CN109810098B

CN109810098B - A dual-target inhibitor of PARP-1 and PI3K containing phthalazine-1(2H)-one structure

Info

Publication number: CN109810098B
Application number: CN201711200376.7A
Authority: CN
Inventors: 徐云根; 朱启华; 王均伟; 李慧; 葛亦然; 彭珂文
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2017-11-21
Filing date: 2017-11-21
Publication date: 2021-08-31
Anticipated expiration: 2037-11-21
Also published as: CN109810098A

Abstract

本发明涉及药物化学领域，具体涉及一类含有酞嗪‑1(2H)‑酮和三嗪或嘧啶结构的PARP‑1和PI3K双靶点抑制剂(I)、它们的制备方法，以及含有这些化合物的药物组合物。药效学试验证明本发明的化合物具有抗肿瘤的功效。

The present invention relates to the field of medicinal chemistry, in particular to a class of PARP-1 and PI3K dual-target inhibitors (I) containing phthalazine-1(2H)-ketone and triazine or pyrimidine structures, a preparation method thereof, and a compound containing these Pharmaceutical compositions of compounds. Pharmacodynamic tests proved that the compounds of the present invention have antitumor efficacy.

Description

PARP-1 and PI3K dual-target inhibitor containing phthalazin-1 (2H) -one structure

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a pair of PARP-1 and PI3K double-target inhibitors containing phthalazin-1 (2H) -one and triazine or pyrimidine structures, a preparation method thereof, a pharmaceutical composition containing the compounds and an application of the pharmaceutical composition in the aspect of tumor resistance.

Background

Poly (adenosine diphosphate ribose) polymerase (PARP) is a multifunctional protein posttranslational modification enzyme existing in most eukaryotic cells, 18 subtypes of the family are discovered at present, wherein the proportion of PARP-1 is the largest, and the PARP-1 plays a leading role in treating diseases such as stroke, neurodegenerative diseases, myocardial ischemia, cancer, inflammation and diabetes and plays a leading role in repairing DNA injury. PARP-1 inhibitors are a class of antitumor drugs that exert cytotoxicity by regulating DNA damage repair, and are one of the most exciting results in the field of tumor treatment research in the early 21 st century. Three PARP inhibitors are currently used clinically, namely Olaparib (Olaparib) marketed in 2014, lucapanib (rucapanib) marketed in 2016 and nilapanib (Niraparib) marketed in 2017, and are mainly used for treating tumors such as breast cancer, ovarian cancer and peritoneal cancer. However, as research progresses and clinical trial results are released successively, the limitations of PARP-1 inhibitors are further revealed. On one hand, when the current PARP-1 inhibitor is used alone, the PARP-1 inhibitor only has curative effect on triple negative breast cancer or ovarian cancer with BRCA1/2 deficiency, which results in narrower indication of the PARP-1 inhibitor; on the other hand, long-term use of PARP-1 inhibitors also faces the problem of drug resistance, and these problems will have adverse effects on the clinical application of PARP-1 inhibitors.

Phosphatidylinositol 3-kinase (PI 3K) is an upstream molecule in the PI3K/Akt/mTOR signaling pathway, and as a key node protein in this pathway, PI3K phosphorylates the hydroxyl group at position 3 of phosphatidylinositol 4, 5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4, 5-trisphosphate (PIP 3). PIP3 acts as a second messenger and plays an important role in essential responses such as cell survival, growth, proliferation and metabolism. The tumor suppressor PTEN can dephosphorize PIP3 to generate PIP2, which is an antagonist for the catalytic action of PI 3K. Abnormal activation of PI3K leads to a disturbance of this pathway, resulting in a range of diseases including cancer, neurological disorders, autoimmune diseases and hematopoietic diseases. PI3K has become one of the important targets for tumor therapy research, and there are two main PI3K inhibitors in clinical application at present, namely PI3K delta inhibitor Idelalisib (Idelalisib) marketed in 2014 and PI3K alpha/PI 3K delta inhibitor Copanlisib marketed in 2017, which are mainly used for treating various lymphomas; in addition, a plurality of PI3K inhibitors are in clinical research stage, but no PARP-1/PI3K dual-target inhibitor is reported at present.

Disclosure of Invention

The invention discloses a compound of a general formula (I), and pharmacodynamic test results show that the compound or pharmaceutically acceptable salt thereof can simultaneously act on two targets of PARP-1 and PI3K, can be used as a single tumor therapeutic agent or be used together with other antitumor drugs, thereby achieving the purposes of improving the tumor curative effect and reducing the dosage and toxicity.

Wherein X is CH or N.

R¹Is composed of

Preferably R¹Is composed of

R²Is composed of

R³Represents H, F, Br, Cl, CF₃、CH₃Or OCH₃(ii) a Y represents CH or N;

preferably R²Is composed of

Preferred partial compounds of the invention are the following:

the partial compounds of the general formula (I) according to the invention can be prepared by the following process:

the above reaction is preferably carried out with the addition of 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 ] palladium dichloride or [1,1' -bis (diphenylphosphino) ferrocene ] nickel dichloride; the base is preferably selected from sodium ethoxide, sodium acetate, potassium phosphate, sodium carbonate or potassium carbonate; the reaction solvent is preferably selected from N, N-dimethylformamide, N-dimethylacetamide, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, toluene, ethanol, water or a mixed solvent of any two or three of the solvents; the reaction temperature is preferably 75 to 115 DEG C

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

In more detail, the preparation from the starting material (II) comprises:

process for the preparation of compound IV by reacting compound II with compound III:

the condensing agent used is preferably selected from benzotriazol-1-yl-oxytripyrrolidinophosphonium 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-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-dimethylacetamide or dimethylsulfoxide. More preferably N, N-dimethylformamide.

The reaction has low requirement on the temperature, and the reaction can be carried out at room temperature.

The process for preparing the compound I by the Suzuki coupling reaction of the compound IV and boric acid ester V comprises the following steps:

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 preferably tetrakis (triphenylphosphine) palladium.

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

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

The reaction temperature is preferably from 75 ℃ to 115 ℃. More preferably 95 to 110 ℃.

The pharmaceutically acceptable salt of the compound has the same effect as the compound, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound shown as the general formula (I), and the acid for forming the salt is: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

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

The compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, powder, syrup, liquid, suspending agents, freeze-dried powder injection and injection, and common medicinal auxiliary materials such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.

The clinical administration mode of the compound of the invention can adopt oral administration, injection and other modes.

Typically, the compounds of the invention are administered to humans in a dosage range of 1mg to 1000mg per day. Dosages outside this range may also be used depending on the dosage form and the severity of the disease.

The pharmacological experiments and results of part of the compounds of the invention are as follows:

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

Experimental methods

The kinase activity test methods used in this experiment are essentially the same, but different concentrations are used to achieve the optimal detection range based on different kinases and corresponding different substrates.

PARP-1 inhibitory Activity assay methods: taking out the 96-well plate which is pre-coated with the histone, and adding the following enzyme reaction system and inhibitors with different concentrations into each well, wherein the enzyme reaction system comprises the following components: 50 μ L of reaction buffer (Tris HCl, pH 8.0), NAD⁺Biotin-labeled activated DNA, PARP-1 enzyme, and inhibitors; after reacting for 1 hour at room temperature, adding 50 mu L of avidin-labeled HRP into each hole, and reacting for 30 minutes; a further 100. mu.L of HRP substrate was added and the chemiluminescence detected on a SpectraMax M instrument. Percent enzyme activity was calculated by the following formula:

percent (%) enzyme activity (OD value-OD value background in OD value administration well)/(OD value-OD value background in control well) × 100%

PI3K α inhibitory activity assay: 40mM Tris, pH 7.4,10mM MgCl₂0.1mg/ml BSA,1mM DTT, 10. mu.M ATP, PI 3K. alpha. kinase, kinase substrate; simultaneously adding compounds to be screened with different concentrations to form a 50 mu L reaction system, reacting at 30 ℃ for 40 minutes, detecting the ADP content in the system by a luciferase method, reacting for 5 minutes, and detecting a chemiluminescence signal on an MD-SpectraMax M5 multifunctional enzyme-linked immunosorbent assay (ELISA), wherein the chemiluminescence signal value intensity and the chemiluminescence signal value intensity are the same as those of the ADP content in the systemThe enzyme activity is inhibited in proportion. Substituting the detected chemiluminescent signal value into the following equation:

Drug concentrations were diluted in a three-fold concentration gradient, with two replicate wells tested for each concentration. The drug concentration was plotted as the abscissa and the percentage of enzyme activity corresponding to each concentration was plotted as the ordinate, and the IC of each test compound was calculated using Graphpad Prism5 as a non-linear regression₅₀The value is obtained.

The results are shown in tables 1 and 2:

TABLE 1 inhibitory Activity of test Compounds against PARP-1 and PI3K α at 100nM concentration

Table 1 the results show that: under the concentration of 100nM, all the compounds of the invention keep higher inhibitory activity to PARP-1, and the inhibitory rate reaches more than 80%; under the concentration of 100nM, the compound also shows a certain inhibitory activity to PI3K alpha, and the inhibition rate of part of the compound to PI3K alpha reaches 30%; the above results show that the compounds of the present invention have inhibitory activity against both PARP-1 and PI3K α.

Selection of a portion of the compounds of the invention for determination of IC's for PARP-1 and PI3K alpha, respectively₅₀The values and results are shown in Table 2.

TABLE 2 IC of part of the tested compounds on PARP-1 and PI3K alpha₅₀Value of

Table 2 the results show: the compound of the invention has better inhibitory activity to PARP-1 and IC thereof₅₀The value is between 0.78 and 8.8 nM; has certain inhibitory activity on PI3K alpha, and IC thereof₅₀Values were around 100 nM. The compound of the present invention is shown to have dual inhibitory activity against PARP-1 and PI 3K.

(2) Detecting proliferation inhibitory Activity of Compounds on tumor cells

Experimental methods

Cells in logarithmic growth phase (tumor cell lines HCT116, HCC1937, MDA-MB-231, and MDA-MB-468) were seeded in a certain amount in a 96-well plate (200. mu.L/well), cultured for 24 hours to adhere to the wall, and then dosed. Each drug concentration is provided with 3 multiple wells, and corresponding zero setting wells and blank control are arranged. After 72 hours of drug action, 50% TCA (50 muL/well) is added into the adherent cells, the cells are fixed for 1 hour at 4 ℃, the fixing solution is poured off, washed 5 times by distilled water and naturally dried. Add 100. mu.L of 4mg/mL SRB to each well, stain at room temperature for 15 minutes, discard, wash with 1% glacial acetic acid 5 times, and dry naturally. Finally, 150. mu.L of 10mM Tris solution was added to each well, shaken well, and OD was measured at 565nm using a variable wavelength microplate reader (VERSAmaxTM, Molecular Device). The cell growth inhibition rate was calculated by the above formula, and the results are shown in Table 3.

Results of in vitro antitumor Activity test of Compounds of Table 3

Table 3 the results show: the compounds have stronger in-vitro anti-tumor activity, can obviously inhibit the proliferation of tumor cells, has obvious inhibition activity on HCC1937 and HCT116 cells, and also has stronger inhibition activity on MDA-MB-231 and MDA-MB-468 cells.

Detailed Description

Example 1

Synthesis of 4- (3- (4- (4- (2-aminopyrimidin-5-yl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-1)

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

Dissolving prochlorperazine (1) (10.00g,54.23mmol) in 100mL dichloromethane, adding DIEA (9.92mL,56.94mmol), cooling to-78 ℃, dropwise adding a solution of morpholine (4.73mL,54.23mmol) in 10mL dichloromethane into the reaction solution, precipitating a large amount of white solid after addition, detecting that the raw material 1 is reacted by TLC (petroleum ether: ethyl acetate: 6:1), stopping the reaction, filtering, washing the filter cake with water, and drying to obtain 7.18g of white solid with the yield of 56.4%.¹H NMR(300MHz,DMSO-d₆)δ(ppm):3.80-3.76(4H,CH₂O),3.69(4H,CH₂).

4- (4-chloro-6-morpholinyl-1, 3, 5-triazin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (3)

Compound 2(7.00g,29.78mmol), 1-tert-butoxycarbonylpiperazine (5.55g,29.80mmol) and K₂CO₃(4.12g,29.81mmol) was added to a 250mL three-necked flask, 100mL DMF was added and dissolved with stirring, the reaction was carried out at 25 ℃ for 5 hours, TLC (petroleum ether: ethyl acetate: 6:1) detected that the reaction of the raw material 2 was completed, the reaction was stopped, the reaction was poured into 300mL water, a large amount of solid was precipitated, the mixture was stirred for 30 minutes, filtered, the filter cake was washed with water, and dried to obtain 10.5g of a white solid with a yield of 91.6%. m.p.169-172 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):3.83-3.75(12H,m,6CH₂),3.52-3.49(4H,m,2CH₂),1.53(9H,s,3CH₃).

4- (4-chloro-6-morpholinyl-1, 3, 5-triazin-2-yl) piperazine hydrochloride (III-1)

Compound 3(10.0g,25.98mmol) was dissolved in 50mL of ethyl acetate, saturated HCl in ethyl acetate (20mL) was added, the reaction was stirred at 25 ℃ for 2 hours, TLC (petroleum ether: ethyl acetate: 6:1) detected that the reaction of starting material 3 was completed, the reaction was stopped, suction filtration was performed, the filter cake was washed with ethyl acetate and dried to give 7.65g of white solid with a yield of 91.6%.¹H NMR(300MHz,MeOD)δ(ppm):4.06(4H,t,J＝5.2Hz,2CH₂O),3.81-3.77(4H,m,2CH₂),3.70-3.67(4H,m,2CH₂),3.27(4H,t,J＝5.4Hz,2CH₂).

4- (3- (4- (4-chloro-6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-yl) -4-fluorobenzyl) phthalazin-1 (2H) -one (IV-1)

2-fluoro-5- ((4-oxo-3, 4-dihydrophthalazinyl) methyl) benzoic acid (II) (7.53g,25.25mmol), 4- (4-chloro-6-morpholinyl-1, 3, 5-triazin-2-yl) piperazine hydrochloride (III-1) (8.10g,25.22mmol) and PyBOP (14.40g,27.67mmol) were charged into a 250mL three-necked flask, 100mL of DMF was added, the mixture was dissolved by stirring, DIEA (12.50mL,75.63mmol) was added, and the mixture was reacted at 25 ℃ for 6 to 8 hours. TLC (dichloromethane: methanol 20:1) detects that the reaction of the raw material II is finished, the reaction is stopped, the reaction solution is poured into 300mL of water, a large amount of solid is precipitated, the mixture is stirred for 15 minutes and then is filtered, a filter cake is washed by water, the drying and the column chromatography purification (eluent: dichloromethane: methanol 100: 1-40: 1 gradient elution) are carried out, 12.50g of light yellow solid (IV-1) is obtained, and the yield is 87.7%. m.p.148-150 ℃.¹H-NMR(300MHz,DMSO-d₆)δ(ppm):12.57(1H,s,CONH),8.27(1H,d,J＝7.8Hz,ArH),7.99-7.81(3H,m,ArH),7.48-7.43(1H,m,ArH),7.38(1H,d,J＝6.5Hz,ArH),7.25(1H,t,J＝9.0Hz,ArH),4.35(2H,s,ArCH₂),3.80-3.63(14H,m,2CH₂O,5CH₂N),3.27-3.20(2H,m,CH₂N).

4- (3- (4- (4- (2-aminopyrimidin-5-yl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-1)

Compound IV-1(600mg,1.06mmol), 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-amine (V-1) (280mg,1.27mmol) was charged into a 50mL three-necked flask, and 25mL of dioxane was added and dissolved with stirring. Get K₂CO₃(586mg,4.24mmol) was dissolved in 2.5mL of water, the reaction mixture was added, tetrakis (triphenylphosphine) palladium (127mg,0.11mmol) was added, nitrogen was used for protection, the mixture was heated to reflux, the reaction was carried out for 6 to 8 hours, TLC (dichloromethane: methanol 20:1) was used to detect completion of the reaction of the raw material IV-1, heating was stopped, the mixture was cooled to room temperature, suction filtration was carried out, the filtrate was concentrated, 40mL of ethyl acetate was added to the residue, the mixture was washed with water (20 mL. times.1) and saturated sodium chloride solution (20 mL. times.2) in this order, and anhydrous Na was added₂SO₄And (5) drying. Suction filtration, filtrate concentration and column chromatography purification (eluent: dichloromethane: methanol: 80: 1-30: 1 gradient elution) to obtain light yellow solid 380mg, yield 57.5%. m.p.182-183 ℃.¹H NMR(300MHz,DMSO-d₆)δ(ppm):12.61(1H,s,CONH),9.06(2H,s,ArH),8.26(1H,d,J＝6.8Hz,ArH),7.99-7.81(3H,m,ArH),7.49-7.43(1H,m,ArH),7.38(1H,d,J＝6.6,1.9Hz,ArH),7.30(2H,s,NH₂),7.25-7.22(1H,m,ArH),4.34(2H,s,ArCH₂),3.94-3.57(14H,m,7CH₂),3.26-3.19(2H,m,CH₂).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):167.29,164.80,164.16,164.01,159.34,158.59,158.01,154.78,144.80,134.82,133.43,131.47,129.07,128.86,127.91,126.04,125.43,123.78,118.45,116.05,115.77,65.99,46.36,43.24,41.20,36.44.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₁H₃₀FN₁₁O₃:624.2590；Found:624.2595.

Example 2

Synthesis of 4- (3- (4- (4- (6-aminopyridin-3-yl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-2)

The same procedure as in I-1 was followed using compound IV-1(300mg,0.53mmol) and 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (V-2) (128mg,0.58mmol) as starting materials, and column chromatography (eluent: dichloromethane: methanol ═ 80:1 to 30:1 gradient elution) to give 160mg of a pale yellow solid in 48.5% yield. m.p.180-182 ℃.¹H NMR(300MHz,DMSO-d₆)δ(ppm):12.61(1H,s,CONH),8.89(1H,s,ArH),8.26-8.19(2H,m,ArH),7.97-7.79(3H,m,ArH),7.46-7.37(2H,m,ArH),7.24(1H,t,J＝8.7Hz,ArH),6.57(2H,s,ArNH₂),6.45(1H,d,J＝8.4Hz,ArH),4.33(2H,s,ArCH₂),3.93-3.64(14H,m,2CH₂O,5CH₂N),3.27-3.18(2H,m,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):168.62,164.31,163.98,161.91,159.34,154.76,149.69,144.82,136.66,134.76,133.44,131.49,129.05,127.88,126.04,125.44,123.75,123.51,120.07,118.23,116.06,115.77,106.87,65.99,46.34,43.19,41.21,36.43.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₂H₃₂FN₁₀O₃:623.2637；Found:623.2647.

Example 3

Synthesis of 4- (3- (4- (4- (6-amino-4- (trifluoromethyl) pyridin-3-yl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-3)

With compound IVStarting with (300mg,0.53mmol) and 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4- (trifluoromethyl) pyridin-2-amine (V-3) (168mg,0.58mmol), column chromatography was performed as in I-1 (eluent: dichloromethane: methanol: 80:1 to 30:1 gradient elution) to give 185mg of off-white solid in 50.6% yield. m.p.159-161 ℃.¹H NMR(300MHz,DMSO-d₆)δ(ppm):12.61(1H,s,CONH),8.61(1H,s,ArH),8.27(1H,d,J＝7.4Hz,ArH),7.97(1H,d,J＝7.4Hz,ArH),7.91-7.80(2H,m,ArH),7.47-7.43(1H,m,ArH),7.39(1H,dd,J＝6.4,1.9Hz,ArH),7.25(1H,t,J＝9.0Hz,ArH),6.97(2H,s,NH₂),6.82(1H,s,ArH),4.34(2H,s,ArCH₂),3.85-3.63(14H,m,2CH₂O,5CH₂N),3.24-3.21(2H,m,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):169.46,164.03,161.18,159.34,158.00,154.75,152.56,144.81,135.87,134.81,133.40,131.47,129.05,127.89,126.04,125.44,124.86,123.74,123.49,121.22,118.59,116.06,115.79,104.63,65.91,46.20,43.19,41.17,36.45.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₃H₃₀F₄N₁₀O₃:691.2511；Found:691.2518.

Example 4

Synthesis of 4- (3- (4- (4- (4-aminophenyl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-4)

The same procedure as in I-1 was carried out using compound IV-1(250mg,0.44mmol) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenylamine (V-4) (107mg,0.49mmol) as starting materials, and separation by column chromatography (eluent: dichloromethane: methanol: 100:1 to 40:1 gradient elution) was carried out to obtain 90mg of an off-white solid with a yield of 32.7%. m.p.168-170 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):10.42(1H,s,CONH),8.47(1H,d,J＝8.0Hz,ArH),8.20(2H,d,J＝8.0Hz,ArH),7.80-7.73(3H,m,ArH),7.39-7.27(2H,m,ArH),7.05(1H,t,J＝8.6Hz,ArH),6.71(2H,d,J＝7.7Hz,ArH),4.30(2H,s,ArCH₂),4.14-3.77(14H,m,2CH₂O,5CH₂N),3.46-3.36(2H,m,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):169.48,164.50,163.79,159.34,158.00,154.77,152.31,144.83,134.79,133.44,131.50,129.78,129.06,128.87,127.88,126.05,125.46,123.77,123.26,116.06,115.78,112.67,66.01,46.33,43.19,41.27,36.43.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₃H₃₂FN₉O₃:622.2685；Found:622.2697.

Example 5

Synthesis of 4- (3- (4- (4- (4-amino-2-fluorophenyl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-5)

The same procedure as in I-1 was followed using compound IV-1(300mg,0.53mmol) and 3-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenylamine (V-5) (138mg,0.58mmol) as starting materials, and column chromatography (eluent: dichloromethane: methanol ═ 100:1 to 50:1 gradient elution) to give 165mg of off-white solid in 48.7% yield. m.p.109-111 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):10.28(1H,s,CONH),8.49(1H,s,ArH),7.97(1H,s,ArH),7.87-7.23(3H,m,ArH),7.40-7.32(2H,m,ArH),7.07(1H,t,J＝8.4Hz,ArH),6.50-6.38(2H,m,ArH),4.31(2H,s,ArCH₂),4.11-3.68(12H,m,2CH₂O,4CH₂N),3.51-3.20(4H,m,2CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):168.54,164.91,164.34,163.98,161.53,159.34,154.77,153.71,144.83,134.76,133.43,132.43,131.48,129.05,128.85,127.88,126.04,125.45,123.75,116.07,115.77,111.17,109.22,100.04,65.98,45.84,43.16,36.43,24.92.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₃H₃₁F₂N₉O₃:640.2591；Found:640.2589.

Example 6

Synthesis of 4- (3- (4- (4- (3-amino-4-fluorophenyl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-6)

The same procedure as in I-1 was followed using compound IV-1(300mg,0.53mmol) and 2-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenylamine (V-6) (138mg,0.58mmol) as starting materials, and column chromatography was performed (eluent: dichloromethane: methanol ═ 100:1 to 80:1 gradient elution) to obtain 157mg of an off-white solid in 46.3% yield. m.p.133-135 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):10.70(1H,s,CONH),8.48(1H,d,J＝7.9Hz,ArH),7.87(1H,d,J＝8.5Hz,ArH),7.80-7.73(3H,m,ArH),7.40-7.32(3H,m,ArH),7.10-7.00(2H,m,ArH),4.31(2H,s,ArCH₂),4.06-3.67(14H,m,2CH₂O,5CH₂N),3.44-3.38(2H,m,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):169.16,164.52,163.99,159.36,158.02,154.78,154.35,151.15,144.85,135.95,134.76,133.46,132.98,131.52,129.06,128.65,127.87,126.05,125.44,116.54,116.18,115.78,114.66,114.41,65.96,63.02,43.22,41.20,36.42.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₃H₃₁F₂N₉O₃:640.2591；Found:640.2597.

Example 7

Synthesis of 4- (3- (4- (4- (1H-indazol-4-yl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-7)

The same procedure as in I-1 was followed using compound IV-1(400mg,0.71mmol) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (V-7) (190mg,0.78mmol) as starting materials, and column chromatography (eluent: dichloromethane: methanol ═ 100:1 to 50:1 gradient elution) to give 180mg of a white solid in 39.3% yield. m.p.178-180 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):11.19(1H,s,NH),10.75(1H,s,CONH),8.85(1H,s,ArH),8.48(1H,d,J＝6.5Hz,ArH),8.28(1H,d,J＝6.6Hz,ArH),7.78-7.72(3H,m,ArH),7.67(1H,d,J＝8.4Hz,ArH),7.49-7.32(3H,m,ArH),7.05(1H,q,J＝9.1Hz,ArH),4.31(2H,s,ArCH₂),4.16-3.71(14H,m,2CH₂O,5CH₂N),3.45-3.31(2H,m,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):173.51,170.09,164.64,164.04,159.35,151.13,144.82,140.62,134.83,134.64,133.43,131.51,129.62,129.05,128.88,127.89,126.04,125.46,123.52,122.05,120.84,116.09,115.79,114.50,113.65,65.98,45.78,43.23,36.45,25.92.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₄H₃₁FN₁₀O₃:647.2637；Found:647.2629.

Example 8

4- (3- (4- (4- (1H-indol-5-yl) -6-morpholinyl-1, 3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (1H) -one (I-8)

The same procedure as in I-1 was followed using compound IV-1(300mg,0.53mmol) and 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole (V-8) (142mg,0.58mmol) as starting materials, and column chromatography (eluent: dichloromethane: methanol ═ 100:1 to 80:1 gradient elution) to give 135mg of a pale yellow solid in 39.4% yield. m.p.123-125 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):10.30(1H,s,CONH),8.73(1H,s,NH),8.48-8.40(2H,m,ArH),8.27-8.23(1H,m,ArH),7.82-7.72(3H,m,ArH),7.40-7.30(3H,m,ArH),7.23(1H,s,ArH),7.06(1H,t,J＝8.9Hz,ArH),6.63(1H,s,ArH),4.29(2H,s,ArCH₂),4.19-3.72(14H,m,2CH₂O,5CH₂N),3.49-3.40(2H,m,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):170.56,164.60,164.03,159.39,154.78,144.89,138.07,134.79,133.47,131.52,129.05,128.62,127.85,127.35,126.39,126.05,125.45,123.74,123.51,121.46,121.14,116.09,115.80,110.80,102.31,90.99,66.04,61.88,43.25,36.43,18.61.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₅H₃₂FN₉O₃:646.2685；Found:646.2691.

Example 9

Synthesis of (S) -4- (3- (4- (4- (2-aminopyrimidin-5-yl) -6- (3-methylmorpholinyl) -1,3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-9)

(S) -4- (3- (4- (4-chloro-6- (3-methylmorpholine) -1,3, 5-triazine-2-substituted) piperazine-1-carbonyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (IV-2)

II (0.45g,1.49mmol), (S) -4- (4-chloro-6- (piperazin-1-yl) -1,3, 5-triazin-2-yl) -3-methylmorpholine hydrochloride (III-2) (0.50g,1.49mmol) and PyBOP (0.93g,1.79mmol) were charged to a 50mL three-necked flask, 15mL of DMF was added and dissolved with stirring, DIEA (0.84mL,4.47mmol) was added and reacted at 25 ℃ for 8 hours. TLC (dichloromethane: methanol ═ 20:1) detected that the reaction of starting material II was complete, the reaction was stopped, the reaction solution was poured into 50mL of water, a large amount of solid precipitated, stirred for 5 minutes, filtered, and the filter cake was washed with water and dried to obtain 0.73g of pale yellow solid (IV-2) with a yield of 84.6%. m.p.168-171 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):10.33(1H,s,CONH),8.50-8.47(1H,m,ArH),7.81-7.73(3H,m,ArH),7.41-7.32(2H,m,ArH),7.07(1H,t,J＝7.8Hz,ArH),4.31(2H,s,ArCH₂),3.98-3.28(13H,m,CH₂),1.70(2H,s,CH₂),1.32(3H,d,J＝6.1Hz,CH₃).

(S) -4- (3- (4- (4- (2-aminopyrimidin-5-yl) -6- (3-methylmorpholinyl) -1,3, 5-triazin-2-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-9)

The same procedure as in I-1 was followed using compound IV-2(400mg,0.69mmol) and compound V-1(162mg,0.73mmol) as starting materials, and column chromatography separation (eluent: dichloromethane: methanol: 100: 1-30: 1 gradient elution) to give 170mg of a pale yellow solid with a yield of 38.8%. m.p.>250℃.¹H NMR(300MHz,DMSO-d₆)δ(ppm):9.02(2H,s,ArH),8.24(1H,s,ArH),7.94-7.79(3H,m,ArH),7.41-7.22(3H,m,ArH),4.73-4.52(2H,m,CH₂),4.31(2H,s,ArCH₂),3.66-2.99(13H,m,6CH₂),1.17(3H,s,CH₃).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):172.01,169.54,168.90,168.74,168.55,164.09,163.33,159.50,149.57,139.55,138.19,136.23,133.80,132.64,130.79,130.20,128.51,125.06,123.19,120.81,120.54,74.94,74.50,70.93,50.42,50.29,41.19,18.70,13.26.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₂H₃₂FN₁₁O₃:638.2746；Found:638.2745.

Example 10

Synthesis of 4- (3- (4- (2 '-amino-2-morpholinyl- [4,5' -bipyrimidinyl ] -6-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-11)

4- (4, 6-dichloropyrimidin-2-yl) morpholine (5)

Adding 2,4, 6-trichloropyrimidine (4) (10.00g,54.52mmol) into a 250mL three-necked bottle, adding 100mL dichloromethane, stirring for dissolving, adding DIEA (8.50mL,48.70mmol), cooling to-78 ℃, slowly dropwise adding morpholine (4.30mL,49.40mmol), after adding, keeping the temperature and stirring for reaction for 1-2 hours, detecting that the raw material 4 is completely reacted by TLC (petroleum ether: ethyl acetate ═ 6:1), stopping the reaction, pouring the reaction liquid into 150mL water, extracting, separating a dichloromethane layer, extracting the water layer with 50mL dichloromethane, combining the dichloromethane layer, washing twice with saturated sodium chloride solution (80mL multiplied by 2), and adding anhydrous Na₂SO₄Drying, vacuum filtering, concentrating the filtrate to obtain crude product, addingThe mixed solvent (petroleum ether: ethyl acetate: 50:1,100mL) was slurried for 2 hours, suction filtered, and dried to give 9.4g of a white solid with a yield of 73.7%. m.p.122-124 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):6.56(1H,s,ArH),3.83-3.80(4H,m,2CH₂O),3.76-3.72(4H,m,2CH₂).

4- (6-chloro-2-morpholinylpyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester (6)

Compound 5(2.00g,8.54mmol) and 1-tert-butoxycarbonylpiperazine (3.98g,21.35mmol) were charged into a 100mL three-necked flask, 50mL of acetone was added, the mixture was stirred to dissolve the compound, triethylamine (4.00mL,28.86mmol) was further added, the mixture was heated under reflux for about 10 hours, TLC (dichloromethane: methanol 20:1) detected that the reaction of raw material 5 was completed, the reaction was stopped, the mixture was cooled to room temperature, a large amount of white solid was precipitated, the filtrate was filtered, the filter cake was washed with acetone, and the filtrate was dried to obtain 2.84g of a white solid with a yield of 86.6%. m.p.215-217 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):5.87(1H,s,ArH),3.78-3.73(8H,m,2CH₂O,2CH₂NCO),3.57-3.54(4H,m,2CH₂),3.48-3.44(4H,m,2CH₂).

4- (4-chloro-6- (piperazin-1-yl) pyrimidin-2-yl) morpholine hydrochloride (III-3)

Adding the compound 6(2.84g,7.40mmol) into a 50mL three-necked flask, adding 15mL ethyl acetate, stirring and dissolving, adding a saturated HCl ethyl acetate solution (5mL), stirring and reacting at 25 ℃ for 2-3 hours to precipitate a large amount of white solid, detecting by TLC (dichloromethane: methanol: 20:1) that the raw material 6 is completely reacted, stopping the reaction, performing suction filtration, washing a filter cake with ethyl acetate, and drying to obtain 2.36g of white solid with the yield of 99.6%.¹H NMR(300MHz,DMSO-d₆)δ(ppm):9.53(1H,s,HCl),6.92(1H,s,NH),6.30(1H,s,ArH),3.90(4H,t,J＝4.8Hz,2CH₂O),3.67-3.58(8H,m,4CH₂N),3.12(4H,s,2CH₂N).

4- (3- (4- (6-chloro-2-morpholinylpyrimidin-4-yl) piperazine 1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (IV-3)

Compound II (436mg,1.46mmol), compound III-3(468mg,1.46mmol) and PyBOP (912mg,1.75mmol) were placed in a 25mL three-necked flask, 10mL of DMF was added thereto, the mixture was dissolved by stirring, DIEA (0.76mL,4.38mmol) was added thereto, and the mixture was reacted at 25 ℃ for 4 to 6 hours. TLC (Dichloromethane methanol 10:1) detecting that the reaction of the raw material II is finished, and stopping the reaction. Pouring the reaction solution into 30mL of water, precipitating a large amount of solid, stirring for 10 minutes, performing suction filtration, washing a filter cake with a small amount of water, drying to obtain a crude product, and performing column chromatography purification (dichloromethane: methanol is subjected to gradient elution at a ratio of 100: 1-50: 1) to obtain 650mg of yellow solid with the yield of 78.9%. m.p.108-110 ℃.¹H NMR(300MHz,DMSO-d₆)δ(ppm):12.57(1H,s,CONH),8.25(1H,d,J＝7.6Hz,ArH),7.97-7.79(3H,m,ArH),7.46-7.41(1H,m,ArH),7.37-7.34(1H,m,ArH),7.22(1H,t,J＝8.7Hz,ArH),6.19(1H,s,ArH),4.32(2H,s,ArCH₂),3.72-3.53(14H,m,7CH₂),3.24-3.17(2H,m,CH₂).

4- (3- (4- (2 '-amino-2-morpholinyl- [4,5' -bipyrimidine ] -6-yl) piperazine-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-11)

The same procedure as in I-1 was followed using compound IV-3(300mg,0.53mmol) and compound V-1(133mg,0.60mmol) as starting materials, and column chromatography separation (eluent: dichloromethane: methanol: 100: 1-40: 1 gradient elution) to obtain an off-white solid 140mg with a yield of 42.4%. m.p.170-172 ℃.¹H NMR(300MHz,DMSO-d₆)δ(ppm):12.62(s,1H,CONH),8.96(s,2H,ArH),8.27(d,1H,J＝7.3Hz,ArH),8.00-7.81(m,3H,ArH),7.47-7.43(m,1H,ArH),7.39(d,1H,J＝5.9Hz,ArH),7.26(t,1H,J＝8.9Hz,ArH),7.07(s,2H,NH₂),6.62(s,1H,ArH),4.35(s,2H,ArCH₂),3.82-3.51(m,14H,2CH₂O,5CH₂N),3.25-3.21(m,2H,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):164.09,163.29,160.73,159.34,157.96,156.92,154.74,145.32,144.86,134.79,133.44,131.50,129.04,128.82,127.87,126.04,125.46,123.91,119.75,116.06,115.77,86.66,65.90,46.47,44.02,41.35,36.43.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₂H₃₂FN₁₀O₃:623.2637；Found:623.2637.

Example 11

Synthesis of 4- (3- (4- (6- (6-aminopyridin-3-yl) -2-morpholinylpyrimidin-4-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-12)

Performing column chromatography with compound IV-3(300mg,0.53mmol) and compound V-2(129mg,0.59mmol) as raw materials in the same manner as I-1And (4) separating (eluent: dichloromethane: methanol: 100: 1-60: 1 gradient elution) to obtain 180mg of light yellow solid, wherein the yield is 54.6%. m.p.159-164 ℃.¹H-NMR(300MHz,DMSO-d₆)δ(ppm):12.59(s,1H,CONH),8.70(s,1H,ArH),8.29-8.21(m,1H,ArH),8.12-8.03(m,1H,ArH),8.01-7.93(m,1H,ArH),7.93-7.78(m,2H,ArH),7.49-7.34(m,2H,ArH),7.29-7.19(m,1H,ArH),6.53(s,1H,ArH),6.46(d,J＝9.1Hz,1H,ArH),6.32(s,2H,ArNH₂),4.33(s,2H,ArCH₂),3.89-3.48(m,14H,2CH₂O,5CH₂N),3.25-3.16(m,2H,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):163.93,163.42,161.43,160.83,159.34,157.98,154.75,147.42,144.86,143.25,135.39,134.75,133.43,131.49,129.05,127.88,126.04,125.47,123.91,121.58,116.06,109.58,107.09,86.72,65.92,46.46,44.05,41.36,36.43.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₃H₃₂FN₉O₃:622.2685；Found:622.2676.

Example 12

Synthesis of 4- (3- (4- (6- (6-amino-4- (trifluoromethyl) pyridin-3-yl) -2-morpholinopyrimidin-4-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-13)

The compound IV-3(200mg,0.36mmol) and the compound V-3(112mg,0.39mmol) were used as raw materials, and subjected to column chromatography separation (eluent: dichloromethane: methanol: 100: 1-40: 1 gradient elution) to obtain 90mg of a pale yellow solid, with a yield of 36.2%. m.p.142-146 ℃.¹H-NMR(300MHz,DMSO+D₂O-d₆)δ(ppm):8.23(d,J＝7.6Hz,1H,ArH),8.11(s,1H,ArH),7.97-7.89(m,1H,ArH),7.89-7.73(m,2H,ArH),7.44-7.36(m,1H,ArH),7.35-7.27(m,1H,ArH),7.20(t,J＝9.0Hz,1H,ArH),6.81(s,1H,ArH),6.17(s,1H,ArH),4.30(s,2H,ArNH₂),3.80-3.72(m,2H,CH₂O),3.68-3.41(m,12H,CH₂O,5CH₂N),3.23-3.08(m,2H,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):164.16,162.85,160.32,160.02,159.45,157.92,154.69,152.59,150.44,145.15,140.10,134.69,133.56,131.62,128.96,128.70,127.66,126.03,125.44,123.69,121.17,120.42,116.08,104.53,92.02,65.82,46.35,43.77,36.39,28.83.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₄H₃₁F₄N₉O₃:690.2559；Found:690.2571.

Example 13

Synthesis of 4- (3- (4- (6- (1H-indol-5-yl) -2-morpholinylpyrimidin-4-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-15)

The same procedure as in I-1 was followed using compound IV-3(300mg,0.53mmol) and V-8(142mg,0.59mmol) as starting materials, and purification was performed by column chromatography (dichloromethane: methanol in a gradient elution of 100:1 to 60: 1) to give a pale yellow solid 170mg with a yield of 49.7%. m.p.178-183 ℃.¹H NMR(300MHz,DMSO-d₆)δ(ppm):12.61(s,1H,CONH),11.22(s,1H,ArNH),8.36(s,1H,ArH),8.25(d,J＝7.7Hz,1H,ArH),8.03-7.76(m,4H,ArH),7.50-7.31(m,4H,ArH),7.24(t,J＝9.0Hz,1H,ArH),6.68(s,1H,ArH),6.54-6.43(m,1H,ArH),4.34(s,2H,ArCH₂),3.98-3.52(m,14H,2CH₂O,5CH₂N),3.30-3.19(m,2H,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm)：164.16,163.95,163.59,160.84,159.34,154.76,144.86,137.03,135.33,134.74,133.43,131.49,128.97,127.88,127.58,126.04,125.46,123.69,120.25,119.05,115.77,110.98,108.87,101.95,98.72,95.62,88.21,65.96,46.51,44.10,41.38,36.44.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₆H₃₃FN₈O₃:645.2692；Found:645.2690.

Example 14

Synthesis of 4- (3- (4- (6- (1H-indol-4-yl) -2-morpholinylpyrimidin-4-yl) piperazin-1-formyl) -4-fluorobenzyl) phthalazin-1 (2H) -one (I-16)

The same procedure as in I-1 was repeated using compound IV-3(300mg,0.53mmol) and 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indole (V-9) (142mg,0.59mmol) as starting materials, and purifying by column chromatography (dichloromethane: methanol in a gradient elution of 100:1 to 60: 1) to obtain 100mg of a pale yellow solid with a yield of 29.3%. m.p.143-148 ℃.¹H NMR(300MHz,CDCl₃)δ(ppm):10.32(s,1H,CONH),8.45(d,J＝7.8Hz,1H,ArH),7.85-7.67(m,3H,ArH),7.52(d,J＝7.2Hz,1H,ArH),7.44-7.34(m,2H,ArH),7.34-7.26(m,2H,ArH),7.24-7.12(m,1H,ArH),7.05(t,J＝8.7Hz,1H,ArH),7.0-6.83(m,1H,ArH),6.43(s,1H,ArH),4.29(s,2H,ArCH₂),4.10-3.61(m,14H,2CH₂O,5CH₂N),3.52-3.41(m,2H,CH₂N).¹³C-NMR(75MHz,DMSO-d₆)δ(ppm):163.99,163.31,160.87,159.34,158.01,154.76,144.86,139.75,136.68,134.79,133.42,131.49,130.74,129.05,127.88,126.08,125.45,123.92,121.78,120.60,118.93,116.98,116.06,115.79,112.85,101.73,91.25,65.92,46.44,44.03,36.43,25.92.HRMS(ESI):m/z[M+H]⁺.Calcd for C₃₆H₃₃FN₈O₃:645.2732；Found:645.2732.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein X represents CH or N;

R¹represents

R²Represents

R³Represents H, F, Br, Cl, CF₃、CN、CH₃Or OCH₃(ii) a Y represents CH or N.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹Represents

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R²Represents

4. A process for the preparation of a compound of claim 1 comprising:

wherein R is¹、R²Is as defined in claim 1.

5. The preparation process of claim 4 carried out with the addition of a catalyst, a base and a reaction solvent, wherein the catalyst is selected from bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium or [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride; the base is selected from sodium ethoxide, sodium acetate, potassium phosphate, sodium carbonate or potassium carbonate; the reaction solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, ethylene glycol dimethyl ether, tetrahydrofuran, dioxane, toluene, ethanol, water or a mixed solvent of any two or three of the solvents; the reaction temperature is 75-115 ℃.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound of formula (I), wherein the acid used to form the salt is: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.

7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament of a dual target inhibitor of PARP-1 and PI 3K.

9. The use of claim 8, wherein the PARP-1 and PI3K dual-target inhibitor drug is an anti-tumor drug.