1423716-54-4Relevant academic research and scientific papers
Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible t-cell kinase inhibitors
Burch, Jason D.,Lau, Kevin,Barker, John J.,Brookfield, Fred,Chen, Yong,Chen, Yuan,Eigenbrot, Charles,Ellebrandt, Claire,Ismaili, M. Hicham A.,Johnson, Adam,Kordt, Daniel,Mackinnon, Colin H.,McEwan, Paul A.,Ortwine, Daniel F.,Stein, Daniel B.,Wang, Xiaolu,Winkler, Dirk,Yuen, Po-Wai,Zhang, Yamin,Zarrin, Ali A.,Pei, Zhonghua
, p. 5714 - 5727 (2014/08/05)
Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.
Highly regioselective organocatalyzed synthesis of pyrazoles from diazoacetates and carbonyl compounds
Wang, Lei,Huang, Jiayao,Gong, Xiaojie,Wang, Jian
supporting information, p. 7555 - 7560 (2013/07/05)
A general, organocatalytic inverse-electron-demand [3+2] cycloaddition reaction between a range of carbonyl compounds and diazoacetates has been developed. This reaction is catalyzed by secondary amines as a "green promoter" to generate substituted pyrazoles with high levels of regioselectivity. It is noteworthy that this [3+2] cycloaddition reaction proceeds efficiently at room temperature with a simple and inexpensive catalyst. Considering the large variety and ready availability of the starting materials (e.g. ketones, β-ketoesters, β-diketones, and aldehydes), as well as the operational simplicity of this process, a convenient, practical, and highly modular pyrazole synthesis has been developed. We believe that this work will arouse more research interest in the organocatalytic synthesis of other biologically active heterocycles. Such studies are currently underway in our laboratory. Dipoles apart: In situ formed enamines react with diazoacetates under mild conditions to afford the corresponding polysubstituted pyrazoles in good-to-excellent yields through an inverse-electron-demand 1,3-dipolar cycloaddition process (see scheme). Copyright
1,2,4-oxadiazole derivatives and their therapeutic use
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Page/Page column 31, (2010/07/08)
New derivatives of general formula (I), or pharmaceutically acceptable salts or N-oxides thereof wherein, A is selected from the group consisting of -N-, -O- and -S-; B and C are independently selected from the group consisting of-N- and -O-, with the proviso that at least two of A, B and C are nitrogen atoms; G1 is selected from the group consisting of -CH2-, -NH- and -O-; G2 is selected from the group consisting of -NR4- and -O-; R1 represents: ? a 8 to 10 membered bicyclic N-containing heteroaryl group optionally substituted with a C1-4 carboxyalkyl group or a C1-4 aminoalkyl group, ? a pyridyl group optionally substituted with one or more substituents selected from hydroxy groups, C1-4 alkyl groups, C1-4 carboxyalkyl groups, C1-4 haloalkyl groups, C1-4 alkoxy groups, amino groups, C1-4 aminoalkyl groups and C1-4 aminoalkoxy groups, ? a pyridone group substituted with one or more C1-4 alkyl groups; C1-4 haloalkyl groups or C1-4 aminoalkyl groups, or ? a group of formula: wherein: ? Ra represents a hydrogen atom, a halogen atom, a C1-4 alkyl group, C3-4 cycloalkyl group or a -CF3 group; ? Rb represents a hydrogen atom, a halogen atom, a C14 alkyl group, a -CF3 group or a C1-4 alkoxy group; ? Rd represents a hydrogen atom, a C1-4 alkyl group or a C1-4 alkoxy group; ? Rc represents: ○ a hydrogen atom, a C1-4 hydroxyalkyl group, a C1-4 aminoalkyl group which is optionally substituted with one or more substituents selected from halogen atoms, hydroxy groups and -CF3 groups; ○ a 4 to 6-membered saturated N-containing heterocyclic ring optionally substituted with a C1-2 carboxyalkyl group; ○ -(CH2)(0-4)-C(O)OR', -(CH2)(0-4)-C(O)NR'R", -(CH2)(0-4)-NHC(O)R", -S(O)2NR'R", -O-(CH2)(2-4)NR'R", -O-(CH2)(1-4)C(O)OR", -O-(CH2)(1-4)-C(O)NR'R", -(CH2)(0-4)-NR'R", -(CH2)(0-4)-CONHS(O)2R', -(CH2)(0-4)-NHS(O)2R' or -(CH2)(0-3)-N H-(CH2)(1-3)-(NH)(0-1)S(O)2R' wherein, ■ R' represents a hydrogen atom or a C1-4 alkyl group, ■ R" represents a hydrogen atom, a C1-4 alkyl group, a C3-4 cycloalkyl group, a C1-4 carboxyalkyl group, a C1-4 haloalkyl group, a C1-4 hydroxyalkyl group or a 6 membered, saturated N-containing heterocyclic ring, or ■ R' and R" together with the nitrogen atom to which they are attached from a 4 to 6 membered heterocyclic group which contains, as heteroatoms, one N atom and, optionally, one further atom selected from N and O, and which is optionally substituted with a carboxy or a C1-4 carboxyalkyl group, or Rc together with Rd form a C5-6 cycloalkyl group optionally substituted by a -NHRf group, wherein Rf is selected from the group consisting of a hydrogen atom and a carboxymethyl group; R2 and R3 are independently selected from the group consisting of hydrogen atoms, halogen atoms and C1-4 alkyl groups; and R4 is selected from the group consisting of a hydrogen atom, a phenyl group, a C3-4 cycloalkyl-C1-4 alkyl group, C1-4 aminoalkyl group, C1-4 haloalkyl group and a linear or branched C1-4 alkyl group which is optionally substituted by a phenyl or a pyridyl group.
