WO2020221358A1 - Wee1抑制剂化合物的晶型及其应用 - Google Patents
Wee1抑制剂化合物的晶型及其应用 Download PDFInfo
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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- A—HUMAN NECESSITIES
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- Wee1 protein kinase is a cell cycle regulator, a member of the serine and threonine protein kinase family in the nucleus, and is a key kinase for the G2/M checkpoint.
- the human "Wee" protein kinase family mainly includes Wee1 and Myt1, both of which can phosphorylate the Tyr15 site on CDC2, inhibit the activation of the CDC2/CyclinB complex, and block cells from entering M phase until DNA repair is completed. And Myt1 can also phosphorylate the Thr14 site on CDC2, which is also a negative regulation of CDC2 activity.
- Wee1 kinase is highly expressed in many kinds of cancerous cells. By inhibiting Wee1 kinase, tumor cells can directly skip the DNA repair in G2 phase, enter mitosis in advance, cause tumor cell death, and achieve the purpose of treating cancer.
- AstraZeneca's Wee1 inhibitor AZD1775 has entered clinical phase II, with more than 30 clinical trials under development, and has shown good therapeutic effects.
- AZD1775 was first developed by Merck, so it is also called MK-1775. In September 2013, Merck transferred the compound to AstraZeneca worldwide.
- the related patents mainly include US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743, etc. Abbott and Abbvie have also conducted research on Wee1 inhibitors.
- the related patents mainly include US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031, WO2013126656, etc.
- Almac's patents on Wee1 inhibitors include WO2014167347, WO2015019037, and WO2015092431.
- the XRPD pattern analysis data of the above-mentioned crystal form B is shown in Table 2:
- the DSC spectrum of the above-mentioned crystal form B is shown in FIG. 5.
- the X-ray powder diffraction pattern of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 5.06 ⁇ 0.2°, 8.34 ⁇ 0.2°, 10.98 ⁇ 0.2°, 15.13 ⁇ 0.2°, 15.91 ⁇ 0.2 °, 16.68 ⁇ 0.2°, 17.63 ⁇ 0.2°, 18.87 ⁇ 0.2°, 20.33 ⁇ 0.2°, 21.44 ⁇ 0.2°, 22.01 ⁇ 0.2°, 24.04 ⁇ 0.2°, 25.32 ⁇ 0.2° and 25.66 ⁇ 0.2°.
- the differential scanning calorimetry (DSC) of the above crystal form F has an onset of an endothermic peak at 48.69 ⁇ 3°C and 225.26 ⁇ 3°C, respectively.
- thermogravimetric analysis curve (TGA) of the above-mentioned crystal form F has a weight loss of 3.404% at 100 ⁇ 3°C.
- Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pan for testing. Heat the sample from 30°C to 300°C at a heating rate of 10°C/min under 50mL/min N 2 conditions.
- Figure 12 is a TGA spectrum of (I) compound crystal form D
- Figure 15 is the TGA spectrum of (I) compound E crystal form
- the liquid nutrient base is made up of powder ( ⁇ -MEM powder from Gibco, Cat#:11900) dissolved in pure water, and added with L-(L-glutamine) and NaHCO 3 . After use, add 10% FBS (fetal bovine serum), 1% PS (double antibody) and 1% NEAA to make it a complete medium.
- FBS fetal bovine serum
- PS double antibody
- NEAA 1% NEAA
- mice are BALB/c nude nude mice, 6-8 weeks old, weighing 18-22 grams.
- TGI tumor growth inhibition rate
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- Peptides Or Proteins (AREA)
Abstract
Description
条件和时间点 | 晶型 | 总杂质% | 含量% |
0天 | F晶型 | 0.63 | 99.38 |
60℃_5天 | F晶型 | 0.74 | 99.39 |
60℃_10天 | F晶型 | 0.84 | 99.98 |
92.5%湿度_5天 | F晶型 | 0.61 | 98.72 |
92.5%湿度_10天 | F晶型 | 0.64 | 98.38 |
避光 | F晶型 | 0.61 | 97.77 |
光照 | F晶型 | 0.67 | 98.58 |
40℃-75%湿度-10天 | F晶型 | 0.63 | 98.01 |
40℃-75%湿度-1个月 | F晶型 | 0.62 | 97.94 |
60℃-75%湿度-10天 | F晶型 | 0.69 | 100.43 |
60℃-75%湿度-1个月 | F晶型 | 0.75 | 99.46 |
化合物编号 | Wee1(IC 50nM) |
AZD1775 | 47 |
式(I)化合物 | 29 |
AZD1775 | 式(I)化合物 | |
A to B | 2.83 | 4.55 |
B to A | 29.3 | 17.38 |
外排比率 | 10.37 | 3.82 |
化合物 | TGI(%) |
AZD1775 | 26.73 |
式(I)化合物 | 84.74 |
化合物 | TGI(%) |
AZD1775 | 24.3 |
式(I)化合物 | 73.3 |
化合物 | TGI(%) |
AZD1775 | 66.43 |
式(I)化合物 | 93.38 |
Claims (45)
- 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:5.71±0.2°、12.68±0.2°、15.32±0.2°、18.04±0.2°、19.72±0.2°、21.44±0.2°、23.61±0.2°和25.68±0.2°。
- 根据权利要求2所述的A晶型的XRPD图谱如图1所示。
- 根据权利要求1~3任意一项所述的A晶型,其差示扫描量热曲线(DSC)在34.95±3℃、174.75±3℃和219.12±3℃处分别有一个吸热峰的起始点。
- 根据权利要求4所述的A晶型的DSC图谱如图2所示。
- 根据权利要求1~3任意一项所述的A晶型,其热重分析曲线(TGA)在70.33±3℃时失重达0.7367%;在209.42±3℃时又失重达3.123%。
- 根据权利要求6所述的A晶型的TGA图谱如图3所示。
- 式(Ⅰ)化合物的B晶型,其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰:5.58±0.2°、12.44±0.2°和22.16±0.2°。
- 根据权利要求8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:5.58±0.2°、11.71±0.2°、12.44±0.2°、14.48±0.2°、15.13±0.2°、18.64±0.2°、22.16±0.2°和26.33±0.2°。
- 根据权利要求9所述的B晶型,其XRPD图谱如图4所示。
- 根据权利要求8~10任意一项所述的B晶型,其差示扫描量热曲线(DSC)在42.88±3℃、198.79±3℃和222.36±3℃处分别有一个吸热峰的起始点。
- 根据权利要求11所述的B晶型,其DSC图谱如图5所示。
- 根据权利要求8~10任意一项所述的B晶型,其热重分析曲线(TGA)在64.21±3℃时失重达3.265%;在243.05±3℃时又失重达1.516%。
- 根据权利要求13所述的B晶型,其TGA图谱如图6所示。
- (Ⅰ)化合物的C晶型,其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰:5.05±0.2°、 5.58±0.2°和12.44±0.2°。
- 根据权利要求15所述的C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:5.05±0.2°、5.58±0.2°、12.44±0.2°、15.91±0.2°、16.68±0.2°、17.61±0.2°、22.19±0.2°和26.37±0.2°。
- 根据权利要求16所述的C晶型,其XRPD图谱如图7所示。
- 根据权利要求15~17任意一项所述的C晶型,其差示扫描量热曲线(DSC)在37.06±3℃、189.16±3℃和218.61±3℃处分别有一个吸热峰的起始点。
- 根据权利要求18所述的C晶型,其DSC图谱如图8所示。
- 根据权利要求15~17任意一项所述的C晶型,其热重分析曲线(TGA)在64.98±3℃时失重达2.211%;在224.71±3℃时又失重达1.127%。
- 根据权利要求20所述的C晶型,其TGA图谱如图9所示。
- 式(Ⅰ)化合物的D晶型,其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰:5.22±0.2°、15.99±0.2°和16.57±0.2°。
- 根据权利要求22所述的D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:5.22±0.2°、15.18±0.2°、15.99±0.2°、16.57±0.2°、17.08±0.2°、18.60±0.2°、21.22±0.2°和21.89±0.2°。
- 根据权利要求23所述的D晶型,其D晶型的XRPD图谱如图10所示。
- 根据权利要求22~24任意一项所述的D晶型,其差示扫描量热曲线(DSC)在56.07±3℃、193.93±3℃和216.54±3℃处分别有一个吸热峰的起始点。
- 根据权利要求25所述的D晶型,其DSC图谱如图11所示。
- 根据权利要求22~24任意一项所述的D晶型,其热重分析曲线(TGA)在79.35±3℃时失重达1.977%;在223.66±3℃时又失重达1.589%。
- 根据权利要求27所述的D晶型,其TGA图谱如图12所示。
- 式(Ⅰ)化合物的E晶型,其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰:8.65±0.2°、14.22±0.2°和24.58±0.2°。
- 根据权利要求29所述的E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:8.65±0.2°、11.41±0.2°、13.13±0.2°、14.22±0.2°、17.35±0.2°、18.34±0.2°、20.39±0.2°、20.94±0.2°和24.58±0.2°。
- 根据权利要求30所述的E晶型,其XRPD图谱如图13所示。
- 根据权利要求29~31任意所述的E晶型,其差示扫描量热曲线(DSC)在121.57±3℃、197.26±3℃和217.23±3℃处分别有一个吸热峰的起始点;在168.31±3℃和212.95±3℃分别有一个放热峰的峰值。
- 根据权利要求32所述的E晶型,其DSC图谱如图14所示。
- 根据权利要求29~31任意所述的E晶型,其热重分析曲线(TGA)在143.31±3℃时失重达6.775%;在213.62±3℃时又失重达0.3184%。
- 根据权利要求34所述的E晶型,其TGA图谱如图15所示。
- 式(Ⅰ)化合物的F晶型,其X射线粉末衍射(XRPD)图谱在下列2θ角处具有特征衍射峰:5.06±0.2°、15.91±0.2°和16.68±0.2°。
- 根据权利要求36所述的F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:5.06±0.2°、8.34±0.2°、10.98±0.2°、15.13±0.2°、15.91±0.2°、16.68±0.2°、17.63±0.2°和18.87±0.2°。
- 根据权利要求37所述的F晶型,其XRPD图谱如图16所示。
- 根据权利要求36~38任意一项所述的F晶型,其差示扫描量热曲线(DSC)在48.69±3℃和225.26±3℃处分别有一个吸热峰的起始点。
- 根据权利要求39所述的F晶型,其DSC图谱如图17所示。
- 根据权利要求36~38任意一项所述的F晶型,其热重分析曲线(TGA)在100±3℃时失重达3.404%。
- 根据权利要求41所述的F晶型,其TGA图谱如图18所示。
- 根据权利要求1~7任意一项所述的A晶型、根据权利要求8~14任意一项所述的B晶型、根据权利要求15~21任意一项所述的C晶型、据权利要求22~28任意一项所述的D晶型、据权利要求29~34任意一项所述的E晶型或根据权利要求35~42任意一项所述的F晶型在制备治疗Wee1相关疾病的药物的应用。
- 式(I)化合物的F晶型的制备方法,包括:(a)将式(I)化合物加入醇类溶剂中搅拌加热至油浴55~65℃;(b)47℃-53℃下搅拌72小时;(c)关闭加热,保持搅拌自然降温1小时后至27℃;(d)静置18小时,过滤,再用甲醇淋洗滤饼;(e)60℃真空烘干48小时。
- 根据权利要求44所述的制备方法,其中,醇类溶剂为甲醇。
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BR112021021230A BR112021021230A8 (pt) | 2019-04-30 | 2020-04-30 | Forma de cristal de composto inibidor de wee1 e uso do mesmo |
CA3138240A CA3138240A1 (en) | 2019-04-30 | 2020-04-30 | Crystal forms of wee1 inhibitor coumpound and use thereof |
JP2021564588A JP2022530812A (ja) | 2019-04-30 | 2020-04-30 | Wee1阻害剤化合物の結晶形及びその応用 |
AU2020266956A AU2020266956A1 (en) | 2019-04-30 | 2020-04-30 | Crystal form of Wee1 inhibitor compound and use thereof |
SG11202111315XA SG11202111315XA (en) | 2019-04-30 | 2020-04-30 | Crystal form of wee1 inhibitor compound and use thereof |
CN202080031816.4A CN113784968B (zh) | 2019-04-30 | 2020-04-30 | Wee1抑制剂化合物的晶型及其应用 |
US17/607,447 US20220220120A1 (en) | 2019-04-30 | 2020-04-30 | Crystal form of wee1 inhibitor compound and use thereof |
EP20798924.5A EP3964510A4 (en) | 2019-04-30 | 2020-04-30 | WEE1 INHIBITOR COMPOUND CRYSTAL FORM AND USE |
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Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070254892A1 (en) | 2006-04-27 | 2007-11-01 | Takeshi Sagara | Dihydropyrazolopyrimidinone derivatives |
WO2008133866A1 (en) | 2007-04-25 | 2008-11-06 | Merck & Co., Inc. | Polymorph of dihydropyrazolopyrimidinone derivative as weel kinase.inhibitor |
EP2213673A1 (en) | 2007-10-23 | 2010-08-04 | Banyu Pharmaceutical Co., Ltd. | Pyridone-substituted-dihydropyrazolopyrimidinone derivative |
WO2011034743A1 (en) | 2009-09-15 | 2011-03-24 | Merck Sharp & Dohme Corp. | Preparation of crystalline forms of dihydropyrazolopyrimidinone |
US20120220572A1 (en) | 2011-02-28 | 2012-08-30 | Abbott Laboratories | Tricyclic inhibitors of kinases |
WO2013013031A1 (en) | 2011-07-19 | 2013-01-24 | Abbvie Inc. | Pyridazino [4, 5 -d] pyrimidin- (6h) -one inhibitors of wee - 1 kinase |
WO2013012681A1 (en) | 2011-07-15 | 2013-01-24 | Abbott Laboratories | Tricyclic inhibitors of kinases useful for the treatment of proliferative diseases |
WO2013059485A1 (en) | 2011-10-20 | 2013-04-25 | Abbvie Inc. | Pyridopyrimidinone inhibitors of kinases |
WO2013126656A1 (en) | 2012-02-23 | 2013-08-29 | Abbvie Inc. | Pyridopyrimidinone inhibitors of kinases |
WO2014167347A1 (en) | 2013-04-11 | 2014-10-16 | Almac Discovery Limited | 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors |
WO2015019037A1 (en) | 2013-08-05 | 2015-02-12 | Almac Discovery Limited | Pharmaceutical compounds |
WO2015092431A1 (en) | 2013-12-19 | 2015-06-25 | Almac Discovery Limited | Pyrimidopyrimidinones useful as wee-1 kinase inhibitors |
CN108623615A (zh) * | 2017-03-23 | 2018-10-09 | 上海迪诺医药科技有限公司 | 吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用 |
WO2019085933A1 (zh) * | 2017-11-01 | 2019-05-09 | 南京明德新药研发股份有限公司 | 作为Wee1抑制剂的大环类化合物及其应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7163939B2 (en) * | 2003-11-05 | 2007-01-16 | Abbott Laboratories | Macrocyclic kinase inhibitors |
JP5523833B2 (ja) * | 2006-10-27 | 2014-06-18 | シグナル ファーマシューティカルズ,エルエルシー | 4−[9−(テトラヒドロ−フラン−3−イル)−8−(2,4,6−トリフルオロ−フェニルアミノ)−9h−プリン−2−イルアミノ]−シクロヘキサン−1−オールを含む固体形態、それらの組成物、及びそれらの使用 |
EP3875460A4 (en) * | 2018-10-26 | 2022-07-20 | Wuxi Biocity Biopharmaceutics Co., Ltd. | PYRIMIDOPYRAZOLONE DERIVATIVE AS A WEE1 INHIBITOR AND USE OF IT |
-
2020
- 2020-04-30 CN CN202080031816.4A patent/CN113784968B/zh active Active
- 2020-04-30 US US17/607,447 patent/US20220220120A1/en active Pending
- 2020-04-30 BR BR112021021230A patent/BR112021021230A8/pt unknown
- 2020-04-30 JP JP2021564588A patent/JP2022530812A/ja active Pending
- 2020-04-30 CA CA3138240A patent/CA3138240A1/en active Pending
- 2020-04-30 SG SG11202111315XA patent/SG11202111315XA/en unknown
- 2020-04-30 AU AU2020266956A patent/AU2020266956A1/en active Pending
- 2020-04-30 EP EP20798924.5A patent/EP3964510A4/en active Pending
- 2020-04-30 WO PCT/CN2020/088451 patent/WO2020221358A1/zh unknown
-
2021
- 2021-10-21 IL IL287472A patent/IL287472A/en unknown
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007126122A1 (en) | 2006-04-27 | 2007-11-08 | Banyu Pharmaceutical Co., Ltd. | Dihydropyrazolopyrimidinone derivatives |
US20070254892A1 (en) | 2006-04-27 | 2007-11-01 | Takeshi Sagara | Dihydropyrazolopyrimidinone derivatives |
WO2008133866A1 (en) | 2007-04-25 | 2008-11-06 | Merck & Co., Inc. | Polymorph of dihydropyrazolopyrimidinone derivative as weel kinase.inhibitor |
EP2213673A1 (en) | 2007-10-23 | 2010-08-04 | Banyu Pharmaceutical Co., Ltd. | Pyridone-substituted-dihydropyrazolopyrimidinone derivative |
WO2011034743A1 (en) | 2009-09-15 | 2011-03-24 | Merck Sharp & Dohme Corp. | Preparation of crystalline forms of dihydropyrazolopyrimidinone |
US20120220572A1 (en) | 2011-02-28 | 2012-08-30 | Abbott Laboratories | Tricyclic inhibitors of kinases |
WO2013012681A1 (en) | 2011-07-15 | 2013-01-24 | Abbott Laboratories | Tricyclic inhibitors of kinases useful for the treatment of proliferative diseases |
WO2013013031A1 (en) | 2011-07-19 | 2013-01-24 | Abbvie Inc. | Pyridazino [4, 5 -d] pyrimidin- (6h) -one inhibitors of wee - 1 kinase |
WO2013059485A1 (en) | 2011-10-20 | 2013-04-25 | Abbvie Inc. | Pyridopyrimidinone inhibitors of kinases |
WO2013126656A1 (en) | 2012-02-23 | 2013-08-29 | Abbvie Inc. | Pyridopyrimidinone inhibitors of kinases |
WO2014167347A1 (en) | 2013-04-11 | 2014-10-16 | Almac Discovery Limited | 2-aminopyrido[4,3-d]pyrimidin-5-one derivatives and their use as wee-1 inhibitors |
WO2015019037A1 (en) | 2013-08-05 | 2015-02-12 | Almac Discovery Limited | Pharmaceutical compounds |
WO2015092431A1 (en) | 2013-12-19 | 2015-06-25 | Almac Discovery Limited | Pyrimidopyrimidinones useful as wee-1 kinase inhibitors |
CN108623615A (zh) * | 2017-03-23 | 2018-10-09 | 上海迪诺医药科技有限公司 | 吡唑[3,4-d]嘧啶-3-酮的大环衍生物、其药物组合物及应用 |
WO2019085933A1 (zh) * | 2017-11-01 | 2019-05-09 | 南京明德新药研发股份有限公司 | 作为Wee1抑制剂的大环类化合物及其应用 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3964510A4 |
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AU2020266956A1 (en) | 2021-10-28 |
EP3964510A1 (en) | 2022-03-09 |
BR112021021230A2 (zh) | 2021-12-21 |
IL287472A (en) | 2021-12-01 |
CN113784968A (zh) | 2021-12-10 |
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