Inhibitors of GLYT1 transporters
View Patent ↗A compound of the formula (I): wherein R 1 , R 2 , R 3 , R 4 , Ar, A, n and m are defined herein, is disclosed as a GlyT1 inhibitor; pharmaceutical compositions containing the compound of the formula (I) are also disclosed as are their use in medicine, for example in the treatment of schizophrenia.
1. A compound of the formula (Ia):
wherein
n is 0-6;
R 1b is a C 3-6 cycloalkyl, which is unsubstituted or substituted with R 2a , R 2b and R 2c ;
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 ;
R 3 is selected from the group consisting of:
(1) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, —NR 10 R 11 , or heterocycle, which is substituted with R 2a , R 2b and R 2c ,
(2) C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(3) —C 1-6 alkyl-(C 3-6 cycloalkyl), which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(4) —NR 10 R 11 , and
(5) heterocycle, which is substituted with R 2a , R 2b and R 2c ;
R 4 is selected from the group consisting of:
(1) hydrogen, and
(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxy;
R 9 is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) benzyl, and
(4) phenyl;
R 10 and R 11 are independently selected from:
(1) hydrogen,
(2) —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,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with hydroxy, 1-6 fluoro or —NR 12 R 13 ,
(4) benzyl,
(5) phenyl;
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;
or a pharmaceutically acceptable salt thereof.
2. A compound of the formula (Ib):
wherein
R 1c is a saturated heterocycle, which is unsubstituted or substituted with R 2a , R 2b and R 2c ;
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 ;
R 3 is selected from the group consisting of:
(1) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, —NR 10 R 11 , or heterocycle, which is substituted with R 2a , R 2b and R 2c ,
(2) C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(3) —C 1-6 alkyl-(C 3-6 cycloalkyl), which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(4) —NR 10 R 11 , and
(5) heterocycle, which is substituted with R 2a , R 2b and R 2c ;
R 4 is selected from the group consisting of:
(1) hydrogen, and
(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxy;
R 9 is independently selected from:
(1) hydrogen,
(2) —C 1-6 alkyl, which is unsubstituted or substituted with 1-6 fluoro,
(3) benzyl, and
(4) phenyl;
R 10 and R 11 are independently selected from:
(1) hydrogen,
(2) —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,
(3) —C 3-6 cycloalkyl, which is unsubstituted or substituted with hydroxy, 1-6 fluoro or —NR 12 R 13 ,
(4) benzyl,
(5) phenyl;
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;
or a pharmaceutically acceptable salt thereof.
3. A compound of the formula (Id):
wherein
B is CH or N;
R 2a , R 2b and R 2c are selected from hydrogen, fluoro, chloro, bromo, OCH 3 , CF 3 , OCF 3 and NH 2 ;
R 1 is —(CH 2 ) n —R 1a , wherein n is 0-6, and R 1a is selected from the group consisting of
(1) C 1-6 alkyl or C 1-6 alkenyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(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 3 is selected from the group consisting of:
(1) C 1-6 alkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy, —NR 10 R 11 , or heterocycle, which is substituted with R 2a , R 2b and R 2c ,
(2) C 3-6 cycloalkyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(3) —C 1-6 alkyl-(C 3-6 cycloalkyl), which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NR 10 R 11 ,
(4) —NR 10 R 11 , and
(5) heterocycle, which is substituted with R 2a , R 2b and R 2c ;
R 4 is selected from the group consisting of:
(1) hydrogen, and
(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxy;
with the proviso that when R 1 is methyl, R 3 is not methyl;
or a pharmaceutically acceptable salt thereof.
4. A compound of the formula (Ie):
wherein
n is 0-6;
B is CH or N;
R 2a , R 2b and R 2c are selected from hydrogen, fluoro, chloro, bromo, OCH 3 , CF 3 , OCF 3 and NH 2 ;
R 1c is a saturated heterocycle, which is unsubstituted or substituted with R 2a , R 2b and R 2c ; and
R 3a is an unsaturated heterocycle optionally substituted by a halogen or a C 1-6 alkyl or C 1-6 haloalkyl group;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4 wherein the unsaturated heterocycle R 3a is triazolyl, pyrazolyl and imidazolyl.
6. A compound of the formula (If):
R 1c is a saturated heterocycle, which is unsubstituted or substituted with R 2a , R 2b and R 2c ;
R 2a , R 2b and R 2c are selected from hydrogen, fluoro, chloro, bromo, OCH 3 , CF 3 , OCF 3 and NH 2 ;
n is 0-6; and
R 3b is a C 1-4 alkyl group optionally substituted by a cyclopropyl group.
7. The compound of claim 6 wherein R 3b is propyl or cyclopropylmethyl.
8. The compound of claim 3 wherein R 2a , R 2b and R 2c are selected from hydrogen, fluoro, chloro, bromo and CF 3 .
9. A pharmaceutical formulation which comprises a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
10. A pharmaceutical formulation which comprises a compound of claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
11. A pharmaceutical formulation which comprises a compound of claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.