Clc-1 inhibitors for use in the treatment of multiple sclerosis and neuromuscular diseases

Abstract

The present disclosure relates to compounds capable of inhibiting the ClC-1 ion channel for use in treating, ameliorating and / or preventing multiple sclerosis and other neuromuscular diseases.

Description

This invention relates to compounds capable of inhibiting ClC-1 ion channels for the treatment, improvement, and / or prevention of multiple sclerosis and other neuromuscular diseases. Abstract

Claims

Claims1.A compound for use in the treatment, prevention and / or amelioration of multiple sclerosis, wherein the compound is a CIC-1 inhibitor.

2. The compound for use according to claim 1 , wherein the CIC-1 inhibitor restores contractile force in the muscles of the subject.

3. The compound for use according to claim 1 , wherein the CIC-1 inhibitor reduces the incidence of NMJ transmission failure in the muscles of the subject.

4. The compound for use according to claim 1 , wherein the CIC-1 inhibitor increases the probability of an action potential firing in the muscles of the subject.

5. The compound for use according to claim 1 , wherein the CIC-1 inhibitor normalises jitter in the muscles of the subject.

6. The compound for use according to any of claims 1 to 5, wherein the compound is of Formula (I):wherein:- R1is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,CN, CF3, NO2, F, Cl, Br, and I;- R2is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2-Ci-5 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;- R3is selected from the group consisting of deuterium, Cl and F;- R4is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;- R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R8;- R6is independently selected from the group consisting of deuterium and F;- R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;- R8is independently selected from the group consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I, and F;- R12is selected from the group consisting of:- R13is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-Ci-s alkyl optionally substituted with one or more,identical or different, substituents R6and -C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6;- R14is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6and phenyl optionally substituted with one or more, identical or different, substituents R8;- R15is selected from the group consisting of -OH, -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R6and -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6;- R16is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-Ci-s alkyl optionally substituted with one or more, identical or different, substituents R6and -C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6;- R17is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R20, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-Ci-s alkyl optionally substituted with one or more, identical or different, substituents R6and -C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6;- R18is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R19, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R19, phenyl optionally substituted with one or more, identical or different, substituents R8, and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R20;- R19is independently selected from the group consisting of F, Cl, Br, I, -CN,=0, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -O-C1-5 alkyl optionally substituted with one ormore, identical or different, substituents R6, -O-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -S- C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, -S-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -SO-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, -SO- C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -SO2-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, - SO2-C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-Ci-s alkyl optionally substituted with one or more, identical or different substituents R6, -C(=O)-OCi-s alkyl optionally substituted with one or more, identical or different, substituents R6, -NH- C(=O)-OCi-5 alkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -NH-C(=O)-Ci-s alkyl optionally substituted with one or more, identical or different, substituents R6, -NH-C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-NH-Ci-s alkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-NH-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, pyrrolidin-1-yl optionally substituted with one or more, identical or different, substituents R20and 4-6 membered heterocycle optionally substituted with one or more, identical or different, substituents R20;- R20is independently selected from the group consisting of F, Cl, Br, I, -CN, =0, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-Ci-s alkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-OCi-s alkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -NH-C(=O)-Ci-s alkyl optionally substituted with one ormore, identical or different, substituents R6, -NH-C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-NH-Ci-s alkyl optionally substituted with one or more, identical or different, substituents R6and -C(=O)-NH-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6;- R21is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -C(=O)-Ci-s alkyl optionally substituted with one or more, identical or different, substituents R6and -C(=O)-C3-s cycloalkyl optionally substituted with one or more, identical or different, substituents R6;- R22is selected from the group consisting of C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6and phenyl optionally substituted with one or more, identical or different, substituents R8;- X is selected from the group consisting of N and CR23;- Y is selected from the group consisting of NH, O and S;- R23is selected from the group consisting of H, NH2, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -OC1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, -OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -NH- C(=O)Ci-5 alkyl optionally substituted with one or more, identical or different, substituents R6and -NH-SO2-C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6;- n is an integer 0, 1 , 2, or 3; or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

7. The compound for use according to claim 6, wherein the compound is of Formula (II):Formula (II) wherein:- R1is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,CN, CF3, NO2, F, Cl, Br, and I;- R2is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycle optionally substituted with one or more, identical or different, substituents R7;- R3is selected from the group consisting of deuterium, Cl and F;- R4is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;- R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different,substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R8;- R6is independently selected from deuterium and F;- R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;- R8is 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.

8. The compound for use according to any one of claims 6 to 7, wherein:- R1is selected from the group consisting of F, Cl, Br and I;- R2is selected from the group consisting of H, deuterium, F, Cl, Br and I;- R3is selected from deuterium, Cl and F;- R4is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;- R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R8;- R6is independently selected from the group consisting of deuterium and F;- R8is 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.

9. The compound for use according to any one of claims 6 to 7, wherein:- R1is selected from the group consisting of F, Cl, Br and I;- R2is a 5-membered aromatic heterocycle which may be optionally substituted with one or more, identical or different, substituents R7;- R3is selected from the group consisting of deuterium, F and Cl;- R4is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;- R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R8;- R6is independently selected from deuterium and F;- R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl;- R8is 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.

10. The compound for use according to any one of claims 6 to 7, wherein:- R1is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,CN, CF3, NO2, F, Cl, Br, and I;- R2is -CF2-C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R6- R3is selected from the group consisting of deuterium, Cl and F- R4is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;- R5is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R6, C2-5 alkenyl optionally substituted with one or more, identical or different,substituents R6, C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R6, C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, phenyl optionally substituted with one or more, identical or different, substituents R8, and benzyl optionally substituted with one or more, identical or different, substituents R8;- R6is independently selected from deuterium and F;- R8is 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 3.11 . The compound for use according to claim 6, wherein the compound is ofFormula (IVa) or Formula (IVb):Formula (IVa) Formula (IVb) wherein:- R1is selected from the group consisting of C1-2 alkyl, C2 alkenyl, C2 alkynyl,CN, CF3, NO2, F, Cl, Br, and I;- R2is selected from the group consisting of H, deuterium, F, Cl, Br, I, C2-5 alkenyl optionally be substituted with one or more, identical or different, substituents R6, C2-5 alkynyl optionally be substituted with one or more, identical or different, substituents R6, C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R6, -CF2- C1-5 alkyl optionally be substituted with one or more, identical or different, substituents R6, and 5-membered aromatic heterocycleoptionally substituted with one or more, identical or different, substituents R7;- R3is selected from the group consisting of deuterium, Cl and F;- R4is selected from the group consisting of H, deuterium, C1-5 alkyl, C1-2 alkoxy-Ci-2 alkyl, C1-2 alkylthio-Ci-2 alkyl, C2-5 alkenyl, C2-5 alkynyl, and C3-5 cycloalkyl, each of which may be optionally substituted with one or more, identical or different, substituents R6;- R6is independently selected from the group consisting of deuterium and F;- R7is independently selected from the group consisting of deuterium, F, methyl, ethyl or cyclopropyl; and- n is an integer 0, 1 , 2, or 3 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

12. The compound for use according to any one of claims 6 to 12, wherein R1is selected from the group consisting of Br and Cl.

13. The compound for use according to any one of claims 6 to 13, wherein R4is selected from the group consisting of methyl, -CH2F, ethyl, -CH2CH2F, n-propyl and isopropyl.

14. The compound for use according to any one of claims 6 to 14, wherein n is 0 or 1.

15. The compound for use according to claim 1 , wherein the compound is selected from the group consisting of:(S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid; (S)-2-[2-(1 ,1-difluoropropyl)-4,5-difluorophenoxy]propionic acid;(R)-2-[2-(1 ,1-difluoropropyl)-4,5-difluorophenoxy]-3-fluoropropionic acid;(S)-2-[4-bromo-2-(1 ,1-difluoropropyl)phenoxy]-4-methoxybutyric acid;(S)-2-[5-chloro-2-(1 ,1-difluoropropyl)-4-fluorophenoxy]propionic acid;(S)-2-[2-(1 ,1-difluoropropyl)-4-nitrophenoxy]propionic acid;(R)-2-[5-chloro-2-(1 , 1 -difluoropropyl)-4-fluorophenoxy]-3-fluoropropionic acid;(S)-2-(4-chloro-2-cyclopropyl-5-fluorophenoxy)-3-methoxypropionic acid;(S)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid; (S)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]butyric acid;(S)-2-[2-(1 , 1 -difluoropropyl)-5-fluoro-4-styrenyloxy]propionic acid;(S)-2-[4-bromo-2-(1 ,1-difluoro-2-methylpropyl)phenoxy]butyric acid;(S)-2-[4-bromo-2-(1 ,1-difluoroethyl)phenoxy]-4-fluorobutyric acid;(R)-2-[4,5-dichloro-2-(1 ,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;(R)-2-[4-bromo-2-(1 ,1-difluoroethyl)-5-fluorophenoxy]-3-fluoropropionic acid;(S)-2-[4,5-dichloro-2-(1 ,1-difluoropropyl)phenoxy]propionic acid;(R)-2-[4-chloro-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;(S)-2-[2-(1 ,1-difluoroethyl)-4-ethynylphenoxy]propionic acid;[4-chloro-2-(1 ,1-difluoropropyl)-5-fluorophenoxy]acetic acid;[4-bromo-2-(1 ,1-difluoro-2-methylpropyl)phenoxy]acetic acid;(S)-2-[2-(1 ,1-difluoropropyl)-4-tolyloxy]propionic acid;[4-bromo-2-(1 ,1-difluoroethyl)-5-fluorophenoxy]acetic acid;(S)-2-[2-(1 ,1-difluoropropyl)-4-styrenyloxy]propionic acid;(R)-2-[4-bromo-2-(1 , 1 -difluoropropyl)-5-fluorophenoxy]-3-fluoropropionic acid;(S)-2-[2-(1 ,1-difluoropropyl)-4-(trifluoromethyl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(1 ,1-difluoropropyl)-5-fluorophenoxy]propionic acid;[4-bromo-2-(1 ,1-difluoropropyl)-5-fluorophenoxy]acetic acid;(S)-2-[4-bromo-2-(1 ,1-difluoropropyl)(3,5,6-2H3)phenoxy]propionic acid;(S)-2-[4-bromo-2-(1 ,1-difluoroethyl)-5-fluorophenoxy]propionic acid;(R)-2-[4-chloro-2-(1 ,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-cyano-2-(1 ,1-difluoropropyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(1 ,1-difluoropropyl)-5-fluorophenoxy]propionic acid;(S)-2-[2-(1 ,1-difluoropropyl)-4-ethynylphenoxy]propionic acid;(R)-2-[4-chloro-2-(1 ,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-bromo-2-(1 ,1-difluoropropyl)phenoxy](2-2H)propionic acid;(S)-2-[2-(1 , 1 -difluoropropyl)-4-iodophenoxy]propionic acid;(S)-2-[4-chloro-2-(1 ,1-difluoroethyl)phenoxy]-4-pentynoic acid;(S)-2-[4-bromo-2-(1 ,1-difluoropropyl)phenoxy]-4-pentynoic acid;(R)-2-[4-bromo-2-(1 ,1-difluoroethyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-bromo-2-(1 ,1-difluoroethyl)phenoxy]-4-pentynoic acid;(S)-2-(4-bromo-2-cyclobutylphenoxy)-3-methoxypropionic acid;(S)-2-[4-bromo-2-(cyclopropyldifluoromethyl)phenoxy]propionic acid;(R)-2-[4-bromo-2-(1 ,1-difluoropropyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-bromo-2-(1 ,1-difluorobutyl)phenoxy]propionic acid;(S)-[4-bromo-2-(1 ,1-difluoroethyl)phenoxy]cyclopropylacetic acid;(S)-2-[4-chloro-2-(1 ,1-difluoropropyl)phenoxy]propionic acid;[4-bromo-2-(1,1-difluoropropyl)phenoxy]acetic acid;(S)-2-[4-bromo-2-(1,1-difluoro-2-methylpropyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]-3-cyclopropylpropionic acid;(S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]butyric acid;(S)-2-[4-bromo-2-(1,1-difluoropropyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(1,1-difluoroethyl)phenoxy]propionic acid;(S)-2-(4-bromo-2-cyclopropylphenoxy)-3-methoxypropionic acid;(S)-(4-bromo-2-cyclopropylphenoxy)cyclopropylacetic acid;(S)-cyclopropyl(2,4-dibromophenoxy)acetic acid;(S)-(4-bromo-2-chlorophenoxy)cyclopropylacetic acid;(2R,3R)-2-(p-bromophenoxy)-3-fluorobutyric acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-ethoxypropionic acid;[4-bromo-2-(1 ,3-oxazol-4-yl)phenoxy]acetic acid;[4-bromo-2-(1 ,2,3-thiadiazol-4-yl)phenoxy]acetic acid;[4-chloro-2-(5-isoxazolyl)phenoxy]acetic acid;(S)-[4-bromo-2-(5-isoxazolyl)phenoxy]cyclopropylacetic acid;(S)-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]cyclopropylacetic acid;(S,E)-2-(p-bromophenoxy)-4-fluoro-3-butenoic acid;(2R,3R)-2-(4-bromo-2-fluorophenoxy)-3-fluorobutyric acid;(4-bromo-2-cyclopropylphenoxy)acetic acid;(S)-2-[4-bromo-2-(1 ,2,3-thiadiazol-4-yl)phenoxy]-3-cyclopropylpropionic acid;[4-bromo-2-(4-methyl-3-isoxazolyl)phenoxy]acetic acid;[4-bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]acetic acid;(S)-2-[4-bromo-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclobutylpropionic acid;(S)-2-[4-bromo-5-fluoro-2-(1,2,3-thiadiazol-4-yl)phenoxy]propionic acid;[4-bromo-2-(5-isoxazolyl)phenoxy]acetic acid;(S)-2-(p-bromophenoxy)(2-2H)butyric acid;(S)-2-(p-bromophenoxy)-4-pentynoic acid;[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]acetic acid;(4-bromo-2-ethynylphenoxy)acetic acid;(S)-2-(4-bromo-2-fluorophenoxy)valeric acid;(S)-2-(2,4-dibromophenoxy)valeric acid;(S)-2-(4-bromo-2-chlorophenoxy)valeric acid;(S)-2-(p-bromophenoxy)-3-cyclopropylpropionic acid;(S)-2-(2,4-dibromophenoxy)-4-pentynoic acid;(S)-2-(4-bromo-2-chlorophenoxy)-4-pentynoic acid;(S)-(p-bromophenoxy)cyclopropylacetic acid;(S)-2-(4-bromo-2-fluorophenoxy)-4-pentynoic acid;(S)-2-[4-bromo-2-(1 ,2,3-thiadiazol-4-yl)phenoxy]butyric acid;(S)-2-(p-bromophenoxy)valeric acid;(R)-2-[4-bromo-2-(1 ,2,3-thiadiazol-4-yl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-bromo-2-(1 ,3,4-thiadiazol-2-yl)phenoxy]propionic acid;(S)-(4-bromo-2-chlorophenoxy)cyclobutylacetic acid;(S)-2-(4-bromo-2-chlorophenoxy)-3-cyclopropylpropionic acid;(S)-2-(4-bromo-2-chlorophenoxy)-3-methylbutyric acid;[4-bromo-2-(3-isoxazolyl)phenoxy]acetic acid;(R)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-chloro-2-(1 ,2,3-thiadiazol-4-yl)phenoxy]propionic acid;(S)-2-(p-bromophenoxy)-3-butenoic acid;(S)-2-[4-bromo-2-(1 H-1 ,2,3-triazol-5-yl)phenoxy]propionic acid;(2S)-2-(p-bromophenoxy)(3,4-2H2)butyric acid;(R)-2-(4-bromo-2-chlorophenoxy)-3-fluoropropionic acid;(S)-2-(4-bromo-2-chlorophenoxy)butyric acid;(S)-2-(4-bromo-3-fluorophenoxy)-3-methylbutyric acid;(S)-2-(4-bromo-2-chlorophenoxy)-4-fluorobutyric acid;(S)-2-(p-ethynylphenoxy)-4-fluorobutyric acid;(S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid;(S)-2-[4-bromo-2-(1 ,2,3-thiadiazol-4-yl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(1 ,3-oxazol-5-yl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-4-fluorobutyric acid;(R)-2-(p-bromophenoxy)-3-fluoro(2-2H)propionic acid;(R)-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-2-(4-bromo-5-fluoro-2-styrenyloxy)propionic acid;(S)-2-[4-bromo-2-(1 ,3-thiazol-4-yl)phenoxy]propionic acid;(S)-2-[4-bromo-5-fluoro-2-(1 ,3-oxazol-4-yl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-methylbutyric acid;(S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid;(R)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-chloro-5-fluoro-2-(5-isoxazolyl)phenoxy]propionic acid;(S)-2-(4-bromo-2-cyclopropyl-5-fluorophenoxy)propionic acid;(S)-2-[4-bromo-2-(2,2-difluoroethenyl)-5-fluorophenoxy]propionic acid;(S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]butyric acid;(S)-2-(4-bromo-2-iodophenoxy)-4-fluorobutyric acid;(S)-(4-bromo-2-ethynylphenoxy)cyclobutylacetic acid;(S)-2-(4-bromo-2-ethynyl-5-fluorophenoxy)propionic acid;(S)-2-(4-chloro-2-ethynyl-5-fluorophenoxy)propionic acid;(S)-2-[4-bromo-2-(4-isoxazolyl)phenoxy]propionic acid;(R)-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-(p-bromophenoxy)cyclobutylacetic acid;(S)-2-(4-bromo-2-cyclopropylphenoxy)-4-fluorobutyric acid;(S)-2-(4-bromo-2-fluorophenoxy)-4-fluorobutyric acid;(S)-2-(4-bromo-2-ethynylphenoxy)-4-fluorobutyric acid;(S)-2-(4-bromo-2-styrenyloxy)-4-fluorobutyric acid;(S)-(4-bromo-2-fluorophenoxy)cyclobutylacetic acid;(S)-2-[4-chloro-2-(1 ,3-oxazol-4-yl)phenoxy]propionic acid;(S)-2-[4,5-dichloro-2-(3-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-bromo-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-chloro-5-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;(S)-2-(p-bromophenoxy)-4-fluorobutyric acid;(S)-2-{2-[(E)-2-fluoroethenyl]-4-bromophenoxy}propionic acid;(S)-2-[4-bromo-2-(1 ,3-oxazol-4-yl)phenoxy]propionic acid;(S)-2-{2-[(E)-2-fluoroethenyl]-4-chlorophenoxy}propionic acid;(S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid;(S)-2-[4-fluoro-2-(3-isoxazolyl)phenoxy]propionic acid;(R)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-chloro-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid;(S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]butyric acid;(S)-2-[4-chloro-2-(3-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-cyclopropylpropionic acid;(S)-2-[4-chloro-2-(1 ,3-oxazol-2-yl)phenoxy]propionic acid;(S)-2-(4-bromo-2-iodophenoxy)-3-methylbutyric acid;(S)-(4-bromo-2-fluorophenoxy)cyclopropylacetic acid;(R)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-2-[4-chloro-2-(3-isothiazolyl)phenoxy]propionic acid;(S)-2-(4-bromo-2-ethynylphenoxy)butyric acid;(S)-2-(4-bromo-2-iodophenoxy)butyric acid;(S)-2-(4-chloro-2-fluorophenoxy)butyric acid;(S)-2-(p-bromophenoxy)butyric acid;(S)-2-[4-bromo-2-(2,2-difluoroethenyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]butyric acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]butyric acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]-3-methylbutyric acid;(S)-2-[4-bromo-2-(4-methyl-3-isoxazolyl)phenoxy]propionic acid;(S)-2-(4-bromo-2-fluorophenoxy)butyric acid;(S)-2-[4-bromo-2-(5-methyl-3-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(3-methyl-1 ,2,4-oxadiazol-5-yl)phenoxy]propionic acid;(R)-2-[p-bromo(3,5-2H2)phenoxy]-3-fluoropropionic acid;(S)-2-[p-bromo(3,5-2H2)phenoxy]propionic acid;(S)-2-[4-bromo-2-(5-cyclopropyl-3-isoxazolyl)phenoxy]propionic acid; ethyl (S)-2-(4-bromo-2-fluorophenoxy)-3-methyl-3-butenoate;(R)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;(R)-2-[p-bromo(2,6-2H2)phenoxy]-3-fluoropropionic acid;(S)-2-[4-chloro-2-(1 ,3-thiazol-2-yl)phenoxy]propionic acid;(S)-2-[p-bromo(2,6-2H2)phenoxy]propionic acid;(S)-2-[4-bromo-2-(3-isoxazolyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(3-methyl-5-isoxazolyl)phenoxy]propionic acid;(S)-2-(4-bromo-2-iodophenoxy)propionic acid;(S)-2-[4-bromo-2-(2-imidazolyl)phenoxy]propionic acid;(S)-2-[4-bromo-2-(5-imidazolyl)phenoxy]propionic acid;(R)-2-(4-bromo-2-cyclobutylphenoxy)-3-fluoropropionic acid;(R)-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropionic acid;(S)-2-(4-bromo-2-ethynylphenoxy)propionic acid;(S)-2-(2-bromo-4-chlorophenoxy)-3-methylbutyric acid;(S)-2-(2-fluoro-4-iodophenoxy)propionic acid;(S)-2-(2-bromo-4-iodophenoxy)propionic acid;(R)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]-3-fluoropropionic acid;(S)-2-(2-chloro-4-iodophenoxy)propionic acid;(S)-2-(2-bromo-4-chlorophenoxy)propionic acid;(S)-2-(4-bromo-2-cyclopropylphenoxy)propionic acid;(S)-2-(4-bromo-2-styrenyloxy)propionic acid;(S)-2-[4-chloro-2-(1-methyl-3-methyl-4-pyrazolyl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(5-pyrazolyl)phenoxy]propionic acid;(S)-2-[4-chloro-2-(5-isoxazolyl)phenoxy]propionic acid;(S)-2-(2-cyclopropyl-4-fluorophenoxy)propionic acid;(S)-2-[4-chloro-2-(1-methyl-4-pyrazolyl)phenoxy]propionic acid;(S)-2-(2-cyclobutyl-4-fluorophenoxy)propionic acid;(S)-2-(4-bromo-2-cyclobutylphenoxy)propionic acid;(R)-2-(4-bromo-2-fluorophenoxy)-3-fluoropropionic acid;(S)-2-(4-chloro-2-fluorophenoxy)-3-methylbutyric acid;(S)-2-(4-chloro-2-cyclobutylphenoxy)propionic acid;(S)-2-[4-bromo-2-(1 ,3,4-oxadiazol-2-yl)phenoxy]propionic acid;(R)-2-(2-bromo-4-chlorophenoxy)-3-fluoropropionic acid;(R)-2-(p-chlorophenoxy)-3-fluoropropionic acid;(R)-2-(4-chloro-2-fluorophenoxy)-3-fluoropropionic acid;(R)-2-(2,4-dibromophenoxy)-3-fluoropropionic acid;(S)-2-[4-bromo-2-(5-isoxazolyl)phenoxy]propionic acid;(R)-2-(p-bromophenoxy)-3-fluoropropionic acid;(S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutyric acid;(S)-2-(4-bromo-2-fluorophenoxy)propionic acid;(S)-2-(4-chloro-2-fluorophenoxy)propionic acid;(S)-2-(2,4-dibromophenoxy)propionic acid;(S)-2-(4-chloro-2-ethynylphenoxy)propionic acid;(S)-2-(4-chloro-2-styrenyloxy)propionic acid;(S)-2-(4-chloro-2-cyclopropylphenoxy)propionic acid;(S)-2-(p-chlorophenoxy)butyric acid; sodium (S)-2-(2,4-dichlorophenoxy)propionate;(S)-2-(p-chlorophenoxy)-3-methylbutyric acid;(S)-2-(p-cyanophenoxy)propionic acid; methyl (S)-2-(p-bromophenoxy)propionate; methyl (S)-2-(p-chlorophenoxy)butyrate; isopropyl (S)-2-(p-chlorophenoxy)propionate; methyl (S)-2-(p-chlorophenoxy)propionate,(2S)-2-(4-bromo-2-fluorophenoxy)- / V-{1-[(cyclopropylmethoxy)imino]ethyl}propanamide;(2S)-2-(4-bromophenoxy)- / V-[1-(methoxyimino)ethyl]propanamide;(2S)-2-(4-bromo-2-fluorophenoxy)- / V-[(4-fluorophenyl)(hydroxyimino)methyl]-3- methylbutanamide;(2S)-2-(4-bromo-2-fluorophenoxy)- / V-[1-(hydroxyimino)ethyl]-3- methylbutanamide;(2S)-2-(4-bromo-2-fluorophenoxy)- / V-[1-(hydroxyimino)ethyl]propanamide;(2S)-2-(4-bromophenoxy)- / V-[1-(hydroxyimino)ethyl]propenamide;(2S)-2-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]- / \ / -cyanopropanamide;(2S)- / V-cyano-2-(2,4-dibromophenoxy)propanamide;(2S)-2-(4-bromophenoxy)- / V-cyanopropanamide;(2S)-2-(4-chlorophenoxy)- / V-cyanopropanamide;(2S)-2-(4-bromophenoxy)- / V-cyano-3-methylbutanamide;(2S)-2-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]- / \ / -cyclobutoxypropanamide;(2S)-2-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]- / \ / -methoxypropanamide;(2S)- / V-acetyl- / V-[(1-acetylazetidin-3-yl)oxy]-2-(4-chlorophenoxy)propanamide;(2S)- / V-[(1-acetylazetidin-3-yl)oxy]-2-(4-chlorophenoxy)propanamide;(2S)- / V-(azetidin-3-yloxy)-2-(4-chlorophenoxy)propanamide;(2S)- / V-acetyl- / V-[(1-acetylpyrrolidin-3-yl)methoxy]-2-(4- chlorophenoxy)propanamide;(2S)- / V-[(1-acetylpyrrolidin-3-yl)methoxy]-2-(4-chlorophenoxy)propanamide;(2S)- / V-[(1-acetylpyrrolidin-3-yl)oxy]-2-(4-bromophenoxy)propanamide; tert-butyl / V-(2-{[(2S)-2-(4-chlorophenoxy)propanamido]oxy}propyl)carbamate;(2S)- / V-acetyl-2-(4-chlorophenoxy)- / \ / -[(1-acetamidopropan-2- yl)oxy]propanamide;(2S)-2-(4-bromophenoxy)- / \ / -(pyrrolidin-3-yloxy)propanamide;(2S)- / V-acetyl- / V-[(1-acetylpyrrolidin-3-yl)oxy]-2-(4- bromophenoxy)propanamide; tert-butyl 3-{[(2S)-2-(4-chlorophenoxy)propanamido]oxy}azetidine-1- carboxylate;(2S)-2-(4-chlorophenoxy)- / V-[(pyrrolidin-3-yl)methoxy]propanamide; tert-butyl 3-({[(2S)-2-(4-chlorophenoxy)propanamido]oxy}methyl)pyrrolidine-1- carboxylate;(2S)- / V-acetyl- / V-[(1 -acetylpyrrolidin-3-yl)oxy]-2-(4- chlorophenoxy)propanamide;(2S)- / V-[(1-acetylpyrrolidin-3-yl)oxy]-2-(4-chlorophenoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(pyrrolidin-3-yloxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(2,2-dimethylpropyl)- / \ / -hydroxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-[2-(pyrrolidin-1-yl)ethoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-[2-(2-oxopyrrolidin-1-yl)ethoxy]propanamide;(2S)- / V-acetyl-2-(4-chlorophenoxy)- / V-(2-acetamidoethoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(2-acetamidoethoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(4,4,4-trifluoro-2-methylbutoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(3-cyclopentylpropyl)- / \ / -hydroxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-{[(2E)-2-methyl-3-phenylprop-2-en-1- yl]oxy}propanamide;(2S)-2-(4-chlorophenoxy)- / V-{2-oxo-2-[2-(trifluoromethyl)pyrrolidin-1- yl]ethoxy}propanamide; tert-butyl / V-(2-{[(2S)-2-(4-chlorophenoxy)propanamidyl]oxy}ethyl)carbamate;(2S)-2-(4-chlorophenoxy)- / V-[(2-methyl-1 H-imidazol-4- yl)methoxy]propanamide; tert-butyl 4-({[(2S)-2-(4-chlorophenoxy)propanamido]oxy}methyl)-2-methyl-1 H- imidazole-1 -carboxylate;(2S)-2-(4-bromo-2-fluorophenoxy)- / \ / -cyclobutoxypropanamide;(2S)-2-(4-bromophenoxy)- / \ / -cyclobutoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-[1-(4-fluorophenyl)ethoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-[1-(1 ,3-thiazol-2-yl)ethoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-{1-[4-(trifluoromethyl)phenyl]ethoxy}propanamide;(2S)-2-(4-chlorophenoxy)- / V-(2-methanesulfinylethoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(2-methanesulfonylethoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-[(1 ,2-oxazol-3-yl)methoxy]propanamide;(2S)-2-(4-chloro-2-fluorophenoxy)- / V-methoxypropanamide;(2S)-2-[4-bromo-2-(1 ,3,4-oxadiazol-2-yl)phenoxy]- / \ / -(cyclopropylmethoxy)propanamide;(2S)-2-[4-chloro-2-(trifluoromethyl)phenoxy]- / \ / -(cyclopropylmethoxy)propanamide;(2S)- / V-(tert-butoxy)-2-(4-chlorophenoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-[2-(methylsulfanyl)ethoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-(1-phenylethoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-[(1-methyl-1 H-imidazol-2- yl)methoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-(2-methoxyethoxy)propanamide;(2S)-2-(4-chloro-2-fluorophenoxy)- / V-cyclobutoxypropanamide;(2S)-2-[4-bromo-2-(1 ,3,4-oxadiazol-2-yl)phenoxy]- / \ / -methoxypropanamide;(2S)-2-[4-chloro-2-(trifluoromethyl)phenoxy]- / V-methoxypropanamide;(2S)- / V-(benzyloxy)-2-(4-chlorophenoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-[(2-methoxycyclopentyl)oxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-cyclobutoxy-5-methylhexanamide;(2S)-2-(4-chlorophenoxy)- / V-cyclobutoxy- / V-methylpropanamide;(2S)-2-(4-chloro-2-methylphenoxy)- / V-cyclobutoxypropanamide;(2S)-2-(4-chloro-3-fluorophenoxy)- / V-cyclobutoxypropanamide;(2S)-2-(4-chloro-2-methylphenoxy)- / V-methoxypropanamide;(2S)-2-(4-chloro-3-fluorophenoxy)- / V-methoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-cyclobutoxy-4-methylpentanamide;(2S)-2-(4-chlorophenoxy)- / V-[(3-methylbut-2-en-1-yl)oxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-cyclobutoxyhexanamide;(2S)-2-(4-chlorophenoxy)- / V-[(1 ,3-oxazol-2-yl)methoxy]propanamide;(2S)-2-(2,4-dibromophenoxy)- / V-methoxypropanamide;(2S)-2-(4-bromo-2-fluorophenoxy)- / V-methoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-(oxan-2-yloxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-[(1 ,3-thiazol-2-yl)methoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-(3,3-difluorocyclobutoxy)propanamide;(2S)-2-[4-bromo-2-(1 ,2-oxazol-5-yl)phenoxy]- / \ / -cyclobutoxypropanamide;(2S)-2-[4-bromo-2-(1 ,2-oxazol-5-yl)phenoxy]- / \ / -methoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-(cyclopentyloxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(2-cyclopentylethoxy)propanamide;(2S)-2-(4-bromo-2-chlorophenoxy)- / V-methoxypropanamide;(2S)-2-(4-bromo-2-methylphenoxy)- / V-methoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-(cyclopropylmethoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-(cyclobutylmethoxy)propanamide;(2S)- / V-(2-aminoethoxy)-2-(4-chlorophenoxy)propanamide;(2S)-2-(4-bromophenoxy)- / V-methoxy-3-methylbutanamide;methyl 2-{[(2S)-2-(4-chlorophenoxy)propanamido]oxy}acetate;(2S)-2-(4-chlorophenoxy)- / V-[2-(2-methoxyethoxy)ethoxy]propanamide;(2S)-2-(4-chlorophenoxy)- / V-cyclobutoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-(2-hydroxyethoxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-ethoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-propoxypropanamide;(2S)-2-(4-chlorophenoxy)- / V-(propan-2-yloxy)propanamide;(2S)-2-(4-chlorophenoxy)- / V-methoxypropanamide;(2S)-2-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]- / \ / -(cyclopropanesulfonyl)propenamide;(2S)-2-(4-bromo-2-fluorophenoxy)- / V-methanesulfonylpropanamide;(2S)-2-(4-bromo-2-fluorophenoxy)- / V-(cyclopropanesulfonyl)propenamide;(2S)-2-(4-chlorophenoxy)- / V-methanesulfonylpropanamide;(2S)-2-(4-bromophenoxy)- / V-methanesulfonyl-3-methylbutanamide;5-[(1 S)-1-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]-3-fluoropropyl]-2H-1 , 2,3,4- tetrazole;5-[(1 S)-1-(4-bromo-2-fluorophenoxy)propyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-bromo-2-fluorophenoxy)-2-methylpropyl]-2H-1 ,2,3,4-tetrazole;5-[(1R)-1-(4-bromophenoxy)-2-fluoroethyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-bromophenoxy)propyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-bromophenoxy)ethyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]ethyl]-1 H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-[4-bromo-2-(1 ,2-oxazol-5-yl)phenoxy]ethyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-[4-chloro-2-(1 ,2-oxazol-3-yl)phenoxy]ethyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-chloro-2-cyclopropylphenoxy)ethyl]-1 H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-chloro-2-ethenylphenoxy)ethyl]-1 H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-chloro-2-ethylphenoxy)ethyl]-1 H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-chloro-2-methylphenoxy)ethyl]-2H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-chlorophenoxy)ethyl]-1 H-1 ,2,3,4-tetrazole; / V-{3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-1 ,2,4-thiadiazol-5-yl}acetamide; / V-{3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-1 ,2,4-thiadiazol-5- yljmethanesulfonamide;3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-1 ,2,4-thiadiazol-5-amine; / V-{3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-yl}acetamide; / \ / -{3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-1 ,2,4-oxadiazol-5- yljmethanesulfonamide;3-[(1 S)-1-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H- 1 ,2,4-triazole;3-[(1 S)-1-[4-chloro-2-(1 ,2-oxazol-3-yl)phenoxy]ethyl]-5-(trifluoromethyl)-4H- 1 ,2,4-triazole;3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methoxy-1 ,2,4-oxadiazole;3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-1 ,2,4-oxadiazol-5-amine;3-[(1 S)-1-[4-bromo-2-(1 ,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1 ,2,4- triazole;3-[(1 S)-1-[4-chloro-2-(1 ,2-oxazol-3-yl)phenoxy]ethyl]-5-methyl-4H-1 ,2,4- triazole;3-[(1 S)-1-(4-bromo-2-fluorophenoxy)ethyl]-5-methyl-4H-1 ,2,4-triazole;5-[(1 S)-1-(4-chlorophenoxy)ethyl]-1 H-1 ,2,4-triazole;(2S)-2-[4-bromo-2-(1 ,1-difluoroethyl)phenoxy]- / \ / -cyanopropanamide;(2S)-2-[4-bromo-2-(1 ,1-difluoropropyl)-5-fluorophenoxy]- / \ / -cyanopropanamide;(2S)-2-[4-bromo-2-(1 ,1-difluoropropyl)phenoxy]- / V- methanesulfonylpropanamide;(2S)-2-[4-bromo-2-(1 ,1-difluoropropyl)phenoxy]- / V- (cyclopropanesulfonyl)propenamide;5-[(1 S)-1-[4-bromo-2-(1 ,1-difluoroethyl)phenoxy]ethyl]-1 H-1 ,2,3,4-tetrazole;5-[(1 S)-1-[4-bromo-2-(1 ,1-difluoropropyl)phenoxy]ethyl]-1 H-1 ,2,3,4-tetrazole;5-[(1 S)-1-(4-bromo-2-cyclobutylphenoxy)-2-methoxyethyl]-1 H-1 ,2,3,4- tetrazole; and5-[(1 S)-1-(4-bromo-2-cyclopropylphenoxy)-2-methoxyethyl]-1 H-1 ,2,3,4- tetrazole, or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof.

16. A method for treating a neuromuscular disorder: subjecting different muscle fibers of the same motor unit in a neuromuscular tissue of a patient being examined for the neuromuscular disorder to a number of activations; detecting, with a medical device and a recording electrode, the number of paired successful action potentials from the number of activations;determining whether the patient is suffering from or at risk of blocking by dividing the number of paired successful action potentials over a total number of activations; and when the number of paired successful action potentials over the total number of activations is below a threshold of 95%, administering a CIC-1 inhibitor to the patient, wherein the administering of the CIC-1 inhibitor increases the number of paired successful action potentials over the total number of activations by at least 5%.

17. The method of claim 16, wherein the CIC-1 inhibitor is a compound according to any one of claims 1-15.

18. The method of claim 16, wherein the method is used in the treatment, prevention and / or amelioration of a neuromuscular disorder.

19. The method of claim 16, wherein the neuromuscular disorder is selected from one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle specific kinase myasthenia gravis (MuSK-MG), Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy, Duchenne muscular dystrophy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disorder, multiple sclerosis and multifocal motor neuropathy.

20. The method of claim 19, wherein the neuromuscular disorder is multiple sclerosis.

21. The method of claim 16, wherein the administering of the CIC-1 inhibitor restores contractile force of the patient’s muscles by at least 5%.

22. The method of claim 16, wherein the administering of the CIC-1 inhibitor reduces incidence of neuromuscular junction transmission failure in the patient’s muscles by at least 5%.

23. A method for treating a neuromuscular disorder comprising: acquiring, with a medical device and a recording electrode, a variation in a time interval between two action potentials of the same motor unit in a neuromuscular tissue of a patient being examined for the neuromuscular disorder; determining whether the variation in the time interval between the two action potentials of the same motor unit exceeds or meets a threshold of 40 ps; and administering a CIC-1 inhibitor to the patient when the variation in the time interval between the two action potentials exceeds or meets the threshold, wherein the administering of the CIC-1 inhibitor reduces the variation in the time interval between the two action potentials between consecutive electrical discharges by at least 10%.

24. The method of claim 23, wherein the CIC-1 inhibitor is a compound according to any one of claims 1-15.

25. The method of claim 23, wherein the method is used in the treatment, prevention and / or amelioration of a neuromuscular disorder.

26. The method of claim 25, wherein the neuromuscular disorder is selected from one of the following: sarcopenia, myasthenia gravis, autoimmune myasthenia gravis, congenital myasthenic syndrome, seronegative myasthenia gravis, muscle specific kinase myasthenia gravis (MuSK-MG), Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie Tooth disease, diabetic polyneuropathy, periodic paralysis, hypokalemic periodic paralysis, hyperkalemic periodic paralysis, myotubular myopathy, Duchenne muscular dystrophy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome, critical illness polyneuropathy, metabolic myopathy, Kennedy's disorder, multiple sclerosis and multifocal motor neuropathy.

27. The method of claim 26, wherein the neuromuscular disorder is multiple sclerosis.

28. The method of claim 23, wherein the administering of the CIC-1 inhibitor restores contractile force of the patient’s muscles by at least 5%.

29. The method of claim 23, wherein the administering of the CIC-1 inhibitor reduces incidence of neuromuscular junction transmission failure in the patient’s muscles by at least 5%.

30. The method of claim 23, wherein the variation in the time interval between two action potentials is measured using single fiber electromyography.

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