Compound with quinazolinone pyrrole dihydropyrrolinone structure as well as preparation method and medical application of compound

Abstract

The invention discloses a compound with a quinazolinone pyrrole dihydropyrrolinone structure as well as a preparation method and medical application of the compound. The invention provides a compound with a novel quinazolinone pyrrole dihydropyrrolinone structure, and provides a synthesis method of the series of compounds. The compound with the quinazolinone pyrrole dihydropyrrolinone structure has excellent double-target inhibition activity of PIM and HDAC (histone deacetylase). The compound with the quinazolinone pyrrole dihydropyrrolinone structure, provided by the invention, has the application prospect of being developed into a PIM / HDAC double-target inhibitor drug and a drug for treating diseases which are treated or relieved by inhibiting PIM / HDAC double targets. The structure of the compound with the quinazolinone pyrrole dihydropyrrolinone structure is as shown in a formula (1),

Description

Technical Field

[0001] The invention relates to a compound with a quinazolinone pyrrole dihydropyrrolidone structure, a preparation method thereof and medical uses thereof, and belongs to the field of compounds with a quinazolinone pyrrole dihydropyrrolidone structure. Background Art

[0002] PIM kinases are a class of serine / threonine-specific kinases associated with cell proliferation, survival, and apoptosis. They possess a specialized catalytic structure and regulate target protein activity and function by phosphorylating them. HDACs are a class of histone deacetylases that primarily regulate gene expression and cellular function by removing acetyl groups from histone and non-histone proteins. Therefore, these two targets are closely linked to a variety of diseases and play a crucial role in acute myeloid leukemia and various tumors.

[0003] PIM / HDAC dual-target inhibitors, by simultaneously inhibiting both PIMs and HDACs, can effectively suppress the PI3K / Akt signaling pathway and the increase in histone acetylation, enhancing tumor cell apoptosis and thus improving anti-tumor efficacy. Furthermore, PIM protein inhibition reduces signals that influence cell proliferation, while HDAC inhibition restores the expression of some tumor suppressor genes. These synergistic effects can effectively reduce tumor cell proliferation. Therefore, by simultaneously interfering with multiple signaling pathways, including cell survival, proliferation, and migration, PIM / HDAC dual-target inhibitors offer a more effective therapeutic strategy, particularly for combating difficult-to-treat tumors such as acute myeloid leukemia and chronic myeloid leukemia. Summary of the Invention

[0004] Purpose of the invention: The technical problem to be solved by the present invention is to provide a compound having a quinazolinone pyrrole dihydropyrrolidone structure, a preparation method thereof and medical use.

[0005] Technical solution: To solve the above technical problems, the present invention provides a compound having a quinazolinone pyrrole dihydropyrrolidone structure, or a pharmaceutically acceptable salt or solvate thereof, wherein the structure of the compound having a quinazolinone pyrrole dihydropyrrolidone structure is shown in formula (1):

[0006]

[0007] in:

[0008] X=C or N;

[0009] Linker is one of them:

[0010]

[0011] ZBG is one of them:

[0012]

[0013] Wherein, the structure of the compound having a quinazolinone pyrrole dihydropyrrolidone structure is as follows:

[0014]

[0015]

[0016] Among them, the compound with the quinazolinone pyrrole dihydropyrrolidone structure has active fragments of both PIM inhibitors and HDAC inhibitors, thus indicating that the molecules protected by the present invention can inhibit PIM / HDAC dual targets (for active fragments of PIM inhibitors and HDAC inhibitors, please refer to the articles: Liping H. Pettus, Kristin L. Discovery and Optimization of Quinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-Pim Kinase Inhibitors. Journal of Medicinal Chemistry 2016, DOI: 10.1021 / acs.jmedchem.6b006101. and Shanchao Wu. Yahui Huang. Evodiamine-Inspired Topoisomerase-Histone Deacetylase Dual Inhibitors: Novel Orally Active Antitumor Agents for Leukemia Therapy. Journal of Medicinal Chemistry2022, DOI:10.1021 / acs.jmedchem.1c02026.).

[0017] The present invention also provides a method for synthesizing the compound having the quinazolinone pyrrole dihydropyrrolidone structure, and the synthesis route is:

[0018] Where: X = C or N; Linker is one of the following:

[0019]

[0020] ZBG is one of them:

[0021]

[0022] The present invention also provides a composition containing the compound having a quinazolinone pyrrole dihydropyrrolidone structure or a pharmaceutically acceptable salt or solvate thereof.

[0023] The present invention also provides use of the compound having a quinazolinone pyrrole dihydropyrrolidone structure or a pharmaceutically acceptable salt, solvate or composition thereof in the preparation of a PIM / HDAC dual-target inhibitor.

[0024] The present invention also provides a PIM / HDAC dual-target inhibitor, which contains the compound having a quinazolinone pyrrole dihydropyrrolidone structure or a pharmaceutically acceptable salt, solvate or composition thereof.

[0025] The present invention also provides use of the compound having a pyrrolopyridine structure or a pharmaceutically acceptable salt, solvate or composition thereof in preparing a drug for treating and / or preventing leukemia or cancer.

[0026] Wherein, the leukemia includes acute myeloid leukemia or chronic myeloid leukemia.

[0027] Wherein, the cancer includes myelodysplastic syndrome, cervical cancer, breast cancer or colorectal cancer.

[0028] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: The present invention provides a novel quinazolinone pyrrole dihydropyrrolidone structure compound, and provides a method for synthesizing this series of compounds. Activity studies have shown that the quinazolinone pyrrole dihydropyrrolidone structure compound has excellent PIM and HDAC dual-target inhibitory activity. Those skilled in the art know that PIM and HDAC dual targets play an important role in the occurrence and development of various diseases, such as various tumor diseases, and inhibiting PIM / HDAC dual targets can treat or alleviate these diseases. Therefore, the quinazolinone pyrrole dihydropyrrolidone structure compound provided by the present invention has the prospect of being developed into a PIM / HDAC dual-target inhibitor drug and a drug for treating diseases that are treated or alleviated by inhibiting PIM / HDAC dual targets. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Figure 15i shows the anti-tumor efficacy of compound 15i in the MV4-11 xenograft tumor model, where (A) shows the growth curve of tumor volume in each group within 21 days of treatment, and (B) shows the changes in body weight of mice in each group within 21 days of treatment;

[0030] Figure 2 Tumor tissue images (A) and tumor weights (B) of each group of mice after treatment with compound 15i. DETAILED DESCRIPTION

[0031] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0032] Example 1: Synthesis of (R)-2-(butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (1i)

[0033] Synthesis route:

[0034]

[0035] Step 1: Synthesis of tert-butyl (R)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (2)

[0036] Round-bottom flask A: In an ice bath, dissolve mono-tert-butyl malonate (17.00 ml, 105.80 mmol) in anhydrous tetrahydrofuran (100 ml). Add anhydrous magnesium chloride (10.00 g, 105.80 mmol). Then, slowly add a solution of potassium tert-butoxide (1.0 mol / L, 105.80 ml, 105.80 mmol) in tetrahydrofuran (3:1 volume ratio of anhydrous tetrahydrofuran to water) dropwise via an addition funnel. The mixture becomes cloudy during the addition and is easily stirred. Remove the ice bath and stir the reaction at room temperature for 3 hours.

[0037] Round-bottom flask B: Under nitrogen protection, Boc-D-alanine (20.00 g, 105.80 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml). 1,1'-Carbonyldiimidazole (17.40 g, 105.80 mmol) was added in three batches. Gas evolution was observed and the mixture was stirred at room temperature for 3 hours.

[0038] The reaction solution in round-bottom flask B was slowly added dropwise to round-bottom flask A via an addition funnel. The resulting mixture gradually turned milky white. N,N-diisopropylethylamine (36.80 ml, 211.60 mmol) was then slowly added dropwise, and the reaction was stirred at room temperature for 39 hours. The resulting white suspension was cooled in an ice bath while 1N aqueous citric acid solution (500 ml) was added dropwise. Ethyl acetate (500 ml) was then added, and the mixture was transferred to a separatory funnel. The layers were separated, and the organic layer was washed sequentially with 1N aqueous citric acid solution (200 ml), saturated aqueous sodium bicarbonate solution (200 ml), and saturated aqueous sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (eluent system: petroleum ether:ethyl acetate = 10:1) to give tert-butyl (R)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (28.20 g, 98.26 mmol, 92.2% yield) as a light yellow oil. 1 HNMR(300MHz,Chloroform-d)δ5.21(d,J=7.1Hz,1H),4.41(q,J=7.3Hz,1H),3.51(d, J=7.4Hz,2H),1.51(d,J=0.6Hz,9H),1.49(s,9H),1.40(d,J=7.2Hz,3H); ESI-MS:m / z 287.1[M+H] + .

[0039] Step 2: Synthesis of tert-butyl (R)-2-(1-((tert-Butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate (3)

[0040] Tert-butyl (R)-4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (34.30 g, 119.00 mmol) was dissolved in a 2.0 M ammonia-methanol solution (597.00 ml, 1194.00 mmol), followed by the addition of ammonium acetate (92.00 g, 1194.00 mmol). Chloroacetaldehyde solution (50% in water, 154.00 ml, 1194.00 mmol) was added dropwise to the resulting mixture, and the mixture was stirred at 50°C. After 40 minutes, the reaction mixture turned dark brown. The reaction was heated for an additional 100 minutes, and the reaction was complete as monitored by TLC. The reaction mixture was concentrated in vacuo, and saturated sodium bicarbonate solution (500 ml) was added. When gas evolution ceased, the mixture was transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (3×250 ml), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The resulting brown oil was separated and purified by column chromatography to give (R)-2-(1-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid tert-butyl ester (23.40 g, 75.00 mmol, 63.4% yield) as a white solid.1 H NMR (300MHz, DMSO-d6) δ10.93(s,1H),6.95(d,J=8.8Hz,1H),6.62(t,J=2.7Hz,1H),6.26(t,J =2.7Hz,1H),5.34-5.22(m,1H),1.48(s,9H),1.37(s,9H),1.27(d,J=6.9Hz,3H).ESI-MS:m / z 310.1[M+H] + .

[0041] Step 3: Synthesis of tert-butyl (R)-2-(1-((tert-butoxycarbonyl)amino)ethyl)-1-toluenesulfonyl-1H-pyrrole-3-carboxylate (4)

[0042] At 0°C, tert-butyl (R)-2-(1-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate (20.00 g, 64.60 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml). A solution of potassium tert-butoxide (1.0 mol / l, 33.90 ml, 67.80 mmol) in tetrahydrofuran (3:1 volume ratio of anhydrous tetrahydrofuran to water) was slowly added dropwise via an addition funnel. The dark brown mixture was stirred for 30 minutes, and then a solution of p-toluenesulfonyl chloride (12.90 g, 67.90 mmol) in tetrahydrofuran (50 ml, 3:1 volume ratio of anhydrous tetrahydrofuran to water) was slowly added dropwise via an addition funnel. The reaction was stirred for 1 hour, and the reaction was monitored for completion by TLC. The reaction mixture was separated using water (30 ml), ethyl acetate (100 ml), and saturated aqueous sodium bicarbonate solution (30 ml). The organic layer was washed with saturated aqueous sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The mixture was separated and purified by column chromatography (eluent system: petroleum ether:ethyl acetate = 10:1) to give (R)-tert-butyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-1-toluenesulfonyl-1H-pyrrole-3-carboxylate (21.00 g, 45.20 mmol, yield 70.3%) as an off-white solid. 1 H NMR(300MHz,Chloroform-d)δ7.95(dd,J=11.6,8.2Hz,2H),7.34(s,1H),7.32(s,1H),7.26(d,J=3.5Hz,1H),6.88(d ,J=10.1Hz,1H),6.58(d,J=3.5Hz,1H),5.91-5.78(m,1H),2.43(s,3H),1.43(s,9H),1.41-1.25(m,12H).ESI-MS:m / z 464.2[M+H] + .

[0043] Step 4: Synthesis of (R)-2-(1-aminoethyl)-1-toluenesulfonyl-1H-pyrrole-3-carboxylic acid (5)

[0044] (R)-tert-Butyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-1-toluenesulfonyl-1H-pyrrole-3-carboxylate (25.10 g, 54.00 mmol) was dissolved in dichloromethane (120 ml). Trifluoroacetic acid (120 ml) was slowly added dropwise in portions. The brown mixture was stirred for 5 minutes. Then, a reflux condenser and drying tube were installed and the mixture was stirred in a preheated 50°C oil bath under nitrogen for 3 hours. The reaction was monitored by TLC. The reaction mixture was cooled and concentrated in vacuo. Dichloromethane (20 ml) was added for slurrying. The mixture was filtered and dried to obtain a crude brown solid (R)-2-(1-aminoethyl)-1-toluenesulfonyl-1H-pyrrole-3-carboxylic acid (14.90 g, 48.60 mmol, 90.1% yield). The crude product was used directly in the next reaction. ESI-MS: m / z 308.1 [M+H] + .

[0045] Step 5: Synthesis of (R)-6-methyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (6)

[0046] At 0°C, (R)-2-(1-aminoethyl)-1-toluenesulfonyl-1H-pyrrole-3-carboxylic acid (22.80 g, 74.12 mmol) was dissolved in anhydrous dimethylformamide (150 ml), and N,N-diisopropylethylamine (28.20 ml, 162.00 mmol) was slowly added dropwise. Ten minutes later, a solution of 1-propanephosphonic acid cyclic anhydride (T3P) (Adamas, ≥50 wt.% in ethyl acetate, 35.00 ml, 59.50 mmol) was added. After ten minutes, the mixture was warmed to room temperature and stirred for reaction. After 4 hours, the reaction mixture turned dark brown and was treated with saturated aqueous sodium bicarbonate solution (400 ml) and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (3×250 ml). The organic layers were combined and washed sequentially with saturated aqueous sodium bicarbonate solution (50 ml) and saturated aqueous sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The mixture was separated and purified by column chromatography (eluent system: dichloromethane:methanol=50:1) to obtain a brown oily product (R)-6-methyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (16.50 g, 56.80 mmol, yield 76.5%). 1H NMR(300MHz,DMSO-d6)δ8.20(s,1H),7.97-7.92(m,2H),7.53-7.51(m,1H),7.48(q,J=3.3,2.6Hz, 2H),6.48(d,J=3.3Hz,1H),4.70(q,J=6.6Hz,1H),2.42(s,3H),1.48(d,J=6.6Hz,3H).ESI-MS:m / z 290.1[M+H] + .

[0047] Step 6: Synthesis of (R)-6-methyl-4-oxo-1-toluenesulfonyl-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (7)

[0048] (R)-6-Methyl-1-tosyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (19.60 g, 67.35 mmol) was dissolved in tetrahydrofuran (150 ml), and di-tert-butyl dicarbonate (57.50 ml, 269.40 ml) was slowly added dropwise, followed by addition of 4-dimethylaminopyridine (0.80 g, 6.73 mmol). The system was stirred at room temperature for 4 hours, and the reaction was completed after monitoring by TLC. The product was treated with saturated aqueous sodium chloride solution (200 ml) and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (3×250 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The product was separated and purified by column chromatography (eluent system: petroleum ether: ethyl acetate = 10:1) to give a yellow solid (R)-6-methyl-4-oxo-1-tosyl-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (23.60 g, 60.62 mmol, yield 90.2%). 1 H NMR(300MHz,Chloroform-d)δ7.81-7.74(m,2H),7.42-7.34(m,2H),7.16(d,J=3.3Hz,1H),6.50(d ,J=3.2Hz,1H),5.05(q,J=6.3Hz,1H),2.46(s,3H),1.75(d,J=6.3Hz,3H),1.59(s,9H).ESI-MS:m / z 390.1[M+H] + .

[0049] Step 7: Synthesis of (R)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (8)

[0050] At 0°C, (R)-6-methyl-4-oxo-1-tosyl-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (23.60 g, 60.62 mmol) was dissolved in anhydrous tetrahydrofuran (200 ml). A tetrahydrofuran solution containing tetrabutylammonium fluoride (Adamas, 1.0 mol / l, 181.80 ml, 181.86 mmol) (the volume ratio of anhydrous tetrahydrofuran to water was 3:1) was slowly added dropwise in batches through an addition funnel. The system was stirred for 4 hours and the reaction was completed after monitoring by TLC. It was treated with saturated aqueous sodium chloride solution (400 ml) and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate (3×250 ml), combined, and the organic layer was concentrated. The resulting product was slurried with methanol, and a white solid precipitated. It was filtered to obtain a white solid (R)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (12.90 g, 54.56 mmol, yield 90.2%). 1 H NMR (300MHz, DMSO-d6) δ11.67(s,,1H),7.01(d,J=2.9Hz,1H),6.23(d,J=2.8Hz,1H ),4.93(q,J=6.4Hz,1H),1.53(s,1H),1.51(d,J=2.9Hz,9H).HRMS(ESI):calcd.For C 12 H 16 N2O3[M+Na] + 259.1123found 259.1109[M+H] + .

[0051] Step 8: Synthesis of (R)-6-methyl-4-oxo-2-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (9)

[0052] Dissolve bis(pinacol)diboronate (9.80 g, 38.98 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (Leyan, 0.40 g, 0.58 mmol), and 3,4,7,8-tetramethyl-1,10-phenanthroline (0.30 g, 1.16 mmol) in anhydrous tetrahydrofuran (50 ml) and transfer to a sealed tube. Compound 8 (4.60 g, 19.49 mmol) was then added. The tube was partially sealed and the atmosphere was replaced with argon for 5 minutes before tightening. The sealed tube was placed in a 65°C oil bath and stirred for 3 hours. The reaction was monitored by TLC. The mixture was transferred to a separatory funnel with water (30 ml), and the aqueous layer was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give (R)-6-methyl-4-oxo-2-(4,4,5,5-tetramethyl-1,3,2-dioxolane-2-yl)-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (4.90 g, 13.64 mmol, 70.2% yield) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ11.72(s,1H),7.69(s,1H),6.53(d,J=1.7Hz,1H),4.42(d,J=6.9Hz,1H),1.34(s,3H),1.19(s,12H).ESI-MS: m / z 362.2[M+H] + .

[0053] Step 9: Synthesis of 2-amino-3-bromo-N-(1-methylcyclopropyl)benzamide (11)

[0054]

[0055] At 0 ° C, 2-amino-3-bromobenzoic acid (8.00g, 37.04mmol) was dissolved in anhydrous dimethylformamide (80mL), and then N, N-diisopropylethylamine (19.30ml, 111.11mmol) was added dropwise and stirred for 10 minutes; then O-(7-azabenzotriazole-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (14.10g, 44.45mmol) was added and stirred for 10 minutes. Finally, cyclopropylamine hydrochloride solid (3.90g, 37.04mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 3 hours. The reaction was monitored by TLC. Saturated sodium bicarbonate solution was added and the mixture was stirred for 5 minutes. The layers were separated, the aqueous layer was extracted with ethyl acetate (3×80 ml), and the combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution (50 ml), saturated aqueous ammonium chloride solution (50 ml), and saturated aqueous sodium chloride solution (50 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The product was separated and purified by column chromatography (eluent system: dichloromethane:methanol=50:1) to give 2-amino-3-bromo-N-(1-methylcyclopropyl)benzamide (6.30 g, 23.50 mmol, yield 64.6%) as a white solid. 1 H NMR(300MHz,Chloroform-d)δ7.54(dd,J=7.8,1.4Hz,1H),7.25(dd,J=7.8,1.4Hz,1H),6.55(t,J=7.8Hz ,1H),6.42(s,1H),4.91(s,2H),1.51(s,3H),0.88(q,J=6.1,5.1Hz,2H),0.83-0.76(m,2H).ESI-MS:m / z 268.0[M+H] + .

[0056] Step 10: Synthesis of 8-bromo-3-(1-methylcyclopropyl)quinazoline-2,4(1H,3H)-dione (12)

[0057] 2-Amino-3-bromo-N-(1-methylcyclopropyl)benzamide 11 (4.00 g, 14.93 mmol) was dissolved in dichloromethane (50 ml), followed by the addition of bis(trichloromethyl) carbonate (2.20 g, 7.46 mmol) in portions. The reaction was stirred at 40°C for 12 hours, and completion was monitored by TLC. The resulting turbid reaction mixture was cooled and concentrated, and then purified by column chromatography (eluent: petroleum ether:ethyl acetate = 10:1) to afford 8-bromo-3-(1-methylcyclopropyl)quinazoline-2,4(1H,3H)-dione (3.90 g, 13.44 mmol, 90.5% yield) as a pale yellow solid. 1H NMR(300MHz,Chloroform-d)δ8.12(dd,J=7.9,1.3Hz,2H),7.81(dd,J=7.8,1.3Hz,1H),7.13(t, J=7.9Hz,1H),1.54(s,3H),1.08(d,J=3.4Hz,2H),1.04(d,J=3.5Hz,2H).ESI-MS:m / z294.0[M+H] + .

[0058] Step 11: Synthesis of 8-bromo-2-chloro-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (13)

[0059] A mixture of 8-bromo-3-(1-methylcyclopropyl)quinazoline-2,4(1H,3H)-dione (5.00 g, 17.01 mmol), phosphorus oxychloride (15.80 ml, 170.1 mmol), and N,N-diisopropylethylamine (11.80 ml, 68.04 mmol) was stirred and refluxed at 110°C for 12 hours. The reaction was monitored by TLC to confirm completion. The reaction was then cooled and concentrated, and the brown mixture was cooled in an ice bath. An ice-water mixture (50 ml) was then slowly poured into the mixture, followed by a 10 M aqueous sodium hydroxide solution (50 ml) that was slowly added dropwise to the mixture and stirred for 20 minutes. The mixture was filtered, and the brown solid was washed with water, then dissolved in dichloromethane and filtered again. The filtrate was dried over anhydrous sodium sulfate, filtered and concentrated. The product was separated and purified by column chromatography (eluent system: petroleum ether: ethyl acetate = 10:1) to give a brown solid 8-bromo-2-chloro-3-(1-methylcyclopropyl)quinazolin-4(3H)-one 13 (4.50 g, 14.46 mmol, yield 85.2%). 1 H NMR(300MHz,Chloroform-d)δ8.22(dd,J=7.9,1.5Hz,1H),8.04(dd,J=7.8,1.5Hz,1H),7.37(t,J=7.9Hz,1H),1.66(s,3H),1.26-1.17(m,4H).HRMS(ESI):calcd.For C 12 H 10 ClBrN2O[M+H] + 312.9813found 312.9800.

[0060] Step 12: Synthesis of 8-bromo-2-(butylamino)-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (14)

[0061] General Synthesis Method 1: Dissolve 8-bromo-2-chloro-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (0.46 g, 1.48 mmol) and liquid n-butylamine (0.26 g, 4.43 mmol) in dimethyl sulfoxide (30 ml), transfer the mixture to a sealed tube, and then add N,N-diisopropylethylamine (0.40 ml, 4.44 mmol) dropwise. The mixture is stirred in a 90°C oil bath for 12 hours. Completion of the reaction is monitored by TLC. The mixture is transferred to a separatory funnel with water (30 ml), and the aqueous layer is extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with a saturated aqueous sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by column chromatography (eluent system: dichloromethane: methanol = 50:1) to give 8-bromo-2-(butylamino)-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (0.40 g, 1.18 mmol, 80.2% yield). 1 H NMR(300MHz,Chloroform-d)δ8.07(dd,J=7.9,1.5Hz,1H),7.87(dd,J=7.7,1.5Hz,1H),7.00(t,J=7.8Hz,1H),5.52(s,1H),3.70 (tt,J=7.1,5.3Hz,2H),1.84-1.74(m,2H),1.57(s,3H),1.55-1.47(m,2H),1.39-1.25(m,5H),1.06(t,J=7.3Hz,4H).ESI-MS:m / z 350.3[M+H] + .

[0062] Step 13: Synthesis of (R)-2-(2-(butylamino)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (15)

[0063] General Synthesis Method 2: Dissolve Intermediate 14 (0.26 g, 0.78 mmol) in 40 ml of tetrahydrofuran (anhydrous tetrahydrofuran:water, 3:1 volume ratio) and transfer to a sealed tube. Potassium phosphate (0.33 g, 1.56 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (Leyan, 0.03 g, 0.04 mmol) were then added. Finally, Intermediate 9 (0.37 g, 0.93 mmol) was added. The tube was partially sealed and the atmosphere was replaced with argon for 5 minutes before being tightened. The sealed tube was placed in an 80°C oil bath and stirred for 12 hours. Completion of the reaction was monitored by TLC. The mixture was transferred to a separatory funnel with water (30 ml). The aqueous layer was extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and separated and purified by column chromatography (eluent system: dichloromethane:methanol=50:1) to give (R)-2-(2-(butylamino)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (0.28 g, 0.55 mmol, yield 70.2%). 1 H NMR (300MHz, DMSO-d6) δ12.25(s,1H),7.99-7.93(m,1H),7.82-7.77(m,1H),7.67(s,1H),7.17(m,1H),6.72(s,1H),4.57(d,J=13.1Hz ,1H),3.66-3.44(m,2H),1.62-1.51(m,5H),1.43(s,9H),1.32(m,2H),1.24(s,3H),0.88(m,3H),0.75(m,4H).ESI-MS:m / z506.3[M+H] + .

[0064] Step 14: Synthesis of (R)-2-(butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (1i)

[0065] General Synthesis Method 3: Intermediate 15 (0.22 g, 0.44 mmol) was dissolved in dichloromethane (20 ml). Trifluoroacetic acid (20 ml) was slowly added dropwise in portions. The mixture was stirred at room temperature for 3 hours. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated in vacuo and purified by column chromatography (eluent: dichloromethane:methanol = 50:1) to afford (R)-2-(butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (0.15 g, 0.36 mmol, 81.8%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ12.25(d,J=8.4Hz,1H),7.99-7.93(m,1H),7.82-7 .77(m,1H),7.67(s,1H),7.17-7.05(m,2H),6.92(t,J=1.6Hz,1H),4.57(d, J=13.1Hz,1H),3.66-3.44(m,2H),1.74(d,J=7.3Hz,2H),1.48(s,3H),1.41-1.36(m,3H),1.08(ddd,J=54.3,10.8,7.0Hz,9H).HRMS(ESI):calcd.ForC 23 H 27 N5O2[M+H] + 406.2243found 406.2237.

[0066] Example 2 Synthesis of (R)-N-hydroxy-5-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-5-oxopentanamide (2i)

[0067] Step 1: Synthesis of tert-butyl 4-((8-bromo-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidine-1-carboxylate (38b)

[0068]

[0069] The general synthetic method 1 in Example 1 was adopted, 8-bromo-2-chloro-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (0.46 g, 1.48 mmol) was used as the reaction substrate, tert-butyl 4-aminopiperidine-1-carboxylate (0.26 g, 1.3 mmol) was used instead of n-butylamine, and other raw materials and amounts remained unchanged to obtain tert-butyl 4-((8-bromo-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidine-1-carboxylate (2.08 g, 4.25 mmol, yield: 68.4%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ7.86(s,1H),7.83(s,1H),6.96(d,J=7.8Hz,1H),6.38(d,J=7.5Hz,1H),4.39-4.16(m,1H),3.99(d, J=13.3Hz,2H),2.84(s,2H),1.93(d,J=12.3Hz,2H),1.68(m,3H),1.41(m,11H),1.13(m,2H),1.01-0.81(m,2H).ESI-MS:m / z 477.1[M+H] + .

[0070] Step 2: Synthesis of (R)-2-(2-((1-(tert-Butyloxycarbonyl)piperidin-4-yl)amino)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (39b)

[0071]

[0072] The general synthetic method 2 in Example 1 was adopted, tert-butyl 4-((8-bromo-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidine-1-carboxylate (0.26 g, 0.55 mmol) was used as the reaction substrate, and other raw materials and amounts remained unchanged to obtain (R)-2-(2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.44 g, 2.28 mmol, yield: 54.3%) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 12.15 (s, 1H), 7.98 (m, 1H), 7.85 (m, 1H), 7.72 (s, 1H), 7.17 (m, 1H), 6.68 (s, 1H), 4.87 (m, 1H), 4.64 (m, 2H), 3.75 (m, 1H), 3.20 (m, 2H), 2.36-2.23 (m, 2H), 2.18 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H), 1.45 (s, 18H), 1.26 (s, 3H), 0.80-0.66 (m, 4H). ESI-MS: m / z 633.3 [M+H] + .

[0073] Step 3: Synthesis of (R)-8-(6-methyl-4-oxo-l,4,5,6-tetrahydropyrrolo[3,4- b]pyrrol-2-yl)-3-(l-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)- one (40b)

[0074]

[0075] Using the general synthesis method 3 in Example 1, (R)-2-(2-((l-(tert- butoxycarbonyl)piperidin-4-yl)amino)-3-(l-methylcyclopropyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(lH)- carboxylate tert-butyl ester (0.22 g, 0.35 mmol) as the reaction substrate, other raw materials and amounts were the same, white solid (R)-8-(6-methyl-4-oxo-l,4,5,6- tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(l-methylcyclopropyl)-2-(piperidin-4- ylamino)quinazolin-4(3H)-one (1.38 g, 2.13 mmol, yield: 82.1%) was obtained. 1 H NMR (300 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.81 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.18 (m, 1H), 6.99 (d, J = 3.7 Hz, 1H), 6.47 (m, 1H), 4.57 (m, 1H), 4.29 (s, 1H), 3.45 (d, J = 12.6 Hz, 2H), 3.01 (s, 2H), 2.21 (s, 2H), 1.98 (s, 2H), 1.50 (s, 3H), 1.41 (m, 3H), 1.17 (m, 2H), 0.99 (s, 2H). ESI-MS: m / z 433.3 [M+H] +.

[0076] Step 4: Synthesis of (R)-N-hydroxy-5-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-5-oxopentanamide (2i)

[0077]

[0078] Synthetic General Procedure 4: A 50 mL round bottom flask was charged with 5-methoxy-5-oxopentanoic acid (Larmer, 0.15 g, 1.03 mmol), 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (Larmer, 0.58 g, 1.55 mmol), N,N- diisopropylethylamine (0.19 g, 1.55 mol) and DMF (5 mL). The solution was stirred at room temperature for 0.5 h, then compound 40b (0.45 g, 1.03 mmol) was added. The mixture was stirred at room temperature for 4 h until TLC showed the reaction was complete. The mixture was quenched with cold water (50 mL), extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (eluent system: dichloromethane:methanol = 20:1) gave (R)-methyl 5-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1- methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-5-oxopentanoate as a white solid (yield: 54%). Then potassium hydroxide (11.2 g, 200 mmol) was dissolved in anhydrous methanol (30 mL) and hydroxylamine hydrochloride (9.34 g, 134.4 mmol) in methanol (10 mL) was added at 0 °C. The mixture was stirred for 1 h and the precipitate was filtered off. The filtrate was collected to obtain a fresh hydroxylamine solution for further reaction. (R)-methyl 5-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1- methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-5-oxopentanoate (0.15 g, 0.26 mmol) was dissolved in the above fresh hydroxylamine solution and stirred at room temperature for 1 h. The reaction was monitored by TLC and the mixture was neutralized with appropriate amount of HCl, the precipitate was collected, washed with water and dried under vacuum to give compound (R)-N-hydroxy-5-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1- methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-5-oxopentanamide as a white solid (yield: 25.6%). 1H NMR(300MHz,DMSO-d6)δ11.94(m,1H),10.40(s,1H),7.94-7.90(m,1H),7.83-7.79(m,1H) ,7.64(s,1H),7.14(m,1H),6.98(d,J=4.2Hz,1H),6.36(s,1H),4.56(m,1H),4.14(s,1H),3 .17(s,2H),2.66(s,2H),2.09(s,1H),1.98(m,4H),1.55(d,J=7.5Hz,2H),1.48(s,3H),1. 41(d,J=6.5Hz,3H),1.25(m,4H),1.18-1.08(m,2H),0.98(m,2H).HRMS(ESI,positive)m / z Calcd.for C 29 H 35 N7O5[M+H] + :562.2700; Found 562.30980.

[0079] Example 3 Synthesis of (R)-N-hydroxy-6-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-6-oxohexanamide (3i)

[0080]

[0081] The general synthetic method 4 in Example 2 was used, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. 6-methoxy-6-oxohexanoic acid (Leyan, 0.15 g, 0.94 mmol) was used as the reaction substrate. l) instead of 5-methoxy-5-oxopentanoic acid, with other raw materials and amounts remaining unchanged, to obtain a white solid (R)-N-hydroxy-6-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-6-oxohexanamide (yield: 23.1%). 1H NMR(300MHz,DMSO-d6)δ11.93(s,1H),10.42(s,1H),8.73(s,1H),7.96-7.91(m,1H),7.8 1(d,J=7.7Hz,1H),7.67(s,1H),7.15(m,1H),6.99(s,1H),6.39(s,1H),4.57(m,1H),4.15 (s,1H),3.12(s,2H),2.10(s,2H),1.99(m,4H),1.66-1.52(m,4H),1.49(s,3H),1.42(d,J =6.5Hz,3H),1.30-1.23(m,4H),1.19-1.11(s,2H),0.99(s,2H).HRMS(ESI,positive)m / z Calcd.for C 30 H 37 N7O5[M+H] + :576.2856; Found 576.29115.

[0082] Example 4 Synthesis of (R)-N-hydroxy-7-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-7-oxoheptamide (4i)

[0083]

[0084] The general synthetic method 4 in Example 2 was used, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. 7-methoxy-7-oxoheptanoic acid (Leyan, 0.15 g, 0.86 mmol) was used as the reaction substrate. l) instead of 5-methoxy-5-oxopentanoic acid, with other raw materials and amounts remaining unchanged, to obtain a white solid (R)-N-hydroxy-7-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-7-oxoheptamide (yield: 26.8%). 1H NMR (300MHz, DMSO-d6) δ11.94(m,1H),10.37(s,1H),8.69(s,1H),7.93(s,1H),7.82(d,J=7.8Hz,1H),7.65 (s,1H),7.15(s,1H),6.97(d,J=7.3Hz,1H),6.33(s,1H),4.57(m,1H),4.47(s,1H),4.31(s,1H),4.04(s,1H ),3.17(m,1H),2.94(m,1H),2.71(s,1H),2.36(s,1H),1.97(s,1H),1.69(s,1H),1.53(s,2H),1.48(s,3H) ,1.41(d,J=6.4Hz,3H),1.32(s,2H),1.25-1.28(m,2H),1.19(m,4H),0.99(m,4H).HRMS(ESI,positive)m / z Calcd.for C 31 H 39 N7O5[M+H] + :590.3013;Found590.3097.

[0085] Example 5 Synthesis of (R)-N-hydroxy-8-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-8-oxooctamide (5i)

[0086]

[0087] The general synthetic method 4 in Example 2 was used, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. 8-methoxy-8-oxooctanoic acid (Leyan, 0.15 g, 0.79 mmol) was used as the reaction substrate. l) instead of 5-methoxy-5-oxopentanoic acid, with other raw materials and amounts remaining unchanged, to obtain a white solid (R)-N-hydroxy-8-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-8-oxooctamide (yield: 28.3%). 1H NMR(300MHz,DMSO-d6)δ11.92(m,1H),10.35(s,1H),8.67(s,1H),7.92(s,1H),7.84-7.78(m,1H),7.64(s,1 H),7.15(m,1H),6.96(d,J=7.5Hz,1H),6.33(d,J=7.5Hz,1H),4.57(d,J=6.7Hz,1H),4.45(s,1H),4.30(s,1 H),3.98(d,J=13.9Hz,1H),3.14(m,1H),2.70(s,1H),2.35(s,2H),2.00(s,1H),1.95(d,J=7.4Hz,2H),1.72 (m,2H),1.47(s,6H),1.40(d,J=6.5Hz,3H),1.29(m,6H),1.19(m,2H),0.98(m,2H).HRMS(ESI,positive)m / z Calcd.for C 32 H 41 N7O5[M+H] + :604.3169;Found604.3250.

[0088] Example 6 Synthesis of (R)-N-hydroxy-9-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-9-oxononanamide (6i)

[0089]

[0090] The general synthetic method 4 in Example 2 was used, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. 9-methoxy-9-nonenoic acid (Leyan, 0.15 g, 0.74 mmol) was used as the reaction substrate. ) instead of 5-methoxy-5-oxopentanoic acid, and other raw materials and amounts remained unchanged to obtain a white solid (R)-N-hydroxy-9-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-9-oxononanamide (yield: 31.2%). 1H NMR (300MHz, DMSO-d6) δ11.92(m,1H),10.35(s,1H),8.67(s,1H),7.91(d,J=7.1Hz,1H),7.81(d,J=7.8Hz,1H ),7.64(s,1H),7.15(m,1H),6.96(m,1H),6.33(d,J=7.6Hz,1H),4.57(m,1H),4.44(s,1H),4.30(s,1H),3.98( d,J=13.4Hz,1H),3.14(m,1H),2.71(m,1H),2.34(d,J=7.5Hz,2H),2.17-1.84(m,6H),1.72(m,2H),1.55(m,2 H),1.47(s,3H),1.40(d,J=6.6Hz,3H),1.28(m,6H),1.15-1.21(m,2H),0.98(m,2H).HRMS(ESI,positive)m / z Calcd.for C 33 H 43 N7O5[M+H] + :618.3326;Found618.3400.

[0091] Example 7 Synthesis of (R)-N-hydroxy-10-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-10-oxodecaamide (7i)

[0092]

[0093] The general synthetic method 4 in Example 2 was used, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. 10-methoxy-10-oxodecanoic acid (Leyan, 0.15 g, 0.69 mmol) was used as the reaction substrate. l) instead of 5-methoxy-5-oxopentanoic acid, with other raw materials and amounts remaining unchanged, to obtain a white solid (R)-N-hydroxy-10-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-10-oxodecaamide (yield: 34.7%). 1H NMR (300MHz, DMSO-d6) δ11.90(m,1H),10.34(s,1H),8.67(s,1H),7.90(d,J=7.2Hz,1H),7.82-7.78(m,1H) ,7.66-7.64(m,1H),7.14(s,1H),6.95(d,J=7.2Hz,1H),6.32(s,1H),4.55(d,J=6.9Hz,1H),4.43(s,1H),4. 29(s,1H),3.97(d,J=13.6Hz,1H),3.13(m,1H),2.67(d,J=12.1Hz,2H),2.34(s,2H),2.02(s,2H),1.93(s,2 H),1.66(m,2H),1.46(m,6H),1.40(s,3H),1.26(m,8H),1.17(m,2H).0.97(m,2H).HRMS(ESI,positive)m / z Calcd.for C 34 H 45 N7O5[M+H] + :632.3482; found632.3562.

[0094] Example 8 Synthesis of (R)-N-hydroxy-4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidine-1-carbonyl)benzamide (8i)

[0095]

[0096] The general synthetic method 4 in Example 2 was adopted, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. 4-(Methoxycarbonyl)benzoic acid (Leyan, 0.15 g, 0.83 mmole) was used as the reaction mixture. The reaction mixture was reacted with 5-methoxy-5-oxopentanoic acid and the other raw materials and amounts remained unchanged to obtain (R)-N-hydroxy-4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidine-1-carbonyl)benzamide as a white solid (yield: 32.6%). 1H NMR(300MHz,DMSO-d6)δ11.91(m,1H),11.35(s,1H),9.15(s,1H),7.92(s,1H),7.85(d, J=8.7Hz,2H),7.66(s,1H),7.53(d,J=7.8Hz,2H),7.18(s,2H),6.97(d,J=7.2Hz,1H),6. 39(m,1H),4.58(s,2H),4.37(s,1H),3.66(s,1H),2.98(s,2H),2.16(s,2H),1.81(s,2H) ,1.49(s,3H),1.41(d,J=6.5Hz,3H),1.20(s,2H),1.00(s,2H).HRMS(ESI,positive)m / z Calcd.for C 32 H 33 N7O5[M+H] + :596.2556; found596.26293.

[0097] Example 9 Synthesis of ((R,E)-N-hydroxy-3-(4-((8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide (9i)

[0098]

[0099] The general synthetic method 4 in Example 2 was adopted, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate, and (E)-4-(3-methoxy-3-oxoprop-1-en-1-yl)benzoic acid (Leyan, 0.15 g, 0.73 mmol) was added to replace 5-methoxy-5-oxopentanoic acid, and other raw materials and amounts remained unchanged to obtain a white solid ((R,E)-N-hydroxy-3-(4-((8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide (yield: 21.5%). 1HNMR (300MHz, DMSO-d6) δ11.89(m,1H),10.83(s,1H),9.09(s,1H),7.91(d,J=6.3Hz,1H),7.80(d,J=7.9Hz ,1H),7.66(d,J=8.4Hz,4H),7.48(d,J=7.2Hz,2H),7.14(m,1H),6.95(d,J=7.4Hz,1H),6.53(d,J=15.8Hz,1 H),6.33(d,J=7.7Hz,1H),4.56(d,J=7.7Hz,2H),4.35(s,1H),3.70(s,1H),3.21(s,1H),2.96(s,1H),2.05( m,2H),1.80(s,2H),1.48(s,3H),1.40(d,J=6.5Hz,3H),1.23(m,2H),0.99(m,2H).HRMS(ESI,positive)m / z Calcd.forC 34 H 35 N7O5[M+H] + :622.2712; found 622.2785.

[0100] Example 10 Synthesis of (R)-N-hydroxy-4-(2-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-2-oxoethyl)benzamide (10i)

[0101]

[0102] The general synthetic method 4 in Example 2 was used, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. 2-(4-(methoxycarbonyl)phenyl)acetic acid (Leyan, 0.15 g, 0.77 mmol) was used as the reaction substrate. ) was used instead of 5-methoxy-5-oxopentanoic acid, and other raw materials and amounts remained unchanged to obtain a white solid (R)-N-hydroxy-4-(2-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-2-oxoethyl)benzamide (yield: 26.3%). 1H NMR (300MHz, DMSO-d6) δ11.90(m,1H),11.19(s,1H),9.02(s,1H),7.92-7.88(m,1H),7.80(m,1H),7.71(d,J=7.8Hz,2H),7 .63(s,1H),7.33(d,J=8.1Hz,2H),7.14(s,1H),6.96-6.93(m,1H),6.32(d,J=7.4Hz,1H),4.54(d,J=6.7Hz,1H),4.44(d,J= 13.0Hz,1H),4.29(s,1H),4.10(d,J=13.7Hz,1H),3.83(d,J=6.6Hz,2H),3.16(t,J=12.4Hz,1H),2.78(d,J=12.2Hz,1H),2. 06-1.99(m,2H),1.73-1.57(m,2H),1.45(s,3H),1.38(d,J=6.6Hz,3H),1.17(m,2H),0.96(m,2H).HRMS(ESI,positive)m / z Calcd.for C 33 H 35 N7O5[M+H] + :610.2700;found610.2773.

[0103] Example 11 Synthesis of (R,E)-N-hydroxy-3-(4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-2-oxoethyl)phenyl)acrylamide (11i)

[0104]

[0105] The general synthetic method 4 in Example 2 was adopted, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate, and (E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acetic acid (Leyan, 0.15 g, 0 0.68mmol) was used instead of 5-methoxy-5-oxopentanoic acid, and other raw materials and amounts remained unchanged to obtain a white solid (R,E)-N-hydroxy-3-(4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-2-oxoethyl)phenyl)acrylamide (yield: 31.5%). 1 H NMR (300MHz, DMSO-d6) δ11.88(m,1H),7.90(m,1H),7.80(m,1H),7.65(d,J=3.4Hz,1H),7.52(d,J=7.8Hz,2H),7.44(d,J=15.7Hz ,1H),7.30(d,J=7.9Hz,2H),7.14(t,J=7.7Hz,1H),6.94(d,J=6.6Hz,1H),6.45(d,J=15.8Hz,1H),6.36-6.25(m,1H),4.55(d,J=6 .7Hz,1H),4.45(d,J=12.6Hz,1H),4.29(s,1H),4.10(d,J=13.5Hz,1H),3.79(s,2H),3.16(s,1H),2.78(d,J=16.1Hz,1H),2.01(m ,2H),1.81-1.55(m,2H),1.45(d,J=2.6Hz,3H),1.38(s,3H),1.16(m,2H),1.03-0.88(m,2H).HRMS(ESI,positive)m / zCalcd.for C 35 H 37 N7O5[M+H] + :636.2856; found 636.2933.

[0106] Example 12 Synthesis of (R)-N-hydroxy-4-(2-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)amino)-2-oxoethyl)benzamide (12i)

[0107] Step 1: Synthesis of tert-butyl (4-((8-bromo-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (41b)

[0108]

[0109] The general synthetic method 1 in Example 1 was adopted, with 8-bromo-2-chloro-3-(1-methylcyclopropyl)quinazolin-4(3H)-one (0.46 g, 1.48 mmol) as the reaction substrate and tert-butyl (4-aminocyclohexyl)carbamate (0.26 g, 1.21 mmol) instead of n-butylamine. Other raw materials and amounts remained unchanged to give tert-butyl 4-((8-bromo-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (2.47 g, 5.05 mmol, yield: 78.6%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ7.87(s,1H),6.96(d,J=7.7Hz,1H),6.76(d,J=8.1Hz,1H),6.28(s,1H),4.15(m,1H),3.41(m,1H),2.06(m,2H),1. 87(d,J=11.4Hz,2H),1.68–1.56(m,2H),1.47(s,1H),1.43(s,3H),1.39(s,9H),1.30(m,2H),1.22–1.09(m,2H),0.93(m,2H).ESI-MS:m / z 491.2[M+H] + .

[0110] Step 2: Synthesis of (R)-tert-butyl 2-(2-((4-(tert-Butyloxycarbonyl)amino)cyclohexyl)amino)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (42b)

[0111]

[0112] The general synthetic method 2 in Example 1 was adopted, and tert-butyl (4-((8-bromo-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)carbamate (0.26 g, 0.53 mmol) was used as the reaction substrate. Other raw materials and amounts were the same to obtain tert-butyl (R)-2-(2-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.38 g, 2.13 mmol, yield: 52.3%) as a brown solid. 1 H NMR (300MHz, DMSO-d6) δ12.23(s,1H),8.08(m,1H),7.95(m,1H),7.76(s,1H),7.37(m,1H),6.58(s,1H),4.75(d,J=13.1Hz,1H),4.64(m,1H),4.34 (m,1H),4.11(m,1H),2.63(m,2H),2.15(s,2H),1.86(m,3H),1.69(m,1H) ,1.52(s,3H),1.48(s,18H),1.24(s,3H),0.91-0.78(m,4H).ESI-MS:m / z 647.3[M+H] + .

[0113] Step 3: Synthesis of (R)-2-((4-aminocyclohexyl)amino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)quinazolin-4(3H)-one ester (43b)

[0114]

[0115] The general synthetic method 3 in Example 1 was used, and (R)-2-(2-((4-((tert-butyloxycarbonyl)amino)cyclohexyl)amino)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-6-methyl-4-oxo-4,6-dihydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (0.22 g, 0.34 mmol) was used as the reaction substrate. , replacing intermediate 39a, with the same other raw materials and amounts, to give (R)-2-((4-aminocyclohexyl)amino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)quinazoline-4(3H)-one ester (0.77 g, 1.72 mmol, yield: 85.3%) as a white solid.1 H NMR(300MHz,DMSO-d6)δ11.98(s,1H),8.84(s,1H),7.92(d,J=7.5Hz,1H),7.8 1(d,J=7.8Hz,1H),7.16(m,1H),6.89(d,J=3.7Hz,1H),6.45(m,1H),4.61(m,1H ),4.31(m,1H),3.45(d,J=12.6Hz,2H),3.21(m,1H),3.01(s,2H),2.21(m,2H) ,1.98(s,2H),1.52(m,5H),1.43(s,3H),1.14(m,2H),0.94(m,2H).ESI-MS:m / z 447.3[M+H] + .

[0116] Step 4: Synthesis of (R)-N-hydroxy-4-(2-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)amino)-2-oxoethyl)benzamide (12i)

[0117]

[0118] The general synthetic method 4 in Example 2 was used, with (R)-2-((4-aminocyclohexyl)amino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)quinazolin-4(3H)-one ester (0.45 g, 1.01 mmol) as the reaction substrate, and 2-(4-(methoxycarbonyl)phenyl)acetic acid (Leyan, 0.15 g, 0.77 mmol) as the reaction substrate. Replacing 5-methoxy-5-oxopentanoic acid, other raw materials and amounts are the same to obtain a white solid (R)-N-hydroxy-4-(2-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)amino)-2-oxoethyl)benzamide (Yield: 31.7%). 1H NMR(300MHz,DMSO-d6)δ11.85(m,1H),11.31(s,1H),9.11(s,1H),7.90(m 1H),7.83(d,J=7.9Hz,2H),7.81(d,J=7.8Hz,1H),7.62(m,1H),7.51(m,1H),7.23(s,1H),7.15 (m,1H),7.07(s,1H),6.95(d,J=13.7Hz,1H),6.30(m,1H),4.58-4.55(m,1H),4.35(s,1H),3.63 (s,1H),3.32(m,3H),2.97(s,1H),2.56(d,J=14.9Hz,1H),2.15(s,1H),1.98(s,1H),1.82(s,3H ),1.48(s,3H),1.40(d,J=6.4Hz,3H),1.23-1.16(m,2H),0.98(m,2H).HRMS(ESI,positive)m / z Calcd.for C 34 H 37 N7O5[M+H] + :624.2856; Found 624.2932.

[0119] Example 13 Synthesis of (R,E)-N-hydroxy-3-(4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)amino)-2-oxoethyl)phenyl)acrylamide (13i)

[0120]

[0121] The general synthetic method 4 in Example 2 was adopted, with (R)-2-((4-aminocyclohexyl)amino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)quinazoline-4(3H)-one ester (0.45 g, 1.01 mmol) as the reaction substrate, and (E)-2-(4-(3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acetic acid (Leyan, 0.15 g, 0.6 8mmol) instead of 5-methoxy-5-oxopentanoic acid, and other raw materials and amounts were the same to obtain a white solid (R,E)-N-hydroxy-3-(4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)cyclohexyl)amino)-2-oxoethyl)phenyl)acrylamide 13i (Yield: 23.9%). 1 H NMR(300MHz,DMSO-d6)δ12.04(s,1H),11.14(s,1H),8.97(s,1H),8.13-8.08(m,1H),7.95-7.92(m,1H),7.84-7.78(m,2 H),7.69(d,J=3.9Hz,2H),7.61(s,1H),7.34(d,J=5.9Hz,2H),7.14-7.12(m,1H),6.88(m,1H),6.17(m,1H),5.93(m,1H) ,4.56(m,1H),4.14(s,1H),3.87-3.75(m,1H),3.47(d,J=2.5Hz,2H),1.90(d,J=13.3Hz,2H),1.73-1.67(m,2H),1.61(d ,J=11.7Hz,2H),1.46(s,3H),1.42(m,3H),1.38-1.37(m,2H),1.15(m,2H),1.08-0.99(m,2H).HRMS(ESI,positive)m / z Calcd.for C 36 H 39 N7O5[MH] - :648.3013; Found 648.2928.

[0122] Example 14 Synthesis of (R)-N-hydroxy-4-((4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)methyl)benzamide (14i)

[0123]

[0124] General Synthesis Method 5: Dissolve (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.50 g, 1.16 mmol), methyl 4-formylbenzoate (0.28 g, 1.74 mmol), and N,N-diisopropylethylamine (0.45 g, 3.48 mmol) in a mixture of anhydrous methanol and anhydrous 1,2-dichloroethane (6 ml, volume ratio of anhydrous methanol to anhydrous 1,2-dichloroethane: 5:1). Stir the mixture at room temperature under nitrogen for 30 minutes. Then, add sodium triacetoxyborohydride (0.78 g, 3.48 mmol), and stir the mixture at room temperature under nitrogen overnight. After completion of the reaction, the mixture was quenched with water and extracted with ethyl acetate (3×50 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography (eluent system: dichloromethane: methanol = 50:1) to give (R)-4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)methyl)benzoic acid methyl ester (0.29 g, 0.49 mmol, yield: 42.9%) as a white solid. Potassium hydroxide (11.2 g, 200 mmol) was then dissolved in anhydrous methanol (30 mL), and a methanol solution (10 mL) of hydroxylamine hydrochloride (9.34 g, 134.4 mmol) was added at 0 ° C. The mixture was stirred for 1 hour and the precipitate was removed by filtration. The filtrate was collected to obtain a fresh hydroxylamine solution for further reaction. (R)-4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)methyl)benzoic acid methyl ester (0.15 g, 0.26 mmol) was dissolved in the above fresh hydroxylamine solution at 0 ° C and stirred at room temperature for 1 hour. The reaction was completed by monitoring with TLC, and the mixture was neutralized with an appropriate amount of HCl. The precipitate was collected, washed with water, and dried in vacuo to give a white solid compound (R)-N-hydroxy-4-((4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)methyl)benzamide (Yield: 29.3%).1 H NMR(300MHz,DMSO-d6)δ12.00(s,1H),11.42(s,1H),9.22(s,1H),8.08-8. 01(m,2H),7.92(d,J=7.6Hz,3H),7.80(s,2H),7.26(s,1H),7.11(s,1H),4. 66-4.60(m,1H),4.38-4.23(m,2H),2.24(s,5H),1.58(s,3H),1.49(m,5H),1.35(s,3H),1.26(m,2H),1.07(s,2H).HRMS(ESI,positive)m / zCalcd.for C 32 H 35 N7O4[M+H] + :582.2751; found 582.2828.

[0125] Example 15 Synthesis of (R,E)-N-hydroxy-3-(4-((8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)methyl)phenyl)acrylamide (15i)

[0126]

[0127] The general synthetic method 5 in Example 14 was adopted, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate. (E)-methyl 3-(4-formylphenyl)acrylate (0.28 g, 1.47 mmol) was used as the reaction mixture. The reaction mixture was stirred for 2 h at room temperature for 1 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 4 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 4 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 5 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. 1H NMR (300MHz, DMSO-d6) δ12.01(m,1H),10.77(s,1H),9.05(s,1H),7.92(s,1H),7.80(d,J=7.7Hz, 1H),7.66(s,1H),7.55(d,J=7.9Hz,2H),7.40(d,J=8.4Hz,3H),7.14(m,1H),6.90(m,1H),6.47(s ,1H),6.25(s,1H),4.53(s,1H),4.05(s,1H),3.61(s,2H),2.90(s,2H),2.26(s,2H),2.01(s,2H) ,1.84(s,2H),1.47(s,3H),1.39(s,3H),1.23(s,2H),1.00-0.91(m,2H).HRMS(ESI,positive)m / z Calcd.for C 34 H 37 N7O4[M+H] + :608.2907; Found 608.2997.

[0128] Example 16 Synthesis of (R)-N-(2-aminophenyl)-8-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-8-oxooctamide (16i)

[0129]

[0130] General Synthesis Method 6: A 50 mL round-bottom flask was charged with 8-methoxy-8-oxooctanoic acid (Leyan, 0.15 g, 1.03 mmol), HATU (0.58 g, 1.55 mmol), N,N-diisopropylethylamine (0.19 g, 1.55 mol) and DMF (5 mL). The solution was stirred at room temperature for 0.5 h, and then compound 40b (0.45 g, 1.03 mmol) was added. The mixture was stirred at room temperature for 4 h until TLC showed the reaction was complete. The mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting product was separated and purified by column chromatography (eluent system: dichloromethane: methanol = 20:1) to give (R)-8-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-8-oxooctanoic acid methyl ester (yield: 56%) as a white solid. Then, compound (R)-8-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-8-oxooctanoic acid methyl ester (0.2 g, 0.33 mmol) and lithium hydroxide (0.08 g, 3.3 mmol) were dissolved in a mixed solvent of methanol and water (4:1 v / v) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted with dilute hydrochloric acid. The resulting solid was precipitated, filtered, and the filter cake was washed with water to obtain the intermediate (R)-8-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-8-oxooctanoic acid (0.15 g, 0.25 mmol, yield: 75%). The above intermediate (0.15 g, 0.25 mmol), (7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (Leyan, 0.14 g, 0.38 mmol), and N,N-diisopropylethylamine (0.06 g, 0.5 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 30 minutes. Subsequently, 1,2-phenylenediamine (0.04 g, 0.38 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction, the mixture was quenched with water and extracted with ethyl acetate (3×50 mL).The combined organic phase was washed with saturated aqueous sodium bicarbonate solution (30 mL) and saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated and purified by column chromatography (eluent system: dichloromethane: methanol = 50:1) to give a white solid (R)-N-(2-aminophenyl)-8-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)-8-oxooctamide (yield: 30%). 1 H NMR (300MHz, DMSO-d6) δ11.93(m,1H),9.11(s,1H),7.92(s,1H),7.82(d,J=7.8Hz,1H),7.62(d,J=4.2Hz,1H),7.16(q,J=7.7Hz,2H),6.96(d ,J=11.2Hz,1H),6.89(m,1H),6.73(d,J=7.9Hz,1H),6.54(m,1H),6.30(d,J=7.6Hz,1H),4.82(s,1H),4.57(m,1H),4.46(s,1H),4.30(s,1H) ,3.97(s,1H),3.14(d,J=14.3Hz,1H),2.71(d,J=12.7Hz,1H),2.35(d,J=9.3Hz,4H),2.05(s,2H),1.69(s,1H),1.59(d,J=32.4Hz,4H),1.47 (s,3H),1.41(d,J=6.6Hz,3H),1.37(s,5H),1.25(s,1H),1.21(s,1H),1.17-1.13(m,1H),1.02(s,1H),0.95(s,1H).HRMS(ESI,positive)m / z Calcd.for C 38 H 46 N8O4[M+H] + :679.3642; found 679.3723.

[0131] Example 17 Synthesis of (R,E)-N-(2-aminophenyl)-3-(4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)methyl)phenyl)acrylamide (17i)

[0132]

[0133] The general synthetic method 5 in Example 14 was adopted, and (R)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-(piperidin-4-ylamino)quinazolin-4(3H)-one (0.45 g, 1.03 mmol) was used as the reaction substrate, and (E)-3-(4-formylphenyl)methyl acrylate (0.28 g, 1.47 mmol) was used as the reaction substrate. Instead of methyl 4-formylbenzoate, other raw materials and amounts were the same to give ((R,E)-N-(2-aminophenyl)-3-(4-(4-(8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)piperidin-1-yl)methyl)phenyl)acrylamide as a white solid (yield: 35.1%). 1 H NMR (300MHz, DMSO-d6) δ11.78(s,1H),10.10(s,1H),9.93(s,1H),7.89(d,J=7.6Hz,1H),7.82(m,2H),7.76(s,3H) ,7.67(d,J=15.1Hz,2H),7.42(m,1H),7.19(m,1H),7.12(m,3H),7.02(d,J=14.8Hz,2H),6.91m,1H),6.60(s,1H),4 .57(s,1H),4.41(s,1H),4.26(s,1H),3.61(s,1H),3.19(s,2H),2.31(d,J=14.0Hz,1H),2.01(s,1H),1.49(s,3H) ,1.41-1.38(m,3H),1.26(s,2H),1.22-1.15(m,2H),0.96(m,2H),0.86(m,2H).HRMS(ESI,positive)m / zCalcd.for C 40 H 42 N8O3[M+H] + :683.3380; Found 683.3448.

[0134] Example 18: Activity Test

[0135] 1. Cell Lines and Cell Culture

[0136] MV4-11 and MOLM-13 cell lines were purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences. All cells were cultured in RPMI 1640 or IMDM supplemented with 10% fetal bovine serum, with a CO2 concentration of 5% and a culture temperature of 37°C.

[0137] 2. CellTiter Lumi TM Luminescent cell viability assay

[0138] Cells were seeded into 96-well cell culture plates at a density of 7000 cells / well. After 96 hours in culture medium with eight concentrations of target compounds: 10 μmol / ml, 3.3 μmol / ml, 1.1 μmol / ml, 0.37 μmol / ml, 0.12 μmol / ml, 0.04 μmol / ml, 0.013 μmol / ml, and 0.004 μmol / ml, CTL stabilizing reagent (100 μL) was added to each well and incubated for another 10 minutes at room temperature. The optical density values ​​were then measured using a Thermo Multiskan spectrum. Cell viability was calculated using the following formula: Cell viability (%) = (experimental well reading / control well reading) × 100%. GraphPadPrism 8.0 software was used to determine the IC of the compound. 50 Values ​​(Table 1 and Table 2). SAHA was purchased from Bidex Pharmaceuticals and its structural formula is C28 Disclosed in Discovery and Optimization ofQuinazolinone-pyrrolopyrrolones as Potent and Orally Bioavailable Pan-PimKinase Inhibitors.

[0139] Table 1

[0140]

[0141]

[0142] Table 2

[0143]

[0144] Example 19: Evaluation of the anti-tumor efficacy of compound 15i in vivo

[0145] The present invention established an MV4-11 transplanted tumor model:

[0146] Female BALB / c-Nude mice (6–8 weeks old) were purchased from Beijing Weitairui Laboratory Animal Technology Co., Ltd. Animal experiments were performed according to protocols approved by the Laboratory Animal Care and Use Committee of China Pharmaceutical University. Mice were housed under standard conditions for 3 days (12 / 12 h light / dark cycle, 22 ± 3°C, 40% relative humidity) and fed a standard laboratory rodent chow and water. MV-4-11 cells were resuspended in serum-free growth medium and mixed with Matrigel (354248, BD Bioscience) at a 1:1 ratio, and then 5 × 10 6 MV-4-11 cells were subcutaneously implanted into the right flank of mice. The tumor grew to 100 mm 3 Afterwards, mice were randomly divided into different groups. Compound 15i was dissolved in a mixed solvent of DMSO / PEG400 / Tween 80 / saline (5:45:5:45) and injected intraperitoneally once a day for 21 consecutive days. Tumor volume and mouse body weight were monitored every two days. Tumor volume (TV) was calculated as (smaller diameter) 2 × (larger diameter) / 2. Pharmacodynamic efficacy was also evaluated by calculating TGI% (TGI% = (mean tumor volume of the control group - mean tumor volume of the control group) / mean tumor volume of the control group × 100%).

[0147] The 30 Balb / c-Nude nude mice were divided into five groups: blank, C28 (50 mg / kg), vorinostat (SAHA, 50 mg / kg), compound 15i (50 mg / kg), and compound 15i (25 mg / kg). They were intraperitoneally injected for 21 consecutive days. The tumor volume and mouse body weight were monitored every two days during the treatment period, and the tumor weight was measured after treatment. The tumor growth inhibition value of each group was calculated as follows: Figure 1 and Figure 2 As shown, compound 15i achieved tumor growth inhibition (TGI) values ​​of 81.3% and 45.9% at doses of 50 mg / kg and 25 mg / kg, respectively. Compound 15i demonstrated superior in vivo antitumor activity compared to the positive controls C28 and SAHA at the same dose, consistent with the in vitro antiproliferative activity results. Furthermore, no significant weight loss or toxic effects were observed during treatment.

Claims

1. A compound having a quinazolinone pyrrole dihydropyrrolidone structure, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The structure of the compound having a quinazolinone pyrrole dihydropyrrolidone structure is shown in formula (1): in: X=C or N; Linker is one of them: ZBG is one of them:

2. The compound of quinazolinone pyrrole dihydropyrrolidone structure according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, characterized in that: The structure of the compound having a quinazolinone pyrrole dihydropyrrolidone structure is shown below:

3. A method for synthesizing the compound having a quinazolinone pyrrole dihydropyrrolidone structure according to claim 1, characterized in that: The synthetic route is: in: X=C or N; Linker is any of the following: ZBG is one of them:

4. A composition, characterized in that The invention contains the compound having the quinazolinone pyrrole dihydropyrrolidone structure according to claim 1 or 2 or a pharmaceutically acceptable salt or solvate thereof.

5. Use of the compound having a quinazolinone pyrrole dihydropyrrolidone structure according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, or the composition according to claim 4 in the preparation of a PIM / HDAC dual-target inhibitor.

6. A PIM / HDAC dual-target inhibitor, characterized in that: It contains the compound having a quinazolinone pyrrole dihydropyrrolidone structure according to claim 1 or 2 or its pharmaceutically acceptable salt, solvate or the composition according to claim 4.

7. Use of the compound having a pyrrolopyridine structure according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, or the composition according to claim 4, in the preparation of a medicament for treating and / or preventing leukemia or cancer.

8. The use according to claim 7, characterized in that: The leukemia includes acute myeloid leukemia or chronic myeloid leukemia.

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