Ion channel modulating compounds and uses thereof

1. A compound of formula (I), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

X is selected from —C(R 6 ,R 14 )—Y—, and —C(R 13 )═CH—;

Y is selected from a direct bond, O, S, and C 1 –C 4 alkylene;

R 13 is selected from hydrogen, C 1 –C 6 alkyl, C 3 –C 8 cycloalkyl, aryl, and benzyl;

R 1 and R 2 taken together with the nitrogen atom to which they are directly attached in formula (I) form a morpholinyl ring where any one or more of the carbon ring atoms may be substituted with one or two substituents selected from hydrogen, hydroxy, C 1 –C 3 hydroxyalkyl, oxo, C 2 –C 4 acyl, C 1 –C 3 alkyl, C 2 –C 4 alkylcarboxy, C 1 –C 3 alkoxy, and C 1 –C 20 alkanoyloxy;

R 3 and R 4 are independently attached to the cyclohexane ring shown in formula (I) at the 3-, 4-, 5- or 6-positions and are independently selected from hydrogen, hydroxy, C 1 –C 6 alkyl, and C 1 –C 6 alkoxy;

R 5 , R 6 and R 14 are independently selected from hydrogen, C 1 –C 6 alkyl, aryl and benzyl;

A is selected from C 5 –C 12 alkyl, a C 3 –C 13 carbocyclic ring, and ring systems selected from formulae (III), (IV), (V), (VI), (VII) and (VIII):

where R 7 , R 8 and R 9 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl;

where R 10 and R 11 are independently selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl;

where R 12 is selected from bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C 2 –C 7 alkanoyloxy, C 1 –C 6 alkyl, C 1 –C 6 alkoxy, C 2 –C 7 alkoxycarbonyl, C 1 –C 6 thioalkyl, and N(R 15 ,R 16 ) where R 15 and R 16 are independently selected from hydrogen, acetyl, methanesulfonyl, and C 1 –C 6 alkyl; and Z is selected from CH, CH 2 , O, N and S, where Z may be directly bonded to “X” as shown in formula (I) when Z is CH or N, or Z may be directly bonded to R 17 when Z is N, and R 17 is selected from hydrogen, C 1 –C 6 alkyl, C 3 –C 8 cycloalkyl, aryl and benzyl;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

2. A compound according to claim 1 having formula (IX), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

X is selected from —C(R 6 ,R 14 )—Y—, and —C(R 13 )═CH—;

Y is selected from a direct bond, O and S; and

R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 14 , A and Z are defined as in claim 1 ;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

3. A compound of claim 1 having formula (X), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

X is selected from —C(R 6 ,R 14 )—Y—, and —C(R 13 )═CH—;

Y is selected from a direct bond, O, and S;

R 1 , R 2 , R 6 and R 14 are defined as in claim 1 ;

R 3 and R 4 are independently selected from hydrogen and C 1 –C 6 alkoxy; and

A is selected from C 5 –C 12 alkyl, C 3 –C 8 cycloalkyl, and any of formulae (III), (IV), (V), and (VI) as defined in claim 1 , wherein Z, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are defined as in claim 1 ;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

4. A compound of claim 1 having formula (XI), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

R 1 and R 2 are defined as in claim 1 ;

R 3 and R 4 are independently selected from hydrogen and methoxy; and

A is selected from C 5 –C 12 alkyl, C 3 –C 8 cycloalkyl, and any of formulae (III), (IV), (V), and (VI) as defined in claim 1 , wherein Z, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are defined as in claim 1 ;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

5. A compound of claim 1 having formula (XII), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

R 1 and R 2 are defined as in claim 1 ;

R 3 and R 4 are independently selected from hydrogen and methoxy; and

A is selected from C 5 –C 12 alkyl, C 3 –C 8 cycloalkyl, and any of formulae (III), (IV), (V) and (VI) as defined in claim 1 , wherein Z, R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are defined as in claim 1 ;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

6. A compound of claim 1 having formula (XIII), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

X is selected from —C(R 6 ,R 14 )—Y— and —CH═CH—;

Y, R 1 , R 2 , R 6 and R 14 are defined as in claim 1 ;

R 3 and R 4 are independently selected from hydrogen and methoxy; and

A is selected from C 3 –C 8 cycloalkyl and any of formulae (III), (IV), (V), (VI), (VII) and (VIII) as defined in claim 1 , where R 8 and R 9 are defined as in claim 1 , R 7 , R 10 , R 11 and R 12 are hydrogen, and Z is selected from O, S and N—R 17 where R 17 is selected from hydrogen and methyl;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

7. A compound of claim 1 having formula (XIV), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

R 1 and R 2 are defined as in claim 1 ; and

A is selected from any of formulae (III), (IV), (V) and (VI) as defined in claim 1 , wherein R 7 , R 10 , R 11 and R 12 are hydrogen, R 8 and R 9 are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NH 2 ; and Z is selected from O and S;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

8. A compound of claim 1 having formula (XV), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

R 1 and R 2 are defined as in claim 1 ; and

A is selected from any of formulae (III), (IV), (V) and (VI) as defined in claim 1 , wherein R 7 , R 10 , R 11 and R 12 are hydrogen, R 8 and R 9 are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulfonamido, methanoyloxy, methoxycarbonyl, nitro, sulfamyl, thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and NH 2 ; and Z is selected from O and S;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

9. A compound of claim 1 having formula (XVI), or a solvate or pharmaceutically acceptable salt thereof:

wherein,

X is selected from trans-CH═CH—, —CH 2 — and —CH 2 —O—;

R 1 and R 2 taken together with the nitrogen atom to which they are attached form; and

A is selected from cyclohexyl, monochlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 2-bromophenyl, 2,4-dibromophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dimethoxyphenyl, 1-naphthyl, 2-naphthyl, 3-benzo(b)thiophenyl, 4-benzo(b)thiophenyl, (2-trifluoromethyl)phenyl, 2,4-di(trifluoromethyl)phenyl, and (4-trifluoromethyl)phenyl;

including isolated enantiomeric, diastereomeric and geometric isomers thereof, and mixtures thereof.

10. A compound, or mixture comprising compounds, selected from the group consisting of:

(+)-trans-[2-(4-morpholinyl)-1-(2-naphthenethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(2-naphthenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(1-naphthenethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(1-naphthenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(4-bromophenethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(4-bromophenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-[2-(2-naphthoxy)ethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-[2-(4-bromophenoxy)ethoxy]]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(3,4-dimethoxyphenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-3-yl)ethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-3-yl)ethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-4-yl)ethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(2-(benzo[b]thiophen-4-yl)ethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(3-bromophenethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(3-bromophenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(2-bromophenethoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(2-bromophenethoxy)]cyclohexane;

(+)-trans-[2-(4-morpholinyl)-1-(3-(3,4-dimethoxyphenyl)-1-propoxy)]cyclohexane;

(−)-trans-[2-(4-morpholinyl)-1-(3-(3,4-dimethoxyphenyl)-1-propoxy)]cyclohexane;

(1R,2R)/(1S,2S)-2-(4-morpholinyl)-1-(3,4-dichlorophenethoxy)cyclohexane; and

(1R,2S)/(1S,2R) 2 (4morpholinyl)-1-[(2-trifluoromethyl)phenethoxy]cyclohexane;

including isolated enantiomeric and diastereomeric isomers thereof, and mixtures thereof; and pharmaceutically acceptable salts thereof.

11. A composition comprising a compound according to any one of claims 1 – 10 in combination with a pharmaceutically acceptable carrier, excipient or diluent.