- Pyrimidine derivative, and preparation method and application thereof
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The invention discloses a compound represented by general formula (I) capable of being used as an ATR protein kinase inhibitor, and an isomer or pharmaceutically acceptable salt thereof. The compound, and the isomer or the pharmaceutically acceptable salt thereof can be used for preparing medicines for treating and/or preventing hyperproliferative diseases.
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Paragraph 0128-0131
(2021/06/12)
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- Synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738
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The invention belongs to the technical field of heterocyclic chemistry, particularly relates to a heterocyclic anti-tumor chemical medicine, and more particularly relates to a synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738. A chiral ligand induced asymmetric oxidation method is used, chiral ligands are combined with cheap oxidizing agents (such as hydrogen peroxide) to oxidize dimethyl sulfide to prepare chiral sulfoxide, conversion of the chiral sulfoxide is efficiently achieved, a chiral sulfoxide compound 7 for the AZD6738 is prepared, and then the final product AZD6738 is prepared through an intermittent reaction. Besides, the AZD6738 is prepared by adopting a fluid chemical method, the total yield of total synthesis of the AZD6738 is remarkably improved compared with that of an intermittent reaction, and the method is suitable for industrial production.
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Paragraph 0027; 0031; 0042
(2020/09/20)
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- Development and Scale-up of a Route to ATR Inhibitor AZD6738
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AZD6738 is currently being tested in multiple phase I/II trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine, and an azaindole, make it a challenging molecule to syn
- Goundry, William R. F.,Dai, Kuangchu,Gonzalez, Miguel,Legg, Daniel,O'Kearney-Mcmullan, Anne,Morrison, James,Stark, Andrew,Siedlecki, Paul,Tomlin, Paula,Yang, Jianbo
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p. 1333 - 1342
(2019/08/12)
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- SUBSTITUTED PYRROLOPYRIDINES AS ATR INHIBITORS
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The disclosure includes compounds of Formula (I) wherein A, W, m, R5, R6, R7, and R8, are defined herein. Also disclosed is a method for treating a neoplastic disease with these compounds.
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- Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent
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The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.
- Foote, Kevin M.,Nissink, J. Willem M.,McGuire, Thomas,Turner, Paul,Guichard, Sylvie,Yates, James W. T.,Lau, Alan,Blades, Kevin,Heathcote, Dan,Odedra, Rajesh,Wilkinson, Gary,Wilson, Zena,Wood, Christine M.,Jewsbury, Philip J.
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p. 9889 - 9907
(2018/11/23)
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- CHEMICAL COMPOUNDS
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There is provided pyrimidinyl compounds of Formula (I), wherein: R2 is or pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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