US 12,440,477 B2
Compounds for the treatment of neuromuscular disorders
Lars J. S. Knutsen, Essex (GB); Nicholas M. Kelly, Bagsværd (DK); Thomas Holm Pedersen, Risskov (DK); Martin E. Cooper, Nottingham (GB); and Andrew W. Brown, Derbyshire (GB)
Assigned to NMD PHARMA A/S, Århus N (DK)
Filed by NMD PHARMA A/S, Århus N (DK)
Filed on Dec. 14, 2018, as Appl. No. 16/221,006.
Application 16/221,006 is a continuation in part of application No. 15/842,823, filed on Dec. 14, 2017, granted, now 10,385,028.
Prior Publication US 2019/0183863 A1, Jun. 20, 2019
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 261/08 (2006.01); A61K 31/341 (2006.01); A61K 31/381 (2006.01); A61K 31/415 (2006.01); A61K 31/421 (2006.01); A61K 31/423 (2006.01); A61K 31/4245 (2006.01); A61K 31/428 (2006.01); A61K 31/433 (2006.01); A61P 21/04 (2006.01)
CPC A61K 31/423 (2013.01) [A61K 31/341 (2013.01); A61K 31/381 (2013.01); A61K 31/415 (2013.01); A61K 31/421 (2013.01); A61K 31/4245 (2013.01); A61K 31/428 (2013.01); A61K 31/433 (2013.01); A61P 21/04 (2018.01)] 24 Claims
 
1. A compound of Formula (I.3.4):

OG Complex Work Unit Chemistry
wherein:
R1 is selected from the group consisting of F, Cl, Br and I;
R2 is a 5-6 membered aromatic heterocycle or an 8-10 membered aromatic bicyclic heterocycle each of which may be optionally substituted with one or more, identical or different, substituents R6, with the proviso that when R4 is methyl, then R2 cannot be 1,2-oxazol-5-yl, with the proviso that when R4 is H, then R2cannot be 1,2-oxazol-5-yl, 1,2-oxazol-3-yl or 1,3-oxazol-4-yl, and with the proviso that when R5 is H, R4 is methyl, R1 is Cl, and n is 0, then R2 cannot be 1,2-oxazol-3-yl;
R3 is selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, CF3, CCl3, CHF2, CHCl2, CH2F, CH2Cl, OCF3, OCCl3 and isocyanide;
R4 is selected from the group consisting of H, deuterium, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;
R5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R8, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R8, phenyl optionally substituted with one or more, identical or different, substituents R9 and benzyl optionally substituted with one or more, identical or different, substituents R9;
R6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, O—C1-5 alkyl, O—C2-5 alkenyl, O—C2-5 alkynyl, O—C3-5 cycloalkyl, O—C5 cycloalkenyl, —C(═O)—C1-5 alkyl, —C(═O)—C2-5 alkenyl, —C(═O)—C2-5 alkynyl, —C(═O)—C3-5 cycloalkyl, —CH2—O—C1-3 alkyl and —CH2—S—C1-3 alkyl, and wherein C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, O—C1-5 alkyl, O—C2-5 alkenyl, O—C2-5 alkynyl, O—C3-5 cycloalkyl, O—C5 cycloalkenyl, —C(═O)—C1-5 alkyl, —C(═O)—C2-5 alkenyl, —C(═O)—C2-5 alkynyl, —C(═O)—C3-5 cycloalkyl, —CH2—O—C1-3 alkyl and —CH2—S—C1-3 alkyl may be optionally substituted with one or more halogens;
R7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, isocyanide, O—C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8, S—C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8, CH2—O—C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8 and CH2—S—C1-3 alkyl optionally substituted with one or more, identical or different, substituents R8;
R8 is independently selected from the group consisting of deuterium and F;
R9 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and
n is an integer 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, with the proviso that when R4 is H then R2 is 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl.