US 12,344,615 B2
Substituted pyridines as ion channel modulators
Andrew Mark Griffin, L'lle Bizard (CA); Brian Edward Marron, Ada, MI (US); Gabriel Martinez Botella, Wayland, MA (US); and Kiran Reddy, Boston, MA (US)
Assigned to Praxis Precision Medicines, Inc., Boston, MA (US)
Filed by PRAXIS PRECISION MEDICINES, INC., Boston, MA (US)
Filed on Oct. 18, 2022, as Appl. No. 17/968,465.
Application 17/968,465 is a continuation of application No. 16/887,906, filed on May 29, 2020, granted, now 11,505,554.
Claims priority of provisional application 62/855,298, filed on May 31, 2019.
Prior Publication US 2023/0286984 A1, Sep. 14, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 213/64 (2006.01); C07D 487/04 (2006.01)
CPC C07D 487/04 (2013.01) 12 Claims
 
1. A method for modulating a voltage gated sodium ion channel current in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound having Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
(i) X1 is N; and
X2 is CRd; or
(ii) X1 is CRd; and
X2 is N;
R1 is CR2R3R4, monocyclic C3-6 cycloalkyl, or monocyclic 4- to 7-membered heterocyclyl, wherein the C3-6 cycloalkyl or 4- to 7-membered heterocyclyl is optionally substituted with one or more independently selected Ra substituents;
R2 is C1-4 haloalkyl or monocyclic C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with one or more independently selected Rb substituents;
R3 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl;
R4 is hydrogen, C1-4 alkyl, or C1-4 haloalkyl;
R5 is halo;
R6 is C1-4 haloalkyl or monocyclic C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted with one or more independently selected Re substituents;
each Ra is independently halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, or OC1-4 haloalkyl;
each Rb is independently halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, or OC1-4 haloalkyl;
each Rc is independently halo, C1-4 alkyl, C1-4 haloalkyl, OC1-4 alkyl, or OC1-4 haloalkyl;
Rd is hydrogen, halo, or C1-4 alkyl; and
t is 0, 1, or 2;
with the provisos that:
(1) when R3 and R4 are each independently hydrogen, then R6 is not CF2Cl, cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, or difluorocyclobutyl;
(2) when R6 is CHF2 or CF3, then R1 is not difluorocyclobutyl;
(3) when R6 is CHF2 or CF3 and R3 and R4 are each independently hydrogen, then R2 is not CF3;
(4) when R6 is CHF2 or CF3, one of R3 or R4 is hydrogen, X1 is N, and X2 is CH, then R2 is not CF3; and
(5) when R6 is CF3, one of R3 or R4 is hydrogen, X1 is CH, and X2 is N, then R2 is not CF3.