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US 2026/0199273 A1Published application
Compounds for the Treatment of Neuromuscular Disorders
AssigneeNmd Pharma A/S
InventorsNicholas Michael KELLY, Lars J.S. KNUTSEN, Neerja SARASWAT, Richard J. HAMLYN, Farman ULLAH, Dastagiri DUDEKULA, Penchal NANDALURU, Rajesh KUMAR
Life of this patent
Estimating the term…
Abstract
The present disclosure 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 can inhibit the CIC-1 ion channel.
Claims15
A compound of Formula (1):
- wherein:
- M is CR5R6, NR9, O or S;
- Q is CR7R6, NR10, O or S;
- T is absent, CR7R6, NR10, O or S;
- X is absent, CR7R6, NR10, O or S;
- Z is CR8R6, NR11, O or S;
- wherein no more than one of M, Q, T, X or Z is selected from the group consisting of NR9, NR10, NR11, O or S;
- wherein R5 and R8, or R5 and R11, or R9 and R3 are optionally joined together to form a ring by —CH2—, —CH2CH2- or —CH2CH2CH2—;
- R1 is selected from the group consisting of F;
- Cl;
- C1-3 alkyl optionally substituted with one or more deuterium;
- C2-3 alkenyl optionally substituted with one or more, identical or different, substituents R12;
- —OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- —OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- —SC1-3 alkyl optionally substituted with one or more, identical or different, substituents R12 and —SC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- R2 is selected from the group consisting of F;
- Cl;
- C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12 and C3 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- R3 is selected from the group consisting of H;
- F and Cl;
- R4 is selected from the group consisting of H;
- C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;
- C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R12;
- C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R12;
- C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- phenyl optionally substituted with one or more, identical or different, substituents R13;
- and benzyl optionally substituted with one or more, identical or different, substituents R13;
- R5 is selected from the group consisting of H, deuterium, F, and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12, or when R5 is linked to R3 or R11, then R5 is a bond or C1-3 alkanediyl;
- R6 is independently selected from the group consisting of H, deuterium, F, C1-3 alkyl substituted with R14 and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- R7 is independently selected from the group consisting of H, deuterium, F and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- R3 is selected from the group consisting of H, deuterium, F and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12, or when R3 is linked to R5 or R9, then R3 is a bond or C1-3 alkanediyl;
- R9 is selected from the group consisting of H, C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12, and C1-3 alkyl substituted with R14 or when R9 is linked to R8, then R9 is a bond or C1-3 alkanediyl;
- R10 is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R13;
- R11 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12, and C1-3 alkyl substituted with R15, or when R11 is linked to R5, then R11 is a bond or C1-3 alkanediyl;
- R12 is independently selected from the group consisting of deuterium, F and OMe;
- R13 is independently selected from the group consisting of deuterium, methoxy, —OCF3, Me, CF3, CF2Cl, CF2H, CFH2, CD3, cyclopropyl, NH2, —NHAc, —C(═O)—NH2, nitro, cyano, Cl, Br, I, and F;
- R14 is independently selected from the group consisting of C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R12, phenyl optionally substituted with one or more, identical or different, substituents R13 and 5-membered heteroaryl optionally substituted with one or more, identical or different, substituents R13;
- and
- R15 is independently selected from the group consisting of C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R12, C610 aryl optionally substituted with one or more, identical or different, substituents R13 and 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R13;
- or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof provided that the compound is not a compound selected from the group consisting of:
- 10-chloro-9-methoxybicyclo[5.4.0]undeca-1(7),8,10-triene-8-carboxylic acid;
- methyl 10-chloro-9-methoxybicyclo[5.4.0]undeca-1(7),8,10-triene-8-carboxylate;
- ethyl 10-chloro-9-methoxybicyclo[5.4.0]undeca-1(7),8,10-triene-8-carboxylate;
- 3-chloro-2-methoxy-5,6,7,8-tetrahydro-1-naphthoic acid;
- methyl 3-chloro-2-methoxy-5,6,7,8-tetrahydro-1-naphthoate;
- ethyl 3-chloro-2-methoxy-5,6,7,8-tetrahydro-1-naphthoate;
- methyl 2-methoxy-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1-naphthoate;
- 2,3-dimethyl-5,6,7,8-tetrahydro-1-naphthoic acid;
- 2,3,4-trichloro-5,6,7,8-tetrahydro-1-naphthoic acid;
- 5,6-dimethyl-4-indancarboxylic acid;
- methyl 5,6-dimethyl-4-indancarboxylate;
- 6-chloro-5-methoxy-1,3-dihydro-4-isobenzofuroic acid;
- methyl 6-chloro-5-methoxy-1,3-dihydro-4-isobenzofuroate;
- ethyl 6-chloro-5-methoxy-1,3-dihydro-4-isobenzofuroate;
- 5,6-dichloro-1,3-dihydro-4-isobenzofuroic acid;
- 5-methoxy-6-methyl-1,3-dihydro-4-isobenzofuroic acid;
- 5-methoxy-6-methyl-2,3-dihydro-1-benzofuran-4-carboxylic acid;
- methyl 5-methoxy-6-methyl-2, 3-dihydro-1-benzofuran-4-carboxylate;
- ethyl 5-methoxy-6-methyl-2,3-dihydro-1-benzofuran-4-carboxylate;
- 5-ethyl-6-methoxy-2,3-dihydro-1-benzofuran-7-carboxylic acid;
- 5,6-difluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylic acid;
- 5-fluoro-6-methyl-2,3-dihydro-1-benzothiophene-4-carboxylic acid;
- 5-chloro-6-methyl-2,3-dihydro-1-benzothiophene-4-carboxylic acid;
- 5,6-dichloro-2,3-dihydro-1-benzothiophene-4-carboxylic acid;
- 6-chloro-5-methyl-2,3-dihydro-1-benzothiophene-7-carboxylic acid;
- and
- 5,6-dimethyl-2,3-dihydro-1-benzothiophene-7-carboxylic acid.
64 more elements
A compound of Formula (1):
- wherein:
- M is CR5R6, NR9, O or S;
- Q is CR7R6, NR10, O or S;
- T is absent, CR7R6, NR10, O or S;
- X is absent, CR7R6, NR10, O or S;
- Z is CR8R6, NR11, O or S;
- wherein no more than one of M, Q, T, X or Z is selected from the group consisting of NR9, NR10, NR11, 0 or S;
- wherein R5 and R8, or R5 and R11, or R9 and R3 are optionally joined together to form a ring by —CH2—, —CH2CH2- or —CH2CH2CH2—;
- R1 is selected from the group consisting of H;
- F;
- Cl;
- Br;
- I;
- C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- C2-3 alkenyl optionally substituted with one or more, identical or different, substituents R12;
- —OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- —OC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- —SC1-3 alkyl optionally substituted with one or more, identical or different, substituents R12 and —SC3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- R2 is selected from the group consisting of H;
- F;
- Cl;
- Br;
- I;
- C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- —OC1-3 alkyl optionally substituted with one or more, identical or different, substituents R12 and C3 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- R3 is selected from the group consisting of H;
- F and Cl;
- R4 is selected from the group consisting of H;
- C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12;
- C2-5 alkenyl optionally substituted with one or more, identical or different, substituents R12;
- C2-5 alkynyl optionally substituted with one or more, identical or different, substituents R12;
- C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R12;
- phenyl optionally substituted with one or more, identical or different, substituents R13;
- and benzyl optionally substituted with one or more, identical or different, substituents R13;
- R5 is selected from the group consisting of H, deuterium, F, and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12, or when R5 is linked to R3 or R11, then R5 is a bond or C1-3 alkanediyl;
- R6 is independently selected from the group consisting of H, deuterium, F, C1-3 alkyl substituted with R14 and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- -R7 is independently selected from the group consisting of H, deuterium, F and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12;
- R3 is selected from the group consisting of H, deuterium, F and C1-3 alkyl optionally substituted with one or more, identical or different, substituents R12, or when R3 is linked to R5 or R9, then R3 is a bond or C1-3 alkanediyl;
- R9 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12, and C1-3 alkyl substituted with R14 or when R9 is linked to R8, then R9 is a bond or C1-3 alkanediyl;
- R10 is independently selected from benzyl optionally substituted with one or more, identical or different, substituents R13;
- R11 is selected from the group consisting of H, C1-5 alkyl optionally substituted with one or more, identical or different, substituents R12, and C1-3 alkyl substituted with R14, or when R11 is linked to R5, then R11 is a bond or C1-3 alkanediyl;
- R12 is independently selected from the group consisting of deuterium, F and OMe;
- R13 is independently selected from the group consisting of deuterium, methoxy, —OCF3, Me, CF3, CF2Cl, CF2H, CFH2, CD3, cyclopropyl, NH2, —NHAc, —C(═O)—NH2, nitro, cyano, Cl, Br, I, and F;
- R14 is independently selected from the group consisting of C3-5 cycloalkyl optionally substituted with one or more, identical or different, substituents R12, phenyl optionally substituted with one or more, identical or different, substituents R13 and 5-membered heteroaryl optionally substituted with one or more, identical or different, substituents R13;
- and
- -R15 is independently selected from the group consisting of C3-6 cycloalkyl optionally substituted with one or more, identical or different, substituents R12, C610 aryl optionally substituted with one or more, identical or different, substituents R13 and 5- to 10-membered heteroaryl optionally substituted with one or more, identical or different, substituents R13;
- 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.
44 more elements
Dependencies are inferred from the claim text.