Synthesis and evaluation of thieno[3,2-d]pyrimidine derivatives as novel FMS inhibitors

Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model

“…Calculated partition coefficient (clogP) and lipophilic efficiency (LipE) values were also calculated for selected analogues (Table 3) to further assess their pharmacokinetic properties. Compounds 11,30,35, and 40 had the best LipE values of about 3.5 to 3.6, and 11, 30, and 40 were selected for PK studies in rats. However, all three compounds (11, 30, and 40) showed moderate systemic drug exposure and poor oral bioavailability (F) (Table 5).…”

“…Following the general synthetic procedure as described for 10, isocyanate 50f was used to obtain 29 (49 mg, 91%) as a white solid. 1 (30). Following the general synthetic procedure as described for 10, isocyanate 50g was used to obtain 30 (157 mg, 80%) as a white solid.…”

“…Many preclinical CSF1R inhibitors have also been reported in the literature. − For example, Ki20227 ( 6 ), a 6,7-dimethoxyquinoline-based derivative with CSF1R and vascular endothelial growth factor receptor 2 (VEGFR2) activities, was studied for the treatment of bone cancer and autoimmune disease, and 7 , which suppressed the production of protumorigenic cytokines and inhibited the migration and invasion of macrophages in vitro . However, the poor kinase selectivity of 7 precluded its further development.…”

An Efficient Second-Generation Manufacturing Process for the pan-RAF Inhibitor Belvarafenib

“…4-Aminothieno[3,2-d]pyrimidine-7-carboxylic Acid (2). To design an efficient and scalable process to the thienopyrimidine starting material 2, 25 the main focus was on achieving a step-economical route that circumvents unnecessary late-stage manipulations. Extensive route scouting and optimization studies culminated in a sixstep process that afforded the starting material thienopyrimidine 2 in an overall yield of 47% and >99.5 A% highperformance liquid chromatography (HPLC) purity on a multikilogram scale (Scheme 2).…”

“…The firstgeneration conditions involved the coupling of 3 with pyrimidone 7 to produce the sensitive chloropyrimidine intermediate 8, which resulted in the formation of several impurities (Scheme 5). We reasoned that the use of thienopyrimidine 2 as the starting material 25 would address this instability problem and ensure a highly robust and scalable process. To prove this rationale, we subjected 3 and thienopyrimidine 2 to the amide coupling conditions of the first-generation endgame process (Scheme 10).…”