CN114014847B - Benzothiophene pyrimidine derivative, preparation method thereof and application thereof in preparation of antitumor drugs - Google Patents
Benzothiophene pyrimidine derivative, preparation method thereof and application thereof in preparation of antitumor drugs Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 8
- DYXNPKNQSCAHFG-UHFFFAOYSA-N 1-benzothiophene pyrimidine Chemical class N1=CN=CC=C1.S1C2=C(C=C1)C=CC=C2 DYXNPKNQSCAHFG-UHFFFAOYSA-N 0.000 title claims description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 8
- FYSIGSQCZXQTIH-UHFFFAOYSA-N 4-fluoro-2-methoxy-5-nitroaniline Chemical compound COC1=CC(F)=C([N+]([O-])=O)C=C1N FYSIGSQCZXQTIH-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 4
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention discloses a pyrimidine derivative containing benzothiophene, a preparation method thereof and application thereof in preparing antitumor drugs. The chemical structural formula is as follows:
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a benzothiophene pyrimidine derivative, a preparation method thereof and application thereof in preparing antitumor drugs.
Background
Malignant tumors are the most common and serious diseases endangering human life and health in the world today. In recent years, through the continuous efforts of scientists, a plurality of medicines for treating tumors are marketed, and the medicines greatly improve the life quality of tumor patients, so that the tumor treatment is greatly advanced. However, the traditional chemotherapy drugs still have the defects of poor curative effect, strong toxic and side effects, easy drug resistance generation and the like. Therefore, searching or finding high-efficiency, low-toxicity and drug-resistant targeted antitumor drugs becomes an important subject in the current medical research. Protein tyrosine kinases (Protein tyrosine kinases, PTKs) are important factors in signaling processes and catalyze the phosphorylation of tyrosine residues of a variety of substrate proteins, thereby signaling, playing an important role in cell proliferation, differentiation, migration and apoptosis. Abnormal expression of tyrosine kinase will lead to disturbance of cell proliferation regulation and is also closely related to invasion and metastasis of tumor, generation of tumor neovascularization and chemotherapy resistance of tumor.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a benzothiophene-containing pyrimidine derivative, a preparation method thereof and application thereof in preparing anti-tumor drugs, and the prepared benzothiophene-containing pyrimidine derivative has excellent in-vivo anti-tumor activity, and the in-vivo tumor inhibition rate TGI value is 90.24%.
In order to achieve the above purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:
a benzothiophene-containing pyrimidine derivative having the chemical structural formula:
wherein R is 1 Is H or F; r is R 2 Is a secondary amine, thiol, alkylpiperazine or piperidine.
Further, R 2 Is that
Further, R 1 Is H, R 2 Is that
Further, R 1 Is F, R 2 Is that
The preparation method of the benzothiophene-containing pyrimidine derivative is characterized by comprising the following steps of:
(1) Benzothiophene-3-boronic acid and (2, 4-dichloropyrimidine) -2b (2, 4-dichloro-6-fluoropyrimidine) are reacted through bell wood;
(2) Carrying out aromatic nucleophilic reaction on 4-fluoro-2-methoxy-5-nitroaniline and the product obtained in the step (1) under an acidic condition;
(3) Reacting the product of step (2) with R under alkaline conditions 2 H or its hydrochloride reacts;
(4) And (3) mixing and dissolving the product obtained in the step (3) with ammonium chloride and a reducing agent, and performing nitro reduction and acylation reaction after the reaction is finished to prepare the benzothiophene-containing pyrimidine derivative.
The reaction flow is as follows:
further, the aromatic nucleophilic reaction in the step (2) comprises the following specific processes: dissolving 4-fluoro-2-methoxy-5-nitroaniline and the product obtained in the step (1), and heating to 80-100 ℃ overnight.
Further, the amount of 4-fluoro-2-methoxy-5-nitroaniline is 1 to 1.5eq.
Further, R is as described in step (3) 2 When being a secondary amine: dissolving the product obtained in the step (2), and then adding R 2 H or the hydrochloride and DIPEA thereof, and reacting for 10-15H at 80-90 ℃.
Further, R is as described in step (3) 2 In the case of thiols or alcohols: r is R 2 Dissolving H, adding NaH at 0 ℃, stirring for 10-20mAfter in, adding the product obtained in the step (2), stirring to enable the reaction solution to be heated to room temperature, and then reacting overnight.
The application of the benzothiophene-containing pyrimidine derivative in preparing antitumor drugs.
Further, the tumor is non-small cell lung cancer.
The invention has the beneficial effects that:
13 pyrimidine derivatives with new structures are designed and synthesized. The research result shows that the preferable compound 6a (VI-1) has good inhibition effect on EGFR L858R/T790M high expression kinase and EGFR L858R/T790M high expression cell H1975, and the IC50 values are respectively 0.26nM and 2.2nM. Mechanical studies have shown that 6a can time-dose dependent inhibit the expression of EGFR and AKT phosphorylating proteins, thereby inducing H1975 apoptosis. In addition, 6a showed less cytotoxicity to all three human normal cell lines and was superior to the positive control drug, octreotide. Further studies have shown that 6a has good pharmacokinetic properties. Finally, in vivo activity studies showed that compound 6a had very good in vivo anti-tumor activity with an in vivo tumor inhibition TGI value of 90.24%. The above results indicate that 6a is further studied in the treatment of non-small cell lung cancer (NSCLC).
Drawings
FIG. 1 is a comparison of EGFR tyrosine kinase inhibitory capacity of 6a and Afatinib, osimitinib.
Detailed Description
The following description of the embodiments of the present invention is provided to facilitate understanding of the present invention by those skilled in the art, but it should be understood that the present invention is not limited to the scope of the embodiments, and all the inventions which make use of the inventive concept are protected by the spirit and scope of the present invention as defined and defined in the appended claims to those skilled in the art.
EXAMPLE 1 Synthesis of target Compounds VI-1 to VI-13
The synthesis route of the target compounds VI-1 to VI-13 is as follows:
1. general procedure for the synthesis of intermediates 3a-3 b:
2, 4-dichloropyrimidine/2, 4-dichloro-6-fluoropyrimidine (2.47 mL,20 mmol), bis-triphenylphosphine palladium dichloride (701.9 mg,1 mmol) were dissolved in 60mL toluene, then aqueous solution (20 mL) of sodium carbonate (4.24 g,40 mmol) and methanol (20 mL) of 3-hydroxymethylphenylboronic acid (3.34 g,22 mmol) were added, and the reaction was performed under argon protection at 90℃for 12h, after the TLC detection was complete, the reaction solution was cooled to room temperature, celite was filtered, the filtrate was extracted with ethyl acetate (100 mL. Times.3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and column chromatography was performed after suspension under reduced pressure to obtain the target intermediate 3a-3b (petroleum ether: ethyl acetate=10:1 to 3:1).
3a, red solid, yield: 62%; 1 H NMR(500MHz,CDCl 3 )δ8.61(s,2H),8.32(s,1H),8.25(m,1H),7.50–7.40(m,2H),4.74(s,2H).
3b, white solid, yield: 60.5%; 1 H NMR(400MHz,CDCl 3 )δ8.83(d,J=8.2Hz,1H),8.53(d,J=3.0Hz,1H),8.40(d,J=1.3Hz,1H),7.91(d,J=8.1Hz,1H),7.53(m,1H),7.45(m,1H).
2. general procedure for the synthesis of intermediates 4a-4 b:
raw materials 3a or 3b and 4-fluoro-2-methoxy-5-nitroaniline (1.05 eq) are dissolved in n-butanol, 2-3 drops of concentrated hydrochloric acid are added into the reaction liquid, then the reaction liquid is gradually heated to 80 ℃ overnight, after TLC detection reaction is completed, the reaction liquid is cooled to room temperature, filtered, ethyl acetate washes a filter cake, and the filter cake is placed into a vacuum drying oven to be dried, thus obtaining target intermediates 4a-4b.
4a yellow solid, yield: 73%; 1 H NMR(500MHz,DMSO-d 6 )δ9.14(bs,1H),8.82(d,J=8.3Hz,1H),8.77(s,1H),8.69(d,J=8.0Hz,1H),8.59(d,J=5.5Hz,1H),8.09(d,J=8.0Hz,1H),7.53(d,J=5.5Hz,1H),7.49–7.32(m,3H).
4b: gray solid, yield: 50%; 1 H NMR(500MHz,DMSO-d 6 )δ8.85(bs,1H),8.76(d,J=8.3Hz,1H),8.72(d,J=3.0Hz,1H),8.57–8.50(m,2H),8.11(d,J=8.0Hz,1H),7.47(t,J=7.5Hz,1H),7.43–7.35(m,2H),4.00(s,3H).
3. synthesis of intermediate 5aa-5al,5ba
(1) When R is 2 In the case of secondary amine structure, the synthesis method is as follows:
compound 4a or 4b (1 eq) was dissolved in DMA and then R was added sequentially 2 H or its hydrochloride (1.2 eq) and DIPEA (2 eq), the reaction solution is placed at 85 ℃ for reaction for 12H, after TLC detection reaction is completed, the reaction solution is cooled to room temperature, saturated sodium bicarbonate solution is used for quenching reaction, dichloromethane extraction is carried out, organic phases and anhydrous sodium sulfate are combined, the mixture is dried and filtered, and the mixture is suspended under reduced pressure and then is passed through a column to obtain an intermediate.
(2) When R is 2 In the case of thiol or alcohol structure, the synthesis method is as follows:
compound R 2 H (1.5 eq) is dissolved in anhydrous DMF, naH (3 eq) is slowly added under the condition of 0 ℃ and stirred for 10-20min, then a DMF solution of 4a or 4b (1 eq) is slowly added dropwise, the reaction solution is slowly warmed to room temperature after the dropwise addition, the reaction is carried out overnight, after TLC detection reaction is complete, saturated sodium bicarbonate solution is added for quenching reaction, dichloromethane extraction is carried out, the organic phases are combined, anhydrous sodium sulfate is dried and filtered, and the mixture is dried under reduced pressure and then passed through a column to obtain an intermediate.
4. General procedure for the synthesis of intermediate 6aa-6al,6 ba:
intermediate 5aa-5al,5ba (1 eq), iron powder (6 eq) and ammonium chloride (5 eq) were dissolved in MeOH: H 2 After the reaction is completed in a mixed solvent of O=4:1 at 80 ℃ for 4 hours, the reaction solution is filtered when the reaction is hot, dichloromethane is extracted, organic phases are combined, dried over anhydrous sodium sulfate and filtered, and the mixture is dried under reduced pressure and then is subjected to column passing to obtain an intermediate.
5. Synthesis of the target compound:
the compound 6aa-6al,6ba (1 eq) is dissolved in anhydrous tetrahydrofuran, triethylamine (1.2 eq) and acryloyl chloride (1.1 eq) are sequentially added under ice bath condition, the reaction is continued for 10min under the condition of 0 ℃, after TLC detection, saturated sodium bicarbonate solution is added to quench the reaction, dichloromethane is extracted, organic phases, anhydrous sodium sulfate are combined, dried and filtered, and the target product is obtained after decompression and suspension.
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl-amino)-ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide(Ⅵ-1)
Yellow solid, yield: 44%; 1 H NMR(500MHz,CDCl 3 )δ10.09(bs,1H),9.74(s,1H),8.61(bs,1H),8.56(d,J=4.9Hz,1H),8.42(d,J=8.0Hz,1H),7.90(d,J=7.9Hz,1H),7.71(s,1H),7.44(t,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.15(d,J=4.9Hz,1H),3.88(s,3H),2.86(t,J=5.0Hz 2H),2.70(s,3H),2.32–2.19(m,8H). 13 C NMR(126MHz,CDCl 3 )δ163.12,161.62,160.14,158.56,144.79,141.18,136.65,135.72,134.53,132.37,131.47,129.53,126.68,125.88,124.74,124.45,123.64,122.90,111.30,110.08,104.65,57.43,56.56,56.07,45.50,43.56.HRMS(ESI)calculated for C 27 H 30 N 6 O 2 S[M+H] + :503.2224,found:503.2213.Purity:99.9%(by HPLC).N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-2-((2-(diethyl-amino)-ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide(Ⅵ-2)
yellow solid, yield: 35%; 1 H NMR(400MHz,CDCl 3 )δ9.72(s,1H),9.63(s,1H),8.59(s,1H),8.55(d,J=5.1Hz,1H),8.42(d,J=8.0Hz,1H),7.89(d,J=7.9Hz,1H),7.70(s,1H),7.43(t,J=7.4Hz,1H),7.37(t,J=7.4Hz,1H),7.14(d,J=5.1Hz,1H),6.77(s,1H),6.47(m,2H),5.70(d,J=11.2Hz,1H),3.87(s,3H),2.90(m,2H),2.66(s,3H),2.61(t,J=7.1Hz,4H),2.48(m,2H),1.02(t,J=7.1Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ163.12,161.63,160.14,158.60,144.80,141.17,136.64,136.02,134.53,132.30,131.45,128.74,126.41,126.20,124.78,124.49,123.67,122.91,111.55,110.09,104.18,56.09,50.53,47.50,43.13,10.98.HRMS(ESI)calculated for C 29 H 34 N 6 O 2 S[M+H] + :531.2537,found:531.2561.Purity:99.7%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-2-((3-(dimethyl-amino)-propyl)(methyl)amino)-4-methoxyphenyl)acrylamide(Ⅵ-3)
yellow-green solid, yield: 47%; 1 H NMR(500MHz,CDCl 3 )δ9.70(s,1H),8.72(s,1H),8.55(d,J=5.1Hz,2H),8.42(d,J=8.1Hz,1H),7.90(d,J=8.0Hz,1H),7.70(s,1H),7.44(t,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.15(d,J=5.1Hz,1H),6.76(s,1H),6.43(d,J=16.8Hz,1H),6.33(dd,J=16.8,10.0Hz,1H),5.74(d,J=9.9Hz,1H),3.88(s,3H),2.89(t,J=7.2Hz,2H),2.62(s,3H),2.34(t,J=7.2Hz,4H),2.23(s,6H),1.69–1.59(m,2H). 13 C NMR(126MHz,CDCl 3 )δ162.80,161.67,160.09,158.57,144.87,141.17,136.63,135.38,134.53,132.11,131.32,128.03,126.60,126.52,124.79,124.53,123.67,122.92,110.88,110.20,103.95,57.43,56.11,55.15,45.27,43.64,25.64.HRMS(ESI)calculated for C 28 H 32 N 6 O 2 S[M+H] + :517.2380,found:517.2396.Purity:98.3%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-piperazin-1-yl)phenyl)acrylamide(Ⅵ-4)
yellow solid, yield: 40.8%; 1 H NMR(500MHz,CDCl 3 )δ9.68(s,1H),8.66–8.49(m,3H),8.42(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.69(s,1H),7.44(t,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.15(d,J=5.1Hz,1H),6.79(s,1H),6.43(d,J=16.9Hz,1H),6.29(dd,J=16.8,10.2Hz,1H),5.76(d,J=10.1Hz,1H),3.87(s,3H),2.91(t,J=5.0Hz,4H),2.61(m,4H),2.39(s,3H). 13 C NMR(126MHz,CDCl 3 )δ162.61,161.65,160.10,158.57,144.83,141.16,136.63,135.22,134.54,132.16,131.27,126.92,126.49,126.45,124.79,124.52,123.68,122.92,111.04,110.20,103.50,56.04,52.45,46.19.HRMS(ESI)calculated for C 27 H 28 N 6 O 2 S[M+H] + :501.2067,found:501.2072.Purity:97.4%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-2-(4-ethyl-piperazin-1-yl)-4-methoxyphenyl)acrylamide(Ⅵ-5)
yellow solid, yield: 58%; 1 H NMR(500MHz,CDCl 3 )δ9.68(s,1H),8.61(s,1H),8.55(d,J=5.0Hz,2H),8.42(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,1H),7.69(s,1H),7.44(t,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.15(d,J=5.1Hz,1H),6.81(s,1H),6.42(d,J=16.9Hz,1H),6.29(dd,J=16.8,10.2Hz,1H),5.75(d,J=10.1Hz,1H),3.86(s,3H),2.92(t,J=4.3Hz,4H),2.63(m,4H),2.51(q,J=7.2Hz,2H),1.15(t,J=7.2Hz,3H). 13 C NMR(126MHz,CDCl 3 )δ162.62,161.65,160.10,158.57,144.82,141.16,136.63,135.31,134.54,132.18,131.29,126.95,126.45,126.43,124.79,124.52,123.69,122.92,111.00,110.19,103.55,56.00,53.75,52.55,52.43,12.14.HRMS(ESI)calculated for C 28 H 30 N 6 O 2 S[M+H] + :515.2224,found:515.2239.Purity:99.9%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-2-(4-isopropyl-piperazin-1-yl)-4-methoxyphenyl)acrylamide(Ⅵ-6)
white solid, yield: 49%; 1 H NMR(500MHz,CDCl 3 )δ9.69(s,1H),8.65(s,1H),8.57(d,J=5.0Hz,2H),8.45(d,J=8.0Hz,1H),7.92(d,J=8.0Hz,1H),7.71(s,1H),7.46(t,J=7.6Hz,1H),7.40(t,J=7.5Hz,1H),7.17(d,J=5.1Hz,1H),6.84(s,1H),6.45(d,J=16.9Hz,1H),6.32(dd,J=16.8,10.2Hz,1H),5.78(d,J=10.1Hz,1H),3.88(s,3H),2.94(t,J=4.4Hz,4H),2.83–2.60(m,5H),1.14(d,J=6.5Hz,6H). 13 C NMR(126MHz,CDCl 3 )δ162.60,161.63,160.10,158.55,144.82,141.15,136.62,135.41,134.53,132.18,131.26,126.92,126.41,126.37,124.77,124.50,123.68,122.90,111.00,110.16,103.59,55.98,54.59,52.90,49.63,18.70.HRMS(ESI)calculated for C 29 H 32 N 6 O 2 S[M+H] + :529.2380,found:529.2364.Purity:97.2%(by HPLC).N-(2-(4-acetylpiperazin-1-yl)-5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)-amino)-4-methoxyphenyl)acrylamide(Ⅵ-7)
yellow solid, yield: 48.8%; 1 H NMR(400MHz,CDCl 3 )δ9.69(s,1H),8.56(d,J=5.1Hz,2H),8.50–8.37(m,2H),7.91(d,J=7.8Hz,1H),7.72(s,1H),7.52–7.34(m,2H),7.17(d,J=5.2Hz,1H),6.71(s,1H),6.43(d,J=16.7Hz,1H),6.28(dd,J=16.9,10.1Hz,1H),5.77(d,J=10.1Hz,1H),3.88(s,3H),3.79(s,2H),3.69–3.56(m,2H),2.86(t,J=4.8Hz,4H),2.15(s,3H). 13 C NMR(101MHz,CDCl 3 )δ169.27,162.76,161.78,160.12,158.67,144.94,141.27,136.70,134.59,132.05,131.47,127.08,126.93,124.92,124.67,123.75,123.06,111.38,110.45,103.36,56.20,52.97,52.27,47.22,42.32,21.53.HRMS(ESI)calculated for C 28 H 28 N 6 O 3 S[M+H] + :529.2016,found:529.2007.Purity:98.6%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide(Ⅵ-8)
yellow solid, yield: 42%; 1 H NMR(400MHz,CDCl 3 )δ9.59(s,1H),8.85(s,1H),8.54(d,J=5.1Hz,2H),8.43(d,J=8.0Hz,1H),7.90(d,J=7.7Hz,1H),7.67(s,1H),7.49–7.41(m,1H),7.41–7.32(m,1H),7.14(d,J=5.2Hz,1H),6.76(s,1H),6.50–6.29(m,2H),5.75(d,J=9.8Hz,1H),3.87(s,3H),3.19–3.07(m,4H),2.84–2.72(m,4H),2.47(s,3H),1.97(m,2H). 13 C NMR(101MHz,CDCl 3 )δ162.86,161.66,160.12,158.57,145.00,141.15,137.94,136.63,134.56,132.16,131.25,126.96,126.48,126.09,124.80,124.53,123.71,122.91,111.44,110.15,105.17,59.48,57.08,56.07,55.61,54.90,47.41,28.77.HRMS(ESI)calculated for C 28 H 30 N 6 O 2 S[M+H] + :515.2224,found:515.2199.Purity:99.4%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-2-(4-(dimethyl-amino)-piperidin-1-yl)-4-methoxyphenyl)acrylamide(Ⅵ-9)
yellow solid, yield: 54%; 1 H NMR(500MHz,CDCl 3 )δ9.63(s,1H),8.54(d,J=4.9Hz,2H),8.48(s,1H),8.42(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.68(s,1H),7.44(t,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.15(d,J=5.1Hz,1H),6.72(s,1H),6.42(d,J=16.8Hz,1H),6.30(dd,J=16.8,10.1Hz,1H),5.75(d,J=10.0Hz,1H),3.88(s,3H),3.06(d,J=11.5Hz,2H),2.71(t,J=11.5Hz,2H),2.46(m,7H),2.08(d,J=11.9Hz,2H),1.76(m,2H). 13 C NMR(126MHz,CDCl 3 )δ162.75,161.64,160.07,158.57,144.82,141.15,136.60,135.67,134.50,132.08,131.31,126.66,126.62,126.32,124.81,124.55,123.68,122.93,111.35,110.20,103.15,62.25,56.10,52.11,41.54,29.37.HRMS(ESI)calculated for C 29 H 32 N 6 O 2 S[M+H] + :529.2380,found:529.2375.Purity:97.3%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide(Ⅵ-10)
yellow-green solid, yield: 41.5%; 1 H NMR(500MHz,CDCl 3 )δ9.65(s,1H),8.63–8.46(m,3H),8.42(d,J=8.0Hz,1H),7.90(d,J=8.0Hz,1H),7.68(s,1H),7.44(t,J=7.6Hz,1H),7.38(t,J=7.5Hz,1H),7.15(d,J=5.1Hz,1H),6.74(s,1H),6.42(d,J=16.9Hz,1H),6.27(dd,J=16.8,10.2Hz,1H),5.75(d,J=10.1Hz,1H),3.88(s,3H),3.04(d,J=11.4Hz,2H),2.72(t,J=11.7Hz,4H),2.65–2.35(m,5H),2.34(m,4H),2.23(m,1H),2.06(d,J=11.8Hz,2H),1.66(q,J=11.6Hz,2H). 13 C NMR(126MHz,CDCl 3 )δ162.68,161.64,160.10,158.56,144.80,141.16,136.62,135.95,134.53,132.10,131.29,126.73,126.53,126.20,124.78,124.51,123.69,122.91,111.20,110.15,103.16,61.44,56.08,55.35,52.59,49.43,45.97,29.92.HRMS(ESI)calculated for C 32 H 37 N 7 O 2 S[M+H] + :584.2802,found:584.2802.Purity:99.8%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethyl-amino)-ethyl)-thio)-4-methoxyphenyl)acrylamide(Ⅵ-11)
yellow solid, yield 68.1%; 1 H NMR(500MHz,CDCl 3 )δ10.19(s,1H),9.73(s,1H),8.62(bs,1H),8.58(d,J=5.1Hz,1H),8.40(d,J=8.1Hz,1H),7.96–7.90(m,2H),7.46(t,J=7.6Hz,1H),7.39(t,J=7.5Hz,1H),7.20(d,J=5.1Hz,1H),7.10(s,1H),6.50(d,J=16.9Hz,1H),6.31(dd,J=16.9,10.2Hz,1H),5.75(d,J=10.2Hz,1H),3.92(s,3H),2.84(t,J=6.0Hz,2H),2.31(t,J=6.0Hz,2H),2.24(s,6H). 13 C NMR(126MHz,CDCl 3 )δ163.25,161.63,159.82,158.58,144.32,141.19,136.56,136.06,134.36,132.09,131.76,131.11,126.57,124.85,124.55,123.50,122.99,117.58,113.42,111.54,110.62,56.31,56.10,44.75,35.43.HRMS(ESI)calculated for C 26 H 27 N 5 O 2 S 2 [M+H] + :506.1679,found:506.1659.Purity:97.5%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-mor-pholinoethoxy)phenyl)acrylamide(Ⅵ-12)
yellow solid, yield: 38.7%; 1 H NMR(500MHz,CDCl 3 )δ9.57(s,1H),8.56–8.47(m,2H),8.44(m,2H),7.90(d,J=8.0Hz,1H),7.58(s,1H),7.43(t,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.12(d,J=5.0Hz,1H),6.60(s,1H),6.47(d,J=16.8Hz,1H),6.37(dd,J=16.8,10.0Hz,1H),5.76(d,J=9.9Hz,1H),4.17(t,J=5.1Hz,2H),3.87(s,3H),3.75(m,4H),2.69(t,J=4.9Hz,2H),2.54(m,4H). 13 C NMR(126MHz,CDCl 3 )δ162.91,161.70,160.20,158.55,145.39,142.75,141.12,136.64,134.60,131.88,131.07,126.93,124.78,124.54,123.79,123.73,122.90,122.52,112.98,110.04,99.30,67.82,66.76,57.70,56.17,53.78.HRMS(ESI)calculated for C 28 H 29 N 5 O 4 S[M+H] + :532.2013,found:532.2006.Purity:99.8%(by HPLC).
N-(5-((4-(benzo[b]thiophen-3-yl)-5-fluoropyrimidin-2-yl)amino)-2-((2-(dimethyl-amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide(Ⅵ-13)
yellow solid, yield: 32%; 1 H NMR(500MHz,CDCl 3 )δ10.11(s,1H),9.55(s,1H),8.50(m,2H),8.40(s,1H),7.90(d,J=7.9Hz,1H),7.64(s,1H),7.41(m,2H),6.79(s,1H),6.43(d,J=16.9Hz,1H),6.31(dd,J=16.9,10.1Hz,1H),5.69(d,J=10.1Hz,1H),3.88(s,3H),2.88(t,J=5.3Hz,2H),2.70(s,3H),2.29(t,J=5.3Hz,3H),2.26(s,6H). 13 C NMR(126MHz,CDCl 3 )δ163.30,156.41,150.08( 1 J=252.5Hz),149.63( 3 J=11.25Hz),146.34( 2 J=25.0Hz),144.95,140.08,136.98,136.04,132.97( 3 J=10.0Hz),132.28,129.41,128.92,128.88,126.52,126.02,124.85,124.82,124.80,124.76,122.46,111.22,104.63,57.38,56.48,56.04,45.48,43.52.HRMS(ESI)calculated for C 27 H 29 FN 6 O 2 S[M+H] + :521.2129,found:521.2122.Purity:98.3%(by HPLC).
example 2 kinase assay
To determine the targeting of 6a and assess its antitumor potential, we performed an in vitro enzymatic assay. Afatinib and Osimertinib were used as positive controls. As shown in fig. 1, fig. 1 (a) is a dose-dependent inhibition of EGFR phosphorylation induced by 6 a; (B) Dose-dependent inhibition of EGFR phosphorylation was induced for Afatinib and Osimertinib. Data are expressed as mean ± standard deviation of triplicate independent experiments.
Wherein 6a showed strong inhibitory activity at nanomolar concentration level and was dose dependent (ic50=1.33±0.02nM for EGFR-L858R), similar to ic50=1.03±0.03nM for positive control Afatinib. For the EGFR T790M/L858R mutation, the inhibition of 6a (ic50=0.26±0.01 nM) was slightly stronger than that of Osimertinib (ic50=0.37±0.04 nM), suggesting that 6a has the potential to overcome EGFR mutation resistance.
EXAMPLE 3 anti-tumor Activity study of benzothiophene pyrimidine derivatives
The in vitro antiproliferative activity of 13 compounds synthesized on H1975, PC9, H229 cells was determined using osimerinib as a positive control, by:
collecting log phase cells, adjusting cell suspension concentration to 5×10 3 The cells/wells were inoculated into 96-well plates and incubated at 37℃in a 5% carbon dioxide incubator for 12-24h. After the cells adhere to the wall, the old culture medium is sucked and removed, and a culture medium without FBS is added; six concentration gradients (10, 1, 0.1, 0.05, 0.01 and 0.001 mu M) are arranged for each compound, three groups of compound holes are arranged for each concentration, after the compound is added, the compound is cultured for 48 hours, then CCK8 solution is added into each hole in a dark place, and the compound is put into a carbon dioxide incubator for continuous incubation for 2 to 4 hours. The absorbance (OD value) of each well was measured at an emission wavelength of 450nM on a microplate reader. Finally, data statistics is carried out, and the inhibition rate under each concentration is calculated according to the following formula:
the half-maximal Inhibition (IC) was then calculated using software GraphPad Prism 5.02 50 ) Each set of experiments was independently repeated three times and averaged to obtain the final data. Detailed description of the inventionThe results are shown in Table 1.
TABLE 1 VI-1 to VI-13 antitumor Activity
EGFR kinase L858R/T790M double mutant cells; EGFR kinase L858R single mutant cells; egfr kinase wild type cells.
The in vitro antiproliferative test results show that: the antiproliferative activity of the compound VI-1 on H1975 cells is 2.2nM and is 1.58 times that of the positive medicine Osimertinib; meanwhile, the compound VI-1 has higher selectivity to double mutant H1975 cells compared with a positive medicine. The in vitro antiproliferative activity of the compounds VI-2 to VI-12 and VI-13 is weaker than that of VI-1.
The in vitro antiproliferative activity research results of 13 Osimertinib derivatives show that the substitution of the N-methylindole ring with a heterocycle with larger hydrophobicity is favorable for the increase of antiproliferative activity, which indicates that the combination of the part of structure and a target point needs hydrophobic action, in addition, the high selectivity of the compound VI-1 to H1975 cells further verifies that a part of toxicity of the compound is derived from the demethylation reaction of N-methylindole; for R 2 Partial structural modification, whether changing the volume, electrical property or fat-solubility of the chain, reduces the activity, which may result in that the small molecule cannot be effectively combined with the target protein due to the change of the spatial conformation of the molecule, and also indicates that the side chain structure has higher conservation; r is R 1 After substitution with fluorine atoms, antiproliferative activity is reduced, probably due to the smaller binding sites there to the target, and the increased volume is not able to effectively bind to the target protein.
Claims (9)
1. The benzothiophene pyrimidine derivative is characterized by comprising the following chemical structural formula:
wherein R is 1 Is H or F; r is R 2 Is that、/>、/>、、
、/>、/>、/>、/>、、/>Or->。
2. Benzothiophene-containing pyrimidine derivative according to claim 1, characterized in thatThe R is 1 Is H, R 2 Is that、/>、/>、/>、/>、
、/>、/>、/>、/>、Or->。
3. The benzothiophene-containing pyrimidine derivative according to claim 1, wherein R is 1 Is F, R 2 Is that。
4. A method for producing a benzothiophene-containing pyrimidine derivative according to any one of claims 1 to 3, comprising the steps of:
(1) Benzothiophene-3-boric acid and (2, 4-dichloropyrimidine) or (2, 4-dichloro-6-fluoropyrimidine) are subjected to suzuki reaction to obtain the compound;
(2) Making 4-fluoro-2-methoxy-5-nitroaniline and the product obtained in step (1) produce aromatic nucleophilic reaction under acid condition so as to obtain the invented compound;
(3) Reacting the product of step (2) with R under alkaline conditions 2 H or its hydrochloride to obtain the compound;
(4) Mixing and dissolving the product obtained in the step (3) with ammonium chloride and a reducing agent, performing a nitro reduction reaction, and performing an acylation reaction after the reaction is finished to prepare the benzothiophene-containing pyrimidine derivative。
5. The method according to claim 4, wherein the aromatic nucleophilic reaction in the step (2) is performed by: and (3) dissolving 4-fluoro-2-methoxy-5-nitroaniline and the product obtained in the step (1), and heating to 80-100 ℃ overnight.
6. The preparation method according to claim 4 or 5, wherein the amount of the 4-fluoro-2-methoxy-5-nitroaniline is 1-1.5 eq.
7. The process of claim 4, wherein R in step (3) 2 When being a secondary amine: dissolving the product obtained in the step (2), and then adding R 2 H or its hydrochloride and DIPEA, reacting for 10-15H at 80-90 ℃.
8. The process of claim 4, wherein R in step (3) 2 In the case of thiols or alcohols: r is R 2 Dissolving H, adding NaH at 0 ℃, stirring for 10-20min, adding the product obtained in the step (2), stirring to enable the reaction liquid to be heated to room temperature, and reacting overnight.
9. The benzothiophene-containing pyrimidine derivative according to any one of claims 1 to 3, or the use of the benzothiophene-containing pyrimidine derivative prepared by the method according to any one of claims 4 to 8 in the preparation of antitumor drugs.
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CN101039919A (en) * | 2004-10-13 | 2007-09-19 | 惠氏公司 | N-benzenesulfonyl substituted anilino-pyrimidine analogs |
CN101460491A (en) * | 2006-04-12 | 2009-06-17 | 惠氏公司 | Anilino-pyrimidine phenyl and benzothiophene analogs |
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