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Title:
PHENOXY ACIDS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS
Document Type and Number:
WIPO Patent Application WO/2019/115780
Kind Code:
A1
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 ClC-1 ion channel.

Inventors:
J.S. KNUTSEN, Lars (10 Queens House, The Esplanade Frinton-on-Sea, Essex CO13 9AY, CO13 9AY, GB)
KELLY, Nicholas (Højgårds Vænge 32, 2880 Bagsværd, 2880, DK)
HOLM PEDERSEN, Thomas (Sejrs Allé 4A, 8240 Risskov, 8240, DK)
ELSBORG OLESEN, Claus (Lyngsiesvej 18, 8230 Åbyhøj, 8230, DK)
LITTLE, Paul, Brian (Pilelunden 30, 4270 Høng, 4270, DK)
E COOPER, Martin (4 Greenwood Crescent Carlton, Nottingham NG4 1AQ, NG4 1AQ, GB)
SARASWAT, Neerja (47 Smuggler’s Cove Winnipeg, Manitoba, R3X 1R4, R3X 1R4, CA)
DUDEKULA, Dastagiri (852 Centennial Street Winnipeg, R3N 1R4 Manitoba, R3N 1R4, DK)
A. TAJ, Rafiq (216-135 Allegheny Drive Winnipeg, Manitoba, R3T 3A1, R3T 3A1, CA)
Application Number:
EP2018/084988
Publication Date:
June 20, 2019
Filing Date:
December 14, 2018
Export Citation:
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Assignee:
NMD PHARMA A/S (8200 Århus N, 8200, DK)
International Classes:
A61K31/192; A61K31/216; A61P21/00; A61P21/04
Domestic Patent References:
WO2016202341A12016-12-22
WO2005105727A12005-11-10
WO2006037982A22006-04-13
WO2016202341A12016-12-22
Foreign References:
US20060211765A12006-09-21
Other References:
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Attorney, Agent or Firm:
HØIBERG P/S (Adelgade 12, 1304 Copenhagen K, 1304, DK)
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Claims:
Claims

1. A compound of Formula (I):

Formula (I)

5 wherein:

- R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, -

CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3;

- R2 is selected from the group consisting of C2-6 alkyl, C2-6 alkenyl, C2-6

alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl, -C(=0)-Ci-5 alkyl, -C(=0)-Ci-50 alkenyl, -C(=0)-Ci-5 alkynyl, -C(=0)-C3-5 cycloalkyl and -C(=0)-C5

cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;

- R3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF3, -CCI3, -CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3, -OCCI35 and isocyanide;

- R4 is selected from the group consisting of C1 -5 alkyl, C1 -5 alkenyl, C1 -5

alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;

- R5 is selected from the group consisting of H, C1 -5 alkyl optionally substituted0 with one or more, identical or different, substituents R11, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R11, phenyl optionally substituted with one or more, identical or different, substituents R1 2 and benzyl optionally substituted with one or more, identical or different, substituents R12; - R6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C1 -3 alkyl, -S-C1 -3 alkyl, -CH2-OH, -CH2-0-C1 -3 alkyl, -0-CH2-Ph, -CH2-SH and -CH^S-C^ alkyl;

- R7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br, I, -CN, isocyanide, -O-C1-3 alkyl, -S-C1-3 alkyl, -CH2-0-Ci-3 alkyl and -CH2-S-CI-3 alkyl;

- R11 is independently selected from the group consisting of deuterium and F;

- R12 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,

for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

2. The compound for use according to claim 1 , wherein:

- R1 is selected from the group consisting of F, Cl, Br and I;

- R2 is selected from the group consisting of ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, -C(=0)-methyl and -C(=0)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;

- R3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I;

- R4 is selected from the group consisting of C1 -5 alkyl, C1 -5 alkenyl, C1 -5

alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;

- R5 is selected from the group consisting of H, C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R11, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R11, phenyl optionally substituted with one or more, identical or different, substituents R12 and benzyl optionally substituted with one or more, identical or different, substituents R12;

- R6 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br, I, -CN, isocyanide, -O-C1 -3 alkyl, -S-C1 -3 alkyl, -CH2-OH, -CH2- 0-Ci-3 alkyl, -0-CH2-Ph, CH2-SH and -CH^S-C^ alkyl; - R7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br and I;

- R11 is independently selected from the group consisting of deuterium and F;

- R12 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

- n is an integer 0 or 1.

3. The compound for use according to any one of claims 1 to 2, wherein the

compound is of Formula (II):

wherein:

R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, - CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3;

R4 is methyl, ethyl, n-propyl, isopropyl or -CH2F;

R8 and R9 are independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -CH2-0·^ alkyl, -CH2-SH, -CH^S-C^ alkyl, Ci-4 alkyl and C1 -4 alkenyl and wherein the C1 -4 alkyl and Ci-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R6; and

R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -CH2-0·^ alkyl, -0-CH2-Ph, -CH2-SH and -CH^S-C^ alkyl. 4. The compound for use according to any one of claims 1 to 2, wherein the

compound is of Formula (III):

Formula (III) wherein:

R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, - CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3;

R4 is methyl, ethyl, n-propyl, isopropyl or -CH2F;

R8 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -CH2-0-Ci-3 alkyl, -CH2-SH, -CH2-S-CI^ alkyl, C^ alkyl and C1 -4 alkenyl and wherein the Ci-4 alkyl and Ci-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R6; and

R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -CH2-0-Ci-3 alkyl, -0-CH2-Ph, -CH2-SH and -CH2-S-CI-3 alkyl.

5. The compound for use according to any one of claims 1 to 2, wherein the

compound is of Formula (IV):

Formula (IV) wherein:

R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, - CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3;

R4 is methyl, ethyl, n-propyl, isopropyl or -CH2F;

R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C1-3 alkyl, -S-C1-3 alkyl, -CH2-OH, -CH2-0·^ alkyl, -0-CH2-Ph, -CH2-SH and -CH^S-C^ alkyl; and

R8, R9 and R10 are independently selected from the group consisting of

hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C1-3 alkyl, -

S-C1-3 alkyl, -CH2-OH, -CH2-0-C1-3 alkyl, -CH2-SH, -CH^S-C^ alkyl, C alkyl and C1-4 alkenyl and wherein the C1-4 alkyl and Ci- alkenyl group may be optionally substituted with one or more, identical or different, substituents R6.

6. The compound for use according to any one of claims 1 to 2, wherein the

compound is of Formula (V):

Formula (V) wherein:

R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, - CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3;

R4 is methyl, ethyl, n-propyl, isopropyl or -CH2F; and

R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C1-3 alkyl, -S-C1-3 alkyl, -CH2-OH, -CH2-0-Ci-3 alkyl, -0-CH2-Ph, -CH2-SH and -CH2-S-CI-3 alkyl.

7. The compound for use according to any one of claims 1 to 2, wherein the

compound is of Formula (VI):

Formula (VI) wherein:

R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, - CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3;

R4 is methyl, ethyl, n-propyl, isopropyl or -CH2F; and

R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -CH2-0-Ci-3 alkyl, -0-CH2-Ph, -CH2-SH and -CH2-S-CI-3 alkyl.

8. The compound for use according to any one of claims 1 to 2, wherein the

compound is of Formula (VII):

Formula (VII) wherein:

R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, - CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3;

R2 is selected from the group consisting of C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl, -C(=0)-Ci-5 alkyl, -C(=0)-Ci-5 alkenyl, - C(=0)-Ci-5 alkynyl, -C(=0)-C3-5 cycloalkyl and -C(=0)-C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;

R4 is selected from the group consisting of Ci-5 alkyl, Ci-5 alkenyl, Ci-5 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;

R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -CH2-0-Ci-3 alkyl, -0-CH2-Ph, -CH2-SH and -CH2-S-CI-3 alkyl; and

R7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-0-Ci-3 alkyl and -CH2-S-CI-3 alkyl.

9. The compound for use according to any one of claims 1 to 2, wherein the

compound is of Formula (VIII):

Formula (VIII) wherein:

R1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF3, -CCI3, -

CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3 and -OCCI3; R2 is selected from the group consisting of C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C5-6 cycloalkenyl, -C(=0)-Ci-5 alkyl, -C(=0)-Ci-5 alkenyl, - C(=0)-Ci-5 alkynyl, -C(=0)-C3-5 cycloalkyl and -C(=0)-C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;

R3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, -CF3, -CCI3, -CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3, -OCCI3 and isocyanide; and

R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -OH,-O-O^ alkyl, -0-CH2-Ph, -CH2-SH and -CH^S-C^ alkyl.

10. The compound for use according to any one of claims 1 to 9, wherein the

compound is an inhibitor of the CIC-1 ion channel. 1 1 . The compound for use according to any one of claims 1 to 10, wherein the

compound is for use in the treatment of symptoms of an indication selected from the group consisting of myasthenia gravis (such as autoimmune and congenital 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, and critical illness polyneuropathy.

12. The compound for use according to any one of claims 1 to 10, wherein the

neuromuscular disorder has been induced by a neuromuscular blocking agent. 13. A compound of Formula (I):

Formula (I) wherein:

- R1 is selected from the group consisting of F, Cl, Br and I;

- R2 is selected from the group consisting of C2 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, -C(=0)-Ci-5 alkyl, -C(=0)-Ci-5 alkenyl, -

C(=0)-Ci-5 alkynyl, -C(=0)-C3-5 cycloalkyl and -C(=0)-C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;

- R3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, -CF3, -CCI3, -CHF2, -CHCI2, -CH2F, -CH2CI, -OCF3, -OCCI3 and isocyanide;

- R4 is selected from the group consisting of C1-5 alkyl, C1-5 alkenyl, C1-5 alkynyl,

C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;

- R5 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R11, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R11, phenyl optionally substituted with one or more, identical or different, substituents R12 and benzyl optionally substituted with one or more, identical or different, substituents R12;

- R6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-OH, -CH^O-C! -S alkyl, -0-CH2-Ph, -CH2-SH and -CH^S-C^ alkyl;

- R7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci-3 alkyl, -S-Ci-3 alkyl, -CH2-0-Ci-3 alkyl and -CH2-S-CI -3 alkyl;

- R11 is independently selected from the group consisting of deuterium and F;

- R12 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 R2 is C(=0)-CH3, R1 is Br and R5 is H or Me then R4 is not Me or CH2CHMe2; and with the proviso that when R2 is CHMe2, R1 is Br and R5 is H or Me then R4 is not Me.

14. The compound according to claim 13, wherein:

- R1 is selected from the group consisting of F, Cl, Br and I;

- R2 is selected from the group consisting of ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, -C(=0)-methyl and -C(=0)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;

- R3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I;

- R4 is selected from the group consisting of Ci-5 alkyl, Ci-5 alkenyl, Ci-5

alkynyl, C3-5 cycloalkyl, C5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R7;

- R5 is selected from the group consisting of H, C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R11, C2-5 alkenyl, C2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R11, phenyl optionally substituted with one or more, identical or different, substituents R12 and benzyl optionally substituted with one or more, identical or different, substituents R12;

- R6 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br, I, -CN, isocyanide, -O-C1 -3 alkyl, -S-C1 -3 alkyl, -CH2-OH, -CH2- O-C1 -3 alkyl, -0-CH2-Ph, -CH2-SH and -CH2-S-CI -3 alkyl;

- R7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br and I;

- R11 is independently selected from the group consisting of deuterium and F;

- R12 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

- n is an integer 0 or 1.

15. The compound according to any one of claims 13 to 14, wherein the compound is selected from the group consisting of:

(2S)-2-{4-bromo-2-[2-(methoxymethyl)cyclopropyl]phenoxy}propanoic acid; (2S)-2-[4-bromo-2-(2,2-dichlorocyclopropyl)phenoxy]propanoic acid;

(2S)-2-{4-bromo-2-[(1 s,3s)-3-methoxycyclobutyl]phenoxy}propanoic acid; (2S)-2-{4-bromo-2-[(E)-2-bromoethenyl]phenoxy}propanoic acid;

(2F?)-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropanoic acid;

(2S)-2-{4-bromo-2-[(1 S,2S)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid; (2S)-2-{4-bromo-2-[(1 R,2/:?)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)propanoic acid;

(2S)-2-{4-bromo-2-[(1 £)-2-cyanoeth-1 -en-1 -yl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)propanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)propanoic acid;

(2S)-2-(2-cyclopropyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(2-cyclobutyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclobutylphenoxy)propanoic acid;

tert-butyl (2S)-2-(4-chloro-2-propanoylphenoxy)propanoate;

(2S)-2-{4-chloro-2-[(2,2-2H2)propanoyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoic acid;

methyl (2S)-2-[4-chloro-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoate;

methyl (2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoate;

(2S)-2-(4-chloro-2-ethynylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-propanoylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethenylphenoxy)propanoate;

(2S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-propylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

methyl (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

(2/:?)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)-3-fluoropropanoic acid; (2S)-2-(2-cyclopropyl-4,6-difluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)propanoic acid;

(2S)-2-(2,4-difluoro-6-propanoylphenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-chlorophenoxy)propanoic acid;

(2S)-2-(4-fluoro-2-propanoylphenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-{2-[2-(benzyloxy)cyclobutyl]-4-chlorophenoxy}propanoic acid;

(2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-[2,4-dibromo-6-(2-methoxyethyl)phenoxy]propanoic acid; (2S)-2-[4-bromo-2-(cyclopropylidenemethyl)phenoxy]propanoic acid; (2S)-2-(4-bromo-2-ethenyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-bromo-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propanoic acid;

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

(2S)-2-(4-bromo-2-ethynylphenoxy)-2-cyclobutylacetic acid;

(2S)-2-(4-bromo-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-chloro-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)-4-fluorobutanoic acid;

(2S)-2-{4-bromo-2-[(1 E)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-{4-chloro-2-[(1 E)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)butanoic acid; and

(2S)-2-[4-bromo-2-(2,2-difluorocyclobutyl)phenoxy]propanoic acid.

Description:
PHENOXY ACIDS FOR THE TREATMENT OF NEUROMUSCULAR DISORDERS

Technical field

The present invention relates to compounds and their use in 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. The invention further relates to methods of treating, preventing and/or ameliorating neuromuscular disorders, by administering said composition to a person in need thereof.

Background

Walking, breathing, and eye movement are examples of essential everyday

physiological activities that are powered by the contractile activity of skeletal muscle. Skeletal muscles are inherently in a resting state and contractile activity occurs exclusively in response to commands from the central nervous system (CNS). Such neuronal commands take the form of action potentials that travel from the brain to the muscle fibres in several steps. The neuromuscular junction (NMJ) is a highly specialized membrane area on muscle fibres where motor neurons come into close contact with the muscle fibres, and it is at the NMJ where neuronal action potentials are transmitted to muscular action potentials in a one-to-one fashion via synaptic transmission.

Neuromuscular transmission refers to the sequence of cellular events at the NMJ whereby an action potential in the lower motor neuron is transmitted to a corresponding action potential in a muscle fibre (Wood SJ, Slater CR. Safety factor at the

neuromuscular junction. Prog. Neurobiol. 2001 , 64, 393-429). When a neuronal action potential arrives at the pre-synaptic terminal it triggers influx of Ca 2+ through voltage gated P/Q-type Ca 2+ channels in the nerve terminal membrane. This influx causes a rise in cytosolic Ca 2+ in the nerve terminal that triggers exocytosis of acetylcholine (ACh). Released ACh next diffuses across the synaptic cleft to activate nicotinic ACh receptors in the post-synaptic, muscle fibre membrane. Upon activation, ACh receptors convey an excitatory current flow of Na + into the muscle fibre, which results in a local depolarization of the muscle fibre at the NMJ that is known as the endplate potential (EPP). If the EPP is sufficiently large, voltage gated Na + channels in the muscle fibre will activate and an action potential in the muscle fibre will ensue. This action potential then propagates from the NMJ throughout the muscle fibre and triggers release of Ca 2+ release from the sarcoplasmic reticulum. The released Ca 2+ activates the contractile proteins within the muscle fibres, thus resulting in contraction of the fibre.

Failure of neuromuscular transmission can arise from both pre-synaptic dysfunction [Lambert Eaton syndrome (Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011 , 10, 1098-107), amyotrophic lateral sclerosis (Killian JM, Wilfong AA, Burnett L, Appel SH, Boland D. Decremental motor responses to repetitive nerve stimulation in ALS. Muscle Nerve, 1994, 17, 747-754), spinal muscular atrophy (Wadman Rl, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3. Neurology, 2012, 79, 2050-2055) and as a result of post-synaptic dysfunction as occurs in myasthenia gravis (Le Panse R, Berrih-Aknin S. Autoimmune myasthenia gravis: autoantibody

mechanisms and new developments on immune regulation. Curr Opin Neurol., 2013, 26, 569-576)]. Failure to excite and/or propagate action potentials in muscle can also arise from reduced muscle excitability such as in critical illness myopathy (CIM) (Latronico, N., Bolton, C.F. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011 , 10, 931 -941 ). In Lambert Eaton syndrome, an autoimmune attack against the pre-synaptic P/Q-type Ca 2+ channels results in markedly reduced Ca 2+ influx into the nerve terminal during the pre-synaptic action potential and consequently a reduced release of ACh into the synaptic cleft. In myasthenia gravis, the most common finding is an autoimmune attack on the post-synaptic membrane either against the nicotinic ACh receptors or the musk- receptor in the muscle fibre membrane 3 . Congenital forms of myasthenia are also known 5 . Common to disorders with neuromuscular transmission failure (Lambert Eaton syndrome, amyotrophic lateral sclerosis, spinal muscular atrophy and myasthenia gravis) is that the current flow generated by ACh receptor activation is markedly reduced, and EPPs therefore become insufficient to trigger muscle fibre action potentials. Neuromuscular blocking agents also reduce EPP by antagonizing ACh receptors. In CIM with reduced muscle excitability, the EPP may be of normal amplitude but they are still insufficient to trigger muscle fibre action potentials because the membrane potential threshold for action potential excitation has become more depolarized because of loss of function of voltage gated Na + channels in the muscle fibres.

While ACh release (Lambert Eaton, amyotrophic lateral sclerosis, spinal muscular atrophy), ACh receptor function (myasthenia gravis, neuromuscular blockade) and function of voltage gated Na + channels (CIM) are essential components in the synaptic transmission at NMJ, the magnitude of the EPP is also affected by inhibitory currents flowing in the NMJ region of muscle fibres. These currents tend to outbalance excitatory current through ACh receptors and, expectedly, they thereby tend to reduce EPP amplitude. The most important ion channel for carrying such inhibitory membrane currents in muscle fibres is the muscle-specific CIC-1 Cl ion channel (Kwiecihski H, Lehmann-Horn F, Rudel R. Membrane currents in human intercostal muscle at varied extracellular potassium. Muscle Nerve. 1984, 7, 465-469; Kwiecihski H, Lehmann-Horn F, Rudel R. Drug-induced myotonia in human intercostal muscle. Muscle Nerve. 1988, 11, 576-581 ; Pedersen, T.H., F. de Paoli, and O.B. Nielsen. Increased excitability of acidified skeletal muscle: role of chloride conductance. J. Gen. Physiol., 2005, 125, 237-246).

ACh esterase (AChE) inhibitors are traditionally used in the treatment of myasthenia gravis. This treatment leads to improvement in most patients but it is associated with side effects, some of which are serious (Mehndiratta MM, Pandey S, Kuntzer T.

Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev. 2014, Oct 13;10). Because ACh is an import neurotransmitter in the autonomic nervous system, delaying its breakdown can lead to gastric discomfort, diarrhea, salivation and muscle cramping. Overdosing is a serious concern as it can lead to muscle paralysis and respiratory failure, a situation commonly referred to as cholinergic crisis. Despite the serious side effects of AChE inhibitors, these drugs are today the treatment of choice for a number of disorders involving neuromuscular impairment. In patients where pyridostigmine (a parasympathomimetic and a reversible ACHE inhibitor) is insufficient, corticosteroid treatment (prednisone) and

immunosuppressive treatment (azathioprine) is used. Plasma exchange can be used to obtain a fast but transient improvement. Unfortunately, all of the currently-employed drug regimens for treatment of myasthenia gravis are associated with deleterious long-term consequences (Howard, J.F. Jr.

Adverse drug effects on neuromuscular transmission. Semin Neurol. 1990, 10, 89 - 102) despite research to identify new treatments (Gilhus, N.E. New England Journal of Medicine, 2016, 375, 2570-2581 ).

The CIC-1 ion channel (Pedersen, T.H., Riisager, A., Vincenzo de Paoli, F., Chen, T-Y, Nielsen, O.B. Role of physiological CIC-1 Cl ion channel regulation for the excitability and function of working skeletal muscle. J. Gen. Physiol. 2016, 147, 291 - 308) is emerging as a target for potential drugs, although its potential has been largely unrealized.

There have been publications of various ligands at the CIC-1 ion channels, see for example: Liantonio, A., Accardi, A., Carbonara, G., Fracchiolla, G., Loiodice, F., Tortorella P, Traverso S, Guida P, Pierno S, De Luca A, Camerino DC, Pusch M.

Molecular requisites for drug binding to muscle CLC-1 and renal CLC-K channel revealed by the use of phenoxy-alkyl derivatives of 2-(p-chlorophenoxy)propionic acid. Mol. Pharmacol., 2002, 62, 265 - 271 and Liantonio, A. et al., Structural requisites of 2- (p-chlorophenoxy)propionic acid analogues for activity on native rat skeletal muscle chloride conductance and on heterologously expressed CLC-1. Br. J. Phamacol., 2003, 129, 1255 - 1264.

In the article Liantonio, A., Pusch, M., Picollo, A., Guida, P., De Luca, A., Pierno, S., Fracchiolla, G., Loiodice, F., Tortorella, P., Conte-Camerino, D. Investigations of pharmacologic properties of the renal CLC-K1 chloride channel co-expressed with barttin by the use of 2-(p-chlorophenoxy)propionic acid derivatives and other structurally unrelated chloride hannels blockers. Journal of the American Society of Nephrology, 2004, 15, 13 - 20, ligands for CLC-K1 chloride channels were disclosed.

In Bettoni, G., Ferorelli, S., Loiodice, F., Tangari, N., Tortorella, V., Gasparrini, F.,

Misiti, D., Villani, C. Chiral oc-substituted oc-aryloxyacetic acids: synthesis, absolute configuration, chemical resolution, and direct separation by HPLC. Chirality, 1992, 4, 193 - 203, some further substituted phenoxyacetic acids were investigated. In the publication Pusch, M., Liantonio, A., Bertorello, L, Accardi, A., De Luca, A., Pierno, S., Tortorella, V., Conte-Camerino, D. Pharmacological characterization of chloride channels belonging to the CIC family by the use of chiral clofibric acid derivatives. Molecular Pharmacology, 2000, 58, 498 - 507, the authors disclosed effects of enantiomers of 2-(p-chlorophenoxy)propionic acid on CLC-1 and CLC-2 ion channels.

In the article Ferorelli, S., Loiodice, F., Tortorella, V., Conte-Camerino, D., De Luca, A.M. Carboxylic acids and skeletal muscle chloride channel conductance: effects on the biological activity induced by the introduction of methyl groups on the aromatic ring of chiral a-(4-chloro-phenoxy)alkanoic acids, Farmaco, 2001 , 56, 239 - 246, derivatives of (4-chloro-phenoxy)alkanoic acids were tested for skeletal muscle chloride

conductance.

In the publication: Conte-Camerino, D., Mambrini, M., DeLuca, A., Tricarico, D., Bryant, S.H., Tortorella, V., Bettoni, G. Enantiomers of clofibric acid analogs have opposite actions on rat skeletal muscle chloride channels, Pfluegers Archiv., 1988, 413, 105 - 107, enantiomers of clofibric acid were investigated, as well as Feller, D.R., Kamanna, V.S., Newman, H.A.I., Romstedt, K.J., Witiak, D.T., Bettoni, G., Bryant, S.H., Conte- Camerino, D., Loiodice, F., Tortorella, V. Dissociation of hypolipidemic and antiplatelet actions from adverse myotonic effects of clofibric acid related enantiomers. Journal of Medicinal Chemistry, 1987, 30, 1265 - 1267.

Edoardo Aromataris investigated 4-chlorophenoxyisobutyric acid derivatives in his PhD thesis“Pharmacology of the CIC-1 Chloride Channel”; see:

https://digital.library.adelaide.edu.aU/dspace/bitstream/ 2440/58973/8/02whole.pdf

In WO 2005/105727, Sandham et ai, reported a range of substituted phenoxyacetic acids, including 2-(4-chloro-2-cycloheptylphenoxy)acetic acid, as CRTh2 receptor antagonists for treating inflammatory or allergic conditions.

In WO 2006/037982, Bonnert et ai described a set of substituted phenoxyacetic acids for the treatment of respiratory disorders. In US 2006/021 1765, Pairaudeau et al. reported a further series of substituted biphenyloxy acetic acids for treatment of respiratory disorders

In WO 2016/202341 , Pedersen et at. reported a series of of phenoxypropionic acids and related compounds that appear to block the CIC-1 ion channel for use in treating, ameliorating and/or preventing neuromuscular disorders. However, they possess alternative structural features to those in the current invention.

Summary

The present invention comprises a new series of compounds that alleviate disorders of the neuromuscular junction through inhibition of CIC-1 channels.

It has been found that a set of novel compounds that inhibit CIC-1 ion channels are capable of restoring neuromuscular transmission, as evidenced by the data generated by investigation of the compound set in biological models described herein. These compounds thus constitute a new group of potential drugs that can be used to treat or ameliorate muscle weakness and muscle fatigue in neuromuscular junction disorders caused by disease or by neuromuscular blocking agents.

The present invention thus concerns the discovery of new CIC-1 ion channel inhibitors with application in the treatment of a range of conditions, such as reversal of block, ALS and myasthenic conditions, in which muscle activation by the nervous system is compromised and symptoms of weakness and fatigue are prominent.

In one aspect, the invention concerns a compound of Formula (I):

Formula (I) wherein:

- R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -

CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6

alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, -C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is selected from the group consisting of C1 -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, C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 1 2 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

- R 7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -0-Ci- 3 alkyl and -CH 2 -S-C I -3 alkyl;

- R 1 1 is independently selected from the group consisting of deuterium and F;

- R 1 2 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, for use in for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade. In another aspect, the invention concerns a compound of Formula (I):

Formula (I) wherein:

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

- R 2 is selected from the group consisting of C 2-6 alkyl * C 2-6 alkenyl, C 2-6 alkynyl,

C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is selected from the group consisting of C1-5 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, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH^O-C ! -S alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl; - 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;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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 2 is C(=0)-CH 3 , R 1 is Br and R 5 is H or Me then R 4 is not Me or CH 2 CHMe2; and with the proviso that when R 2 is CHMe2, R 1 is Br and R 5 is H or Me then R 4 is not Me.

In yet another aspect, the invention concerns a composition comprising a compound as defined herein.

Description of Drawings

Figure 1 : Panel A shows a schematic representation of the positioning of the three microelectrodes (\L, V 2 and V 3 ) when inserted in a single skeletal muscle fibre for G m determination. Please note that the drawing illustrates only the impaled fibre although it is part of an intact muscle that contains many such fibres. All electrodes recorded the membrane potential of the fibre and the two peripheral electrodes were used to inject current (-30 nA, 50 ms). The electrodes were inserted with known inter-electrode distances (X 1 , X 2 and X 3 ). After insertion, current was passed first via the Vi electrode and then via the V 3 electrode. The resulting deflections in the membrane voltage were measured by the other electrodes. The steady state deflections in membrane potential were measured and divided by the magnitude of the injected current (-30 nA) to obtain transfer resistances. These were next plotted against inter-electrode distances, and fitted to an exponential function (Panel B), from which G m could be calculated using linear cable theory. The approach described in panel A and B, was repeated for several muscle fibres in the muscle during exposure at increasing concentrations of compound A-19, with approx. 10 fibres at each concentration. Average G m at each concentration was plotted as a function of compound concentration in panel C, and fitted to a 4- parameter sigmoidal function from which the EC 50 value for the compound was obtained (dashed line) Figure 2: Panel A shows representative force traces before and after exposure to compound A-19. Force traces from a representative muscle stimulated to contract in 1 ) control condition before addition of neuromuscular blocking agent, 2) the force response to stimulation after 90 minutes incubation with Tubocurarine. Here the muscle displays severe neuromuscular transmission impediment, and 3) The muscle force response after addition of 50 mM compound A-19. Panel B shows average force (AUC) from 3 muscles relative to their initial force. The traces presented in panel A (1 , 2, 3), correspond to the dotted lines in panel B, respectively. Thus, force is lost due to 90 min incubation in tubocurarine and is subsequently recovered when compound A-19 is added.

Figure 3: Panel A illustrates the voltage protocol used to evoke currents in whole cell patches of CHO cells expressing human CIC-1 channels. Panel B shows

representative whole cell current traces from a patched CHO cell expressing human CIC-1 channels. Currents were evoked by applying the voltage protocol shown in Panel A.

Figure 4: Panel A shows a representative l/V plot of constant current density in a CIC- 1 expressing CHO cell before (circles) and after (squares) application of 100 mM of the CIC-1 inhibitor, 9-anthracenecarboxylic acid (9-AC, Sigma A89405). Panel B shows a l/V plot of instant tail current density from the same CIC-1 expressing CHO cell as illustrated in Panel A, before (circles) and after (squares) application of 100 mM 9-AC. Figure 5: Figure 5 shows representative plots of normalized instant tail currents from a CIC-1 expressing CHO cell patch before (circles) and after (squares) application of 100 mM 9-AC. The instant tail currents at each voltage step were normalized to the maximal tail current obtained following the (+)120 mV voltage step and fitted to a Boltzmann function to determine the half activation potential, Vi /2 .

Detailed description

Definitions

The terms “C1 -3 alkyl”, "Ci- 5 -alkyl" and "C 2-6 -alkyl" refers to a branched or unbranched alkyl group having from one to three, one to five or two to six carbon atoms

respectively, including but not limited to methyl, ethyl, prop-1 -yl, prop-2-yl, 2-methyl- prop-1 -yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop-1 -yl, but-1 -yl, but-2-yl, 3-methyl-but-1 - yl, 3-methyl-but-2-yl, pent-1 -yl, pent-2-yl, pent-3-yl, hex-1 -yl, hex-2-yl and hex-3-yl. The term "Ci- 5 -alkenyl" and "C 2-6 -alkenyl" refers to a branched or unbranched alkenyl group having from one to five or two to six carbon atoms respectively, two of which are connected by a double bond, including but not limited to ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl and hexenyl.

The term "Ci- 5 -alkynyl" and "C 2-6 -alkynyl" refers to a branched or unbranched alkynyl group having from one to five or two to six carbon atoms respectively, two of which are connected by a triple bond, including but not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl.

The term“-C(=0)-” refers to a carbonyl group and is used herein followed by a specification of the group connected thereto, such as for example the term“-C(=0)-Ci- 5 alkyl” which refers to a carbonyl group connected to a branched or unbranched alkyl group having from one to five carbon atoms, including but not limited to a carbonyl group connected to methyl, ethyl, prop-1 -yl, prop-2-yl, 2-methyl-prop-1 -yl, 2-methyl- prop-2-yl, 2,2-dimethyl-prop-1 -yl, but-1 -yl, but-2-yl, 3-methyl-but-1 -yl, 3-methyl-but-2-yl, pent-1 -yl, pent-2-yl or pent-3-yl.

The term "C 3 -5-cycloalkyl" and“C 3-6 cycloalkyl” refers to a group having three to five or three to six carbon atoms respectively including a monocyclic or bicyclic carbocycle, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl and cyclohexyl.

The term "Cs-e-cycloalkenyl" and“C 5 cycloalkenyl” refers to a group having five to six or five carbon atoms respectively including a monocyclic or bicyclic carbocycle wherein two carbon atoms in the ring are connected by a double bond, including but not limited to cyclobutenylmethyl, cyclobutenylethyl, cyclopentenyl, cyclopentenylmethyl and cyclohexenyl.

The term“half-life” as used herein is the time it takes for the compound to lose one-half of its pharmacologic activity. The term "plasma half-life" is the time that it takes the compound to lose one-half of its pharmacologic activity in the blood plasma.

The term“treatment” refers to the combating of a disease or disorder.“Treatment” or “treating,” as used herein, includes any desirable effect on the symptoms or pathology of a disease or condition as described herein, and may include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated. “Treatment” or“treating” does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof. In some

embodiments, the term“treatment” encompasses amelioration and prevention.

The term“amelioration” refers to moderation in the severity of the symptoms of a disease or condition. Improvement in a patient's condition, or the activity of making an effort to correct, or at least make more acceptable, conditions that are difficult to endure related to patient's conditions is considered“ameliorative” treatment.

The term“prevent” or“preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.

The term“reversal” or“reversing” refers to the ability of a compound to restore nerve- stimulated force in skeletal muscle exposed either ex vivo or in vivo to a non depolarizing neuromuscular blocking agent or another pharmaceutical that is able to depress neuromuscular transmission

The term“ester hydrolysing reagent” refers to a chemical reagent which is capable of converting an ester functional group to a carboxylic acid with elimination of the alcohol moiety of the original ester, including but not limited to acid, base, a fluoride source, PBr 3 , PCI 3 and lipase enzymes.

The term“non-depolarizing blockers” refers to pharmaceutical agents that antagonize the activation of acetylcholine receptors at the post-synaptic muscle fibre membrane by blocking the acetylcholine binding site on the receptor. These agents are used to block neuromuscular transmission and induce muscle paralysis in connection with surgery.

The term“recovery of force in muscle with neuromuscular dysfunction” refers to the ability of a compound to recover contractile force in nerve-stimulated healthy rat muscle after exposure to submaximal concentration of (1 15 nM) tubocurarine for 90 mins. Recovery of force is quantified as the percentage of the force prior to tubocurarine that is recovered by the compound. The term“total membrane conductance (Gm)” is the electrophysiological measure of the ability of ions to cross the muscle fibre surface membrane. It reflects the function of ion channels that are active in resting muscle fibres of which CIC-1 is known to contribute around 80 % in most animal species.

Compounds

It is within the scope of the present invention to provide a compound for use in treating, ameliorating and/or preventing neuromuscular disorders characterized in that the neuromuscular function is reduced. As disclosed herein, inhibition of CIC-1 improves or restores neuromuscular function. The compounds of the present invention comprise compounds capable of inhibiting the CIC-1 channel thereby improving or restoring neuromuscular function.

In one aspect, the invention relates to a compound of Formula (I):

Formula (I) wherein:

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

- R 2 is selected from the group consisting of C 2 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,

C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyi, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide; - R 4 is selected from the group consisting of Ci- 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 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH^O-C ! -S alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

- 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 -0-Ci- 3 alkyl and -CH 2 -S-CI- 3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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 2 is -C(=0)-CH 3 and R 1 is Br and R 5 is H or Me then R 4 is not -CH 3 or -CH 2 CH(CH 3 ) 2 and with the proviso that when R 2 is -CH(CH 3 ) 2 and R 1 is Br and R 5 is H or Me then R 4 is not -CH 3 .

In one aspect, the invention relates to a compound of Formula (I), wherein:

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

- R 2 is selected from the group consisting of ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, -C(=0)-methyl and -C(=0)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I;

- 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, Ci -5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 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 -OH, -CH 2 - 0-Ci- 3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

- R 7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br, I and -O-C 1-3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

- n is an integer 0 or 1 ;

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In an embodiment, R 5 is H.

In an embodiment, R 4 is selected from the group consisting of C 1-5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 .

In an embodiment, R 6 is selected from the group consisting of deuterium, F and -O-C 1-3 alkyl.

In an embodiment, R 7 is selected from the group consisting of deuterium, F and -O-C 1-3 alkyl.

In an embodiment, R 5 is H and R 4 is selected from the group consisting of C 1-5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 .

In an embodiment, R 5 is H and R 4 is selected from the group consisting of C 1-5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 , wherein R 7 is selected from the group consisting of deuterium, F and -O-C 1-3 alkyl.

In an embodiment, R 5 is H, R 6 is selected from the group consisting of deuterium, F and -O-C 1-3 alkyl and R 4 is selected from the group consisting of C 1-5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 , wherein R 7 is selected from the group consisting of deuterium, F and -O-C 1-3 alkyl.

In one embodiment, the invention relates to a compound of Formula (II):

wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 8 and R 9 are independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-C 1-3 alkyl, -CH 2 -SH, -CH^S-C^ alkyl, C 1-4 alkyl and C 2-4 alkenyl and wherein the C 1-4 alkyl and C 2-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

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

In one embodiment, the invention relates to a compound of Formula (III):

Formula (III) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 8 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-C 1-3 alkyl, -CH 2 -SH, -CH^S-C^ alkyl, C 1-4 alkyl and C 2-4 alkenyl and wherein the C 1-4 alkyl and C 2-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

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

In one embodiment, the invention relates to a compound of Formula (IV):

Formula (IV) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl; and

R 8 , R 9 and R 10 are independently selected from the group consisting of

hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, - S-C 1 -3 alkyl, -CH 2 -OH, -CH 2 -0-Ci- 3 alkyl, -CH 2 -SH, -CH 2 -S-CI- 3 alkyl, Ci -4 alkyl and C 2-4 alkenyl and wherein the Ci -4 alkyl and Ci -4 alkenyl group 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.

In one embodiment, the invention relates to a compound of Formula (V):

Formula (V) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl;

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In one embodiment, the invention relates to a compound of Formula (VI):

Formula (VI) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-CI -3 alkyl;

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

In one embodiment, the invention relates to a compound of Formula (VII):

Formula (VII) wherein:

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

R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2 -5 alkynyl, -C(=0)-C 3 -5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

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 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl; and

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 -0-Ci- 3 alkyl and -CH 2 -S-CI- 3 alkyl;

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

In one embodiment, the invention relates to a compound of Formula (VIII):

Formula (VIII) wherein:

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

R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ; R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, -CF 3 , -CCI3, -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. In one aspect, the invention relates to a compound of Formula (I):

Formula (I) wherein:

- R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6

alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, -C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is H;

- 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 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C1-3 alkyl, -S-C1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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.

In a specific embodiment, the compound is selected from the group consisting of:

In a specific embodiment, the compound is selected from the group consisting of:

(2S)-2-{4-bromo-2-[2-(methoxymethyl)cyclopropyl]phenoxy}prop anoic acid; (2S)-2-[4-bromo-2-(2,2-dichlorocyclopropyl)phenoxy]propanoic acid;

(2S)-2-{4-bromo-2-[(1 s,3s)-3-methoxycyclobutyl]phenoxy}propanoic acid; (2S)-2-{4-bromo-2-[(E)-2-bromoethenyl]phenoxy}propanoic acid;

(2/ : ?)-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropanoic acid;

(2S)-2-{4-bromo-2-[(1 S,2S)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-{4-bromo-2-[(1 R,2/ : ?)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)propanoic acid;

(2S)-2-{4-bromo-2-[(1 £)-2-cyanoeth-1 -en-1 -yl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)propanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)propanoic acid;

(2S)-2-(2-cyclopropyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(2-cyclobutyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclobutylphenoxy)propanoic acid;

tert-butyl (2S)-2-(4-chloro-2-propanoylphenoxy)propanoate;

(2S)-2-{4-chloro-2-[(2,2- 2 H 2 )propanoyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoic acid;

methyl (2S)-2-[4-chloro-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoate;

methyl (2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoate;

(2S)-2-(4-chloro-2-ethynylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-propanoylphenoxy)propanoic acid; sodium (2S)-2-(4-chloro-2-ethenylphenoxy)propanoate;

(2S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-propylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

methyl (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

(2/ : ?)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)-3-fluoro propanoic acid; (2S)-2-(2-cyclopropyl-4,6-difluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)propanoic acid;

(2S)-2-(2,4-difluoro-6-propanoylphenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-chlorophenoxy)propanoic acid;

(2S)-2-(4-fluoro-2-propanoylphenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-{2-[2-(benzyloxy)cyclobutyl]-4-chlorophenoxy}propa noic acid; (2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-[2,4-dibromo-6-(2-methoxyethyl)phenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(cyclopropylidenemethyl)phenoxy]propano ic acid; (2S)-2-(4-bromo-2-ethenyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-bromo-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(2,2-difluoroethenyl)-5-fluorophenoxy]p ropanoic acid; (2S)-2-(4-bromo-2-ethynylphenoxy)-2-cyclobutylacetic acid;

(2S)-2-(4-bromo-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-chloro-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)-4-fluorobutanoic acid;

(2S)-2-{4-bromo-2-[(1 E)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-{4-chloro-2-[(1 E)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)butanoic acid;

2-(4-bromo-2-cyclopropylphenoxy)acetic acid;

2-(4-bromo-2-ethynylphenoxy)acetic acid, and

(2S)-2-[4-bromo-2-(2,2-difluorocyclobutyl)phenoxy]propano ic acid. Methods of Treatment

In one aspect, the invention relates to the use of compounds of Formula (I) in treating, ameliorating and/or preventing a neuromuscular disorder. In one aspect, the invention relates to the use of compounds of Formula (I) in reversing and/or ameliorating a neuromuscular blockade. Thus in one aspect, the invention relates to a compound of Formula (I):

Formula (I) wherein:

- R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -

CHF 2 , -CHCI2, -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6

alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-Ci- 5 alkenyl, -C(=0)-Ci- 5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is selected from the group consisting of C1 -5 alkyl, C1 -5 alkenyl, C1 -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, C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3.6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1 -3 alkyl, -S-C 1 -3 alkyl, -CH 2 -OH, -CH 2 -0-C 1 -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

- 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 -0-Ci- 3 alkyl and -CH 2 -S-CI- 3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to a compound of Formula (I), wherein:

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

- R 2 is selected from the group consisting of ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, -C(=0)-methyl and -C(=0)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I;

- 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 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ; - R 6 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 -OH, -CH 2 - 0-Ci- 3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C 1 -3 alkyl;

- R 7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br and I;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

- n is an integer 0 or 1 ,

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

In an embodiment, R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-Ci- 5 alkenyl, - C(=0)-Ci- 5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

In an embodiment, R 5 is H.

In an embodiment, R 4 is selected from the group consisting of C 1 -5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 .

In an embodiment, R 6 is selected from the group consisting of deuterium, F and -O-C 1 -3 alkyl.

In an embodiment, R 7 is selected from the group consisting of deuterium, F and -O-C 1 -3 alkyl.

In an embodiment, R 5 is H and R 4 is selected from the group consisting of C 1 -5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 .

In an embodiment, R 5 is H and R 4 is selected from the group consisting of C 1 -5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 , wherein R 7 is selected from the group consisting of deuterium, F and -O-C 1 -3 alkyl.

In an embodiment, R 5 is H, R 6 is selected from the group consisting of deuterium, F and -O-C 1 -3 alkyl and R 4 is selected from the group consisting of C 1 -5 alkyl and C 3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 7 , wherein R 7 is selected from the group consisting of deuterium, F and -O-C 1-3 alkyl.

In one embodiment, the invention is related to a compound of Formula (II):

wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 8 and R 9 are independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -CH 2 -SH, -CH^S-C^ alkyl, C 1-4 alkyl and C 2-4 alkenyl and wherein the C 1-4 alkyl and C 2-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade. In one embodiment, the invention is related to a compound of Formula (III): wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 8 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -CH 2 -SH, -CH 2 -S-C I -3 alkyl, C^ alkyl and C 2- alkenyl and wherein the Ci -4 alkyl and C 2- alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl,

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

In one embodiment, the invention is related to a compound of Formula (IV):

Formula (IV) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci -3 alkyl, -S-Ci -3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl; and

R 8 , R 9 and R 10 are independently selected from the group consisting of

hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci -3 alkyl, - S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0-Ci- 3 alkyl, -CH 2 -SH, -CH 2 -S-C I ^ alkyl, Ci -4 alkyl and C 2- alkenyl and wherein the Ci -4 alkyl and C 2- alkenyl group 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, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

In one embodiment, the invention is related to a compound of Formula (V):

Formula (V) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci -3 alkyl, -S-Ci -3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl,

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

In one embodiment, the invention is related to a compound of Formula (VI):

Formula (VI) wherein: R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl,

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

In one embodiment, the invention is related to a compound of Formula (VII):

Formula (VII) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI2, -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,

C 3- 5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 4 is selected from the group consisting of C1 -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 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci -3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl; and

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 -0-Ci- 3 alkyl and -CH 2 -S-C I -3 alkyl,

or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade. In one embodiment, the invention is related to a compound of Formula (VIII):

Formula (VIII) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade. In one aspect, the invention relates to a compound of Formula (I):

Formula (I) wherein:

- R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -

CHF 2 , -CHCI2, -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6

alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, -C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is H;

- R 5 is selected from the group consisting of H, C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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 for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

In one embodiment, the compound for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a

neuromuscular blockade is selected from the group consisting of Compound A-1 , Compound A-2, Compound A-3, Compound A-4, Compound A-5, Compound A-6, Compound A-7, Compound A-8, Compound A-9, Compound A-10, Compound A-1 1 , Compound A-12, Compound A-13, Compound A-14, Compound A-15, Compound A- 16, Compound A-17, Compound A-18, Compound A-19, Compound A-20, Compound A-21 , Compound A-22, Compound A-23, Compound A-24, Compound A-25,

Compound A-26, Compound A-27, Compound A-28, Compound A-29, Compound A- 30, Compound A-31 , Compound A-32, Compound A-33, Compound A-34, Compound A-35, Compound A-36, Compound A-37 and Compound A-38.

In a specific embodiment, the compound for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade is selected from the group consisting of:

(2S)-2-{4-bromo-2-[2-(methoxymethyl)cyclopropyl]phenoxy}prop anoic acid; (2S)-2-[4-bromo-2-(2,2-dichlorocyclopropyl)phenoxy]propanoic acid;

(2S)-2-{4-bromo-2-[(1 s,3s)-3-methoxycyclobutyl]phenoxy}propanoic acid; (2S)-2-{4-bromo-2-[(E)-2-bromoethenyl]phenoxy}propanoic acid;

(2 ?)-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropanoic acid;

(2S)-2-{4-bromo-2-[(1 S,2S)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-{4-bromo-2-[(1 / : ?,2/ : ?)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid; (2S)-2-(4-bromo-2-ethynylphenoxy)propanoic acid;

(2S)-2-{4-bromo-2-[(1 £)-2-cyanoeth-1 -en-1 -yl]phenoxy}propanoic acid; (2S)-2-(4-bromo-2-cyclopropylphenoxy)propanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)propanoic acid;

(2S)-2-(2-cyclopropyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(2-cyclobutyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclobutylphenoxy)propanoic acid;

tert-butyl (2S)-2-(4-chloro-2-propanoylphenoxy)propanoate;

(2S)-2-{4-chloro-2-[(2,2- 2 H 2 )propanoyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoic acid;

methyl (2S)-2-[4-chloro-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoate; methyl (2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoate;

(2S)-2-(4-chloro-2-ethynylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-propanoylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethenylphenoxy)propanoate;

(2S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-propylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

methyl (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

(2/ : ?)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)-3-fluoro propanoic acid; (2S)-2-(2-cyclopropyl-4,6-difluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)propanoic acid;

(2S)-2-(2,4-difluoro-6-propanoylphenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-chlorophenoxy)propanoic acid;

(2S)-2-(4-fluoro-2-propanoylphenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-{2-[2-(benzyloxy)cyclobutyl]-4-chlorophenoxy}propa noic acid; (2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-[2,4-dibromo-6-(2-methoxyethyl)phenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(cyclopropylidenemethyl)phenoxy]propano ic acid; (2S)-2-(4-bromo-2-ethenyl-5-fluorophenoxy)propanoic acid; (2S)-2-(2-acetyl-4-bromo-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(2,2-difluoroethenyl)-5-fluorophenoxy]prop anoic acid; (2S)-2-(4-bromo-2-ethynylphenoxy)-2-cyclobutylacetic acid;

(2S)-2-(4-bromo-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-chloro-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)-4-fluorobutanoic acid;

(2S)-2-{4-bromo-2-[(1 £)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-{4-chloro-2-[(1 £)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)butanoic acid;

2-(4-bromo-2-cyclopropylphenoxy)acetic acid;

2-(4-bromo-2-ethynylphenoxy)acetic acid; and

(2S)-2-[4-bromo-2-(2,2-difluorocyclobutyl)phenoxy]propanoic acid.

In one embodiment, the compound or the compound for use according to the present invention has been modified in order to increase its half-life when administered to a patient, in particular its plasma half-life.

In one embodiment, the compound or the compound for use according to the present invention further comprises a moiety conjugated to said compound, thus generating a moiety-conjugated compound. In one embodiment, said moiety-conjugated compound has a plasma and/or serum half-life being longer than the plasma and/or serum half-life of the non-moiety conjugated compound.

In one embodiment, the moiety conjugated to the compound or compound for use according to the present invention, is one or more type(s) of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.

Neuromuscular disorders

The compound or compound for use of the present invention is used for treating, ameliorating and/or preventing a neuromuscular disorder, or reversing neuromuscular blockade caused by non-depolarizing neuromuscular blocker or antibiotic agent. The inventors of the present invention have shown that inhibition of CIC-1 channels strengthens neuromuscular transmission. CIC-1 function may therefore contribute to muscle weakness in conditions of compromised neuromuscular transmission.

Thus, in one embodiment of the present invention, the compound or the compound for use as described herein inhibits CIC-1 channels. Thus, it is appreciated that

compounds and/or compounds for use of Formula (I) inhibit CIC-1 channels.

The neuromuscular disorder may also include neuromuscular dysfunctions.

Neuromuscular disorders include for example disorders with symptoms of muscle weakness and fatigue. Such disorders may include conditions with reduced

neuromuscular transmission safety factor. In one embodiment the neuromuscular disorders are motor neuron disorders. Motor neuron disorders are disorders with reduced safety in the neuromuscular transmission. In one embodiment motor neuron disorders are selected from the group consisting of amyotrophic lateral sclerosis (ALS) (Killian JM, Wilfong AA, Burnett L, Appel SH, Boland D. Decremental motor responses to repetitive nerve stimulation in ALS. Muscle Nerve, 1994, 17, 747-754), spinal muscular atrophy (SMA) (Wadman Rl, Vrancken AF, van den Berg LH, van der Pol WL. Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3. Neurology, 2012, 79, 2050-2055), Charcot-Marie Tooth disease (Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A, Kleinle S, Boczonadi V, Steele H, Ramesh V, Franko E, Pyle A, Lochmuller H, Chinnery PF, Horvath R. Genetic heterogeneity of motor neuropathies. Neurology, 2017, 28;88(13):1226-1234), X-linked spinal and bulbar muscular atrophy (Yamada, M., Inaba, A., Shiojiri, T. X-linked spinal and bulbar muscular atrophy with myasthenic symptoms. Journal of the Neurological Sciences, 1997, 146, 183-185), Kennedy ' s disorder (Stevie, Z., Peric, S., Pavlovic, S., Basta, I., Lavrnic, D.,

Myasthenic symptoms in a patient with Kennedy's disorder. Acta Neurologica Belgica, 2014, 114, 71 -73), multifocal motor neuropathy (Roberts, M., Willison, H.J., Vincent, A., Newsom-Davis, J. Multifocal motor neuropathy human sera block distal motor nerve conduction in mice. Ann Neurol. 1995, 38, 1 1 1 -1 18), Guillain-Barre syndrome (Ansar, V., Valadi, N. Guillain-Barre Syndrome Prim. Care, 2015, 42, 189-193; poliomyelitis (Trojan, D.A., Gendron, D., Cashman, N.R. Electrophysiology and electrodiagnosis of the post-polio motor unit. Orthopedics, 1991 , 14, 1353-1361 , and Birk T.J. Poliomyelitis and the post-polio syndrome: exercise capacities and adaptation - current research, future directions, and widespread applicability. Med. Sci. Sports Exerc., 1993, 25, 466- 472), post-polio syndrome (Garcia, C.C., Potian, J.G., Hognason, K., Thyagarajan, B., Sultatos, L.G., Souayah, N., Routh, V.H., McArdle, J.J. Acetylcholinesterase deficiency contributes to neuromuscular junction dysfunction in type 1 diabetic neuropathy. Am. J. Physiol. Endocrinol. Metab., 2012, 15, E551 - 561 ) and sarcopenia (Gilmore K.J.,

Morat T., Doherty T.J., Rice C.L., Motor unit number estimation and neuromuscular fidelity in 3 stages of sarcopenia. 2017 55(5):676-684).

Thus, in one preferred embodiment of the present invention the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). In another preferred embodiment the neuromuscular disorder is spinal muscular atrophy (SMA). In another preferred embodiment the neuromuscular disorder is Charcot-Marie tooth disease (CMT). In another preferred embodiment the neuromuscular disorder is sarcopenia. In yet another preferred embodiment, the neuromuscular disorder is critical illness myopathy (CIM).

As stated above the neuromuscular disorders include for example disorders with symptoms of muscle weakness and fatigue. Such disorder may for example include diabetes (Burton, A. Take your pyridostigmine: that's an (ethical?) order! Lancet Neurol., 2003, 2, 268).

In one embodiment the compound or the compound for use of the present invention is used to prevent neuromuscular disorder. The compound or the compound for use may for example be used prophylactically against nerve gas that is known to cause symptoms of muscle weakness and fatigue (Kawamura, Y., Kihara, M., Nishimoto, K., Taki, M. Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports. Pathophysiology, 2003, 9, 189-194.

In another embodiment the neuromuscular disorders is chronic fatigue syndrome. Chronic fatigue syndrome (CFS) (Fletcher, S.N., Kennedy, D.D., Ghosh, I.R., Misra, V.P., Kiff, K., Coakley, J.H., Hinds, C.J. Persistent neuromuscular and

neurophysiologic abnormalities in long-term survivors of prolonged critical illness. Crit. Care Med. 2003, 31, 1012 - 1016) is the common name for a medical condition characterized by debilitating symptoms, including fatigue that lasts for a minimum of six months in adults. CFS may also be referred to as systemic exertion intolerance disorder (SEID), myalgic encephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronic fatigue immune dysfunction syndrome (CFIDS), or by several other terms. Symptoms of CFS include malaise after exertion; unrefreshing sleep, widespread muscle and joint pain, physical exhaustion, and muscle weakness.

In a further embodiment the neuromuscular disorder is a critical illness polyneuropathy (Angelini C. Spectrum of metabolic myopathies. Biochim. Biophys. Acta., 2015, 1852, 615 - 621 ) or CIM (Latronico, N., Bolton, C.F. Critical illness polyneuropathy and myopathy: a major cause of muscle weakness and paralysis. Lancet Neurol. 2011 , 10, 931 -941 ). Critical illness polyneuropathy and CIM are overlapping syndromes of widespread muscle weakness and neurological dysfunction developing in critically ill patients.

The neuromuscular disorder may also include metabolic myopathy (Milone, M., Wong, L.J. Diagnosis of mitochondrial myopathies. Mol. Genet. Metab., 2013, 1 10, 35 - 41 ) and mitochondrial myopathy (Srivastava, A., Hunter, J.M. Reversal of neuromuscular block. Br. J. Anaesth. 2009, 103, 1 15 - 129). Metabolic myopathies result from defects in biochemical metabolism that primarily affects muscle. These may include glycogen storage disorders, lipid storage disorder and 3-phosphocreatine stores disorder.

Mitochondrial myopathy is a type of myopathy associated with mitochondrial disorder. Symptoms of mitochondrial myopathies include muscular and neurological problems such as muscle weakness, exercise intolerance, hearing loss and trouble with balance and coordination.

In another embodiment the neuromuscular disorder is periodic paralysis, in particular hypokalemic periodic paralysis which is a disorder of skeletal muscle excitability that presents with recurrent episodes of weakness, often triggered by exercise, stress, or carbohydrate-rich meals (Wu, F., Mi, W., Cannon, S.C., Neurology, 2013, 80, 1 1 1 Q- 1 1 16 and Suetterlin, K. et at, Current Opinion Neurology, 2014, 27, 583-590) or hyperkalemic periodic paralysis which is an inherited autosomal dominant disorder that affects sodium channels in muscle cells and the ability to regulate potassium levels in the blood (Ammat, T. et at, Journal of General Physiology, 2015, 146, 509-525). In a preferred embodiment the neuromuscular disorder is a myasthenic condition. Myasthenic conditions are characterized by muscle weakness and neuromuscular transmission failure. Congenital myasthenia gravis (Finlayson, S., Beeson, D., Palace, J. Congenital myasthenic syndromes: an update. Pract. Neurol., 2013, 13, 80 - 91 ) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction.

Myasthenia gravis and Lambert-Eaton syndrome (Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011 , 10, 1098-107) are examples of myasthenic conditions. Myasthenia gravis is either an autoimmune or congenital neuromuscular disorder that leads to fluctuating muscle weakness and fatigue. In the most common cases, muscle weakness is caused by circulating antibodies that block ACh receptors at the postsynaptic neuromuscular junction, inhibiting the excitatory effects of the

neurotransmitter ACh on nicotinic ACh-receptors at neuromuscular junctions (Gilhus, N.E., Owe, J.F., Hoff, J.M., Romi, F., Skeie, G.O., Aarli, J.A. Myasthenia Gravis: A Review of Available Treatment Approaches, Autoimmune Diseases, 2011 , Article ID 84739). Lambert-Eaton myasthenic syndrome (also known as LEMS, Lambert-Eaton syndrome, or Eaton-Lambert syndrome) is a rare autoimmune disorder that is characterized by muscle weakness of the limbs. It is the result of an autoimmune reaction in which antibodies are formed against presynaptic voltage-gated calcium channels, and likely other nerve terminal proteins, in the neuromuscular junction.

Thus, in one embodiment of the present invention the neuromuscular disorder is myasthenia gravis. In another preferred embodiment the neuromuscular disorder is Lambert-Eaton syndrome.

Neuromuscular blockade is used in connection with surgery under general anesthesia. Reversing agents are used for more rapid and safer recovery of muscle function after such blockade. Complications with excessive muscle weakness after blockade during surgery can result in delayed weaning from mechanical ventilation and respiratory complications after the surgery. Since such complications have pronounced effects on outcome of the surgery and future quality of life of patients, there is a need for improved reversing agents (Murphy GS, Brull SJ. Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg. 2010 1 1 1 (1 ):120-8). Thus, in one embodiment, the neuromuscular disorder has been induced by a neuromuscular blocking agent. In one particular embodiment the neuromuscular disorder is muscle weakness caused by neuromuscular blockade after surgery. In another preferred embodiment of the present invention the compound or the compound for use is used for reversing and/or ameliorating neuromuscular blockade after surgery. In one embodiment, the neuromuscular blockade is drug induced. In one embodiment the neuromuscular blockade is induced by an antibiotic. In one embodiment the

neuromuscular blockade is induced by a non-depolarizing neuromuscular blocker.

Pharmaceutical formulations

In one embodiment, a composition comprising the compound or the compound for use, according to the present invention, is provided. The composition according to the present invention is used for treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade. Thus, it is preferred that the compositions and compounds described herein are pharmaceutically acceptable. In one embodiment the composition as described herein is in the form of a pharmaceutical formulation. In one embodiment, the composition as described herein further comprises a pharmaceutically acceptable carrier.

Combination therapy

The composition of the present invention may comprise further active

ingredients/agents or other components to increase the efficiency of the composition. Thus, in one embodiment the composition further comprises at least one further active agent. It is appreciated that the active agent is suitable for treating, preventing or ameliorating said neuromuscular disorder.

The active agent is in a preferred embodiment an acetylcholine esterase inhibitor. Said acetylcholine esterase inhibitor may for example be selected from the group consisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine,

pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin. Preferably the acetylcholine esterase inhibitor is selected from the group consisting of neostigmine, physostigmine and pyridostigmine. It is preferred that the acetylcholine esterase inhibitor is neostigmine or pyridostigmine.

The active agent may also be an immunosuppressive drug. Immunosuppressive drugs are drugs that suppress or reduce the strength of the body’s immune system. They are also known as anti-rejection drugs. Immunosuppressive drugs include but are not limited to glucocorticoids, corticosteroids, cytostatics, antibodies and drugs acting on immunophilins. In one embodiment the active agent is prednisone.

The active agent may also be an agent that is used in anti-myotonic treatment. Such agents include for example blockers of voltage gated Na + channels, and

aminoglycosides.

The active agent may also be an agent for reversing a neuromuscular blockade after surgery. Such agents include for example neostigmine or sugammadex (Org 25969, tradename Bridion). The active agent may also be an agent for increasing the Ca 2+ sensitivity of the contractile filaments in muscle. Such agents include tirasemtiv and CK-2127107 (Hwee, D.T., Kennedy, A.R., Hartman, J.J., Ryans, J., Durham, N., Malik, F.I., Jasper, J.R. The small-molecule fast skeletal troponin activator, CK-2127107, improves exercise tolerance in a rat model of heart failure. Journal of Pharmacology and Experimental Therapeutics, 2015, 353, 159 - 168).

The active agent may also be an agent for increasing ACh release by blocking voltage gated K + channels in the pre-synaptic terminal. Such agent includes 3,4-aminopyridine.

Methods

In one aspect, the present invention relates to a method of treating, preventing and/or ameliorating a neuromuscular disorder, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.

In one aspect, the present invention relates to a method of reversing and/or

ameliorating a neuromuscular blockade, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.

In one aspect, the present invention relates to a method for recovery of neuromuscular transmission, said method comprising administering a therapeutically effective amount of the compound or the compound for use as defined herein to a person in need thereof.

The person in need thereof may be a person having a neuromuscular disorder or a person at risk of developing a neuromuscular disorder or a person having symptoms of muscle weakness and/or fatigue. In another embodiment the person in need thereof is a person with reduced neuromuscular transmission safety with prolonged recovery after neuromuscular blockade. Types of neuromuscular disorders are defined herein above. In a preferred embodiment the person has, amyotrophic lateral sclerosis, spinal muscular atrophy, myasthenia gravis or Lambert-Eaton syndrome.

A therapeutically effective amount is an amount that produces a therapeutic response or desired effect in the person taking it. Administration routes, formulations and dosages can be optimized by persons of skill in the art.

The method of treatment may be combined with other methods that are known to treat, prevent and/or ameliorate neuromuscular disorders. The treatment method may for example be combined with administration of any of the agents mentioned herein above. In one embodiment the treatment is combined with administration of acetylcholine esterase inhibitor such as for example neostigmine or pyridostigmine.

Another aspect of the invention relates to use of a compound as defined herein, for the manufacture of a medicament for the treatment, prevention and/or amelioration of a neuromuscular disorder.

Another aspect relates to use of a compound as defined herein, for the manufacture of a medicament or a reversal agent for reversing and/or ameliorating a neuromuscular blockade after surgery. Method of manufacturing

In one aspect, the present invention relates to methods of manufacturing compounds or compounds for use according to formula (I).

One method for manufacturing the compounds or compounds for use according to the present invention comprises the steps of

a. reacting a compound having formula (IX)

wherein R 4 is as defined herein and R 1 1 is a protecting group, such as

selected from the group consisting of alkyl, alkenyl, akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring and -alkylene-Si-alkyl, with first a reagent capable of converting the alcohol (OH) into a leaving group and secondly with a compound having formula (X)

wherein R 1 , R 2 , R 3 and n are as defined herein and Y is O to generate a compound having formula (XI)

; and

duct compound of a) with an ester hydrolysing reagent thus generating a compound as defined herein. A second method for manufacturing the compounds or compounds for use according to the present invention comprises the steps of

a. reacting a compound having formula (XII)

wherein R 1 , R 2 , R 3 and n are as defined herein and Q is a leaving group, such as selected from the group consisting of fluorine and iodine, with a compound having formula (IX)

wherein R 4 is as defined herein, and R 1 1 a protecting group, such as selected from the group consisting of alkyl, alkenyl, akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring and -alkylene-Si-alkyl and Y is O to generate a compound having formula (XI)

wherein Y is O; and

b. reacting the product compound of a) with an ester hydrolysing reagent thus generating a compound as defined herein.

Yet a third method for manufacturing the compounds or compounds for use according to the present invention comprises the steps of a. reacting a compound having formula (XIII)

wherein R 4 is as defined herein, Z is OH and R 12 is a protecting group, such as an -Si-alkyl, with first a reagent capable of converting the alcohol (Z) into a leaving group and secondly with a compound having formula (X)

wherein R 1 , R 2 , R 3 and n are as defined herein, and Y is O to generate a

compound having formula (XIV)

b. reacting the product compound of a) with an ether cleaving reagent to generate a compound having formula (XV)

( cn ) ; and

c. reacting the product compound of b) with an oxidising agent thus generating a compound as defined herein. Items

1. A compound of Formula (I):

Formula (I) wherein:

- R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -

CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6

alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, -C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is selected from the group consisting of C1 -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, C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 1 2 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl;

- 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 -0-Ci- 3 alkyl and -CH 2 -S-CI- 3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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,

for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

2. The compound for use according to item 1 , wherein n is 0.

3. The compound for use according to any of the preceding items, wherein n is 1.

4. The compound for use according to any one of the preceding items, wherein R 1 is selected from the group consisting of F, Cl, Br and I.

5. The compound for use according to any one of the preceding items, wherein R 1 is Br or Cl.

6. The compound for use according to any one of the preceding items, wherein R 1 is -CF 3 or -CCI3.

7. The compound for use according to any one of the preceding items, wherein R 2 is selected from the group consisting of C 2.6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, -C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

8. The compound for use according to any one of the preceding items, wherein R 2 is selected from the group consisting of C 2.6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, and -C(=0)-Ci- 5 alkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 . 9. The compound for use according to any one of the preceding items, wherein R 2 is C alkyl or C 3-6 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

10. The compound for use according to any one of the preceding items, wherein R 2 is cyclopropyl or cyclobutyl, optionally substituted with one or more, identical or different, substituents R 6 .

11. The compound for use according to any one of the preceding items, wherein R 2 is selected from the group consisting of ethyl, n-propyl, iso-propyl, n-butyl, iso butyl, sec-butyl, tert-butyl, n-pentyl, 1 -methylbutyl, 1 -ethylpropyl, 2-methylbutyl, 1 ,1 -dimethylpropyl, 2,2-dimethylpropyl, 3,3-dimethylpropyl, 3,3-dimethylbutyl and hexyl, optionally substituted with one or more, identical or different, substituents R 6 .

12. The compound for use according to any one of the preceding items, wherein R 2 is ethyl or propyl. 13. The compound for use according to any one of the preceding items, wherein R 2 is C 2-6 alkenyl, C 2-6 alkynyl, or C 5-6 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

14. The compound for use according to any one of the preceding items, wherein R 2 is selected form the group consisting of allyl, homo-allyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, optionally substituted with one or more, identical or different, substituents R 6 .

15. The compound for use according to any one of the preceding items, wherein R 2 is vinyl, ethynyl or cyclopentenyl.

16. The compound for use according to any one of the preceding items, wherein R 2 is -C(=0)-Ci- 5 alkyl, optionally substituted with one or more, identical or different, substituents R 6 .

17. The compound for use according to any one of the preceding items, wherein R 2 is selected from the group consisting of -C(=0)-methyl, -C(=0)-ethyl, -C(=0)-n- propyl, -C(=0)-CHMe 2 , -C(=0)-n-butyl, -C(=0)-CH(Me)-Et, -C(=0)-CH 2 - CH(CH 3 ) 2 , -C(=0)-C(CH 3 ) 3 , -C(=0)-n-pentyl, -C(=0)-CH((CH 3 ))-CH 2 CH 2 CH 3 , - C(=0)-CH 2 -CH((CH 3 ))-CH 2 CH 3 , -C(=0)-CH 2 -CH 2 -CH(CH 3 ) 2 , -C(=0)- CH 2 C(CH 3 ) 3 , -C(=0)-CHEt 2 , -C(=0)-allyl, -C(=0)-homo-allyl, -C(=0)-vinyl, - C(=0)-crotyl, -C(=0)-butenyl, -C(=0)-pentenyl, -C(=0)-butadienyl, -C(=0)- pentadienyl, -C(=0)-ethynyl, -C(=0)-propynyl, -C(=0)-butynyl, -C(=0)-pentynyl, -C(=0)-cyclopropyl, -C(=0)-cyclobutyl, -C(=0)-cyclopentyl, and -C(=0)- cyclopentenyl, optionally substituted with one or more, identical or different, substituents R 6 . 18. The compound for use according to any one of the preceding items, wherein R 2 is -C(=0)CH 2 CH 3 or -C(=0)CH 3 , optionally substituted with one or more deuterium.

19. The compound for use according to any one of the preceding items, wherein R 3 is deuterium or tritium.

20. The compound for use according to any one of the preceding items, wherein R 3 is F, Cl, Br or I.

21. The compound for use according to any one of the preceding items, wherein R 3 is F.

22. The compound for use according to any one of the preceding items, wherein R 4 is C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R 7 .

23. The compound for use according to any one of the preceding items, wherein R 4 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, 1 -ethylpropyl, 2-methylbutyl, pentyl, allyl, homo-allyl, vinyl, crotyl, butenyl, pentenyl, butadienyl, pentadienyl, ethynyl, propynyl, butynyl, pentynyl, cyclopropyl, cyclobutyl, cyclopentyl and

cyclopentenyl optionally substituted with one or more, identical or different, substituents R 7 .

24. The compound for use according to any one of the preceding items, wherein R 4 is methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more, identical or different, substituents R 7 . 25. The compound for use according to any one of the preceding items, wherein R 4 is methyl.

26. The compound for use according to any one of the preceding items, wherein R 4 is ethyl. 27. The compound for use according to any one of the preceding items, wherein R 4 is n-propyl or isopropyl.

28. The compound for use according to any one of the preceding items, wherein R 4 is C1 -5 alkyl substituted with one or more F.

29. The compound for use according to any one of the preceding items, wherein R4 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

30. The compound for use according to any one of the preceding items, wherein R 4 is -CH 2 F.

31. The compound for use according to any one of the preceding items, wherein R 4 is selected from the group consisting of fluoromethyl, fluoroethyl and

fluoropropyl.

32. The compound for use according to any one of the preceding items, wherein R 4 is selected from the group consisting of fluoromethyl, difluoromethyl, 2- fluoroeth-1 -yl, (1 S)-1 -fluoroeth-1 -yl, (1 /=?)-1 -fluoroeth-1 -yl, (1 S)-1 ,2-difluoroeth-1 - yl, (1 ?)-1 ,2-difluoroeth-1 -yl, 3-fluoroprop-1 -yl, (1 S)- 1 -fluoroprop-1 -yl, (1 R)- 1 - fluoroprop-1 -yl, (2S)-2-fluoroprop-1 -yl, (2/=?)-2-fluoroprop-1 -yl, (1 S)-2-fluoro-1 - methyl-eth-1 -yl, (1 S)-2-fluoro-1 -methyl-eth-1 -yl and 2-fluoro-1 -(fluoromethyl)eth- 1 -yl.

33. The compound for use according to any one of the preceding items, wherein R 4 is selected from the group consisting of fluoromethyl, 2-fluoroeth-1 -yl, (1 S)-1 - fluoroeth-1 -yl and (1 R)-1 -fluoroeth-1 -yl.

34. The compound for use according to any one of the preceding items, wherein R 4 is C 3 -5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 7 . 35. The compound for use according to any one of the preceding items, wherein R 4 is selected from the group consisting of cyclopropyl, cyclopropylmethyl and cyclobutyl each of which may be optionally substituted with one or more, identical or different, substituents R 7 .

36. The compound for use according to any one of the preceding items, wherein R 5 is hydrogen.

37. The compound for use according to any one of the preceding items, wherein R 5 is C1 -5 alkyl.

38. The compound for use according to any one of the preceding items, wherein R 5 is methyl or tert-butyl.

39. The compound for use according to any one of the preceding items, wherein R 6 is deuterium or tritium.

40. The compound for use according to any one of the preceding items, wherein R 6 is F, Cl, Br, or I, preferably F.

41. The compound for use according to any one of the preceding items, wherein R 6 is -CN or isocyanide.

42. The compound for use according to any one of the preceding items, wherein R 6 is -O-C1 -3 alkyl or -CH2-O-C1 -3 alkyl.

43. The compound for use according to any one of the preceding items, wherein R 6 is selected from the group consisting of deuterium, F and -O-C1 -3 alkyl.

44. The compound for use according to any one of the preceding items, wherein R 7 is selected from the group consisting of deuterium, F and -O-C1 -3 alkyl.

45. The compound for use according to any one of the preceding items, wherein R 7 is F. 46. The compound for use according to any one of the preceding items, wherein:

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

- R 2 is selected from the group consisting of ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, -C(=0)-methyl and -C(=0)-ethyl, each of which may be optionally substituted with one or more, identical or different,

substituents R 6 ;

- R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I;

- 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 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 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 -OH, -CH 2 - 0-Ci- 3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

- R 7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br and I;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

- n is an integer 0 or 1.

47. The compound for use according to item 46, wherein R 1 is Cl or Br.

48. The compound for use according to any of items 46 to 47, wherein R 3 is

selected from the group consisting of deuterium and tritium. 49. The compound for use according to any of items 46 to 48, wherein R 4 is

selected from the group consisting of methyl, ethyl, cyclopropyl, n-propyl, - CH(CH 3 ) 2 , n-butyl, -CH 2 CH(CH 3 ) 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 and -CH 2 CF 3 .

50. The compound for use according to any one of the preceding items, wherein the compound is of Formula (II):

Formula (II) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI2, -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 8 and R 9 are independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -CH 2 -SH, -CH^S-C^ alkyl, Ci- 4 alkyl and C 2- alkenyl and wherein the Ci- alkyl and C 2- alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl.

51. The compound for use according to item 50, wherein R 1 is Br or Cl.

52. The compound for use according to any one of items 50 to 51 , wherein R 8 and R 9 are independently hydrogen, Br, F or -CN. 53. The compound for use according to any one of items 50 to 52, wherein R 4 is methyl.

54. The compound for use according to any one of the preceding items, wherein the compound is of Formula (III):

Formula (III) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI2, -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 8 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -CH 2 -SH, -CH^S-C^ alkyl, Ci- 4 alkyl and C 2- alkenyl and wherein the Ci- alkyl and C 2- alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl.

55. The compound for use according to item 54, wherein R 1 is Br or Cl.

56. The compound for use according to any one of items 54 to 55, wherein R 4 is methyl. 57. The compound for use according to any one of items 54 to 56, wherein R 8 is hydrogen.

58. The compound for use according to any one of the preceding items, wherein the compound is of Formula (IV):

Formula (IV) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI2, -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl; and

R 8 , R 9 and R 10 are independently selected from the group consisting of

hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, - S Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -CH 2 -SH, -CH^S-C^ alkyl, Ci -4 alkyl and C 2- alkenyl and wherein the Ci -4 alkyl and C 2- alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 .

59. The compound for use according to item 58, wherein R 1 is F, Br or Cl.

60. The compound for use according to any one of items 58 to 59, wherein R 9 and R 10 are independently hydrogen or deuterium. 61. The compound for use according to any one of items 58 to 60, wherein R 8 is hydrogen, methyl or ethyl.

62. The compound for use according to any one of items 58 to 61 , wherein R 4 is methyl. 63. The compound for use according to any one of the preceding items, wherein R 8 , R 9 and R 1 0 are identical groups.

64. The compound for use according to any one of the preceding items, wherein R 8 and R 9 are identical groups. 65. The compound for use according to any one of the preceding items, wherein R 9 and R 1 0 are identical groups.

66. The compound for use according to any one of the preceding items, wherein R 8 and R 9 and are different groups.

67. The compound for use according to any one of the preceding items, wherein R 8 , R 9 and R 1 0 are different groups.

68. The compound for use according to any one of the preceding items, wherein R 8 is different from R 9 and R 10 .

69. The compound for use according to any one of the preceding items, wherein the compound is of Formula (V):

Formula (V) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl.

70. The compound for use according to item 69, wherein R 1 is Br, F or Cl.

71. The compound for use according to any one of items 69 to 70, wherein R 6 is independently hydrogen or -OCH 3 .

72. The compound for use according to any one of items 69 to 71 , wherein R 4 is methyl.

73. The compound for use according to any one of the preceding items, wherein the compound is of Formula (VI):

Formula (VI) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl. 74. The compound for use according to item 73, wherein R 1 is Br, F or Cl.

75. The compound for use according to any one of items 73 to 74, wherein R 6 is independently hydrogen, Cl, -CH 2 OCH 3 or -CH 2 OH. 76. The compound for use according to any one of items 73 to 75, wherein R 4 is methyl.

77. The compound for use according to any one of the preceding items, wherein the compound is of Formula (VII):

Formula (VII) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI2, -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl,

C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

R 4 is selected from the group consisting of C1 -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 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl; and

R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -0-Ci- 3 alkyl and -CH 2 -S-C I -3 alkyl.

78. The compound for use according to item 77, wherein R 1 is Br, F or Cl. 79. The compound for use according to any one of items 77 to 78, wherein R 2 is cyclopropyl.

80. The compound for use according to any one of items 77 to 79, wherein R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F

81. The compound for use according to any one of items 77 to 80, wherein R 4 is methyl.

82. The compound for use according to any one of the preceding items, wherein the compound is of Formula (VIII):

Formula (VIII) wherein:

R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2 -5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl. The compound for use according to item 82, wherein R 1 is Br, F or Cl. The compound for use according to any one of items 82 to 83, wherein R 2 is cyclopropyl or cyclobutyl. The compound for use according to any one of items 82 to 84, wherein R 3 is hydrogen, deuterium, tritium or F. The compound for use according to any one of the preceding items wherein the compound is selected from the group consisting of:

(2S)-2-{4-bromo-2-[2-(methoxymethyl)cyclopropyl]phenoxy}prop anoic acid; (2S)-2-[4-bromo-2-(2,2-dichlorocyclopropyl)phenoxy]propanoic acid;

(2S)-2-{4-bromo-2-[(1 s,3s)-3-methoxycyclobutyl]phenoxy}propanoic acid; (2S)-2-{4-bromo-2-[(E)-2-bromoethenyl]phenoxy}propanoic acid;

(2 ?)-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropanoic acid;

(2S)-2-{4-bromo-2-[(1 S,2S)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-{4-bromo-2-[(1 F?,2/ : ?)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)propanoic acid;

(2S)-2-{4-bromo-2-[(1 £)-2-cyanoeth-1 -en-1 -yl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)propanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)propanoic acid;

(2S)-2-(2-cyclopropyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(2-cyclobutyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclobutylphenoxy)propanoic acid;

tert-butyl (2S)-2-(4-chloro-2-propanoylphenoxy)propanoate;

(2S)-2-{4-chloro-2-[(2,2- 2 H 2 )propanoyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoic acid;

methyl (2S)-2-[4-chloro-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoate;

methyl (2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoate;

(2S)-2-(4-chloro-2-ethynylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-propanoylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethenylphenoxy)propanoate;

(2S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid; sodium (2S)-2-(4-chloro-2-propylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

methyl (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

(2/ : ?)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)-3-fluoro propanoic acid;

(2S)-2-(2-cyclopropyl-4,6-difluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)propanoic acid;

(2S)-2-(2,4-difluoro-6-propanoylphenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-chlorophenoxy)propanoic acid;

(2S)-2-(4-fluoro-2-propanoylphenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-{2-[2-(benzyloxy)cyclobutyl]-4-chlorophenoxy}propanoi c acid;

(2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-[2,4-dibromo-6-(2-methoxyethyl)phenoxy]propanoic acid;

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

(2S)-2-(4-bromo-2-ethenyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-bromo-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(2,2-difluoroethenyl)-5-fluorophenoxy]prop anoic acid; (2S)-2-(4-bromo-2-ethynylphenoxy)-2-cyclobutylacetic acid;

(2S)-2-(4-bromo-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-chloro-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)-4-fluorobutanoic acid;

(2S)-2-{4-bromo-2-[(1 E)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-{4-chloro-2-[(1 E)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)butanoic acid; and

(2S)-2-[4-bromo-2-(2,2-difluorocyclobutyl)phenoxy]propanoic acid. The compound for use according to any one of the preceding items, wherein the compound has activity on CIC-1 receptor. 88. The compound for use according to any one of the preceding items, wherein the compound is an inhibitor of the CIC-1 ion channel.

89. The compound for use according to item 86, wherein the EC 5 o <50 mM,

preferably <40 mM, more preferably <30 mM, more preferably <20 mM, more preferably <15 mM, even more preferably <10 mM and most preferably <5 mM.

90. The compound for use according to any one of the preceding items, wherein the recovery of force in muscles with neuromuscular dysfunction is >5%, preferably >10%, more preferably >15%, more preferably >20%, more preferably >25%, even more preferably >30% and most preferably >35%. 91. The compound for use according to any one of the preceding items, wherein the compound improves the recovered force in isolated rat soleus muscles after exposure to tubocurarine.

92. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is myasthenia gravis. 93. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is autoimmune myasthenia gravis.

94. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is congenital myasthenia gravis.

95. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is Lambert-Eaton Syndrome.

96. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is critical illness myopathy.

97. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). 98. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is spinal muscular atrophy (SMA).

99. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is critical illness myopathy (CIM). 100. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is Charcot-Marie tooth disease (CMT).

101. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is sarcopenia. 102. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is reversal diabetic polyneuropathy.

103. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is periodic paralysis.

104. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is hyperkalemic periodic paralysis or hypokalemic periodic paralysis.

105. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is selected from the group consisting of Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, and critical illness polyneuropathy.

106. The compound for use according to any one of the preceding items, wherein the compound is for use in the treatment of symptoms of an indication selected from the group consisting of myasthenia gravis (such as autoimmune and congenital 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, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. 107. The compound for use according to any one of the preceding items wherein the neuromuscular disorder has been induced by a neuromuscular blocking agent.

108. The compound for use according to any one of the preceding items, wherein the neuromuscular blockade is neuromuscular blockade after surgery.

109. The compound for use according to any one of the preceding items, wherein the neuromuscular blockade is drug induced. 110. The compound for use according to item 109, wherein the drug is an antibiotic.

1 1 1. The compound for use according to item 109, wherein the drug is a non

depolarizing neuromuscular blocker.

112. The compound for use according to any one of the preceding items, wherein said compound further has been modified in order to increase its half-life when administered to a patient, in particular its plasma half-life.

113. The compound for use according to any one of the preceding items, wherein said compound further comprises a moiety conjugated to said compound, thus generating a moiety-conjugated compound. 114. The compound for use according to any one of the preceding items, wherein the moiety-conjugated compound has a plasma and/or serum half-life being longer than the plasma and/or serum half-life of the non-moiety conjugated compound.

115. The compound for use according to any one of the preceding items, wherein the moiety conjugated to the compound is one or more type(s) of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.

116. The compound for use according to any one of the preceding items, wherein said compound is comprised in a composition.

117. The compound for use according to item 1 16, wherein the composition is a pharmaceutical composition.

118. The compound for use according to any one of items 1 16 to 1 17, wherein the composition further comprises a pharmaceutically acceptable carrier.

119. The compound for use according to any one of items 1 16 to 1 18, wherein the composition further comprises at least one further active agent. 120. The compound for use according to item 1 19, wherein said further active agent is suitable for treating, preventing or ameliorating said neuromuscular disorder.

121. The compound for use according to any one of itemsl 19 to 120, wherein said further active agent is an acetylcholine esterase inhibitor. 122. The compound for use according to item 121 , wherein said acetylcholine esterase inhibitor is selected from the group consisting of delta-9- tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives,

galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin.

123. The compound for use according to item 121 , wherein said acetylcholine

esterase inhibitor is neostigmine or pyridostigmine.

124. The compound for use according to any one of items 1 19 to 120, wherein said further active agent is suggamadex.

125. The compound for use according to any one of items 1 19 to 120, wherein said further active agent is tirasemtiv.

126. The compound for use according to any one of items 1 19 to 120, wherein said further active agent is 3,4-aminopyridine. 127. A method of treating, preventing and/or ameliorating a neuromuscular disorder, said method comprising administering a therapeutically effective amount of the compound as defined in any one of the preceding items to a person in need thereof.

128. Use of a compound as defined in any one of items 1 to 86, for the manufacture of a medicament for the treatment, prevention and/or amelioration of a neuromuscular disorder, and/or for reversing and/or ameliorating of a neuromuscular blockade.

129. A method of reversing and/or ameliorating a neuromuscular blockade, said

method comprising administering a therapeutically effective amount of the compound as defined in any one of items 1 to 86 to a person in need thereof.

130. A method for recovery of neuromuscular transmission, said method comprising administering a therapeutically effective amount of the compound as defined in any one of items 1 to 86 to a person in need thereof. A method for recovering neuromuscular transmission, the method comprising administering a compound as defined in any one of items 1 to 86 to an individual in need thereof. A compound of Formula (I):

Formula (I) wherein:

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

- R 2 is selected from the group consisting of C 2 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, -

C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is selected from the group consisting of C1-5 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, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ; - R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH2-OH, -CH 2 -0-C 1-3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C 1-3 alkyl;

- R 7 is independently selected from the group consisting of deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -0-C I -3 alkyl and -CH2-S-C I -3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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.

133. The compound according to item 132, with the proviso that when R 2 is

cyclohexane, R 1 is Cl, n is 0 and R 4 is -CH 3 then R 5 is not H or -CH2CH3 134. The compound according to any of items 132 to 133, with the proviso that when

R 2 is C(=0)-CH 3 , R 1 is Br, n is 0 and R 5 is H then R 4 is not Me or CH 2 CHMe2; and with the proviso that when R 2 is CHMe2, R 1 is Br, n is 0 and R 5 is H then R 4 is not Me.

135. The compound according to any of items 132 to 134, with the proviso that when R 2 is Et, R 1 is Cl, n is 0 and R 5 is H then R 4 is not Me; and with the proviso that when R 2 is ethenyl, R 1 is Cl, n is 0 and R 5 is Et then R 4 is not prop-1 -en-3-yl; and with the proviso that when R 2 is -C(=0)-CH 3 , R 1 is Cl, n is 0 or 1 , R 3 is Cl, and R 5 is Et then R 4 is not Me; and with the proviso that when R 2 is -C(=0)-CH 3 , R 1 is Br, n is 0 and R 5 is Et then R 4 is not Me.

136. The compound according to any of items 132 to 135, wherein n is 0.

137. The compound according to any of items 132 to 135, wherein n is 1 .

138. The compound according to any one of items 132 to 137, wherein R 1 is Br or Cl.

139. The compound according to any one of items 132 to 138, wherein R 1 is Br.

140. The compound according to any one of items 132 to 139, wherein R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-5 cycloalkyl, C 5 cycloalkenyl, and -C(=0)-Ci- 5 alkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

141. The compound according to any one of items 132 to 139, wherein R 2 is C 2-6 alkyl or C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 .

142. The compound according to any one of items 132 to 139, wherein R 2 is

cyclopropyl or cyclobutyl, optionally substituted with one or more, identical or different, substituents R 6 .

143. The compound according to any one of items 132 to 142, wherein R 2 is selected from the group consisting of ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl, n-pentyl, 1 -methylbutyl, 1 -ethylpropyl, 2-methylbutyl, 1 ,1 - dimethylpropyl, 2,2-dimethylpropyl, 3,3-dimethylpropyl, 3,3-dimethylbutyl and hexyl, optionally substituted with one or more, identical or different, substituents R 6 .

144. The compound according to any one of items 132 to 143, wherein R 2 is ethyl or propyl.

145. The compound according to any one of items 132 to 144, wherein R 2 is C 2-6 alkenyl, C 2-6 alkynyl, or C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 . 146. The compound according to any one of items 132 to 145, wherein R 2 is selected form the group consisting of allyl, homo-allyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclopentenyl, optionally substituted with one or more, identical or different, substituents R 6 . 147. The compound according to any one of items 132 to 146, wherein R 2 is vinyl, ethynyl or cyclopentenyl.

148. The compound according to any one of items 132 to 147, wherein R 2 is -C(=0)- C1 -5 alkyl, optionally substituted with one or more, identical or different, substituents R 6 . 149. The compound according to any one of items 132 to 148, wherein R 2 is selected from the group consisting of -C(=0)-methyl, -C(=0)-ethyl, -C(=0)-n-propyl, - C(=0)-CH(CH 3 ) 2 , -C(=0)-n-butyl, -C(=0)-CH((CH 3 ))-Et, -C(=0)-CH 2 -CH(CH 3 ) 2 , - C(=0)-C(CH 3 ) 3 , -C(=0)-n-pentyl, -C(=0)-CH(CH 3 )-CH 2 CH 2 CH 3 , -C(=0)-CH 2 - CH(CH 3 )-CH 2 CH 3 , -C(=0)-CH 2 -CH 2 -CH(CH 3 ) 2 , -C(=0)-CH 2 C(CH 3 ) 3 , -C(=0)-

CHEt 2 , -C(=0)-allyl, -C(=0)-homo-allyl, -C(=0)-vinyl, -C(=0)-crotyl, -C(=0)- butenyl, -C(=0)-pentenyl, -C(=0)-butadienyl, -C(=0)-pentadienyl, -C(=0)- ethynyl, -C(=0)-propynyl, -C(=0)-butynyl, -C(=0)-pentynyl, -C(=0)-cyclopropyl, -C(=0)-cyclobutyl, -C(=0)-cyclopentyl, and -C(=0)-cyclopentenyl, optionally substituted with one or more, identical or different, substituents R 6 .

150. The compound according to any one of items 132 to 149, wherein R 2 is - C(=0)CH 2 CH 3 or -C(=0)CH 3 , optionally substituted with one or more deuterium.

151. The compound according to any one of items 132 to 150, wherein R 3 is

deuterium or tritium. 152. The compound according to any one of items 132 to 151 , wherein R 3 is F, Cl, Br or I.

153. The compound according to any one of items 132 to 152, wherein R 3 is F.

154. The compound according to any one of items 132 to 153, wherein R 4 is Ci -5 alkyl optionally substituted with one or more, identical or different, substituents R 7 .

155. The compound according to any one of items 132 to 154, wherein R 4 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1 -ethylpropyl, 2-methylbutyl, pentyl, allyl, homo-allyl, vinyl, crotyl, butenyl, pentenyl, butadienyl, pentadienyl, ethynyl, propynyl, butynyl, pentynyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclopentenyl optionally substituted with one or more, identical or different, substituents R 7 .

156. The compound according to any one of items 132 to 155, wherein R 4 is methyl, ethyl, n-propyl or isopropyl, optionally substituted with one or more, identical or different, substituents R 7 .

157. The compound according to any one of items 132 to 156, wherein R 4 is methyl. 158. The compound according to any one of items 132 to 156, wherein R 4 is ethyl.

159. The compound according to any one of items 132 to 156, wherein R 4 is n-propyl or isopropyl.

160. The compound according to any one of items 132 to 156, wherein R 4 is Ci -5 alkyl substituted with one or more F.

161. The compound according to any one of items 132 to 160, wherein R 4 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

162. The compound according to any one of items 132 to 161 , wherein R 4 is -CH 2 F. 163. The compound according to any one of items 132 to 161 , wherein R 4 is selected from the group consisting of fluoromethyl, fluoroethyl and fluoropropyl.

164. The compound according to any one of items 132 to 163, wherein R 4 is selected from the group consisting of fluoromethyl, difluoromethyl, 2-fluoroeth-1 -yl, (1 S)- 1 -fluoroeth-1 -yl, (1 R)-1 -fluoroeth-1 -yl, (1 S)-1 ,2-difluoroeth-1 -yl, (1 R)-1 ,2- difluoroeth-1 -yl, 3-fluoroprop-1 -yl, (1 S)-1 -fluoroprop-1 -yl, (1 R)- 1 -fluoroprop-1 -yl,

(2S)-2-fluoroprop-1 -yl, (2R)-2-fluoroprop-1 -yl, (1 S)-2-fluoro-1 -methyl-eth-1 -yl,

(1 S)-2-fluoro-1 -methyl-eth-1 -yl and 2-fluoro-1 -(fluoromethyl)eth-l -yl.

165. The compound according to any one of items 132 to 164, wherein R 4 is selected from the group consisting of fluoromethyl, 2-fluoroeth-1 -yl, (1 S)-1 -fluoroeth-1 -yl and (1 R)-1 -fluoroeth-1 -yl.

166. The compound for use according to any one of items 132 to 161 , wherein R 4 is C 3 -5 cycloalkyl optionally substituted with one or more, identical or different, substituents R 7 .

167. The compound for use according to any one of items 132 to 161 , wherein R 4 is selected from the group consisting of cyclopropyl, cyclopropylmethyl and cyclobutyl each of which may be optionally substituted with one or more, identical or different, substituents R 7 .

168. The compound according to any one of items 132 to 167, wherein R 5 is H. 169. The compound according to any one of items 132 to 168, wherein R 5 is Ci -5 alkyl.

170. The compound according to any one of items 132 to 169, wherein R 5 is methyl or tert-butyl.

171. The compound according to any one of items 132 to 170, wherein R 6 is

deuterium or tritium.

172. The compound according to any one of items 132 to 171 , wherein R 6 is F, Cl, Br, or I, preferably F.

173. The compound according to any one of items 132 to 172, wherein R 6 is -CN or isocyanide.

174. The compound according to any one of items 132 to 173, wherein R 6 is -O-C1 -3 alkyl or -CH2-O-C1 -3 alkyl.

175. The compound for use according to any one of items 132 to 174, wherein R 6 is selected from the group consisting of deuterium, F and -O-C1-3 alkyl. 176. The compound for use according to any one of items 132 to 175, wherein R 7 is selected from the group consisting of deuterium, F and -O-C1-3 alkyl.

177. The compound according to any one of items 132 to 176, wherein R 7 is F.

178. The compound according to any one of items 132 to 177, wherein:

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

- R 2 is selected from the group consisting of ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, -C(=0)-methyl and -C(=0)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of deuterium, tritium, F, Cl, Br and I; - R 4 is selected from the group consisting of C1-5 alkyl, C 2-5 alkenyl, C 2-5

alkynyl, C3-5 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, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 12 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ;

- R 6 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 -OH, -CH 2 -

0-Ci- 3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl;

- R 7 is independently selected from the group consisting of deuterium, tritium,

F, Cl, Br and I;

- R 11 is independently selected from the group consisting of deuterium and F; - R 12 is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and

- n is an integer 0 or 1.

The compound according to item 178, wherein R 1 is Cl or Br.

The compound according to any one of items 178 to 179, wherein R 3 is selected from the group consisting of deuterium and tritium. The compound according to any one of items 178 to 180, wherein R 4 is selected from the group consisting of methyl, ethyl, cyclopropyl, n-propyl, -CHMe 2 , n- butyl, -CH 2 CHMe 2 , -CH 2 F, -CH 2 CH 2 F, -CH 2 CHF 2 and -CH 2 CF 3 . The compound according to any one of items 132 to 181 , wherein the compound is of Formula (II):

Formula (II) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; R 8 and R 9 are independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1 -3 alkyl, -S-C 1 -3 alkyl, -CH 2 -OH, -CH 2 -0-C 1 -3 alkyl, -CH 2 -SH, -CH^S-C^ alkyl, C 1 -4 alkyl and C 2-4 alkenyl and wherein the C 1 -4 alkyl and C 2-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1 -3 alkyl, -S-C 1 -3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl.

183. The compound according to item 182, wherein R 1 is Br or Cl.

184. The compound according to any one of items 182 to 183, wherein R 8 and R 9 are independently hydrogen, Br, F or -CN.

185. The compound according to any one of items 182 to 184, wherein R 4 is methyl.

186. The compound according to any one of items 132 to 185, wherein the

compound is of Formula (III):

Formula (III) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 8 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1 -3 alkyl, -S-C 1 -3 alkyl, -CH 2 -OH, -CH 2 -0·^ alkyl, -CH 2 -SH, -CH^S-C^ alkyl, Ci- 4 alkyl and C 2-4 alkenyl and wherein the Ci- 4 alkyl and C 2-4 alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 ; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1 -3 alkyl, -S-C 1 -3 alkyl, -CH 2 -OH, -CF^-O-C^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CF^-S-C^ alkyl.

The compound according to item 186, wherein R 1 is Br or Cl.

The compound according to any one of items 186 to 187, wherein R 4 is methyl.

The compound according to any one of items 186 to 188, wherein R 8 is hydrogen.

The compound according to any one of items 132 to 188, wherein the compound is of Formula (IV):

Formula (IV) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F;

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1 -3 alkyl, -S-C 1 -3 alkyl, -CH 2 -OH, -CH 2 -0-C 1-3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl; and

R 8 , R 9 and R 10 are independently selected from the group consisting of

hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -

S-Ci alkyl, -CH 2 -OH, -CH^O-C^ alkyl, -CH 2 -SH, -CH^S-C^ alkyl, C alkyl and C 2- alkenyl and wherein the C 1 -4 alkyl and C 2- alkenyl group may be optionally substituted with one or more, identical or different, substituents R 6 .

191. The compound according to item 190, wherein R 1 is Br or Cl.

192. The compound according to any one of items 190 to 191 , wherein R 9 and R 10 are independently hydrogen or deuterium.

193. The compound according to any one of items 190 to 192, wherein R 8 is

hydrogen, methyl or ethyl.

194. The compound according to any one of items 190 to 193, wherein R 4 is methyl.

195. The compound according to any one of items 132 to 194, wherein R 8 , R 9 and R 10 are identical groups.

196. The compound according to any one of items 132 to 195, wherein R 8 and R 9 are identical groups.

197. The compound according to any one of items 132 to 196, wherein R 9 and R 10 are identical groups.

198. The compound according to any one of items 132 to 197, wherein R 8 and R 9 and are different groups.

199. The compound according to any one of items 132 to 198, wherein R 8 , R 9 and R 10 are different groups.

200 The compound according to any one of items 132 to 199, wherein R 8 is different from R 9 and R 10 .

201 The compound according to any one of items 132 to 200, wherein the

compound is of Formula (V):

Formula (V) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-C 1-3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl. 202. The compound according to item 201 , wherein R 1 is Br or Cl.

203. The compound according to any one of items 201 to 202, wherein R 6 is

independently hydrogen or -OCH 3 .

204. The compound according to any one of items 201 to 203, wherein R 4 is methyl.

205. The compound according to any one of items 132 to 204, wherein the

compound is of Formula (VI):

Formula (VI) wherein:

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

R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1 -3 alkyl, -S-C 1 -3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-CI -3 alkyl.

The compound according to item 205, wherein R 1 is Br or Cl.

The compound according to any one of items 205 to 206, wherein R 6 is independently hydrogen, Cl, -CH 2 OCH 3 or -CH 2 OH.

The compound according to any one of items 205 to 207, wherein R 4 is methyl.

The compound according to any one of items 132 to 208, wherein the compound is of Formula (VII):

Formula (VII) wherein:

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

R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci -5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

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 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-C 1-3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH^S-C^ alkyl; and

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 -0-Ci- 3 alkyl and -CH 2 -S-CI- 3 alkyl. The compound according to item 209, wherein R 1 is Br or Cl. The compound according to any one of items 209 to 210, wherein R 2 is cyclopropyl. The compound according to any one of items 209 to 21 1 , wherein R 4 is methyl, ethyl, n-propyl, isopropyl or -CH 2 F The compound according to any one of items 209 to 212, wherein R 4 is methyl. The compound according to any one of items 132 to 213, wherein the compound is of Formula (VIII):

Formula (VIII) wherein:

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

R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-5 cycloalkyl, C 5 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, - C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ; R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide; and

R 6 is independently selected from the group consisting of hydrogen,

deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -0-Ci- 3 alkyl, -S-Ci- 3 alkyl, -CH 2 -OH, -OH,-O-O^ alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CF^-S-C^ alkyl. The compound according to item 214, wherein R 1 is Br or Cl. The compound according to any one of items 214 to 215, wherein R 2 is cyclopropyl or cyclobutyl. The compound according to any one of items 214 to 216, wherein R 3 is hydrogen, deuterium, tritium or F.

The compound according to any one of items 132 to 217Fejl !

Henvisningskilde ikke fundet., wherein the compound is selected from the group consisting of:

(2S)-2-{4-bromo-2-[2-(methoxymethyl)cyclopropyl]phenoxy}prop anoic acid; (2S)-2-[4-bromo-2-(2,2-dichlorocyclopropyl)phenoxy]propanoic acid;

(2S)-2-{4-bromo-2-[(1 s,3s)-3-methoxycyclobutyl]phenoxy}propanoic acid; (2S)-2-{4-bromo-2-[(E)-2-bromoethenyl]phenoxy}propanoic acid;

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

(2S)-2-{4-bromo-2-[(1 S,2S)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-{4-bromo-2-[(1 R,2R)-2-(hydroxymethyl)cyclopropyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)propanoic acid;

(2S)-2-{4-bromo-2-[(1 E)-2-cyanoeth-1 -en-1 -yl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)propanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)propanoic acid;

(2S)-2-(2-cyclopropyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(2-cyclobutyl-4-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclobutylphenoxy)propanoic acid;

tert-butyl (2S)-2-(4-chloro-2-propanoylphenoxy)propanoate; (2S)-2-{4-chloro-2-[(2,2- 2 H 2 )propanoyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoic acid;

methyl (2S)-2-[4-chloro-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoate; methyl (2S)-2-(4-bromo-2-propanoylphenoxy)-3-methylbutanoate;

(2S)-2-(4-chloro-2-ethynylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-propanoylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethenylphenoxy)propanoate;

(2S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-propylphenoxy)propanoic acid;

sodium (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

methyl (2S)-2-(4-chloro-2-ethylphenoxy)propanoate;

(2R)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)-3-fluorop ropanoic acid; (2S)-2-(2-cyclopropyl-4,6-difluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-propanoylphenoxy)propanoic acid;

(2S)-2-(4-chloro-2-cyclopropyl-6-fluorophenoxy)propanoic acid;

(2S)-2-(2,4-difluoro-6-propanoylphenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-chlorophenoxy)propanoic acid;

(2S)-2-(4-fluoro-2-propanoylphenoxy)propanoic acid;

(2S)-2-[4-chloro-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid;

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

(2S)-2-{2-[2-(benzyloxy)cyclobutyl]-4-chlorophenoxy}propa noic acid; (2S)-2-[4-bromo-2-(cyclopent-1 -en-1 -yl)phenoxy]propanoic acid

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

(2S)-2-[2,4-dibromo-6-(2-methoxyethyl)phenoxy]propanoic acid;

(2S)-2-[4-bromo-2-(cyclopropylidenemethyl)phenoxy]propano ic acid; (2S)-2-(4-bromo-2-ethenyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(2-acetyl-4-bromo-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propanoic acid;

(2S)-2-[4-bromo-2-(2,2-difluoroethenyl)-5-fluorophenoxy]p ropanoic acid; (2S)-2-(4-bromo-2-ethynylphenoxy)-2-cyclobutylacetic acid;

(2S)-2-(4-bromo-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-chloro-2-ethynyl-5-fluorophenoxy)propanoic acid;

(2S)-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutanoic acid;

(2S)-2-(4-bromo-2-ethenylphenoxy)-4-fluorobutanoic acid; (2S)-2-{4-bromo-2-[(1 £)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-{4-chloro-2-[(1 E)-2-fluoroethenyl]phenoxy}propanoic acid;

(2S)-2-(4-bromo-2-ethynylphenoxy)butanoic acid; and

(2S)-2-[4-bromo-2-(2,2-difluorocyclobutyl)phenoxy]propanoic acid. 219. A compound of Formula (I):

Formula (I) wherein:

- R 1 is selected from the group consisting of F, Cl, Br, I, -CN, -CF 3 , -CCI 3 , - CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 and -OCCI 3 ;

- R 2 is selected from the group consisting of C 2-6 alkyl, C 2-6 alkenyl, C 2-6

alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, -C(=0)-Ci- 5 alkyl, -C(=0)-C 2-5 alkenyl, -C(=0)-C 2-5 alkynyl, -C(=0)-C 3-5 cycloalkyl and -C(=0)-C 5 cycloalkenyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 ;

- R 3 is selected from the group consisting of hydrogen, deuterium, tritium, F,

Cl, Br, I, -CN, -CF 3 , -CCI 3 , -CHF 2 , -CHCI 2 , -CH 2 F, -CH 2 CI, -OCF 3 , -OCCI 3 and isocyanide;

- R 4 is H;

- R 5 is selected from the group consisting of H, C1 -5 alkyl optionally substituted with one or more, identical or different, substituents R 11 , C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 , phenyl optionally substituted with one or more, identical or different, substituents R 1 2 and benzyl optionally substituted with one or more, identical or different, substituents R 12 ; - R 6 is independently selected from the group consisting of hydrogen, deuterium, tritium, F, Cl, Br, I, -CN, isocyanide, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -CH 2 -OH, -CH 2 -0-Ci -3 alkyl, -0-CH 2 -Ph, -CH 2 -SH and -CH 2 -S-C I-3 alkyl;

- R 11 is independently selected from the group consisting of deuterium and F;

- R 12 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. The compound according to item 219, wherein R 1 is selected from the group consisting of F, Cl, Br, I, preferably Br or Cl. The compound according to any one of items 219 to 220, wherein R 1 is Br.

The compound according to any one of items 219 to 221 , wherein R 2 is selected from the group consisting of ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, -

C(=0)-methyl and -C(=0)-ethyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 . The compound according to any one of items 219 to 221 , wherein R 2 is cyclopropyl or cyclobutyl, each of which may be optionally substituted with one or more, identical or different, substituents R 6 . The compound according to any one of items 219 to 221 , wherein R 2 is C 2- e alkynyl, preferably ethynyl, which may be optionally substituted with one or more, identical or different, substituents R 6 . The compound according to any one of items 219 to 224, wherein R 3 is selected from the group consisting of deuterium and F.

The compound according to any one of items 219 to 225, wherein R 5 is H. The compound according to any one of items 219 to 225, wherein R 5 is C 1-5 alkyl optionally substituted with one or more, identical or different, substituents R 11 . 228. The compound according to any one of items 219 to 225, wherein R 5 is C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R 11 .

229. The compound according to any one of items 219 to 225, wherein R 5 is phenyl optionally substituted with one or more, identical or different, substituents R 12 .

230. The compound according to any one of items 219 to 225, wherein R 5 is benzyl optionally substituted with one or more, identical or different, substituents R 12 .

231. The compound according to any one of items 219 to 230, wherein R 6 is selected from the group consisting of hydrogen, F and -O-C1 -3 alkyl. 232. The compound according to any one of items 219 to 231 , wherein the

compound is 2-(4-bromo-2-cyclopropylphenoxy)acetic acid or 2-(4-bromo-2- ethynylphenoxy)acetic acid.

233. The compound according to any one of items 132 to 232, wherein the

compound has activity on CIC-1 receptor. 234. The compound according to any one of items 132 to 232, wherein the

compound is an inhibitor of the CIC-1 ion channel.

235. The compound according to item 234, wherein the EC50 <50 mM, preferably <40 mM, more preferably <30 mM, more preferably <20 mM, more preferably <15 mM, even more preferably <10 mM and most preferably <5 mM.

236. The compound according to any one of items 132 to 236, wherein the recovery of force in muscles with neuromuscular dysfunction is >5%, preferably >10%, more preferably >15%, more preferably >20%, more preferably >25%, even more preferably >30% and most preferably >35%.

237. The compound according to any one of items 132 to 236, wherein the

compound improves the recovered force in isolated rat soleus muscles after exposure to tubocurarine.

238. A composition comprising the compound according to any one of items 132 to 237. 239. The composition according to item 238, wherein the composition is a pharmaceutical composition.

240. The compound according to any one of items 132 to 237, or the composition according to any one of items 238 to 239, for use as a medicament.

241. The composition according to any one of items 238 to 240, wherein the

composition further comprises a pharmaceutically acceptable carrier.

242. The composition according to any one of items 238 to 241 , wherein the

composition further comprises at least one further active agent.

243. The composition according to item 242, wherein said further active agent is suitable for treating, preventing or ameliorating said neuromuscular disorder.

244. The composition according to any one of items 242 to 243, wherein said further active agent is an acetylcholine esterase inhibitor.

245. The composition according to item 244, wherein said acetylcholine esterase inhibitor is selected from the group consisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine, phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin.

246. The composition according to item 244, wherein said acetylcholine esterase inhibitor is neostigmine or pyridostigmine.

247. The composition according to any one of items 242 to 243, wherein said further active agent is suggamadex.

248. The composition according to any one of items 242 to 243, wherein said further active agent is tirasemtiv or CK-2127107. 249. The composition according to any one of items 242 to 243, wherein said further active agent is 3,4-aminopyridine.

250 The compound according to any one of items 132 to 237, or the composition according to any one of items 238 to 239, for use in treating, ameliorating and/or preventing a neuromuscular disorder, and/or for use in reversing and/or ameliorating a neuromuscular blockade.

251. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is myasthenia gravis.

252. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is autoimmune myasthenia gravis.

253. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is congenital myasthenia gravis.

254. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is Lambert-Eaton Syndrome.

255. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is critical illness myopathy.

256. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS).

257. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is spinal muscular atrophy (SMA).

258. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is critical illness myopathy (CIM).

259. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is Charcot-Marie tooth disease (CMT).

260. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is sarcopenia.

261. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is reversal diabetic polyneuropathy.

262. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is hypokalemic periodic paralysis. 263. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is hyperkalemic periodic paralysis.

264. The compound for use according to any one of the preceding items wherein the neuromuscular disorder is selected from the group consisting of Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, and critical illness polyneuropathy.

265. The compound for use according to any one of the preceding items, wherein the compound is for use in the treatment of symptoms of an indication selected from the group consisting of myasthenia gravis (such as autoimmune and congenital 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, hypokalemic periodic paralysis and hyperkalemic periodic paralysis.

266. The compound for use according to any one of the preceding items wherein the neuromuscular disorder has been induced by a neuromuscular blocking agent.

267. The compound for use according to any one of the preceding items, wherein the neuromuscular blockade is neuromuscular blockade after surgery. 268. The compound for use according to any one of the preceding items, wherein the neuromuscular blockade is drug induced.

269. The compound for use according to item 268, wherein the drug is an antibiotic.

270. The compound for use according to item 268, wherein the drug is a non

depolarizing neuromuscular blocker. 271. The compound for use according to any one of the preceding items, wherein said compound further has been modified in order to increase its half-life when administered to a patient, in particular its plasma half-life.

272. The compound for use according to any one of the preceding items, wherein said compound further comprises a moiety conjugated to said compound, thus generating a moiety-conjugated compound. 273. The compound for use according to any one of the preceding items, wherein the moiety-conjugated compound has a plasma and/or serum half-life being longer than the plasma and/or serum half-life of the non-moiety conjugated compound.

274. The compound for use according to any one of the preceding items, wherein the moiety conjugated to the compound is one or more type(s) of moieties selected from the group consisting of albumin, fatty acids, polyethylene glycol (PEG), acylation groups, antibodies and antibody fragments.

275. The compound for use according to any one of the preceding items, wherein said compound is comprised in a composition. 276. A method for manufacturing the compound according to any one of items 132 to

237, the method comprising the steps of

a. reacting a compound having a formula of

wherein R 4 is as defined in any one of items 132 to 237 and R 11 is selected from the group consisting of alkyl, alkenyl, akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring and -alkylene-Si-alkyl, with first a reagent capable of converting the alcohol (OH) into a leaving group and secondly with a compound having a formula of

wherein R 1 , R 2 , R 3 and n are as defined in any one of items 132 to 237 and Y is

O to generate a compound having a formula of

( C| ) ; and

b. reacting the product compound of a) with an ester hydrolysing reagent thus generating a compound according to any one of items 132 to 237. A method for manufacturing the compound according to any one of items 132 to 237, the method comprising the steps of

a. reacting a compound having a formula of

wherein R 1 , R 2 , R 3 and n are as defined in any one of items 132 to 237 and Q is a leaving group selected from the group consisting of fluorine and iodine, with a compound having a formula of

wherein R 4 is as defined in any one of items 132 to 237 and R 11 is selected from the group consisting of alkyl, alkenyl, akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring and -alkylene-Si-alkyl and Y is O to generate a compound having a formula of

wherein Y is O; and

b. reacting the product compound of a) with an ester hydrolysing reagent thus generating a compound according to any one of items 132 to 237. 278. A method for manufacturing the compound according to any one of items 132 to

237, the method comprising the steps of

a. reacting a compound having a formula of

wherein R 4 is as defined in any one of items 132 to 237, Z is OH and R 12 is selected from the group consisting of -Si-alkyl, with first a reagent capable of converting the alcohol (Z) into a leaving group and secondly with a compound having a formula of

wherein R 1 , R 2 , R 3 and n are as defined in any one of items 132 to 237 and Y is O to generate a compound having a formula of

b. reacting the product compound of a) with an ether cleaving reagent to

generate a compound having a formula of

( cn| ) ; and

c. reacting the product compound of b) with an oxidising agent thus generating a compound according to any one of items 132 to 237.

a.

Examples

Materials and methods

Chemicals

Compounds for testing were obtained from different suppliers including Enamine, Vitas, and CanAm Bioresearch. For synthesis of particular compounds please see below.

General synthetic strategies

Compounds of formula (I) may be synthesized by the following synthetic strategies, general methods A-C:

NMR Spectra

1 H-NMR spectra were recorded on a Bruker AM-300 spectrometer and were calibrated using residual nondeuterated solvent as internal reference. Spectra were processed using Spinworks version 4.0 (developed by Dr. Kirk Marat, Department of Chemistry, University of Manitoba).

HPLC method 1

The product was analysed by Waters 2695 HPLC consisting of a Waters 996 photodiode array detector, Kromasil Eternity C18, 5 pm, 4.6 X 150 mm column. Flow rate: 1 mL/minute, run time 20 minutes. Solvent A: methanol; solvent B: 0.1 % formic acid in water. Gradient 0-100 % Solvent B over 15 minutes with monitoring at 280 nm.

HPLC method 2

Waters Acquity UPLC, X-Select; column: Waters X-Select UPLC C18, 1 .7 pm, 2.1 x 30mm. Solvent A: 0.1 % formic acid in water; solvent B: 0.1% formic acid in MeCN. Gradient 5-95 % Solvent B over 10 minutes; detector: diode array.

HPLC method 3

Waters Acquity UPLC, X-Select; column: Waters X-Select UPLC C18, 1 .7 pm, 2.1 x 30mm. Solvent A: 0.1 % formic acid in water; solvent B: 0.1% formic acid in MeCN. Gradient 5-95 % Solvent B over 3 minutes; detector: diode array. HPLC method 4

Waters Acquity UPLC, X-Select; column: Waters X-Select UPLC C18, 1 .7 mhi, 2.1 x 30mm. Solvent A: 0.1 % formic acid in water; solvent B: 0.1% formic acid in MeCN. Gradient 5-95 % Solvent B over 4 minutes; detector: diode array.

General Method A

Method A involves the synthesis of compounds of Formula (XII) (which is the same as Formula (I) in which R 5 is H), which is an ether structure wherein Y = oxygen, and -Ri, - R 2 , -R 3 and -R 4 , are as defined in Formula (I) above. Compound (X), in the case where Y = O is a phenol, is available either commercially or synthetically (see below), and can be converted into an ether (XI) by methods which include Mitsunobu reaction conditions. This ether contains an ester functionality -CO2R 11 , which can be hydrolysed under a range of standard conditions, involving treatment with acid or base, to provide the carboxylic acid structure (XII), Y = O. Standard conditions for hydrolysis of the ester can also for example involve an enzymatic hydrolysis, employing for example an esterase or lipase. Furthermore, if an ester molecule (XI) comprises for example a (CH 3 ) 3 SiCH 2 CH 2 0- group as -OR 11 , then a fluoride ion source such as tetra-n- butylammonium fluoride can be employed to convert (XI) into the corresponding carboxylic acid (XII).

Substituted phenols of general formula (X), Y = O, can be prepared by a variety of standard methods, for example by an ester rearrangement in the Fries rearrangement, by a rearrangement of A/-phenylhydroxylamines in the Bamberger rearrangement, by hydrolysis of phenolic esters or ethers, by reduction of quinones, by replacement of an aromatic amine or by a hydroxyl group with water and sodium bisulfide in the Bucherer reaction. Other methods include hydrolysis of diazonium salts, by rearrangement reaction of dienones in the dienone phenol rearrangement, by the oxidation of aryl silanes or by the Hock process. General Method B

Carboxylic acids of Formula (XII) (which is the same as Formula (I) in which R 5 is H) can also be prepared by the procedure illustrated as General Method B. A phenolic ether of formula (XI) can be prepared by displacement of a suitable leaving group Q in (XIII) with the nucleophilic YH in (IX) (wherein Y=0). Q can for example be a halogen such as fluorine or iodine, and the ether product of formula (XI) can be converted into the carboxylic acid derivative (XII) by one of a range of methods outlined in General Method A, involving hydrolysis of the ester functionality.

General Method C

Carboxylic acids of Formula (XII) (which is the same as Formula (I) in which R 5 is H) can be prepared by the procedure illustrated as General Method C. A phenolic ether of formula (XV) can be prepared by utilising e.g. Mitsunobu conditions when (X) is a phenol structure, i.e. Y = O, and (XIV) is a suitable secondary alcohol, i.e. Z = OH, and -R 12 is a suitable protecting group, such as a silyl-containing moiety. On removal of the protecting group -R 12 , the primary alcohol in (XVI) can be oxidised to a carboxylic acid under standard conditions involving potassium permanganate, Jones oxidation conditions, the Heyns oxidation, ruthenium tetroxide or TEMPO, generating (XII).

Table 1 below illustrates Example compounds defined by the general Formula (I). In table 1 , the HPLC System is one of the methods as defined in the Materials and methods section.

Table 1 : Illustrative Examples of the Invention

Specific examples of Syntheses

Example 1 : Synthesis of (S)-2-(4-bromo-2-ethynylphenoxy)propanoic acid; following the synthetic strategy of General Method A

(S)-Methyl 2-(4-bromo-2-iodophenoxy)propanoate (1.2)

To a solution of (F?)-methyl 2-hydroxypropanoate (1.1 ) (1 mmol), 4-bromo-2-iodophenol (1 mmol) and triphenylphosphine (1 .2 mmol) in THF (15 ml_) at 0°C was added DIAD (1.2 mmol) dropwise over 20 min. The solution was stirred for a further 15 min at 0 q C.

The bright yellow solution was allowed to warm to RT and stirred overnight. Volatiles were removed in vacuo to afford a dark orange oil. The crude product was purified by chromatography on silica gel (0-10% EtOAc/hexane) to afford (S)-methyl 2-(4-bromo-2- iodophenoxy)propanoate (1.2) (75% yield) as a colourless oil. 1 H NMR (300 MHz, CDCIs) d 7.91 (d, 1 H); 7.37 (dd, 1 H); 6.58 (d, 1 H); 4.73 (q, 1 H); 3.77 (s, 3H); 1.70 (d, 3H); ES-MS: 386 [M+1 ]

(S)-Methyl 2-(4-bromo-2-ethvnylphenoxy) propanoate (1 .3)

1 ) A mixture of (S)-methyl 2-(4-bromo-2-iodophenoxy)propanoate (1.2) (1 mmol), PdCI 2 (PPh 3 )2 (4 mol%), copper Iodide (4 mol%) and ethynyltrimethylsilane (1.5 mmol) in triethylamine (10 ml_) was evacuated and purged with argon 3 times and the mixture was heated at 80‘O for 8 h then allowed to cool to room temperature. Volatiles were removed in vacuo and the crude product was purified by chromatography on silica gel (0-10% EtOAc/hexane) to afford (S)-methyl 2-(4-bromo-2- ((trimethylsilyl)ethynyl)phenoxy) propanoate as a brown oil. The crude product was used with no further purification in step 2.

2) (S)-Methyl 2-(4-bromo-2-((trimethylsilyl)ethynyl)phenoxy)propanoate (1 mmol) was dissolved in dry THF (16 ml_) and cooled to 0°C. TBAF (1 .2 mmol) was added and the mixture was stirred at room temperature for 60 min. The reaction was quenched with water and extracted with EtOAc (3 x 500 ml_). Organics were washed with brine (50 ml_) dried over sodium sulphate, filtered and evaporated. The crude product was purified by chromatography on silica gel (0-10% EtOAc/hexane) to afford (S)-methyl 2- (4-bromo-2-ethynylphenoxy) propanoate (1.3) (82% yield) as a colourless oil. 1 H-NMR (300MHz, CDCIs): d 7.58 (d, 1 H), 7.36 (dd, 1 H), 6.68 (d, 1 H), 4.79 (q, 1 H), 3.75 (s, 3H), 3.33 (s, 1 H), 1 .67 (d, 3H). ES-MS: 284 [M+1 ].

(S)-2-(4-bromo-2-ethvnylphenoxy)propanoic acid (1 .4)

To a stirred solution of (S)-methyl 2-(4-bromo-2-ethynylphenoxy) propanoate (1.3) (1 .0 mmol) in MeOH: H 2 0 (3:1 ) at room temperature solid NaOH (1 .1 eq) was added and the resulting mixture was stirred at room temperature for 40 min. After completion of the reaction, volatiles were removed and the crude product was diluted with water and the aqueous layer was washed with DCM (2X50 ml_) (to remove unreacted ester and other impurities). The aqueous phase was acidified with aq. HCI (1 M) and extracted with EtOAc. The combined organic phases were dried over MgS0 4 . The solvents were removed and dried under vacuum to afford (S)-2-(4-bromo-2- ethynylphenoxy)propanoic acid (1.4) (95% yield) as an off-white solid. 1 H-NMR (300MHz, CDCIs): d 9.13-8.37 (br, 1 H), 7.61 (s, 1 H), 7.40 (dd, 1 H), 6.74 (d, 1 H), 4.84 (q, 1 H), 3.36 (s, 1 H), 1 .72 (d, 3H). ES-MS: 268 [M-1 ]

In conclusions, this example demonstrates that compound 1.4 can be prepared using the synthetic strategy of general method A. Example 2: Synthesis of (2S)-2-(4-bromo-2-ethenylphenoxy)propanoic acid; following the synthetic strategy of General Method A

4-Bromo-2-vinylphenol (2.2)

To a solution of sodium hydride (6 mmol) in THF (15 ml_) at 0°C, methyl- triphenylphosphonium bromide (2 mmol) was added and the mixture stirred for 1 h before 5-bromo-2-hydroxybenzaldehyde (2.1 ) (1 mmol) in THF was introduced dropwise over 20 min. The solution was stirred for a further 15 min. at 0°C. The bright yellow solution was allowed to warm to RT and stirred overnight. The reaction was quenched with aqueous sat. ammonium chloride solution and the aqueous solution was extracted with EtOAc (2x100ml_). The combined organics were dried over MgS0 4 and adsorbed onto silica. The crude product was purified by chromatography on silica gel (0-10% EtOAc/hexane) to afford 4-bromo-2-vinylphenol (2.2) (65% yield) as a colourless liquid. 1 H NMR (300 MHz, CDCI 3 ) d 7.58 (d, 1 H); 7.34 (dd, 1 H); 6.98 (dd, 1 H); 6.75 (d, 1 H); 5,75 (d, 1 H); 5.32(d, 1 H); 3.84 (s, 3H); ES-MS: 198 [M-1]

(Si-Methyl 2-(4-bromo-2-vinylphenoxyl propanoate (2.3)

To a solution of ( ?)-methyl 2-hydroxypropanoate (7) (1 mmol), 4-bromo-2-vinylphenol (6) (1 mmol) and triphenylphosphine (1 .2 mmol) in THF (15 ml_) at 0 °C was added

DIAD (1.2 mmol) dropwise over 20 min. The solution was stirred for a further 15 min at 0 q C. The bright yellow solution was allowed to warm to RT and stirred overnight.

Volatiles were removed in vacuo to afford a dark orange oil. The crude product was purified by chromatography on silica gel (0-10% EtOAc/hexane) to afford (S)-methyl 2- (4-bromo-2-vinylphenoxy) propanoate (2.3) (78% yield) as a colourless oil. 1 H NMR (300 MHz, CDCIs) d 7.61 (d, 1 H); 7.27 (dd, 1 H); 7.05 (dd, 1 H); 6.62 (d, 1 H); 5.76 (d, 1 H); 5.33 (d, 1 H); 4.74 (q, 1 H); 3.76 (s, 3H); 1 .65 (d, 3H); ES-MS: 286 [M+1 ]

(S)-2-(4-Bromo-2-vinylphenoxy)propanoic acid (2.4)

To a stirred solution of (S)-methyl 2-(4-bromo-2-vinylphenoxy)propanoate (2.3) (1 .0 mmol) in MeOH and H 2 0 (3:1 ) at room temperature solid NaOH (1 .1 eq) was added and the resultant mixture was stirred at room temperature for 40 min. After completion of the reaction, volatiles were removed and water was added to the residue. The aqueous layer was washed with DCM (2 x 50 ml_) (to remove unreacted ester and other impurities). The aqueous layer was acidified with aq. HCI (1 M) and extracted with EtOAc (2 x 50 ml_). The combined organic extracts were dried over MgSC>4. The solvents were removed and dried under vacuum to afford (S)-2-(4-bromo-2- vinylphenoxy)propanoic acid (2.4) (93 % yield) as an off-white solid. 1 H-NMR

(300MHz, CDCIs): d 10.17-9.48 (br, 1 H), 7.62 (s, 1 H), 7.30 (d, 1 H), 7.03 (dd, 1 H), 6.66 (d, 1 H), 5.77 (d, 1 H), 5.34 (d, 1 H), 4.77 (q, 1 H), 1.69 (d, 3H). ES-MS: 270 [M-1 ]

In conclusions, this example demonstrates that compound 2.4 can be prepared using the synthetic strategy of general method A. Example 3: Synthesis of (2S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid and sodium salt thereof, following the synthetic strategy of General Method A

3.5 3.6 2-( 1 -HvdroxycvclobutvDphenol (3.2)

2-Bromophenol (3.1 ) (8.04 ml_, 69.4 mmol) was dissolved in dry diethyl ether (144 ml_) and cooled to -78 °C under nitrogen. N-butyllithium (2.5 M in hexane) (61 .0 ml_, 153 mmol) was added dropwise maintaining the reaction temperature below - 70 q C. Once the addition was complete the cooling bath was removed and the reaction mixture allowed to warm to RT and stirred for 2.5 hours. The reaction mixture was cooled to - 78 q C whereafter cyclobutanone (5.18 ml, 69.4 mmol) was added dropwise while maintaining the reaction temperature below -70 q C. Once the addition was complete, the cooling bath was removed and the reaction mixture was allowed to warm to RT and left to stir overnight. The reaction mixture was quenched into ice cold ammonium chloride solution (500 ml_) then extracted with EtOAc (3 x 500 ml_). Organics were washed with brine (500 ml_) dried over sodium sulphate, filtered and evaporated to give 2-(1 -hydroxycyclobutyl)phenol (3.2) as a viscous orange oil (10.78 g, 57.1 mmol, 82 % yield). The product was analysed by LCMS (Agilent, X-Select, Waters X-Select C18, 2.5 pm, 4.6x30 mm, Acidic (0.1 % Formic acid) 4 min method, 5-95% MeCN/ water): M/Z 163 (M+H)+ (ES+); at 1 .54 min, 53% purity @ 254 nm.

2-Cvclobutylphenol (3.3)

2-(1 -Hydroxycyclobutyl)phenol (3.2) (10.7 g, 56.7 mmol) was dissolved in dry DCM (160 ml_) and cooled to O'O. Triethylsilane (19.47 ml_, 122 mmol) was added and the clear solution maintained at O 'O for 20 min. before TFA (17.47 ml_, 227 mmol) was added dropwise. The stirring was continued for a further 10 min. whereafter the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was quenched into ice-water (500 ml_) and extracted with DCM (3 x 200 ml_). The combined organics were dried using a phase separating cartridge and evaporated to give a deep orange oil (16.63 g, crude) The product was purified by liquid loading in DCM onto a 330g silica cartridge which was slow gradient eluted (100% isohexane to 20% EA) to give 2- cyclobutylphenol (3.3) (6.78 g, 43.9 mmol, 77 % yield). The product was analysed by LCMS (Agilent, X-Select, Waters X-Select C18, 2.5 pm, 4.6x30 mm, Acidic (0.1 % Formic acid) 4 min method, 5-95% MeCN/water): 1916-91 -2, M/Z 147 (M-H)- (ES-), at 2.152 min, 97% purity @ 254 nm.

4-Bromo-2-cvclobutylphenol (3.4)

Tetra-n-butylammonium tribromide (TBATBr) (22.06 g, 45.7 mmol) was added in a single portion to a stirred solution of 2-cyclobutylphenol (3.3) (6.78 g, 45.7 mmol) in dry DCM (136 ml, 2109 mmol) at room temperature. After 30 minutes, the reaction mixture was quenched by pouring it into a solution of sodium metabisulphite (500 ml_) and extracted with DCM (500 ml_). The aqueous phase was extracted with further DCM (2 x 100 ml_). The combined organic extracts were dried using a phase separating cartridge and evaporated to give an opaque oil which was purified by liquid loading in DCM onto a 330g silica cartridge which was slow gradient eluted (100% isohexane to 20% EA- isohexane) to give 4-bromo-2-cyclobutylphenol (3.4) (4.35g, 18.01 mmol, 39.4 % yield). The product was analysed by LCMS (Agilent, X-Select, Waters X-Select C18, 2.5 pm, 4.6x30 mm, Acidic (0.1 % Formic acid) 4 min method, 5-95% MeCN/water): M/Z 225/227 (M-H)- (ES-), at 2.453 min, 97.7% purity @ 254 nm.

(S)-2-(4-Bromo-2-cvclobutylphenoxy)propanoic acid (3.5)

DIAD (5.59 ml, 28.7 mmol) was added to a stirred solution of 4-bromo-2- cyclobutylphenol (3.4) (4.35 g, 19.15 mmol), (R)-tert- butyl 2-hydroxypropanoate (3.5) (3.08 g, 21 .07 mmol) and triphenylphosphine (7.54 g, 28.7 mmol) in anhydrous THF (180 ml_) at room temperature. After 16 hours, the solvent was removed under reduced pressure, the residue dissolved in formic acid (73.5 ml, 1915 mmol) and heated to 70 'Ό for 1 hour. The solution was evaporated to give a yellow oil which was co

evaporated with toluene (3 x 50ml_). The residue was dissolved in ethyl acetate (100ml) and extracted with 2M sodium hydroxide solution (100ml_). The aqueous phase was washed with ethyl acetate (2 x 10OmL) then acidified to pH 2 with 1 N HCI and extracted with EtOAc (3 x 100ml_). The organic extracts were dried over magnesium sulphate, filtered and then evaporated to give a pale yellow oil which purified by was liquid loading in DCM onto a 80 g silica cartridge and gradient eluted (100% isohexane to 40% ethyl acetate-isohexane) to afford (S)-2-(4-bromo-2- cyclobutylphenoxy)propanoic acid (3.5) (1 .33 g, 5.04 mmol, 26.3 % yield); 1 H NMR (400 MHz, DMSO-d6) d 13.02 (s, 1 H), 7.28 (d, J = 8.2 Hz, 2H), 6.70 (d, J = 8.3 Hz,

1 H), 4.80 (q, J = 6.7 Hz, 1 H), 3.66 (p, J = 8.8 Hz, 1 H), 2.25 (dqt, J = 12.1 , 6.2, 2.0 Hz, 2H), 2.17 - 1 .89 (m, 3H), 1 .80 - 1 .72 (m, 1 H), 1 .49 (d, J = 6.7 Hz, 3H).

Sodium (S)-2-(4-bromo-2-cvclobutylphenoxy)propanoate (3.6)

To a solution of (S)-2-(4-bromo-2-cyclobutylphenoxy)propanoic acid (3.5) (688 mg, 2.300 mmol) in a mixture of MeCN (15 ml_) and H 2 0 (5 ml_) was added 1 M sodium hydroxide solution(2.185 ml_, 2.185 mmol). The mixture was stirred at room

temperature for 30 minutes whereafter solvent was removed under reduced pressure at 50 °C. The residue was co-evaporated with dry toluene (2 x 10 ml_) then dried in vacuo at 50 °C overnight. The resulting solid was triturated with a mixture of isohexane- diethyl ether (10mL:1 ml_), the resulting solid was filtered and dried in vacuo at 50 °C for 3 hours to give pure sodium (S)-2-(4-bromo-2-cyclobutylphenoxy)propanoate (3.6) (732 mg, 2.234 mmol, 97 % yield), as a slightly hygroscopic light cream coloured solid. The product was analysed by LCMS (Waters Acquity UPLC, Acidic (0.1 % Formic acid) 10 min method, 5-95% MeCN/water): (ES+); 297/299 (M-H)- (ES-), at 5.058 min, 98.9% purity @ 200-400 nm. Ή NMR (400 MHz, DMSO-d 6 ) d 7.16 (d, J = 8.3 Hz, 2H), 6.63 (d, J = 8.3 Hz, 1 H), 4.17 (q, J = 6.7 Hz, 1 H), 3.66 (p, J = 8.8 Hz, 1 H), 2.32 - 2.08 (m, 3H), 2.04 - 1.87 (m, 2H), 1.82 - 1.69 (m, 1 H), 1 .36 (d, J = 6.7 Hz, 3H).

In conclusions, this example demonstrates that compound 15 and the sodium salt thereof, can be prepared using the synthetic strategy of general method A.

Example 4: Synthesis of (2S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid and sodium salt thereof, following the synthetic strategy of General Method A

4.3 4.4 4-Chloro-2-cvclopropylphenol (4.2)

A mixture of 2-bromo-4-chlorophenol (4.1) (4.15 g, 20 mmol), cyclopropylboronic acid (3.44 g, 40.0 mmol) and potassium phosphate (5.44 g, 40.0 mmol) in DMF (28.6 ml) was evacuated and purged with nitrogen 3 times. Pd(dba) 2 (0.230 g, 0.400 mmol) and Q-phos (0.569 g, 0.800 mmol) were added and the mixture was evacuated and purged with nitrogen 3 further times. The mixture was heated at 120‘O under microwave irradition for 8 h then allowed to cool to room temperature. The mixture was poured into water (50 ml_) and acidified by addition of 1 M aq. HCI. The mixture was extracted with EtOAc (3 x 50 ml_) and the combined organics were washed with water (150 ml_), brine (150 ml_), dried (MgS04), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (80 g column, 0-10% EtOAc/isohexane), giving a mixture of orange solid and brown oil. The mixture was suspended in isohexane then filtered and the solvent removed under reduced pressure to afford 4-chloro-2-cyclopropylphenol (4.2) (1.9985 g, 1 1 .45 mmol, 57.2% yield) as a clear brown oil. 1 H NMR in CDCI 3 was consistent with product structure at 97% purity.

(S)-2-(4-Chloro-2-cvclopropylphenoxy)propanoic acid (4.3)

DIAD (3.12 ml, 16.03 mmol) was added to a stirred solution of {R)-tert- butyl 2- hydroxypropanoate (14) (1 .841 g, 12.60 mmol), 4-chloro-2-cyclopropylphenol (4.2)

(1 .931 g, 1 1 .45 mmol) and triphenylphosphine (4.20 g, 16.03 mmol) in anhydrous tetrahydrofuran (67.4 ml_) at O 'O and stirred for 30 minutes whereafter the reaction mixture was allowed to warm to room temperature. After 16 hours, the mixture was evaporated in vacuo to a syrup which was re-dissolved in formic acid (44ml) and heated to 70 °C for 1 hour. The resulting solution was evaporated in vacuo and the residue co-evaporated with toluene (2 x 30ml_). The residue was dissolved in ethyl acetate (100ml_) and extracted with 0.5M sodium hydroxide solution (100ml_). The aqueous phase was washed with ethyl acetate (2 x 100ml_) then acidified to pH 2-3 by dropwise addition of cone hydrochloric acid. The resulting cloudy solution was extracted with ethyl acetate (3x 100ml_). Organic extracts were filtered through a phase separating funnel. The residue was purified by column chromatography (40g Grace silica cartridge) with 0-30% ethyl acetate in isohexane gradient elution to give an oil which was dried in vacuo at 40‘O overnight to give: (S)-2-(4-chloro-2- cyclopropylphenoxy)propanoic acid (4.3) (0.792 g, 3.09 mmol, 27.0 % yield) as a colourless solid. (600 mg). The product was analysed by LCMS (Waters Acquity UPLC, X-Select, Waters X-Select UPLC C18, 1 .7 pm, 2.1 x30mm, Acidic (0.1 % Formic acid) 10 min method, 5-95% MeCN/water): M/Z 239.106 (M-H)- (ES-), at 4.184 min, 94% purity @ 210-400 nm. 1 H NMR in DMSO-d 6 1974-1 1 -a1 was consistent with product structure at >95% purity.

1 H NMR (400 MHz, DMSO-d6) d 13.05 (s, 1 H), 7.1 1 (dd, J = 8.7, 2.6 Hz, 1 H), 6.82 (d,

J = 2.7 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 4.83 (q, J = 6.7 Hz, 1 H), 2.23 - 2.13 (m, 1 H),

1 .53 (d, J = 6.7 Hz, 3H), 0.99 - 0.87 (m, 2H), 0.79 - 0.71 (m, 1 H), 0.71 - 0.60 (m, 1 H).

Sodium (S)-2-(4-chloro-2-cvclopropylphenoxy)propionate (4.4)

To (S)-2-(4-chloro-2-cyclopropylphenoxy)propanoic acid (4.3) (0.604 g, 2.510 mmol) in MeCN (25 ml_) was added NaHC0 3 (0.21 1 g, 2.510 mmol) in H 2 0 (8 ml_) and the mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure to give a white solid which was dissolved in H 2 0 (30 ml_) and washed with DCM (3 x 30 ml_). The water was removed under reduced pressure and the resultant solid was dried at 45 °C in vacuo for 24 hours to afford pure sodium (S)-2- (4-chloro-2-cyclopropylphenoxy)propanoate (4.4) (0.652 g, 2.383 mmol, 95 % yield) as a white solid. The product was analysed by LCMS (Waters Acquity UPLC, X-Select, Waters X-Select UPLC C18, 1 .7 pm, 2.1 x30mm, Acidic (0.1 % Formic acid) 10 min method, 5-95% MeCN/water): M/Z 239.106 (M-H)- (ES-), at 4.181 min, 96% purity @ 210-400 nm. 1 H NMR (400 MHz, DMSO-d 6 ) d 6.98 (dd, J = 8.8, 2.7 Hz, 1 H), 6.74 - 6.63 (m, 2H), 4.20 (q, J = 6.7 Hz, 1 H), 2.20 (tt, J = 8.6, 5.3 Hz, 1 H), 1 .38 (d, J = 6.6 Hz, 3H), 0.97 - 0.83 (m, 2H), 0.77 - 0.66 (m, 1 H), 0.66 - 0.56 (m, 1 H).

In conclusions, this example demonstrates that compound 4.4 can be prepared using the synthetic strategy of general method A.

Description of Pharmacological Methods and Drawings

Example 5: Electrophysiological measurement of compound inhibition of CIC-1 in rat muscle

The investigatory goal of these experiments was to evaluate whether compounds inhibit CIC-1 channels in native tissue of rat skeletal muscle fibres. Apparent CIC-1 affinity was reported by the concentration of compound at which 50% of the

compound’s full inhibition of CIC-1 was observed (EC 5 o). CIC-1 Cl ion channels generate around 80% of the total membrane conductance (G m ) in resting skeletal muscle fibres of most animals including rat and human (Bretag, A H. Muscle chloride channels. Physiological Reviews, 1987, 67, 618-724). Other ion channels that contribute to G m can therefore be considered negligible, and it is possible to evaluate whether a compound inhibits CIC-1 in rat muscle by comparing G m measurements before and after exposure to a compound. CIC-1 inhibition would in such recordings be reflected by a reduction of G m .

Experimentally, G m was measured in individual fibres of whole rat soleus muscles using a three micro-electrodes technique described in this example and in full detail elsewhere (Riisager et a!., Determination of cable parameters in skeletal muscle fibres during repetitive firing of action potentials. Journal of Physiology, 2014, 592, 4417- 4429). Briefly, intact rat soleus muscles were dissected out from 12-14 week old Wistar rats and placed in an experimental chamber that was perfused with a standard Krebs Ringer solution containing 122 mM NaCI, 25 mM NaHCOs, 2.8 mM KCI, 1 .2 mM KH2PO4, 1 .2 mM MgS0 4 , 1 .3 mM CaCl2, 5.0 mM D-glucose. During experiments, the solution was kept at approx. 30 °C and continuously equilibrated with a mixture of 95% 0 2 and 5% C0 2 , pH ~7.4. The experimental chamber was placed in Nikon upright microscope that was used to visualize individual muscle fibres and the three electrodes (glass pipettes filled with 2 M potassium citrate). For G m measurements, the electrodes were inserted into the same fibre with known inter-electrode distances of 0.35 - 0.5 mm (V1 -V2, X1 ) and 1 .1 -1 .5 mm (V1 -V3, X3) (Figure 1 A). The membrane potential of the impaled muscle fibre was recorded by all electrodes. Two of the electrodes were furthermore used to inject 50 ms current pulses of -30 nA. Given the positions of the electrodes, three different inter-electrode distances could be identified (X1 -X2, X1 -X3, X2-X3) and hence the membrane potential responses to the current injections could be obtained at three distances from the point of current injection. The steady state voltage deflection at each distance was divided by the magnitude of current injected (-30 nA) and the resulting transfer resistances were plotted against inter-electrode distance and the data was fitted to a mono-exponential function from which G m could be calculated using linear cable theory (Figure 1 B).

To establish a dose response relationship, G m was first determined in 10 muscle fibres in the absence of compound and then at four increasing compound concentrations with G m determinations in 5-10 fibres at each concentration. The average G m values at each concentration were plotted against compound concentration and the data was fitted to sigmoidal function to obtain an EC 5 o value (Figure 1 C). Table 2 shows the EC 5 o values for a range of compounds with n values referring to number of experiments that each reflect recordings from around 50 fibres.

Table 2: Inhibition of CIC-1 ion channel using compounds of the invention

In conclusion, this example demonstrates that the compounds of the present invention have an EC 5 o value in the range of 3-10 mM.

Example 6: Measurement of force in an in vitro model

The current invention relates to compounds that inhibit CIC-1 ion channels and increase muscle excitability and thereby improve muscle function in clinical conditions where muscle activation is failing. Such conditions result in loss of contractile function of skeletal muscle, weakness and excessive fatigue. In this series of experiments the compounds were tested for their ability to restore contractile function of isolated rat muscle when the neuromuscular transmission had been compromised akin to neuromuscular disorders.

Experimentally, soleus muscles from 4-5 week old rats were isolated with the motor nerve remaining attached. The nerve-muscle preparations were mounted in experimental setups that enabled electrical stimulation of the motor nerve. Stimulation of the motor nerve led to activation of the muscle fibres and ensuing force production that was recorded. The nerve-muscle preparations were also in these experiments incubated in the standard Krebs Ringer (see example 5) and the solution was heated to 30°C and continuously equilibrated with a mixture of 95% 0 2 and 5% C0 2 , pH ~7.4.

After mounting the nerve-muscle preparation in the experimental setup, the contractile function of the muscle was initially assessed under the control conditions (Figure 2A). Sub-maximal concentration of tubocurarine (1 15 nM), an acetylcholine receptors antagonist, was then added to the experimental bath to impose partial inhibition of the ability of the motor nerve to activate the muscle fibres. The experimental condition mimics the failing neuromuscular transmission in a range of neuromuscular disorders. After addition of tubocurarine the contractile force declined over the next 90 mins to 10- 50 % of the control force. 50 mM of the test compound was then added and the contractile force recovered despite the continued presence of tubocurarine. T o quantify the ability of the compound to restore force the percentage of the initial force that was restored was determined after 40 mins of compound exposure (Figure 2B) and the point increase is reported in Table 3. Table 3: Percentage increase of initial force that was restored

In conclusion, this example demonstrates that the compounds of the present invention are able to increase muscle excitability and thereby improve muscle function in clinical conditions. The muscle contractility was recovered by 15-40 % points, which meant almost complete restoration of the force.

Example 7: Screening of compounds on the human isoform of CIC-1 expressed in CHO cells using automated patch-clamp

The investigatory goal of these experiments was to evaluate how compounds affect the open probability and current amplitude of human CIC-1 channels expressed in CHO cells. Experiments were performed using an automated patch clamp system that allowed high throughput testing of whole cell patches together with both intracellular and extracellular addition of compound.

Automated voltage clamp measurements

Automated whole cell patch clamp experiments were performed with the Qpatch 16 system (Sophion Bioscience, Ballerup, Denmark) at room temperature. Data acquisition and analysis were performed in the Qassay software (ver. 5.6, Odense).

Voltage protocol and analysis of whole cell CIC-1 currents

To evoke CIC-1 currents in whole cell patches, the membrane potential was initially stepped from a holding potential of -30 mV to +60 mV for 100 ms and then to various test voltages (sweeps) ranging from +120 mV to -140 mV in steps of 20 mV for 300 ms. To obtain tail currents, the membrane potential was stepped to -100 mV after each test voltage for 300 ms and then relaxed to -30 mV for 2 sec between sweeps (Figure 3).

I/V relationships for whole cell instant and steady state current amplitudes were obtained by plotting average current densities at the beginning and at the end of the 300 ms step against the membrane potential (Figure 4).

In order to determine the relative overall open probability (P 0 ), the instantaneous tail currents were normalized to the maximal tail current obtained following the most positive voltage step and plotted against the test voltage. Plots of normalized tail currents from each whole cell patch were then fitted to a Boltzmann function allowing determination of half activation voltages (Vi /2 , Figure 5). Solutions

For automated patch clamp experiments extracellular solutions contained: 2 mM CaCI 2 , 1 mM MgCl2, 10 mM HEPES, 4 mM KOI, 145 mM NaCI, 10 mM Glucose, pH adjusted to 7.4 with NaOH (2 M). Osmolality adjusted to -320 using sucrose.

Intracellular solutions contained: 80 mM CsF, 60 mM CsCI, 5/1 mM KOH/EGTA, 10 mM HEPES, 10 mM NaCI, pH adjusted to 7.2 with NaOH (2 M). Osmolality adjusted to -320 mOsm using sucrose.

Cell line information:

Cells used in patch clamp experiments were Chinese hamster ovary cells (CHO) constitutively expressing human CIC-1 channels. The amino acid sequence encoded by the cDNA used to create this cell line was identical to the translated sequence for GenBank accession number NM 000083.2. Cells were produced by Charles River (Catalogue CT6175, Cleveland OH, USA) in a cryopreserved format. Experiments were performed on the cells directly after thawing (3 x 10 6 cells used in each experiment).

Test protocol

To evaluate the compound effect on CIC-1 , when applied directly to the intracellular side of the cell membrane, the half activation voltage, Vi /2 , was determined from whole cell patches with compound added to the intracellular solution and then compared to V1/2 determined from control cell patches with only vehicle added to the intracellular solution. Additionally, the effect of extracellular added compound was evaluated by determine Vi /2 and steady state current amplitudes before and after exchanging the extracellular solution to contain compound.

The difference in half activation voltage of CIC-1 channels, A\fy 2 , was determined as the difference between the cell patches treated intracellularly with compound and control cells patches and is reported in Table 4 below. A positive shift in A\/y 2 is reflecting CIC-1 channel inhibition by the tested compound. P-values of <0.05 is considered significant.

Table 4: Percentage increase of initial force that was restored

Example 8: Measurement of In Situ Muscle Contractile Characteristics

Isometric hindlimb force was measured in 12-week old female Lewis rats in the presence and absence of compound.

Rats were placed under anesthesia with isoflurane (2-4%), intubated and subsequently connected to a micro ventilator (Microvent 1 , Hallowell EMC, US). Two stimulation electrodes were inserted through the skin to stimulate the sciatic nerve. A small incision was made proximal to the ankle, to expose the Achilles tendon, which was tied by cotton string, and connected to a force transducer (Fort250, World Precision

Instruments) with adjustable position (Vernier control). The Achilles tendon was then cut distal to the attached cotton string. The rat was placed on a heated pad, and to prevent movement artefacts from contraction of the ankle dorsiflexors, the foot was fixated by tape on a footplate.

Muscle contractile properties were assessed by applying an electrical current (under supramaximal voltage conditions) to the nerve and recording the force generated by the muscle. The muscle was stretched until maximal force was obtained, when assessed by 2 Hz stimulation. Isometric force was measured every 30 seconds at 12 Hz (Twitch), 10 pulses, and at every 5 minutes at 80 Hz (Tetanic) for 1 second (80 pulses). This stimulation pattern was employed throughout the experiment, expect in few cases where 80 Hz stimulation was replaced by 12 Hz (10 pulses). Neuromuscular transmission was partially inhibited by constant infusion of Cisatracurium (Nimbex, GlaxoSmithKline) at a concentration of 0.1 mg/kg at an adjustable infusion speed, adjusted individually for each animal to obtain a level of inhibition of ca. 50% of the forced generated at 12 Hz stimulation on the 4 th pulse. When the level of

neuromuscular inhibition was stable, the test article was injected i.v. at the chosen concentration. The effect of test article was assessed on its ability to increase force generated from the stimulation pattern applied. The effect was assessed in the ability to increase force per se (tetanic, 80 Hz, stimulation), and the ratio between individual twitch peaks (12 Hz stimulation). The effect was monitored for at least 1 hour after injection of test article. In addition, the time from injection of test article to maximal effect on force (both twitch and tetanic) was noted and the time for the effect to disappear (return to baseline), if possible. When appropriate the infusion of neuromuscular blocking agent was ceased, with the stimulation pattern continued, and the return of force to control levels was monitored. Animals were sacrificed by cervical dislocation while still fully sedated.

Compound A-2 was dosed 21.5 mg/kg i.v. The average increase in tetanic force was 28.5% but there was no significant change in twitch peaks (3 experiments).

Compound A-19 was dosed 40 mg/kg i.v. The average increase in tetanic force was 44.5% and the average increase in twitch peaks was 9.6% (3 experiments).

This demonstrates that compounds of the invention, such as Compounds A-2 and A-19 can restore force to muscles in vivo which have been partially inhibited by a neuromuscular blocker.