3-Fluoro-Piperidine T-Type Calcium Channel Antagonists

1 . A compound of the formula I:

wherein:

R 1 and R 2 are independently selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl,

or R 1 and R 2 taken together form a C 3-6 cycloalkyl ring, which is unsubstituted or substituted with C 1-6 alkyl or halogen;

R 3 is selected from the group consisting of:

(1) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ,

(2) C 1-8 alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ,

(b) halogen,

(c) hydroxyl,

(d) —O—C 1-6 alkyl,

(e) —CO 2 R 9 , where R 9 is independently selected from:

(i) hydrogen,

(ii) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,

(iii) benzyl, and

(iv) phenyl,

(f) —NR 10 R 11 , wherein R 10 and R 11 are independently selected from hydrogen, —C 1-6 alkyl and —C 1-6 alkyl-O—C 1-6 alkyl, or R 10 and R 11 together form a pyrrolidine, piperidine, oxazolidine or morpholine ring, which is unsubstituted or substituted with halogen, C 1-6 alkyl or halogen-substituted C 1-6 alkyl,

(3) C 3-10 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ,

(b) halogen,

(c) hydroxyl,

(d) —O—C 1-6 alkyl,

(e) —CO 2 R 9 ,

(f) —NR 10 R 11 ,

(4) —C 1-6 alkyl-(C 3-10 cycloalkyl), which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ,

(b) halogen,

(c) hydroxyl,

(d) —O—C 1-6 alkyl,

(e) —CO 2 R 9 ,

(f) —NR 10 R 11 ,

(5) heteroaryl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e , or oxo;

R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) hydroxyl,

(4) —C 1-6 alkyl,

(5) —O—C 1-6 alkyl,

(6) —CF 3 ,

(7) —OCF 3 ,

(8) —OCHF 2 ,

(9) —OCH 2 F,

(10) —OCF 2 CHF 2 ,

(11) —CN, and

(12) —NR 10 R 11 ;

R 4 and R 5 are independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-8 alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ,

(b) halogen,

(c) hydroxyl,

(d) —O—C 1-6 alkyl,

(e) —CO 2 R 9 ,

(f) —NR 10 R 11 ;

(3) C 3-10 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ,

(b) halogen,

(c) hydroxyl,

(d) —O—C 1-6 alkyl,

(e) —CO 2 R 9 ,

(f) —NR 10 R 11 ;

(4) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ;

(5) heterocycle, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e , or oxo,

(6) —CO—C 1-8 alkyl, which is unsubstituted or substituted with one or more substituents selected from:

(a) phenyl, which is substituted with R 3a , R 3b , R 3c , R 3d and R 3e ,

(b) halogen,

(c) hydroxyl,

(d) —O—C 1-6 alkyl,

(e) —CO 2 R 9 ,

(f) —NR 10 R 11 ;

(7) —SO 2 R 9 ,

(8) —CO 2 R 9 , and

(9) —CONR 10 R 11 ,

or R 4 and R 5 taken together form a C 3-6 cycloalkyl ring, which is unsubstituted or substituted with C 1-6 alkyl or halogen;

and N-oxides thereof, and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

2 . The compound of claim 1 wherein:

R 1 and R 2 are independently selected from the group consisting of:

(1) hydrogen, and

(2) C 1-6 alkyl;

R 3 is selected from the group consisting of:

(1) phenyl, which is substituted with R 3a , R 3b and R 3c ,

(2) C 1-8 alkyl, which is unsubstituted or substituted with phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c ,

(3) C 3-10 cycloalkyl, which is unsubstituted or substituted with phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c , and

(4) —C 1-6 alkyl-(C 3-10 cycloalkyl), which is unsubstituted or substituted with phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c ;

R 3a , R 3b and R 3c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl,

(4) —O—C 1-6 alkyl,

(5) —CF 3 ,

(6) —OCF 3 ,

(7) —OCHF 2 ,

(8) —OCH 2 F,

(9) —OCF 2 CHF 2 ,

(10) —CN, and

(11) —NR 10 R 11 , wherein R 10 and R 11 are independently selected from hydrogen and —C 1-6 alkyl;

R 4 and R 5 are independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-8 alkyl, which is unsubstituted or substituted with hydroxy or phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c ,

(3) C 3-10 cycloalkyl, which is unsubstituted or substituted with C 1-8 alkyl or phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c ,

(4) C 3-10 cycloalkyloxy, which is unsubstituted or substituted with C 1-8 alkyl or phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c , and

(5) —CO—C 1-8 alkyl, and

(6) —CONR 10 R 11 ;

and N-oxides thereof, and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

3 . The compound of claim 1 of the formula Ia′:

or a pharmaceutically acceptable salt thereof or an individual enantiomer or diastereomer thereof.

4 . The compound of claim 1 wherein R 1 is hydrogen and R 2 is hydrogen.

5 . The compound of claim 1 wherein R 3 is phenyl which is substituted with R 3a , R 3b and R 3c .

6 . The compound of claim 5 wherein R 3a , R 3b and R 3c are independently selected from the group consisting of:

(1) hydrogen,

(2) fluoro,

(3) chloro,

(4) bromo,

(5) —CH 3 ,

(6) —C(CH 3 ) 3 ,

(7) —CF 3 ,

(8) —CN,

(9) —O—CH 3 ,

(10) —OCF 3 ,

(11) —OCHF 2 ,

(12) —OCH 2 F,

(13) —OCF 2 CHF 2 , and

(14) —N(CH 3 ) 2 .

7 . The compound of claim 1 wherein R 3 is adamantyl.

8 . The compound of claim 1 wherein R 3 is C 4-6 cycloalkyl-phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c .

9 . The compound of claim 1 wherein R 3 is cyclobutyl-phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c .

10 . The compound of claim 1 wherein R 3 is cyclopentyl-phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c .

11 . The compound of claim 1 wherein R 3 is cyclohexyl-phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c .

12 . The compound of claim 2 wherein R 4 is hydrogen.

13 . The compound of claim 12 wherein R 4 is hydrogen and R 5 is selected from the group consisting of:

(1) C 1-8 alkyl, which is unsubstituted or substituted with hydroxy or phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c ,

(2) C 3-10 cycloalkyl, which is unsubstituted or substituted with C 1-8 alkyl or phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c , and

(3) C 3-10 cycloalkyloxy, which is unsubstituted or substituted with C 1-8 alkyl or phenyl, where the phenyl is substituted with R 3a , R 3b and R 3c , and

(4) —CO—C 1-8 alkyl, and

(5) —CONR 10 R 11 .

14 . The compound of claim 13 wherein R 4 is hydrogen and R 5 is selected from the group consisting of:

(1) C 1-8 alkyl, which is unsubstituted or substituted with hydroxy,

(2) C 3-10 cycloalkyl,

(3) —CO—C 1-8 alkyl,

(4) tetrahydrofuranyl, which is unsubstituted or substituted with one or more C 1-6 alkyl, and

(5) tetrahydropyranyl, which is unsubstituted or substituted with one or more C 1-6 alkyl.

15 . The compound of claim 14 wherein R 4 is hydrogen and R 5 is selected from the group consisting of:

(1) —CH 2 CH 2 C(CH 3 ) 3 ,

(2) adamantyl,

(3) dimethyl-tetrahydrofuranyl, and

(4) dimethyl-tetrahydropyranyl.

16 . A compound which is selected from the group consisting of:

N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}adamantane-1-carboxamide;

3,5-dichloro-N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

3,5-dichloro-N-({(3S,4R)-1-[(3,3-dimethyltetrahydrofuran-2-yl)methyl]-3-fluoropiperidin-4-yl}methyl)benzamide;

3-chloro-N-{[(3S,4R)-1-(3,3-dimethyl-2-oxobutyl)-3-fluoropiperidin-4-yl]methyl}-5-methoxybenzamide;

3-chloro-N-({(3S,4R)-3-fluoro-1-[(2S)-2-hydroxy-3,3-dimethylbutyl]piperidin-4-yl}methyl)-5-methoxybenzamide;

3-chloro-N-({(3S,4R)-3-fluoro-1-[(2R)-2-hydroxy-3,3-dimethylbutyl]piperidin-4-yl}methyl)-5-methoxybenzamide;

N-({(3S,4R)-1-[2-(tert-butylamino)-2-oxoethyl]-3-fluoropiperidin-4-yl}methyl)-3,5-dichlorobenzamide;

3,5-dichloro-N-{[(3R,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

3,5-dimethyl-N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

3,5-dichloro-N-({1-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]-3-fluoropiperidin-4-yl}methyl)benzamide;

N-{[1-(1-adamantylmethyl)-3-fluoropiperidin-4-yl]methyl}-3,5-dichlorobenzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}adamantane-1-carboxamide;

3-chloro-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-5-fluorobenzamide;

3,5-dichloro-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}adamantane-1-carboxamide;

N-({1-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl]-3-fluoropiperidin-4-yl}methyl)adamantane-1-carboxamide;

3,5-methoxy-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-fluoro-5-(trifluoromethyl)benzamide;

3-tert-butyl-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-5-methoxybenzamide;

3-chloro-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

3-cyano-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-5-fluorobenzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3,5-difluorobenzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-(trifluoromethoxy)benzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-(1,1,2,2-tetrafluoroethoxy)benzamide;

3,5-dibromo-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-(trifluoro)benzamide;

3-(dimethylamino)-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

3-bromo-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-methylbenzamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(4-fluorophenyl)cyclohexanecarboxamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(3-fluorophenyl)cyclopenanecarboxamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(4-chlorophenyl)cyclobuanecarboxamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(4-chlorophenyl)cyclohexanecarboxamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(4-methoxyphenyl)cyclopenanecarboxamide;

1-(2-chloro-4-fluorophenyl)-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}cyclopentane-carboxamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(4-fluorophenyl)cyclopenanecarboxamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(3-fluorophenyl)cyclohexanecarboxamide;

N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-1-(4-methoxyphenyl)cyclohexanecarboxamide;

2-(1-adamantyl)-N-{[1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}acetamide;

3,5-dichloro-N-{[(3R,4S)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

3,5-dichloro-N-({1-[(6,6-dimethyltetrahydro-2H-pyran-2-yl)methyl]-3-fluoropiperidin-4-yl}methyl)-benzamide;

3,5-dichloro-N-({1-[(3,3-dimethyltetrahydrofuran-2-yl)methyl]-3-fluoropiperidin-4-yl}methyl)-benzamide;

N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-fluoro-5-methoxybenzamide;

3-chloro-N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-5-(trifluoromethyl)benzamide;

N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-methyl-5-(trifluoromethyl)benzamide;

N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-methoxy-5-methylbenzamide;

3-chloro-N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-5-methylbenzamide;

3-chloro-N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-5-(fluoromethoxy)benzamide;

3-chloro-N-({(3S,4R)-3-fluoro-1-[(2R)-2-hydroxy-3,3-dimethylbutyl]piperidin-4-yl}methyl)-5-methoxybenzamide;

3-chloro-N-({(3S,4R)-3-fluoro-1-[(2S)-2-hydroxy-3,3-dimethylbutyl]piperidin-4-yl}methyl)-5-methoxybenzamide;

3-chloro-N-{[(3S,4R)-1-(3,3-dimethyl-2-oxobutyl)-3-fluoropiperidin-4-yl]methyl}-5-methoxybenzamide;

4-chloro-N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-fluorobenzamide;

3,5-dichloro-N-({(3S,4R)-3-fluoro-1-[(2R)-2-hydroxy-3,3-dimethylbutyl]piperidin-4-yl}methyl)benzamide;

3,5-dichloro-N-({(3S,4R)-3-fluoro-1-[(2S)-2-hydroxy-3,3-dimethylbutyl]piperidin-4-yl}methyl)benzamide;

3,5-dichloro-N-{[(3S,4R)-1-(3,3-dimethyl-2-oxobutyl)-3-fluoropiperidin-4-yl]methyl}benzamide;

N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3,5-dimethoxybenzamide;

N-{[(3S,4R)-1-(3,3-dimethylbutyl)-3-fluoropiperidin-4-yl]methyl}-3-fluoro-5-(trifluoromethyl)benzamide;

N-({(3S,4R)-1-[2-(tert-butylamino)-2-oxoethyl]-3-fluoropiperidin-4-yl}methyl)-2-(4-tert-butylphenyl)acetamide;

N-[((3S,4R)-1-{2[tert-butyl(2-methoxyethyl)amino]-2-oxoethyl}-3-fluoropiperidin-4-yl)methyl]-3,5-dichlorobenzamide;

3,5-dichloro-N-({(3S,4R)-3-fluoro-1-[2-(2-methylpiperidin-1-yl)-2-oxoethyl]piperidin-4-yl}methyl)benzamide;

3,5-dichloro-N-({(3S,4R)-1-[2-(4,4-dimethyl-1,3-oxazolidin-3-yl)-2-oxoethyl]-3-fluoropiperidin-4-yl}methyl)benzamide;

N-[((3S,4R)-1-{2-[tert-butyl(ethyl)amino]-2-oxoethyl}-3-fluoropiperidin-4-yl)methyl]-3,5-dichlorobenzamide;

N-({(3S,4R)-1-[2-(tert-butylamino)-2-oxoethyl]-3-fluoropiperidin-4-yl}methyl)-3,5-dichlorobenzamide;

or a pharmaceutically acceptable salt thereof.

17 . A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

18 . (canceled)

19 . (canceled)

20 . (canceled)

21 . A method for the treatment of a disorder or disease in which T-type calcium channels are involved which comprises administering to a mammalian patient in need of such treatment an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof.

22 . The method of claim 21 wherein said disorder or disease is selected from the group consisting of: epilepsy; pain; neuropathic pain; movement disorder; Parkinson's disease; essential tremor; cognitive disorder; decreased cognition; decreased memory retention; psychosis; schizophrenia; sleep disorder; insomnia; decreased quality of sleep; increased time to sleep onset; decreased REM sleep; decreased slow-wave sleep; increased fragmentation of sleep patterns; decreased sleep maintenance; increased wake after sleep onset; decreased total sleep time; hot flashes; fibromyalgia; mood disorder; anxiety disorder; and substance withdrawal.