CN111440174B

CN111440174B - Pyridine amide compound and preparation method and application thereof

Info

Publication number: CN111440174B
Application number: CN202010257388.9A
Authority: CN
Inventors: 张超
Original assignee: Moqi Guangzhou Technology Innovation Co ltd; Guangzhou Medical University
Current assignee: Moqi Guangzhou Technology Innovation Co ltd; Guangzhou Medical University
Priority date: 2020-04-02
Filing date: 2020-04-02
Publication date: 2021-07-09
Anticipated expiration: 2040-04-02
Also published as: CN111440174A

Abstract

The invention discloses a pyridine amide compound, which has a structural general formula shown in formulas (I) and (II). The invention also discloses a preparation method of the pyridine amide compound and application of the pyridine amide compound in preparing antitumor drugs.

Description

Pyridine amide compound and preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a pyridine amide compound, and a preparation method and application thereof.

Background

c-Met is a receptor for Hepatocyte Growth Factor (HGF), and when HGF binds to the receptor c-Met, cell signaling is widely transmitted, including involvement in cell proliferation, motility, migration and invasion. The abnormally conducted HGF/c-Met signal is a driving factor of various malignant tumors and can promote the growth, invasion, propagation and angiogenesis of tumors. The poor clinical treatment effect of some medicines and the drug resistance of approved targeted therapeutic medicines are related to the abnormal HGF/c-Met signal.

The PARP-1 inhibitor can affect the self-replication mode of cancer cells, inhibit the DNA damage repair of the cancer cells and promote the apoptosis of the cancer cells, thereby enhancing the curative effects of radiotherapy and alkylating agent and platinum drug chemotherapy, and being used for treating advanced ovarian cancer patients with BRCA1 and BRCA2 germline mutations and treating BRCA2 HER2 negative metastatic breast cancer. Besides breast cancer, the medicine can also treat hereditary cancers such as ovarian cancer, prostatic cancer, pancreatic cancer and the like which have the same 'rogue gene'. Unfortunately, clinically used PARP inhibitors also present the problem of drug resistance.

It has been found that the combined use of c-Met and PARP-1 inhibitors synergistically prevents the growth of breast cancer cells. Moreover, the combination has similar effect in a lung cancer model of a mouse. For those patients with high c-Met expression and at the same time a PARP-1 inhibitor insensitivity, it may be possible to benefit from the combined use of c-Met and PARP-1 inhibitors, and such combined treatment may have an effect on a wide variety of tumors of this type. In this context, dual-target inhibitors that selectively target c-Met and PARP-1 are new hopes for being explored as tumor patients.

Disclosure of Invention

The invention aims to provide a pyridine amide compound which can effectively inhibit tumors caused by HGF/c-Met and PARP related signal channel abnormality, has good antitumor activity and can be used for preparing antitumor drugs; the invention also aims to provide a preparation method and medical application of the pyridine amide compound.

In order to realize the purpose, the invention adopts the technical scheme that:

a pyridine amide compound has a structural general formula shown in formulas (I) and (II):

wherein:

R₁and R₂Are independently selected from hydrogen, methyl, ethyl, halo, phenyl, benzyl, pyrimidinyl, pyridinyl, pyrazinyl, halo-substituted phenyl, methoxy-substituted pyrimidinyl, methoxy-substituted pyrazinyl, methoxy-and halo-substituted phenyl, methoxy-and halo-substituted pyrimidinyl, methoxy-and halo-substituted pyridinyl, or methoxy-and halo-substituted pyrazinyl;

R₃selected from methyl, ethyl, halogen, methoxy, trifluoromethoxy, or trifluoromethyl.

Preferably, the halogen in the halogen and the halogen substituted phenyl is selected from F, Cl or Br, respectively.

Preferably, the picolinamide compound is selected from the group consisting of 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-picolinamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-picolinamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-chloro-4-methoxyphenyl) -2-picolinamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethylphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6' -methoxy- [2,3' -bipyridine ] -6-carboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6' -fluoro- [2,3' -bipyridine ] -6-carboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, a salt thereof, a mixture thereof, and a pharmaceutically acceptable carrier, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine -picolinamide) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamidophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-methoxy-4-fluorophenyl) -2-pyridinecarboxamidophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) - 2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine.

Preferably, the picolinamide compound is selected from the group consisting of 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-picolinamide) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-methoxy-4-fluorophenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine.

The pyridine amide compound is synthesized by performing chlorination reaction, ether forming reaction, reduction reaction and amide forming reaction on a pyrazolo [1,5-a ] pyrimidine derivative.

The synthetic raw materials of the pyrazolo [1,5-a ] pyrimidine derivative comprise 3-aminopyrazole and an ethyl acetoacetate derivative. Preferably, the ethyl acetoacetate derivative comprises at least one of ethyl acetoacetate, ethyl 2-methylacetoacetate, ethyl 2-ethylacetoacetate and ethyl 4-methoxybenzoyl acetate.

The pyrazolo [1,5-a ] pyrimidine derivative includes at least one of 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, and 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine.

The invention also provides a preparation method of the pyridine amide compound, which comprises the following steps:

(1) synthesis of intermediates 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, or 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine:

taking 3-aminopyrazole and ethyl acetoacetate or ethyl 2-methylacetoacetate or ethyl 2-ethylacetoacetate, adding glacial acetic acid as a reaction solvent, heating and stirring for reaction, and separating and purifying after the reaction is finished to obtain solid products, namely the 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine;

(2) synthesis of intermediate 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine:

taking 4-methoxybenzoyl ethyl acetate and 3-aminopyrazole, adding acetic acid as a reaction solvent, carrying out reflux reaction, and separating and purifying after the reaction is finished to obtain a solid product, namely the 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine;

(3) synthesis of intermediates 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, or 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine:

taking 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, N-dimethylaniline or diethylamine or triethylamine and phosphorus oxychloride, reacting for 24-48 h at 20-60 ℃, slowly pouring the reaction system into ice water while stirring under the ice bath condition, adjusting the pH value to be neutral after recovering the normal temperature, separating and purifying to obtain oily liquid products, namely the 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine and 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, or 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine;

or taking 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine and phosphorus oxychloride, carrying out reflux reaction for 4-8 h at 110-130 ℃, slowly pouring a reaction system into ice water while stirring under an ice bath condition, recovering to normal temperature, and carrying out separation and purification to obtain a solid product, namely the 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine;

(4) synthesis of intermediates 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, or 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine:

dissolving 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine in chlorobenzene or toluene or xylene, adding 2-fluoro-4-nitrophenol, heating, stirring, reacting, separating and purifying to obtain a solid product, namely the 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, or 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine;

(5) synthesis of intermediates 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, or 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine:

adding acetic acid solution or formic acid solution or ammonium chloride solution, and 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine into reduced iron powder, separating and purifying after the reaction is finished, the obtained solid product is the 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, or 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine;

(6) synthesis of intermediate 6- (phenyl or pyridyl) -2-pyridinecarboxylic acid Compounds:

taking 2-bromo-6-pyridinecarboxylic acid, substituted phenylboronic acid or phenylboronic acid pinacol ester, cesium carbonate and Pd (PPh)₃)₄Or PdCl₂Or PdCl₂(dppf) or Pd (OAc)₂Or Pd (PPh)₃)₂Cl₂Carrying out reflux reaction under the protection of nitrogen, and separating and purifying after the reaction is finished to obtain a solid product, namely the 6- (phenyl or pyridyl) -2-pyridine carboxylic acid compound; (Note: Pd (PPh)₃)₄The Chinese name of (A) is "tetrakis (triphenylphosphine) palladium"; PdCl₂Is named as "palladium chloride"; PdCl₂(dppf) referred to herein as "1, 1' -bis-diphenylphosphinoferrocene palladium dichloride"; pd (OAc)₂Is named as "palladium acetate"; pd (PPh)₃)₂Cl₂The Chinese name of (1) is "bis (triphenylphosphine) palladium (II) chloride")

(7) Synthesizing the pyridine amide compound:

taking 6- (phenyl or pyridyl) -2-pyridine carboxylic acid compounds, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), N, N-Diisopropylethylamine (DIPEA), and 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4- And (2) reacting the amino phenoxy) -pyrazolo [1,5-a ] pyrimidine at 0-60 ℃ for 8-25 h, and separating and purifying after the reaction is finished to obtain a solid product, namely the pyridine amide compound.

In some embodiments, in step (1), the ratio of 3-aminopyrazole: ethyl acetoacetate, ethyl 2-methylacetoacetate or ethyl 2-ethylacetoacetate (1-1.2): 1; the conditions of the heating stirring reaction are as follows: stirring and reacting for 1-3 h at 100-140 ℃, preferably stirring and reacting for 1.5h at 120 ℃.

In some embodiments, in step (2), the molar ratio of ethyl 4-methoxybenzoylacetate: 3-aminopyrazole ═ 1: 1; the conditions of the reflux reaction are as follows: reflux reaction is carried out for 4-8 h at 110-130 ℃, and preferably for 6h at 120 ℃.

In some embodiments, in step (3), 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, in terms of mole ratios: n, N-dimethylaniline or diethylamine or triethylamine: 1, (3-5) and (6-10) of phosphorus oxychloride.

In some embodiments, in step (3), 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, in terms of mole ratios: n, N-dimethylaniline or diethylamine or triethylamine: phosphorus oxychloride (1: 4: 8).

In some embodiments, in step (3), when the 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, or 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine is prepared: adding sodium hydroxide or potassium hydroxide or ammonia water solution to adjust the pH value to be neutral; the separation and purification comprises filtering, extracting the filtrate with dichloromethane or trichloromethane, drying the extract with anhydrous sodium sulfate, filtering, rotary-steaming the filtrate to obtain purple black aqueous liquid, and purifying with silica gel column chromatography to obtain oily liquid product.

In some embodiments, in step (3), when the 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine is prepared: the separation and purification comprises extracting with dichloromethane or trichloromethane, drying the extract with anhydrous sodium sulfate, filtering, concentrating the filtrate by rotary evaporation, and purifying with silica gel column chromatography to obtain solid product.

In some embodiments, in step (4), the 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine: 2-fluoro-4-nitrophenol (3.5 to 7.5): 4.5 to 8.5); the conditions of the heating stirring reaction are as follows: reacting for 1-10 h at 100-130 ℃.

When the 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine is prepared, carbonate is added into chlorobenzene or toluene or xylene; preferably, the carbonate is potassium carbonate.

In some embodiments, in step (5), the ratio of reduced iron powder: 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine ═ 1 (2-4): 1.

In some embodiments, in step (5), the ratio of reduced iron powder: 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine ═ 3: 1.

In some examples, in the step (5), the reduced iron powder is mixed with an acetic acid solution or a formic acid solution or an ammonium chloride solution, heated and stirred, activated at 90 ℃ for 1-1.5 h, and then added with 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine reacts for 3-8 h at 80-100 ℃, after the reaction is finished, the filtration is carried out, acetone or ethyl acetate or n-butyl alcohol is used for extracting filtrate, anhydrous sodium sulfate is used for drying extract liquor, rotary evaporation is carried out to remove solvent, and the solid product is obtained after silica gel column chromatography purification.

In some embodiments, in step (6), the ratio, in terms of mole ratios, of 2-bromo-6-pyridinecarboxylic acid: substituted phenylboronic acid or phenylboronic acid pinacol ester: cesium carbonate: pd (PPh)₃)₄Or PdCl₂Or PdCl₂(dppf) or Pd (OAc)₂Or Pd (PPh)₃)₂Cl₂2.458:2.048:4.097: 0.0819; the substituted phenylboronic acid is preferably 4-fluorobenzeneboronic acid; the conditions of the reflux reaction are as follows: carrying out reflux reaction at 70-110 ℃ for 1-6 h, preferably at 90 ℃ for 3 h; the reaction solvent of the reflux reaction is a mixed solution of toluene and ethanol; the separation step after the completion of the reflux reaction comprises: removing the solvent by rotary evaporation, redissolving the solid by water, extracting by acetone or ethyl acetate or n-butyl alcohol, removing the organic phase, adjusting the pH of the water phase to 3-5 by hydrochloric acid or acetic acid or formic acid, extracting by acetone or ethyl acetate or n-butyl alcohol, collecting the organic phase, drying, and carrying out rotary evaporation and concentration to obtain a solid product.

In some embodiments, in step (7), the 6- (phenyl or pyridyl) -2-pyridinecarboxylic acid compound is HATU: DIPEA: 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine (0.5-1.0) to (0.5-1.0):

(0.9～1.7):(0.5～0.8)。

in some embodiments, in step (7), the reaction solvent of the reaction is DCM or dichloromethane, and the isolation comprises: washing the organic phase with saturated sodium chloride solution for three times, washing off reaction by-products, drying the organic phase with anhydrous sodium sulfate, filtering to obtain a crude product, and purifying the crude product; or adjusting the pH to 6-7 by using a saturated sodium bicarbonate solution, extracting by using dichloromethane, drying the extract by using anhydrous sodium sulfate, filtering, and purifying the filtrate.

Preferably, in the preparation method of the pyridine amide compound, petroleum ether and ethyl acetate are used as eluent when the pyridine amide compound passes through a chromatographic column.

The invention also provides a synthesis method of the 4-methoxybenzoyl ethyl acetate, which comprises the following steps: taking diethyl carbonate, cooling to 0 ℃, adding sodium hydride or potassium hydroxide or ammonia, stirring uniformly, adding 4' -methoxyacetophenone, reacting for 1-2 h, adding an acid solution, reacting for 1-2 h at normal temperature, extracting with ethyl acetate or dichloromethane or trichloromethane, drying, filtering, and performing rotary evaporation to obtain an oily liquid product, namely the 4-methoxybenzoyl ethyl acetate.

In some embodiments, in the method for synthesizing ethyl 4-methoxybenzoyl acetate, the molar ratio of diethyl carbonate: sodium or potassium hydroxide or ammonia: 4' -methoxyacetophenone ═ 2.5:3.5: 1.

In some embodiments, in the method for synthesizing ethyl 4-methoxybenzoyl acetate, the acidic solution is selected from one of hydrochloric acid, formic acid and acetic acid, and preferably acetic acid.

In some embodiments, in the method of synthesizing ethyl 4-methoxybenzoyl acetate, the extraction is performed as a reaction product: 1-extractant: 1, adding ethyl acetate or dichloromethane or trichloromethane, and extracting for three times.

The synthetic route of the pyridine amide compound is as follows:

the invention also provides application of the pyridine amide compound in preparation of antitumor drugs.

The pyridine amide compound provided by the invention has good anti-tumor activity and can be used for preparing anti-tumor drugs.

Preferably, the tumor is caused by an abnormality in HGF/c-Met and PARP-associated signaling pathways.

Preferably, the tumor comprises human breast cancer, human lung cancer, human liver cancer and human neuroblastoma.

The invention also provides an anti-tumor medicament which contains the pyridine amide compound and a pharmaceutically acceptable carrier.

Preferably, the dosage forms of the anti-tumor drug comprise injection dosage forms and oral dosage forms.

Preferably, the injection preparation comprises injection and freeze-dried powder.

Preferably, the oral dosage forms include tablets, granules, capsules, powders and solutions.

Compared with the prior art, the invention has the beneficial effects that: (1) the preparation method takes 3-aminopyrazole and ethyl acetoacetate derivatives as raw materials, synthesizes intermediate pyrazolo [1,5-a ] pyrimidine derivatives, synthesizes a series of pyridine amide compounds with anti-tumor activity for the first time through chlorination, ether formation, reduction and amide formation reactions, and confirms the structure of the pyridine amide compounds through high-resolution mass spectrometry, nuclear magnetic resonance hydrogen spectrum and carbon spectrum; (2) the test of in vitro tumor cell inhibition activity shows that the pyridine amide compounds have good inhibition effect on tumor cells such as human breast cancer cells MDA-MB-231, human breast cancer cells MCF-7, human lung adenocarcinoma cells A549 and human liver cancer cells Hep G2 (IC 50: 0.1-100 mu M), have anti-tumor activity and can be used for preparing anti-tumor drugs; (3) the growth test of the xenograft tumor in the body of the mouse shows that the pyridine amide compound has good tumor inhibiting effect and can be used for treating the tumor; (4) the pyridine amide compound has the effect of inhibiting or killing tumor cells, and can be used for preparing antitumor drugs for treating human breast cancer, human lung cancer and human liver cancer; (5) the method for preparing the pyridine amide compound has the advantages of simple operation process, short synthetic route, low cost and the like.

Drawings

FIG. 1 shows 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy group]-5-methylpyrazolo [1,5-a]Process for preparing pyrimidines¹A HNMR map;

FIG. 2 shows 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy group]-a 5-methylpyrazolo [1,5-a]process for preparing pyrimidines¹³A C NMR spectrum;

FIG. 3 is an HR-MS-ESI spectrum of 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine.

Detailed Description

To better illustrate the objects, aspects and advantages of the present invention, the present invention is further illustrated by the following examples. It is apparent that the following examples are only a part of the embodiments of the present invention, and not all of them. It should be understood that the embodiments of the present invention are only for illustrating the technical effects of the present invention, and are not intended to limit the scope of the present invention.

The embodiment of the invention provides a pyridine amide compound, which has the structural general formulas shown as the following formula (I) and (II):

the pyridine amide compound is selected from 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine carboxamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine carboxamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-chloro-4-methoxyphenyl) -2-pyridine carboxamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethylphenyl) -2-pyridine carboxamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine -picolinamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6' -methoxy- [2,3' -bipyridine ] -6-carboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6' -fluoro- [2,3' -bipyridine ] -6-carboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, a salt thereof, a mixture thereof, and a pharmaceutically acceptable carrier, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine -picolinamide) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamidophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-methoxy-4-fluorophenyl) -2-pyridinecarboxamidophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) - 2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine.

The preparation methods of the thirty picolinamide compounds are shown in examples 1-30. The following examples are only some examples of the present invention, and should not be construed as limiting the scope of the present invention. The target products can be obtained by other conditions in the preparation method of the pyridine amides of the invention, which are not specifically exemplified herein for reasons of space.

Example 1

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine carboxamide) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃Methyl, R₂Is H, R₃Is 4-F, and the compound number is GMZC-Q-1.

The preparation method of the compound GMZC-Q-1 comprises the following steps:

(1) synthesis of intermediate 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine

Weighing 4.860g (58.000mmol) of 3-aminopyrazole and 7.541g (58.000mmol) of ethyl acetoacetate, adding into a round-bottom flask, adding 20mL of glacial acetic acid as a reaction solvent, heating and stirring, reacting at 120 ℃ for 1.5h, and detecting by TLC; after the reaction is finished, cooling, suction filtration and washing of the upper-layer precipitate with absolute ethyl alcohol are carried out to obtain 6.103g of white solid which is the intermediate 5-methyl-7-hydroxy-pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI shown below), yield 70%;

¹H NMR(400MHz,DMSO-d₆)δ12.28(s,1H),7.82(t,J＝2.4Hz,1H),6.11～6.03(m,1H),5.59～5.52(m,1H),2.28(d,J＝0.6Hz,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ156.83,150.70,143.14,142.12,95.36,88.74,19.10；

HR-ESI-MS Calcd.for C₇H₇N₃O[M+H]⁺：150.06619；found:150.06609。

(2) synthesis of intermediate 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine

Weighing 5-methyl-7-hydroxy-pyrazolo [1,5-a ]]2.500g (16.800mmol) of pyrimidine is added into a round-bottom flask, 8.450mL (67.100mmol) of N, N-dimethylaniline and 12.25mL (134.400mmol) of phosphorus oxychloride are added in sequence, stirred, reacted at 35 ℃ for 36h, and detected by TLC; after the reaction is finished, slowly pouring the reaction system into a beaker filled with 100mL of ice water while stirring under the ice bath condition, quenching phosphorus oxychloride, adding a sodium hydroxide solution to adjust the pH to be neutral after the reaction system is recovered to the normal temperature, filtering, extracting the filtrate for three times by using DCM (100 mL each time), drying the extract by using anhydrous sodium sulfate, filtering, carrying out rotary evaporation on the filtrate to obtain a purple black aqueous liquid, and purifying by silica gel column chromatography (taking ethyl acetate and petroleum ether as eluent, and taking the ethyl acetate and the petroleum ether (V: V) ═ 1: 12)]To obtain 2.013g of a transparent oily liquid, which was an intermediate 5-methyl-7-chloro-pyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI shown below), yield 70%;

¹H NMR(400MHz,CDCl₃)δ7.97(t,J＝3.3Hz,1H),6.64(s,1H),6.46(d,J＝2.3Hz,1H),2.39(d,J＝3.4Hz,3H)；

¹³C NMR(101MHz,CDCl₃)δ158.37,149.39,145.22,138.11,108.75,97.24,24.52；

HR-ESI-MS Calcd.for C₇H₆N₃Cl[M+H]⁺：168.03230；found:168.03207。

(3) synthesis of intermediate 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine

Weighing 5-methyl-7-chloro-pyrazolo [1,5-a ]]Adding 1.210g (7.100mmol) of pyrimidine into a round-bottom flask, adding 2mL of chlorobenzene for dissolving, pouring 1.354g (8.500mmol) of 2-fluoro-4-nitrophenol, heating and stirring, and reacting at 110 ℃ for 2 hours; after the reaction is finished, rotary evaporation is carried out, and the mixture is purified by silica gel column chromatography (ethyl acetate and petroleum ether are used as eluent, and the ratio of ethyl acetate to petroleum ether (V: V) is 1: 10]To obtain 1.030g of yellow-green solid which is the intermediate 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI shown below), yield 50%;

¹H NMR(400MHz,CDCl₃)δ8.22～8.15(m,2H),8.13(d,J＝2.2Hz,1H),7.52～7.46(m,1H),6.64～6.60(m,1H),5.90(s,1H),2.52(d,J＝0.5Hz,3H)；

¹³C NMR(101MHz,CDCl₃)δ160.56,154.56,151.99,150.76,145.97,144.72,123.37,121.07,114.26,114.03,96.56,90.71,25.20；

HR-ESI-MS Calcd.for C₁₃H₉N₄O₃F[M+H]⁺：289.07214；foun d:289.07263。

(4) synthesis of intermediate 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine

0.588g (10.500mmol) of reduced iron powder is weighed, added into a round-bottom flask containing 20mL of acetic acid solution with the pH value of 2-3, heated and stirred, activated at 90 ℃ for 1h, and added with 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine 1.008g (3.500mmol) and reacting at 90 ℃ for 5 h; after the reaction, the mixture is filtered while the reaction is still hot, the filtrate is extracted with ethyl acetate for three times, 50mL each time, the upper layer is taken, dried by anhydrous sodium sulfate, the solvent is removed by rotary evaporation, and the mixture is purified by silica gel column chromatography (taking ethyl acetate and petroleum ether as eluent, and the ratio of ethyl acetate to petroleum ether (V: V) is 1: 8]Obtaining 0.650g of white solid, namely the intermediate 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI shown below), yield 72%;

¹H NMR(400MHz,DMSO-d₆)δ9.96(s,1H),9.60(s,1H),8.08(d,J＝2.2Hz,1H),7.25(dd,J＝12.3,2.4Hz,1H),7.06(ddd,J＝28.4,10.3,4.6Hz,2H),6.35(d,J＝2.2Hz,1H),6.03(s,1H),2.34(s,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ159.47,152.43,150.03,149.43,145.87,143.93,129.11,121.96,118.49,113.96,94.36,86.61,25.04；

HR-ESI-MS Calcd.for C₁₃H₁₁N₄OF[M+H]⁺：259.09897；found:259.09827。

(5) synthesis of intermediate 6- (4-fluorophenyl) -2-pyridinecarboxylic acid

Weighing 2-bromo-60.5g (2.458mmol) of pyridine carboxylic acid, 0.287g (2.048mmol) of 4-fluorobenzeneboronic acid, 1.335g (4.097mmol) of cesium carbonate and 0.095g (0.0819mmol) of tetrakis (triphenylphosphine) palladium are added into a two-neck round-bottom flask in sequence, vacuum pumping is carried out in a sealed manner, nitrogen is introduced for protection, 30mL of a reaction solvent (the reaction solvent consists of toluene and ethanol, and the ratio of toluene to ethanol (V: V) is 1: 1) is added by a syringe, and reflux reaction is carried out for 3 hours at 90 ℃; after the reaction is finished, the solvent is removed by rotary evaporation, the solid is re-dissolved by distilled water, the ethyl acetate is used for extraction once, and the organic phase is discarded. Adjusting the pH value of the water phase to 4 by using a dilute hydrochloric acid solution, extracting the water phase by using ethyl acetate for three times, collecting an organic phase, drying by using anhydrous sodium sulfate, and performing spin drying to obtain a light yellow solid, namely an intermediate 6- (4-fluorophenyl) -2-pyridinecarboxylic acid (0.356 g)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 80%;

¹H NMR(400MHz,CDCl₃)δ8.20～8.15(m,1H),8.05～8.01(m,1H),8.01～7.99(m,1H),7.99～7.97(m,1H),7.97～7.94(m,1H),7.24～7.21(m,1H),7.21～7.17(m,1H)；

¹³C NMR(101MHz,CDCl₃)δ165.42,164.20,162.93,155.61,146.00,139.51,133.32,129.09,124.62,122.04,116.33,116.11；

HR-ESI-MS Calcd.for C₁₂H₈NO₂F[M+H]⁺:218.06126；foun d:218.06116。

(6) synthesis of the product 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine

0.171g (0.788mmol) of 6- (4-fluorophenyl) -2-pyridinecarboxylic acid and 0.300g (0.788mmol) of 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) were put in a round-bottomed flask, dissolved in 8mL of DCM, stirred for 10min, then added with 0.239mL (1.444mmol) of N, N-Diisopropylethylamine (DIPEA), stirred for 10min, slowly added dropwise with 10mL of 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] containing]0.169g (0.657mmol) of pyrimidine in DCM for 10min, reacting the system at 30 ℃ for 12h, and detecting by thin layer chromatography; washing the organic phase with saturated sodium chloride solution for three times after the reaction is finished, washing off reaction by-products, and drying with anhydrous sodium sulfateDrying the organic phase, filtering to obtain crude product, and purifying with silica gel column chromatography [ using ethyl acetate and petroleum ether as eluent, and ethyl acetate/petroleum ether (V: V) ═ 1: 6]Obtaining 0.146g of white solid, namely the product 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI spectra shown in FIG. 1, FIG. 2 and FIG. 3, respectively), yield was 49%;

¹H NMR(400MHz,CDCl₃)δ8.21(dd,J＝6.5,1.9Hz,1H),8.12(d,J＝5.4Hz,1H),8.10(d,J＝5.4Hz,1H),8.01(d,J＝2.2Hz,1H),7.98(s,1H),7.96～7.93(m,1H),7.42(t,J＝8.4Hz,1H),7.29(dd,J＝10.7,2.4Hz,1H),7.22(dd,J＝5.3,4.1Hz,1H),7.18(s,1H),7.16(s,1H),6.49(d,J＝2.2Hz,1H),6.30(s,1H),2.53(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ165.30,163.03,159.98,157.11,148.93,146.59,143.96,143.85,138.13,136.30,135.85,134.35,129.27,129.19,125.01,124.34,124.11,119.40,116.10,115.88,112.24,112.02,95.55,87.00,25.29；

HR-ESI-MS Calcd.for C₂₅H₁₇N₅O₂F₂[M+H]⁺:458.14139；found:458.14176。

example 2

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 3-F and 4-OCH₃The compound is numbered as GMZC-Q-2.

The preparation method of the compound GMZC-Q-2 comprises the following steps:

(1) synthesis of intermediate 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine: same as in step (1) of example 1.

(2) Synthesis of intermediate 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine: same as in step (2) of example 1.

(3) Synthesis of intermediate 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (3) of example 1.

(4) Synthesis of intermediate 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (4) of example 1.

(5) Synthesis of intermediate 6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxylic acid: the synthesis method is similar to step (5) of example 1, except that this step replaces 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 3-fluoro-4-methoxybenzeneboronic acid, and the rest of the conditions are unchanged. Finally obtaining 0.412g of light yellow solid which is the intermediate 6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxylic acid (b)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 81%.

¹H NMR(400MHz,CDCl₃)δ8.13(d,J＝8.3Hz,1H),8.03～7.96(m,1H),7.92(d,J＝8.6Hz,1H),7.76(s,1H),7.73(s,1H),7.08(t,J＝8.6Hz,1H),3.96(s,3H)；

¹³C NMR(101MHz,CDCl₃)δ164.24,155.09,153.94,151.48,145.91,139.44,132.65,124.17,123.12,121.84,114.81,113.52,56.41；

HR-ESI-MS Calcd.for C₁₃H₁₀NO₃F[M+H]⁺:248.07183；found:248.07175。

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally obtaining 0.160g of white solid, namely the product 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 50%.

¹H NMR(400MHz,DMSO-d₆)δ9.96(d,J＝26.7Hz,1H),8.29(dd,J＝7.6,1.3Hz,1H),8.15(dd,J＝7.7,1.3Hz,1H),8.12(d,J＝7.8Hz,1H),8.11～8.08(m,1H),8.05～8.01(m,1H),7.99(dt,J＝4.5,2.3Hz,1H),7.59(dt,J＝8.6,3.4Hz,1H),7.56～7.53(m,1H),7.41(d,J＝8.6Hz,1H),7.29(dd,J＝10.9,7.0Hz,1H),6.39(d,J＝2.2Hz,1H),6.37(s,1H),3.88(s,3H),2.36(d,J＝11.9Hz,3H).

¹³C NMR(101MHz,DMSO-d₆)δ163.12,159.78,155.76,152.74,151.06,149.50,149.07,146.22,144.59,144.03,139.55,137.50,135.06,132.06,130.95,129.21,125.22,124.80,123.93,120.55,114.51,112.53,94.78,87.60,56.68,25.14.

HR-ESIMS Calcd.for C₂₆H₁₉N₅O₃F₂[M+H]⁺:488.15295；found:488.15239。

Example 3

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-chloro-4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 3-Cl and 4-OCH₃The compound is numbered as GMZC-Q-3.

The preparation method of the compound GMZC-Q-3 comprises the following steps:

(5) Synthesis of intermediate 6- (3-chloro-4-methoxyphenyl) -2-pyridinecarboxylic acid: the synthesis was similar to step (5) of example 1, except that this step replaced 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 3-chloro-4-methoxybenzeneboronic acid, and the rest of the conditions were unchanged. Finally obtaining 0.487g of light yellow solid which is the intermediate 6- (3-chloro-4-methoxyphenyl) -2-pyridinecarboxylic acid (¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 90%.

¹H NMR(400MHz,CDCl₃)δ8.14(d,J＝8.5Hz,1H),8.02(s,1H),7.99(d,J＝7.5Hz,1H),7.92(d,J＝7.9Hz,1H),7.88(d,J＝10.3Hz,1H),7.05(d,J＝8.6Hz,1H),3.98(s,3H).

¹³C NMR(101MHz,CDCl₃)δ164.17,156.65,154.98,145.92,139.46,130.38,128.88,126.58,124.19,123.43,121.84,112.26,56.43.

HR-ESI-MSCalcd.forC₁₃H₁₀NO₃Cl[M+H]⁺:264.04228；found:264.04208.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-chloro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3-chloro-4-methoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally, 0.173g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 52%.

¹H NMR(400MHz,DMSO-d₆)δ9.99(s,1H),8.32(dd,J＝7.7,1.3Hz,1H),8.24(d,J＝2.2Hz,1H),8.16(dd,J＝7.6,1.2Hz,1H),8.13(dd,J＝5.6,2.2Hz,1H),8.12～8.11(m,1H),8.10(d,J＝2.8Hz,1H),7.59～7.57(m,1H),7.57～7.54(m,1H),7.45～7.38(m,1H),7.30～7.25(m,1H),6.38(t,J＝2.3Hz,1H),6.37(s,1H),3.90(d,J＝4.9Hz,3H),2.38(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.13,159.79,156.35,155.59,152.74,149.51,146.23,144.60,144.05,139.60,135.06,131.96,131.30,129.22,128.60,127.49,125.25,124.85,122.27,120.59,113.58,94.78,87.59,86.59,56.89,25.14.

HR-ESI-MS Calcd.for C₂₆H₁₉N₅O₃FCl[M+H]⁺:504.12340；found:504.12301.

Example 4

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-trifluoromethylphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine belonging to the genus of knotGeneral formula (I), R₁Is CH₃，R₂Is H, R₃Is 4-CF₃The compound is numbered as GMZC-Q-4.

The preparation method of the compound GMZC-Q-4 comprises the following steps:

(5) Synthesis of intermediate 6- (4-trifluoromethylphenyl) -2-pyridinecarboxylic acid: the synthesis method is similar to step (5) of example 1, except that this step replaces 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 4-trifluoromethylphenylboronic acid, and the rest of the conditions are unchanged. Finally obtaining 0.466g of light yellow solid, namely the intermediate 6- (4-trifluoromethylphenyl) -2-pyridinecarboxylic acid (b)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 85%.

¹H NMR(400MHz,DMSO-d₆)δ8.41(d,J＝7.1Hz,1H),8.39(s,1H),8.30(s,1H),8.16～8.09(m,1H),8.08(s,1H),7.90(d,J＝2.9Hz,1H),7.87(s,1H).

¹³C NMR(101MHz,DMSO-D₆)δ166.54,154.86,149.01,142.07,139.48,130.26,129.95,128.15,128.15,126.26,124.68,124.56,123.41.

HR-ESI-MSCalcd.forC₁₃H₈NO₂F₃[M+H]⁺:268.05707；found:268.05794.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (4-trifluoromethylphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -one-carboxylic acid of example 1 with an equimolar amount of 6- (4-trifluoromethylphenyl) -2-pyridinecarboxylic acid2-pyridine carboxylic acid, and the rest conditions are unchanged. Finally, 0.189g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (4-trifluoromethylphenyl) -2-pyridine carboxamide) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 56%.

¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),8.46(dd,J＝7.8,1.0Hz,1H),8.42(s,1H),8.40(s,1H),8.31(dd,J＝7.7,1.0Hz,1H),8.26(t,J＝7.8Hz,1H),8.15(d,J＝2.2Hz,1H),7.93(s,1H),7.92～7.89(m,1H),7.63(dd,J＝10.8,7.9Hz,1H),7.59(d,J＝8.7Hz,1H),7.46(d,J＝8.7Hz,1H),6.43(d,J＝2.2Hz,1H),6.41(s,1H),2.42(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.01,159.79,155.60,155.19,152.73,149.51,146.56,144.56,144.03,141.78,139.96,137.65,135.12,130.53,130.21,128.20,128.20,126.39,125.99,125.22,123.38,120.51,112.50,94.79,87.62,25.14.

HR-ESI-MS Calcd.for C₂₆H₁₇N₅O₃F₄[M+H]⁺:508.13819；found:508.13890.

Example 5

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 4-OCH₃The compound is numbered as GMZC-Q-5.

The preparation method of the compound GMZC-Q-5 comprises the following steps:

(5) Synthesis of intermediate 6- (4-methoxyphenyl) -2-pyridinecarboxylic acid: the synthesis method is similar to step (5) of example 1, except that this step replaces 4-fluorophenylboronic acid of example 1 with an equimolar amount of 4-methoxyphenylboronic acid, and the remaining conditions are unchanged. Finally obtaining 0.403g of light yellow solid, namely the intermediate 6- (4-methoxyphenyl) -2-pyridinecarboxylic acid (b)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 86%.

¹H NMR(400MHz,DMSO-d₆)δ8.16(s,1H),8.14(s,1H),8.10(s,1H),8.03～7.97(m,1H),7.92(s,1H),7.06(s,1H),3.82(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ166.79,165.31,161.04,156.28,148.57,141.24,138.93,130.72,128.84,124.85,123.05,114.68,55.79.

HR-ESI-MS Calcd.forC₁₃H₁₁NO₃[M+H]⁺:230.08125；found:230.08134.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (4-methoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally obtaining 0.178g of white solid, namely the product 7- [ 2-fluoro-4- (6- (4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 58%.

¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),8.30～8.24(m,1H),8.19～8.17(m,1H),8.17～8.15(m,1H),8.15(s,1H),8.14(d,J＝1.0Hz,1H),8.14～8.08(m,1H),7.65～7.60(m,1H),7.58(t,J＝5.3Hz,1H),7.45(dd,J＝8.7,1.4Hz,1H),7.13～7.10(m,1H),7.09～7.08(m,1H),6.43(d,J＝2.2Hz,1H),6.40(s,1H),3.83(s,3H),2.42(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.27,161.27,157.00,155.22,152.76,149.45,146.20,145.85,144.60,144.03,139.33,135.09,130.43,128.85,128.85,125.24,124.30,120.54,114.84,114.84,112.72,112.50.94.76,87.60,55.83,26.86.

HR-ESI-MS Calcd.forC₂₆H₂₀N₅O₃F[M+H]⁺470.16237; found 470.16216 EXAMPLE 6

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 4-OCF₃The compound is numbered as GMZC-Q-8.

The preparation method of the compound GMZC-Q-8 comprises the following steps:

(5) Synthesis of intermediate 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid: the synthesis was similar to step (5) of example 1, except that this step replaced 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 4-trifluoromethoxyphenylboronic acid, and the remaining conditions were unchanged. Finally obtaining 0.471g of light yellow solid, namely the intermediate 6- (4-trifluoromethoxyphenyl) -2-pyridine carboxylic acid (b)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 81%.

¹H NMR(400MHz,DMSO-d₆)δ8.33(s,1H),8.30(d,J＝5.2Hz,1H),8.24(d,J＝8.4Hz,1H),8.13～8.06(m,1H),8.03(s,1H),7.53(d,J＝3.5Hz,1H),7.50(s,1H).

¹³C NMR(101MHz,DMSO-D₆)δ166.59,155.10,149.82,148.87,139.36,137.50,136.69,129.47,129.47,124.11,121.88,121.76,119.33.

HR-ESI-MS Calcd.for C₁₃H₈NO₃F₃[M+H]⁺:284.05298；found:284.05258.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally obtaining 0.188g of white solid, namely the product 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 55%.

¹H NMR(400MHz,DMSO-d₆)δ9.99(s,1H),8.33(dd,J＝7.8,1.2Hz,1H),8.30～8.27(m,1H),8.27～8.24(m,1H),8.22(dd,J＝7.7,1.1Hz,1H),8.20～8.13(m,1H),8.10(d,J＝2.2Hz,1H),7.58(dd,J＝7.7,4.0Hz,1H),7.56～7.52(m,1H),7.52～7.49(m,1H),7.48(t,J＝1.9Hz,1H),7.44～7.39(m,1H),6.38(dd,J＝3.8,1.4Hz,1H),6.36(s,1H),2.37(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ163.06,159.77,155.83,155.20,152.74,149.99,149.51,146.42,144.55,144.01,139.76,137.63,137.17,135.01,129.47,129.47,125.41,125.19,121.84,121.84,120.47,112.69,112.48,94.78,87.60,25.13.

HR-ESI-MS Calcd.for C₂₆H₁₇N₅O₃F₄[M+H]⁺:524.13311；found:524.13372.

Example 7

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-formyl 4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 3-CHO and 4-OCH₃The compound is numbered as GMZC-Q-9.

The preparation method of the compound GMZC-Q-9 comprises the following steps:

(5) Synthesis of intermediate 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid: the synthesis method is similar to step (5) of example 1, except that this step replaces 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 3-formyl-4-methoxybenzeneboronic acid, and the rest of the conditions are unchanged. Finally, 0.449g of light yellow solid is obtained, namely the intermediate 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid (I)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 85%.

¹H NMR(400MHz,)δ10.36(d,J＝1.5Hz,1H),8.45(d,J＝2.3Hz,1H),8.42(dd,J＝8.7,2.5Hz,1H),8.14(dt,J＝6.3,3.1Hz,1H),8.01～7.96(m,1H),7.94～7.91(m,1H),7.32(d,J＝8.8Hz,1H),3.97～3.92(m,3H).

¹³C NMR(101MHz,)δ189.61,166.69,162.89,155.20,148.77,141.22,139.16,135.07,130.78,126.88,124.74,123.31,113.68,56.80.

HR-ESI-MS Calcd.for C₁₄H₁₁NO₄[M+H]⁺:258.07516；found:258.07592.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally, 0.166g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 51%.

¹H NMR(400MHz,DMSO-d₆)δ10.39～10.39(m,1H),9.98(d,J＝28.7Hz,1H),8.49(t,J＝3.0Hz,1H),8.45(dd,J＝8.8,2.5Hz,1H),8.32(dt,J＝4.2,2.1Hz,1H),8.20～8.16(m,1H),8.15(dd,J＝7.3,3.0Hz,1H),8.11(t,J＝1.5Hz,1H),7.60～7.56(m,1H),7.55(dd,J＝6.5,3.7Hz,1H),7.44～7.40(m,1H),7.40～7.36(m,1H),6.39～6.38(m,1H),6.37(d,J＝3.4Hz,1H),3.97(d,J＝2.9Hz,3H),2.38(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ189.59,172.54,170.86,163.15,163.11,155.93,155.20,152.75,149.34,146.30,144.67,144.07,139.66,135.07,130.47,126.84,125.26,124.91,124.83,120.59,113.91,112.79,100.00,94.71,87.64,56.87,31.66.

HR-ESI-MS-ESI Calcd.for C₂₇H₂₀N₅ O₄F[M+H]⁺:498.15629；found:498.15658.

Example 8

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 3-OCH₃And 4-OCH₃The compound is numbered as GMZC-Q-12.

The preparation method of the compound GMZC-Q-12 comprises the following steps:

(5) Synthesis of intermediate 6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxylic acid: the synthesis was similar to step (5) of example 1, except that this step replaced 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 3, 4-dimethoxyphenylboronic acid, and the rest of the conditions were unchanged. Finally, 0.449g of light yellow solid is obtained, namely the intermediate 6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxylic acid (I)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 85%.

¹H NMR(400MHz,DMSO-d₆)δ8.12(s,1H),8.02(s,1H),7.99～7.93(m,1H),7.84(s,1H),7.70(s,1H),7.04(s,1H),3.83(s,3H),3.78(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ166.75,165.31,156.38,150.76,149.48,148.49,141.23,138.87,132.08,124.84,120.29,112.21,56.18,56.08.

HR-ESI-MS Calcd.for C₁₄H₁₃NO₄[M+H]⁺:260.09181；found:260.09174.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that in this step 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 is replaced by an equimolar amount of 6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally, 0.163g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 50%.

¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),8.37～8.29(m,1H),8.19～8.16(m,1H),8.15(d,J＝1.4Hz,1H),8.15～8.10(m,1H),7.82～7.78(m,1H),7.78(d,J＝1.4Hz,1H),7.61(d,J＝8.7Hz,1H),7.60～7.57(m,1H),7.45(dd,J＝8.7,1.4Hz,1H),7.15～7.08(m,1H),6.43(d,J＝2.2Hz,1H),6.40(s,1H),3.87(d,J＝4.0Hz,3H),3.84(s,3H),2.42(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.24,159.79,157.08,155.22,152.76,151.01,149.55,147.63,146.14,144.61,144.04,139.28,137.54,135.25,130.61,125.25,124.60,124.37,120.39,112.38,110.70,100.00,94.78,87.59,56.15,56.13,31.67.

HR-MS-ESI Calcd.for C₂₇H₂₂N₅O₄F[M+H]⁺:500.17294；found:500.17233.

Example 9

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 3-OCH₃And 5-OCH₃The compound is numbered as GMZC-Q-13.

The preparation method of the compound GMZC-Q-13 comprises the following steps:

(5) Synthesis of intermediate 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid: the synthesis was similar to step (5) of example 1, except that this step replaced 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 3, 5-dimethoxyphenylboronic acid, and the rest of the conditions were unchanged. Finally obtaining 0.429g of light yellow solid, namely the intermediate 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid (II)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 81%.

¹H NMR(400MHz,)δ8.20(dd,J＝7.7,1.2Hz,1H),8.08～8.02(m,1H),8.00(dd,J＝7.6,1.2Hz,1H),7.33(s,1H),7.33(s,1H),6.61(t,J＝2.3Hz,1H),3.83(s,6H).

¹³C NMR(101MHz,)δ166.68,165.32,161.39,156.17,148.59,141.23,140.37,139.06,132.09,124.28,105.52,101.87,55.90,55.90.

HR-ESI-MS Calcd.for C₁₄H₁₃NO₄[M+H]⁺:260.09181；found:260.09177.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that in this step 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 is replaced by an equimolar amount of 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally, 0.170g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 52%.

¹H NMR(400MHz,DMSO-d₆)δ10.04(s,1H),8.36(dd,J＝7.9,1.1Hz,1H),8.24(dd,J＝7.7,1.0Hz,1H),8.17(dd,J＝9.3,5.8Hz,1H),8.15(d,J＝2.2Hz,1H),7.65～7.61(m,1H),7.59(dd,J＝8.6,4.0Hz,1H),7.45(dd,J＝8.8,1.4Hz,1H),7.37～7.35(m,1H),7.35(s,1H),6.66(t,J＝2.3Hz,1H),6.42(d,J＝2.2Hz,1H),6.40(s,1H),3.84(s,6H),2.41(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ175.03,163.13,161.50,161.50,159.79,156.81,155.20,152.74,149.50,147.62,146.20,144.59,144.03,140.04,139.51,132.06,129.33,125.21,120.57,112.75,105.58,101.98,94.78,87.58,55.93,55.93,31.66.

HR-ESI-MS Calcd.for C₂₇H₂₂N₅O₄F[M+H]⁺:500.17294；found:500.17260.

Example 10

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is H, R₃Is 3-OCH₃The compound is numbered as GMZC-Q-19.

The preparation method of the compound GMZC-Q-19 comprises the following steps:

(5) Synthesis of intermediate 6- (3-methoxyphenyl) -2-pyridinecarboxylic acid: the synthesis method is similar to step (5) of example 1, except that this step replaces 4-fluorophenylboronic acid of example 1 with an equimolar amount of 3-methoxyphenylboronic acid, and the remaining conditions are unchanged. Finally obtaining 0.384g of light yellow solid, namely the intermediate 6- (3-methoxyphenyl) -2-pyridinecarboxylic acid (b)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 82%.

¹H NMR(400MHz,)δ8.20(td,J＝7.5,1.2Hz,1H),8.08～8.02(m,1H),8.00(dd,J＝7.6,1.2Hz,1H),7.74(d,J＝1.8Hz,1H),7.73(dd,J＝3.2,1.3Hz,1H),7.46～7.38(m,1H),7.04(ddd,J＝8.2,2.5,0.8Hz,1H),3.84(s,3H).

¹³C NMR(101MHz,)δ166.70,160.23,156.25,148.71,139.73,139.05,130.40,124.07,123.86,119.71,115.59,112.80,55.71.

HR-ESI-MS Calcd.for C₁₃H₁₁NO₃[M+H]⁺:230.08125；found:230.08136.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3-methoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions are unchanged. Finally obtaining 0.166g of white solid, namely the product 7- [ 2-fluoro-4- (6- (3-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 56%.

¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),8.36(dd,J＝7.9,1.1Hz,1H),8.24(dd,J＝7.7,1.1Hz,1H),8.21～8.16(m,1H),8.15(d,J＝2.2Hz,1H),7.77(ddd,J＝7.8,1.6,0.9Hz,1H),7.74(dd,J＝2.4,1.6Hz,1H),7.65～7.60(m,1H),7.60～7.57(m,1H),7.47(dd,J＝6.4,4.6Hz,1H),7.45(ddd,J＝3.5,3.0,1.0Hz,1H),7.09(ddd,J＝8.3,2.6,0.9Hz,1H),6.45～6.42(m,1H),6.41(s,1H),3.86(d,J＝1.9Hz,3H),2.42(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.16,160.33,159.80,156.97,155.21,152.75,149.51,146.29,144.59,144.04,139.56,139.45,137.58,137.48,135.08,130.63,125.22,120.57,119.75,115.80,112.93,112.75,94.78,87.60,55.78,25.14.

HR-ESI-MS Calcd.for C₂₆H₂₀N₅O₃F[M+H]⁺:470.16237；found:470.16229.

Example 11

The pyridine amide compound is 7- [ 2-fluoro-4- (6 '-methoxy- [2,3' -bipyridine)]-6-carboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines, of the general structural formula (II), R₁Is CH₃，R₂Is H, R₃Is 6-OCH₃The compound is numbered as GMZC-Q-21.

The preparation method of the compound GMZC-Q-21 comprises the following steps:

(5) Synthesis of intermediate 6 '-methoxy- [2,3' -bipyridine]-6-carboxylic acid: the synthesis is similar to step (5) of example 1, except that this step is carried out using an equimolar amount of 2-methoxy-5-pyridineboronic acid instead of4-Fluorophenylboronic acid from example 1, with the remaining conditions unchanged. Finally obtaining 0.386g of light yellow solid, namely the intermediate 6 '-methoxy- [2,3' -bipyridine]6-carboxylic acid(s) (iii)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 82%.

¹H NMR(400MHz,DMSO-d₆)δ8.92(dd,J＝2.5,0.7Hz,1H),8.45(ddd,J＝7.3,2.8,1.3Hz,1H),8.15(dd,J＝7.9,1.1Hz,1H),8.04～7.98(m,1H),7.97～7.87(m,1H),6.95～6.87(m,1H),3.88(d,J＝1.9Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ166.57,164.85,154.38,148.71,146.40,139.17,138.19,127.74,123.51,123.38,111.10,53.99.

HR-ESI-MS Calcd.for C₁₂H₁₀N₂O₃[M+H]⁺:231.07650；found:231.07643.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6 '-methoxy- [2,3' -bipyridine)]-6-carboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (6) of example 1, except that this step uses an equimolar amount of 6 '-methoxy- [2,3' -bipyridine]-6-Carboxylic acid instead of 6- (4-fluorophenyl) -2-pyridinecarboxylic acid from example 1, the other conditions remaining unchanged. Finally, 0.175g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6 '-methoxy- [2,3' -bipyridine)]-6-carboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 56%.¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.00～8.89(m,1H),8.45(dd,J＝8.7,2.6Hz,1H),8.32(dd,J＝7.5,1.4Hz,1H),8.18(dd,J＝7.7,1.3Hz,1H),8.14(dd,J＝9.3,5.8Hz,1H),8.11(d,J＝2.2Hz,1H),7.57(t,J＝5.3Hz,1H),7.54(dd,J＝10.1,3.1Hz,1H),7.41(dd,J＝8.6,1.5Hz,1H),6.96(dd,J＝8.7,0.6Hz,1H),6.39(d,J＝2.2Hz,1H),6.37(s,1H),3.89(d,J＝8.4Hz,3H),2.38(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ182.93,169.07,165.03,163.09,159.78,156.69,155.13,152.73,146.45,146.37,144.59,144.05,139.62,138.13,129.72,127.54,125.24,124.94,124.68,120.53,111.34,100.00,87.60,54.07,30.34.

HR-ESI-MS Calcd.for C₂₅H₁₉N₆O₃F[M+H]⁺:471.15762；foun d:471.15760.

Example 12

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is CH₃，R₃Is 3-CHO and 4-OCH₃The compound is numbered as GMZC-Q-22.

The preparation method of the compound GMZC-Q-22 comprises the following steps:

(1) synthesis of intermediate 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (1) of example 1, except that this step replaces the ethyl acetoacetate of example 1 with an equimolar amount of ethyl 2-methylacetoacetate, and the remaining conditions are unchanged. Finally, 5.901g of white solid is obtained, namely the intermediate 5, 6-dimethyl-7-hydroxy-pyrazolo [1, 5-a)]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 57%.

¹H NMR(400MHz,DMSO-d₆)δ12.10(s,1H),7.81～7.77(m,1H),6.02(dd,J＝2.5,1.4Hz,1H),2.29～2.21(m,3H),1.94(t,J＝2.3Hz,3H).

¹³C NMR(101MHz,DMSO-d₆)δ157.58,146.37,143.10,141.28,100.91,87.74,17.92,10.82.

HR-ESI-MS Calcd.for C₈H₉N₃O[M+H]⁺:164.08159；found:164.08184.

(2) Synthesis of intermediate 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (2) of example 1, except that this step uses an equimolar amount of 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ]]Pyrimidine substituted 5-methyl-7-hydroxy-pyrazolo [1,5-a ] of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 1.501g of yellow liquid is obtained, namely the intermediate 5, 6-dimethyl-7-chloro-pyrazolo [1, 5-a)]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 50%.

¹H NMR(400MHz,CDCl₃)δ8.06(t,J＝2.0Hz,1H),6.59(dd,J＝3.3,1.5Hz,1H),2.57(d,J＝2.5Hz,3H),2.39(d,J＝2.6Hz,3H).

¹³C NMR(101MHz,CDCl₃)δ158.78,147.74,144.41,115.50,97.10,24.22,14.81.

HR-ESI-MS Calcd.for C₈H₈N₃Cl[M+H]⁺:182.04795；found:182.04771.

(3) Synthesis of intermediate 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (3) of example 1, except that this step uses an equimolar amount of 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ]]Pyrimidine substitution of 5-methyl-7-chloro-pyrazolo [1,5-a ] of example 1]Pyrimidine, the rest conditions were unchanged. Finally obtaining 0.903g of yellow-green solid, namely the intermediate 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 50%.

¹H NMR(400MHz,CDCl₃)δ8.12(dt,J＝8.5,4.3Hz,1H),7.96(ddd,J＝9.1,2.6,1.6Hz,1H),7.93(d,J＝2.3Hz,1H),6.79(dd,J＝9.0,7.8Hz,1H),6.61(d,J＝2.3Hz,1H),2.66(s,3H),2.32(d,J＝2.7Hz,3H).

¹³C NMR(101MHz,CDCl₃)δ161.21,152.46,149.93,148.86,148.08,144.84,120.58,116.99,113.80,113.58,106.79,96.64,23.80,11.02.

HR-ESI-MS Calcd.for C₁₄H₁₁N₄O₃F[M+H]⁺:303.08979；found:303.08970.

(4) Synthesis of intermediate 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (4) of example 1, except that this step is carried out using an equimolar amount of 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.650g of white solid is obtained, namely the intermediate 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo[1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 72%.

¹H NMR(400MHz,DMSO-d6)δ9.64(s,1H),9.04(s,1H),8.02(dd,J＝3.9,1.6Hz,1H),6.89(dd,J＝8.5,1.5Hz,1H),6.88～6.85(m,1H),6.67(ddd,J＝7.1,4.4,2.7Hz,1H),6.40(d,J＝2.3Hz,1H),2.43(s,3H),1.81(s,3H).

¹³C NMR(101MHz,DMSO-d6)δ160.46,152.32,149.93,147.71,143.07,141.86,141.28,132.74,117.96,110.38,100.29,94.64,24.21,14.57.

HR-ESI-MS Calcd.for C₁₄H ₁₃N₄OF[M+H]⁺:273.11462；found:273.11463.

(5) Synthesis of intermediate 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid: the synthesis method was the same as in step (5) of example 7.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid, and 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] with an equimolar amount of 5, 6-dimethyl]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally obtaining 0.167g of white solid, namely the product 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 48%.

¹H NMR(400MHz,DMSO-d₆)δ10.39(s,1H),9.48(d,J＝14.8Hz,1H),8.49(s,1H),8.48～8.43(m,1H),8.32(dd,J＝7.5,1.4Hz,1H),8.29～8.16(m,1H),8.14(dd,J＝6.3,3.6Hz,1H),8.08(dd,J＝28.8,5.0Hz,1H),7.40(s,1H),7.37(dd,J＝10.3,7.3Hz,1H),6.95(dd,J＝12.3,2.5Hz,1H),6.83(dd,J＝27.0,8.3Hz,1H),6.47(d,J＝2.2Hz,1H),4.12～3.92(m,3H),2.76～2.49(m,3H),2.13～1.95(m,3H).

¹³C NMR(101MHz,DMSO-D₆)δ189.58,163.32,163.07,160.69,155.85,147.87,146.42,143.29,141.16,140.42,139.62,137.34,136.21,135.35,135.08,130.46,126.81,124.76,124.55,117.26,115.17,113.89,104.59,100.00,95.22,56.85,24.23,14.70.

HR-ESI-MS Calcd.for C₂₈H₂₂N₅O₄F[M+H]⁺:512.17294；found:512.17285.

Example 13

The pyridine amide compound is 7- [ 2-fluoro-4- (6 '-fluoro- [2,3' -bipyridine)]-6-carboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidines, of the general structural formula (II), R₁Is CH₃，R₂Is H, R₃Is 6-F, and the compound number is GMZC-Q-23.

The preparation method of the compound GMZC-Q-23 comprises the following steps:

(5) Synthesis of intermediate 6 '-fluoro- [2,3' -bipyridine]-6-carboxylic acid: the synthesis method is similar to step (5) of example 1, except that this step replaces 4-fluorobenzeneboronic acid of example 1 with an equimolar amount of 2-fluoro-5-pyridineboronic acid, and the rest of the conditions are unchanged. Finally, light yellow solid 0.345g is obtained, namely the intermediate 6 '-fluoro- [2,3' -bipyridine]6-carboxylic acid(s) (iii)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 77%.

¹H NMR(400MHz,DMSO-d₆)δ9.02(s,1H),8.75(s,1H),8.27(d,J＝8.2Hz,1H),8.10(d,J＝9.0Hz,1H),8.04(d,J＝7.4Hz,1H),7.58(dd,J＝20.1,9.6Hz,1H),7.34(d,J＝8.7Hz,1H)；

¹³C NMR(101MHz,DMSO-d₆)δ166.41,162.97,153.20,148.88,146.85,141.20,139.48,133.72,129.33,124.33,110.42；

HR-MS-ESI Calcd.for C₁₁H₇N₂O₂F[M+H]⁺:219.05651；found:219.05634。

(6) Synthesis of the product 7- [ 2-fluoro-4- (6 '-fluoro- [2,3' -bipyridine)]-6-carboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (6) of example 1, except that this step uses an equimolar amount of 6 '-fluoro- [2,3' -bipyridine]-6-Carboxylic acid instead of 6- (4-fluorophenyl) -2-pyridinecarboxylic acid from example 1, the other conditions remaining unchanged. Finally, 0.146g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6 '-fluoro- [2,3' -bipyridine)]-6-carboxamido) phenoxy]-5-methylpyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 48%.

¹H NMR(400MHz,DMSO-d₆)δ10.02(s,1H),9.00(d,J＝2.6Hz,1H),8.70(tt,J＝12.8,3.7Hz,1H),8.41(dd,J＝7.7,1.2Hz,1H),8.30～8.24(m,1H),8.21(dd,J＝9.6,5.9Hz,1H),8.11(d,J＝2.2Hz,1H),7.61～7.56(m,1H),7.56～7.52(m,1H),7.45～7.38(m,1H),7.38～7.33(m,1H),6.39(t,J＝2.8Hz,1H),6.37(s,1H),2.38(s,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ175.03,165.47,163.10,162.94,155.17,153.99,152.71,147.03,146.52,144.59,144.06,141.24,139.96,134.97,132.37,125.73,125.20,120.56,112.72,110.30,100.00,94.76,87.62,22.63；

HR-MS-ESI Calcd.for C₂₄H₁₆N₆O₂F₂[M+H]⁺:459.137 64；found:459.13768。

Example 14

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridine formamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is CH₃，R₃Is 6-OCF₃The compound is numbered as GMZC-Q-24.

The preparation method of the compound GMZC-Q-24 comprises the following steps:

(1) synthesis of intermediate 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine: same as in step (1) of example 12.

(2) Synthesis of intermediate 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine: same as in step (2) of example 12.

(3) Synthesis of intermediate 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (3) of example 12.

(4) Synthesis of intermediate 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (4) of example 12.

(5) Synthesis of intermediate 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 6.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid, and 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] with an equimolar amount of 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ]]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.153g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 43%.

¹H NMR(400MHz,DMSO-d₆)δ9.47(s,1H),8.34～8.31(m,1H),8.27(d,J＝2.0Hz,1H),8.26(d,J＝2.1Hz,1H),8.22～8.18(m,1H),8.15(t,J＝7.6Hz,1H),8.03(d,J＝2.2Hz,1H),7.53～7.50(m,1H),7.50～7.47(m,1H),7.35(t,J＝8.8Hz,1H),6.94(dd,J＝12.2,2.5Hz,1H),6.81～6.73(m,1H),6.46(d,J＝2.3Hz,1H),2.64(s,3H),1.95(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.25,160.66,155.76,155.18,152.74,149.97,147.90,146.56,143.28,141.08,140.44,137.19,132.16,129.47,129.47,125.33,124.53,121.86,121.86,119.32,115.18,107.17,104.59,95.22,38.74,24.20,14.66.

HR-ESI-MS Calcd.for C₂₇H₁₉N₅ O₃F₄[M+H]⁺:538.14972；found:538.14935.

Example 15

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is CH₃，R₃Is 3-OCH₃And 5-OCH₃The compound is numbered as GMZC-Q-25.

The preparation method of the compound GMZC-Q-25 comprises the following steps:

(5) Synthesis of intermediate 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 9.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid, and an equimolar amount of 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] is used]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, a white solid 0.1 was obtained97g is the product 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 58%.

¹H NMR(400MHz,DMSO-d₆)δ9.47(s,1H),8.32(dd,J＝7.8,0.8Hz,1H),8.19(d,J＝6.7Hz,1H),8.13(t,J＝7.7Hz,1H),8.04(d,J＝2.3Hz,1H),7.42～7.33(m,1H),7.31(s,1H),7.30(s,1H),6.95(dd,J＝12.2,2.5Hz,1H),6.79(dd,J＝8.7,1.9Hz,1H),6.63(t,J＝2.2Hz,1H),6.48(d,J＝2.2Hz,1H),3.82(d,J＝4.9Hz,3H),3.80(s,3H),2.49(s,3H),1.97(d,J＝6.0Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.30,161.48,161.48,160.68,156.78,155.19,152.74,147.89,146.34,143.30,141.16,140.45,140.07,139.48,132.19,125.28,124.56,115.14,107.14,105.56,105.56,104.64,101.96,95.22,55.93,55.93,24.23,14.67.

HR-ESI-MS Calcd.for C₂₈H₂₄N₅O₄F[M+H]⁺:514.18859；found:514.18872.

Example 16

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine carboxamide) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is CH₃，R₃Is 4-F, and the compound number is GMZC-Q-26.

The preparation method of the compound GMZC-Q-26 comprises the following steps:

(5) Synthesis of intermediate 6- (4-fluorophenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 1.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis procedure is similar to step (6) of example 1, except that this step is carried out using an equimolar amount of 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1, 5-a)]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.187g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine carboxamide) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 61%.

¹H NMR(400MHz,DMSO-d₆)δ9.49(s,1H),8.33(dd,J＝7.3,1.6Hz,1H),8.28～8.24(m,1H),8.23(d,J＝5.5Hz,1H),8.19(t,J＝3.9Hz,1H),8.15(d,J＝7.7Hz,1H),8.05(t,J＝5.2Hz,1H),7.42～7.38(m,1H),7.37(s,1H),7.35(d,J＝2.1Hz,1H),6.97(dd,J＝12.2,2.4Hz,1H),6.81(dd,J＝8.7,2.1Hz,1H),6.50(d,J＝2.2Hz,1H),2.50(s,3H),1.98(d,J＝5.8Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ165.03,163.32,162.57,160.69,156.12,155.18,147.90,146.46,143.30,141.17,140.45,139.65,134.50,132.29,129.65,124.94,124.94,124.55,116.50,116.29,115.15,107.15,104.63,95.23,24.24,14.68.

HR-ESI-MSCalcd.for C₂₆H₁₉N₅O₂F₂[M+H]⁺:472.15704；found:472.15780.

Example 17

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is CH₃，R₃Is 3-F and 4-OCH₃The compound is numbered as GMZC-Q-27.

The preparation method of the compound GMZC-Q-27 comprises the following steps:

(5) Synthesis of intermediate 6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 2.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis procedure is similar to step (6) of example 2, except that this step uses an equimolar amount of 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 2]Pyrimidine, the rest conditions were unchanged. Finally obtaining 0.203g of white solid, namely the product 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 62%.

¹H NMR(400MHz,DMSO-d₆)δ9.49(s,1H),8.30(dd,J＝7.2,1.7Hz,1H),8.15(dd,J＝7.3,1.4Hz,1H),8.11(d,J＝7.5Hz,1H),8.05(d,J＝2.3Hz,1H),8.03(dd,J＝5.6,2.6Hz,1H),8.00(dd,J＝5.7,2.6Hz,1H),7.37(t,J＝8.8Hz,1H),7.31(dd,J＝12.2,5.7Hz,1H),6.96(dd,J＝12.2,2.5Hz,1H),6.83～6.77(m,1H),6.49(d,J＝2.3Hz,1H),3.89(d,J＝6.3Hz,3H),2.49(s,3H),1.97(d,J＝5.5Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.31,160.68,155.69,155.19,153.46,152.74,151.04,149.04,147.89,146.36,143.30,141.16,140.45,139.52,132.18,130.96,124.55,123.93,115.16,114.68,114.49,107.38,104.62,95.23,56.67,24.23,14.68.

HR-ESI-MS Calcd.for C₂₇H₂₁N₅ O₃F₂[M+H]⁺:502.16860；found:502.16856.

Example 18

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is CH₃，R₃Is 3-OCH₃And 4-OCH₃The compound is numbered as GMZC-Q-28.

The preparation method of the compound GMZC-Q-28 comprises the following steps:

(5) Synthesis of intermediate 6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 8.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine: similar to step (6) of example 8, except that this step was performed with an equimolar amount of 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 8]Pyrimidine, the rest conditions were unchanged. Obtaining 0.165g of white solid, namely the product 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5, 6-dimethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 49%.

¹H NMR(400MHz,DMSO-d₆)δ9.48(s,1H),8.29(dd,J＝7.3,1.7Hz,1H),8.14～8.07(m,2H),8.05(d,J＝2.2Hz,1H),7.77(dd,J＝8.3,2.0Hz,1H),7.75(d,J＝1.9Hz,1H),7.38(t,J＝8.8Hz,1H),7.09(t,J＝6.0Hz,1H),6.96(dd,J＝12.2,2.5Hz,1H),6.80(dd,J＝8.7,1.9Hz,1H),6.49(d,J＝2.2Hz,1H),3.85(s,3H),3.82(s,3H),2.50(s,3H),1.99(s,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.41,160.67,157.03,155.21,152.76,150.97,149.53,147.90,146.29,143.30,141.14,140.46,139.23,132.37,130.63,124.56,124.26,120.38,115.15,112.36,110.68,107.15,104.64,95.23,56.15,56.11,24.22,14.66.

HR-ESI-MS Calcd.for C₂₈H₂₄N₅O₄F[M+H]⁺:514.18859；found:514.18871.

Example 19

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridine formamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is C₂H₅，R₃Is 4-OCF₃The compound is numbered as GMZC-Q-29.

The preparation method of the compound GMZC-Q-29 comprises the following steps:

(1) synthesis of intermediate 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (1) of example 1, except that this step replaces the ethyl acetoacetate of example 1 with an equimolar amount of ethyl 2-ethylacetoacetate, and the remaining conditions are unchanged. Finally, 5.012g of white solid is obtained, namely the intermediate 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 49%.

¹H NMR(400MHz,DMSO-d₆)δ12.03(s,1H),7.76～7.74(m,1H),6.05～5.82(m,1H),2.40(q,J＝7.4Hz,2H),2.27(s,3H),0.97(t,J＝7.4Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ157.17,146.07,143.13,141.32,107.33,87.80,18.65,17.22,14.09.

HR-ESI-MS Calcd.for C₉H₁₁N₃O[M+H]⁺:178.09757；found:178.09752.

(2) Synthesis of intermediate 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (2) of example 1, except that this step uses an equimolar amount of 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ]]Pyrimidine substituted 5-methyl-7-hydroxy-pyrazolo [1,5-a ] of example 1]Pyrimidine, the rest conditions were unchanged. Finally obtaining 1.902g of light yellow liquid, namely the intermediate 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 57%.

¹H NMR(400MHz,CDCl₃)δ8.06(t,J＝3.4Hz,1H),6.58(d,J＝2.3Hz,1H),2.85～2.77(m,2H),2.60(s,3H),1.22～1.16(m,3H).

¹³C NMR(101MHz,CDCl₃)δ158.33,147.77,144.58,136.51,121.11,97.08,23.45,22.39,13.09.

HR-ESI-MS Calcd.for C₉H₁₀N₃Cl[M+H]⁺:196.06337；found:196.06373.

(3) Synthesis of intermediate 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine: the synthesis is similar to step (3) of example 1, except that this step uses an equimolar amount of 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ]]Pyrimidine substitution of 5-methyl-7-chloro-pyrazolo [1,5-a ] of example 1]Pyrimidine, the rest conditions were unchanged. Finally obtaining 1.209g of yellow-green solid, namely the intermediate 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 54%.

¹H NMR(400MHz,CDCl₃)δ8.13(dt,J＝13.0,4.1Hz,1H),8.02～7.93(m,1H),7.93(d,J＝2.3Hz,1H),6.84～6.71(m,1H),6.60(d,J＝2.3Hz,1H),2.78(q,J＝7.5Hz,2H),2.70(s,3H),1.48～1.31(m,3H).

¹³C NMR(101MHz,CDCl₃)δ160.73,152.41,149.88,148.85,146.49,144.98,143.81,120.57,116.98,113.55,112.74,96.55,23.14,19.00,14.12.

HR-ESI-MS Calcd.for C₁₅H₁₃N₄O₃F[M+H]⁺:317.10425；found:317.10441.

(4) Synthesis of intermediate 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a]Pyrimidine: the synthesis procedure is similar to step (4) of example 1, except that this step is carried out using an equimolar amount of 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.650g of white solid is obtained, namely the intermediate 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 72%.

¹H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.77(s,1H),8.04～7.84(m,1H),6.84(dd,J＝5.1,2.5Hz,1H),6.82(dd,J＝7.4,2.1Hz,1H),6.66～6.60(m,1H),6.37～6.32(m,1H),2.45(s,3H),2.43～2.35(m,2H),0.85(t,J＝7.4Hz,3H).

¹³C NMR(101MHz,DMSO-D6)δ159.55,152.22,149.82,147.75,143.21,142.10,132.79,119.12,117.92,111.46,107.29,94.54,23.75,19.68,13.94.

HR-ESI-MS Calcd.for C₁₃H₁₁N₄OF[M+H]⁺:287.13054；found:287.13004.

(5) Synthesis of intermediate 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid: the synthesis method was the same as in step (5) of example 6.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid, and an equimolar amount of 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] is used]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, a white solid of 0.21 is obtained0g is the product 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridine formamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 58%.

¹H NMR(400MHz,DMSO-d₆)δ9.23(s,1H),8.33(dd,J＝7.3,1.7Hz,1H),8.28～8.25(m,1H),8.23(dd,J＝5.2,3.0Hz,1H),8.20(dd,J＝7.7,1.6Hz,1H),8.19～8.13(m,1H),8.05～8.02(m,1H),7.42～7.38(m,1H),7.38～7.35(m,1H),7.33(t,J＝8.8Hz,1H),6.80(dd,J＝12.2,2.6Hz,1H),6.69～6.63(m,1H),6.50(d,J＝2.3Hz,1H),2.66(dddd,J＝16.0,12.6,4.3,2.8Hz,2H),2.58(s,3H),1.05(t,J＝7.4Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ165.02,163.34,162.56,159.62,156.11,155.05,152.61,148.04,146.46,143.57,141.94,140.30,139.66,134.52,131.91,129.74,124.95,124.37,116.51,116.29,113.07,106.92,100.00,95.21,38.76,23.69,20.24,14.24.

HR-ESI-MS Calcd.forC₂₈H₂₁N₅O₃F₄[M+H]⁺:552.50361；found:552.50301.

Example 20

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is C₂H₅，R₃Is 3-OCH₃And 5-OCH₃The compound is numbered as GMZC-Q-30.

The preparation method of the compound GMZC-Q-30 comprises the following steps:

(1) synthesis of intermediate 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine: same as in step (1) of example 19.

(2) Synthesis of intermediate 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine: same as in step (2) of example 19.

(3) Synthesis of intermediate 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (3) of example 19.

(4) Synthesis of intermediate 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (4) of example 19.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid, and 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] with an equimolar amount of 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ]]Pyrimidine substituted for 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.227g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 66%.

¹H NMR(400MHz,CDCl₃)δ8.24～8.17(m,1H),7.99～7.96(m,1H),7.95(t,J＝2.0Hz,1H),7.94(d,J＝2.3Hz,1H),7.70(s,1H),7.35～7.31(m,1H),7.31～7.26(m,1H),7.24～7.23(m,1H),6.97(dd,J＝10.7,2.4Hz,1H),6.94(dd,J＝6.0,3.4Hz,1H),6.55(t,J＝2.3Hz,1H),6.51(d,J＝2.3Hz,1H),3.87(s,6H),2.61(s,3H),2.50(q,J＝7.4Hz,2H),1.03～0.95(m,3H).

¹³CNMR(101MHz,CDCl₃)δ163.09,161.34,160.44,157.88,155.54,153.04,147.29,146.58,143.28,140.93,140.38,138.95,138.01,135.40,124.63,124.38,123.57,119.10,117.87,110.76,107.96,105.53,101.76,95.69,55.63,55.63,23.62,20.33,13.28.

HR-ESI-MS Calcd.for C₂₉H₂₆N₅O₄F[M+H]⁺:528.20424；found:528.20403.

Example 21

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine carboxamide) phenoxy]-5-A6-ethylpyrazolo [1,5-a ] yl]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is C₂H₅，R₃Is 4-F, and the compound number is GMZC-Q-31.

The preparation method of the compound GMZC-Q-31 comprises the following steps:

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid, and an equimolar amount of 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ]]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.202g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine carboxamide) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 63%.

¹H NMR(400MHz,DMSO-d₆)δ9.18(s,1H),8.29(dd,J＝7.3,1.7Hz,1H),8.22(dd,J＝5.4,3.2Hz,1H),8.19(dd,J＝5.2,3.0Hz,1H),8.15(dd,J＝5.0,3.3Hz,1H),8.15～8.10(m,1H),8.01～7.97(m,1H),7.40～7.34(m,1H),7.34～7.31(m,1H),7.29(t,J＝8.8Hz,1H),6.76(dd,J＝12.2,2.6Hz,1H),6.65～6.60(m,1H),6.48～6.45(m,1H),2.64～2.58(m,2H),2.54(s,3H),1.01(t,J＝7.4Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ165.03,163.34,162.57,159.62,156.12,155.06,152.61,148.05,146.47,143.57,141.85,140.30,139.65,134.50,132.05,129.65,124.93,124.39,116.50,116.28,114.71,113.07,106.70,95.21,23.69,20.24,14.24.

HR-ESI-MS Calcd.for C₂₇H₂₁N₅O₂F₂[M+H]⁺:486.17369；found:486.17359.

Example 22

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is C₂H₅，R₃Is 3-F and 4-OCH₃The compound is numbered as GMZC-Q-32.

The preparation method of the compound GMZC-Q-32 comprises the following steps:

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step is carried out by substituting an equimolar amount of 6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxylic acidExample 1 6- (4-fluorophenyl) -2-pyridinecarboxylic acid, and 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] in equimolar amounts]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.223g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 66%.¹H NMR(400MHz,DMSO-d₆)δ9.18(s,1H),8.28(dd,J＝7.0,2.1Hz,1H),8.12(dd,J＝7.0,1.4Hz,1H),8.11～8.07(m,1H),8.03～8.00(m,1H),7.99(t,J＝1.8Hz,1H),7.98(d,J＝2.9Hz,1H),7.30(d,J＝8.4Hz,1H),7.29～7.26(m,1H),6.76(dd,J＝12.2,2.6Hz,1H),6.63(ddd,J＝8.8,3.4,2.1Hz,1H),6.46(d,J＝2.3Hz,1H),3.87(d,J＝5.9Hz,3H),2.67～2.57(m,2H),2.53(d,J＝6.5Hz,3H),1.06～0.98(m,3H).

¹³C NMR(101MHz,DMSO-D₆)δ178.90,170.61,163.33,159.61,158.48,152.62,151.03,149.15,148.05,148.01,146.38,143.57,141.85,140.30,139.54,132.06,130.90,124.71,124.40,114.74,114.48,113.07,100.00,95.21,56.67,23.70,20.24,14.24.

HR-ESI-MS Calcd.for C₂₈H₂₃N₅O₃F₂[M+H]⁺:516.18325；found:516.18394.

Example 23

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridine formamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is C₂H₅，R₃Is 3-CHO and 4-OCH₃The compound is numbered as GMZC-Q-33.

The preparation method of the compound GMZC-Q-33 comprises the following steps:

(5) Synthesis of intermediate 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 7.

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid, and 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] with an equimolar amount of 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ]]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally obtaining 0.197g of white solid, namely the product 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridine carboxamide) phenoxyl]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 57%.

¹H NMR(400MHz,DMSO-d₆)δ10.38(d,J＝0.7Hz,1H),9.18(s,1H),8.47(d,J＝2.3Hz,1H),8.45(dd,J＝8.7,2.5Hz,1H),8.31(dt,J＝10.5,5.2Hz,1H),8.15(dd,J＝7.7,1.6Hz,1H),8.14～8.09(m,1H),7.99(d,J＝2.3Hz,1H),7.38(d,J＝8.8Hz,1H),7.34～7.25(m,1H),6.77(dd,J＝12.2,2.6Hz,1H),6.65～6.60(m,1H),6.46(d,J＝2.3Hz,1H),3.97(s,3H),2.67～2.57(m,2H),2.54(s,3H),1.02(t,J＝7.4Hz,4H).

¹³C NMR(101MHz,DMSO-D₆)δ189.60,178.03,163.34,163.09,159.61,155.88,152.62,148.05,146.47,143.57,141.86,140.30,139.64,135.09,132.05,131.92,130.50,126.85,124.80,124.58,114.75,113.92,113.07,95.21,91.52,56.88,23.70,20.24,14.25.

HR-ESI-MSCalcd.forC₂₉H₂₄N₅O₄F[M+H]⁺:526.18859；found:526.18889

Example 24

The pyridine amide compound is 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidines of the general structural formula (I), R₁Is CH₃，R₂Is C₂H₅，R₃Is 3-OCH₃And 4-OCH₃The compound is numbered as GMZC-Q-34.

The preparation method of the compound GMZC-Q-34 comprises the following steps:

(6) Synthesis of the product 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine: the synthesis method is similar to step (6) of example 1, except that this step replaces 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 1 with an equimolar amount of 6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxylic acid, and 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] with an equimolar amount of 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ]]Pyrimidine substituted 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a of example 1]Pyrimidine, the rest conditions were unchanged. Finally, 0.187g of white solid is obtained, namely the product 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridine carboxamide) phenoxy]-5-methyl-6-ethylpyrazolo [1,5-a ]]Pyrimidine (A)¹H NMR、¹³C NMR andHR-MS-ESI shown below), yield 62%.

¹H NMR(400MHz,DMSO-d₆)δ9.19(s,1H),8.27(dd,J＝7.1,1.9Hz,1H),8.10(dd,J＝7.3,1.6Hz,1H),8.09～8.04(m,1H),7.99(d,J＝2.3Hz,1H),7.74(dd,J＝8.3,2.1Hz,1H),7.72(d,J＝2.0Hz,1H),7.33～7.26(m,1H),7.07(dd,J＝8.1,4.0Hz,1H),6.76(dd,J＝12.2,2.6Hz,1H),6.64～6.59(m,1H),6.46(d,J＝2.3Hz,1H),3.82(s,3H),3.79(s,3H),2.66～2.58(m,2H),2.54(s,3H),1.01(t,J＝7.4Hz,3H).

¹³C NMR(101MHz,DMSO-D₆)δ163.43,159.60,157.01,155.08,152.64,150.94,149.50,148.05,146.29,143.57,141.92,140.29,139.25,131.96,130.60,129.35,124.27,120.35,114.71,113.09,112.31,110.59,106.66,95.21,56.12,56.09,23.70,20.25,14.26.

HR-ESI-MS Calcd.for C₂₉H₂₆N₅O₄F[M+H]⁺:528.20424；found:528.20450.

Example 25

The pyridine amide compound is 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridine amido phenoxy)]Pyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is 4-methoxyphenyl, R₂Is H, R₃Is 4-F, and the compound number is GMZC-Q-35.

The preparation method of the compound GMZC-Q-35 comprises the following steps:

(1) synthesis of intermediate 4-methoxybenzoyl ethyl acetate

Weighing 9g (0.0762mol) of diethyl carbonate, cooling to 0 ℃, adding 2.539g (0.106mol) of sodium hydride, stirring uniformly, adding 4.576g (0.0305mol) of 4' -methoxyacetophenone after 5 minutes, reacting for 40 minutes, transferring to normal temperature to react for 20 minutes, adding 40mL of acetic acid solution, reacting for 1 hour at normal temperature until a layer of oily matter is on the surface, and adding ethyl acetate according to the proportion of 1:1, drying the extract by using anhydrous sodium sulfate, filtering, and carrying out rotary evaporation to obtain 5.46g of oily liquid, namely the intermediate 4-methoxy benzoyl ethyl acetate with the yield of 81%.

¹H NMR(400MHz,DMSO-d₆)δ7.96～7.90(m,2H),7.09～7.02(m,2H),4.15～4.06(m,4H),3.85(s,3H),1.17(t,J＝7.1Hz,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ192.23,168.37,164.12,131.36,129.31,114.54,61.06,56.12,45.82,14.52；

HR-MS-ESI Calcd.for C₁₂H₁₄O₄[M+H]⁺:223.08921；found:223.09646。

(2) Synthesis of intermediate 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine

Weighing 6.7g (0.0301mol) of 4-methoxybenzoyl ethyl acetate, adding 2.5g (0.0301mol) of 3-aminopyrazole and 20mL of acetic acid, and refluxing for 6 hours at 120 ℃; and adding distilled water into the product, stirring, carrying out suction filtration, washing with absolute ethyl alcohol, and airing to obtain 4.53g of light yellow solid, namely the intermediate 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine, wherein the yield is 62%.

¹H NMR(400MHz,DMSO-d₆)δ12.39(s,1H),7.88(d,J＝1.9Hz,1H),7.82(d,J＝2.1Hz,1H),7.80(d,J＝2.2Hz,1H),7.12(d,J＝2.1Hz,1H),7.10(d,J＝2.2Hz,1H),6.19(d,J＝1.9Hz,1H),6.02(s,1H),3.83(s,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ162.05,157.05,149.90,143.48,142.39,129.28,129.28,124.71,114.98,114.98,93.03,89.94,56.03；

ESI-HR-MS Calcd.for C₁₃H₁₁N₃O₂[M+H]⁺:242.08513；found:242.09238。

(3) Synthesis of intermediate 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine

Weighing 1.50g (0.0062mol) of 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine, adding into a round-bottom flask, adding 15mL (164.571mmol) of phosphorus oxychloride, and carrying out reflux reaction at 110 ℃ for 4 hours; after the reaction is finished, slowly pouring the reaction system into a beaker filled with 100mL of ice water while stirring under the ice bath condition, quenching phosphorus oxychloride, and after the reaction system is recovered to normal temperature, adding dichloromethane according to the ratio of 1:1, drying the extract by using anhydrous sodium sulfate, filtering, carrying out rotary evaporation on the filtrate, concentrating, and purifying by silica gel column chromatography [ using ethyl acetate and petroleum ether as eluent, wherein the ratio of ethyl acetate to petroleum ether (V: V) is 1: 8], so as to obtain 1.23g of light yellow solid, namely the intermediate 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine, and the yield is 76%.

¹H NMR(400MHz,DMSO-d₆)δ8.29(d,J＝2.3Hz,1H),8.20(d,J＝2.2Hz,1H),8.18(d,J＝2.2Hz,1H),7.97(s,1H),7.07(d,J＝2.2Hz,1H),7.05(d,J＝2.2Hz,1H),6.83(d,J＝2.3Hz,1H),3.84(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ162.09,155.34,149.63,146.12,138.66,129.55,129.55,128.64,114.84,114.84,105.77,98.26,55.92.

HR-MS-ESI Calcd.for C₁₃H₁₀ClN₃O[M+H]⁺:260.05124；found:260.05839。

(4) Synthesis of intermediate 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine

Weighing 1g (0.00385mol) of 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine, 1.59g of potassium carbonate, 12mL of chlorobenzene, 0.73g (0.00465mol) of 2-fluoro-4-nitrophenol, reacting at 100 ℃ for 3 hours, then performing microwave reaction for 4 hours, performing spin drying, extracting by using ethyl acetate, and purifying by silica gel column chromatography (using ethyl acetate and petroleum ether as eluent, and using ethyl acetate and petroleum ether (V: V) ═ 1: 10) to obtain 0.98g of yellow-green solid, namely the intermediate 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine with the yield of 67 percent.

¹H NMR(400MHz,DMSO-d₆)δ8.51(dd,J＝10.3,2.7Hz,1H),8.24(d,J＝2.3Hz,1H),8.20(ddd,J＝9.1,2.7,1.4Hz,1H),8.14(d,J＝2.1Hz,1H),8.12(d,J＝2.1Hz,1H),7.81(dd,J＝8.9,8.2Hz,1H),7.19(s,1H),7.04(d,J＝1.9Hz,1H),7.03(d,J＝1.9Hz,1H),6.79(d,J＝2.3Hz,1H),3.82(s,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ161.98,157.39,153.91,152.59,151.40,150.87,146.38,145.88,145.80,129.59,129.29,123.01,122.07,114.46,97.23,89.81,55.89,29.56；

HR-MS-ESI Calcd.for C₁₉H₁₃FN₄O₄[M+H]⁺:381.09208；found:381.09932。

(5) Synthesis of intermediate 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine

Weighing 1.5g of reduced iron powder, adding the reduced iron powder into a round-bottomed flask containing 30mL of acetic acid solution with the pH value of 2-3, activating and reacting at 90 ℃ for 1.5h, adding 1g (0.00263mol) of 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, and reacting at 90 ℃ for 6 h; filtering, extracting with ethyl acetate, drying with anhydrous sodium sulfate, spin-drying, and purifying with petroleum ether and ethyl acetate as eluent by silica gel column chromatography to obtain solid 0.436g, which is the intermediate 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine with 47% yield.

¹H NMR(400MHz,DMSO-d₆)δ10.01(s,1H),9.76(s,1H),8.15(d,J＝2.2Hz,1H),7.94(d,J＝2.0Hz,1H),7.93(d,J＝2.0Hz,1H),7.33(dd,J＝12.3,2.5Hz,1H),7.20～7.14(m,1H),7.09～7.03(m,1H),7.02(d,J＝1.8Hz,1H),7.00(d,J＝1.9Hz,1H),6.52(d,J＝1.2Hz,1H),6.51(s,1H),3.79(s,3H)；

¹³C NMR(101MHz,DMSO-d₆)δ161.16,156.22,152.49,150.09,149.67,146.51,144.51,143.69,130.91,129.18,128.91,122.00,118.55,114.53,114.23,95.53,82.74,55.76,29.55；

HR-MS-ESI Calcd.for C₁₉H₁₅FN₄O₂[M+H]⁺:351.11790；found:351.12522。

(6) Synthesis of intermediate 6- (4-fluorophenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 1.

(7) Synthesis of the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine

0.186g (0.00085mol) of 6- (4-fluorophenyl) -2-pyridinecarboxylic acid and 0.407g of HATU were placed in a 50mL flask at 0 ℃ and 10mL of methylene chloride was added to activate the reaction for 10 minutes, then 0.277g of DIPEA was added to react for 10 minutes, and then 0.25g (0.00071mol) of 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine was added to react for 10 minutes, and the mixture was allowed to stand at room temperature for 24 hours. Adjusting the pH value to 6-7 by using a saturated sodium bicarbonate solution, extracting by using dichloromethane, drying an extract by using anhydrous sodium sulfate, filtering, and purifying by using petroleum ether and ethyl acetate as eluent through silica gel column chromatography to obtain 0.162g of a white solid, namely the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, wherein the yield is 41%.

¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H),8.36(dd,J＝7.7,1.3Hz,1H),8.30～.27(m,1H),8.27～8.25(m,1H),8.23(d,J＝1.3Hz,1H),8.23～8.22(m,1H),8.19(d,J＝7.7Hz,1H),8.04(d,J＝2.1Hz,1H),8.02(d,J＝2.1Hz,1H),7.69(dd,J＝11.7,2.4Hz,1H),7.63(t,J＝8.7Hz,1H),7.54(dd,J＝8.8,1.7Hz,1H),7.42(s,1H),7.38(s,1H),7.05(d,J＝1.9Hz,1H),7.04(d,J＝2.1Hz,1H),6.86(s,1H),6.59(d,J＝2.3Hz,1H),3.81(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ163.16,161.31,156.41,156.17,149.71,146.31,145.37,144.66,139.73,137.52,135.15,134.51,130.80,129.75,129.66,129.10,125.06,120.73,116.53,116.32,114.58,95.91,83.83,55.81,31.82,31.67,30.87,30.34,29.53,22.62,14.49.

HR-ESI-MS Calcd.for C₃₁H₂₁F₂N₅O₃[M+H]⁺:550.16125；found:550.16882.

Example 26

The pyridine amide compound is 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-methoxy-4-fluorophenyl) -2-pyridine amido phenoxy)]Pyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is 4-methoxyphenyl, R₂Is H, R₃Is 3-F and 4-OCH₃The compound is numbered as GMZC-Q-36.

The preparation method of the compound GMZC-Q-36 comprises the following steps:

(1) synthesizing an intermediate 4-methoxybenzoyl ethyl acetate: same as in step (1) of example 25.

(2) Synthesis of intermediate 5- (4-methoxyphenyl) -7-hydroxy-pyrazolo [1,5-a ] pyrimidine: same as in step (2) of example 25.

(3) Synthesis of intermediate 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine: same as in step (3) of example 25.

(4)5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (4) of example 25.

(5) Synthesis of intermediate 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine: same as in step (5) of example 25.

(6) Synthesis of intermediate 6- (3-methoxy-4-fluorophenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 2.

(7) Synthesis of the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-methoxy-4-fluorophenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine: the synthesis was similar to step (7) of example 25, except that 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 25 was replaced with an equimolar amount of 6- (3-methoxy-4-fluorophenyl) -2-pyridinecarboxylic acid, and the remaining conditions were unchanged. Finally, 0.195g of white solid is obtained, namely the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-methoxy-4-fluorophenyl) -2-pyridine amido phenoxy)]Pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 47%.

¹H NMR(400MHz,DMSO-d₆)δ10.18(s,1H),8.31(dd,J＝7.8,1.2Hz,1H),8.21(d,J＝2.3Hz,1H),8.19(dd,J＝7.6,1.1Hz,1H),8.16–8.13(m,1H),8.03(d,J＝1.3Hz,1H),8.02(d,J＝2.0Hz,1H),8.01(d,J＝2.0Hz,1H),7.68(dd,J＝11.7,2.4Hz,1H),7.62(t,J＝8.7Hz,1H),7.54(dd,J＝8.9,2.4Hz,1H),7.32(d,J＝8.7Hz,1H),7.04(d,J＝2.0Hz,1H),7.02(d,J＝2.1Hz,1H),7.00(d,J＝8.9Hz,1H),6.85(s,1H),6.58(d,J＝2.3Hz,1H),3.91(s,3H),3.80(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ163.15,161.29,156.40,151.04,149.70,149.16,149.05,146.49,146.19,145.35,139.53,135.29,135.16,130.78,129.10,128.90,125.33,124.78,123.93,120.67,114.54,95.89,83.80,56.64,55.77,31.81,31.63,30.86,30.31,29.56,22.61,14.45.

HR-ESI-MS Calcd.for C₃₂H₂₃F₂N₅O₄[M+H]⁺:580.17181；found:580.17915.

Example 27

The pyridine amide compound is 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridine amido phenoxy)]Pyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is 4-methoxyphenyl, R₂Is H, R₃Is 4-OCF₃The compound is numbered as GMZC-Q-37.

The preparation method of the compound GMZC-Q-37 comprises the following steps:

(6) Synthesis of intermediate 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 6.

(7) Synthesis of the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine: the synthesis was similar to step (7) of example 25, except that this step was carried out by substituting 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 25 with an equimolar amount of 6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions were unchanged. Finally, 0.187g of white solid is obtained, namely the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 42%.

¹H NMR(400MHz,DMSO-d₆)δ10.20(s,1H),8.40(dd,J＝7.8,1.2Hz,1H),8.33(d,J＝2.1Hz,1H),8.32(d,J＝2.1Hz,1H),8.28–8.25(m,1H),8.23(d,J＝2.8Hz,1H),8.22–8.15(m,1H),8.03(d,J＝2.1Hz,1H),8.02(d,J＝2.1Hz,1H),7.69(dd,J＝11.8,2.5Hz,1H),7.63(t,J＝8.6Hz,1H),7.58–7.56(m,1H),7.56(s,1H),7.54(d,J＝6.4Hz,1H),7.05(d,J＝2.1Hz,1H),7.03(d,J＝2.0Hz,1H),6.86(s,1H),6.59(d,J＝2.3Hz,1H),3.81(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ163.09,161.30,161.16,156.40,156.22,155.82,152.83,149.98,149.70,146.40,145.35,144.66,139.87,137.19,135.25,130.78,129.50,129.10,128.92,125.49,121.93,114.57,95.91,83.83,55.81,34.94,34.81,31.66,30.86,30.32,22.63,14.08.

HR-ESI-MS Calcd.for C₃₂H₂₁F₄N₅O₄[M+H]⁺:616.15297；found:616.15984.

Example 28

The pyridine amide compound is 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridine amido phenoxy)]Pyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is 4-methoxyphenyl, R₂Is H, R₃Is 3-CHO and 4-OCH₃The compound is numbered as GMZC-Q-38.

The preparation method of the compound GMZC-Q-38 comprises the following steps:

(6) Synthesis of intermediate 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 7.

(7) Synthesis of the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine: the synthesis was similar to step (7) of example 25, except that this step was carried out in the same manner as in example 25 except that 6- (4-fluorophenyl) -2-pyridinecarboxylic acid was replaced with an equimolar amount of 6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions were changed. Finally, 0.180g of white solid is obtained, namely the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 44%.

¹H NMR(400MHz,DMSO-d₆)δ10.43(s,1H),10.20(s,1H),8.53(d,J＝2.4Hz,1H),8.49(dd,J＝8.8,2.5Hz,1H),8.37(dd,J＝7.8,1.2Hz,1H),8.22(s,1H),8.20(d,J＝7.2Hz,1H),8.18–8.15(m,1H),8.04(d,J＝2.2Hz,1H),8.02(d,J＝2.1Hz,1H),7.69(dd,J＝11.8,2.5Hz,1H),7.63(t,J＝8.7Hz,1H),7.54(dd,J＝9.1,1.8Hz,1H),7.42(d,J＝8.9Hz,1H),7.05(d,J＝2.1Hz,1H),7.03(d,J＝2.0Hz,1H),6.88(s,1H),6.59(d,J＝2.3Hz,1H),4.01(s,3H),3.81(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ189.59,175.05,168.37,163.11,161.29,156.39,155.91,152.84,149.70,146.29,145.35,144.63,139.67,137.63,135.07,130.77,130.45,129.11,128.91,126.81,124.79,114.56,113.89,83.81,56.86,55.79,31.83,31.66,30.32,29.58,24.33,22.63,14.49.

HR-ESI-MS Calcd.for C₃₃H₂₄FN₅O₅[M+H]⁺:590.17615；found:590.18347.

Example 29

The pyridine amide compound is 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridine amido phenoxy)]Pyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is 4-methoxyphenyl, R₂Is H, R₃Is 3-OCH₃And 4-OCH₃The compound is numbered as GMZC-Q-39.

The preparation method of the compound GMZC-Q-39 comprises the following steps:

(6) Synthesis of intermediate 6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 8.

(7) Synthesis of the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine: the synthesis was similar to step (7) of example 25, except that 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 25 was replaced with an equimolar amount of 6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions were unchanged. Finally, 0.183g of white solid was obtained, which was the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 43%.

¹H NMR(400MHz,DMSO-d₆)δ10.19(s,1H),8.33(dd,J＝7.6,1.3Hz,1H),8.22(d,J＝2.3Hz,1H),8.19–8.16(m,1H),8.16–8.11(m,1H),8.04(d,J＝2.0Hz,1H),8.02(d,J＝2.0Hz,1H),7.82–7.78(m,1H),7.78(d,J＝2.0Hz,1H),7.69(dd,J＝11.8,2.3Hz,1H),7.63(t,J＝8.7Hz,1H),7.54(dd,J＝8.8,1.7Hz,1H),7.12(d,J＝8.4Hz,1H),7.05(d,J＝2.0Hz,1H),7.03(d,J＝1.7Hz,1H),6.87(s,1H),6.59(d,J＝2.2Hz,1H),3.87(s,3H),3.84(s,3H),3.81(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ163.25,161.30,157.07,156.41,150.99,149.70,149.52,146.13,145.35,144.64,139.30,135.20,130.80,130.59,129.10,125.35,124.62,124.38,120.66,120.38,114.57,112.92,112.34,110.65,95.90,83.82,56.15,56.11,55.80,31.67,30.87,30.34,29.56.

HR-ESI-MS Calcd.for C₃₃H₂₆FN₅O₅[M+H]⁺:592.19180；found:592.19939.

Example 30

The pyridine amide compound is 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridine amido phenoxy)]Pyrazolo [1,5-a]Pyrimidines of the general structural formula (I), R₁Is 4-methoxyphenyl, R₂Is H, R₃Is 3-OCH₃And 5-OCH₃The compound is numbered as GMZC-Q-40.

The preparation method of the compound GMZC-Q-40 comprises the following steps:

(6) Synthesis of intermediate 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid: same as in step (5) of example 9.

(7) Synthesis of the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine: the synthesis was similar to step (7) of example 25, except that 6- (4-fluorophenyl) -2-pyridinecarboxylic acid of example 25 was replaced with an equimolar amount of 6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxylic acid, and the remaining conditions were unchanged. Finally obtaining white0.190g of a colored solid, i.e., the product 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridylaminophenoxy)]Pyrazolo [1,5-a]Pyrimidine (A)¹H NMR、¹³C NMR and HR-MS-ESI are shown below), yield 46%.

¹H NMR(400MHz,DMSO-d₆)δ10.03(s,1H),9.78(s,1H),8.16(d,J＝2.2Hz,1H),7.94(d,J＝1.9Hz,1H),7.93(d,J＝1.9Hz,1H),7.74–7.70(m,1H),7.70–7.67(m,1H),7.67–7.63(m,1H),7.52–7.34(m,1H),7.34–7.30(m,1H),7.26–7.16(m,1H),7.16–7.05(m,1H),7.03(s,1H),7.02(s,1H),7.00(s,1H),6.52–6.52(m,1H),6.51(s,1H),4.21(t,J＝6.6Hz,3H),3.90–3.80(m,3H),3.79(s,3H).

¹³C NMR(101MHz,DMSO-d₆)δ167.50,161.18,156.21,150.09,149.64,146.52,144.53,143.69,143.57,132.22,132.05,130.89,129.19,128.92,122.01,118.56,118.52,114.54,114.24,114.04,95.52,82.76,65.56,55.93,55.77,31.82,31.66,30.52,30.33,29.55,22.63,19.18,14.08.

HR-ESI-MS Calcd.for C₃₃H₂₆FN₅O₅[M+H]⁺:592.19280；found:592.19913.

Table 1 shows the pyridine amides obtained in examples 1 to 30.

Table 1 Compounds and corresponding substituents

Antitumor Activity test

The antitumor activity of the picolinamide compounds with the serial numbers of GMZC-Q-1 to GMZC-Q-40 is researched.

1. Pretreatment of pharmaceutical agents

Preparing a compound to be tested: the compound with the corresponding number is dissolved into stock solution with the concentration of 100mM by DMSO, and the stock solution is diluted to 0-500 mu M by serum-free culture medium during measurement and is used as the reagent.

2. Experimental methods

(1) Testing of antitumor Activity Using MDA-MB-231 cells

Using high-glucose DMEM medium, 10% south American Fetal Bovine Serum (FBS), 100U/mL penicillin and 100mg/mL streptomycin, 5% CO at 37 ℃₂Culturing in an incubator. When the MDA-MB-231 cells are in good state, the cells are inoculated into a 96-well plate, the density is 4000 per well, and the temperature is 37 ℃ and the CO content is 5 percent₂The culture is continued in the incubator, and after the attachment is complete, 100 mul of serum-free culture medium containing different compound concentrations is added. After 72h incubation, the medium was aspirated off, 110. mu.L of a mixture containing 10. mu.L of CCK8 and 100. mu.L of medium was added and incubation continued for 1-4 h. Cabozantinib and 5-fluorourcral are selected as positive control drugs, and a blank group and a zero-setting group are set simultaneously. The absorbance was measured at 450nm and 630nm using a microplate reader. The data obtained were processed to calculate the inhibition rate of each compound. The inhibition was plotted against the corresponding concentration of the different compounds, and the data were processed using SPSS19.0 statistical software to calculate IC₅₀The value is obtained. The calculation formula of the inhibition rate is as follows: [1- (Experimental group-background group)/(blank group-zero adjustment group)]X 100%. Each experimental group was set with 6 replicates and the experimental results are expressed as mean ± SD of 3 independent experiments.

(2) Testing of antitumor Activity Using MCF-7 cells

Using high-glucose DMEM medium, 10% south American Fetal Bovine Serum (FBS), 1% double antibody (100U/mL penicillin and 100mg/mL streptomycin), 5% CO at 37 ℃₂Culturing in an incubator. When MCF-7 cells are in good state, the cells are inoculated into a 96-well plate at 100 uL/well and the cell density of 4000/well, and 5% CO is carried out at 37 DEG C₂And (3) continuing culturing in the incubator, adding 100 mu L of serum-free culture medium containing different compound concentrations after the attachment is complete, incubating for 72h, sucking the culture solution, adding 110 mu L of mixed solution containing 10 mu L of CCK8 and 100 mu L of culture medium, and continuing incubating for 2.5 h. The absorbance was measured at 450nm and 630nm using a microplate reader. From the obtained OD values, the inhibition ratios corresponding to the set concentrations were calculated, and the IC50 values were calculated using SPSS19.0 software. Inhibition rate ═ 1- (experimental group-background group)/(blank group-zero adjustment group)]X 100%. Each experimental group was set to 6 replicates and the results are expressed as mean ± SD of three independent experiments.

(3) Anti-tumor activity test using A549 cells

Using RPMI Medium 1640 Medium, 10% south American Fetal Bovine Serum (FBS), 1% double antibody (100U/mL penicillin and 100mg/mL streptomycin), 5% CO at 37 deg.C₂Culturing in an incubator. When the A549 cells are in good state, inoculating the cells into a 96-well plate at 100 uL/well and 6000 cells/well, and carrying out 5% CO treatment at 37 DEG C₂And (3) continuing culturing in the incubator, adding 100 mu L of serum-free culture medium containing different compound concentrations after the attachment is complete, incubating for 72h, sucking the culture solution, adding 110 mu L of mixed solution containing 10 mu L of CCK8 and 100 mu L of culture medium, and continuing incubating for 1.5 h. The absorbance was measured at 450nm and 630nm using a microplate reader. From the obtained OD values, the inhibition ratios corresponding to the set concentrations were calculated, and the IC50 values were calculated using SPSS19.0 software. Inhibition rate ═ 1- (experimental group-background group)/(blank group-zero adjustment group)]X 100%. Each experimental group was set to 6 replicates and the results are expressed as mean ± SD of three independent experiments.

(4) Antitumor activity test Using Hep G2 cells

Using high-sugar DMEM medium, 10% south American Fetal Bovine Serum (FBS), 1% double antibody (100U/mL penicillin and 100mg/mL streptomycin), 5% CO at 37 ℃₂Culturing in an incubator. When the Hep G2 cells are in good condition, the cells are inoculated into a 96-well plate at 100 uL/well and 6000 cells/well at 37 ℃ with 5% CO₂And (3) continuing culturing in the incubator, adding 100 mu L of serum-free culture medium containing different compound concentrations after the attachment is complete, incubating for 72h, sucking the culture solution, adding 110 mu L of mixed solution containing 10 mu L of CCK8 and 100 mu L of culture medium, and continuing incubating for 2.5 h. The absorbance was measured at 450nm and 630nm using a microplate reader. From the obtained OD values, the inhibition ratios corresponding to the set concentrations were calculated, and the IC50 values were calculated using SPSS software. Inhibition rate ═ 1- (experimental group-background group)/(blank group-zero adjustment group)]X 100%. Each experimental group was set to 6 replicates and the results are expressed as mean ± SD of three independent experiments.

3. Results of the experiment

The results of the cell experiments are shown in table 2.

TABLE 2 antitumor Activity test results of picolinamide compounds of the present invention

The experimental results show that the pyridine amide compounds provided by the invention can inhibit or kill tumor cells, the anti-tumor effect of part of the compounds is superior to that of the marketed drugs 5-fluorourcil and Cabozantinib, the compounds have good anti-tumor activity, and the compounds can be used for preparing drugs for treating tumors such as human breast cancer, human lung cancer and human liver cancer, and can effectively treat tumors.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.

Claims

1. A picolinamide compound characterized in that the picolinamide compound is 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-picolinamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-picolinamide) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6 '-methoxy- [2,3' -bipyridine ] -6-carboxamido) phenoxy ] -5-methylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxybenzene) benzamide Yl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5, 6-dimethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-fluoro-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridinecarboxamido) phenoxy ] -5-methyl-6-ethylpyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-fluorophenyl) -2-pyridinecarboxamido phenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-methoxy-4-fluorophenyl) -2-pyridinecarboxamido phenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (4-trifluoromethoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3-formyl-4-methoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 4-dimethoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine, 5- (4-methoxyphenyl) -7- [ 2-fluoro-4- (6- (3, 5-dimethoxyphenyl) -2-pyridylaminophenoxy) ] pyrazolo [1,5-a ] pyrimidine.

2. The process for producing a picolinamide compound as defined in claim 1, which comprises the steps of:

(1) synthesis of intermediates 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine:

(3) synthesis of intermediates 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7-chloro-pyrazolo [1,5-a ] pyrimidine:

taking 5-methyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-hydroxy-pyrazolo [1,5-a ] pyrimidine, N-dimethylaniline or diethylamine or triethylamine and phosphorus oxychloride, reacting for 24-48 h at 20-60 ℃, slowly pouring the reaction system into ice water while stirring under the ice bath condition, adjusting the pH value to be neutral after recovering the normal temperature, separating and purifying to obtain oily liquid products, namely the 5-methyl-7-chloro-pyrazolo [1,5-a ] pyrimidine and 5, 6-dimethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7-chloro-pyrazolo [1,5-a ] pyrimidine;

(4) synthesis of intermediates 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine:

(5) synthesis of intermediates 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine:

adding acetic acid solution or formic acid solution or ammonium chloride solution, and 5-methyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-nitrophenoxy) -pyrazolo [1,5-a ] pyrimidine into reduced iron powder, separating and purifying after the reaction is finished, the obtained solid product is the 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine, 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine;

(6) synthesizing an intermediate 6- (phenyl) -2-pyridinecarboxylic acid compound or 6- (pyridyl) -2-pyridinecarboxylic acid compound:

taking 2-bromo-6-pyridinecarboxylic acid, substituted phenylboronic acid or phenylboronic acid pinacol ester, cesium carbonate and Pd (PPh)₃)₄Or PdCl₂Or PdCl₂(dppf) or Pd (OAc)₂Or Pd (PPh)₃)₂Cl₂Carrying out reflux reaction under the protection of nitrogen, and separating and purifying after the reaction is finished to obtain a solid product, namely the 6- (phenyl) -2-pyridine carboxylic acid compound or the 6- (pyridyl) -2-pyridine carboxylic acid compound;

(7) synthesizing the pyridine amide compound:

taking 6- (phenyl) -2-pyridine carboxylic acid compounds or 6- (pyridyl) -2-pyridine carboxylic acid compounds, 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate, N, N-diisopropylethylamine, and 5-methyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5, 6-dimethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5-methyl-6-ethyl-7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine or 5- (4-methoxyphenyl) -7- (2-fluoro-4-aminophenoxy) -pyrazolo [1,5-a ] pyrimidine reacts for 8-25 h at the temperature of 0-60 ℃, and is separated and purified after the reaction is finished, so that the solid product is the pyridine amide compound.

3. The process for producing a picolinamide compound as defined in claim 2, wherein the heating and stirring reaction in step (1) is: stirring and reacting for 1-3 h at 100-140 ℃; the reflux reaction in the step (2) is as follows: carrying out reflux reaction at 110-130 ℃ for 4-8 h; the heating stirring reaction in the step (4) is as follows: reacting for 1-10 h at 100-130 ℃; the reaction of the step (5) is as follows: reacting for 3-8 h at 80-100 ℃; the reflux reaction in the step (6) is as follows: reflux reaction is carried out for 1-6 h at 70-110 ℃.

4. The use of picolinamide compounds as defined in claim 1 in the preparation of anti-tumor medicaments.

5. An antitumor agent comprising the picolinamide compound as defined in claim 1 and a pharmaceutically acceptable carrier.