CN109810100A - A benzofuran-containing dual-target inhibitor of PARP-1 and PI3K - Google Patents

Abstract

The invention relates to the field of medicinal chemistry, in particular to a class of PARP-1 and PI3K dual-target inhibitors (I) containing benzofuran structures, their preparation methods, and pharmaceutical compositions containing these compounds. Pharmacodynamic test proves that the compound of the present invention has anti-tumor effect.

Description

A benzofuran-containing dual-target inhibitor of PARP-1 and PI3K

technical field

The invention relates to the field of medicinal chemistry, in particular to a class of PARP-1 and PI3K dual-target inhibitors containing benzofuran structures, their preparation methods, and pharmaceutical compositions containing these compounds and their uses in antitumor.

Background technique

Poly(ADP-ribose) polymerase (PARP) is a multifunctional protein post-translational modification enzyme that exists in most eukaryotic cells. At present, 18 isoforms of this family have been found, of which PARP-1 accounts for the largest proportion. , involved in the treatment of stroke, neurodegenerative diseases, myocardial ischemia, cancer, inflammation and diabetes, and plays a leading role in DNA damage repair. PARP-1 inhibitors are a class of antitumor drugs that exert cytotoxicity by regulating DNA damage repair, and are one of the most exciting achievements in the field of tumor therapy research in the early 21st century. At present, three PARP inhibitors have been used in clinical practice, they are Olaparib (Olaparib) launched in 2014, Rucaparib (Rucaparib) launched in 2016 and Niraparib (Niraparib) launched in 2017. It is mainly used for the treatment of tumors such as breast cancer, ovarian cancer and peritoneal cancer. However, with the in-depth research and the successive release of clinical trial results, the limitations of PARP-1 inhibitors are further presented. On the one hand, when the current PARP-1 inhibitor is used alone, it is only effective against triple-negative breast or ovarian cancer with BRCA1/2 deletion, which leads to a narrow indication of PARP-1 inhibitor; on the other hand However, the long-term use of PARP-1 inhibitors also faces the problem of drug resistance, which will adversely affect the clinical application of PARP-1 inhibitors.

Phosphatidylinositol-3-kinase (PI3K) is an upstream molecule in the PI3K/Akt/mTOR signal transduction pathway. As a key node protein in this pathway, PI3K can phosphorylate phosphatidylinositol 4, The 3-hydroxyl group of 5-bisphosphate (PIP2) generates phosphatidylinositol 3,4,5-triphosphate (PIP3). As a second messenger, PIP3 plays an important role in basic responses such as cell survival, growth, proliferation, and metabolism. The tumor suppressor gene PTEN can dephosphorylate PIP3 to generate PIP2, which is an antagonist of PI3K catalysis. Aberrant activation of PI3K leads to disturbance of this pathway, leading to a range of diseases, including cancer, neurological disorders, autoimmune diseases, and hematopoietic diseases. PI3K has become one of the important targets in tumor treatment research. There are two PI3K inhibitors currently in clinical use, namely the PI3Kδ inhibitor Idelalisib, which was launched in 2014, and the PI3Kα/PI3Kδ inhibitor, which was launched in 2017. Copanlisib is mainly used for the treatment of various lymphomas; in addition, there are still many PI3K inhibitors in the clinical research stage, but there is no report on PARP-1/PI3K dual-target inhibitors.

SUMMARY OF THE INVENTION

The present invention discloses a class of compounds of general formula (I). The results of pharmacodynamics tests show that the compounds of the present invention or their pharmaceutically acceptable salts can simultaneously act on two targets of PARP-1 and PI3K, and can be used as tumors or combined with other anti-tumor drugs, so as to improve the curative effect of existing anti-tumor drugs and reduce the dose and toxicity.

where X represents CH or N;

R ¹ stands for R ¹ preferably represents

R ² stands for R ³ represents H, F, Br, Cl, CF ₃ , CN, CH ₃ or OCH ₃ , Y represents CH or N, Z represents O, NH, NCH ₃ or CH ₂ , m=1 or 2; R ² preferably represents

The preferred partial compounds of the present invention are as follows:

When ^R2 does not represent , the compounds of the general formula (I) of the present invention can be prepared by the following methods:

The above reaction is preferably carried out by adding a catalyst, a base and a reaction solvent, wherein the catalyst is preferably selected from palladium chloride, palladium acetate, bis(triphenylphosphine) palladium dichloride, tetrakis(triphenylphosphine) palladium, [1,1 '-bis(diphenylphosphino)ferrocene]dichloride palladium or [1,1'-bis(diphenylphosphino)ferrocene]nickel dichloride; the base is preferably selected from sodium ethoxide, sodium acetate , potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate; the reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane , toluene, ethanol, water or a mixed solvent of any two or three of them; the reaction temperature is preferably 70°C to 115°C.

The catalyst is more preferably tetrakis(triphenylphosphine)palladium; the base is more preferably potassium carbonate; the solvent is more preferably a mixed solvent of dioxane/water; the reaction temperature is more preferably 95°C to 110°C.

In more detail, if prepared from the starting material (1), it includes:

The process of preparing compound 2 from compound 1 by cyano reaction:

The cyanide used is preferably selected from zinc cyanide, copper cyanide or cuprous cyanide. Cuprous cyanide is more preferred.

The catalyst is preferably selected from palladium chloride, palladium acetate, bis(triphenylphosphine) palladium dichloride, tetrakis(triphenylphosphine) palladium, [1,1'-bis(diphenylphosphino)ferrocene]bis Palladium chloride or [1,1'-bis(diphenylphosphino)ferrocene]nickel dichloride. More preferred is tetrakis(triphenylphosphine)palladium.

The reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide. More preferred is N,N-dimethylformamide.

The reaction temperature is preferably from 30°C to 90°C. More preferably, it is 70 degreeC - 80 degreeC.

The process of preparing compound 3 from compound 2 through hydrolysis reaction:

The base used is preferably selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate or potassium carbonate. Sodium hydroxide is more preferred.

The reaction solvent is preferably a mixed solvent of methanol/water, ethanol/water or tetrahydrofuran/water, more preferably a mixed solvent of methanol/water.

The reaction temperature is preferably from 20°C to 70°C, more preferably 30°C to 40°C.

The process of preparing compound III by acylation of compound 3 and compound II:

The condensing agent is preferably selected from benzotriazol-1-yl-oxytripyrrolidinophosphorus hexafluorophosphate (PyBOP), 1-hydroxybenzotriazole (HOBt)/1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) or N,N'-carbonyldiimidazole (CDI), more preferably PyBOP.

The acid binding agent is preferably selected from triethylamine, N,N-diisopropylethylamine (DIEA), 4-dimethylaminopyridine (DMAP), pyridine, sodium acetate, sodium carbonate or potassium carbonate, more preferably DIEA.

The reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide, more preferably N,N-dimethylformamide.

The reaction temperature is preferably from 10°C to 80°C, more preferably from 20°C to 40°C.

Process for the preparation of compound I from compound III and boronate IV via Suzuki reaction:

The catalyst used is preferably selected from palladium chloride, palladium acetate, bis(triphenylphosphine) palladium dichloride, tetrakis(triphenylphosphine) palladium, [1,1'-bis(diphenylphosphino)ferrocene ] palladium dichloride or [1,1'-bis(diphenylphosphino)ferrocene]nickel dichloride. More preferred is tetrakis(triphenylphosphine)palladium.

The base is preferably selected from sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate, more preferably potassium carbonate.

The reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, toluene, ethanol, water or any two or three of them. A mixed solvent of various solvents, more preferably a mixed solvent of dioxane/water.

The reaction temperature is preferably from 70°C to 115°C, more preferably 95°C to 110°C.

When R ² stands for , the compounds of the general formula (I) of the present invention can be prepared by the following methods:

Above-mentioned reaction is preferably carried out by adding condensing agent, acid binding agent, alkali and reaction solvent conditions, wherein condensing agent is preferably selected from PyBOP, HOBt/EDCI, DCC or CDI; acid binding agent is preferably selected from triethylamine, DIEA, DMAP, pyridine, acetic acid sodium, sodium carbonate or potassium carbonate; the reaction solvent is preferably selected from N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide; the reaction temperature is preferably from 10°C to 80°C.

The condensing agent is more preferably PyBOP; the acid binding agent is more preferably DIEA; the reaction solvent is more preferably N,N-dimethylformamide; and the reaction temperature is more preferably 20°C to 40°C.

The process of preparing compound I·A from compound (I) through salt formation, reactant A is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, horse sulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid; the solvent is methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene, tetrahydrofuran or a mixture of any two or three of them solvent.

The present invention also discloses a pharmaceutical composition, which comprises a pharmaceutically effective dose of compound (I) or a salt thereof of the present invention and a pharmaceutically acceptable carrier.

The compounds of the present invention can be added with pharmaceutically acceptable carriers to prepare common pharmaceutical preparations, such as tablets, capsules, powders, syrups, liquids, suspensions, freeze-dried powder injections, and injections. Commonly used pharmaceutical excipients such as flavors, liquid or solid fillers or diluents.

The clinical administration of the compounds of the present invention can be oral administration, injection, or the like.

Generally, when the compounds of the present invention are used in therapy, the dosage for human use is in the range of 1 mg to 1000 mg/day. Dosages outside this range may also be employed, depending on the dosage form and the severity of the disease.

Pharmacological experiments and results of some compounds of the present invention are as follows:

(1) Detection of the inhibitory activity of compounds on PARP-1 and PI3K at the enzyme level

experimental method

The kinase activity test methods used in this experiment are basically the same, except that different concentrations are adopted to achieve the best detection range according to different kinases and corresponding different substrates.

PARP-1 inhibitory activity assay method: Take out the pre-coated histone 96-well plate, add the following enzyme reaction system and different concentrations of inhibitors to each well, including: 50 μL of reaction buffer (Tris*HCl, pH 8.0) , NAD ⁺ , biotin-labeled activated DNA, PARP-1 enzyme, and inhibitor; after 1 hour of reaction at room temperature, add 50 μL of avidin-labeled HRP to each well, and react for 30 minutes; then add 100 μL of HRP base The chemiluminescence value was detected on a SpectraMax M instrument. The following formula calculates the percent enzyme activity:

Percentage of enzyme activity (%)=(OD value administration well-OD value background)/(OD value control well-OD value background)×100%

PI3Kα inhibitory activity experimental method: 40mM Tris, pH 7.4, 10mM MgCl ₂ , 0.1mg/ml BSA, 1mM DTT, 10μM ATP, PI3Kα kinase, kinase substrate; at the same time, different concentrations of compounds to be screened were added to form a 50μL reaction system, and the The reaction was carried out at 30 °C for 40 minutes, and then the ADP content in the system was detected by luciferase. After another 5 minutes of reaction, the chemiluminescence signal was detected on the MD-SpectraMax M5 multifunctional microplate reader. The intensity of the chemiluminescence signal value was related to the enzyme. proportional to the inhibition of activity. The detected chemiluminescence signal value is substituted into the following formula:

Percentage of enzyme activity (%)=(OD value administration well-OD value background)/(OD value control well-OD value background)×100%

The experimental results are shown in Table 1.

Drug concentrations were diluted in a three-fold concentration gradient, and each concentration was tested in two duplicate wells. Taking the drug concentration as the abscissa, and the enzyme activity percentage corresponding to each concentration as the ordinate, using Graphpad Prism5 for nonlinear regression, the IC ₅₀ value of each test compound was calculated. The experimental results are shown in Table 2.

Table 1. Inhibitory activity of test compounds on PARP-1 and PI3Kα

The results in Table 1 show that the compounds of the present invention have high inhibitory activity on PARP-1, and most of the compounds have an inhibitory rate of more than 50% on PARP-1 at a concentration of 10 nM; the compounds also have high inhibitory activity on PI3Kα, and some compounds The inhibition rate of PI3Kα at 100nM concentration was more than 70%. The above results show that the compounds of the present invention have dual inhibitory activities on PARP-1 and PI3K.

Some compounds were selected to determine their _IC50 values for PARP-1 and PI3Kα, and the results are shown in Table 2.

Table 2. _IC50 values of some test compounds against PARP-1 and PI3Kα

The results in Table 2 show that the compounds of the present invention have higher inhibitory activities on PARP-1 and PI3K, and most of the compounds have better inhibitory activity on PARP-1 than on PI3Kα. The IC ₅₀ was 6.3 nM and the IC ₅₀ against PI3Kα was 5.8 nM, showing almost the same inhibitory activity against both targets.

(2) Detection of the inhibitory activity of the compound on tumor cell proliferation

experimental method

Cells in logarithmic growth phase (HCT116, HCC1937, MDA-MB-231 and MDA-MB-468) were seeded in a certain number in 96-well plates (200 μL/well), cultured for 24 hours to make them adhere to the wall and then added with drugs. Three duplicate wells were set for each drug concentration, and corresponding zero-adjustment wells and blank controls were set. After 72 hours of drug action, adherent cells were added with 50% TCA (50 μL/well), fixed at 4° C. for 1 hour, poured off the fixative, washed with distilled water 5 times, and naturally dried. 100 μL of 4 mg/mL SRB was added to each well, stained at room temperature for 15 minutes, discarded, washed 5 times with 1% glacial acetic acid, and naturally dried. Finally, 150 μL of 10 mM Tris solution was added to each well, shaken well, and the OD value was measured with a wavelength-tunable microplate microplate reader at a wavelength of 565 nm. The cell growth inhibition rate was calculated by the above formula, and the results are shown in Table 3.

Table 3. In vitro antitumor activity test results of compounds

The results in Table 3 show that the compounds of the present invention all have strong anti-tumor activity in vitro and can significantly inhibit the proliferation of tumor cells. Not only has significant inhibitory activity on BRCA-deficient HCC1937 and HCT116 cells, but also has strong inhibitory activity on BRCA wild-type MDA-MB-231 and MDA-MB-468 cells. Among them, compound I-1 has the strongest inhibitory activity on tumor cells HCT116 and HCC1937, with IC ₅₀ of 0.094 μM and 0.061 μM, respectively; compound I-10 has the strongest inhibitory activity on tumor cells MDA-MB-231 and MDA-MB-468 , IC ₅₀ reached 0.244 μM and 1.402 μM, respectively.

(3) To detect the inhibitory activity of compounds on the growth of human breast cancer MDA-MB-468 cells in nude mice transplanted

The test groupings are shown in Table 4.

Table 4. Trial grouping and drug concentration selection

experimental method

The MDA-MB-468 cell line in the logarithmic growth phase was taken and prepared into a cell suspension of 2×10 ⁷ /mL under sterile conditions, and 0.1 mL was subcutaneously inoculated into the right axilla of nude mice. The diameter of the transplanted tumor in nude mice was measured with a vernier caliper, and the animals were randomly divided into groups after the tumor grew to about 100 mm ³ . Using the method of measuring tumor diameter, the anti-tumor effect of the test substance was dynamically observed. Tumor diameters were measured every 6 days. The dosing volume was 0.4 mL/20 g. After 34 days, the mice were sacrificed, and the tumor mass was surgically removed and weighed. The tumor volume (TV) was calculated as:

TV=1/2×a×b ² , where a and b represent length and width, respectively.

The results are shown in Tables 5 and 6. At the given doses, Compounds I-1, I-10 and the combination of olaparib/BKM120 can significantly inhibit the growth of MDA-MB-468 nude mice xenografts, and inhibit the growth of MDA-MB-468 nude mice. The tumor effect was stronger than that of the positive drugs olaparib and BKM120, and the effect of compounds I-I and I-10 was better than that of the combination group of olaparib (50mg/kg)/BKM120 (27.5mg/kg).

Table 5. Effects of compounds on tumor volume in nude mice of human breast cancer MDA-MB-468 cells

Table 6. Effects of compounds on tumor weight of human breast cancer MDA-MB-468 cells in nude mice xenografted

Detailed ways

Example 1

2-(4-(4-(2-Aminomelidin-5-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)benzofuran Synthesis of -7-carboxamide (I-1)

Methyl 7-cyanobenzofuran-2-carboxylate (2)

7-Bromobenzofuran-2-carboxylic acid methyl ester (1) (9.3 g, 36.46 mmol), Zn(CN) ₂ (8.56 g, 72.92 mmol), tetrakis(triphenylphosphine)palladium (2.10 g, 1.82 mmol) mmol) into a 250 mL three-necked flask, add 100 mL of DMF, stir and dissolve, and it is white and opalescent, under nitrogen protection, and heated to 80° C. to react for 6 to 8 hours. TLC (petroleum ether:ethyl acetate=10:1) detected the reaction of raw material 1, cooled to room temperature, suction filtered, the filter cake was washed with 20 mL of DMF, the filtrate was poured into 300 mL of water, a large amount of white solids were precipitated, stirred for 15 minutes, Filtration, the filter cake was washed with 100 mL of water, and dried to obtain the crude product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 7.97 (1H, dd, J=8.0, 1.0 Hz, ArH), 7.79 (1H, dd, J=7.6, 1.0 Hz, ArH), 7.62 (1H, s, ArH), 7.43 (1H, t, J=7.8 Hz, ArH), 4.02 (3H, s, CH ₃ ).

7-carbamoylbenzofuran-2-carboxylic acid (3)

Compound 2 (4.7 g, 23.36 mmol) was dissolved in 50 mL of methanol, added with 30% H ₂ O ₂ (16 mL), 1 mol/L NaOH (47 mL), heated to 40° C. and reacted for 1 hour, TLC (dichloromethane:methanol= 20:1) Detect the reaction of raw material 2, stop heating, cool to room temperature, add 2mol/L dilute hydrochloric acid to adjust pH=1～2, separate out a large amount of white solid, stir at room temperature for 15 minutes, suction filtration, and dry to obtain 4.5g of white solid , yield 93.8%, mp178-180℃. ¹ H-NMR (300MHz, DMSO-d ₆ )δ(ppm): 13.77(1H,s,COOH),7.92(1H,d,J=7.5Hz,ArH) ,7.85(1H,s,1/ _2CONH2 ),7.83(1H,d,J=7.6Hz,ArH),7.74(1H,s,ArH),7.66(1H,s,1/ _2CONH2 ),7.42( 1H,t,J=7.4Hz,ArH).

(2,6-Dichloro-4-morpholinyl)-1,3,5-triazine (5)

Dissolve trimerazine (4) (10.00 g, 54.23 mmol) in 100 mL of dichloromethane, add DIEA (9.92 mL, 56.94 mmol), cool down to -78 °C, dissolve morpholine (4.73 mL, 54.23 mmol) The solution in 10 mL of dichloromethane was added dropwise to the reaction solution, and after the addition was completed, a large amount of white solids were precipitated. TLC (petroleum ether: ethyl acetate=6:1) detected that the reaction of raw material 4 was completed, the reaction was stopped, and the filter cake was filtered with water. Washed and dried to obtain a white solid 7.18g, yield 56.4%. ¹ H NMR (300MHz, DMSO-d ₆ )δ(ppm): 3.80-3.76 (4H, CH ₂ O), 3.69 (4H, CH ₂ ).

4-(4-Chloro-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-carboxylate tert-butyl ester (6)

Compound 5 (7.00 g, 29.78 mmol), N-tert-butoxycarbonylpiperazine (5.55 g, 29.80 mmol) and K ₂ CO ₃ (4.12 g, 29.81 mmol) were added to a 250 mL three-neck flask, and 100 mL of DMF was added and stirred to dissolve , reacted at 25 ° C for 5 hours, TLC (petroleum ether: ethyl acetate = 6:1) detected raw material 5 reacted, stopped the reaction, poured into 300 mL of water, precipitated a large amount of solid, stirred for 30 minutes, suction filtered, and the filter cake was washed with water , and dried to obtain 10.5 g of white solid with a yield of 91.6%. mp 169-172°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 3.83-3.75 (12H, m, 6CH ₂ ), 3.52-3.49 (4H, m, 2CH ₂ ), 1.53 (9H, s, 3CH ₃ ).

4-(4-Chloro-6-morpholino-1,3,5-triazin-2-yl)piperazine hydrochloride (II-1)

Compound 6 (10.0 g, 25.98 mmol) was dissolved in 50 mL of ethyl acetate, saturated HCl in ethyl acetate solution (20 mL) was added, and the reaction was stirred at 25° C. for 2 hours. TLC (petroleum ether:ethyl acetate=6:1) ) After the reaction of raw material 6 was detected, the reaction was stopped, suction filtration, and the filter cake was washed with ethyl acetate and dried to obtain 7.65 g of white solid with a yield of 91.6%. ¹ H-NMR (300 MHz, MeOD) δ (ppm): 4.06 (4H, t, J=5.2 Hz, 2CH ₂ O), 3.81-3.77 (4H, m, 2CH ₂ ), 3.70-3.67 (4H, m, 2CH ₂ ), 3.27 (4H, t, J=5.4Hz, 2CH ₂ ).

2-(4-(4-Chloro-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)benzofuran-7-carboxamide (III-1)

Compound 3 (1.35g, 6.60mmol), II-1 (2.12g, 6.60mmol) and PyBOP (4.12g, 7.92mmol) were added to a 100mL three-neck flask, 50mL of DMF was added and stirred to dissolve, then DIEA (3.82mL, 23.10mmol), stirred and reacted at 25°C for 4 to 6 hours, TLC (dichloromethane: methanol=20:1) detected the reaction of raw material 3, stopped the reaction, poured the reaction solution into 150 mL of water, separated out a large amount of solid, and stirred for 10 minutes , suction filtered, the filter cake was washed with 50 mL of water, and dried to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=120:1～80:1 gradient elution) to obtain 2.5 g of a white solid with a yield of 80.3%, mp 142-144°C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 7.94 (1H, d, J=7.8 Hz, ArH), 7.86 (1H, d, J=7.1 Hz, ArH), 7.84(1H,s,1/ _2CONH2 ),7.77(1H,s,1/ _2CONH2 ),7.58(1H,s,ArH),7.46(1H,t,J=7.7Hz,ArH),3.90-3.66 (16H,m,6CH ₂ N,2CH ₂ O).

2-(4-(4-(2-Aminomelidin-5-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)benzofuran -7-Carboxamide (I-1)

Compound III-1 (2.5 g, 5.30 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyrimidine-2 - Amine (IV-1) (1.76 g, 7.95 mmol) was added to a 250 mL three-necked flask, and 80 mL of dioxane was added and stirred to dissolve. K ₂ CO ₃ (2.92 g, 21.20 mmol) was dissolved in 8 mL of water, and the reaction solution was added, followed by tetrakis(triphenylphosphine)palladium (0.62 g, 0.53 mmol). Under nitrogen protection, the reaction was heated and refluxed for 6-8 h, TLC (dichloromethane:methanol=20:1) detected that the reaction of raw material III-1 was completed, and a large amount of light yellow solid was precipitated, heating was stopped, and the mixture was cooled to room temperature. After suction filtration, the filter cake was washed with 20 mL of water and 20 mL of ethyl acetate successively, and dried to obtain a crude product. 30 mL of ethyl acetate was added to make a slurry for 2 h, suction filtered and dried to obtain 1.67 g of a white solid with a yield of 59.4%. mp>250℃. ¹ H-NMR (300MHz, DMSO-d ₆ )δ(ppm): 9.06(2H,s,ArH),7.90(1H,d,J=7.3Hz,ArH),7.82(1H,s ,1/2CONH ₂ ),7.81(1H,d,J=5.4Hz,ArH),7.74(1H,s,1/2CONH ₂ ),7.55(1H,s,ArH),7.42(1H,t,J= 7.1Hz, ArH), 7.30 (2H, s, NH ₂ ), 4.00-3.64 (16H, m, 6CH ₂ N, 2CH ₂ O). ¹³ C-NMR (75MHz, DMSO-d ₆ )δ (ppm): 170.89,169.81,168.69,165.88,163.43,162.49,155.64,153.48,147.68,132.41,131.42,130.17,128.39,124.68,123.38,115.86,70.73,51.14,48.02,47.48.HRMS(ESI):m/z[M +H] ⁺ .Calcd for C ₂₅ H ₂₆ N ₁₀ O ₄ : 531.2211; Found: 531.2209.

Example 2

2-(4-(4-(6-Aminopyridin-3-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)benzofuran- Synthesis of 7-carboxamide (I-2)

Compound III-1 (300 mg, 0.64 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)pyridine-2- Amine (IV-2) (154 mg, 0.70 mmol) was added to a 50 mL three-neck flask, 20 mL of dioxane was added, and stirred to dissolve. K ₂ CO ₃ (354 mg, 2.56 mmol) was dissolved in 2 mL of water and added to the reaction solution, followed by tetrakis(triphenylphosphine)palladium (74 mg, 0.06 mmol). Under nitrogen protection, the reaction was heated and refluxed for 4 to 6 hours. TLC (dichloromethane:methanol=20:1) was used to detect the completion of the reaction of raw material III-1. The heating was stopped, cooled to room temperature, suction filtered, the filtrate was concentrated, and 40 mL of acetic acid was added to the residue. Ethyl ester, the mixture was washed successively with water (20 mL×1) and saturated sodium chloride solution (20 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered with suction, the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane : methanol=80:1～20:1 gradient elution) to obtain 156 mg of light yellow solid, yield 46.0%. mp>250℃. ¹ H-NMR (300MHz, DMSO-d ₆ )δ(ppm): 8.88(1H,s,ArH),8.34(1H,d,J=7.7Hz,ArH),7.90(1H,d ,J=7.8Hz,ArH),7.82(1H,s,ArH),7.80(1H,s,1/ _2CONH2 ),7.75(1H,s,1/ _2CONH2 ),7.55(1H,s,ArH) , 7.42(1H,t,J=7.6Hz,ArH),7.06(2H,s, _NH2 ),6.62(1H,d,J=8.6Hz,ArH),4.00-3.57(16H,m, _6CH2N , 2CH ₂ O). ¹³ C-NMR (75MHz, DMSO-d ₆ )δ(ppm): 168.63, 165.07, 164.28, 161.90, 158.67, 150.87, 149.66, 148.74, 136.66, 131.46, 127.66, 126.66, 125.44, 123. ,120.11,119.92,111.08,106.90,66.01,43.22,28.94,26.51.HRMS(ESI): m/z[M+H] ⁺ .Calcd for C ₂₆ H ₂₇ N ₉ O ₄ : 530.2259; Found: 530.2252.

Example 3

2-(4-(4-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine- Synthesis of 1-formyl)benzofuran-7-carboxamide (I-3)

With compound III-1 (300 mg, 0.64 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-4-( Trifluoromethyl)pyridin-2-amine (IV-3) (202 mg, 0.70 mmol) was used as raw material, the operation was the same as that of I-2, and purified by column chromatography (dichloromethane:methanol=80:1～20:1 , gradient elution) to obtain 185 mg of off-white solid with a yield of 48.4%. mp>250℃. ¹ H-NMR(300MHz, DMSO-d ₆ )δ(ppm): 8.62(1H,s,ArH),7.92(1H,d,J=7.8Hz,ArH),7.83(1H,d , J=7.4Hz, ArH), 7.77 (1H, s, 1/2CONH ₂ ), 7.71 (1H, s, 1/2CONH ₂ ), 7.55 (1H, s, ArH), 7.43 (1H, t, J= 7.7Hz, ArH), 6.94 (2H, s, NH ₂ ), 6.83 (1H, s, ArH), 3.92-3.65 (16H, m, 6CH ₂ N, 2CH ₂ O). ¹³ C-NMR (75MHz, DMSO) -d ₆ )δ(ppm):174.24,169.82,168.83,165.92,163.46,157.27,155.63,153.42,140.63,132.41,131.40,130.18,129.61,128.37,125.99,124.66,123.40,115.80,109.39,70.67,59.63 ,47.94,47.24.HRMS(ESI): m/z[M+H] ⁺ .Calcd for C ₂₇ H ₂₆ F ₃ N ₉ O ₄ : 598.2133; Found: 598.2136.

Example 4

2-(4-(4-(4-Amino-3-fluorophenyl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)benzofuran Synthesis of -7-carboxamide (I-4)

With compound III-1 (300 mg, 0.64 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) Aniline (IV-4) (166 mg, 0.70 mmol) was used as the raw material, the operation was the same as that of I-2, and purified by column chromatography (dichloromethane:methanol=80:1～20:1, gradient elution) to obtain light yellow Solid 170 mg, yield 48.6%. mp>250℃. ¹ H-NMR (300MHz, DMSO-d ₆ )δ(ppm): 7.96-7.91(3H,m,ArH),7.84(1H,d,J=7.2Hz,ArH),7.80(1H) ,s,1/2CONH ₂ ),7.73(1H,s,1/2CONH ₂ ),7.56(1H,s,ArH),7.44(1H,t,J=7.7Hz,ArH),6.80(1H,t, J=8.9Hz, ArH), 5.78 (2H, s, NH ₂ ), 4.02-3.62 (16H, m, 6CH ₂ N, 2CH ₂ O). ¹³ C-NMR (75MHz, DMSO-d ₆ )δ(ppm) ):168.77,165.39,164.38,159.01,150.82,148.16,139.69,127.64,126.89,125.97,125.19,124.32,123.80,121.69,119.10,114.96,114.55,114.30,111.19,72.86,65.98,43.19,42.42.HRMS( ESI): m/z[M+H] ⁺ .Calcd for C ₂₇ H ₂₇ FN ₈ O ₄ : 547.2212; Found: 547.2211.

Example 5

2-(4-(4-(1H-Indol-5-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine-1-formyl)benzofuran- Synthesis of 7-carboxamide (I-5)

With compound III-1 (300 mg, 0.64 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-indium Indole (IV-5) (170 mg, 0.70 mmol) was used as the raw material, the operation was the same as that of I-2, and purified by column chromatography (dichloromethane:methanol=100:1～30:1, gradient elution) to obtain light yellow Solid 160 mg, yield 45.2%. mp 164-166°C. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ (ppm): 11.28 (1H, s, NH), 8.65 (1H, s, ArH), 8.17 (1H, d, J=8.6 Hz) ,ArH),7.91(1H,d,J=7.8Hz,ArH),7.82(1H,d,J=7.5Hz,ArH),7.79(1H,s,1/2CONH ₂ ),7.72(1H,s, 1/2CONH ₂ ), 7.55(1H,s,ArH),7.45-7.38(3H,m,ArH),6.55(1H,s,ArH),4.08-3.67(16H,m,6CH ₂ N,2CH ₂ O ). ¹³ C-NMR (75MHz, DMSO-d ₆ )δ(ppm): 177.92, 170.63, 165.46, 164.51, 159.05, 150.83, 148.06, 137.85, 127.62, 127.44, 127.28, 126.95, 126.19, 126.483, 123.83 ,121.13,118.95,111.21,110.82,102.37,66.00,45.70,43.19,42.50.HRMS(ESI): m/z[M+H] ⁺ .Calcd for C ₂₉ H ₂₈ N ₈ O ₄ :553.2306; Found: 553.2306 .

Example 6

2-(4-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholinyl-1,3,5-triazin-2-yl ) Synthesis of piperazine-1-formyl)benzofuran-7-carboxamide (I-6)

4-(4-Chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (V -1)

Combine 2-(difluoromethyl)-1H-benzo[d]imidazole (7) (1.43 g, 8.51 mmol), compound 5 (2.00 g, 8.51 mmol) and K ₂ CO ₃ (1.18 g, 8.51 mmol) Add into 50mL three-neck flask, add 25mL DMF, stir and dissolve, react at 25°C for 4 hours, TLC (petroleum ether: ethyl acetate=5:1) detects that raw material 5 has reacted, stop the reaction, pour the reaction solution into 80mL water, A large amount of white solid was precipitated, stirred for 10 minutes, suction filtered, and the filter cake was washed with water and dried to obtain 2.7 g of white solid with a yield of 86.5%. mp244-247°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.44 (1H, d, J=7.7 Hz, ArH), 7.91 (1H, d, J=7.5 Hz, ArH), 7.59 ( 1H, CHF ₂ ), 7.53-7.43 (2H, m, ArH), 4.02-3.95 (4H, m, CH ₂ ), 3.87-3.81 (4H, m, CH ₂ ).

4-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholinyl-1,3,5-triazin-2-yl)piperazine - tert-Butyl 1-carboxylate (VI-1)

Compound V-1 (2.70 g, 7.36 mmol), N-tert-butoxycarbonylpiperazine (1.44 g, 7.73 mmol) and K ₂ CO ₃ (1.53 g, 11.0.4 mmol) were added to a 100 mL three-neck flask, and 50 mL of acetone was added It was turbid when stirred and reacted at 30°C for 8 hours. TLC (petroleum ether:ethyl acetate=5:1) detected that the reaction of raw material V-1 was completed, the reaction was stopped, the solvent was evaporated under reduced pressure, and 50 mL of dichloromethane was added to dissolve the residue. , 50 mL of water was added to extract and wash, the aqueous layer was extracted with 30 mL of dichloromethane, the dichloromethane layers were combined, washed with saturated sodium chloride solution (50 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered with suction, and the filtrate was concentrated to obtain Foamy solid 3.50 g, yield 92.1%. mp 184-187°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.34 (1H, d, J=7.6 Hz, ArH), 7.90 (1H, d, J=6.9 Hz, ArH), 7.57 ( 1H, t, J=53.6Hz, CHF ₂ ), 7.48-7.39 (2H, m, ArH), 3.92-3.85 (8H, m, CH ₂ ), 3.80 (4H, s, CH ₂ ), 3.55 (4H, s, CH ₂ ), 1.50 (9H, s, CH ₃ ).

4-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(piperazin-1-yl)-1,3,5-triazine-2 -yl)morpholine hydrochloride (VII-1)

Compound VI-1 (3.50 g, 6.78 mmol) was added to a 50 mL three-necked flask, 20 mL of ethyl acetate was added and stirred to dissolve, a saturated HCl solution in ethyl acetate (5 mL) was added dropwise, a large amount of white solids were precipitated, and the mixture was stirred at 25° C. for 4 hours , TLC (petroleum ether: ethyl acetate = 5: 1) detected raw material VI-1 after the reaction was completed, suction filtered, the filter cake was washed with ethyl acetate, and dried to obtain 2.72 g of white solid with a yield of 88.6%. mp 230-232°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.36 (1H, d, J=7.3 Hz, ArH), 7.91 (1H, d, J=7.1 Hz, ArH), 7.59 (1H , CHF ₂ ), 7.49-7.39 (2H, m, ArH), 3.98-3.87 (8H, m, CH ₂ ), 3.81 (4H, s, CH ₂ ), 3.02 (4H, s, CH ₂ ).

2-(4-(4-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholinyl-1,3,5-triazin-2-yl )piperazine-1-formyl)benzofuran-7-carboxamide (I-6)

Compound 3 (180 mg, 0.88 mmol), compound VII-1 (400 mg, 0.88 mmol) and PyBOP (550 mg, 1.06 mmol) were added to a 50 mL three-neck flask, 20 mL of DMF was added and stirred to dissolve, and then DIEA (0.44 mL, 2.64 mmol) was added. ), added, reacted at 25 ° C for 8 to 10 hours, TLC (dichloromethane: methanol=20:1) detected raw material 3 reacted, stopped the reaction, poured the reaction solution into 60 mL of water, separated out a large amount of white solids, stirred for 10 minutes, suction filtration, the filter cake is washed with 20 mL of water, and dried to obtain the crude product. Purified by column chromatography (dichloromethane:methanol=100:1～60:1, gradient elution) to obtain 220 mg of white solid with a yield of 41.4%. mp 189-191°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.33 (1H, d, J=7.7 Hz, ArH), 8.22 (1H, d, J=7.3 Hz, ArH), 7.92 ( 1H, d, J=7.1Hz, ArH), 7.86 (1H, d, J=8.0Hz, ArH), 7.56 (1H, t, J=53.6Hz, CHF ₂ ), 7.45 (3H, m, ArH), 7.35(1H,s,ArH),7.22(1H,s,1/ _2CONH2 ),6.02(1H,s,1/ _2CONH2 ),4.03-3.81(16H,m, _6CH2N , _2CH2O ). ¹³ C-NMR (75MHz, DMSO-d ₆ )δ(ppm): 165.07, 164.33, 161.28, 158.81, 150.92, 148.61, 145.83, 141.30, 132.88, 127.68, 126.68, 125.90, 125.44, 124.31, 11962, 124.31, 1196.5. ,115.83,111.03,108.56,87.07,65.84,45.99,43.65,43.08.HRMS(ESI): m/z[M+H] ⁺ .Calcd for C ₂₉ H ₂₇ F ₂ N ₉ O ₄ : 604.2227; Found: 604.2233 .

Example 7

2-(4-2'-Amino-2-morpholinyl-[4,5'-dipyrimidin]-6-yl)piperazine-1-formyl)benzofuran-7-carboxamide (I-7 )Synthesis

4-(4,6-Dichloropyrimidin-2-yl)morpholine (9)

2,4,6-Trichloropyrimidine (8) (10.00g, 54.52mmol) was added to a 250mL three-neck flask, 100mL of dichloromethane was added, stirred to dissolve, DIEA (8.50mL, 48.70mmol) was added, and the temperature was lowered to -78 ℃, slowly add morpholine (4.30mL, 49.40mmol) dropwise, after adding, keep stirring and react for 1～2 hours, TLC (petroleum ether: ethyl acetate=6:1) detects that raw material 8 has reacted, stop the reaction, and react The liquid was poured into 150 mL of water, extracted, the dichloromethane layer was separated, the aqueous layer was extracted with 50 mL of dichloromethane, the dichloromethane layers were combined, washed twice with saturated sodium chloride solution (80 mL×2), and anhydrous Na ₂ SO _4. Dry, filter with suction, concentrate the filtrate to obtain crude product, add mixed solvent (petroleum ether:ethyl acetate=50:1, 100mL) to make slurry for 2 hours, filter with suction and dry to obtain 9.4g of white solid, yield 73.7%. mp 122-124°C. ¹ H NMR (300 MHz, CDCl ₃ ) δ (ppm): 6.56 (1H, s, ArH), 3.83-3.80 (4H, m, 2CH ₂ O), 3.76-3.72 (4H, m, 2CH ₂ ).

4-(6-Chloro-2-morpholinopyrimidin-4-yl)piperazine-1-carboxylate tert-butyl ester (10)

Compound 9 (2.00g, 8.54mmol) and N-tert-butoxycarbonylpiperazine (3.98g, 21.35mmol) were added to a 100mL three-necked flask, 50mL of acetone was added, stirred to dissolve, and then triethylamine (4.00mL, 28.86 mL) was added. mmol), heated and refluxed for about 10 hours, TLC (dichloromethane: methanol=20:1) detected the reaction of raw material 9, stopped the reaction, cooled to room temperature, separated out a large amount of white solids, suction filtered, and the filter cake was washed with acetone and dried. , 2.84g of white solid was obtained, and the yield was 86.6%. mp215-217°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 5.87 (1H, s, ArH), 3.78-3.73 (8H, m, 2CH ₂ O, 2CH ₂ NCO), 3.57-3.54 ( 4H,m,2CH ₂ ),3.48-3.44(4H,m,2CH ₂ ).

4-(4-Chloro-6-(piperazin-1-yl)pyrimidin-2-yl)morpholine hydrochloride (II-2)

Compound 10 (2.84 g, 7.40 mmol) was added to a 50 mL three-neck flask, 15 mL of ethyl acetate was added and stirred to dissolve, and then saturated HCl in ethyl acetate solution (5 mL) was added, and the reaction was stirred at 25°C for 2 to 3 hours, and a large amount of white was precipitated. The solid was detected by TLC (dichloromethane:methanol=20:1) after the reaction of raw material 10 was completed, the reaction was stopped, filtered with suction, the filter cake was washed with ethyl acetate, and dried to obtain 2.36 g of white solid with a yield of 99.6%. ¹ H NMR (300MHz, DMSO-d ₆ )δ(ppm): 9.53(1H,s,HCl), 6.92(1H,s,NH), 6.30(1H,s,ArH), 3.90(4H,t,J = 4.8Hz, 2CH ₂ O), 3.67-3.58 (8H, m, 4CH ₂ N), 3.12 (4H, s, 2CH ₂ N).

2-(4-(6-Chloro-2-morpholinepyrimidine-4-substituted)piperazine-1-formyl)benzofuran-7-carboxamide (III-2)

Compound 3 (500 mg, 2.44 mmol), II-2 (780 mg, 2.44 mmol) and PyBOP (1.52 g, 2.92 mmol) were added to a 50 mL three-neck flask, 25 mL of DMF was added and stirred to dissolve, and then DIEA (1.21 mL, 7.32 mmol) was added. ), stirred and reacted at 25°C for 3 to 5 hours, TLC (dichloromethane: methanol=20:1) detected that the raw material 3 had reacted, stopped the reaction, poured the reaction solution into 80 mL of water, separated out a large amount of solid, stirred for 10 minutes, and pumped Filtration, the filter cake was washed with 20 mL of water, and dried to obtain 0.9 g of white solid (VI-1) with a yield of 78.3%, which was directly used in the one-step reaction without purification.

2-(4-2'-Amino-2-morpholinyl-[4,5'-dipyrimidin]-6-yl)piperazine-1-formyl)benzofuran-7-carboxamide (I-7 )

Compound III-2 (300 mg, 0.64 mmol) and IV-1 (155 mg, 0.70 mmol) were added to a 50 mL three-neck flask, 20 mL of dioxane was added, and stirred to dissolve. K ₂ CO ₃ (354 mg, 2.56 mmol) was dissolved in 2 mL of water and added to the reaction solution, followed by tetrakis(triphenylphosphine)palladium (74 mg, 0.06 mmol). Under nitrogen protection, the reaction was heated and refluxed for 4 to 6 hours, TLC (dichloromethane:methanol=20:1) was used to detect the completion of the reaction of raw material III-2, heating was stopped, cooled to room temperature, suction filtration, the filtrate was concentrated, and 40 mL of acetic acid was added to the residue. Ethyl ester, the mixture was washed successively with water (20 mL×1) and saturated sodium chloride solution (20 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered with suction, the filtrate was concentrated, and the residue was purified by column chromatography (dichloromethane : methanol=80:1～60:1 gradient elution), to obtain 160 mg of light yellow solid, yield 47.4%, mp>250℃. ¹ H-NMR (300MHz, DMSO-d ₆ +D ₂ O)δ(ppm ): 8.92(2H,s,ArH),7.93(1H,d,J=7.7Hz,ArH),7.83(1H,d,J=7.2Hz,ArH),7.53(1H,s,ArH),7.43( 1H, t, J=7.7Hz, ArH), 6.55 (1H, s, ArH), 3.86-3.61 (16H, m, 6CH ₂ N, 2CH ₂ O). ¹³ C-NMR (75MHz, DMSO-d ₆ ) δ(ppm):164.99,163.94,163.34,160.75,159.39,158.73,156.90,154.93,150.85,148.73,127.68,126.65,125.49,123.64,119.89,119.72,110.88,86.68,65.91,44.05,43.41.HRMS(ESI ): m/z[M+H] ⁺ .Calcd for C ₂₆ H ₂₇ N ₉ O ₄ : 530.2259; Found: 530.2250.

Example 8

2-(4-(6-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-2-morpholinopyrimidin-4-yl)piperazine-1-formyl)benzofuran Synthesis of -7-carboxamide (I-8)

Using compound III-2 (300 mg, 0.64 mmol) and compound IV-3 (202 mg, 0.70 mmol) as raw materials, the procedure was the same as that of I-7, and purified by column chromatography (dichloromethane:methanol=80:1～60: 1, gradient elution) to obtain light yellow solid 175mg, yield 45.8%, mp208-210℃. ¹ H-NMR (300MHz, DMSO-d ₆ )δ(ppm): 8.17(1H,s,ArH), 7.91 (1H,d,J=8.3Hz,ArH),7.82(1H,d,J=7.1Hz,ArH),7.79(1H,s,1/ _2CONH2 ),7.72(1H,s,1/ _2CONH2 ) , 7.53(1H,s,ArH),7.42(1H,t,J=7.6Hz,ArH),6.82(1H,s,ArH),6.73(2H,s,NH ₂ ),6.25(1H,s,ArH) ), 4.03-3.59 (16H, m, 6CH ₂ N, 2CH ₂ O). ¹³ C-NMR (75MHz, DMSO-d ₆ )δ(ppm): 165.33, 162.88, 162.71, 160.33, 159.95, 159.00, 150.80, 150.34,148.22,136.06,127.64,126.82,125.89,124.80,123.75,121.29,119.14,110.99,104.62,92.01,65.82,49.83,43.79,43.32.HRMS(ESI):m/z[M ⁺ HRMS(ESI)] for C ₂₈ H ₂₇ F ₃ N ₈ O ₄ : 597.2180; Found: 597.2177.

Example 9

2-(4-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-2-morpholinopyrimidin-4-yl)piperazine-1-formyl ) Synthesis of benzofuran-7-carboxamide (I-9)

4-(4-Chloro-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)morpholine (V-2)

Using compound 7 (500 mg, 2.97 mmol) and compound 9 (700 mg, 2.99 mmol) as raw materials, the same method as compound V-1 was performed to obtain 1.00 g of a white solid with a yield of 92.1%. mp 197-200°C. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ (ppm): 8.31 (1H, d, J=8.1 Hz, ArH), 7.86 (1H, d, J=7.7 Hz, ArH), 7.69 (1H, CHF ₂ ), 7.55-7.42 (2H, m, ArH), 7.09 (1H, s, ArH), 3.74 (8H, brs, 2CH ₂ O, 2CH ₂ ).

4-(6-(2-(Difluoromethyl)-1H-benzo[d]imidazol-1-yl)-2-morpholinopyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester ( VI-2)

Using compound V-2 (1.00 g, 2.73 mmol) and N-tert-butoxycarbonylpiperazine (0.54 g, 2.87 mmol) as raw materials, operate the same method as compound VI-1 to obtain a white solid 1.25 g, yield 88.8% . mp 195-198°C. ¹ H-NMR (300 MHz, CDCl ₃ ) δ (ppm): 8.22 (1H, d, J=7.1 Hz, ArH), 7.90 (1H, d, J=7.1 Hz, ArH), 7.51 ( 1H, CHF ₂ ), 7.44-7.35 (2H, m, ArH), 5.52 (1H, s, ArH), 3.84-3.81 (4H, m, 2CH ₂ O), 3.65-3.57 (12H, m, 6CH ₂ ) .4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(piperazin-1-yl)pyrimidin-2-yl)morpholine hydrochloride Salt (VII-2)

Using compound VI-2 (1.20 g, 2.33 mmol) as the raw material, the same method as compound VII-1 was used to obtain 0.89 g of a white solid with a yield of 84.5%. mp 196-198°C. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ (ppm): 9.10 (2H, brs, NH, HCl), 8.20 (1H, d, J=8.1 Hz, ArH), 7.82 (1H , d, J=7.7Hz, ArH), 7.68 (1H, CHF ₂ ), 7.49-7.39 (2H, m, ArH), 6.08 (1H, s, ArH), 3.88-3.65 (12H, m, 2CH ₂ O ,4CH ₂ ),3.18(4H,brs,2CH ₂ ).

2-(4-(6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-2-morpholinopyrimidin-4-yl)piperazine-1-formyl ) benzofuran-7-carboxamide (I-9)

Using compound 3 (90 mg, 0.44 mmol) and compound VII-2 (199 mg, 0.44 mmol) as raw materials, operate the same method as compound I-6, and purify by column chromatography (dichloromethane:methanol=100:1～50:1 , gradient elution) to obtain an off-white solid 120 mg with a yield of 45.4%. mp 126-128°C. ¹ H-NMR (300MHz, DMSO-d ₆ ) δ (ppm): 8.23 (1H, d, J=8.1 Hz, ArH), 7.91 (1H, d, J=7.8 Hz, ArH), 7.84-7.80(2H,m,ArH),7.75(1H,s,1/ _2CONH2 )7.70(1H,t,J=52.7Hz, _CHF2 ),7.56(1H,s,ArH),7.49-7.36( 3H, m, ArH), 6.04 (1H, s, ArH), 3.96-3.64 (16H, m, 6CH ₂ N, 2CH ₂ O). ¹³ C-NMR (75MHz, DMSO-d ₆ )δ(ppm): 229.53,197.77,165.05,163.81,163.32,162.48,158.79,153.78,150.93,148.66,141.22,127.69,126.65,125.45,123.81,121.86,120.50,119.92,114.94,111.04,108.61,79.51,65.78,45.80,44.52, 25.82.HRMS(ESI): m/z[M+H] ⁺ .Calcd for C ₃₀ H ₂₈ F ₂ N ₈ O ₄ : 603.2274; Found: 603.2278.

Example 10

2-(4-(4-Morpholinyl-6-(6-(2-morpholinylacetamido)-4-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine Synthesis of -2-yl)piperazine-1-formyl)benzofuran-7-carboxamide (I-10)

2-Chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-4-(trifluoromethyl) Pyridin-2-yl)acetamide (11)

Compound IV-3 (600 mg, 2.08 mmol) was dissolved in 15 mL of dichloromethane, DIEA (1.03 mL, 6.24 mmol) was added, the temperature was lowered to -15°C, and under nitrogen protection, chloroacetyl chloride (235 μL, 3.12 mmol) was slowly added , the addition was completed, the reaction was incubated for 1-2 hours, TLC (dichloromethane:methanol=20:1) detected that the reaction of the raw material IV-3 was completed, the reaction was stopped, and 15 mL of water was added to quench the reaction. The organic layer was separated by extraction, and the aqueous layer was extracted once more with 15 mL of dichloromethane. The organic layers were combined, washed with saturated sodium chloride solution (15 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered with suction, and the filtrate was concentrated and subjected to column chromatography. Purification (petroleum ether:ethyl acetate=50:1～10:1 gradient elution) to obtain 580 mg of yellow oil with a yield of 76.5%. ¹ H-NMR (300MHz, CDCl ₃ ) δ (ppm): 9.08 (1H, s, CONH), 8.71 (1H, s, ArH), 8.53 (1H, s, ArH), 4.24 (2H, s, COCH ₂ Cl), 1.39(12H,s,4CH ₃ ). MS(ESI(+)70V) m/z: 387.1[M+Na] ⁺ .

2-Morpholinyl-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-4-(trifluoromethyl) yl)pyridin-2-yl)acetamide (IV-6)

Compound 11 (500 mg, 1.37 mmol) was dissolved in 15 mL of dichloromethane, triethylamine (380 μL, 2.74 mmol) and morpholine (170 μL, 2.05 mmol) were added, and the reaction was heated under reflux for 8 to 10 hours, TLC (dichloromethane: Methanol=20:1) After the reaction of raw material 11 was detected, the heating was stopped, cooled to room temperature, 15 mL of water was added, the organic layer was extracted and separated, and the aqueous layer was extracted once with 15 mL of dichloromethane, and the organic layers were combined and washed with saturated sodium chloride solution. (15mL×2), dried over anhydrous Na ₂ SO ₄ , filtered with suction, concentrated the filtrate, purified by column chromatography (dichloromethane:methanol=100:1～40:1 gradient elution) to obtain a pale yellow solid (IV- 6) 465 mg, yield 81.7%. mp144-146℃. ¹ H-NMR (300MHz, CDCl ₃ )δ(ppm): 9.75(1H,s,CONH),8.68(1H,s,ArH),8.57(1H,s,ArH),3.83(4H) , t, J=4.5Hz, 2CH ₂ O), 3.22 (2H, s, COCH ₂ N), 2.66 (4H, t, J=4.4 Hz, 2CH ₂ N), 1.38 (12H, s, 4CH ₃ ). MS(ESI(+)70V)m/z:416.2[M+H] ⁺ .

2-(4-(4-Morpholinyl-6-(6-(2-morpholinylacetamido)-4-(trifluoromethyl)pyridin-3-yl)-1,3,5-triazine -2-yl)piperazine-1-formyl)benzofuran-7-carboxamide (I-10)

Using compound III-1 (300 mg, 0.64 mmol) and IV-6 (290 mg, 0.70 mmol) as raw materials, operate the same method as compound I-2, and purify by column chromatography (dichloromethane:methanol=100:1～50: 1, gradient elution) to obtain 300 mg of pale yellow solid (I-10), yield 65.1%. mp120-122℃. ¹ H-NMR (300MHz, DMSO-d ₆ )δ(ppm): 10.70(1H,s,CONH),8.90(1H,s,ArH),8.56(1H,s,ArH),7.92 (1H,d,J=7.7Hz,ArH),7.83(1H,d,J=7.2Hz,ArH),7.81(1H,s,1/ _2CONH2 ),7.74(1H,s,1/ _2CONH2 ) ,7.56(1H,s,ArH),7.43(1H,t,J=7.6Hz,ArH),3.94-3.63(20H,m,10CH ₂ ),3.29(2H,s,COCH ₂ N),2.56(4H ,s,2CH ₂ ).

Compound I-10 (250 mg) was dissolved in 4 mL of ethyl acetate, HCl saturated ethyl acetate solution was added dropwise, a white solid was precipitated, until the pH of the solution = 1~2, stirred at room temperature for 15 minutes, suction filtered, washed with ethyl acetate The filter cake was dried in vacuo to obtain 235 mg of the hydrochloride of I-10, HPLC: 99.40%. ¹ H-NMR (300 MHz, DMSO-d ₆ +D ₂ O) δ (ppm): 8.95 (1 H, s, ArH), 8.51(1H,s,ArH),7.96(1H,d,J=7.9Hz,ArH),7.85(1H,d,J=7.5Hz,ArH),7.58(1H,s,ArH),7.46(1H, t, J=7.6Hz, ArH), 4.34 (2H, s, COCH ₂ N), 4.09-3.86 (12H, m, 6CH ₂ ), 3.75-3.31 (12H, m, 6CH ₂ ). ¹³ C-NMR ( 75MHz,DMSO-d ₆ )δ(ppm):168.73,165.08,163.98,158.77,152.72,151.29,150.91,148.65,146.44,137.01,127.67,126.68,125.45,123.63,120.77,120.14,119.87,114.50,111.10, 110.03,65.89,63.27,57.32,52.05,43.28,28.32,13.80.HRMS(ESI): m/z[M+H] ⁺ .Calcd for C ₃₃ H ₃₆ F ₃ N ₁₀ O ₆ : 725.2766; Found: 725.2760.

Claims (10)

1. the compound of logical formula (I) or its pharmaceutically acceptable salt:

Wherein X represents CH or N；

R¹It represents

R²It represents R³Represent H, F, Br, Cl, CF₃、CN、CH₃Or OCH₃；Y represents CH or N；Z represent O, NH、NCH₃Or CH₂；M=1 or 2.

2. the compound (I) of claim 1 or its pharmaceutically acceptable salt, wherein R¹It represents R²It represents

3. a kind of method for the compound for preparing claim 1, works as R²It does not representWhen, comprising:

Wherein R¹、R²Definition with claim 1.

4. method for claim 3 is carried out under the conditions of catalyst, alkali and reaction dissolvent is added, wherein catalyst is selected from double (triphenylphosphine) palladium chloride, tetrakis triphenylphosphine palladium or [bis- (diphenylphosphino) ferrocene of 1,1'-] palladium chloride；Alkali is selected from Sodium ethoxide, sodium acetate, potassium acetate, potassium phosphate, sodium carbonate or potassium carbonate；Reaction dissolvent is selected from N,N-dimethylformamide, N, N- Dimethyl acetamide, glycol dimethyl ether, tetrahydrofuran, dioxane, toluene, ethyl alcohol, water or in which two or three any The mixed solvent of solvent；Reaction temperature is 95 DEG C~110 DEG C.

5. a kind of method for the compound for preparing claim 1, works as R²It representsWhen, comprising:

Wherein R¹、R³Definition with claim 1.

6. method for claim 5 is carried out under the conditions of condensing agent, acid binding agent and reaction dissolvent is added, wherein condensing agent is Hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus, acid binding agent is n,N-diisopropylethylamine；Reaction dissolvent is N, Dinethylformamide.

7. the compound of claim 1 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt is logical formula (I) chemical combination The acid-addition salts of object, wherein for the acid at salt are as follows: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, wine Stone acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid or ferulic acid.

8. a kind of pharmaceutical composition, wherein the compound containing claim 1 or its pharmaceutically acceptable salt and pharmaceutically may be used The carrier of receiving.

9. the compound of claim 1 or its pharmaceutically acceptable salt are in the preparation bis- target spot inhibitor medicaments of PARP-1 and PI3K In purposes.

10. the purposes of claim 9, wherein the bis- target spot inhibitor medicaments of PARP-1 and PI3K are anti-tumor drugs.