Phthalazinone compound containing aryl malonamide structure and application thereof

Abstract

The invention relates to a phthalazinone compound containing an aryl malonamide structure and application of the phthalazinone compound, and belongs to the technical field of medicines, the phthalazinone compound containing the aryl malonamide structure has a structure shown in a general formula (I), and the phthalazinone compound containing the aryl malonamide structure can be pharmaceutically added with acid to form salt. Pharmacological activity screening results show that the compound has significant inhibition effects on human breast cancer cells MDA-MB-453, human lung adenocarcinoma cells A549 and human colon cancer cells HCT116, and has good prospects in development and application of antitumor drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a phthalazinone compound containing an aryl malonamide structure and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the compound. The present application also relates to the use of the compound and the pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer. BACKGROUND

[0002] Cancer is the second leading cause of human death in the world, and its treatment has been a research focus of the global medical community for a long time. According to the data of the Global Cancer Observatory (GCO), the number of global cancer patients reached 20 million by 2023, and the number of cancer-related deaths is expected to continue to rise, bringing a heavy burden to global public health. The poly (ADP-ribose) polymerase (PARP) family, as an important post-translational modification enzyme, is widely present in eukaryotic cells and plays a key role in DNA damage repair, genome stability maintenance, and cell signal transduction. The family contains 17 members (PARP1-16), among which PARP-1 is the most abundant and most in-depth functional research core member. PARP-1 protein has a typical modular structure, including three functional domains: the N-terminal DNA binding domain (DBD) is responsible for recognizing and binding to DNA damage sites; the central auto-modification domain (AD) mediates the modification process of the protein itself; and the C-terminal catalytic domain (CAT) uses NAD+ as a substrate to catalyze the transfer of ADP-ribose units to the target protein, thereby regulating the function of the target protein. PARP-1 is a key enzyme in the base excision repair (BER) pathway, which is the main pathway for repairing DNA damage caused by alkylation, oxidation and other factors. PARP-1 can be activated by DNA damage, and its overexpression can lead to DNA damage accumulation and cell death. Therefore, PARP-1 has become a hot target for the development of cancer drugs. It catalyzes the synthesis of poly-ADP-ribose (PAR) chains. PARP-1 is mainly involved in the base excision repair (BER) pathway during DNA damage repair, responsible for repairing DNA single-strand breaks. When damage occurs, PARP-1 quickly recognizes and binds to the break site, recruits repair proteins such as XRCC1 by synthesizing PAR chains, forms a repair complex, and completes the damage repair. In addition, PARP-1 is also involved in regulating repair pathways such as non-homologous end joining (NHEJ) and homologous recombination (HR). However, mutations in BRCA1 and BRCA2 genes can cause defects in homologous recombination repair function, significantly increasing genomic instability, and thus promoting tumor occurrence. PARP inhibitors specifically inhibit the enzyme activity of PARP-1, and in cancer cells with existing DNA repair defects (such as BRCA1 / 2 mutations), they trigger a "synthetic lethal" effect. By inhibiting the function of PARP-1, single-strand breaks accumulate, and these damages are further converted into double-strand breaks during DNA replication. In cells with normal homologous recombination function, such damage can be repaired through alternative pathways; but in BRCA1 / 2 mutant cells, double-strand breaks cannot be effectively repaired, ultimately leading to cell apoptosis, thus exerting an anti-tumor effect. Currently, PARP inhibitors have become an important breakthrough in targeted therapy for tumors, and have shown significant efficacy in the treatment of various malignancies such as ovarian cancer, breast cancer, and prostate cancer. With the in-depth understanding of the function of the PARP family and the continuous development of new inhibitors, PARP-targeted therapy is expected to achieve breakthroughs in more cancer types. SUMMARY

[0003] The present application aims to design and synthesize a series of new phthalazinone compounds containing aryl malonamide structure. Through in vitro activity screening, it is shown that the compounds have anti-tumor activity.

[0004] The present application provides a phthalazinone compound containing aryl malonamide structure with a general formula (I),

[0005] wherein, Ar is selected from 6-10 membered aryl; wherein the 6-10 membered aryl can be optionally substituted with 1-3 same or different R1; R1 is hydrogen, hydroxyl, halogen, alkyl containing 1-6 carbons, alkoxy containing 1-6 carbons, alkyl containing 1-6 carbons optionally substituted with halogen, alkoxy containing 1-6 carbons optionally substituted with halogen, amino substituted with mono or di alkyl containing 1-6 carbons, alkyl amido containing 1-6 carbons.

[0006] Further, the above-mentioned phthalazinone compound containing aryl malonamide structure, wherein, Ar is phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl unsubstituted or substituted by 1 to 3 identical or different R1; R1 is hydrogen, halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, alkyl having 1 to 6 carbons optionally substituted by halogen, alkoxy having 1 to 6 carbons optionally substituted by halogen, amino substituted by mono or di alkyl having 1 to 6 carbons; Further, the above-mentioned phthalazinone compound having an aryl malonamide structure has the following structural formula, but these compounds are not meant to limit the present application in any way:

[0007] The following synthetic routes describe the preparation of the phthalazinone compounds having an aryl malonamide structure of the present application of general formula (I), all starting materials are prepared by the following synthetic routes, by methods well known to one of ordinary skill in the art of organic chemistry or are commercially available. All final compounds of the present application are prepared by the following synthetic routes or by methods analogous thereto, which are well known to one of ordinary skill in the art of organic chemistry. All variable factors used in the following synthetic routes are defined below or as defined in the above claims.

[0008] The synthetic routes are shown below:

[0009] The substituent Ar in the above routes is defined as above.

[0010] A pharmaceutical composition comprising the above-mentioned phthalazinone compound having an aryl malonamide structure and pharmaceutically acceptable salts thereof as an active ingredient and a pharmaceutically acceptable excipient.

[0011] Use of the above-mentioned phthalazinone compound having an aryl malonamide structure and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition in the manufacture of a medicament for the treatment and / or prevention of a malignant tumor carrying a BRCA1 / 2 gene mutation or having other homologous recombination repair deficiency (HRD).

[0012] Use of the above-mentioned phthalazinone compound having an aryl malonamide structure and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition in the manufacture of a medicament for the treatment and / or prevention of a proliferative disease.

[0013] Use of the above-mentioned phthalazinone compound having an aryl malonamide structure and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical composition in the manufacture of a medicament for the treatment and / or prevention of a cancer.

[0014] Further, the use of any one of the above phthalazinone compounds having an aryl malonamide structure and pharmaceutically acceptable salts thereof or the above pharmaceutical composition in the preparation of a medicament for treating and / or preventing prostate cancer, breast cancer and lung cancer.

[0015] Further, the phthalazinone compounds having an aryl malonamide structure of general formula (I) in the present application can form pharmaceutically acceptable salts with acids according to some common methods in the field of the present application. The pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salts, and the salts with the following acids are particularly preferred: hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid and the like.

[0016] The beneficial effects of the present application are: 1. Through in vitro inhibition of human breast cancer cell MDA-MB-453, human lung adenocarcinoma cell A549 and human colon cancer cell HCT116 activity test, the compounds of the present application have significant inhibitory effect on the above tumor cells, and are particularly used for preparing medicaments for treating and / or preventing breast cancer, lung cancer and colon cancer.

[0017] 2. The phthalazinone compounds having an aryl malonamide structure involved in the present application have novel chemical structures, and most of the compounds have strong anti-proliferative activity on the tested cells in in vitro biological activity studies. The compounds can be used for the development of therapeutic and prophylactic drugs for cancer. DETAILED DESCRIPTION

[0018] The examples and preparation examples provided below further illustrate and exemplify the compounds of the present application and methods for preparing them. It should be understood that the scope of the application is in no way limited by the following examples and preparation examples. The nuclear magnetic resonance hydrogen spectrum of the compounds was determined by Bruker ARX-400, and the mass spectrum was determined by Agilent 6460 QQQ. The reagents used were analytical pure or chemically pure.

[0019] Example 1: N Preparation of (3-chlorophenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl] benzoyl}piperazine-1-carbonyl)cyclopropane-1-carboxamide (Compound 1)

[0020] Step 1: Synthesis of (3-oxo-1,3-dihydroisobenzofuran-1-yl)dimethyl phosphate (b)

[0021] To a solution of sodium methoxide (28.10 g, 0.52 mol) in anhydrous methanol (500 mL) was added dimethyl phosphite (52.90 g, 0.48 mol) slowly under ice-bath cooling. The reaction was kept below 5 °C and 2-carboxybenzaldehyde (60.00 g, 0.52 mol) was added slowly dropwise. The reaction was allowed to warm to room temperature and stirred for 2 h. To the reaction flask was added methylsulfonic acid (50.00 g, 1.26 mol) dropwise. The solvent was removed by evaporation under reduced pressure and water (300 mL) was added to the residue. The mixture was extracted with dichloromethane (200 mL x 3). The organic phase was combined and extracted with water (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure to give a yellow solid, which was used directly in the next step without further purification.

[0022] Step 2: Synthesis of 2-fluoro-5-{[3-oxoisobenzofuranyl-l(3H)- ylidene]methyl}benzonitrile (c)

[0023] To a reaction flask was added intermediate b (7.75 g, 32.0 mmol), 2-fluoro-5- formylbenzonitrile (4.77 g, 32.0 mmol) and tetrahydrofuran (100 mL). The reaction was cooled to about 0 °C and triethylamine (3.24 g, 32.0 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 12 h. The solvent was removed by evaporation under reduced pressure. To the reaction flask was added water (40 mL) and stirred for 1 h. The mixture was filtered and the filter cake was washed with water and cold methanol (2-3 times each). The product was dried to give 7.15 g of intermediate c in 84.2% yield. The product contained both Z and E isomers and was used directly in the next step without further purification.

[0024] Step 3: Synthesis of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-l- yl)methyl]benzoic acid (d)

[0025] To a reaction flask was added intermediate c (15.00 g, 56.7 mmol), water (120 mL) and 13 mol / L aqueous sodium hydroxide solution (21.0 mL). The mixture was heated to 90 °C and stirred for 4 h. The reaction was cooled to 70 °C and hydrazine hydrate (40.0 mL) was added. The reaction was stirred for 24 h and then cooled to room temperature. The pH was adjusted to about 4 with 10 mol / L hydrochloric acid. The mixture was filtered and the filter cake was washed with water and dried to give the crude product. The crude product was purified by column chromatography on silica gel to give 10.50 g of intermediate d in 62.3% yield, MS (ESI), m / z: 299.1 [M+H] -1 . + .

[0026] Step 4: Synthesis of 4-[3-(tert-Butoxycarbonyl)benzyl]-2H-phthalazin-1-one(e)

[0027] Intermediate d (5.00 g, 0.17 mol), 1-Boc-piperazine (3.90 g, 0.21 mol), HBTU (8.60 g, 0.22 mol), and DIPEA (6.7 ml, 0.38 mol) were added to the reaction flask. N,N 40 mL of dimethylformamide was stirred at room temperature for 18 h. After the reaction was complete, 100 mL of water was added to the reaction mixture, and the solution was heated to 100 °C and maintained at that temperature for 1 h. The reaction solution was then cooled to room temperature, filtered, and the filter cake was washed with water and dried to obtain 6.10 g of intermediate e, yield 78.0%, MS (ESI), m / z: 467.2 [M+H]. + .

[0028] Step 5: Synthesis of 4-[3-(piperazine-1-carbonyl)benzyl]-2H-phthalazine-1-one (f)

[0029] Intermediate e (6.00 g, 0.13 mol), 20 mL of ethanol, and 40 mL of 6 mol / L hydrochloric acid were added to a reaction flask. The mixture was stirred at room temperature for 3 h. Most of the ethanol was removed by evaporation under reduced pressure. The remaining solution was alkalized to approximately pH 9 with ammonia, extracted three times with dichloromethane, and the organic phases were combined. The organic phases were washed twice successively with water and saturated brine, dried over anhydrous Na₂SO₄, and the drying agent was filtered off. The filtrate was evaporated under reduced pressure to obtain 3.40 g of intermediate f, with a yield of 72.1%. MS (ESI), m / z: 367.1 [M+H] + .

[0030] Step 6: Synthesis of N-(3-chlorophenyl)-1-[4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperazin-1-carbonyl]cyclopropane-1-carboxamide (Compound 1)

[0031] Intermediate f (0.40 g, 1.09 mmol), 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid (0.29 g, 1.21 mmol), HATU (0.63 g, 1.65 mmol), Et3N (0.33 g, 3.30 mmol), and [other components] were added to the reaction flask. N,N- dimethylformamide 15 mL. The reaction was stirred at room temperature for 10 h. The reaction was poured into water and extracted with dichloromethane for 3 times. The combined organic phase was washed with water and brine for 2-3 times, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 0.48 g of compound 1 in 74.8% yield. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.60 (s, 1H), 9.77 (s, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.06 – 7.70 (m, 4H), 7.56 (d, J = 8.1 Hz, 1H), 7.48 – 7.31 (m,3H), 7.23 (s, 1H), 7.15 (d, J = 7.5 Hz, 1H), 4.33 (s, 2H), 3.94 – 3.39 (m,6H), 3.30 – 3.09 (m, 2H), 1.57 – 1.37 (m, 2H), 1.33 – 1.20 (m, 2H); MS (ESI), m / z: 588.2 [M+H] + .

[0032] By replacing the appropriate raw materials and reagents, the preparation method of example 1, finally prepared example 2-23 (compound 2-23)

[0033] Example 2: N -(2-Fluorophenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazine-1-yl)methyl] benzoyl}piperazine-1-carbonyl)cyclopropane-1-carboxamide (compound 2) was synthesized.

[0034]

[0035] By replacing 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid in example 1 step 6 with 1-[(2-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid, and the remaining steps are the same as example 1, compound 2 is obtained. 1 H NMR (400 MHz,DMSO- d 6 ) δ 12.61 (s, 1H), 9.44 (s, 1H), 8.38 – 8.19 (m, 1H), 7.98 (d, J= 8.1 Hz, 1H), 7.94 - 7.79 (m, 2H), 7.51 - 7.43 (m, 1H), 7.42 - 7.33 (m, 2H), 7.31- 7.15 (m, 4H), 4.35 (s, 2H), 3.81 - 3.57 (m, 4H), 3.54 - 3.42 (m, 2H), 3.30- 3.16 (m, 2H), 1.45 - 1.20 (m, 4H).

[0036] Example 3: N Synthesis of N-(4-dimethylaminophenyl)-l-[4-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazine-l-yl)methyl)benzoyl)piperazine-l-carbonyl]cyclopropane-l- carboxamide (Compound 4).

[0037]

[0038] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid in Example 1, Step 6 with 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid and follow the remaining steps of Example 1 to obtain Compound 3. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.60 (s, 1H), 9.64 (s, 1H), 8.27 (d, J = 7.4 Hz, 1H), 8.09 - 7.75 (m, 3H), 7.60 (dd, J = 9.1, 5.0 Hz, 2H), 7.51 - 7.33 (m, 2H), 7.23 (s, 1H),7.15 (t, J = 8.8 Hz, 2H), 4.33 (s, 2H), 3.80 - 3.53 (m, 4H), 3.51 - 3.40 (m,2H), 3.30 - 3.04 (m, 2H), 1.47 - 1.34 (m, 2H), 1.30 - 1.21 (m, 2H).

[0039] Example 4: Synthesis of N-(4-dimethylaminophenyl)-l-[4-(2-fluoro-5-((4-oxo-3,4- dihydrophthalazine-l-yl)methyl)benzoyl)piperazine-l-carbonyl]cyclopropane-l- carboxamide (Compound 4).

[0040]

[0041] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1 -carboxylic acid in Example 1, Step 6 with 1-[(4-methoxyphenyl)carbamoyl]cyclopropane-1 -carboxylic acid, and the remaining steps are the same as Example 1 to give Compound 6. MS (ESI), m / z: 597.2 [M+H] + .

[0042] Example 5: N Synthesis of (4-methoxyphenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1- yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1-carboxamide (Compound 6).

[0043]

[0044] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1 -carboxylic acid in Example 1, Step 6 with 1-[(4-methoxyphenyl)carbamoyl]cyclopropane-1 -carboxylic acid, and the remaining steps are the same as Example 1 to give Compound 6. MS (ESI), m / z: 597.2 [M+H] 1 H NMR (400MHz, DMSO- d 6 ) δ 12.60 (s, 1H), 9.51 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 8.04 –7.74 (m, 3H), 7.52 – 7.32 (m, 4H), 7.23 (s, 1H), 7.11 (d, J = 8.0 Hz, 2H),4.33 (s, 2H), 3.72 – 3.54 (m, 4H), 3.51 – 3.41 (m, 2H), 3.29 – 3.14 (m, 2H),2.26 (s, 3H), 1.44 – 1.35 (m, 2H), 1.24 (s, 2H); MS (ESI), m / z: 568.2 [M+H] + .

[0045] Example 6: N Synthesis of (4-methoxyphenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1- yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1-carboxamide (Compound 6).

[0046]

[0047] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1 -carboxylic acid in step 6 of example 1 with 1-[(4- methoxyphenyl)carbamoyl]cyclopropane-1 -carboxylic acid and follow the rest of the procedure of example 1 to obtain compound 6. 1 H NMR (400MHz, DMSO- d 6 ) δ 12.60 (s, 1H), 9.46 (s, 1H), 8.27 (d, J = 7.7 Hz, 1H), 7.90(m, 3H), 7.42 (m, 4H), 7.23 (s, 1H), 6.88 (d, J = 8.8 Hz, 2H), 4.33 (s, 2H),3.73 (s, 3H), 3.71 – 3.52 (m, 4H), 3.51 – 3.41 (m, 2H), 3.31 – 3.03 (m, 2H),1.46 – 1.31 (m, 2H), 1.30 – 1.16 (m, 2H); MS (ESI), m / z: 584.2 [M+H] + .

[0048] Example 7: N Synthesis of (4-acetylamino-phenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1- carboxamide (Compound 7).

[0049]

[0050] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1 -carboxylic acid in step 6 of example 1 with 1-[(4- acetylamino-phenyl)carbamoyl]cyclopropane-1 -carboxylic acid and follow the rest of the procedure of example 1 to obtain compound 7. MS (ESI), m / z: 611.2 [M+H] + .

[0051] Example 8: N Synthesis of (2-methoxy-phenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1- carboxamide (Compound 8).

[0052]

[0053] Example 1, step 6, replacing 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1- carboxylic acid with 1-[(2-methoxyphenyl)carbamoyl]cyclopropane-1-carboxylic acid to give compound 8. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 8.66 (s, 1H), 8.28 (d, J = 7.7 Hz, 1H), 7.98(d, J = 6.8 Hz, 1H), 7.53 –7.42 (m, 1H), 7.38 (d, J = 6.3 Hz, 1H), 7.25 (t, J = 9.1 Hz, 1H), 7.19 – 7.11(m, 1H), 7.07 (d, J = 7.3 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 4.34 (s, 2H),3.81 (s, 3H), 3.74 – 3.58 (m, 4H), 3.55 – 3.45 (m, 2H), 3.31 – 3.20 (m, 2H),1.46 – 1.34 (m, 2H), 1.29 – 1.22 (m, 2H).

[0054] Example 9: N Synthesis of 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid.

[0055]

[0056] Example 1, step 6, replacing 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1- carboxylic acid with 1-[(2-methoxyphenyl)carbamoyl]cyclopropane-1-carboxylic acid to give compound 8. 1 H NMR (400 MHz, DMSO- d 6 )δ 12.60 (s, 1H), 9.60 (s, 1H), 8.27 (d, J= 7.6 Hz, 1H), 8.07-7.72 (m, 3H),7.59(d, J = 7.8Hz, 2H), 7.49-7.17(m, 5H), 7.09(t, J =7.3Hz,1H), 4.33(s, 2H),3.77-3.53(m, 4H), 3.52-3.41(m, 2H), 3.30-3.05(m, 2H),1.49-1.34(m, 2H), 1.31-1.20 (m, 2H); MS (ESI), m / z: 554.2 [M+H] + .

[0057] Example 10: N Synthesis of -(1-naphthyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl}piperazin-1-carbonyl)cyclopropane-1-carboxamide (compound 10).

[0058]

[0059] In Example 1, step 6, 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid was replaced with 1-[(1-naphthyl)carbamoyl]cyclopropane-1-carboxylic acid, and the remaining steps were the same as in Example 1, yielding compound 10. MS (ESI), m / z: 604.2 [M+H] + .

[0060] Example 11: N Synthesis of -(4-chlorophenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl}piperazin-1-carbonyl)cyclopropane-1-carboxamide (compound 11).

[0061]

[0062] In Example 1, step 6, 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid was replaced with 1-[(4-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid, and the remaining steps were the same as in Example 1, to obtain compound 11. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.60 (s, 1H), 9.73 (s, 1H), 8.27 (d, J = 7.7 Hz, 1H), 8.10 – 7.75(m, 3H), 7.64 (d, J= 8.9 Hz, 2H), 7.43 (s, 1H), 7.37 (d, J = 8.8 Hz, 3H),7.23 (s, 1H), 4.33 (s, 2H), 3.85 – 3.52 (m, 4H), 3.50 – 3.38 (m, 2H), 3.27 –3.10 (m, 2H), 1.41 (s, 2H), 1.27 (s, 2H)。

[0063] Example 12: N Synthesis of (2-bromophenyl)-l-(4-{2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-l- yl)methyl]benzoyl}piperazine-l-carbonyl)cyclopropane-l-carboxamide (Compound 12).

[0064]

[0065] Example 1, Step 6, using l-[(2-bromophenyl)carbamoyl]cyclopropane-l-carboxylic acid in place of l-[(3-chlorophenyl)carbamoyl]cyclopropane-l-carboxylic acid to give Compound 12. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.22 (s, 1H), 8.28 (d, J = 7.7 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.94 – 7.80 (m, 2H), 7.68 (d, J = 7.8 Hz, 1H), 7.56 – 7.43 (m,2H), 7.42 – 7.34 (m, 2H), 7.32 – 7.13 (m, 2H), 4.35 (s, 2H), 3.79 – 3.61 (m,4H), 3.59 – 3.47 (m, 2H), 3.32 – 3.17 (m, 2H), 1.49 – 1.37 (m, 2H), 1.31 –1.23 (m, 2H); MS (ESI), m / z: 632.2 [M+H] + .

[0066] Example 13: NSynthesis of (4-trifluoromethylphenyl)-l-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazine- 1 -yl)methyl]benzoyl} piperazine- 1 -carbonyl)cyclopropane- 1 - carboxamide (Compound 13).

[0067]

[0068] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid in Example 1, Step 6 with 1-[(4-trifluoromethylphenyl)carbamoyl]cyclopropane-1-carboxylic acid, and the remaining steps are the same as Example 1 to give Compound 13. MS (ESI), m / z: 622.2 [M+H] + .

[0069] Example 14: N Synthesis of (2,6-difluorophenyl)-l-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazine- 1 -yl)methyl]benzoyl} piperazine- 1 -carbonyl)cyclopropane- 1 - carboxamide (Compound 14).

[0070]

[0071] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid in Example 1, Step 6 with 1-[(2,6-difluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid, and the remaining steps are the same as Example 1 to give Compound 14. 1 H NMR (400MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.50(s, 1H), 8.28(d, J =7.7 Hz, 1H),7.99(d, J =7.8 Hz, 1H), 7.94-7.80 (m, 2H), 7.52-7.33(m, 3H), 7.26 (t, J =9.0 Hz, 1H),7.22-7.09(m, 2H), 4.35(s, 2H), 3.78-3.55 (m, 4H), 3.53-3.43 (m, 2H), 3.33-3.18(m, 2H),1.48-1.33(m, 2H),1.32-1.12(m, 2H); MS (ESI), m / z: 590.2 [M+H] + .

[0072] Example 15: NSynthesis of (2,4-difluorophenyl)-l-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-l-yl)methyl]benzoyl}piperazine-l-carbonyl)cyclopropane-l- carboxamide (Compound 15).

[0073]

[0074] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-l-carboxylic acid in Example 1, Step 6 with 1-[(2,4-difluorophenyl)carbamoyl]cyclopropane-l-carboxylic acid and follow the remaining steps of Example 1 to obtain Compound 15. 1 H NMR (400MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.45 (s, 1H), 8.28 (dd, J = 7.8, 1.1 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.49 - 7.43 (m, 1H), 7.42 - 7.23 (m, 4H), 7.08 (t, J = 8.1 Hz, 1H), 4.35 (s, 2H), 3.77 - 3.55 (m, 4H), 3.52 - 3.43 (m, 2H), 3.29 - 3.21 (m, 2H), 1.44 - 1.34 (m, 2H), 1.30 - 1.24 (m, 2H); MS (ESI), m / z: 590.2 [M+H] + .

[0075] Example 16: N Synthesis of (4-hydroxyphenyl)-l-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-l-yl)methyl]benzoyl}piperazine-l-carbonyl)cyclopropane-l- carboxamide (Compound 16).

[0076]

[0077] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-l-carboxylic acid in Example 1, Step 6 with 1-[(4-hydroxyphenyl)carbamoyl]cyclopropane-l-carboxylic acid and follow the remaining steps of Example 1 to obtain Compound 16. MS (ESI), m / z: 570.2 [M+H] + .

[0078] Example 17: NSynthesis of (2,4-dichlorophenyl)-l-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-l-yl)methyl]benzoyl}piperazine-l-carbonyl)cyclopropane-l- carboxamide (Compound 17).

[0079]

[0080] Replace l-[(3-chlorophenyl)carbamoyl]cyclopropane-l-carboxylic acid in Example 1, Step 6 with l-[(2,4-dichlorophenyl)carbamoyl]cyclopropane-l-carboxylic acid and follow the remaining steps of Example 1 to obtain Compound 17. 1 H NMR (400MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.38 (s, 1H), 8.28 (dd, J = 7.8, 1.1 Hz, 1H),7.99 (d, J = 7.7 Hz, 1H), 7.94 – 7.81 (m, 2H), 7.69 (d, J = 2.2 Hz, 1H), 7.54– 7.42 (m, 3H), 7.38 (dd, J = 6.4, 2.1 Hz, 1H), 7.26 (t, J = 9.0 Hz, 1H),4.35 (s, 2H), 3.77 – 3.59 (m, 4H), 3.57 – 3.44 (m, 2H), 3.29 – 3.15 (m, 2H),1.49 – 1.37 (m, 2H), 1.32 – 1.23 (m, 2H); MS (ESI), m / z: 622.2 [M+H] + .

[0081] Example 18: N Synthesis of (2,4-dichlorophenyl)-l-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-l-yl)methyl]benzoyl}piperazine-l-carbonyl)cyclopropane-l- carboxamide (Compound 18).

[0082]

[0083] Replace l-[(3-chlorophenyl)carbamoyl]cyclopropane-l-carboxylic acid in Example 1, Step 6 with l-[(2,4-dichlorophenyl)carbamoyl]cyclopropane-l-carboxylic acid and follow the remaining steps of Example 1 to obtain Compound 17. 1H NMR (400 MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.41 (s, 1H), 8.28 (dd, J = 7.8, 1.1 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.55 - 7.44 (m, 2H), 7.43 - 7.32 (m, 4H), 7.26 (t, J = 9.1 Hz, 1H), 4.35 (s, 2H), 3.78 - 3.57 (m, 4H), 3.55 - 3.43 (m, 2H), 3.31 - 3.17 (m, 2H), 1.45 - 1.34 (m, 2H), 1.32 - 1.23 (m, 2H); MS (ESI), m / z: 638.2 [M+H] + .

[0084] Example 19: N Synthesis of 1-(4-difluoromethoxyphenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-1-yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1- carboxamide (Compound 19).

[0085]

[0086] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid in Example 1, Step 6 with 1-[(4-difluoromethoxyphenyl)carbamoyl]cyclopropane-1-carboxylic acid and follow the remaining steps of Example 1 to obtain Compound 19. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.41 (s, 1H), 8.28 (dd, J = 7.8, 1.1 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.94 - 7.80 (m, 2H), 7.55 - 7.44 (m, 2H), 7.43 - 7.32 (m, 4H), 7.26 (t, J= 9.1 Hz, 1H), 4.35 (s, 2H), 3.78 – 3.57 (m, 4H),3.55 – 3.43 (m, 2H), 3.31 – 3.17 (m, 2H), 1.45 – 1.34 (m, 2H), 1.32 – 1.23(m, 2H); MS (ESI), m / z: 638.2 [M+H] + .

[0087] Example 20: N Synthesis of (3-chloro-4-fluorophenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazine-1-yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1- carboxamide (Compound 20).

[0088]

[0089] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid in Example 1, Step 6 with 1-[(3-chloro-4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid and follow the remaining steps of Example 1 to obtain Compound 20. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.60 (s, 1H), 9.79 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.05 – 7.75 (m, 4H), 7.63 – 7.52 (m, 1H), 7.50 – 7.32 (m, 3H), 7.31 – 7.16 (m, 1H), 4.33 (s, 2H), 3.58 (s, 4H), 3.44 (s, 2H), 3.22 (s, 2H), 1.51 – 1.36 (m, 2H), 1.31 – 1.22 (m, 2H); MS (ESI), m / z: 588.2 [M+H] + .

[0090] Example 21: N Synthesis of (2-methyl-5-chlorophenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophthalazine-1-yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1- carboxamide (Compound 21).

[0091]

[0092] The procedure of Example 1, Step 6 was followed using 1-[(3,4- dimethoxyphenyl)carbamoyl]cyclopropane-1 -carboxylic acid in place of 1-[(3- chlorophenyl)carbamoyl]cyclopropane-1 -carboxylic acid to give Compound 22. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.61 (s, 1H), 9.18 (s, 1H), 8.33 – 8.24 (m, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.0 Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.52– 7.43 (m, 1H), 7.39 (dd, J = 6.5, 2.2 Hz, 1H), 7.34 – 7.18 (m, 4H), 4.35 (s,2H), 3.90 – 3.59 (m, 4H), 3.56 – 3.44 (m, 2H), 3.30 – 3.15 (m, 2H), 2.13 (s,3H), 1.49-1.36 (m, 2H), 1.33-1.21 (m, 2H); MS (ESI), m / z: 602.2 [M+H] + .

[0093] Example 22: N Synthesis of 1-[(3,4-dimethoxyphenyl)carbamoyl]cyclopropane-1- carboxylic acid (Compound 23).

[0094]

[0095] The procedure of Example 1, Step 6 was followed using 1-[(3,4- dimethoxyphenyl)carbamoyl]cyclopropane-1 -carboxylic acid in place of 1-[(3- chlorophenyl)carbamoyl]cyclopropane-1 -carboxylic acid to give Compound 22. 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.60 (s, 1H), 9.44 (s, 1H), 8.27 (d, J= 7.6 Hz, 1H),8.06 – 7.74 (m, 3H), 7.55 – 7.35 (m, 2H), 7.33 – 7.10 (m, 3H), 6.88 (d, J =8.9 Hz, 1H), 4.33 (s, 2H), 3.79 – 3.56 (m, 10H), 3.50 – 3.41 (m, 2H), 3.28 –3.09 (m, 2H), 1.47 – 1.35 (m, 2H), 1.32 – 1.23 (m, 2H); MS (ESI), m / z: 614.2[M+H] + .

[0096] Example 23: N Synthesis of (3,4,5-trimethoxyphenyl)-1-(4-{2-fluoro-5-[(4-oxo-3,4- dihydrophtalazin-1-yl)methyl]benzoyl}piperazine-1-carbonyl)cyclopropane-1- carboxamide (Compound 23).

[0097]

[0098] Replace 1-[(3-chlorophenyl)carbamoyl]cyclopropane-1-carboxylic acid in Example 1, Step 6 with 1-[(3,4,5-trimethoxyphenyl)carbamoyl]cyclopropane-1-carboxylic acid, and the rest of the steps are the same as Example 1 to give Compound 23. MS (ESI), m / z: 644.2 [M+H] + .

[0099] Example 23 In vitro anti-tumor cell activity

[0100] The compounds obtained in Examples 1-23 were subjected to in vitro screening for inhibiting the activity of human breast cancer cells MDA-MB-453, human lung adenocarcinoma cells A549 and human colon cancer cells HCT116.

[0101] (1) After the cells were recovered and subcultured for 2-3 times stably, they were digested from the bottom of the culture bottle with trypsin solution (0.25%). After the cell digestion solution was poured into a centrifuge tube, culture solution was added to terminate the digestion. The centrifuge tube was centrifuged at 800 r / min for 10 min, and after the supernatant was discarded, 5 mL of culture solution was added, the cells were mixed by blowing, 10 μL of cell suspension was taken and added to a cell counting plate for counting, and the cell concentration was adjusted to 6 103 cells / well. Except that A1 well in the 96-well plate was a blank well without cells, 100 μL of cell suspension was added to the rest. The 96-well plate was placed in an incubator for 24 h.

[0102] (2) Use 50 μL dimethyl sulfoxide to dissolve the test sample, then add appropriate amount of culture solution to dissolve the sample into 2 mg / mL drug solution, and then dilute the sample into 20, 4, 0.8, 0.16, 0.032 μg / mL in a 24-well plate.

[0103] Add 3 holes for each concentration, and the cell growth of the surrounding two rows and two columns is greatly affected by the environment, and only blank cell holes are used. Place the 96-well plate in the incubator for 72 h.

[0104] (3) Discard the drug-containing culture solution in the 96-well plate, rinse the cells with phosphate buffer solution (PBS) twice, add MTT (tetrazolium) 20 μL in each hole, and place it in the incubator for 4 h. After discarding the MTT solution, add dimethyl sulfoxide 150 μL. Place in the enzyme marker instrument and shake for 180 s, detect the optical density value at 490 nm, and use SPSS to calculate the half inhibitory concentration IC 50 value.

[0105] The results of the inhibitory activity of the compounds on human breast cancer cells MDA-MB-453, human lung adenocarcinoma cells A549, and human colon cancer cells HCT116 are shown in Table 1, and in Table 1, IC 50 ≦ 10.0 μM, represented by A, 10.0 μM﹤IC 50 ≦ 50.0 μM, represented by B, 50.0 μM﹤IC 50 ≦ 500.0 μM, represented by C, and ND represents not tested.

[0106] Table 1 Inhibitory activity of examples on MDA-MB-453, A549, and HCT116 tumor cell strains

[0107] From the above test results, it can be clearly seen that the phthalazinone compounds containing aryl malonamide structure of general formula (I) to be protected by the present application have good in vitro anti-tumor activity. The compounds have good application prospects for the development of anti-tumor drugs.

[0108] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details in the above embodiments. Within the technical concept of the present application, various equivalent transformations of the technical solutions of the present application can be made. In order to avoid unnecessary repetition, the present application does not further describe various possible combination methods. Any modification, equivalent replacement or improvement made within the technical concept of the present application is included in the protection scope of the present application.

Claims

1. A phthalazinone compound having an arylmalonamide structure, characterized by, The phthalazinone compound having an aryl malonamide structure has a structural formula as shown in general formula (I), wherein, Ar is selected from a 6-10 membered aryl group; wherein the 6-10 membered aryl group can be optionally substituted with 1-3 R1 which are the same or different; R1 is hydrogen, hydroxyl, halogen, alkyl having 1-6 carbons, alkoxy having 1-6 carbons, alkyl having 1-6 carbons optionally substituted with halogen, alkoxy having 1-6 carbons optionally substituted with halogen, amino substituted with mono or di alkyl having 1-6 carbons, alkyl amido having 1-6 carbons.

2. The phthalazinone compound having an aryl malonamide structure according to claim 2, and a pharmaceutically acceptable salt thereof, wherein, Ar is phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl which is unsubstituted or substituted with 1-3 R1 which are the same or different; R1 is hydrogen, halogen, alkyl having 1-6 carbons, alkoxy having 1-6 carbons, alkyl having 1-6 carbons optionally substituted with halogen, alkoxy having 1-6 carbons optionally substituted with halogen, amino substituted with mono or di alkyl having 1-6 carbons.

3. The phthalazinone compound according to claim 1, wherein having a structural formula as shown in general formula (I): 。 4. A pharmaceutical composition, characterized by, The phthalazinone compound having an aryl malonamide structure according to any one of claims 1-4, and a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptable excipient.

5. Use of the phthalazinone compound having an aryl malonamide structure according to any one of claims 1-3, and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4, in the manufacture of a medicament for treating and / or preventing a malignant tumor carrying a BRCA1 / 2 gene mutation or other homologous recombination repair deficiency (HRD).

6. Use of the phthalazinone compound having an aryl malonamide structure according to any one of claims 1-3, and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4, in the manufacture of a medicament for treating and / or preventing a proliferative disease.

7. Use of the phthalazinone compound having an aryl malonamide structure according to any one of claims 1-3, and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 4, in the manufacture of a medicament for treating and / or preventing a cancer.

8. Use according to claim 7, characterized in that, The cancer includes breast cancer, lung cancer and colon cancer.

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