Compounds for use in treating neuromuscular disorders

1. 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 of Formula (II):

wherein

A is selected from the group consisting of

m is 0, 1 or 2;

Y is selected from the group consisting of O, NH, N—CH 3 , CH 2 , CH 2 —O, CH 2 CH 2 —O, S, and SO 2 ;

X 1 , X 2 and X 3 are independently selected from CH or C(R 4 );

R 1 is H and R 2 is selected from the group consisting of H, C 1-4 -alk(en)yl, C 3-6 -cycloalk(en)yl, wherein said C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl may be substituted with up to two substituents selected from the group consisting of —NR 9 —CO—R 10 , —N(R 10 )—SO 2 —R 12 , —CO—NR 9 R 10 , —SO 2 —NR 9 R 10 , —R 13 —O—R 11 , NR 9 R 10 , —S(O)R 12 , S(O) 2 R 12 , cyano, O—R 11 , fluorinated C 1-3 -alkyl, nitro and halo; or R 1 and R 2 , together, form a C 3-6 -cycloalkyl R 4 is selected from the group consisting H, halo, cyano, —CHO, C 1-4 alk(en)yl, halo-C 1-4 alk(en)yl, and —O—C 1-4 -alk(en)yl;

R 9 , R 10 , R 11 are independently selected from H or C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 13 is selected from C 1-4 -alk(an/en/yn)diyl and C 3-6 -cycloalk(an/en)diyl; and

R 14 is C(O)OH;

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, with the proviso that when A is

 m is 0, Y is O, X 1 and X 2 are CH, X 3 is C(R 4 ), and R 2 is H, then R 4 is not —O—C 1-2 -alkyl.

2. 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 of Formula (II):

wherein

A is selected from the group consisting of

Y is selected from the group consisting of O, NH, N—CH 3 , CH 2 , CH 2 —O, CH 2 CH 2 —O, S, and SO 2 ;

X 1 , X 2 and X 3 are independently selected from CH or C(R 4 );

R 1 is H and R 2 is selected from the group consisting of H, C 1-4 -alk(en)yl, C 3-6 -cycloalk(en)yl, wherein said C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl may be substituted with up to two substituents selected from the group consisting of —NR 9 —CO—R 10 , —N(R 10 )—SO 2 —R 12 , —CO—NR 9 R 10 , —SO 2 —NR 9 R 10 , —R 13 —O—R 11 , NR 9 R 10 , —S(O)R 12 , S(O) 2 R 12 , cyano, O—R 11 , fluorinated C 1-3 -alkyl, nitro and halo; or R 1 and R 2 , together, form a C 3-6 -cycloalkyl R 4 is selected from the group consisting H, halo, cyano, —CHO, C 1-4 alk(en)yl, halo-C 1-4 alk(en)yl, and —O—C 1-4 -alk(en)yl;

R 9 , R 10 , R 11 are independently selected from H or C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 13 is selected from C 1-4 -alk(an/en/yn)diyl and C 3-6 -cycloalk(an/en)diyl; and

R 14 is C(O)OH;

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof, with the proviso that when A is

m is 0, Y is 0, X 1 and X 2 are CH, X 3 is C(R 4 ), and R 2 is H, then R 4 is not —O—C 1-2 -alkyl.

3. The method according to claim 1 , wherein R 1 is H and R 2 is selected from the group consisting of H, C 1-4 -alkyl, C 3-6 -cycloalkyl and amino-C 1-4 -alkyl, wherein said C 1-4 -alkyl and C 3-6 -cycloalkyl may be substituted with O—R 11 , wherein R 11 is selected from H, C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl,

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

4. The method according to claim 2 , wherein R 1 is H and R 2 is selected from the group consisting of H, C 1-4 -alkyl, C 3-6 -cycloalkyl and amino-C 1-4 -alkyl, wherein said C 1-4 -alkyl and C 3-6 -cycloalkyl may be substituted with O—R 11 , wherein R 11 is selected from H, C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl,

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

5. The method according to claim 1 , wherein R 1 is H and R 2 is selected from the group consisting of H, —CH 3 , —CH(CH 3 ) 2 and cyclopropyl, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

6. The method according to claim 2 , wherein R 1 is H and R 2 is selected from the group consisting of H, —CH 3 , —CH(CH 3 ) 2 and cyclopropyl, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

7. The method according to claim 1 , wherein the compound of Formula (II) is further defined by Formula (VII):

wherein

m is 1 or 2;

Y is selected from the group consisting of O, NH, N—CH 3 , CH 2 , CH 2 —O, S and SO 2 ;

X 1 and X 2 are independently selected from CH;

R 2 is selected from the group consisting of H, C 1-4 -alk(en)yl, C 3-6 -cycloalk(en)yl, wherein said C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl may be substituted with up to two substituents selected from the group consisting of —NR 9 —CO—R 10 , —N(R 10 )—SO 2 —R 12 , —CO—NR 9 R 10 , —SO 2 —NR 9 R 10 , —R 13 —O—R 11 , NR 9 R 10 , —S(O)R 12 , —S(O) 2 R 12 , cyano, —O—R 11 , fluorinated C 1-3 -alkyl, nitro and halo, wherein R 9 , R 10 , and R 11 are independently selected from H, C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl, whereas R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 4 is selected from the group consisting of H, halo, cyano, —CHO, C 1-4 -alk(en)yl, halo-C 1-4 -alk(en)yl, —O—C 1-4 -alk(en)yl;

R 9 , R 10 , R 11 are independently selected from H or C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl

R 13 is selected from C 1-4 -alk(an/en/yn)diyl and C 3-6 -cycloalk(an/en)diyl, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

8. The method according to claim 2 , wherein the compound of Formula (II) is further defined by Formula (VII):

wherein

m is 1 or 2;

Y is selected from the group consisting of O, NH, N—CH 3 , CH 2 , CH 2 —O, S and SO 2 ;

X 1 and X 2 are independently selected from CH;

R 2 is selected from the group consisting of H, C 1-4 -alk(en)yl, C 3-6 -cycloalk(en)yl, wherein said C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl may be substituted with up to two substituents selected from the group consisting of —NR 9 —CO—R 10 , —N(R 10 )—SO 2 —R 12 , —CO—NR 9 R 10 , —SO 2 —NR 9 R 10 , —R 13 —O—R 11 , NR 9 R 10 , —S(O)R 12 , —S(O) 2 R 12 , cyano, —O—R 11 , fluorinated C 1-3 -alkyl, nitro and halo, wherein R 9 , R 10 , and R 11 are independently selected from H, C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl, whereas R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 4 is selected from the group consisting of H, halo, cyano, —CHO, C 1-4 -alk(en)yl, halo-C 1-4 -alk(en)yl, —O—C 1-4 -alk(en)yl;

R 9 , R 10 , R 11 are independently selected from H or C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl

R 13 is selected from C 1-4 -alk(an/en/yn)diyl and C 3-6 -cycloalk(an/en)diyl, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

9. The method according to claim 7 , wherein the compound of Formula (VII) is further defined by Formula (VIII)

wherein

m is 1 or 2;

Y is selected from the group consisting of O, NH, N—CH 3 , CH 2 , CH 2 —O, S and SO 2 ;

X 2 is selected from CH;

R 2 is selected from the group consisting of H, C 1-4 -alk(en)yl, C 3-6 -cycloalk(en)yl, wherein said C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl may be substituted with up to two substituents selected from the group consisting of

—NR 9 —CO—R 10 , —N(R 10 )—SO 2 —R 12 , —CO—NR 9 R 10 , —SO 2 —NR 9 R 10 , —R 13 —O—R 11 , NR 9 R 10 , —S(O)R 12 , —S(O) 2 R 12 , cyano, —O—R 11 , fluorinated C 1-3 -alkyl, nitro and halo;

R 4 is selected from the group consisting of H, halo, cyano, —CHO, C 1-4 -alk(en)yl, halo-C 1-4 -alk(en)yl, —O—C 1-4 -alk(en)yl;

R 9 , R 10 , R 11 are independently selected from H or C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl

R 13 is selected from C 1-4 -alk(an/en/yn)diyl and C 3-6 -cycloalk(an/en)diyl, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

10. The method according to claim 8 , wherein the compound of Formula (VII) is further defined by Formula (VIII)

wherein

m is 1 or 2;

Y is selected from the group consisting of O, NH, N—CH 3 , CH 2 , CH 2 —O, S and SO 2 ;

X 2 is selected from CH;

R 2 is selected from the group consisting of H, C 1-4 -alk(en)yl, C 3-6 -cycloalk(en)yl, wherein said C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl may be substituted with up to two substituents selected from the group consisting of

—NR 9 —CO—R 10 , —N(R 10 )—SO 2 —R 12 , —CO—NR 9 R 10 , —SO 2 —NR 9 R 10 , —R 13 —O—R 11 , NR 9 R 10 , —S(O)R 12 , —S(O) 2 R 12 , cyano, —O—R 11 , fluorinated C 1-3 -alkyl, nitro and halo;

R 4 is selected from the group consisting of H, halo, cyano, —CHO, C 1-4 -alk(en)yl, halo-C 1-4 -alk(en)yl, —O—C 1-4 -alk(en)yl;

R 9 , R 10 , R 11 are independently selected from H or C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl;

R 12 is selected from C 1-4 -alk(en/yn)yl and C 3-6 -cycloalk(en)yl

R 13 is selected from C 1-4 -alk(an/en/yn)diyl and C 3-6 -cycloalk(an/en)diyl, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

11. The method according to claim 1 , wherein said compound is further defined by Formula (IX):

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

12. The method according to claim 2 , wherein said compound is further defined by Formula (IX):

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

13. The method according to claim 7 , wherein the compound of Formula (VII) is further defined by Formula (X):

wherein R 2 is selected from the group consisting of —CH 3 , —CH 2 —CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH(CH 3 )CH 2 —O—CH 3 , —CH 2 —CH 2 —CH 3 , —CH 2 —NH 2 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —NH—CO—CH 3 and —CH 2 —NH—SO 2 —CH 3 and cyclopropyl, and R 4 is selected from the group consisting of H, Br, Cl, F and I, or a pharmaceutically acceptable salt, solvate, polymorph, or tautomer thereof.

14. The method according to claim 8 , wherein the compound of Formula (VII) is further defined by Formula (X):

wherein R 2 is selected from the group consisting of —CH 3 , —CH 2 —CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH(CH 3 )CH 2 —O—CH 3 , —CH 2 —CH 2 —CH 3 , —CH 2 —NH 2 , —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —NH—CO—CH 3 and —CH 2 —NH—SO 2 —CH 3 and cyclopropyl, and R 4 is selected from the group consisting of H, Br, Cl, F and I,

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

15. The method according to claim 7 , wherein the compound of Formula (VII) is further defined by any one of the following Formulas (XI) to (XXVIII):

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

16. The method according to claim 8 , wherein the compound of Formula (VII) is further defined by any one of the following Formulas (XI) to (XXVIII):

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

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

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

18. The compound according to claim 2 , wherein the compound has the following structure:

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

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

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

20. The method according to claim 2 , wherein the compound has the following structure:

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

21. The method according to claim 1 , wherein the compound of Formula (II) is further defined by any one of the following Formulas (XXXVI) to (LIX)

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

22. The method according to claim 2 , wherein the compound of Formula (II) is further defined by any one of the following Formulas (XXXVI) to (LIX)

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

23. The method according to claim 1 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS).

24. The method according to claim 1 , wherein the neuromuscular disorder is spinal muscular atrophy (SMA).

25. The method according to claim 1 , wherein the neuromuscular disorder is chronic fatigue syndrome.

26. The method according to claim 1 , wherein the neuromuscular disorder is critical illness myopathy (CIM).

27. The method according to claim 1 , wherein the neuromuscular disorder is myasthenia gravis.

28. The method according to claim 1 , wherein the neuromuscular disorder is further defined as being selected from the group consisting of X-linked spinal and bulbar muscular atrophy, Kennedy's disorder, multifocal motor neuropathy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, diabetes, muscle weakness and fatigue, systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), metabolic myopathy, mitochondrial myopathy, congenital myasthenia gravis, Lambert-Eaton syndrome, or Lambert-Eaton myasthenic syndrome.