Therapeutic 5-HT ligand compounds

Abstract

The present invention provides compounds of Formula (I): wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 have any of the values defined in the specification, as well as pharmaceutical compositions comprising the compounds. The invention also provides therapeutic methods as well as processes and intermediates useful for preparing compounds of Formula (I). The compounds are 5-HT ligands, and are useful for treating diseases whereas modulation of 5-HT activity is desired.

What is claimed is:  
     
         1 . A compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein Z is —CHR 9 —, —C(O)—, —O—, —S—, —S(O)—, —SO 2 —, —N(R 9 )—, —C(O)N(R 9 )—, or —N(R 9 )C(O)—; 
 l is 1 or 2;  
 m is 0, 1 or 2;  
 n is 1 or 2;  
 R 1  and R 2  are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl; provided that R 1  and R 2  are not both hydrogen;  
 R 3  is hydrogen or C 1-6 alkyl;  
 R 4 , R 5 , and R 9  are independently hydrogen, C 1-6 alkyl or arylC 1-6 alkylene;  
 R 6 , R 7 , and R 8  are independently hydrogen, fluoro, chloro, bromo, CF 3 , —OCF 3 , —N(R 10 ) 2 , C 1-6 alkyl, C 1-6 alkoxy, heteroaryl or aryl;  
 each R 10  is independently hydrogen, or —C 1-6 alkyl;  
 wherein any C 1-6 alkyl, C 1-6 alkylene, or C 1-6 alkoxy of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is optionally partially unsaturated;  
 wherein any heteroaryl or aryl is optionally substituted with one or two substituents independently selected from halo, —CF 3 , —OCF 3 , C 1-6 alkoxy, —N(R 10 ) 2 , and C 1-6 alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is hydrogen.  
     
     
         3 . The compound of  claim 1 , wherein R 1  is C 1-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl.  
     
     
         4 . The compound of  claim 1 , wherein R 1  is C 2-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl.  
     
     
         5 . The compound of  claim 1 , wherein R 1  is C 3-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl.  
     
     
         6 . The compound of  claim 1 , wherein R 1  is methyl, ethyl, propyl, isopropyl, or cyclopropylmethyl.  
     
     
         7 . The compound of  claim 1 , wherein R 1  is ethyl, propyl, isopropyl, or cyclopropylmethyl.  
     
     
         8 . The compound of  claim 1 , wherein R 1  is propyl, isopropyl, or cyclopropylmethyl.  
     
     
         9 . The compound of  claim 1 , wherein R 2  is hydrogen.  
     
     
         10 . The compound of  claim 1 , wherein R 2  is C 1-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl.  
     
     
         11 . The compound of  claim 1 , wherein R 2  is C 2-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl.  
     
     
         12 . The compound of  claim 1 , wherein R 2  is C 3-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl.  
     
     
         13 . The compound of  claim 1 , wherein R 2  is methyl, ethyl, propyl, isopropyl, or cyclopropylmethyl.  
     
     
         14 . The compound of  claim 1 , wherein R 2  is ethyl, propyl, isopropyl, or cyclopropylmethyl.  
     
     
         15 . The compound of  claim 1 , wherein R 2  is propyl, isopropyl, or cyclopropylmethyl.  
     
     
         16 . The compound of  claim 10 , wherein R 1  is hydrogen.  
     
     
         17 . The compound of  claim 1 , wherein R 1  is C 2-3 alkyl and R 2  is hydrogen, or C 2-6 alkyl.  
     
     
         18 . The compound of  claim 1 , wherein R 1  is hydrogen, or C 2-3 alkyl; and R 2  is C 2-6 alkyl.  
     
     
         19 . The compound of  claim 1 , wherein R 1  is C 2-3 alkyl and R 2  is C 2-6 alkyl.  
     
     
         20 . The compound of  claim 1 , wherein R 1  is ethyl or propyl and R 2  is ethyl, propyl or butyl.  
     
     
         21 . The compound of  claim 1 , wherein R 3  is hydrogen.  
     
     
         22 . The compound of  claim 1 , wherein R 3  is C 1-6 alkyl.  
     
     
         23 . The compound of  claim 23 , wherein; and R 3  is methyl, ethyl, propyl, or butyl.  
     
     
         24 . The compound of  claim 23 , wherein; and R 3  is methyl or ethyl.  
     
     
         25 . The compound of  claim 1 , wherein R 4  and R 5  are independently hydrogen, methyl, ethyl, propyl, butyl, 2-phenylethyl, or benzyl.  
     
     
         26 . The compound of  claim 25 , wherein R 4  and R 5  are independently hydrogen, methyl, ethyl, propyl, or benzyl.  
     
     
         27 . The compound of  claim 25 , wherein R 4  and R 5  are independently methyl, ethyl, or benzyl.  
     
     
         28 . The compound of  claim 1 , wherein R 6 , R 7 , or R 8  is phenyl optionally substituted with one or two substituents independently selected from halo, —CF 3 , —OCF 3 , C 1-6 alkoxy, —N(R 10 ) 2 , and C 1-6 alkyl.  
     
     
         29 . The compound of  claim 28 , wherein R 6 , R 7 , or R 8  is phenyl optionally substituted with one or two substituents independently selected from fluoro, chloro, bromo, —CF 3 , —OCF 3 , C 1-6 alkoxy and —N(R 10 ) 2 .  
     
     
         30 . The compound of  claim 28 , wherein R 6 , R 7 , or R 8  is phenyl optionally substituted with one or two substituents independently selected from fluoro, chloro, and bromo.  
     
     
         31 . The compound of  claim 28 , wherein R 6  is 2,4-dichlorophenyl or 2,6-difluorophenyl.  
     
     
         32 . The compound of  claim 28 , wherein R 7  is 2,4-dichlorophenyl or 2,6-difluorophenyl.  
     
     
         33 . The compound of  claim 28 , wherein R 8  is 2,4-dichlorophenyl or 2,6-difluorophenyl.  
     
     
         34 . The compound of  claim 1  which is 6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole; or a pharmaceutically acceptable salt thereof.  
     
     
         35 . The compound of  claim 1  which is 
 5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole;  
 5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole;  
 5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole;  
 5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole;  
 5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole;  
 5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole;  
 5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole; or  
 5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][[1,4]thiazino[2,3,4-hi]indole;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         36 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         37 . A compound of  claim 1  for use in medical diagnosis or therapy.  
     
     
         38 . The compound of  claim 37 , wherein the therapy is the treatment of a disease or disorder of the central nervous system.  
     
     
         39 . The compound of  claim 37 , wherein the therapy is the treatment of anxiety, obesity, depression, or a stress related disease.  
     
     
         40 . The use of a compound of  claim 1  to prepare a medicament for treating or preventing a disease or disorder of the central nervous system.  
     
     
         41 . The use of  claim 40 , wherein the disease or disorder of the central nervous system is anxiety, obesity, depression, or a stress related disease.  
     
     
         42 . A method for treating a disease or condition in a mammal in need thereof wherein the 5-HT receptor is implicated and modulation of 5-HT function is desired comprising administering a therapeutically effective amount of a compound of  claim 1  to the mammal.  
     
     
         43 . The method of  claim 42 , wherein the disease is anxiety, obesity, depression, or a stress related disease.  
     
     
         44 . A method for treating or preventing a disease or disorder of the central nervous system in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of  claim 1  to the mammal.  
     
     
         45 . A compound of Formula (II):  
       
         
           
           
               
               
           
         
       
       wherein Z is —CHR 9 —, —C(O)—, —O—, —S—, —S(O)—, —SO 2 —, —N(R 9 )—, —C(O)N(R 9 )—, or —N(R 9 )C(O)—; 
 l is 1 or 2;  
 m is 0, 1 or 2;  
 n is 1 or 2;  
 R 1  and R 2  are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or (C 3-6 cycloalkyl)C 1-6 alkyl; provided that R 1  and R 2  are not both hydrogen;  
 R 3  is —C(O)-aryl, —C(O)-heteroaryl, —C(O)—C 1-6 alkyl, —C(O)—C 1-6 haloalkyl, —C(O)O—C 1-6 alkyl, or —C(O)O—C 1-6 haloalkyl, where aryl or heteroaryl is optionally substituted with one or two halo, —CF 3 , —OCF 3 , C 1-6 alkoxy, —N(R 10 ) 2 , or —C 1-6 alkyl;  
 R 4 , R 5 , and R 9  are independently hydrogen, C 1-6 alkyl or arylC 1-6 alkylene;  
 R 6 , R 7 , and R 8  are independently hydrogen, fluoro, chloro, bromo, CF 3 , —OCF 3 , —N(R 10 ) 2 , C 1-6 alkyl, C 1-6 alkoxy, heteroaryl or aryl;  
 each R 10  is independently hydrogen, or —C 1-6 alkyl;  
 wherein any C 1-6 alkyl, C 1-6 alkylene, or C 1-6 alkoxy of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10  is optionally partially unsaturated;  
 wherein any heteroaryl or aryl is optionally substituted with one or two substituents independently selected from halo, —CF 3 , —OCF 3 , C 1-6 alkoxy, —N(R 10 ) 2 , and C 1-6 alkyl.  
 
     
     
         46 . The compound of  claim 45  which is 
 tert-Butyl 6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;  
 tert-butyl-5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydro[l,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;  
 tert-butyl-5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(H)-carboxylate;  
 tert-butyl-5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-.8(7H)-carboxylate;  
 tert-butyl-5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate;  
 tert-butyl-5-(2,4-dichlorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate;  
 tert-butyl-5-(2,6-difluorophenyl)-10a-methyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate;  
 tert-butyl-5-(2,4-dichlorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][l,4]thiazino[2,3,4-hi]indole-8(7H)-carboxlate; or  
 tert-butyl-5-(2,6-difluorophenyl)-10a-ethyl-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole.  
 
     
     
         47 . The compound of  claim 46 , which is tert-butyl 6b-methyl-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate.