Isoquinolinone potassium channels inhibitors

1. A compound of structural Formula Ia:

or a pharmaceutically acceptable salts, hydrates, solvates, crystal forms, or stereoisomers thereof, wherein:

R 1 is:

(1) (C 1 -C 6 )-alkoxy,

(2) (C 1 -C 4 )-perfluoroalkyl,

(3) (C 1 -C 4 )-perfluoroalkoxy, or

(4) halo, wherein halo is fluoro, chloro, bromo, or iodo;

R 2 is:

(1) (C 1 -C 6 )-alkyl,

(2) (CH 2 ) n —(T)[S(O) m ] p R 3 , or

(3) (CH 2 ) n —(T)COR 3 ;

wherein T is —NH or

n is: 1, 2, or 3;

m is: 0, 1, or 2;

p is: 0 or 1;

R 3 is;

(1) aryl, wherein aryl is defined as phenyl or naphthyl which is optionally substituted with one, two or three of the substituents selected from the group consisting of:

(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,

(b) (C 1 -C 6 )-alkyl,

(c) (C 1 -C 6 )-alkoxy,

(d) (C 1 -C 4 )-perfluoroalkyl,

(e) (C 1 -C 4 )-perfluoroalkoxy,

(f) phenyl, and

(g) benzyl;

(2) heteroaryl, wherein heteroaryl is defined as a monocyclic or bicyclic aromatic ring of 5 to 10 carbon atoms containing from 1 to 3 heteroatoms selected from O, N or S, and heteroaryl being optionally substituted with one, two, or three substituents selected from the group consisting of:

(a) halo, as defined above,

(b) (C 1 -C 6 )-alkyl,

(c) (C 1 -C 4 )-perfluoroalkyl, and

(d) (C 1 -C 6 )-alkoxy;

(3) (C 1 -C 6 )-alkyl optionally substituted with phenyl; or

(4) (C 1 -C 6 )-alkoxy;

R 4 and R 4′ are independently:

(1) H,

(2) (C 1 -C 4 -alkyl,

(3) (C 3 -C 7 )-cycloalkyl,

(4) halo,

(5) (C 1 -C 4 )-perfluoroalkyl, or

(6) R 4 and R 4′ are taken together form a (C 3 -C 7 )-cycloalkyl ring;

Q is:

(1) NR 5 R 6 , wherein R 5 and R 6 are independently:

(a) H,

(b) (C 1 -C 4 )-perfluoroalkyl,

(c) (C 3 -C 7 )-cycloalkyl,

(d) (C 2 -C 6 )-alkyl-aryl, wherein aryl is defined as phenyl or naphthyl which is substituted with one, two or three of the substituents selected from the group consisting of halo, hydroxy, (C 1 -C 6 )-alkyl, (C 1 -C 4 )-perfluoroalkyl, (C 1 -C 6 )-alkoxy, phenyl, phenoxy, and nitro,

(e) (C 1 -C 10 )-alkyl, which is optionally substituted with one, two, or three of the substituents selected from the group consisting of:

(a′) halo, wherein halo is fluoro, chloro, bromo, or iodo,

(b′) hydroxy,

(c′) oxo,

(d′) (C 1 -C 6 )-alkoxy,

(e′) phenyl, and

(f′) (C 3 -C 7 )-cycloalkyl; or

(f) optionally, R 5 or R 6 can be joined with the R 2 substituent in Formula Ia to form a 5 to 8 atom heterocyclic ring, and the other of R 5 or R 6 is as defined above;

(2) heterocyclyl, wherein heterocyclyl is defined as a monocyclic or bicyclic ring of 5 to 10 carbon atoms which can be aromatic or nonaromatic, wherein the heterocyclyl is attached to the methylene bearing the R 4 and R 5 substituents through a N from the heterocyclyl and may optionally contain 1 to 3 additional heteroatoms selected from N, O or S and is optionally substituted with one, two, or three substituents selected from the group consisting of:

(a) H,

(b) (C 1 -C 6 )-alkyl,

(c) (C 1 -C 4 )-perfluoroalkyl,

(d) (C 1 -C 4 )-alkyl-aryl,

(e) CO 2 (C 1 -C 6 )-alkyl,

(f) CO 2 H

(g) oxo, and

(h) hydroxy; or

(3) NH(C═O)R 7 , wherein R 7 is:

(a) (C 1 -C 13 )-alkyl or (C 1 -C 12 )-alkenyl, which is optionally substituted with one, two, or three substituents selected from the group consisting of:

(a′) halo, wherein halo is fluoro, chloro, bromo, or iodo,

(b′) hydroxy,

(c′) oxo,

(d′) nitro,

(e′) (C 1 -C 6 )-alkoxy,

(f′) NR 5 R 6 ,

(g′) NH(CO)O(C 1 -C 6 )-alkyl, wherein (C 1 -C 6 )-alkyl is optionally substituted with phenyl,

(h′) CO(C 1 -C 10 )-alkyl,

(i′) OC(O)(C 1 -C 6 )-alkyl,

(j′) CONR 5 R 6 ,

(k′) O-aryl, wherein aryl as defined in (o′) below,

(l′) S-aryl, wherein aryl as defined in (o′) below,

(m′) (C 3 -C 7 )-cycloalkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of (C 1 -C 6 )-alkoxy, CO(C 1 -C 6 )-alkyl, oxo and (C 1 -C 6 )-alkyl optionally substituted with NO 2 ,

(n′) (C 5 -C 7 )-cycloalkyl fused with phenyl, wherein (C 5 -C 7 )-cycloalkyl fused with phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of (C 1 -C 6 )-alkoxy, oxo, and (C 1 -C 6 )-alkyl,

(o′) aryl, wherein aryl is defined as phenyl or naphthyl, which is optionally substituted with one, two or three of the substituents selected from the group consisting of:

(a″) halo, as defined above,

(b″) hydroxy,

(c″) (C 1 -C 6 )-alkyl,

(d″) (C 1 -C 4 )-perfluoroalkyl,

(e″) (C 1 -C 6 )-alkoxy, optionally substituted with phenyl,

(f″) phenyl,

(g″) phenoxy, and

(h″) nitro;

(p′) heterocyclyl, wherein heterocyclyl is defined as a monocyclic, bicyclic, or tricyclic ring of 5 to 14 carbon atoms which can be aromatic or nonaromatic and containing from 1 to 3 heteroatoms selected from O, N or S, and the heterocyclyl being optionally substituted or with one, two, or three substituents selected from the group consisting of:

(a″) H,

(b″) halo, as defined above,

(c″) (C 1 -C 6 )-alkyl,

(d″) (C 1 -C 4 )-perfluoroalkyl,

(e″) (C 1 -C 4 )-alkyl-aryl,

(f′) (C 1 -C 6 )-alkoxy,

(g″) phenyl,

(h″) phenoxy,

(i″) nitro,

(j″) CO 2 (C 1 -C 6 )-alkyl, and

(k″) oxo; and

(q′) S-heterocyclyl, wherein heterocyclyl as defined under (p′) above;

(b) aryl, wherein aryl is defined as phenyl or naphthyl which is optionally substituted with one, two or three of the substituents selected from the group consisting of:

(a′) halo, wherein halo is fluoro, chloro, bromo, or iodo,

(b′) (C 1 -C 6 )-alkyl,

(c′) (C 1 -C 6 )-alkoxy,

(d′) (C 1 -C 4 )-perfluoroalkyl;

(e′) phenoxy,

(f′) benzyl, and

(g′) phenyl optionally substituted with (C 1 -C 4 )-perfluoroalkyl;

(c) (C 3 -C 7 )-cycloalkyl, optionally substituted with phenyl; or

(d) heteroaryl, wherein heteroaryl is defined as a monocyclic or bicyclic aromatic ring of 5 to 10 carbon atoms containing from 1 to 3 heteroatoms selected from O, N or S, and heteroaryl being optionally substituted with one, two, or three substituents selected from the group consisting of:

(a′) halo, as defined above,

(b′) (C 1 -C 6 )-alkyl,

(c′) (C 1 -C 4 )-perfluoroalkyl, and

(d′) (C 1 -C 6 )-alkoxy.

2. The compound of Formula Ib,

wherein the R 1 , R 2 , R 4 , R 4′ , and Q are as defined in claim 1 .

3. The compound of Formula Ic, as recited in claim 2

wherein R 1 , R 2 and Q are as defined below:

R 1 is (C 1 -C 6 )-alkoxy, (C 1 -C 4 )-perfluoroalkyl, (C 1 -C 4 )-perfluoroalkoxy, or halo, wherein halo is fluoro, chloro, bromo, or iodo;

R 2 is (C 1 -C 6 )-alkyl; and

Q is heterocyclyl which is selected from the group consisting of: pyrrolidinyl, piperazinyl, imidazolyl, morpholinyl, 1,4-dioxa-8-aza-spiro[4,5]decyl, piperidinyl, and 2,3-dihydroindolyl and the heterocyclyl is optionally substituted with one, two, or three substituents selected from the group consisting of H, (C 1 -C 4 )-alkyl, CF 3 , benzyl, and CO 2 Et.

4. The compound of Formula Id, as recited in claim 2

wherein R 1 , R 2 , R 5 , and R 6 are as defined below:

R 1 is (C 1 -C 6 )-alkoxy, (C 1 -C 4 )-perfluoroalkyl, (C 1 -C 4 )-perfluoroalkoxy, or halo, wherein halo is fluoro, chloro, bromo, or iodo;

R 2 is (C 1 -C 6 )-alkyl; and

R 5 and R 6 are independently: (C 1 -C 10 )-alkyl optionally substituted with (C 3 -C 7 )-cycloalkyl, (C 1 -C 4 )-perfluoroalkyl, and phenyl.

5. The compound of Formula Ie, as recited in claim 2

wherein R 1 , R 2 , and R 7 are as defined below:

R 1 is (C 1 -C 6 )-alkoxy, (C 1 -C 4 )-perfluoroalkyl, (C 1 -C 4 )-perfluoroalkoxy, or halo, wherein halo is fluoro, chloro, bromo, or iodo;

R 2 is (C 1 -C 6 )-alkyl; and

R 7 is:

(a) (C 1 -C 13 )-alkyl or (C 1 -C 12 )-alkenyl, which is optionally substituted with one, two, or three substituents selected from the group consisting of:

(a′) hydroxy,

(b′) oxo,

(c′) NR 5 R 6 ,

(d′) NH(CO)O(C 1 -C 6 )-alkyl, wherein (C 1 -C 6 )-alkyl is optionally substituted with phenyl,

(e′) CO(C 1 -C 10 )-alkyl,

(f′) OC(O)(C 1 -C 6 )-alkyl,

(g′) CONR 5 R 6 ,

(h′) O-aryl, wherein aryl as defined in (l′) below,

(i′) S-aryl, wherein aryl as defined in (l′) below,

(j′) (C 3 -C 7 )-cycloalkyl, which is optionally substituted with 1 to 3 substituents selected from the group consisting of (C 1 -C 6 )-alkoxy, CO(C 1 -C 6 )-alkyl, and oxo, and (C 1 -C 6 )-alkyl optionally substituted with NO 2 ,

(k′) (C 5 -C 7 )-cycloalkyl fused with phenyl, wherein (C 5 -C 7 )-cycloalkyl fused with phenyl is optionally substituted with 1 to 3 substituents selected from the group consisting of (C 1 -C 6 )-alkoxy, oxo, and (C 1 -C 6 )-alkyl,

(l′) aryl, wherein aryl is defined as phenyl or naphthyl, which is optionally substituted with one, two or three of the substituents selected from the group consisting of;

(a″) halo, as defined above,

(b″) hydroxy,

(c″) (C 1 -C 6 )-alkyl,

(d″) (C 1 -C 4 )-perfluoroalkyl,

(e″) (C 1 -C 6 )-alkoxy, optionally substituted with phenyl,

(f″) phenyl,

(g″) phenoxy, and

(h″) nitro;

(m′) heterocyclyl, wherein heterocyclyl is defined as a monocyclic, bicyclic, or tricyclic ring of 5 to 14 carbon atoms which can be aromatic or nonaromatic and containing from 1 to 3 heteroatoms selected from O, N or S, and the heterocyclyl being optionally substituted or with one, two, or three substituents selected from the group consisting of:

(a″) H,

(b″) halo, as defined above,

(c″) (C 1 -C 6 )-alkyl,

(d″) (C 1 -C 4 )-perfluoroalkyl,

(e″) (C 1 -C 4 )-alkyl-aryl,

(f″) (C 1 -C 6 )-alkoxy,

(g″) phenyl,

(h″) phenoxy,

(i″) nitro,

(j″) CO 2 (C 1 -C 6 )-alkyl, and

(k″) oxo; and

(n′) S-heterocyclyl, wherein heterocyclyl as defined under (m′) above;

(b) aryl, wherein aryl is defined as phenyl or naphthyl which is optionally substituted with one, two or three of the substituents selected from the group consisting of:

(a′) halo, wherein halo is fluoro, chloro, bromo, or iodo,

(b′) (C 1 -C 6 )-alkoxy,

(c′) phenoxy,

(d′) benzyl, and

(e′) phenyl optionally substituted with (C 1 -C 4 )-perfluoroalkyl;

(c) (C 3 -C 7 )-cycloalkyl, optionally substituted with phenyl; or

(d) heteroaryl, wherein heteroaryl is defined as a monocyclic or bicyclic aromatic ring of 5 to 10 carbon atoms containing from 1 to 3 heteroatoms selected from O, N or S, and heteroaryl being optionally substituted with one, two, or three substituents selected from the group consisting of:

(a′) halo, as defined above,

(b′) (C 1 -C 6 )-alkyl,

(c′) (C 1 -C 4 )-perfluoroalkyl, and

(d′) (C 1 -C 6 )-alkoxy.

6. The compound of Formula If, as recited in claim 2

wherein R 1 , R 2 , R 3 , R 5 , R 6 , and n are as defined below:

R 1 is (C 1 -C 6 )-alkoxy, (C 1 -C 4 )-perfluoroalkyl, (C 1 -C 4 )-perfluoroalkoxy, or halo, wherein halo is fluoro, chloro, bromo, or iodo;

R 2 is (CH 2 ) n (T)SO 2 R 3 or (CH 2 ) n (T)COR 3 ,

R 3 is:

(a) (C 1 -C 6 )-alkyl optionally substituted with phenyl;

(b) phenyl or naphthyl optionally substituted with one, two, or three substituents selected from the group consisting of OCF 3 , O(CH 3 ) 3 , CH 3 , CF 3 and halo;

(c) (C 1 -C 6 )-alkoxy; and

(d) heteroaryl, wherein heteroaryl is defined as a monocyclic or bicyclic aromatic ring of 5 to 10 carbon atoms containing from 1 to 3 heteroatoms selected from O, N or S, and heteroaryl being optionally substituted with one, two, or three substituents selected from the group consisting of (C 1 -C 6 )-alkyl and (C 1 -C 6 )-alkoxy;

R 5 and R 6 are independently:

(a) (C 1 -C 4 )-perfluoroalkyl,

(b) phenyl, and

(c) (C 1 -C 10 )-alkyl optionally substituted with (C 3 -C 7 )-cycloalkyl; and

n is 1, 2, or 3.

7. The compound of Formula Ig, as recited in claim 2

wherein R 1 , R 3 , R 5 , R 6 , and n are as defined below:

R 1 is (C 1 -C 6 )-alkoxy, (C 1 -C 4 )-perfluoroalkyl, (C 1 -C 4 )-perfluoroalkoxy, or halo, wherein halo is fluoro, chloro, bromo, or iodo;

R 3 is:

(a) (C 1 -C 6 )-alkyl optionally substituted with phenyl;

(b) phenyl or naphthyl optionally substituted with one, two, or three substituents selected from the group consisting of OCF 3 , O(CH 3 ) 3 , CH 3 , CF 3 and halo;

(c) (C 1 -C 6 )-alkoxy; and

(d) heteroaryl, wherein heteroaryl is defined as a monocyclic or bicyclic aromatic ring of 5 to 10 carbon atoms containing from 1 to 3 heteroatoms selected from O, N or S, and heteroaryl being optionally substituted with one, two, or three substituents of (C 1 -C 6 )-alkyl;

R 5 and R 6 are independently:

(a) (C 1 -C 4 )-perfluoroalkyl,

(b) phenyl, and

(c) (C 1 -C 10 )-alkyl optionally substituted with (C 3 -C 7 )-cycloalkyl; and

n is 1, 2, or 3.

8. The compound of claim 2 wherein the compound is selected from the group consisting of:

3-dimethylaminomethyl-6-methoxy-2-methyl-4-phenyl-2H-isoquinoline-1-one;

3-(2,3-dihydro-indol-1-ylmethyl)-6-methoxy-2-methyl-4-phenyl-2H-isoquinoline-1-one;

3-[(ethyl-methyl-amino)-methyl]-6-methoxy-2-methyl-4-phenyl-2H-isoquinoline-1-one;

6-methoxy-2-methyl-4-phenyl-3-piperidin-1-ylmethyl-2H-isoquinoline-1-one;

3-[(tert-butyl-methyl-amino)-methyl]-6-methoxy-2-methyl-4-phenyl-2H-isoquinoline-1-one;

3-[(isopropyl-methyl-amino)-methyl]-6-methoxy-2-methyl-4-phenyl-2H-isoquinoline-1-one;

3-[(isopropyl-methyl-amino)-methyl]-6-methoxy-2-methyl-4-phenyl-2H-isoquinoline-1-one;

6-methoxy-2-methyl-4-phenyl-3-[(2,2,2-trifluoro-ethylamino)-methyl]-2H-isoquinoline-1-one;

2-(5-methoxy-2-methyl-1H-indol-3-yl)-N-(6-methoxy-2-methyl-1-oxo-4-phenyl-1,2-dihydro-isoquinoline-3-ylmethyl)-acetamide;

N-[2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinoline-2-yl)-ethyl]-methanesulfonamide;

butane-1-sulfonic acid [2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-amide;

thiophene-2-sulfonic acid [2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-amide;

N-[2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-benzenesulfonamide;

furan-2-carboxylic acid [2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-amide;

N-[2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-2-phenyl-acetamide hydrochloride;

N-[2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-nicotinamide;

9-methoxy-2-methyl-11-phenyl-1,2,3,4-tetrahydro-pyrazino[1,2-b]isoquinolin-6-one;

2-(1-acetyl-peperidin-4-ylmethyl)-3-dimethylaminomethyl-6-methoxy-4-phenyl-2H-isoquinolin-1-one;

3-dimethylaminomethyl-2-(1-methanesulfonyl-piperidin-4-ylmethyl)-6-methoxy-4-phenyl-2H-isoquinolin-1-one;

[2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester;

N-[2-(3-dimethylaminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-isonicotinamide; and

[2-(3-aminomethyl-6-methoxy-1-oxo-4-phenyl-1H-isoquinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester.

9. The compound of claim 2 wherein the compound is 3-dimethylaminomethyl-6-methoxy-2-methyl-4-phenyl-2H-isoquinolin-1-one or a pharmaceutically acceptable salt, hydrate, solvate, crystal forms and stereoisomer thereof as shown below:

10. A pharmaceutical composition for the treatment of an atrial arrhythmia, comprising a pharmaceutically acceptable carrier and at least one compound of Formula I or its pharmaceutically acceptable salt, hydrate, solvate, crystal form, and stereoisomer thereof as recited in claim 1 .