Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same

1. A compound of a formula:

or a pharmaceutically acceptable salt thereof, and stereoisomers and tautomers thereof; wherein:

W represents O, CR 8a R 8b , or NR 8c ;

X represents N, O, CR 8a , CR 8a R 8b , or NR 8c ;

Y represents CR 8d R 8e ;

at least one of W′, X′, and Y′ represents N and the rest each independently represents CR 8 ;

Z represents CR 8 or N; provided that W′, X′ and Y′ are not all N at the same time;

R 1 and R 2 each independently represent hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl;

R 3 represents hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, acyl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino,substituted or unsubstituted dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl;

R 4 and R 5 each independently represent hydrogen or substituted or unsubstituted alkyl;

R 7 represents (C 1 -C 6 )alkyl;

each R 8 independently represents hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, acyl, substituted or unsubstituted amino, substituted or unsubstituted alkylamino,substituted or unsubstituted dialkylamino, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, alkylthio, alkylsulfinyl or alkylsulfonyl;

each R 8a , R 8b , R 8d , R 8e and R 8f independently represents hydrogen, halo, hydroxy, or substituted or unsubstituted alkyl; provided that when the dotted bond is a double bond R 8f is absent;

R 8c represents hydrogen, or substituted or unsubstituted alkyl; and

the dotted bond represents a single or a double bond;

provided that

i) when W and X both are O, and Y′ is CR 8 ; then at least one of R 3 and R 8 is other than H; and

ii) when W and X both are CH 2 , W′ is N, and Y′ is CR 8 ; then at least one of R 3 and R 8 is other than H.

2. A compound according to claim 1 wherein

W, W′, X, X′, Y′, Z, and R 7 are as in claim 1 ;

R 1 and R 2 each independently represent hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl or (C 1 -C 6 )alkylsulfonyl;

R 3 represents

hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, halo hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )acyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, [(C 1 -C 6 )alkyl]NH—, [(C 1 -C 6 )alkyl] 2 N—, [hydroxy(C 1 -C 6 )alkyl]NH—, substituted or unsubstituted 3-6 membered cycloalkyl, [3-6 membered cycloalkyl]oxy, or [3-6 membered heterocycloalkyl]oxy or

3-6 membered heterocycloalkyl, unsubstituted or substituted with halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, [(C 1 -C 6 )alkyl] 2 N—, or hydroxy, or

3-6 membered heteroaryl, 3-6 membered cycloalkyl (C 1 -C 6 )alkyl, or 3-6 membered cycloalkyl hydroxy (C 1 -C 6 )alkyl;

R 4 represents hydrogen, (C 1 -C 6 )alkyl, halogen, halo(C 1 -C 6 ) alkyl, or hydroxy(C 1 -C 6 )alkyl;

each R 8 independently represents

hydrogen, halogen, hydroxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylsulfinyl, [(C 1 -C 6 )alkyl]NH—, [(C 1 -C 6 )cycloalkyl]NH—, [(C 1 -C 6 )alkyl] 2 N—, [hydroxy(C 1 -C 6 )alkyl]NH—, [3-6 membered cycloalkyl]oxy, [3-6 membered heterocycloalkyl]oxy or

3-6 membered heterocycloalkyl, unsubstituted or substituted with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, [(C 1 -C 6 )alkyl] 2 N—, (C 1 -C 6 )carbalkoxy, hydroxy, aryl, (C 1 -C 6 )alkylaryl, halo(C 1 -C 6 )alkylaryl, haloaryl, (C 1 -C 6 )alkoxyaryl, or

3-10 membered heteroaryl, 3-6 membered cycloalkyl (C 1 -C 6 )alkyl, or 3-6 membered cycloalkyl hydroxy (C 1 -C 6 )alkyl or (C 1 -C 6 )alkylsulfonyl;

each R 8a , R 8b , R 8d , R 8e and R 8f independently represents hydrogen, halo, hydroxy, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl; provided that when the dotted bond is a double bond R 8f is absent;

R 8c represents hydrogen, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-(C 1 -C 6 )alkyl, cycloalkyl, or halo(C 1 -C 6 )alkyl; and

the dotted bond represents a single or a double bond.

3. A compound according to claim 1 , wherein one of W′, X′, Y′ and Z represent N and the rest each independently represent CR 8 .

4. A compound according to claim 1 , wherein two of W′, X′, Y′ and Z represent N and the rest each independently represent CR 8 .

5. A compound according to claim 1 , wherein W and X each independently represent CR 8a R 8b ; and the dotted bond is a single bond.

6. A compound according to claim 1 , wherein W and X each independently represent CH 2 ; and the dotted bond is a single bond.

7. A compound according to claim 1 , wherein W represents CR 8a R 8b ; X represents CR 8a ; and the dotted bond is a double bond.

8. A compound according to claim 1 , wherein W represents CH 2 ; X represents CH; and the dotted bond is a double bond.

9. A compound according to claim 1 , wherein X represents NR 8c ; and the dotted bond is a single bond.

10. A compound according to claim 1 , wherein X represents O; and the dotted bond is a single bond.

11. A compound according to claim 1 , wherein W represents NR 8c .

12. A compound according to claim 1 , wherein W represents O.

13. A compound according to claim 1 , wherein Y represents CR 8d R 8e .

14. A compound according to claim 1 , wherein Y represents CH 2 .

15. A compound according to claim 1 wherein the compound is according to formulae IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh or IIi:

or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein W′, X′, Y′, Z, R 1 , R 2 , R 3 , R 4 , R 7 , R 8a and R 8c are as in claim 1 .

16. A compound according to claim 1 , wherein R 1 represents hydrogen, halogen or (C 1 -C 6 )alkyl.

17. A compound according to claim 1 , wherein R 1 represents H or F.

18. A compound according to claim 15 , wherein the compound is according to formula IIa, IIb or IIc and the dotted bond is a single bond.

19. A compound according to claim 15 wherein the compound is according to formula IIa, IIb or IIc and the dotted bond is a double bond.

20. A compound according to claim 15 wherein one of W′, X′, and Y′ represents N and the rest each independently represents CR 8 .

21. A compound according to claim 15 wherein W′ is N and each of X′, and Y′ is independently CR 8 .

22. A compound according to claim 15 wherein W′ is N and each of X′, and Y′ is independently CH.

23. A compound according to claim 1 wherein the compound is according to formulae IVa, IVb, IVc, IVd, IVe, IVf, IVg, IVh or IVi :

or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein Z, R 2 , R 3 , R 4 , R 7 , R 8 , and R 8C are as in claim 1 .

24. A compound according to claim 1 wherein the compound is according to formulae Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh or Vi :

or a pharmaceutically acceptable salt, and stereoisomers and tautomers thereof, wherein Z, R 2 , R 3 , R 4 , R 7 , and R 8c are as in claim 1 .

25. A compound according to claim 1 wherein Z represents CH, CF or CCl.

26. A compound according to claim 1 wherein Z represents N.

27. A compound according to claim 1 wherein R 2 represents halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl or hydroxy(C 1 -C 6 )alkyl.

28. A compound according to claim 1 wherein R 2 represents F or methyl.

29. A compound according to claim 1 wherein R 2 represents Me and Z represents CF.

30. A compound according to claim 1 wherein the compound is according to formula IVa-IVc, and Va-Vc, and the dotted bond is a single bond.

31. A compound according to claim 23 or 27 wherein the compound is according to formula IVa-IVc, and Va-Vc, and the dotted bond is a double bond.

32. A compound according to claim 1 wherein R 3 or R 8 is H.

33. A compound according to claim 1 wherein R 3 or R 8 independently represents OMe, OEt, COMe, NMe 2 , or NEt 2 .

34. A compound according to claim 1 wherein R 3 or R 8 is independently F, Br, or Cl.

35. A compound according to claim 1 wherein R 3 or R 8 is independently Me, i-Pr, t-Bu, 1-methyl-1-trifluoromethylethyl, or 1-methyl-1-hydroxyethyl.

36. A compound according to claim 1 wherein R 3 or R 8 is independently CF 3 .

37. A compound according to claim 1 wherein R 3 or R 8 is independently 3-6 membered cycloalkyl.

38. A compound according to claim 1 wherein R 3 or R 8 is independently cyclopropyl, 1-methylcyclopropyl, 1-hydroxycyclopropyl, 1-trifluoromethylcyclopropyl, cyclobutyl or cyclopentyl.

39. A compound according to claim 1 wherein R 3 or R 8 is independently 3-6 membered heterocycloalkyl.

40. A compound according to claim 1 wherein R 3 or R 8 is independently

41. A compound according to claim 1 wherein R 3 or R 8 is independently —C(OMe)(Me)CF 3 , —C(OH)(Me)CF 3 , —C(Me) 2 OH or —C(Me)(OH)-cyclopropyl.

42. A compound according to claim 1 wherein R 4 is hydrogen.

43. A compound according to claim 1 wherein R 4 is (C 1 -C 6 )alkyl.

44. A compound according to claim 1 wherein R 4 is methyl.

45. A compound according to claim 1 wherein R 7 is alkyl.

46. A compound according to claim 1 wherein R 7 is Me, Et, Pr, i-Pr, or t-butyl.

47. A compound according to claim 1 wherein R 8C is H or Me.

48. A compound according to claim 1 , selected from

2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

2-(2,2,2-Trifluoro-1,1-dimethyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

(S)-5,6,7,8-Tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

(R)-5,6,7,8-Tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

2-(1-Hydroxy-1-methyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

(R)-2-(1-Methoxy-l-methyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

(S)-2-(1-Methoxy-l-methyl-ethyl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

(S)-2-(2-Methyl-[1,3]dioxolan-2-yl)-5,6,7,8-tetrahydro-quinoline-6-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide; and

6-Trifluoromethyl-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-2-carboxylic acid [(R)-1-(2-fluoro-4-methanesulfonylamino-5-methyl-phenyl)-ethyl]-amide;

or a pharmaceutically acceptable salt thereof, and stereoisomers and tautomers thereof.

49. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 .

50. The pharmaceutical composition of claim 49 wherein the carrier is a parenteral carrier, oral or topical carrier.

51. A method for treating a disease or condition which comprises administering to a patient in need of a therapeutically effective amount of a compound of claim 1 , or the pharmaceutical composition of claim 49 , wherein the disease or condition is a pain condition.

52. A method for treating a disease or condition which comprises administering to a patient in need of a therapeutically acceptable amount of a compound of claim 1 , or the pharmaceutical composition of claim 49 , wherein the disease is: pain including acute, inflammatory and neuropathic pain; chronic pain; dental pain; and headache including migraine, cluster headache and tension headache.

53. The method of claim 52 wherein the disease or condition is neuropathic pain.

54. The method of claim 53 wherein the pain is associated with a condition selected from the group consisting of postmastectomy pain syndrome, stump pain, phantom limb pain, oral neuropathic pain, Charcot's pain, toothache, venomous snake bite, spider bite, insect sting, postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, trigeminal neuralgia, osteoarthritis, rheumatoid arthritis, fibromyalgis, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, bilateral peripheral neuropathy, causalgia, sciatic neuritis, peripheral neuritis, polyneuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, egniculate neuralgia, glossopharyngial neuralgia, migranous neuralgia, idiopathic neuralgia, intercostals neuralgia, mammary neuralgia, mandibular joint neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, vidian neuralgia, sinus headache, tension headache, labor, childbirth, intestinal gas, menstruation, cancer, and trauma.