Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators

1. A compound of formula I

where the dashed line represents an optional double bond; where R 1 is phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, imidazolyl, pyrazyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, optionally substituted with one or two substituents selected independently from halogen, C 1 -C 6 alkyl, mono-halo C 1 -C 6 alkyl, di-halo C 1 -C 6 alkyl, CF 3 , CN, S—C 1 -C 6 alkyl, or O—C 1 -C 6 alkyl; R 2 is H, methyl, or halogen; R 3 and R 4 are, independently, CF 3 , OCF 3 , OC 1 -C 3 alkyl, halo or C 1 -C 3 alkyl, where the C 1 -C 3 alkyl groups are optionally substituted with one or more halogen atoms; X═O or S; Y is O or S; q=1 or 0; R 5 is C 1 -C 6 alkyl where the C 1 -C 6 alkyl group is optionally substituted with one or two groups selected, independently, from OH, OMe, OEt, F, CF 3 , Cl, or CN; (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where w=0-3, Ar 1 is phenyl, pyridyl, pyrrolyl, thienyl, or furyl, and R 6 is hydrogen, methyl, halogen, or methoxy; where all cyclic groups are optionally substituted with one or two substituents selected independently from C 1 -C 3 alkyl, halogen, OH, OMe, SMe, CN, CH 2 F, and trifluoromethyl; or a pharmaceutically acceptable salt or ester thereof.

2. The compound of claim 1 , where R 1 is phenyl, naphthyl, pyrimidyl, optionally substituted with one or two substituents selected independently from halogen, C 1 -C 4 alkyl, mono-halo C 1 -C 3 alkyl, CF 3 , CN, S—CH 3 , or O—C 1 -C 3 alkyl; or R 1 is pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, optionally substituted with halogen, halomethyl, or C 1 -C 4 alkyl; R 2 is H, methyl, or halogen; R 5 is C 3 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , where R 6 is H or methyl; where w is 1 or 2; and where the C 3 -C 6 alkyl group is optionally substituted with one F or Cl.

3. The compound of claim 2 where R 1 is phenyl, naphthyl, or pyridyl, optionally substituted with one substituent chosen from methyl, ethyl, halomethyl, halogen, cyano, SCH 3 , methoxy, and CF 3 and optionally further substituted with halogen or methyl; or R 1 is thienyl, oxazolyl, or isothiazolyl, optionally substituted with halogen or C 1 -C 4 alkyl; R 2 is H; R 3 and R 4 are, independently, Cl, CH 3 , or methoxy; and R 5 is C 3 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, Ar 1 , (CHR 6 ) w Ar 1 , or CH 2 (CHR 6 ) w Ar 1 .

4. The compound of claim 3 , where R 1 is para-halo phenyl or difluorophenyl.

5. The compound of claim 3 , where R 1 is substituted with methyl or trifluoromethyl.

6. The compound of claim 3 , 4 , or 5 , where X is S.

7. The compound of claim 2 , which is a compound of formula IA

8. The compound of claim 2 , which is a compound of formula IB

9. The compound of claim 2 , which is a compound of formula IC

10. The compound of claim 2 , which is a compound of formula ID

11. The compound of claim 7 , 8 , 9 , or 10 , where R 3 and R 4 are, independently, methyl, chloro, or methoxy.

12. The compound of claim 6 , 7 , 8 , 9 , or 10 , where R 2 is H and R 3 and R 4 are both methyl.

13. The compound of claim 7 , 8 , 9 , or 10 , where R 3 and R 4 are both methyl; R 1 is phenyl, naphthyl, or pyridyl, optionally substituted with halogen or trifluoromethyl; and R 5 is C 5 -C 6 alkyl.

14. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

15. The compound of claim 7 , where R 3 and R 4 are both methyl, and R 5 is C 5 -C 6 alkyl.

16. The compound of claim 15 , where R 1 is mono-substituted phenyl.

17. The compound of claim 16 , where R 1 is para fluoro phenyl or para trifluoromethyl phenyl.

18. The compound of claim 15 , where R 1 is 3,5-difluorophenyl or 3-fluorophenyl.

19. The compound of claim 9 , where R 3 and R 4 are both methyl, and R 5 is C 5 -C 6 alkyl.

20. The compound of claim 19 , where R 1 is pyridyl or phenyl, optionally substituted with one additional substituent.

21. The compound of claim 20 , where R 1 is para fluoro phenyl or para trifluoromethyl phenyl.

22. The compound of claim 19 , where R 1 is 3,5-difluorophenyl or 3-fluorophenyl.

23. A composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier.

24. A composition comprising the compound of claim 9 and a pharmaceutically acceptable carrier.

25. A composition comprising a pharmaceutically acceptable carrier and either a compound chosen from one of the following or a pharmaceutically acceptable salt or ester thereof:

N-[1-(4-Trifluoromethylbenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

N-[1-(4-Fluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

N-[1-(3-Chlorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

N-[1-(4-Bromobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

N-[1-(3,4-Difluorobenzyl)-4,6-dimethylindoline-5-yl]-3,3-dimethyl-butyramide

N-(4,6-Dimethyl-1-(naphthalen-2-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide

N-(4,6-Dimethyl-1-(pyridin-4-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide

N-(4,6-Dimethyl-1-(pyridin-3-ylmethyl)indolin-5-yl)-3,3-dimethylbutanamide

N-(4,6-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-indol-5-yl)-3,3-dimethyl butanamide

N-(4,6-Dimethyl-1-(4-(fluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

N-(4,6-Dimethyl-1-(3,4-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

N-(4,6-Dimethyl-1-(3,5-difluorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide

N-(4,6-Dimethyl-1-(3-chlorobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide and

N-(4,6-Dimethyl-1-(4-bromobenzyl)-1H-indol-5-yl)-3,3-dimethylbutanamide.