Quinoline potassium channel inhibitors

1. A compound of the structure:

or a pharmaceutically acceptable salt thereof, wherein

A is fluorophenyl or chlorophenyl;

R 1 is selected from the group consisting of hydrogen, —CH 2 CH(OH)CH 2 OH, CH 2 CHCH 2 ,

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 ),

wherein one of R 2 , R 8 , R 9 and R 10 represents —OCH 3 ;

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 , 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 4 , R 40 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 51 , and R 52 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 6 , R 60 , R 61 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 26 , R 27 , R 28 , and R 29 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 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;

R 5 is selected from the group consisting of —CN and —NHC(O)CF 3 ;

R 11 is selected from the group consisting of

1) aryl, and

2) an unsubstituted or substituted heterocyclic ring 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

R 13 is selected from the group consisting of

1) C 1-6 alkyl,

2) C 1-6 alkyloxy,

3) C 1-6 alkenyl,

4) C 1-6 alkynyl, and

5) CF 3 ;

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

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of

1-(2,4-Dimethoxybenzyl)-4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile,

4-(3-Fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile,

1-Allyl-4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile,

1-(2,3-Dihydroxypropyl)-4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile,

4-(3-Fluorophenyl)-6-methoxy-2-oxo-1-[(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)methyl]1,2-dihydroquinoline-3-carbonitrile,

4-(3-Fluorophenyl)-6-methoxy-1-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-2-oxo-1,2-dihydroquinoline-3-carbonitrile,

4-(3-Fluorophenyl)-6-methoxy-2-oxo-1-(pyridin-3-ylmethyl)-1,2-dihydroquinoline-3-carbonitrile,

(±)-4-(3-Fluorophenyl)-6-methoxy-2-oxo-1-[(2-oxo-1,3-oxazolidin-5-yl)methyl]-1,2-dihydroquinoline-3-carbonitrile,

4-(3-Fluorophenyl)-6-methoxy-2-oxo-1-(pyridin-2-ylmethyl)-1,2-dihydroquinoline-3-carbonitrile,

4-(3-Fluorophenyl)-6-methoxy-2-oxo-1-(4-penten-1-yl)-1,2-dihydroquinoline-3-carbonitrile,

(±)-1-(4,5-Dihydroxypentyl)-4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile,

4-(3-Chlorophenyl)-1-(2,4-dimethoxybenzyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile,

4-(3-Chlorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile, and

2,2,2-Trifluoro-N-[4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl]acetate.

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 wherein the condition is cardiac arrhythmia.

4. A method of claim 3 , wherein the cardiac arrhythmia is atrial fibrillation.

5. A method of claim 3 , wherein the cardiac arrhythmia is selected from the group consisting of atrial flutter, atrial arrhythmia and supraventricular tachycardia.

6. A method of treating cardiac arrhythmia 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.

7. 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 .

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

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