US 12,226,400 B2
Neuroprotective disruption of Kv2.1/syntaxin interaction by small molecules
Elias Aizenman, Pittsburgh, PA (US); and Carlos Jaime Camacho, Pittsburgh, PA (US)
Assigned to UNIVERSITY OF PITTSBURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION, Pittsburgh, PA (US)
Appl. No. 17/264,982
Filed by UNIVERSITY OF PITTSBURGH-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION, Pittsburgh, PA (US)
PCT Filed Jul. 31, 2019, PCT No. PCT/US2019/044393
§ 371(c)(1), (2) Date Feb. 1, 2021,
PCT Pub. No. WO2020/028515, PCT Pub. Date Feb. 6, 2020.
Claims priority of provisional application 62/716,734, filed on Aug. 9, 2018.
Claims priority of provisional application 62/712,514, filed on Jul. 31, 2018.
Prior Publication US 2021/0322383 A1, Oct. 21, 2021
Int. Cl. A61K 31/4155 (2006.01); A61K 31/4178 (2006.01); A61K 31/428 (2006.01); A61K 31/4409 (2006.01); A61K 31/506 (2006.01); A61K 31/53 (2006.01); A61P 25/28 (2006.01)
CPC A61K 31/4155 (2013.01) [A61K 31/4178 (2013.01); A61K 31/428 (2013.01); A61K 31/4409 (2013.01); A61K 31/506 (2013.01); A61K 31/53 (2013.01); A61P 25/28 (2018.01)] 17 Claims
 
1. A method of treating a neurological condition in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
Z is O;
R1 and R2 are each hydrogen;
Q1 and Q2 are each absent; or Q1 is absent and Q2 is a group having the formula —(CRq2Rq2′)—, wherein Rq2 is hydrogen and Rq2′ is hydrogen, OH, or C1-6alkyl;
L1 is —(CR4R4′)n-, wherein:
n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
R4 is in each case independently hydrogen or C1-8alkyl;
R4′ is in each case independently hydrogen or C1-8alkyl;
Ar1 has the formula:

OG Complex Work Unit Chemistry
wherein,
R5 is F, Cl, Br, R5a, or OR5a, wherein R5a is hydrogen or C1-8alkyl;
R6 is F, Cl, Br, R7a, or OR6a, wherein R6a is hydrogen or C1-8alkyl;
R7 is F, Cl, Br, R7a, or OR7a, wherein R7a is hydrogen or C1-8alkyl;
R8 is F, Cl, Br, R8a, or OR8a, wherein R8a is hydrogen or C1-8alkyl;
R9 is F, Cl, Br, R9a, or OR9a, wherein R9a is hydrogen or C1-8alkyl;
wherein any two or more of R5, R6, R7, R8, and R9 may together form a ring;
L2 is absent, a group having the formula —(CR10*R10′)n′-, or —(CH2)p-Cy-(CH2)o—,
wherein:
p is 0, 1, 2, 3, 4, 5, or 6;
o is 0, 1, 2, 3, 4, 5, or 6;
Cy is an optionally substituted aryl group; an optionally substituted C1-8heteroaryl group; an optionally substituted C3-8cycloalkyl group; or an optionally substituted C1-8heterocyclyl group;
n′ is from 0-8;
R10* is in each case independently hydrogen or C1-8alkyl;
R10′ is in each case independently hydrogen or C1-8alkyl; and
Ar2 has the formula:

OG Complex Work Unit Chemistry
wherein
R10 is F, Cl, Br, or R10a, wherein R10a is in each case independently selected from hydrogen, C1-13alkyl, C1-8heteroaryl, or C1-8heterocyclyl;
R11 is F, Cl, Br, or R11a, wherein R11a is in each case independently selected from hydrogen, C1-13alkyl, C1-8heteroaryl, or C1-8heterocyclyl;
R12 is F, Cl, Br, or R12a wherein R12a is in each case independently selected from hydrogen, C1-13alkyl, C1-8heteroaryl, or C1-8heterocyclyl;
R13 is F, Cl, Br, or R13a, wherein R13a is in each case independently selected from hydrogen, C1-13alkyl, C1-8heteroaryl, or C1-8heterocyclyl;
R14 is F, Cl, Br, or R14a, wherein R14a is in each case independently selected from hydrogen, C1-13alkyl, C1-8heteroaryl, or C1-8heterocyclyl;
wherein any two or more of R10, R11, R12, R13, and R14 may together form a ring, wherein one of R10, R11, R12, R13, or R14 is a C1-8heteroaryl having the formula:

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry