By: Sidrauski, Carmela; Pliuschev, Marina; Frost, Jennifer M.; Black, Lawrence A.; Xu, Xiangdong; Sweis, Ramzi Farah; Shi, Lei; Zhang,
Qinwei I.; Tong, Yunsong; Hutchins, Charles W.; et al

World Intellectual Property Organization, WO2017193063 A1 2017-11-09 |

Provided herein are compounds of formula I, compositions, and methods useful for modulating the integrated stress response (I S
R) and for treating related diseases; disorders and condit ions. Compounds of formula I wherein A and W are indepen dently (un)
substituted Ph and (un)substituted 5- to 6-membered heteroaryl; D is (un)substituted bridge monocyclic cycloalkyl, (un)substituted
bridged monocyclic heterocyclyl, and (un)substituted cubanyl; L is (un)substituted C alkyl, (un)substituted C alkenyl, (un)substi
tuted 2- to 7-membered heteroalkylene; Q is absent, CO and SO ; R and R are independently H, C alkyl, C alkoxy-C alkyl,
C hydroxyalkyl and C silyloxyalkyl; and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoi somers
thereof, are claimed. Example compound II was prepared by hydrolysis to bicyclo[2.2.2]octane-1,4-diamine hydrochloride followed
by N-Boc protection; the resulting tert-Bu (4-aminobicyclo[2.2.2]octan-1-yl)carbamate underwent N-acylation with 2-(4-chloro-3-
fluorophenoxy)acetic acid to give tert-Bu (4-(2-(4-chloro-3-fluorophenoxy)acetamido)bicyclo[2.2.2]octan-1-yl)carbamate, which
underwent deprotection to give N-(4-aminobicyclo[2.2.2]octan-1-yl)-2-(4-chloro-3-fluorophenoxy)acetamide hydrochloride, which
underwent N-arylation with 2-bromo-5-trifluoromethylpyrazine to give compound II. The invention compounds were evaluated for
their modulatory activity of the ISR pathway. From the assay, it was determined that compound II exhibited EC value of less than
50 nM in the ATF4 assay.