Isoquinoline potassium channel inhibitors

1. A compound of formula I

or a pharmaceutically acceptable salt, wherein:

A is

a) an aryl ring selected from phenyl, wherein any stable phenyl ring atom is independently unsubstituted or substituted with

1) halogen,

2) NO 2 ,

3) CN,

4) CR 46 ═C(R 47 R 48 ) 2 ,

5) C≡CR 46 ,

6) (CR i R j ) r OR 46 ,

7) (CR i R j ) r N(R 46 R 47 ),

8) (CR i R j ) r C(O)R 46 ,

9) (CR i R j ) r C(O)OR 46 ,

10) (CR i R j ) r R 46 ,

11) (CR i R j ) r S(O) 0-2 R 61 ,

12) (CR i R j ) r S(O) 0-2 N(R 46 R 47 ),

13) OS(O) 0-2 R 61 ,

14) N(R 46 )C(O)R 47 ,

15) N(R 46 )S(O) 0-2 R 61 ,

16) (CR i R j ) r N(R 46 )R 61 ,

17) (CR i R j ) r N(R 46 )R 61 OR 47 ,

18) (CR i R j ) r N(R 46 )(CR k R 1 ) s C(O)N(R 47 R 48 ),

19) N(R 46 )(CR i R j ) r R 61 ,

20) N(R 46 )(CR i R j ) r N(R 47 R 48 ),

21) (CR i R j ) r C(O)N(R 47 R 48 ),

22) oxo,

b) a heteroaryl ring selected from the group consisting of pyridine, pyrimidine, pyrazine, pyridazine, indole, pyrrolopyridine, benzimidazole, benzoxazole, benzothiazole, and benzoxadiazole

wherein any stable S heteroaryl ring atom is unsubstituted or mono- or di-substituted with oxo, and any stable C or N heteroaryl ring atom is independently unsubstituted or substituted with

1) halogen,

2) NO 2 ,

3) CN,

4) CR 46 ═C(R 47 R 48 ) 2 ,

5) C≡CR 46 ,

6) (CR i R j ) r OR 46 ,

7) (CR i R j ) r N(R 46 R 47 ),

8) (CR i R j ) r C(O)R 46 ,

9) (CR i R j ) r C(O)OR 46 ,

10) (CR i R j ) r R 46 ,

11) (CR i R j ) r S(O) 0-2 R 61 ,

12) (CR i R j ) r S(O) 0-2 N(R 46 R 47 ),

13) OS(O) 0-2 R 61 ,

14) N(R 46 )C(O)R 47 ,

15) N(R 46 )S(O) x R 61 ,

16) (CR i R j ) r N(R 46 )R 61 ,

17) (CR i R j ) r N(R 46 )R 61 OR 47 ,

18) (CR i R j ) r N(R 46 )(CR k R 1 ) s C(O)N(R 47 R 48 ),

19) N(R 46 )(CR i R j ) r R 61 ,

20) N(R 46 )(CR i R j ) r N(R 47 R 48 ),

21) (CR i R j ) r C(O)N(R 47 R 48 ), or

22) oxo, or

c) a 4-, 5- or 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms, unsubstituted, mono-substituted or di-substituted with C 1 -C 6 alkyl;

Y is CH 2 , NR 53 , NC(O)R 53 , S(O) 0-2 or O;

G is H 2 or O;

R a , R b , R i , R j , R k , and R l are independently selected from the group consisting of:

1) hydrogen,

2) C 1 -C 6 alkyl,

3) halogen,

4) aryl,

5)R 80 ,

6) C 3 -C 10 cycloalkyl, and

7)OR 4 ,

said alkyl, aryl, and cycloalkyl being unsubstituted, monosubstituted with R 7 , disubstituted with R 7 and R 15 , trisubstituted with R 7 , R 15 and R 16 , or tetrasubstituted with R 7 , R 15 , R 16 , and R 17 ;

R 1 is independently selected from:

1) hydrogen,

2) halogen,

3) CN,

4) OR 40 ,

5) N(R 40 R 41 ),

6) C(O)OR 40 ,

7) R 81 ,

8) S(O) 0-2 R 6 ,

9) N(R 40 )(CR a R b ) n R 6 , wherein R 6 ═R 83 ,

10) N(R 40 )(CR a R b ) n N(R 41 R 42 ),

13) C(O)N(R 41 R 42 ), and

14) a 4-, 5-, or 6-membered heterocyclic ring containing 1 nitrogen atom, unsubstituted, or mono-, di- or tri-substituted with —OH,

R 2 , R 8 , and R 10 are independently selected from hydrogen and halogen;

R 9 is OCH 3 or OCHF 2 ,

R 4 , R 40 , R 41 , R 42 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , and R 53 are independently selected from:

1) hydrogen,

2) C 1 -C 6 alkyl,

3) C 3 -C 10 cycloalkyl,

4) aryl,

5) R 81 ,

6) CF 3 ,

7) C 2 -C 6 alkenyl, and

8) C 2 -C 6 alkynyl,

said alkyl, aryl, and cycloalkyl is unsubstituted, mono-substituted with R 18 , di-substituted with R 18 and R 19 , tri-substituted with R 18 , R 19 and R 20 , or tetra-substituted with R 18 , R 19 , R 20 and R 21 ;

R 5 is independently selected from:

1) hydrogen,

2) halogen,

3) CN,

4) C(O)N(R 49 R 50 ),

5) C(O)OR 49 ,

6) S(O) 0-2 N(R 49 R 50 ),

7) S(O) 0-2 R 62 ,

8) C 1 -C 6 alkyl,

9) C 3 -C 10 cycloalkyl,

10) R 82 ,

said alkyl, aryl, and cycloalkyl is unsubstituted, mono-substituted with R 22 , di-substituted with R 22 and R 23 , tri-substituted with R 22 , R 23 and R 24 , or tetra-substituted with R 22 , R 23 , R 24 and R 25 ;

R 6 , R 61 , R 62 and R 63 are independently selected from:

1) C 1 -C 6 alkyl,

2) aryl,

3) R 83 , and

4) C 3 -C 10 cycloalkyl;

said alkyl, aryl, and cycloalkyl is unsubstituted, mono-substituted with R 26 , di-substituted with R 26 and R 27 , tri-substituted with R 26 , R 27 and R 28 , or tetra-substituted with R 26 , R 27 , R 28 and R 29 ;

R 7 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , and R 70 are independently selected from:

1) C 1 -C 6 alkyl,

2) halogen,

3) OR 51 ,

4) CF 3 ,

5) aryl,

6) C 3 -C 10 cycloalkyl,

7) R 84 ,

8) S(O) 0-2 N(R 51 R 52 ),

9) C(O)OR 51 ,

10) C(O)R 51 ,

11) CN,

12) C(O)N(R 51 R 52 ),

13) N(R 51 )C(O)R 52 ,

14) S(O) 0-2 R 63 ,

15) NO 2 , and

16) N(R 51 R 52 );

R 80 , R 81 , R 82 , R 83 and R 84 are independently selected from a group of unsubstituted or substituted heterocyclic rings consisting of a 4-6 membered unsaturated or saturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting N, O and S, and a 9- or 10-membered unsaturated or saturated bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S;

n, r, s and t are independently 0, 1, 2, 3, 4, 5 or 6;

u is 0, 1 or 2; and

v is 0, 1 or 2, wherein said compound is selected from the group consisting of

[(6-methoxy-4-phenylisoquinolin-3-yl)methyl]dimethylamine,

1-(1-chloro-6-methoxy-4-phenylisoquinolin-3-yl)-N,N-dimethylmethanamine,

{[6-methoxy-1-(methylthio)-4-phenylisoquinolin-3-yl]methyl}dimethylamine,

[6-methoxy-1-(methylsulfonyl)-4-phenylisoquinolin-3-yl]methyl(dimethyl)amine oxide,

1-[6-methoxy-1-(methylsulfonyl)-4-phenylisoquinolin-3-yl]-N,N-dimethylmethanamine,

3-[(dimethylamino)methyl]-6-methoxy-4-phenylisoquinoline-1-carbonitrile,

2,3-Dimethyl-6-methoxy-4-phenylisoquinolinium hydroxide,

6-methoxy-1-(2-methoxyethoxy)-3-methyl-4-phenylisoquinoline,

{3-[(6-methoxy-3-methyl-4-phenylisoquinolin-1-yl)oxy]propyl}amine,

2-[(6-methoxy-3-methyl-4-phenylisoquinolin-1-yl)amino]ethanol,

6-methoxy-3-methyl-1-(methylsulfonyl)-4-phenylisoquinoline,

6-methoxy-N-(2-methoxyethyl)-3-methyl-4-phenylisoquinolin-1-amine,

N-(6-methoxy-3-methyl-4-phenylisoquinolin-1-yl)ethane-1,2-diamine,

6-methoxy-3-methyl-4-phenylisoquinoline,

N-(3,4-dimethoxybenzyl)-6-methoxy-3-methyl-4-phenylisoquinolin-1-amine,

6-methoxy-3-methyl-4-phenylisoquinolin-1-amine,

1-(ethylsulfonyl)-6-methoxy-3-methyl-4-phenylisoquinoline,

1-(benzylsulfonyl)-6-methoxy-3-methyl-4-phenylisoquinoline,

6-methoxy-3-methyl-4-phenyl-1-(phenylsulfonyl)isoquinoline,

6-methoxy-3-methyl-4-phenylisoquinoline-1-carbonitrile,

3-tert-butyl-6-methoxy-1-(2-methoxyethoxy)-4-phenylisoquinoline,

1-chloro-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

6-methoxy-4-phenylisoquinoline-1,3-dicarbonitrile,

1-(allyloxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-(2,3-dihydroxypropoxy)-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

(+/−)-1-[(2,3-dihydroxypropyl)amino]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-{[(2S)-2,3-dihydroxypropyl]amino}-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-{[(2R)-2,3-dihydroxypropyl]amino}-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

(+/−)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-{[(2R)-2,3-dihydroxypropyl]oxy}-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-{[(2S)-2,3-dihydroxypropyl]oxy}-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

(+/−)-1-{[2,3-dihydroxypropyl]oxy}-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-[(3R)-3-hydroxypyrrolidin-1-yl]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-[(3S)-3-hydroxypyrrolidin-1-yl]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

(+/−)-1-[3-hydroxypyrrolidin-1-yl]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-[cis-3,4-dihydroxypyrrolidin-1-yl]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

6-methoxy-4-phenyl-1-pyrrolidin-1-ylisoquinoline-3-carbonitrile,

6-methoxy-1-(methylsulfonyl)-4-phenylisoquinoline-3-carbonitrile,

6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1,6-dimethoxy-4-phenylisoquinoline-3-carbonitrile,

1-chloro-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

4-(3-fluorophenyl)-6-methoxy-1-methylisoquinoline-3-carbonitrile,

4-(3-fluorophenyl)-1-[(2-hydroxyethyl)amino]-6-methoxyisoquinoline-3-carbonitrile,

1-amino-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

4-(3-fluorophenyl)-1-[(3-hydroxypropyl)amino]-6-methoxyisoquinoline-3-carbonitrile,

1-(but-3-enyloxy)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

(+/−)-1-(2,3-dihydroxypropoxy)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(2R)-2,3-dihydroxypropoxy]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(2S)-2,3-dihydroxypropoxy]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

(+/−)-1-(3,4-dihydroxybutoxy)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

(+/−)-1-[(3R)-3,4-dihydroxybutoxy]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(3S)-3,4-dihydroxybutoxy]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

(+/−)-1-[(1,4-dioxan-2-ylmethyl)amino]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(1,4-dioxan-(2R)-2-ylmethyl)amino]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(1,4-dioxan-(2S)-2-ylmethyl)amino]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

4-(3-fluorophenyl)-6-methoxy-1-[(1-methyl-1H-imidazol-4-yl)methoxy]isoquinoline-3-carbonitrile,

(+/−)-1-(1,3-dioxolan-4-ylmethoxy)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-(1,3-dioxolan-(4R)-4-ylmethoxy)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-(1,3-dioxolan-(4S)-4-ylmethoxy)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-(1,3-dioxan-5-yloxy)-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

4-(3-fluorophenyl)-1-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}-6-methoxyisoquinoline-3-carbonitrile,

4-(3-fluorophenyl)-1-(1H-imidazol-5-ylmethoxy)-6-methoxyisoquinoline-3-carbonitrile,

1-{[(2R)-2,3-dihydroxypropyl]amino}-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-{[(2S)-2,3-dihydroxypropyl]amino}-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

(+/−)-1-{[2,3-dihydroxypropyl]amino}-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-(1H-imidazol-1-yl)-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

6-methoxy-4-phenyl-1-[(pyridin-2-ylmethyl)amino]isoquinoline-3-carbonitrile,

6-methoxy-4-phenyl-1-[(2-pyridin-2-ylethyl)amino]isoquinoline-3-carbonitrile,

(+/−)-1-[(3,4-dihydroxybutyl)amino]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(3R)-(3,4-dihydroxybutyl)amino]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(3S)-(3,4-dihydroxybutyl)amino]-4-(3-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-chloro-4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

(+/−)-1-[(2,3-dihydroxypropyl)amino]-4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(2S)-(2,3-dihydroxypropyl)amino]-4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

1-[(2R)-(2,3-dihydroxypropyl)amino]-4-(2-fluorophenyl)-6-methoxyisoquinoline-3-carbonitrile,

(+/−)-6-(difluoromethoxy)-1-{[2,3-dihydroxypropyl]amino}-4-(3-fluorophenyl)isoquinoline-3-carbonitrile,

6-(difluoromethoxy)-1-{[(2S)-2,3-dihydroxypropyl]amino}-4-(3-fluorophenyl)isoquinoline-3-carbonitrile,

6-(difluoromethoxy)-1-{[(2R)-2,3-dihydroxypropyl]amino}-4-(3-fluorophenyl)isoquinoline-3-carbonitrile,

(+/−)-6-(difluoromethoxy)-1-{[2,3-dihydroxypropyl]oxy}-4-(3-fluorophenyl)isoquinoline-3-carbonitrile,

6-(difluoromethoxy)-1-{[(2S)-2,3-dihydroxypropyl]oxy}-4-(3-fluorophenyl)isoquinoline-3-carbonitrile,

6-(difluoromethoxy)-1-{[(2R)-2,3-dihydroxypropyl]oxy}-4-(3-fluorophenyl)isoquinoline-3-carbonitrile,

1-(4-hydroxypiperidin-1-yl)-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-azetidin-1-yl-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

(+/−)-1-[trans-3,4-dihydroxypyrrolidin-1-yl]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-6-methoxy-4-phenylisoquinoline-3-carbonitrile,

1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-6-methoxy-4-phenylisoquinoline-3-carbonitrile, and

6-methoxy-N-(3-methoxypropyl)-3-methyl-4-phenylisoquinolin-1-amine.

2. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound claim 1 or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.