Preparation of aminopyrazine compounds useful as inhibitors of ATR kinase.

Abstract

The invention relates to aminopyrazine compds. of formula I and pharmaceutically acceptable salts thereof useful as inhibitors of ATR protein kinase. Compds. of formula I wherein ring D is isoxazolyl and oxadiazolyl; ring A is 5- to 6-membered monocyclic aryl and heteroaryl; J is halo and C1-6 alkyl, where up to 2 methylene units are replaced with O; J1 is halo and (X)qY; X is (un)substituted C1-10 alkyl wherein up to 2 methylene units are replaced with NR, O and S; Y is H, C1-4 alkyl and 3- to 6-membered (un)satd. cycloaliph. and (un)substituted heterocyclyl; J and J1 together form (un)substituted 5- to 7-membered heterocyclyl; n and q are independently 0 and 1; J2 is H and C1-6 alkyl; J3 is H and C1-6 alkyl; J2 and J3 together form (un)substituted 3- to 7-membered monocyclic ring; J4 is CN, OH, etc.; J5 is H and F; and pharmaceutically acceptable salts thereof, are claimed. Example compd. II was prepd. by Boc-deprotection of di-tert-Bu (4-[4-[5-amino-6-[3-(2-fluorophenyl)isoxazol-5-yl]pyrazin-2-yl]-2-pyridyl]piperidine-4-carbonitrile)carbamate. All the invention compds. were evaluated for their ATR kinase inhibitory activity. From the assay, it was detd. that example compd. II exhibited Ki value ranged from > 5 nM to ≤ 1 nM. [on SciFinder(R)]