Compounds for the treatment of neuromuscular disorders

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.

What is claimed is: 
     
       1. A compound of Formula (I.3.4): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of deuterium, F, Cl, Br and I; 
 R 2  is a 5-6 membered aromatic heterocycle or an 8-10 membered bicyclic heterocycle each of which may be optionally substituted with one or more, identical or different, substituents R 6 ; or alternatively, R 1  can be H and if R 1  is H, then 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  and wherein R 2  is not a 3-thiophene, an N-linked pyrrole, a 2,3-dihydro-2-benzothiazolyl or a 2-benzothiazolyl; 
 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 1-5  alkenyl, C 1-5  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, C 1-5  alkenyl and C 1-5  alkynyl; 
 R 6  is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5  alkyl, C 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl, C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl,
 —C(═O)—C 1-5  alkenyl, —C(═O)—C 1-5  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 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl, C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl, —C(═O)—C 1-5  alkenyl, 
 —C(═O)—C 1-5  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, S—C 1-3  alkyl, CH 2 —O—C 1-3  alkyl and CH 2 —S—C 1-3  alkyl; 
 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 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 ,
 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
 
     
     
       3. The compound according to  claim 1 , wherein the compound is 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 C 1-5  alkyl, C 1-5  alkenyl, C 1-5  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, C 1-5  alkenyl and C 1-5  alkynyl; 
 R 6  is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5  alkyl, C 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl, C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl,
 —C(═O)—C 1-5  alkenyl, —C(═O)—C 1-5  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 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl, C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl, —C(═O)—C 1-5  alkenyl, 
 —C(═O)—C 1-5  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, S—C 1-3  alkyl, CH 2 —O—C 1-3  alkyl and CH 2 —S—C 1-3  alkyl; 
 m is an integer 0, 1 or 2; and 
 n is an integer 0, 1, 2 or 3, 
 
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       4. The compound according to  claim 1 , wherein the compound is 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 C 1-5  alkyl, C 1-5  alkenyl, C 1-5  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, C 1-5  alkenyl and C 1-5  alkynyl; 
 R 6  is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5  alkyl, C 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl, C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl, —C(═O)—C 1-5  alkenyl, —C(═O)—C 1-5  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 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl, C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl, —C(═O)—C 1-5  alkenyl,
 —C(═O)—C 1-5  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, S—C 1-3  alkyl, CH 2 —O—C 1-3  alkyl and CH 2 —S—C 1-3  alkyl; 
 m is an integer 0, 1 or 2; and 
 n is an integer 0, 1, 2 or 3, 
 
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       5. The compound according to  claim 1 , wherein n is 0, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
     
     
       6. 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 a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
 
     
     
       7. The compound according to  claim 1 , wherein R 5  is hydrogen,
 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
 
     
     
       8. The compound according to  claim 1 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       9. The compound according to  claim 1 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       10. A method of inhibiting a CIC-1 ion channel 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. 
     
     
       11. A method of treating 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, wherein the neuromuscular 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-Barré syndrome, poliomyelitis, post-polio syndrome, Charcot-Marie Tooth disease (CMT), sarcopenia, critical illness myopathy (CIM), diabetes, chronic fatigue syndrome, systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), critical illness polyneuropathy, metabolic myopathy, mitochondrial myopathy, a myasthenic condition, congenital myasthenia gravis, myasthenia gravis, and Lambert-Eaton syndrome. 
     
     
       12. 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. 
     
     
       13. The method according to  claim 11 , wherein the neuromuscular disorder is myasthenia gravis. 
     
     
       14. The method according to  claim 11 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). 
     
     
       15. The method according to  claim 11 , wherein the neuromuscular disorder is selected from the group consisting of spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease (CMT) and sarcopenia. 
     
     
       16. The method according to  claim 11 , wherein the neuromuscular disorder has been induced by a neuromuscular blocking agent. 
     
     
       17. A compound of Formula (I.3.4): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of H, deuterium, F, Cl, Br and I; 
 R 2  is a 5 membered aromatic heterocycle which may be optionally substituted with one or more, identical or different, substituents R 6 ; and wherein R 2  is not a 3-thiophene or an N-linked pyrrole; 
 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 1-5  alkenyl, C 1-5  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, C 1-5  alkenyl and C 1-5  alkynyl; 
 R 6  is independently selected from the group consisting of H, deuterium, tritium, F, Cl, Br, I, CN, isocyanide, C 1-5  alkyl, C 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl, C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl, —C(═O)—C 1-5  alkenyl, —C(═O)—C 1-5  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 1-5  alkenyl, C 1-5  alkynyl, C 3-5  cycloalkyl,
 C 5  cycloalkenyl, O—C 1-5  alkyl, O—C 1-5  alkenyl, O—C 1-5  alkynyl, O—C 3-5  cycloalkyl, O—C 5  cycloalkenyl, —C(═O)—C 1-5  alkyl, —C(═O)—C 1-5  alkenyl, 
 —C(═O)—C 1-5  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, S—C 1-3  alkyl, CH 2 —O—C 1-3  alkyl and CH 2 —S—C 1-3  alkyl; 
 n is an integer 0, 1, 2 or 3, 
 
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       18. The compound according to  claim 17 , wherein the R 2  is selected from the group consisting of isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isthiazol-3-yl, isthiazol-4-yl, isthiazol-5-yl, thiazol-2-yl and thiazol-4-yl, thiazol-5-yl,
 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
 
     
     
       19. The compound according to  claim 17 , 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-[3-(propan-2-yl)-1,2-oxazol-5-yl]phenoxy}propanoic 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-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-[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-(3-methyl-1,2-oxazol-5-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-(1,2-oxazol-5-yl)phenoxy]propanoic acid; 
 (2S)-2-[4-chloro-2-(1-methyl-1H-pyrazol-4-yl)phenoxy]propanoic acid; 
 (2S)-2-[4-bromo-2-(1,3,4-oxadiazol-2-yl)phenoxy]propanoic acid; 
 (2S)-2-[4-bromo-2-(1,2-oxazol-5-yl)phenoxy]propanoic acid; and 
 (2S)-2-[4-chloro-2-(1H-pyrazol-1-yl)phenoxy]propanoic acid, 
 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.