Purine ketone derivative as well as preparation method and medical application thereof

Abstract

The invention belongs to the field of medicines, and discloses a purinone derivative as well as a preparation method and medical application thereof. The purinone derivative has a structure as shown in a general formula I. The purinone derivative selectively has a strong inhibition effect on proliferation of tumor cells such as liver cancer, lung cancer, colon cancer, pancreatic cancer, prostatic cancer and breast cancer, and can be applied to preparation of medicines for treating and / or preventing malignant tumors.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a purine ketone derivative, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Cancer, as one of the leading causes of death worldwide, suffers from complex pathogenesis (such as genetic heterogeneity, multidrug resistance, and the ability to metastasize to distant sites), making it difficult for current treatments to achieve a complete cure. Therefore, identifying highly specific molecular targets and developing targeted drugs has become a core direction in the field of cancer research.

[0003] S-phase kinase-associated protein 2 (SKP2), a key substrate recognition subunit of the SKP1-CUL1-ROC1-F-box (SCF)E3 ubiquitin ligase complex, regulates cell cycle progression through ubiquitination. Studies have confirmed that SKP2 specifically binds to phosphorylated tumor suppressors p27 and p21, promoting their proteasome degradation via K48-linked polyubiquitination, ultimately relieving cell cycle arrest and promoting tumor cell proliferation. SKP2 exhibits high-frequency overexpression in various malignant tumors, including lung cancer, breast cancer, and colon cancer, and its expression level is significantly negatively correlated with tumor stage, lymph node metastasis, and patient prognosis. Gene knockout mouse models further validate that SKP2 deficiency significantly inhibits tumor development and progression, clarifying its core role as a carcinogenic driver. Based on these mechanisms, targeted inhibition of SKP2 function has become a crucial breakthrough in overcoming traditional treatment bottlenecks and developing novel anti-cancer strategies. Summary of the Invention

[0004] The purpose of this invention is to provide a purine ketone derivative, its preparation method, and its pharmaceutical uses. This purine ketone derivative can directly target Skp2, induce tumor cell cycle arrest, and promote apoptosis via the mitochondrial pathway, thereby exerting anti-tumor effects through multiple pathways.

[0005] In a first aspect, the present invention provides a purine ketone derivative having the structure of the following general formula I:

[0006]

[0007] Wherein, R1 is selected from one of methoxy-substituted phenyl, naphthyl, biphenyl, and methoxyfluoro-disubstituted phenyl; R2 is selected from phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, dimethylamino-substituted phenyl, ethoxy-substituted phenyl, isopropoxy-substituted phenyl, methylaminophenyl, ethyl-substituted phenyl, ethylaminophenyl, diethylamino-substituted phenyl, ... , , , One of the following: methoxyfluoride disubstituted phenyl, ethoxyfluoride disubstituted phenyl, and isopropoxyfluoride disubstituted phenyl.

[0008] Furthermore, R1 is selected from one of phenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 1-naphthyl, 4-biphenyl, 2-naphthyl, and 3-biphenyl; R2 is selected from phenyl, 3-methoxyphenyl, 3-methylphenyl, 3-(N,N-dimethylamino)-phenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-ethoxyphenyl, 3-isopropoxyphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-methylaminophenyl, and 3-ethylaminophenyl. , , , One of 2-fluoro-5-ethoxyphenyl, 3-fluoro-5-ethoxyphenyl, 3-fluoro-5-isopropoxyphenyl, 2-fluoro-5-isopropoxyphenyl and 3-(N,N-diethylamino)-phenyl.

[0009] The preferred compound designations and corresponding structures of the above general formula I are shown in Table 1:

[0010] Table 1. Compound designations for some compounds of general formula I and their corresponding structures.

[0011]

[0012] In a second aspect, the present invention provides a method for preparing the above-mentioned purine ketone derivative, the synthetic route of which is shown in the following formula:

[0013]

[0014] The preparation method includes the following steps:

[0015] S1.R1-CH2NH2 undergoes a substitution reaction with compound 1 under organic basic conditions to give compound 2;

[0016] R1 is selected from one of methoxy-substituted phenyl, naphthyl, biphenyl and methoxyfluoro-disubstituted phenyl;

[0017] S2. Compound 2 reacts with excess carbonyl diimidazole (CDI) via a Dieckmann condensation reaction to give compound 3;

[0018] S3. Compound 3 and R2 boric acid were coupled via a Suzuki reaction catalyzed by sodium carbonate, Pd(OAc)2 and sodium triphenylphosphine tris(m-sulfonate) to obtain a purine derivative;

[0019] R2 is selected from phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, dimethylamino-substituted phenyl, ethoxy-substituted phenyl, isopropoxy-substituted phenyl, methylaminophenyl, ethyl-substituted phenyl, ethylaminophenyl, diethylamino-substituted phenyl, etc. , , , One of the following: methoxyfluoride disubstituted phenyl, ethoxyfluoride disubstituted phenyl, and isopropoxyfluoride disubstituted phenyl.

[0020] Furthermore, the organic base is triethylamine or N,N-diisopropylethylamine.

[0021] Furthermore, in step S1, the molar ratio of compound 1 to R1-CH2NH2 is 3:3.3; the solvent is n-butanol; the reaction conditions are: N2 protection, reaction at 120 °C for 2 days.

[0022] Furthermore, in step S2, the molar ratio of compound 2 to CDI is 2.59:(12-13); the reaction conditions for the Dieckmann condensation reaction are: N2 protection, reaction at 30 °C for 12 h.

[0023] Furthermore, in step S3, the molar ratio of compound 3 to R2 boric acid is 1:1.2.

[0024] Furthermore, in step S3, the conditions for the Suzuki coupling reaction are: N2 protection, reaction at 100 °C for approximately 3 h.

[0025] In a third aspect, the present invention provides the use of the above-mentioned purine ketone derivatives or pharmaceutically acceptable salts thereof as active ingredients in the preparation of medicaments for the treatment and / or prevention of malignant tumors, wherein the malignant tumor is one of prostate cancer, colon cancer, breast cancer, liver cancer, lung cancer, and pancreatic cancer.

[0026] Compared with existing technologies, the compounds of this invention use an 8-carbonylpurine structure as the parent nucleus, with different substituents introduced at positions 6 and 9. When the substituent at position 6 is a dimethylamino-substituted phenyl, a methoxyfluorine-disubstituted phenyl, an ethoxyfluorine-disubstituted phenyl, or an isopropoxyfluorine-disubstituted phenyl, and the substituent at position 9 is a biphenyl or a methoxyfluorine-disubstituted phenyl, their antitumor cell activity can be significantly enhanced. Currently, there are no reports on this type of purine ketone derivative. Activity tests on various types of cancer cells revealed that this class of purine ketone derivatives selectively exhibits strong inhibitory effects on the proliferation of various tumor cells (including prostate cancer, colon cancer, breast cancer, liver cancer, lung cancer, and pancreatic cancer). Most compounds show an IC50 inhibitory activity against lung cancer and pancreatic cancer. 50The activity levels are in the single digits, with some compounds having activity below 1.0 μM, and even a few compounds having activity at the nanomolar level. Meanwhile, the compounds of this invention exhibit an inhibition rate of over 80% against prostate cancer, colon cancer, breast cancer, and liver cancer cells at 20 μM, demonstrating strong tumor cell inhibitory activity.

[0027] Based on the in vivo antitumor activity results of a clinical lung cancer PDX model, compound I3 of this invention significantly inhibited the growth of clinical lung cancer tumors at low doses (10 and 20 mg / kg), with tumor inhibition rates of 65.6% and 82.6%, respectively. These effects were significantly superior to the positive control drug, indicating that the compound of this invention has a strong antitumor effect on clinical lung cancer tumors. Therefore, the compound of this invention has significant potential for pharmaceutical applications. Attached Figure Description

[0028] Figure 1 The in vivo antitumor activity results of the compounds of the present invention are shown. Detailed Implementation

[0029] To further illustrate the present invention, a series of embodiments are given below. These embodiments are purely illustrative and are only used to specifically describe the present invention, and should not be construed as limiting the present invention. It should be understood that, within the scope of the present invention, the above-described technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to constitute preferred technical solutions.

[0030] Example 1 Preparation of 9-(3-fluoro-4-methoxybenzyl)-6-(3-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I1)

[0031] (1) Preparation of compound 2a

[0032] Compound 1 (534 mg, 3 mmol), 3-fluoro-4-methoxybenzylamine (354 mg, 3.3 mmol), TEA (1.1 ml, 9 mmol), and n-butanol (6 ml) were added sequentially to a Schlenk tube. The mixture was protected with N2 and reacted at 120 °C for 2 days. After the reaction was completed by TLC monitoring, the reaction mixture was evaporated to dryness. Dichloromethane / methanol (100:1, v / v) was used as the eluent for column chromatography to purify the mixture into a white solid, namely compound 2a, with a yield of 86%. 1H NMR (400 MHz, DMSO-d6) δ 7.37 (m, 1H, ArH), 7.27 (s, 1H, NH), 7.20-7.11 (m, 2H, ArH), 7.08 (m, 1H, ArH), 4.84 (s, 2H,NH2), 4.63 (d, J = 5.6 Hz, 2H, CH2), 2.22 (s, 3H, CH3).

[0033] (2) Preparation of compound 3a

[0034] Compound 2a (645 mg, 2.59 mmol) was dissolved in anhydrous tetrahydrofuran (13 ml) under N2 protection. CDI (2 g, 12.97 mmol) was added to the solution, and the reaction was carried out at 30 °C for 12 h. After the reaction was completed by TLC monitoring, water was slowly added to the reaction solution to quench excess CDI, and then an appropriate amount of water was added and stirred. After a large amount of solid precipitated, the mixture was filtered and the filter cake was dried to obtain a white solid, namely compound 3a, with a yield of 67%. 1 H NMR (400 MHz, DMSO-d6) δ 12.03 (s, 1H, CONH), 7.43-7.21 (m, 5H, ArH), 4.99 (s, 2H, CH2), 2.52 (s, 3H, CH3).

[0035] (3) Preparation of compound I1

[0036] Compound 3a (77 mg, 0.28 mmol), 3-methoxyphenylboronic acid (41.5 mg, 0.34 mmol), sodium carbonate (59.4 mg, 0.56 mmol), palladium acetate (3.2 mg, 0.014 mmol), and trisodium triphenylphosphine tris(m-sulfonate) (20 mg, 0.035 mmol) were added to a Schlenk tube under N2 protection. Water:acetonitrile (2:1, 6 mL) was added to the Schlenk tube as solvent, and the reaction was carried out at 100 °C for about 3 h. After the reaction was completed by TLC monitoring, the reaction solution was extracted with ethyl acetate and water. The ethyl acetate layer was evaporated to dryness, and dichloromethane / methanol (100:1, v / v) was used as the eluent for column chromatography. After purification, a white solid, namely compound I1, was obtained, with a yield of 80%. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H, CONH), 7.55-7.42 (m, 3H,ArH), 7.26-7.20 (m, 1H, ArH), 7.17-7.05 (m, 3H, ArH), 4.97 (s, 2H, CH2), 3.86(s, 3H, OCH3), 3.80 (s, 3H, OCH3), 2.60 (s, 3H, CH3).

[0037] 13 C NMR (101 MHz, DMSO-d6) δ 159.83, 159.48, 154.15, 151.66, 147.05,146.94, 141.36, 136.86, 130.28, 129.87, 129.81, 124.38, 124.35, 121.01,116.55, 116.38, 115.81, 115.63, 114.35, 114.33, 113.36, 56.43, 55.61, 42.12,26.01.

[0038] Example 2 Preparation of 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(m-tolyl)-7,9-dihydro-8H-purine-8-one (I2).

[0039] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-methylphenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I2 was obtained with a yield of 62%. 1 H NMR (400 MHz, CDCl3) δ9.99 (s, 1H, CONH), 7.75-7.61 (m, 2H, ArH), 7.36 (m, 1H, ArH), 7.26-7.20 (m,2H, ArH), 7.19-7.14 (m, 1H, ArH), 6.81 (m, 1H, ArH), 5.00 (s, 2H, CH2), 3.78 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.40 (s, 3H, CH3).

[0040] 13C NMR (101 MHz, DMSO-d6) δ 159.48, 154.17, 152.87, 151.59, 150.44,147.04, 146.94, 141.54, 138.47, 135.31, 130.98, 129.89, 129.83, 129.05,125.69, 124.36, 124.33, 116.36, 115.80, 115.62, 114.35, 114.33, 56.42, 42.11,26.01, 21.42.

[0041] Example 3 Preparation of 6-(3-dimethylaminophenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I3).

[0042] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-(N,N-dimethylamino)-phenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I3 was obtained with a yield of 55%. 1 H NMR (400MHz, DMSO-d6) δ 11.55 (s, 1H, CONH), 7.32 (m, 1H, ArH), 7.25-7.11 (m, 5H,ArH), 6.86 (dd, J = 8.2, 2.6 Hz, 1H, ArH), 4.96 (s, 2H, CH2), 3.80 (s, 3H,OCH3), 2.98 (s, 6H, NCH3), 2.59 (s, 3H, CH3).

[0043] 13 C NMR (101 MHz, DMSO-d6) δ 159.44, 154.13, 151.46, 150.92, 147.04,146.93, 142.72, 136.16, 129.94, 129.88, 129.71, 124.39, 124.35, 116.60,116.46, 115.82, 115.64, 114.36, 114.33, 111.89, 56.43, 42.09, 40.59, 26.06.

[0044] Example 4 Preparation of 6-(3-dimethylaminophenyl)-2-methyl-9-(naphth-2-ylmethyl)-7,9-dihydro-8H-purine-8-one (I4).

[0045] Referring to the preparation method of compound 2a in step (1) of Example 1, 3-fluoro-4-methoxybenzylamine was replaced by compound 2-(aminomethyl)naphthalene, and after purification, white solid compound 2d was obtained with a yield of 92%. 1 H NMR (400 MHz, DMSO-d6) δ 7.89-7.32(m, 7H, ArH), 7.31(s, 2H, NH2), 4.87(s, H, NH), 4.79(m, 2H,CH2), 2.23(s, 3H, CH3).

[0046] Referring to the preparation method of compound 3a in step (2) of Example 1, compound 2d was used to replace 2a in the method to obtain white solid compound 3d with a yield of 93%. 1 H NMR (400 MHz, DMSO-d6) δ 12.07(s, H, NH), 7.90-7.77(m, 3H, ArH), 7.51(s, H, ArH), 7.50-7.47(m, 3H, ArH), 5.15(s, 2H, CH2),2.54(s, 3H, CH3).

[0047] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-(N,N-dimethylamino)phenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I4 was obtained with a yield of 71%. 1 H NMR (400 MHz, DMSO-d6) δ 11.58(s, H, NH), 7.91-7.50(m, 4H, ArH), 7.49-7.38(m, 3H, ArH), 7.35-7.22(m, 3H, ArH), 7.19(s, H, ArH), 5.20(s, 2H, CH2), 2.97(s, 6H, CH3), 2.58(s, 3H, CH3).

[0048] 13 C NMR (101 MHz, DMSO-d6) δ 159.50, 154.29, 151.70, 150.95, 142.73,136.19, 134.68, 133.26, 132.75, 129.74, 128.79, 128.19, 128.03, 126.84,126.52, 126.21, 126.02, 116.64, 116.55, 114.36, 111.91, 43.17, 40.36, 26.07.

[0049] Example 5 Preparation of 9-(4-(difluoromethoxy)benzyl)-2-methyl-6-phenyl-7,9-dihydro-8H-purine-8-one (I5).

[0050] Referring to the preparation method of compound 2a in step (1) of Example 1, 3-fluoro-4-methoxybenzylamine was replaced by compound 4-aminomethyl-1,1'-biphenyl, and after purification, a white solid 2e was obtained with a yield of 55%. 1 H NMR (400 MHz, DMSO-d6) δ 7.66-7.27(m, 9H, ArH), 7.26(s, H, NH), 4.87(s, 2H, NH2), 4.67(d, 2H,CH2), 2.25(s, 3H, CH3).

[0051] Referring to the preparation method of compound 3a in step (2) of Example 1, compound 2e was used to replace 2a in the method to obtain white solid 3e with a yield of 94%. 1 H NMR (400 MHz, DMSO-d6) δ 12.06(s, H, NH), 7.62-7.32(m,9H, ArH), 5.03(s, 2H, CH2), 2.52(s, 3H, CH3).

[0052] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-(N,N-dimethylamino)phenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I5 was obtained with a yield of 68%. 1 H NMR (400 MHz, DMSO-d6) δ 11.57(s, H, NH), 7.68-7.60(m, 4H, ArH), 7.36-7.22(m, 8H, ArH), 7.21(s, H, ArH), 5.07(s, 2H, CH2), 2.96(s, 6H, CH3), 2.59(s, 3H, CH3).

[0053] 13C NMR (101 MHz, DMSO-d6) δ 159.51, 154.22, 151.59, 150.94, 142.76,140.21, 139.92, 136.32, 129.73, 129.39, 129.14, 128.51, 127.94, 127.42,127.10, 116.62, 116.47, 114.35, 111.90, 55.39, 40.20, 26.08.

[0054] Example 6 Preparation of 6-(3-dimethylaminophenyl)-2-methyl-9-(naphth-1-ylmethyl)-7,9-dihydro-8H-purine-8-one (I6)

[0055] Referring to the preparation method of compound 2a in step (1) of Example 1, 3-fluoro-4-methoxybenzylamine was replaced by compound 1-(aminomethyl)naphthalene, and after purification, a white solid 2f was obtained with a yield of 65%. 1 H NMR (400 MHz, DMSO-d6) δ8.12-7.19(m, 8H, ArH), 7.07(s, 2H, NH2), 5.05(s, H, NH), 4.87(d, 2H, CH2),2.25(s, 3H, CH3).

[0056] Referring to the preparation method of compound 3a in step (2) of Example 1, compound 2f was used to replace 2a in the method to obtain white solid 3f with a yield of 94%. 1 H NMR (400 MHz, DMSO-d6) δ 12.06(s, H, NH), 7.62-7.32(m,9H, ArH), 5.03(s, 2H, CH2), 2.52(s, 3H, CH3).

[0057] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-(N,N-dimethylamino)phenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I6 was obtained with a yield of 68%. 1 H NMR (400 MHz, DMSO-d6) δ 11.63(s, H, NH), 8.40-7.65, 7.64(m, 3H, ArH), 7.64-6.84(m, 8H, ArH), 5.49(s, 2H, CH2), 2.97(s, 6H, CH3), 2.55(s, 3H, CH3).

[0058] 13 C NMR (101 MHz, DMSO-d6) δ 159.48, 154.30, 151.78, 150.95, 142.82,136.18, 133.71, 131.97, 130.83, 129.75, 129.08, 128.38, 126.99, 126.52,125.91, 125.00, 123.73, 116.65, 116.62, 114.37, 111.93, 55.38, 40.13, 25.99.

[0059] Example 7 Preparation of 9-([1,1'-biphenyl]-3-ylmethyl)-6-(3-dimethylaminophenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I7)

[0060] Referring to the preparation method of compound 2a in step (1) of Example 1, 3-aminomethyl-1,1'-biphenyl was used to replace 3-fluoro-4-methoxybenzylamine in the method, and after purification, 2g of white solid was obtained with a yield of 91%. 1 H NMR (400 MHz, DMSO-d6) δ 7.66-7.23(m, 9H, ArH), 7.24(s, H, NH), 4.86(s, 2H, NH2), 4.69(d, 2H,CH2),2.25(s, 3H, CH3).

[0061] Referring to the preparation method of compound 3a in step (2) of Example 1, 2g of compound 2g was used to replace 2a in the method to obtain 3g of white solid with a yield of 94%. 1 H NMR (400 MHz, DMSO-d6) δ 12.12(s, H, NH),7.66-7.46(m,4H, ArH), 7.46-7.26(m, 5H, ArH), 5.06(s, 2H, CH2), 2.52(s, 3H, CH3).

[0062] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-(N,N-dimethylamino)phenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I7 was obtained with a yield of 61%. 1 H NMR (400 MHz, DMSO-d6) δ 11.56(s, H, NH), 7.71-6.82(m, 13H, ArH), 5.10(s, 2H, CH2), 2.96(s,6H, CH3), 2.59(s, 3H, CH3).

[0063] 13 C NMR (101 MHz, DMSO-d6) δ 159.46, 154.27, 151.62, 150.93, 142.75,140.94, 137.83, 136.16, 129.78, 129.47, 128.38, 128.08, 127.15, 126.89,126.59, 126.42, 118.87, 116.62, 116.51, 114.34, 111.90, 43.03, 40.78, 26.06.

[0064] Example 8 Preparation of 6-(4-fluoro-3-methylphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I8)

[0065] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-methoxy-2-fluorophenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I8 was obtained with a yield of 60%. 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H, NH), 7.79 – 6.67 (m, 7H, ArH), 4.96 (s, 2H, CH2), 3.86 (d, J = 42.0 Hz, 6H, CH3), 2.60 (s, 3H, CH3).

[0066] 13 C NMR (101 MHz, DMSO-d6) δ 159.48, 154.17, 152.87, 151.59, 150.44,147.04, 146.94, 141.54, 138.47, 135.31, 130.98, 129.89, 129.83, 129.05,125.69, 124.36, 124.33, 116.36, 115.80, 115.62, 114.35, 114.33, 56.42, 42.11,26.01, 21.42.

[0067] Example 9 Preparation of 9-(3-fluoro-4-methoxybenzyl)-6-(3-fluoro-5-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I9)

[0068] Referring to the preparation method of compound I1 in step (3) of Example 1, 5-methoxy-2-fluorophenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, white solid compound I9 was obtained with a yield of 55%. 1 H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H, NH), 7.39 – 7.03 (m, 7H, ArH), 4.97 (s, 2H, CH2), 3.81 (d, J = 1.2 Hz, 6H, CH3), 2.60 (s, 3H, CH3).

[0069] Example 10 6-(4-fluoro-3-methoxyphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 10 Preparation of )

[0070] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-methoxy-4-fluorophenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 10 Yield: 61%. 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H, NH), 7.63 (dd, J = 8.4, 2.1 Hz, 1H, ArH), 7.53 (ddd,J = 8.4, 4.5, 2.1 Hz, 1H, ArH), 7.37 (dd, J = 11.3, 8.5 Hz, 1H, ArH), 7.27 –7.19 (m, 1H, ArH), 7.14 (dd, J = 4.0, 1.6 Hz, 2H, ArH), 4.98 (s, 2H, CH2), 3.97 (s, 3H, CH3), 3.81 (s, 3H, CH3), 2.61 (s, 3H, CH3).

[0071] Example 11 9-(3-fluoro-4-methoxybenzyl)-6-(3-fluoro-5-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 11 Preparation of )

[0072] Referring to the preparation method of compound I1 in step (3) of Example 1, 5-methoxy-3-fluorophenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 11 Yield: 53%. 1H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H, NH), 7.32 (dd, J = 8.2, 2.3 Hz, 2H, ArH), 7.26 –7.18 (m, 1H, ArH), 7.15 – 7.08 (m, 2H, ArH), 6.98 (m, 1H, ArH), 4.97 (s, 2H,CH2), 3.88 (s, 3H, CH3), 3.81 (s, 3H, CH3), 2.60 (s, 3H, CH3).

[0073] Example 12 6-(3-ethoxyphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I 12 Preparation of )

[0074] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-ethoxyphenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 12 Yield: 60%. 1 H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H, NH), 7.51 (d, J = 7.7 Hz, 1H, ArH), 7.47 – 7.39 (m, 2H,ArH), 7.23 (d, J = 12.2 Hz, 1H, ArH), 7.16 – 7.11 (m, 2H, ArH), 7.05 (dd, J =8.2, 2.5 Hz, 1H, ArH), 4.97 (s, 2H, CH2), 4.13 (q, J = 6.9 Hz, 2H, CH2), 3.80(s, 3H, CH3), 2.60 (s, 3H, CH3), 1.37 (t, J = 6.9 Hz, 3H, CH3).

[0075] Example 13 9-(3-fluoro-4-methoxybenzyl)-6-(3-isopropoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 13 Preparation of )

[0076] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-methoxyphenylboronic acid was substituted for 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 13 Yield: 65%. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H, NH), 7.53 – 7.37 (m, 3H, ArH), 7.27 – 7.19 (m, 1H, ArH), 7.16 – 6.98 (m, 3H, ArH), 4.97 (s, 2H, CH2), 4.75 (m, 1H, CH), 3.81 (s,3H, CH3), 2.60 (s, 3H, CH3), 1.30 (d, J = 5.9 Hz, 6H, CH3).

[0077] Example 14 6-(3-Ethylphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I 14 Preparation of )

[0078] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-ethylphenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 14 Yield: 57%. 1 H NMR (400 MHz, DMSO-d6)δ 11.68 (s, 1H, NH), 7.85 – 7.78 (m, 2H, ArH), 7.49 – 7.39 (m, 1H, ArH), 7.35(m, 1H, ArH), 7.27 – 7.18 (m, 1H, ArH), 7.13 (dd, J = 4.1, 1.9 Hz, 2H, ArH), 4.98 (s, 2H, CH2), 3.81 (s, 3H, CH3), 2.72 (q, J = 7.6 Hz, 2H, CH2), 2.60 (s,3H, CH3), 1.28 – 1.23 (m, 3H, CH3).

[0079] Example 15 9-(3-fluoro-4-methoxybenzyl)-6-(3-isopropylphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 15 Preparation of )

[0080] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-isopropylphenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 15 Yield: 52%. 1H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H, NH), 7.82 – 7.75 (m, 2H, ArH), 7.46 (m, 1H, ArH), 7.40 (m, 1H, ArH), 7.27 – 7.19 (m, 1H, ArH), 7.16 – 7.11 (m, 2H, ArH), 4.98 (s,2H, CH2), 3.81 (s, 3H, CH3), 3.03 (m, 1H, CH), 2.60 (s, 3H, CH3), 1.27 (d, J =6.9 Hz, 6H, CH3).

[0081] Example 16 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(piperazin-1-yl)phenyl)-7,9-dihydro-8H-purine-8-one (I) 16 Preparation of )

[0082] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-piperazine phenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 16 Yield: 62%. 1 H NMR (400 MHz, DMSO-d6)δ 11.49 (s, 1H, NH), 7.25 (d, J = 7.8 Hz, 1H, ArH), 7.22 (m, 2H, ArH), 7.16(d, J = 4.0 Hz, 1H, ArH), 7.14 – 7.09 (m, 2H, ArH), 6.75 (dd, J = 7.9, 2.5Hz, 1H, ArH), 4.96 (s, 2H, CH2), 4.25 (dd, J = 8.9, 7.0 Hz, 2H, CH2), 3.81 (s,3H, CH3), 3.66 – 3.54 (m, 2H, CH2), 3.37 (d, J = 6.3 Hz, 2H, CH2), 3.32 – 3.26(m, 2H, CH2), 2.59 (s, 3H, CH3).

[0083] Example 17 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(pyrrolidone-1-yl)phenyl)-7,9-dihydro-8H-purine-8-one (I) 17 Preparation of )

[0084] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-pyrrolephenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 17 Yield: 60%. 1 H NMR (400 MHz, DMSO-d6)δ 11.51 (s, 1H, NH), 7.29 (m, 1H, ArH), 7.23 (d, J = 11.8 Hz, 1H, ArH), 7.13(s, 3H, ArH), 7.03 (s, 1H, ArH), 6.65 (d, J = 8.1 Hz, 1H, ArH), 4.96 (s, 2H,CH2), 3.80 (s, 3H, CH3), 3.35 (m, 4H, CH2), 2.59 (s, 3H, CH3), 1.97 (m, 4H,CH2).

[0085] Example 18 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(piperidin-1-yl)phenyl)-7,9-dihydro-8H-purine-8-one (I) 18 Preparation of )

[0086] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-piperidinephenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 18 Yield: 58%. 1 H NMR (400 MHz, DMSO-d6)δ 11.57 (s, 1H, NH), 7.42 (m, 1H, ArH), 7.35 (d, J = 7.7 Hz, 1H, ArH), 7.30 (dd, J = 7.7, 6.3 Hz, 1H, ArH), 7.27 – 7.19 (m, 1H, ArH), 7.16 – 7.11 (m, 2H,ArH), 7.08 (ddd, J = 8.1, 2.6, 1.3 Hz, 1H, ArH), 4.96 (s, 2H, CH2), 3.81 (s,3H, CH3), 3.21 (t, J = 5.3 Hz, 4H, CH2), 2.59 (s, 3H, CH3), 1.67 – 1.62 (m,4H, CH2), 1.55 (q, J =5.2 Hz, 2H, CH2).

[0087] Example 19 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-morpholinophenyl)-7,9-dihydro-8H-purine-8-one (I) 19 Preparation of )

[0088] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-morpholinophenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 19 Yield: 60%. 1 H NMR (400 MHz, DMSO-d6)δ 11.59 (s, 1H, NH), 7.41 (d, J = 2.6 Hz, 1H, ArH), 7.39 – 7.35 (m, 2H, ArH),7.27 – 7.19 (m, 1H, ArH), 7.17 – 7.12 (m, 2H, ArH), 7.12 – 7.04 (m, 1H, ArH), 4.97 (s, 2H, CH2), 3.81 (s, 3H, CH3), 3.77 (dd, J = 5.9, 3.8 Hz, 4H, CH2), 3.24 – 3.14 (m, 4H, CH2), 2.60 (s, 3H, CH3).

[0089] Example 20 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(methylamino)phenyl)-7,9-dihydro-8H-purine-8-one (I 20 Preparation of )

[0090] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-methoxyphenylboronic acid was substituted for 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 20 Yield: 55%. 1 H NMR (400 MHz, DMSO-d6)δ 11.48 (s, 1H, NH), 7.28 – 7.23 (m, 1H, ArH), 7.21 (d, J = 1.3 Hz, 1H, ArH), 7.14 (s, 1H, ArH), 7.12 (s, 3H, ArH), 7.11 – 7.08 (m, 1H, NH), 4.96 (s, 2H,CH2), 3.81 (s, 3H, CH3), 2.77 – 2.72 (m, 3H, CH3), 2.59 (s, 3H, CH3).

[0091] Example 21 6-(3-(diethylamino)phenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 21 Preparation of )

[0092] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-methoxyphenylboronic acid was substituted for compound 3-diethylaminophenylboronic acid in the method, and after purification, a white solid compound I was obtained. 21 Yield: 56%. 1 H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H, NH), 7.33 – 7.20 (m, 2H, ArH), 7.18 – 7.10 (m, 3H, ArH), 7.07 (d, J = 7.5 Hz, 1H, ArH), 6.79 (dd, J = 8.4, 2.6 Hz, 1H, ArH), 4.96 (s,2H, CH2), 3.81 (s, 3H, CH3), 3.40 (q, J = 8.0 Hz, 4H, CH2), 2.59 (s, 3H, CH3), 1.11 (t, J = 7.0 Hz, 6H, CH3).

[0093] Example 22 6-(3-(ethylamino)phenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I 22 Preparation of )

[0094] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-methoxyphenylboronic acid was substituted for compound 3-ethylaminophenylboronic acid in the method, and after purification, a white solid compound I was obtained. 22 Yield: 60%. 1 H NMR (400 MHz, DMSO-d6) δ 9.56 (s, 1H, NH), 7.32 (s, 1H, NH), 7.26 (s, 2H, ArH), 7.15 (d, J = 8.1Hz, 2H, ArH), 6.92 – 6.83 (m, 1H, ArH), 6.71 (m, 2H, ArH), 5.06 (s, 2H, CH2), 3.84 (s, 2H, CH3), 3.22 (q, J = 7.4 Hz, 2H, CH3), 2.75 (s, 2H, CH2), 1.29 (s,3H, CH3).

[0095] Example 23 6-(3-ethoxy-5-fluorophenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 23 Preparation of )

[0096] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-ethoxy-5-fluorophenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 23 Yield: 53%. 1 H NMR (400MHz, DMSO-d6) δ 11.75 (s, 1H, NH), 7.26 – 7.15 (m, 2H, ArH), 7.10 (dd, J =19.6, 6.1 Hz, 2H, ArH), 6.96 (s, 1H, ArH), 6.80 (d, J = 11.3 Hz, 1H, ArH), 4.97 (s, 2H, CH2), 4.03 (q, J = 7.0 Hz, 2H, CH2), 3.80 (s, 3H, CH3), 2.51 (d,J = 3.7 Hz, 3H, CH3), 1.40 – 1.32 (m, 3H, CH3).

[0097] Example 24 9-(3-fluoro-4-methoxybenzyl)-6-(3-fluoro-5-isopropoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 24 Preparation of )

[0098] Referring to the preparation method of compound I1 in step (3) of Example 1, 3-fluoro-5-isopropoxyphenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 24 Yield: 60%. 1 H NMR (400MHz, DMSO-d6) δ 11.77 (s, 1H, NH), 7.29 (d, J = 2.2 Hz, 2H, ArH), 7.28 – 7.19(m, 1H, ArH), 7.16 – 7.02 (m, 2H, ArH), 6.97 (m, 1H, ArH), 4.92 (s, 2H, CH2), 4.78 (p, J = 6.1 Hz, 1H, CH), 3.81 (s, 3H, CH3), 2.60 (s, 3H, CH3), 1.30 (d, J= 5.9 Hz, 6H, CH3).

[0099] Example 25 9-(3-fluoro-4-methoxybenzyl)-6-(2-fluoro-5-isopropoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 25 Preparation of )

[0100] Referring to the preparation method of compound I1 in step (3) of Example 1, 2-fluoro-5-isopropoxyphenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 25 Yield: 56%. 1 H NMR (400MHz, DMSO-d6) δ 11.43 (s, 1H, NH), 7.31 – 7.19 (m, 2H, ArH), 7.18 – 7.12 (m,3H, ArH), 7.11 – 7.06 (m, 1H, ArH), 4.96 (s, 2H, CH2), 4.62 (t, J = 6.0 Hz, 1H, CH), 3.80 (s, 3H, CH3), 2.60 (s, 3H, CH3), 1.27 (d, J = 6.0 Hz, 6H, CH3).

[0101] Example 26 6-(5-ethoxy-2-fluorophenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I 26 Preparation of )

[0102] Referring to the preparation method of compound I1 in step (3) of Example 1, 2-fluoro-5-ethoxyphenylboronic acid was used to replace 3-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 26 Yield: 55%. 1 H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H, NH), 7.32 – 7.23 (m, 2H, ArH), 7.19 – 7.12 (m, 2H, ArH), 7.10 (s, 2H, ArH), 4.96 (s, 2H, CH2), 4.06 (q, J = 6.9 Hz, 2H, CH2), 3.80 (s, 3H, CH3), 2.60 (s, 3H, CH3), 1.34 (t, J = 6.9 Hz, 3H, CH3).

[0103] Example 27 In vitro antitumor activity experiment

[0104] PC3 (human prostate cancer cells), HT29 (human colon cancer cells), MCF7 (human breast cancer cells), HepG2 (human liver cancer cells), A549 (human lung cancer cell line), and QGP-1 (human pancreatic cancer cells) were selected to determine the inhibitory rate of the target compound I on the test cells. SKPin C1 was used as a positive control. Detailed test results are shown in Tables 2 and 3.

[0105] Table 2. Inhibitory activity of the compounds of the present invention against human tumor cells.

[0106]

[0107] ND: Not detected

[0108] Table 3. Inhibitory activity of the compounds of the present invention against human lung cancer and pancreatic cancer tumor cells.

[0109]

[0110] ND: Not detected

[0111] Tables 2 and 3 show that, after activity tests on various types of cancer cells, the compounds of this invention exhibit strong inhibitory effects on the proliferation of tumor cells such as lung cancer, pancreatic cancer, prostate cancer, colon cancer, breast cancer, and liver cancer. Most compounds showed IC50 inhibitory activity against lung cancer and pancreatic cancer. 50 The activity levels are in the single digits, with some compounds having activity below 1.0 μM, and even a few compounds having activity at the nanomolar level. Meanwhile, the compounds of this invention exhibit an inhibition rate of over 80% against prostate cancer, colon cancer, breast cancer, and liver cancer cells at 20 μM, demonstrating strong tumor cell inhibitory activity.

[0112] Example 28: In vivo antitumor activity experiment of compound I3

[0113] (1) Establish PDX model library

[0114] After obtaining fresh lung cancer surgical specimens (human tumor tissue), necrotic tissue was removed under aseptic conditions, and viable tissue was cut into 1-3 mm³ fragments. Single-cell suspensions were prepared using a combined collagenase IV and DNase I digestion method. After erythrocyte lysis and washing, tumor cells were mixed with pre-cooled matrix gel at a 1:1 ratio, and then injected at 5 × 10⁻⁶ cells per spot. 6 Cells were subcutaneously inoculated into the flanks of 6-8 week old NOD / SCID mice. Tumor growth was monitored regularly after transplantation, and the cells were passaged and expanded when the volume reached 1000-1500 mm³. A stable PDX model library was established through cryopreservation.

[0115] (2) Activity test

[0116] Third-generation tumor tissue was cut into 2-3mm pieces 3 Fragments were subcutaneously transplanted into the flank region of immunodeficient mice. The transplanted tumor grew to 100-200 mm. 3 Afterwards (designated as day 0), mice were randomly divided into a control group, a positive drug group (SKPinC1, 20 mg / kg), and a drug group containing the preferred compound I3 of this invention (10 mg / kg and 20 mg / kg), with 5 mice in each group. The drug was administered intraperitoneally every two days for 21 days. Tumor length (L) and width (W) were measured every 3 days using digital calipers, and mouse weight was recorded until the end of the study. Tumor volume (v) was calculated using the formula v = 0.5 × (L × W²). After 21 days, mice with cervical dislocation were euthanized, and the tumor tissue was isolated and weighed.

[0117] Figure 1 The results of in vivo antitumor activity in a clinical lung cancer PDX model are shown. Figure A shows the tumor size and morphology in different groups after drug administration, and Figure B shows the comparison of tumor weight in different groups after drug administration.

[0118] like Figure 1 As shown, compound I3 of the present invention can significantly inhibit the growth of clinical lung cancer tumors at low doses (10 and 20 mg / kg), and exhibits significant dose-dependent tumor inhibition at low dose levels, with tumor inhibition rates of 65.6% and 82.6%, respectively. The effects are significantly better than those of positive control drugs, indicating that the compound of the present invention has a strong anti-tumor effect on clinical lung cancer tumors.

[0119] The fresh lung cancer surgical specimens used in this embodiment were obtained from a cooperating tertiary hospital. Written informed consent from the patient or their family was obtained before acquisition, and the specimens were approved by the relevant hospital's ethics review committee (approval number: 2025-L111). All patient information was anonymized to fully protect personal privacy.

[0120] All animal experiments in this embodiment were conducted in accordance with the animal protocols approved by the Experimental Animal Welfare and Ethics Committee of Nantong University, with ethics approval number: S20210325-903.

[0121] While some embodiments of the present general inventive concept have been shown and described, those skilled in the art will understand that changes may be made to these embodiments without departing from the principles and spirit of the present general inventive concept, the scope of which is defined by the claims and their equivalents.

Claims

1. A purine ketone derivative, characterized in that, The purine ketone derivative has the structure shown in general formula I: ， Wherein, R1 is selected from one of methoxy-substituted phenyl, naphthyl, biphenyl, and methoxyfluoro-disubstituted phenyl; R2 is selected from phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, dimethylamino-substituted phenyl, ethoxy-substituted phenyl, isopropoxy-substituted phenyl, methylaminophenyl, ethyl-substituted phenyl, ethylaminophenyl, diethylamino-substituted phenyl, ... , , , One of the following: methoxyfluoride disubstituted phenyl, ethoxyfluoride disubstituted phenyl, and isopropoxyfluoride disubstituted phenyl.

2. The purine ketone derivative according to claim 1, characterized in that, R1 is selected from one of phenyl, 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 1-naphthyl, 4-biphenyl, 2-naphthyl, and 3-biphenyl; R2 is selected from phenyl, 3-methoxyphenyl, 3-methylphenyl, 3-(N,N-dimethylamino)-phenyl, 2-fluoro-3-methoxyphenyl, 2-fluoro-5-methoxyphenyl, 4-fluoro-3-methoxyphenyl, 3-fluoro-5-methoxyphenyl, 3-ethoxyphenyl, 3-isopropoxyphenyl, 3-ethylphenyl, 3-isopropylphenyl, 3-methylaminophenyl, and 3-ethylaminophenyl. , , , One of 2-fluoro-5-ethoxyphenyl, 3-fluoro-5-ethoxyphenyl, 3-fluoro-5-isopropoxyphenyl, 2-fluoro-5-isopropoxyphenyl and 3-(N,N-diethylamino)-phenyl.

3. The purine ketone derivative according to claim 1, characterized in that, The purine ketone derivative is any of the following compounds: 9-(3-fluoro-4-methoxybenzyl)-6-(3-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(m-tolyl)-7,9-dihydro-8H-purine-8-one; 6-(3-Dimethylaminophenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 6-(3-Dimethylaminophenyl)-2-methyl-9-(naphth-2-ylmethyl)-7,9-dihydro-8H-purine-8-one 9-(4-(difluoromethoxy)benzyl)-2-methyl-6-phenyl-7,9-dihydro-8H-purine-8-one; 6-(3-Dimethylaminophenyl)-2-methyl-9-(naphth-1-ylmethyl)-7,9-dihydro-8H-purine-8-one; 9-([1,1'-biphenyl]-3-ylmethyl)-6-(3-dimethylaminophenyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 6-(4-fluoro-3-methylphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-6-(3-fluoro-5-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 6-(4-fluoro-3-methoxyphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-6-(3-fluoro-5-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one 6-(3-ethoxyphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-6-(3-isopropoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 6-(3-Ethylphenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-6-(3-isopropylphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(piperazin-1-yl)phenyl)-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(pyrrolidone-1-yl)phenyl)-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(piperidin-1-yl)phenyl)-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-morpholinophenyl)-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-2-methyl-6-(3-(methylamino)phenyl)-7,9-dihydro-8H-purine-8-one; 6-(3-(diethylamino)phenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 6-(3-(ethylamino)phenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 6-(3-ethoxy-5-fluorophenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-6-(3-fluoro-5-isopropoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 9-(3-fluoro-4-methoxybenzyl)-6-(2-fluoro-5-isopropoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one; 6-(5-ethoxy-2-fluorophenyl)-9-(3-fluoro-4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one.

4. A method for preparing the purine ketone derivative as described in claim 1, characterized in that, The synthetic route of the preparation method is shown in the following formula: ， The preparation method includes the following steps: S1.R1-CH2NH2 undergoes a substitution reaction with compound 1 under organic basic conditions to give compound 2; R1 is selected from one of methoxy-substituted phenyl, naphthyl, biphenyl and methoxyfluoro-disubstituted phenyl; S2. Compound 2 reacts with excess carbonyl diimidazole via a Dieckmann condensation reaction to give compound 3; S3. Compound 3 and R2 boric acid were coupled via a Suzuki reaction catalyzed by sodium carbonate, Pd(OAc)2 and sodium triphenylphosphine tris(m-sulfonate) to obtain a purine derivative; Wherein, R2 is selected from phenyl, methoxy-substituted phenyl, methyl-substituted phenyl, dimethylamino-substituted phenyl, ethoxy-substituted phenyl, isopropoxy-substituted phenyl, methylaminophenyl, ethyl-substituted phenyl, ethylaminophenyl, diethylamino-substituted phenyl, etc. , , , One of the following: methoxyfluoride disubstituted phenyl, ethoxyfluoride disubstituted phenyl, and isopropoxyfluoride disubstituted phenyl.

5. The preparation method according to claim 4, characterized in that, The organic base is triethylamine or N,N-diisopropylethylamine.

6. The preparation method according to claim 4, characterized in that, In step S1, the molar ratio of compound 1 to R1-CH2NH2 is 3:3.3; the solvent is n-butanol; the reaction conditions are: N2 protection, reaction at 120 °C for 2 days.

7. The preparation method according to claim 4, characterized in that, In step S2, the molar ratio of compound 2 to carbonyl diimidazole is 2.59:(12-13); the reaction conditions for the Dieckmann condensation reaction are: N2 protection, reaction at 30 °C for 12 h.

8. The preparation method according to claim 4, characterized in that, In step S3, the molar ratio of compound 3 to R2 boric acid is 1:1.

2.

9. The preparation method according to claim 4, characterized in that, In step S3, the conditions for the Suzuki coupling reaction are: N2 protection, reaction at 100°C for about 3 hours.

10. The use of the purine ketone derivative or a pharmaceutically acceptable salt thereof as an active ingredient in the preparation of a medicament for the treatment and / or prevention of malignant tumors, wherein the malignant tumor is one of prostate cancer, colon cancer, breast cancer, liver cancer, lung cancer, and pancreatic cancer.

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