloropyrimidine-4-carbonitrile 3 is subjected to hydrocarbonization reaction with methanol or an amine derivative to obtain an intermediate 2-chloro-6-methoxypyrimidine-4-carbonitrile B4-1 and intermediate 2-chloropyrimidine-4-carbonitrile derivatives B4-1, B4-2, B4-4 to B4-11, B4-13 to B4-40 respectively;

[0070] The intermediate 2-chloro-6-methoxypyrimidine-4-carbonitrile B4-1 and the intermediate 2-chloropyrimidine-4-carbonitrile derivatives B4-1, B4-2, B4-4 to B4-11, B4-13 to B4-40 are subjected to an aminolysis reaction with hydrazine hydrate to obtain the intermediate 2-hydrazinopyrimidine-4-carbonitrile B5-1, B5-2, B5-4 to B5-11, B5-13 to B5-40;

[0071] Using tert-butyl cyanoacetate as a starting material, a Knoevenagel reaction is carried out with triethyl orthoformate (iia) or triethyl orthoacetate (iib) to obtain intermediates tert-butyl 2-cyano-3-ethoxyacrylate iiia and tert-butyl 2-cyano-3-ethoxybutenoate iiib, and then a cyclization reaction is carried out with the intermediates 2-hydrazinopyrimidine-4-carbonitrile B5-1, B5-2, B5-4 to B5-11, B5-13 to B5-40 to obtain intermediates B6-1, B6-2, B6-4, B6-6 to B6-11, B6-13 to B6-40;

[0072] The intermediates B6-1, B6-2, B6-4, B6-6, B6-8, B6-10, B6-13 to B6-40 are cleaved by tert-butyl ester to obtain B series compounds 1-(4-cyano-6-substituted pyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid B7-1, B7-2, B7-4, B7-6, B7-8, B7-10, B7-13 to B7-40;

[0073] At the same time, the intermediate B6-1 is demethylated to obtain the intermediate B6-12, and then the tert-butyl ester is cleaved to obtain the compound B7-12. At the same time, the intermediate B6-12 is condensed with isobutylamine to obtain the intermediate B6-12a, and then the tert-butyl ester is cleaved to obtain the compound B7-3;

[0074] The intermediates B6-1, B6-2, B6-4, B6-7 to B6-11 are subjected to diazotization and dediazotization reaction with tert-butyl nitrite to obtain intermediates A6-1, A6-2, A6-4, A6-7 to A6-11, and then the tert-butyl ester is cleaved to obtain the target compounds of the A series, 1-(4-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid A7-1, A7-2, A7-4, A7-7 to A7-11;

[0075] The intermediates B5-1, B5-4 to B5-6, B5-8 are subjected to cyclization reaction with the intermediate iiib to obtain the intermediates C6-1, C6-4 to C6-6, C6-8, and then the tert-butyl ester is cleaved to obtain the C series target compounds 1-(4-cyano-6-substituted pyrimidin-2-yl)-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid C7-1, C7-4 to C7-6, C7-8;

[0076] Route 2: Preparation of compound D7-30;

[0077] 2,4-dichloropyrimidine-5-carbonitrile D3 is used as a starting material and dissolved in tetrahydrofuran, and then subjected to alkylation reaction with 3,4-dimethoxyaniline to obtain 2-chloro-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D4-30;

[0078] The 2-chloro-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D4-30 and hydrazine hydrate are mixed to perform an aminolysis reaction to obtain 2-hydrazine-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D5-30;

[0079] The 2-hydrazino-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D5-30 is subjected to a cyclization reaction with tert-butyl 2-cyano-3-ethoxyacrylate iiia to obtain tert-butyl 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-2-yl}-1H-pyrazole-4-carboxylate D6-30, and then the tert-butyl ester is cleaved to obtain the target compound 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-2-yl}-1H-pyrazole-4-carboxylic acid D7-30;

[0080]

[0081] Optionally, in the route 1, the reagents and conditions include: (a) N,N'-carbonyldiimidazole, dry tetrahydrofuran, 25°C, 3h, the molar ratio of orotic acid: N,N'-carbonyldiimidazole: dry tetrahydrofuran is 1:1.2:5; (b) ammonia water, dichloromethane, -10°C, overnight, the molar ratio of orotic acid: ammonia water: dichloromethane is 1:2:5; (c) phosphorus oxychloride, 1,4-dioxane, 100°C, 8h, orotic acid: trichloroethane The molar ratio of phosphorus oxide: 1,4-dioxane: is 1:3:6; (d) substituted amine, tetrahydrofuran, 0°C or N,N-diisopropylethylamine, methanol, -10°C, the molar ratio of orotic acid: substituted amine: tetrahydrofuran: N,N-diisopropylethylamine: methanol is 1:1.05:10:2:10; (e) hydrazine hydrate, dry tetrahydrofuran, 25°C, the molar ratio of orotic acid: hydrazine hydrate: dry tetrahydrofuran is 1:2.2:5; (f) acetic anhydride , 125°C, 3h, nitrogen, the molar ratio of orotic acid: acetic anhydride is 1:1; (g) ethanol, reflux, the molar ratio of orotic acid: ethanol is 1:5; (h) tert-butyl nitrite, tetrahydrofuran, 65°C, overnight, the molar ratio of orotic acid: tert-butyl nitrite: tetrahydrofuran is 1:1.5:5; (i) trifluoroacetic acid, dichloromethane, acetonitrile, 25°C, the molar ratio of orotic acid: trifluoroacetic acid: dichloromethane: acetonitrile is 1:5:5:5; (j ) lithium chloride, N,N-dimethylformamide, 120°C, the molar ratio of orotic acid: lithium chloride: N,N-dimethylformamide is 1:10:5; (k) Carter condensation agent, 1,8-diazabicyclo[5.4.0]undec-7-ene, isobutylamine, acetonitrile, 70°C, the molar ratio of orotic acid: Carter condensation agent: 1,8-diazabicyclo[5.4.0]undec-7-ene: isobutylamine: acetonitrile is 1:1.5:2:1.5:5.

[0082] Optionally, in the second route, the reagents and conditions include: (a) 3,4-dimethoxyaniline, tetrahydrofuran, 0°C, 2,4-dichloropyrimidine-5-carbonitrile: 3,4-dimethoxyaniline: tetrahydrofuran in a molar ratio of 1:1.05:10; (b) hydrazine hydrate, dry tetrahydrofuran, 25°C, 2,4-dichloropyrimidine-5-carbonitrile: hydrazine hydrate: dry tetrahydrofuran in a molar ratio of 1:2.2:5 ; (c) tert-butyl 2-cyano-3-ethoxyacrylate iiia, ethanol, reflux, the molar ratio of 2,4-dichloropyrimidine-5-carbonitrile: tert-butyl 2-cyano-3-ethoxyacrylate iiia: ethanol is 1:1.1:5; (d) trifluoroacetic acid, dichloromethane, acetonitrile, 25°C, the molar ratio of 2,4-dichloropyrimidine-5-carbonitrile: trifluoroacetic acid: dichloromethane: acetonitrile is 1:5:5:5.

[0083] The present invention also discloses a pharmaceutical composition, which comprises the above-mentioned 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound and its pharmaceutically acceptable salt, isomer, polymorph or solvate and pharmaceutically acceptable excipients, diluents or carriers.

[0084] Alternatively, the pharmaceutical composition 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.

[0085] Optionally, the dosage form of the pharmaceutical composition includes one of capsules, tablets, powders, solutions, suspensions, syrups, aerosols and injections. They may contain suitable solid or liquid carriers, or form injection solutions or suspensions in suitable sterile media.

[0086] Optionally, the mass percentage of 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds and pharmaceutically acceptable salts, isomers, polymorphs or solvates thereof in the pharmaceutical composition is 5% to 20%, preferably 5% to 10%.

[0087] Optionally, the composition of the present invention contains a compound or a solvate thereof as shown in formula I, and a pharmaceutically acceptable excipient, which may be a carrier or diluent, or diluted by a carrier, or packaged into a carrier, which may be in the form of a capsule, a pouch, paper or other container. When the carrier is used as a diluent, it may be a solid, semisolid or liquid substance, which may be used as a carrier, excipient or medium for the active compound. The active compound may be absorbed in the form of a granular solid in a container such as a pouch. Some suitable carriers are water, saline solution, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, coconut oil, gelatin, lactose, gypsum powder, sucrose, cyclodextrin, straight-chain starch, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, quaternary tetraol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

[0088] Alternatively, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0089] Optionally, the preparation may also include one of a wetting agent, an emulsifier, a suspending agent, a preservative, a sweetener and a flavoring agent. The preparation of the present invention may be formulated by methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to the patient.

[0090] Optionally, the pharmaceutical composition of the present invention may be sterile, and if necessary, may be mixed with an adjuvant, an emulsifier, a buffer and / or a colorant, etc., as long as they do not react with the active compound.

[0091] Alternatively, the pharmaceutical composition may be administered by any route that effectively delivers the active drug to the appropriate or desired active site, including one of oral, nasal, transdermal, pulmonary and parenteral administration, such as rectal, depot, subcutaneous, intravenous, intraurethral, ​​intramuscular, intranasal, ophthalmic solution or ointment, preferably by oral administration.

[0092] Alternatively, if a solid carrier is used for oral administration, the preparation can be compressed into tablets, or placed in capsules in powder or pellet form, or made into troches or lozenges; if a liquid carrier is used, the preparation can be a syrup, emulsion, soft gelatin capsule or a sterile injection, such as an aqueous or non-aqueous liquid suspension or solution.

[0093] Alternatively, for intranasal administration, the formulation may contain a compound of formula I dissolved or suspended in a liquid carrier, especially an aqueous carrier, for administration as an aerosol. It may also contain additives, including solubilizers such as propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrins and preservatives such as one of the parabens.

[0094] Alternatively, for parenteral administration, particularly suitable are injection solutions or suspensions, preferably aqueous solutions of the active compound in polyhydroxylated castor oil.

[0095] Optionally, carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch. When a sugar-added carrier can be used, a syrup or syrup may be used.

[0096] The present invention also discloses a use of the above-mentioned 1-(4 / 5-cyano-6-substituted pyrimidine-2-yl)-1H-pyrazole-4-carboxylic acid compound and its pharmaceutically acceptable salt, isomer, polymorph or solvate, or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing hyperuricemia and gout.

[0097] Implementing the embodiments of the present invention will have the following beneficial effects:

[0098] The present invention innovatively designs and synthesizes 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds, and tests the synthesized target compounds for in vitro xanthine oxidase inhibition activity test. The results show that the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds prepared by the present invention have the effect of inhibiting xanthine oxidase (XO). At the same time, the preparation method of the present invention is simple and easy, and can be used to prepare drugs for treating and / or preventing hyperuricemia and gout. DETAILED DESCRIPTION

[0099] The present invention is further described below in conjunction with specific embodiments, but the present invention is not limited in any way.

[0100] Example 1. Synthesis of tert-butyl 2-cyano-3-ethoxyacrylate (iiia)

[0101] Tert-butyl cyanoacetate (100 g, 0.7084 mol), triethyl orthoformate (157.6 g, 1.0632 mol), acetic anhydride (71.4 g, 0.7084 mol) were added to a 500 mL round-bottom flask, replaced with nitrogen three times, and then heated to 125 ° C. and reacted for 3 hours. The reaction was monitored by thin layer chromatography (dichloromethane: methanol = 1 mL: 1 drop) and completed. The mixture was cooled to room temperature, the excess solvent was concentrated under reduced pressure, an equal volume of water was added, and ethyl acetate (200 mL x 2) was used for extraction. The organic layers were combined, washed twice with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated to obtain a light reddish brown oil. Column chromatography (petroleum ether: ethyl acetate) was performed to concentrate the light yellow oil. The mixture was placed under a cold trap (-10 ° C) and 20 mL of n-hexane was added. The mixture was stirred for 30 minutes. Solids were precipitated, filtered, and dried to obtain 86 g of light yellowish white solids with a yield of 62%. Mp 78.8-80.2℃.ESI-MS m / z:198.1[M+H] + ,220.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.27(s,1H),4.43(q,J=7.1Hz,2H),1.46(s,9H),1.30(t,J=7.1Hz,3H).

[0102] Example 2. Synthesis of tert-butyl 2-cyano-3-ethoxybut-2-enoate (iiib)

[0103] Tert-butyl cyanoacetate (100g, 0.7084mol), triethyl orthoacetate (114.9g, 1.0632mol), acetic anhydride (71.4g, 0.7084mol) were added to a 500mL round-bottom flask, replaced with nitrogen three times, and then heated to 125°C for 3h. The reaction was completed by thin layer chromatography monitoring (dichloromethane: methanol = 1mL: 1 drop), cooled to room temperature, and the excess solvent was concentrated under reduced pressure. An equal volume of water was added, and ethyl acetate (200mL x 2) was extracted. The organic layers were combined, washed twice with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated to obtain a light reddish brown oil. Column chromatography (petroleum ether: ethyl acetate) was performed to obtain 80g of a light yellow oil with a yield of 54%. ESI-MS m / z: 212.1 [M + H] + ,234.1[M+Na] + .

[0104] Example 3. Synthesis of 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide (2)

[0105] Orotic acid (40g, 0.256mol), N, N'-carbonyldiimidazole (48g, 0.277mol), added to a 250mL round-bottom flask, added 160mL anhydrous tetrahydrofuran, heated to 25°C, reacted for 3h, thin layer chromatography detected the completion of the reaction, and cooled to room temperature; 40mL ammonia water and 40mL dichloromethane were added to a 500mL three-necked bottle, stirred for 10 minutes under a cold trap (-10°C), and then the prepared mixed anhydride was added dropwise to the above solvent, the temperature was controlled at about -5°C, and the cold trap was continued to stir for 30 minutes after the addition was completed, and then transferred to room temperature and reacted overnight. The reaction was monitored by thin layer chromatography, the excess solvent was concentrated under reduced pressure, 100mL methanol was added for pulping, suction filtered, and dried to obtain 20.8g of white solid with a yield of 60%. Mp 258.5-259.2℃.ESI-MS m / z:156.0[M+H] + ,178.0[M+Na] + ,153.9[MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δ11.25(s,1H),10.53(s,1H),8.22(s,1H),7.97(s,1H),6.07(s,1H).

[0106] Example 4. Synthesis of 2,6-dichloropyrimidine-4-carbonitrile (3)

[0107] Add intermediate 2 (15.6 g, 0.1144 mol) to a 500 mL round-bottom flask, add 120 mL 1,4-dioxane and stir evenly, then add 20 mL phosphorus oxychloride dropwise under a cold trap, after the addition is complete, heat to 100 ° C, react for 8 h, monitor the reaction by thin layer chromatography (petroleum ether: ethyl acetate = 2:1), cool to room temperature, concentrate the excess solvent under reduced pressure, add ice water under a cold trap to quench the reaction, add ethyl acetate (150 mL x 2) for extraction, collect the organic layer, wash twice with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain a black oil, column chromatography (petroleum ether: ethyl acetate = 4:1), concentrate under reduced pressure, and dry to obtain 7 g of a white crystalline solid with a yield of 25%. Mp 58.5-59.2 ° C. 1 H NMR (400MHz, Chloroform-d) δ7.65 (s, 1H).

[0108] Example 5. Synthesis of 2-chloro-6-methoxypyrimidine-4-carbonitrile (B4-1)

[0109] Add intermediate 3 (15g, 0.0867mol) to a 250ml round-bottom flask, add 60mL methanol, stir for 10 minutes under a cold trap (-5°C), then dissolve N,N-diisopropylethylamine (11.2g, 0.0867mol) in 20mL methanol and dropwise add to the above reaction solution, and stir for 30 minutes at 0°C. The reaction was completed by monitoring by thin layer chromatography (petroleum ether: ethyl acetate = 4:1). Add an equal volume of water, extract with ethyl acetate (100mL x 2), wash the organic layer once with an equal volume of 0.5M hydrochloric acid, wash twice with saturated saline solution, add anhydrous sodium sulfate to dry, filter and concentrate to obtain a transparent oily solution, add a small amount of petroleum ether under a cold trap and stir for 10 minutes, solid precipitates, filter and dry to obtain 7.5g of white crystalline solid, with a yield of 53%. Mp 153.5-154.3°C.ESI-MS m / z:170.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.27(s,1H),3.97(s,3H).

[0110] Example 6. Synthesis of 2-chloro-6-dimethylaminopyrimidine-4-carbonitrile (B4-2)

[0111] Add intermediate 3 (5g, 0.0289mol) to a 100mL round-bottom flask, add 20mL of anhydrous tetrahydrofuran, stir for 10 minutes in an ice-water bath, then dissolve morpholine (1.3g, 0.0289mol) in 5mL of anhydrous tetrahydrofuran and dropwise add to the above reaction solution, stir for 3h at 0℃. Monitor the reaction by thin layer chromatography (petroleum ether: ethyl acetate = 4:1). Concentrate excess tetrahydrofuran under reduced pressure at room temperature, add 30mL of ethyl acetate for extraction, collect the organic layer, wash twice with saturated saline solution, dry with anhydrous sodium sulfate, filter and concentrate, column chromatography (petroleum ether: ethyl acetate), concentrate to obtain 3.4g of white solid, yield 65%. Mp159.4-159.5℃. 1 H NMR (400 MHz, DMSO-d 6 )δ7.47(s,1H),3.12(s,3H),3.10(s,3H).

[0112] Example 7. Synthesis of 2-chloro-6-(pyrrolidin-1-yl)pyrimidine-4-carbonitrile (B4-4)

[0113] Using intermediate 3 and pyrrolidine as raw materials, the preparation method is the same as B4-2 to obtain 3.9 g of white solid with a yield of 65%. Mp178.0-179.1℃.ESI-MS m / z:209.1[M+H] + ,231.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.28(s,1H),3.49(t,J=6.7Hz,2H),3.43(t,J=6.7Hz,2H),2.03–1.86(m,4H).

[0114] Example 8. Synthesis of 2-chloro-6-(piperidin-1-yl)pyrimidine-4-carbonitrile (B4-5)

[0115] Using intermediate 3 and piperidine as raw materials, the preparation method was the same as B4-2 to obtain 4.1 g of crude product as white solid with a yield of 64%. It was directly carried out to the next step without purification. ESI-MS m / z: 223.1 [M+H] + ,245.1[M+Na] + .

[0116] Example 9. Synthesis of 2-chloro-6-morpholinopyrimidine-4-carbonitrile (B4-6)

[0117] Using intermediate 3 and morpholine as raw materials, the preparation method is the same as B4-2 to obtain 4.4 g of white solid with a yield of 68%. Mp 212.6-213.1℃.ESI-MS m / z: 225.0[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 )δ7.64(s,1H),3.76–3.59(m,8H).

[0118] Example 10. Synthesis of 2-chloro-6-[(2,2,2-trifluoroethyl)amino]pyrimidine-4-carbonitrile (B4-7)

[0119] Using intermediate 3 and 2,2,2-trifluoroethylamine as raw materials, the preparation method is the same as B4-2 to obtain 5.1 g of white solid with a yield of 72%. Mp 182.6-183.4℃. ESI-MS m / z: 237.0[M+H] + ,235.3[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.18(s,1H),7.16(s,1H),4.27(q,J=9.6Hz,2H).

[0120] Example 11. Synthesis of 2-chloro-6-(phenylamino)pyrimidine-4-carbonitrile (B4-8)

[0121] Using intermediate 3 and aniline as raw materials, the preparation method is the same as B4-2 to obtain 5.3 g of white solid with a yield of 80%. Mp 167.2-168.1℃.ESI-MS m / z: 230.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),7.59(s,2H),7.46–7.37(m,2H),7.24(s,1H),7.18(t,J=7.4Hz,1H).

[0122] Example 12. Synthesis of 2-chloro-6-(benzylamino)pyrimidine-4-carbonitrile (B4-9)

[0123] Using intermediate 3 and benzylamine as raw materials, the preparation method is the same as B4-2 to obtain 4.6 g of white solid with a yield of 65%. Mp 99.2-101.1℃.ESI-MS m / z: 245.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.04(t,J=5.7Hz,1H),7.41–7.33(m,1H),7.34(d,J=2.1Hz,3H),7.33–7.25(m,1H),7.05(s,1H),4.55(d,J=5.7Hz,2H).

[0124] Example 13. Synthesis of 2-chloro-6-[(4-methoxybenzyl)amino]pyrimidine-4-carbonitrile (B4-10)

[0125] Using intermediate 3 and p-methoxybenzylamine as raw materials, the preparation method is the same as B4-2 to obtain 6.3 g of white solid with a yield of 84%. Mp 189.4-191.3℃.ESI-MS m / z: 275.0[M+H] + ,297.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.97(t,J=5.7Hz,1H),7.26(d,J=8.7Hz,2H),7.02(s,1H),6.91(d,J=8.7Hz,2H),4.46(d,J=5.6Hz,2H),3.73(s,3H).

[0126] Example 14. Synthesis of 2-chloro-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidine-4-carbonitrile (B4-11)

[0127] Using intermediate 3 and p-trifluoromethylbenzylamine as raw materials, the preparation method is the same as B4-2 to obtain 6.6 g of white solid with a yield of 86%. Mp 164.2-165.5℃.ESI-MS m / z: 313.0[M+H] + ,310.9[MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δ9.13(t,J=5.9Hz,1H),7.72(d,J=8.1Hz,2H),7.54(d,J=8.0Hz,2H),7.11(s,1H),4.65(d,J=5.6Hz,2H).

[0128] Example 15. Synthesis of 2-chloro-6-[(4-methoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-13)

[0129] Using intermediate 3 and p-methoxyaniline as raw materials, the preparation method is the same as B4-2 to obtain 5.1 g of yellow solid with a yield of 68%. Mp 168.2-169.6℃.ESI-MS m / z: 261.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.48(s,1H),7.70–7.35(m,2H),7.14(s,1H),7.02–6.94(m,2H),3.76(s,3H).

[0130] Example 16. Synthesis of 2-chloro-6-[(4-methylphenyl)amino]pyrimidine-4-carbonitrile (B4-14)

[0131] Using intermediate 3 and p-methylaniline as raw materials, the preparation method is the same as B4-2 to obtain 4.2 g of white solid with a yield of 69%. Mp170.6-172.0℃.ESI-MS m / z:245.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.51(s,1H),7.63–7.34(m,2H),7.19(d,J=8.1Hz,2H),7.16(s,1H),2.29(s,3H).

[0132] Example 17. Synthesis of 2-chloro-6-[(4-fluorophenyl)amino]pyrimidine-4-carbonitrile (B4-15)

[0133] Using intermediate 3 and p-fluoroaniline as raw materials, the preparation method is the same as B4-2 to obtain 3.84 g of yellow solid with a yield of 54%. Mp189.2-190.0℃.ESI-MS m / z:248.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.62(s,1H),7.69–7.50(m,2H),7.29–7.23(m,2H),7.21(s,1H).

[0134] Example 18. Synthesis of 2-chloro-6-[(4-chlorophenyl)amino]pyrimidine-4-carbonitrile (B4-16)

[0135] Using intermediate 3 and p-chloroaniline as raw materials, the preparation method is the same as B4-2 to obtain 3.95 g of light yellow solid with a yield of 54%. Mp161.2-163.0℃.ESI-MS m / z:264.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.62(s,1H),7.69–7.50(m,2H),7.29–7.23(m,2H),7.21(s,1H).

[0136] Example 19. Synthesis of 2-chloro-6-[(4-bromophenyl)amino]pyrimidine-4-carbonitrile (B4-17)

[0137] Using intermediate 3 and p-bromoaniline as raw materials, the preparation method is the same as B4-2 to obtain 2.8 g of white solid with a yield of 35%. Mp144.3-146.0℃.ESI-MS m / z:310.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.65(s,1H),7.64–7.45(m,4H),7.21(s,1H).

[0138] Example 20. Synthesis of 2-chloro-6-[(2-methoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-18)

[0139] Using intermediate 3 and o-anisidine as raw materials, the preparation method is the same as B4-2 to obtain 4.7 g of yellow solid with a yield of 63%. Mp 100.3-101.8℃.ESI-MS m / z: 216.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.17(s,1H),7.42–7.12(m,5H),2.20(s,3H).

[0140] Example 21. Synthesis of 2-chloro-6-[(3-methoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-19)

[0141] Using intermediate 3 and m-methoxyaniline as raw materials, the preparation method is the same as B4-2 to obtain 5.6 g of yellow solid with a yield of 75%. Mp 106.3-107.5℃. ESI-MS m / z: 261.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.53(s,1H),7.57–7.31(m,2H),7.28(t,J=7.8Hz,1H),7.20(s,1H),6.99(d,J=7.5Hz,1H),2.31(s,3H).

[0142] Example 22. Synthesis of 2-chloro-6-[(2-methylphenyl)amino]pyrimidine-4-carbonitrile (B4-20)

[0143] Using intermediate 3 and o-methylaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.1 g of crude yellow solid product with a yield of 51%. It was directly carried out to the next step without purification. ESI-MS m / z: 245.1 [M+H] + .

[0144] Example 23. Synthesis of 2-chloro-6-[(3-methylphenyl)amino]pyrimidine-4-carbonitrile (B4-21)

[0145] Using intermediate 3 and m-methylaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.94 g of crude yellow solid product with a yield of 65%. It was directly carried out to the next step without purification. ESI-MS m / z: 244.8 [M+H] + .

[0146] Example 24. Synthesis of 2-chloro-6-[(2-fluorophenyl)amino]pyrimidine-4-carbonitrile (B4-22)

[0147] Using intermediate 3 and o-fluoroaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.37 g of white solid with a yield of 47%. Mp197.0-198.0℃.ESI-MS m / z:248.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.73(s,1H),9.73(s,1H),7.78–7.62(m,1H),7.47(td,J=8.0,2.0Hz,1H),7.36–7.31(m,1H),7.27–7.23(m,1H).

[0148] Example 25. Synthesis of 2-chloro-6-[(2-chlorophenyl)amino]pyrimidine-4-carbonitrile (B4-23)

[0149] Using intermediate 3 and o-chloroaniline as raw materials, the preparation method is the same as B4-2 to obtain 2.74 g of white solid with a yield of 37%. Mp209.3-210.7℃.ESI-MS m / z:248.8[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.44(s,1H),7.64–7.57(m,2H),7.42(td,J=7.7,1.6Hz,1H),7.34(td,J=7.7,1.7Hz,1H),7.26(s,1H).

[0150] Example 26. Synthesis of 2-chloro-6-[(3-chlorophenyl)amino]pyrimidine-4-carbonitrile (B4-24)

[0151] Using intermediate 3 and m-chloroaniline as raw materials, the preparation method is the same as B4-2 to obtain 3.7 g of light yellow solid with a yield of 50%. Mp199.3-201.8℃.ESI-MS m / z:248.8[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.73(s,1H),7.78(s,1H),7.52–7.47(m,1H),7.42(t,J=8.1Hz,1H),7.25(s,1H),7.23–7.18(m,1H).

[0152] Example 27. Synthesis of 2-chloro-6-[(2-bromophenyl)amino]pyrimidine-4-carbonitrile (B4-25)

[0153] Using intermediate 3 and o-bromoaniline as raw materials, the preparation method is the same as B4-2 to obtain 2.56 g of white solid with a yield of 32%. Mp145.7-147.5℃.ESI-MS m / z:331.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.73(s,1H),7.97–7.87(m,1H),7.60–7.52(m,1H),7.41–7.33(m,2H),7.26(s,1H).

[0154] Example 28. Synthesis of 2-chloro-6-[(3-bromophenyl)amino]pyrimidine-4-carbonitrile (B4-26)

[0155] Using intermediate 3 and m-bromoaniline as raw materials, the preparation method was the same as B4-2 to obtain 2.94 g of crude product as a white solid with a yield of 37%. It was directly used for the next step without purification. ESI-MS m / z: 331.1 [M+H] + .

[0156] Example 29. Synthesis of 2-chloro-6-[(2,3-dimethylphenyl)amino]pyrimidine-4-carbonitrile (B4-27)

[0157] Using intermediate 3 and 2,3-dimethylaniline as raw materials, the preparation method was the same as B4-2 to obtain 5.4 g of crude product as a light yellow solid with a yield of 64%. It was directly carried out to the next step without purification. ESI-MS m / z: 259.1 [M+H] + .

[0158] Example 30. Synthesis of 2-chloro-6-[(2,6-dimethylphenyl)amino]pyrimidine-4-carbonitrile (B4-28)

[0159] Using intermediate 3 and 2,6-dimethylaniline as raw materials, the preparation method was the same as B4-2 to obtain a crude yellow solid product 4.6 with a yield of 55%. It was directly used for the next step without purification. ESI-MS m / z: 259.1 [M+H] + .

[0160] Example 31. Synthesis of 2-chloro-6-[(3,5-dimethylphenyl)amino]pyrimidine-4-carbonitrile (B4-29)

[0161] Using intermediate 3 and 3,5-dimethylaniline as raw materials, the preparation method was the same as B4-2 to obtain 4.87 g of crude yellow solid product with a yield of 59%. It was directly used for the next step without purification. ESI-MS m / z: 259.1 [M+H] + .

[0162] Example 32. Synthesis of 2-chloro-6-[(3,4-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-30)

[0163] Using intermediate 3 and 3,4-dimethoxyaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.46 g of yellow solid with a yield of 42%. Mp 214.3-215.8℃.ESI-MS m / z: 291.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.57(s,1H),7.22(s,1H),6.95–6.76(m,2H),6.34(s,1H),3.75(s,7H).

[0164] Example 33. Synthesis of 2-chloro-6-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-31)

[0165] Using intermediate 3 and 3,5-dimethoxyaniline as raw materials, the preparation method is the same as B4-2 to obtain 3.78 g of yellow solid with a yield of 45%. Mp 216.1-217.5℃.ESI-MS m / z: 291.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.45(s,1H),7.49–7.01(m,3H),6.96(d,J=8.6Hz,1H),3.75(d,J=2.5Hz,6H).

[0166] Example 34. Synthesis of 2-chloro-6-[(benzo(d)(1,3)dioxol-5-yl)amino]pyrimidine-4-carbonitrile (B4-32)

[0167] Using intermediate 3 and 3,4-methylenedioxyaniline as raw materials, the preparation method was the same as B4-2, and 5.2 g of crude product as white solid was obtained with a yield of 66%. It was directly carried out to the next step without purification, ESI-MS m / z: 275.1 [M+H] + .

[0168] Example 35. Synthesis of 2-chloro-6-[(naphthalen-2-yl)amino]pyrimidine-4-carbonitrile (B4-33)

[0169] Using intermediate 3 and 2-aminonaphthalene as raw materials, the preparation method was the same as B4-2 to obtain 5.47 g of crude product as white solid with a yield of 68%. It was directly carried out to the next step without purification. ESI-MS m / z: 281.1 [M+H] + .

[0170] Example 36. Synthesis of 2-chloro-6-[(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino]pyrimidine-4-carbonitrile (B4-34)

[0171] Using intermediate 3, 5-amino-2,2-difluoro-1,3-benzodioxole as raw materials, the preparation method was the same as B4-2, and the crude product was obtained as a white solid (3.45 g) with a yield of 39%. It was directly carried out to the next step without purification, ESI-MS m / z: 311.0 [M+H] + .

[0172] Example 37. Synthesis of 2-chloro-6-[(2,6-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-35)

[0173] Using intermediate 3 and 2,6-dimethoxyaniline as raw materials, the preparation method is the same as B4-2 to obtain 3.32 g of light yellow solid with a yield of 40%. Mp 169.3-170.7℃.ESI-MS m / z: 291.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.89(s,1H),7.50–7.06(m,2H),6.77(d,J=8.4Hz,2H),3.76(s,6H).

[0174] Example 38. Synthesis of 2-chloro-6-[(2,3-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-36)

[0175] Using intermediate 3 and 2,3-dimethoxyaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.57 g of crude product as a light yellow solid with a yield of 43%. The next step was carried out directly without purification. ESI-MS m / z: 291.1 [M+H]+ .

[0176] Example 39. Synthesis of 2-chloro-6-[(2,4-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B4-37)

[0177] Using intermediate 3 and 2,4-dimethoxyaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.29 g of light yellow solid with a yield of 40%. The next step was carried out directly without purification. ESI-MS m / z: 291.1 [M+H] + .

[0178] Example 40. Synthesis of 2-chloro-6-[(2,4,6-trimethylphenyl)amino]pyrimidine-4-carbonitrile (B4-38)

[0179] Using intermediate 3 and 2,4,6-trimethylaniline as raw materials, the preparation method was the same as B4-2 to obtain 2.47 g of crude product as a light yellow solid with a yield of 31%. It was directly carried out to the next step without purification. ESI-MS m / z: 273.2 [M+H] + .

[0180] Example 41. Synthesis of 2-chloro-6-[(3-cyanophenyl)amino]pyrimidine-4-carbonitrile (B4-39)

[0181] Using intermediate 3 and m-cyanoaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.69 g of light yellow solid with a yield of 50%. The solid was directly used for the next step without purification.

[0182] Example 42. Synthesis of 2-chloro-6-[(4,5-dimethylisoxazol-3-yl)amino]pyrimidine-4-carbonitrile (B4-40)

[0183] Using intermediate 3, 3-amino-4,5-dimethylisoxazole as raw materials, the preparation method was the same as B4-2 to obtain 2.99 g of crude product as a white solid with a yield of 42%. The product was directly carried out to the next step without purification.

[0184] Example 43. 2-Chloro-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile (D4-30)

[0185] Using intermediate D3 and 3,4-dimethoxyaniline as raw materials, the preparation method was the same as B4-2 to obtain 3.5 g of light yellow solid with a yield of 46%. The product was directly carried out to the next step without purification. 1 H NMR (400 MHz, DMSO-d 6)δ10.21(s,1H),8.69(s,1H),7.14(d,J=2.4Hz,1H),7.05(dd,J=8.6,2.4Hz,1H),6.99–6.95(m,1H),3.77(s,3H),3.74(s,3H).

[0186] Example 44. Synthesis of 2-hydrazino-6-methoxypyrimidine-4-carbonitrile (B5-1)

[0187] The intermediate B4-1 (5 g, 0.0296 mol) was added to a 100 mL round-bottom flask, and 15 mL of anhydrous tetrahydrofuran was added. The mixture was stirred at room temperature for 10 minutes. 80% hydrazine hydrate (3.7 g, 0.0592 mol) was dissolved in 5 mL of anhydrous tetrahydrofuran and added dropwise to the above reaction flask. The mixture was stirred at room temperature for 1 hour. Solids were precipitated. The reaction was completed by thin layer chromatography (petroleum ether: ethyl acetate = 2:1). The excess tetrahydrofuran was concentrated under reduced pressure to obtain a light yellow solid. 2 mL of ethanol and 1 mL of water were added to the mixture for 20 minutes. The mixture was filtered and dried to obtain 3 g of a light yellow solid with a yield of 61%. Mp115.3-115.8°C. ESI-MS m / z:166.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.73(s,1H),6.67(s,1H),4.30(s,2H),3.88(s,3H).

[0188] Example 45. Synthesis of 2-hydrazino-6-dimethylaminopyrimidine-4-carbonitrile (B5-2)

[0189] The intermediate B4-2 (2.5 g, 0.0137 mol) was added to a 50 mL round-bottom flask, and 10 mL of anhydrous tetrahydrofuran was added. The mixture was stirred in an ice-water bath for 10 minutes. 80% hydrazine hydrate (1.71 g, 0.0274 mol) was dissolved in 3 mL of anhydrous tetrahydrofuran and added dropwise to the above reaction flask. The mixture was then transferred to room temperature and stirred for 4 h. The reaction was completed by monitoring by thin layer chromatography (petroleum ether: ethyl acetate = 2:1). The excess tetrahydrofuran was concentrated under reduced pressure, and 20 mL of dichloromethane was added for extraction. The mixture was washed twice with saturated brine, dried with anhydrous sodium sulfate, filtered and concentrated. The mixture was subjected to column chromatography (dichloromethane: methanol), and concentrated under reduced pressure to obtain a light yellow solid. The solid was added with 2 mL of ethanol and 1 mL of water for 20 minutes, filtered, and dried to obtain 1.2 g of a light yellow-white solid with a yield of 49%. Mp 121.4-123.1°C. 1 H NMR (400 MHz, DMSO-d 6 )δ8.04(s,1H),6.56(s,1H),4.11(s,2H),3.04(s,6H).

[0190] Example 46. Synthesis of 2-hydrazino-6-(pyrrolidin-1-yl)pyrimidine-4-carbonitrile (B5-4)

[0191] Using intermediate B4-4 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.4 g of white solid is obtained, with a yield of 50%. Mp132.8-133.9℃.ESI-MS m / z:205.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.02(s,1H),6.38(s,1H),4.10(s,2H),3.52–3.33(m,4H),1.99–1.83(m,4H).

[0192] Example 47. Synthesis of 2-hydrazino-6-(piperidin-1-yl)pyrimidine-4-carbonitrile (B5-5)

[0193] Using intermediate B4-5 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.6 g of white solid is obtained with a yield of 54%. Mp129.6-131.5℃.ESI-MS m / z:219.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.01(s,1H),6.70(s,1H),4.09(s,2H),3.60(s,4H),1.66–1.57(m,2H),1.53–1.45(m,4H).

[0194] Example 48. Synthesis of 2-hydrazino-6-morpholinopyrimidine-4-carbonitrile (B5-6)

[0195] Using intermediate B4-6 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.4 g of white solid is obtained with a yield of 47%. Mp117.1-118.5℃.ESI-MS m / z:221.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.14(s,1H),6.71(s,1H),4.14(s,2H),3.65–3.59(m,8H).

[0196] Example 49. Synthesis of 2-hydrazino-6-[(2,2,2-trifluoroethyl)amino]pyrimidine-4-carbonitrile (B5-7)

[0197] Using intermediate B4-7 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.8 g of white solid is obtained, with a yield of 51%. Mp159.6-161.3℃.ESI-MS m / z:233.0[M+H] + ,255.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.27(s,1H),8.15(s,1H),6.33(s,1H),4.25(s,2H),4.17(s,2H).

[0198] Example 50. Synthesis of 2-hydrazino-6-(phenylamino)pyrimidine-4-carbonitrile (B5-8)

[0199] Using intermediate B4-8 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.5 g of white solid is obtained, with a yield of 45%. Mp195.9-196.5℃.ESI-MS m / z:227.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.70(s,1H),8.39(s,1H),7.76(d,J=7.9Hz,2H),7.35–7.26(m,2H),7.07–6.98(m,1H),6.45(s,1H),4.22(s,2H).

[0200] Example 51. Synthesis of 2-hydrazino-6-(benzylamino)pyrimidine-4-carbonitrile (B5-9)

[0201] Using intermediate B4-9 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.3 g of white solid is obtained with a yield of 42%. Mp208.3-210.1℃.ESI-MS m / z:241.0[M+H] + ,263.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.14–8.00(m,2H),7.33(d,J=4.5Hz,4H),7.29–7.22(m,1H),6.27(s,1H),4.53(d,J=5.6Hz,2H),4.10(s,2H).

[0202] Example 52. Synthesis of 2-hydrazino-6-[(4-methoxybenzyl)amino]pyrimidine-4-carbonitrile (B5-10)

[0203] Using intermediate B4-10 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.7 g of white solid is obtained with a yield of 52%. Mp186.7-186.9℃.ESI-MS m / z:271.1[M+H] + ,293.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.08(s,1H),7.99(s,1H),7.26(d,J=8.3Hz,2H),6.93–6.85(m,2H),6.24(s,1H),4.45(s,2H),4.10(s,2H),3.72(s,3H).

[0204] Example 53. Synthesis of 2-hydrazino-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidine-4-carbonitrile (B5-11)

[0205] Using intermediate B4-11 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.5 g of white solid is obtained with a yield of 50%. Mp203.8-204.5℃.ESI-MS m / z:309.1[M+H] + ,306.9[MH] - . 1 H NMR (400 MHz, DMSO-d 6 )δ8.17(s,1H),8.11(s,1H),7.69(d,J=8.0Hz,2H),7.54(d,J=7.9Hz,2H),6.29(s,1H),4.62(s,2H),4.09(d,J=3.8Hz,2H).

[0206] Example 54. Synthesis of 2-hydrazino-6-[(4-methoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-13)

[0207] Using intermediate B4-13 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 1.5 g of light yellow solid with a yield of 43%. Mp 218.5-219.6℃.ESI-MS m / z: 241.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.58(s,1H),8.29(s,1H),7.63(d,J=8.4Hz,2H),6.93–6.83(m,2H),6.38(s,1H),4.18(s,2H),3.73(s,3H).

[0208] Example 55. Synthesis of 2-hydrazino-6-[(4-methylphenyl)amino]pyrimidine-4-carbonitrile (B5-14)

[0209] Using intermediate B4-14 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.4 g of white solid is obtained with a yield of 42%. Mp176.9-178.5℃.ESI-MS m / z:257.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.61(s,1H),8.34(s,1H),7.61(d,J=8.0Hz,2H),7.12(d,J=8.2Hz,2H),6.41(s,1H),4.19(s,2H),2.26(s,3H).

[0210] Example 56. Synthesis of 2-hydrazino-6-[(4-fluorophenyl)amino]pyrimidine-4-carbonitrile (B5-15)

[0211] Using intermediate B4-15 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 1.6 g of white solid. Yield 47%. Mp 169.9-171.5℃. ESI-MS m / z: 245.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.73(s,1H),8.39(s,1H),7.77(dd,J=9.0,4.9Hz,2H),7.19–7.09(m,2H),6.41(s,1H),4.21(s,2H).

[0212] Example 57. Synthesis of 2-hydrazino-6-[(4-chlorophenyl)amino]pyrimidine-4-carbonitrile (B5-16)

[0213] Using intermediate B4-16 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 1.8 g of light yellow solid with a yield of 51%. Mp 219.7-220.8℃.ESI-MS m / z: 261.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.82(s,1H),8.44(s,1H),7.84–7.75(m,2H),7.38–7.30(m,2H),6.43(s,1H),4.23(s,1H).

[0214] Example 58. Synthesis of 2-hydrazino-6-[(4-bromophenyl)amino]pyrimidine-4-carbonitrile (B5-17)

[0215] Using intermediate B4-17 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.8 g of white solid is obtained with a yield of 43%. Mp155.4-156.7℃.ESI-MS m / z:305.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.82(s,1H),8.44(s,1H),7.75(d,J=8.9Hz,2H),7.46(d,J=8.9Hz,2H),6.44(s,1H),4.23(s,2H).

[0216] Example 59. Synthesis of 2-hydrazino-6-[(2-methoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-18)

[0217] Using intermediate B4-18 and hydrazine hydrate as raw materials, the preparation method was the same as B5-2 to obtain 1.7 g of crude product as white solid with a yield of 49%. It was directly carried out to the next step without purification. ESI-MS m / z: 241.1 [M+H] + ,263.2[M+Na] + .

[0218] Example 60. Synthesis of 2-hydrazino-6-[(3-methoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-19)

[0219] Using intermediate B4-19 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 1.6 g of yellow solid with a yield of 46%. Mp147.9-149.5℃.ESI-MS m / z:241.1[M+H] + ,263.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.62(s,1H),8.39(s,1H),7.59(s,1H),7.54(d,J=8.2Hz,1H),7.19(t, J=7.8Hz,1H),6.87–6.82(m,1H),6.43(s,1H),4.22(s,2H),2.30(s,3H).

[0220] Example 61. Synthesis of 2-hydrazino-6-[(2-methylphenyl)amino]pyrimidine-4-carbonitrile (B5-20)

[0221] Using intermediate B4-20 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 1.4 g of yellow solid with a yield of 42%. Mp153.7-154.1℃.ESI-MS m / z:257.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.95(s,1H),8.28(s,1H),8.21–8.11(m,1H),7.11–7.03(m,2H),6.95–6.88(m,1H),6.66(s,1H),4.16(s,2H),3.84(s,3H).

[0222] Example 62. Synthesis of 2-hydrazino-6-[(3-methylphenyl)amino]pyrimidine-4-carbonitrile (B5-21)

[0223] Using intermediate B4-21 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.6 g of white solid is obtained with a yield of 48%. Mp156.2-158.1℃.ESI-MS m / z:257.1[M+H] + ,279.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.70(s,1H),8.42(s,1H),7.56(s,1H),7.26–7.13(m,2H),6.68–6.54(m,1H),6.44(s,1H),4.24(s,2H),3.76(s,3H).

[0224] Example 63. Synthesis of 2-hydrazino-6-[(2-fluorophenyl)amino]pyrimidine-4-carbonitrile (B5-22)

[0225] Using intermediate B4-22 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.7 g of white solid is obtained, with a yield of 50%. Mp168.6-168.7℃.ESI-MS m / z:245.1[M+H] + ,266.9[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.45(s,1H),8.38(s,1H),8.21(s,1H),7.32–7.24(m,1H),7.21–7.09(m,2H),6.61(s,1H),4.18(s,2H).

[0226] Example 64. Synthesis of 2-hydrazino-6-[(2-chlorophenyl)amino]pyrimidine-4-carbonitrile (B5-23)

[0227] Using intermediate B4-23 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.7 g of white solid is obtained with a yield of 48%. Mp191.9-192.7℃.ESI-MS m / z:261.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.26(s,1H),8.31(s,1H),7.93(s,1H),7.52(dd,J=8.0,1.5Hz,1H),7.34( td,J=7.8,1.6Hz,1H),7.19(td,J=7.7,1.6Hz,1H),6.55(s,1H),4.14(s,2H).

[0228] Example 65. Synthesis of 2-hydrazino-6-[(3-chlorophenyl)amino]pyrimidine-4-carbonitrile (B5-24)

[0229] Using intermediate B4-24 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.7 g of white solid is obtained with a yield of 48%. Mp211.0-211.4℃.ESI-MS m / z:261.1[M+H] + ,283.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.85(s,1H),8.53(s,1H),7.94(t,J=2.1Hz,1H),7.67(d,J=8.3Hz,1H),7.32(t,J=8.1Hz,1H),7.08–7.02(m,1H),6.44(s,1H),4.24(s,2H).

[0230] Example 66. Synthesis of 2-hydrazino-6-[(2-bromophenyl)amino]pyrimidine-4-carbonitrile (B5-25)

[0231] Using intermediate B4-25 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.9 g of white solid is obtained, with a yield of 51%. Mp149.7-150.4℃.ESI-MS m / z:305.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.84(s,1H),8.53(t,J=3.3Hz,1H),8.03(s,1H),7.76(d,J=8.1Hz,1H),7.26(t,J =8.0Hz,1H),7.20(ddd,J=8.0,1.9,1.1Hz,1H),6.44(s,1H),4.24(d,J=3.5Hz,2H).

[0232] Example 67. Synthesis of 2-hydrazino-6-[(3-bromophenyl)amino]pyrimidine-4-carbonitrile (B5-26)

[0233] Using intermediate B4-26 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 2.0 g of white solid is obtained, with a yield of 54%. Mp152.3-152.4℃.ESI-MS m / z:305.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.84(s,1H),8.53(t,J=3.7Hz,1H),8.03(s,1H),7.76(d,J=8.1Hz,1H),7.27( t,J=8.0Hz,1H),7.20(dt,J=8.2,1.3Hz,1H),6.44(s,1H),4.24(d,J=3.8Hz,2H).

[0234] Example 68. Synthesis of 2-hydrazino-6-[(2,3-dimethylphenyl)amino]pyrimidine-4-carbonitrile (B5-27)

[0235] Using intermediate B4-27 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 2.4 g of yellow solid is obtained with a yield of 70%. Mp173.5-174.1℃.ESI-MS m / z:255.1[M+H] + ,277.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.16(s,1H),8.15(s,1H),7.18(d,J=7.7Hz,1H),7.10(d,J=7.5Hz,1H) ,7.08–7.05(m,1H),6.21(s,1H),4.08(s,2H),2.26(s,3H),2.07(s,3H).

[0236] Example 69. Synthesis of 2-hydrazino-6-[(2,6-dimethylphenyl)amino]pyrimidine-4-carbonitrile (B5-28)

[0237] Using intermediate B4-28 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain a crude product of yellow solid 2.6 with a yield of 75%. It was directly carried out to the next step without purification. ESI-MS m / z: 255.1 [M+H] + ,277.1[M+Na] + .

[0238] Example 70. Synthesis of 2-hydrazino-6-[(3,5-dimethylphenyl)amino]pyrimidine-4-carbonitrile (B5-29)

[0239] Using intermediate B4-29 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and the crude product is a yellow solid of 2.5 g, with a yield of 72%. It is directly carried out to the next step without purification. ESI-MS m / z: 255.1 [M+H] + ,277.1[M+Na] + .

[0240] Example 71. Synthesis of 2-hydrazino-6-[(3,4-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-30)

[0241] Using intermediate B4-30 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 2.3 g of yellow solid with a yield of 59%. Mp125.8-125.9℃.ESI-MS m / z:287.2[M+H] + ,309.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.67(s,1H),8.45(s,1H),7.02(s,2H),6.43(s,1H),6.18(t,J=2.2Hz,1H),4.25(s,2H),3.73(s,6H).

[0242] Example 72. Synthesis of 2-hydrazino-6-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-31)

[0243] Using intermediate B4-31 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 2.2 g of yellow solid with a yield of 58%. Mp128.3-128.9℃.ESI-MS m / z:287.2[M+H] + ,309.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6)δ9.61(s,1H),8.35(s,1H),7.59(s,1H),7.13–7.05(m,1H),6.88(d,J=8.7Hz,1H),6.40(s,1H),4.66–4.42(m,2H),3.77(s,3H),3.72(s,3H).

[0244] Example 73. Synthesis of 2-hydrazino-6-[benzo(d)(1,3)dioxol-5-ylamino]-4-carbonitrile (B5-32)

[0245] Using intermediate B4-32 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 2.3 g of yellow solid with a yield of 62%. Mp223.6-224.9℃.ESI-MS m / z:271.1[M+H] + ,293.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.70(s,1H),8.38(s,1H),7.56(s,1H),7.02(d,J=8.3Hz,1H),6.85(d,J=8.4Hz,1H),6.42(s,1H),5.99(s,2H),4.48(s,2H).

[0246] Example 74. Synthesis of 2-hydrazino-6-(naphthalen-2-ylamino)pyrimidine-4-carbonitrile (B5-33)

[0247] Using intermediate B4-33 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 2.5 g of white solid is obtained with a yield of 66%. Mp198.2-198.5℃.ESI-MS m / z:277.1[M+H] + ,299.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.93(s,1H),8.69(s,1H),8.52(s,1H),7.92–7.80(m,3H),7.62(d,J=8. 9Hz,1H),7.51–7.44(m,1H),7.42–7.35(m,1H),6.53(s,1H),4.31(s,2H).

[0248] Example 75. Synthesis of 2-hydrazino-6-[(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino]pyrimidine-4-carbonitrile (B5-34)

[0249] Using intermediate B4-34 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and the crude product is a light yellow solid of 1.28 g, with a yield of 52%. It is directly carried out to the next step without purification. ESI-MS m / z: 307.2 [M+H] + .

[0250] Example 76. Synthesis of 2-hydrazino-6-[(2,6-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-35)

[0251] Using intermediate B4-35 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.8 g of white solid is obtained with a yield of 46%. Mp166.3-167.4℃.ESI-MS m / z:287.2[M+H] + .

[0252] Example 77. Synthesis of 2-hydrazino-6-[(2,3-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-36)

[0253] Using intermediate B4-36 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.1 g of white solid is obtained with a yield of 28%. Mp166.7-168.1℃.ESI-MS m / z:287.2[M+H] + .

[0254] Example 78. Synthesis of 2-hydrazino-6-[(2,4-dimethoxyphenyl)amino]pyrimidine-4-carbonitrile (B5-37)

[0255] Using intermediate B4-37 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and 1.3 g of white solid is obtained with a yield of 33%. Mp171.3-173.2℃.ESI-MS m / z:287.2[M+H] + .

[0256] Example 79. Synthesis of 2-hydrazino-6-[(2,4,6-trimethylphenyl)amino]pyrimidine-4-carbonitrile (B5-38)

[0257] Using intermediate B4-38 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and the crude product is light yellow solid 1.1g, the yield is 25%. It is directly carried out to the next step without purification. ESI-MS m / z: 269.2[M+H] + .

[0258] Example 80. Synthesis of 2-hydrazino-6-[(3-cyanophenyl)amino]pyrimidine-4-carbonitrile (B5-39)

[0259] Using intermediate B4-39 and hydrazine hydrate as raw materials, the preparation method was the same as B5-2 to obtain 1.0 g of crude yellow solid product with a yield of 41%. The product was directly carried out to the next step without purification.

[0260] Example 81. Synthesis of 2-hydrazino-6-[(4,5-dimethylisoxazol-3-yl)amino]pyrimidine-4-carbonitrile (B5-40)

[0261] Using intermediate B4-40 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2, and the crude product is light yellow solid 1.2g, the yield is 49%. It is directly carried out to the next step without purification. ESI-MS m / z: 246.3[M+H] + .

[0262] Example 82. 2-Hydrazino-4-[(3,4-dimethoxyphenyl)amino]-pyrimidine-5-carbonitrile (D5-30)

[0263] Using intermediate D4-30 and hydrazine hydrate as raw materials, the preparation method is the same as B5-2 to obtain 1.1 g of crude product as light yellow solid with a yield of 42%. 1 H NMR (400 MHz, DMSO-d 6 )δ9.12(s,0.74H),8.93(d,J=28.8Hz,1H),8.71(s,0.31H),8.41(s,0.29H),8.26(s,1H),7.52(s,0.73H),7 .26(s,1H),7.18(dd,J=8.7,2.5Hz,1H),6.86(dd,J=8.7,5.8Hz,1H),4.35(s,2H),3.74(s,3H),3.73(s,3H).

[0264] Example 83. Synthesis of tert-butyl 1-[(4-cyano-6-methoxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-1)

[0265] Add intermediate B5-1 (3g, 0.0182mol) to a 50mL round-bottom flask, add 10mL ethanol, dropwise add intermediate iiia (3.58g, 0.0182mol), heat to 80℃, and react for 5h. Monitor the reaction by thin layer chromatography (petroleum ether: ethyl acetate = 2:1) until it is complete, cool to room temperature, concentrate the residual solvent under reduced pressure, add 20mL water, extract with 30mL ethyl acetate, collect the organic layer, wash twice with saturated saline solution, dry with anhydrous sodium sulfate, filter and concentrate, column chromatography (petroleum ether: ethyl acetate), concentrate to obtain a light yellow crude product, dry the crude product with ethanol and water, filter, dry to obtain 1.25g of white solid, yield 22%. Mp 153.6-157.8℃. 1H NMR (400 MHz, DMSO-d 6 )δ7.73(s,1H),7.64(s,1H),7.36(s,2H),4.07(s,3H),1.52(s,9H).

[0266] Example 84. Synthesis of tert-butyl 1-[(4-cyano-6-dimethylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-2)

[0267] Using intermediate B5-2 and intermediate iiia as raw materials, the preparation method is the same as B6-1. White solid 100 mg, yield 11%. Mp 213.6-214.9℃. ESI-MS m / z: 330.2[M+H] + ,352.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.65(s,1H),7.36(s,1H),7.34(s,2H),3.18(s,3H),3.15(s,3H),1.51(s,9H).

[0268] Example 85. Synthesis of tert-butyl 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-4)

[0269] Using intermediate B5-4 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 156 mg of white solid is obtained, with a yield of 11%. Mp 167.2-167.5℃. ESI-MS m / z: 356.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.64(s,1H),7.36(s,2H),7.17(s,1H),3.56(t,J=6.6Hz,2H),3.48(t,J=6.5Hz,2H),2.03–1.98(m,2H),1.98–1.93(m,2H),1.51(s,9H).

[0270] Example 86. Synthesis of tert-butyl 1-[(4-cyano-6-morpholinyl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-6)

[0271] Using intermediate B5-6 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 166 mg of crude product as white solid with a yield of 12%. The product was directly used for the next step without purification.

[0272] Example 87. Synthesis of tert-butyl 1-{4-cyano-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-7)

[0273] Using intermediate B5-7 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 170 mg of crude product as white solid with a yield of 13%. The product was directly used for the next step without purification.

[0274] Example 88. Synthesis of tert-butyl 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-8)

[0275] Using intermediate B5-8 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 150 mg of crude product as white solid with a yield of 11%. The product was directly carried out to the next step without purification.

[0276] Example 89. Synthesis of tert-butyl 1-[4-cyano-6-(benzylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-9)

[0277] Using intermediate B5-9 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 123 mg of crude product as white solid with a yield of 9%. The product was directly used for the next step without purification.

[0278] Example 90. Synthesis of tert-butyl 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-10)

[0279] Using intermediate B5-10 and intermediate iiia as raw materials, the preparation method was the same as B6-1, and the crude product was obtained as a white solid of 170 mg, with a yield of 14%. It was directly carried out to the next step without purification. ESI-MS m / z: 422.1 [M+H] + ,444.1[M+Na] + .

[0280] Example 91. Synthesis of tert-butyl 1-{4-cyano-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}}-5-amino-1H-pyrazole-4-carboxylate (B6-11)

[0281] Intermediate B5-11 and intermediate iiia were used as raw materials, and the preparation method was the same as B6-1 to obtain 170 mg of crude product as a white solid, with a crude product yield of 14%. The product was directly used for the next step without purification. ESI-MS m / z: 460.1 [M+H] + ,482.0[M+Na] + .

[0282] Example 92. Synthesis of tert-butyl 1-[(4-cyano-6-hydroxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-12)

[0283] Add intermediate B6-1 (300 mg, 0.948 mmol), LiCl (8 eq), and 2 mL of dry DMF to a 25 mL round-bottom flask, heat to 130°C, react for 1 h, monitor the completion of the reaction by TLC (dichloromethane: methanol = 1 mL: 1 drop), cool to room temperature, use a vacuum oil pump to decompress the excess DMF and spin dry, add water, adjust the pH to 3-4 with 1 M hydrochloric acid, filter, and dry to obtain 180 mg of a white solid with a yield of 63%. Mp 261.2-261.8°C. ESI-MS m / z: 301.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.71(s,1H),7.54(s,2H),7.03(s,1H),1.51(s,9H).

[0284] Example 93. Synthesis of tert-butyl 1-[(4-cyano-6-hydroxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-12)

[0285] Add intermediate B6-1 (300 mg, 0.948 mmol), LiCl (8 eq), and 2 mL of dry DMF to a 25 mL round-bottom flask, heat to 130°C, react for 1 h, monitor the completion of the reaction by TLC (dichloromethane: methanol = 1 mL: 1 drop), cool to room temperature, use a vacuum oil pump to decompress the excess DMF and spin dry, add water, adjust the pH to 3-4 with 1 M hydrochloric acid, filter, and dry to obtain 180 mg of a white solid with a yield of 63%. Mp 261.2-261.8°C. ESI-MS m / z: 301.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.71(s,1H),7.54(s,2H),7.03(s,1H),1.51(s,9H).

[0286] Example 94. Synthesis of tert-butyl 1-[(4-cyano-6-isobutylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-12a)

[0287] Take intermediate B6-12 as raw material, add 1.5 times amount of Carter condensation agent, 1.8 times amount of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1.8 times amount of isobutylamine, 10mL acetonitrile, heat to 70℃, add water and ethyl acetate to extract after the reaction is completed, collect the organic layer, wash twice with saturated salt solution, add anhydrous sodium sulfate to dry, filter and concentrate, column chromatography (petroleum ether: ethyl acetate), concentrate to obtain 30mg of white solid, yield 30%. Mp 164.5-166.2℃. 1 H NMR(400MHz,Chloroform-d)δ7.73(s,1H),7.31(s,2H),6.55(s,1H),6.05(s,1H) ,3.09(t,J=6.3Hz,2H),1.92(q,J=6.6Hz,1H),1.56(s,9H),1.01(d,J=6.7Hz,6H).

[0288] Example 95. Synthesis of tert-butyl 1-{4-cyano-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-13)

[0289] Using intermediate B5-13 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 156 mg of light yellow solid is obtained, with a yield of 13%. Mp 177.9-178.9℃.ESI-MS m / z:392.1[M+H] + ,414.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.40(s,1H),7.67(s,1H),7.63(s,2H),7.32(s,2H),7.08–6.97(m,3H),3.78(s,3H),1.51(s,9H).

[0290] Example 96. Synthesis of tert-butyl 1-{4-cyano-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-14)

[0291] Using intermediate B5-14 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 148 mg of white solid is obtained, with a yield of 12%. Mp 143.6-144.5℃.ESI-MS m / z:408.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.48(s,1H),7.69(s,1H),7.60(s,2H),7.36(s,2H),7.24(d,J=7.9Hz,2H),7.08(s,1H),2.31(s,3H),1.51(s,9H).

[0292] Example 97. Synthesis of tert-butyl 1-{4-cyano-6-[(4-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-15)

[0293] Using intermediate B5-15 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 166 mg of white solid is obtained, with a yield of 13%. Mp 256.5-256.9℃.ESI-MS m / z: 396.0[M+H] + ,418.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.56(s,1H),7.96–7.69(m,2H),7.69(s,1H),7.37(s,2H),7.27(t,J=8.8Hz,2H),7.10(s,1H),1.51(s,9H).

[0294] Example 98. Synthesis of tert-butyl 1-{4-cyano-6-[(4-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-16)

[0295] Using intermediate B5-16 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 184 mg of light yellow solid is obtained, with a yield of 15%. Mp 243.2-243.7℃.ESI-MS m / z:411.9[M+H] + ,434.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.64(s,1H),7.75(s,2H),7.70(s,1H),7.50–7.45(m,2H),7.45–7.34(m,2H),7.15(s,1H),1.51(s,9H).

[0296] Example 99. Synthesis of tert-butyl 1-{4-cyano-6-[(4-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-17)

[0297] Using intermediate B5-17 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 178 mg of crude product as white solid with a yield of 13%. It was directly carried out to the next step without purification. ESI-MS m / z: 477.9 [M+H] + .

[0298] Example 100. Synthesis of tert-butyl 1-{4-cyano-6-[(2-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-18)

[0299] Using intermediate B5-18 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 167 mg of white solid is obtained, with a yield of 14%. Mp 216.7-216.8℃.ESI-MS m / z: 392.2[M+H] + ,414.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.18(s,1H),7.63(s,1H),7.47–6.92(m,7H),2.23(s,3H),1.49(s,9H).

[0300] Example 101. Synthesis of tert-butyl 1-{4-cyano-6-[(3-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-19)

[0301] Using intermediate B5-19 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 156 mg of yellow solid is obtained, with a yield of 13%. Mp 213.2-213.7℃.ESI-MS m / z: 392.2[M+H] + ,414.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.50(s,1H),7.69(s,1H),7.59–7.25(m,5H),7.12(s,1H),7.01(d,J=7.5Hz,1H),2.34(s,3H),1.51(s,9H).

[0302] Example 102. Synthesis of tert-butyl 1-{4-cyano-6-[(2-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (A6-20)

[0303] Using intermediate B5-20 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 146 mg of crude yellow solid product with a yield of 12%. It was directly carried out to the next step without purification. ESI-MS m / z: 408.2 [M+H] + ,430.2[M+Na] + .

[0304] Example 103. Synthesis of tert-butyl 1-{4-cyano-6-[(3-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-21)

[0305] Using intermediate B5-21 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 156 mg of white solid is obtained, with a yield of 13%. Mp 146.9-147.7℃.ESI-MS m / z:408.2[M+H] + ,430.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.56(s,1H),8.04–7.73(m,1H),7.69(s,1H),7.41(s,2H),7.30(t,J= 8.1Hz,1H),7.14(s,2H),6.73(d,J=8.2Hz,1H),3.82(s,3H),1.51(s,9H).

[0306] Example 104. Synthesis of tert-butyl 1-{4-cyano-6-[(2-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-22)

[0307] Using intermediate B5-22 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 173 mg of white solid is obtained, with a yield of 14%. Mp 190.1-190.6℃.ESI-MS m / z: 396.2[M+H] + ,418.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.45(s,1H),7.67(s,1H),7.42–7.27(m,4H),7.19(s,1H),1.50(s,9H).

[0308] Example 105. Synthesis of tert-butyl 1-{4-cyano-6-[(2-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-23)

[0309] Using intermediate B5-23 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 175 mg of white solid is obtained, with a yield of 14%. Mp 250.0-250.3℃.ESI-MS m / z:434.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.44(s,1H),7.71(d,J=7.9Hz,1H),7.65(s,1H),7.63(d,J=1.5Hz,1H),7.46(td,J =7.7,1.5Hz,1H),7.37(td,J=7.7,1.7Hz,1H),7.27(s,2H),7.12(s,1H),1.50(s,9H).

[0310] Example 106. Synthesis of tert-butyl 1-{4-cyano-6-[(3-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-24)

[0311] Using intermediate B5-24 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 169 mg of white solid is obtained, with a yield of 13%. Mp 247.1-248.3℃.ESI-MS m / z:412.2[M+H] + ,434.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.68(s,1H),8.03(s,1H),7.71(s,1H),7.63(d,J=8.0Hz,1H),7.43(t,J=8 .1Hz,1H),7.38(s,2H),7.22(dt,J=7.9,1.6Hz,1H),7.17(s,1H),1.52(s,9H).

[0312] Example 107. Synthesis of tert-butyl 1-{4-cyano-6-[(2-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-25)

[0313] Using intermediate B5-25 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 192 mg of white solid is obtained, with a yield of 16%. Mp 163.6-164.7℃. ESI-MS m / z: 478.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.67(s,1H),8.13(s,1H),7.70(s,2H),7.48–7.26(m,4H),7.16(s,1H),1.51(s,9H).

[0314] Example 108. Synthesis of tert-butyl 1-{4-cyano-6-[(3-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-26)

[0315] Using intermediate B5-26 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 201 mg of white solid is obtained, with a yield of 17%. Mp 161.7-162.1℃. ESI-MS m / z: 478.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.67(s,1H),8.14(s,1H),7.71(s,2H),7.47–7.27(m,4H),7.17(s,1H),1.52(s,9H).

[0316] Example 109. Synthesis of tert-butyl 1-{4-cyano-6-[(2,3-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-27)

[0317] Using intermediate B5-27 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 214 mg of crude yellow solid product with a yield of 17%. The product was directly processed to the next step without purification. ESI-MS m / z: 406.2 [M+H] + ,428.2[M+Na] + .

[0318] Example 110. Synthesis of tert-butyl 1-{4-cyano-6-[(2,6-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-28)

[0319] Using intermediate B5-28 and intermediate iiia as raw materials, the preparation method was the same as B6-1 to obtain 206 mg of crude yellow solid product with a yield of 16%. The product was directly processed to the next step without purification. ESI-MS m / z: 406.2 [M+H] + ,428.2[M+Na] + .

[0320] Example 111. Synthesis of tert-butyl 1-{4-cyano-6-[(3,5-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-29)

[0321] Using intermediate B5-29 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 215 mg of yellow solid is obtained, with a yield of 17%. Mp 189.0-189.7℃.ESI-MS m / z:406.2[M+H] + ,428.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.44(s,1H),7.68(s,1H),7.35(s,4H),7.10(s,1H),6.84(s,1H),2.29(s,6H),1.51(s,9H).

[0322] Example 112. Synthesis of tert-butyl 1-{4-cyano-6-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-30)

[0323] Using intermediate B5-30 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 236 mg of yellow solid is obtained, with a yield of 19%. Mp 241.7-242.5℃.ESI-MS m / z:438.2[M+H] + ,460.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.45(s,1H),7.99(s,1H),7.67(s,1H),7.38(s,2H),7.11–7.00(m,2H),6.98(d,J=8.2Hz,1H),3.83(s,3H),3.76(s,3H),1.51(s,9H).

[0324] Example 113. Synthesis of tert-butyl 1-{4-cyano-6-[(3,5-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-31)

[0325] Using intermediate B5-31 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 223 mg of yellow solid is obtained, with a yield of 18%. Mp 243.2-243.7℃.ESI-MS m / z:438.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.52(s,1H),7.69(s,1H),7.41(s,2H),7.33–6.89(m,3H),6.30(s,1H),3.79(s,6H),1.51(s,9H).

[0326] Example 114. Synthesis of tert-butyl 1-{4-cyano-6-[benzo(d)(1,3)dioxol-5-ylamino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-32)

[0327] Using intermediate B5-32 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 243 mg of yellow solid is obtained, with a yield of 19%. Mp 137.9-138.3℃. ESI-MS m / z: 422.2[M+H] + ,444.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.44(s,1H),7.69(s,1H),7.36(s,2H),7.05(s,1H),6.96(d,J=7.4Hz,2H),6.06(s,2H),3.32(s,2H),1.51(s,9H).

[0328] Example 115. Synthesis of tert-butyl 1-{[4-cyano-6-(naphthalen-2-ylamino)]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-33)

[0329] Using intermediate B5-33 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 275 mg of white solid is obtained, with a yield of 22%. Mp 166.7-167.5℃. ESI-MS m / z: 428.2[M+H] + ,450.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.79(s,1H),8.52(s,1H),7.98(d,J=8.8Hz,1H),7.90(t,J=9.1Hz,2H),7.79–7.63 (m,2H),7.57–7.51(m,1H),7.51–7.45(m,1H),7.41(s,2H),7.24(s,1H),1.52(s,9H).

[0330] Example 116. tert-Butyl 1-{4-cyano-6-[(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-34)

[0331] Using intermediate B5-33 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 120 mg of light yellow solid is obtained, with a yield of 12%. Mp 152.3-154.3℃. ESI-MS m / z: 458.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.71(s,1H),8.18(s,1H),7.72(s,1H),7.54–7.23(m,4H),7.15(s,1H),1.51(s,9H).

[0332] Example 117. tert-Butyl 1-{4-cyano-6-[(2,6-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-35)

[0333] Using intermediate B5-35 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 240 mg of white solid is obtained, with a yield of 19%. Mp 176.3-177.9℃. ESI-MS m / z: 438.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.11–9.77(m,1H),7.77–7.53(m,2H),7.32(t,J=8.4Hz,1H),7.17(s,0.49H),6 .96(s,1H),6.80(d,J=8.5Hz,2H),6.37(s,0.46H),3.79(s,6H),1.68–1.29(m,9H).

[0334] Example 118. tert-Butyl 1-{4-cyano-6-[(2,3-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-36)

[0335] Using intermediate B5-36 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 210 mg of white solid is obtained, with a yield of 17%. Mp 181.3-183.0℃.ESI-MS m / z:438.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.12(s,1H),7.74–7.17(m,5H),7.13(t,J=8.2Hz,1H),6.98(d,J=8.4Hz,1H),3.85(s,3H),3.73(s,3H),1.51(s,9H).

[0336] Example 119. tert-Butyl 1-{4-cyano-6-[(2,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-37)

[0337] Using intermediate B5-37 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 255 mg of white solid is obtained, with a yield of 21%. Mp 180.3-181.5℃. ESI-MS m / z: 438.3[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.22–9.79(m,1H),7.76–7.38(m,3H),7.34–7.04(m,2H),6.72(d,J=2.7Hz,1H),6.60(dd,J=8.7,2.7Hz,1H),3.85–3.78(m,6H),1.50(s,9H).

[0338] Example 120. tert-Butyl 1-{4-cyano-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-38)

[0339] Using intermediate B5-38 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 110 mg of white solid is obtained, with a yield of 15%. Mp 186.3-187.4℃.ESI-MS m / z:420.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.18–9.97(m,1H),7.72–7.44(m,2H),7.19(s,0.62H),7.09–6.95(m,2H),6 .75(s,1H),6.19(s,0.44H),2.28(s,3H),2.17–2.08(m,6H),1.55–1.44(m,9H).

[0340] Example 121. tert-Butyl 1-{4-cyano-6-[(3-cyanophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-39)

[0341] Using intermediate B5-33 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and 106 mg of white solid is obtained, with a yield of 18%. Mp 199.3-199.9℃.ESI-MS m / z:403.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.76(s,1H),8.37(s,1H),8.07–7.84(m,1H),7.68(s,1H),7.62–7.54(m,2H),7.36(s,2H),7.17(s,1H),1.52(s,9H).

[0342] Example 122. tert-Butyl 1-{4-cyano-6-{[(4,5-dimethyl)isoxazol-3-yl]amino}pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-40)

[0343] Using intermediate B5-33 and intermediate iiia as raw materials, the preparation method is the same as B6-1, and a light yellow solid of 100 mg is obtained with a yield of 19%. Mp 146.6-148.5℃.ESI-MS m / z:397.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),8.87–7.77(m,2H),7.69(s,1H),7.64–7.26(m,1H),2.35(s,3H),1.99(s,3H),1.52(s,9H).

[0344] Example 123. Synthesis of tert-butyl 1-(4-cyano-6-methoxypyrimidin-2-yl)-1H-pyrazole-4-carboxylate (A6-1)

[0345] The intermediate B6-1 (200 mg, 0.633 mmol), tert-butyl nitrite (130 mg, 0.001265 mol) and 5 mL of tetrahydrofuran were added to a 25 mL round-bottom flask, heated to 65 ° C, and reacted overnight. The reaction was monitored by thin layer chromatography (petroleum ether: ethyl acetate = 2: 1) and completed. It was cooled to room temperature, an equal volume of water was added, and ethyl acetate was extracted. The organic layer was collected, washed twice with saturated saline solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate), concentrated under reduced pressure, and dried to obtain 110 mg of a white solid with a yield of 58%. Mp 164.2-164.7 ° C. ESI-MS m / z: 302.1 [M+H] + ,324.0[M+Na] + .1 H NMR (400 MHz, DMSO-d 6 )δ8.97(d,J=0.7Hz,1H),8.18(d,J=0.7Hz,1H),7.76(s,1H),4.12(s,3H),1.54(s,9H).

[0346] Example 124. Synthesis of tert-butyl 1-[(4-cyano-6-dimethylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (A6-2)

[0347] Using intermediate B6-2 as the starting material, the preparation method was the same as A6-1 to obtain 109 mg of a white solid with a yield of 56%. Mp183.1-184.5℃.ESI-MS m / z:315.2[M+H] + ,337.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ8.86(s,1H),8.08(s,1H),7.45(s,1H),3.24(s,3H),3.15(s,3H),1.53(s,9H).

[0348] Example 125. Synthesis of tert-butyl 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (A6-4)

[0349] Using intermediate B6-4 as the starting material, the preparation method was the same as A6-1 to obtain 120 mg of white solid with a yield of 59%. Mp 201.4-203.0℃. 1 H NMR (400 MHz, DMSO-d 6 )δ8.85(s,1H),8.08(s,1H),7.27(s,1H),3.64(t,J=6.7Hz,2H),3.49(t,J=6.7Hz,2H),2.05–1.98(m,2H),1.98–1.91(m,2H),1.53(s,9H).

[0350] Example 126. Synthesis of tert-butyl 1-{4-cyano-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylate (A6-7)

[0351] Using intermediate B6-7 as the starting material, the preparation method was the same as A6-1 to obtain 124 mg of white solid with a yield of 57%. Mp 243.2-243.7℃. ESI-MS m / z: 368.9 [M+H] + ,391.1[M+Na]+ . 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(t,J=6.4Hz,1H),9.05(s,1H),8.11(s,1H),7.14(s,1H),4.51–4.43(m,2H),1.54(s,9H).

[0352] Example 127. Synthesis of tert-butyl 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (A6-8)

[0353] Using intermediate B6-8 as the starting material, the preparation method was the same as A6-1 to obtain 119 mg of white solid with a yield of 70%. Mp193.2-194.1℃. 1 H NMR (400 MHz, DMSO-d 6 )δ10.66(s,1H),8.77(s,1H),8.15(s,1H),7.76(s,2H),7.45–7.40(m,2H),7.24(s,1H),7.18(t,J=7.4Hz,1H),1.54(s,9H).

[0354] Example 128. Synthesis of tert-butyl 1-[4-cyano-6-(benzylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (A6-9)

[0355] Using intermediate B6-9 as the starting material, the preparation method was the same as A6-1 to obtain 117 mg of white solid with a yield of 68%. Mp183.2-183.5℃. 1 H NMR (400 MHz, DMSO-d 6 )δ9.05(t,J=5.6Hz,1H),8.81(s,1H),8.08(s,1H),7.41–7.33(m,4H),7.34–7.25(m,1H),7.06(s,1H),4.68(d,J=5.5Hz,2H),1.53(s,10H).

[0356] Example 129. Synthesis of tert-butyl 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylate (A6-10)

[0357] Using intermediate B6-10 as the starting material, the preparation method was the same as A6-1 to obtain 126 mg of white solid with a yield of 69%. Mp178.6-179.7℃.ESI-MS m / z:407.1[M+H] + ,429.1[M+Na] + .1 H NMR (400 MHz, DMSO-d 6 )δ8.96(t,J=5.9Hz,1H),8.84(s,1H),8.09(s,1H),7.35–7.29(m,2H),7.02(s ,1H),6.91(d,J=8.3Hz,2H),4.59(d,J=5.6Hz,2H),3.73(s,3H),1.53(s,9H).

[0358] Example 130. Synthesis of tert-butyl 1-{4-cyano-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}}-1H-pyrazole-4-carboxylate (A6-11)

[0359] Using intermediate B6-11 as the starting material, the preparation method was the same as A6-1 to obtain 124 mg of white solid with a yield of 54%. Mp173.2-174.4℃. 1 H NMR (400 MHz, DMSO-d 6 )δ9.16–9.08(m,1H),8.75(s,1H),8.08(s,1H),7.71(d,J=8.3Hz,2H),7.61(d,J=8.2Hz,2H),7.10(s,1H),4.79(d,J=5.7Hz,2H),1.52(s,9H).

[0360] Example 131. Synthesis of tert-butyl 1-[(4-cyano-6-methoxy)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-1)

[0361] Using intermediate B5-1 as the starting material, the preparation method was the same as C6-1 to obtain 169 mg of white solid with a yield of 12%. Mp 253.1-254.7℃. ESI-MS m / z: 331.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.94(s,1H),10.16(s,1H),7.05(s,1H),3.90(s,3H),2.19(s,3H),1.47(s,8H).

[0362] Example 132. Synthesis of tert-butyl 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-4)

[0363] Using intermediate B5-4 as the starting material, the preparation method was the same as C6-1 to obtain 201 mg of a white solid with a yield of 19%. Mp 243.2-243.7°C. ESI-MS m / z: 370.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.40(s,2H),7.13(s,1H),3.56(d,J=7.4Hz,2H),3.47(s,2H),2.24(s,3H),1.98(s,4H),1.52(s,9H).

[0364] Example 133. Synthesis of tert-butyl 1-[4-cyano-6-(piperidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-5)

[0365] Using intermediate B5-5 as the starting material, the preparation method was the same as C6-1 to obtain 195 mg of a white solid with a yield of 17%. Mp 213.2-215.1°C. ESI-MS m / z: 384.2 [M+H] + ,406.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ7.47(s,1H),7.33(s,2H),3.88–3.56(m,4H),2.24(s,3H),1.70–1.63(m,2H),1.58(d,J=4.8Hz,4H),1.52(s,9H).

[0366] Example 134. Synthesis of tert-butyl 1-[4-cyano-6-(morpholin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-6)

[0367] Using intermediate B5-6 as the starting material, the preparation method was the same as C6-1 to obtain 166 mg of crude product as a white solid with a yield of 14%. The product was directly used for the next step without purification.

[0368] Example 135. Synthesis of tert-butyl 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-8)

[0369] Using intermediate B5-8 as the starting material, the preparation method was the same as C6-1 to obtain 175 mg of white solid with a yield of 13%. Mp 270.8-271.2℃. 1 H NMR (400 MHz, DMSO-d 6)δ10.53(s,1H),7.67(s,2H),7.53–7.31(m,4H),7.20(t,J=7.5Hz,1H),7.09(s,1H),2.26(s,3H),1.52(s,9H).

[0370] Example 136. Synthesis of tert-butyl 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylate (D6-30)

[0371] Using intermediate D5-30 as the starting material, the preparation method was the same as C6-1 to obtain 260 mg of a white solid with a yield of 30%. The solid was directly used for the next step without purification.

[0372] Example 137. Synthesis of 1-(4-cyano-6-methoxypyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid (B7-1)

[0373] Add intermediate B6-1 (100 mg, 0.316 mmol) to a 10 mL round-bottom flask, add 2 mL of dichloromethane, 10 drops of acetonitrile, stir evenly, add 2 mL of trifluoroacetic acid, and stir at room temperature for 3 h. Monitor the reaction by thin layer chromatography (dichloromethane: methanol: glacial acetic acid = 1 mL: 1 drop: 1 drop). The reaction is complete, and the excess solvent is concentrated under reduced pressure at 0 ° C. Leave 0.5 mL of the reaction solution in the bottle, add 5 mL of water, and stir at room temperature for 30 minutes. Solid precipitates, filter, and dry to obtain a white crude product. The crude product is recrystallized with ethanol and water, and dried to obtain 60 mg of a white solid with a yield of 73%. Mp 153.8-155.2 ° C. ESI-MS m / z: 261.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.27(s,1H),7.79(s,1H),7.64(s,1H),7.39(s,2H),4.07(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ171.44,165.23,157.15,152.98,143.46,140.47,115.98,111.16,95.10,55.91.

[0374] Example 138. Synthesis of 1-[(4-cyano-6-dimethylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-2)

[0375] Using intermediate B6-2 as raw material, the preparation method is the same as B7-1, and 63 mg of white solid is obtained, with a yield of 75%. Mp 164.1-165.2℃. ESI-MS m / z: 274.0[M+H] + ,296.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.14(s,1H),7.71(s,1H),7.42–7.33(m,3H),3.18(s,3H),3.14(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.26,162.30,157.02,152.81,142.50,138.20,116.93,106.71,94.87,38.23,37.70.

[0376] Example 139. Synthesis of 1-[(4-cyano-6-isobutylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-3)

[0377] Using intermediate B6-12a as raw material, the preparation method is the same as B7-1, and 20 mg of white solid is obtained, with a yield of 66%. Mp 173.2-174.5℃. ESI-MS m / z: 302.1[M+H] + ,324.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 +D 2 O)δ7.70(s,0.69H),7.68(s,0.26H),7.20(s,29H),6.91(s,0.65H),3.19(d,J =6.9Hz,1H),3.08(d,J=7.0Hz,1H),1.92–1.83(m,1H),0.92(d,J=6.6Hz,6H). 13 C NMR (150 MHz, DMSO-d 6 )δ165.07,162.86,157.62,152.73,142.56,137.08,116.69,109.20,94.76,48.37,27.85,20.56.

[0378] Example 140. Synthesis of 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-4)

[0379] Using intermediate B6-4 as raw material, the preparation method was the same as B7-1 to obtain 66 mg of white solid with a yield of 78%. Mp 163.8-163.9℃.ESI-MS m / z: 300.0[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.13(s,1H),7.70(s,1H),7.40(s,2H),7.18(s,1H),3.57(t,J=6.6Hz,2H),3.48(t,J=6.6Hz,2H),2.03–1.93(m,4H). 13 C NMR (150 MHz, DMSO-d 6 )δ165.25,159.73,157.15,152.86,142.48,137.99,116.90,107.64,94.86,47.53,47.45,25.37,24.70.

[0380] Example 141. Synthesis of 1-[(4-cyano-6-morpholinyl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-6)

[0381] Using intermediate B6-6 as raw material, the preparation method is the same as B7-1, and 64 mg of white solid is obtained, with a yield of 75%. Mp 173.2-174.2℃. ESI-MS m / z: 261.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),7.71(s,1H),7.53(s,1H),7.32(s,2H),3.86–3.64(m,8H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.25,162.16,157.18,152.79,142.60,138.55,116.84,106.89,94.89,66.07.

[0382] Example 142. Synthesis of 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-8)

[0383] Using intermediate B6-8 as raw material, the preparation method is the same as B7-1, and 68 mg of white solid is obtained, with a yield of 80%. Mp 156.8-157.2℃. ESI-MS m / z: 322.1[M+H] + . 1H NMR (400 MHz, DMSO-d 6 )δ12.17(s,1H),10.55(s,1H),7.85–7.63(m,3H),7.49–7.36(m,4H),7.19(t,J=7.6Hz,1H),7.14(s,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.25,157.35,152.89,142.97,129.76,121.66,116.56,94.91.

[0384] Example 143. Synthesis of 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-10)

[0385] Using intermediate B6-10 as raw material, the preparation method is the same as B7-1, and 71 mg of white solid is obtained with a yield of 90%. Mp 168.2-169.4℃. 1 H NMR (400 MHz, DMSO-d 6 )δ8.98(t,J=6.0Hz,1H),7.71(s,1H),7.34(s,1H),7.32(s,1H),6.96(t,J =2.3Hz,1H),6.92(s,1H),6.90(s,1H),4.52(d,J=5.6Hz,2H),3.73(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.24,162.61,159.09,152.84,142.61,137.23,129.93,129.61,129.44,116.70,114.50,114.41,109.34,94.84,55.56,44.06.

[0386] Example 144. Synthesis of 1-{4-cyano-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-13)

[0387] Using intermediate B6-13 as raw material, the preparation method is the same as B7-1, and a light yellow solid of 70 mg is obtained with a yield of 91%. Mp163.8-165.2℃.ESI-MS m / z:352.0[M+H] + ,374.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6)δ12.15(s,1H),10.40(s,1H),7.74(s,1H),7.66(s,2H),7.45–7.27(m,2H),7.05(s,1H),7.00(d,J=8.6Hz,2H),3.78(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.24,157.42,152.87,142.86,123.21,116.63,114.92,110.24,94.87,55.77.

[0388] Example 145. Synthesis of 1-{4-cyano-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-14)

[0389] Using intermediate B6-14 as raw material, the preparation method is the same as B7-1, and 68 mg of white solid is obtained, with a yield of 82%. Mp 166.5-168.1℃.ESI-MS m / z: 336.1[M+H] + ,358.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),10.47(s,1H),7.75(s,1H),7.62(s,2H),7.39(s,2H),7.24(d,J=7.8Hz,2H),7.09(s,1H),2.31(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.26,152.86,142.91,130.19,121.47,116.60,94.91,21.01.

[0390] Example 146. Synthesis of 1-{4-cyano-6-[(4-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-15)

[0391] Using intermediate B6-15 as raw material, the preparation method is the same as B7-1, and 66 mg of white solid is obtained, with a yield of 77%. Mp 167.8-168.2℃. ESI-MS m / z: 340.1[M+H] + ,362.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6)δ12.17(s,1H),10.54(s,1H),7.75(s,3H),7.39(s,2H),7.28(t,J=8.8Hz,2H),7.10(s,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.22,157.32,152.88,142.98,123.50,116.53,116.34,94.91.

[0392] Example 147. Synthesis of 1-{4-cyano-6-[(4-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-16)

[0393] Using intermediate B6-16 as raw material, the preparation method is the same as B7-1, and 54 mg of light yellow solid is obtained, with a yield of 63%. Mp157.2-158.2℃.ESI-MS m / z:355.9[M+H] + ,378.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.15(s,1H),10.64(s,1H),7.87–7.66(m,3H),7.47(d,J=8.8Hz,2H),7.42(s,2H),7.15(s,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.21,157.27,152.88,143.06,129.62,116.50,94.94.

[0394] Example 148. Synthesis of 1-{4-cyano-6-[(4-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-17)

[0395] Using intermediate B6-17 as raw material, the preparation method is the same as B7-1, and 58 mg of white solid is obtained, with a yield of 66%. Mp 166.8-168.2℃. ESI-MS m / z: 399.9[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.18(s,1H),10.63(s,1H),7.84–7.67(m,3H),7.59(d,J=8.3Hz,2H),7.42(s,2H),7.15(s,1H). 13 C NMR (100 MHz, DMSO-d6 )δ165.26,161.11,157.26,152.86,143.08,137.86,132.51,123.42,116.50,95.01.

[0396] Example 149. Synthesis of 1-{4-cyano-6-[(2-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-18)

[0397] Using intermediate B6-18 as raw material, the preparation method is the same as B7-1, and 67 mg of white solid is obtained, with a yield of 87%. Mp 153.8-155.2℃.ESI-MS m / z: 336.1[M+H] + ,358.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.15(s,1H),10.16(s,1H),7.69(s,1H),7.41(s,1H),7.37(d,J=7.3Hz,1H),7.34–7.23(m,3H),2.24(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.26,157.44,152.87,142.73,135.72,134.13,131.63,127.45,126.47,116.59,94.81,18.19.

[0398] Example 150. Synthesis of 1-{4-cyano-6-[(3-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-19)

[0399] Using intermediate B6-19 as raw material, the preparation method is the same as B7-1, and 56 mg of yellow solid is obtained, with a yield of 73%. Mp 154.6-155.9℃.ESI-MS m / z: 336.1[M+H] + ,358.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),10.50(s,1H),7.75(s,1H),7.44–7.36(m,2H),7.31(t,J=7.8Hz,1H),7.13(s,1H),7.01(d,J=7.6Hz,1H),2.34(s,3H). 13 C NMR (100 MHz, DMSO-d6 )δ165.26,157.44,152.87,142.73,135.72,131.63,127.45,126.47,116.59,94.81,18.19.

[0400] Example 151. Synthesis of 1-{4-cyano-6-[(2-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-20)

[0401] Using intermediate B6-20 as raw material, the preparation method is the same as B7-1, and 66 mg of yellow solid is obtained, with a yield of 79%. Mp163.5.8-164.5℃.ESI-MS m / z:352.1[M+H] + ,374.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),10.07(s,1H),7.95(s,1H),7.71(s,1H),7.50–7.21(m,3 H),7.17(dd,J=8.3,1.3Hz,2H),7.03(td,J=7.6,1.4Hz,1H),3.85(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.27,157.29,152.86,142.81,121.22,116.64,94.81,56.14.

[0402] Example 152. Synthesis of 1-{4-cyano-6-[(3-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-21)

[0403] Using intermediate B6-21 as raw material, the preparation method is the same as B7-1, and 56 mg of white solid is obtained, with a yield of 67%. Mp 171.1-172.2℃.ESI-MS m / z: 352.2[M+H] + ,374.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.17(s,1H),10.54(s,1H),7.75(s,1H),7.42(s,2H),7.31(t,J=8.1Hz ,1H),7.23–7.15(m,1H),7.13(s,1H),6.73(d,J=8.2Hz,1H),3.82(s,3H). 13C NMR (100 MHz, DMSO-d 6 )δ165.25,160.32,157.25,152.86,142.97,130.37,116.56,94.93,55.66.

[0404] Example 153. Synthesis of 1-{4-cyano-6-[(2-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-22)

[0405] Using intermediate B6-22 as raw material, the preparation method is the same as B7-1, and 73 mg of white solid is obtained, with a yield of 85%. Mp 168.9-170.3℃. ESI-MS m / z: 340.1[M+H] + ,362.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.51(s,1H),7.95(s,1H),7.73(s,1H),7.43–7.21(m,6H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.28,161.14,157.19,152.85,143.07,140.21,131.55,127.42,122.41,116.47,95.05.

[0406] Example 154. Synthesis of 1-{4-cyano-6-[(2-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-23)

[0407] Using intermediate B6-23 as raw material, the preparation method is the same as B7-1, and 55 mg of white solid is obtained, with a yield of 64%. Mp 163.8-165.2℃.ESI-MS m / z: 356.0[M+H] + ,378.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.28(s,1H),10.41(s,1H),7.76–7.71(m,1H),7.71(s,1H),7.63(dd,J=8.0,1.5Hz, 1H),7.46(td,J=7.7,1.5Hz,1H),7.36(td,J=7.7,1.7Hz,1H),7.27(s,2H),7.14(s,1H). 13 C NMR (100 MHz, DMSO-d6 )δ165.23,162.42,157.30,152.87,142.92,139.45,134.45,130.76,128.78,128.00,116.49,94.85.

[0408] Example 155. Synthesis of 1-{4-cyano-6-[(3-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-24)

[0409] Using intermediate B6-24 as raw material, the preparation method is the same as B7-1, and 59 mg of white solid is obtained, with a yield of 68%. Mp 161.8-163.2℃. ESI-MS m / z: 356.1[M+H] + ,378.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.97(s,1H),10.67(s,1H),8.01(s,1H),7.76(s,1H),7.68(d,J=8.0Hz,1H),7.47–7.35(m,3H),7.21(dd,J=7.9,2.1Hz,1H),7.18(s,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.33,161.16,157.21,152.84,143.11,140.09,133.97,131.24,124.44,121.03,116.47,95.16.

[0410] Example 156. Synthesis of 1-{4-cyano-6-[(2-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-25)

[0411] Using intermediate B6-25 as raw material, the preparation method is the same as B7-1, and 52 mg of white solid is obtained, with a yield of 59%. Mp 163.4-165.8℃. ESI-MS m / z: 400.1[M+H] + ,422.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.18(s,1H),10.66(s,1H),8.11(s,1H),7.82–7.66(m,2H),7.46–7.30(m,4H),7.17(s,1H). 13C NMR (100 MHz, DMSO-d 6 )δ165.28,161.14,157.19,152.85,143.07,140.21,131.55,127.42,122.41,116.47,95.05.

[0412] Example 157. Synthesis of 1-{4-cyano-6-[(3-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-26)

[0413] Using intermediate B6-26 as raw material, the preparation method is the same as B7-1, and 61 mg of white solid is obtained, with a yield of 69%. Mp 169.8-170.2℃.ESI-MS m / z: 400.0[M+H] + ,422.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.17(s,1H),10.66(s,1H),8.11(s,1H),7.83–7.65(m,2H),7.45–7.32(m,4H),7.17(s,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.28,161.15,157.19,152.85,143.07,140.21,131.54,127.39,123.89,122.41,116.47,95.07.

[0414] Example 158. Synthesis of 1-{4-cyano-6-[(2,3-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-27)

[0415] Using intermediate B6-27 as raw material, the preparation method is the same as B7-1, and 54 mg of yellow solid is obtained, with a yield of 63%. Mp 188.9-190.2℃.ESI-MS m / z: 350.2[M+H] + ,372.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.15(s,1H),10.19(s,1H),7.68(s,1H),7.19(s,3H),6.96(s,1H),2.30(s,3H),2.12(s,3H). 13 C NMR (100 MHz, DMSO-d 6)δ165.26,157.45,152.89,142.70,126.74,124.39,116.61,94.80,20.60,14.53.

[0416] Example 159. Synthesis of 1-{4-cyano-6-[(2,6-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-28)

[0417] Using intermediate B6-28 as raw material, the preparation method is the same as B7-1, and 56 mg of yellow solid is obtained, with a yield of 65%. Mp 189.3-191.1℃. ESI-MS m / z: 350.2[M+H] + ,372.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.15(s,1H),10.19(s,1H),7.68(s,1H),7.19(s,3H),6.96(s,1H),2.30(s,3H),2.12(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.26,157.45,152.89,142.70,126.74,124.39,116.61,94.80,20.60,14.53.

[0418] Example 160. Synthesis of 1-{4-cyano-6-[(3,5-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-29)

[0419] Using intermediate B6-29 as raw material, the preparation method is the same as B7-1, and 55 mg of yellow solid is obtained, with a yield of 64%. Mp 187.8-189.0℃.ESI-MS m / z: 350.1[M+H] + ,372.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),10.43(s,1H),7.73(s,1H),7.56–7.19(m,4H),7.11(s,1H),6.84(s,1H),2.29(s,6H). 13 C NMR (100 MHz, DMSO-d 6)δ165.27,157.33,152.84,142.88,138.96,116.62,94.94,21.50.

[0420] Example 161. Synthesis of 1-{4-cyano-6-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-30)

[0421] Using intermediate B6-30 as raw material, the preparation method is the same as B7-1, and 66 mg of yellow solid is obtained, with a yield of 76%. Mp 201.4-203.6℃.ESI-MS m / z: 382.1[M+H] + ,404.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),10.44(s,1H),7.91(s,1H),7.73(s,1H),7.54–7.28(m,2H) ,7.10(s,1H),7.06(s,1H),6.98(d,J=8.1Hz,1H),3.83(s,3H),3.76(s,3H). 13 C NMR (150 MHz, DMSO-d 6 )δ165.24,160.51,157.28,152.82,149.19,145.95,142.86,137.27,132.12,116.65,112.85,112.56,110.38,106.36,94.88,56.16,55.98.

[0422] Example 162. Synthesis of 1-{4-cyano-6-[(3,5-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-31)

[0423] Using intermediate B6-31 as raw material, the preparation method is the same as B7-1, and 63 mg of yellow solid is obtained, with a yield of 73%. Mp 207.5-208.2℃. ESI-MS m / z: 382.1[M+H] + ,404.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.17(s,1H),10.51(s,1H),7.74(s,1H),7.43(s,2H),7.30–7.01(m,3H),6.30(s,1H),3.78(s,6H). 13C NMR (100 MHz, DMSO-d 6 )δ165.24,161.16,157.17,152.84,142.97,116.56,94.92,55.76.

[0424] Example 163. Synthesis of 1-{4-cyano-6-[benzo(d)(1,3)dioxol-5-ylamino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-32)

[0425] Using intermediate B6-32 as raw material, the preparation method is the same as B7-1, and 63 mg of yellow solid is obtained, with a yield of 72%. Mp 201.7-208.2℃. ESI-MS m / z: 366.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.11(s,1H),10.40(s,1H),7.71(s,1H),7.61(s,1H),7.35(s,2H),7.01(s,1H),6.98(s,1H),6.92(d,J=7.8Hz,1H),2.46(s,2H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.27,152.88,142.94,116.60,108.91,101.86,94.94.

[0426] Example 164. Synthesis of 1-{[4-cyano-6-(naphthalen-2-ylamino)]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-33)

[0427] Using intermediate B6-33 as raw material, the preparation method is the same as B7-1, and a white solid of 75 mg is obtained with a yield of 86%. Mp 210.2-212.2℃.ESI-MS m / z: 372.1[M+H] + ,394.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.19(s,1H),10.78(s,1H),8.48(s,1H),7.98(d,J=8.8Hz,1H),7.91(d,J=8.2Hz,1H),7.88(d,J=8. 0Hz,1H),7.80(s,1H),7.76(s,1H),7.54(ddd,J=8.2,6.8,1.4Hz,1H),7.51–7.36(m,3H),7.24(s,1H).13 C NMR (100 MHz, DMSO-d 6 )δ165.27,157.37,152.90,143.05,133.90,129.44,128.09,127.99,127.18,125.78,116.60,94.96.

[0428] Example 165. 1-{4-cyano-6-[(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-34)

[0429] Using intermediate B6-34 as raw material, the preparation method is the same as B7-1, and 59 mg of white solid is obtained, with a yield of 67%. Mp 184.1-185.5℃. ESI-MS m / z: 402.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.18(s,1H),10.69(s,1H),8.20(s,1H),7.78(s,1H),7.52–7.36(m,3H),7.32(d,J=8.6Hz,1H),7.14(s,1H). 13 C NMR (101 MHz, DMSO-d 6 )δ165.22,157.20,152.90,143.41,143.16,131.83,131.81,129.30,116.47,110.94,94.97.

[0430] Example 166. 1-{4-cyano-6-[(2,6-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-35)

[0431] Using intermediate B6-35 as raw material, the preparation method is the same as B7-1, and 60 mg of white solid is obtained, with a yield of 69%. Mp 184.1-185.2℃. ESI-MS m / z: 274.0[M+H] + ,382.2[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.03–9.81(m,1H),7.68(d,J=27.3Hz,2H),7.34(t,J=8.5Hz,1H),7.15( s,0.61H),6.94(s,1H),6.81(d,J=8.5Hz,2H),6.36(s,0.44H),3.78(s,6H). 13 C NMR (101 MHz, DMSO-d 6 )δ165.28,165.24,161.40,161.30,161.23,161.16,157.23,157.17,152.84,142.97,116.56,99.35,97.36,94.92,55.76.

[0432] Example 167. 1-{4-cyano-6-[(2,3-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-36)

[0433] Using intermediate B6-36 as raw material, the preparation method is the same as B7-1, and 55 mg of white solid is obtained, with a yield of 63%. Mp 184.5-185.7℃. ESI-MS m / z: 382.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.10(s,1H),10.08(s,1H),7.95–7.18(m,5H),7.14(t,J=8.2Hz,1H),6.97(d,J=8.2Hz,1H),3.85(s,3H),3.73(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ165.25,161.83,158.95,157.37,153.70,152.86,142.72,128.17,126.21,118.99,116.67,109.81,105.29,99.98,94.78,56.19,55.93.

[0434] Example 168. 1-{4-cyano-6-[(2,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-37)

[0435] Using intermediate B6-37 as raw material, the preparation method is the same as B7-1, and 68 mg of white solid is obtained, with a yield of 78%. Mp 187.3-188.2℃.ESI-MS m / z: 382.2[M+H] + .1 H NMR (400 MHz, DMSO-d 6 )δ12.13(s,1H),10.33–9.57(m,1H),7.70(s,1H),7.63(s,1H),7.32–7.10(m,2H ),6.72(d,J=2.7Hz,1H),6.60(dd,J=8.7,2.7Hz,1H),3.82(s,3H),3.81(s,3H). 13 C NMR (101 MHz, DMSO-d 6 )δ165.28,165.24,161.23,161.16,157.17,152.84,142.97,116.56,99.31,97.41,97.36,97.32,94.92,55.76.

[0436] Example 169. 1-{4-cyano-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-38)

[0437] Using intermediate B6-38 as raw material, the preparation method is the same as B7-1, and 40 mg of white solid is obtained, with a yield of 46%. Mp 174.2-175.9℃.ESI-MS m / z: 364.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.14(s,1H),7.76–7.39(m,2H),7.20(s,0.67H),7.09–6.94(m,2H),6.68(s,1H),6.14(s,0.33H),2.28(s,3H),2.18–2.03(m,6H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.20,163.47,162.24,157.59,152.86,142.66,140.09,138.75,137.17,135.99,135. 31,132.10,131.19,129.78,129.42,116.66,108.75,104.55,94.84,21.08,18.37,18.17.

[0438] Example 170. 1-{4-cyano-6-[(3-cyanophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-39)

[0439] Using intermediate B6-39 as raw material, the preparation method is the same as B7-1, and 56 mg of white solid is obtained, with a yield of 65%. Mp 180.1-182.0℃. ESI-MS m / z: 347.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.19(s,1H),10.80(s,1H),8.36(s,1H),7.99(d,J=6.6Hz,1H),7.76(s,1H),7.66–7.56(m,2H),7.41(s,2H),7.21(s,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.22,161.21,157.14,152.88,143.15,139.52,138.61,130.99,128.16,125.85,124.25,119.05,116.42,112.58,95.01.

[0440] Example 171. 1-{4-cyano-6-{[(4,5-dimethyl)isoxazol-3-yl]amino}pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-40)

[0441] Using intermediate B6-40 as raw material, the preparation method is the same as B7-1, and 61 mg of white solid is obtained, with a yield of 86%. Mp 167.4-167.9℃.ESI-MS m / z: 341.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),10.62(s,1H),7.75-8.14(m,3H),7.48(s,1H),2.35(s,3H),2.00(s,3H).

[0442] Example 172. Synthesis of 1-(4-cyano-6-hydroxypyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid (B7-12)

[0443] Using intermediate B6-12 as raw material, the preparation method is the same as B7-1, and 50 mg of white solid is obtained, with a yield of 61%. Mp 166.8-167.2℃.ESI-MS m / z: 247.0[M+H] + ,269.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6)δ7.74(s,1H),7.63(s,1H),7.58(s,2H),6.85(s,1H). 13 C NMR (150 MHz, DMSO-d 6 )δ165.12,152.85,142.85,137.81,135.03,120.06,116.86,115.70,94.93.

[0444] Example 173. Synthesis of 1-(4-cyano-6-methoxypyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid (A7-1)

[0445] Using intermediate A6-1 as the starting material, the preparation method is the same as B7-1, white solid 46 mg, yield 57%. Mp 153.8-155.2℃.ESI-MS m / z: 246.1[M+H] + ,268.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.95(s,1H),9.04(s,1H),8.21(s,1H),7.75(s,1H),4.12(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ171.87,163.49,155.24,144.68,141.22,133.47,118.77,112.90,56.08.

[0446] Example 174. Synthesis of 1-[(4-cyano-6-dimethylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-2)

[0447] Using intermediate A6-2 as the starting material, the preparation method was the same as B7-1 to obtain 43 mg of a white solid with a yield of 55%. Mp166.8-168.2℃.ESI-MS m / z:259.1[M+H] + ,281.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.81(s,1H),8.92(s,1H),8.11(s,1H),7.44(s,1H),3.24(s,3H),3.14(s,3H). 13 C NMR (100 MHz, DMSO-d 6)δ163.67,162.65,154.98,143.83,138.94,132.81,118.01,116.91,108.10,38.13,37.45.

[0448] Example 175. Synthesis of 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-4)

[0449] Using intermediate A6-4 as the starting material, the preparation method was the same as B7-1 to obtain 53 mg of white solid with a yield of 52%. Mp173.4-175.2℃.ESI-MS m / z:285.1[M+H] + ,307.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.80(s,1H),8.89(s,1H),8.10(s,1H),7.25(s,1H),3.63(t,J=6.8Hz,2H),3.48(t,J=6.7Hz,2H),2.04–1.91(m,4H). 13 C NMR (100 MHz, DMSO-d 6 )δ163.70,160.23,155.06,143.81,138.42,132.74,118.06,116.87,109.05,47.51,47.37,25.40,24.67.

[0450] Example 176. Synthesis of 1-{4-cyano-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid (A7-7)

[0451] Using intermediate A6-7 as the starting material, the preparation method was the same as B7-1 to obtain 47 mg of white solid with a yield of 49%. Mp167.8-169.1℃.ESI-MS m / z:313.1[M+H] + ,335.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.82(s,1H),9.14(s,1H),9.08(t,J=6.3Hz,1H),8.14(s,1H),7.14(s,1H),4.55–4.45(m,2H). 13 C NMR (100 MHz, DMSO-d 6)δ164.06,163.69,155.32,144.21,139.04,133.53,118.30,116.45,110.65.

[0452] Example 177. Synthesis of 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-8)

[0453] Using intermediate A6-8 as the starting material, the preparation method was the same as B7-1 to obtain 55 mg of a white solid with a yield of 57%. Mp168.9.8-169.9℃.ESI-MS m / z:307.1[M+H] + ,329.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),8.80(s,1H),8.17(s,1H),7.76(s,2H),7.48–7.39(m,2H),7.22(s,1H),7.17(t,J=7.4Hz,1H). 13 C NMR (100 MHz, DMSO-d 6 )δ163.66,155.36,144.20,138.46,132.64,129.56,121.28,118.59,116.52.

[0454] Example 178. Synthesis of 1-[4-cyano-6-(benzylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-9)

[0455] Using intermediate A6-9 as the starting material, the preparation method was the same as B7-1 to obtain 61 mg of white solid with a yield of 59%. Mp166.8-168.7℃.ESI-MS m / z:321.1[M+H] + ,343.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.87(s,1H),9.01(t,J=5.6Hz,1H),8.91(s,1H),8.11(s,1H),7.40–7.28(m,5H),7.05(s,1H),4.69(d,J=5.7Hz,2H). 13 C NMR (100 MHz, DMSO-d 6)δ163.65,163.24,143.94,138.51,137.99,132.92,128.98,128.29,127.77,118.06,110.79,44.44.

[0456] Example 179. Synthesis of 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid (A7-10)

[0457] Using intermediate A6-10 as the starting material, the preparation method was the same as B7-1 to obtain 67 mg of white solid with a yield of 77%. Mp169.8-169.7℃.ESI-MS m / z:351.1[M+H] + ,373.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.83(s,1H),8.98–8.90(m,2H),8.12(s,1H),7.33(d,J=8.6Hz,2H),7.02(s,1H),6.93–6.89(m,2H),4.61(d,J=5.6Hz,2H),3.73(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ163.67,163.07,159.06,143.94,137.91,132.93,130.33,129.74,118.06,116.69,114.37,110.77,55.56,43.93.

[0458] Example 180. Synthesis of 1-{4-cyano-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}}-1H-pyrazole-4-carboxylic acid (A7-11)

[0459] Using intermediate A6-11 as the starting material, the preparation method was the same as B7-1 to obtain 56 mg of white solid with a yield of 63%. Mp174.3-175.7℃.ESI-MS m / z:389.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.82(s,1H),9.09(t,J=5.9Hz,1H),8.88(s,1H),8.11(s,1H),7.71(d ,J=8.2Hz,2H),7.61(d,J=8.2Hz,2H),7.09(s,1H),4.81(d,J=5.7Hz,2H). 13C NMR (100 MHz, DMSO-d 6 )δ163.64,163.37,155.52,143.99,143.58,138.14,128.85,125.84,125.80,118.10,116.63,110.82,43.89.

[0460] Example 181. Synthesis of 1-[(4-cyano-6-methoxy)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-1)

[0461] Using intermediate C6-1 as raw material, the preparation method is the same as B7-1, and 55 mg of white solid is obtained, with a yield of 64%. Mp 164.6-166.5℃. ESI-MS m / z: 275.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.28(s,1H),7.59(s,1H),7.42(s,2H),4.06(s,3H),2.28(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ171.33,165.90,156.97,154.00,152.36,140.61,116.02,110.56,93.59,55.91,14.97.

[0462] Example 182. Synthesis of 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-4)

[0463] Using intermediate C6-4 as the starting material, the preparation method was the same as B7-1 to obtain 53 mg of white solid with a yield of 60%. Mp166.8-168.7℃.ESI-MS m / z:314.2[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.14(s,1H),7.44(s,2H),7.13(s,1H),3.56(t,J=6.5Hz,2H),3.47(t,J=6.6Hz,2H),2.25(s,3H),2.02–1.93(m,4H). 13 C NMR (100 MHz, DMSO-d 6)δ165.95,159.63,157.02,153.88,151.27,138.18,116.93,107.16,93.37,47.49,47.43,25.36,24.69,14.95.

[0464] Example 183. Synthesis of 1-[4-cyano-6-(piperidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-5)

[0465] Using intermediate C6-5 as the starting material, the preparation method was the same as B7-1 to obtain 55 mg of a white solid with a yield of 59%. Mp178.3-179.7℃.ESI-MS m / z:328.1[M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.11(s,1H),7.47(s,1H),7.36(s,2H),3.88–3.51(m,4H),2.25(s,3H),1.69–1.53(m,6H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.95,161.43,157.21,153.78,151.23,138.63,116.98,106.31,93.38,25.69,24.25,14.98.

[0466] Example 184. Synthesis of 1-[4-cyano-6-(morpholin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-6)

[0467] Using intermediate C6-6 as the starting material, the preparation method was the same as B7-1 to obtain 58 mg of white solid with a yield of 66%. Mp176.8-178.7℃.ESI-MS m / z:330.1[M+H] + ,352.0[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.14(s,1H),7.49(s,1H),7.35(s,2H),3.81–3.65(m,8H),2.25(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.25,162.16,157.18,152.79,142.60,138.55,116.84,106.89,94.89,66.07.

[0468] Example 185. Synthesis of tert-butyl 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C7-8)

[0469] Using intermediate C6-8 as the starting material, the preparation method was the same as B7-1 to obtain 60 mg of a white solid with a yield of 69%. Mp166.2-168.1℃.ESI-MS m / z:336.1[M+H] + ,358.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.16(s,1H),10.53(s,1H),7.67(s,2H),7.53–7.32(m,4H),7.20(t,J=7.4Hz,1H),7.09(s,1H),2.27(s,3H). 13 C NMR (100 MHz, DMSO-d 6 )δ165.97,157.17,153.86,151.66,129.82,122.06,116.60,93.41,15.12.

[0470] Example 186. Synthesis of 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid (D7-30)

[0471] Using intermediate D6-30 as the starting material, the preparation method was the same as B7-1 to obtain 62 mg of white solid with a yield of 74%. Mp163.1-164.6℃.ESI-MS m / z:382.2[M+H] + ,404.1[M+Na] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.18(s,1H),10.10(s,1H),8.81(s,1H),7.74(s,1H),7.54(s,1H),7.46(s ,2H),7.16(d,J=8.5Hz,1H),6.98(d,J=8.7Hz,1H),3.79(s,3H),3.78(s,3H).

[0472] Example 187. Preparation of Compound B7-38 Tablets

[0473] The formulation composition and content are shown in Table 1.

[0474]

[0475]

[0476] The coating solution prescription and content are shown in Table 2.

[0477]

[0478] Process: Mix the auxiliary materials that have passed through a 100-mesh sieve with the main drug through a 60-mesh sieve, make a soft material with 95% ethanol, granulate with a 18-mesh sieve, dry with ventilation at 60℃, granulate with a 16-mesh sieve and mix evenly with magnesium stearate, and punch tablets with a Φ6mm shallow concave.

[0479] Preparation of coating solution: Add an appropriate amount of 95% ethanol to a suitable container, start the mixer, and evenly add the prescribed amount of Opadry (03B28796) solid powder into the vortex, while trying to avoid powder floating on the liquid surface. If necessary, increase the speed to maintain an appropriate vortex. After all the Opadry (03B28796) has been added, reduce the stirring speed to make the vortex disappear, and continue stirring for 45 minutes.

[0480] Preparation of film-coated tablets: Place the tablet cores in a coating pan, maintain the temperature at 60°C ± 5°C, and coat the tablets.

[0481] Example 188. Study on the xanthine oxidase inhibitory activity of the target compound

[0482] 1. Test materials

[0483] 1.1 Reagents: xanthine oxidase (Sigma, USA), xanthine (98.0%, Anaiji), sodium pyrophosphate (99.0%, Tianjin Bodi Chemical Co., Ltd.), disodium ethylenediaminetetraacetate (99.0%, Tianjin Bodi Chemical Co., Ltd.)

[0484] 1.2 Instruments: electronic analytical balance (AR1140), electric constant temperature water bath (DK-98-1), microplate reader (Synergy H1)

[0485] 1.3 Test samples: positive drugs febuxostat, Y700, allopurinol and prepared compounds

[0486] 2. Test methods

[0487] 2.1 Preparation method

[0488] Preparation of buffer: 0.1mol / L sodium pyrophosphate, 0.3mmol / L disodium EDTA, pH 8.3

[0489] Compound solution preparation: Prepare the corresponding compound into a 10mM DMSO solution, then dilute it with buffer to the required concentration for testing

[0490] Preparation of xanthine solution: Accurately weigh 30.42 mg of xanthine, place in a 100 mL volumetric flask, first add 2 mL of 1 M sodium hydroxide solution to dissolve, then add buffer to dilute to the mark to obtain a mother solution with a concentration of 2000 μM. Dilute with buffer as needed. The concentration of xanthine solution for in vitro activity test is 500 μM

[0491] 2.2 Enzyme activity detection method

[0492] Add 40 μL of xanthine oxidase solution and 100 μL of inhibitor solution to a 96-well plate, incubate at 25°C for 15 minutes, then add 50 μL of xanthine solution (since the reaction starts as soon as xanthine is added, the sample should be added quickly and tested immediately to prevent the reaction rate from decreasing), and then measure the absorbance at 295 nm every 60 seconds for a total of 5 tests. The blank group uses the corresponding drug solvent as a control.

[0493] V = (A2-A1) / T inhibition rate = (v 空白 -v 测试 ) / v 空白 x 100%

[0494] Among them, A1: absorbance value obtained in the first test; A2: absorbance value obtained in the fifth test; T: test time, 5 minutes.

[0495] The initial screening concentration was 10 μM, and IC 50 test.

[0496] 2.2 Statistical methods

[0497] All data were analyzed using SPSS (17.0) statistical software package. The results were expressed as mean ± standard error, and the variance homogeneity analysis was performed for the comparison of means between groups, and Dunnett's test analysis method was used for comparison between groups.

[0498] 3. Experimental results:

[0499] The experimental results showed that all 50 synthesized target compounds showed strong xanthine oxidase inhibitory activity (experimental data see Table 3).

[0500] Table 3 Effects of target compounds on xanthine oxidase activity

[0501] Compound <![CDATA[IC 50 (μM, mean ± SD)]]> Compound <![CDATA[IC 50 (μM mean ± SD)]]> A7-1 NA B7-24 0.095±0.012 A7-2 NA B7-25 0.117±0.027 A7-4 NA B7-26 0.169±0.024 A7-7 2.260±0.094 B7-27 0.012±0.0014 A7-8 NA B7-28 0.011±0.0013 A7-9 NA B7-29 0.0210±0.0079 A7-10 NA B7-30 0.0069±0.0008 A7-11 NA B7-31 0.028±0.0065 B7-1 NA B7-32 0.0119±0.0050 B7-2 NA B7-33 0.0072±0.0036 B7-3 0.044±0.0036 B7-34 0.121±0.0008 B7-4 NA B7-35 0.351±0.245 B7-6 NA B7-36 0.0189±0.0061 B7-8 0.036±0.0027 B7-37 0.0113±0.0062 B7-10 0.470±0.092 B7-38 0.0034±0.0007 B7-12 0.047±0.022 B7-39 0.624±0.113 B7-13 0.017±0.0022 B7-40 0.028±0.0065 B7-14 0.017±0.0023 C7-1 NA B7-15 0.058±0.0055 C7-4 NA B7-16 0.051±0.0061 C7-5 NA B7-17 0.034±0.0046 C7-6 NA B7-18 0.015±0.0036 C7-8 1.074±0.048 B7-19 0.019±0.0053 D7-30 6.141±1.728 B7-20 0.0086±0.0026 Febuxostat 0.0066±0.0004 B7-21 0.027±0.0013 Y700 0.0074±0.0019 B7-22 0.017±0.0015 Allopurinol 3.091±1.540 B7-23 0.015±0.0067

[0502] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds and pharmaceutically acceptable salts, isomers, polymorphs or solvates thereof, characterized in that: The structure of the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound is shown in general formula I: wherein R1 is methoxy, dimethylamino, isobutylamino, pyrrolidinyl, piperidinyl, morpholinyl, trifluoroethylamino, phenylamino, benzylamino, 4-methoxybenzylamino, 4-trifluoromethylbenzylamino, 2-methoxyphenylamino, 3-methoxyphenylamino, 4-methoxyphenylamino, 2-methylphenylamino, 3-methylphenylamino, 4-methylphenylamino, 2-fluorophenylamino, 4-fluorophenylamino, 2-chlorophenylamino, 3-chlorophenylamino, 4-chlorophenylamino, 2-bromophenylamino, 3-bromophenylamino, 4-bromophenylamino, 2,3-dimethylphenylamino, 2,6-dimethylphenylamino, 3,5- One of dimethylaniline, 3,4-dimethoxyaniline, 3,5-dimethoxyaniline, 2,6-dimethoxyaniline, 2,3-dimethoxyaniline, 2,4-dimethoxyaniline, 2,4,6-trimethylaniline, benzo[d][1,3]dioxol-5-amino, 2,2-difluorobenzo[d][1,3]dioxol-5-amino, 3-cyanoaniline, and 4,5-dimethylisoxazole-3-amino; R2 is a hydrogen atom or a cyano group; R3 is a hydrogen atom or a cyano group; R4 is a hydrogen atom or an amino group; R5 is a hydrogen atom or a methyl group.

2. The 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound and its pharmaceutically acceptable salt, isomer, polymorph or solvate according to claim 1, characterized in that: The 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound is any one of the following compounds A7-1 to D7-30: A7-1: 1-(4-cyano-6-methoxypyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid; A7-2: 1-[4-cyano-6-(dimethylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid; A7-4: 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid; A7-7: 1-{4-cyano-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid; A7-8: 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid; A7-9: 1-[4-(Benzylamino)-6-cyanopyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid; A7-10: 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid; A7-11: 1-{4-cyano-6-{[4(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid; B7-1: 1-[4-cyano-6-methoxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid; B7-2: 1-[4-cyano-6-(dimethylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid; B7-3: 1-[4-cyano-6-(isobutylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid; B7-4; 1-[4-cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid; B7-6: 1-(4-cyano-6-morpholinopyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid; B7-8: 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid; B7-10: 1-{4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-12: 1-(4-cyano-6-hydroxypyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid; B7-13: 1-{4-cyano-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-14: 1-{4-cyano-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-15: 1-{4-cyano-6-[(4-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-16: 1-{4-cyano-6-[(4-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-17: 1-{4-cyano-6-[(4-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-18: 1-{4-cyano-6-[(2-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-19: 1-{4-cyano-6-[(3-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-20: 1-{4-cyano-6-[(2-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-21: 1-{4-cyano-6-[(3-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-22: 1-{4-cyano-6-[(2-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-23: 1-{4-cyano-6-[(2-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-24: 1-{4-cyano-6-[(3-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-25: 1-{4-cyano-6-[(2-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-26: 1-{4-cyano-6-[(3-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-27: 1-{4-cyano-6-[(2,3-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-28: 1-{4-cyano-6-[(2,6-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-29: 1-{4-cyano-6-[(3,5-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-30: 1-{4-cyano-6-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-31: 1-{4-cyano-6-[(3,5-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-32: 1-[4-Cyano-6-(benzo[d][1,3]dioxol-5-ylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid; B7-33: 1-[4-Cyano-6-(naphthalen-2-ylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid; B7-34: 1-{4-cyano-6-[(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-35: 1-{4-cyano-6-[(2,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-36: 1-{4-cyano-6-[(2,6-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-37: 1-{4-cyano-6-[(2,3-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-38: 1-{4-cyano-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-39: 1-{4-cyano-6-[(3-cyanophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; B7-40: 1-{4-cyano-6-{[(4,5-dimethyl)isoxazol-3-yl]amino}pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; C7-1: 1-(4-cyano-6-methoxypyrimidin-2-yl)-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid; C7-4: 1-[4-Cyano-6-(pyrrolidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid; C7-5: 1-[4-Cyano-6-(piperidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid; C7-6: 1-[(4-cyano-6-morpholinyl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid; C7-8: 1-[4-Cyano-6-(phenylamino)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid; D7-30: 1-{5-cyano-6-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid; 3. A method for preparing the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound and its pharmaceutically acceptable salt, isomer, polymorph or solvate as claimed in any one of claims 1 to 2, characterized in that: The following steps are involved: Route 1: Preparation of compounds A7-1, A7-2, A7-4, A7-7 to A7-11, B7-1 to B7-4, B7-6, B7-8, B7-10, B7-12 to B7-40, C7-1, C7-4 to C7-6, C7-8; Orotic acid is used as a starting material and dissolved in tetrahydrofuran, and reacted with N,N'-carbonyldiimidazole to prepare a mixed anhydride, and then ammonia water is added for condensation reaction to obtain the intermediate 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 2; The intermediate 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide 2 is subjected to a two-step chlorination and dehydration reaction in one pot to obtain the key intermediate 2,6-dichloropyrimidine-4-carbonitrile 3; The key intermediate 2,6-dichloropyrimidine-4-carbonitrile 3 is subjected to hydrocarbonization reaction with methanol or an amine derivative to obtain an intermediate 2-chloro-6-methoxypyrimidine-4-carbonitrile B4-1 and intermediate 2-chloropyrimidine-4-carbonitrile derivatives B4-1, B4-2, B4-4 to B4-11, B4-13 to B4-40 respectively; The intermediate 2-chloro-6-methoxypyrimidine-4-carbonitrile B4-1 and the intermediate 2-chloropyrimidine-4-carbonitrile derivatives B4-1, B4-2, B4-4 to B4-11, B4-13 to B4-40 are subjected to an aminolysis reaction with hydrazine hydrate to obtain the intermediate 2-hydrazinopyrimidine-4-carbonitrile B5-1, B5-2, B5-4 to B5-11, B5-13 to B5-40; Using tert-butyl cyanoacetate as a starting material, a Knoevenagel reaction is carried out with triethyl orthoformate (iia) or triethyl orthoacetate (iib) to obtain intermediates tert-butyl 2-cyano-3-ethoxyacrylate iiia and tert-butyl 2-cyano-3-ethoxybutenoate iiib, and then a cyclization reaction is carried out with the intermediates 2-hydrazinopyrimidine-4-carbonitrile B5-1, B5-2, B5-4 to B5-11, B5-13 to B5-40 to obtain intermediates B6-1, B6-2, B6-4, B6-6 to B6-11, B6-13 to B6-40; The intermediates B6-1, B6-2, B6-4, B6-6, B6-8, B6-10, B6-13 to B6-40 are cleaved by tert-butyl ester to obtain B series compounds 1-(4-cyano-6-substituted pyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid B7-1, B7-2, B7-4, B7-6, B7-8, B7-10, B7-13 to B7-40; At the same time, the intermediate B6-1 is demethylated to obtain the intermediate B6-12, and then the tert-butyl ester is cleaved to obtain the compound B7-12. At the same time, the intermediate B6-12 is condensed with isobutylamine to obtain the intermediate B6-12a, and then the tert-butyl ester is cleaved to obtain the compound B7-3; The intermediates B6-1, B6-2, B6-4, B6-7 to B6-11 are subjected to diazotization and dediazotization reaction with tert-butyl nitrite to obtain intermediates A6-1, A6-2, A6-4, A6-7 to A6-11, and then the tert-butyl ester is cleaved to obtain the target compounds of the A series, 1-(4-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid A7-1, A7-2, A7-4, A7-7 to A7-11; The intermediates B5-1, B5-4 to B5-6, B5-8 are subjected to cyclization reaction with the intermediate iiib to obtain the intermediates C6-1, C6-4 to C6-6, C6-8, and then the tert-butyl ester is cleaved to obtain the C series target compounds 1-(4-cyano-6-substituted pyrimidin-2-yl)-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid C7-1, C7-4 to C7-6, C7-8; Route 2: Preparation of compound D7-30; 2,4-dichloropyrimidine-5-carbonitrile D3 is used as a starting material and dissolved in tetrahydrofuran, and then subjected to alkylation reaction with 3,4-dimethoxyaniline to obtain 2-chloro-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D4-30; The 2-chloro-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D4-30 and hydrazine hydrate are mixed to perform an aminolysis reaction to obtain 2-hydrazine-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D5-30; The 2-hydrazino-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carbonitrile D5-30 is subjected to a cyclization reaction with tert-butyl 2-cyano-3-ethoxyacrylate iiia to obtain tert-butyl 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-2-yl}-1H-pyrazole-4-carboxylate D6-30, and then the tert-butyl ester is cleaved to obtain the target compound 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-2-yl}-1H-pyrazole-4-carboxylic acid D7-30; 4. The preparation method according to claim 3, characterized in that: In the route 1, the reagents and conditions include: (a) N,N'-carbonyldiimidazole, dry tetrahydrofuran, 25°C, 3h, the molar ratio of orotic acid: N,N'-carbonyldiimidazole: dry tetrahydrofuran is 1:1.2:5; (b) ammonia water, dichloromethane, -10°C, overnight, the molar ratio of orotic acid: ammonia water: dichloromethane is 1:2:5; (c) phosphorus oxychloride, 1,4-dioxane, 100°C, 8h, orotic acid: phosphorus oxychloride: The molar ratio of 1,4-dioxane: is 1:3:6; (d) substituted amine, tetrahydrofuran, 0°C or N,N-diisopropylethylamine, methanol, -10°C, the molar ratio of orotic acid: substituted amine: tetrahydrofuran: N,N-diisopropylethylamine: methanol is 1:1.05:10:2:10; (e) hydrazine hydrate, dry tetrahydrofuran, 25°C, the molar ratio of orotic acid: hydrazine hydrate: dry tetrahydrofuran is 1:2.2:5; (f) acetic anhydride, 1 25°C, 3h, nitrogen, the molar ratio of orotic acid: acetic anhydride is 1:1; (g) ethanol, reflux, the molar ratio of orotic acid: ethanol is 1:5; (h) tert-butyl nitrite, tetrahydrofuran, 65°C, overnight, the molar ratio of orotic acid: tert-butyl nitrite: tetrahydrofuran is 1:1.5:5; (i) trifluoroacetic acid, dichloromethane, acetonitrile, 25°C, the molar ratio of orotic acid: trifluoroacetic acid: dichloromethane: acetonitrile is 1:5:5:5; (j) Lithium chloride, N,N-dimethylformamide, 120°C, the molar ratio of orotic acid: lithium chloride: N,N-dimethylformamide is 1:10:5; (k) Carter condensation agent, 1,8-diazabicyclo[5.4.0]undec-7-ene, isobutylamine, acetonitrile, 70°C, the molar ratio of orotic acid: Carter condensation agent: 1,8-diazabicyclo[5.4.0]undec-7-ene: isobutylamine: acetonitrile is 1:1.5:2:1.5:

5.

5. The preparation method according to claim 3, characterized in that: In the second route, the reagents and conditions include: (a) 3,4-dimethoxyaniline, tetrahydrofuran, 0°C, 2,4-dichloropyrimidine-5-carbonitrile: 3,4-dimethoxyaniline: tetrahydrofuran in a molar ratio of 1:1.05:10; (b) hydrazine hydrate, dry tetrahydrofuran, 25°C, 2,4-dichloropyrimidine-5-carbonitrile: hydrazine hydrate: dry tetrahydrofuran in a molar ratio of 1:2.2:5; c) tert-butyl 2-cyano-3-ethoxyacrylate iiia, ethanol, reflux, the molar ratio of 2,4-dichloropyrimidine-5-carbonitrile: tert-butyl 2-cyano-3-ethoxyacrylate iiia: ethanol is 1:1.1:5; (d) trifluoroacetic acid, dichloromethane, acetonitrile, 25°C, the molar ratio of 2,4-dichloropyrimidine-5-carbonitrile: trifluoroacetic acid: dichloromethane: acetonitrile is 1:5:5:

5.

6. A pharmaceutical composition, characterized in that It includes the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound as described in any one of claims 1-2 and its pharmaceutically acceptable salt, isomer, polymorph or solvate and a pharmaceutically acceptable excipient, diluent or carrier.

7. The pharmaceutical composition according to claim 6, characterized in that The dosage form of the pharmaceutical composition includes one of capsule, tablet, powder, solution, suspension, syrup, aerosol and injection; The administration route of the pharmaceutical composition includes one of oral, nasal, transdermal, pulmonary and parenteral administration.

8. The pharmaceutical composition according to claim 6, characterized in that The mass percentage of 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds and pharmaceutically acceptable salts, isomers, polymorphs or solvates thereof in the pharmaceutical composition is 5% to 20%.

9. Use of a 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound as claimed in any one of claims 1 to 2 and a pharmaceutically acceptable salt, isomer, polymorph or solvate thereof, or a pharmaceutical composition as claimed in claim 6 in the preparation of a drug for treating and / or preventing hyperuricemia and gout.

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