CN115304605B - Oxetane derivatives with antitumor activity, and preparation method and application thereof - Google Patents
Oxetane derivatives with antitumor activity, and preparation method and application thereof Download PDFInfo
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Abstract
The application belongs to the technical field of compound synthesis, and relates to an oxetane derivative with anti-tumor activity, a preparation method and application thereof, wherein the structural formula is shown as formula (I):the oxetane derivative provided by the application has excellent anti-tumor activity and can inhibit the growth of tumor cells; the toxicity is lower, the synthesis process is simple, the condition is mild, and the control is easy.
Description
Technical Field
The application belongs to the technical field of compound synthesis, and relates to an oxetane derivative with anti-tumor activity, and a preparation method and application thereof.
Background
Malignant tumor is one of diseases seriously endangering human health, and the number of cancer deaths is counted to show a trend of increasing year by year, especially lung cancer, which has a rapid growth progressive speed, and has a trend of death caused by substituting liver cancer, wherein non-small cell lung cancer (non-small cell lung cancer, NSCLC) accounts for more than 80% of all lung cancers; however, only one third of NSCLC patients currently have the opportunity for surgical treatment, and about 70% of patients already have locally advanced or distant metastasis at the time of visit, losing the opportunity for surgical treatment. Therefore, the development of NSCLC drugs is still a hot spot and difficult problem in the future anti-tumor drug research field.
Oxetanes are a class of heterocyclic compounds of special structure that are found in many active natural products and in commercially available drugs. It is due to its unique chemical structure that oxetane derivatives exhibit a broad range of biological activities, on the one hand, as good hydrogen bond donors oxetanes are prone to hydrogen bond interactions with drug targets; on the other hand, the oxetane structure is stable in alkaline and weak acid environments, and has a good drug-forming basis. It is found that the oxetane nucleus structure can be used as bioisostere of active groups such as gem-dimethyl, carbonyl, morpholinyl and the like, and the oxetane is introduced into the molecular structure of the medicine through group substitution, so that the rigidity of the molecule can be enhanced, and the water solubility, metabolic stability and the like of the molecule can be improved. Therefore, in recent years, research on the use of oxetane structures as bioisosteres in the design and synthesis of drug molecules has received extensive attention from pharmaceutical chemists.
Crnolanib is a tyrosine kinase inhibitor, is an oral medicine for gastrointestinal stromal tumor and acute myelogenous leukemia, which is developed by combining a company of pyroxene and AROG Pharmaceuticals, contains a non-bridged oxetane group, and currently enters a clinical experiment three-stage, so that the potential of the structure as a pharmacophore in the field of drug molecule research and development is further reflected.
Disclosure of Invention
The application discloses an oxetane derivative with anti-tumor activity, a preparation method and application thereof, which have excellent anti-tumor activity and can inhibit the growth of tumor cells; and the toxicity is lower; the preparation and synthesis process is simple, the condition is mild, and the control is easy.
In order to achieve the above purpose, the technical scheme adopted by the application is as follows:
an oxetane derivative having the structural formula (i):
a process for the preparation of said oxetane derivatives comprising the steps of:
1) By reacting compound AAdding into dichloromethane, adding organic base and compound BConcentrating under reduced pressure, adding ethyl acetate and saturated saline water, washing, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow brown oily liquidCompound C->
2) Dissolving the compound C in a first solvent, adding a hydrogen chloride/methanol mixed solution, reacting, concentrating under reduced pressure, adding ethyl acetate for washing, and performing suction filtration on an organic phase under reduced pressure to obtain a tan solid, namely the compound D
3) Mixing the compound D, a second solvent, oxetanone and trimethylnitrile silane, carrying out reflux reaction, concentrating under reduced pressure, and separating and purifying the crude product by column chromatography to obtain a white solid, namely the compound E:
4) Mixing the compound E, a third solvent, hydrogen peroxide and inorganic base, adding water for dilution after reaction, extracting by ethyl acetate, drying an organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the obtained crude product by column chromatography to obtain a white solid, namely the compound shown in the formula (I).
Further, in the step 1), the mass volume ratio of the compound A to the dichloromethane to the organic base to the compound B is (1.0-2.0) g (20-30) mL (2.0-10.0) g (1.0-5.0) g; the organic base is triethylamine, diisopropylethylamine or pyridine.
Further, in the step 2), the mass volume ratio of the compound C, the solvent I and the hydrogen chloride/methanol mixed solution is (2.0-3.0) g (20-40) mL (15-40) mL; the concentration of hydrogen chloride in the hydrogen chloride/methanol mixed solution is 2mol/L; the first solvent is methanol solution, ethanol solution, dioxane solution or tetrahydrofuran solution.
Further, in the step 3), the mass volume ratio of the compound D, the solvent II, the oxetanone and the trimethylnitrile silane is (50-100) mg (4-10) mL (10-20) mg (40-80) mg; the second solvent is methanol solution or ethanol solution.
Further, in the step 4), the mass volume ratio of the compound E to the third solvent to the hydrogen peroxide to the inorganic base is (20-30) mg (0.5-2.0) mL (0.5-1.0) mg; the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate; the third solvent is dimethyl sulfoxide solution, N-dimethylformamide solution or dioxane solution.
Further, in the steps 1), 2) and 4), the reaction temperature is 20-25 ℃ and the reaction time is 2 hours.
The application of the oxetane derivative in preparing antitumor drugs.
Further, the tumor is liver cancer, colon cancer, lung cancer, breast cancer or cervical cancer.
The beneficial effects of the application are as follows: the application provides an oxetane structure derivative (formula I) with a novel structure, the structure of which is characterized by nuclear magnetic resonance hydrogen spectrum, mass spectrum and XRD single crystal derivative; the provided compound has obvious activity of inhibiting the growth of tumor cells, has obvious inhibition activity on human liver cancer cells HepG2, colon cancer cells LoVo, human non-small cell lung cancer A549, human breast cancer MCF-7 and human cervical cancer HeLa, particularly has excellent inhibition activity on human liver cancer HepG2 cells, has lower toxicity, can be used as a medicine for resisting tumor diseases, and provides a new path and method for the research and development of antitumor medicines, particularly NSCLC medicines.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound with a structural formula (E) provided by the application;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of a compound of formula (I);
FIG. 3 is a crystal structure diagram of a compound of formula (I);
FIG. 4 is a unit cell stacking diagram of a compound of formula (I) along the a-axis
FIG. 5 is a unit cell stacking diagram of a compound of formula (I) along the b-axis.
Detailed Description
The application will now be described in detail with reference to the drawings and examples.
The structural formula of the oxetane derivative provided by the application is shown as the formula (I):
the preparation route of the compound shown in the formula (I) provided by the application comprises four steps:
the first step:
wherein the organic base is selected from triethylamine, diisopropylethylamine, pyridine and the like; the solvent is methylene dichloride; and a second step of:
wherein the solvent is common organic solvents such as methanol, ethanol, dioxane, tetrahydrofuran and the like;
and a third step of:
wherein the solvent is methanol or ethanol;
fourth step:
wherein the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, etc. The solvent is selected from dimethyl sulfoxide, N-dimethylformamide, dioxane, etc.
Specifically, the preparation method of the oxetane derivative comprises the following steps:
by reacting compound AAdding into dichloromethane, adding organic base and compound BConcentrating under reduced pressure, adding ethyl acetate and saturated saline, washing, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow brown oily liquid, namely compound C->
2) Dissolving the compound C in a first solvent, adding a hydrogen chloride/methanol mixed solution, reacting, concentrating under reduced pressure, adding ethyl acetate for washing, and performing suction filtration on an organic phase under reduced pressure to obtain a tan solid, namely the compound D
3) Mixing the compound D, a second solvent, oxetanone and trimethylnitrile silane, carrying out reflux reaction, concentrating under reduced pressure, and separating and purifying the crude product by column chromatography to obtain a white solid, namely the compound E:
4) Mixing the compound E, a third solvent, hydrogen peroxide and inorganic base, reacting for 2 hours at room temperature, adding water for dilution, extracting by ethyl acetate, drying an organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the obtained crude product by column chromatography to obtain a white solid, namely the compound shown in the formula (I).
In the step 1), the mass volume ratio of the compound A to the dichloromethane to the organic base to the compound B is (1.0-2.0) g (20-30) mL (2.0-10.0) g (1.0-5.0) g; the reaction temperature is 20-25 ℃ and the reaction time is 2 hours; the organic base is triethylamine, diisopropylethylamine or pyridine.
In the step 2), the mass volume ratio of the compound C, the solvent I and the mixed solution of hydrogen chloride and methanol is (2.0-3.0) g (20-40) mL (15-40) mL; the concentration of hydrogen chloride in the mixed solution of hydrogen chloride and methanol is 2mol/L; the first solvent is methanol solution, ethanol solution, dioxane solution or tetrahydrofuran solution; the reaction temperature is 20-25 ℃ and the reaction time is 2h.
In the step 3), the mass volume ratio of the compound D, the solvent II, the oxetanone and the trimethylnitrile silane is (50-100) mg (4-10) mL (10-20) mg (40-80) mg; the second solvent is methanol solution or ethanol solution.
In the step 4), the mass volume ratio of the compound E to the third solvent to the hydrogen peroxide to the inorganic base is (20-30) mg (0.5-2.0) mL (0.5-1.0) mg; the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate; the third solvent is dimethyl sulfoxide solution, N-dimethylformamide solution or dioxane solution; the reaction temperature is 20-25 ℃ and the reaction time is 2h.
The oxetane derivative provided by the application has a novel structure, has obvious inhibitory activity on tumors, can be used in therapeutic drugs for resisting liver cancer, colon cancer, lung cancer, breast cancer and cervical cancer, and has obvious inhibitory activity on human liver cancer cells HepG2, colon cancer cells LoVo, human non-small cell lung cancer A549 cells, human breast cancer MCF-7 and human cervical cancer HeLa cells.
The present application will be described in detail with reference to specific embodiments according to the preparation methods given above. But the preparation of the present application is not limited thereto.
Examples
The preparation method of the oxetane derivative provided in the embodiment comprises the following steps:
1) A compound represented by the following structural formula (C): 5- { [4- (difluoromethoxy) phenyl ] sulfonyl } -3,4,5, 6-tetrahydropyrrolo [3,4-c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester
Compound (A) (1.38 g,5.69 mmol) was added to methylene chloride (30 mL), then dipropylethylamine (2.3 g,17.80 mmol) and compound (B) (1.5 g,7.13 mmol) were added, reacted at room temperature for 2 hours, after the reaction was completed, concentrated under reduced pressure, ethyl acetate (80 mL) was added to the crude product, and then washed with saturated brine (3X 30 mL), and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to give a tan oily liquid which was used directly for the next reaction without further purification.
The compound C is obtained in the step, and the result is that by ESI-MS mass spectrum analysis: m/z 358.25[ M-Boc+CH 3 CN+H] + 。
2) A compound represented by the following structural formula (D): 2- { [4- (difluoromethoxy) phenyl ] sulfonyl } -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole hydrochloride
The compound (2.2 g,5.28 mmol) having the structural formula (C) obtained in the previous step was dissolved in a solvent-methanol solution (20 mL), then a hydrogen chloride/methanol solution (20 mL) of 2mol/L was added, the reaction was carried out at room temperature for 2 hours, the concentration was carried out under reduced pressure, ethyl acetate (20 mL) was added to the obtained crude product for washing, the filtration was carried out under reduced pressure to obtain 1.4g of a tan solid, and the yield was calculated to be 75%.
Compound D prepared in this step, using nuclear magnetic resonance deodrogen spectroscopy results: 1 H NMR(300MHz,CDCl 3 ):δ 7.88～7.83(m,2H),7.31(d,J＝9.6Hz,2H),6.87(t,J＝12.6Hz,1H),4.12(s,4H),3.58(s,4H)。
analysis by ESI-MS mass spectrometry gave the following results: m/z 317.14[ M-HCl+H ]] + 。
3) A compound represented by the following structural formula (E): 3- {5- [ (4-Dimethoxyphenyl) sulfonyl ] -5, 6-dihydropyrrolo [3,4-c ] pyrrole-2 (1H, 3H, 4H) -yl } oxetane-3-carbonitrile
The compound (80 mg,0.2 mmol) with the structural formula (D), a second solvent-ethanol solution (5 mL), oxetanone (15 mg,0.2 mmol) and TMSCN (50 mg,0.5 mmol) are reacted for 8h after the addition, the reaction is finished, the mixture is concentrated under reduced pressure, and the crude product is separated and purified by column chromatography (V) Dichloromethane (dichloromethane) :V Methanol =50:1, giving 48mg of white solid,the yield was calculated to be 61%.
And (3) performing nuclear magnetic resonance on the synthesized compound with the structural formula (E) to obtain a nuclear magnetic resonance hydrogen spectrogram, wherein the result is shown in figure 1.
As can be seen from the figure 1 of the drawings, 1 H NMR(300MHz,CDCl 3 ):δ7.89～7.84(m,2H),7.28(d,J＝9.6Hz,2H),6.87 (t,J＝12.6Hz,1H),4.82(d,J＝6.0Hz,2H),4.59(d,J＝6.0Hz,2H),4.10(s,4H),3.53(s,4H)。
results obtained by ESI-MS analysis m/z 398.16[ M+H ]] + 。
4) The compound with the structural formula (I) is synthesized: 2- { [4- (difluoromethoxy) phenyl ] sulfonyl } -5- (oxetan-3-yl) -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole
Sequentially adding a compound (25 mg,0.06 mmol) with a structural formula (E), a third solvent-dimethyl sulfoxide (1 mL), hydrogen peroxide (0.5 mL) and potassium carbonate (5 mg,0.04 mmol) into a reaction bottle, reacting at room temperature for 2h, adding water (5 mL) for dilution after the reaction is finished, extracting with ethyl acetate (3X 15 mL), drying an organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the obtained crude product by column chromatography (V) Dichloromethane (dichloromethane) :V Methanol =15:1), 16mg of a white solid was obtained, and 58% of yield was calculated.
And (2) performing nuclear magnetic resonance on the synthesized compound with the structural formula (I) to obtain a nuclear magnetic resonance hydrogen spectrum, wherein the result is shown in figure 2.
As can be seen from the figure 2 of the drawings, 1 H NMR(300MHz,CD 3 OD):δ7.98～7.91(m,2H),7.37(d,J＝9.0Hz,2H), 7.27-6.78(m,1H),4.99～4.85(m,2H),4.68(d,J＝9.0Hz,2H),4.12(s,4H),3.69(s,4H)。
LC-MS (ESI) analysis was then carried out to obtain a result m/z of 416.18[ M+H ]] + 。
In the above examples, only a preferred set of preparation processes are listed, but the method for preparing oxetane derivatives provided by the application is not limited thereto.
In the step 1), the mass volume ratio of the compound A to the dichloromethane to the organic base to the compound B is (1.0-2.0) g (20-30) mL (2.0-10.0) g (1.0-5.0) g, and the compound A, the dichloromethane, the organic base and the compound B are arbitrarily selected and replaced; in the step 2), the compound C, the solvent I and the mixed solution of hydrogen chloride and methanol are arbitrarily selected and replaced within the range of (2.0-3.0) g (20-40) mL (15-40) mL; in the step 3), the mass volume ratio of the compound D, the solvent II, the oxetanone and the trimethylnitrile silane is (50-100) mg (4-10) mL (10-20) mg (40-80) mg, and the replacement is arbitrarily selected; in the step 4), the mass volume ratio of the compound E to the third solvent to the hydrogen peroxide to the inorganic base is (20-30) mg (0.5-2.0) mL (0.5-1.0) mg, and the final target product prepared by the application can be obtained by arbitrarily selecting and replacing the compound E and the third solvent.
In the above examples, the solvent one can be replaced with ethanol, the solvent two can be replaced with methanol, and the solvent three can be replaced with N, N-dimethylformamide or dioxane.
In the above examples, the reaction temperatures in step 1), step 2) and step 4) were all 20 to 25℃and the reaction time was 2 hours.
Example 2
To examine the structure of the oxetane derivative provided by the present application, the oxetane derivative 2- { [4- (difluoromethoxy) phenyl ] sulfonyl } -5- (oxetan-3-yl) -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole prepared in the examples was subjected to single crystal cultivation.
The specific culture process is as follows: under heating, 50mg of 2- { [4- (difluoromethoxy) phenyl ] sulfonyl } -5- (oxetan-3-yl) -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole (I) is dissolved in 10mL of methanol, and the mixture is left to volatilize naturally at 10 ℃ for 3 to 5 days to precipitate colorless crystals, thereby obtaining a single crystal of the compound of formula (I).
Further, the single crystal structure of 2- { [4- (difluoromethoxy) phenyl ] sulfonyl } -5- (oxetan-3-yl) -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole (formula I) was determined.
The measuring process is as follows: single crystals of 0.19mm by 0.12mm by 0.06mm were selected, diffraction data were collected on a Bruker APX-II CCD diffractometer and single color was obtained using a graphite monochromatorConverted Mo-K alpha rayAt 205K +.>Diffraction data are collected in a scanning mode, 12761 data are collected in the range of theta being more than or equal to 1.4 and less than or equal to 25.0 degrees, 3154 diffraction points are independent, the data are restored by using the SAINT v8.34A program of Bruker, and the SADABS program is used for empirical absorption correction. The structure was resolved and refined directly using the SHELXS-97 (Sheldrick, 2008) program, and the relevant parameters and results are shown in tables 1 to 3. The measurement results are shown in figures 3-5.
TABLE 1 Crystal data and refinement parameters for Compounds of formula (I)
TABLE 2 partial bond lengths for the compounds of formula (I)Key angle (°)
TABLE 3 Hydrogen bond Length of Compounds of formula (I)Bond angle (°).
Symmetrycodes：(a)1-x,1-y,2-z；(b)+x,3/2-y,1/2+z；(c)1-x,1/2+y,3/2-z；(d)+x,1/2-y,-1/2+z； (e)-x,-1/2+y,1/2-z；(f)+x,+y,-1+z。
The correctness of structure E can be demonstrated from fig. 1. From FIGS. 2 to 5, and tables 1 to 3, it can be demonstrated that the oxetane derivative 2- { [4- (difluoromethoxy) phenyl ] sulfonyl } -5- (oxetan-3-yl) -1,2,3,4,5, 6-hexahydropyrrolo [3,4-c ] pyrrole provided by the present application has structural correctness.
EXAMPLE 3 in vitro anti-tumor Activity of oxetane derivatives of formula (I)
This example is mainly illustrative of the antitumor activity of oxetane derivatives.
Tumor cells were selected as: hepG2 liver cancer cells, colon cancer cells LoVo cells, human non-small cell lung cancer A549 cells, human breast cancer MCF-7, human cervical cancer HeLa cells and normal liver cells LO2 are test cell lines.
The samples selected were: oxetane derivatives prepared in example 1
The in vitro antitumor activity of the compound shown in the formula (I) is evaluated by adopting an MTT method.
The specific method is as follows: after the samples were dissolved in DMSO, they were diluted to different concentrations of 50, 20, 10, 5, 1, 0.5, 0.1, 0.01. Mu. Mol/L in DMEM medium. Suspending the test cell strain in the logarithmic growth phase in DMEM medium containing 10% fetal calf serum, spreading in 96-well cell culture plate, and adding 100 μl (4-10) ×10 into each well 4 Cell suspension, wherein no cells were added to the blank. After the cells are completely adhered, the original culture solution is discarded, 100 mu L of culture medium containing the test drug is added, wherein the positive control group is added with the DMEM culture medium with the same volume, and the cells are treated at 37 ℃ and 5% CO 2 Incubation in incubator for 3 days, 30 μl of 5mg/mL MTT was added to each well, incubation was continued in incubator for 4 hours, the culture broth was discarded, then 100 μl of Dimethylsulfoxide (DMSO) was added to each well, and shaking was performed on a shaker for 15min. The absorbance (OD) value of each well was measured at 490nm wavelength using an enzyme-labeled instrument, the survival rate (%) of tumor cells under different drugs was calculated, while the S-type dose-response curve was drawn using a nonlinear regression model, and the median Inhibitory Concentration (IC) was calculated using OriginPro software 50 ) Values, results are shown in Table 4.
Cell viability (%) = [1- (OD) 1 -OD 2 )/(OD 3 -OD 2 )]×100％
Wherein OD 1 : absorbance value, OD of the drug to be tested 2 : absorbance, OD of blank control 3 : absorbance value of positive control.
TABLE 4 antitumor Activity of Compounds of formula (I)n＝3)
From the test results in table 4, it can be seen that: the test sample has obvious inhibition activity on six tumor cells, especially on HepG2 liver cancer cells, and IC 50 The value is 0.9+/-0.24 mu M, and the compound has no toxicity to normal liver cells LO2, so that the results show that the structure has potential anti-tumor activity and can be used as an anti-tumor activity lead compound.
Claims (8)
1. An oxetane derivative, characterized in that the structural formula is shown in formula (I):
2. a process for the preparation of an oxetane derivative according to claim 1, wherein said process comprises the steps of:
by reacting compound AAdding into dichloromethane, adding organic base and compound BConcentrating under reduced pressure, adding ethyl acetate and saturated saline, washing, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to obtain yellow brown oily liquid, namely compound C->The organic base is triethylamine, diisopropylethylamine or pyridine;
2) Dissolving the compound C in a first solvent, adding a hydrogen chloride/methanol mixed solution, reacting, concentrating under reduced pressure, adding ethyl acetate for washing, and performing suction filtration on an organic phase under reduced pressure to obtain a tan solid, namely the compound DThe first solvent is methanol solution, ethanol solution, dioxane solution or tetrahydrofuran solution;
3) Mixing the compound D, a second solvent, oxetanone and trimethylnitrile silane, carrying out reflux reaction, concentrating under reduced pressure, and separating and purifying the crude product by column chromatography to obtain a white solid, namely the compound E:the second solvent is methanol solution or ethanol solution;
4) Mixing a compound E, a third solvent, hydrogen peroxide and inorganic base, adding water for dilution after reaction, extracting by ethyl acetate, drying an organic phase by anhydrous sodium sulfate, concentrating under reduced pressure, and separating and purifying the obtained crude product by column chromatography to obtain a white solid, namely the compound shown in the formula (I); the inorganic base is potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate; the third solvent is dimethyl sulfoxide solution, N-dimethylformamide solution or dioxane solution.
3. The preparation method according to claim 2, wherein in the step 1), the mass-volume ratio of the compound A, the dichloromethane, the organic base and the compound B is (1.0-2.0) g, (20-30) mL, (2.0-10.0) g, (1.0-5.0) g.
4. The preparation method according to claim 2, wherein in the step 2), the mass volume ratio of the compound C, the solvent I and the mixed solution of hydrogen chloride and methanol is (2.0-3.0) g (20-40) mL (15-40) mL; the concentration of hydrogen chloride in the hydrogen chloride/methanol mixed solution is 2mol/L.
5. The preparation method according to claim 2, wherein in the step 3), the mass volume ratio of the compound D, the solvent II, the oxetanone and the trimethylnitrile silane is (50-100) mg (4-10) mL (10-20) mg (40-80) mg.
6. The preparation method according to claim 2, wherein in the step 4), the mass-volume ratio of the compound E, the third solvent, the hydrogen peroxide and the inorganic base is (20-30) mg (0.5-2.0) mL (0.5-1.0) mg.
7. The method according to claim 2, wherein in the steps 1), 2) and 4), the reaction temperature is 20-25 ℃ and the reaction time is 2h.
8. Use of an oxetane derivative according to claim 1 for the preparation of an anti-tumor drug, wherein said tumor is liver cancer, colon cancer, lung cancer, breast cancer or cervical cancer.
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| WO2016145045A1 (en) * | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Compositions for use in treating glioblastoma |
| WO2019191227A1 (en) * | 2018-03-28 | 2019-10-03 | Peloton Therapeutics, Inc. | Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha |
| US20200087309A1 (en) * | 2018-09-19 | 2020-03-19 | Forma Therapeutics, Inc. | Activating pyruvate kinase r and mutants thereof |
| CN113166060A (en) * | 2018-09-19 | 2021-07-23 | 福马治疗股份有限公司 | Treatment of sickle cell disease with pyruvate kinase activating compounds |
| CN113226356A (en) * | 2018-09-19 | 2021-08-06 | 福马治疗股份有限公司 | Activating pyruvate kinase R |
| CN113924146A (en) * | 2019-05-29 | 2022-01-11 | 加拉帕戈斯股份有限公司 | Novel compounds and pharmaceutical compositions thereof for the treatment of diseases |
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