US 11,896,591 B2
Compositions and methods for preparing and using mitochondrial uncouplers
Kyle Hoehn, Charlottesville, VA (US); Webster L. Santos, Blacksburg, VA (US); Elizabeth S. Childress, Christiansburg, VA (US); Yumin Dai, Blacksburg, VA (US); Jacob Murray, Blacksburg, VA (US); and Jose Santiago-Rivera, Blacksburg, VA (US)
Assigned to UNIVERSITY OF VIRGINIA PATENT FOUNDATION, Charlottesville, VA (US)
Appl. No. 16/615,567
Filed by UNIVERSITY OF VIRGINIA PATENT FOUNDATION, Charlottesville, VA (US); VIRGINIA TECH INTELLECTUAL PROPERTIES, INC., Blacksburg, VA (US); and NEWSOUTH INNOVATIONS PTY LIMITED, Sydney (AU)
PCT Filed May 22, 2018, PCT No. PCT/US2018/033901
§ 371(c)(1), (2) Date Nov. 21, 2019,
PCT Pub. No. WO2018/217757, PCT Pub. Date Nov. 29, 2018.
Claims priority of provisional application 62/509,249, filed on May 22, 2017.
Prior Publication US 2020/0323846 A1, Oct. 15, 2020
Int. Cl. A61K 31/4985 (2006.01); C07D 498/04 (2006.01); C07D 487/04 (2006.01); C07D 241/20 (2006.01); A61P 3/04 (2006.01); A61K 31/4965 (2006.01)
CPC A61K 31/4985 (2013.01) [A61K 31/4965 (2013.01); A61P 3/04 (2018.01); C07D 241/20 (2013.01); C07D 487/04 (2013.01); C07D 498/04 (2013.01)] 11 Claims
 
1. A compound or pharmaceutically acceptable salt thereof, wherein the compound is
N5-(2-fluorophenyl)-N6-(pyridin-2-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4b);
N5-(2-fluorophenyl)-N6-(3-fluorophenyl)-[1,2,]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4c);
N5-(2,3-difluorophenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4e);
N5-(2,4-difluorophenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4f);
N5-(2-fluorophenyl)-N6-(o-tolyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4g);
N5-(2-fluorophenyl)-N6-(m-tolyl)[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4h);
N5-(2-fluorophenyl)-N6-(3-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4k);
N5-(2-fluorophenyl)-N6-(4-methoxyphenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4l);
N5-(2-ethoxyphenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4m);
N5-(3-ethoxyphenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4n);
N5-(4-ethoxyphenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4o);
3-((6-(2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenol (4p);
N5-(2-fluorophenyl)-N6-(2-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4q);
N5-(2-fluorophenyl)-N6-(3-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4r);
N5-(2-fluorophenyl)-N6-(4-(trifluoromethoxy)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4s);
2,2,2-Trifluoro-N-(4-((6-(2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenyl)acetamide (4t);
N5-(2-fluorophenyl)-N6-(2-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4u);
N5-(2-fluorophenyl)-N6-(3-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4v);
N5-(2-fluorophenyl)-N6-(4-(trifluoromethyl)phenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4w);
Methyl 4-((6-((2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)benzoate (4y);
4-Fluoro-3-((6-((2-fluorophenyl)amino)-[1,2,5]oxadiazolo[3,4-b]pyrazin-5-yl)amino)phenol (4z);
N5-(3,5-bis(trifluoromethyl)phenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4aa);
N5-(2-fluoro-3-(trifluoromethyl)phenyl)-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (4bb);
N5-(2-fluorophenyl)-N6-methyl[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7a);
N5-ethyl-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7b);
N5-(2-fluorophenyl)-N6-propyl[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7c);
N5-(2-fluorophenyl)-N6-(3,3,3-trifluoropropyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7d);
N5-(2-fluorophenyl)-N6-(1-methylpiperidin-4-yl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7e); or
N5-cyclohexyl-N6-(2-fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (7f).