CN114656451A - Benzamide derivative, preparation method and application - Google Patents

Benzamide derivative, preparation method and application Download PDF

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CN114656451A
CN114656451A CN202210319544.9A CN202210319544A CN114656451A CN 114656451 A CN114656451 A CN 114656451A CN 202210319544 A CN202210319544 A CN 202210319544A CN 114656451 A CN114656451 A CN 114656451A
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amino
methyl
phenyl
pyrimidin
pyridin
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徐俊裕
李友宾
郑丹阳
王雪松
王燕
谭银丰
王勇
杨宸淇
张雨晨
郭同
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Hainan Medical College
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Abstract

The invention provides a benzamide derivative and a preparation method and application thereof, wherein the derivative is formed by covalently connecting an N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide segment with T, or covalently connecting an N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide segment with Q and T; the compound can effectively inhibit the activity of human chronic granulocytic leukemia cells and human gastrointestinal stromal tumor cells, can be applied to the preparation of medicaments for treating and/or preventing hyperproliferative diseases, and is particularly used for treating chronic granulocytic leukemia and gastrointestinal stromal tumor.

Description

Benzamide derivative, preparation method and application
Technical Field
The invention relates to the technical field of medical chemistry, and particularly relates to N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivatives, and a preparation method and application thereof.
Background
Chronic Myeloid Leukemia (CML) is a clonal hematopoietic stem cell disorder, a myeloproliferative disease, most of which exhibit Philadelphia chromosome (Ph) as positive. According to the disease progression of CML, there are divided into a chronic phase, an accelerated phase and an acute phase. Currently, about 85% to 90% of CML patients are diagnosed in the chronic phase and, if reasonable treatment regimens are not taken in time, the patients undergo an accelerated phase and rapidly deteriorate to the acute phase after 3-4 years, eventually leading to patient death.
A review of the clinical treatment regimen of recent 20 years has been given with imatinib (trade name: gleevec; chemical name: 4- [ (4-methyl-1-piperazinyl) methyl group]-N- [ 4-methyl-3- [4- (3-pyridinyl) -2-pyrimidinyl]Amino group]Phenyl radical]Benzamide) provides a long-term prognosis improvement in most chronic CML patients, and only oral administration of the drug provides long-term remission and a near-normal life expectancy. Therefore, imatinib, as a classical small molecule targeted drug, is currently used as a cost effective treatment for: treatment of Philadelphia chromosome positive chronic myelogenous leukemia (Ph)+CML) in a chronic, accelerated or acute adult patient in combination with chemotherapy to treat newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph)+ALL) in children to treat relapsed or refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph)+ALL) in adult patients for the treatment of hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemiaAdult patients with a disease (CEL) associated with the FIP1L1-PDGFR alpha fusion gene, adult patients treated for myelodysplastic syndrome/myeloproliferative disorders (MDS/MPD) associated with a rearrangement of the platelet-derived growth factor receptor (PDGFR) gene, adult patients treated for gastrointestinal stromal tumors that are unresectable and/or metastatic, and patients treated for malignant melanoma who are unresectable and/or metastatic KIT mutations.
However, with the discovery of long-term drug feedback, a few patients lose the effective response to imatinib or develop rapid disease progression during the drug taking process, and the drug resistance to imatinib gradually increases at the later stage of the CML disease progression, which is manifested by poor therapeutic effect or therapeutic failure, so that it is of great significance to continue to intensively study the treatment of imatinib structural derivatives and related diseases with high activity and safety.
Disclosure of Invention
Therefore, the invention provides a N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivative, and a preparation method and application thereof.
The technical scheme of the invention is realized as follows:
a N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivative is characterized in that an N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide fragment is connected with T through covalent, or the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide fragment is connected with Q and T through covalent, and the chemical structure general formula of the derivative is as follows:
Figure BDA0003571142130000021
wherein Q is a linking group of 1-10 CH2Or CH, said straight or branched alkylene chain being covalently linked to T by-NH-;
t is any one of the following fragments:
Figure BDA0003571142130000031
further, the chemical structural formula of the N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) formamide derivative is as follows:
Figure BDA0003571142130000032
the reaction steps of the preparation method of the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivative are as follows:
Figure BDA0003571142130000033
wherein, the reaction conditions and reagents of the reaction formula are as follows: 1,2, 4-trimellitic anhydride, sodium acetate and glacial acetic acid are heated and refluxed for 5 hours to react; n- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N, N-dimethylformamide, at room temperature, for 2 hours.
Further disclosed are N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives having the chemical formula:
Figure BDA0003571142130000034
the reaction steps of the preparation method of the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivatives are as follows:
Figure BDA0003571142130000041
wherein, the reaction conditions and reagents of the reaction formula are as follows: heating and refluxing 3-fluorophthalic anhydride, sodium acetate and glacial acetic acid, and reacting for 5 hours; b. heating and refluxing the corresponding amino acid, N, N-diisopropylethylamine and N, N-dimethylformamide for 12-36 hours; c.N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N, N-dimethylformamide, and reacting at room temperature for 12-48 hours.
Further, the N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) formamide derivative has the chemical structural formula:
Figure BDA0003571142130000042
the reaction steps of the preparation method of the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivative are as follows:
Figure BDA0003571142130000043
Figure BDA0003571142130000051
wherein, the reaction conditions and reagents of the reaction formula are as follows: reacting 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N, N-dimethylformamide at room temperature for 12-24 hours; b. trifluoroacetic acid and dichloromethane are reacted for 0.5 hour at room temperature; c, reacting 2- (2, 6-dioxopiperidine-3-yl) -4-fluoroisoindoline-1, 3-dione, N, N-diisopropylethylamine and N-methylpyrrolidone at 90 ℃ for 12 hours.
Further, the N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) formamide derivative has the chemical structural formula:
Figure BDA0003571142130000052
the reaction steps of the preparation method of the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivative are as follows:
Figure BDA0003571142130000053
wherein, the reaction conditions and reagents of the reaction formula are as follows: a. acrylic acid and toluene at 100 ℃ for 12 hours; b. urea, glacial acetic acid, 120 ℃, 8 hours; c.N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N, N-dimethylformamide, at room temperature for 20 hours.
The application of the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivatives prepared by the preparation method is application in preparing inhibitors of human chronic granulocytic leukemia cell hyperproliferation and human gastrointestinal stromal tumor cell hyperproliferation.
According to the above preparation method, the following compounds were prepared:
2- (2, 6-dioxopiperidin-3-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -1, 3-dioxoisoindoline-5-carboxamide (I-1)
2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acetamide (I-2)
4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) butanamide (I-3)
6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) hexanamide (I-4)
8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) octanamide (I-5)
11- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) undecanamide (I-6)
4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (I-7)
4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) cyclohexane-1-carboxamide (I-8)
4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (I-9).
4- (4- ((4- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) piperazin-1-yl) methyl) piperidin-1-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (I-10)
Compared with the prior art, the invention has the beneficial effects that: the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivatives prepared by the invention can effectively inhibit the activity of human chronic granulocytic leukemia cells and human gastrointestinal stromal tumor cells, have a remarkable inhibiting effect, can be applied to preparation of medicines for treating and/or preventing hyperproliferative diseases, and is particularly applied to treatment of chronic granulocytic leukemia and gastrointestinal stromal tumor.
The activity inhibition rate of the prepared 2- (2, 6-dioxopiperidine-3-yl) -N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) -1, 3-dioxoisoindoline-5-formamide on human chronic granulocytic leukemia cells can reach over 50 percent.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Examples
The invention prepares a class of N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivatives according to the following preparation method:
the method comprises the following steps:
Figure BDA0003571142130000081
wherein, the reaction conditions and reagents of the reaction formula are as follows: heating and refluxing 1,2, 4-trimellitic anhydride, sodium acetate and glacial acetic acid, and reacting for 5 hours; n- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N, N-dimethylformamide, at room temperature, for 2 hours.
The second method comprises the following steps:
Figure BDA0003571142130000082
wherein, the reaction conditions and reagents of the reaction formula are as follows: heating and refluxing 3-fluorophthalic anhydride, sodium acetate and glacial acetic acid, and reacting for 5 hours; b. heating and refluxing the corresponding amino acid, N, N-diisopropylethylamine and N, N-dimethylformamide for 12-36 hours; c.N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N, N-dimethylformamide, and reacting at room temperature for 12-48 hours.
The third method comprises the following steps:
Figure BDA0003571142130000083
Figure BDA0003571142130000091
wherein, the reaction conditions of the reaction formula are as follows: reacting 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N, N-dimethylformamide at room temperature for 12-24 hours; b. trifluoroacetic acid and dichloromethane are reacted for 0.5 hour at room temperature; c, reacting 2- (2, 6-dioxopiperidine-3-yl) -4-fluoroisoindoline-1, 3-dione, N, N-diisopropylethylamine and N-methylpyrrolidone at 90 ℃ for 12 hours.
The method comprises the following steps:
Figure BDA0003571142130000092
wherein, the reaction conditions and reagents of the reaction formula are as follows: a. acrylic acid and toluene at 100 ℃ for 12 hours; b. urea, glacial acetic acid, 120 ℃, 8 hours; c.N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N, N-dimethylformamide at room temperature for 20 hours.
Example 1
Preparation of 2- (2, 6-dioxopiperidin-3-yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) -1, 3-dioxoisoindoline-5-carboxamide (I-1)
(1) Preparation of 2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxylic acid:
1,2, 4-trimellitic anhydride (1.0g, 5.2mmol), 3-aminopiperidine-2, 6-dione hydrochloride (940mg, 5.7mmol), sodium acetate (640mg, 7.8mmol) and 3mL glacial acetic acid are added into a reaction bottle, heated to 90 ℃ for 5 hours to react, then slowly poured into 200mL of water and stirred for 10 minutes, and the solution is filtered by suction to obtain 1.5g of an off-white solid with a yield of 96%;1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),8.39(dd,J＝7.8,1.4Hz,1H),8.26(dd,J＝1.5,0.7Hz,1H),8.03(dd,J＝7.7,0.7Hz,1H),5.18(dd,J＝12.8,5.4Hz,1H),2.88(ddd,J＝16.7,13.7,5.2Hz,1H),2.69–2.50(m,2H),2.06(m,1H).ESI-MS m/z:303[M+H]+.
(2) n- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (277mg, 1.0mmol), 2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindoline-5-carboxylic acid (332mg, 1.1mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (249mg, 1.3mmol), 1-hydroxybenzotriazole (176mg, 1.3mmol) and N, N-dimethylmethaneAdding 2mL of amide solvent into a reaction bottle, reacting at room temperature for 2 hours, slowly pouring into 30mL of water, stirring for 5 minutes, filtering the solution to obtain a crude product, and purifying by silica gel column chromatography (methanol/dichloromethane) to obtain light yellow powder 0.38g with the yield of 68%;1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.56(s,1H),9.31–9.25(m,1H),8.99(s,1H),8.67(dd,J＝4.8,1.7Hz,1H),8.51(d,J＝5.1Hz,1H),8.47(dt,J＝8.5,1.9Hz,2H),8.41(dd,J＝7.8,1.5Hz,1H),8.12(d,J＝2.2Hz,1H),8.10–8.05(m,1H),7.54–7.48(m,2H),7.43(d,J＝5.2Hz,1H),7.23(d,J＝8.4Hz,1H),5.20(dd,J＝13.0,5.3Hz,1H),2.89(ddd,J＝17.5,14.0,5.5Hz,1H),2.66–2.52(m,2H),2.23(s,3H),2.09(m,1H).13C-NMR(101MHz,DMSO-D6)δ173.36,170.35,167.25,167.15,163.96,162.19,161.70,160.09,151.98,148.76,141.21,138.48,137.25,135.10,135.03,133.90,132.76,132.00,130.76,128.68,124.40,124.25,122.84,117.76,117.33,108.19,49.76,31.49,22.50,18.26.ESI-MS m/z:562[M+H]+.
example 2
Preparation of 2- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) acetamide (I-2)
N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (55mg, 0.20mmol), (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycine (73mg, 0.22mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50mg, 0.26mmol), 1-hydroxybenzotriazole (35mg, 0.26mmol) and 1mL of N, N-dimethylformamide solvent were added to a reaction flask at room temperature for reaction overnight, and then slowly poured into 10mL of water to stir, ethyl acetate 30mL was extracted 3 times, ethyl acetate layers were combined, dried over anhydrous sodium sulfate for 2 hours and then filtered, the filtrate is decompressed and dried to obtain a crude product, and the crude product is further purified by silica gel column chromatography (methanol/dichloromethane) and C18 column chromatography (methanol/water) to obtain light yellow powder 25mg with the yield of 22%;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.79(s,1H),9.24(s,1H),8.92(s,1H),8.68(d,J＝4.2Hz,1H),8.49(d,J＝5.2Hz,1H),8.49–8.45(m,1H),7.89(d,J＝2.2Hz,1H),7.58–7.50(m,2H),7.41(d,J＝5.2Hz,1H),7.25(dd,J＝8.2,2.2Hz,1H),7.11(d,J＝8.3Hz,1H),7.07(d,J＝8.6Hz,1H)6.99(d,J＝7.0Hz,1H),6.53(t,J＝5.9Hz,1H),5.03(dd,J＝12.8,5.4Hz,1H),3.85(s,2H),2.93–2.85(m,1H),2.67–2.58(m,2H),2.21(s,3H),2.13–2.07(m,1H).ESI-MS m/z:591[M+H]+.
example 3
Preparation of 4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) butanamide (I-3)
N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (55mg, 0.20mmol), 4- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyric acid (79mg, 0.22mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50mg, 0.26mmol), 1-hydroxybenzotriazole (35mg, 0.26mmol) and 1mL of N, N-dimethylformamide solvent were added to a reaction flask at room temperature for reaction overnight, and then slowly poured into 10mL of water for stirring, ethyl acetate 30mL was extracted 3 times, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate for 2 hours and filtered, performing rotary drying on the filtrate under reduced pressure to obtain a crude product, and further purifying by silica gel column chromatography (methanol/dichloromethane) and C18 column chromatography (methanol/water) to obtain a light yellow solid 13mg with a yield of 11%;1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.80(s,1H),9.25(s,1H),8.92(s,1H),8.69(d,J＝4.2Hz,1H),8.50(d,J＝5.2Hz,1H),8.49–8.45(m,1H),7.89(d,J＝2.1Hz,1H),7.60–7.50(m,2H),7.41(d,J＝5.2Hz,1H),7.25(dd,J＝8.2,2.2Hz,1H),7.11(d,J＝8.3Hz,1H),7.07(d,J＝8.6Hz,1H)7.00(d,J＝7.0Hz,1H),6.54(t,J＝5.8Hz,1H),5.04(dd,J＝12.8,5.4Hz,1H),3.35–3.31(m,2H),2.41–2.28(m,3H),2.17(s,3H),2.18–2.05(m,3H),2.05–1.95(m,2H).ESI-MS m/z:619[M+H]+.
example 4
Preparation of 6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) hexanamide (I-4)
N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (55mg, 0.20mmol), 6- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoIsoindolin-4-yl) amino) hexanoic acid (85mg, 0.22mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloride (50mg, 0.26mmol), 1-hydroxybenzotriazole (35mg, 0.26mmol) and 1mL of N, N-dimethylformamide solvent are added into a reaction bottle to react at room temperature overnight, then slowly poured into 10mL of water and stirred, ethyl acetate is extracted for 3 times by 30mL of ethyl acetate, an ethyl acetate layer is combined, anhydrous sodium sulfate is dried for 2 hours and then filtered, the filtrate is dried by spinning under reduced pressure to obtain a crude product, and the crude product is further purified by silica gel column chromatography (methanol/dichloromethane) and C18 column chromatography (methanol/water) to obtain a light yellow solid of 8mg with the yield of 6%;1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),9.80(s,1H),9.25(s,1H),8.92(s,1H),8.68(d,J＝4.8Hz,1H),8.49(d,J＝5.2Hz,1H),8.48–8.45(m,1H),7.89(d,J＝2.2Hz,1H),7.58–7.50(m,2H),7.41(d,J＝5.2Hz,1H),7.26(dd,J＝8.2,2.2Hz,1H),7.12(d,J＝8.4Hz,1H),7.07(d,J＝8.6Hz,1H)6.99(d,J＝7.0Hz,1H),6.53(t,J＝5.9Hz,1H),5.03(dd,J＝12.8,5.4Hz,1H),3.29(d,J＝6.2Hz,2H),2.30(t,J＝7.2Hz,3H),2.17(s,3H),2.16–2.11(m,1H),2.11–1.92(m,2H),1.67–1.58(m,4H),1.42–1.34(m,2H).ESI-MS m/z:647[M+H]+.
example 5
Preparation of 8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) octanamide (I-5)
N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (55mg, 0.20mmol), 8- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) octanoic acid (91mg, 0.22mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50mg, 0.26mmol), 1-hydroxybenzotriazole (35mg, 0.26mmol) and 1mL of N, N-dimethylformamide solvent were added to a reaction flask at room temperature for reaction overnight, then slowly poured into 10mL of water and stirred, ethyl acetate 30mL was extracted 3 times, the ethyl acetate layers were combined, dried over anhydrous sodium sulfate for 2 hours and filtered, performing rotary drying on the filtrate under reduced pressure to obtain a crude product, and further purifying by silica gel column chromatography (methanol/dichloromethane) and C18 column chromatography (methanol/water) to obtain a light yellow solid 11mg with a yield of 8%;1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.80(s,1H),9.24(s,1H),8.92(s,1H),8.69(d,J＝4.6Hz,1H),8.48(d,J＝5.1Hz,1H),8.47–8.45(m,1H),7.89(d,J＝2.1Hz,1H),7.61–7.51(m,2H),7.40(d,J＝5.2Hz,1H),7.26(dd,J＝8.1,2.1Hz,1H),7.12(d,J＝8.4Hz,1H),7.06(d,J＝8.6Hz,1H),6.99(d,J＝7.0Hz,1H),6.52(t,J＝5.9Hz,1H),5.03(dd,J＝12.8,5.4Hz,1H),3.30–3.26(m,2H),2.36–2.27(m,3H),2.16(s,3H),2.16–2.10(m,1H),2.06–1.93(m,2H),1.62–1.54(m,4H),1.38-1.26(m,6H).ESI-MS m/z:675[M+H]+.
example 6
Preparation of 11- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) undecanamide (I-6)
N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (55mg, 0.20mmol), 11- ((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) undecanoic acid (101mg, 0.22mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50mg, 0.26mmol), 1-hydroxybenzotriazole (35mg, 0.26mmol) and 1mL of N, N-dimethylformamide solvent were added to a reaction flask at room temperature for overnight reaction, and then slowly poured into 10mL of water for stirring, ethyl acetate 30mL was extracted 3 times, ethyl acetate layers were combined, dried over anhydrous sodium sulfate for 2 hours and filtered, performing rotary drying on the filtrate under reduced pressure to obtain a crude product, and further purifying by silica gel column chromatography (methanol/dichloromethane) and C18 column chromatography (methanol/water) to obtain a light yellow solid 29mg with a yield of 20%;1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),9.78(s,1H),9.24(s,1H),8.91(s,1H),8.68(d,J＝4.1Hz,1H),8.48(d,J＝5.1Hz,1H),8.47–8.45(m,1H),7.89(d,J＝2.1Hz,1H),7.60–7.47(m,2H),7.40(d,J＝5.2Hz,1H),7.25(dd,J＝8.2,2.2Hz,1H),7.11(d,J＝8.3Hz,1H),7.06(d,J＝8.6Hz,1H),6.99(d,J＝7.0Hz,1H),6.50(t,J＝5.8Hz,1H),5.03(dd,J＝12.8,5.4Hz,1H),3.25(d,J＝6.3Hz,2H),2.26(t,J＝7.4Hz,3H),2.16(s,3H),2.18–2.14(m,1H),2.05–1.93(m,2H),1.58–1.51(m,4H),1.28-1.22(m,12H).ESI-MS m/z:717[M+H]+.
example 7
Preparation of 4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) cyclohexane-1-carboxamide (I-8)
(1) Preparation of 4- (aminomethyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) cyclohexane-1-carboxamide:
dissolving N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (100mg, 0.36mmol), trans-4- (tert-butoxycarbonylaminomethyl) cyclohexanecarboxylic acid (93mg, 0.36mmol), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (225mg, 0.43mmol) and triethylamine (132mg, 1.30mmol) in 2mL of N, reacting N-dimethylformamide at room temperature for 6 hours, adding water, extracting with ethyl acetate, washing the combined organic phases with saturated brine, drying over anhydrous sodium sulfate for 2 hours, removing the solvent under reduced pressure, dissolving the residue in 2mL of dichloromethane solution, slowly dropping 0.5mL of trifluoroacetic acid under stirring, removing the solvent under reduced pressure again after stirring at room temperature for 0.5 hour, separating the residue by silica gel column chromatography to obtain a white solid (110 mg), the yield is 72 percent; ESI-MS M/z 417[ M + H ]]+.
(2) Dissolving 4- (aminomethyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) cyclohexane-1-carboxamide (100mg, 0.24mmol), 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione (60mg, 0.22mmol) in 2mL of N-methylpyrrolidone solution, slowly dropping N, N-diisopropylethylamine (76. mu.L, 0.44mmol), reacting at 90 ℃ for 12 hours in a pressure tube, adding 20mL of water after the reaction solution is cooled to room temperature, extracting with 50mL of ethyl acetate for 3 times, combining the organic phases, washing with saturated saline water for 2 times, drying with anhydrous sodium sulfate for 2 hours, removing the solvent in vacuo, separating the residue by silica gel column chromatography (methanol/dichloromethane) to obtain light yellow solid 25mg with yield of 17%;1H NMR(400MHz,DMSO-d6)δ11.10(s,1H),9.76(s,1H),9.26(s,1H),8.91(s,1H),8.71(s,1H),8.49(t,J＝7.0Hz,2H),7.93(d,J＝2.1Hz,1H),7.58(t,J＝7.8Hz,1H),7.53(dd,J＝7.9,4.6Hz,1H),7.42(d,J＝5.1Hz,1H),7.27(dd,J＝8.3,2.1Hz,1H),7.13(dd,J＝8.5,6.6Hz,2H),7.02(d,J＝7.0Hz,1H),6.60(t,J＝6.2Hz,1H),5.05(d,J＝13.0Hz,1H),3.20(t,J＝6.5Hz,2H),2.87(ddd,J＝17.9,14.0,5.4Hz,1H),2.65–2.54(m,1H),2.29(td,J＝11.1,10.0,6.5Hz,1H),2.17(s,3H),2.08–1.99(m,1H),1.91–1.78(m,4H),1.58(d,J＝23.3Hz,1H),1.51–1.36(m,2H),1.23(s,1H),1.17(t,J＝7.1Hz,1H),1.05(q,J＝12.5,11.7Hz,2H).ESI-MS m/z:673[M+H]+.
example 8
Preparation of 4- (((2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) methyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (I-7)
4- (aminomethyl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (90mg, 0.22mmol), 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione (55mg, 0.20mmol) were dissolved in 2mL of an N-methylpyrrolidone solution, N-diisopropylethylamine (76. mu.L, 0.44mmol) was slowly dropped thereto, the reaction was carried out at 90 ℃ for 12 hours in a pressure-resistant tube, 20mL of water was added after the reaction mixture was cooled to room temperature, extraction was carried out with 50mL of ethyl acetate 3 times, the organic phase was combined and washed with a saturated saline solution 2 times, the solvent was removed in vacuo after drying over anhydrous sodium sulfate for 2 hours, the remaining residue was separated by silica gel column chromatography (methanol/dichloromethane), 9mg of light yellow solid is obtained, and the yield is 7 percent;1H NMR(400MHz,DMSO-d6)11.09(s,1H),9.76(s,1H),9.26(s,1H),8.91(s,1H),8.70(s,1H),8.49(t,J＝7.0Hz,2H),8.09–7.95(m,3H),7.58(d,J＝7.8Hz,2H),7.57–7.54(m,1H),7.48(d,J＝7.9Hz,1H),7.42(d,J＝5.1Hz,1H),7.27(dd,J＝8.3,2.1Hz,1H),7.13(dd,J＝8.5,6.6Hz,2H),7.02(d,J＝7.0Hz,1H),6.60(t,J＝6.2Hz,1H),5.05(d,J＝13.0Hz,1H),4.13(s,2H),2.35–2.25(m,1H),2.17(s,3H),2.16–1.99(m,3H).ESI-MS m/z:667[M+H]+.
example 9
Preparation of 4- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide (I-9)
(1) Preparation of 3- ((4- (tert-butoxycarbonyl) phenyl) amino) propionic acid:
tert-butyl 4-aminobenzoate (500mg, 2.6mmol) and acrylic acid (200mg, 2.8mmol) were dissolved in 5mL of toluene and reacted at 100 ℃ for 12 hours, the solvent was removed by evaporation under reduced pressure after the reaction solution was cooled to room temperature, the remaining residue was dissolved in 1mL of ethyl acetate and stirredSlowly adding 20mL of petroleum ether under the condition, performing suction filtration and drying to obtain 642mg of a crude product of the 3- ((4- (tert-butoxycarbonyl) phenyl) amino) propionic acid with the yield of 94%; ESI-MS M/z 266[ M + H ]]+.
(2) Preparation of 4- (2, 4-Dioxymethyl-tetrahydropyrimidin-1 (2H) -yl) benzoic acid
3- ((4- (tert-butoxycarbonyl) phenyl) amino) propionic acid (642mg, 2.4mmol) and urea (360mg, 6mmol) were dissolved in 5mL of glacial acetic acid and reacted at 120 ℃ under reflux for 8 hours, the reaction solution was cooled to room temperature and the solvent was removed by evaporation under reduced pressure, the remaining residue was dissolved in 10mL of ethyl acetate and stirred for 10 minutes, and after suction filtration and drying, 171mg of crude 4- (2, 4-dioxomethyltetrahydropyrimidin-1 (2H) -yl) benzoic acid was obtained in 30% yield;
(3) adding N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine (55mg, 0.2mmol), 4- (2, 4-dioxy methyl tetrahydropyrimidin-1 (2H) -yl) benzoic acid (47mg, 0.2mmol), 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (50mg, 0.26mmol), 1-hydroxybenzotriazole (35mg, 0.26mmol) and 1mL of N, N-dimethylformamide solvent into a reaction bottle at room temperature for reaction overnight, slowly pouring into 10mL of water for stirring, extracting 30mL of ethyl acetate for 3 times, combining ethyl acetate layers, drying for 2 hours by anhydrous sodium sulfate, filtering, drying the filtrate under reduced pressure to obtain a crude product, and further performing column chromatography (methanol/dichloromethane) and C18 (methanol/water) by silica gel column chromatography (methanol/dichloromethane) and C18 (methanol/water) sequentially Purification gave 9mg of a pale yellow solid in 9% yield;1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.21(s,1H),9.26(d,J＝2.3Hz,1H),8.97(s,1H),8.67(dd,J＝4.8,1.7Hz,1H),8.50(d,J＝5.2Hz,1H),8.46(dt,J＝8.0,2.1Hz,1H),8.08(d,J＝2.2Hz,1H),7.96(d,J＝8.7Hz,2H),7.53–7.45(m,4H),7.41(d,J＝5.1Hz,1H),7.20(d,J＝8.4Hz,1H),3.86(t,J＝6.6Hz,2H),2.72(t,J＝6.6Hz,2H),2.21(s,3H).ESI-MS m/z:494[M+H]+.
example 10
An in vitro tumor cell anti-tumor proliferation activity test was performed on N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivative compounds prepared in examples 1 to 9.
MTT method is used for measuring the inhibition effect on human chronic granulocytic leukemia cell strain K562 and human gastrointestinal stromal tumor cell strain GIST-T1, and the MTT method for in vitro testing of the anti-tumor proliferation activity is a method for detecting the survival and growth of cells, and the detection principle is that NADP related dehydrogenase (succinate dehydrogenase) in mitochondria of living cells can reduce exogenous MTT into insoluble blue-purple crystalline Formazan (Formazan) and deposit the blue-purple crystalline Formazan (Formazan) in the cells, while dead cells do not have the function.
Purple crystal formazan in cells was dissolved in dimethyl sulfoxide (DMSO) or a triple solution (10% SDS-5% isobutanol-0.01 mol/L HCl), and the light absorption (OD value) at a wavelength of 570nm was detected by an enzyme-linked immunosorbent assay, which indirectly reflected the amount of living cells.
The specific operation method comprises the following steps: inoculating tumor cells in logarithmic growth phase into 96-well culture plate according to certain cell amount, culturing for 24 hr, adding test compound (directly adding after suspending cells are connected with plate), culturing at 37 deg.C with 5% CO2Continuously culturing for 48 hr, adding MTT, continuously culturing for 4 hr, dissolving with DMSO for crystallization, measuring OD value at 570nm with enzyme linked immunosorbent assay device, and calculating the inhibition rate and IC of the compound50The value is obtained. The results of the pharmacological experiments on the above compounds are counted, and the results of the in vitro antitumor activity of the target compound at a concentration of 20 μ M on the tumor cell lines are shown in table 1 below:
(-cell viability > 50%, + cell viability < 50%, + 80% cell viability and ND not measured).
TABLE 1
Figure BDA0003571142130000171
The results of the in vitro tumor cell antiproliferative activity experiments in the table show that the compounds provided by the invention all have certain inhibitory activity of human chronic granulocytic leukemia cell strain K562, and the inhibitory activity of I-1 can reach more than 50 percent, wherein, I-1, I-4 and I-6 have inhibitory activity to human gastrointestinal stromal tumor cell strains, therefore, the N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivative compound prepared by the invention has the activity of inhibiting human chronic granulocytic leukemia and human gastrointestinal stromal tumor cell strains, can be used for preparing medicine for treating and/or preventing hyperproliferation diseases, especially for treating chronic granulocytic leukemia and gastrointestinal stromal cell tumor.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (10)

1. A N- (4-methyl-3- ((4- (pyridine-3-yl) pyrimidine-2-yl) amino) phenyl) formamide derivative is characterized by comprising the following components in percentage by weight:
the N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide fragment is covalently linked to T, or the N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide fragment is covalently linked to Q and T, and the chemical structure formula is as follows:
Figure FDA0003571142120000011
wherein Q is a linking group of 1-10 CH2Or CH, said straight or branched alkylene chain being covalently linked to T by-NH-;
t is any one of the following fragments:
Figure FDA0003571142120000012
2. a class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives as claimed in claim 1, wherein: the chemical structural formula is as follows:
Figure FDA0003571142120000013
3. a process for the preparation of a class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives according to claim 2, wherein: the reaction steps are as follows:
Figure FDA0003571142120000021
wherein, the reaction conditions and reagents of the reaction formula are as follows: heating and refluxing 1,2, 4-trimellitic anhydride, sodium acetate and glacial acetic acid, and reacting for 5 hours; n- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N, N-dimethylformamide at room temperature for 2 hours.
4. A class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives as claimed in claim 1, wherein: the chemical structural formula is as follows:
Figure FDA0003571142120000022
5. a process for the preparation of a class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives as claimed in claim 4 wherein: the reaction steps are as follows:
Figure FDA0003571142120000023
wherein, the reaction conditions and reagents of the reaction formula are as follows: heating and refluxing 3-fluorophthalic anhydride, sodium acetate and glacial acetic acid, and reacting for 5 hours; b. heating and refluxing the corresponding amino acid, N, N-diisopropylethylamine and N, N-dimethylformamide for 12-36 hours; c.N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N, N-dimethylformamide, and reacting at room temperature for 12-48 hours.
6. A class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives as claimed in claim 1, wherein: the chemical structural formula is as follows:
Figure FDA0003571142120000031
7. a process for the preparation of a class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives as claimed in claim 6 wherein: the reaction steps are as follows:
Figure FDA0003571142120000032
wherein, the reaction conditions and reagents of the reaction formula are as follows: reacting 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N, N-dimethylformamide at room temperature for 12-24 hours; b. trifluoroacetic acid and dichloromethane are reacted for 0.5 hour at room temperature; 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindoline-1, 3-dione, N, N-diisopropylethylamine and N-methylpyrrolidone, at 90 ℃ for 12 hours.
8. A class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives as claimed in claim 1, wherein: the chemical structural formula is as follows:
Figure FDA0003571142120000041
9. a process for the preparation of a class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives as claimed in claim 8 wherein: the reaction steps are as follows:
Figure FDA0003571142120000042
wherein, the reaction conditions and reagents of the reaction formula are as follows: a. acrylic acid and toluene at 100 ℃ for 12 hours; b. urea, glacial acetic acid, 120 ℃, 8 hours; c.N- (5-amino-2-methylphenyl) -4- (3-pyridyl) -2-aminopyrimidine, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole, N, N-dimethylformamide, at room temperature for 20 hours.
10. Use according to any one of claims 2,4, 6 and 8 of a class of N- (4-methyl-3- ((4- (pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) carboxamide derivatives wherein: the application of the compound in preparing the inhibitor for the hyperproliferation of human chronic granulocytic leukemia cells and the hyperproliferation of human gastrointestinal stromal tumor cells.
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