Pyrimido imidazolone derivative and preparation method and medical application thereof

Abstract

The invention belongs to the field of medicines, and discloses pyrimido imidazolone derivatives as well as a preparation method and medical application thereof. The pyrimidino imidazolone derivative has a structure as shown in a general formula I. The preparation method comprises the following steps: carrying out substitution reaction on 1-(4-methoxyphenyl)-1-R2-methylamine and a compound 1 under the catalysis of an organic base to obtain a compound 2; carrying out Dieckmann condensation reaction on the compound 2 and excessive CDI to obtain a compound 3; and carrying out Suzuki coupling reaction on the compound 3 and different substituted arylboronic acid or morpholine under the catalysis of sodium carbonate, Pd (OAc) 2 and TPPTS to obtain the pyrimido imidazolone derivative. The pyrimido imidazolone derivative selectively has a strong inhibition effect on proliferation of tumor cells of lung cancer, prostatic cancer, colon cancer, breast cancer, liver cancer and the like, 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 class of pyrimidine imidazolidinone derivatives, their preparation methods, and pharmaceutical uses. Background Technology

[0002] Cancer treatment has entered the era of precision medicine, but three core challenges remain in clinical practice: first, the variability in treatment response due to tumor heterogeneity; second, multidrug resistance caused by long-term treatment; and third, the toxicity of drugs to normal tissues. These issues make it difficult for existing treatment regimens to balance efficacy and safety, necessitating the exploration of treatment strategies that better meet clinical needs.

[0003] Pyrimidine imidazolides, due to their unique chemical structure and biological activity, possess an ideal kinase inhibitor backbone. Their nitrogen atoms form hydrogen bond networks with key amino acids in the ATP binding pockets of various kinases (such as EGFR, VEGFR, and CDK), making them highly promising candidates for the treatment of cancer and inflammatory diseases. These compounds, structurally similar to purine backbones, can integrate into DNA or RNA, interfering with DNA synthesis and repair in cancer cells, thus inhibiting cancer cell proliferation. Furthermore, the introduction of hydrophobic or electronic effector groups at specific positions can enhance interactions with the hydrophobic pockets of target proteins, improving activity and selectivity. In addition, they can target multiple key cancer-related signaling pathways, such as the PI3K / AKT / mTOR and RAS / MAPK pathways, inhibiting tumor growth and metastasis. Simultaneously, these compounds can induce apoptosis in cancer cells by activating mitochondrial-dependent apoptosis pathways or upregulating pro-apoptotic proteins (such as Bax and p53), thus exerting their anti-cancer effects. Due to their unique and highly modifiable heterocyclic structure, pyrimidine imidazolide scaffolds can exert antitumor effects by interfering with multiple key processes (kinase signaling, DNA function, cell cycle, etc.) of tumor cell proliferation, survival, and spread. This invention patent, through systematic structure-activity relationship studies and rational drug design targeting specific structural modifications, holds promise for developing novel, highly effective, and low-toxicity antitumor drugs from this scaffold. Summary of the Invention

[0004] The purpose of this invention is to provide a pyrimidine imidazolidinone derivative, its preparation method, and its pharmaceutical uses.

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

[0006]

[0007] Wherein, R1 is selected from phenyl, pyridyl, thiophene, pyrazolyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, amino-substituted phenyl, nitro-substituted phenyl, hydroxy-substituted phenyl, dimethylamino-substituted phenyl, trifluoromethoxy-substituted phenyl, methoxyfluoro-disubstituted phenyl, diethylamino-substituted phenyl, etc. One of them; R2 is selected from H or methyl.

[0008] Furthermore, R1 is selected from phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-nitrophenyl, 3-methylphenyl, 2-methoxyphenyl, 3-aminophenyl, 3-hydroxyphenyl, 3-diethylaminophenyl, 3-trifluoromethoxyphenyl, 3-methoxy-4-fluorophenyl, 3-fluoro-4-methoxyphenyl, One of them; R2 is selected from H or methyl.

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

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

[0011]

[0012] In a second aspect, the present invention provides a method for preparing a compound of general formula I, wherein the synthetic route of the preparation method is shown below:

[0013]

[0014] The preparation method includes the following steps:

[0015] S1,1-(4-methoxyphenyl)-1-R2-methylamine under organic base catalysis undergoes a substitution reaction with compound 1 to give compound 2;

[0016] S2. Compound 2 reacts with excess carbonyl diimidazole (CDI) via a Dieckmann condensation reaction to give compound 3;

[0017] S3. Compound 3 was coupled with arylboronic acids or morpholine with different substitutions via a Suzuki coupling reaction catalyzed by sodium carbonate, Pd(OAc)2 and sodium triphenylphosphine trimethylsulfonate (TPPTS) to obtain pyrimidine imidazoline derivative I.

[0018] Furthermore, the substituted arylboronic acids are selected from one of 4-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 4-nitrophenylboronic acid, 3-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-aminophenylboronic acid, 3-hydroxyphenylboronic acid, 3-(N,N-dimethylamino)phenylboronic acid, 3-trifluoromethoxyphenylboronic acid, 3-(N,N-diethylamino)phenylboronic acid, 3-methoxy-4-fluorophenylboronic acid, 3-fluoro-4-methoxyphenylboronic acid, 4-phenoxyphenylboronic acid, pyridine-4-boronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, (1H-pyrazole-4-yl)boronic acid, and 1H-pyrazole-3-boronic acid.

[0019] Furthermore, the organic base is triethylamine or N,N-diisopropylethylamine.

[0020] Furthermore, in step S1, the molar ratio of compound 1 to 1-(4-methoxyphenyl)-1-R2-methylamine is 3:3.3; the reaction conditions for the substitution reaction are: N2 protection, reaction at 120°C for 2 days.

[0021] 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 hours.

[0022] Furthermore, in step S3, the molar ratio of compound 3 to the arylboronic acid with different substitutions is 0.28:0.34; the conditions for the Suzuki coupling reaction are: N2 protection, reaction at 100°C for about 3 hours.

[0023] Thirdly, the present invention provides the use of the above-mentioned pyrimidine imidazolidinone 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 lung cancer, prostate cancer, colon cancer, breast cancer, and liver cancer.

[0024] Fourthly, the present invention provides an antitumor drug, wherein the active ingredient of the antitumor drug is a pyrimidine imidazolidinone derivative as described in claim 1 or a pharmaceutically acceptable salt thereof, and the antitumor drug is used to treat and / or prevent malignant tumors, wherein the malignant tumor is one of lung cancer, prostate cancer, colon cancer, breast cancer and liver cancer.

[0025] Compared with existing technologies, this invention, referencing the potential therapeutic value of pyrimidine imidazolidinone analogs in antitumor activity, utilizes the principle of electron isosterism to research and develop novel pyrimidine imidazolidinone derivatives with better antitumor activity. Currently, no reports on such compounds have been found. The compounds of this invention use a pyrimidine imidazolidinone structure as the parent nucleus, introducing different substituents onto the parent nucleus. When the 6-position substituent is a meta-electron-donating phenyl group (such as 3-methoxyphenyl, 3-methylphenyl, 3-aminophenyl, 3-hydroxyphenyl, etc.), it is beneficial to enhance antitumor activity. Furthermore, the meta-substituent group on the 6-position benzene ring exhibits significantly better activity than the para- or ortho-substituent groups. For example, a meta-fluorinated phenyl group has six times the anti-lung cancer activity of a para-fluorinated phenyl group. Activity tests on various types of cancer cells have revealed that these compounds selectively exhibit strong inhibitory effects on the proliferation of various tumor cells (including lung cancer, breast cancer, prostate cancer, colon cancer, and liver cancer). Therefore, the compounds of this invention have significant potential for pharmaceutical applications. Detailed Implementation

[0026] 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.

[0027] Example 19: Preparation of 9-(4-methoxybenzyl)-6-(4-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I1)

[0028] Compound 1 (534 mg, 3 mmol), 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 tube 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 and give a white solid 2a with a yield of 86%. 1 H NMR(400MHz,DMSO-d6)δ7.32-7.22(m,2H,ArH),7.11(m,1H,ArH),6.93-6.82(m,2H,Ar H),4.80(s,2H,NH2),4.52(d,J=5.5Hz,2H,CH2),3.73(s,3H,OCH3),2.23(s,3H,CH3).

[0029] 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 white solid 3a with a yield of 67%. 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H,CONH),7.27(d,J=8.7Hz,2H,ArH),6.89(d,J=8.7Hz,2H,ArH),4.91(s,2H,CH2),3.71(s,3H,OCH3),2.53(s,3H,CH3).

[0030] Compound 3a (77 mg, 0.28 mmol), 4-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 I1 was obtained with a yield of 80%. 1 HNMR (400MHz, DMSO-d6) δ11.58(s,1H,CONH),7.98(d,J=8.9Hz,2H,ArH),7.30(d,J=8.7Hz,2H,ArH),7.07(d,J=8. 9Hz, 2H, ArH), 6.90 (d, J = 8.7Hz, 2H, ArH), 4.95 (s, 2H, CH2), 3.84 (s, 3H, CH3), 3.72 (s, 3H, CH3), 2.59 (s, 3H, CH3).

[0031] 13C NMR (101 MHz, DMSO-d6) δ 161.06, 159.44, 159.12, 154.18, 151.53, 141.30, 130.14, 129.46, 129.14, 127.76, 116.14, 115.51, 115.02, 114.54, 114.40, 55.80, 55.52, 42.43, 40.39, 26.06 Example 2 Preparation of 6-(3-fluorophenyl)-9-(4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I2).

[0032] Referring to the preparation method of I1 in Example 1, 3-fluorophenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I2 was obtained with a yield of 87%. 1 H NMR (400MHz, DMSO-d6) δ11.74(s,1H,CONH),7.83(d,J=7.8Hz,1H,ArH),7.76(m,1H,ArH),7.57(m,1H,ArH) ,7.38-7.27(m,3H,ArH),6.90(d,J=8.6Hz,2H,ArH),4.96(s,2H,CH2),3.72(s,3H,CH3),2.61(s,3H,CH3).

[0033] 13 C NMR(101MHz,DMSO-d6)δ163.94,161.51,159.50,159.16,154.18,151.96,139.69,139.67,137.80,137.72,131.25,13 1.16,129.51,128.99,124.73,124.71,117.27,117.06,116.64,115.29,115.06,114.42,55.53,42.52,40.42,26.00.

[0034] Example 39: Preparation of 9-(4-methoxybenzyl)-6-(3-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I3).

[0035] Referring to the preparation method of I1 in Example 1, 3-methoxyphenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I3 was obtained with a yield of 82%. 1H NMR(400MHz,DMSO-d6)δ11.66(s,1H,CONH),8.10(s,1H,ArH),7.54-7.50(m,1H,ArH),7.48-7.41(m,2H,ArH),7.39-7.34(m,1H,ArH),7.3 1(d,J=8.4Hz,2H,ArH),7.07(m,1H,ArH),6.93-6.88(m,2H,ArH),4.96(s,2H,CH2),3.86(s,3H,CH3),3.39(s,3H,CH3),2.61(s,3H,CH3).

[0036] 13 C NMR(101MHz,DMSO-d6)δ159.84,159.49,159.15,159.03,154.18,151.72,141.29,136.88,130.30,129.49,129.07,1 28.99,126.82,121.00,119.43,116.47,116.38,116.23,114.41,113.35,101.59,55.61,55.53,55.27,42.48,26.04.

[0037] Example 46: Preparation of 6-(4-fluorophenyl)-9-(4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I4).

[0038] Referring to the preparation method of I1 in Example 1, 4-fluorophenylboronic acid was substituted for 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I2 was obtained with a yield of 87%.

[0039] 1 H NMR(400MHz,DMSO-d6)δ11.80-11.59(m,1H,CONH),8.12-7.98(m,2H,ArH),7.45-7.25(m,4 H, ArH), 6.90 (d, J = 8.2Hz, 2H, ArH), 4.96 (s, 2H, CH2), 3.72 (s, 3H, OCH3), 2.60 (s, 3H, CH3).

[0040] Example 59: Preparation of 9-(4-methoxybenzyl)-2-methyl-6-(4-nitrophenyl)-7,9-dihydro-8H-purine-8-one (I5).

[0041] Referring to the preparation method of I1 in Example 1, 4-nitrophenylboronic acid was substituted for 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I5 was obtained with a yield of 60%.

[0042] 1 H NMR (400MHz, DMSO-d6) δ11.90(s,1H,CONH),8.35(d,J=8.8Hz,2H,ArH),8.26(d,J=8.7Hz,2H,ArH),7.31 (d,J=8.6Hz,2H,ArH),6.90(d,J=8.7Hz,2H,ArH),4.98(s,2H,CH2),3.72(s,3H,CH3),2.63(s,3H,CH3). 13 C NMR(101MHz,DMSO-d6)δ159.61,159.18,154.22,152.23,148.27,141.55,138.44,129.82 ,129.53,129.41,128.88,124.16,117.49,114.42,114.38,113.88,55.53,42.59,25.97.

[0043] Example 6: Preparation of 9-(4-methoxybenzyl)-2-methyl-6-(m-tolyl)-7,9-dihydro-8H-purine-8-one (I6).

[0044] Referring to the preparation method of I1 in Example 1, 3-methylphenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I6 was obtained with a yield of 74%. 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H,CONH),7.79(d,J=7.3Hz,2H,ArH),7.44-7.38(m,1H,ArH),7.34-7.27(m ,3H,ArH),6.90(d,J=8.6Hz,2H,ArH),4.96(s,2H,CH2),3.72(s,3H,CH3),2.60(s,3H,CH3),2.41(s,3H,CH3).

[0045] 13 C NMR(101MHz,DMSO-d6)δ159.47,159.14,154.25,141.46,138.50,135.34,131.0 0,129.46,129.10,129.04,125.69,114.43,55.54,42.46,40.41,26.05,21.45.

[0046] Example 7: Preparation of 9-(4-methoxybenzyl)-6-(2-methoxyphenyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I7).

[0047] Referring to the preparation method of I1 in Example 1, 2-methoxyphenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I7 was obtained with a yield of 64%. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H,CONH),7.54-7.46(m,2H,ArH),7.33(d,J=8.7Hz,2H,ArH),7.13(d,J=8.3Hz,1H,Ar H),7.07(m,1H,ArH),6.91(d,J=8.7Hz,2H,ArH),4.94(s,2H,CH2),3.79(s,3H,CH3),3.72(s,3H,CH3),2.58(s,3H,CH3).

[0048] 13 C NMR(101MHz,DMSO-d6)δ159.42,159.19,157.22,153.40,150.41,140.47,131.52,131.2 8,129.70,129.26,124.57,120.61,118.18,114.41,111.67,55.68,55.48,42.41,25.97.

[0049] Example 86: Preparation of 6-(3-aminophenyl)-9-(4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I8).

[0050] Referring to the preparation method of I1 in Example 1, 3-aminophenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method to obtain 3g of white solid. After purification, white solid compound I8 was obtained with a yield of 71%. 1 H NMR(400MHz,DMSO-d6)δ11.41(s,1H,CONH),7.33-7.27(m,2H,ArH),7.22(m,1H,ArH),7.15(m,1H,ArH),7.09(m,1H ,ArH),6.93-6.87(m,2H),6.69(m,1H,ArH),5.21(s,2H,NH2),4.95(s,2H,CH2),3.72(s,3H,CH3),2.58(s,3H,CH3).

[0051] 13C NMR(101MHz,DMSO-d6)δ159.37,159.13,154.12,151.53,149.42,142.35,136.00,12 9.66,129.45,129.14,116.22,116.11,116.02,114.42,113.69,55.52,42.43,26.05.

[0052] Example 96: Preparation of 6-(3-hydroxyphenyl)-9-(4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I9).

[0053] Following the preparation method of 3a in Example 1, a white solid 3h was obtained with a yield of 94%.

[0054] Referring to the preparation method of I1 in Example 1, 3-hydroxyphenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I9 was obtained with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H,CONH),9.63(s,1H,OH),7.44(s,1H,ArH),7.37(d,J=7.7Hz,1H, ArH),7.33-7.28(m,3H,ArH),6.89(m,3H,ArH),4.95(s,2H,CH2),3.72(s,3H,CH3),2.59(s,3H,CH3).

[0055] 13 C NMR(101MHz,DMSO-d6)δ159.45,159.13,158.07,154.16,151.69,141.51,136.74,13 0.24,129.48,129.09,119.47,117.51,116.32,115.07,114.41,55.52,42.46,26.03.

[0056] Example 106-(3-Dimethylaminophenyl)-9-(4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I 10 Preparation of )

[0057] Referring to the preparation method of I1 in Example 1, 3-(N,N-dimethylamino)phenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 10 Yield: 60%. 1H NMR(400MHz,DMSO-d6)δ11.51(s,1H,CONH),7.32(m,3H,ArH),7.21-7.16(m,2H,ArH),6.92-6.88(m ,2H,ArH),6.85(m,1H,ArH),4.95(s,2H,CH2),3.72(s,3H,CH3),2.97(s,6H,CH3),2.59(s,3H,CH3).

[0058] 13 C NMR (101MHz, DMSO-d6) δ159.44,159.14,154.16,151.52,150.92,142.63,136.17,129. 72,129.49,129.14,116.59,116.38,114.37(d,J=8.8Hz),111.87,55.53,40.58,26.09.

[0059] Example 119-(4-methoxybenzyl)-2-methyl-6-(3-trifluoromethoxyphenyl)-7,9-dihydro-8H-purine-8-one (I 11 Preparation of )

[0060] Referring to the preparation method of I1 in Example 1, 3-(trifluoromethoxy)phenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 11 Yield 61%. ¹H NMR (400MHz, DMSO) δ 11.78 (s, H, NH), 7.99–7.63 (m, 4H, ArH), 7.50–7.48 (d, 2H, ArH), 7.31–7.29 (d, 2H, ArH), 4.95 (s, 2H, CH₂), 3.70 (s, 3H, CH₃), 2.60 (s, 3H, CH₃).

[0061] 13C NMR(101MHz,DMSO)δ159.61,159.16,154.24,149.14,139.25,137.69,136.18,132.98, 131.29,129.49,128.95,127.69,122.66,120.80,116.79,114.42,55.53,42.53,25.97.

[0062] Example 127-(4-fluoro-3-methoxyphenyl)-9-(4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 12 Preparation of )

[0063] Referring to the preparation method of I1 in Example 1, 4-methoxyphenylboronic acid was substituted for 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 12 Yield: 57%. 1 HNMR(400MHz,DMSO)δ11.65(s,H,NH),7.82-7.30(m,2H,ArH),7.29-6.89(m,5 H,ArH),4.9(s,2H,CH2),3.91(s,3H,CH3),3.70(s,3H,CH3),2.57(s,3H,CH3).

[0064] 13 C NMR (101MHz, DMSO) δ159.53,159.16,154.09,151.68,151.62,147.58,140.67,132. 37,132.34,129.04,121.61,116.35,114.41,113.71,113.69,56.41,42.49,26.02.

[0065] Example 136-(3-fluoro-4-methoxyphenyl)-9-(4-methoxybenzyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I) 13 Preparation of )

[0066] Referring to the preparation method of I1 in Example 1, 3-fluoro-4-methoxyphenylboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 13 Yield: 58%. 1 HNMR(400MHz,DMSO)δ11.65(s,H,NH),7.82-7.30(m,2H,ArH),7.29-6.89(m,5 H,ArH),4.9(s,2H,CH2),3.91(s,3H,CH3),3.70(s,3H,CH3),2.57(s,3H,CH3).

[0067] 13 C NMR (101MHz, DMSO) δ159.53,159.16,154.09,151.68,151.62,147.58,140.67,132. 37,132.34,129.04,121.61,116.35,114.41,113.71,113.69,56.41,42.49,26.02.

[0068] Example 149-(4-methoxybenzyl)-2-methyl-6-(4-phenoxyphenyl)-7,9-dihydro-8H-purine-8-one (I 14 Preparation of )

[0069] Referring to the preparation method of I1 in Example 1, 4-methoxyphenylboronic acid was substituted for compound 4-phenoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 14 Yield: 53%. 1 H NMR(400MHz,DMSO-d6)δ11.62(s,1H,CONH),8.04-7.98(m,2H,ArH),7.49-7.43(m,2H,ArH),7.34-7.29(m,2H,ArH),7.25 -7.19(m,1H,ArH),7.14-7.08(m,4H,ArH),6.93-6.88(m,2H,ArH),4.96(s,2H,CH2),3.72(s,3H,CH3),2.60(s,3H.CH3).

[0070] 13 C NMR(101MHz,DMSO-d6)δ159.50,159.14,158.80,156.25,154.16,151.65,140.78,130.71,130.54,130.24, 129.50,129.08,124.66,119.86,118.49,115.94,114.41,55.52,42.47,40.05,39.84,39.64,39.43,26.02.

[0071] Example 159-(4-methoxybenzyl)-2-methyl-6-morpholino-7,9-dihydro-8H-purine-8-one (I 15 Preparation of )

[0072] Following the preparation method of I1 in Example 1, morpholine was substituted for 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 15 Yield: 62%. 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H,CONH),7.26-7.22(m,2H,ArH),6.90-6.86(m,2H,ArH),4.86( s,2H,CH2),3.71(s,3H,CH3),3.69-3.65(m,4H,CH2),3.51(t,J=4.7Hz,4H,CH2),2.39(s,3H,CH3).

[0073] Example 169-(4-methoxybenzyl)-2-methyl-6-(4-pyridyl)-7,9-dihydro-8H-purine-8-one (I) 16 Preparation of )

[0074] Referring to the preparation method of I1 in Example 1, pyridine-4-phenylboronic acid was used instead of 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 16 Yield: 62%. 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H,CONH),8.76-8.72(m,2H,ArH),7.96-7.91(m,2H,ArH),7.32(d, J=8.6Hz,2H,ArH),6.90(d,J=8.6Hz,2H,ArH),4.97(s,2H,CH2),3.72(s,3H,CH3),2.63(s,3H,CH3). 13 C NMR(101MHz,DMSO-d6)δ159.65,159.18,154.17,152.22,151.04,150.65,142.54,13 8.24,129.52,128.88,122.62,121.75,117.44,114.43,55.53,42.58,40.42,25.98.

[0075] ESI-MS(m / z):calcd for C19H18N5O2[M+H] + :348.1460,found 348.1455.

[0076] Example 179-(4-methoxybenzyl)-2-methyl-6-(2-thienyl)-7,9-dihydro-8H-purine-8-one (I) 17 Preparation of )

[0077] Following the preparation method of I1 in Example 1, 2-thiopheneboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 16 Yield: 62%. 1 H NMR(400MHz,DMSO-d6)δ11.83(s,1H,CONH),8.76-8.72(m,2H,ArH),7.96-7.91(m,2H,ArH),7.32(d, J=8.6Hz,2H,ArH),6.90(d,J=8.6Hz,2H,ArH),4.97(s,2H,CH2),3.72(s,3H,CH3),2.63(s,3H,CH3).

[0078] 13 C NMR(101MHz,DMSO-d6)δ159.65,159.18,154.17,152.22,151.04,150.65,142.54,13 8.24,129.52,128.88,122.62,121.75,117.44,114.43,55.53,42.58,40.42,25.98.

[0079] ESI-MS(m / z):calcd for C19H18N5O2[M+H] + :348.1460,found 348.1452.

[0080] Example 189-(4-methoxybenzyl)-2-methyl-6-(2-thienyl)-7,9-dihydro-8H-purine-8-one (I) 18 Preparation of )

[0081] Following the preparation method of I1 in Example 1, 3-thiopheneboronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 16 Yield: 62%. 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H,CONH),8.35(m,1H,ArH),7.84(m,1H,ArH),7.72(m,1H,ArH),7 .32-7.27(m,2H,ArH),6.92-6.87(m,2H,ArH),4.95(s,2H,CH2),3.71(s,3H,CH3),2.58(s,3H,CH3). 13 C NMR(101MHz,DMSO-d6)δ159.42,159.14,154.21,151.72,137.64,137.34,129.4 4,129.07,127.68,127.46,127.41,115.01,114.43,55.53,42.47,40.42,26.06.

[0082] Example 199-(4-methoxybenzyl)-2-methyl-6-(1H-pyrazol-4-yl)-7,9-dihydro-8H-purine-8-one (I) 19 Preparation of )

[0083] Referring to the preparation method of I1 in Example 1, the compound (1H-pyrazole-4-yl)boronic acid was used to replace 4-methoxyphenylboronic acid in the method, and after purification, a white solid compound I was obtained. 19 Yield: 80%.1 HNMR(400MHz,DMSO-d6)δ14.23(s,1H,NH),12.21(s,1H,CONH),9.38(s,1H,CH),9.04(s,1H,CH),8.10( d,J=8.6Hz,2H,ArH),7.70(d,J=8.7Hz,2H,ArH),5.75(s,2H,CH2),4.52(s,3H,CH3),3.36(s,3H,CH3).

[0084] 13 C NMR (101MHz, DMSO-d6) δ159.59,159.09,154.08,150.95,137.00,129.39,129.14,117.62,114.40,113.72,55.53,42.35,40.29,26.02.

[0085] Example 209-(4-methoxybenzyl)-2-methyl-6-(1H-pyrazol-3-yl)-7,9-dihydro-8H-purine-8-one (I) 20 Preparation of )

[0086] Referring to the preparation method of I1 in Example 1, 4-methoxyphenylboronic acid was replaced by compound 1H-pyrazole-3-boronic acid, and after purification, a white solid compound I was obtained. 20 Yield: 80%. 1 H NMR(400MHz,CDCl3)δ9.16(s,1H,CONH),7.60-7.55(m,1H,ArH),7.41-7.35(m,2H,ArH),7.1 9(m,2H,ArH),6.81-6.75(m,2H,ArH),4.97(s,2H,CH2),3.70(s,3H,CH3),2.62(s,3H,CH3).

[0087] 13 C NMR (101MHz, DMSO-d6) δ159.92,159.19,153.37,151.47,134.80,129.43,128.67,117.61,114.42,104.67,55.53,42.88,40.63,40.42,25.49.

[0088] Example 21(R)-6-(3-(dimethylamino)phenyl)-9-(1-(4-methoxyphenyl)ethyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I 21 Preparation of )

[0089] Compound 1 (534 mg, 3 mmol), (R)-1-(1-bromoethyl)-4-methoxybenzene (413 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 reacted at 120 °C under N2 protection 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 and give a white solid 2b in 78% yield.

[0090] Compound 2b (570 mg, 2.14 mmol) was dissolved in anhydrous tetrahydrofuran (6 ml) under N2 protection. CDI (1.74 g, 10.7 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 compound 3b with a yield of 65%.

[0091] Compound 3b (50 mg, 0.17 mmol), 3-dimethylaminophenylboronic acid (23 mg, 0.19 mmol), sodium carbonate (36 mg, 0.34 mmol), palladium acetate (2 mg, 0.009 mmol), and trisodium triphenylphosphine tris(m-sulfonate) (12 mg, 0.02 mmol) were added to a Schlenk tube under N2 protection. A water:acetonitrile ratio of 2:1 (6 mL) was added as a solvent to the Schlenk tube, and the reaction was carried out at 100 °C for approximately 3 h. The reaction was monitored by TLC until completion, and after purification, a white solid compound I was obtained. 21 Yield: 70%. 1 H NMR (400MHz, DMSO-d6) δ11.46(s,1H,NH),7.40(d,J=8.7Hz,2H,ArH),7.31(s,1H,ArH),7.21–7.15(m,2H,ArH),6.90(d,J=8.8Hz,2H,Ar H),6.86–6.81(m,1H,ArH),5.68(q,J=7.2Hz,1H,ArH),3.72(s,3H,CH3),2.97(s,6H,CH3),2.60(s,3H,CH3),1.95(d,J=7.3Hz,3H,CH3).

[0092] Example 22 (S)-6-(3-(dimethylamino)phenyl)-9-(1-(4-methoxyphenyl)ethyl)-2-methyl-7,9-dihydro-8H-purine-8-one (I 22 Preparation of )

[0093] Compound 1 (534 mg, 3 mmol), (S)-1-(1-bromoethyl)-4-methoxybenzene (413 mg, 3.3 mmol), TEA (1.1 ml, 9 mmol), and n-butanol (6 ml) were added sequentially to a Schlenk tube. The tube 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 and give a white solid 2c with a yield of 75%.

[0094] Compound 2c (570 mg, 2.14 mmol) was dissolved in anhydrous tetrahydrofuran (6 ml) under N2 protection. CDI (1.74 g, 10.7 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 the 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 compound 3c.

[0095] Compound 3c (50 mg, 0.17 mmol), 3-dimethylaminophenylboronic acid (23 mg, 0.19 mmol), sodium carbonate (36 mg, 0.34 mmol), palladium acetate (2 mg, 0.009 mmol), and trisodium triphenylphosphine tris(m-sulfonate) (12 mg, 0.02 mmol) were added to a Schlenk tube under N2 protection. A water:acetonitrile ratio of 2:1 (6 mL) was added as a solvent to the Schlenk tube, and the reaction was carried out at 100 °C for approximately 3 h. The reaction was monitored by TLC until completion, and the purified product was a white solid, compound I. 22 Yield: 67%. 1 H NMR (400MHz, DMSO-d6) δ11.44(s,1H,NH),7.39(d,J=8.7Hz,2H,ArH),7.31(t,J=7.9Hz,1H,ArH),7.19–7.12(m,2H,ArH),6.89(d,J=8.8Hz ,2H,ArH),6.86–6.81(m,1H,ArH),5.67(q,J=7.2Hz,1H),3.71(s,3H,CH3),2.96(s,6H,CH3),2.58(s,3H,CH3),1.94(d,J=7.3Hz,3H,CH3).

[0096] Example 23 In vitro antitumor activity experiment

[0097] A549 (human lung cancer cell line), PC3 (human prostate cancer cells), HT29 (human colon cancer cells), MCF7 (human breast cancer cells), and HepG2 (human liver cancer cells) were selected to determine the target compound I. 1-20The inhibition rate of the positive control drug SKPin C1 on the test cells was compared with that of the test cells. Detailed test results are shown in Table 2.

[0098] Table 2. Inhibitory activity of the compounds of the present invention on human tumor cells

[0099]

[0100] After testing the activity of various cancer cells, it was found that the compounds of this invention have a strong inhibitory effect on the proliferation of tumor cells such as lung cancer, prostate cancer, colon cancer, breast cancer, and liver cancer. Most of the compounds have single-digit IC50 values ​​for lung cancer, and some are even below 1.0 μM. At the same time, they have an inhibition rate of more than 80% for prostate cancer, colon cancer, breast cancer, and liver cancer at 20 μM, showing strong inhibitory activity.

[0101] 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 pyrimidinimidazole derivative, characterized in that, The pyrimidine imidazolidinone derivative has the structure shown in general formula I: Wherein, R1 is selected from phenyl, pyridyl, thiophene, pyrazolyl, methyl-substituted phenyl, methoxy-substituted phenyl, halogen-substituted phenyl, amino-substituted phenyl, nitro-substituted phenyl, hydroxy-substituted phenyl, dimethylamino-substituted phenyl, trifluoromethoxy-substituted phenyl, methoxyfluoro-disubstituted phenyl, diethylamino-substituted phenyl, etc. One of them; R2 is selected from H or methyl.

2. The pyrimidine imidazolidinone derivative according to claim 1, characterized in that, R1 is selected from 4-methoxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, 4-fluorophenyl, 4-nitrophenyl, 3-methylphenyl, 2-methoxyphenyl, 3-aminophenyl, 3-hydroxyphenyl, 3-(N,N-dimethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 3-trifluoromethoxyphenyl, 3-methoxy-4-fluorophenyl, 3-fluoro-4-methoxyphenyl. One of them; R2 is selected from H or methyl.

3. A method for preparing the pyrimidine imidazolidinone 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: S1.1-(4-methoxyphenyl)-1-R2-methylamine undergoes a substitution reaction with compound 1 under organic base catalysis to give compound 2, where R2 is selected from H or methyl; S2. Compound 2 reacts with excess carbonyl diimidazole via a Dieckmann condensation reaction to give compound 3; S3. Compound 3 was coupled with arylboronic acids or morpholine with different substitutions via a Suzuki coupling reaction catalyzed by sodium carbonate, Pd(OAc)2 and sodium triphenylphosphine tris(m-sulfonate) to obtain pyrimidine imidazolidinone derivative I; The different substituted arylboronic acids are selected from one of 4-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 4-nitrophenylboronic acid, 3-methylphenylboronic acid, 2-methoxyphenylboronic acid, 3-aminophenylboronic acid, 3-hydroxyphenylboronic acid, 3-(N,N-dimethylamino)phenylboronic acid, 3-trifluoromethoxyphenylboronic acid, 3-(N,N-diethylamino)phenylboronic acid, 3-methoxy-4-fluorophenylboronic acid, 3-fluoro-4-methoxyphenylboronic acid, 4-phenoxyphenylboronic acid, pyridine-4-boronic acid, 2-thiopheneboronic acid, 3-thiopheneboronic acid, (1H-pyrazole-4-yl)boronic acid, and 1H-pyrazole-3-boronic acid.

4. The preparation method according to claim 3, characterized in that, The organic base is triethylamine or N,N-diisopropylethylamine.

5. The preparation method according to claim 3, characterized in that, In step S1, the molar ratio of compound 1 to 1-(4-methoxyphenyl)-1-R2-methylamine is 3:3.

3.

6. The preparation method according to claim 3, characterized in that, In step S1, the reaction conditions for the substitution reaction are: N2 protection, reaction at 120°C for 2 days.

7. The preparation method according to claim 3, characterized in that, 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.

8. The preparation method according to claim 3, characterized in that, In step S3, the molar ratio of compound 3 to the arylboronic acid with different substitutions is 0.28:0.34; the conditions for the Suzuki coupling reaction are: N2 protection, reaction at 100°C for about 3 hours.

9. The use of the pyrimidine imidazolidinone 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 lung cancer, prostate cancer, colon cancer, breast cancer, and liver cancer.

10. An antitumor drug, characterized in that, The active ingredient of the antitumor drug is a pyrimidine imidazolidinone derivative as described in claim 1 or a pharmaceutically acceptable salt thereof, and the antitumor drug is used to treat and / or prevent malignant tumors, wherein the malignant tumor is one of lung cancer, prostate cancer, colon cancer, breast cancer, and liver cancer.

Images