Fused bicyclic derivatives of 2,4-diaminopyrimidine as c-Met inhibitors

Weinberg, Linda R.; Albom, Mark S.; Angeles, Thelma S.; Husten, Jean; Lisko, Joseph G.; McHugh, Robert J.; Milkiewicz, Karen L.; Murthy, S. N. Prasanna; Ott, Gregory R.; Theroff, Jay; Tripathy, Rabindranath; Underiner, Ted L.; Zificsak, Craig A.; Dorsey, Bruce D.

doi:10.1016/j.bmcl.2010.11.045

Cited by 23 publications

(8 citation statements)

References 6 publications

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“…C2 benzazepinone were found to be the most potent c-Met inhibitors, 9 (IC 50 = 10 nM) being the best analog. Incorporation of fluorine at C3 position of aminobenzamide moiety led to selectivity for c-Met kinase [12].…”

Section: 4 5-trisubstituted Pyrimidinesmentioning

confidence: 99%

Pyrimidine: a review on anticancer activity with key emphasis on SAR

2021

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Background Cancer is a global health challenge, it impacts the quality of life and its treatment is associated with several side effects. Resistance of the cancer cells to the existing drugs has led to search for novel anticancer agents. Pyrimidine, a privileged scaffold, is part of living organisms and plays vital role in various biological procedures as well as in cancer pathogenesis. Due to resemblance in structure with the nucleotide base pair of DNA and RNA, it is recognized as valuable compound in the treatment of cancer. Main text Many novel pyrimidine derivatives have been designed and developed for their anticancer activity in the last few years. The present review aims to focus on the structure activity relationship (SAR) of pyrimidine derivatives as anticancer agent from the last decade. Conclusion This review intends to assist in the development of more potent and efficacious anticancer drugs with pyrimidine scaffold. Graphical abstract

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Section: 4 5-trisubstituted Pyrimidinesmentioning

confidence: 99%

Pyrimidine: a review on anticancer activity with key emphasis on SAR

2021

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“…Reductive amination with hydroxyethyl piperazine, followed by nitro reduction led to the racemic A-ring, which was resolved by supercritical-fluid chromatography (SFC) to give enantiopure chiral A-ring 9 . The B,C-ring system 12 was generated through a coupling of the C-ring (commercially available or made in one step from isotoic anhydride) with 2,4,5-trichloropyrimidine. Finally, the coupling of the two subunits used the process chemistry conditions originally developed for CEP-28122, albeit with a low yield (<50%), to generate TEV-37440 ( 2 ) as the free base.…”

Section: Medicinal Chemistry Routementioning

confidence: 99%

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Allwein

Mowrey

Petrillo

et al. 2017

Org. Process Res. Dev.

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The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND (inversigational new drug) enabling activities within CMC (Chemistry, Manufacturing, and Controls). The identification and development of an improved route that was performed in the pilot plant to supply early phase clinical supplies are discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.

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“…4,4-Dimethyl-7-nitro-3,4-dihydronaphthalen-1(2H)-one was prepared following the literature procedure. 17 To a freshly prepared solution of LDA (11 mmol using 1.44 mL of i-Pr 2 NH and 4.58 mL of n-BuLi 2.4 M) in THF (5 mL) at −78 °C, a solution of 4,4-dimethyl-7-nitro-3,4-dihydronaphthalen-1(2H)-one (2.19 g, 10 mmol) in THF (5 mL) was added dropwise and the solution was stirred at this temperature during 30 min. Then DMPU (1.2 mL, 10 mmol) was added to the resulted solution followed by adding a solution of ethyl carbonocyanidate (2.0 g, 20 mmol) in THF (5 mL).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Hypervalent-Iodine-Mediated Formation of Epoxides from Carbon(sp²)–Carbon(sp³) Single Bonds

et al. 2017

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We have developed an efficient method for direct formation of epoxide groups from carbon(sp)-carbon(sp) single bonds of β-keto esters; the reaction is mediated by the water-soluble hypervalent iodine(V) reagent AIBX (5-trimethylammonio-1,3-dioxo-1,3-dihydro-1λ-benzo[d][1,2]iodoxol-1-ol anion). On the basis of the results of density functional theory calculations and experimental studies, we propose that the reaction proceeds by a two-stage mechanism involving dehydrogenation of the β-keto ester substrates and epoxidation of the resulting enone intermediates. The rate-limiting step is abstraction of the β'-C-H (calculated free energy of activation, 24.5 kcal/mol).

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Fused bicyclic derivatives of 2,4-diaminopyrimidine as c-Met inhibitors

Cited by 23 publications

References 6 publications

Pyrimidine: a review on anticancer activity with key emphasis on SAR

Pyrimidine: a review on anticancer activity with key emphasis on SAR

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Hypervalent-Iodine-Mediated Formation of Epoxides from Carbon(sp²)–Carbon(sp³) Single Bonds

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Fused bicyclic derivatives of 2,4-diaminopyrimidine as c-Met inhibitors

Cited by 23 publications

References 6 publications

Pyrimidine: a review on anticancer activity with key emphasis on SAR

Pyrimidine: a review on anticancer activity with key emphasis on SAR

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Hypervalent-Iodine-Mediated Formation of Epoxides from Carbon(sp2)–Carbon(sp3) Single Bonds

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Hypervalent-Iodine-Mediated Formation of Epoxides from Carbon(sp²)–Carbon(sp³) Single Bonds