Granted Patent B2

US 12,415,771 · App. 17/620,294 · Granted Sep 16, 2025

Inventors: Lars J. S. Knutsen (Essex, GB); Nicholas Kelly (Bagsværd, DK); Martin Brandhøj Skov (Aarhus C, DK); Anders Riisager (Skødstrup, DK); Neerja Saraswat (Winnipeg, CA)

Assignee: NMD PHARMA A/S

C07C59/70A61P21/00C07C59/68C07C59/72C07C255/54C07D277/24C07C2601/04

Abstract

Claims (100)

1. A compound of Formula (I):

wherein:

R 1 is selected from the group consisting of C 1-2 alkyl, C 2 alkenyl, C 2 alkynyl, CN, CF 3 , NO 2 , F, Cl, Br, and I;

R 2 is selected from the group consisting of C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;

R 3 is selected from the group consisting of deuterium, Cl and F;

R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, and C 3-5 cycloalkyl, 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 optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 8 , 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 deuterium, F, —CN, —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl, wherein the —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;

R 7 is independently selected from the group consisting deuterium, F, C 1 , —CN, C 3-5 cycloalkyl, —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl, —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl may optionally be 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;

X is a bond or selected from the group consisting of —O—, —S—, —CH 2 —, —CHR 6 —, and —C(R 6 ) 2 —; and

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

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

2. The compound according to claim 1 , wherein the compound is of Formula (II)

wherein:

R 1 is selected from the group consisting of C 1-2 alkyl, C 2 alkenyl, C 2 alkynyl, CN, CF 3 , NO 2 , F, Cl, Br, and I;

R 2 is selected from the group consisting of C 1-5 alkyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R 6 , C 2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R 6 , C 3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 6 , phenyl optionally substituted with one or more, identical or different, substituents R 9 , and 5-6 membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R 7 ;

R 3 is selected from the group consisting of deuterium, Cl and F;

R 4 is selected from the group consisting of H, deuterium, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, and C 3-5 cycloalkyl, 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 optionally substituted with one or more, identical or different, substituents R 8 , C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 8 , 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 deuterium, F, —CN, —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl, wherein the —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl may optionally be substituted with one or more, identical or different, substituents R 8 ;

R 7 is independently selected from the group consisting deuterium, F, Cl, —CN, C 3-5 cycloalkyl, —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl, wherein the C 3-5 cycloalkyl, —O—C 1-5 alkyl, —O—C 3-5 cycloalkyl, —S—C 1-5 alkyl, and —S—C 3-5 cycloalkyl may optionally be 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.

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

4. The compound according to claim 2 , wherein R 2 is C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 6 .

5. The compound according to claim 2 , wherein R 3 is F and n is 1.

6. The compound according to claim 2 , wherein R 4 is C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 6 .

7. The compound according to claim 2 , wherein R 4 is CH 2 F.

8. The compound according to claim 2 , wherein R 4 is C 2-5 alkynyl optionally substituted with one or more, identical or different, substituents R 6 .

9. The compound according to claim 2 , wherein R 5 is H.

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

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

(2S)-2-[4-bromo-2-(1,1-difluoroethyl) phenoxy]butanoic acid;

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

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

(2S)-2-[4-chloro-2-(1,1-difluoropropyl) phenoxy]propanoic acid;

2-[4-bromo-2-(1,1-difluoropropyl) phenoxy]acetic acid;

(2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl) phenoxy]propanoic acid;

(2S)-2-{4-bromo-2-[difluoro (phenyl)methyl]phenoxy}propanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoroethyl) phenoxy]-2-cyclopropylacetic acid;

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

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

(2S)-2-[4-bromo-2-(cyclopropyldifluoromethyl) phenoxy]propanoic acid;

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

(2S)-2-[4-bromo-2-(1,1-difluoroethyl) phenoxy]pent-4-ynoic acid;

(2S)-2-[4-bromo-2-(cyclobutyldifluoromethyl) phenoxy]propanoic acid;

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

(2R)-2-[4-bromo-2-(1,1-difluoropropyl) phenoxy]-3-chloropropanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoropropyl) phenoxy]pent-4-ynoic acid;

(2S)-2-[4-chloro-2-(1,1-difluoroethyl) phenoxy]pent-4-ynoic acid;

(2S)-2-[2-(1,1-difluoropropyl)-4-iodophenoxy]propanoic acid;

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

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

(2S)-2-[2-(1,1-difluoropropyl)-4-ethynylphenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoropropyl)-6-fluorophenoxy]propanoic acid;

(2S)-2-[4-cyano-2-(1,1-difluoropropyl) phenoxy]propanoic acid;

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

(2S)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoropropyl) (3,5,6- 2 H 3 ) phenoxy]propanoic acid;

2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

(2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]propanoic acid;

(2S)-2-[2-(1,1-difluoropropyl)-4-(trifluoromethyl) phenoxy]propanoic acid;

(2R)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid;

(2S)-2-[2-(1,1-difluoropropyl)-4-ethenylphenoxy]propanoic acid;

2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]acetic acid;

(2S)-2-[2-(1,1-difluoropropyl)-4-methylphenoxy]propanoic acid;

2-[4-bromo-2-(1,1-difluoro-2-methylpropyl) phenoxy]acetic acid;

2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]acetic acid;

(2S)-2-[2-(1,1-difluoroethyl)-4-ethynylphenoxy]propanoic acid;

(2R)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]-3-fluoropropanoic acid;

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

(2R)-2-[4-bromo-2-(1,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropanoic acid;

(2R)-2-[4,5-dichloro-2-(1,1-difluoroethyl) phenoxy]-3-fluoropropanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoroethyl) phenoxy]-4-fluorobutanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl) phenoxy]butanoic acid;

(2S)-2-[2-(1,1-difluoropropyl)-4-ethenyl-5-fluorophenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

(2S)-2-[4-chloro-2-(1,1-difluoropropyl)-5-fluorophenoxy]butanoic acid;

(2R)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]-3-fluoropropanoic acid;

(2S)-2-[2-(1,1-difluoropropyl)-4-nitrophenoxy]propanoic acid;

(2S)-2-[5-chloro-2-(1,1-difluoropropyl)-4-fluorophenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(1,1-difluoropropyl) phenoxy]-4-methoxybutanoic acid;

(2R)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropanoic acid;

(2S)-2-[2-(1,1-difluoropropyl)-4,5-difluorophenoxy]propanoic acid; and

(2S)-2-[4-bromo-2-(1,1-difluoro-3-methoxypropyl) phenoxy]propanoic acid.

11. The compound according to claim 2 , wherein the compound is an inhibitor of the CIC-1 ion channel.

12. A composition comprising the compound according to claim 1 .

13. A method of treating a patient comprising administering to a patient a therapeutically effective amount of the compound according to claim 2 ,

for use in the treatment of symptoms of an indication selected from the group consisting of myasthenia gravis, Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), reversal diabetic polyneuropathy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, periodic paralysis, sarcopenia, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy and Duchenne muscular dystrophy.

14. A method of reversing and/or ameliorating a neuromuscular blockade in a patient comprising administering to a patient a therapeutically effective amount of the compound according to claim 2 .

15. A method of claim 13 wherein in Formula (I), R 3 is F and n is 1.

16. A method of claim 14 wherein in Formula (II), R 3 is F and n is 1.

17. The method of claim 13 wherein in Formula (I), R 1 is C 1 or Br.

18. The method of claim 13 wherein in Formula (I), R 2 is C 1-3 alkyl optionally substituted with one or more, identical or different, substituents R 6 .

19. The method of claim 14 wherein in Formula (II), R 1 is Cl or Br.

Assignments (1)

Priority Claims (1)

Continuity (1)

References Cited (59)