1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds, their preparation methods and applications

Abstract

This invention discloses a 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound, its preparation method, and its applications, belonging to the field of pharmaceutical technology. This invention innovatively designs and synthesizes 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds, and tests the in vitro xanthine oxidase inhibitory activity of the synthesized target compounds. The results demonstrate that the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds prepared by this invention have an inhibitory effect on xanthine oxidase (XO). Furthermore, the preparation method of this invention is simple and easy to implement, and can be used to prepare drugs for the treatment and / or prevention of hyperuricemia and gout.

Description

Technical Field

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

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

[0003] The main cause of gout is an increase in uric acid levels due to increased uric acid production or decreased excretion. When uric acid levels exceed their solubility limit, they deposit in joints and soft tissues, causing inflammation. Uric acid is the final product of purine metabolism in the human body. Xanthine oxidase (XO), a key enzyme in purine metabolism, first oxidizes hypoxanthine to xanthine, which is then further oxidized to uric acid. Xanthine oxidase inhibitors generally bind to the catalytically active site at the molybdenum atom center, reversibly or irreversibly inhibiting xanthine oxidase activity, preventing substrate hydroxylation, reducing uric acid production, and lowering serum uric acid concentration, thus achieving the therapeutic effect of treating hyperuricemia.

[0004] Currently available xanthine oxidase inhibitors include allopurinol and febuxostat, but the variety is very limited and they have certain toxic side effects. Therefore, the development of highly effective and low-toxicity xanthine oxidase inhibitors has good application prospects. Summary of the Invention

[0005] The purpose of this invention is to overcome the above-mentioned defects in the prior art and provide a 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compound, 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 objectives, 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 their pharmaceutically acceptable salts, isomers, polymorphs, or solvates, wherein the structure of the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds is shown in general formula I:

[0008]

[0009] Wherein, R1 is methoxy, dimethylamino, isobutylamino, pyrrolyl, 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 the following: dimethylphenylamino, 3,4-dimethoxyphenylamino, 3,5-dimethoxyphenylamino, 2,6-dimethoxyphenylamino, 2,3-dimethoxyphenylamino, 2,4-dimethoxyphenylamino, 2,4,6-trimethylphenylamino, benzo[d][1,3]dioxacyclopentadien-5-amino, 2,2-difluorobenzo[d][1,3]dioxacyclopentadien-5-amino, 3-cyanophenylamino, 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 salts refer to the organic and inorganic salts of the compounds described in this invention, including but not limited to: salts of the carboxylic acid moiety, which may be alkali metal salts such as Li, Na, and K salts; alkaline earth metal salts such as Ca 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 salts may be acid addition salts, including but not limited to hydrochlorides, sulfates, nitrates, phosphates, perchlorates, borates, tartrates, maleates, citrates, succinates, palmitates, methanesulfonates, benzoates, benzenesulfonates, salicylates, glycerophosphates, ketoglutarate, ascorbic acid salts, etc.

[0011] The solvates include, but are not limited to, hydrates or those containing other crystalline solvents such as alcohols.

[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-cyanopyrimidine-2-yl]-1H-pyrazole-4-carboxylic acid;

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

[0020] A7-11: 1-{4-cyano-6-{[4(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}-1H-pyrazol-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-morpholinidin-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]dioxacyclopenten-5-ylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid;

[0049] B7-33: 1-[4-cyano-6-(naphth-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]dioxacyclopenten-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-morpholino)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazol-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] This invention also discloses a method for preparing 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds as described above, and their pharmaceutically acceptable salts, isomers, polymorphs, or solvates, comprising the following steps:

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

[0067] Starting with orotic acid dissolved in tetrahydrofuran, it reacts with N,N'-carbonyldiimidazole to prepare a mixed acid anhydride, which is then added with ammonia to carry out a condensation reaction to obtain 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 was subjected to a one-pot reaction of chlorination and dehydration with phosphorus oxychloride to obtain the key intermediate 2,6-dichloropyrimidine-4-carboxynitrile 3.

[0069] The key intermediate 2,6-dichloropyrimidine-4-carboxylon 3 was reacted with methanol or an amine derivative to obtain intermediate 2-chloro-6-methoxypyrimidine-4-carboxylon B4-1 and intermediate 2-chloropyrimidine-4-carboxylon derivatives B4-1, B4-2, B4-4 to B4-11, B4-13 to B4-40, respectively.

[0070] The intermediate 2-chloro-6-methoxypyrimidine-4-carboxynitrile B4-1 and the intermediate 2-chloropyrimidine-4-carboxynitrile derivatives B4-1, B4-2, B4-4 to B4-11, B4-13 to B4-40 were subjected to ammonolysis with hydrazine hydrate to obtain the intermediate 2-hydrazylpyrimidine-4-carboxynitrile B5-1, B5-2, B5-4 to B5-11, B5-13 to B5-40;

[0071] Starting with tert-butyl cyanoacetate, it undergoes a Knoevenagel reaction 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). Subsequently, it undergoes a cyclization reaction with the intermediates 2-hydrazinopyrimidin-4-carboxynitrile 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 were cleaved to obtain the 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] Meanwhile, intermediate B6-1 was demethylated to obtain intermediate B6-12, and then tert-butyl ester was cleaved to obtain compound B7-12. Intermediate B6-12 was then condensed with isobutylamine to obtain intermediate B6-12a, and then tert-butyl ester was cleaved to obtain compound B7-3.

[0074] Intermediates B6-1, B6-2, B6-4, B6-7 to B6-11 were subjected to diazotization and dediazotization reactions with tert-butyl nitrite to obtain intermediates A6-1, A6-2, A6-4, A6-7 to A6-11. Then, tert-butyl nitrite was cleaved to obtain the A series target compounds 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] Intermediates B5-1, B5-4 to B5-6, and B5-8 were cyclized with intermediate iiib to obtain intermediates C6-1, C6-4 to C6-6, and C6-8. Then, tert-butyl ester was 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, and C7-8.

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

[0077] Starting with 2,4-dichloropyrimidin-5-carboxynitrile D3 dissolved in tetrahydrofuran, and reacted with 3,4-dimethoxyaniline by alkylation reaction to obtain 2-chloro-4-[(3,4-dimethoxyphenyl)amino]pyrimidin-5-carboxynitrile D4-30;

[0078] The 2-chloro-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carboxylon D4-30 was mixed with hydrazine hydrate and subjected to ammonolysis to obtain 2-hydrazino-4-[(3,4-dimethoxyphenyl)amino]pyrimidine-5-carboxylon D5-30;

[0079] The 2-hydrazino-4-[(3,4-dimethoxyphenyl)amino]pyrimidin-5-carboxylon D5-30 was cyclized with tert-butyl 2-cyano-3-ethoxyacrylate IIIa to obtain tert-butyl 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid D6-30. Subsequently, the tert-butyl ester was cleaved to obtain the target compound 5-amino-1-{5-cyano-4-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid D7-30.

[0080]

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

[0082] Optionally, in Route Two, the reagents and conditions include: (a) 3,4-dimethoxyaniline, tetrahydrofuran, 0°C, with a molar ratio of 2,4-dichloropyrimidin-5-carboxynitrile:3,4-dimethoxyaniline:tetrahydrofuran of 1:1.05:10; (b) hydrazine hydrate, dry tetrahydrofuran, 25°C, with a molar ratio of 2,4-dichloropyrimidin-5-carboxynitrile:hydrazine hydrate:dry tetrahydrofuran of 1:2.2:5. (c) 2-Cyano-3-ethoxyacrylate tert-butyl ester IIIa, ethanol, reflux, the molar ratio of 2,4-dichloropyrimidin-5-carboxynitrile:2-cyano-3-ethoxyacrylate tert-butyl ester IIIa:ethanol is 1:1.1:5; (d) Trifluoroacetic acid, dichloromethane, acetonitrile, 25°C, the molar ratio of 2,4-dichloropyrimidin-5-carboxynitrile:trifluoroacetic acid:dichloromethane:acetonitrile is 1:5:5:5.

[0083] The present invention also discloses a pharmaceutical composition comprising the above-described 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds and their pharmaceutically acceptable salts, isomers, polymorphs or solvates, as well as pharmaceutically acceptable excipients, diluents or carriers.

[0084] Optionally, the pharmaceutical compositions of the present invention can be prepared by conventional methods, such as those 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 a suitable solid or liquid carrier, or be formed into an injection solution or suspension in a suitable sterile medium.

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

[0087] Optionally, the compositions of the present invention contain a compound of Formula I or a solvation thereof, and a pharmaceutically acceptable excipient, which may be a carrier or diluent, or diluted by a carrier, or packaged in a carrier, which may be in the form of capsules, sachets, paper, or other containers. When the carrier is used as a diluent, it may be a solid, semi-solid, or liquid substance, which may serve as a carrier, excipient, or medium for the active compound. The active compound may be absorbed in the form of a particulate solid in a container, such as a sachet. Some suitable carriers are water, salt solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, coconut oil, gelatin, lactose, gypsum powder, sucrose, cyclodextrin, amylose, 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 alcohol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone.

[0088] Optionally, the carrier or diluent may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, which may be used alone or mixed with wax.

[0089] Optionally, the formulation may also include one of a wetting agent, emulsifier, suspending agent, preservative, sweetener, and flavoring agent. The formulations of the present invention can be formulated using 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 compositions of the present invention may be sterile and may be mixed with excipients, emulsifiers, buffers and / or colorants, if desired, provided that they do not react with the active compound.

[0091] Optionally, the pharmaceutical composition can be administered via any route, provided that it effectively delivers the active pharmaceutical ingredient to the appropriate or desired site of activity, including oral, nasal, transdermal, pulmonary, and parenteral administration, such as rectal, reservoir, subcutaneous, intravenous, intraurethral, ​​intramuscular, intranasal, ophthalmic solution, or ointment, preferably via oral administration.

[0092] Optionally, if a solid carrier is used for oral administration, the formulation may be compressed into tablets, or encapsulated in powder or pellet form, or made into lozenges or sugar tablets; if a liquid carrier is used, the formulation may be a syrup, emulsion, soft gelatin capsule, or sterile injection, such as an aqueous or non-aqueous liquid suspension or solution.

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

[0094] Optionally, for parenteral administration, an injectable solution or suspension is particularly suitable, preferably an aqueous solution of the active compound in polyhydroxylated castor oil.

[0095] Optionally, the carrier for tablets, sugar-coated pills, or capsules may include lactose, corn starch, and / or potato starch. When a sweetened carrier is available, a syrup or syrup may be used.

[0096] The present invention also discloses the use of 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds as described above, and their pharmaceutically acceptable salts, isomers, polymorphs or solvates, or pharmaceutical compositions as described above, in the preparation of medicaments for the treatment and / or prevention of hyperuricemia and gout.

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

[0098] This invention innovatively designs and synthesizes 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds, and tests the in vitro xanthine oxidase inhibitory activity of the synthesized target compounds. The results demonstrate that the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid compounds prepared in this invention have the effect of inhibiting xanthine oxidase (XO). At the same time, the preparation method of this invention is simple and easy to implement, and can be used to prepare drugs for the treatment and / or prevention of hyperuricemia and gout. Detailed Implementation

[0099] The present invention will be further described below with reference to specific embodiments, but this does not limit the present invention in any way.

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

[0101] 100 g (0.7084 mol) of tert-butyl cyanoacetate, 157.6 g (1.0632 mol) of triethyl orthoformate, and 71.4 g (0.7084 mol) of acetic anhydride were added to a 500 mL round-bottom flask. The mixture was purged with nitrogen three times, then heated to 125 °C and reacted for 3 h. Thin-layer chromatography (dichloromethane:methanol = 1 mL:1 drop) was used to monitor the reaction completion. The mixture was cooled to room temperature, and excess solvent was concentrated under reduced pressure. An equal volume of water was added, and the mixture was extracted with ethyl acetate (200 mL x 2). 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, and the concentrate yielded a light yellow oil. The oil was placed in a cold trap (-10 °C), and 20 mL of n-hexane was added. The mixture was stirred for 30 minutes, and a solid precipitated. The solid was filtered, dried, and yielded 86 g of a light yellowish-white solid, 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 (400MHz, DMSO-d6) 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 cyano-3-ethoxybut-2-enoic acid (iiib)

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

[0104] Example 3.2 Synthesis of 6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxamide (2)

[0105] Orotic acid (40 g, 0.256 mol) and N,N'-carbonyldiimidazole (48 g, 0.277 mol) were added to a 250 mL round-bottom flask, followed by 160 mL of anhydrous tetrahydrofuran. The mixture was heated to 25 °C and reacted for 3 h. The reaction was confirmed by thin-layer chromatography (TLC) and then cooled to room temperature. 40 mL of ammonia and 40 mL of dichloromethane were added to a 500 mL three-necked flask and stirred for 10 min under a cold trap (-10 °C). The prepared mixed anhydride was then added dropwise to the solvent mixture while maintaining the temperature at approximately -5 °C. After the addition was complete, the mixture was stirred under a cold trap for another 30 min, then transferred to room temperature and allowed to react overnight. The reaction was confirmed by TLC. Excess solvent was concentrated under reduced pressure, and 100 mL of methanol was added to slurry the mixture. The slurry was filtered, dried, and yielded 20.8 g of a white solid (60% yield). Mp 258.5-259.2℃.ESI-MS m / z:156.0[M+H] + 178.0 [M+Na] + 153.9 [MH] - . 1 H NMR (400MHz, DMSO-d6) δ11.25(s,1H),10.53(s,1H),8.22(s,1H),7.97(s,1H),6.07(s,1H).

[0106] Example 4.2 Synthesis of 6-dichloropyrimidine-4-carboxynitrile (3)

[0107] Intermediate 2 (15.6 g, 0.1144 mol) was added to a 500 mL round-bottom flask, followed by 120 mL of 1,4-dioxane, and stirred until homogeneous. Then, 20 mL of phosphorus oxychloride was added dropwise under a cold trap. After the addition was complete, the temperature was raised to 100 °C, and the reaction was allowed to proceed for 8 h. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) was used to monitor the reaction until complete. The mixture was cooled to room temperature, and excess solvent was concentrated under reduced pressure. The reaction was quenched with ice water under a cold trap, and the mixture was extracted with ethyl acetate (150 mL x 2). The organic layer was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a black oily substance. Column chromatography (petroleum ether:ethyl acetate = 4:1) was performed, followed by concentration under reduced pressure and drying 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-carboxynitrile (B4-1)

[0109] Intermediate 3 (15 g, 0.0867 mol) was added to a 250 mL round-bottom flask, followed by 60 mL of methanol. The mixture was stirred for 10 minutes under a cold trap (-5 °C). Then, N,N-diisopropylethylamine (11.2 g, 0.0867 mol) was dissolved in 20 mL of methanol and added dropwise to the above reaction solution. The mixture was stirred at 0 °C for 30 minutes. Thin-layer chromatography (petroleum ether:ethyl acetate = 4:1) was used to monitor the completion of the reaction. An equal volume of water was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic layer was washed once with an equal volume of 0.5 M hydrochloric acid, twice with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a transparent oily solution. A small amount of petroleum ether was added under a cold trap and stirred for 10 minutes, resulting in the precipitation of a solid. The solid was filtered, dried, and yielded 7.5 g of a 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 (400MHz, DMSO-d6) δ7.27(s,1H),3.97(s,3H).

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

[0111] Intermediate 3 (5 g, 0.0289 mol) was added to a 100 mL round-bottom flask, followed by 20 mL of anhydrous tetrahydrofuran. The mixture was stirred for 10 minutes in an ice-water bath. Then, morpholine (1.3 g, 0.0289 mol) dissolved in 5 mL of anhydrous tetrahydrofuran was added dropwise to the above reaction solution. The mixture was stirred at 0 °C for 3 h. Thin-layer chromatography (petroleum ether: ethyl acetate = 4:1) confirmed the completion of the reaction. Excess tetrahydrofuran was concentrated under reduced pressure at room temperature, extracted with 30 mL of ethyl acetate, and the organic layer was collected. The layer was washed twice with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether: ethyl acetate) was performed, and the concentrated solid yielded 3.4 g of white solid (65% yield). Mp 159.4-159.5 °C. 1 H NMR (400MHz, DMSO-d6) δ7.47(s,1H),3.12(s,3H),3.10(s,3H).

[0112] Example 7.2 Synthesis of chloro-6-(pyrrolidone-1-yl)pyrimidin-4-carboxynitrile (B4-4)

[0113] Using intermediate 3 and pyrrolidine as raw materials, the preparation method was the same as B4-2, yielding 3.9 g of a white solid, with a yield of 65%. Mp 178.0-179.1℃. ESI-MS m / z: 209.1 [M+H] + 231.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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)pyrimidin-4-carboxynitrile (B4-5)

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

[0116] Example 9.2 Synthesis of chloro-6-morpholinopyrimidine-4-carboxynitrile (B4-6)

[0117] Using intermediate 3 and morpholine as raw materials, the preparation method was the same as B4-2, yielding 4.4 g of a white solid, with a yield of 68%. Mp 212.6-213.1℃. ESI-MS m / z: 225.0 [M+H] + . 1H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-7)

[0119] Using intermediate 3,2,2,2-trifluoroethylamine as a raw material, the preparation method was the same as B4-2, yielding 5.1 g of a 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 (400MHz, DMSO-d6) δ9.18 (s, 1H), 7.16 (s, 1H), 4.27 (q, J = 9.6Hz, 2H).

[0120] Example 11. Synthesis of 1,2-chloro-6-(phenylamino)pyrimidine-4-carboxynitrile (B4-8)

[0121] Using intermediate 3 and aniline as raw materials, the preparation method was the same as B4-2, yielding 5.3 g of a white solid, with a yield of 80%. Mp 167.2-168.1℃. ESI-MS m / z: 230.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-9)

[0123] Using intermediate 3 and benzylamine as raw materials, the preparation method was the same as B4-2, yielding 4.6 g of a white solid, with a yield of 65%. Mp 99.2-101.1℃. ESI-MS m / z: 245.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-10)

[0125] Using intermediate 3 and p-methoxybenzylamine as raw materials, the preparation method was the same as B4-2, yielding 6.3 g of a 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 (400MHz, DMSO-d6) 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-carboxynitrile (B4-11)

[0127] Using intermediate 3 and p-trifluoromethylbenzylamine as raw materials, the preparation method was the same as B4-2, yielding 6.6 g of a 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 (400MHz, DMSO-d6) 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-carboxynitrile (B4-13)

[0129] Using intermediate 3 and p-methoxyaniline as raw materials, the preparation method was the same as B4-2, yielding 5.1 g of a yellow solid, with a yield of 68%. Mp 168.2-169.6℃. ESI-MS m / z: 261.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-14)

[0131] Using intermediate 3 and p-methylaniline as raw materials, the preparation method was the same as B4-2, yielding 4.2 g of a white solid, with a yield of 69%. Mp 170.6-172.0℃. ESI-MS m / z: 245.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-15)

[0133] Using intermediate 3 and p-fluoroaniline as raw materials, the preparation method was the same as B4-2, yielding 3.84 g of a yellow solid, with a yield of 54%. Mp 189.2-190.0℃. ESI-MS m / z: 248.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-16)

[0135] Using intermediate 3 and p-chloroaniline as raw materials, the preparation method was the same as B4-2, yielding 3.95 g of a pale yellow solid, with a yield of 54%. Mp 161.2-163.0℃. ESI-MS m / z: 264.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-17)

[0137] Using intermediate 3 and p-bromoaniline as raw materials, the preparation method was the same as B4-2, yielding 2.8 g of a white solid, with a yield of 35%. Mp 144.3-146.0℃. ESI-MS m / z: 310.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-18)

[0139] Using intermediate 3 and o-methoxyaniline as raw materials, the preparation method was the same as B4-2, yielding 4.7 g of a yellow solid, with a yield of 63%. Mp 100.3-101.8℃. ESI-MS m / z: 216.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.17(s,1H),7.42–7.12(m,5H),2.20(s,3H).

[0140] Example 21. Synthesis of 1,2-chloro-6-[(3-methoxyphenyl)amino]pyrimidine-4-carboxynitrile (B4-19)

[0141] Using intermediate 3 and m-methoxyaniline as raw materials, the preparation method was the same as B4-2, yielding 5.6 g of a yellow solid, with a yield of 75%. Mp 106.3-107.5℃. ESI-MS m / z: 261.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-20)

[0143] Using intermediate 3 and o-methylaniline as raw materials, the preparation method was the same as B4-2, yielding 3.1 g of crude yellow solid (51% yield). It was proceeded directly 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-carboxynitrile (B4-21)

[0145] Using intermediate 3 and m-methylaniline as raw materials, the preparation method was the same as B4-2, yielding 3.94 g of crude yellow solid (65% yield). It was proceeded directly 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-carboxynitrile (B4-22)

[0147] Using intermediate 3 and o-fluoroaniline as raw materials, the preparation method was the same as B4-2, yielding 3.37 g of a white solid, with a yield of 47%. Mp 197.0-198.0℃. ESI-MS m / z: 248.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-23)

[0149] Using intermediate 3 and o-chloroaniline as raw materials, the preparation method was the same as B4-2, yielding 2.74 g of a white solid, with a yield of 37%. Mp 209.3-210.7℃. ESI-MS m / z: 248.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-24)

[0151] Using intermediate 3 and m-chloroaniline as raw materials, the preparation method was the same as B4-2, yielding 3.7 g of a pale yellow solid, with a yield of 50%. Mp 199.3-201.8℃. ESI-MS m / z: 248.8 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-25)

[0153] Using intermediate 3 and o-bromoaniline as raw materials, the preparation method was the same as B4-2, yielding 2.56 g of a white solid, with a yield of 32%. Mp 145.7-147.5℃. ESI-MS m / z: 331.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-26)

[0155] Using intermediate 3 and m-bromoaniline as raw materials, the preparation method was the same as B4-2, yielding 2.94 g of crude white solid (37% yield). It was directly proceeded to 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-carboxynitrile (B4-27)

[0157] Using intermediate 3,2,3-dimethylaniline as a starting material, the preparation method was the same as B4-2, yielding 5.4 g of a crude, light yellow solid, with a yield of 64%. It was proceeded directly 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-carboxynitrile (B4-28)

[0159] Using intermediate 3,2,6-dimethylaniline as a starting material, the preparation method was the same as B4-2, yielding 4.6g of crude yellow solid (55% yield). It was proceeded directly to the next step without purification. ESI-MS m / z: 259.1 [M+H] + .

[0160] Example 31. Synthesis of 1,2-chloro-6-[(3,5-dimethylphenyl)amino]pyrimidine-4-carboxynitrile (B4-29)

[0161] Using intermediate 3,3,5-dimethylaniline as a starting material, the preparation method was the same as B4-2, yielding 4.87 g of crude yellow solid (59% yield). It was proceeded directly to 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-carboxynitrile (B4-30)

[0163] Using intermediate 3,3,4-dimethoxyaniline as a starting material, the preparation method was the same as B4-2, yielding 3.46 g of a yellow solid, with a yield of 42%. Mp 214.3-215.8℃. ESI-MS m / z: 291.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-31)

[0165] Using intermediate 3,3,5-dimethoxyaniline as a starting material, the preparation method was the same as B4-2, yielding 3.78 g of a yellow solid, with a yield of 45%. Mp 216.1-217.5℃. ESI-MS m / z: 291.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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)dioxacyclopenten-5-yl)amino]pyrimidine-4-carboxylonitrile (B4-32)

[0167] Using intermediate 3,3,4-methylenedioxyaniline as a starting material, the preparation method was the same as B4-2, yielding 5.2 g of crude white solid (66% yield). It was directly proceeded to the next step without purification. ESI-MS m / z: 275.1 [M+H] + .

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

[0169] Using intermediate 3,2-aminonaphthalene as a raw material, the preparation method was the same as B4-2, yielding 5.47 g of crude white solid, with a yield of 68%. It was proceeded directly 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]dioxacyclopenten-5-yl)amino]pyrimidine-4-carboxylonitrile (B4-34)

[0171] Using intermediate 3,5-amino-2,2-difluoro-1,3-benzodioxane as a starting material, the preparation method was the same as B4-2, yielding 3.45 g of crude white solid (39% yield). It was directly proceeded 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-carboxynitrile (B4-35)

[0173] Using intermediate 3,2,6-dimethoxyaniline as a raw material, the preparation method was the same as B4-2, yielding 3.32 g of a pale yellow solid, with a yield of 40%. Mp 169.3-170.7℃. ESI-MS m / z: 291.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B4-36)

[0175] Using intermediate 3,2,3-dimethoxyaniline as a starting material, the preparation method was the same as B4-2, yielding 3.57 g of a crude, light yellow solid, with a yield of 43%. It was proceeded directly to the next step without purification. ESI-MS m / z: 291.1 [M+H] + .

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

[0177] Using intermediate 3,2,4-dimethoxyaniline as a starting material, the preparation method was the same as B4-2, yielding 3.29 g of a pale yellow solid, with a yield of 40%. It was directly proceeded to the next step 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-carboxynitrile (B4-38)

[0179] Using intermediate 3,2,4,6-trimethylaniline as a starting material, the preparation method was the same as B4-2, yielding 2.47 g of a crude, pale yellow solid, with a yield of 31%. It was proceeded directly to the next step without purification. ESI-MS m / z: 273.2 [M+H] + .

[0180] Example 41. Synthesis of 1,2-chloro-6-[(3-cyanophenyl)amino]pyrimidine-4-carboxynitrile (B4-39)

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

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

[0183] Using intermediate 3,3-amino-4,5-dimethylisoxazole as a raw material, the preparation method was the same as B4-2, yielding 2.99 g of crude white solid, with a yield of 42%. It was directly proceeded to the next step without purification.

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

[0185] Using intermediates D3 and 3,4-dimethoxyaniline as raw materials, the preparation method was the same as B4-2, yielding 3.5 g of a light yellow solid with a yield of 46%. It was directly proceeded to the next step without purification. 1 H NMR (400MHz, DMSO-d6) 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 44.2 Synthesis of hydrazino-6-methoxypyrimidine-4-carboxynitrile (B5-1)

[0187] Intermediate B4-1 (5 g, 0.0296 mol) was added to a 100 mL round-bottom flask, followed by 15 mL of anhydrous tetrahydrofuran. 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 reaction flask. The mixture was stirred at room temperature for 1 hour, resulting in the precipitation of a solid. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) confirmed the completion of the reaction. Excess tetrahydrofuran was concentrated under reduced pressure to obtain a pale yellow solid. 2 mL of ethanol and 1 mL of water were added, and the mixture was stirred for 20 minutes. The mixture was filtered and dried to obtain 3 g of a pale yellow solid, with a yield of 61%. Mp 115.3-115.8℃. ESI-MS m / z: 166.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-2)

[0189] Intermediate B4-2 (2.5 g, 0.0137 mol) was added to a 50 mL round-bottom flask, followed by 10 mL of anhydrous tetrahydrofuran. 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 reaction flask. The mixture was then transferred to room temperature and stirred for 4 hours. Thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) was used to monitor the completion of the reaction. Excess tetrahydrofuran was concentrated under reduced pressure, extracted with 20 mL of dichloromethane, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (dichloromethane: methanol) was performed, and the solid was concentrated under reduced pressure to obtain a pale yellow solid. This solid was then mixed with 2 mL of ethanol and 1 mL of water and stirred for 20 minutes. The mixture was filtered, dried, and yielded 1.2 g of a pale yellow-white solid, with a yield of 49%. Mp 121.4-123.1℃. 1 H NMR (400MHz, DMSO-d6) δ8.04(s,1H),6.56(s,1H),4.11(s,2H),3.04(s,6H).

[0190] Example 46.2 Synthesis of hydrazyl-6-(pyrrolidone-1-yl)pyrimidine-4-carboxynitrile (B5-4)

[0191] Using intermediate B4-4 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.4 g of a white solid, with a yield of 50%. Mp 132.8-133.9℃. ESI-MS m / z: 205.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) 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 47.2 Synthesis of hydrazyl-6-(piperidin-1-yl)pyrimidine-4-carboxynitrile (B5-5)

[0193] Using intermediate B4-5 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.6 g of a white solid, with a yield of 54%. Mp 129.6-131.5℃. ESI-MS m / z: 219.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 48.2 Synthesis of hydrazino-6-morpholinylpyrimidine-4-carboxynitrile (B5-6)

[0195] Using intermediate B4-6 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.4 g of a white solid, with a yield of 47%. Mp 117.1-118.5℃. ESI-MS m / z: 221.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),6.71(s,1H),4.14(s,2H),3.65–3.59(m,8H).

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

[0197] Using intermediate B4-7 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.8 g of a white solid, with a yield of 51%. Mp 159.6-161.3℃. ESI-MS m / z: 233.0 [M+H] + 255.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-8)

[0199] Using intermediate B4-8 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.5 g of a white solid, with a yield of 45%. Mp 195.9-196.5℃. ESI-MS m / z: 227.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-9)

[0201] Using intermediate B4-9 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.3 g of a white solid, with a yield of 42%. Mp 208.3-210.1℃. ESI-MS m / z: 241.0 [M+H] + 263.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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-hydrazyl-6-[(4-methoxybenzyl)amino]pyrimidine-4-carboxynitrile (B5-10)

[0203] Using intermediate B4-10 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.7 g of a white solid, with a yield of 52%. Mp 186.7-186.9℃. ESI-MS m / z: 271.1 [M+H] + 293.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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-hydrazyl-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidine-4-carboxynitrile (B5-11)

[0205] Using intermediate B4-11 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.5 g of a white solid, with a yield of 50%. Mp 203.8-204.5℃. ESI-MS m / z: 309.1 [M+H] + 306.9 [MH] - . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-13)

[0207] Using intermediate B4-13 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.5 g of a pale yellow solid, with a yield of 43%. Mp 218.5-219.6℃. ESI-MS m / z: 241.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-14)

[0209] Using intermediate B4-14 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.4 g of a white solid, with a yield of 42%. Mp 176.9-178.5℃. ESI-MS m / z: 257.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-15)

[0211] Using intermediate B4-15 and hydrazine hydrate as raw materials, the preparation method was the same as for B5-2, yielding 1.6 g of a white solid. Yield: 47%. Mp: 169.9-171.5℃. ESI-MS m / z: 245.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-16)

[0213] Using intermediate B4-16 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.8 g of a pale yellow solid, with a yield of 51%. Mp 219.7-220.8℃. ESI-MS m / z: 261.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-17)

[0215] Using intermediate B4-17 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.8 g of a white solid, with a yield of 43%. Mp 155.4-156.7℃. ESI-MS m / z: 305.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-18)

[0217] Using intermediate B4-18 and hydrazine hydrate as raw materials, the preparation method was the same as for B5-2, yielding 1.7 g of crude white solid (49% yield). It was proceeded directly 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-carboxynitrile (B5-19)

[0219] Using intermediate B4-19 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.6 g of a yellow solid, with a yield of 46%. Mp 147.9-149.5℃. ESI-MS m / z: 241.1 [M+H] + 263.2 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)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-carboxynitrile (B5-20)

[0221] Using intermediate B4-20 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.4 g of a yellow solid, with a yield of 42%. Mp 153.7-154.1℃. ESI-MS m / z: 257.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-21)

[0223] Using intermediate B4-21 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.6 g of a white solid, with a yield of 48%. Mp 156.2-158.1℃. ESI-MS m / z: 257.1 [M+H] +279.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-22)

[0225] Using intermediate B4-22 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.7 g of a white solid, with a yield of 50%. Mp 168.6-168.7℃. ESI-MS m / z: 245.1 [M+H] + 266.9 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-23)

[0227] Using intermediate B4-23 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.7 g of a white solid, with a yield of 48%. Mp 191.9-192.7℃. ESI-MS m / z: 261.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)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-carboxynitrile (B5-24)

[0229] Using intermediate B4-24 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.7 g of a white solid, with a yield of 48%. Mp 211.0-211.4℃. ESI-MS m / z: 261.1 [M+H] + 283.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-25)

[0231] Using intermediate B4-25 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.9 g of a white solid, with a yield of 51%. Mp 149.7-150.4℃. ESI-MS m / z: 305.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)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-carboxynitrile (B5-26)

[0233] Using intermediate B4-26 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 2.0 g of a white solid, with a yield of 54%. Mp 152.3-152.4℃. ESI-MS m / z: 305.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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-carboxynitrile (B5-27)

[0235] Using intermediate B4-27 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 2.4 g of a yellow solid, with a yield of 70%. Mp 173.5-174.1℃. ESI-MS m / z: 255.1 [M+H] + 277.1 [M+Na] + . 1 H NMR(400MHz, DMSO-d6)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-carboxynitrile (B5-28)

[0237] Using intermediate B4-28 and hydrazine hydrate as raw materials, the preparation method was the same as for B5-2, yielding 2.6g of crude yellow solid (75% yield). This crude product was proceeded directly 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-carboxynitrile (B5-29)

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

[0240] Example 7. Synthesis of 1,2-hydrazino-6-[(3,4-dimethoxyphenyl)amino]pyrimidine-4-carboxynitrile (B5-30)

[0241] Using intermediate B4-30 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 2.3 g of a yellow solid, with a yield of 59%. Mp 125.8-125.9℃. ESI-MS m / z: 287.2 [M+H] + 309.1 [M+Na] + .1 H NMR (400MHz, DMSO-d6) 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-hydrazyl-6-[(3,5-dimethoxyphenyl)amino]pyrimidine-4-carboxynitrile (B5-31)

[0243] Using intermediate B4-31 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 2.2 g of a yellow solid, with a yield of 58%. Mp 128.3-128.9℃. ESI-MS m / z: 287.2 [M+H] + 309.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)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 73.2 Synthesis of hydrazyl-6-[benzo(d)(1,3)dioxacyclopenten-5-ylamino]-4-carboxynitrile (B5-32)

[0245] Using intermediate B4-32 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 2.3 g of a yellow solid, with a yield of 62%. Mp 223.6-224.9℃. ESI-MS m / z: 271.1 [M+H] + 293.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 74.2 Synthesis of hydrazyl-6-(naphth-2-ylamino)pyrimidine-4-carboxynitrile (B5-33)

[0247] Using intermediate B4-33 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 2.5 g of a white solid, with a yield of 66%. Mp 198.2-198.5℃. ESI-MS m / z: 277.1 [M+H] + 299.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)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]dioxacyclopenten-5-yl)amino]pyrimidine-4-carboxylonitrile (B5-34)

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

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

[0251] Using intermediate B4-35 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.8 g of a white solid, with a yield of 46%. Mp 166.3-167.4℃. ESI-MS m / z: 287.2 [M+H] + .

[0252] Example 77.2 Synthesis of hydrazyl-6-[(2,3-dimethoxyphenyl)amino]pyrimidine-4-carboxynitrile (B5-36)

[0253] Using intermediate B4-36 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.1 g of a white solid, with a yield of 28%. Mp 166.7-168.1℃. ESI-MS m / z: 287.2 [M+H] + .

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

[0255] Using intermediate B4-37 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.3 g of a white solid, with a yield of 33%. Mp 171.3-173.2℃. ESI-MS m / z: 287.2 [M+H] + .

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

[0257] Using intermediate B4-38 and hydrazine hydrate as raw materials, the preparation method was the same as for B5-2, yielding 1.1 g of a crude, pale yellow solid (25% yield). It was proceeded directly 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-carboxynitrile (B5-39)

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

[0260] Example 8. Synthesis of 1,2-hydrazino-6-[(4,5-dimethylisoxazol-3-yl)amino]pyrimidine-4-carboxynitrile (B5-40)

[0261] Using intermediate B4-40 and hydrazine hydrate as raw materials, the preparation method was the same as for B5-2, yielding 1.2 g of a crude, pale yellow solid, with a yield of 49%. It was proceeded directly to the next step without purification. ESI-MS m / z: 246.3 [M+H] + .

[0262] Example 82.2-Hydroxy-4-[(3,4-dimethoxyphenyl)amino]-pyrimidine-5-carboxynitrile (D5-30)

[0263] Using intermediate D4-30 and hydrazine hydrate as raw materials, the preparation method was the same as that for B5-2, yielding 1.1 g of crude product, a light yellow solid, with a yield of 42%. 1 H NMR (400MHz, DMSO-d6) 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 83.1 - Synthesis of [(4-cyano-6-methoxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-1)

[0265] Intermediate B5-1 (3 g, 0.0182 mol) was added to a 50 mL round-bottom flask, followed by 10 mL of ethanol. Intermediate IIIa (3.58 g, 0.0182 mol) was then added dropwise. The mixture was heated to 80 °C and reacted for 5 h. Thin-layer chromatography (petroleum ether: ethyl acetate = 2:1) was used to monitor the reaction completion. The mixture was cooled to room temperature, and the residual solvent was concentrated under reduced pressure. 20 mL of water was added, followed by extraction with 30 mL of ethyl acetate. The organic layer was collected, washed twice with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether: ethyl acetate) was performed, and the concentrated product yielded a pale yellow crude product. After drying, the crude product was recrystallized from ethanol and water, filtered, and dried to give 1.25 g of a white solid, with a yield of 22%. Mp 153.6-157.8 °C. 1 H NMR (400MHz, DMSO-d6) δ7.73(s,1H),7.64(s,1H),7.36(s,2H),4.07(s,3H),1.52(s,9H).

[0266] Example 84.1 Synthesis of [(4-cyano-6-dimethylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-2)

[0267] Using intermediates B5-2 and iiia as raw materials, the preparation method was the same as for B6-1. 100 mg of white solid was obtained, with a yield of 11%. Mp 213.6-214.9℃. ESI-MS m / z: 330.2 [M+H] + 352.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 85.1 Synthesis of tert-butyl 4-[4-cyano-6-(pyrrolidone-1-yl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylate (B6-4)

[0269] Using intermediates B5-4 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 156 mg of a white solid, with a yield of 11%. Mp 167.2-167.5℃. ESI-MS m / z: 356.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) 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 86.1 Synthesis of [(4-cyano-6-morpholinyl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-6)

[0271] Using intermediates B5-6 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 166 mg of crude white solid product, with a yield of 12%. The product was not purified and proceeded directly to the next step.

[0272] Example 87.1 Synthesis of {4-cyano-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-7)

[0273] Using intermediates B5-7 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 170 mg of crude white solid product, with a yield of 13%. The product was not purified and proceeded directly to the next step.

[0274] Example 88.1 Synthesis of [4-cyano-6-(phenylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-8)

[0275] Using intermediates B5-8 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 150 mg of crude white solid product, with a yield of 11%. The product was not purified and proceeded directly to the next step.

[0276] Example 89.1 Synthesis of [4-cyano-6-(benzylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-9)

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

[0278] Example 90.1 Synthesis of tert-butyl 4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-10)

[0279] Using intermediates B5-10 and iiia as raw materials, the preparation method was the same as B6-1, yielding 170 mg of crude white solid (yield 14%). The product was not purified and proceeded directly to the next step. ESI-MS m / z: 422.1 [M+H] + 444.1[M+Na] + .

[0280] Example 91.1 Synthesis of tert-butyl 4-{4-cyano-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}}-5-amino-1H-pyrazole-4-carboxylate (B6-11)

[0281] Using intermediates B5-11 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 170 mg of crude product as a white solid, with a crude product yield of 14%. The product was not purified and proceeded directly to the next step. ESI-MS m / z: 460.1 [M+H] + 482.0 [M+Na] + .

[0282] Example 92.1 - Synthesis of [(4-cyano-6-hydroxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-12)

[0283] Intermediate B6-1 (300 mg, 0.948 mmol), LiCl (8 eq), and 2 mL of dry DMF were added to a 25 mL round-bottom flask. The mixture was heated to 130 °C and reacted for 1 h. The reaction was monitored by thin-layer chromatography (dichloromethane:methanol = 1 mL: 1 drop) until completion. After cooling to room temperature, excess DMF was evaporated under reduced pressure using a vacuum oil pump. Water was added, and the pH was adjusted to 3-4 with 1 M hydrochloric acid. The mixture was filtered and dried 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 (400MHz, DMSO-d6) δ7.71(s,1H),7.54(s,2H),7.03(s,1H),1.51(s,9H).

[0284] Example 93.1 Synthesis of [(4-cyano-6-hydroxy)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-12)

[0285] Intermediate B6-1 (300 mg, 0.948 mmol), LiCl (8 eq), and 2 mL of dry DMF were added to a 25 mL round-bottom flask. The mixture was heated to 130 °C and reacted for 1 h. The reaction was monitored by thin-layer chromatography (dichloromethane:methanol = 1 mL: 1 drop) until completion. After cooling to room temperature, excess DMF was evaporated under reduced pressure using a vacuum oil pump. Water was added, and the pH was adjusted to 3-4 with 1 M hydrochloric acid. The mixture was filtered and dried 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 (400MHz, DMSO-d6) δ7.71(s,1H),7.54(s,2H),7.03(s,1H),1.51(s,9H).

[0286] Example 94.1 Synthesis of [(4-cyano-6-isobutylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-12a)

[0287] Using intermediate B6-12 as a starting material, 1.5 times the amount of Carter condensing agent, 1.8 times the amount of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1.8 times the amount of isobutylamine, and 10 mL of acetonitrile were added. The mixture was heated to 70 °C. After the reaction was complete, water and ethyl acetate were added for extraction. The organic layer was collected, washed twice with saturated saline solution, dried with anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate). The concentrated product yielded 30 mg of a white solid, with a yield of 30%. Mp 164.5-166.2 °C. 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 95.1 Synthesis of {4-cyano-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-13)

[0289] Using intermediates B5-13 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 156 mg of a pale yellow solid, with a yield of 13%. Mp 177.9-178.9℃. ESI-MS m / z: 392.1 [M+H] + 414.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) 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 96.1 Synthesis of tert-butyl 4-cyano-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-14)

[0291] Using intermediates B5-14 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 148 mg of a white solid, with a yield of 12%. Mp 143.6-144.5℃. ESI-MS m / z: 408.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 97.1 Synthesis of {4-cyano-6-[(4-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-15)

[0293] Using intermediates B5-15 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 166 mg of a white solid, 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 (400MHz, DMSO-d6) 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 98.1 Synthesis of {4-cyano-6-[(4-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-16)

[0295] Using intermediates B5-16 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 184 mg of a pale yellow solid, 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 (400MHz, DMSO-d6) 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 99.1 Synthesis of {4-cyano-6-[(4-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-17)

[0297] Using intermediates B5-17 and iiia as raw materials, the preparation method was the same as for B6-1, yielding 178 mg of crude white solid (yield 13%). The product was not purified and proceeded directly to the next step. ESI-MS m / z: 477.9 [M+H] + .

[0298] Example 100.1 Synthesis of tert-butyl 4-cyano-6-[(2-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-18)

[0299] Using intermediates B5-18 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 167 mg of a white solid, 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 (400MHz, DMSO-d6) δ10.18(s,1H),7.63(s,1H),7.47–6.92(m,7H),2.23(s,3H),1.49(s,9H).

[0300] Example 101.1 Synthesis of {4-cyano-6-[(3-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-19)

[0301] Using intermediates B5-19 and iiia as raw materials, the preparation method was the same as B6-1, yielding 156 mg of a yellow solid, 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 (400MHz, DMSO-d6) 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 102.1 Synthesis of {4-cyano-6-[(2-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (A6-20)

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

[0304] Example 103.1 Synthesis of tert-butyl 4-cyano-6-[(3-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-21)

[0305] Using intermediates B5-21 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 156 mg of a white solid, 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(400MHz,DMSO-d6)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 104.1 Synthesis of {4-cyano-6-[(2-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-22)

[0307] Using intermediates B5-22 and iiia as raw materials, the preparation method was the same as B6-1, yielding 173 mg of a white solid, 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 (400MHz, DMSO-d6) 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 4-cyano-6-[(2-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-23)

[0309] Using intermediates B5-23 and iiia as raw materials, the preparation method was the same as B6-1, yielding 175 mg of a white solid, with a yield of 14%. Mp 250.0-250.3℃. ESI-MS m / z: 434.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 106.1 Synthesis of tert-butyl 4-cyano-6-[(3-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylate (B6-24)

[0311] Using intermediates B5-24 and iiia as raw materials, the preparation method was the same as B6-1, yielding 169 mg of a white solid, with a yield of 13%. Mp 247.1-248.3℃. ESI-MS m / z: 412.2 [M+H] + 434.1[M+Na] + . 1H NMR (400MHz, DMSO-d6) 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 107.1 Synthesis of {4-cyano-6-[(2-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-25)

[0313] Using intermediates B5-25 and iiia as raw materials, the preparation method was the same as B6-1, yielding 192 mg of a white solid, with a yield of 16%. Mp 163.6-164.7℃. ESI-MS m / z: 478.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 108.1 Synthesis of {4-cyano-6-[(3-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-26)

[0315] Using intermediates B5-26 and iiia as raw materials, the preparation method was the same as B6-1, yielding 201 mg of a white solid, with a yield of 17%. Mp 161.7-162.1℃. ESI-MS m / z: 478.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 109.1 Synthesis of {4-cyano-6-[(2,3-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-27)

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

[0318] Example 110.1 Synthesis of {4-cyano-6-[(2,6-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-28)

[0319] Using intermediates B5-28 and iiia as raw materials, the preparation method was the same as B6-1, yielding 206 mg of crude yellow solid (yield 16%). It was proceeded directly to the next step without purification. ESI-MS m / z: 406.2 [M+H] + 428.2 [M+Na] + .

[0320] Example 111.1 Synthesis of {4-cyano-6-[(3,5-dimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-29)

[0321] Using intermediates B5-29 and iiia as raw materials, the preparation method was the same as B6-1, yielding 215 mg of a yellow solid, 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 (400MHz, DMSO-d6) 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 112.1 Synthesis of {4-cyano-6-[(3,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-30)

[0323] Using intermediates B5-30 and iiia as raw materials, the preparation method was the same as B6-1, yielding 236 mg of a yellow solid, with a yield of 19%. Mp 241.7-242.5℃. ESI-MS m / z: 438.2 [M+H] + 460.2 [M+Na] + . 1H NMR(400MHz,DMSO-d6)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 113.1 Synthesis of {4-cyano-6-[(3,5-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-31)

[0325] Using intermediates B5-31 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 223 mg of a yellow solid, with a yield of 18%. Mp 243.2-243.7℃. ESI-MS m / z: 438.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 114.1 Synthesis of {4-cyano-6-[benzo(d)(1,3)dioxacyclopenten-5-ylamino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-32)

[0327] Using intermediates B5-32 and iiia as raw materials, the preparation method was the same as B6-1, yielding 243 mg of a yellow solid, 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 (400MHz, DMSO-d6) 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 115.1 - Synthesis of {[4-cyano-6-(naphthyl-2-ylamino)]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-33)

[0329] Using intermediates B5-33 and iiia as raw materials, the preparation method was the same as B6-1, yielding 275 mg of a white solid, 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 (400MHz, DMSO-d6) 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 116.1-{4-cyano-6-[(2,2-difluorobenzo[d][1,3]dioxacyclopenten-5-yl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-34)

[0331] Using intermediates B5-33 and iiia as raw materials, the preparation method was the same as B6-1, yielding 120 mg of a light yellow solid, with a yield of 12%. Mp 152.3-154.3℃. ESI-MS m / z: 458.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 117.1-{4-cyano-6-[(2,6-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-35)

[0333] Using intermediates B5-35 and iiia as raw materials, the preparation method was the same as B6-1, yielding 240 mg of a white solid, with a yield of 19%. Mp 176.3-177.9℃. ESI-MS m / z: 438.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) 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 118.1-{4-cyano-6-[(2,3-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-36)

[0335] Using intermediates B5-36 and iiia as raw materials, the preparation method was the same as that for B6-1, yielding 210 mg of a white solid, with a yield of 17%. Mp 181.3-183.0℃. ESI-MS m / z: 438.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 119.1-{4-cyano-6-[(2,4-dimethoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-37)

[0337] Using intermediates B5-37 and iiia as raw materials, the preparation method was the same as B6-1, yielding 255 mg of a white solid, with a yield of 21%. Mp 180.3-181.5℃. ESI-MS m / z: 438.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)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 120.1-{4-cyano-6-[(2,4,6-trimethylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-38)

[0339] Using intermediates B5-38 and iiia as raw materials, the preparation method was the same as B6-1, yielding 110 mg of a white solid, with a yield of 15%. Mp 186.3-187.4℃. ESI-MS m / z: 420.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.18–9.97(m,1H),7.72–7.44(m,2H),7.19(s,0.62H),7.09–6.9 5(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 121.1-{4-cyano-6-[(3-cyanophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-39)

[0341] Using intermediates B5-33 and iiia as raw materials, the preparation method was the same as B6-1, yielding 106 mg of a white solid, with a yield of 18%. Mp 199.3-199.9℃. ESI-MS m / z: 403.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 122.1-{4-cyano-6-{[(4,5-dimethyl)isoxazol-3-yl]amino}pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (B6-40)

[0343] Using intermediates B5-33 and iiia as raw materials, the preparation method was the same as B6-1, yielding 100 mg of a pale yellow solid, with a yield of 19%. Mp 146.6-148.5℃. ESI-MS m / z: 397.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 123.1 Synthesis of tert-butyl 4-(4-cyano-6-methoxypyrimidin-2-yl)-1H-pyrazole-4-carboxylate (A6-1)

[0345] 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. The mixture was heated to 65 °C and reacted overnight. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) was used to monitor the reaction completion. After cooling to room temperature, an equal volume of water was added, and the mixture was extracted with ethyl acetate. The organic layer was collected, washed twice with saturated saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then subjected to column chromatography (petroleum ether:ethyl acetate), concentrated under reduced pressure, and dried to give 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 (400MHz, DMSO-d6) 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 124.1 Synthesis of tert-butyl 4-pyrazole-4-carboxylate (A6-2)

[0347] Starting with intermediate B6-2, the preparation method was the same as for A6-1, yielding 109 mg of a white solid, with a yield of 56%. Mp 183.1-184.5℃. ESI-MS m / z: 315.2 [M+H] + 337.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 125.1 Synthesis of tert-butyl 4-[4-cyano-6-(pyrrolidone-1-yl)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (A6-4)

[0349] Starting with intermediate B6-4, the preparation method was the same as that for A6-1, yielding 120 mg of a white solid, with a yield of 59%. Mp 201.4-203.0℃. 1H NMR (400MHz, DMSO-d6) 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 4-(4-cyano-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylate (A6-7)

[0351] Starting with intermediate B6-7, the preparation method was the same as A6-1, yielding 124 mg of a 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 (400MHz, DMSO-d6) 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 127.1 Synthesis of tert-butyl 4-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (A6-8)

[0353] Starting with intermediate B6-8, the preparation method was the same as that for A6-1, yielding 119 mg of a white solid, with a yield of 70%. Mp: 193.2-194.1℃. 1 H NMR (400MHz, DMSO-d6) 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 128.1 Synthesis of tert-butyl 4-[4-cyano-6-(benzylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylate (A6-9)

[0355] Starting with intermediate B6-9, the preparation method was the same as that for A6-1, yielding 117 mg of a white solid, with a yield of 68%. Mp: 183.2-183.5℃. 1H NMR(400MHz,DMSO-d6)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 129.1 Synthesis of {4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid tert-butyl ester (A6-10)

[0357] Starting with intermediate B6-10, the preparation method was the same as for A6-1, yielding 126 mg of a white solid, with a yield of 69%. Mp 178.6-179.7℃. ESI-MS m / z: 407.1 [M+H] + 429.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ8.96(t,J=5.9Hz,1H),8.84(s,1H),8.09(s,1H),7.35–7.29(m,2 H),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 1-{4-cyano-6-{[4-(trifluoromethyl)benzyl]amino}pyrimidin-2-yl}}-1H-pyrazole-4-carboxylic acid tert-butyl ester (A6-11)

[0359] Starting with intermediate B6-11, the preparation method was the same as that for A6-1, yielding 124 mg of a white solid, with a yield of 54%. Mp: 173.2-174.4℃. 1 H NMR(400MHz,DMSO-d6)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 131.1 Synthesis of tert-butyl 4-[(4-cyano-6-methoxy)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-1)

[0361] Starting with intermediate B5-1, the preparation method was the same as for C6-1, yielding 169 mg of a white solid, with a yield of 12%. Mp 253.1-254.7℃. ESI-MS m / z: 331.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 132.1 Synthesis of [4-cyano-6-(pyrrolidone-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid tert-butyl ester (C6-4)

[0363] Starting with intermediate B5-4, the preparation method was the same as for C6-1, yielding 201 mg of a white solid, with a yield of 19%. Mp 243.2-243.7℃. ESI-MS m / z: 370.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 133.1 Synthesis of tert-butyl 4-[4-cyano-6-(piperidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-5)

[0365] Starting with intermediate B5-5, the preparation method was the same as for C6-1, yielding 195 mg of a white solid, with a yield of 17%. Mp 213.2-215.1℃. ESI-MS m / z: 384.2 [M+H] + 406.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 134.1 Synthesis of tert-butyl 4-[4-cyano-6-(morpholin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C6-6)

[0367] Starting with intermediate B5-6, the preparation method was the same as that for C6-1, yielding 166 mg of crude white solid product, with a yield of 14%. The product was then directly proceeded to the next step without purification.

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

[0369] Starting with intermediate B5-8, the preparation method was the same as that for C6-1, yielding 175 mg of a white solid, with a yield of 13%. Mp: 270.8-271.2℃. 1 H NMR (400MHz, DMSO-d6) 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] Starting with intermediate D5-30, the preparation method was the same as for C6-1, yielding 260 mg of a white solid with a yield of 30%. It was then directly proceeded to the next step without purification.

[0372] Example 137.1 Synthesis of (4-cyano-6-methoxypyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid (B7-1)

[0373] Intermediate B6-1 (100 mg, 0.316 mmol) was added to a 10 mL round-bottom flask, along with 2 mL of dichloromethane and 10 drops of acetonitrile. The mixture was stirred until homogeneous, and then 2 mL of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 3 h. Thin-layer chromatography (TLC) was used to monitor the reaction (dichloromethane:methanol:glacial acetic acid = 1 mL:1 drop:1 drop) until completion. Excess solvent was concentrated under reduced pressure at 0 °C, leaving approximately 0.5 mL of reaction solution in the flask. 5 mL of water was added dropwise, and the mixture was stirred at room temperature for 30 min. A solid precipitated, which was filtered and dried to obtain a white crude product. The crude product was recrystallized from 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 (400MHz, DMSO-d6) δ12.27(s,1H),7.79(s,1H),7.64(s,1H),7.39(s,2H),4.07(s,3H). 13C NMR (100MHz, DMSO-d6) δ171.44,165.23,157.15,152.98,143.46,140.47,115.98,111.16,95.10,55.91.

[0374] Example 138.1 Synthesis of [(4-cyano-6-dimethylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-2)

[0375] Using intermediate B6-2 as a raw material, the preparation method was the same as that for B7-1, yielding 63 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.26,162.30,157.02,152.81,142.50,138.20,116.93,106.71,94.87,38.23,37.70.

[0376] Example 139.1 - Synthesis of [(4-cyano-6-isobutylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-3)

[0377] Using intermediate B6-12a as a raw material, the preparation method was the same as that for B7-1, yielding 20 mg of a white solid, 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(400MHz,DMSO-d6+D2O)δ7.70(s,0.69H),7.68(s,0.26H),7.20(s,29H),6.91(s,0.65 H),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). 13C NMR (150MHz, DMSO-d6) 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 140.1 Synthesis of 4-[4-cyano-6-(pyrrolidone-1-yl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-4)

[0379] Using intermediate B6-4 as the starting material, the same method as B7-1 was followed to obtain 66 mg of a white solid, with a yield of 78%. Mp 163.8-163.9℃. ESI-MS m / z: 300.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 (150MHz, DMSO-d6) 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 141.1 Synthesis of [(4-cyano-6-morpholinyl)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-6)

[0381] Using intermediate B6-6 as a raw material, the preparation method was the same as that for B7-1, yielding 64 mg of a white solid, with a yield of 75%. Mp 173.2-174.2℃. ESI-MS m / z: 261.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.25,162.16,157.18,152.79,142.60,138.55,116.84,106.89,94.89,66.07.

[0382] Example 142.1 Synthesis of [4-cyano-6-(phenylamino)pyrimidin-2-yl]-5-amino-1H-pyrazole-4-carboxylic acid (B7-8)

[0383] Using intermediate B6-8 as a raw material, the preparation method was the same as that for B7-1, yielding 68 mg of a white solid in 80% yield. Mp 156.8-157.2℃. ESI-MS m / z: 322.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.25,157.35,152.89,142.97,129.76,121.66,116.56,94.91.

[0384] Example 143.1 Synthesis of {4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-10)

[0385] Using intermediate B6-10 as a raw material, the preparation method was the same as that for B7-1, yielding 71 mg of a white solid with a yield of 90%. Mp 168.2-169.4℃. 1 H NMR(400MHz,DMSO-d6)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(100MHz,DMSO-d6)δ165.24,162.61,159.09,152.84,142.61,137.23,12 9.93,129.61,129.44,116.70,114.50,114.41,109.34,94.84,55.56,44.06.

[0386] Example 144.1 Synthesis of {4-cyano-6-[(4-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-13)

[0387] Using intermediate B6-13 as a raw material, the preparation method was the same as that for B7-1, yielding 70 mg of a light yellow solid, with a yield of 91%. Mp 163.8-165.2℃. ESI-MS m / z: 352.0 [M+H] + 374.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 {4-cyano-6-[(4-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-14)

[0389] Using intermediate B6-14 as a raw material, the preparation method was the same as that for B7-1, yielding 68 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.26,152.86,142.91,130.19,121.47,116.60,94.91,21.01.

[0390] Example 146.1 Synthesis of {4-cyano-6-[(4-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-15)

[0391] Using intermediate B6-15 as a raw material, the preparation method was the same as that for B7-1, yielding 66 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.22,157.32,152.88,142.98,123.50,116.53,116.34,94.91.

[0392] Example 147.1 Synthesis of {4-cyano-6-[(4-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-16)

[0393] Using intermediate B6-16 as a raw material, the preparation method was the same as that for B7-1, yielding 54 mg of a light yellow solid, with a yield of 63%. Mp 157.2-158.2℃. ESI-MS m / z: 355.9 [M+H] + 378.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.21,157.27,152.88,143.06,129.62,116.50,94.94.

[0394] Example 148.1 Synthesis of {4-cyano-6-[(4-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-17)

[0395] Using intermediate B6-17 as a raw material, the preparation method was the same as that for B7-1, yielding 58 mg of a white solid, with a yield of 66%. Mp 166.8-168.2℃. ESI-MS m / z: 399.9 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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). 13C NMR (100MHz, DMSO-d6) δ165.26,161.11,157.26,152.86,143.08,137.86,132.51,123.42,116.50,95.01.

[0396] Example 149.1 Synthesis of {4-cyano-6-[(2-methoxyphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-18)

[0397] Using intermediate B6-18 as a raw material, the preparation method was the same as that for B7-1, yielding 67 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 a raw material, the preparation method was the same as that for B7-1, yielding 56 mg of a yellow solid, 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(400MHz,DMSO-d6)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). 13C NMR (100MHz, 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 151.1 Synthesis of {4-cyano-6-[(2-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-20)

[0401] Using intermediate B6-20 as a raw material, the preparation method was the same as that for B7-1, yielding 66 mg of a yellow solid, with a yield of 79%. Mp 163.5.8-164.5℃. ESI-MS m / z: 352.1 [M+H] + 374.1 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.07(s,1H),7.95(s,1H),7.71(s,1H),7.50 –7.21(m,3H),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 (100MHz, DMSO-d6) δ165.27,157.29,152.86,142.81,121.22,116.64,94.81,56.14.

[0402] Example 152.1 Synthesis of {4-cyano-6-[(3-methylphenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-21)

[0403] Using intermediate B6-21 as a raw material, the preparation method was the same as that for B7-1, yielding 56 mg of a white solid, 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(400MHz,DMSO-d6)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 (100MHz, DMSO-d6) δ165.25,160.32,157.25,152.86,142.97,130.37,116.56,94.93,55.66.

[0404] Example 153.1 Synthesis of {4-cyano-6-[(2-fluorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-22)

[0405] Using intermediate B6-22 as a raw material, the preparation method was the same as that for B7-1, yielding 73 mg of a white solid in 85% yield. Mp 168.9-170.3℃. ESI-MS m / z: 340.1 [M+H] + 362.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.95(s,1H),7.73(s,1H),7.43–7.21(m,6H). 13 C NMR (100MHz, DMSO-d6) δ165.28,161.14,157.19,152.85,143.07,140.21,131.55,127.42,122.41,116.47,95.05.

[0406] Example 154.1 Synthesis of {4-cyano-6-[(2-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-23)

[0407] Using intermediate B6-23 as a raw material, the preparation method was the same as that for B7-1, yielding 55 mg of a white solid, 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 (400MHz, DMSO-d6) 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). 13C NMR (100MHz, 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 {4-cyano-6-[(3-chlorophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-24)

[0409] Using intermediate B6-24 as a raw material, the preparation method was the same as that for B7-1, yielding 59 mg of a white solid, 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(400MHz,DMSO-d6)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 (100MHz, DMSO-d6) 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 {4-cyano-6-[(2-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-25)

[0411] Using intermediate B6-25 as a raw material, the preparation method was the same as B7-1, yielding 52 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.28,161.14,157.19,152.85,143.07,140.21,131.55,127.42,122.41,116.47,95.05.

[0412] Example 157.1 Synthesis of {4-cyano-6-[(3-bromophenyl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-26)

[0413] Using intermediate B6-26 as a raw material, the preparation method was the same as that for B7-1, yielding 61 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 158.1 Synthesis of {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 a raw material, the preparation method was the same as B7-1, yielding 54 mg of a yellow solid, 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 (400MHz, DMSO-d6) 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). 13C NMR (100MHz, DMSO-d6) δ165.26,157.45,152.89,142.70,126.74,124.39,116.61,94.80,20.60,14.53.

[0416] Example 159.1 Synthesis of {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 a raw material, the preparation method was the same as that for B7-1, yielding 56 mg of a yellow solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 a raw material, the preparation method was the same as that for B7-1, yielding 55 mg of a yellow solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.27,157.33,152.84,142.88,138.96,116.62,94.94,21.50.

[0420] Example 161.1 Synthesis of {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 a raw material, the preparation method was the same as that for B7-1, yielding 66 mg of a yellow solid, 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(400MHz,DMSO-d6)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(150MHz,DMSO-d6)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 162.1 Synthesis of {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 a raw material, the preparation method was the same as that for B7-1, yielding 63 mg of a yellow solid, 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 (400MHz, DMSO-d6) 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). 13 C NMR (100MHz, DMSO-d6) δ165.24,161.16,157.17,152.84,142.97,116.56,94.92,55.76.

[0424] Example 163.1 Synthesis of {4-cyano-6-[benzo(d)(1,3)dioxacyclopenten-5-ylamino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-32)

[0425] Using intermediate B6-32 as a raw material, the preparation method was the same as that for B7-1, yielding 63 mg of a yellow solid, with a yield of 72%. Mp 201.7-208.2℃. ESI-MS m / z: 366.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)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 (100MHz, DMSO-d6) δ165.27,152.88,142.94,116.60,108.91,101.86,94.94.

[0426] Example 164.1 - Synthesis of {[4-cyano-6-(naphth-2-ylamino)]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-33)

[0427] Using intermediate B6-33 as a raw material, the preparation method was the same as B7-1, yielding 75 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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]dioxacyclopenten-5-yl)amino]pyrimidin-2-yl}-5-amino-1H-pyrazole-4-carboxylic acid (B7-34)

[0429] Using intermediate B6-34 as a raw material, the preparation method was the same as that for B7-1, yielding 59 mg of a white solid, with a yield of 67%. Mp 184.1-185.5℃. ESI-MS m / z: 402.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 (101MHz, DMSO-d6) 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 a raw material, the preparation method was the same as B7-1, yielding 60 mg of a white solid, 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 (400MHz, DMSO-d6) 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 (101MHz, DMSO-d6) 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 a raw material, the preparation method was the same as that for B7-1, yielding 55 mg of a white solid, with a yield of 63%. Mp 184.5-185.7℃. ESI-MS m / z: 382.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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(101MHz,DMSO-d6)δ165.25,161.83,158.95,157.37,153.70,152.86,142.7 2,128.17,126.21,118.99,116.67,109.81,105.29,99.98,94.78,56.19,55.93.

[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 a raw material, the preparation method was the same as B7-1, yielding 68 mg of a white solid, with a yield of 78%. Mp 187.3-188.2℃. ESI-MS m / z: 382.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)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 (101MHz, DMSO-d6) 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 a raw material, the preparation method was the same as B7-1, yielding 40 mg of a white solid, with a yield of 46%. Mp 174.2-175.9℃. ESI-MS m / z: 364.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.14(s,1H),7.76–7.39(m,2H),7.20(s,0.67H),7.0 9–6.94(m,2H),6.68(s,1H),6.14(s,0.33H),2.28(s,3H),2.18–2.03(m,6H). 13 C NMR(100MHz,DMSO-d6)δ165.20,163.47,162.24,157.59,152.86,142.66,140.09,138.75,137.17,13 5.99,135.31,132.10,131.19,129.78,129.42,116.66,108.75,104.55,94.84,21.08,18.37,18.17.

[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 a raw material, the preparation method was the same as B7-1, yielding 56 mg of a white solid, with a yield of 65%. Mp 180.1-182.0℃. ESI-MS m / z: 347.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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(100MHz,DMSO-d6)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 a raw material, the preparation method was the same as that for B7-1, yielding 61 mg of a white solid, with a yield of 86%. Mp 167.4-167.9℃. ESI-MS m / z: 341.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 172.1 Synthesis of (4-cyano-6-hydroxypyrimidin-2-yl)-5-amino-1H-pyrazole-4-carboxylic acid (B7-12)

[0443] Using intermediate B6-12 as a raw material, the preparation method was the same as that for B7-1, yielding 50 mg of a white solid, 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 (400MHz, DMSO-d6) δ7.74(s,1H),7.63(s,1H),7.58(s,2H),6.85(s,1H). 13 C NMR (150MHz, DMSO-d6) 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] Starting with intermediate A6-1, the preparation method was the same as for B7-1. 46 mg of white solid was obtained, with a yield of 57%. Mp 153.8-155.2℃. ESI-MS m / z: 246.1 [M+H] + 268.0 [M+Na] + . 1H NMR (400MHz, DMSO-d6) δ12.95(s,1H),9.04(s,1H),8.21(s,1H),7.75(s,1H),4.12(s,3H). 13 C NMR (100MHz, DMSO-d6) δ171.87,163.49,155.24,144.68,141.22,133.47,118.77,112.90,56.08.

[0446] Example 174.1 Synthesis of 1-[(4-cyano-6-dimethylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-2)

[0447] Starting with intermediate A6-2, the preparation method was the same as B7-1, yielding 43 mg of a white solid in 55% yield. Mp 166.8-168.2℃. ESI-MS m / z: 259.1 [M+H] + 281.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ163.67,162.65,154.98,143.83,138.94,132.81,118.01,116.91,108.10,38.13,37.45.

[0448] Example 175.1 Synthesis of [4-cyano-6-(pyrrolidone-1-yl)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-4)

[0449] Starting with intermediate A6-4, the preparation method was the same as B7-1, yielding 53 mg of a white solid in 52% yield. Mp 173.4-175.2℃. ESI-MS m / z: 285.1 [M+H] + 307.0 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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). 13C NMR (100MHz, DMSO-d6) 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] Starting with intermediate A6-7, the preparation method was the same as B7-1, yielding 47 mg of a white solid, with a yield of 49%. Mp 167.8-169.1℃. ESI-MS m / z: 313.1 [M+H] + 335.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ164.06,163.69,155.32,144.21,139.04,133.53,118.30,116.45,110.65.

[0452] Example 177.1 Synthesis of 1-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-8)

[0453] Starting with intermediate A6-8, the preparation method was the same as B7-1, yielding 55 mg of a white solid in 57% yield. Mp 168.9.8-169.9℃. ESI-MS m / z: 307.1 [M+H] + 329.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ163.66,155.36,144.20,138.46,132.64,129.56,121.28,118.59,116.52.

[0454] Example 178.1 Synthesis of 4-[4-cyano-6-(benzylamino)pyrimidin-2-yl]-1H-pyrazole-4-carboxylic acid (A7-9)

[0455] Starting with intermediate A6-9, the preparation method was the same as B7-1, yielding 61 mg of a white solid, with a yield of 59%. Mp 166.8-168.7℃. ESI-MS m / z: 321.1 [M+H] + 343.1[M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 179.1 Synthesis of {4-cyano-6-[(4-methoxybenzyl)amino]pyrimidin-2-yl}-1H-pyrazole-4-carboxylic acid (A7-10)

[0457] Starting with intermediate A6-10, the preparation method was the same as B7-1, yielding 67 mg of a white solid in 77% yield. Mp 169.8-169.7℃. ESI-MS m / z: 351.1 [M+H] + 373.0 [M+Na] + . 1 H NMR(400MHz,DMSO-d6)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 (100MHz, DMSO-d6) 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] Starting with intermediate A6-11, the preparation method was the same as B7-1, yielding 56 mg of a white solid in 63% yield. Mp 174.3-175.7℃. ESI-MS m / z: 389.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),9.09(t,J=5.9Hz,1H),8.88(s,1H),8.11(s,1 H),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). 13 C NMR (100MHz, DMSO-d6) 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 181.1 Synthesis of [(4-cyano-6-methoxy)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-1)

[0461] Using intermediate C6-1 as a raw material, the preparation method was the same as that for B7-1, yielding 55 mg of a white solid, with a yield of 64%. Mp 164.6-166.5℃. ESI-MS m / z: 275.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),7.59(s,1H),7.42(s,2H),4.06(s,3H),2.28(s,3H). 13 C NMR (100MHz, DMSO-d6) δ171.33,165.90,156.97,154.00,152.36,140.61,116.02,110.56,93.59,55.91,14.97.

[0462] Example 182.1 Synthesis of [4-cyano-6-(pyrrolidone-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-4)

[0463] Starting with intermediate C6-4, the preparation method was the same as for B7-1, yielding 53 mg of a white solid in 60% yield. Mp 166.8-168.7℃. ESI-MS m / z: 314.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 183.1 Synthesis of 4-cyano-6-(piperidin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-5)

[0465] Starting with intermediate C6-5, the preparation method was the same as B7-1, yielding 55 mg of a white solid in 59% yield. Mp 178.3-179.7℃. ESI-MS m / z: 328.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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 184.1 Synthesis of 4-[4-cyano-6-(morpholin-1-yl)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylic acid (C7-6)

[0467] Starting with intermediate C6-6, the preparation method was the same as for B7-1, yielding 58 mg of a white solid in 66% yield. Mp 176.8-178.7℃. ESI-MS m / z: 330.1 [M+H] + 352.0 [M+Na]+ . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) δ165.25,162.16,157.18,152.79,142.60,138.55,116.84,106.89,94.89,66.07.

[0468] Example 185.1 Synthesis of tert-butyl 4-[4-cyano-6-(phenylamino)pyrimidin-2-yl]-3-methyl-5-amino-1H-pyrazole-4-carboxylate (C7-8)

[0469] Starting with intermediate C6-8, the preparation method was the same as B7-1, yielding 60 mg of a white solid in 69% yield. Mp 166.2-168.1℃. ESI-MS m / z: 336.1 [M+H] + 358.1 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) 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 (100MHz, DMSO-d6) 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] Starting with intermediate D6-30, the preparation method was the same as B7-1, yielding 62 mg of a white solid in 74% yield. Mp 163.1-164.6℃. ESI-MS m / z: 382.2 [M+H] + 404.1[M+Na] + . 1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),10.10(s,1H),8.81(s,1H),7.74(s,1H),7.54(s,1 H),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 tablets containing compound B7-38

[0473] The composition and content of the prescription are shown in Table 1.

[0474]

[0475]

[0476] The formulation and content of the coating solution are shown in Table 2.

[0477]

[0478] Process: Mix the excipients that have passed through a 100-mesh sieve with the active pharmaceutical ingredient that has passed through a 60-mesh sieve, prepare a soft mass with 95% ethanol, granulate with an 18-mesh sieve, dry in a ventilated environment at 60℃, granulate with a 16-mesh sieve, mix evenly with magnesium stearate, and then form tablets with a Φ6mm shallow concave punch.

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

[0480] Preparation of film-coated tablets: Place the tablet core in a coating pan and maintain the temperature at 60℃±5℃ for coating to obtain the final product.

[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 type), electric thermostatic water bath (DK-98-1 type), microplate reader (Synergy H1 type)

[0485] 1.3 Test samples: positive control drug febuxostat, Y700, allopurinol and the prepared compounds

[0486] 2. Test Methods

[0487] 2.1 Preparation method

[0488] Buffer solution preparation: 0.1 mol / L sodium pyrophosphate, 0.3 mmol / L disodium EDTA, pH 8.3

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

[0490] Preparation of xanthine solution: Accurately weigh 30.42 mg of xanthine and place it in a 100 mL volumetric flask. First, add 2 mL of 1 M sodium hydroxide solution to dissolve it completely, then add buffer solution to dilute to the mark, obtaining a stock solution with a concentration of 2000 μM. Dilute with buffer solution as needed. For in vitro activity testing, the xanthine solution concentration is 500 μM.

[0491] 2.2 Enzyme Activity Detection Methods

[0492] Add 40 μL of xanthine oxidase solution and 100 μL of inhibitor solution sequentially to a 96-well plate. Incubate at 25°C for 15 minutes, then add 50 μL of xanthine solution (since the reaction begins immediately upon addition of xanthine, the sample should be added quickly and tested immediately to prevent a decrease in the reaction rate). Measure the absorbance at 295 nm every 60 seconds for a total of 5 measurements. A blank control group uses the corresponding drug solvent as a reference.

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

[0494] Where A1: the absorbance value obtained from the first test; A2: the absorbance value obtained from the fifth test; T: the test duration, 5 minutes.

[0495] Using 10 μM as the initial screening concentration, compounds with inhibition rates greater than 50% were subjected to IC50 assay. 50 test.

[0496] 2.2 Statistical Methods

[0497] All data were analyzed using SPSS (17.0) statistical software. Results are expressed as mean ± standard error. Homogeneity of variance analysis was performed to compare means between groups, and Dunnett's test was used for inter-group comparisons.

[0498] 3. Experimental Results:

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

[0500] Table 3. Effects of the target compound on xanthine oxidase activity

[0501] compound <![CDATA[IC 50 (μM, mean ± standard deviation) compound <![CDATA[IC 50 (μM mean ± standard deviation) 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 embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1,1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1 H pyrazole-4-carboxylic acid compounds and their pharmaceutically acceptable salts, characterized in that... The 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1 H The pyrazole-4-carboxylic acid compound is any one of the following compounds:

2. A 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1 as described in claim 1 H A method for preparing pyrazole-4-carboxylic acid compounds and their pharmaceutically acceptable salts, characterized in that... Includes the following steps:

3. The preparation method according to claim 2, characterized in that, In Route 1, the reagents and conditions include: (a) N , N '-Carbonyldiimidazole, dried tetrahydrofuran, 25°C, 3h, orotic acid: N , N (a) '-Carbonyldiimidazole:dry tetrahydrofuran in a molar ratio of 1:1.2:5; (b) ammonia, dichloromethane, -10°C, overnight, orotic acid:ammonia:dichloromethane in a molar ratio of 1:2:5; (c) phosphorus oxychloride, 1,4-dioxane, 100°C, 8h, orotic acid:phosphorus oxychloride:1,4-dioxane in a molar ratio of 1:3:6; (d) substituted amine, tetrahydrofuran, 0°C or N , N -Diisopropylethylamine, methanol, -10℃, orotic acid:substituted amine:tetrahydrofuran: N , N - Diisopropylethylamine:methanol molar ratio is 1:1.05:10:2:10; (e) hydrazine hydrate, dry tetrahydrofuran, 25°C, orotic acid:hydrazine hydrate:dry tetrahydrofuran molar ratio is 1:2.2:5; (f) acetic anhydride, 125°C, 3h, nitrogen, orotic acid:acetic anhydride molar ratio is 1:1; (g) ethanol, reflux, orotic acid:ethanol molar ratio is 1:5; (h) tert-butyl nitrite, tetrahydrofuran, 65°C, overnight, orotic acid:tert-butyl nitrite:tetrahydrofuran molar ratio is 1:1.5:5; (i) trifluoroacetic acid, dichloromethane, acetonitrile, 25°C, orotic acid:trifluoroacetic acid:dichloromethane:acetonitrile molar ratio is 1:5:5:5; (j) lithium chloride, N , N -Dimethylformamide, 120℃, orotic acid:Lithium chloride: N , N - The molar ratio of dimethylformamide is 1:10:5; (k) Carter condensing agent, 1,8-diazabicyclo[5.4.0]undec-7-ene, isobutylamine, acetonitrile, 70°C, orotic acid: Carter condensing agent: the molar ratio of 1,8-diazabicyclo[5.4.0]undec-7-ene:isobutylamine:acetonitrile is 1:1.5:2:1.5:

5.

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

5.

5. A pharmaceutical composition, characterized in that, It includes the 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1 as described in claim 1. H -Pyrazole-4-carboxylic acid compounds and their pharmaceutically acceptable salts, as well as pharmaceutically acceptable excipients, diluents, or carriers.

6. The pharmaceutical composition according to claim 5, characterized in that, The dosage form of the pharmaceutical composition includes one of the following: capsules, tablets, powders, solutions, suspensions, syrups, aerosols, and injections; The drug composition can be administered via one of the following routes: oral, nasal, transdermal, pulmonary, or parenteral.

7. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition contains 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1 H The mass percentage of pyrazole-4-carboxylic acid compounds and their pharmaceutically acceptable salts is 5% to 20%.

8. A 1-(4 / 5-cyano-6-substituted pyrimidin-2-yl)-1 as described in claim 1 H The use of pyrazole-4-carboxylic acid compounds and their pharmaceutically acceptable salts, or the pharmaceutical compositions as described in claim 5, in the preparation of medicaments for the treatment and / or prevention of hyperuricemia and gout.

Images