Pyrrolopyrimidinone derivatives and preparation method and application thereof

Abstract

The present invention discloses a pyrrolopyrimidone derivative having a structure as shown in formula I, wherein R1 is selected from C1-C3 alkoxy, halogen, cyano, n=1, 2; R2 is selected from cyano, formamide; R3 is selected from prothrombin time (PT) test, FXa in vitro inhibition test, rat in vivo antithrombotic test, and anticoagulant activity test. The pyrrolopyrimidone derivative has a significant anticoagulant effect. Therefore, the present invention also discloses the use of the pyrrolopyrimidone derivative in the preparation of a blood anticoagulant, and the blood anticoagulant is a factor Xa inhibitor.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry and relates to pyrrolopyrimidone derivatives and preparation methods and applications thereof. Background Art

[0002] Cardiovascular and cerebrovascular diseases are known as the "number one killer of human health". Studies have shown that 80% of cardiovascular and cerebrovascular events are related to thrombosis, including stroke, angina pectoris, myocardial infarction, acute coronary syndrome, deep vein thrombosis and pulmonary embolism. Therefore, it is of great clinical significance to explore antithrombotic drugs with better anticoagulant activity and safety.

[0003] Coagulation factor Xa is at a key position connecting the common pathway of intrinsic and extrinsic coagulation pathways. Factor Xa inhibitors can block both the intrinsic and extrinsic coagulation pathways, and do not have the side effects of thrombin inhibitors. In recent years, factor Xa inhibitors have become one of the hot spots in the research of anticoagulant drugs. As early as the late 1990s, researchers began to study N-aryl pyrazole carboxamide type Xa factor inhibitors, among which DPC423 has a good inhibitory ability against factor Xa and high oral bioavailability. Razaxaban contains an aminooxazole group, which improves the selectivity for trypsin and has entered Phase II clinical research for the treatment of deep vein thrombosis. Both of the above compounds contain pyrazole carboxamide structures, which may be hydrolyzed under physiological conditions to produce the corresponding pyrazole carboxylic acid and mutagenic aniline. In order to avoid the hydrolysis of amide, the amino group on pyrazole was cyclized with C-4 to form a bicyclic structure pyrazolopyridone, which was further modified to obtain the potential compound BMS740808, which is a selective factor Xa inhibitor with a strong affinity for thrombin. In order to further reduce the binding with proteins, the trifluoromethyl group at the 3-position of pyrazole was replaced by a carbamoyl group, and a cyclopentylamide structure was introduced to obtain Apixaban, which has good pharmacokinetic properties and anticoagulant activity.

[0004]

[0005] By exploring the structure-activity relationship between apixaban and coagulation factor Xa, pyrazolopyridone is the skeleton structure of apixaban. Its pyrazole N-2 atom is bound to GLN-192, the carbonyl oxygen is bound to GLY-216, and the carboxamide at the C-3 position is bound to GLU-146. The hydrogen bond formed gives it a strong affinity, which is an important structure for apixaban to have anticoagulant activity. Although the p-methoxy group does not interact with the amino acid residues in the S1 pocket, it remains in the same plane as the benzene ring on the pyrazole ring. The phenylpiperidone side chain is in the S4 pocket of factor Xa, inserted between TYR-99 and PHE-174. The oxygen group in the piperidone can bind to water molecules, is hydrophilic, and is also beneficial to activity.

[0006] The pyrrolopyrimidine structure is a purine analogue, and purine derivatives exist in organisms in various forms and play an important role in life activities. Pyrrolopyrimidine compounds have good biological activity and pharmacological effects. A large number of literature reports that such derivatives have antibacterial, antitumor, antiviral and other biological activities. However, there are no reports of pyrrolopyrimidine compounds with anticoagulant activity. Therefore, the search for pyrrolopyrimidine derivatives with anticoagulant activity may be of certain significance for the exploration of new factor Xa inhibitors. Summary of the invention

[0007] The object of the present invention is to provide a pyrrolopyrimidinone derivative having a structure as shown in Formula I:

[0008]

[0009] Wherein, R1 is selected from C1-C3 alkoxy, halogen, cyano (-CN), n=1, 2;

[0010] R2 is selected from cyano, formamide (-CONH2);

[0011] R3 is selected from

[0012] Preferably, R1 is methoxy, Cl, cyano substituted at position 3 and / or position 4;

[0013] R2 is selected from cyano and formamide;

[0014] R3 is selected from

[0015] More preferably, R1 is methoxy or Cl substituted at position 3 and / or position 4; R2 is selected from cyano or formamide; R3 is selected from

[0016] or R1 is methoxy, Cl substituted at position 3 and / or position 4; R2 is selected from cyano; R3 is selected from

[0017] or R1 is Cl substituted at position 3 and / or position 4; R2 is selected from cyano; R3 is selected from

[0018] The pyrrolopyrimidone derivatives are preferably selected from:

[0019] 5-(4-methoxyphenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0020] 5-(4-methoxyphenyl)-7-formamido-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0021] (S)-1-(4-(7-cyano-5-(4-methoxyphenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide;

[0022] 5-(4-methoxyphenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0023] 5-(3-cyanophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0024] 5-(3,4-dichlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0025] (S)-1-(4-(7-cyano-5-(3,4-dichlorophenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide;

[0026] 5-(3,4-dichlorophenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0027] 5-(3,4-dimethoxyphenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0028] (S)-1-(4-(7-cyano-5-(3,4-dimethoxyphenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide;

[0029] 5-(4-chlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0030] (S)-1-(4-(7-cyano-5-(4-chlorophenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide;

[0031] 5-(4-chlorophenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0032] 5-(3-chlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one;

[0033] 5-(3,4-dimethoxyphenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one.

[0034] Another object of the present invention is to provide a method for preparing a pyrrolopyrimidinone derivative as shown in formula I. When R2 is selected from cyano, the reaction route is:

[0035]

[0036] The following steps are involved:

[0037] Step (1), using tetrahydrofuran as a reaction solvent and potassium carbonate as an acid-binding agent, stirring compound V and compound IV to react to obtain compound III;

[0038] Step (2), using anhydrous ethanol as a reaction solvent, stirring compound III and sodium borohydride to react to obtain compound II;

[0039] Step (3), in the presence of anhydrous formic acid and acetic anhydride, compound II is reacted to obtain a pyrrolopyrimidinone derivative.

[0040] In step (1), the molar ratio of compound V to compound IV is 1:1, and the molar ratio of compound V to potassium carbonate is 1:2.5; the reaction temperature is room temperature; after the reaction is completed, the filtrate is filtered to remove the solvent, and ice water is added to the residue and stirred to precipitate compound III.

[0041] In step (2), the molar ratio of compound III to sodium borohydride is 1.4 to 1.5: 1. Specifically, compound III and a reaction solvent are first mixed, sodium borohydride is added in an ice-water bath, and then stirred at room temperature for reaction; after the reaction is completed, ice water is added to quench the reaction, stirred until a solid is precipitated, filtered, washed with water, and then ultrasonically washed with methanol to obtain pure compound II.

[0042] In step (3), the mass ratio of anhydrous formic acid to acetic anhydride is 1:1; the molar ratio of acetic anhydride to compound II is 16 to 20:1. After the reaction is completed, ice water is added to the reaction solution, stirred, and a crude product is precipitated. The crude product is recrystallized using DMF to obtain a pure pyrrolopyrimidone derivative.

[0043] When R2 is selected from formamide, the reaction scheme is:

[0044]

[0045] The method comprises: using dichloromethane as a reaction solvent, in the presence of anhydrous ethanol, using a pyrrolopyrimidone derivative shown in formula Ⅰa as a reaction raw material, introducing hydrogen chloride gas to saturation under an ice-water bath, and reacting to obtain a pyrrolopyrimidone derivative shown in formula Ⅰb; wherein the molar ratio of the pyrrolopyrimidone derivative shown in formula Ⅰa to the anhydrous ethanol is 1:1.

[0046] The reaction route of compound V is:

[0047]

[0048] The method comprises: using DMF as a reaction solvent and potassium carbonate as an acid-binding agent, reacting 4-fluoronitrobenzene with R3H to obtain compound VI; using a mixed solvent of ethanol and water (ethanol: water = 3-4:1 V / V) as a reaction solvent, reacting in the presence of reduced iron powder and ammonium chloride to obtain compound V.

[0049] The reaction route of compound IV is:

[0050]

[0051] Unless otherwise specified, the compounds used as raw materials in the preparation of the pyrrolopyrimidinone derivatives represented by formula I of the present invention are known compounds available from commercial sources, or can be prepared from known compounds by known literature methods, methods analogous to known methods, or methods analogous to the methods described in the examples.

[0052] The prothrombin time (PT) test, the FXa in vitro inhibition test, the rat in vivo antithrombotic test, and the anticoagulant activity test show that the pyrrolopyrimidone derivatives shown in formula I have significant anticoagulant effects and are ideal coagulation factor Xa inhibitors. Therefore, another object of the present invention is to provide the use of the pyrrolopyrimidone derivatives shown in formula I in the preparation of a blood anticoagulant, which is a factor Xa inhibitor.

[0053] Another object of the present invention is to provide the use of the pyrrolopyrimidinone derivatives shown in formula I in the preparation of drugs for treating or preventing cardiovascular and cerebrovascular diseases, wherein the cardiovascular and cerebrovascular diseases refer to stroke, angina pectoris, myocardial infarction, acute coronary syndrome, deep vein thrombosis and pulmonary embolism. DETAILED DESCRIPTION

[0054] Experimental instruments and materials

[0055] Rotary evaporator RE-52AA (Shanghai Yarong Biochemical Instrument Factory), SHB-III circulating water multi-purpose vacuum pump (Nanjing Wener Instrument Equipment Co., Ltd.), JJ-1 precision force-enhancing stirrer (Jintan Chengdong Xinrui Instrument Factory), 85-1 magnetic stirrer (Nanjing Wener Instrument Equipment Co., Ltd.), ZF-I three-purpose UV analyzer, thin layer chromatography silica gel plate (silica gel GF254, Yantai Dexin Biotechnology Co., Ltd.), X-4 digital melting point meter (Beijing Fukai Instrument Co., Ltd.), Bruker AV-300 nuclear magnetic resonance instrument (TMS as internal standard, DMSO-d6 as solvent), mass spectrometry using Agilent Technologies 6520BAccurate-Mass A-TOF LC / MS mass spectrometer, and the purity of the compound was determined using Shimadzu LC-20AT high performance liquid chromatograph (Inertsustain C 18 Column), SAP-10 UV detector, detection wavelength 220nM, mobile phase: methanol-water (70:30V / V), DMF used Molecular sieve drying, ethanol use Molecular sieve drying, other reagents were commercially available analytical grade or chemically pure; most of the reagents were sourced from Aladdin Reagent Co., Ltd.

[0056] Example 1

[0057] Synthesis of Compound AR-1

[0058]

[0059] Preparation of 4-(4-nitrophenyl)-3-morpholinone (Compound 1)

[0060] 30.3 g (0.3 mol) of 3-morpholinone, 300 mL of dry DMF, 42.3 g (0.3 mol) of 4-fluoronitrobenzene, and 55.2 g (0.4 mol) of anhydrous potassium carbonate were added to a 500 mL eggplant-shaped bottle with a drying tube and a magnetic stirrer, and the mixture was heated at 100°C for 6-8 h. The reaction was complete as detected by TLC (PE:EA=3:1 V / V). The mixture was stopped, cooled to room temperature, poured into 1500 mL of ice water, stirred, and a white solid (Compound 1) was precipitated. The solid was filtered, washed with ice water, and directly used for the next step without treatment.

[0061] Preparation of 4-(4-aminophenyl)-3-morpholinone (Compound 2)

[0062] Add 300mL ethanol and 80mL water to a 500mL three-necked round-bottom flask with a condenser and mechanical stirring, add compound 1 under mechanical stirring, then add 134.4g (2.4mol) reduced iron powder and 12.8g (0.24mol) ammonium chloride, heat to reflux at 80°C for 4h, and the reaction is complete as detected by TLC (PE:EA=1:1V / V). Stop heating, filter with diatomaceous earth while hot, wash with hot ethanol, concentrate the filtrate to dryness, pour into 300mL ice water, stir, filter, and wash impurities with water. Dissolve the crude product in 300mL dichloromethane, add 3g activated carbon, decolorize and filter, concentrate the filtrate under reduced pressure, and recrystallize the crude product with 65% ethanol to obtain 40.3g white solid (compound 2, theoretical yield 57.6g), and the total yield of the two-step reaction is 70%.

[0063]

[0064] Preparation of 4-methoxyaniline malononitrile (Compound 6)

[0065] 50g (0.785mol) of malononitrile and 90g (0.608mol) of triethyl orthoformate were added to a 500mL three-necked round-bottom flask with a drying tube and mechanical stirring, and the mixture was heated and stirred at 80°C for 1h. 61.5g (0.5mol) of 4-methoxyaniline (compound 5) was dissolved in 250mL of anhydrous ethanol and added dropwise to the reaction solution at the same temperature. During the addition, a yellow solid gradually precipitated (easy to agglomerate, requiring vigorous stirring). The mixture was heated and stirred at 80°C for 3h. The reaction was complete as detected by TLC (PE:EA=1:2V / V). The mixture was cooled to room temperature, filtered, washed with ethanol, and dried to obtain 92.3g (theoretical yield 99.5g) of compound 6 as an off-white solid with a yield of 92.8%.

[0066] Preparation of ethyl 3-amino-4-cyano-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (Compound 7)

[0067] To a 1L eggplant-shaped flask equipped with a drying tube and a magnetic stirrer, 90 g (0.452 mol) of compound 6, 450 mL of DMF, and 162 g (1.174 mol) of anhydrous potassium carbonate were added in sequence. 84 g (0.503 mol) of ethyl bromoacetate was added dropwise under an ice-water bath. Finally, 2 g of DMAP was added as a catalyst. The mixture was heated and stirred at 100°C for 3 h. The reaction was complete as detected by TLC (PE:EA=1:1V / V). The mixture was cooled to room temperature, poured into ice water, and the precipitate was washed with water and filtered. The filter cake was dried to obtain 122.3 g (theoretical yield: 128.9 g) of compound 7 as a light yellow solid with a yield of 94.9%.

[0068] Preparation of ethyl 3-azido-4-cyano-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (Compound 8)

[0069] Add 70g (0.246mol) of compound 7 and 350mL of trifluoroacetic acid to a 500mL three-necked flask equipped with a drying tube, a thermometer and a mechanical stirring device, cool to 0-3°C in an ice-water bath, slowly add 17.5g (0.253mol) of sodium nitrite in batches (strictly control the temperature at 0-3°C during the addition process to prevent the decomposition of nitrous acid), continue to stir and react at 0-3°C for 30min, then slowly add 17g (0.262mol) of sodium azide (gas is generated), and react at room temperature for 2h. TLC (PE / EA=1 / 1V / V) detected that the reaction was complete, vacuum concentrated at room temperature to recover trifluoroacetic acid, pour the residual liquid into ice water, stir continuously until solid precipitates, filter, wash with water, and dry to obtain 72.3g (theoretical yield 76.4g) of compound 8 as a yellow solid with a yield of 94.6%.

[0070] Preparation of 3-azido-4-cyano-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylic acid (Compound 9)

[0071] In a 1L eggplant-shaped flask with a magnetic stirrer, 72.3 g (0.23 mol) of compound 8 and 480 mL of tetrahydrofuran were added and stirred to dissolve, and then 120 mL of lithium hydroxide monohydrate (64 g, 1.52 mol) aqueous solution was added, and finally 2 g of TEBA was added as a catalyst. The reaction was stirred at room temperature for 24 h. The reaction was completed by HPLC (mobile phase: 70% methanol-water solution, detection wavelength: 220 nm). The solvent was removed under reduced pressure, 300 mL of water was added, and then extracted with 300 mL of ethyl acetate to remove impurities. The aqueous layer was acidified with 6N HCl to precipitate a white solid, which was filtered, washed with water, and dried to obtain 62.2 g (theoretical yield: 65.8 g) of compound 9 as a brown solid with a yield of 94.5%.

[0072] Preparation of 3-azido-4-cyano-1-(4-methoxyphenyl)-1H-pyrrole-2-yl chloride (Compound 10)

[0073] Under ice-water cooling, 62.2 g (0.22 mol) of the crude product of the previous step, compound 9, and 300 mL of dry dichloromethane were added to a 1 L eggplant-shaped flask equipped with a drying tube, a thermometer and a magnetic stirrer. The temperature was cooled to 0-10°C in an ice-water bath, and 84 g (0.66 mol) of oxalyl chloride was slowly added dropwise using a constant pressure dropping funnel under stirring. The temperature in the reaction flask was controlled to be below 10°C during the addition. After the addition was completed, the reaction was allowed to proceed at room temperature for more than 24 h. The reaction was complete as determined by TLC (PE:EA=1:1V / V). The reaction solution was distilled under reduced pressure, and 200 mL of anhydrous tetrahydrofuran was repeatedly added and vortexed under reduced pressure to remove unreacted oxalyl chloride. The solution was concentrated to dryness under vacuum at room temperature and air-dried to obtain 66.3 g (theoretical yield: 66.3 g) of compound 10, which was directly reacted in the next step without treatment as a yellow solid with a yield of 100%.

[0074]

[0075] Preparation of 3-azido-4-cyano-1-(4-methoxyphenyl)-N-(4-(3-morpholinone)phenyl)-1H-pyrrole-2-carboxamide (Compound 16)

[0076] Into a 500mL three-necked round-bottom flask with a drying tube and mechanical stirring, 19.2g (0.1mol) of compound 2, 300mL of tetrahydrofuran and 34.5g (0.25mol) of anhydrous potassium carbonate were added in sequence, and 30.2g (0.1mol) of compound 10 was slowly added under stirring. The reaction was carried out at room temperature for 24h. The reaction was completed as detected by TLC (CH2Cl2:MeOH=20:1V / V). The insoluble salt was filtered out, the filter cake was washed with an appropriate amount of THF, and the filtrate was distilled under reduced pressure to remove the solvent. The residue was added to 200mL of ice water with stirring, filtered, washed with water, and dried to obtain 42.9g (theoretical yield: 45.7g) of compound 16 as an off-white solid with a yield of 93.9%.

[0077] Preparation of 3-amino-4-cyano-1-(4-methoxyphenyl)-N-(4-(3-morpholinone)phenyl)-1H-pyrrole-2-carboxamide (Compound 17)

[0078] 42.9 g (0.0939 mol) of compound 16 and 600 mL of anhydrous ethanol were added to a 1L three-necked round-bottom flask with a drying tube and a magnetic stirrer, cooled in an ice-water bath, and 2.49 g (0.0657 mol) of sodium borohydride were slowly added, stirred at room temperature, and the reaction was complete when detected by TLC (CH2Cl2: MeOH = 20: 1 V / V). The reaction solution was slowly poured into 1L of ice water (note that a large number of bubbles were generated) to quench the reaction, stirred, and a yellow solid was precipitated, filtered, washed with water, and the filter cake was added to 500 ml of methanol for ultrasonic dispersion, stirred overnight, filtered, and the filter cake was dried to obtain 22.9 g (theoretical yield 40.5 g) of compound 17 as an off-white solid with a yield of 56.5%.

[0079] Preparation of 5-(4-methoxyphenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-1)

[0080] 100g (2.174mol) of anhydrous formic acid and 100g (0.98mol) of acetic anhydride were added to a 500mL eggplant-shaped bottle with a drying tube, a condenser and a magnetic stirrer, and stirred at room temperature for 30min. 22.9g (0.0531mol) of compound 17 was added under an ice-water bath, and the reaction was continued at room temperature for 1h, and then heated at 100°C for 3h. The reaction was complete as detected by TLC (CH2Cl2: MeOH = 20: 1V / V), and the mixture was cooled to room temperature, added to 100mL of ice water, stirred, precipitated, filtered, washed with water, and dried to obtain 17.3g of crude product. The crude product was recrystallized with 170ml of LDMF and dried to obtain 13.5g (theoretical yield 23.4g) of compound AR-1 as a white solid with a yield of 57.7% and a HPLC purity of 99.3%.

[0081] mp above 250℃. ESI-MS m / z: 442.15 [M+H] + IR(KBr,cm -1 ):v 3414.2,3109.3,3090.7,3054.5,2968.3,2887.5,2835.2,2228.4,1698.4,1660.2,1606.3,1590.0,1575.2,1533.0,1515.4,147 2.6,1447.0,1418.3,1381.1,1353.3,1316.2,1294.5,1280.8,1259.4,1214.4,1179.1,1158.1,1124.1,1082.0,1035.4,1021.3.

[0082] Example 2

[0083] Preparation of 5-(4-methoxyphenyl)-7-formamido-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-2)

[0084] Add 5g (0.013mol) of compound AR-1 and 150mL of dichloromethane to a 250mL eggplant-shaped bottle with a magnetic stirrer, add 0.6g of anhydrous ethanol, cool in an ice-water bath, and continuously introduce hydrogen chloride gas to saturation. TLC (CH2Cl2 / MeOH=20:1) detects that the reaction is complete, pour into 300mL of ice water, stir, precipitate, filter, wash, and dry to obtain 2.8g of crude product. The crude product is recrystallized with 15mL of DMF and dried to obtain 2.1g (theoretical yield 5.2g) of compound AR-2, a white solid, with a yield of 40.4% and a HPLC purity of 99.6%.

[0085] mp above 250℃. ESI-MS m / z: 460.16[M+H] + IR(KBr,cm -1 ):v 3422.2,3320.2,3201.4,3126.8,3107.7,3056.5,2995.8,2967.5,2939.9,291 3.5,2891.0,2843.3,1689.2,1665.5,1611.7,1579.7,1541.6,1517.0,1471.7, 1445.6,1412.9,1389.9,1368.8,1347.6,1329.7,1313.7,1292.5,1281.9,1253.1,1208.8,1195.0,1183.8,1159.8,1125.1,1101.4,1074.9,1021.5,1001.3.

[0086] Example 3

[0087] Preparation of (S)-1-(4-aminophenyl)pyrrole-2-carboxamide (Compound 3)

[0088] Referring to the synthesis method of compound 2 in Example 1, 4-fluoronitrobenzene was reacted with 34.2 g (0.3 mol) of L-prolineamide under the same conditions, and then the nitro group was reduced using iron powder and ammonium chloride to obtain 31.2 g (theoretical yield 61.5 g) of compound 3 as an off-white solid. The total yield of the two steps was 51%.

[0089]

[0090] Preparation of (S)-1-(4-(7-cyano-5-(4-methoxyphenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide (Compound AR-3)

[0091] Referring to the synthesis of compound AR-1, compound 2 was replaced by compound 3 to obtain a crude compound AR-3. The crude product was dissolved in dichloromethane, decolorized with activated carbon, filtered and dried, and methanol was added to the residue for dispersion and stirring. The filter cake was recrystallized with acetonitrile to obtain 30 g (theoretical yield 42.6 g) of compound AR-3 as a white solid with a yield of 70.4% and a HPLC purity of 99.5%.

[0092] mp above 250℃. ESI-MS m / z: 455.18 [M+H] + IR(KBr,cm -1 ):v3433.9,3297.2,3233.4,3136.2,3061.8,2997.4,2967.4,2944.5,2906.5,2879 .1,2827.4,2230.0,1702.7,1688.3,1643.6,1607.3,1594.2,1532.0,1514.4,1506. 9,1468.1,1446.6,1429.8,1400.7,1373.0,1354.6,1343.3,1310.8,1295.0,1281.2,1247.6,1217.0,1186.9,1165.0,1152.4,1114.9,1082.8,1047.5,1024.9,1016.5.

[0093] Example 4

[0094] Preparation of 1-(4-aminophenyl)pyridin-2(1H)-one (Compound 4)

[0095] Referring to the synthesis method of compound 2 in Example 1, 4-fluoronitrobenzene and 28.5 g (0.3 mol) of pyridine-2(1H)-one were reacted under the same conditions, and then the nitro group was reduced using iron powder and ammonium chloride to obtain 31.2 g (theoretical yield 55.8 g) of compound 4 as a white solid. The total yield of the two steps was 56%.

[0096]

[0097] Preparation of 5-(4-methoxyphenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-4)

[0098] Referring to the synthesis of compound AR-1, compound 2 was replaced by compound 4 to obtain 1.2 g of compound AR-4 as a white solid with a yield of 42.9% and a HPLC purity of 98.2%.

[0099] mp above 250℃. ESI-MS m / z: 436.14 [M+H] + .

[0100] Example 5

[0101] Preparation of compound 11

[0102] Referring to the preparation method of compound 10 in Example 1, 4-methoxyaniline (compound 5) was replaced by m-cyanoaniline to prepare 3-azido-4-cyano-1-(3-cyanophenyl)-1H-pyrrole-2-yl chloride (compound 11) to obtain 20 g (theoretical yield 20.2 g) of compound 11 as a light yellow solid with a yield of 99.0%.

[0103]

[0104] Preparation of 5-(3-cyanophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-5)

[0105] Referring to the synthesis of compound AR-1, compound 11 was used to replace compound 10 to obtain 16.5 g (theoretical yield: 22.8 g) of compound AR-5 as a white solid with a yield of 72.4% and a HPLC purity of 99.8%.

[0106] mp above 250℃. ESI-MS m / z: 437.14 [M+H] + IR(KBr,cm -1 ):v3125.1,3100.4,2971.5,2917.6,2880.4,2236.4,1686.8,1661.3,1604.8,1574.7,1530.7,1513.6,1487.7,1471.3,14 40.8,1415.1,1380.2,1348.7,1332.1,1313.5,1279.4,1245.5,1207.6,1160.5,1128.5,1101.2,1082.3,1025.6,1014.6.

[0107] Example 6

[0108] Preparation of compound 13

[0109] Referring to the preparation method of compound 10 in Example 1, 4-methoxyaniline (compound 5) was replaced with 3,4-dichloroaniline to prepare 3-azido-4-cyano-1-(3,4-dichlorophenyl)-1H-pyrrole-2-yl chloride (compound 13) to obtain 68.9 g of yellow solid (theoretical yield 69.8 g) with a yield of 98.7%.

[0110]

[0111] Preparation of 5-(3,4-dichlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-6)

[0112] Referring to the synthesis of compound AR-1, compound 13 was used to replace compound 10 to obtain 1.23 g (theoretical yield: 3.07 g) of compound AR-6 as a yellow solid with a yield of 40% and a HPLC purity of 98.0%.

[0113] mp above 250℃. ESI-MS m / z: 480.06[M+H] + IR(KBr,cm -1 ):v3459.6,3427.1,3388.2,3125.8,3098.4,3060.8,2966.7,2917.4 ,2881.1,2850.9,2231.9,1697.0,1659.4,1605.0,1574.2,1558.7,15 30.2,1510.5,1474.8,1442.7,1415.2,1382.9,1349.8,1314.5,1279 .3,1240.2,1207.3,1158.0,1126.0,1100.2,1079.7,1030.4,1013.7.

[0114] Example 7

[0115] Preparation of (S)-1-(4-(7-cyano-5-(3,4-dichlorophenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide (Compound AR-7)

[0116] Referring to the synthesis of compound AR-1, compound 3 and compound 13 were used as starting materials to obtain 0.92 g (theoretical yield: 2 g) of compound AR-7 as a yellow solid with a yield of 46% and a HPLC purity of 98.7%.

[0117] mp above 250℃. ESI-MS m / z: 493.09[M+H] +IR(KBr,cm -1 ):v3391.1,3304.3,3184.6,3131.2,3096.4,3063.2,2922.0,2851.3,2232.4,1689.0,1673.9,1610.3,1581.4,1569.5,15 18.7,1475.5,1444.7,1406.3,1370.7,1282.3,1244.7,1206.1,1190.2,1160.8,1131.5,1083.3,1032.5,1018.1,1001.8.

[0118] Example 8

[0119] Preparation of 5-(3,4-dichlorophenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-8)

[0120] Referring to the synthesis of compound AR-1, compound 4 and compound 13 were used as starting materials to obtain 1.14 g (theoretical yield: 3.03 g) of compound AR-8 as a white solid with a yield of 37.6% and a HPLC purity of 98.2%.

[0121] mp above 250℃. ESI-MS m / z: 474.05[M+H] + IR(KBr,cm -1 ):v3408.3,3074.6,3039.8,2958.3,2932.0,2855.7,2231.5,1896.3,1699.7,1667.6,1610.1,1587.3,1569.8,1537.0,1526. 0,1507.7,1476.4,1442.0,1422.4,1372.6,1339.4,1320.9,1303.7,1273.9,1246.9,1206.5,1134.3,1082.5,1030.0,1012.3.

[0122] Example 9

[0123] Preparation of compound 12

[0124] Referring to the preparation method of compound 10 in Example 1, 4-methoxyaniline (compound 5) was replaced with 3,4-dimethoxyaniline to prepare 3-azido-4-cyano-1-(3,4-dimethoxyphenyl)-1H-pyrrole-2-yl chloride (compound 12) to obtain 2.72 g (theoretical yield 2.81 g) of brown solid with a yield of 96.7%.

[0125]

[0126] Preparation of 5-(3,4-dimethoxyphenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-9)

[0127] Referring to the synthesis of compound AR-1, compound 12 was used to replace compound 10 to obtain 3.72 g (theoretical yield: 6.22 g) of compound AR-9 as a white solid with a yield of 59.8% and a HPLC purity of 98.1%.

[0128] mp above 250℃. ESI-MS m / z: 472.16[M+H] + .

[0129] Example 10

[0130] Preparation of (S)-1-(4-(7-cyano-5-(3,4-dimethoxyphenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide (Compound AR-10)

[0131] Referring to the synthesis of compound AR-1, compound 3 and compound 12 were used as starting materials to obtain 2.1 g (theoretical yield: 3.29 g) of compound AR-10 as a white solid with a yield of 63.8% and a HPLC purity of 98.3%.

[0132] mp above 250℃. ESI-MS m / z: 485.19 [M+H] + IR(KBr,cm -1 ):v3436.1,3336.5,3205.0,3122.7,3060.6,2962.2,2936.7,2873.5,2838.1,2230.7,1696.2,1608.5,1577. 3,1517.9,1443.8,1405.9,1362.0,1320.8,1264.0,1239.5,1207.3,1189.0,1177.5,1136.1,1083.4,1020.0.

[0133] Embodiment 11

[0134] Preparation of compound 14

[0135] Referring to the preparation method of compound 10 in Example 1, 4-chloroaniline was used to replace 4-methoxyaniline (compound 5) to prepare 3-azido-4-cyano-1-(4-chlorophenyl)-1H-pyrrole-2-yl chloride (compound 14) to obtain 9.18 g (theoretical yield 9.49 g) of brown solid with a yield of 96.7%.

[0136]

[0137] Preparation of 5-(4-chlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-11)

[0138] Referring to the synthesis of compound AR-1, compound 14 was used to replace compound 10 to obtain 2.98 g (theoretical yield: 7.13 g) of compound AR-11 as a white solid with a yield of 41.8% and a HPLC purity of 98.1%.

[0139] mp above 250℃. ESI-MS m / z: 446.10 [M+H] + IR(KBr,cm -1 ):v3120.6,3096.9,3058.9,2969.8,2952.2,2926.1,2913.3,2876.7,2 231.8,1701.4,1656.7,1604.6,1576.8,1532.8,1510.8,1494.3,1470. 4,1444.9,1417.9,1405.8,1375.2,1352.2,1335.3,1315.9,1283.8,12 56.2,1243.8,1210.7,1157.2,1126.0,1098.5,1077.3,1024.2,1015.5.

[0140] Example 12

[0141] Preparation of (S)-1-(4-(7-cyano-5-(4-chlorophenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide (Compound AR-12)

[0142] Referring to the synthesis of compound AR-1, compound 3 and compound 14 were used as starting materials to obtain 3.02 g (theoretical yield: 5.74 g) of compound AR-12 as a yellow solid with a yield of 52.6% and a HPLC purity of 98.6%.

[0143] mp above 250℃. ESI-MS m / z: 459.13 [M+H]+ IR(KBr,cm -1 ):v3443.3,3327.9,3193.0,3123.7,3096.8,3058.0,2956.4,2924.9,2871.5,2853.7,2231.0,1693.0,1609.3,1575. 5,1517.0,1493.1,1443.4,1403.9,1365.7,1284.5,1252.2,1205.9,1186.9,1158.7,1080.5,1044.5,1018.4,1009.2.

[0144] Example 13

[0145] Preparation of 5-(4-chlorophenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-13)

[0146] Referring to the synthesis of compound AR-1, compound 4 and compound 14 were used as starting materials to obtain 6.72 g (theoretical yield: 14.1 g) of compound AR-13 as a white solid with a yield of 47.7% and a HPLC purity of 98.1%.

[0147] mp above 250℃. ESI-MS m / z: 440.09[M+H] + .

[0148] Embodiment 14

[0149] Preparation of compound 15

[0150] Referring to the preparation method of compound 10 in Example 1, 4-methoxyaniline (compound 5) was replaced by 3-chloroaniline to prepare 3-azido-4-cyano-1-(3-chlorophenyl)-1H-pyrrole-2-yl chloride (compound 15) to obtain 6.12 g (theoretical yield 6.3 g) of brown solid with a yield of 97.1%.

[0151]

[0152] Preparation of 5-(3-chlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-14)

[0153] Referring to the synthesis of compound AR-1, compound 3 and compound 15 were used as starting materials to obtain 3.20 g (theoretical yield: 5.80 g) of compound AR-14 as an off-white solid with a yield of 55.2% and a HPLC purity of 98.0%.

[0154] mp above 250℃. ESI-MS m / z: 446.10 [M+H] + IR(KBr,cm -1 ):v 3426.8,3154.0,3123.5,3093.3,3054.9,2965.4,2920.0,2883.2,223 2.6,1698.8,1658.8,1605.6,1592.3,1574.9,1530.3,1510.4,1478.0, 1450.5,1440.1,1415.8,1402.5,1377.9,1352.7,1334.5,1314.0,128 1.9,1241.9,1223.6,1206.7,1156.8,1124.2,1100.3,1078.5,1021.7.

[0155] Embodiment 15

[0156] Preparation of 5-(3,4-dimethoxyphenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one (Compound AR-15)

[0157] Referring to the synthesis of compound AR-1, compound 4 and compound 12 were used as starting materials to obtain 1.22 g (theoretical yield: 2.51 g) of compound AR-15 as a white solid with a yield of 48.6% and a HPLC purity of 98.4%.

[0158] mp above 250℃. ESI-MS m / z: 466.15[M+H] + .

[0159]

[0160] Table 1. Structures of pyrrolopyrimidinone derivatives

[0161]

[0162]

[0163] Example 16

[0164] In vitro and in vivo bioactivity assays

[0165] 1. In vitro determination of factor Xa inhibitors

[0166] Factor Xa (HFXa) can act on the specific chromogenic substrate S-2765 to cause the terminal p-nitroaniline (pNA) to fall off. The free pNA produces an absorption peak at a wavelength of 405nm, and its absorbance is measured by an ELISA instrument to infer the inhibitory effect of the compound.

[0167] Test drugs and reagents:

[0168] HFXa (molecular weight 46000, product of molecular innovations) was prepared into a 50 nM solution using a buffer solution (0.02 M Bis-Tris; 0.7 M NaCl; pH 6.0) for later use during the experiment.

[0169] The HFXa chromogenic substrate S-2765 (diapharma product) was prepared into a 3 mM solution with water for injection during the test.

[0170] Test compounds: Compounds AR-1, AR-2, AR-3, and Apixaban. During the test, DMSO (product of Sigma) was used to prepare a sample solution with a concentration of 200 nM for later use.

[0171] The positive drug was rivaroxaban (molecular weight 435.88). During the test, DMSO was used to prepare a rivaroxaban solution with a concentration of 200 nM for later use.

[0172] Experimental method: Take a 96-well plate, add 75 μL buffer (50 mNTris-Hcl; 150 mM NaCl; 0.1% BSA) and 10 μL HFXa solution (final concentration is 2.5 nM, and the negative control wells are added with an equal amount of buffer to replace the HFXa solution as a negative control); each test compound is set at six concentrations of 20 nM, 10 nM, 5 nM, 2.5 nM, 1.25 nM, and 0.625 nM, add 10 μL sample solution or rivaroxaban solution to the sample wells, and add an equal amount of DMSO solution to the solvent control wells as a solvent control; shake on a shaker for 5 min to mix, incubate at 25 ° C for 10 min; add 5 μL of substrate to each well, shake on a shaker to mix, and measure the absorbance at a wavelength of 405 nm, once every 10 min, for a total of 3 times. Calculate the maximum slope, which is the reaction rate, then the relative enzyme activity (%) = (inhibitor rate / solvent control rate) × 100.

[0173] Experimental results:

[0174] Table 2. Relative enzyme activity of apixaban

[0175]

[0176] Note: 1.605 to 4.684 refers to the upper and lower limits calculated by the regression equation established based on experimental data.

[0177] Table 3. Relative enzyme activity of 20nM samples

[0178]

[0179] Table 4. Inhibition rate of different samples on factor Xa inhibitors

[0180]

[0181] Note: Compound AR-2, compound AR-3 and apixaban were tested twice; experiments on the same batch showed that compound AR-2 was superior to rivaroxaban and apixaban for factor Xa inhibitors.

[0182] 2. Antithrombotic experiment

[0183] The anti-thrombotic experimental model is to cover the inferior vena cava of rats with filter paper strips soaked in 20% ferric chloride. Through the generation of oxygen free radicals, lipid peroxidation damage to the vascular endothelium is caused, the endogenous coagulation system is activated, and intravascular thrombosis is promoted.

[0184] Experimental Materials:

[0185] Healthy adult SPF SD rats, half male and half female, weighing 200-240 g, were purchased from Zhejiang Provincial Experimental Animal Center.

[0186] Scalpel, surgical scissors, tweezers, hemostatic forceps, mouse plate, gavage needle, syringe, ultrasonic cleaner, nylon thread, watch glass, stopwatch, filter paper, analytical balance.

[0187] DMSO, saline, rivaroxaban, apixaban, compounds AR-1, AR-2, AR-3, 20% urethane, 75% alcohol, 20% FeCl3.

[0188] Antithrombotic effects of compounds AR-2 and AR-3

[0189] Experimental methods: 50 SD rats were randomly divided into 5 groups according to sex and weight: rivaroxaban group, AR-2 group, AR-3 group, apixaban group, and model group (equal volume solvent), with 10 rats in each group. The dose of rats was 1 mg / kg, and the DMSO dosage was 50 μL / mg (solvent / drug). Rats were gavaged at 1 mL / 100 g according to body weight. Rats were fasted for 12 hours before surgery, and drinking water was not limited. 60 minutes after gavage, rats were anesthetized with 20% urethane 0.5 mL / 100 g. After 15 minutes, the abdominal cavity was opened, and the inferior vena cava was exposed with hemostatic forceps, and two nylon threads were placed between the renal vein and the iliac vein. After 15 minutes, a piece of filter paper stained with 20% FeCl3 was wrapped around the inferior vena cava. After 1 minute, the filter paper was removed and the incision was closed with hemostatic forceps. After 60 minutes, the blood vessels at both ends of the filter paper strip were ligated and cut off, the blood vessel cavity was cut open longitudinally, the blood in the blood vessel was sucked out, the thrombus was taken out, and the floating blood on the surface was washed away in normal saline. The normal saline on the surface of the thrombus was wiped off with filter paper, and the wet weight was measured after 1 minute (see Table 5).

[0190] Antithrombotic effect of compound AR-1

[0191] 60 SD rats were randomly divided into 6 groups: rivaroxaban group (dosage 3 mg / kg), AR-1 group (6 mg / kg, 3 mg / kg, 1.5 mg / kg, 3 groups in total), model group (equal volume of solvent), normal sham operation group (normal rats, no surgical modeling), 10 rats in each group, and the rest of the steps were the same as the above experimental method. The results are shown in Table 6.

[0192] Antithrombotic effect of compound AR-2

[0193] Forty-eight SD rats were randomly divided into 6 groups according to sex and weight, with 8 rats in each group: rivaroxaban group (1.0 mg / kg), apixaban group (0.5 mg / kg), AR-2 group (0.5 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 3 groups in total), and model group (equal volume of solvent) for oral administration. The rest of the steps were the same as the above experimental method. The results are shown in Table 7.

[0194]

[0195] Table 5. Wet weight of thrombus in the rat inferior vena cava thrombosis model induced by ferric chloride ( n=10)

[0196]

[0197] Note: Compared with the model group, **P<0.01.

[0198] Table 6. Wet weight of thrombus in rat inferior vena cava thrombosis model induced by compound AR-1 ferric chloride ( n=10)

[0199]

[0200] Note: *P<0.05; **P<0.01 compared with the model group.

[0201] Table 7. Wet weight of thrombus in rat inferior vena cava thrombosis model induced by compound AR-2 ferric chloride ( n=8)

[0202]

[0203] Note: *P<0.05; **P<0.01 compared with the model group.

[0204] 3. Anticoagulant activity test

[0205] When an excess of calcium-containing tissue thromboplastin is added to the test plasma, the recalcified plasma activates factor X to become Xa. Coagulation factor Xa can convert prothrombin into thrombin, and thrombin converts fibrinogen into insoluble fibrin. The time required for coagulation is measured, which is the thrombin time (PT) of the test plasma.

[0206] Experimental Materials:

[0207] Compound AR-1-Compound AR-15, rivaroxaban (positive drug).

[0208] Big-eared white rabbit (provided by the Experimental Animal Center of the Fourth Military Medical University), sex: male. Number of animals: 1.

[0209] Experimental methods:

[0210] 1. Take 18 ml of blood from the rabbit abdominal aorta, anticoagulant with sodium citrate (the volume ratio of anticoagulant to whole blood is 1:9), centrifuge at 3000 rpm / min for 10 min, and take no less than 10 mL of upper plasma.

[0211] 2. Use DMSO as solvent to prepare samples of compound AR-1-compound AR-15, take 10 μL and add it to 240 μL plasma. For the negative control group, add 10 μL DMSO to 240 μL plasma. Repeat 3 tubes for each sample. Mix well with a vortex mixer, place in a 37°C water bath for incubation for 2 minutes, take out and place in a cold water bath to terminate the reaction. Use a fully automatic coagulation analyzer to measure the plasma prothrombin time (PT).

[0212] 3. First determine the 2PT concentration of rivaroxaban. Six concentrations of rivaroxaban samples, 1nM, 10nM, 20nM, 50nM, 100nM, and 200nM, are selected to determine the PT value of each concentration, with three replicates for each concentration. The 2PT concentration of rivaroxaban is calculated.

[0213] 4. Refer to the concentration of rivaroxaban 2PT to preliminarily screen the NPT of each group of samples.

[0214] 5. Determine the PT dose-effect curve of the positive drug and the test sample. It is planned to select samples with concentrations of 20nM, 100nM, 500nM, 2500nM, and 12500nM, determine the PT value of each concentration, and perform three replicates for each concentration. Draw the dose-effect curve of the positive drug and the test sample.

[0215] Experimental results:

[0216] Table 8. Prothrombin time (PT) for rivaroxaban

[0217]

[0218] Table 9. Prothrombin time PT (100 nM) of different compounds

[0219]

Claims

1. Pyrrolopyrimidinone derivatives having a structure as shown in formula I: in, n＝1、2； R1 is methoxy, Cl substituted at position 3 and / or position 4; R2 is selected from cyano; R3 is selected from or R1 is a methoxyl group substituted at position 4; R2 is selected from a carboxamide group; R3 is selected from or R1 is a 3-substituted cyano group; R2 is selected from a cyano group; R3 is selected from or R1 is methoxy, Cl substituted at position 3 and / or position 4; R2 is selected from cyano; R3 is selected from or R1 is Cl substituted at position 3 and / or position 4; R2 is selected from cyano; R3 is selected from 2. A pyrrolopyrimidinone derivative, characterized in that: The pyrrolopyrimidinone derivatives are: 5-(4-methoxyphenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; 5-(4-methoxyphenyl)-7-formamido-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; (S)-1-(4-(7-cyano-5-(4-methoxyphenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide; 5-(4-methoxyphenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; 5-(3-cyanophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; 5-(3,4-dichlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; (S)-1-(4-(7-cyano-5-(3,4-dichlorophenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide; 5-(3,4-dichlorophenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; 5-(3,4-dimethoxyphenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; (S)-1-(4-(7-cyano-5-(3,4-dimethoxyphenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide; 5-(4-chlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; (S)-1-(4-(7-cyano-5-(4-chlorophenyl)-4-keto-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidinyl)phenyl)pyrrole-2-carboxamide; 5-(4-chlorophenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; 5-(3-chlorophenyl)-7-cyano-3-(4-(3-morpholinone)phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one; 5-(3,4-dimethoxyphenyl)-7-cyano-3-(4-(2-pyridone-1(2H))phenyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-4-one.

3. A method for preparing the pyrrolopyrimidone derivatives according to claim 1, characterized in that: When R2 is selected from cyano, the reaction route is: When R2 is selected from formamide, the reaction scheme is:

4. The method for preparing the pyrrolopyrimidone derivatives according to claim 3, characterized in that: When R2 is selected from cyano, the method comprises the following steps: Step (1), using tetrahydrofuran as a reaction solvent and potassium carbonate as an acid-binding agent, stirring compound V and compound IV to react to obtain compound III; Step (2), using anhydrous ethanol as a reaction solvent, stirring compound III and sodium borohydride to react to obtain compound II; Step (3), in the presence of anhydrous formic acid and acetic anhydride, compound II is reacted to obtain a pyrrolopyrimidinone derivative.

5. The method for preparing the pyrrolopyrimidone derivatives according to claim 4, characterized in that: In step (1), the molar ratio of compound V to compound IV is 1:1, and the molar ratio of compound V to potassium carbonate is 1:2.5; In step (2), the molar ratio of compound III to sodium borohydride is 1.4-1.5:

1.

6. The method for preparing the pyrrolopyrimidone derivatives according to claim 3, characterized in that: When R2 is selected from formamide, the process comprises: using dichloromethane as a reaction solvent, in the presence of anhydrous ethanol, using the pyrrolopyrimidone derivatives shown in formula Ⅰa as a reaction raw material, introducing hydrogen chloride gas to saturation under an ice-water bath, and reacting to obtain the pyrrolopyrimidone derivatives shown in formula Ⅰb.

7. Use of the pyrrolopyrimidinone derivatives according to claim 1 in the preparation of blood anticoagulants.

8. The use according to claim 7, characterized in that: The blood anticoagulant is a factor Xa inhibitor.

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