Omipalisib

Omipalisib (GSK2126458) is a highly selective and potent inhibitor of PI3K with Kis of 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM for p110α/β/δ/γ, mTORC1/2, respectively.

2,4-difluoro-N-[2-methoxy-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl]benzenesulfonamide is a member of quinolines.|Omipalisib has been used in trials studying the treatment of CANCER, Solid Tumours, and Idiopathic Pulmonary Fibrosis.|Omipalisib is a small-molecule pyridylsulfonamide inhibitor of phosphatidylinositol 3-kinase (PI3K) with potential antineoplastic activity. Omipalisib binds to and inhibits PI3K in the PI3K/mTOR signaling pathway, which may trigger the translocation of cytosolic Bax to the mitochondrial outer membrane, increasing mitochondrial membrane permeability and inducing apoptotic cell death. Bax is a member of the proapoptotic Bcl2 family of proteins. PI3K, often overexpressed in cancer cells, plays a crucial role in tumor cell regulation and survival.

b) A suspension of 7 (570.0 mg, 2.0 mmol), bis(pinacolato)diboron (559.4 mg, 2.2 mmol), PdClb) 2, 4-difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide A slurry of 6-bromo-4-(4-pyridazinyl)quinoline (4.8 g, 16.78 mmol), bis(pinacolato)diboron (4.69 g, 18.45 mmol), PdCl2(dppf)-CH2Cl2 (530 mg, 0.649 mmol) and potassium acetate (3.29 g, 33.6 mmol) in anhydrous 1, 4-dioxane (120 ml) was heated at 100 C. for 3 h. The complete disappearance of the starting bromide was observed by LCMS. The reaction was then treated with N[5-bromo-2-(methyloxy)-3-pyridinyl]-2, 4-difluorobenzenesulfonamide (6.68 g, 17.61 mmol) and another portion of PdCl2(dppf)-CH2Cl2 (550 mg, 0.673 mmol), then heated at 110 C. for 16 h. The reaction was allowed to cool to room temperature, filtered, and concentrated. Purification of the residue by chromatography (Analogix; 5% MeOH/5% CH2Cl2/90% EtOAC) gave 6.5 g (76%) desired product. MS(ES)+ m/e 505.9 [M+H]+.A suspension of 7 (570.0 mg, 2.0 mmol), bis(pinacolato)diboron (559.4 mg, 2.2 mmol), PdCl2(dppf)-CH2Cl2 (82.0 mg, 0.1 mmol) and KOAc (392.7 mg, 4.0 mmol) in anhydrous 1, 4-dioxane (20 mL) was stirred and heated at reflux for 3 h. The reaction mixture was treated with 19 (790.0 mg, 2.1 mmol), 2 M Na2CO3 (4 mL), and another portion of PdCl2(dppf)-CH2Cl2 (82.0 mg, 0.2 mmol), then heated at reflux overnight. After the reaction mixture was allowed to cool to rt, it was filtered through a pad of Celite, washed with abundant CH2Cl2, and concentrated in vacuo. The crude product was purified by silica gel column (90:5:5 EtOAc/CH2Cl2/MeOH) to afford 22 (717.0 mg, 71%) as a pale brown solid, mp 183-184 C (lit1 187-189 C). 1H NMR (DMSO-d6) delta 10.3 (br s, 1H, NH), 9.57-9.56 (m, 1H, Ar-H), 9.47 (dd, J = 5.0, 1.0 Hz, 1H, Ar-H), 9.05 (d, J = 4.5 Hz, 1H, Ar-H), 8.42 (d, J = 4.5 Hz, 1H, Ar-H), 8.25 (d, J = 8.5 Hz, 1H, Ar-H), 8.12 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 8.07 (dd, J = 5.0, 2.0 Hz, 1H, Ar-H), 7.94 (dd, J = 4.0, 2.0 Hz, 2H, Ar-H), 7.74-7.70 (m, 1H, Ar-H), 7.67 (d, J = 4.5 Hz, 1H, Ar-H), 7.58-7.53 (m, 1H, Ar-H), 7.19 (td, J = 8.5, 2.5 Hz, 1H, Ar-H), 3.64 (s, 3H, OCH3). HRMS (ESI, m/z): calcd for C25H18N5O3F2S ([M+H]+) 506.1098, found 506.1101.

A highly potent inhibitor of PI3K and the mammalian target of Rapamycin.

Molecular Weight:505.5
XLogP3:3.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:6
Exact Mass:505.10201692
Monoisotopic Mass:505.10201692
Topological Polar Surface Area:115
Heavy Atom Count:36
Complexity:833
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes