US 12,129,242 B2
Substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors
Yufeng Jane Tseng, Stafford, VA (US); Yu-Li Liu, Miaoli County (TW); Chung-Ming Sun, Hsinchu (TW); Wen-Sung Lai, Taipei (TW); Chih-Min Liu, Taipei (TW); and Hai-Gwo Hwu, Taipei (TW)
Assigned to Yufeng Jane Tseng, Stafford, VA (US); NATIONAL TAIWAN UNIVERSITY, Taipei (TW); NATIONAL YANG MING CHIAO TUNG UNIVERSITY, Hsinchu (TW); and NATIONAL HEALTH RESEARCH INSTITUTES, Miaoli County (TW)
Filed by NATIONAL TAIWAN UNIVERSITY, Taipei (TW); NATIONAL YANG MING CHIAO TUNG UNIVERSITY, Hsinchu (TW); NATIONAL HEALTH RESEARCH INSTITUTES, Miaoli County (TW); and Yufeng Jane Tseng, Stafford, VA (US)
Filed on Mar. 30, 2022, as Appl. No. 17/709,242.
Application 17/709,242 is a continuation of application No. 16/332,628, granted, now 11,370,775, previously published as PCT/US2017/051610, filed on Sep. 14, 2017.
Claims priority of provisional application 62/394,479, filed on Sep. 14, 2016.
Prior Publication US 2022/0306605 A1, Sep. 29, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 401/12 (2006.01); A61P 25/18 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 409/14 (2006.01); C07D 413/14 (2006.01)
CPC C07D 401/12 (2013.01) [A61P 25/18 (2018.01); C07D 401/14 (2013.01); C07D 405/14 (2013.01); C07D 409/14 (2013.01); C07D 413/14 (2013.01)] 19 Claims
 
1. A method of inhibiting a DAAO, comprising contacting a cell with a compound of formula (I),

OG Complex Work Unit Chemistry
wherein n is 0 or 1,
X is —S—, —S(═O)— or —NRn—; wherein
Rn is H or

OG Complex Work Unit Chemistry
A is —CH, —CRc or N;
Ra is —C(═O)ORa1, —ORa2, —O—C(═O)Ra3 or —O—C(═O)-T-ORa4; wherein
Ra1 is H or linear or branched C1-15alkyl;
Ra2 is H, linear or branched C1-15alkyl, phosphonate, diarylphosphonate or an O-protecting group;
Ra3 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, -T-C3-10cycloalkyl, -T-NHRa3p, -T-C3-10cycloalkenyl, -T-C6-10aryl, -T-C5-10heteroaryl, -T-NH—C(═O)—O—C1-10alkyl, -T-adamantyl or —C1-3alkylene-C6-10aryl where the alkylene is substituted with -T-NHRa3p;
Ra3p is H or an N-protecting group;
Rb is H, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, C1-3alkoxy-C1-15alkyl-, -T′-C3-10cycloalkyl, -T′-C3-10cycloalkenyl, -T′-C6-10 aryl or -T′-C5-10heteroaryl;
Rc each is independently linear or branched C1-15alkyl, linear or branched C1-15alkoxyl, unprotected or protected hydroxyl group, or —C1-10alkylene-Y—C6-10heteroaryl wherein —Y— is —CH2—, —NH—, —O— or —S—;
symbol * represents the bonding position;
m is an integer from 0 to 4;
-T- is absent, C1-3alkylene or C2-3alkenylene;
-T′- is C1-3alkylene or C2-3alkenylene; and
wherein the heteroaryl contains at least one heteroatom, each heteroatom being independently S, N or O;
wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or substituted with at least one substituent;
wherein the substituent is each independently a halogen, a protecting group, protected or unprotected amino group, nitro, nitroso, linear or branched C1-15 alkyl, or linear or branched C1-15 alkoxy or C3-10cycloalkyl; and
when Rb is H, the tautomers are included,
with the proviso that
when X is —S— or —S(═O)—, Ra is —ORa2 and Ra2 is H or linear or branched C1-15alkyl, then A is —CH or —CRc;
when X is —S— or —S(═O)— and Ra is —C(═O)ORa1, Rb is linear or branched C6-15alkyl, linear or branched C6-15alkenyl, C1-3alkoxy-C1-15alkyl-, -T′-C3-10cycloalkyl, -T′-C3-10cycloalkenyl, -T′-C6-10 aryl or -T′-C5-10heteroaryl;
or a pharmaceutically acceptable salt thereof.