14277-03-3Relevant articles and documents
Discovery of 6-[(3 S,4 S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor
Burke, Jason P.,Carroll, Christopher L.,Cross, Jason B.,Czako, Barbara,Di Francesco, Maria Emilia,Draetta, Giulio,Feng, Ningping,Harris, Angela L.,Heffernan, Timothy,Jiang, Yongying,Jones, Philip,Kang, Zhijun,Kohl, Nancy E.,Kovacs, Jeffrey J.,Leonard, Paul G.,Mandal, Pijus,Marszalek, Joseph. R.,McAfoos, Timothy,Meyers, Brooke A.,Mseeh, Faika,Parker, Connor A.,Sun, Yuting,Williams, Christopher C.,Wu, Qi,Yu, Simon S.
, p. 15141 - 15169 (2021/11/01)
Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) plays a role in receptor tyrosine kinase (RTK), neurofibromin-1 (NF-1), and Kirsten rat sarcoma virus (KRAS) mutant-driven cancers, as well as in RTK-mediated resistance, making the identification of small-molecule therapeutics that interfere with its function of high interest. Our quest to identify potent, orally bioavailable, and safe SHP2 inhibitors led to the discovery of a promising series of pyrazolopyrimidinones that displayed excellent potency but had a suboptimal in vivo pharmacokinetic (PK) profile. Hypothesis-driven scaffold optimization led us to a series of pyrazolopyrazines with excellent PK properties across species but a narrow human Ether-à-go-go-Related Gene (hERG) window. Subsequent optimization of properties led to the discovery of the pyrimidinone series, in which multiple members possessed excellent potency, optimal in vivo PK across species, and no off-target activities including no hERG liability up to 100 μM. Importantly, compound 30 (IACS-15414) potently suppressed the mitogen-activated protein kinase (MAPK) pathway signaling and tumor growth in RTK-activated and KRASmut xenograft models in vivo.
Synthesis of indoles and quinazolines via additive-controlled selective C-H activation/annulation of N -arylamidines and sulfoxonium ylides
Lai, Ruizhi,Wu, Xiaohua,Lv, Songyang,Zhang, Chen,He, Maoyao,Chen, Yuncan,Wang, Qiantao,Hai, Li,Wu, Yong
supporting information, p. 4039 - 4042 (2019/04/10)
Selective synthesis of indole and quinazoline products was achieved through a precise control of the C-H activation/annulation by changing the additives from NaOAc to CuF2/CsOAc. This strategy constructs indole and quinazoline scaffolds efficie
Synthesis of 2-Substituted Quinolines via Rhodium(III)-Catalyzed C–H Activation of Imidamides and Coupling with Cyclopropanols
Zhou, Xukai,Qi, Zisong,Yu, Songjie,Kong, Lingheng,Li, Yang,Tian, Wan-Fa,Li, Xingwei
, p. 1620 - 1625 (2017/05/22)
An efficient synthesis of 2-substituted quinolines from readily available cyclopropanols and imidamides has been developed, where the cyclopropanol acts as a C3 synthon. With the assistance of a bifunctional imidamide directing group, the reaction occurred via sequential C–H/C–C cleavage and C–C/C–N bond formation. (Figure presented.).
