CN113999210B - Group of 2-phenylamino-4-triazolyl pyrimidine derivatives and application thereof - Google Patents
Group of 2-phenylamino-4-triazolyl pyrimidine derivatives and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a 2-phenylamino-4-triazolyl pyrimidine derivative which has the following structureThe illustration is:
the method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 1 Hydrogen, chlorine, fluorine, trifluoromethyl; r is R 2 Methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; r is R 3 Is that
or-SO 2 NH 2 . Pharmacological experiments show that the compounds and pharmaceutically acceptable salts thereof have the effect of inhibiting tumor cell proliferation.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a group of 2-phenylamino-4-triazolyl pyrimidine derivatives and application thereof in the field of tumor treatment.
Background
Tumors are one of the major refractory diseases that seriously threaten human life and health. Malignant tumor becomes the first cause of death of residents in China. Although the antitumor drugs play an important role in clinical treatment of tumor patients as an important means of tumor treatment, most of the antitumor drugs clinically applied at present are cytotoxic drugs, and have the problems of large toxic and side effects, easy drug resistance and the like. Therefore, searching for a compound with novel structure and strong tumor killing power is one of the efforts of pharmaceutical chemists.
Cyclin-dependent kinases (CDKs) are a class of cell cycle regulated kinases belonging to the Ser/Thr family, which are the core of cell cycle regulation and which form a cell cycle regulated network with cyclin (cyclin) and cyclin-dependent kinase inhibitors (CKIs) to regulate the progression of the cell cycle. There are 21 members of the CDK family that have been found. Up-regulation of expression of a portion of CDK family kinases is intimately involved in the development of tumors. For example, up-regulation of CDK2, CDK4, CDK6, CDK8, CDK11 is positively correlated with development and exacerbation of breast and rectal cancer. Therefore, selectively inhibiting the activity of CDK and preventing abnormal proliferation of tumor cells is one of the important ideas for tumor treatment. Currently marketed inhibitors of the CDK family include the CDK4/6 dual inhibitor palbociclib developed by the company Condui, the CDK4/6 inhibitor ribociclib developed by the company Norhua, and the Abemacilib from the company Gift, for use in combination with letrozole in the treatment of ER+/HER 2-advanced breast cancer. In addition to these three drugs that have been marketed, ten or more active small molecules targeting CDKs are currently in early stages of marketing or clinical trials.
Disclosure of Invention
The invention aims to provide a 2-phenylamino-4-triazolyl pyrimidine derivative with proliferation inhibition effect on tumor cells.
The invention also aims to provide the application of the 2-phenylamino-4-triazolyl pyrimidine derivative in medical anticancer.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the 2-phenylamino-4-triazolyl pyrimidine derivative and pharmaceutically acceptable salt thereof provided by the invention have the following structural general formula:
wherein R is 1 Hydrogen, chlorine, fluorine, trifluoromethyl;
R 2 methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
R 3 is that
or-SO 2 NH 2 。
The 4-triazole-2-anilinopyrimidine derivative and the pharmaceutically acceptable salt thereof can be selected from one of the following compounds:
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzamide;
oxy- (2-aminophenyl) -4- ((5-fluoro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
4- (1-cyclopentyl-1-hydro-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-cyclohexyl-1-hydro-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- ((4- (1-cyclopentyl-1-hydro-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzenesulfonamide;
4- (1-cyclohexyl-1-hydro-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-isopropyl-1-hydro-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-cyclopentyl-1-hydro-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
4- (1-cyclohexyl-1-hydro-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-isopropyl-1-hydro-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine.
The invention provides application of the 2-phenylamino-4-triazolyl pyrimidine derivative or pharmaceutically acceptable salt thereof in preparing anticancer drugs, namely tumor treatment.
Furthermore, the invention also provides application of the 2-phenylamino-4-triazolyl pyrimidine derivative or pharmaceutically acceptable salt thereof in preparing medicines for preventing and treating liver cancer and colon cancer.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively provides a class of 2-phenylamino-4-triazolyl pyrimidine derivatives. The test results show that: the 2-phenylamino-4-triazolyl pyrimidine derivative has better CDK inhibition activity, thereby playing a role in inhibiting tumor proliferation, and can be used for preventing and treating cancers, especially lung cancer and colon cancer.
Detailed Description
The following describes the technical scheme of the present invention in further detail with reference to examples, but the scope of the present invention is not limited thereto.
In the examples described below, unless otherwise specified, the starting materials used were either commercially available products which are commercially available as they are or can be synthesized by reference to the prior art.
Example 1: 2-chloro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 a)
2-chloro-4-ethynyl pyrimidine (1, 178mg,1.28 mmol), azidocyclopropane (2-Azidopropane, 130mg,1.53 mmol) were added to a mixed solvent of tetrahydrofuran (THF, 5 mL) and water (5 mL) and stirred at room temperature. Copper sulfate pentahydrate (CuSO) 4 .5H 2 O,65mg,0.26 mmol)) and sodium ascorbate (103 mg,0.52 mmol) were dissolved in water (5 mL), and the solution was added to the above-mentioned stirring system to react for 1h. After the completion of the reaction, ethyl acetate (20 mL) was added to the reaction system, extraction was performed 3 times with water, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate=10:1, volume ratio) to give a white solid (2 a). Yield: 55%. 1 H NMR(500MHz,CDCl 3 ):δ＝8.67(d,1H,J＝6.5Hz,Ar-H),8.35(s,1H,triazole-H),8.07(d,1H,J＝6.5Hz,Ar-H),4.97-4.89(m,1H,CH),1.65(d,6H,J＝6.5Hz,CH 3 )；ESI-MS:m/z＝224[M+H] + 。
Example 2: 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 b)
Preparation method referring to example 1, wherein azidocyclopropane was replaced with Azidocyclopentane (Azidocyclopentane), a white solid (2 b) was obtained in yield: 81%. 1 H NMR(500MHz,CDCl 3 ):δ＝8.67(d,1H,J＝6.0Hz,Ar-H),8.33(s,1H,triazole-H),8.07(d,1H,J＝6.5Hz,Ar-H),5.07-5.00(m,1H,CH),2.36-2.30(m,2H,CH 2 ),2.12-2.07(m,2H,CH 2 ),1.97-1.90(m,2H,CH 2 ),1.84-1.78(m,2H,CH 2 )；ESI-MS:m/z＝250[M+H] + 。
Example 3: 2-chloro-4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 c)
Preparation method referring to example 1, wherein azidocyclopropane was replaced with azidocyclohexane (Azido-cyclohexane), a white solid (2 c) was obtained in yield: 79%. 1 H NMR(500MHz,CDCl 3 ):δ＝8.66(d,1H,J＝6.5Hz,Ar-H),8.34(s,1H,triazole-H),8.06(d,1H,J＝6.5Hz,Ar-H),4.58-4.52(m,1H,CH),2.30-2.26(m,2H,CH 2 ),1.99-1.94(m,2H,CH 2 ),1.82-1.72(m,3H,CH 2 ),1.53-1.41(m,2H,CH 2 ),1.32-1.29(m,1H,CH 2 )；ESI-MS:m/z＝264[M+H] + 。
Example 4: 2-chloro-4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidine (2 d)
Preparation method reference example 1 wherein 2-chloro-4-ethynyl pyrimidine and azidocyclopropane are replaced with 2-chloro-4-ethynyl-5-fluoropyrimidine (2-chloro)o-4-ethyl-5-fluoromatridine) and azidocyclohexane. White solid (2 d) was obtained in yield: 74%. 1 H NMR(500MHz,CDCl 3 ):δ＝8.56(d,1H,J＝3.0Hz,Ar-H),8.31(s,1H,triazole-H),4.63-4.55(m,1H,CH),2.31-2.27(m,2H,CH 2 ),1.99-1.95(m,2H,CH 2 ),1.85-1.76(m,3H,CH 2 ),1.55-1.46(m,2H,CH 2 ),1.37-1.32(m,1H,CH 2 )；ESI-MS:m/z＝282[M+H] + 。
Example 5:4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid methyl ester (3 a)
Palladium bis dibenzylidene acetonate (Pd (dba)) 2 0.03 mmol), 4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene (Xantphos, 0.01 mmol), cesium carbonate (Cs) 2 CO 3 0.60 mmol) was added to a mixed solution of 2-chloro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 a,0.30 mmol) and methyl 4-aminobenzoate (0.33 mmol) in dioxane (10 mL), the air in the reaction system was replaced with nitrogen, the reaction was allowed to react at 110℃for 5 hours, then cooled to room temperature, the solvent was removed under reduced pressure, methylene chloride was added to the residue, extracted with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography (methylene chloride: methanol=15:1, volume ratio), to give a white solid, yield: 80%. 1 H NMR(400MHz,DMSO)δ10.17(s,1H),8.79(s,1H),8.63(d,J＝5.1Hz,1H),7.99(dd,J＝25.8,8.9Hz,4H),7.50(d,J＝5.1Hz,1H),4.97(hept,J＝6.7Hz,1H),3.83(s,3H),1.60(s,3H),1.59(s,3H). 13 C NMR(101MHz,DMSO)δ166.06,159.70,159.14,157.48,145.13(2C),130.29(2C),122.97,121.66,117.74(2C),108.23,52.90,51.66,22.53(2C).ESI-MS m/z:339.2[M+H] + 。
Example 6:4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid methyl ester (3 b)
Preparation method referring to example 5, wherein 2-chloro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 a) was replaced with 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 b), white solid (3 b) was obtained, yield: 84%. 1 H NMR(400MHz,DMSO)δ10.17(s,1H),8.77(s,1H),8.64(d,J＝5.1Hz,1H),8.09–7.89(m,4H),7.50(d,J＝5.1Hz,1H),5.12(p,J＝7.0Hz,1H),3.84(s,3H),2.34–2.17(m,2H),2.16–2.00(m,2H),1.96–1.80(m,2H),1.81–1.62(m,2H). 13 C NMR(101MHz,DMSO)δ166.05,159.70,159.13,157.45,145.15,145.13,130.26(2C),123.83,121.67,117.74(2C),108.26,61.46,51.66,32.82(2C),23.66(2C).ESI-MS m/z:365.2[M+H] + 。
Example 7:4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid methyl ester (3 c)
Preparation method referring to example 5, wherein 2-chloro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 a) was replaced with 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2 c), white solid (3 c) was obtained, yield: 83%. 1 H NMR(400MHz,DMSO)δ10.19(s,1H),8.78(s,1H),8.63(d,J＝5.0Hz,1H),7.99(dd,J＝24.6,8.7Hz,4H),7.50(d,J＝5.0Hz,1H),4.77–4.48(m,1H),3.83(s,3H),2.25–2.06(m,2H),1.98–1.80(m,4H),1.78–1.63(m,1H),1.58–1.39(m,2H),1.37–1.19(m,1H). 13 C NMR(101MHz,DMSO)δ166.55,160.18,159.67,157.94,145.63,145.46,130.81(2C),123.69,122.10,118.21(2C),108.70,60.05,52.08,33.17(2C),25.14(2C),25.08.ESI-MS m/z:379.2[M+H] + 。
Example 8:4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 a)
Methyl 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3 a,250 mg) was added to 6mL of methanol for dissolution. Sodium hydroxide (NaOH, 50 mg) was dissolved in 0.5mL of water, and the above solution was added and reacted at 60℃for about 5 hours until the reaction of the raw materials was completed. And (3) treatment: the reaction solution was cooled to room temperature, the pH was adjusted to neutrality with 2N hydrochloric acid, and the reaction solution was evaporated to dryness to give crude 4a (white solid) which was directly taken to the next step without further purification. 1 H NMR(400MHz,DMSO)δ10.11(s,1H),8.78(s,1H),8.63(d,J＝5.0Hz,1H),7.96(dd,J＝22.9,8.7Hz,4H),7.49(d,J＝5.1Hz,1H),5.04–4.88(m,1H),1.61(s,3H),1.59(s,3H). 13 C NMR(101MHz,DMSO)δ167.18,159.75,159.11,157.49,145.15,144.73,130.40(2C),122.94,122.90,117.67(2C),108.13,52.89,22.52(2C).ESI-MS m/z:325.1[M+H] + 。
Example 9:4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 b)
Preparation method referring to example 8, methyl 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3 a) was replaced with methyl 4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3 b) to give white solid (4 b). 1 H NMR(400MHz,DMSO)δ10.13(s,1H),8.79(s,1H),8.62(d,J＝5.1Hz,1H),7.95(dd,J＝26.7,8.8Hz,4H),7.48(d,J＝5.1Hz,1H),5.12(p,J＝6.9Hz,1H),2.33–2.17(m,2H),2.13–1.97(m,2H),1.92–1.78(m,2H),1.77–1.61(m,2H). 13 C NMR(101MHz,DMSO)δ167.27,159.74,159.10,157.42,145.15,144.64,130.35(2C),123.90,123.87,117.66(2C),108.13,61.42,32.82(2C),23.66(2C).ESI-MS m/z:351.2[M+H] + 。
Example 10:4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 c)
Preparation method referring to example 8, methyl 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3 a) was replaced with methyl 4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3 c) to give white solid (4 c). 1 H NMR(400MHz,DMSO)δ12.56(s,1H),10.13(s,1H),8.77(s,1H),8.62(d,J＝5.1Hz,1H),7.96(dd,J＝22.2,8.7Hz,4H),7.48(d,J＝5.1Hz,1H),4.78–4.50(m,1H),2.23–2.06(m,2H),2.01–1.80(m,4H),1.77–1.62(m,1H),1.46(q,J＝13.2Hz,2H),1.37–1.13(m,2H). 13 C NMR(101MHz,DMSO)δ167.68,160.23,159.64,157.94,145.49,145.24,130.93(2C),123.66,123.32,118.14(2C),108.60,60.03,33.17(2C),25.14(2C),25.08.ESI-MS m/z:365.2[M+H] + 。
Example 11: (2- (4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide) phenyl) carbamic acid tert-butyl ester (5 a)
4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 a,250mg,0.77 mmol) and tert-butyl 2-aminophenylcarbamate (161 mg,0.77 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (HATU, 322mg,0.85 mmol) was added to N, N-dimethylformamide (5 mL), diisopropylethylamine (0.5 mL) was added and reacted overnight at room temperature. And (3) treatment: dichloromethane was added to the reaction solution, the mixture was extracted with saturated brine, and the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column to give a white solid (5 a), yield: 71%. 1 H NMR(400MHz,DMSO)δ10.10(s,1H),9.76(s,1H),8.79(s,1H),8.69(s,1H),8.63(d,J＝5.1Hz,1H),8.00(dd,J＝25.5,8.8Hz,4H),7.61–7.50(m,2H),7.49(d,J＝5.1Hz,1H),7.26–7.11(m,2H),4.97(hept,J＝6.7Hz,1H),1.60(s,3H),1.58(s,3H),1.46(s,9H). 13 C NMR(101MHz,DMSO)δ165.46,160.29,159.65,157.97,153.96,145.69,144.46,132.02,130.54(2C),129.05,126.74,126.40,125.85,124.64,124.38,123.40,118.19(2C),108.58,80.15,53.40,28.50(3C),23.05(2C).ESI-MS m/z:515.3[M+H] + 。
Example 12: (2- (4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamido) phenyl) carbamic acid tert-butyl ester (5 b)
Preparation method referring to example 11, wherein 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 a) was replaced with 4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 b) to give a white solid (5 b), yield: 74%. 1 H NMR(400MHz,CDCl 3 )δ9.05(s,1H),8.54(d,J＝5.1Hz,1H),8.17(s,1H),7.97(d,J＝8.7Hz,2H),7.83–7.71(m,3H),7.61(d,J＝5.1Hz,1H),7.51(s,1H),7.33–7.28(m,1H),7.24–7.12(m,2H),6.96(s,1H),5.09–4.94(m,1H),2.39–2.25(m,2H),2.20–2.06(m,2H),2.03–1.89(m,2H),1.87–1.76(m,2H),1.52(s,9H). 13 C NMR(101MHz,CDCl 3 )δ165.30,159.60,158.84,158.12,154.61,146.27,143.12,131.02,130.13,128.57(2C),127.47,125.89,125.87,125.76,124.55,122.07,118.16(2C),109.02,81.22,62.28,33.49(2C),28.31(3C),24.06(2C).ESI-MS m/z:541.3[M+H] + 。
Example 13: (2- (4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamido) phenyl) carbamic acid tert-butyl ester (5 c)
Preparation method referring to example 11, wherein 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 a) was replaced with 4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4 c) to give a white solid (5 c), yield: 74%. 1 H NMR(400MHz,CDCl 3 )δ9.23(s,1H),8.52(d,J＝5.0Hz,1H),8.18(s,1H),8.07–7.91(m,3H),7.76(d,J＝7.5Hz,2H),7.70(d,J＝7.1Hz,1H),7.58(t,J＝10.9Hz,1H),7.47–7.31(m,2H),7.22–7.05(m,2H),4.68–4.36(m,1H),2.36–2.15(m,2H),2.00–1.72(m,4H),1.63–1.40(m,11H),1.39–1.21(m,2H). 13 C NMR(101MHz,CDCl 3 )δ165.48,159.63,158.74,158.12,154.62,146.02,143.20,130.83(2C),130.43,128.60,127.35,125.84,125.74,125.61,124.52,121.40,118.18(2C),108.88,81.00,60.52,38.60(2C),33.49,28.32(2C),25.11(2C),25.00.ESI-MS m/z:555.3[M+H] + 。
Example 14: n- (2-aminophenyl) -4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide (6 a)
Tert-butyl (2- (4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide) phenyl) carbamate (5 a,150 mg) was dissolved in 5mL dichloromethane, trifluoroacetic acid (1 mL) was added dropwise, and after 1H of reaction, the solvent was distilled off to give a white solid 6a, yield: 100%. 1 H NMR(400MHz,DMSO)δ10.04(s,1H),9.58(s,1H),8.77(s,1H),8.62(d,J＝5.1Hz,1H),7.98(s,4H),7.47(d,J＝5.1Hz,1H),7.17(d,J＝7.5Hz,1H),6.98(t,J＝7.6Hz,1H),6.79(d,J＝7.9Hz,1H),6.62(t,J＝7.5Hz,1H),5.08–4.73(m,3H),1.59(s,3H),1.57(s,3H). 13 C NMR(101MHz,DMSO)δ165.46,160.31,159.62,157.95,145.69,143.97,143.54,129.17(2C),127.25,127.08,126.80,124.14,123.39,118.09(2C),116.87,116.68,108.48,53.41,23.03(2C).ESI-MS m/z:415.2[M+H] + 。
Example 15: n- (2-aminophenyl) -4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide (6 b)
Preparation method referring to example 14, wherein tert-butyl (2- (4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide) phenyl) carbamate (5 a) is replaced with(2- (4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide) phenyl) carbamic acid tert-butyl ester (5 b) to give a white solid (6 b), yield: 100%. 1 H NMR(400MHz,DMSO)δ10.10(s,1H),9.98(s,1H),8.76(s,1H),8.64(d,J＝5.1Hz,1H),8.11–7.95(m,4H),7.49(d,J＝5.1Hz,1H),7.35(d,J＝7.3Hz,1H),7.25–6.97(m,3H),5.18–5.07(m,1H),2.32–2.19(m,2H),2.14–1.98(m,2H),1.96–1.81(m,2H),1.80–1.64(m,2H).ESI-MS m/z:441.2[M+H] + 。
Example 16: n- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide (6 c)
Preparation method referring to example 14, wherein tert-butyl (2- (4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide) phenyl) carbamate (5 a) was replaced with tert-butyl (2- (4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide) phenyl) carbamate (5 c), yield was obtained as a white solid (6 c): 100%. 1 H NMR(400MHz,DMSO)δ10.04(s,1H),9.55(s,1H),8.77(s,1H),8.63(d,J＝5.1Hz,1H),8.01(s,4H),7.48(d,J＝5.1Hz,1H),7.20(d,J＝7.0Hz,1H),7.07–6.92(m,1H),6.90–6.74(m,1H),6.74–6.49(m,1H),4.91(s,2H),4.73–4.52(m,1H),2.24–2.07(m,2H),1.97–1.79(m,4H),1.79–1.64(m,1H),1.58–1.39(m,2H),1.38–1.22(m,1H). 13 C NMR(101MHz,DMSO)δ164.91,159.84,159.10,157.47,145.06,143.49,143.04,128.67(2C),126.82,126.54,126.23,123.73,123.05,117.60(2C),116.33,116.18,107.97,59.53,32.69,24.62(2C),24.60.ESI-MS m/z:455.2[M+H] + .
Example 17:4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (7 a)
Preparation method referring to example 6, wherein methyl 4-aminobenzoate was replaced with 4- (4-methylpiperazin-1-yl) aniline, a white solid (7 a) was obtained, yield: 48%. 1 H NMR(400MHz,MeOD)δ8.40(s,1H),8.30(d,J＝5.1Hz,1H),7.52–7.42(m,2H),7.21(d,J＝5.1Hz,1H),6.92–6.83(m,2H),5.02–4.90(m,1H),3.12–2.99(m,4H),2.62–2.47(m,4H),2.27(s,3H),2.25–2.13(m,2H),2.06-1.96(m,2H),1.89–1.78(m,2H),1.75–1.63(m,2H). 13 C NMR(101MHz,MeOD)δ162.05,159.82,159.12,148.08,147.48,134.62,124.48,122.25(2C),118.30(2C),107.90,63.68,55.98(2C),50.78(2C),45.99,34.31(2C),25.08(2C).ESI-MS m/z:405.3[M+H] + 。
Example 18:4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (7 b)
Preparation method referring to example 17, wherein 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine was replaced with 2-chloro-4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidine, a white solid (7 b) was obtained, yield: 51%. 1 H NMR(400MHz,MeOD)δ8.43(s,1H),8.31(d,J＝5.1Hz,1H),7.58–7.45(m,2H),7.22(d,J＝5.1Hz,1H),6.98–6.83(m,2H),4.46(tt,J＝11.6,3.7Hz,1H),3.29–3.04(m,8H),2.70(s,3H),1.89–1.66(m,5H),1.44-1.38(m,2H),1.30-1.12(m,3H). 13 C NMR(101MHz,MeOD)δ162.00,159.83,159.15,147.25,146.92,135.42,123.83,122.13(2C),118.73(2C),108.09,61.91,55.18(2C),54.82,47.90,44.26,34.41(2C),26.21(2C),26.17.ESI-MS m/z:419.3[M+H] + 。
Example 19:4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzenesulfonamide (7 c)
Preparation method is described in example 6, wherein methyl 4-aminobenzoate is replaced by sulfanilamide (4-aminobenzene)Sulfonamide), to give a white solid (7 c), yield: 67%. 1 H NMR(400MHz,MeOD)δ8.62(s,1H),8.56(d,J＝5.1Hz,1H),7.97(d,J＝8.8Hz,2H),7.87(d,J＝8.8Hz,2H),7.48(d,J＝5.0Hz,1H),4.68–4.54(m,1H),2.32–2.18(m,2H),2.07–1.74(m,6H),1.68–1.34(m,4H). 13 C NMR(101MHz,MeOD)δ161.46,160.06,159.14,145.48,137.03,128.22(2C),124.03,119.28(2C),109.50,107.76,62.00,34.42(2C),26.23(2C),26.19.ESI-MS m/z:386.1[M+H] + 。
Example 20:4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine (7 d)
Preparation method referring to example 17, wherein 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine was replaced with 2-chloro-4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidine, a white solid (7 d) was obtained in yield: 41%. 1 H NMR(400MHz,MeOD)δ8.45(d,J＝2.1Hz,1H),8.28(d,J＝2.7Hz,1H),7.49(d,J＝9.0Hz,2H),6.87(d,J＝9.1Hz,2H),4.57–4.40(m,1H),3.11–2.99(m,4H),2.62–2.47(m,4H),2.26(s,3H),2.16–2.05(m,2H),1.90–1.64(m,5H),1.52–1.23(m,3H). 13 C NMR(101MHz,MeOD)δ157.20,148.73(d,J C-F ＝252.9Hz),146.45,146.11(d,J C-F ＝23.5Hz),144.44(d,J C-F ＝11.9Hz),140.65(d,J C-F ＝6.3Hz),133.61,124.71(d,J C-F ＝8.8Hz),120.04(2C),116.96(2C),60.62,54.61(2C),49.49(2C),44.63,32.96(2C),24.82(2C),24.76.ESI-MS m/z:437.3[M+H] + 。
Example 21: cell cycle dependent kinase 2/4/6 (Cyclin-dependent protein kinase 2/4/6, CDK 2/4/6) inhibition Activity assay
1, CDK2 inhibitory Activity test procedure
(1) Preparing a 1 Xkinase buffer: enzymatic buffer kinase 5X (manufacturer: cisbio) was diluted 5-fold with deionized water, with the addition of magnesium chloride (MgCl) 2 ) Manganese chloride (MnCl) 2 ) And Dithiothreitol (DTT), mgCl 2 Final concentrationDegree 10mM, mnCl 2 1mM final concentration, 1mM final concentration of DTT;
(2) Starting with 10 mu M, diluting the test compound 4 times, preparing working solution of the compound to be tested with the concentration of 7 times by using 1 Xkinase buffer, and then adding DMSO (dimethyl sulfoxide) control holes with the same concentration as the holes of the compound to be tested into 2.5 mu L/Kong Jiaru 384-hole reaction plates by using a solvent (DMSO used for preparing the compound is allocated here);
(3) Biotinylated ATF2 (ATF 2 biotin, manufacturer: cisbio) was prepared at a final concentration of 4-fold with a 1 Xkinase buffer, and then in 2.5. Mu.L/Kong Jiaru 384 well reaction plates;
(4) Preparing ATP with a final concentration of 4 times by using a 1 Xkinase buffer, and adding the ATP into 2.5 mu L/Kong Jiaru 384-well reaction plates;
(5) Preparing CDK2 enzyme solution with 4 times of final concentration by using 1 Xkinase buffer, uniformly mixing in 2.5 mu L/Kong Jiaru 384-well reaction plate to initiate reaction, adding 2.5 mu L of 1 Xkinase buffer into a negative control well, and incubating for 60min at room temperature;
(6) 1 Xdetection buffer (manufacturer: cisbio) was added with europium-cryptate (pAb anti-phosphoATF 2-Eucryptate, manufacturer: ciscib) and avidinated XL665 (strepitavidin-XL 665, manufacturer: cisbio), 10. Mu.L/Kong Jiaru 384-well reaction plates, and incubated at room temperature for 60min;
(7) Fluorescence signals at 665nM and 625nM were detected in an microplate reader using HTRF.
2, CDK4/6 inhibitory Activity test procedure
(1) Preparing a 1 Xkinase buffer: enzymatic buffer kinase 5X (manufacturer: cisbio) was diluted 5-fold with deionized water, with the addition of magnesium chloride (MgCl) 2 ) And Dithiothreitol (DTT), mgCl 2 Final concentration 50mM, final concentration of DTT 1mM;
(2) The test compound is diluted 4 times with 10 mu M as the starting point, 7 concentrations are obtained, working solution of the compound to be tested with the final concentration of 4 times is prepared by using 1 Xkinase buffer, then 25 mu L/Kong Jiaru 384 well reaction plates are added with DMSO control with the same concentration as the compound to be tested in the control wells;
(3) Biotinylated phosphorylable retinoblastoma gene substrate (Rb biotinylated peptide, manufacturer: cisbio) was prepared at a final concentration of 4-fold with a 1 Xkinase buffer and then added to 2.5. Mu.L/Kong Jiaru 384 well reaction plates;
(4) Preparing ATP with a final concentration of 4 times by using a 1 Xkinase buffer, and adding the ATP into 2.5 mu L/Kong Jiaru 384-well reaction plates;
(5) Preparing CDK4 and CDK6 enzyme solutions with the final concentration of 4 times by using 1 Xkinase buffer, uniformly mixing in a 2.5 mu L/Kong Jiaru 384-well reaction plate to initiate reaction, adding 2.5 mu L of 1 Xkinase buffer into a negative control well, and incubating for 90min at room temperature;
(6) 1 Xdetection buffer (manufacturer: cisbio) was added with europium-hole-like compound (Anti-p-Rb-K) of phosphorylated Rb antibody and avidinated XL665 (strepitavidin-XL 665, manufacturer: cisbio), 10. Mu.L/Kong Jiaru 384-well reaction plate, and incubated at room temperature for 60min;
(7) Fluorescence signals at 665nM and 625nM were detected in an microplate reader using HTRF.
3 data analysis
Calculating 665/625 ratio, setting negative control group as Tz, solvent control group as C, test compound group as Ti, and calculating enzyme activity inhibition rate of test compound hole; inhibition% = (Ti-Tz)/(C-Tz) 100. The inhibitory effect profile of log (inhibitor) vs. normalized response-Variable slope of GraphPad Prism 5 was used to derive the IC for each compound to inhibit enzyme activity 50 Values. The results are shown in Table 1 below.
Table 1 test results for CDK2, CDK4 and CDK6
As can be seen in table 1: the compounds all had certain enzyme inhibitory activity, with examples 17, 18, 19 and 20 having the best inhibitory activity against CDK2, CDK4 and CDK6 enzymes, and particularly significant inhibitory activity against CDK4 enzymes.
Example 22: cell inhibition Activity test
1 test procedure
(1) Cell seeding
Collecting logarithmic growth phase cells (human liver cancer cell HepG2, human colon cancer cell HCT 116), countingPost-regulatory cell concentration (HepG 2:1.5X10) 5 /mL，HCT116：1.1×10 5 Per mL), 100. Mu.L/well was seeded in 96-well plates and then incubated at 37℃with 5% CO 2 Incubate overnight in incubator.
(2) Fixing parallel control plate, adding to-be-measured object into to-be-measured plate
Parallel control plates: pre-cooling trichloroacetic acid (Trichloroacetic acid, TCA) is added into 25 mu L/hole, the mixture is fixed for 1h at 4 ℃, the plate is washed 5 times by deionized water, and the mixture is naturally dried;
adding the to-be-measured object into the to-be-measured plate: the test compound concentration was 50 μm starting, 10-fold dilution, 5 concentrations. Preparing working solution of compound to be tested with 2 times final concentration by using DMEM complete medium containing 10% FBS, adding 100 mu L/well into 96 wells, adding DMSO control with the same concentration as that of the compound to be tested into solvent control wells, adding complete medium into zeroing wells, and adding 5% CO at 37deg.C 2 Culturing in an incubator for 72 hours.
(3) OD value of the plate to be measured
Adding 50 mu L/hole of precooled 50% TCA, fixing for 1h at 4 ℃, washing the plate with deionized water for 5 times, and naturally airing; adding 0.4% of sulforhodamine B into 100 mu L/hole, dyeing for 10min at room temperature, then adding 1% of acetic acid into 100 mu L/Kong Xi plate for 5 times, and naturally airing; 150. Mu.L/well of 10mM Tris-base was added and the mixture was shaken for about 5min; OD was measured at 515 nm.
2 data analysis
The OD value of the parallel control group is marked as Tz, the OD value of the solvent control group is marked as C, and the OD value of the to-be-measured group is marked as Ti:
growth rate = [ (Ti-Tz)/(C-Tz) ]x100
Inhibition ratio% = 100- [ (Ti-Tz)/(C-Tz) ]x100
Using log value of compound concentration as X axis, corresponding cell growth inhibition rate as Y axis, using log (inhibitor) vs. response-Variable slope fit curve of GraphPad Prism 5 to obtain IC of test compound for inhibiting cell growth 50 Values. The results are shown in the following table.
It can be seen in the table that: the compounds have certain cell growth inhibition activity, wherein the cell growth inhibition activity of the embodiment 14, the embodiment 15, the embodiment 16 and the embodiment 19 is the best, and the compounds can be used as potential drugs for clinically preventing and treating liver cancer and colon cancer.
Claims (4)
1. A group of 2-phenylamino-4-triazolyl pyrimidine derivatives or pharmaceutically acceptable salts thereof, the structures of which are shown as follows:
wherein R is 1 Hydrogen, chlorine, fluorine or trifluoromethyl;
R 2 methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R 3 is that
or-SO 2 NH 2 。
2. The 4-triazole-2-anilinopyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the 4-triazole-2-anilinopyrimidine derivative is selected from any one of the following compounds:
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzamide;
nitrogen- (2-aminophenyl) -4- ((5-fluoro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
4- (1-cyclopentyl-1-hydro-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-cyclohexyl-1-hydro-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- ((4- (1-cyclopentyl-1-hydro-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzenesulfonamide;
4- (1-cyclohexyl-1-hydro-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-isopropyl-1-hydro-1, 2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-cyclopentyl-1-hydro-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzenesulfonamide;
4- (1-isopropyl-1-hydro-1, 2, 3-triazol-4-yl) -5-fluoro-N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine.
3. Use of a 4-triazole-2-anilinopyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the manufacture of an anticancer drug.
4. The use of the 4-triazole-2-anilinopyrimidine derivative or the pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a medicament for preventing and treating liver cancer and colon cancer.
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