Pyrrolotriazines as potassium ion channel inhibitors

1. A compound of formula I

or an enantiomer, diastereomer, tautomer, or salt thereof wherein:

A is —(CH 2 ) m —R 2 , —CH(R 26 )—R 2 , —(CH 2 ) n-1 —O—R 2 , —(CH 2 ) n-1 —NR 25 —R 2 , —CH(R 26 )—CO 2 —R 2 , or —(CH 2 ) n-1 —NR 25 —CO 2 —R 2 ;

R 1 is C 1-10 alkyl substituted with 1-2 —OH, haloC 1-10 alkyl, C 2-12 alkenyl, C 3-10 cycloalkyl, wherein the cycloalkyl may be substituted with 0-2 R 13 ; or

R 1 is

any of which may be substituted with 0-2 R 13 ;

R 2 is phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl, pyridinone, pyrrolidinyl, tetrahydropyran, or thiazolyl, any of which are substituted with 0-2 R 2a ;

R 2a , at each occurrence, is independently H, —OH, F, Cl, Br, I, C 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkyl, C 3-10 cycloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-10 aryl, a 4- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C 1-10 alkyl, —CN, —NO 2 , —(CH 2 ) m —SO 2 R 14 , —NR 14 SO 2 R 14 , ═O, —CONR 14 R 14 , —(CH 2 ) m —SO 2 NR 14 R 14 , —(CH 2 ) m —NR 14 SO 2 R 14 , —(CH 2 ) n —NR 14 SO 2 NR 14 R 14 , —NR 14 SO 2 NR 14 R 1 4 , —CO n NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 COR 14 , —SO 2 NR 14 COR 14 , —SO 2 NR 14 CONR 14 R 14 , —NR 14 CO 2 R 14 , —CO 2 R 14 , —NR 14 R 14 , —NR 14 CONR 14 R 14 , —C(═NOR 14 )NR 14 R 14 , —CONR 14 OR 14 or —NCOR 14 , wherein the alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;

R 3 is phenyl, pyridinyl, pyrimidinyl, or dihydropyran, tetrahydropyran any of which may be substituted with 0-1 R 3a ;

R 3a is halo, CN, NH 2 , —O—C 1-3 alkyl, or morpholinyl;

R 13 , at each occurrence, is independently H, F, Cl, Br, I, CN, C 1-10 alkyl, C 1-10 alkoxy, haloC 1-10 alkyl, C 3-10 cycloalkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 6-10 aryl, a 4- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C 1-10 alkyl, —NO 2 , —(CH 2 ) m —SO 2 R 14 , —NR 14 SO 2 R 14 , ═O, —CONR 14 R 14 , —(CH 2 ) m —SO 2 NR 14 R 14 , —(CH 2 ) m —NR 14 SO 2 R 14 , —(CH 2 ) n —NR 14 SO 2 NR 14 R 14 , —NR 14 SO 2 NR 14 R 14 , −CO 2 NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 COR 14 , —SO 2 NR 14 COR 14 , —SO 2 NR 14 CONR 14 R 14 , —NR 14 CO 2 R 14 , —CO 2 R 14 , NR 14 R 14 , —NR 14 CONR 14 R 14 , —C(═NOR 14 )NR 14 R 14 , —CONR 14 OR 14 or —NCOR 14 , OR 14 , wherein the alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;

R 14 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, a 4- to 12-membered heteroaryl or a 4- to 12-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may be substituted with 0-3 R 14a and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O; or

alternatively, two R 14 's are taken together with the atoms to which they are attached to form a heterocyclic ring, wherein the cyclic ring may be substituted with 0-1 R 14a and optionally contain 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;

R 14a , at each occurrence, is independently selected from F, Cl, Br, I, C 1-10 alkyl, haloC 1-10 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, a 4- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, —CN, —NO 2 , —CO 2 R 26 , —CO 2 NR 24 R 24 , —OCF 3 , —OR 25 , ═O, —CONR 24 R 24 —COR 24 , —SO 2 R 24 , —NR 24 R 24 , —NR 24 CO 2 R 24 , —SO 2 NR 24 R 24 , or C 6-10 arylC 1-10 alkyl, wherein the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;

R 24 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-6 cycloalkyl, or phenyl; or

R 25 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-6 cycloalkyl, or phenyl;

R 26 , at each occurrence, is independently selected from hydrogen, C 1-10 alkyl, C 3-6 cycloalkyl, or phenyl;

m is 0 to 4;

n is 0 to 4; or

n−1 is 2 to 4.

2. The compound of claim 1 , wherein:

one of R 1 or R 1a is C 1-10 alkyl substituted with 1-2 —OH, haloC 1-10 alkyl, C 3-10 cycloalkyl, wherein the cycloalkyl may be substituted with 0-2 R 13 ; or

or

any of which may be substituted with 0-2 R 13 .

3. The compound, of claim 2 , wherein:

R 13 , at each occurrence, is independently H, —OH, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkyl, C 3-6 cycloalkyl, phenyl, a 4- to 12-membered heteroaryl, wherein the heteroaryl is selected from tetrazolyl, —CN, —NO 2 , —(CH 2 ) m —SO 2 R 14 , —NR 14 SO 2 R 14 , —CONR 14 R 14 , —(CH 2 ) m —SO 2 NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 CO 2 NR 14b R 14b , —NR 14 COR 14 , —NR 14 CO 2 R 14 , —CO 2 R 14 , or —NR 14 R 14 , wherein the alkyl, cycloalkyl, phenyl, and heteroaryl may be substituted with 0-2 R 14a , and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, S, or O;

R 14 , at each occurrence, is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R 14a ; or

alternatively, two R 14b 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, piperidinyl, or piperazinyl, and may be substituted with 0-1 C 1-6 alkyl;

R 14a , at each occurrence, is independently selected from F, Cl, Br, I, C 1-6 alkyl, haloC 1-6 alkyl, phenyl, C 3-6 cycloalkyl.

4. The compound of claim 3 , wherein:

A is —(CH 2 ) m —R 2 , —CH(R 26 )—R 2 , —(CH 2 ) n-1 —O—R 2 , —(CH 2 ) n-1 —NR 25 —R 2 , —CH(R 26 )—CO 2 —R 2 , or —(CH 2 ) n-1 —NR 25 —CO 2 —R 2 ;

R 2 is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, or pyridinone, any of which are substituted with 0-2 R 2a ; or

R 2a , at each occurrence, is independently H, —OH, F, C 1-6 alkyl, C 1-6 alkoxy, 6-SO 2 NR 14 R 14 .

5. The compound of claim 4 , wherein:

R 1 is C 1-10 alkyl substituted with 1-2 —OH, haloC 1-10 alkyl, C 3-10 cycloalkyl, wherein the cycloalkyl may be substituted with 0-1 R 13 ; or

R 1 is

or

or

any of which may be substituted with 0-2 R 13 .

6. The compound of claim 5 , wherein:

R 13 , at each occurrence, is independently H, C 1-6 alkyl, a 4- to 12-membered heteroaryl, wherein the heteroaryl is, selected from tetrazolyl, —CN, —NR 14 SO 2 R 14 , —CONR 14 R 14 , —SO 2 NR 14 R 14 , —NR 14 CO 2 NR 14 R 14 , —NR 14 CO 2 NR 14b R 14b , —NR 14 COR 14 , —CO 2 R 14 , or —NR 14 R 14 , wherein the alkyl, and heteroaryl may be substituted with 0-2 R 14a ;

R 14 , at each occurrence, is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substituted with 0-3 R 14a ; or

two R 14b 's are taken together with the atoms to which they are attached to form a cyclic ring, wherein the cyclic ring is morpholinyl, and may be substituted with 0-1 C 1-6 alkyl;

R 14a , at each occurrence, is independently selected from F, Cl, Br, I, C 1-6 alkyl, haloC 1-6 alkyl, phenyl, C 3-6 cycloalkyl.

7. The compound of claim 6 , wherein:

A is —(CH 2 )—R 2 ;

R 2 is phenyl,

or

any of which are substituted with 0-1 R 2a ; or

R 2a , at each occurrence, is independently H, —OH, F, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or SO 2 NR 14 R 14 .

8. The compound of claim 7 , wherein:

R 3 is phenyl.

9. The compound of claim 8 , wherein:

R 24 , at each occurrence, is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or phenyl; or

R 25 , at each occurrence, is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or phenyl; or

R 26 , at each occurrence, is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or phenyl.

10. The compound of claim 9 , wherein:

R 13 , at each occurrence, is independently H, —CN, —NHSO 2 R 14 , —CONH 2 , —SO 2 NR 14 R 14 , —NHCO 2 NR 14b R 14b , —NHCOR 14 , or —NH 2 ;

R 14 , at each occurrence, is independently selected from hydrogen, or methyl.

11. A compound, enantiomer, diastereomer, or salt thereof, selected from:

12. A pharmaceutical composition comprising a therapeutically effective amount of one or more compound of claim 1 .

13. The pharmaceutical composition of claim 12 , further comprising at least one other therapeutic agent.

14. A method of treating arrhythmia comprising administering to a patient in need thereof an effective amount of one or more compound of claim 1 .

15. A method of controlling heart rate comprising administering to a patient in need thereof an effective amount of one or more compound of claim 1 .

16. A pharmaceutical composition comprising a therapeutically effective amount of one or more compound of claim 11 .

17. The pharmaceutical composition of claim 16 , further comprising at least one other therapeutic agent.

18. A method of treating arrhythmia comprising administering to a patient in need thereof an effective amount of one or more compound of claim 11 .

19. A method of controlling heart rate comprising administering to a patient in need thereof an effective amount of one or more compound of claim 11 .