US 11,925,637 B2
Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators and their use
Thomas E. Barta, Carrboro, NC (US); Jonathan William Bourne, Fairport, NY (US); Kyle D. Monroe, Pittsford, NY (US); Michael M. Muehlemann, Liverpool, NY (US); Anjali Pandey, Fremont, CA (US); and Simeon Bowers, Oakland, CA (US)
Assigned to SRX Cardio, LLC, Pittsford, NY (US)
Filed by SRX Cardio, LLC, Pittsford, NY (US)
Filed on Mar. 30, 2021, as Appl. No. 17/217,848.
Application 17/217,848 is a continuation of application No. 16/739,544, filed on Jan. 10, 2020, granted, now 10,980,801.
Application 16/739,544 is a continuation of application No. 15/753,790, granted, now 10,568,882, previously published as PCT/US2016/047816, filed on Aug. 19, 2016.
Claims priority of provisional application 62/298,890, filed on Feb. 23, 2016.
Claims priority of provisional application 62/208,072, filed on Aug. 21, 2015.
Prior Publication US 2022/0047582 A1, Feb. 17, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/495 (2006.01); A61K 31/4409 (2006.01); A61K 45/06 (2006.01); A61P 3/06 (2006.01); C07C 237/20 (2006.01); C07D 213/64 (2006.01)
CPC A61K 31/495 (2013.01) [A61K 31/4409 (2013.01); A61K 45/06 (2013.01); A61P 3/06 (2018.01); C07C 237/20 (2013.01); C07D 213/64 (2013.01); A61K 2300/00 (2013.01); C07B 2200/07 (2013.01)] 17 Claims
 
1. A method of inhibiting PCSK9 in a subject with a metabolic disease, wherein the method comprises administering to the subject a compound of formula I:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
A is —SO2— and B is —NH—; or
A is —O— or —CH2— and B is —CH2— or absent;
ring C is a 5 or 6 membered heteroaryl or heterocyclic ring, or a 6 membered aryl ring;
E1, E2, and E3 are independently selected from C, CH, and N, wherein one of E1, E2, and E3 may be absent;
R1 and R2 are independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH2, —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo; or
R1 and R2 with the atoms attached thereto form a 5-6 membered fused aryl, heteroaryl, carbocyclic or heterocyclic ring D containing 0-3 heteroatoms, where ring D may further be substituted at a position two atoms away from the juncture with ring C;
R3 is independently selected from the group consisting of H, lower alkyl, hydroxy, amino, aminoalkyl, hydroxyalkyl, haloalkyl, carboxy, —CONH2, —CON-alkyl, nitrile, —S-alkyl, —O-alkyl, acyl, and oxo;
R4 is selected from the group consisting of H, OH, halogen, and lower alkyl;
each R5 is hydrogen or taken together are oxo;
Y is selected from the group consisting of N and CH; and
X1, X2, X3, and X4 are independently selected from the group consisting of CH, C-R4, and N.