Cyclohexanesulfonyl derivatives as GLYT1 inhibitors to treat schizophrenia
The present invention provides compounds of formula I: wherein R 1 is an alkyl, phenyl, heterocyclyl, cycloalkyl, alkoxy, ester, amino or amide group; R 2 is a phenyl, heterocyclyl, alkyl, cycloalkyl or cycloalkylalkyl group; R 3 is an alkyl, cycloalkyl, cycloalkylalkyl, amino or heterocyclyl group; R 4 and R 5 are hydrogen or alkyl or form a cycloalkyl ring; A is O or N; and m is zero or one; as inhibitors of GlyT1 and thus as useful for treating or preventing diseases such as schizophrenia; with the provision of pharmaceutical compositions, first and second medical uses and methods of treatment.
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) heterocycle substituted with R 2a , R 2b and R 2c ,
(4) C 3-6 cycloalkyl, which is unsubstituted or substituted with C 1-6 alkyl, 1-6 halogen, hydroxy or —NR 10 R 11 ,
(5) —O—C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(6) —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,
(7) —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
(8) —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) heterocycle, which is substituted with R 2a , R 2b and R 2c ,
(3) 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 ,
(4) C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 , and
(5) —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 ,
or two of R 2a , R 2b and R 2c are linked to form a
group wherein r is 1 to 3;
R 3 is selected from the group consisting of:
(1) C 1-6 alkyl, which is substituted with heterocycle, which is substituted with R 2a , R 2b and R 2c ,
and
(2) heterocycle, which is substituted with R 2a , R 2b and R 2c ;
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 1 , R 3 , R 4 are as defined in claim 1 and 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 Ie:
wherein n, R 2a , R 2b and R 2c are as defined in claim 1 ;
R 1b is a C 3-6 cycloalkyl, which is unsubstituted or substituted with C 1-6 alkyl, 1-6 halogen, hydroxy or —NR 10 R 11 ;
D and E are each independently CH or N, and
R 3a is an unsaturated heterocycle optionally substituted by a halogen or a C 1-6 alkyl or C 1-6 haloalkyl group.
4. A compound according to claim 1 wherein R 1 is C 3-6 cycloalkyl.
5. 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 .
6. A compound according to claim 1 wherein R 4 and R 5 are hydrogen.
7. A compound according to claim 1 wherein n is zero or one.
8. A compound according to claim 1 which is:
2,4-dichloro-N-({1-cyclopropylmethyl-4-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]cyclohexyl}methyl)benzamide;
2-chloro-N-({1-(cyclopropylmethyl)-4-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]cyclohexyl}methyl)-4-(trifluoromethyl)benzamide;
2,4-dichloro-N-({1-(1-hydroxy-1-methylethyl)-4-[(1-methyl-1H-1,2,3-triazol-4-yl)sulfonyl]cyclohexyl}methyl)benzamide;
2,4-dichloro-N-({1-(cyclopropylmethyl)-4-[(5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl]cyclohexyl}methyl)benzamide;
or a pharmaceutically acceptable salt thereof, or an enantiomer or disasteromer thereof.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof, and a pharmaceutically acceptable carrier.