Cyclohexanesulfonyl derivatives as GlyT1 inhibitors to treat schizophrenia

1. A compound of formula I:

wherein:

R 1 is —(CH 2 ) n —R 1a , wherein n is independently 0-6, and R 1a is selected from the group consisting of:

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

(2) phenyl substituted with R 2a , R 2b and R 2c ,

(3) C 3-6 cycloallyl, which is unsubstituted or substituted with C 1-6 alkyl, 1-6 halogen, hydroxy or —NR 10 R 11 ,

(4) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,

(5) —CO 2 R 9 ,

wherein R 9 is independently selected from:

(a) hydrogen,

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

(c) benzyl, and

(d) phenyl,

(6) —NR 10 R 11 ,

wherein R 10 and R 11 are independently selected from:

(a) hydrogen,

(b) —C 1-6 alkyl, which is unsubstituted or substituted with hydroxy, 1-6 fluoro or —NR 12 R 13 , where R 12 and R 13 are independently selected from hydrogen and —C 1-6 alkyl,

(c) —C 3-6 cycloalkyl, which is unsubstituted or substituted with hydroxy, 1-6 fluoro or —NR 12 R 13 ,

(d) benzyl,

(e) phenyl, and

(7) —CONR 10 R 11 ;

R 2 is selected from the group consisting of:

(1) phenyl, which is substituted with R 2a , R 2b and R 2c ,

(2) C 1-8 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, —NR 10 R 11 , phenyl or heterocycle, where the phenyl or heterocycle is substituted with R 2a , R 2b and R 2c ,

(3) C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 , and

(4) —C 1-6 alkyl-(C 3-6 cycloalkyl), which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ;

R 2a , R 2b and R 2c are independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl, which is unsubstituted or substituted with:

(a) 1-6 halogen,

(b) phenyl,

(c) C 3-6 cycloalkyl, or

(d) —NR 10 R 11 ,

(4) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halogen,

(5) hydroxy,

(6) —SCF 3 ,

(7) —SCHF 2 ,

(8) —SCH 3 ,

(9) —CO 2 R 9 ,

(10) —CN,

(11) —SO 2 R 9 ,

(12) —SO 2 —NR 10 R 11 ,

(13) —NR 10 R 11 ,

(14) —CONR 10 R 11 , and

(15) —NO 2 ;

R 3 is selected from the group consisting of:

(1) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl, or —NR 10 R 11 ,

(2) C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxyl or —NR 10 R 11 ,

R 4 and R 5 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 4 and R 5 taken together form a C 3-6 cycloalkyl ring;

A is selected from the group consisting of:

(1) —O—, and

(2) —NR 10 —;

m is zero or one, whereby when m is zero R 2 is attached directly to the carbonyl;

and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

2. A compound according to claim 1 of formula Id:

wherein R 2a , R 2b and R 2c are selected from hydrogen, fluoro, chloro, bromo, OCH 3 CF 3 , OCF 3 and NH 2 .

3. A compound according to claim 1 of formula If:

wherein R 1b is C 3-6 cycloalkyl, which is unsubstituted or substituted with R 2a , R 2b and R 2c ; D and E are CH and R 3a is a group CH 2 R 3b wherein R 3b is methyl, ethyl or cyclopropyl.

4. A compound according to claim 1 wherein R 3a is —C 1-6 alkyl-(C 3-6 cycloalkyl).

5. A compound according to claim 1 wherein R 1 is C 3-6 cycloalkyl.

6. A compound according to claim 1 wherein R 2 is phenyl substituted by R 2a , R 2b and R 2c which are independently selected from hydrogen, fluoro, chloro, bromo, OCH 3 , CF 3 , OCF 3 and NH 2 .

7. A compound according to claim 1 wherein R 4 and R 5 are hydrogen.

8. A compound according to claim 1 wherein n is zero or one.

9. A compound according to claim 1 which is:

2,4-dichloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexyl-methyl) benzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-4-fluorobenzamide;

2,4,6-trichloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)benzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-4-(trifluoromethyl)benzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-4-(methylsulfonyl)benzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-(trifluoromethoxy)benzamide;

4-bromo-2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)benzamide;

4-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-methylbenzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-4-(methylsulfonyl)benzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2,4,6-trimethylbenzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2,6-dimethylbenzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-6-methylbenzamide;

2-chloro-N-{[1-(cyclopropylmethyl)-4-(propylsulfonyl)cyclohexyl]methyl)}-4-(trifluoromethyl)benzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-nitro-4-(trifluoromethyl)benzamide;

2,4-dichloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)benzamide;

2,4-dichloro-N-{[1-(cyclopropylmethyl)-4-(propylsulfonyl)cyclohexyl]methyl}benzamide;

2,6-dichloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)benzamide;

2,4-dichloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-3-fluorobenzamide;

4-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-(trifluoromethyl)benzamide;

2,4,6-trichloro-N-{[1-(cyclopropylmethyl)-4-(propylsulfonyl)cyclohexyl]methyl}benzamide;

2,4-dichloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-5-fluorobenzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-4-nitrobenzamide;

2-chloro-N-{[1-(cyclopropylmethyl)-4-(ethylsulfonyl)cyclohexyl]methyl}4-(trifluoromethyl)benzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-3-(trifluoromethyl)benzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-6-fluorobenzamide;

4-chloro-N-{[1-(cyclopropylmethyl)-4-(propylsulfonyl)cyclohexyl]methyl}-2-(trifluoromethyl)benzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-3,6-difluorobenzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2,4-dimethylbenzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-methylbenzamide;

4-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2,5-difluorobenzamide;

2-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-6-fluoro-3-methylbenzamide;

4-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-fluorobenzamide;

2,4-dichloro-N-{[1-(cyclopropylmethyl)-4-(ethylsulfonyl)cyclohexyl]methyl}benzamide;

N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-(1,1,2,2-tetrafluoroethoxy)benzamide;

3-chloro-biphenyl-4-carboxylic acid (4-cyclopropylmethanesulfonyl-1-cyclopropylmethyl-cyclohexylmethyl)-amide;

2,4-dichloro-N-(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)thio]cyclohexyl}ethyl)benzamide;

2,4-dichloro-N-(1-{1-(cyclopropylmethyl)-4[(cyclopropylmethyl)sulfonyl]cyclohexyl}ethyl) benzamide;

2-chloro-N-(1-{1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}ethyl)-4-(trifluoromethyl)benzamide;

2,4-dichloro-N-[1-(cyclopropyl-hydroxyl-methyl)-4-cyclopropylmethanesulfonyl-cyclohexylmethyl]-benzamide;

or a pharmaceutically acceptable salt thereof, or an enantiomer or disasteromer thereof.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an enantiomer or diasteromer thereof, and a pharmaceutically acceptable carrier.

11. A compound which is

or a pharmaceutically acceptable salt thereof.