32821-75-3Relevant articles and documents
Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12CInhibitor for the Treatment of Cancer
Fell, Jay B.,Fischer, John P.,Baer, Brian R.,Blake, James F.,Bouhana, Karyn,Briere, David M.,Brown, Karin D.,Burgess, Laurence E.,Burns, Aaron C.,Burkard, Michael R.,Chiang, Harrah,Chicarelli, Mark J.,Cook, Adam W.,Gaudino, John J.,Hallin, Jill,Hanson, Lauren,Hartley, Dylan P.,Hicken, Erik J.,Hingorani, Gary P.,Hinklin, Ronald J.,Mejia, Macedonio J.,Olson, Peter,Otten, Jennifer N.,Rhodes, Susan P.,Rodriguez, Martha E.,Savechenkov, Pavel,Smith, Darin J.,Sudhakar, Niranjan,Sullivan, Francis X.,Tang, Tony P.,Vigers, Guy P.,Wollenberg, Lance,Christensen, James G.,Marx, Matthew A.
supporting information, p. 6679 - 6693 (2020/04/20)
Capping off an era marred by drug development failures and punctuated by waning interest and presumed intractability toward direct targeting of KRAS, new technologies and strategies are aiding in the target's resurgence. As previously reported, the tetrahydropyridopyrimidines were identified as irreversible covalent inhibitors of KRASG12C that bind in the switch-II pocket of KRAS and make a covalent bond to cysteine 12. Using structure-based drug design in conjunction with a focused in vitro absorption, distribution, metabolism and excretion screening approach, analogues were synthesized to increase the potency and reduce metabolic liabilities of this series. The discovery of the clinical development candidate MRTX849 as a potent, selective covalent inhibitor of KRASG12C is described.
Towards the synthesis of osteoclast inhibitor SB-242784
Conde, Jose J.,McGuire, Michael,Wallace, Michael
, p. 3081 - 3084 (2007/10/03)
Osteoclast inhibitor SB-242784 (1) was prepared from pivotal indol intermediate 4. A 'Stille' cross coupling of organotin 2c with bromo acrylate 11 afforded diene 12 which was also obtained via a reduction-isomerization process of enyne 16. Bromoamide 3 was prepared from the corresponding acid 7 which was readily obtained from bromopyruvic acid.
Experiments Towards the Synthesis of the Ergot Alkaloids and Related Structures. Part 4. Lysergic Acid-An Attempted 'Endo-amide' Approach
Bowman, Ralph E.
, p. 1897 - 1904 (2007/10/02)
Two attempts to synthesise the tricyclic α-keto-amide (6) are described.In the first, 1,2,3,4-tetradihydro-2-methylaminonaphthalen-1-one (3) was allowed to react with pyridine-hydroxymaleic anhydride at -20 deg C and then at room temperature to give a complex mixture from which the naphth-1,4-oxazinone (14), 2-pyruvamido-1-tetralone (16; R=Ac) contaminated with the oxazinone (14) and the phenolic acid (13c) were isolated.A tetracyclic oxazinone was also obtained from the appropriate methylaminotetrahydroacenaphthenone but not from the corresponiding benzindolone (7; R=NHMe.HCl).In the second, the N-methyldione (10) was converted in three stages into the tricyclic acid (13c) which proved unexpectedly stable.However, its triethylamine salt lost carbon dioxide at 140 deg C to give not the required keto-amide (6) but the isomeric hydroxybenzquinolone (13d).Both the oxazinone (14) and the impure pyruvamido-ketone (16; R=Ac) were converted within seconds by treatment with 2 M-sodium hydroxide into the sparingly soluble sodium salt of the phenol (13d) as was the pure pyruvamido ketone whose synthesis is described.
