Substituted diazepan orexin receptor antagonists

Abstract

The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

1 . A compound of the formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is phenyl, which is substituted with R 1a , R 1b  and R 1c ; 
 R 2  is heteroaryl, which is substituted with R 2a , R 2b  and R 2c ; 
 R 1a , R 1b , R 1c , R 2a , R 2b  and R 2c  are independently selected from the group consisting of:
 (1) hydrogen, 
 (2) halogen, 
 (3) hydroxyl, 
 (4) —(C═O) m —O n —C 1-6 alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present), wherein adjacent R 2a  and R 2b  or R 2b  and R 2c  may be joined together to form a cycloalkyl or cycloalkoxy ring, and where the alkyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (5) —(C═O) m —O n —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (6) —(C═O) m —C 2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (7) —(C═O) m —C 2-4 alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (8) —(C═O) m —O n -phenyl or —(C═O) m —O n -napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (9) —(C═O) m —O n -heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (10) —(C═O) m —NR 10 R 11 , wherein R 10  and R 11  are independently selected from the group consisting of:
 (a) hydrogen, 
 (b) C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (c) C 3-6 alkenyl, which is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (d) cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (e) phenyl, which is unsubstituted or substituted with one or more substituents selected from R 13 , and 
 (f) heterocycle, which is unsubstituted or substituted with one or more substituents selected from R 13 , 
 
 (11) —S(O) 2 —NR 10 R 11 , 
 (12) —S(O) q —R 12 , where q is 0, 1 or 2 and where R 12  is selected from the definitions of R 10  and R 11 , 
 (13) —CO 2 H, 
 (14) —CN, 
 (15) —NO 2 , 
 (16) ═O, and 
 (17) —B(OH) 2 , 
 with proviso that at least one of R 2a , R 2b  or R 2c  is halogen or C 1-6 alkyl, or wherein adjacent R 2a  and R 2b  or R 2b  and R 2c  are joined together to form a cycloalkyl or cycloalkoxy ring, where the alkyl, cycloalkyl or cycloalkoxy is unsubstituted or substituted with one or more substituents selected from R 13 ; 
 
 R 3  is —C 1-6 alkyl or —C 3-6 cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R 13 ; 
 R 13  is selected from the group consisting of:
 (1) halogen, 
 (2) hydroxyl, 
 (3) —(C═O) m —O n —C 1-6 alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R 14 , 
 (4) —O n —(C 1-3 )perfluoroalkyl, 
 (5) —(C═O) m —O n —C 3-6 cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R 14 , 
 (6) —(C═O) m —C 2-4 alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R 14 , 
 (7) —(C═O) m —O n -phenyl or —(C═O) m —O n -napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R 14 , 
 (8) —(C═O) m —O n -heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R 14 , 
 (9) —(C═O) m —NR 10 R 11 , 
 (10) —S(O) 2 —NR 10 R 11 , 
 (11) —S(O) T R 12 , 
 (12) —CO 2 H, 
 (13) —CN, 
 (14) ═O, and 
 (15) —NO 2 ; 
 
 R 14  is selected from the group consisting of:
 (1) hydroxyl, 
 (2) halogen, 
 
 (3) C 1-6 alkyl,
 (4) —C 3-6 cycloalkyl, 
 (5) —O—C 1-6 alkyl, 
 (6) —O(C═O)—C 1-6 alkyl, 
 (7) —NH—C 1-6 alkyl, 
 (8) phenyl, 
 (9) heterocycle, 
 (10) —CO 2 H, and 
 (11) —CN; 
 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1  of the formula Ia: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound of  claim 1  of the formula Ie: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound of  claim 1  wherein R 1  is phenyl, which is unsubstituted or substituted with one or more of:
 (1) halogen, 
 (2) hydroxyl, 
 (3) —O n —C 1-6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (4) —O n -phenyl, where the phenyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (5) -heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (6) —NR 10 R 11 , wherein R 10  and R 11  are independently selected from the group consisting of:
 (a) hydrogen, 
 (b) C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R 13 , 
 
 (7) —S(O) 2 —NR 10 R 11 , 
 (8) —CO 2 H, 
 (9) —CN, 
 (10) —NO 2 , and 
 (11) —B(OH) 2 . 
 
     
     
         5 . The compound of  claim 4  wherein R 1  is phenyl, which is unsubstituted or substituted with one or more methyl, —CF 3 , halo, —OCF 3 , —OCH 3 , —OCH 2 CH 3 , —CO 2 CH 3 , —CN, —N(CH 3 ), —NH(CH 2 CH 3 ), —NO 2 , —B(OH) 2 , triazolyl or phenyl. 
     
     
         6 . The compound of  claim 5  wherein R 1  is phenyl, which is unsubstituted or substituted with one or more methyl or triazolyl. 
     
     
         7 . The compound of  claim 1  wherein R 2  is heteroaryl, which is unsubstituted or substituted with one or more of:
 (1) halogen, 
 (2) hydroxyl, 
 (3) —O n —C 1-6 alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (4) —O n -phenyl, where the phenyl is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (5) -heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R 13 , 
 (6) —NR 10 R 11 , wherein R 10  and R 11  are independently selected from the group consisting of:
 (a) hydrogen, 
 (b) C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from R 13 , 
 
 (7) —S(O) 2 —NR 10 R 11 , 
 (8) —CO 2 H, 
 (9) —CN, and 
 (10) —NO 2 , 
 with proviso that at least one of the substituents is halogen or C 1-6 alkyl, or wherein two adjacent substituents are joined together to form a cycloalkyl ring. 
 
     
     
         8 . The compound of  claim 7  wherein R 2  is selected from the group consisting of:
 (1) benzimidazolyl, 
 (2) benzothiazolyl, 
 (3) benzoxazolyl, 
 (4) cyclopentylpyrimidinyl, 
 (5) dihydrocyclopentapyrimidinyl, 
 (6) dihydroquinolinyl, 
 (7) furopyrimidinyl, 
 (8) pyrazolopyrimidinyl, 
 (9) pyridinyl, 
 (10) pyridopyrimidinyl, 
 (11) pyrimidinyl, 
 (12) quinazolinyl, 
 (13) quinolinyl, 
 (14) quinoxalinyl, 
 (15) tetrahydroquinazolinyl, 
 (16) thiadiazolyl, and 
 (17) thienopyrimidinyl, 
 which is substituted with halogen or C 1-6 alkyl, and optionally substituted with hydroxyl, —O—C 1-6 alkyl, keto, —NH 2 , or phenyl. 
 
     
     
         9 . The compound of  claim 8  wherein R 2  is selected from the group consisting of:
 (1) 1,3-benzoxazol-2-yl, 
 (2) 2-(6,7-dihydro-5H-cyclopenta[d]pyrimidin)-yl, 
 (3) 2-(7,8-dihydroquinolin-5(6H)-on)-yl, 
 (4) 2-(furo[2,3]pyrimidine)-yl, 
 (5) 2-(pyrazolo[3,4]pyrimidine)-yl, 
 (6) 2-pyridinyl, 
 (7) 2-(pyrido[2,3-d]pyrimidin-7(8H)-on)-yl, 
 (8) 2-pyrimidinyl, 
 (9) 2-quinazolinyl, 
 (10) 2-quinoxalinyl, 
 (11) 2-(5,6,7,8-tetrahydroquinazolin)-yl, 
 (12) 2-(thieno[2,3-d]pyrimidin)-yl, and 
 (13) 2-(thieno[2,3]pyrimidin-4-amine)-yl, 
 which is substituted with methyl, chloro or fluoro. 
 
     
     
         10 . The compound of  claim 1  wherein one of R 2a , R 2b  or R 2c  is halogen or C 1-6 alkyl, and the others of R 2a , R 2b  and R 2c  are hydrogen. 
     
     
         11 . The compound of  claim 1  wherein R 3  is —C 1-6 alkyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of:
 (1) halogen, 
 (2) hydroxyl, 
 (3) —C 1-6 alkyl, 
 (4) —(C 1-3 )perfluoroalkyl, 
 (5) —O—(C 1-3 )perfluoroalkyl, 
 (6) —C 3-6 cycloalkyl, and 
 (7) —C 2-4 alkenyl. 
 
     
     
         12 . The compound of  claim 11  wherein R 3  is —C 1-6 alkyl. 
     
     
         13 . The compound of  claim 12  wherein R 3  is methyl. 
     
     
         14 . A compound which is selected from the group consisting of:
 6-fluoro-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}quinazoline;   methyl 3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)benzoate;   3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)benzoic acid;   [3-{[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl]carbonyl}-4-(2H-1,2,3-triazol-2-yl)phenyl]methanol;   6,7-difluoro-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}quinoxaline;   5-methyl-2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;   2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazoline;   2-{(5R)-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopenta[d]pyrimidine;   2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-7,8-dihydroquinolin-5(6H)-one;   6-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}pyrido[2,3-d]pyrimidin-7(8H)-one;   5-methyl-2-(4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3]pyrimidin-4-amine;   5-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3]pyrimidine;   2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine;   (5R)-5-methyl-1-(5-methyl-4-propylpyrimidin-2-yl)-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;   (5R)-1-[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;   (5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1-[4-methyl-5-(trifluoromethyl)pyrimidin-2-yl]-1,4-diazepane;   (5R)-1-[4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;   2-methyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}pyridin-3-yl)methanol;   4-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;   5-methyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}thieno[2,3-d]pyrimidine;   2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-5,6,7,8-tetrahydroquinazoline;   2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-6,7-dihydro-5H-cyclopenta[d]pyrimidine;   5,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3-d]pyrimidine;   4-ethoxy-5,6-dimethyl-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}furo[2,3-d]pyrimidine;   1,3-dimethyl-6-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1H-pyrazolo[3,4-d]pyrimidine;   5-bromo-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzoxazole;   (5R)-5-methyl-1-[4-methyl-5-(trifluoromethyl)-pyrimidin-2-yl]-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;   (5R)-1-[4-methoxy-5-(trifluoromethyl)pyrimidin-2-yl]-5-methyl-4-[2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane;   
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . A pharmaceutical composition which comprises an inert carrier and a compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . A method for treating a disease or disorder in which orexin receptors are involved in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of the compound of  claim 1  or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 21  wherein the disease or disorder is selected from a sleep disorder, a sleep disturbance, decreased sleep maintenance, decreased quality of sleep, decreased REM sleep, decreased stage 2 sleep, increased fragmentation of sleep patterns, insomnia, decreased cognition, decreased memory retention, obesity, epilepsy, absence epilepsy, pain, neuropathic pain, Parkinson's disease, psychosis and schizophrenia.