WO2023060904A1 - 一种作为fgfr4抑制剂的萘啶酮类化合物及其用途 - Google Patents
一种作为fgfr4抑制剂的萘啶酮类化合物及其用途 Download PDFInfo
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- WO2023060904A1 WO2023060904A1 PCT/CN2022/095973 CN2022095973W WO2023060904A1 WO 2023060904 A1 WO2023060904 A1 WO 2023060904A1 CN 2022095973 W CN2022095973 W CN 2022095973W WO 2023060904 A1 WO2023060904 A1 WO 2023060904A1
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- WIPO (PCT)
- Prior art keywords
- naphthyridin
- oxo
- dimethoxyphenyl
- dihydro
- propyl
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the invention belongs to the field of medicinal chemistry, and specifically relates to a class of 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl compounds targeting FGFR4, a preparation method and application thereof.
- FGFR4 selective inhibitors have the advantage of less toxicity, but at this stage, FGFR4 inhibitors are used to fight liver cancer, etc. Tumor research is far from enough, and it is still necessary to research and develop new FGFR4 inhibitors.
- One of the purposes of the present invention is to provide a class of 2-oxo-1,2-dihydro-1,6-naphthyridin-7-based compounds targeting FGFR4 and its preparation method in order to solve the above technical problems and uses, the compound can selectively inhibit FGFR4.
- a 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl compound the general structural formula is as follows:
- R 1 is selected from one or more of halogen or alkoxy, and the alkoxy is preferably C 1 -C 6 alkoxy;
- “multiple” means that different positions on the benzene ring can have substituents, and these substituents are selected from halogen or alkyl, that is It can be expressed as Wherein, R 11 is selected from halogen or alkoxy, R 12 is selected from halogen or alkoxy, R 13 is selected from halogen or alkoxy, R 14 is selected from halogen or alkoxy, R 15 is selected from halogen or alkoxy group, and R 11 to R 15 may be the same or different.
- R 2 is -(CH 2 ) n NR 3 R 4 or -(CH 2 ) n OH, wherein, n is 2 or 3, R 3 and R 4 are ringed together with the N atom connecting R 3 and R 4 to form 5-6 membered rings.
- said R 1 is selected from one or more of Cl or methoxy.
- n 3
- R 3 and R 4 are ringed together with the N atom connecting R 3 and R 4 to form a 5-6 membered ring group
- m is 1 or 2
- M is S, O or N
- R 5 is H or C 1 -C 4 alkyl; Indicates the replacement position.
- said R 1 is 3,5-dimethoxy or 3,5-dimethoxy-2,6-dichloro;
- R 2 is selected from any of the following substituent groups: Indicates the replacement position.
- the 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl compound is the following compound, its stereoisomer, its tautomer or its pharmaceutically acceptable
- the present invention also provides an application of the 2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl compound in the preparation of medicine, and the medicine is an antineoplastic medicine.
- the antitumor drug targets FGFR4.
- the antitumor drug selectively inhibits FGFR4, but has almost no inhibition on FGFR1, FGFR2 and FGFR3.
- the drug is used to treat liver cancer.
- Fig. 1 is the proliferation inhibitory activity of active compound to hepatoma cell HePG2 at 20 ⁇ M concentration
- Figure 2 is the inhibitory activity of the active compound on the proliferation of liver cancer cells HuH-7 at a concentration of 20 ⁇ M;
- Figure 3 is the inhibitory activity of the active compound on the proliferation of liver cancer cells MIHA at a concentration of 20 ⁇ M;
- Fig. 4 is the proliferation inhibitory activity of active compound 23 to colon cancer cell HCT-116 at a concentration of 3-100 ⁇ M;
- Fig. 5 is the proliferation inhibitory activity of active compound 23 to colon cancer cell SW480 at the concentration of 3-100 ⁇ M;
- Fig. 6 shows the growth inhibitory activity of active compound 23 on colon cancer cell RKO at a concentration of 3-100 ⁇ M.
- the thin-layer chromatography silica gel plate uses Yantai Xincheng silica gel plate.
- the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.2mm-0.25mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm-0.5mm.
- Column chromatography generally uses Yantai silica gel 200-300 mesh silica gel as the carrier.
- CDCl 3 deuterated chloroform
- DMSO-d6 deuterated dimethylsulfoxide.
- the reaction bottle is connected to a balloon with a volume of about 1 IL.
- the solution in the reaction refers to an aqueous solution.
- the compound is purified, using silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum peony and ethyl acetate system; B: dichloromethane and methanol system; wherein the solvent
- A petroleum peony and ethyl acetate system
- B dichloromethane and methanol system
- the solvent The volume ratio varies according to the polarity of the compound, and a small amount of acidic or basic reagent can also be added, such as acetic acid or triethylamine.
- Embodiment 1 route and preparation process are as follows:
- Lithium aluminum hydride (1.16g, 30.69mmol) was placed in a 500ml double-necked bottle under nitrogen protection. At -78°C, 100ml of anhydrous THF was slowly added, and then 6-chloro- 4-((3-(piperidin-1-yl)propyl)amino)nicotinic acid ethyl ester (5g, 15.35mmol) (pre-dissolved in anhydrous THF), then reacted at room temperature for 3h, at -78°C Add 2ml of saturated ammonium chloride solution dropwise to quench the reaction (a large amount of solids precipitated), then add 3ml of 1N NaOH solution, stir at room temperature for 0.5h, filter with suction, and take the filtrate.
- tert-butyl (3-(3,5-dimethoxyphenyl)-2-oxo-1-(3-(piperidin-1-yl)propyl)-1,2-2H -1,6-naphthyridin-7-yl)(2-methyl-6-nitrophenyl)carbamate (350 mg, 532.10 ⁇ mol) was dissolved in anhydrous THF solution, 20% Pd/C was added, Under the condition of hydrogen, reduce at room temperature, react for 48h, remove palladium carbon by suction filtration, and distill the filtrate to remove the solvent under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: B system) to obtain tert-butyl (2-amino -6-nitrophenyl)(3-(3,5-dimethoxyphenyl)-2-oxo-1-(3-(piperidin-1-yl)propyl)-1,2- 2H-1,6-naphthyridin-7-
- Embodiment 2 route and preparation process are as follows:
- reaction solution was concentrated, 150ml of dichloromethane was added, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the layers were separated, the organic phase was concentrated, extracted repeatedly with ethyl acetate/distilled water system, the organic layers were combined, and the solvent was distilled off under reduced pressure.
- the residue was purified by silica gel column chromatography (eluent: system B) to obtain 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3- (3-(piperidin-1-yl)propyl)-1,6-naphthyridin-2(1H)-one (877 mg, white solid), yield 75.6%.
- Embodiment 3 route and preparation process are as follows:
- Lithium aluminum hydride (1.11g, 29.34mmol) was placed in a 500ml double-neck flask, under nitrogen protection, at -78°C, slowly added 100ml of anhydrous THF, and then slowly added dropwise ethyl 6- Ethyl chloro-4-((3-(4-methylpiperazin-1-yl)propyl)amino)nicotinate (5g, 14.67mmol) (pre-dissolved in anhydrous THF), then placed at room temperature for reaction 3h, add 2ml of saturated ammonium chloride solution dropwise at -78°C to quench the reaction (a large amount of solids precipitated), then add 3ml of 1N NaOH solution, stir at room temperature for 0.5h, filter with suction, and take the filtrate.
- tert-butyl (3-(3,5-dimethoxyphenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)-2-oxo-1 , 2-2H-1,6-naphthyridin-7-yl)(2-methyl-6-nitrophenyl)carbamate (300.00mg, 445.91 ⁇ mol) was dissolved in anhydrous THF solution, added 20 %Pd/C, under the condition of hydrogen, reduced at room temperature, reacted for 48h, removed palladium carbon by suction filtration, the filtrate was distilled off under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain tert-butyl Base(2-amino-6-nitrophenyl)(3-(3,5-dimethoxyphenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)2 -Oxo-1,2-2H-1,
- Embodiment 4 route and preparation process are as follows:
- reaction solution was concentrated, 150ml of dichloromethane was added, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the layers were separated, the organic phase was concentrated, extracted repeatedly with ethyl acetate/distilled water system, the organic layers were combined, and the solvent was distilled off under reduced pressure.
- the residue was purified by silica gel column chromatography (eluent: system B) to obtain 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3- (4-Methylpiperazin-1-yl)propyl)-1,6-naphthyridin-2(1H)-one (785 mg, white solid), yield 78.5%.
- Embodiment 5 route and preparation process are as follows:
- Lithium aluminum hydride (1.16g, 30.51mmol) was placed in a 500ml double-neck flask, under nitrogen protection, at -78°C, slowly added 100ml of anhydrous THF, and then slowly added dropwise 6-chloro- 4-((3-morpholinopropyl)amino)nicotinic acid ethyl ester (5g, 15.25mmol) (pre-dissolved in anhydrous THF), and then reacted at room temperature for 3h, added dropwise saturated 2ml of ammonium chloride solution was used to quench the reaction (a lot of solids were precipitated), then 3ml of 1N NaOH solution was added, stirred at room temperature for 0.5h, filtered with suction, and the filtrate was taken.
- tert-butyl (3-(3,5-dimethoxyphenyl)-1-(3-morpholinopropyl)-2-oxo-1,2-2H-1,6- Naphthyridin-7-yl)(2-methyl-6-nitrophenyl)carbamate (350mg, 530.51 ⁇ mol) was dissolved in anhydrous THF solution, added 20% Pd/C, under hydrogen, at room temperature Reduction, reaction for 48h, suction filtration to remove palladium carbon, the filtrate was distilled off under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (eluent: B system) to obtain tert-butyl (2-amino-6-nitro Phenyl)(3-(3,5-dimethoxyphenyl)-2-oxo-1-(3-morpholinopropyl)-1,2-2H-1,6-naphthyridine-7 -yl) carbamate (143 mg, white solid), yield 42.
- Embodiment 6 route and preparation process are as follows:
- reaction solution was concentrated, 150ml of dichloromethane was added, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the layers were separated, the organic phase was concentrated, extracted repeatedly with ethyl acetate/distilled water system, the organic layers were combined, and the solvent was distilled off under reduced pressure.
- the residue was purified by silica gel column chromatography (eluent: system B) to obtain 7-chloro-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(3- Morpholinopropyl)-1,6-naphthyridin-2(1H)-one (884 mg, white solid), yield 76.2%.
- Embodiment 7 route and preparation process are as follows:
- Embodiment 8 route and preparation process are as follows:
- reaction system was extracted with ethyl ester/saturated sodium chloride solution several times, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain tert-butyl (2-acrylamide-6- Methylphenyl)(1-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)- 2-oxo-1,2-2H-1,6-naphthyridin-7-yl)carbamate (80 mg, white solid), yield 83.90%.
- the inhibitory activity of compound 22-30 was carried out on FGFR1-4 kinase by using Mobility shift assay.
- Conversion%_sample is the conversion rate reading of the sample
- Conversion%_min the average value of negative control wells, representing the conversion rate readings of wells without enzyme activity
- Conversion%_max the average value of positive control wells, representing the conversion rate readings of wells without compound inhibition.
- the dose-effect curve was fitted using the log(inhibitor) vs. response–Variable slope of the analysis software GraphPad Prism 5, so as to obtain the IC50 value of each compound on the enzyme activity .
- Example 10 Effects of active compounds on the proliferation of liver cancer cells HepG2, HuH-7 and MiHA.
- test compound is firstly dissolved in DMSO to prepare a stock solution, and then serially diluted with the culture medium of the corresponding cells to prepare a test sample.
- the final concentration range of the compound is 20uM.
- the cells in the logarithmic culture phase were inoculated into a 96-well cell culture plate at an appropriate density, and after culturing overnight under corresponding conditions, the test compound samples were added and cultured for 72 hours.
- test compound 23 was first dissolved in DMSO to prepare a stock solution, and then serially diluted with the culture medium of the corresponding cells to prepare a test sample. The final concentration of the compound ranged from 3-100uM.
- the cells in the logarithmic culture phase were inoculated into a 96-well cell culture plate at an appropriate density, and after culturing overnight under corresponding conditions, the test compound samples were added and cultured for 72 hours.
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Abstract
本发明公开了一种2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物,为结构如式(I)的化合物、其立体异构体、其互变异构体或其可药用的盐:其中,R1选自卤素或者C1~C6烷氧基中的一个或者多个;R2为-(CH2)nNR3R4或-(CH2)nOH,其中,n为2或3;R3和R4独立地选自烷基,或者R3和R4与连接R3和R4的N原子一起环合起来形成5~6元环基。该化合物该化合物可以选择性地抑制FGFR4,可以作为一种潜在的抗肿瘤药物。
Description
本发明属于药物化学领域,具体涉及一类以FGFR4为靶点的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物及其制备方法和用途。
目前已有一系列研究FGFR抑制剂的专利,但对于FGFR4选择性抑制的专利公开较少,相对于FGFR抑制剂,FGFR4选择性抑制剂具有毒性小的优势,但现阶段对于FGFR4抑制剂对抗肝癌等肿瘤的研究是远远不够的,仍有必要研究和开发新的FGFR4抑制剂。
发明内容
本发明的目的之一是为解决上述技术问题,提供一类以FGFR4为靶点的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物及其制备方法和用途,该化合物可以选择性地抑制FGFR4。
一种2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物,结构通式如下:
其中,R
1选自卤素或者烷氧基中的一个或者多个,所述的烷氧基优选为C
1~C
6烷氧基;
其中,“多个”的意思表示苯环上的不同的位置都可以有取代基,这些取代基选自卤素或者烷基,即
可以表示为
其中,R
11选自卤素或者烷氧基,R
12选自卤素或者烷氧基,R
13选自卤素或者烷氧基,R
14选自卤素或者烷氧基,R
15选自卤素或者烷氧基,R
11~R
15可以相同,也可以不同。
R
2为-(CH
2)
nNR
3R
4或-(CH
2)
nOH,其中,n为2或3,R
3和R
4与连接R
3和R
4的N原子一起环合起来形成5~6元环。
作为优选,所述的R
1选自Cl或者甲氧基中的一个或者多个。
作为优选,n为3,R
3和R
4与连接R
3和R
4的N原子一起环合起来形成5~6元环 基;
作为优选,所述的R
1为3,5-二甲氧基或3,5-二甲氧基-2,6-二氯;
作为优选,所述2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物为以下化合物、其立体异构体、其互变异构体或其可药用的盐中的一种:
本发明还提供了一种所述的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物在药物制备中的应用,所述的药物为抗肿瘤药物。
作为优选,所述的抗肿瘤药物以FGFR4为靶点。作为优选,所述的抗肿瘤药物选 择性抑制FGFR4,而对FGFR1、FGFR2和FGFR3几乎无抑制。作为优选,所述的药物用来治疗肝癌。
图1为活性化合物在20μM浓度下对肝癌细胞HePG2的增殖抑制活性;
图2为活性化合物在20μM浓度下对肝癌细胞HuH-7的增殖抑制活性;
图3为活性化合物在20μM浓度下对肝癌细胞MIHA的增殖抑制活性;
图4为活性化合物23在3-100μM浓度下对结肠癌细胞HCT-116的增殖抑制活性;
图5为活性化合物23在3-100μM浓度下对结肠癌细胞SW480的增殖抑制活性;
图6为活性化合物23在3-100μM浓度下对结肠癌细胞RKO的增殖抑制活性。
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
1H NMR图谱是用Bruker仪器(400MHz)测定而得,化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)
1H NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=变宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。质谱是用LC/MS仪测定得到,离子化方式可为ESI。
薄层层析硅胶板使用烟台新诚硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.2mm~0.25mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。柱层析一般使用烟台硅胶200~300目硅胶为载体。
在下列实施例中,除非另有指明,所有温度为摄氏温度,除非另有指明,各种起始原料和试剂来自市售或者是根据已知的方法合成,市售原料和试剂均不经进一步纯化直接使用,除非另有指明。
CDCl
3:氘代氯仿;DMSO-d6:氘代二甲基亚砜。氢气,氮气环境下是指反应瓶连接一个约IL容积的气球。实施例中无特殊说明,反应中的溶液是指水溶液。
对化合物进行纯化,采用硅胶柱层析洗脱剂体系和薄层色谱法,其中洗脱剂体系选自:A:石油醍和乙酸乙酯体系;B:二氯甲烷和甲醇体系;其中溶剂的体积比根据化合物的极性不同而不同,也可以加入少量的酸性或碱性试剂进行条件,如醋酸或三乙胺等。
实施例1路线和制备过程如下:
(1)将4,6-二氯烟酸乙酯(5g,22.72mmol)和三乙胺(TEA)(9.45ml,68.17mmol)溶于四氢呋喃(THF)中,再滴加3-(4-哌啶-1-基)丙基-1-氨基(6.46g,45.44mmol),室温下反应过夜,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到6-氯-4-((3-(哌啶-1-基)丙基)氨基)烟酸乙酯(5.6g,淡黄色油状液体),产率75.8%。(2)将氢化锂铝(1.16g,30.69mmol)置于500ml双颈瓶中,氮气保护,在-78℃条件下,缓缓加入100ml无水THF,然后再缓缓滴加6-氯-4-((3-(哌啶-1-基)丙基)氨基)烟酸乙酯(5g,15.35mmol)(预溶于无水THF),再置于室温下反应3h,在-78℃下逐滴加入饱和氯化铵溶液2ml淬灭反应(有大量固体析出),再加入1N NaOH溶液3ml,室温搅拌0.5h,抽滤,取滤液。减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到(6-氯-4-((3-(哌啶-1-基)丙基)氨基)吡啶-3-基)甲醇(3.1g,淡黄色油状液体),产率72.0%。(3)将(6-氯-4-((3-(哌啶-1-基)丙基)氨基)吡啶-3-基)甲醇(3g,10.57mmol)投入无水二氯甲烷中,加入二氧化锰(9.19g,105.71mmol),室温下反应过夜,抽滤除去二氧化锰,取滤液,减压蒸馏除去溶液,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到6-氯-4-((3-(哌啶-1-基)丙基)氨基)烟碱醛(2.0g,淡黄色油状液体),产率68.6%。(4)将6-氯-4-((3-(哌啶-1-基)丙基)氨基)烟碱醛(1.5g,5.32mmol)、K
2CO
3(2.21g,15.97mmol)以及2-(3,5-二甲氧基苯基)乙酸乙酯(1.79g,7.98mmol)投入10ml无水N,N-二甲基甲酰胺(DMF),氮气保护,100℃反应12h。加入大量乙酸乙酯溶解反应体系,再以饱和氯化钠溶液水洗,减压蒸馏除去溶液,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到7-氯-3-(3,5-二甲氧基苯基)-1-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮(1.4g,淡黄色油状物),产率62.6%。(5)将7-氯-3-(3,5-二甲氧基苯基)-1-(3-(哌啶-1- 基)丙基)-1,6-萘啶-2(1H)-酮(1g,2.26mmol)、2-硝基-6-甲基苯胺(516.41mg,3.39mmol)、Pd
2(dba)
3(207.20mg,226.27μmol)、BrettPhos(242.91mg,452.53μmol)、碳酸铯(2.21g,6.79mmol)投入30ml甲苯中,氮气保护下,120℃回流6h。减压蒸馏除去溶剂甲苯,再以乙酸乙酯/饱和氯化钠体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮(730mg,红棕色固体),产率58.0%。(6)将3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮(500mg,896.62μmol)、二碳酸二叔丁酯(391.37mg,1.79mmol)、4-二甲氨基吡啶(10.95mg,89.66μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(363mg,淡黄色固体),产率61.50%。(7)将叔丁基(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(350mg,532.10μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液以减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(136mg,白色固体),产率40.8%。(8)将叔丁基(2-氨基-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,159.29μmol)和三乙胺(88.32mmL,637.16μmol)溶于无水THF中,再滴加丙烯酰氯(25.89mmL,318.58μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(71mg,白色固体),产率65.4%。(9)将叔丁基(2-丙烯酰胺-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(50mg,73.33μmol)溶于4ml二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,再以乙酸乙酯/饱和氯化钠溶液多次萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得化合物N-(2-((3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-二氢-1,6-萘啶-7-基)氨基3-甲基苯基)丙烯酰胺(22mg,淡黄色色固体),记为化合物22,产率52.7%。表征 数据如下:
1H NMR(400MHz,DMSO)δ9.66(s,1H),9.46(s,1H),8.56(s,1H),8.50(s,1H),8.08(s,1H),7.72(d,J=7.7Hz,1H),7.25(t,J=7.8Hz,1H),7.16(d,J=7.4Hz,1H),6.87(s,2H),6.51(s,1H),6.23(s,1H),5.69(d,J=10.4Hz,1H),4.10(s,2H),3.79(s,6H),3.64(s,6H),3.11(s,2H),2.84(dd,J=21.1,10.1Hz,2H),2.21(s,3H),1.99(s,2H),1.81(d,J=13.6Hz,2H)。
实施例2路线和制备过程如下:
(1)将7-氯-3-(3,5-二甲氧基苯基)-1-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮(1g,2.26mmol)溶于50ml无水乙腈中,冷却至-20℃,滴加磺酰氯(365.71mmL,4.53mmol)(预溶于无水乙腈),室温反应10min。反应液浓缩,加入150ml二氯甲烷,用饱和碳酸氢钠溶液调节pH=8~9,分层,有机相浓缩,用乙酸乙酯/蒸馏水体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮(877mg,白色固体),产率75.6%。(2)将7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮(877mg,白色固体)(800mg,1.57mmol)、2-硝基-6-甲基苯胺(357.42mg,2.35mmol)、Pd
2(dba)
3(143.41mg,156.60μmol)、BrettPhos(168.12mg,313.21μmol)、碳酸铯(1.53g,4.70mmol)投入30ml甲苯中,氮气保护下,120℃回流6h,减压蒸馏除去溶剂,再以乙酸乙酯/饱和氯化钠体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮 (608mg,红棕色固体),产率62.0%。(3)将3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(哌啶-1-基)丙基)-1,6-萘啶-2(1H)-酮(500mg,798.04μmol)、二碳酸二叔丁酯(348.34mg,1.60mmol)、4-二甲氨基吡啶(9.75mg,79.80μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(337mg,淡黄色固体),产率58.2%。(4)将叔丁基(3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(300mg,412.85μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(180mg,白色固体),产率62.6%。(5)将叔丁基(2-氨基-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,143.54μmol)和三乙胺(79.59mmL,574.16μmol)溶于无水THF中,再滴加丙烯酰氯(23.33mmL,287.08μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(73mg,白色固体),产率68.2%。(6)将叔丁基(2-丙烯酰胺-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(50.00mg,66.60μmol)溶于4ml二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,再以乙酸乙酯/饱和氯化钠溶液多次萃取,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得N-(2-((3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基-3-甲基苯基)丙烯酰胺(26mg,淡黄色色固体),记为化合物23,产率61.0%,表征数据如下:
1H NMR(400MHz,DMSO)δ9.61(s,1H),9.21(s,1H),8.55(s,1H),8.48(s,1H),7.79(s,1H),7.71(d,J=7.7Hz,1H),7.25(t,J=7.8Hz,1H),7.17(d,J=7.4Hz,1H),7.00(s,1H),6.50(dd,J=17.0,10.2Hz,1H),6.23(s,1H),5.69(d,J=10.3Hz,1H),4.11(s,2H),3.97(s,6H),3.53–3.47(m,1H),3.46–3.41(m,1H),3.37(d,J=11.8Hz,2H),3.01(s,2H),2.83(dd,J=21.4,10.1Hz,2H),2.22(s,3H),1.98(s,2H),1.80(d,J=14.0Hz,2H),1.72–1.62 (m,2H)。
实施例3路线和制备过程如下:
(1)乙基6-氯-4-((3-(4-甲基哌嗪-1-基)丙基)氨基)烟酸乙酯
将4,6-二氯烟酸乙酯(5g,22.72mmol)和三乙胺(TEA)(9.45ml,68.17mmol)溶于四氢呋喃(THF)中,再滴加3-(4-甲基哌嗪-1-基)丙基-1-氨基(7.15g,45.44mmol),室温下反应过夜,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到乙基6-氯-4-((3-(4-甲基哌嗪-1-基)丙基)氨基)烟酸乙酯(5.2g,淡黄色油状液体),产率68.0%。(2)将氢化锂铝(1.11g,29.34mmol)置于500ml双颈瓶中,氮气保护,在-78℃条件下,缓缓加入100ml无水THF,然后再缓缓滴加乙基6-氯-4-((3-(4-甲基哌嗪-1-基)丙基)氨基)烟酸乙酯(5g,14.67mmol)(预溶于无水THF),再置于室温下反应3h,在-78℃下逐滴加入饱和氯化铵溶液2ml淬灭反应(有大量固体析出),再加入1N NaOH溶液3ml,室温搅拌0.5h,抽滤,取滤液。减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到(6-氯-4-((3-(4-甲基哌嗪-1-基)丙基)氨基)吡啶-3-基)甲醇(3.1g,淡黄色油状液体),产率71.9%。(3)将(6-氯-4-((3-(4-甲基哌嗪-1-基)丙基)氨基)吡啶-3-基)甲醇(3g,10.04mmol)投入无水二氯甲烷中,加入二氧化锰(8.73g,100.40mmol),室温下反应过夜,抽滤除去二氧化锰,取滤液,减压蒸馏除去溶液,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到6-氯-4-((3-(4-甲基哌嗪-1-基)丙基)氨基)烟碱醛(1.9g,淡黄色油状液体),产率65.0%。(4)将6-氯-4-((3-(哌啶-1-基)丙基)氨基)烟碱醛(1.5g,5.05mmol)、K2CO3(2.10g,15.16mmol)以及2-(3,5-二甲氧基苯基)乙酸乙酯(1.70g,7.58mmol)投入10ml无水N,N-二甲基甲酰胺(DMF),氮气保护, 100℃反应12h。加入大量乙酸乙酯溶解反应体系,再以饱和氯化钠溶液水洗,减压蒸馏除去溶液,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到7-氯-3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(1.3g,淡黄色油状液体),产率58.0%。(5)将7-氯-3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(1g,2.19mmol)、2-硝基-6-甲基苯胺(499.44mg,3.28mmol)、Pd2(dba)3(200.39mg,218.83μmol)、BrettPhos(234.93mg,437.66μmol)、碳酸铯(2.14g,6.56mmol)投入30ml甲苯中,氮气保护下,120℃回流6h。减压蒸馏除去溶剂甲苯,再以乙酸乙酯/饱和氯化钠体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(673mg,红棕色固体),产率52.6%。(6)将3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(500mg,873.11μmol)、二碳酸二叔丁酯(381.11mg,1.75mmol)、4-二甲氨基吡啶(10.67mg,87.31μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(397mg,淡黄色固体),产率67.5%。(7)将叔丁基(3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(300.00mg,445.91μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液以减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-硝基苯基)(3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(110mg,白色固体),产率38.3%。(8)将叔丁基(2-氨基-6-硝基苯基)(3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,155.57μmol)和三乙胺(86.26mmL,622.28μmol)溶于无水THF中,再滴加丙烯酰氯(25.29mmL,311.14μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-硝基苯基)(3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(67mg,白色固体),产率61.7%。(9)将叔丁基(2-丙烯酰胺-6-硝基苯基)(3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(50mg,71.75μmol)溶于4ml 二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,再以乙酸乙酯/饱和氯化钠溶液多次萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得化合物N-(2-((3-(3,5-二甲氧基苯基)-2-氧代-1-(3-(哌啶-1-基)丙基)-1,2-二氢-1,6-萘啶-7-基)氨基3-甲基苯基)丙烯酰胺(21mg,淡黄色色固体),记为化合物24,产率48.1%,产物表征数据如下:
1H NMR(400MHz,CDCl
3)δ8.39(s,2H),7.99(d,J=7.3Hz,1H),7.69(s,1H),7.28(d,J=6.6Hz,1H),7.14(d,J=7.5Hz,1H),6.77(d,J=2.2Hz,2H),6.47(t,J=2.2Hz,1H),6.31(d,J=16.9Hz,1H),6.18(dd,J=16.9,10.1Hz,1H),5.88(s,1H),5.67(d,J=9.0Hz,1H),4.06–3.98(m,2H),3.81(s,6H),3.75(s,1H),3.61(s,1H),2.67(s,4H),2.50(s,2H),2.24(s,3H),1.73(s,2H),1.28(s,1H),1.25(s,3H),0.88(t,J=6.7Hz,1H)。
实施例4路线和制备过程如下:
(1)将7-氯-3-(3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(1g,2.19mmol)溶于50ml无水乙腈中,冷却至-20℃,滴加磺酰氯(353.69mmL,4.38mmol)(预溶于无水乙腈),室温反应10min。反应液浓缩,加入150ml二氯甲烷,用饱和碳酸氢钠溶液调节pH=8~9,分层,有机相浓缩,用乙酸乙酯/蒸馏水体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(785mg,白色固体),产率78.5%。(2)将7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(750.00mg,1.43mmol)、2-硝基-6- 甲基苯胺(325.51mg,2.14mmol)、Pd
2(dba)
3(130.61mg,142.62μmol)、BrettPhos(153.12mg,285.25μmol)、碳酸铯(1.39g,4.28mmol)投入30ml甲苯中,氮气保护下,120℃回流6h,减压蒸馏除去溶剂,再以乙酸乙酯/饱和氯化钠体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(534mg,红棕色固体),产率58.4%。(3)将3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-(4-甲基哌嗪-1-基)丙基)-1,6-萘啶-2(1H)-酮(500mg,779.36μmol)、二碳酸二叔丁酯(340.19mg,1.56mmol)、4-二甲氨基吡啶(9.52mg,77.94μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(362mg,淡黄色固体),产率62.7%。(4)将叔丁基(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(300mg,404.49μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(165mg,白色固体),产率57.6%。(5)将叔丁基(2-氨基-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,140.51μmol)和三乙胺(77.91mmL,562.05μmol)溶于无水THF中,再滴加丙烯酰氯(22.84mmL,281.02μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(76mg,白色固体),产率71.3%。(6)将叔丁基(2-丙烯酰胺-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-(4-甲基哌嗪-1-基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(50.00mg,65.30μmol)溶于4ml二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,再以乙酸乙酯/饱和氯化钠溶液多次萃取,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得N-(2-((3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1-(3-(4-甲基哌嗪-1-基)丙基)-1,2-2H-1,6-萘啶-7-基)氨基-3-甲基苯基)丙烯酰胺(25mg, 淡黄色色固体),,记为化合物25,产率58.3%,表征数据如下:
1H NMR(400MHz,DMSO)δ9.63(s,1H),8.48(s,1H),8.03(s,1H),7.74(s,1H),7.25(s,1H),7.17(s,1H),6.51(t,J=13.6Hz,2H),5.69(d,J=10.1Hz,1H),4.02(s,2H),3.79(s,6H),3.45(s,2H),2.45(s,4H),2.19(s,4H),2.01(s,2H),1.71(s,3H)。
实施例5路线和制备过程如下:
(1)将4,6-二氯烟酸乙酯(5g,22.72mmol)和三乙胺(TEA)(9.45ml,68.17mmol)溶于四氢呋喃(THF)中,再滴加3-(4-吗啉基-1-基)丙基-1-氨基(6.55g,45.44mmol),室温下反应过夜,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到6-氯-4-((3-吗啉基丙基)氨基)烟酸乙酯(5.8g,淡黄色油状液体),产率78.2%。(2)将氢化锂铝(1.16g,30.51mmol)置于500ml双颈瓶中,氮气保护,在-78℃条件下,缓缓加入100ml无水THF,然后再缓缓滴加6-氯-4-((3-吗啉基丙基)氨基)烟酸乙酯(5g,15.25mmol)(预溶于无水THF),再置于室温下反应3h,在-78℃下逐滴加入饱和氯化铵溶液2ml淬灭反应(有大量固体析出),再加入1N NaOH溶液3ml,室温搅拌0.5h,抽滤,取滤液。减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到(6-氯-4-((3-吗啉基丙基)氨基)吡啶-3-基)甲醇(3.1g,淡黄色油状液体),产率71.2%。(3)将(6-氯-4-((3-吗啉基丙基)氨基)吡啶-3-基)甲醇(3g,10.50mmol)投入无水二氯甲烷中,加入二氧化锰(9.13g,104.98mmol),室温下反应过夜,抽滤除去二氧化锰,取滤液,减压蒸馏除去溶液,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到6-氯-4-((3-(吗啉基丙基)氨基)烟碱醛(2.1g,淡黄色油状液体),产率71.4%。(4)将6-氯-4-((3-(吗啉基丙基)氨基)烟碱醛(1.5g,5.29mmol)、K
2CO
3(2.19g,15.86mmol)以及 2-(3,5-二甲氧基苯基)乙酸乙酯(1.78g,7.93mmol)投入10ml无水N,N-二甲基甲酰胺(DMF),氮气保护,100℃反应12h。加入大量乙酸乙酯溶解反应体系,再以饱和氯化钠溶液水洗,减压蒸馏除去溶液,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到7-氯-3-(3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-1,6-萘啶-2(1H)-酮(1.5g,淡黄色油状物),产率65.9%。(5)将7-氯-3-(3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-1,6-萘啶-2(1H)-酮(1g,2.25mmol)、2-硝基-6-甲基苯胺(514.11mg,3.38mmol)、Pd
2(dba)
3(206.28mg,225.26μmol)、BrettPhos(209.35mg,390.01μmol)、碳酸铯(1.91g,5.85mmol)投入30ml甲苯中,氮气保护下,120℃回流6h。减压蒸馏除去溶剂甲苯,再以乙酸乙酯/饱和氯化钠体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-吗啉基丙基)-1,6-萘啶-2(1H)-酮(766mg,红棕色固体),产率62.3%。(6)将3-(3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-吗啉基丙基)-1,6-萘啶-2(1H)-酮(500mg,893.46μmol)、二碳酸二叔丁酯(389.99mg,1.79mmol)、4-二甲氨基吡啶(10.92mg,89.35μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(3-(3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(403mg,淡黄色固体),产率68.4%。(7)将叔丁基(3-(3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(350mg,530.51μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液以减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-吗啉基丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(143mg,白色固体),产率42.9%。(8)将叔丁基(2-氨基-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-吗啉基丙基)-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,158.79μmol)和三乙胺(88.05mmL,635.16μmol)溶于无水THF中,再滴加丙烯酰氯(25.81mmL,317.58μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(74mg,白色固体),产率68.6%。(9)将叔丁基(2-丙烯酰胺-6-硝基苯基)(3-(3,5-二甲氧基苯基)-2-氧代-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(50mg,73.12μmol)溶 于4ml二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,再以乙酸乙酯/饱和氯化钠溶液多次萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到N-(2-((3-(3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-二氢-1,6-萘啶-7-基)氨基3-甲基苯基)丙烯酰胺(17mg,淡黄色色固体),记为化合物26,产率40.5%,表征数据如下:
1H NMR(400MHz,DMSO)δ9.36(s,1H),8.50(s,1H),8.07(s,1H),7.92(s,1H),7.66(d,J=3.7Hz,1H),7.19(t,J=7.8Hz,1H),7.04(d,J=7.4Hz,1H),6.83(d,J=2.2Hz,2H),6.54–6.45(m,2H),6.06(d,J=15.1Hz,1H),5.57(d,J=12.1Hz,1H),4.21(t,J=7.6Hz,2H),3.73(s,6H),2.48–2.44(m,6H),2.40(t,J=6.4Hz,2H),2.07(s,3H),1.82(d,J=11.0Hz,2H)。
实施例6路线和制备过程如下:
(1)将7-氯-3-(3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-1,6-萘啶-2(1H)-酮(1g,2.25mmol)溶于50ml无水乙腈中,冷却至-20℃,滴加磺酰氯(364.08mmL,4.51mmol)(预溶于无水乙腈),室温反应10min。反应液浓缩,加入150ml二氯甲烷,用饱和碳酸氢钠溶液调节pH=8~9,分层,有机相浓缩,用乙酸乙酯/蒸馏水体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-1,6-萘啶-2(1H)-酮(884mg,白色固体),产率76.2%。(2)将7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-1,6-萘啶-2(1H)-酮(800.00mg,1.56mmol)、2-硝基-6-甲基苯胺(356.04mg,2.34mmol)、 Pd2(dba)3(142.86mg,156.00μmol)、BrettPhos(167.48mg,312.01μmol)、碳酸铯(1.52g,4.68mmol)投入30ml甲苯中,氮气保护下,120℃回流6h,减压蒸馏除去溶剂,再以乙酸乙酯/饱和氯化钠体系反复萃取,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-吗啉基丙基)丙基)-1,6-萘啶-2(1H)-酮(552mg,红棕色固体),产率56.3%。(3)将3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1-(3-吗啉基丙基)丙基)-1,6-萘啶-2(1H)-酮(500mg,795.54μmol)、二碳酸二叔丁酯(347.25mg,1.59mmol)、4-二甲氨基吡啶(9.72mg,79.55μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,合并有机层,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(372mg,淡黄色固体),产率64.3%。(4)将叔丁基(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(300mg,411.73μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(165mg,白色固体),产率57.6%。(5)将叔丁基(2-氨基-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,143.13μmol)和三乙胺(79.37mmL,572.54μmol)溶于无水THF中,再滴加丙烯酰氯(23.27mmL,286.27μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(84mg,白色固体),产率78.2%。(6)将叔丁基(2-丙烯酰胺-6-甲基苯基)(3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(50.00mg,66.43μmol)溶于4ml二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,再以乙酸乙酯/饱和氯化钠溶液多次萃取,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到N-(2-((3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-吗啉基丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基-3-甲基苯基)丙烯酰胺(23mg,淡黄色色固体),记为化合物27,产率54.2%,表征数据如下:
1H NMR(400MHz,DMSO)δ9.40(s,1H),8.55(s,1H), 8.12(s,1H),7.96(s,1H),7.71(d,J=7.4Hz,1H),7.23(t,J=7.8Hz,1H),7.08(d,J=7.4Hz,1H),6.88(d,J=2.2Hz,2H),6.57–6.49(m,2H),6.10(dd,J=16.0,1.9Hz,1H),5.61(dd,J=12.0,4.0Hz,1H),4.25(t,J=7.6Hz,2H),3.77(s,6H),3.49(s,1H),3.41(dd,J=7.8,2.9Hz,2H),2.44(t,J=6.4Hz,2H),2.23(s,6H),2.11(s,3H)。
实施例7路线和制备过程如下:
(1)将7-氯-3-(3,5-二甲氧基苯基)-1,6-萘啶-2(1H)-醛(900mg,2.84mmol)溶于10ml二甲基亚砜(DMSO)中,于室温下加入K
2CO
3(706.86mg,5.11mmol)搅拌10min后,加入1-(叔丁基二甲基硅基)-3-氯丙烷(949.27mg,4.55mmol),升温至90℃,反应5h,加入200ml乙酸乙酯,再以20ml超纯水洗涤,重复2次,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到1-(3-((叔丁基二甲基硅烷)氧基)丙基)-7-氯-3-(3,5-二甲氧基苯基)-1,6-萘啶-2(1H)-醛(863mg,白色固体),产率62.1%。(2)将1-(3-((叔丁基二甲基硅烷)氧基)丙基)-7-氯-3-(3,5-二甲氧基苯基)-1,6-萘啶-2(1H)-醛(800mg,1.64mmol)、2-硝基-6-甲基苯胺(373.32mg,2.45mmol)、Pd
2(dba)
3(149.79mg,163.57μmol)、BrettPhos(175.60mg,327.14μmol)、碳酸铯(1.60g,4.91mmol)投入25ml甲苯中,氮气保护下,120℃回流7h,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠体系多次萃取,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨基)-1,6-萘啶-2(1H)-醛(477mg,棕黄色固体),产率48.2%。(3)将1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-7-((2-甲基-6-硝基苯基)氨 基)-1,6-萘啶-2(1H)-醛(450mg,744.07μmol)、二碳酸二叔丁酯(181.81mg,1.49mmol)、4-二甲氨基吡啶(32.48mg,148.81μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(338mg,淡黄色固体),产率64.5%。(4)将叔丁基(1-(2-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(300mg,425.59μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液以减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(138mg,白色固体),产率48.2%。(5)将叔丁基(2-氨基-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,148.17μmol)和三乙胺(82.16mmL,592.67μmol)溶于无水THF中,再滴加丙烯酰氯(24.08mmL,296.33μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(56mg,白色固体),产率52.3%。(6)将叔丁基(2-丙烯酰胺-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(50mg,68.59μmol)溶于10ml二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,以乙酸乙酯/饱和氯化钠溶液多次萃取,通过减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到N-(2-((3-(3,5-二甲氧基苯基)-1-(3-羟乙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基)-3-甲基苯基)丙烯酰胺(15mg,淡黄色色固体),记为化合物29,产率42.6%,表征数据如下:
1H NMR(400MHz,DMSO)δ9.49(s,1H),8.41(s,1H),8.28(s,1H),7.97(s,1H),7.68(d,J=7.7Hz,1H),7.17(t,J=7.8Hz,1H),7.08(d,J=3.0Hz,1H),6.80(s,2H),6.45(s,1H),6.15(d,J=18.9Hz,2H),5.63(d,J=12.1Hz,1H),4.07-3.96(m,2H),3.73(s,6H),3.40(s,2H),2.13(s,4H),1.69-1.59(m,2H)。
实施例8路线和制备过程如下:
(1)将7-氯-3-(3,5-二甲氧基苯基)-1,6-萘啶-2(1H)-醛(900mg,2.33mmol)溶于10ml二甲基亚砜(DMSO)中,于室温下加入K
2CO
3(580.59mg,4.20mmol)搅拌10min后,加入1-(叔丁基二甲基硅基)-3-氯丙烷(876.07mmL,3.73mmol),升温至90℃,反应5h,加入200ml乙酸乙酯,再以20ml超纯水洗涤,重复2次,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到1-(3-((叔丁基二甲基硅烷)氧基)丙基)-7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1,6-萘啶-2(1H)-醛(890mg,白色固体),产率68.4%。(2)将1-(3-((叔丁基二甲基硅烷)氧基)丙基)-7-氯-3-(2,6-二氯-3,5-二甲氧基苯基)-1,6-萘啶-2(1H)-醛(800mg,1.43mmol)、2-硝基-6-甲基苯胺(327.23mg,2.15mmol)、Pd
2(dba)
3(131.30mg,143.38μmol)、BrettPhos(153.92mg,286.75μmol)、碳酸铯(1.40g,4.30mmol)投入25ml甲苯中,氮气保护下,120℃回流7h,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠体系多次萃取,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-7-氯-((2-甲基-6-硝基苯基)氨基-1,6-萘啶-2(1H)-醛(620mg,棕黄色固体),产率64.24%。(3)将1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-7-氯-((2-甲基-6-硝基苯基)氨基-1,6-萘啶-2(1H)-醛(600mg,890.65μmol)、二碳酸二叔丁酯(217.6mg,1.78mmol)、4-二甲氨基吡啶(38.88mg,178.13μmol)投入无水二氯甲烷中,室温反应4h,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(480mg,淡黄色固体),产率69.6%。(4)将叔丁基(1-(3-((叔丁基二 甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)(2-甲基-6-硝基苯基)氨基甲酸酯(300.00mg,268.89μmol)溶于无水THF溶液中,加入20%Pd/C,氢气条件下,室温还原,反应48h,抽滤除去钯碳,滤液以减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-氨基-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(150mg,白色固体),产率52.01%。(5)将叔丁基(2-氨基-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(100mg,134.45μmol)和三乙胺(74.55mmL,537.78μmol)溶于无水THF中,再滴加丙烯酰氯(21.85mmL,268.89μmol),室温下反应2h,加入饱和氯化铵溶液淬灭反应,减压蒸馏除去溶剂,以乙酸乙酯/饱和氯化钠溶液多次萃取反应体系,减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到叔丁基(2-丙烯酰胺-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(80mg,白色固体),产率83.90%。(6)将叔丁基(2-丙烯酰胺-6-甲基苯基)(1-(3-((叔丁基二甲基硅烷)氧基)丙基)-3-(2,6-二氯-3,5-二甲氧基苯基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基甲酸酯(60mg,75.20μmol)溶于10ml二氯甲烷中,加入1ml三氟乙酸,室温下反应2h,加入饱和碳酸氢钠溶液淬灭反应,以乙酸乙酯/饱和氯化钠溶液多次萃取,通过减压蒸馏除去溶剂,残留物通过硅胶柱层析法(洗脱剂:B体系)纯化,得到N-(2-((3-(2,6-二氯-3,5-二甲氧基苯基)-1-(3-羟丙基)-2-氧代-1,2-2H-1,6-萘啶-7-基)氨基)-3-甲基苯基)丙烯酰胺(35mg,淡黄色色固体),记为化合物30,产率79.76%,表征数据如下:
1H NMR(400MHz,DMSO)δ8.74(s,1H),8.15(s,1H),7.68(s,2H),7.12(d,J=7.5Hz,1H),6.76(d,J=2.2Hz,2H),6.48(s,1H),6.38(d,J=15.8Hz,1H),6.29(d,J=9.8Hz,1H),6.15(s,1H),5.71(d,J=10.1Hz,1H),4.05(s,2H),3.80(s,6H),2.23(s,3H),1.62(m,2H)。
实施例9生物活性筛选
利用Mobility shift assay的方法,在FGFR1-4激酶上进行化合物22-30的抑制活性。
具体实验方法如下:
(1)配制1×Kinase buffer。(2)化合物浓度的配制:化合物测试浓度为300nM,3倍稀释,8个或9个浓度,单孔检测。在384source板中稀释成100倍终浓度的100%DMSO溶液。使用分液器Echo 550向目的板3573板转移250nL100倍终浓度的化合物。(3)用1×Kinase buffer配制2.5倍终浓度的激酶溶液。(4)在化合物孔和阳性对照 孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μl的1×Kinase buffer。(5)1000rpm离心30秒,反应板振荡混匀后室温孵育60分钟。(6)用1×Kinase buffer配制25/15倍终浓度的ATP和Kinase substrate22的混合溶液。(7)加入15μl的5/3倍终浓度的ATP和底物的混合溶液,起始反应。(8)将384孔板1000rpm离心30秒,振荡混匀后室温孵育30分钟。(9)加入30μl终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀。(10)用Caliper EZ Reader读取转化率。
数据分析:
计算公式%Inhibition=(Conversion%_max-Conversion%_sample)/(Conversion%_max-Conversion%_min)×100
其中:Conversion%_sample是样品的转化率读数;Conversion%_min:阴性对照孔均值,代表没有酶活孔的转化率读数;Conversion%_max:阳性对照孔均值,代表没有化合物抑制孔的转率读数。
拟合量效曲线
以浓度的log值作为X轴,百分比抑制率为Y轴,采用分析软件GraphPad Prism 5的log(inhibitor)vs.response–Variable slope拟合量效曲线,从而得出各个化合物对酶活性的IC50值。计算公式是Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
实验结果
实验结果表明:该系列化合物22-30可以有效抑制FGFR4的表达,而对同源激酶FGFR-3基本无抑制活性,相对于FGFR抑制剂BLU9931和BGJ398,具有更加优秀 的激酶选择性。其中,BLU9931和BGJ398的结构式如下:
实施例10活性化合物对肝癌细胞HepG2、HuH-7和MiHA增殖的影响。
通过采用MTT法进行测定。实验方法简述如下:受试化合物首先溶解于DMSO中制备为储备液,随后以对应细胞的培养基进行梯度稀释,配制成测试样品,化合物的终浓度范围在20uM。将处于对数培养期的细胞以适宜的密度接种至96孔细胞培养板中,在对应的条件下培养过夜后,加入测试化合物样品后继续培养72小时。培养结束后,向每孔加入适宜体积的MTT检测液,并在37℃下孵育1-4小时,小心弃去培养基,然后每孔加入100μL DMSO溶解孔底部的结晶,置于微量振荡器上避光室温下震荡10min,待结晶充分溶解后,用酶标仪检测各个孔在560nm处的吸光值,计算各化合物抑制肝癌细胞的抑制率。结果见图1~3,从图1-3可以看出,本发明的优选化合物对FGFR4异常的肝癌细胞具有显著的增殖抑制作用。
实施例11活性化合物对结肠癌细胞HCT-116,SW480和RKO增殖的影响。
通过采用MTT法进行测定。实验方法简述如下:受试化合物23首先溶解于DMSO中制备为储备液,随后以对应细胞的培养基进行梯度稀释,配制成测试样品,化合物的终浓度范围在3-100uM。将处于对数培养期的细胞以适宜的密度接种至96孔细胞培养板中,在对应的条件下培养过夜后,加入测试化合物样品后继续培养72小时。培养结束后,向每孔加入适宜体积的MTT检测液,并在37℃下孵育1-4小时,小心弃去培养基,然后每孔加入100μL DMSO溶解孔底部的结晶,置于微量振荡器上避光室温下震荡10min,待结晶充分溶解后,用酶标仪检测各个孔在560nm处的吸光值,计算各化合物抑制肝癌细胞的抑制率。结果见图4~6,从图4-6可以看出,本发明的化合物23在3-100μM浓度下可以剂量依赖性抑制3种结肠癌细胞HCT-116,SW480和RKO的增殖,具有较好的抗结肠癌活性。
Claims (10)
- 根据权利要求1所述的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物,其特征在于,所述的R 1选自Cl或者甲氧基中的一个或者多个。
- 一种如权利要求1~5任一项所述的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物在药物制备中的应用,其特征在于,所述的药物为抗肿瘤药物。
- 根据权利要求6所述的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物在药物制备中的应用,其特征在于,所述的抗肿瘤药物以FGFR4为靶点。
- 根据权利要求7所述的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物在药物制备中的应用,其特征在于,所述的抗肿瘤药物选择性抑制FGFR4,而对FGFR1、FGFR2和FGFR3几乎无抑制。
- 根据权利要求6所述的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物在药物制备中的应用,其特征在于,所述的药物用来治疗肝癌、胆管癌、乳腺癌或尿路上皮癌。
- 根据权利要求6所述的2-氧代-1,2-二氢-1,6-萘啶-7-基类化合物在药物制备中的应用,其特征在于,所述的药物用于治疗白血病、结肠癌、直肠癌、胃癌、卵巢癌、绒毛膜上皮癌、恶性葡萄胎、头颈部鳞癌、皮肤癌、膀胱癌、肺癌、前列腺癌、子宫癌、肾癌、淋巴瘤、宫颈癌中的一种或者多种。
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