CN113999210A - 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 PDF

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CN113999210A
CN113999210A CN202111463946.8A CN202111463946A CN113999210A CN 113999210 A CN113999210 A CN 113999210A CN 202111463946 A CN202111463946 A CN 202111463946A CN 113999210 A CN113999210 A CN 113999210A
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triazol
pyrimidin
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cyclopentyl
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田鑫
王素华
程伟彦
韩思远
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First Affiliated Hospital of Zhengzhou University
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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to 2-phenylamino-4-triazolyl pyrimidine derivatives, which have the following structures:
Figure DEST_PATH_IMAGE001
(ii) a Wherein R is1Hydrogen, chlorine, fluorine, trifluoromethyl; r2Is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; r3Is composed of
Figure 728069DEST_PATH_IMAGE002
or-SO2NH2. Pharmacological experiments show that the compounds and the pharmaceutically acceptable salts thereof have the effect of inhibiting the proliferation of tumor cells.

Description

Group of 2-phenylamino-4-triazolyl pyrimidine derivatives and application thereof
Technical Field
The invention belongs to the field of medicinal 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 intractable diseases seriously threatening human life and health. In China, malignant tumors have become the first cause of death of residents. Although the antitumor drug plays an important role in the clinical treatment of tumor patients as an important means for tumor treatment, most of the antitumor drugs clinically applied at present are cytotoxic drugs, and have the problems of high toxic and side effects, easy generation of drug resistance and the like. Therefore, the search for compounds with novel structures and strong tumor killing power is one of the efforts of pharmaceutical chemists.
Cyclin-dependent kinases (CDKs) are a class of cell cycle regulatory kinases belonging to the Ser/Thr family, which are the core of cell cycle regulation, and constitute, with cyclins and cyclin-dependent kinase inhibitors (CKIs), a cell cycle regulatory network system that regulates cell cycle progression. It has now been found that there are 21 members of the CDK family. The up-regulation of the expression of some CDK family kinases is closely related to the generation and development of tumors. For example, the up-regulation of CDK2, CDK4, CDK6, CDK8, CDK11 is positively correlated with the development and progression of breast and rectal cancer. Therefore, selective inhibition of CDK activity and prevention of abnormal proliferation of tumor cells are important ideas for tumor therapy. CDK family inhibitors currently on the market include the CDK4/6 dual inhibitor palbociclib developed by Peucedanum, the CDK4/6 inhibitor ribociclib developed by Nowa, and abemaciclib developed by Pariety, for use in combination with letrozole in the treatment of advanced breast cancer of ER +/HER 2-. In addition to these three drugs already on the market, over ten active small molecules targeting CDKs are currently in pre-market 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 derivatives of the 2-phenylamino-4-triazolyl pyrimidine derivatives in the medicine anticancer.
In order to achieve the purpose, the invention adopts the following technical scheme:
the 2-phenylamino-4-triazolyl pyrimidine derivatives and the pharmaceutically acceptable salts thereof provided by the invention have the following structural general formula:
Figure BDA0003390522750000011
wherein R is1Hydrogen, chlorine, fluorine, trifluoromethyl;
R2is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R3is composed of
Figure BDA0003390522750000021
or-SO2NH2。
The 4-triazole-2-phenylamino pyrimidine derivatives and pharmaceutically acceptable salts thereof can be selected from one of the following compounds:
Figure BDA0003390522750000022
n- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
n- (2-aminophenyl) -4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
n- (2-aminophenyl) -4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
n- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzamide;
n- (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 h-1,2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-cyclohexyl-1 h-1,2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- ((4- (1-cyclopentyl-1 h-1,2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzenesulfonamide;
4- (1-cyclohexyl-1 h-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 h-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 h-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 derivatives or pharmaceutically acceptable salts thereof in preparing anti-cancer drugs, namely, in treating tumors.
Furthermore, the invention also provides application of the 2-phenylamino-4-triazolyl pyrimidine derivatives or pharmaceutically acceptable salts 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 innovatively provides a class of 2-phenylamino-4-triazolyl pyrimidine derivatives. The test results show that: the 2-phenylamino-4-triazolyl pyrimidine derivatives have good CDK inhibitory activity, so that the tumor proliferation inhibition effect is exerted, and the 2-phenylamino-4-triazolyl pyrimidine derivatives can be used for preventing and treating cancers, particularly lung cancer and colon cancer.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following examples, but the scope of the present invention is not limited thereto.
In the following examples, unless otherwise specified, all the raw materials used were general commercial products which were directly available, or they were synthesized by referring to the existing literature.
Example 1: 2-chloro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2a)
Figure BDA0003390522750000031
2-chloro-4-ethynylpyrimidine (1,178mg, 1.28mmol), azidocyclopropane (2-Azidopropane, 130mg, 1.53mmol) were added to a mixed solvent of tetrahydrofuran (THF, 5mL) and water (5mL) and stirred at ordinary temperature. Mixing copper sulfate pentahydrate (CuSO)4.5H2O, 65mg,0.26mmol)) and sodium ascorbate (103mg,0.52mmol) were dissolved in water (5mL) and the solution was added to the above stirred system for 1 h. After completion of the reaction, ethyl acetate (20mL) was added to the reaction system, and the mixture was extracted with water 3 times, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (petroleum ether: ethyl acetate: 10:1, volume ratio) to obtain a white solid (2 a). Yield: and 55 percent.1H NMR(500MHz,CDCl3):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,CH3)；ESI-MS:m/z＝224[M+H]+。
Example 2: 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2b)
Figure BDA0003390522750000032
Preparation method referring to example 1, wherein azidocyclopropane was replaced with Azidocyclopentane (azidolyclopentane), a white solid (2b) was obtained in yield: 81 percent.1H NMR(500MHz,CDCl3):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,CH2),2.12-2.07(m,2H,CH2),1.97-1.90(m,2H,CH2),1.84-1.78(m,2H,CH2)；ESI-MS:m/z＝250[M+H]+。
Example 3: 2-chloro-4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2c)
Figure BDA0003390522750000041
Preparation method referring to example 1, wherein azidocyclopropane was replaced with azidocyclohexane (Azido-cyclohexane), white solid (2c) was obtained in yield: 79 percent.1H NMR(500MHz,CDCl3):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,CH2),1.99-1.94(m,2H,CH2),1.82-1.72(m,3H,CH2),1.53-1.41(m,2H,CH2),1.32-1.29(m,1H,CH2)；ESI-MS:m/z＝264[M+H]+。
Example 4: 2-chloro-4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidine (2d)
Figure BDA0003390522750000042
The preparation method is as described in example 1, wherein 2-chloro-4-ethynylpyrimidine and azidocyclopropane are replaced with 2-chloro-4-ethynyl-5-fluoropyrimidine (2-chloro-4-ethyl-5-fluoropyrridine) and azidocyclohexane, respectively. White solid (2d) was obtained, yield: 74 percent.1H NMR(500MHz,CDCl3):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,CH2),1.99-1.95(m,2H,CH2),1.85-1.76(m,3H,CH2),1.55-1.46(m,2H,CH2),1.37-1.32(m,1H,CH2)；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 (3a)
Figure BDA0003390522750000043
Bis (dibenzylidene) acetone palladium (Pd (dba)20.03mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos, 0.01mmol), cesium carbonate (Cs)2CO30.60mmol) was added to a solution containing 2-chloro-4- (1-iso-propyl) -benzeneIn a mixed solution of propyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2a, 0.30mmol) and methyl 4-aminobenzoate (0.33mmol) in dioxane (10mL), replacing air in a reaction system with nitrogen, reacting at 110 ℃ for 5 hours, cooling to room temperature, removing the solvent under reduced pressure, adding dichloromethane to the residue, extracting with saturated brine, drying and concentrating the organic phase with anhydrous sodium sulfate, and separating and purifying the obtained crude product by column chromatography (dichloromethane: methanol 15:1 by volume) to give a white solid in yield: 80 percent.1H 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).13C 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 (3b)
Figure BDA0003390522750000051
The preparation process is as in example 5, wherein 2-chloro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2a) is replaced by 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2b) to give white solid (3b) in yield: 84 percent.1H 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).13C 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 (3c)
Figure BDA0003390522750000052
The preparation process is as in example 5, wherein 2-chloro-4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2a) is replaced by 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine (2c) to give white solid (3c) in yield: 83 percent.1H 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).13C 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 (4a)
Figure BDA0003390522750000061
Methyl 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3a, 250mg) was dissolved in 6mL of methanol. Sodium hydroxide (NaOH, 50mg) was dissolved in 0.5mL of water, and the above solution was added to react at 60 ℃ for about 5 hours until the starting material was reacted completely. And (3) treatment: the reaction solution was cooled to room temperature, pH was adjusted to neutral with 2N hydrochloric acid, and the reaction solution was evaporated to dryness to obtain crude 4a (white solid) which was used directly in the next step without further purification.1H 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).13C 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 (4b)
Figure BDA0003390522750000062
The preparation process is as described in example 8, wherein methyl 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3a) is replaced with methyl 4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3b) to give a white solid (4 b).1H 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).13C 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 (4c)
Figure BDA0003390522750000063
The preparation process is as described in example 8, wherein methyl 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3a) is replaced by methyl 4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoate (3c), yielding a white solid (4 c).1H 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).13C 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) benzamido) phenyl) carbamic acid tert-butyl ester (5a)
Figure BDA0003390522750000071
4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4a, 250mg, 0.77mmol) and tert-butyl 2-aminophenylcarbamate (161mg, 0.77mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 322mg, 0.85mmol) were added to N, N-dimethylformamide (5mL), diisopropylethylamine (0.5mL) was added, and the reaction was allowed to proceed overnight at room temperature. And (3) treatment: adding dichloromethane into the reaction solution, extracting with saturated saline, collecting the organic phase, drying with anhydrous sodium sulfate, concentrating, separating with silica gel column to obtain white solid (5a), yield: 71 percent.1H 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).13C 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 (5b)
Figure BDA0003390522750000072
The preparation process is as in example 11, wherein 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4a) is replaced by 4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4b) to give a white solid (5b) in yield: 74 percent.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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: (tert-butyl 2- (4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamido) phenyl) carbamate (5c)
Figure BDA0003390522750000081
Preparation method referring to example 11, wherein 4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4a) was replaced with 4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzoic acid (4c), a white solid (5c) was obtained, yield: 74 percent.1H NMR(400MHz,CDCl3)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).13C NMR(101MHz,CDCl3)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 (6a)
Figure BDA0003390522750000082
Adding tert-butyl (2- (4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamido) phenyl) carbamate (5a, 150mg) into 5mL of dichloromethane for dissolving, and dropwise adding tris (tert-butyl) chlorideFluoroacetic acid (1mL), after 1h of reaction, the solvent was evaporated off to give a white solid 6a, yield: 100 percent.1H 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).13C 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 (6b)
Figure BDA0003390522750000091
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) benzamido) phenyl) carbamate (5a) was replaced with tert-butyl (2- (4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamido) phenyl) carbamate (5b), white solid (6b) was obtained, yield: 100 percent.1H 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 (6c)
Figure BDA0003390522750000092
Preparation method referring to example 14, wherein (2- (4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamido) phenyl) ammoniaTert-butyl carbamate (5a) was replaced with tert-butyl (2- (4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamido) phenyl) carbamate (5c) to give a white solid (6c) with yield: 100 percent.1H 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).13C 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 (7a)
Figure BDA0003390522750000101
Preparation method referring to example 6, wherein methyl 4-aminobenzoate was replaced with 4- (4-methylpiperazin-1-yl) aniline, white solid (7a) was obtained in yield: 48 percent.1H 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).13C 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 (7b)
Figure BDA0003390522750000102
The preparation process referred 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, gave a white solid (7b) in yield: 51 percent.1H 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).13C 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 (7c)
Figure BDA0003390522750000111
The preparation method was as described in example 6, in which methyl 4-aminobenzoate was replaced with sulfanilamide (4-aminobenzenesulfonamide), and white solid (7c) was obtained in yield: 67%.1H 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).13C 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 (7d)
Figure BDA0003390522750000112
The preparation process is as in example 17, where 2-chloro-4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidine is replaced by 2-chloro-4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidineTo obtain a white solid (7d), yield: 41 percent.1H 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).13C NMR(101MHz,MeOD)δ157.20,148.73(d,JC-F＝252.9Hz),146.45,146.11(d,JC-F＝23.5Hz),144.44(d,JC-F＝11.9Hz),140.65(d,JC-F＝6.3Hz),133.61,124.71(d,JC-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 kinase 2/4/6, CDK2/4/6) inhibitory Activity test
1, CDK2 inhibitory Activity test procedure
(1) Preparing 1 × kinase buffer: enzymic buffer kinase 5X (manufacturer: Cisbio) was diluted 5-fold with deionized water and magnesium chloride (MgCl)2) Manganese chloride (MnCl)2) And Dithiothreitol (DTT), MgCl2Final concentration 10mM, MnCl2The final concentration is 1mM, and the final concentration of DTT is 1 mM;
(2) the test compound is diluted 4 times by using 10 mu M as an initial, 7 concentrations are prepared, 1 xkinase buffer is used for preparing a working solution of the test compound with 4 times of final concentration, then 2.5 mu L/hole is added into a 384-hole reaction plate, and a DMSO control with the same concentration as that of the hole of the test compound is added into a solvent (DMSO used for preparing the compound is assigned here) control hole;
(3) biotinylated ATF2(ATF2 biotin, Cisbio) was prepared at 4-fold final concentration using 1 Xkinase buffer, and 2.5. mu.L/well was added to a 384-well reaction plate;
(4) preparing ATP with 4 times final concentration by using 1 × kinase buffer, and adding 2.5 μ L/hole into a 384-hole reaction plate;
(5) preparing CDK2 enzyme solution with 4 times of final concentration by using 1 × kinase buffer, adding 2.5 μ L/hole into a 384-hole reaction plate, uniformly mixing to start reaction, adding 2.5 μ L of 1 × kinase buffer into a negative control hole, and incubating for 60min at room temperature;
(6) europium cryptate of phosphorylated ATF2 antibody (pAb anti-phospho ATF2-Eu cryptate, Ciscib) and avidin XL665(Streptavidin-XL665, Cisbio) were added to 1 XDetection buffer (manufacturer: Cisbio) at 10. mu.L/well in 384-well reaction plates and incubated at room temperature for 60 min;
(7) fluorescent signals at 665nM and 625nM were detected in the microplate reader using HTRF.
2, CDK4/6 inhibitory Activity test procedure
(1) Preparing 1 × kinase buffer: enzymic buffer kinase 5X (manufacturer: Cisbio) was diluted 5-fold with deionized water and magnesium chloride (MgCl)2) And Dithiothreitol (DTT), MgCl2The final concentration is 50mM, and the final concentration is 1 mM;
(2) the test compound is diluted by 4 times and has 7 concentrations by taking 10 mu M as an initial, 1 xkinase buffer is used for preparing a working solution of the compound to be tested with 4 times of final concentration, 25 mu L/hole is added into a 384-hole reaction plate, and DMSO with the same concentration as that of the hole of the compound to be tested is added into a control hole;
(3) preparing 4-fold final concentration of biotinylated retinoblastoma gene substrate (Rb biotinylated peptide, Cisbio) with 1 × kinase buffer, adding 2.5 μ L/well into 384-well reaction plate;
(4) preparing ATP with 4 times final concentration by using 1 × kinase buffer, and adding 2.5 μ L/hole into a 384-hole reaction plate;
(5) preparing CDK4 and CDK6 enzyme solutions with 4 times of final concentration by using 1 xkinase buffer, adding 2.5 mu L/hole into a 384-hole reaction plate, uniformly mixing to start reaction, adding 2.5 mu L of 1 xkinase buffer into a negative control hole, and incubating for 90min at room temperature;
(6)1 XDetection buffer (manufacturer: Cisbio) was added with europium cryptate of phosphorylated Rb antibody (Anti-p-Rb-K, manufacturer: Cisbio) and avidin XL665(Streptavidin-XL665, manufacturer: Cisbio), 10. mu.L/well was added to 384-well reaction plates and incubated at room temperature for 60 min;
(7) fluorescent signals at 665nM and 625nM were detected in the microplate reader using HTRF.
3 data analysis
665/625 ratio is calculated, negative control group is set as Tz, solvent control group is set as C, and group of compounds to be tested is set asRecording as Ti, and calculating the enzyme activity inhibition rate of the compound hole to be detected; the inhibition rate is (Ti-Tz)/(C-Tz) × 100, and a dose-response curve is fitted by using log (inhibitor) vs. normalized response-Variable slope of GraphPad Prism 5, so as to obtain IC of each compound for inhibiting enzyme activity50The value is obtained. The results are shown in Table 1 below.
TABLE 1CDK2, CDK4 and CDK6 test results
Figure BDA0003390522750000131
As can be seen in table 1: the compounds all had certain enzyme inhibitory activity, of which example 17, example 18, example 19 and example 20 had the best enzyme inhibitory activity against CDK2, CDK4 and CDK6, and were particularly significant in CDK 4.
Example 22: cytostatic activity assay
1 test procedure
(1) Cell seeding
Cells in logarithmic growth phase (human liver cancer cell HepG2, human colon cancer cell HCT116) were collected and cell concentration was adjusted after counting (HepG 2: 1.5X 10)5/mL，HCT116：1.1×105mL), 100. mu.L/well was seeded in a 96-well plate, then at 37 ℃ with 5% CO2Incubate overnight in the incubator.
(2) Fixing parallel control plate, adding substance to be tested into board to be tested
Parallel control plate: adding precooled Trichloroacetic acid (TCA) into 25 mu L/hole, fixing for 1h at 4 ℃, washing the plate with deionized water for 5 times, and naturally drying;
adding a to-be-detected substance into a to-be-detected plate: test compound concentrations were 50 μ M starting, 10-fold dilutions, 5 concentrations. Preparing working solution of compound to be detected with 2 times final concentration by using DMEM complete medium containing 10% FBS, adding 100 mu L/hole into 96 holes, adding DMSO control with the same concentration as the hole of the compound to be detected into the solvent control hole, adding complete medium into the zero setting hole, and adding 5% CO at 37 DEG C2Culturing for 72h in an incubator.
(3) OD value of the board to be tested
Adding 50 mu L/hole of precooled 50% TCA, fixing for 1h at 4 ℃, washing the plate for 5 times by deionized water, and naturally drying; adding 0.4% sulforhodamine B into 100 muL/hole, dyeing for 10min at room temperature, washing the plate with 1% acetic acid 100 muL/hole for 5 times, and naturally drying; adding 10mM Tris-base into 150 μ L/well, and oscillating for about 5 min; the OD was measured at 515 nm.
2 data analysis
And (3) recording the OD value of the parallel control group as Tz, the OD value of the solvent control group as C, and the OD value of the to-be-detected group as Ti:
growth rate [ (% Ti-Tz)/(C-Tz) ] × 100
Inhibition rate [ (% Ti-Tz)/(C-Tz) ] × 100
Taking the log value of the concentration of the compound as an X axis and the corresponding cell growth inhibition rate as a Y axis, and fitting a dose-effect curve by using the log (inhibitor) vs. response-Variable slope of GraphPad Prism 5, thereby obtaining the IC of the compound to be detected for inhibiting the cell growth50The value is obtained. The results are shown in the following table.
Figure BDA0003390522750000141
As can be seen in the table: the compounds all have certain cell growth inhibitory activity, wherein the cell growth inhibitory activity is the best in example 14, example 15, example 16 and example 19, 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 have the following structures:
Figure DEST_PATH_IMAGE002
，
wherein R is1Is hydrogen, chlorine, fluorine or trifluoromethyl;
R2is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
R3is composed of
Figure DEST_PATH_IMAGE004
or-SO2NH2。
2. The 4-triazole-2-phenylamino pyrimidine derivatives or pharmaceutically acceptable salts thereof according to claim 1, characterized in that the 4-triazole-2-phenylamino pyrimidine derivatives are selected from any one of the following compounds:
n- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
n- (2-aminophenyl) -4- ((4- (1-cyclopentyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
n- (2-aminophenyl) -4- ((4- (1-isopropyl-1H-1, 2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzamide;
n- (2-aminophenyl) -4- ((4- (1-cyclohexyl-1H-1, 2, 3-triazol-4-yl) -5-fluoropyrimidin-2-yl) amino) benzamide;
n- (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 h-1,2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- (1-cyclohexyl-1 h-1,2, 3-triazol-4-yl) -N- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2-amine;
4- ((4- (1-cyclopentyl-1 h-1,2, 3-triazol-4-yl) pyrimidin-2-yl) amino) benzenesulfonamide;
4- (1-cyclohexyl-1 h-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 h-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 h-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.
3. The use of the 4-triazole-2-anilinopyrimidine derivative of claim 1 or 2 or a pharmaceutically acceptable salt thereof in preparing an anticancer drug.
4. The use of the 4-triazole-2-phenylamino pyrimidine derivatives or pharmaceutically acceptable salts thereof according to claim 1 or 2 in the preparation of medicaments for preventing and treating liver cancer and colon cancer.
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