Tricyclic Derivatives and Their Pharmaceutical Use and Compositions

Abstract

This application relates to tricyclic compounds of Formula I: including all stereoisomeric forms, all mixtures of stereoisomeric forms, and salts of these compounds. This application also relates to compositions comprising compounds of Formula I, stereoisomeric forms, all mixtures of stereoisomeric forms, and salts thereof and uses therefor.

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein:
 R 1  at each occurrence is independently selected from CN, NO 2 , NR 5 R 6 , COR 5 , CO 2 R 5 , CONR 5 , (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl(C 1 -C 6 )haloalkoxy, (C 3 -C 10 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 10 )cycloalkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryloxy, (C 1 -C 6 )alkoxy(C 6 -C 10 )aryl, (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heterocycloalkyloxy, (C 1 -C 6 )alkoxy(C 2 -C 9 )heterocyclo-alkyl, (C 1 -C 6 )alkyl(C 2 -C 9 )heterocycloalkyl, (C 5 -C 9 )heteroaryl, (C 5 -C 9 )heteroaryloxy, (C 1 -C 6 )alkoxy(C 5 -C 9 )heteroaryl, and (C 1 -C 6 )alkyl(C 5 -C 9 )heteroaryl, and p is 1 or 2; 
 R 2  at each occurrence is H, and q is 0; 
 R 3  is selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )hydroxyalkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkyl(C 1 -C 6 )alkoxy, CO(C 1 -C 6 )alkyl, CO 2 (C 1 -C 6 )alkyl, SO 2 (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 6 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )alkyl(C 2 -C 9 )heterocycloalkyl; 
 Y is CH 2  or O; 
 X is absent; 
 R 5  and R 6  at every occurrence are each independently selected from H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 6 -C 10 )aryl, (C 1 -C 6 )alkyl(C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 1 -C 6 )alkyl(C 2 -C 9 )heterocycloalkyl, (C 5 -C 9 )heteroaryl, and (C 1 -C 6 )alkyl(C 5 -C 9 )heteroaryl; 
 m is 1 or 2; and 
 Z is selected from phenyl, naphthyl and pyridyl, wherein any of the foregoing is optionally substituted with one or more substituents selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, O(C 1 -C 6 )haloalkyl, CONH(C 1 -C 6 )alkyl, and CON((C 1 -C 6 )alkyl) 2 . 
 
       
     
     
         2 . A compound according to  claim 1  having the structure of Formula II: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         3 . A compound according to  claim 2  or a salt thereof, wherein:
 Z is phenyl, optionally substituted with one or more substituents selected from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, O(C 1 -C 6 )haloalkyl, CONH(C 1 -C 6 )alkyl, and CON((C 1 -C 6 )alkyl) 2 . 
 
     
     
         4 . A compound according to  claim 2  or a salt thereof, wherein p is 1. 
     
     
         5 . A compound according to  claim 3  or a salt thereof, wherein m is 2. 
     
     
         6 . A compound according to  claim 1  having the structure of Formula III: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         7 . A compound according to  claim 6  or a salt thereof, wherein p is 1. 
     
     
         8 . A compound according to  claim 7  or a salt thereof, wherein m is 2. 
     
     
         9 . A compound according to  claim 1  having the structure of Formula IV: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         10 . A compound according to  claim 9  or a salt thereof, wherein p is 1. 
     
     
         11 . A compound according to  claim 10  or a salt thereof, wherein m is 2. 
     
     
         12 . A compound according to  claim 1  having the structure of Formula V: 
       
         
           
           
               
               
           
         
         or a salt thereof. 
       
     
     
         13 . A compound according to  claim 12  or a salt thereof, wherein p is 1. 
     
     
         14 . A compound according to  claim 13  or a salt thereof, wherein m is 2. 
     
     
         15 . A composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         16 . A method of treating a condition, disorder or disease comprising administering a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the condition, disorder or disease to be treated is selected from memory disorders, anxiety, epilepsy, migraine, panic attacks, depression, bipolar disorder, obsessive compulsive disorders, cognition/cognitive disorders, mild cognitive impairment (MCI), senile dementia, psychosis, schizophrenia, ADHD/ADD; pain including neuropathic pain and chronic pain; head trauma or injury; Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis; addiction and/or withdrawal from substances such as narcotics, ethanol (alcoholism), nicotine, and/or benzodiazepines; sleep/wakefulness disorders; or for the treatment of gastrointestinal (GI) conditions, disorders or diseases such as irritable bowel syndrome (IBS), functional bowel disorder; or for the treatment of conditions, disorders or diseases related to feeding behaviors or food intake such as anorexia, cachexia, and obesity. 
     
     
         17 . A method according to  claim 16  wherein the condition, disorder or disease to be treated is selected from ADHD/ADD, mild cognitive impairment (MCI), or sleep/wakefulness disorder. 
     
     
         18 . A method according to  claim 16 , wherein the condition, disorder or disease to be treated is selected from Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) or multiple sclerosis. 
     
     
         19 . A method of improving cognition or memory in a subject comprising administering a compound according to  claim 1  or a pharmaceutically acceptable salt thereof.