IP Library › Granted Patent US 12,440,477
Granted Patent B2
US 12,440,477 · App. 16/221,006 · Granted Oct 14, 2025

Compounds for the treatment of neuromuscular disorders

Inventors: Lars J. S. Knutsen (Essex, GB); Nicholas M. Kelly (Bagsværd, DK); Thomas Holm Pedersen (Risskov, DK); Martin E. Cooper (Nottingham, GB); Andrew W. Brown (Derbyshire, GB)
Assignee: NMD PHARMA A/S
A61K31/423A61K31/341A61K31/381A61K31/415A61K31/421A61K31/4245A61K31/428A61K31/433A61P21/04
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Quick Facts
Patent No.
US 12,440,477
App. No.
16/221,006
Granted
Oct 14, 2025
Kind
B2
Abstract

The present invention relates to compounds suitable for treating, ameliorating and/or preventing neuromuscular disorders, including the reversal of drug-induced neuromuscular blockade. The compounds as defined herein preferably inhibit the CIC-1 ion channel.

Claims (158)

1. A compound of Formula (I.3.4):

wherein:

R 1 is selected from the group consisting of F, Cl, Br and I;

R 2 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 R 6 , with the proviso that when R 4 is methyl, then R 2 cannot be 1,2-oxazol-5-yl, with the proviso that when R 4 is H, then R 2 cannot be 1,2-oxazol-5-yl, 1,2-oxazol-3-yl or 1,3-oxazol-4-yl, and with the proviso that when R 5 is H, R 4 is methyl, R 1 is Cl, and n is 0, then R 2 cannot be 1,2-oxazol-3-yl;

R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, CF 3 , CCl 3 , CHF 2 , CHCl 2 , CH 2 F, CH 2 Cl, OCF 3 , OCCl 3 and isocyanide;

R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;

R 5 is selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 , phenyl optionally substituted with one or more, identical or different, substituents R 9 and benzyl optionally substituted with one or more, identical or different, substituents R 9 ;

R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;

R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, isocyanide, O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , CH 2 —O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 and CH 2 —S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 ;

R 8 is independently selected from the group consisting of deuterium and F;

R 9 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 R 4 is H then R 2 is 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl.

2. The compound according to claim 1 , wherein R 1 is Cl or Br.

3. The compound according to claim 1 , wherein R 2 is a 5-membered aromatic heterocycle, wherein each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

4. The compound according to claim 1 , wherein R 2 is selected from the group consisting of 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, 1,2-thiazol-3-yl, 1,2-oxazol-3-yl, 1,2-oxazol-5-yl and 1,3-oxazol-4-yl each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

5. The compound according to claim 1 , wherein R 4 is C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 7 or C 1-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 7 .

6. The compound according to claim 1 , wherein R 4 is H or deuterium.

7. The compound according to claim 1 , wherein R 5 is hydrogen.

8. The compound according to claim 1 , wherein n is 0 or 1.

9. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

(2S)-2-[4-bromo-2-(1,2-oxazol-5-yl) phenoxy] butanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy] butanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy]-3-methylbutanoic acid;

(2S)-2-[4-bromo-2-(4-methyl-1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-chloro-6-(1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(pyridin-2-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(5-methyl-1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(5-cyclopropyl-1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[2-(1,3-benzothiazol-2-yl)-4-bromophenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(1,3-thiazol-2-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1H-imidazol-2-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1H-imidazol-4-yl) phenoxy] propanoic acid;

(2R)-2-[4-bromo-2-(1,2-oxazol-5-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-chloro-2-(1,3-dimethyl-1H-pyrazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(1H-pyrazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(thiophen-2-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(1-methyl-1H-pyrazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[2-(1,3-benzothiazol-2-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(1H-pyrazol-1-yl) phenoxy] propanoic acid;

(2S)-2-[4,5-dichloro-2-(1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-5-fluoro-2-(1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1,3-oxazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(1,2-oxazol-3-yl) phenoxy]-3-cyclopropylpropanoic acid;

(2S)-2-[4-fluoro-2-(1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2R)-2-[4-chloro-2-(1,2-oxazol-3-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-chloro-2-(4-methyl-1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(5-cyclopropyl-1,2-oxazol-3-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(1,2-oxazol-3-yl) phenoxy]-3-methylbutanoic acid;

(2S)-2-[4-chloro-2-(1,2-oxazol-3-yl) phenoxy] butanoic acid;

(25) 2 [4 chloro 2 (1,2 oxazol 3 y1) phenoxy |propanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy]-3-cyclopropylpropanoic acid;

(2S)-2-[4-chloro-2-(1,3-oxazol-2-yl) phenoxy] propanoic acid;

(2R)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-bromo-2-(2H-1,2,3-triazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl) phenoxy]-4-fluorobutanoic acid;

(2S)-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy]-4-fluorobutanoic acid;

(2R)-2-[4-chloro-5-fluoro-2-(1,2-oxazol-5-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-bromo-2-(1,3-thiazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-5-fluoro-2-(1,3-oxazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-chloro-2-(1,2-oxazol-5-yl) phenoxy]-3-methylbutanoic acid;

(2S)-2-[4-chloro-2-(1,2-oxazol-5-yl) phenoxy]-3-cyclopropylpropanoic acid;

(2R)-2-[4-chloro-2-(1,2-oxazol-5-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-chloro-2-(1,2-oxazol-5-yl) phenoxy] butanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-4-yl) phenoxy] propanoic acid;

(2R)-2-[4-chloro-5-fluoro-2-(1,2-oxazol-3-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-chloro-2-(1,3-oxazol-4-yl) phenoxy] propanoic acid;

2-[4-bromo-2-(1,2,3-thiadiazol-4-yl) phenoxy] acetic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-5-yl) phenoxy]-2-cyclopropylacetic acid;

(2S)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl) phenoxy]-2-cyclopropylacetic acid;

(2S)-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl) phenoxy]-3-cyclopropylpropanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy]-3-cyclobutylpropanoic acid;

(2S)-2-[4-bromo-5-fluoro-2-(1,2,3-thiadiazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl) phenoxy] butanoic acid;

(2R)-2-[4-bromo-2-(1,2,3-thiadiazol-4-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-bromo-2-(1,3,4-thiadiazol-2-yl) phenoxy] propanoic acid;

(2R)-2-[4-bromo-5-fluoro-2-(1,2-oxazol-3-yl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-chloro-2-(1,2,3-thiadiazol-4-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1,3-oxazol-5-yl) phenoxy] propanoic acid;

(2S)-2-[4-bromo-2-(1,2-oxazol-3-yl) phenoxy]-3-ethoxypropanoic acid; and

(2S)-2-[4-chloro-2-(1,2-thiazol-3-yl) phenoxy] propanoic acid.

10. A method of treating and/or ameliorating a neuromuscular disorder in a subject or reversing and/or ameliorating a neuromuscular blockade in a subject, comprising administering to a subject in need thereof a compound of Formula (L3.4):

wherein:

R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I;

R 2 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 R 6 , with the proviso that when R 4 is methyl, then R 2 cannot be 1,2-oxazol-5-yl, with the proviso that when R 4 is H, then R 2 cannot be 1,2-oxazol-5-yl, 1,2-oxazol-3-yl or 1,3-oxazol-4-yl, with the proviso that when R 4 is H then R 2 is 1,2,3-thiadiazol-4-yl, 1,3,4-thiadiazol-2-yl, or 1,2-thiazol-3-yl, and with the proviso that when R 5 is H, R 4 is methyl, R 1 is Cl, and n is 0, then R 2 cannot be 1,2-oxazol-3-yl;

R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, CF 3 , CCl 3 , CHF 2 , CHCl 2 , CH 2 F, CH 2 Cl, OCF 3 , OCCl 3 and isocyanide;

R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;

R 5 is selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 , phenyl optionally substituted with one or more, identical or different, substituents R 9 and benzyl optionally substituted with one or more, identical or different, substituents R 9 ;

R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;

R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, isocyanide, O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , CH 2 —O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 and CH 2 —S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 ;

R 8 is independently selected from the group consisting of deuterium and F;

R 9 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,

wherein the neuromuscular disorder is selected from the group consisting of myasthenia gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie tooth disease (CMT), sarcopenia, Lambert-Eaton Syndrome, reversal diabetic polyneuropathy, Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, and critical illness polyneuropathy.

11. The method according to claim 10 , wherein R 2 is a 5-membered aromatic heterocycle, wherein each R 2 may be optionally substituted with one or more, identical or different, substituents R 6 .

12. The method according to claim 10 , wherein R 2 is selected from the group consisting of 1,2-oxazol-3-yl, 1,2-oxazol-4-yl, 1,2-oxazol-5-yl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-thiazol-3-yl, 1,2-thiazol-4-yl, 1,2-thiazol-5-yl, 1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,5-thiadiazol-3-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl and 1,2,5-oxadiazol-3-yl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

13. The method according to claim 10 , wherein the compound is a compound of Formula (II.4):

wherein:

R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I;

R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, CF 3 , CCl 3 , CHF 2 , CHCl 2 , CH 2 F, CH 2 Cl, OCF 3 , OCCl 3 and isocyanide;

R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;

R 5 is selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 , phenyl optionally substituted with one or more, identical or different, substituents R 9 and benzyl optionally substituted with one or more, identical or different, substituents R 9 ;

R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;

R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, isocyanide, O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , CH 2 —O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 and CH 2 —S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 ;

R 8 is independently selected from the group consisting of deuterium and F;

R 9 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F,

m is an integer 0, 1 or 2; and

n is an integer 0, 1, 2 or 3.

14. The method according to claim 10 , wherein the compound is a compound of Formula (III.4):

wherein:

R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I;

R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, CF 3 , CCl 3 , CHF 2 , CHCl 2 , CH 2 F, CH 2 Cl, OCF 3 , OCCl 3 and isocyanide;

R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;

R 5 is selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 , phenyl optionally substituted with one or more, identical or different, substituents R 9 and benzyl optionally substituted with one or more, identical or different, substituents R 9 ;

R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;

R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, isocyanide, O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , CH 2 —O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 and CH 2 —S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 ;

R 8 is independently selected from the group consisting of deuterium and F;

R 9 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

m is an integer 0, 1 or 2; and

n is an integer 0, 1, 2 or 3.

15. The method according to claim 10 , wherein the compound is a compound of Formula (XVI.4):

wherein:

R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I;

R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, CF 3 , CCl 3 , CHF 2 , CHCl 2 , CH 2 F, CH 2 Cl, OCF 3 , OCCl 3 and isocyanide;

R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;

R 5 is selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 , phenyl optionally substituted with one or more, identical or different, substituents R 9 and benzyl optionally substituted with one or more, identical or different, substituents R 9 ;

R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;

R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, isocyanide, O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , CH 2 —O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 and CH 2 —S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 ;

R 8 is independently selected from the group consisting of deuterium and F;

R 9 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

m is an integer 0, 1 or 2; and

n is an integer 0, 1, 2 or 3.

16. The method according to claim 10 , wherein the compound is a compound of Formula (XVII.4):

wherein:

R 1 is selected from the group consisting of H, deuterium, F, Cl, Br and I;

R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, CF 3 , CCl 3 , CHF 2 , CHCl 2 , CH 2 F, CH 2 Cl, OCF 3 , OCCl 3 and isocyanide;

R 4 is selected from the group consisting of C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 ;

R 5 is selected from the group consisting of H, C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 8 , phenyl optionally substituted with one or more, identical or different, substituents R 9 and benzyl optionally substituted with one or more, identical or different, substituents R 9 ;

R 6 is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, O—C 3-5 cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, —CH 2 —O—C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl, and wherein C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, O—C 1-5 alkyl, O—C 2-5 alkenyl, O—C 2-5 alkynyl, cycloalkyl, O—C 5 cycloalkenyl, —C(═O)—C 1-5 alkyl, —C(═O)—C 2-5 alkenyl, —C(═O)—C 2-5 alkynyl, —C(═O)—C 3-5 cycloalkyl, C 1-3 alkyl and —CH 2 —S—C 1-3 alkyl may be optionally substituted with one or more halogens;

R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, CN, isocyanide, O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 , CH 2 —O—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 and CH 2 —S—C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 8 ;

R 8 is independently selected from the group consisting of deuterium and F;

R 9 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;

m is an integer 0 or 1; and

n is an integer 0, 1, 2 or 3.

17. The method according to claim 10 , wherein n is 0 or 1.

18. The method according to claim 10 , wherein R 4 is C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 7 or C 1-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 7 .

19. The method according to claim 10 , wherein R 1 is selected from the group consisting of F, Cl, Br and I.

20. The method according to claim 10 , wherein R 5 is hydrogen.

21. The method according to claim 10 , wherein the compound is an inhibitor of the CIC-1 ion channel.

22. The method according to claim 10 , wherein the neuromuscular disorder is selected from the group consisting of myasthenia gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie tooth disease (CMT) and sarcopenia.

23. The method according to claim 10 , wherein the method is a method of reversing and/or ameliorating a neuromuscular blockade in a subject, wherein the neuromuscular blockade has been induced by a neuromuscular blocking agent.

24. The compound according to claim 1 , with the proviso that when R 4 is H, R 3 is not Cl.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 28, 2019
From: KNUTSEN, LARS J.S.; COOPER, MARTIN E.; BROWN, ANDREW W.; PEDERSEN, THOMAS HOLM; KELLY, NICHOLAS M.
To: NMD PHARMA A/S
Reel/Frame 048728/0130 →
Continuity (2)
Continuation In Part 15842823 · Dec 14, 2017
Related Publication 20190183863A1 · Jun 20, 2019
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