US 11,718,589 B2
Compositions and methods of modulating short-chain dehydrogenase
Sanford Markowitz, Cleveland, OH (US); Yiyuan Yuan, Cleveland, OH (US); Yongyou Zhang, Cleveland, OH (US); Joseph Ready, Carrollton, TX (US); and Bin Hu, Shanghai (CN)
Assigned to Case Western Reserve University, Cleveland, OH (US); and Board of Regents of the University of Texas System, Austin, TX (US)
Appl. No. 16/484,045
Filed by CASE WESTERN RESERVE UNIVERSITY, Cleveland, OH (US); and Board of Regents of the University of Texas System, Austin, TX (US)
PCT Filed Feb. 6, 2018, PCT No. PCT/US2018/017044
§ 371(c)(1), (2) Date Aug. 6, 2019,
PCT Pub. No. WO2018/145080, PCT Pub. Date Aug. 9, 2018.
Claims priority of provisional application 62/455,399, filed on Feb. 6, 2017.
Claims priority of provisional application 62/510,589, filed on May 24, 2017.
Prior Publication US 2020/0095206 A1, Mar. 26, 2020
Int. Cl. C07D 235/18 (2006.01); C07D 239/74 (2006.01); C07D 241/42 (2006.01); C12N 9/04 (2006.01); A61K 45/06 (2006.01); A61K 31/4164 (2006.01)
CPC C07D 235/18 (2013.01) [C07D 239/74 (2013.01); C07D 241/42 (2013.01); C12N 9/0006 (2013.01); A61K 31/4164 (2013.01); A61K 45/06 (2013.01)] 7 Claims
 
1. A method of inhibiting the activity of 15-PGDH enzyme, the method comprising:
administering to the enzyme a compound having the structure of formula (II), or a pharmaceutically acceptable salt thereof;

OG Complex Work Unit Chemistry
wherein
X3 is CR8, the compound forming a polycyclic heteroaryl with 10 ring atoms;
X4 is N, NH, or CR7;
X5 is N, C═O, or CR16, wherein:
X5 is N if X4 is CR7;
X4 is NH if X5 is C═O;
X5 is CR16 if X4 is N and X3 is CR8;
R9, R10, and R16 are the same or different and are independently selected from the group consisting of hydrogen, oxygen, substituted or unsubstituted C1-C24 alkyl, C2-C24 alkenyl, C2-C24 alkynyl, C5-C20 aryl, heterocycloalkenyl containing from 5-7 ring atoms, heteroaryl or heterocyclyl containing from 5-14 ring atoms, C6-C24 alkaryl, C6-C24 aralkyl, halo, silyl, hydroxyl, sulfhydryl, C1-C24 alkoxy, C2-C24 alkenyloxy, C2-C24 alkynyloxy, C5-C20 aryloxy, acyl, acyloxy, C2-C24 alkoxycarbonyl, C6-C20 aryloxycarbonyl, C2-C24 alkylcarbonato, C6-C20 arylcarbonato, carboxy, carboxylato, carbamoyl, C1-C24 alkyl-carbamoyl, arylcarbamoyl, thiocarbamoyl, carbamido, cyano, isocyano, cyanato, isocyanato, isothiocyanato, azido, formyl, thioformyl, amino, C1-C24 alkyl amino, C5-C20 aryl amino, C2-C24 alkylamido, C6-C20 arylamido, sulfanamido, imino, alkylimino, arylimino, nitro, nitroso, sulfo, sulfonato, C1-C24 alkylsulfanyl, arylsulfanyl, C1-C24 alkylsulfinyl, C5-C20 arylsulfinyl, C1-C24 alkylsulfonyl, C5-C20 arylsulfonyl, sulfonamide, phosphono, phosphonato, phosphinato, phospho, phosphino, polyalkyl ethers, phosphates, phosphate esters, and combinations thereof;
R7 and R8 are same or different and are each independently selected from the group consisting of H, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, and a substituted or unsubstituted heterocyclyl, and at least one of R7 or R8 is not H; and
wherein the compound of formula (II) is not

OG Complex Work Unit Chemistry