The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.

No abstract

Under the conditions of ruthenium catalyzed transfer hydrogenation, 1,1-disubstituted allenes 1a-1c and alcohols 2a-2g engage in redox-triggered generation of allylruthenium-aldehyde pairs to form products of hydrohydroxyalkylation 3a-3g, 4a-4g and 5a-5g with complete branched regioselectivity. By exploiting Curtin-Hammett effects, good to excellent levels of antidiastereoselectivity (4:1 ->20:1) are obtained. Thus, all carbon quaternary centers are formed in a diastereoselective fashion upon carbonyl addition from the alcohol oxidation level in the absence of pre-metallated nucleophiles or stoichiometric byproducts. Exposure of allene 1b to equimolar quantities of alcohol 2a and aldehyde 6b under standard reaction conditions delivers adducts 4a and 4b in a 1:1 ratio. Similarly, exposure of allene 1b to equimolar quantities of aldehyde 6a and alcohol 2b provides adducts 4a and 4b in an identical equimolar ratio. Exposure of allene 1b to d 2 -para-nitrobenzyl alcohol, deuterio-2a, under standard reaction conditions delivers the product of hydrohydroxymethylation deuterio-4a, which incorporates deuterium at the carbinol position (>95% 2 H) and the interior vinylic position (34% 2 H). Competition experiments involving exposure of allene 1b to equimolar quantities of benzylic alcohols 2a and deuterio-2a reveal no significant kinetic effect. The collective data corroborate rapid, reversible alcohol dehydrogenation, allene hydrometallation and (E)-, (Z)-isomerization of the transient allylruthenium in advance of turn-over limiting carbonyl addition. Notably, analogous allenealdehyde reductive C-C couplings employing isopropanol as the terminal reductant display poor levels of anti-diastereoselectivity, suggesting carbonyl addition is not turn-over limiting in reactions conducted from the aldehyde oxidation level.

The ruthenium catalyst generated in situ from Ru3(CO)12 and tricyclohexylphosphine, PCy3, promotes the redox-neutral C-C coupling of aryl substituted α-hydroxy esters to isoprene and myrcene at the diene C4-position, resulting in direct carbinol C-H prenylation and geranylation, respectively. This process enables direct conversion of secondary to tertiary alcohols in the absence of stoichiometric byproducts or premetallated reagents, and is the first example of C4-regioselectivity in catalytic C-C couplings of 2-substituted dienes to carbonyl partners. Mechanistic studies corroborate a catalytic cycle involving diene-carbonyl oxidative coupling.

Carbonyl propargylation has been the topic of intensive investigation for over half a century. [1,2] An effective approach to enantioselective carbonyl propargylation involves the addition of chirally modified allenylmetal reagents, [3][4][5][6][7] including axially chiral derivatives. [5] Contributions include allenylboron reagents that are chirally modified at boron, as reported by Yamamoto, [3a] Corey, [3b] and Soderquist, [3c,d] allenylstannanes that are chirally modified at tin, as first reported by Mukaiyama, [4] as well as axially chiral allenylstannanes, allenylsilanes, allenylboron, and allenylzinc reagents that engage aldehydes in enantioselective propargylation, as described by Marshall, [5a,b,e,f] Hayashi, [5d] and Panek, [5c] respectively. Increasingly effective protocols for carbonyl propargylation, which involve stoichiometric chirality transfer, continue to be developed. [6,7] Enantioselective aldehyde propargylation using allenyltin [8] and allenylsilicon [9] reagents may be catalyzed by chiral Lewis acids or chiral Lewis bases, as first reported by Keck [8a] and Denmark, [8f] respectively. Copper catalysts promote enantioselective carbonyl propargylation by employing allenylboron and propargylboron reagents, as reported by Kanai and Shibasaki and Boehringer-Ingelheim Pharmaceuticals Inc. [10] More recently, Schaus, Antilla, and Reddy reported chiral H-bond donor and Brønsted acid catalyzed propargylations using allenylboron reagents. [11] Finally, catalytic enantioselective Nozaki-Hiyama coupling of propargyl halides delivers products of carbonyl propargylation. [12] Withstanding the Nozaki-Hiyama protocol, [12] methods available for enantioselective carbonyl propargylation have relied on stoichiometric allenylor propargylmetal reagents. Moreover, while carbonyl propargylations for the construction of non-methylated polyacetate subunits are common, catalytic diastereo-and enantioselective propargylations that convert achiral reactants to polypropionate substructures remain undeveloped. We envisioned an alternative strategy for carbonyl propargylation based on the "transfer hydrogenative coupling" [13] of 1,3-Angewandte Chemie