IP Library › Granted Patent US 9,045,445

Granted Patent B2

US 9,045,445 · App. 13/151,992 · Granted Jun 2, 2015

Glycine transporter-1 inhibitors, methods of making them, and uses thereof

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Patent No.: US 9,045,445
App. No.: 13/151,992
Granted: Jun 2, 2015
Kind: B2

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Abstract

The compounds of the present invention are represented by the following formula (I): wherein the substituents R 1 , R 2 , R 3 , R 4 , (R 5 ) m , R 6 , A, X, and Y are as defined herein. The compounds are useful in methods of treating a disorder which is created by or is dependent upon inhibiting GlyT-1.

Claims (182)

1. A compound of the formula (I):

wherein:

R 1 is phenyl independently substituted from 1 to 5 times with halogen, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, OR 9 , or SR 10 , wherein C 1 -C 3 alkyl and C 3 -C 6 cycloalkyl are optionally substituted with 1 to 10 times with R 7 ;

R 2 is H;

R 3 and R 4 are each individually H or CH 3 ;

R 5 is selected from the group consisting of:

(1) hydrogen,

(2) C 1 -C 6 alkyl which is optionally substituted from 1 to 11 times with R 7 ,

(3) gem-dialkyl, and

(4) gem-dihalo; or

two R 5 substituents on the same carbon, together with the carbon atom to which they are attached, may form a 3-, 4-, or 5-membered cycloalkyl optionally substituted from 1 to 10 times with R 7 ; or

two R 5 substituents on adjacent carbons of the ring to which they are attached, together may form a 3-, 4-, 5- or 6-membered cycloalkyl optionally substituted from 1 to 10 times with R 7 ;

R 6 is

wherein E, F, and G are each independently nitrogen or carbon and R 6a is C 1 -C 2 alkyl, which is optionally substituted 1 to 5 times with halogen or deuterium;

R 7 is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) deuterium,

(4) gem-dialkyl,

(5) gem-dihalo,

(6) —OR 9 , —NR 11 R 12 , —NR 11 C(O) p R 10 , —S(O) p R 10 , —CN, —NO 2 , —C(O) p R 10 , — C(O)NR 11 R 12 , or —NR 11 C(S)R 10 , and

(7) oxo or thio;

R 8 is selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, or C 4 -C 7 cycloalkylalkyl, wherein each of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is independently and optionally substituted from 1 to 11 times with R 7 , or

(4) —OR 9 , —NR 11 R 12 , —NR 11 C(O) p R 10 , —S(O) p R 10 , —CN, —NO 2 , —C(O) p R 10 , —C(O)NR 11 R 12 , or —NR 11 C(S)R 10 ;

R 9 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)NR 11 R 12 , and —C(O) p R 10 , wherein each of C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 11 times with R 7 ;

R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl C 4 -C 7 cycloalkylalkyl, aryl, and heteroaryl, wherein each of C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 11 times with substituents as defined in R 7 and aryl or heteroaryl is optionally substituted from 1 to 10 times with R 8 ;

R 11 and R 12 are each independently selected from the group consisting hydrogen, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 4 -C 7 cycloalkylalkyl, aryl, and heteroaryl, wherein each of C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, and C 4 -C 7 cycloalkylalkyl is optionally substituted from 1 to 11 times with substituents as defined in R 7 and aryl or heteroaryl is optionally substituted from 1 to 10 times with R 8 , or

R 11 and R 12 are taken together with the nitrogen to which they are attached to form a saturated or partially saturated monocyclic or fused bicyclic heterocycle optionally substituted from 1 to 11 times with R 7 ;

A is

X is N;

Y is N;

p is 1, or 2; and

m is 0;

with the following provisos that: R 6 cannot be (a) 1H-1,2,3-triazol-4-yl, or (b) 5-methylisoxazol-4-yl;

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

2. The compound according to claim 1 , wherein:

R 1 is phenyl, independently substituted at the 2-, 2,4-, 2,6-, 2,4,6-, 2,3-, 2,5-, 2,3,4-, 2,3,5-, 2,3,6-, or 2,5,6-positions with F, Cl, Br, CH 3 , CF 3 , OCH 3 , CF 2 H, SCH 3 , NH 2 , OCF 3 , or OCF 2 H.

3. The compound according to claim 1 , wherein:

R 6 is

4. The compound according to claim 1 , wherein

A is

and

R 6 is

wherein R 6a is CH 3 , CF 2 H, or CD 3 .

5. The compound according to claim 1 , wherein the compound is selected from the group consisting of:

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)benzamide;

N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-(trifluoromethoxy)benzamide;

N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,4-difluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,6-difluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,6-dimethylbenzamide;

4-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-fluorobenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-fluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,4,6-trifluorobenzamide;

4-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-methylbenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-fluoro-2-(trifluoromethyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-fluoro-4-(trifluoromethyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-chloro-4-(trifluoromethyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-fluoro-6-(trifluoromethyl)benzamide;

2-Chloro-N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-6-methoxybenzamide;

2,6-Dichloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-fluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-(trifluoromethyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-methoxybenzamide;

2,4-Dichloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)benzamide;

N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-methylbenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-6-fluorobenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-6-methylbenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-fluoro-6-methylbenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-(difluoromethoxy)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-fluoro-2-methylbenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-6-(trifluoromethyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-fluoro-6-(trifluoromethoxy)benzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-6-(trifluoromethoxy)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-(difluoromethoxy)-6-fluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,6-difluorobenzamide;

2,6-Dichloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)benzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-6-(trifluoromethoxy)benzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-fluorobenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-(trifluoromethyl)benzamide;

N-(1-(4,4-Difluoro-1-(4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)ethyl)-2,6-difluorobenzamide;

2-Chloro-N-(1-(4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)ethyl)-4-fluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,4-bis(trifluoromethyl)benzamide;

2-Chloro-N-(1-(4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)ethyl)-4-(trifluoromethyl)benzamide;

N-(1-(4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)ethyl)-2,4-bis(trifluoromethyl)benzamide;

2,4-Dichloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,4-difluorobenzamide;

4-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,6-difluorobenzamide;

2,4-Dichloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-5-fluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2-fluoro-4-(trifluoromethyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-fluoro-2-(trifluoromethyl)benzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,4,6-trifluorobenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4,5-difluorobenzamide;

2-Chloro-N-((1-(4-(1-(difluoromethyl)-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)-4,4-difluorocyclohexyl)methyl)-4-(trifluoromethyl)benzamide;

4-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,5-difluorobenzamide;

N-((4,4-Difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-2,5-difluoro-4-methylbenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-(tris-deutero)methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-(trifluoromethyl)benzamide;

2,4-Dichloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-6-fluorobenzamide;

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-3-fluoro-4-methylbenzamide;

N-((4,4-Difluoro-1-(1-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperidin-4-yl)cyclohexyl)methyl)-2,4-bis(trifluoromethyl)benzamide; and

2-Chloro-N-((4,4-difluoro-1-(4-(1-methyl-1H-1,2,4-triazol-3-ylsulfonyl)piperazin-1-yl)cyclohexyl)methyl)-4-(trifluoromethyl)benzamide.

6. The compound according to claim 1 , wherein the compound is selected from the group consisting of: