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However, developing novel phosphatase inhibitors that combine high potency, selectivity, cellular permeability, and drug\u2010like properties remains challenging. The discovery of an allosteric mode of inhibition for SHP2 was a breakthrough, enabling the development of selective inhibitors that stabilize the phosphatase in its inactive conformation. We identified 2\n                    <jats:italic>H<\/jats:italic>\n                    \u2010indazoles as a privileged and underexplored scaffold. Using our recently described palladium\u2010catalyzed domino reaction as a key synthetic step, 3\u2010amino\u20102\n                    <jats:italic>H<\/jats:italic>\n                    \u2010indazoles were efficiently accessed from readily available precursors, enabling rapid exploration of novel allosteric inhibitors of SHP2. This approach led to compound\n                    <jats:bold>17g<\/jats:bold>\n                    , a potent and selective allosteric SHP2 inhibitor (SHP2\n                    <jats:sup>WT<\/jats:sup>\n                    IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200949\u2009nM). High\u2010resolution structural characterization by X\u2010ray crystallography revealed binding within the SHP2 allosteric tunnel. Consistent with its biological activity, compound\n                    <jats:bold>17g<\/jats:bold>\n                    also effectively suppressed ERK phosphorylation in MV\u20104\u201011, Panc\u20101, and KYSE520 cells with an IC\n                    <jats:sub>50<\/jats:sub>\n                    of 50, 250, and 410\u2009nM, respectively. These findings not only highlight the therapeutic potential of 2\n                    <jats:italic>H<\/jats:italic>\n                    \u2010azaindazoles as a new class of SHP2 inhibitors but also underscore the importance of advances in efficient synthetic methodologies for constructing novel heterocyclic scaffolds and substitution patterns.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70341","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T02:05:54Z","timestamp":1781489154000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Probing 3\u2010Amino\u20102\n                    <i>H<\/i>\n                    \u2010Azaindazoles as Allosteric Inhibitors of the Protein Tyrosine Phosphatase SHP2"],"prefix":"10.1002","volume":"21","author":[{"given":"Machoud","family":"Amoussa","sequence":"first","affiliation":[{"name":"Leibniz\u2010Forschungsinstitut f\u00fcr Molekulare 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