Isoquinolinone potassium channel inhibitors

1. A compound of the structure:

or a pharmaceutically acceptable salt or crystal form, wherein:

A is

a) an aryl ring, wherein any stable aryl ring atom is independently substituted or substituted with

1) halogen,

2) NO 2 ,

3) CN,

4) CR 46 ═C(R 47 R 48 ) 2 ,

5) C═C R 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 l ) 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

b) a heteroaryl ring selected from the group consisting of

a 5-membered unsaturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S,

a 6-membered unsaturated 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 bicyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting or N, O or S;

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) 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 l ) 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;

R 1 and R 5 together with the atoms to which they are attached, form a ring selected from the group of structures consisting of

where u is 0 or 1, R 99 is hydrogen or —OH, and X is 0 or ═NOH;

R 2 , R 8 , R 9 and R 10 are independently selected from:

1) hydrogen,

2) halogen,

3) NO 2 ,

4) CN,

5) CR 43 ═C(R 44 R 45 ),

6) C≡CR 43 ,

7) (CR e R f ) p OR 43 ,

8) (CR e R f ) p N(R 43 R 44 ),

9) (CR e R f ) p C(O)R 43 ,

10) (CR e R f ) p C(O)OR 43 ,

11) (CR e R f ) p R 43 ,

12) (CR e R f ) p S(O) 0-2 R 60 ,

13) (CR e R f ) p S(O) 0-2 N(R 43 R 44 ),

14) OS(O) 0-2 R 60 ,

15) N(R 43 )C(O)R 44 ,

16) N(R 43 )S(O) 0-2 R 60 ,

17) (CR e R f ) p N(R 43 )R 60 ,

18) (CR e R f ) p N(R 43 )R 60 OR 44 ,

19) (CR e R f ) p N(R 43 )(CR g R h ) q C(O)N(R 44 R 45 ),

20) N(R 43 )(CR e R f ) p R 60 ,

21) N(R 43 )(CR e R f ) p N(R 44 R 45 ), and

22) (CR e R f ) p C(O)N(R 43 R 44 ),

or R 2 and R 8 are independently as defined above, and R 9 and R 10 , together with the atoms to which they are attached, form the ring

 where R m is C 1-6 alkyl;

R a , R b , R c , R d , R e , R f , R g , R h , 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 4 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , and R 53 and are independently selected from the group consisting of

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 6 , R 60 , R 61 , R 62 and R 63 are independently selected from the group consisting of

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 , and R 29 are independently selected from the group consisting of

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; and

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

provided that

when R 9 is OCH 3 , R 1 is CH 3 and R 5 is C(CH 3 ) 3 , then A is substituted,

when R 9 is hydrogen, R 1 is CH 3 , and R 5 is hydrogen, then A is substituted,

when R 9 is hydrogen, R 1 is CH 3 , and R 5 is C(CH 3 ) 3 , then A is substituted, provided the substituent is not CH 3 , and

when R 9 is OCH 3 , R 1 is CH 3 , R 5 is CH 3 , then A is substituted;

wherein the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of

3-tert-butyl-4-(3-fluorophenyl)-6-methoxy-2-methylisoquinolin-1(2H)-one,

3-tert-butyl-4-(4-fluorophenyl)-6-methoxy-2-methylisoquinolin-1(2H)-one,

6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one,

4-(3-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one,

4-(4-fluorophenyl)-6-methoxy-2,3-dimethylisoquinolin-1(2H)-one,

(1E)-11-(3-fluorophenyl)-9-methoxy-3,4-dihydro-2H-pyrido[1,2-b]isoquinoline-1,6-dione 1-oxime,

3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one,

2,3-dimethyl-4-phenylisoquinolin-1(2H)-one,

3-tert-butyl-2-ethyl-6-methoxy-4-phenylisoquinolin-1(2H)-one,

3-tert-butyl-6-methoxy-4-phenylisoquinolin-1(2H)-one,

2-ethyl-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,

6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,

6-methoxy-2-(2-methoxyethyl)-3-methyl-4-phenylisoquinolin-1(2H)-one,

2-(2-aminoethyl)-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,

2-(3-aminopropyl)-6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one,

3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carbonitrile,

3-tert-butyl-8-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one,

3-tert-butyl-2-methyl-1-oxo-4-phenyl-1,2-dihydroisoquinoline-6-carboxamide,

3-tert-butyl-2-methyl-4-phenyl-6-(4-phenylbutoxy)isoquinolin-1(2H)-one,

3-tert-butyl-2-methyl-4-phenyl-6-[(5-phenylpentyl)oxy]isoquinolin-1(2H)-one,

(+/−)-11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one,

(1S)-11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one,

(1R)-11-(3-fluorophenyl)-1-hydroxy-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one, and

11-(3-fluorophenyl)-9-methoxy-1,2,3,4-tetrahydro-6H-pyrido[1,2-b]isoquinolin-6-one.

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

3. A method of treating a condition in a mammal, the treatment of which is effected or facilitated by K v 1.5 inhibition, which comprises administering a compound of claim 1 in an amount that is effective at inhibiting K v 1.5.

4. A method of claim 3 , wherein the condition is cardiac arrythmia.

5. A method of claim 4 , wherein the cardiac arrythmia is selected from the group consisting of atrial flutter, atrial arrhythmia and supraventricular tachycardia.

6. A method of claim 3 , wherein the cardiac arrythmia is atrial fibrillation.

7. A method of preventing a condition in a mammal, the prevention of which is effected or facilitated by K v 1.5 inhibition, which comprises administering a compound of claim 1 in an amount that is effective at inhibiting K v 1.5.

8. A method of claim 7 , wherein the condition is cardiac arrythmia.

9. A method of claim 8 , wherein the cardiac arrythmia is selected from the group consisting of atrial flutter, atrial arrhythmia and supraventricular tachycardia.

10. A method of claim 8 , wherein the cardiac arrythmia is atrial fibrillation.

11. A method of claim 7 , wherein the condition is a thromboembolic event.

12. A method of claim 11 , wherein the thromboembolic event is a stroke.

13. A method of claim 7 , wherein the condition is congestive heart failure.

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

15. A method of treating cardiac arrythmia comprising administering a compound of claim 1 with a compound selected from one of the classes of compounds consisting of antiarrhythmic agents having Kv1.5 blocking activities, ACE inhibitors, angiotensin II antagonists, cardiac glycosides, L-type calcium channel blockers, T-type calcium channel blockers, selective and nonselective beta blockers, endothelin antagonists, thrombin inhibitors, aspirin, nonselective NSAIDs, warfarin, factor Xa inhibitors, low molecular weight heparin, unfractionated heparin, clopidogrel, ticlopidine, IIb/IIIa receptor antagonists, 5HT receptor antagonists, integrin receptor antagonists, thromboxane receptor antagonists, TAFI inhibitors and P2T receptor antagonists.

16. A method for inducing a condition of normal sinus rhythm in a patient having atrial fibrillation, which comprises treating the patient with a compound of claim 1 .

17. A method for treating tachycardia in a patient which comprises treating the patient with an antitachycardia device in combination with a compound of claim 1 .