US 12,351,574 B2
Selective ligands for modulation of GIRK channels
Ganeshsingh A. Thakur, Cambridge, MA (US); Diomedes E. Logothetis, Brookline, MA (US); Lucas Cantwell, Plymouth, MA (US); Yu Xu, Malden, MA (US); and Anantha Shekhar, Indianapolis, IN (US)
Assigned to Northeastern University, Boston, MA (US); and Indiana University Reearch and Technology Corporation, Bloomington, IN (US)
Filed by Northeastern University, Boston, MA (US); and Indiana University Research and Technology Corporation, Bloomington, IN (US)
Filed on Dec. 21, 2023, as Appl. No. 18/392,203.
Application 18/392,203 is a division of application No. 17/053,458, granted, now 11,952,370, previously published as PCT/US2019/036639, filed on Jun. 11, 2019.
Claims priority of provisional application 62/683,424, filed on Jun. 11, 2018.
Prior Publication US 2024/0199591 A1, Jun. 20, 2024
Int. Cl. A61P 25/22 (2006.01); A61K 31/415 (2006.01); C07D 231/40 (2006.01); C07D 401/12 (2006.01); C07D 403/12 (2006.01); C07D 405/12 (2006.01); C07D 409/12 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01)
CPC C07D 409/12 (2013.01) [A61K 31/415 (2013.01); A61P 25/22 (2018.01); C07D 231/40 (2013.01); C07D 401/12 (2013.01); C07D 403/12 (2013.01); C07D 405/12 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01)] 12 Claims
OG exemplary drawing
 
1. A method of treating a neurological disease or disorder, the method comprising administering to a subject in need thereof an effective amount of a compound having a structure according to Formula I:

OG Complex Work Unit Chemistry
wherein R1 is chosen from hydrogen, halo, methyl, halomethyl, deuteromethyl, cyclopropyl, and cyclopropylmethyl;
wherein R2 is —(CH2)—RC or —RC; RC can be piperidine, thiane, tetrahydropyran, cyclohexyl, or phenyl optionally substituted with one RD, one carbon atom of the phenyl optionally replaced with N, S, or O, wherein RD can be C1-C6 alkyl, halogen, or CF3;
wherein R3 is chosen from —RE—RG, —RF—RG, —RH, and —RI; RE is C2 alkene with trans configuration; RF is cyclopropyl or oxirane; RG is a 5 or 6 membered aromatic ring wherein one or two carbon atoms are optionally each replaced with N, S, or O, the 5 or 6 membered aromatic ring can be optionally substituted with RH; RH can be halogen, CF3, or CD3; RI is a substituted or unsubstituted ring or ring system chosen from thiophene, benzo [b]thiophene, 4,5,6,7-tetrahydrobenzo [b]thiophene, pyrimidine, isoxazole, thiazole, adamantane, benzo [d][1,3]dioxole, and isoquinoline; and wherein Rr is optionally substituted with one or more functional groups chosen from halo, and C1-C6 branched or unbranched alkyl optionally substituted with one or more halogens;
or a pharmaceutically-acceptable salt thereof,
wherein the compound activates GIRK 1/2 channels; and
wherein the neurological disease or disorder is selected from the group consisting of post-traumatic stress disorder (PTSD), epilepsy, stroke, general anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, pain, chronic pain, neuropathic pain, cancer-related pain, headache, pain related to traumatic brain injury, and inflammatory pain.