Potassium channel inhibitors
View Patent ↗The present invention relates to dipyridin-3-ylmethoxy compounds and derivatives thereof having the structure I useful as potassium channel inhibitors to treat cardiac arrhythmias, and the like.
1. A compound of formula I,
or a pharmaceutically acceptable salt, wherein:
A is pyridyl;
L is
D is pyridyl;
E-G is
G, attached to a carbon ring atom of ring E, is selected from the group consisting of
—C 1-6 alkylene-L,
—CH(OH)-L,
—NH-L,
—N(C 1-6 alkyl)-L,
—NHC(O)NH-L,
—NH(C(O)C 1-6 alkyl)-L,
—O-L,
—O-C 1-6 alkylene-L,
—C(O)-L,
—C(O)NH-L,
—C(O)N(C 1-6 alkyl)-L,
—C(O)NH(C 1-6 alkylene)-L,
—C(O)N(C 1-6 alkyl)C 1-6 alkylene-L, and
-L,
wherein C 1-6 alkyl and C 1-6 alkylene are unsubstituted or substituted with halogen;
M is selected from the group consisting of O, NH and N(C 1-6 alkyl);
R a , in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) C 1 -C 6 alkyl,
3) halogen,
4) aryl,
5) heterocycle,
6) C 3 -C 10 cycloalkyl,
7) OR 5 , and
8) CH 2 OR 5 ,
said alkyl, aryl, heterocycle and cycloalkyl is unsubstituted or substituted with at least one substituent selected from R 6 ;
R 4 , in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) halogen,
3) NO 2 ,
4) CN,
5) CR 4 ═C(R 5 ) 2 ,
6) C≡CR 5 ,
7) (CR a 2 ) n OR 5 ,
8) (CR a 2 ) n N(R 5 ) 2 ,
9) (CR a 2 ) n C(O)R 5 ,
10) (CR a 2 ) n C(O)OR 5 ,
11) (CR a 2 ) n R 5 ,
12) (CR a 2 ) n S(O) m R 5 ,
13) (CR a 2 ) n S(O) m N(R 5 ) 2 ,
14) OS(O) m R 5 ,
15) N(R 5 )C(O)R 5 ,
16) N(R 5 )S(O) m R 5 ,
17) (CR a 2 ) n N(R 6 )R 5 ,
18) (CR a 2 ) n N(R 5 )(CR a 2 ) n C(O)N(R 5 ) 2 ,
19) (CR a 2 ) n N(R 5 )(CR a 2 ) n C(O)OR 5 ,
20) N(R 5 )(CR a 2 ) n R 5 ,
21) N(R 5 )(CR a 2 ) n N(R 5 ) 2 ,
22) (CR a 2 ) n C(O)N(R 5 ) 2 ,
23) (CR a 2 ) n C(O)NH(CR a 2 ) n R 5 ,
24) (CR a 2 ) n C(O)NHC(R 5 ) 2 (CR a 2 ) n N(R 5 ) 2 and
25) C(O)NH(CR a 2 )(CR a 3 );
R 5 , in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) unsubstituted or substituted C 1 -C 6 alkyl,
3) unsubstituted or substituted C 3 -C 10 cycloalkyl,
4) unsubstituted or substituted aryl,
5) unsubstituted or substituted heterocycle,
6) CF 3 ,
7) unsubstituted or substituted C 2 -C 6 alkenyl, and
8) unsubstituted or substituted C 2 -C 6 alkynyl,
or in the case where R 5 is attached to a nitrogen atom that is disubstituted with R 5 , each R 5 is independently selected from C 1 -C 6 alkyl, and the nitrogen atom together with each R 5 form a ring;
R 6 , in each instance in which it appears, is independently selected from the group consisting of
1) hydrogen,
2) unsubstituted or substituted C 1 -C 6 alkyl,
3) halogen,
4) oxo,
5) OR 5 ,
6) CF 3 ,
7) unsubstituted or substituted aryl,
8) unsubstituted or substituted C 3 -C 10 cycloalkyl,
9) unsubstituted or substituted heterocycle,
10) S(O) m N(R 5 ) 2 ,
11) C(O)OR 5 ,
12) C(O)R 5 ,
13) CN,
14) C(O)N(R 5 ) 2 ,
15) N(R 5 )C(O)R 5 ,
16) N(R 5 )C(O)OR 5 ,
17) N(R 5 )C(O)N(R 5 ) 2 ,
18) OC(O)N(R 5 ) 2 ,
19) S(O) m R 5 ,
20) OS(O) m R 5 ,
21) NO 2 ,
22) N(R 5 ) 2 ;
23) SC(O)R 5 , and
24) N(R 5 )S(O) m R 5 ;
m is independently 0, 1 or 2; and
n, in each instance in which it occurs, is independently selected from 0, 1, 2, 3, 4, 5 or 6.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an optical isomer thereof, wherein G is selected from the group consisting of
—NH-L,
—N(CH 3 )-L,
—CH 2 -L,
—CH(OH)-L,
—OCH 2 -L,
—C(O)-L,
—C(O)N(CH 3 )-L,
—C(O)N(CH 3 )CH 2 -L,
—C(O)NHCH 2 -L, and
-L;
wherein L is selected from the group consisting of
3. A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
N-[2-(dipyridin-3-ylmethoxy)phenyl]pyridin-2-amine,
3-[(1,1-biphenyl-2-yloxy)(pyridin-3-yl)methyl]pyridine,
[2-(dipyridin-3-ylmethoxy)phenyl](phenyl)methanone,
[2-(dipyridin-3-ylmethoxy)phenyl](phenyl)methanol,
3-[[2-(benzyloxy)phenoxy](pyridin-3-yl)methyl]pyridine,
3-[(2-benzylphenoxy)(pyridin-3-yl)methyl]pyridine,
2-(dipyridin-3-ylmethoxy)-N-methyl-N-phenylbenzamide,
3-{pyridin-3-yl[2-(pyrrolidin-1-ylcarbonyl)phenoxy]methyl}pyridine,
N-benzyl-2-(dipyridin-3-ylmethoxy)benzamide,
N-benzyl-2-(dipyridin-3-ylmethoxy)-N-methylbenzamide,
3-[[2-(1-naphthyl)phenoxy](pyridin-3-yl)methyl]pyridine,
3-[[2-(2-naphthyl)phenoxy](pyridin-3-yl)methyl]pyridine, and
N-cyclohexyl-2-(dipyridin-3-ylmethoxy)-N-methylbenzamide.
4. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound claim 1 or a pharmaceutically acceptable crystal form or hydrate thereof.