Compounds for the treatment of neuromuscular disorders

1. A compound of Formula (II.2):

wherein:

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

R 2 is independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, —CN, —CF 3 and -oxime optionally substituted with C 1 alkyl;

R 3 is C 1-5 alkyl substituted with one or more substituents R 5 ;

R 4 is H;

R 5 is independently F; and

n is an integer 0, 1 or 2;

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

2. The compound according to claim 1 , wherein

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

R 3 is C 1-5 alkyl substituted with one or more F;

R 4 is H; and

n is 0;

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

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

wherein:

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

R 2 is selected from the group consisting of deuterium, F, Cl, Br, I, and

oxime optionally substituted with C 1 alkyl;

R 3 is C 1-5 alkyl substituted with one or more F; and

R 4 is H;

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

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

wherein:

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

R 2 is selected from the group consisting of deuterium, F, Cl, Br, and I;

R 3 is C 1-5 alkyl substituted with one or more F; and

R 4 is H;

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

5. The compound according to claim 1 , wherein the compound is of Formula (V.2) or (VI.2):

wherein:

R 1 is Br, Cl or I;

R 2 is independently deuterium, F, Cl, Br, or I;

R 3 is C 1-5 alkyl substituted with one or more F; and

R 4 is H;

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

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

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

(2R)-2-[4-bromo(2,6-H)phenoxy]-3-fluoropropanoic acid;

(2R)-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropanoic acid;

(2R)-2-(4-bromo-2-fluorophenoxy)-3-fluoropropanoic acid;

(2R)-2-(2-bromo-4-chlorophenoxy)-3-fluoropropanoic acid;

(2R)-2-(4-chlorophenoxy)-3-fluoropropanoic acid;

(2R)-2-(4-chloro-2-fluorophenoxy)-3-fluoropropanoic acid;

(2R)-2-(2,4-dibromophenoxy)-3-fluoropropanoic acid; and

(2R)-2-(4-bromophenoxy)-3-fluoropropanoic acid;

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

7. The compound according to claim 1 , wherein the compound has the following structure:

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

8. A method of treating and/or ameliorating a disorder in a patient by inhibiting a ClC-1 receptor in a patient, comprising administering to a patient in need thereof a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), X-linked spinal and bulbar muscular atrophy, Kennedy's disorder, multifocal motor neuropathy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, myasthenia gravis, critical illness myopathy (CIM), critical illness polyneuropathy, Charcot-Marie tooth disease (CMT), sarcopenia, Chronic fatigue syndrome (CFS), metabolic myopathy, mitochondrial myopathy, and Lambert-Eaton syndrome.

9. A method of treating and/or ameliorating a neuromuscular disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

10. A method of reversing and/or ameliorating a neuromuscular blockade in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

11. The method according to claim 9 , wherein the neuromuscular disorder is myasthenia gravis.

12. The method according to claim 9 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS).

13. The method according to claim 9 , wherein the neuromuscular disorder is spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie tooth disease (CMT) or sarcopenia.

14. The method according to claim 9 , wherein the neuromuscular disorder has been induced by a neuromuscular blocking agent.

15. The compound according to claim 1 , wherein:

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

R 2 is independently selected from the group consisting of deuterium, F, Cl, Br and I, and

n is an integer 1 or 2.

16. The compound of claim 1 , wherein:

wherein R 3 is selected from the group consisting of —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2 and —CH 2 CF 3 .