Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives

Abstract

The present invention provides cycloalkylfused indole, benzothiophene, benzofuran, and indene derivatives, and methods for using them to, for example, treat, prevent and/or ameliorate central nervous system diseases by antagonizing 5-HT 1A receptors and modulating serotonin levels.

1 . A compound of formula I:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof; 
 wherein:  
 R 1 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, OR 9 , trifluoromethoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, or phenyl;  
 W is N, NR 6 , or CR 6 ;  
 R 6  is hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, OR 9 , trifluoromethoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, or phenyl;  
 R 2  is hydrogen, alkyl, cycloalkyl, CH 2 cycloalkyl, or benzyl;  
 X and Y are independently hydrogen, halo, hydroxy, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, phenyl, X and Y together with the atoms to which they are attached, form —N═C(R 7 )C(R 8 )═N—, —N═C(R 7 )C(R 9 )═CH—, —N═C(R 7 )N═C(R 9 )—, —CH═C(R 7 )C(R 9 )═CH—, —N═C(R 10 )O—, —NH—C(R 11 )═CH—, NH—C(R 17 )O—, ═N—O—C(R 18 )═, —NH—N—C(R 13 )—, —NH—(CR 17 )═N—, —NH—C(R 10 )═CH—, —O—C(═O)C(R 9 )—, —O—C(R 7 )C(R 9 )—, —O—C(═O)—NR 9 —, —O—C(R 9 )═CH—, —O—N═C(R 9 )—, or —O—C(R 9 )═N;  
 R 7  and R 8  are independently hydrogen, halo, amino, monoalkylamino, dialkylamino, or alkyl;  
 R 9  is hydrogen or alkyl;  
 R 10  is hydrogen, halo, trifluoromethyl, pentafluoroethyl, amino, monoalkylamino, dialkylamino, alkoxy, or alkyl;  
 R 11  is hydrogen, halo, trifluoromethyl, pentafluoroethyl, or alkyl;  
 Z is N(R 12 ), O, S, or C(R 13 R 14 );  
 R 12 , R 13  and R 14  are independently hydrogen or alkyl;  
 R 15  and R 16  are independently at each occurrence, H or C 1 -C 3  alkyl;  
 R 17  is hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, or alkanesulfonamido;  
 R 18  is hydrogen, carboxy, cyano, carboxamido, carboalkoxy, trifluoromethyl, amino, monoalkylamino, dialkylamino, monoalkylamino, dialkylamino, alkoxy, or alkyl;  
 Q is O, S, or CH 2 ;  
 a dotted line represents an optional double bond; and  
 n and m are independently integers of 0, 1, 2 or 3.  
 
     
     
         2 . A compound according to  claim 1  wherein R 1  is hydrogen.  
     
     
         3 . A compound according to  claim 1  wherein R 2  is hydrogen, methyl, ethyl, propyl, isobutyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, or cyclohexyl.  
     
     
         4 . A compound according to  claim 1  wherein R 3 , R 4 , and R 5  are independently hydrogen, fluoro, chloro, trifluoromethoxy, or cyano.  
     
     
         5 . A compound according to  claim 1  wherein R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , and R 14  are independently hydrogen or methyl.  
     
     
         6 . A compound according to  claim 1  wherein X and Y together with the atoms to which they are attached form —N═C(R 7 )C(R 5 )═CH—, N═C(R 7 )N═C(R 9 )—, or —NH—C(R 11 )═CH—.  
     
     
         7 . A compound according to  claim 1  wherein Z is NR 12  or S and R 12  is hydrogen or methyl.  
     
     
         8 . A compound according to  claim 1  wherein Q is O or CH 2 .  
     
     
         9 . A compound according to  claim 1 , wherein W is CR 6  and R 6  is hydrogen, fluoro, chloro, trifluoromethoxy, or cyano.  
     
     
         10 . A compound according to  claim 1  wherein n is 1 or 2.  
     
     
         11 . A compound according to  claim 1  wherein m is 1 or 2.  
     
     
         12 . A composition comprising at least one compound of  claim 1  and one or more pharmaceutically acceptable carriers.  
     
     
         13 . A compound of formula II:  
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof;  
         wherein:  
         R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, OR 9 , trifluoromethoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, or phenyl;  
         W is N, NR 6  or CR 6 ;  
         R 6  is hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, OR 9 , trifluoromethoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, or phenyl;  
         R 9  is hydrogen or alkyl;  
         Z is N(R 12 ), O, S, or C(R 13 R 14 );  
         R 12 , R 13  and R 14  are independently hydrogen or alkyl;  
         R 15  and R 16  are independently at each occurrence, H or C 1 -C 3  alkyl;  
         R 19  is —C(═O)—O—C 2 H 5 , —C(═O)—OH, —C(═O)—NH 2 , —(CH 2 ) p —NH 2 , —C(═O)H, —C(≡N), —OH, ═O, or ═N—OH;  
         n, m, and p are independently integers of 0, 1, 2, or 3.  
       
     
     
         14 . The compound of  claim 13 , wherein R 19  is —(CH 2 ) p —NH 2 .  
     
     
         15 . The compound of  claim 13  which is one of the following: 
 (1,2,3,4-tetrahydrodibenzo[b,d]thien-2-ylmethyl)amine;    2-(6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-ethylamine;    C-(6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-methylamine;    {[(3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]methyl}amine;    C-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-methylamine;    C-(7-Chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-methylamine;    C-(5-chloro-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-methylamine;    C-(6,7-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-methylamine;    C-(5,6-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-methylamine;    (3S)-6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid;    (3S)-6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide; or 
 a pharmaceutically acceptable salt thereof.  
   
     
     
         16 . A process for preparing a compound of formula I:  
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof; 
 wherein:  
 
         R 1 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, OR 9 , trifluoromethoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, or phenyl;  
         W is N, NR 6 , or CR 6 ;  
         R 6  is hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, OR 9 , trifluoromethoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, or phenyl;  
         R 2  is hydrogen, alkyl, cycloalkyl, CH 2 cycloalkyl, or benzyl;  
         X and Y are independently hydrogen, halo, hydroxy, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, alkoxy, alkanoyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, alkanesulfonyl, alkanesulfonamido, phenyl, X and Y together with the atoms to which they are attached, form —N═C(R 7 )C(R 8 )═N—, —N═C(R 7 )C(R 9 )═CH—, —N═C(R 7 )N═C(R 9 )—, —CH═C(R 7 )C(R 9 )═CH—, —N═C(R 10 )O—, —NH—C(R 11 )═CH—, NH—C(R 17 )O—, ═N—O—C(R 18 )═, —NH—N—C(R 18 )—, —NH—(CR 17 )═N—, —NH—C(R 10 )═CH—, —O—C(═O)C(R 9 )—, —O—C(R 7 )C(R 9 )—, —O—C(═O)—NR 9 —, —O—C(R 9 )═CH—, —O—N═C(R 9 )—, or —O—C(R 9 )═N;  
         R 7  and R 8  are independently hydrogen, halo, amino, monoalkylamino, dialkylamino, or alkyl;  
         R 9  is hydrogen or alkyl;  
         R 10  is hydrogen, halo, trifluoromethyl, pentafluoroethyl, amino, monoalkylamino, dialkylamino, alkoxy or alkyl;  
         R 11  is hydrogen, halo, trifluoromethyl, pentafluoroethyl, or alkyl;  
         Z is N(R 12 ), O, S, or C(R 13 R 14 );  
         R 12 , R 13  and R 14  are independently hydrogen or alkyl;  
         R 15  and R 16  are independently at each occurrence, H or C 1 -C 3  alkyl;  
         R 17  is hydrogen, halo, cyano, carboxamido, carboalkoxy, trifluoromethyl, alkyl, alkanoyloxy, amino, monoalkylamino, dialkylamino, alkanamido, or alkanesulfonamido;  
         R 18  is hydrogen, carboxy, cyano, carboxamido, carboalkoxy, trifluoromethyl, amino, monoalkylamino, dialkylamino, monoalkylamino, dialkylamino, alkoxy, or alkyl;  
         Q is O, S, or CH 2 ;  
         a dotted line represents an optional double bond; and  
         n and m are independently integers of 0, 1, 2 or 3;  
         comprising:  
         condensing a compound of formula III:  
         
           
             
             
                 
                 
             
           
         
         with a compound of formula A:  
         
           
             
             
                 
                 
             
           
         
         wherein the variables are as defined in  claim 1 , to produce a compound of formula I.  
       
     
     
         17 . The process of  claim 16 , wherein 
 the compound of formula I is S,S-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylmethyl)-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine;    the compound of formula III is {[(3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]methyl}amine; and    the compound of formula A is [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate.    
     
     
         18 . The process of  claim 16 , in which the compound of formula III is prepared by a process comprising: 
 reducing a compound of formula IV:                           where p is 0, 1, or 2,    with lithium aluminum hydride in the presence of tetrahydrofuran.    
     
     
         19 . The process of  claim 18 , wherein the compound of formula IV is (3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide.  
     
     
         20 . The process of  claim 16 , in which the compound of formula IV is prepared by a process comprising: 
 reacting a compound of formula V:                          with 
 i) methylene chloride and oxalyl chloride; and  
 ii) acetone and ammonia.  
   
     
     
         21 . The process of  claim 20 , wherein the compound of formula V is (3S)-6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid.  
     
     
         22 . The process of  claim 20 , in which the compound of formula V is prepared by a process comprising: 
 a. combining racemic compound of formula VI:                        with acetonitrile and a first optically active base to form a first solution;      b. incubating said first solution for a first period of time to form first crystals;    c. separating said first crystals from the mother liquor;    d. combining said mother liquor with a second optically active base to form a second solution;    e. incubating said second solution for a second period of time to form second crystals, wherein said second crystals; and    f. converting said second crystals to a compound of formula V.    
     
     
         23 . The process of  claim 22 , wherein the compound of formula VI is 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid.  
     
     
         24 . The process of  claim 22 , wherein said first optically active base is (−)-cinchonidine.  
     
     
         25 . The process of  claim 22 , wherein said second optically active base is (+)-pseudoephedrine.  
     
     
         26 . The process of  claim 22 , in which the compound of formula VI is prepared by a process comprising: 
 hydrolyzing a compound of formula VII:                          in an alcohol and base.    
     
     
         27 . The process of  claim 26 , wherein the compound of formula VII is 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ethyl ester.  
     
     
         28 . The process of  claim 26 , in which the compound of formula VII is prepared by a process comprising: 
 refluxing a compound of formula VIII:                          and compound of formula IX:                          in an alcohol.