US 12,404,263 B2
ASK1 inhibiting agents
Felix Gonzalez Lopez de Turiso, Cambridge, MA (US); Michael Dechantsreiter, Allston, MA (US); Zhili Xin, Cambridge, MA (US); John H. Jones, Framingham, MA (US); and Martin Himmelbauer, Cambridge, MA (US)
Assigned to BIOGEN MA INC., Cambridge, MA (US)
Filed by BIOGEN MA INC., Cambridge, MA (US)
Filed on Oct. 5, 2023, as Appl. No. 18/377,125.
Application 18/377,125 is a division of application No. 17/253,269, granted, now 11,814,362, previously published as PCT/US2019/039156, filed on Jun. 26, 2019.
Claims priority of provisional application 62/690,674, filed on Jun. 27, 2018.
Prior Publication US 2024/0109867 A1, Apr. 4, 2024
Int. Cl. A61K 31/4427 (2006.01); C07D 401/14 (2006.01)
CPC C07D 401/14 (2013.01) [A61K 31/4427 (2013.01)] 16 Claims
 
1. A method for treating a disorder responsive to inhibition of apoptosis signal-regulating kinase 1 (ASK1) in a subject comprising administering to the subject an effective amount of a compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
X is CR4 or N;
n is 1 or 2;
R1 in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, halo, —CN, —C(O)R1a, —C(O)OR1a, —C(O)N(R1a)2, —N(R1a)2, —N(R1a)C(O)R1a, —N(R1a)C(O)OR1a, —N(R1a)C(O)N(R1a)2, —N(R1a)S(O)2R1a, —OR1a, —OC(O)R1a, —OC(O)N(R1a)2, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)N(R1a)2, and —S(O)2N(R1a)2, wherein said C1-6alkyl, C2-6alkenyl, and C2-6alkynyl are optionally substituted with one or more R10;
R1a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more R10;
R10 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, —CN, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, —N(R10a)S(O)2R10a, —OR10a, —OC(O)R10a, —OC(O)N(R10a)2, —SR10a, —S(O)R10a, —S(O)2R10a, —S(O)N(R10a)2, and —S(O)2N(R10a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more substituents independently selected from halo, —CN, —C(O)R10a, —C(O)OR10a, —C(O)N(R10a)2, —N(R10a)2, —N(R10a)C(O)R10a, —N(R10a)C(O)OR10a, —N(R10a)C(O)N(R10a)2, —N(R10a)S(O)2R10a, —OR10a, —OC(O)R10a, —OC(O)N(R10a)2, —SR10a, —S(O)R10a, —S(O)2R10a, —S(O)N(R10a)2, and —S(O)2N(R10a)2;
R10a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl;
R2 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally and independently substituted with one or more R20;
R20 in each occurrence is independently selected from C1-6alkyl, halo and —OR20a;
R20a is H or C1-4alkyl;
R3 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R30;
R30 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, —CN, —C(O)R30a, —C(O)OR30a, —C(O)N(R30a)2, —N(R30a)2, —N(R30a)C(O)R30a, —N(R30a)C(O)OR30a, —N(R30a)C(O)N(R30a)2, —N(R30a)S(O)2R30a, —OR30a, —OC(O)R30a, —OC(O)N(R30a)2, —SR30a, —S(O)R30a, —S(O)2R30a, —S(O)N(R30a)2, and —S(O)2N(R30a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more substituents independently selected from halo, —CN, —C(O)R30a, —C(O)OR30a, —C(O)N(R30a)2, —N(R30a)2, —N(R30a)C(O)R30a, —N(R30a)C(O)OR30a, —N(R30a)C(O)N(R30a)2, —N(R30a)S(O)2R30a, —OR30a, —OC(O)R30a, —OC(O)N(R30a)2, —SR30a, —S(O)R30a, —S(O)2R30a, —S(O)N(R30a)2, and —S(O)2N(R30a)2;
R30a in each occurrence is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said carbocyclyl, and heterocyclyl are each optionally substituted with with one or more substituents independently selected from C1-4alkyl and halo;
R4 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, and —CN, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl, are optionally substituted with one or more R40;
R40 in each occurrence is independently selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, heterocyclyl, halo, —CN, —C(O)R40a, —C(O)OR40a, —C(O)N(R40a)2, —N(R40a)2, —N(R40a)C(O)R40a, —N(R40a)C(O)OR40a, —N(R40a)C(O)N(R40a)2, —N(R40a)S(O)2R40a, —OR40a, —OC(O)R40a, —OC(O)N(R40a)2, —SR40a, —S(O)R40a, —S(O)2R40a, —S(O)N(R40a)2, and —S(O)2N(R40a)2, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, carbocyclyl, and heterocyclyl in each occurrence are optionally and independently substituted with one or more substituents independently selected from halo, —CN, —C(O)R40a, —C(O)OR40a, —C(O)N(R40a)2, —N(R40a)2, —N(R40a)C(O)R40a, —N(R40a)C(O)OR40a, —N(R40a)C(O)N(R40a)2, —N(R40a)S(O)2R40a, —OR40a, —OC(O)R40a, —OC(O)N(R40a)2, —SR40a, —S(O)R40a, —S(O)2R40a, —S(O)N(R40a)2, and —S(O)2N(R40a) 2; and
R40a in each occurrence is independently selected from H and C1-4alkyl; and
wherein the disorder is amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, or Huntington's disease.