Structurally novel PI3Kδ/γ dual inhibitors characterized by a seven-membered spirocyclic spacer: The SARs investigation and PK evaluation

Discovery of Orally Bioavailable SOS1 Inhibitors for Suppressing KRAS-Driven Carcinoma

“…Visualization was achieved by UV light (254 and 365 nm). 1 H NMR and 13 C NMR spectra were measured on an Agilent DD2 600 (600 MHz) spectrometer. The purity for all the compounds was >95%.…”

“…HPLC purity is >95%; 1 H NMR (600 MHz, methanol-d 4 ): δ 7.71 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.1 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 55.0 Hz, 1H), 6.92 (d, J = 34.8 Hz, 1H), 5.81 (q, J = 7.1 Hz, 1H), 4.77−4.68 (m, 1H), 4.17 (dq, J = 8.1, 2.5 Hz, 1H), 3.58 (t, J = 5.5 Hz, 2H), 3.42−3.37 (m, 1H), 3.35 (s, 3H), 3.14 (d, J = 11.6 Hz, 1H), 3.07−2.98 (m, 2H), 2.83−2.75 (m, 1H), 2.66 (q, J = 3.5 Hz, 2H), 2.46−2.38 (m, 1H), 2.34 (s, 3H), 2.30 (d, J = 10.7 Hz, 1H), 2.19 (d, J = 9.4 Hz, 1H), 1.77 (dd, J = 16.4, 2.6 Hz, 1H), 1.65 (d, J = 7.1 Hz, 3H). 13 ]oxazepino[3,2-g]quinazolin-12-amine (13n) was obtained as a white solid with 38% yield. HPLC purity is >95%; 1 H NMR (600 MHz, methanol-d 4 ): δ 7.76 (s, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.1 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 55.0 Hz, 1H), 6.92 (d, J = 31.5 Hz, 1H), 5.84 (q, J = 7.1 Hz, 1H), 4.84−4.80 (m, 2H), 4.74 (td, J = 11.1, 1.6 Hz, 1H), 4.45 (t, J = 6.4 Hz, 2H), 4.20 (dd, J = 10.9, 1.9 Hz, 1H), 3.39−3.31 (m, 2H), 3.16 (d, J = 11.7 Hz, 1H), 3.03 (dt, J = 6.9, 3.3 Hz, 1H), 2.90−2.84 (m, 1H), 2.81 (d, J = 7.2 Hz, 2H), 2.64 (s, 1H), 2.38 (s, 3H), 2.28 (t, J = 10.5 Hz, 1H), 2.25−2.15 (m, 1H), 1.92 (s, 1H), 1.86−1.78 (m, 1H), 1.67 (d, J = 7.1 Hz, 3H).…”

“…HPLC purity is >95%; 1 H NMR (600 MHz, methanol-d 4 ): δ 7.76 (s, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.1 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 55.0 Hz, 1H), 6.92 (d, J = 31.5 Hz, 1H), 5.84 (q, J = 7.1 Hz, 1H), 4.84−4.80 (m, 2H), 4.74 (td, J = 11.1, 1.6 Hz, 1H), 4.45 (t, J = 6.4 Hz, 2H), 4.20 (dd, J = 10.9, 1.9 Hz, 1H), 3.39−3.31 (m, 2H), 3.16 (d, J = 11.7 Hz, 1H), 3.03 (dt, J = 6.9, 3.3 Hz, 1H), 2.90−2.84 (m, 1H), 2.81 (d, J = 7.2 Hz, 2H), 2.64 (s, 1H), 2.38 (s, 3H), 2.28 (t, J = 10.5 Hz, 1H), 2.25−2.15 (m, 1H), 1.92 (s, 1H), 1.86−1.78 (m, 1H), 1.67 (d, J = 7.1 Hz, 3H). 13…”

Focused Libraries for Epigenetic Drug Discovery: The Importance of Isosteres

“…38 Kinase inhibitors, like umbralisib, often employ hinge-binding motifs that mimic ATP to gain affinity toward the protein target and are very effective scaffolds for the design of kinase inhibitors. 39,40 Understandably, hinge binding motifs are therefore well represented in compound collections used for drug discovery and many synthetic methods have been developed which can readily deliver them. 41−47 However, epigenetic targets require distinct chemotypes for the successful discovery of ligands or inhibitors and these are not often included in current compound collections (see below).…”

“… , Tazemetostat targets the histone methyl transferase EZH2, and umbralisib targets the kinase PIK3δ . Kinase inhibitors, like umbralisib, often employ hinge-binding motifs that mimic ATP to gain affinity toward the protein target and are very effective scaffolds for the design of kinase inhibitors. , Understandably, hinge binding motifs are therefore well represented in compound collections used for drug discovery and many synthetic methods have been developed which can readily deliver them. − However, epigenetic targets require distinct chemotypes for the successful discovery of ligands or inhibitors and these are not often included in current compound collections (see below). During the discovery of tazemetostat, an initial hit with the dimethylpyridone chemotype was identified as critical for EZH2 inhibition and preserved throughout the hit-to-lead medicinal chemistry campaign (Figure ).…”