Substituted spirocyclic piperidine derivatives as histamine-3 (h3) receptor ligands

Abstract

The present invention is directed to methods of treating disorders mediated by Histamine H 3 receptors by administering novel substituted spirocyclic piperidine derivatives according to Formula (I). In particular, the substituted spirocyclic piperidine derivatives may be effective in the treatment of diseases or disease states, including narcolepsy or sleep/wake disorders, feeding behavior disorders, eating disorders, obesity, cognition disorders, arousal disorders, memory disorders, mood disorders, mood attention alteration, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain, stress, migraine, motion sickness, depression, psychiatric disorders, epilepsy, gastrointestinal disorders, respiratory disorders, inflammation, and myocardial infarction.

What is claimed: 
     
         1 . A method for treating a disorder selected from the group consisting of narcolepsy or sleep/wake disorders, feeding behavior disorders, eating disorders, obesity, cognition disorders, arousal disorders, memory disorders, mood disorders, mood attention alteration, attention deficit hyperactivity disorder (ADHD), Alzheimer's disease/dementia, schizophrenia, pain, stress, migraine, motion sickness, depression, psychiatric disorders, epilepsy, gastrointestinal disorders, respiratory disorders, inflammation, and myocardial infarction, said method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  is C 3 -C 8  cycloalkyl; 
         W is —CH 2 —, —CH 2 CH 2 —, or —CH 2 —O—; 
         k is 0, 1, or 2; m is 0, 1, or 2; and the sum of m and k is 1, 2, or 3; 
         Y 2 ═Y 3  is —C(X)═CH— or —CH═C(X)—; 
         X is R 2 , —OR 2 , —(C 1 -C 3  alkyl)-R 2 , —O—(C 1 -C 3  alkyl)-R 2 , —NHR 2 , —NHC(═O)R 2 , or —NHC(═O)NHR 2 ; wherein said C 1 -C 3  alkyl is optionally substituted with —OH or C 1 -C 4  alkoxy; 
         R 2  is: 
       
       
         
           
           
               
               
           
         
         A is F, Cl, or Br; 
         R 3  is H, F, or C 1 -C 4  alkyl; 
         R 4  is H, F, or C 1 -C 4  alkyl; 
         R 4A  is H, F, Cl, Br, or C 1 -C 4  alkyl; 
         R 5  is H, F, or C 1 -C 4  alkyl; 
         R 5A  is H, F, Cl, Br, C 1 -C 4  alkyl or phenyl; 
         or, R 4  and R 5 , together with the carbon atoms to which they are attached, form a fused C 3 -C 6  cycloalkyl ring optionally substituted with 1, 2, or 3 R 14 ; 
         or, R 4A  and R 5A , together with the carbon atoms to which they are attached, form a fused phenyl ring optionally substituted with 1, 2, or 3 R 14 ; 
         a C 3 -C 6  cycloalkyl ring optionally substituted with 1, 2 or 3 R 14 ; 
         a 5 to 6 membered fused heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1, 2, or 3 R 14 ; or 
         a 5 to 6 membered fused heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, S, SO, and SO 2 , wherein said heterocycloalkyl ring system is optionally substituted with 1, 2, or 3 R 14 ; 
         R 6  is H, F, or C 1 -C 4  alkyl; 
         R 7  is H, F, Cl, Br, or C 1 -C 4  alkyl; 
         R 8  is H, —C(═O)R 27 , —CO 2 R 27 , C 1 -C 6  alkyl optionally substituted by 1-3 R 20 ; 
         C 3 -C 8  cycloalkyl optionally substituted by 1-3 R 20A ; 
         C 6 -C 10  aryl optionally substituted by 1-3 R 20A ; 
         C 7 -C 15  arylalkyl optionally substituted by 1-3 R 20A ; or 
         a 5 to 10 membered heteroaryl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heteroaryl ring system is optionally substituted with 1-3 R 20A ; 
         R 9 , at each occurrence, is independently F, Cl, Br, C 1 -C 4  alkyl, or C 1 -C 4  alkoxy; 
         R 10  is F, Cl, Br, C 1 -C 3  alkyl, or C 1 -C 3  alkoxy; 
         R 14  at each occurrence is independently F, Cl, Br, I, —OR 21 , —OR 22 , —NR 23 R 24 , —NHOH, —NO 2 , —CN, —CF 3 , (═O), —C(═O)R 21 , —CO 2 R 21 , —OC(═O)R 21 , —C(═O)NR 23 R 24 , —NR 27 C(═O)R 21 , —NR 27 C(═O)OR 21 , —OC(═O)NR 23 R 24 , —NR 27 C(═S)R 21 , —SR 21 , —S(O)R 21 , or —S(O) 2 R 21 ; C 1 -C 6  alkyl optionally substituted with OR 26 ; C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
         R 20  at each occurrence is independently F, Cl, Br, I, —OR 21 , —OR 22 , —NR 23 R 24 , —NHOH, —NO 2 , —CN, —CF 3 , (═O), —C(═O)R 21 , —CO 2 R 21 , —OC(═O)R 21 , —C(═O)NR 23 R 24 , —NR 27 C(═O)R 21 , —NR 27 C(═O)OR 21 , —OC(═O)NR 23 R 24 , —NR 27 C(═S)R 21 , —SR 21 , —S(O)R 21 , or —S(O) 2 R 21 ; C 1 -C 6  alkyl optionally substituted with OR 26 ; C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, phenyl, 3- to 7-membered heterocycloalkyl group, or 5- or 6-membered heteroaryl group; 
         R 20A  at each occurrence is independently F, Cl, Br, I, —OR 21 , —OR 22 , —NR 23 R 24 , —NHOH, —NO 2 , —CN, —CF 3 , (═O), —C(═O)R 21 , —CO 2 R 21 , —OC(═O)R 21 , —C(═O)NR 23 R 24 , —NR 27 C(═O)R 21 , —NR 27 C(═O)OR 21 , —OC(═O)NR 23 R 24 , —NR 27 C(═S)R 21 , —SR 21 , —S(O)R 21 , or —S(O) 2 R 21 ; C 1 -C 6  alkyl optionally substituted with OR 26 ; C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl; 
         R 21  at each occurrence is independently H, C 1 -C 6  alkyl, C 6 -C 10  aryl, or C 7 -C 15  arylalkyl; 
         R 22  at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; 
         R 23  and R 24  at each occurrence are independently selected from H, C 1 -C 6  alkyl, and C 6 -C 10  aryl; 
         or, R 23  and R 24 , together with the nitrogen atom to which they are attached, form a 3 to 7 membered heterocycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, and S, wherein said heterocycloalkyl ring system is optionally substituted with ═O; 
         R 26  is H or C 1 -C 6  alkyl; 
         R 27  is H or C 1 -C 6  alkyl; 
         n is 0, 1, 2, or 3; and 
         z is 0, 1, 2, 3, 4, 5, or 6. 
       
     
     
         2 . A method according to  claim 1  wherein the disorder is narcolepsy or sleep/wake disorders. 
     
     
         3 . A method according to  claim 1  wherein the disorder is attention deficit hyperactivity disorder. 
     
     
         4 . A method according to  claim 1  wherein the disorder is cognition disorder. 
     
     
         5 . A method according to  claim 1  wherein R 1  is C 3 -C 8  cycloalkyl. 
     
     
         6 . A method according to  claim 1  wherein W is —CH 2 — or —CH 2 —CH 2 —. 
     
     
         7 . A method according to  claim 1  wherein R 2  is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A method according to  claim 1  wherein R 4  and R 5 , together with the carbon atoms to which they are attached, form a fused cyclopropyl or cyclobutyl ring. 
     
     
         9 . A method according to  claim 1  wherein R 4A  and R 5A , together with the carbon atoms to which they are attached, form a fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. 
     
     
         10 . A method according to  claim 1  wherein k is 1. 
     
     
         11 . A method according to  claim 1  wherein m is 1. 
     
     
         12 . A method according to  claim 1  wherein the sum of m and k is 2. 
     
     
         13 . A method according to  claim 1  wherein Y 2 ═Y 3  is —C(X)═CH—. 
     
     
         14 . A method according to  claim 1  wherein X is R 2 . 
     
     
         15 . A method according to  claim 1  wherein X is —OR 2 . 
     
     
         16 . A method according to  claim 1  wherein R 8  is H. 
     
     
         17 . A method according to  claim 1  wherein R 8  is C 1 -C 6  alkyl optionally substituted by 1-3 R 20 . 
     
     
         18 . A method according to  claim 1  wherein R 9  is C 1 -C 4  alkyl. 
     
     
         19 . A method according to  claim 1  wherein n is 0. 
     
     
         20 . A method according to  claim 1  wherein n is 1. 
     
     
         21 . A method according to  claim 1  wherein z is 0. 
     
     
         22 . A method according to  claim 1  wherein the compound according to formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt thereof.