General methods for the synthesis and late-stage diversification of 2,4-substituted 7-azaindoles

Varnes, Jeffrey; McGuire, Thomas M.; Meadows, Rebecca E.; Barlaam, Bernard; Clark, J. Stephen; Cook, Calum; Davison, Gemma; Dishington, Allan; Savi, Chris De; Donald, Craig S.; Grebe, Tyler; Hande, Sudhir M.; Hawkins, Janet; Hird, Alexander W.; Holmes, J. L.; Lister, Andrew; Lucas, Simon; Moore, Jane E.; Moore, Elaine; Patel, Anil S.; Pike, Kurt G.; Roberts, Bryan; Stark, Andrew; Stead, Darren; Thakur, Kumar; Turner, Peter G.; Vasbinder, Melissa M.; Yang, Bin

doi:10.1016/j.tetlet.2016.09.029

Cited by 6 publications

(13 citation statements)

References 14 publications

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“…Azaindoles 7 – 40 were synthesized using routes allowing late-stage diversification to 2,4-substituted 7-azaindoles. We have previously reported on the strengths and weaknesses of these routes . The azaindoles 7 – 9 were made according to Scheme .…”

Section: Chemistrymentioning

confidence: 99%

“…Regioselective Suzuki coupling of previously described azaindole 44 with boronic ester 45 , followed by another Suzuki coupling with 2-methoxy-4-fluorophenylboronic acid afforded compound 7 after 2-trimethylsilylethyoxymethyl (SEM) protection with trifluoroacetic acid (TFA). Compound 8 (previously described in refs , ) was obtained from previously described intermediate 46 after hydrogenation and amine deprotection. Compound 9 was obtained from Suzuki coupling of previously described intermediate 47 with boronic ester 42 , followed by amine deprotection.…”

Section: Chemistrymentioning

confidence: 99%

“…Compound 8 (previously described in refs , ) was obtained from previously described intermediate 46 after hydrogenation and amine deprotection. Compound 9 was obtained from Suzuki coupling of previously described intermediate 47 with boronic ester 42 , followed by amine deprotection.…”

Section: Chemistrymentioning

confidence: 99%

“…Separation of trans ( 49 ) and the cis diastereoisomers, followed by an amine deprotection/acetylation sequence, afforded compound 10 . Suzuki coupling of previously described compound 50 with boronic ester 51 followed by tosyl removal and hydrogenation gave compound 11 .…”

Section: Chemistrymentioning

confidence: 99%

“…Compound 12 was made according to Scheme . Previously described intermediate 52 was subjected to Suzuki coupling with boronic ester 51 to give intermediate 53 after tosyl removal. After deprotonation with sodium hydride of 53 , treatment with n -butyl lithium at −70 °C and trapping of the anion with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane followed by hydrogenation gave boronate ester 54 .…”

Section: Chemistrymentioning

confidence: 99%

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Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement

et al. 2021

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Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.

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Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

See 3 more Smart Citations

Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement

et al. 2021

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Nucleophilic Halogenation of HeterocyclicN‐Oxides: Recent Progress and a Practical Guide

Malykhin

Sukhorukov

2021

Adv Synth Catal

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The review summarizes recent advances in the synthesis of C2‐halogenated nitrogen heterocycles via nucleophilic halogenation of corresponding N‐oxides as well as application of this methodology in the synthesis of pharmaceuticals. Both scientific and patent literature is reviewed mostly over the period of the last ten years. The review contains a practical guide (typical procedures and infographic based on extensive literature analysis), which can help practitioners in choosing optimal reagents/conditions for nucleophilic halogenation of N‐heterocycles of different types. The bibliography contains 199 references.

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Recent Developments in the Cyclization of Alkynes and Nitrogen Compounds for the Synthesis of Indole Derivatives

Neto

Zeni

2021

Asian J Org Chem

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This review is intended to highlight the most useful approaches for the synthesis of indole derivatives (azaindoles, carbazoles, carbolines, indazoles, 3H-indoles, indolines, indolizines, isoindoles, and isoindolines), which were described by using transition-metal catalyzed cyclization reactions of alkynes and nitrogen compounds. The methodologies carried out under metal-free conditions will also be illustrated herein. This review will cover the data published mostly in the past decade. Synthesis of 6-AzaindolesAzaindoles, although rare in nature, have attracted a significant attention because some synthetic structures containing this nucleus exhibit biological activities. [17] The synthetic methods describing the preparation of azaindoles are limited. Usually their synthesis was achieved from the cyclization reaction of substrates containing aminopyridines. [18] Transition Metal-Free Synthesis of 6-AzaindolesWe have nominated two methodologies for the preparation of 6-azaindoles, which were developed using alkynes and nitrogen compounds in a metal-free protocol. In the first, an electrophilic cyclization condition, using iodine as an electrophilic source, was applied to 2-(azidomethyl)-3-alkynyl-pyrroles in the preparation of 4-iodo-6-azaindoles 1 (Scheme 1, eq 1). [19] The second approach described the preparation of 2,5-disubstituted 6azaindoles 2 from base-catalyzed intramolecular cyclization of 2-(azidomethyl)-3-alkynyl-pyrroles (Scheme 1, eq 2). [20] 3. Synthesis of 7-Azaindoles Transition Metal-Catalyzed Synthesis of 7-Azaindoles Silver-Catalyzed Synthesis of 7-AzaindolesSilver-catalyzed cyclization reactions of alkynes constitute powerful strategies for the construction of heterocycles. In particular, the 7-azaindoles could be obtained by these approaches. A general method for the preparation of aryl-[a] Dr. J.

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General methods for the synthesis and late-stage diversification of 2,4-substituted 7-azaindoles

Cited by 6 publications

References 14 publications

Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement

Discovery of a Series of 7-Azaindoles as Potent and Highly Selective CDK9 Inhibitors for Transient Target Engagement

Nucleophilic Halogenation of HeterocyclicN‐Oxides: Recent Progress and a Practical Guide

Recent Developments in the Cyclization of Alkynes and Nitrogen Compounds for the Synthesis of Indole Derivatives

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