Ripretinib

Uses

Ripretinib is used in the treatment of gastrointestinal stromal tumors (GISTs).

brand name

Qinlock

General Description

Class: receptor tyrosine kinase; Treatment: GIST; Other name: DCC-2618; Elimination half-life = 15 h; Protein binding = 98.8%

Biological Activity

Ripretinib is a highly effective inhibitor of both wild-type KIT and PDGFRA, with IC50 values around 3 nM. It also targets a wide range of KIT and PDGFRA mutants in GIST. Additionally, it inhibits various tumor-driving kinases such as PDGFRβ, TIE2, VEGFR2, and BRAF.

Synthesis

The diethyl ester 297 was reacted with triethyl orthoformate and acetic anhydride by heating. Subsequent addition of aqueous ammonia afforded pyridine 298. Pyridine 298 was treated neat with phosphorus oxychloride at reflux to afford dichloride 299 in 90% yield. The 4-chloro group of pyridine 299 was selectively replaced by ethylamine in cooled acetonitrile to afford the product. Oxidation state adjustment using lithium aluminum hydride followed by MnO2 afforded 4-aminopyridine 300. Starting from acid 301, a three-step reaction process involving nitration, esterification, and reduction provided ester 302 directly. Ester 302 reacted with intermediate 300 in DMA (N,N-dimethylacetamide) with the aid of KF on alumina to form naphthyridinone ring system 303 via Knoevenagel cyclization. Methylamine groups were installed on naphthyridinone ring system 303. Reaction with phenylisocyanate to form urea completed the preparation of ripretinib.

target

Primary targets: PDGFRA, KIT