US 12,084,414 B2
Therapeutic compounds and compositions
Robert A. Chrusciel, Portage, MI (US); Robert C. Gadwood, Portage, MI (US); Neil J. Hayward, Westborough, MA (US); Michael J. Melnick, Portage, MI (US); Manuel A. Navia, Lexington, MA (US); Toni J. Poel, Plainwell, MI (US); Frans L. Stassen, Cambridge, MA (US); and Catherine A. Stewart, Wayland, MI (US)
Assigned to eXIthera Pharmaceuticals, Inc., Westborough, MA (US)
Filed by eXIthera Pharmaceuticals, Inc., Westborough, MA (US)
Filed on Oct. 20, 2021, as Appl. No. 17/506,276.
Application 17/506,276 is a continuation of application No. 16/287,222, filed on Feb. 27, 2019, granted, now 11,198,673.
Application 16/287,222 is a continuation of application No. 15/950,545, filed on Apr. 11, 2018, granted, now 10,259,785, issued on Apr. 16, 2019.
Application 15/950,545 is a continuation of application No. 15/290,565, filed on Oct. 11, 2016, granted, now 9,994,521, issued on Jun. 12, 2018.
Application 15/290,565 is a continuation of application No. 14/614,169, filed on Feb. 4, 2015, granted, now 9,499,532, issued on Nov. 22, 2016.
Claims priority of provisional application 61/937,031, filed on Feb. 7, 2014.
Prior Publication US 2022/0281813 A1, Sep. 8, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 205/08 (2006.01); C07D 401/06 (2006.01); C07D 401/14 (2006.01); C07D 403/06 (2006.01); C07D 405/14 (2006.01); C07D 409/06 (2006.01); C07D 417/06 (2006.01); C07D 417/14 (2006.01)
CPC C07D 205/08 (2013.01) [C07D 401/06 (2013.01); C07D 401/14 (2013.01); C07D 403/06 (2013.01); C07D 405/14 (2013.01); C07D 409/06 (2013.01); C07D 417/06 (2013.01); C07D 417/14 (2013.01)] 13 Claims
 
1. A method of treating a subject in need thereof to maintain an extracorporeal blood circuit, the method comprising contacting the blood of the subject with:
a) a compound of Formula (II):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
R1 is H or —C1-6 alkyl;
R2 is H, —C1-6 alkyl, —CO2R5, —C(O)NR9R10, —CN, —CHN(OR5) or a heteroaryl;
R3 is H or —C1-6 alkyl;
A is a bond, C1-6 alkylene, C2-6 alkenylene or C2-6 alkynylene;
R4 is cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is substituted with 0-3 occurrences of —NH2 or R6;
each R5 is independently H, —C1-6 alkyl, aralkyl, or aryl substituted with 0-3 occurrences of —NH2 or R6;
X is —C(O)O—, —OC(O)—, —C(O)S(O)2—, —S(O)2C(O)—, —C(O)N(R5)— or —N(R5)C(O)—;
Y is cycloalkyl, heteroaryl, or heterocyclyl, each of which is substituted with 0-3 occurrences of —NH2 or R6; or substituted —C1-6 alkyl or phenyl substituted with 1-2 occurrences of R6; R7 is H, —C1-6 alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is substituted with 0-3 occurrences of —NH2 or R6;
wherein when R6 is a substituent for any of R4, R5, or R7, then each R6 is independently halo, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, —NR9R10, —NHR10, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —C(NR8)(N(R8)2), —SOqR11, —SO2NR9R10, —NHC(O)OR11, —NHC(O)R11, aryl, heteroaryl, aralkyl, cycloalkyl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; or
two R6 groups taken together with the atoms to which they are attached form a 5-7-membered ring; and
when R6 is a substituent for Y, each R6 is independently halo, haloalkoxy; or
two R6 groups taken together with the atoms to which they are attached form:

OG Complex Work Unit Chemistry
each R8 is independently H, —C1-6 alkyl, —C(O)R5, —C(O)OR5, aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;
each of R9 and R10 is independently —C1-6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or
R9 and R10 together form an optionally substituted 5-7-membered ring;
each R11 is independently H, —C1-10 alkyl, aralkyl, or aryl;
q is an integer from 0 to 2; and
n is an integer from 0 to 2; and
b) an additional anticoagulant agent.