- Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: Design, synthesis and biological evaluation
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As a receptor tyrosine kinase (RTK), tropomyosin receptor kinase (Trk) is a key drug target in solid tumors. However, the use of the First-generation Trk inhibitors was greatly restricted due to mutant drug resistance. Fortunately, the emergence of the Second-generation of Trk inhibitors has brought an effective solution to this mutant resistance, such as TPX-0005 (Repotrectinib). Here, we reported a series of pyrizolo[1,5-a]pyrimidine derivatives as the second-generation Trk inhibitors, and carried out the subsequent biological activity evaluation. Among them, the best compound 14h (IC50 = 1.40, 1.80 nM, against TrkA, TrkAG595R, respectively) and 14j (IC50 = 0.86, 6.92 nM, against TrkA, TrkAG595R, respectively) has a kinase activity comparable to TPX-0005, and 14j (IC50 = 350 nM against ALK) has a higher selectivity of Trk inhibition than TPX-0005, which may be of great significance for reducing toxicity.
- Fan, Weizheng,Fan, Yiqing,Jiang, Hongyu,Liu, Yan,Tang, Chunlei,Zhang, Yongjie,Zhou, Ying
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- Substituted chiral diaryl macrocyclic compound as TRK inhibitors
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The invention relates to a substituted chiral diaryl macrocyclic compound as a TRK inhibitor, and belongs to the technical field. The structure of the chiral diaryl macrocyclic compound is shown as a general formula (I), and the chiral diaryl macrocyclic
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- Synthesis method for tert-butyl 1,2,3-oxathiazolidine-3-carboxylic ester 2,2-dioxide compound
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The invention relates to a synthesis method for a tert-butyl 1,2,3-oxathiazolidine-3-carboxylic ester 2,2-dioxide compound. The tert-butyl 1,2,3-oxathiazolidine-3-carboxylic ester 2,2-dioxide compoundhas a structural formula as shown in a formula I which is described in the specification. The synthesis method comprises the step of allowing a compound as shown in a formula II which is described inthe specification with sulfonyl chloride in the presence of an organic solvent to generate the compound as shown in the formula I. The structural formula of the compound as shown in the formula I andthe structural formula of the compound as shown in the formula II are described in the specification. The synthesis method disclosed by the invention is simple to operate; compared with a conventional published two-step method, the synthesis method provided by the invention only needs one step; and the synthesis method is more convenient, reduces byproducts, is high in yield, does not need to usea catalyst and a highly-toxic substance in the reaction, and is safe and low in cost.
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Paragraph 0041-0047; 0055-0061
(2020/07/13)
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- Construction of a Shape-Diverse Fragment Set: Design, Synthesis and Screen against Aurora-A Kinase
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Historically, chemists have explored chemical space in a highly uneven and unsystematic manner. As an example, the shape diversity of existing fragment sets does not generally reflect that of all theoretically possible fragments. To assess experimentally the added value of increased three dimensionality, a shape-diverse fragment set was designed and collated. The set was assembled by both using commercially available fragments and harnessing unified synthetic approaches to sp3-rich molecular scaffolds. The resulting set of 80 fragments was highly three-dimensional, and its shape diversity was significantly enriched by twenty synthesised fragments. The fragment set was screened by high-throughput protein crystallography against Aurora-A kinase, revealing four hits that targeted the binding site of allosteric regulators. In the longer term, it is envisaged that the fragment set could be screened against a range of functionally diverse proteins, allowing the added value of more shape-diverse screening collections to be more fully assessed.
- Zhang, Rong,McIntyre, Patrick J.,Collins, Patrick M.,Foley, Daniel J.,Arter, Christopher,von Delft, Frank,Bayliss, Richard,Warriner, Stuart,Nelson, Adam
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p. 6831 - 6839
(2019/05/10)
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- Synthesis of Chiral Tryptamines via a Regioselective Indole Alkylation
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A practical synthesis of chiral tryptamines from simple, unprotected indoles has been developed. Indole nucleophiles prepared with MeMgCl in the presence of CuCl reacted with chiral cyclic sulfamidates almost exclusively at the C3-position of i
- Wolfard, Jens,Xu, Jie,Zhang, Haiming,Chung, Cheol K.
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p. 5431 - 5434
(2018/09/12)
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- Ring opening of cyclic sulfamidates with bromophenyl metal reagents: Complementarity of sulfamidates and aziridines
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Bromophenyl magnesium reagents generated via a Knochel type magnesium-halogen exchange of aryl iodides undergo regioselective ring opening of cyclic primary and secondary N-Boc sulfamidates in good to excellent yields. With secondary sulfamidates the reaction proceeds with clean inversion of the stereochemistry. This protocol complements the ring opening of aziridines with bromophenyl metal reagents and extends its scope to secondary substrates.
- Hebeisen, Paul,Weiss, Urs,Alker, André,Staempfli, Andreas
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p. 5229 - 5233
(2011/10/31)
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- Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists
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Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a- hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT2 receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT2C receptor agonists.
- Roever,Adams,Benardeau,Bentley,Bickerdike,Bourson,Cliffe,Coassolo,Davidson,Dourish,Hebeisen,Kennett,Knight,Malcolm,Mattei,Misra,Mizrahi,Muller,Porter,Richter,Taylor,Vickers
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p. 3604 - 3608
(2007/10/03)
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