WO2022135580A1 - 吡啶并吡咯类化合物的晶型、制备方法及其应用 - Google Patents
吡啶并吡咯类化合物的晶型、制备方法及其应用 Download PDFInfo
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the invention relates to a crystal form of a pyridopyrrole compound, as well as a preparation method and application of the crystal form.
- CDKs cell cycle-dependent kinases
- CDK9 is a member of the CDK family and is mainly involved in transcriptional regulation.
- the heterodimer composed of CDK9 and cyclin (T1, T2a, T2b, K) participates in the formation of positive transcription elongation factor (p-TEFb), of which about 80% of CDK9 binds to cyclinT1.
- P-TEFb regulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II, primarily Ser-2.
- Inhibition and transcriptional repression of CDK9 results in rapid depletion of short-lived mRNA transcripts and associated proteins, including Myc and Mcl-1, resulting in the death of cancer cells that are highly dependent on these anti-apoptotic proteins.
- Targeting CDK9 thus represents a therapeutic strategy for tumor types that are highly dependent on these anti-apoptotic proteins.
- CDK9 small molecule inhibitors have entered the clinical research stage for the treatment of cancer, namely Bayer's BAY1251152 and AstraZeneca's AZD4573. These patents include WO2012160034, WO2014076091, WO2009047359, WO2011110612, US2016376287.
- CDK9 inhibitors for the treatment of cancer and other diseases
- no drugs targeting this target have been marketed so far.
- the most important clinical grade 3/4 and dose-limiting adverse side effect of BAY1251152 is neutropenia, while AZD4573 has poor kinase selectivity and metabolism, which limits its performance. the medicinal effect. Therefore, there is still an urgent need to develop novel, safer and more effective CDK9 inhibitors that can treat a variety of cancers, including leukemia and lymphoma.
- the present invention provides crystal form A of the compound of formula (I), whose X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 7.22 ⁇ 0.20°, 17.16 ⁇ 0.20° and 22.34 ⁇ 0.20°;
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.22 ⁇ 0.20°, 15.24 ⁇ 0.20°, 15.80 ⁇ 0.20°, 17.16 ⁇ 0.20°, 20.70 ⁇ 0.20 °, 22.34 ⁇ 0.20°, 24.46 ⁇ 0.20° and 31.74 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.22 ⁇ 0.20°, 8.76 ⁇ 0.20°, 15.24 ⁇ 0.20°, 15.80 ⁇ 0.20°, 17.16 ⁇ 0.20 °, 19.66 ⁇ 0.20°, 20.70 ⁇ 0.20°, 22.34 ⁇ 0.20°, 24.46 ⁇ 0.20°, 25.84 ⁇ 0.20°, 29.76 ⁇ 0.20° and 31.74 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned Form A has characteristic diffraction peaks at the following 2 ⁇ angles: 7.22 ⁇ 0.20°, 17.16 ⁇ 0.20°, and/or 22.34 ⁇ 0.20°, and/or 8.76 ⁇ 0.20°, and/or 9.84 ⁇ 0.20°, and/or 12.24 ⁇ 0.20°, and/or 15.24 ⁇ 0.20°, and/or 15.80 ⁇ 0.20°, and/or 16.22 ⁇ 0.20°, and/or 17.52 ⁇ 0.20° , and/or 18.40 ⁇ 0.20°, and/or 19.26 ⁇ 0.20°, and/or 19.66 ⁇ 0.20°, and/or 20.70 ⁇ 0.20°, and/or 21.46 ⁇ 0.20°, and/or 23.64 ⁇ 0.20°, and /or 24.46 ⁇ 0.20°, and/or 25.84 ⁇ 0.20°, and/or 27.10 ⁇ 0.20°, and/or 27.62 ⁇ 0.20°, and/or 28.02
- the X-ray powder diffraction pattern of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.22°, 8.76°, 9.84°, 12.24°, 15.24°, 15.80°, 16.22°, 17.16° , 17.52°, 18.40°, 19.26°, 19.66°, 20.70°, 21.46°, 22.34°, 23.64°, 24.46°, 25.84°, 27.10°, 27.62°, 28.02°, 29.26°, 29.76°, 30.88°, 31.74 °, 33.38°, 37.10° and 37.68°.
- the XRPD pattern of the above-mentioned crystal form A is basically as shown in FIG. 1 .
- the differential scanning calorimetry curve of the differential scanning calorimetry curve has an endothermic peak starting point at 77.71 ⁇ 3°C and 236.85 ⁇ 3°C, respectively.
- the DSC spectrum of the above-mentioned crystal form A is shown in FIG. 2 .
- thermogravimetric analysis curve (TGA) of the above crystal form A has a weight loss of 3.420% at 200 ⁇ 3°C.
- the TGA spectrum of the above-mentioned A crystal form is shown in FIG. 3 .
- the present invention also provides the B crystal form of the compound of formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 19.72 ⁇ 0.20°, 21.52 ⁇ 0.20° and 23.20 ⁇ 0.20°;
- the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 10.74 ⁇ 0.20°, 16.22 ⁇ 0.20°, 19.72 ⁇ 0.20°, 20.58 ⁇ 0.20°, 21.52 ⁇ 0.20 °, 22.30 ⁇ 0.20°, 23.20 ⁇ 0.20° and 28.04 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 7.92 ⁇ 0.20°, 10.74 ⁇ 0.20°, 16.22 ⁇ 0.20°, 17.66 ⁇ 0.20°, 19.72 ⁇ 0.20 °, 20.58 ⁇ 0.20°, 21.52 ⁇ 0.20°, 22.30 ⁇ 0.20°, 23.20 ⁇ 0.20°, 23.88 ⁇ 0.20°, 26.54 ⁇ 0.20°, 27.48 ⁇ 0.20° and 28.04 ⁇ 0.20°.
- the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 19.72 ⁇ 0.20°, 21.52 ⁇ 0.20°, and/or 23.20 ⁇ 0.20°, and/or 7.92 ⁇ 0.20°, and/or 10.74 ⁇ 0.20°, and/or 11.42 ⁇ 0.20°, and/or 13.52 ⁇ 0.20°, and/or 13.76 ⁇ 0.20°, and/or 15.86 ⁇ 0.20°, and/or 16.22 ⁇ 0.20° , and/or 16.52 ⁇ 0.20°, and/or 17.66 ⁇ 0.20°, and/or 17.90 ⁇ 0.20°, and/or 18.22 ⁇ 0.20°, and/or 18.92 ⁇ 0.20°, and/or 20.58 ⁇ 0.20°, and /or 22.30 ⁇ 0.20°, and/or 23.88 ⁇ 0.20°, and/or 25.32 ⁇ 0.20°, and/or 26.12 ⁇ 0.20°, and/or 26.54
- the X-ray powder diffraction pattern of the above crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 7.92°, 10.74°, 11.42°, 13.52°, 13.76°, 15.86°, 16.22°, 16.52° , 17.66°, 17.90°, 18.22°, 18.92°, 19.72°, 20.58°, 21.52°, 22.30°, 23.20°, 23.88°, 25.32°, 26.12°, 26.54°, 27.14°, 27.48°, 27.72°, 28.04 degrees 37.96°, 38.74° and 39.50°.
- the XRPD pattern of the above-mentioned crystal form B is basically as shown in FIG. 4 .
- the differential scanning calorimetry curve has an endothermic peak starting point at 257.81 ⁇ 3°C.
- the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 5 .
- thermogravimetric analysis curve of the above-mentioned crystal form B loses weight up to 0.326% at 200 ⁇ 3°C.
- the TGA spectrum of the above-mentioned B crystal form is shown in FIG. 6 .
- the present invention also provides a method for preparing crystal form A, comprising the following steps:
- the above reflux temperature is 65°C-80°C, preferably 65°C.
- the above stirring time is 10-12 hours, preferably 12 hours.
- the present invention also provides a preparation method of crystal form B, comprising the following steps:
- the stirring temperature is 20°C;
- the stirring time is 20-21 hours.
- the present invention also provides the application of the above-mentioned A crystal form and the above-mentioned B crystal form in the preparation of CDK9 inhibitor drugs.
- the compound of formula (I) of the present application has good efficacy for in vivo administration, and its crystal form is stable, less affected by light, heat and humidity, and has good solubility.
- the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the solvent used in the present invention is commercially available.
- DCM dichloromethane
- DMF N,N-dimethylformamide
- DMSO dimethyl sulfoxide
- EtOH stands for ethanol
- MeOH stands for methanol
- ACN stands for acetonitrile
- THF tetrahydrofuran
- H 2 O water
- NCS 1-chloropyrrolidine-2,5-dione
- NIS for N-iodosuccinimide
- DMAC for dimethylacetamide
- Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane adduct.
- the XRPD test used the DX-2700BH X-ray diffractometer of Dandong Haoyuan Company. The test parameters are shown in Table 3.
- the DSC spectra were collected on a TA 2500 differential scanning calorimeter, and the test parameters are shown in Table 4.
- TGA was collected on a TA 5500 thermogravimetric analyzer, and the test parameters are shown in Table 5.
- Figure 1 XRPD pattern of Form A
- step 1
- the filter cake was dissolved in 1.50L of water, the organic phase was discarded, and the aqueous phase was transferred into a 5.0-liter there-necked flask, and under stirring, 1 mol/liter aqueous sodium hydroxide solution was added dropwise to pH ⁇ 11, and a large amount of white solid was separated out, and filtered to obtain the formula ( I) Compounds.
- the A crystal form (50 g, 0.158 mol) of the compound of formula (I) was stirred in 250 mL of ethanol for 21 hours, the mixture was filtered, the filter cake was transferred to an oven, and dried under reduced pressure to obtain the compound of formula (I)
- the B crystal form, the XRPD detection results are shown in Figure 4, and the TGA and DSC detection results are shown in Figure 5 and Figure 6, respectively.
- test sample marked S1-condition-time is used for content and related substance detection; the test sample marked S2-condition-time is used as a preparation sample, and the test sample marked S3-condition-time is used for XRPD detection .
- CDK9/CyclinT1 kinase was purchased from Carna
- ADP-Glo assay kit was purchased from Promega
- PKDTide substrate and kinase reaction buffer were purchased from Signalchem. Nivo Multilabel Analyzer (PerkinElmer).
- the compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, from 50 ⁇ M to 0.65 nM, and the DMSO concentration was 5%, and a double-well experiment was set up.
- Add 1 ⁇ L of each concentration gradient of inhibitor, 2 ⁇ L CDK9/CyclinT1 enzyme (4ng), 2 ⁇ L mixture of substrate and ATP (100 ⁇ M adenosine triphosphate, 0.2 ⁇ g/ ⁇ L substrate) to the microplate, and the final compound concentration gradient is 10 ⁇ M dilution at this time to 0.13 nM.
- the reaction system was placed at 25°C for 120 minutes.
- the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
- Table 8 provides the CDK9/CyclinT1 enzymatic inhibitory activity of the compounds of the present invention.
- the compound of formula (I) has good activity on CDK9 kinase, similar to the activity of reference compounds BAY1251152 and AZD4573.
- CDK1/CyclinB1 Kinase Assay Kit was purchased from Promega. Nivo Multilabel Analyzer (PerkinElmer).
- the compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, from 50 ⁇ M to 0.65 nM, and the DMSO concentration was 5%, and a double-well experiment was set up.
- the reaction system was placed at 25°C for 120 minutes.
- the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
- Table 6 provides the CDK1/CyclinB1 enzymatic inhibitory activity of the compounds of the present invention.
- the compounds of formula (I) have weak inhibitory activity on CDK1 kinase, so the compounds of the present invention show better selectivity to CDK1 than BAY1251152 and AZD4573.
- the experimental results are shown in Table 8.
- CDK2/CyclinE1 Kinase Assay Kit was purchased from Promega. Nivo Multilabel Analyzer (PerkinElmer).
- the compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, from 50 ⁇ M to 0.65 nM, and the DMSO concentration was 5%, and a double-well experiment was set up.
- Add 1 ⁇ L of each concentration gradient of inhibitor, 2 ⁇ L CDK2/CyclinE1 enzyme (2ng), 2 ⁇ L mixture of substrate and ATP (150 ⁇ M adenosine triphosphate, 0.1 ⁇ g/ ⁇ L substrate) to the microplate, and the final compound concentration gradient is 10 ⁇ M dilution at this time to 0.13 nM.
- the reaction system was placed at 25°C for 60 minutes.
- the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
- Table 8 provides the CDK2/CyclinE1 enzymatic inhibitory activity of the compounds of the present invention.
- the compound of formula (I) does not have strong inhibitory activity on CDK2 kinase, so the compound of the present invention exhibits better selectivity to CDK2 than BAY1251152 and AZD4573.
- the experimental results are shown in Table 8.
- IMDM medium fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Promega (Madison, WI).
- MV-4-11 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. Nivo Multilabel Analyzer (PerkinElmer).
- MV-4-11 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 6000 MV-4-11 cells. Cell plates were incubated overnight in a carbon dioxide incubator.
- the compounds to be tested were diluted 5-fold to the 8th concentration, that is, from 2 mM to 26 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Final compound concentrations ranged from 10 ⁇ M to 0.13 nM.
- the cell plates were placed in a carbon dioxide incubator for 3 days.
- the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
- Table 8 provides the inhibitory activity of the compounds of the present invention on the proliferation of MV-4-11 cells.
- mice Female, 6-8 weeks, weighing approximately 18-22 grams, were kept in a special pathogen-free environment in a single ventilated cage (3 mice per cage). All cages, bedding and water were sterilized before use. All animals had free access to standard certified commercial laboratory diets. A total of 36 mice purchased from Shanghai Lingchang biological science and technology Co., LTD. were used for the study. Tumor cells (10 ⁇ 10 6 in 0.2 ml phosphate buffered saline) were implanted subcutaneously in the right flank of each mouse for tumor growth. Dosing was initiated when the mean tumor volume reached approximately 121 cubic millimeters. The test compound was administered weekly by injection at a dose of 10 mg/kg.
- Antitumor efficacy is determined by dividing the mean tumor increase volume in animals treated with the compound by the mean tumor increase volume in untreated animals.
Abstract
Description
参数 | METTLER TOLEDO DSC1 |
样品盘 | 高压坩埚 |
温度范围 | 40~350℃ |
扫描速率(℃/分钟) | 10 |
保护气体 | 氮气 |
参数 | TA TGA5500 |
样品盘 | 铝盘,开盖 |
温度范围 | 40~500℃ |
扫描速率(℃/分钟) | 10 |
保护气体 | 氮气 |
Claims (23)
- 根据权利要求1所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.22±0.20°、15.24±0.20°、15.80±0.20°、17.16±0.20°、20.70±0.20°、22.34±0.20°、24.46±0.20°和31.74±0.20°。
- 根据权利要求2所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.22±0.20°、8.76±0.20°、15.24±0.20°、15.80±0.20°、17.16±0.20°、19.66±0.20°、20.70±0.20°、22.34±0.20°、24.46±0.20°、25.84±0.20°、29.76±0.20°和31.74±0.20°。
- 根据权利要求3所述的A晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.22°、8.76°、9.84°、12.24°、15.24°、15.80°、16.22°、17.16°、17.52°、18.40°、19.26°、19.66°、20.70°、21.46°、22.34°、23.64°、24.46°、25.84°、27.10°、27.62°、28.02°、29.26°、29.76°、30.88°、31.74°、33.38°、37.10°和37.68°。
- 根据权利要求4所述的A晶型,其XRPD图谱基本如图1所示。
- 根据权利要求1~5所述的A晶型,其差示扫描量热曲线在77.71±3℃和236.85±3℃分别有一个吸热峰的起始点。
- 根据权利要求6所述的A晶型,其DSC图谱如图2所示。
- 根据权利要求1~5所述的A晶型,其热重分析曲线在200±3℃时失重达3.420%。
- 根据权利要求8所述的A晶型,其TGA图谱如图3所示。
- 根据权利要求10所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:10.74±0.20°、16.22±0.20°、19.72±0.20°、20.58±0.20°、21.52±0.20°、22.30±0.20°、23.20±0.20°和28.04±0.20°。
- 根据权利要求11所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.92±0.20°、10.74±0.20°、16.22±0.20°、17.66±0.20°、19.72±0.20°、20.58±0.20°、21.52±0.20°、22.30±0.20°、23.20±0.20°、23.88±0.20°、26.54±0.20°、27.48±0.20°和28.04±0.20°。
- 根据权利要求12所述的B晶型,其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰:7.92°、10.74°、11.42°、13.52°、13.76°、15.86°、16.22°、16.52°、17.66°、17.90°、18.22°、18.92°、19.72°、20.58°、21.52°、22.30°、23.20°、23.88°、25.32°、26.12°、26.54°、27.14°、27.48°、27.72°、28.04°、28.52°、28.96°、29.20°、29.74°、30.24°、30.58°、31.56°、32.54°、32.82°、33.38°、34.36°、34.75°、35.44°、36.00°、36.56°、37.08°、37.96°、38.74°和39.50°。
- 根据权利要求13所述的B晶型,其XRPD图谱基本如图4所示。
- 根据权利要求10~14所述的B晶型,其差示扫描量热曲线在257.81±3℃有一个吸热峰的起始点。
- 根据权利要求15所述的B晶型,其DSC图谱如图5所示。
- 根据权利要求10~14所述的B晶型,其热重分析曲线在200±3℃时失重达0.326%。
- 根据权利要求17所述的B晶型,其TGA图谱如图6所示。
- 根据权利要求1-9任意一项所述的式(Ⅰ)化合物A晶型的制备方法,包含如下步骤:1)式(I)化合物加入到无水甲醇中回流;2)式(I)化合物完全溶解,趁热过滤;3)滤液在回流状态下滴加蒸馏水,析出白色固体,自然降温至室温,室温搅拌;4)混合物过滤,滤饼减压烘干。
- 根据权利要求19所述的制备方法,其中,所述回流温度为65℃-80℃,优选为65℃。
- 根据权利要求19所述的制备方法,其中,搅拌时间为10-12小时,优选为12小时。
- 根据权利要求10-17任意一项所述的式(Ⅰ)化合物B晶型的制备方法,包含如下步骤:1)权利要求1-9任意一项所述的式(Ⅰ)化合物A晶型在乙醇中搅拌,过滤、滤饼减压烘干。
- 权利要求1~9任意一项所述的A晶型或权利要求10~18任意一项所述的B晶型在制备CDK9抑制剂药物中的应用。
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CN102143746A (zh) * | 2008-07-03 | 2011-08-03 | 埃克塞利希斯股份有限公司 | Cdk 调节剂 |
CN105246890A (zh) * | 2013-03-14 | 2016-01-13 | 艾伯维公司 | 吡咯并[2,3-b]吡啶cdk9激酶抑制剂 |
US20200247824A1 (en) * | 2017-09-22 | 2020-08-06 | The University Of Nottingham | Heterocyclyl substituted pyrrolopyridines that are inhibitors of the cdk12 kinase |
WO2020259556A1 (zh) * | 2019-06-27 | 2020-12-30 | 南京明德新药研发有限公司 | 作为cdk9抑制剂的氮杂吲哚连吡唑类化合物 |
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