Derivatives of 4-(n-azacycloalkyl) anilides as potassium channel modulators

1. A compound of formula IA

wherein

R 1 and R 2 , vary independently, and are selected from the group consisting of H, CN, halogen, CH 2 CN, OH, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, C(═O)C 1 -C 6 alkyl; NH—C 1 -C 6 alkyl; N(C 1 -C 6 alkyl)-C 1 -C 6 alkyl, NHC(═O)C 1 -C 6 alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH 2 , C(═O)NH—C 1 -C 6 alkyl, SO 2 NH 2 , NHSO 2 —C 1 -C 6 alkyl; C(═O)OC 1 -C 6 alkyl, OC(═O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, (CH 2 ) m C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar, (CH 2 ) m thienyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, and (CH 2 ) m pyrimidyl,

wherein

m=zero, 1, or 2;

Ar is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S;

or

R 1 and R 2 , together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring;

wherein said fused ring may be saturated, unsaturated, or aromatic, and said fused ring optionally contains one or two heteroatoms selected independently from the group consisting of O, N, and S;

R′ is selected from the group consisting of H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF 3 , OC 1 -C 3 alkyl and C 1 -C 3 alkyl;

R 3 and R 4 vary independently, and are selected from the group consisting of H, CN, halogen, CF 3 , OCF 3 , OC 1 -C 3 alkyl, and C 1 -C 3 alkyl;

X is O or S;

Y is O or S;

q=1 or zero; and

R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar, (CHR 6 ) w Ar, CH 2 (CHR 6 ) w Ar, and (CHR 6 ) w CH 2 Ar,

wherein

w=zero, 1, 2, or 3;

Ar is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from the group consisting of N, O, and S; and

R 6 is selected from the group consisting of H or C 1 -C 3 alkyl; where all cycloalkyl and cycloalkenyl optionally contain one or two ring heteroatoms selected independently from N, O, and S;

wherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R 1 , R 2 , R′, R 3 , R 4 , R 5 , R 6 , and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C 1 -C 3 alkyl, halogen, OH, OEt, OMe, CN, CH 2 F, OCF 3 , and CF 3 ; and

wherein, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with a carbonyl group.

2. The compound of claim 1 , wherein:

R 1 and R 2 , vary independently, and are selected from the group consisting of H, halogen, CF 3 , C 1 -C 6 alkyl, C(═O)C 1 -C 6 alkyl, C(═O)OC 1 -C 6 alkyl, OC(═O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SCH 3 , C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, phenyl, pyridyl, pyrrolyl, thienyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, and (CH 2 ) m pyridyl;

wherein said cycloalkyl groups optionally contain one or two heteroatoms selected independently from the group consisting of O, N, and S;

wherein said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups are optionally substituted with one or two groups selected, independently, from halogen, methyl, ethyl, or trifluoromethyl; and

wherein m is zero, 1, or 2;

R′ is selected from the group consisting of H, halogen, phenyl, 2-(N,N-dimethylamino)ethyl, CF 3 , OC 1 -C 3 alkyl and C 1 -C 3 alkyl;

R 3 and R 4 vary independently, and are selected from the group consisting of H, halogen, CF 3 , OCF 3 , OC 1 -C 3 alkyl, and C 1 -C 3 alkyl;

X is O or S;

Y is O or S;

q=1 or 0;

R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar, (CHR 6 ) w Ar, CH 2 (CHR 6 ) w Ar, and (CHR 7 ) w CH 2 Ar;

wherein w=0-3;

Ar is selected from the group consisting of phenyl, pyrimidyl, or pyridyl, and a 5-member heteroaromatic ring;

wherein said heteroaromatic ring contains 1 or 2 ring heteroatoms selected independently from the group consisting of N, O, and S; and

R 6 is selected from the group consisting of H and methyl;

wherein all cycloalkyl and cycloalkenyl groups in R 5 optionally contain one or two ring heteroatoms selected independently from the group consisting of N, O, and S; and

wherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C 1 -C 3 alkyl, halogen, OEt, OMe, and trifluoromethyl.

3. The compound of claim 1 , wherein:

R 1 and R 2 , vary independently, and are selected from the group consisting of H, halogen, CF 3 , C 1 -C 6 alkyl, C(═O)C 1 -C 6 alkyl, C(═O)OC 1 -C 6 alkyl, OC(═O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SCH 3 , (CH 2 ) m cyclopropyl, (CH 2 ) m cyclobutyl, (CH 2 ) m cyclopentyl, (CH 2 ) m cyclohexyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, and (CH 2 ) m pyrimidyl;

wherein said cyclopentyl and said cyclohexyl groups optionally contain one or two ring heteroatoms selected independently from the group consisting of O, N, and S;

wherein said alkyl, cycloalkyl, phenyl, pyrrolyl, and pyridyl groups are optionally substituted with one or two groups selected, independently, from the group consisting of halogen, CH 3 , ethyl, and CF 3 ; and

m is zero, 1, or 2;

R′ is selected from the group consisting of H, halogen, CF 3 , and C 1 -C 3 alkyl;

R 3 and R 4 vary independently, and are selected from the group consisting of H, halogen, CF 3 , OCF 3 , OC 1 -C 3 alkyl, and C 1 -C 3 alkyl;

X is O or S;

Y is O;

q=1 or 0;

R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar, (CHR 6 ) w Ar, CH 2 (CHR 6 ) w Ar, and (CHR 6 ) w CH 2 Ar;

wherein w=0-3,

Ar is selected from the group consisting of phenyl, pyridyl, and a 5-member heteroaromatic ring,

wherein said heteroaromatic ring contains 1 or 2 ring heteroatoms selected independently from the group consisting of N, O, and S;

R 6 is H or methyl;

wherein all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from the group consisting of N, O, and S; and

wherein all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C 1 -C 3 alkyl, halogen, OMe, OEt, and CF 3 .

4. The compound of claim 2 , wherein:

R 1 and R 2 , vary independently, and are selected from the group consisting of H, halogen, CF 3 , OC 1 -C 3 alkyl, C 1 -C 6 alkyl, C(═O)OC 1 -C 3 alkyl, OC(═O)C 1 -C 3 alkyl, and C(═O)C 1 -C 3 alkyl;

R′ is selected from the group consisting of H, F, CH 3 , and ethyl;

R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OC 1 -C 3 alkyl, and C 1 -C 3 alkyl; and

R 5 is C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, or (CHR 6 ) w Ar, CH 2 (CHR 6 ) w Ar, or (CHR 6 ) w CH 2 Ar.

5. The compound of claim 1 , wherein:

R 2 is H or F;

R′ is H;

R 3 is selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , and Cl;

R 4 is selected from the group consisting of CH 3 , OCH 3 , CF 3 , OCF 3 , and Cl; and

R 5 is C 3 -C 6 alkyl or (CH 2 ) w C 3 -C 6 cycloalkyl.

6. The compound of claim 1 or claim 2 , wherein:

R 1 is halogen or CF 3 ;

R 2 is H or F;

R′ is H;

R 3 and R 4 vary independently, and are selected from the group consisting of H, CH 3 , OCH 3 , CF 3 , OCF 3 , or Cl; and

R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar, (CHR 6 ) w Ar, CH 2 (CHR 6 ) w Ar, and (CHR 6 ) w CH 2 Ar.

7. The compound of claim 1 which is a compound of formula IA-1

wherein:

R 1 is selected from the group consisting of H, halogen, CN, CH 2 CN, CF 3 , C 1 -C 6 alkyl, OCH 3 , (C═O)OCH 3 , O(C═O)CH 3 , OCF 3 , (CH 2 ) m C 3 -C 6 cycloalkyl, phenyl, and pyridyl;

R 2 is selected from the group consisting of H, F, OCH 3 , CH 3 , and CF 3 ;

R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OC 1 -C 3 alkyl, or C 1 -C 3 alkyl; and

R 5 is selected from the group consisting of C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar, (CHR 6 ) w Ar, CH 2 (CHR 6 ) w Ar, and (CHR 6 ) w CH 2 Ar,

wherein w=0-3;

Ar is phenyl, furyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, or pyridyl; and

R 6 is C 1 -C 3 alkyl;

wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and Ar are optionally substituted with one or two substituents selected independently from the group consisting of C 1 -C 3 alkyl, halogen, OCH 3 , OCH 2 CH 3 , CN, and CF 3 .

8. The compound of claim 7 , wherein:

R 1 is selected from the group consisting of H, F, Cl, Br, CF 3 , C 1 -C 6 alkyl, OCH 3 , CH 2 OCH 3 , CH 2 CH 2 OCH 3 , CH 2 OCH 2 CH 3 , and OCH 2 CH 3 ;

R′ is selected from the group consisting of H, CH 3 , CH 2 CH 3 , or halogen;

R 3 and R 4 vary independently, and are selected from the group consisting of H, F, Cl, CF 3 , OCF 3 , OCH 3 , and CH 3 ; and

R 5 is selected from the group consisting of C 1 -C 6 alkyl, CH 2 C 3 -C 6 cycloalkyl, CH 2 CH 2 C 3 -C 6 cycloalkyl, CH═CH—C 3 -C 6 cycloalkyl, CH═CH—C 5 -C 6 cycloalkenyl, CH 2 C 5 -C 6 cycloalkenyl, CH 2 CH 2 C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, and (CH 2 ) w Ar;

wherein w=1 or 2;

Ar is selected from the group consisting of phenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furyl, thienyl, pyrrolyl, and pyridyl;

wherein all alkyl, cycloalkyl, aryl, and heteroaryl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and Ar are optionally substituted with one or two substituents selected independently from the group consisting of CH 3 , halogen, OCH 3 , OCH 2 CH 3 , CN, and CF 3 .

9. The compound of claim 8 , wherein:

R 1 is selected from the group consisting of F, CF 3 , Cl, CH 3 , CH 2 CH 3 , SCH 3 , OCH 3 , CH 2 OCH 3 , CH 2 OCH 2 CH 3 , OCF 3 , phenyl, thienyl, and H;

R 2 is selected from the group consisting of H, F, Cl, and OCH 3 ;

R′ is selected from the group consisting of H, F, CH 2 CH 3 , and CH 3 ;

R 3 and R 4 vary independently, and are selected from the group consisting of H, Cl, CH 3 , CF 3 , OCH 3 , and OCF 3 ; and

R 5 is selected from the group consisting of C 4 -C 6 alkyl, (CH 2 ) w Ar, and (CH 2 ) w C 5 -C 6 cycloalkyl;

wherein w is 1, 2, or 3.

10. The compound of claim 9 , wherein:

R 1 is selected from the group consisting of F, CF 3 , Cl, CH 3 , OCH 3 , CH 2 OCH 3 , and H;

R 2 is selected from the group consisting of H, F, CH 3 , and Cl;

R′ is H;

R 3 is selected from the group consisting of H, Cl, CH 3 , CF 3 , OCH 3 , and OCF 3 ;

R 4 is selected from the group consisting of Cl, OCH 3 , and CH 3 ; and

R 5 is C 4 -C 6 alkyl or 2-cyclopentyl ethyl.

11. The compound of claim 10 , wherein R 3 and R 4 are both CH 3 or both OCH 3 ; and R 5 is C 5 -C 6 alkyl.

12. The compound of claim 3 , wherein:

R′ and R 2 are H;

R 3 and R 4 are both methyl; and

R 5 is C 5 -C 6 alkyl or (CH 2 ) w C 5 -C 6 cycloalkyl;

wherein w is 1, 2, or 3.

13. A compound according to claim 1 , wherein said compound is one of the following:

N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3,3-dimethylbutanamide;

N-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide;

N-(2-chloro-4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethyl)phenyl)-3-cyclopentylpropanamide;

N-(2-chloro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(trifluoromethylphenyl)-3,3-dimethylbutanamide;

N-[2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl phenyl]-3-cyclopentylpropionamide;

N-[2,6-dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-6-trifluoromethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl phenyl]-3,3-dimethylbutanamide;

N-[4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide;

N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethyl-phenyl]-3,3-dimethylbutanamide;

N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methylphenyl]-3,3-dimethylbutanamide;

N-[2-chloro-6-methyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(6-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;

N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-phenyl]-3,3-dimethylbutanamide;

N-[4-(6-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethylphenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethylbutanamide;

N-[4-(7-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-2-trifluoromethyl-phenyl]-3,3-dimethylbutanamide;

3,3-dimethyl-N-[2-trifluoromethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]butanamide;

N-[4-(6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,6-dimethyl-phenyl]-3,3-dimethylbutanamide;

N-[4-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methoxy-6-methyl-phenyl]-3,3-dimethylbutanamide;

N-[2-chloro-4-(3,4-dihydro-1H-isoquinolin-2-yl)-6-trifluoromethoxy-phenyl]-3,3-dimethylbutanamide;

N-[4-(3,4-dihydro-M-isoquinolin-2-yl)-2,6-dimethoxy-phenyl]-3,3-dimethylbutanamide;

N-[2,6-dimethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl butanamide;

N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-thiobutanamide;

[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-carbamic acid ethyl ester; and

N-[2,6-Dimethyl-4-(7-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl butanamide.