CN108069938A - 2,4- disubstituted pyridines and its preparation method and application - Google Patents

Abstract

The present invention relates to 2 shown in logical formula (I), 4 disubstituted pyridines and its pharmaceutically acceptable salt, hydrate or prodrug, these compounds have preferable antitumor activity as c Met and 2 dual antagonists of VEGFR.The invention further relates to these compounds preparation method and contain their pharmaceutical preparation and these compounds and application of its Pharmaceutical composition in tumour is treated.

Description

2,4-disubstituted pyridine compounds and their preparation methods and applications

technical field

The present invention relates to new 2,4-disubstituted pyridine compounds and their pharmaceutically acceptable salts, hydrates or prodrugs. These compounds have better c-Met and VEGFR-2 dual inhibitor activities. The invention also discloses its preparation method and pharmaceutical preparations containing them, as well as the application of these compounds and their pharmaceutical compositions in treating tumors.

Background technique

Cancer is one of the diseases that seriously endanger human health and life in the world today. With the deepening of tumor molecular biology research, intracellular signal transduction, cell cycle regulation and induction of apoptosis, angiogenesis, and the interaction between extracellular matrix and cells in malignant tumors have been gradually elucidated. Among them, receptor tyrosine kinases (Tyrosine Kinases Receptors, RTKs) are closely related to the occurrence and development of tumors. Its functions include activating downstream signal transduction molecules, promoting cell proliferation, migration, survival and so on. Therefore, RTKs have become interesting molecular therapeutic targets in antitumor therapy.

c-Met is a heterodimer receptor tyrosine kinase linked by disulfide bonds, which is expressed in both normal cells and malignant tumor cells in the human body. Mutations in the c-Met receptor tyrosine kinase have been found in hereditary and secondary renal and liver cancers and a variety of other tumors. The c-Met-HGF/SF signaling pathway plays an important physiological role in embryonic development and tissue regeneration. In normal cells, the c-Met-HGF/SF signaling pathway is strictly regulated; however, in tumor cells, it is abnormally regulated. A large number of studies have shown that c-Met in tumor tissue can interact functionally with a variety of signaling molecules, which has become an important reason for tumor carcinogenesis and treatment resistance.

Angiogenesis and lymphangiogenesis are important links in tumor formation and metastasis, and the vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) families play a major role in the above two links. The VEGFR family includes three specific tyrosine kinase receptors, VEGFR-1, VEGFR-2 (KDR) and VEGFR-3. VEGFR-2 is an important regulator of endothelial cell proliferation caused by VEGF signal transduction, increasing vascular permeability and promoting angiogenesis, and the affinity of VEGFR-2 and VEGF is greater than that of VEGFR-1. Studies have shown that only VEGFR-2 is expressed in endothelial cells, and activation of VEGFR-2 can efficiently stimulate angiogenesis. Therefore, VEGFR-2 is the main target for the development of anti-angiogenesis drugs.

Studies have shown that HGF/SF-c-Met and VEGFA-VEGFR2 play a synergistic role in inducing angiogenesis. In the vascular endothelial cell experiment, the simultaneous administration of HGF and VEGFA significantly enhanced the activation of downstream signaling molecules (including: ERK-MAPK, AKT and FAK), thereby enhancing the proliferation, migration and cell survival of vascular endothelial cells.

According to statistics, more than a quarter of the anti-tumor drug targets are protein kinases, and the study of the structure of protein tyrosine kinases is of great significance for the discovery of new drug-making chemical frameworks. The structures of different protein tyrosine kinases have a high degree of similarity. The first small-molecule inhibitor of c-Met kinase was reported as Staurosporine analogue K-252a, which is a broad-spectrum kinase inhibitor and inhibits c-Met kinase at the millimolar level. Research on c-Met/VEGFR-2 dual inhibitors has also made great progress, and Cabozantinib was approved for marketing in the end of 2012 for the treatment of medullary thyroid carcinoma (MTC). In addition, several dual inhibitors are in clinical research.

Through literature research, it is found that pyridine cores are widely used in drug development, especially in the research field of receptor tyrosine kinase inhibitors. Pyridine backbones have already been used in VEGFR, c-Met inhibitors, multi-target kinase inhibitors and Bcr-Abl kinase inhibitors, such as Regorafenib, Sorefinib, Rebastinib and Golvatinib.

The present invention is based on the structures of Foretinib and AMG458, uses pyrazolone fragments as the side chain hydrogen bonding region, uses pyridine as the mother core, and uses different amide structures to replace the side chain regions, and preferentially adopts the most favorable for entering the hydrophilic channel. Substituting the neutral amide structure, a series of compounds with better activity were obtained.

Contents of the invention

The object of the present invention is to provide some new 2,4-disubstituted pyridine compounds and their pharmaceutically acceptable salts, hydrates or prodrugs. These compounds have the effect of inhibiting c-Met and VEGFR-2, and can be used to prepare novel antitumor drugs.

The object of the present invention is also to provide a preparation method for synthesizing new 2,4-disubstituted pyridine compounds.

Another object of the present invention is to provide a pharmaceutical preparation containing novel 2,4-disubstituted pyridine compounds.

Detailed invention content is as follows:

The present invention has synthesized a series of compounds described in the general structural formula (I) or pharmaceutically acceptable salts thereof:

in,

R ¹ , R ² , and R ³ are the same or different, and are independently selected from H, D, halogen, NO ₂ , NH ₂ , and OH;

A is CONR ^a R ^b , COOR ^c , 4-R ^d replaces -1,2,4-triazole;

R ^a , R ^b are not H or methyl at the same time, and are independently selected from H, C _1-3 alkyl, alkenyl or alkynyl-C _1-3 alkylene, C _3-6 cycloalkyl, C _1-3 alkoxy-C _2-6 alkylene, C _3-6 heterocyclyl-C _1-3 alkylene, heteroaryl-C _1-3 alkylene consisting of 5-10 atoms, When R ^a and R ^b are connected to the same nitrogen atom, R ^a and R ^b together with the nitrogen atom connected to them can optionally form a substituted or unsubstituted heterocyclic ring consisting of 5-8 atoms;

R ^c is selected from C _1-3 alkyl;

R ^d is (CH ₂ ) _n X R ^e ;

n is selected from an integer between 1-3;

X is selected from heteroatoms such as N, O and S;

R ^e is selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy;

Or ^Re and its connected nitrogen atom together form a 5-6 membered saturated heterocyclic group, which optionally contains 1-4 members selected from N, O and S in addition to the nitrogen atom connected to ^Re . A heteroatom, the saturated heterocyclic group is optionally substituted by 1-3 identical or different R ^f ;

R ^f is H, (C ₁ -C ₃ ) alkyl, hydroxyl.

The present invention preferably relates to pyridine compounds represented by general formula (I) and pharmaceutically acceptable salts, hydrates or prodrugs thereof, wherein,

R ¹ , R ² , and R ³ are the same or different, and are independently selected from H, F, Cl, and Br;

R ^a , R ^b are not H or methyl at the same time, independently selected from H, C _1-2 alkyl, alkynyl-C _1-2 alkylene, C _3-5 cycloalkyl, C _1-2 alkane Oxygen-C _2-3 alkylene, C _5-6 heterocyclyl-C _1-3 alkylene, heteroaryl-C _1-2 alkylene consisting of 5-6 atoms, when R ^a and When R ^b is connected to the same nitrogen atom, R ^a , R ^b , together with the nitrogen atom connected to them, can optionally form a substituted or unsubstituted heterocyclic ring consisting of 5-6 atoms;

R ^c and R ^e are selected from (C ₁ -C ₃ ) alkyl groups;

Or R ^e forms a 5-6 membered saturated heterocyclic group together with the nitrogen atom to which it is connected, and the saturated heterocyclic group optionally contains 1-2 heterocyclic groups selected from N and O in addition to the nitrogen atom connected to R ^e atom, the saturated heterocyclic group is optionally substituted by 1-2 identical or different R ^f ;

R ^f is H, methyl, ethyl, hydroxyl;

n is 2, 3;

X is selected from N, O.

The present invention more preferably relates to pyridine compounds represented by general formula (I) and pharmaceutically acceptable salts, hydrates or prodrugs thereof, wherein,

R ¹ is F, R ² and R ³ are both H;

R ^a , R ^b are not H or methyl at the same time, independently selected from H, methyl, propargyl, cyclopropyl, methoxy-C _2-3 alkylene, morpholine-C _2-3 alkylene Alkyl, thiophene-methylene, when R ^a and R ^b are bonded to the same nitrogen atom, R ^a , R ^b , together with the nitrogen atom to which they are bonded, can optionally form a substituted or unsubstituted 5 -Heterocyclic rings consisting of 6 atoms selected from the group consisting of: tetrahydropyrrole, piperidine, piperazine, morpholine;

R ^c and R ^e are selected from methyl or ethyl;

Or R ^e and its attached nitrogen atom form 4-morpholinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 1-piperazinyl, 4-methyl-1-piperidinyl Base, 1-pyrrolidinyl, 4-thiomorpholinyl.

The compound of general formula (I) of the present invention and its pharmaceutically acceptable salt, hydrate or prodrug are preferably selected from the following compounds:

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- Methyl 2-picolinate (I-01);

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- 2-pyridine propargylamide (I-02);

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-methylpicolinamide (I-03);

N-(3-fluoro-4-((2-(piperidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-carboxamide (I-04);

N-(3-fluoro-4-((2-(4-methylpiperazine-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-methyl-3-oxo-2 -Phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-05);

N-(3-fluoro-4-((2-(morpholine-4-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-carboxamide (I-06);

N-cyclopropyl-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2- Fluorophenyl) pyridinecarboxamide (I-07);

N-(3-fluoro-4-((2-(4-(furan-2-carbonyl)piperazine-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-08);

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(3-morpholinopropyl)pyridinecarboxamide (I-09);

N-(4-((2-(4-acetylpiperazine-1-carbonyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2 - phenyl-2,3-dihydro-1H-pyridine-4-carboxamide (I-10);

N-(4-((2-(4-ethylpiperazine-1-carbonyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-11);

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(3-methoxypropyl)pyridinecarboxamide (I-12);

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(2-morpholinoethyl)pyridinamide (I-13);

4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(thiophene-2-methyl)pyridinamide (I-14);

N-(3-fluoro-4-((2-(pyrrole-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-dihydro-1H-pyrazole-4-carboxamide (I-15);

N-(4-((2-([1,4′-dipiperidine]-1′-carbonyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-16);

N-(3-fluoro-4-((2-(4-(3-methoxypropyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)benzene Base)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-17);

N-(4-((2-(4-(3-(dimethylamino)propyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)-3 -fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-18);

N-(3-fluoro-4-((2-(4-(3-morpholinopropyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)benzene Base)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-19);

N-(3-fluoro-4-((2-(4-(3-(4-methylpiperazin-1-yl)propyl)-4H-1,2,4-triazol-3-yl) Pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-20 ).

The structures of some compounds are:

According to the present invention, pharmaceutically acceptable salts include addition salts formed with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc. Hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, succinic acid and similar known acceptable acids form salts.

Furthermore, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are derivatives of general formula (I), which themselves may have weak activity or even no activity, but after administration, under physiological conditions (for example, by metabolism, solvolysis or other means) ) is converted into the corresponding biologically active form.

The present invention can contain 2,4-disubstituted pyridine derivatives of the above formula (I) and pharmaceutically acceptable salts and hydrates thereof as active ingredients, mixed with pharmaceutically acceptable excipients to prepare compositions, And be prepared into a clinically acceptable dosage form, the above-mentioned excipient refers to a diluent, adjuvant or carrier that can be used in the field of pharmacy. The above dosage forms refer to clinically commonly used injections, tablets, capsules and the like.

The compounds involved in the present invention or their pharmaceutically acceptable salts, hydrates, and prodrugs can be used alone as the only anti-tumor drug, or can be used in combination with existing anti-tumor drugs to treat and/prevent tumors, etc. .

The Examples and Preparations provided hereinafter further illustrate and illustrate the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations does not limit the scope of the invention in any way.

The preparation method of the compound of general formula (I), the method is as follows:

Using methyl 4-chloropicolinate (1) as raw material, under the reflux of chlorobenzene, the 4-position chlorine is replaced by 2-fluoro-4-nitro (2), and hydrogen reduces the nitro group (3); the reduced amine Then condense with the key intermediate (12) to form the amide (4); hydrolyze the methyl ester with LiOH to obtain the carboxylic acid (5), and then react with various amines to obtain the target compound (6); Decomposition generates hydrazide (7); reacts with DMF-DMA under toluene reflux to generate intermediate (8), and then undergoes cyclization with substituted primary amine under acetic acid heating conditions to generate target compound (9).

Concrete reaction steps are:

In the preparation method of the compound of general formula (I) involved in the present invention, the preparation method of the key intermediate (12) is as follows:

Using ^R3 substituted antipyrine (10) as starting material, formylation under DMF/ _POCl3 conditions to obtain formylated product (11); oxidized to carboxylic acid under alkaline potassium permanganate conditions The key intermediate (12) was obtained.

The specific implementation method is as follows:

The following are the pharmacological experiment data of some compounds of the present invention:

1. Compound's inhibitory activity on cell proliferation

Evaluation of the inhibitory activity of the synthesized compounds on the cell level of c-Met and VEGFR-2, and the inhibition of the proliferation of BaF3-TPR-Met cells and human umbilical vein endothelial cells (HUVEC) by tetrazolium salt (MTT) assay . In order to evaluate the inhibitory effect of compounds on the c-Met signaling pathway, BaF3-TPR-Met cells were first used to screen the synthetic compounds for activity. Preliminary screening was carried out at a concentration of 2.5 μM, and IC ₅₀ was determined for compounds with higher inhibition rates.

Ba/F3 cells are IL-3 (interleukin-3)-dependent proto-B lymphocytes, and must be stimulated by IL-3 to grow and differentiate. The recombinant plasmid expressing TPR-Met was transfected into Ba/F3 cells to induce malignant transformation to form BaF3-TPR-Met cells. The cells have no interference from the extracellular segment of c-Met, and the TPR-Met fusion protein in the cells is expressed in the cytoplasm, and can be continuously activated independently of HGF stimulation, and is a c-Met-dependent sensitive cell line.

Human umbilical vein endothelial cells (HUVEC) are isolated from the umbilical cord vein and are an ideal cell model for the study of tumor angiogenesis and signaling pathways dependent on growth factors (VEGF, bFGF, HGF, etc.). The compound's inhibition of VEGF-induced HUVEC proliferation can indirectly reflect the compound's ability to inhibit VEGFR. Therefore, HUVEC is often used as a cell line for screening inhibitors of VEGFR signaling pathways.

The specific implementation method is:

(1) Cells in the logarithmic growth phase were inoculated on a 96-well plate at a density of 5×10 ³ /well (BaF3-TPR-Met) or 3×10 ⁵ /well (HUVEC) and cultured for 24 hours before adding drugs.

(2) Set positive control group, blank group and zero adjustment wells, add 100 μL of compounds with different concentration gradients to each well, and set five duplicate wells for each concentration.

(3) After continuing to culture for 72h (BaF3-TPR-Met) or 96h (HUVEC), add 20μL of MTT solution (5mg/ml) to each well to make the final concentration reach 1mg/ml, continue to culture for 4h, centrifuge (3000r, 10 min) the supernatant was discarded, and 150 μL DMSO was added to each well. The OD value of each microwell was measured by a microplate reader at a wavelength of 490 nm.

(4) Calculate the IC ₅₀ value of each compound with GraphPad Prism5.0 software.

The inhibitory rate of each compound of class I to BaF3-TPR-Met cells is shown in Table 1:

Table 1. The inhibition rate of each compound on BaF3-TPR-Met cells at a concentration of 2.5uM

The preferred compound BaF3-TPR-Met cell and HUVEC cell inhibitory activity test results are shown in Table 2:

Table 2. The inhibitory activity of preferred compounds on BaF3-TPR-Met cells and HUVEC cells

2. The inhibitory activity of the compound on c-Met and VEGFR-2 molecular level

Using enzyme-linked immunosorbent assay (ELISA) technology, the inhibitory activity of some compounds with better cell activity on the two tyrosine kinase targets of c-Met and VEGFR-2 was determined.

The specific implementation method is:

(1) Enzyme reaction substrate Poly(Glu, Tyr) was diluted 4:1 with potassium ion-free PBS (10mM sodium phosphate buffer, 150mM NaCl, pH7.2-7.4) to 20μg/mL, and 125μL/well was coated with enzyme labeling plate, and react at 37°C for 12-16 hours. Discard the liquid in the well. To wash the plate, wash the plate three times with 200 μL/well of T-PBS (potassium ion-free PBS containing 0.1% Tween-20), 5 minutes each time. Dry the plate in an oven at 37°C for 1-2 hours.

(2) Add 49 μL of ATP solution diluted with reaction buffer (50 mM HEPES pH7.4, 50 mM MgCl ₂ , 0.5 mM MnCl ₂ , 0.2 mM Na ₃ VO ₄ , 1 mM DTT) into each well, and add 1 μL of the compound to be tested in each well, Then add 50 μL c-Met kinase domain recombinant protein or VEGFR-2 kinase domain recombinant protein diluted with reaction buffer to start the reaction, and two wells without ATP control wells are required for each experiment. Put it on a shaker (100 rpm) at 37°C for 1 hour. The liquid in the well was discarded, and the plate was washed three times with T-PBS.

(3) Add 100 μL/well of antibody PY99 (the antibody is diluted 1:500 with T-PBS containing 5 mg/mL BSA), and react on a shaker at 37° C. for 0.5 hours. The liquid in the well was discarded, and the plate was washed three times with T-PBS.

(4) Add 100 μL/well of horseradish peroxidase-labeled goat anti-mouse secondary antibody (the antibody is diluted 1:2000 with T-PBS containing 5 mg/ml BSA), and react on a shaker at 37°C for 0.5 hours. The liquid in the well was discarded, and the plate was washed three times with T-PBS.

(5) Add 100 μL/well of 2 mg/ml OPD chromogenic solution (diluted with 0.1M citric acid-sodium citrate buffer (pH=5.4) containing 0.03% H ₂ O ₂ ), and react in the dark at 25°C for 1- 10 minutes.

(6) Add 50 μL/well of 2M H ₂ SO ₄ to stop the reaction, and read with VERSAmax on a wavelength-tunable microplate microplate reader with a wavelength of 490 nm.

(7) Calculate the IC ₅₀ value of each compound with GraphPad Prism5.0 software

The experimental results of some compounds are shown in Table 3:

Table 3 _IC50 values of compounds on c-Met and VEGFR-2 receptors

The present invention also includes pharmaceutical preparations, which contain the compound of general formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable carrier as an active agent. The above-mentioned pharmaceutically acceptable carrier refers to the conventional drug carrier in the field of pharmacy, and refers to one or more inert, non-toxic solid or liquid fillers, diluents, auxiliary agents, etc., which do not reversely interact with active compounds or patients. take effect.

The dosage forms of the composition of the present invention can be commonly used pharmaceutical dosage forms such as tablets, capsules, pills, suppositories, soft capsules, oral liquids, suspensions, and injections.

Tablets and capsules for oral use contain conventional excipients such as fillers, diluents, lubricants, dispersants and binders.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to well-known methods in the field of pharmacy.

Dosages of the above active agents will vary from formulation to formulation.

In general, amounts which have proven advantageous, to achieve the desired result, are in the total range of about 0.01-800 mg per kilogram of compound of formula (1) administered every 24 hours, preferably in the total range of 0.1-80 mg/kg. Administer in several single doses, if necessary.

However, it is also possible, if necessary, to deviate from the above-mentioned dosages, i.e. it depends on the type and body weight of the subject to be treated, the individual's behavior towards the drug, the nature and severity of the disease, the type of formulation and administration, and the time of administration. and interval.

The present invention will be further described below by embodiment:

Detailed ways

Example 1

Preparation of methyl 4-(2-fluoro-4-nitrophenoxy)-2-pyridinecarboxylate

Dissolve methyl 4-chloro-2-pyridinecarboxylate (20g, 0.117mol) in 400mL chlorobenzene, add 2-fluoro-4-nitrophenol (27.5g, 0.175mol) to reflux for 12h, TLC detects that the reaction is complete, cool After reaching room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in dichloromethane, washed three times with saturated sodium carbonate solution, washed three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered with suction, and the reaction solution was concentrated to dryness to obtain a brown solid. Ethanol was recrystallized and suction filtered to obtain 15.5 g of white solid with a yield of 45.4%.

MS (ESI, m/z): 293.2 [M+H] ⁺ .

¹ H NMR (300MHz, CDCl ₃ ): δ: 8.70(d, J=5.5Hz, 1H), 8.19～8.17(m, 1H), 8.16(t, J=3.0Hz, 1H), 7.69(d, J =2.5Hz, 1H), 7.40～7.34(m, 1H), 7.11(dd, J=5.5, 2.5Hz, 1H), 4.01(s, 3H).

Example 2

Preparation of methyl 4-(4-amino-2-fluorophenoxy)-2-pyridinecarboxylate

Dissolve methyl 4-(2-fluoro-4-nitrophenoxy)-2-pyridinecarboxylate (10 g, 34.22 mmol) in a mixed solution of 10 mL of dichloromethane and 20 mL of ethanol, add 0.5 g of 10% palladium carbon, Replaced with hydrogen three times, reacted at room temperature for 20 h, after the completion of the reaction as detected by TLC, suction filtered, and the reaction solution was concentrated to dryness to obtain 8.3 g of a light yellow solid with a yield of 92.5%.

MS (ESI, m/z): 263.2[M+H] ⁺ .

¹ H NMR (300MHz, DMSO-d ₆ ): δ: 8.78(s, 1H), 8.12(s, 1H), 8.08(d, J=3.0Hz, 1H), 8.03(d, J=3.0Hz, 1H ), 3.90(s, 3H).

Example 3

4-[4-(1,5-Dimethyl-3-oxyl-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy]- Preparation of methyl 2-picolinate (I-1)

Dissolve methyl 4-(2-fluoro-4-nitrophenoxy)-2-pyridinecarboxylate (2.57g, 9.9mmol) in dichloromethane, add EDCI (2.2g, 12mmol), HOBT (1.6g, 12 mmol), stirred at room temperature for 2 h, TLC detected that the reaction was complete, the reaction solution was concentrated to dryness, and column chromatography gave 3.8 g of white solid with a yield of 80.8%. mp: 156-158°C.

MS (ESI, m/z): 477.5 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3130.57，1727.15，1680.32，1634.96，1499.01，1588.85，1557.26，1456.14，1440.85，1429.01，1414.62，1301.14，1221.69，1191.49，1116.69，991.16，823.86，790.04，778.83，756.82， 743.91, 696.96.

¹ H NMR (300MHz, DMSO-d ₆ ): δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=8.9Hz, 1H), 7.56(d, J =7.5Hz, 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=8.9Hz, 2H), 3.83(s, 3H), 3.35(s, 3H ), 2.68(s, 3H).

¹³ C NMR (75MHz, DMSO-d ₆ ): δ: 161.43, 151.76, 129.46, 128.95, 127.22, 123.97, 115.78, 114.10, 111.46, 54.88, 52.57, 40.00, 39.72, 39.45, 39.17, 334.24, 2,

Example 4

4-[4-(1,5-Dimethyl-3-oxyl-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy]- Preparation of 2-pyridinecarboxylic acid

4-[4-(1,5-dimethyl-3-oxyl-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy] - Methyl 2-pyridinecarboxylate (5g, 10.5mmol) was dissolved in 20mLTHF, 6mL of water and 6mL of methanol were added, lithium hydroxide (0.5g, 21mmol) was added, stirred at room temperature for 2h, TLC detected that the reaction was complete, and most of the reaction was evaporated under reduced pressure Solvent, add 1N hydrochloric acid solution to adjust the pH to 2, and filter with suction to obtain 4.2 g of white solid with a yield of 85.7%.

MS (ESI, m/z): 463.4 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO-d ₆ ): δ: 12.15(s, 1H) 10.95(s, 1H), 8.58(dJ=5.5Hz, 1H), 7.94(d, J=9.0, 1H), 7.58( d, J=7.8Hz, 3H), 7.53(d, J=7.8, 1H), 7.45(s, 3H), 7.35(d, J=9.0, 2H), 2.39(s, 3H), 1.69(s, 1H).

Example 5

4-[4-(1,5-Dimethyl-3-oxyl-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy]- Preparation of 2-pyridine propargylamide (I-2)

4-[4-(1,5-dimethyl-3-oxyl-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy] -2-pyridinecarboxylic acid (70mg, 0.15mmol), dissolved in 10mL of dichloromethane, added EDCI (35mg, 0.18mmol), HOBT (24.5mg, 0.18mmol), DIEA (45.5mg, 0.36mmol), after 15min of reaction, Propargylamine (28mg, 0.36mmol) was added, and the reaction was complete as detected by TLC. The reaction solution was concentrated to dryness and subjected to column chromatography to obtain 60mg of a white solid with a yield of 80%. mp: 128-130°C.

MS (ESI, m/z): 500.5[M+H] ⁺ .

IR(KBr，cm ^-1 )v：3385.90，3129.92，2962.34，2110.20，1681.56，1633.99，1592.55，1552.83，1495.72，1471.66，1406.64，1362.30，1295.11，12631.13，1192.36，1116.19，811.59，778.04，757.37，745.15， 700.22, 551.77.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.89(s, 1H), 9.25(s, 1H), 8.40(d, J=5.6Hz, 1H), 8.21(t, J=5.2Hz, 1H), 7.92 (d, J=8.7Hz, 1H), 7.72(d, J=2.4Hz, 1H), 7.57(t, J=7.4Hz, 1H), 7.49(t, J=7.4Hz, 1H), 7.37(d , J=7.4Hz, 3H), 7.27(d, J=6.8Hz, 1H), 7.10(t, J=8.7Hz, 1H), 6.96(dd, J=5.5, 2.4Hz, 2H), 4.25(dd , J=5.5, 2.4Hz, 2H), 3.38(s, 3H), 2.80(s, 3H), 2.27(s, 1H).

¹³ C NMR (75MHz, CDCl ₃ ): δ: 149.31, 129.03, 126.12, 122.83, 115.30, 112.93, 109.39, 108.70, 108.41, 71.11, 33.00, 28.69, 11.47.

Example 6

4-[4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluoro-phenoxy]- Preparation of N-Methylpyridinamide (I-3)

The synthesis procedure is the same as that of I-2, and the raw material used is methylamine tetrahydrofuran (3.0M) dissolved in 1 mL to obtain 72 mg of white solid with a yield of 68%. mp: 116-118°C.

MS (ESI, m/z): 476.5 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3387.27，3129.44，2962.85，1681.33，1634.95，1592.14，1554.71，1497.21，1468.40，1427.37，1412.74，1366.78，1293.22，1260.71，1191.06，1118.62，1024.49，995.56，918.45，866.33， 824.90, 800.46, 788.71, 778.85, 757.00, 743.12, 699.23, 552.99.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 3.37(s, 3H), 3.00(s, 3H), 2.79 (s, 3H).

¹³ C NMR(75MHz，CDCl ₃ )δ：165.52，163.99，163.33，161.17，155.54，154.35，152.05，151.74，149.18，132.42，135.00，129.35，128.70，126.13，122.85，115.29，112.55，109.11，108.67，108.35 , 32.97, 25.64, 11.45.

Example 7

N-{3-fluoro-4-[(2-(piperidine-1-formyl)pyridin-4-yl)oxo]phenyl}-1,5-dimethyl-3-oxo-2- Preparation of phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-4)

The synthesis procedure is the same as that of I-2, the raw material used is morpholine, and 65 mg of off-white solid is obtained with a yield of 48.4%. mp: 226-228°C.

MS (ESI, m/z): 530.6 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3129.06，2934.69，2861.22，1637.66，1618.47，1687.75，1590.95，1553.99，1457，56，1445.79，1427.58，1401.68，1289.22，1259.86，1194.60，1116.96，952.33，824.99，801.06， 742.12, 694.29.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.53(s, 2H), 3.31 (s, 5H), 2.65 (s, 3H), 1.59 (s, 4H), 1.47 (s, 2H).

¹³ C NMR (75MHz, CDCl ₃ ) δ: 163.81, 150.32, 129.86, 129.23, 126.66, 123.44, 115.84, 111.43, 110.29, 108.98, 48.20, 43.19, 33.47, 26.42, 25.47, 102.939, 1.1

Example 8

N-{3-fluoro-4-[(2-(4-methylpiperazine-1-formyl)pyridin-4-yl)oxo]phenyl}-1,5-dimethyl-3-oxo Preparation of Sub-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-5)

The synthesis procedure is the same as that of I-2, and the raw material used is N-methylpiperazine to obtain 72 mg of light yellow solid with a yield of 67.8%. mp: 236-238°C.

MS (ESI, m/z): 545.6 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3448.37，3127.33，2967.55，2849.56，2230.09，1684.99，1629.37，1590.49，1569.02，1505.28，1455.98，1400.95，1290.91，1261.63，1199.01，1114.62，959.85，821.36，405.02.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.76(s, 3H), 3.54 (s, 2H), 3.32(s, 3H), 2.73(s, 3H), 2.49(s, 2H), 2.40(s, 2H), 2.29(s, 2H).

¹³ C NMR (75MHz, CDCl ₃ ) δ: 163.81, 150.32, 129.86, 129.23, 126.66, 123.44, 115.84, 111.43, 110.29, 108.98, 77.53, 77.13, 48.20, 43.19, 33.47, 11.93, 1.

Example 9

N-{3-fluoro-4-[(2-(morpholine-4-formyl)pyridin-4-yl)oxy]phenyl}-1,5-dimethyl-3-oxo-2- Preparation of phenyl-2-3-dihydro-1H-pyrazole-4-carboxamide (I-6)

The synthesis procedure is the same as that of I-2, the raw material used is morpholine, and 80 mg of white solid is obtained with a yield of 96.5%. mp: 245-247°C.

MS (ESI, m/z): 532.5 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3448.37，3127.33，2967.55，2849.56，2230.09，1684.99，1590，49，1569.02，1505.28，1455.98，1400.95，1290.91，1261.63，1199.01，1114.62，959.85，821.36，405.02.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 4.04-3.48(m, 8H) , 3.38(s, 3H), 2.79(s, 3H).

¹³ C NMR (75MHz, CDCl ₃ ) δ: 129.87, 129.26, 126.66, 123.39, 115.86, 111.34, 109.04, 66.80, 47.60, 42.67, 33.48, 11.97.

Example 10

N-cyclopropyl-4-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-4-carboxamide)-2-fluorophenoxy ] The preparation of pyridinecarboxamide (I-7)

The synthesis procedure was the same as that of I-2, the raw material used was cyclopropylamine, and 56 mg of off-white solid was obtained with a yield of 87%. mp: 206-208°C.

MS (ESI, m/z): 502.5 [M+H] ⁺ .

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.56(d, J=5.5Hz , 2H), 3.37(s, 3H), 3.06(d, J=5.5Hz, 2H), 2.76(s, 3H).

¹³ C NMR(75MHz，CDCl ₃ )δ：166.54，164.98，163.20，161.23，155.30，154.05，151.97，149.65，137.47，132.28，129.34，128.76，126.20，122.92，115.32，111.24，110.40，108.58，108.28，98.55 , 54.58, 53.91, 46.34, 45.34, 42.02, 41.49, 32.91, 14.77, 11.39.

Example 11

N-{3-fluoro-4-[(2-(4-(furan-2-formyl)piperazine-1-formyl)pyridin-4-yl)oxy]phenyl}-1,5-di Preparation of methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-8)

The synthesis procedure is the same as that of I-2, and the raw material used is 2-furoylpiperazine to obtain 89 mg of yellow solid with a yield of 78%. mp: 256-258°C.

MS (ESI, m/z): 625.6 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3128.65，3053.06，2926.53，2865.31，1683.39，1620.05，1585.83，1560.75，1503.33，1485.83，1428.18，1366.39，1286.39，1264.96，1196.29，1168.63，1120.06，1008.16，865.31，756.41， 743.90.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 6.47(s, 1H), 3.75 (s, 8H), 3.34(s, 3H), 2.74(s, 3H).

¹³ C NMR(75MHz，CDCl ₃ )δ：166.70，165.14，161.21，158.68，154.82，149.54，143.49，137.59，129.35，128.74，126.16，122.93，116.54，115.34，111.27，108.50，46.64，41.19，32.96，11.43 .

Example 12

4-[4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy]- Preparation of N-(3-morpholinopropyl)pyridinecarboxamide (I-09)

The synthesis procedure is the same as that of I-2, and the raw material used is 3-aminopropylmorpholine to obtain 98 mg of white solid with a yield of 87%. mp: 267-269°C.

MS (ESI, m/z): 589.6 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3128.01，2963.49，2865.07，2811.66，1670.01，1640.79，1608.95，1591.14，1562.96，1499.64，1471.23，1402.03，1291.34，1261.54，1195.45，1115.73，1073.14，745.19.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.82(s, 4H), 3.45 (s, 4H), 3.37(s, 3H), 2.78(s, 3H), 2.55(s, 6H).

¹³ C NMR (75MHz, CDCl ₃ ) δ: 149.67, 129.86, 129.19, 126.61, 123.36, 115.78, 113.11, 109.63, 66.61, 57.80, 53.67, 38.95, 33.49, 25.23, 11.97.

Example 13

N-{4-[(2-(4-acetylpiperazine-1 formyl)pyridin-4-yl)oxo-3-fluorophenoxy]}-1,5-dimethyl-3-oxo Preparation of Sub-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-10)

The synthesis procedure is the same as that of I-2, and the raw material used is N-acetylpiperazine to obtain 36 mg of light yellow solid with a yield of 67%. mp: 275-277°C.

MS (ESI, m/z): 573.6 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3129.61，2970.67，2857.14，2775.51，1686.95，1633.44，1591.00，1557.71，1497.76，1425.65，1286.80，1191.78，1135.71，1119.00，992.90，966.13，845.36，829.29，747.31，695.47， 557.87.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 4.21-3.93(m, 4H) , 3.82-3.54(m, 4H), 2.39(s, 3H), 2.07(s, 3H), 1.69(s, 4H).

¹³ C NMR (75MHz, CDCl ₃ ) δ: 129.36, 128.79, 126.23, 122.92, 115.38, 110.82, 56.48, 44.61, 43.39, 38.61, 34.71, 32.93, 26.91, 20.90, 19.72, 14.76, 11.40.

Example 14

N-[4-[2-(4-Ethylpiperazine-1-formyl)pyridin-4-yl)oxo-3-fluorophenoxy]-1,5-dimethyl-3-oxo - Preparation of 2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-11)

The synthesis procedure is the same as that of I-2, and the raw material used is N-ethylpiperazine to obtain 90 mg of light gray solid with a yield of 67%. mp: 199-201°C.

MS (ESI, m/z): 559.61 [M+H] ⁺ .

IR(KBr, cm ^-1 ) v: 3127.81, 2808.16, 2714.29, 2363.27, 1680.65, 1636.75, 1504.48, 1401.49, 1294.26, 1198.26, 1122.04, 841.73, 781.01, 743.975, 6556.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.84(s, 4H), 3.65 (s, 4H), 3.37(s, 3H), 2.77(s, 3H), 1.35(s, 3H), 1.13(s, 2H).

Example 15

4-[4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy]- Preparation of N-(3-methoxypropyl)pyridinecarboxamide (I-12)

The synthesis procedure is the same as that of I-2, and the raw material used is 3-methoxypropylamine to obtain 42 mg of light yellow solid with a yield of 67%. mp: 225-227°C.

MS (ESI, m/z): 534.6 [M+H] ⁺ .

IR (KBr, cm ^-1 ) v: 3124.78, 2959.18, 2914.29, 2869.39, 2808.16, 2355.10, 2334.69, 1638.48, 1606.11, 1504.01, 1295.64, 1261.15, 1209.48, 1102.45, 16

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.65-3.49(m, 2H) , 3.44-3.24(m, 2H), 3.14(t, J=0.8Hz, 3H), 2.39(s, 3H), 2.09-1.77(m, 2H), 1.69(s, 4H).

Example 16

4-[4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazoline-4-carboxamide)-2-fluorophenoxy] Preparation of -N-(2-morpholinoethyl)pyridineamide (I-13)

The synthesis procedure is the same as that of I-2, and the raw material used is aminoethylmorpholine to obtain 66 mg of white solid with a yield of 46.6%. mp: 236-238°C.

MS (ESI, m/z): 575.6 [M+H] ⁺ .

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.83(t, J=6.1Hz , 2H), 3.42-3.30(m, 4H), 3.00-2.83(m, 4H), 2.72-2.24(m, 2H), 2.39(s, 3H), 1.69(s, 4H).

Example 17

4-[4-(1,5-Dimethyl-3-oxo-2-phenyl)-2,3-dihydro-1H-pyrazoline-4-formyl)-2-fluorophenoxy Preparation of ]-N-(2-thiophenemethylamine)pyridineamide (I-14)

The synthesis procedure is the same as that of I-2, and the raw material used is 2-thienylamine to obtain 49 mg of light yellow solid with a yield of 65.8%. mp: 316-318°C.

MS (ESI, m/z): 558.6 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3389.29，3127.86，2371.68，1680.07，1637.57，1606.12，1590，89，1570.73，1554.25，1521.93，1465.79，1498.71，1401.23，1286.75，1196.20，1115.96，909.76，865.56，812.36， 743.03, 691.18, 543.99.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=75Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.88(s, 1H), 6.77(s, 1H), 4.81( s, 2H), 3.38(s, 3H), 2.80(s, 3H).

Example 18

N-{4-[(2-(1-carbonylpyrrole)pyridin-4-yl)oxy]-3-fluorophenyl}-1,5-dimethyl-3-oxo-2-phenyl- Preparation of 2,3-dihydro-1H-pyrazoline-4-carboxamide (I-15)

The synthesis procedure was the same as that of I-2, the raw material used was pyrrolidine, and 50 mg of a light yellow solid was obtained with a yield of 72.3%. mp: 164-166°C.

MS (ESI, m/z): 516.6 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3128.56，1686.23，1609.61，1589.22，1560.71，1507.16，1450.95，1400.98，1291.59，1261.05，1198.56，1120.35，870.11，828.81，746.93，694.67，596.16，548.44.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.68(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.56(t, 4H), 3.40 (s, 3H), 2.81(s, 3H), 1.93(t, 4H).

Example 19

N-{4-[(2-(1,4'-piperidinylpiperidine)-1'-carbonyl)pyridin-4-yl)oxy]-3-fluorophenyl}-1,5-dimethyl Preparation of base-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazoline-4-carboxamide (I-16)

The synthesis procedure is the same as that of I-2, and the raw material used is 4-piperidinylpiperidine to obtain a white solid, 32 mg, with a yield of 29%. mp: 119-121°C.

MS (ESI, m/z): 613.7 [M+H] ⁺ .

IR (KBr, cm ^-1 ) v: 3128.68, 2925.15, 2359.28, 1670.51, 1637.34, 1565.85, 1505.28, 1289.10, 1197.56, 1118.20, 861.41.

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.95(s, 1H), 8.58(d, J=5.4Hz, 1H), 7.95(d, J=9.9Hz, 1H), 7.56(d, J=7.5Hz , 3H), 7.51(d, J=7.5Hz, 1H), 7.43(s, 3H), 7.35(d, J=9.9Hz, 2H), 6.77(s, 1H), 3.39(s, 3H), 3.27 -2.88(m, 2H), 2.96-2.68(m, 4H), 2.57(s, 4H), 2.36-1.69(m, 3H), 1.55(d, J=44.2Hz, 5H).

Example 20

N-3-fluoro-4-{[2-(hydrazinecarbonyl)pyridin-4-yloxy]phenyl}-1,5-dimethyl-3-oxo-2-phenyl-2,3- Preparation of Dihydro-1H-pyrazole-4-carboxamide

I-1 (10g, 20.9mmol) was dissolved in 50mL of acetonitrile, 10mL of hydrazine hydrate was added, stirred at room temperature for 3h, TLC detected that the reaction was complete, a large amount of water was added to precipitate, and filtered by suction to obtain 9g of white solid with a yield of 90%.

MS (ESI, m/z): 477.5 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 10.95(s, 1H), 8.76(d, J=5.5Hz, 1H), 8.95(d, J=8.8Hz, 1H), 7.67(d, J= 5.5Hz, 1H), 7.41(d, J=8.8Hz, 1H), 7.31(d, 1H), 7.23(d, J=2.0, 1H), 7.19(t, J=2.8Hz, 1H), 7.18- 7.15(m, 1H), 7.16-7.12(m, 1H), 7.05(dd, J=5.5, 2.0Hz, 1H), 2.39(s, 3H), 1.69(s, 3H).

Example 21

(E)-N-{4-[(2-(2-((Dimethylamino)methylene)hydrazine-1-oxo)pyridin-4-yl]oxy-3-fluorophenyl}-1 , Preparation of 5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide

N-3-fluoro-4-{[2-(hydrazinecarbonyl)pyridin-4-yloxy]phenyl}-1,5-dimethyl-3-oxo-2-phenyl-2,3 -Dihydro-1H-pyrazole-4-carboxamide (5g, 10mmol) was dissolved in 10mL of toluene, DMF-DMA (3.6g, 30mmol) was added, heated to reflux overnight, TLC detected that the reaction was complete, and the reaction solution was concentrated to dryness, Diethyl ether was added, stirred for 1 h, and filtered with suction to obtain 4.8 g of a light yellow solid with a yield of 90.56%.

MS (ESI, m/z): 432.6 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 11.03(s, 1H), 10.82(s, 1H), 8.82(d, J=7.5, 1H), 8.01(dd, J=7.5, 1.7Hz, 1H ), 7.67(dd, J=8.8, 2.7Hz, 1H), 7.41(dd, J=8.8, 2.7, 1.7Hz, 1H), 7.35-7.24(m, 3H), 7.19(t, J=1.1Hz, 1H), 7.18-7.13(m, 2H), 2.97(d, J=1.1Hz, 7H), 2.39(s, 3H), 1.69(s, 3H).

Example 22

N-(3-fluoro-4-((2-(4-(3-methoxypropyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy) Preparation of phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-17)

Dissolve Example 26 (0.2g, 0.38mmol) in 2mL of acetic acid, add 3-methoxypropylamine (34mg, 0.38mmol), react at 90°C for 3h, TLC detects that the reaction is complete, add sodium carbonate to neutralize to alkalinity, two Chloromethane was extracted three times, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the reaction solution was concentrated to dryness, followed by column chromatography to obtain 170 mg of a light yellow solid with a yield of 80.18%. mp: 208-210°C.

MS (ESI, m/z): 558.7 [M+H] ⁺ .

IR(KBr，cm ^-1 )v：3135.18，3057.14，2975.51，2930.61，2828.57，1681.50，1561.03，1417.22，1364.75，1293.54，1261.30，1200.46，1121.66，1037.15，904.97，869.66，780.75，743，94，696.20， 616.42.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.05 (d, J = 5.4Hz, 1H), 8.68 (s, 1H), 8.02-7.87 (m, 3H), 7.67 (dd, J = 7.5, 3.0 Hz, 2H), 7.41(dd, J=8.8, 3.0Hz, 1H), 7.38(d, J=1.5Hz, 1H), 7.30(dd, J=7.5, 1.5Hz, 1H), 7.17(dd, J =7.5, 1.5Hz, 1H), 7.13-7.07(m, 2H), 4.45(t, J=6.0Hz, 2H), 3.52(d, J=6.0Hz, 2H), 3.13(s, 3H), 2.39 (s, 3H), 2.04 (p, J=6.0Hz, 2H), 1.69 (s, 3H).

Example 23

N-(3-fluoro-4-((2-(4-(3-dimethylaminopropyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy) Preparation of phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (I-18)

The synthesis procedure is the same as that of I-17, and the raw material used is N,N-dimethylaminopropylamine to obtain 80 mg of white solid with a yield of 75%. mp: 248-250°C.

MS (ESI, m/z): 571.6 [M+H] ⁺ .

IR (KBr, cm ^-1 ) v: 3116.25, 2363.27, 1555.75, 1504.36, 1453.46, 1401.40, 1286.60, 1206.94, 1192.78, 1120.11, 909.34, 745.96, 696.54.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.05 (d, J = 5.4Hz, 1H), 8.68 (s, 1H), 8.02-7.87 (m, 3H), 7.67 (dd, J = 7.5, 3.0 Hz, 2H), 7.41(dd, J=8.8, 3.0Hz, 1H), 7.38(d, J=1.5Hz, 1H), 7.30(dd, J=7.5, 1.5Hz, 1H), 7.17(dd, J =7.5, 1.5Hz, 1H), 7.13-7.07(m, 2H), 4.41(d, J=6.0Hz, 1H), 2.47-2.40(m, 2H), 2.39(s, 3H), 2.23(s, 1H), 2.21(s, 3H), 2.16(q, J=0.7Hz, 2H), 1.80-1.75(m, 1H), 1.69(s, 3H).

Example 24

N-{3-fluoro-4-[(2-(4-(3-morpholinopropyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy] Preparation of phenyl}-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazoline-4-carboxamide (I-19)

The synthesis procedure is the same as that of I-17, the raw material used is aminopropylmorpholine, and 80 mg of a light yellow solid is obtained with a yield of 87%. mp: 228-230°C.

MS (ESI, m/z): 614.6 [M+H] ⁺ .

IR (KBr, cm ^-1 ) v: 3127.50, 2844.90, 1679.35, 1637.87, 1592.19, 1502.39, 1454.30, 1400.87, 1291.31, 1200.44, 1115.88, 914.29, 741.86.

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 9.05 (d, J = 5.4Hz, 1H), 8.68 (s, 1H), 8.02-7.87 (m, 3H), 7.67 (dd, J = 7.5, 3.0 Hz, 2H), 7.41(dd, J=8.8, 3.0Hz, 1H), 7.38(d, J=1.5Hz, 1H), 7.30(dd, J=7.5, 1.5Hz, 1H), 7.17(dd, J =7.5, 1.5Hz, 1H), 7.13-7.07(m, 2H), 4.44(d, J=6.0Hz, 1H), 3.57(t, J=6.0Hz, 4H), 2.92(t, J=6.0Hz , 4H), 2.39(s, 3H), 2.16(q, J=6.0Hz, 1H), 1.69(s, 3H).

Example 25

N-{3-fluoro-4-[(2-(4-(3-(4-methylpiperazinyl)propyl)-4H-1,2,4-triazol-3-yl)pyridine- 4-yl)oxy]phenyl}-1,5 dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazoline-4-carboxamide (I-20) preparation of

The synthesis procedure is the same as that of I-17, and the raw material used is N-methylaminopropylpiperazine to obtain 105 mg of off-white solid with a yield of 83.5%. mp: 201～203℃.

MS (ESI, m/z): 627.4 [M+H] ⁺ .

¹ H NMR (300MHz, DMSO-d ₆ ) δ: 11.05(s, 1H), 9.03(s, 1H), 8.68(d, 7.5Hz, 1H), 8.02-7.87(m, 3H), 7.67(dd, J=7.5, 3.0Hz, 2H), 7.41(dd, J=8.8, 3.0Hz, 1H), 7.38(d, J=1.5Hz, 1H), 7.31(dd, J=7.5, 1.5Hz, 1H), 7.17(dd, J=7.5, 1.5Hz, 1H), 7.13-7.07(m, 2H), 4.44(d, J=6.0Hz, 1H), 3.57(t, J=6.0Hz, 4H), 2.92(t , J=6.0Hz, 4H), 2.39(s, 3H), 2.16(q, J=6.0Hz, 1H), 1.69(s, 3H).

Example 26: Tablets

Contain 10g of the compound in claim 1 (taking the compound of Example 25 as an example), add 20g of auxiliary materials according to the general tableting method of pharmacy and mix, and then compress into 100 tablets, each weighing 300mg.

Example 27: Capsules

With 10g containing compound (taking embodiment 12 compound as example) in claim 1, according to the requirement of pharmacy capsule after adjuvant 20g is mixed, pack into hollow capsule, each capsule weighs 300mg.

Embodiment 28: Injection

Use 10g of the compound (taking Example 19 compound as an example) containing the compound in claim 1, according to the conventional method of pharmacy, carry out activated carbon adsorption, after filtering through a 0.65 μm microporous membrane, fill it into a nitrogen tank to make a water injection preparation, each Fill 2mL and fill 100 bottles in total.

While this invention has been described in terms of specific embodiments, it is apparent that modifications and equivalents will be apparent to those skilled in the art, and these are intended to be encompassed within the scope of this invention.

Claims (6)

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, in: R ¹ , R ² , and R ³ are the same or different, and are independently selected from H, D, halogen, NO ₂ , NH ₂ , and OH; A is CONR ^a R ^b , COOR ^c , 4-R ^d replaces -1,2,4-triazole; R ^a , R ^b are not H or methyl at the same time, and are independently selected from H, C _1-3 alkyl, alkenyl or alkynyl-C _1-3 alkylene, C _3-6 cycloalkyl, C _1-3 alkoxy-C _2-6 alkylene, C _3-6 heterocyclyl-C _1-3 alkylene, heteroaryl-C _1-3 alkylene consisting of 5-10 atoms, When R ^a and R ^b are connected to the same nitrogen atom, R ^a and R ^b together with the nitrogen atom connected to them can optionally form a substituted or unsubstituted heterocyclic ring consisting of 5-8 atoms; R ^c is selected from C _1-3 alkyl; R ^d is (CH ₂ ) _n X R ^e ; n is selected from an integer between 1-3; X is selected from heteroatoms such as N, O and S; R ^e is selected from (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) alkoxy; Or ^Re and its connected nitrogen atom together form a 5-6 membered saturated heterocyclic group, which optionally contains 1-4 members selected from N, O and S in addition to the nitrogen atom connected to ^Re . A heteroatom, the saturated heterocyclic group is optionally substituted by 1-3 identical or different R ^f ; R ^f is H, (C ₁ -C ₃ ) alkyl, hydroxyl. 2. the compound as claimed in claim 1 and pharmaceutically acceptable salt, hydrate or prodrug thereof, in: R ¹ , R ² , and R ³ are the same or different, and are independently selected from H, F, Cl, and Br; R ^a , R ^b are not H or methyl at the same time, independently selected from H, C _1-2 alkyl, alkynyl-C _1-2 alkylene, C _3-5 cycloalkyl, C _1-2 alkane Oxygen-C _2-3 alkylene, C _5-6 heterocyclyl-C _1-3 alkylene, heteroaryl-C _1-2 alkylene consisting of 5-6 atoms, when R ^a and When R ^b is connected to the same nitrogen atom, R ^a , R ^b , together with the nitrogen atom connected to them, can optionally form a substituted or unsubstituted heterocyclic ring consisting of 5-6 atoms; R ^c and R ^e are selected from (C ₁ -C ₃ ) alkyl groups; Or R ^e forms a 5-6 membered saturated heterocyclic group together with the nitrogen atom to which it is connected, and the saturated heterocyclic group optionally contains 1-2 heterocyclic groups selected from N and O in addition to the nitrogen atom connected to R ^e atom, the saturated heterocyclic group is optionally substituted by 1-2 identical or different R ^f ; R ^f is H, methyl, ethyl, hydroxyl; n is 2, 3; X is selected from N, O. 3. the compound as claimed in claim 1 or 2 and pharmaceutically acceptable salt, hydrate or prodrug thereof, in: R ¹ is F, R ² and R ³ are both H; R ^a , R ^b are not H or methyl at the same time, independently selected from H, methyl, propargyl, cyclopropyl, methoxy-C _2-3 alkylene, morpholine-C _2-3 alkylene Alkyl, thiophene-methylene, when R ^a and R ^b are bonded to the same nitrogen atom, R ^a , R ^b , together with the nitrogen atom to which they are bonded, can optionally form a substituted or unsubstituted 5 -Heterocyclic rings consisting of 6 atoms selected from the group consisting of: tetrahydropyrrole, piperidine, piperazine, morpholine; R ^c and R ^e are selected from methyl or ethyl; Or R ^e and its attached nitrogen atom form 4-morpholinyl, 1-piperidinyl, 4-methyl-1-piperazinyl, 1-piperazinyl, 4-methyl-1-piperidinyl Base, 1-pyrrolidinyl, 4-thiomorpholinyl. 4. The compound of general formula (I) and its pharmaceutically acceptable salt, hydrate or prodrug are preferably selected from the following compounds: 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)pyridine Methyl formate; 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-propargylpyridinamide; 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-methylpicolinamide; N-(3-fluoro-4-((2-(piperidin-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-carboxamide; N-(3-fluoro-4-((2-(4-methylpiperazine-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-methyl-3-oxo-2 - phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; N-(3-fluoro-4-((2-(morpholine-4-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl -2,3-dihydro-1H-pyrazole-4-carboxamide; N-cyclopropyl-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2- Fluorophenyl) pyridine carboxamide; N-(3-fluoro-4-((2-(4-(furan-2-carbonyl)piperazine-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(3-morpholinopropyl)pyridinamide; N-(4-((2-(4-acetylpiperazine-1-carbonyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2 - phenyl-2,3-dihydro-1H-pyridine-4-carboxamide; N-(4-((2-(4-ethylpiperazine-1-carbonyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo- 2-Phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(3-methoxypropyl)pyridinamide; 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(2-morpholinoethyl)pyridinamide; 4-(4-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide)-2-fluorophenoxy)- N-(thiophene-2-methyl)pyridinecarboxamide; N-(3-fluoro-4-((2-(pyrrole-1-carbonyl)pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl- 2,3-Dihydro-1H-pyrazole-4-carboxamide; N-(4-((2-([1,4′-dipiperidine]-1′-carbonyl)pyridin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl- 3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; N-(3-fluoro-4-((2-(4-(3-methoxypropyl)4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)phenyl )-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; N-(4-((2-(4-(3-(dimethylamino)propyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)-3 -fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; N-(3-fluoro-4-((2-(4-(3-morpholinopropyl)-4H-1,2,4-triazol-3-yl)pyridin-4-yl)oxy)benzene Base)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide; N-(3-fluoro-4-((2-(4-(3-(4-methylpiperazin-1-yl)propyl)-4H-1,2,4-triazol-3-yl) pyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide. 5. A pharmaceutical composition comprising the compound of any one of claims 1-4 and a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or their combination. 6. Use of the compound according to any one of claims 1-4 and the pharmaceutically acceptable salt thereof or the composition according to claim 5 in the preparation of medicaments for treating and/or preventing cancer.