Preparation of quinoline-substituted pyridazine compounds or their salts as EGFR inhibitors, antitumor agents, and preventive and therapeutic methods for cancer.

Abstract

The quinoline-substituted pyridazine compds. or their salts are represented by formula I (A = II, III, IV; B = NR1COR2, C≡CR6; R1 = H, C1-6 alkyl; R2 = CR3:CR4R5; R3-R5 = H, halo, C1-6 alkyl, C6-12 aryl, etc.; R6 = H, C1-6 alkyl; R7, R8 = H, C1-6 alkyl; m = 0, 1; n = 1, 2; R9 = H, C1-6 alkyl; R10 = C1-6 alkyl). Thus, coupling (S)-tert-Bu (1-hydroxybut-3-en-2-yl)carbamate with 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine, aminating with ammonia, cross-coupling with 3-quinolineboronic acid, brominating with NBS, intramol. cyclizing in the presence of Pd catalyst, removing tert-butoxycarbonyl group with hydrochloric acid, and amidating with acryloyl chloride gave (S)-N-[4-amino-6-methylene-5-(quinolin-3-yl)-7,8-dihydro-6H-pyrimido[5,4-b]pyrrolidin-7-yl]acrylamide with epidermal growth factor receptor (T790M/L858R) inhibitory activity (IC50) <0.50 nM. [on SciFinder(R)]