Quinoline compounds suitable for treating disorders that respond to the modulation of the serotonin 5-ht6 receptor

Abstract

The present invention relates to quinoline compounds of formula I wherein the variables are defined as in the claims and the description. The invention further relates to a pharmaceutical composition containing such compounds, to their use as modulators of the 5-HT 6 receptor, their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of the 5-HT 6 receptor, and to methods for preventing or treating conditions and disorders which respond to the modulation of the 5-HT 6 receptor.

1 .- 23 . (canceled) 
     
     
         24 . A method for treating disorders which respond to the modulation of the 5-HT 6  receptor, which method comprises administering to a subject in need thereof at least one compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of a ring R a , halogen, C 1 -C 2 -haloalkyl, C 1 -C 2 -alkoxy, C 1 -C 2 -haloalkoxy, an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclic ring containing one or two nitrogen atoms as ring members; and an N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic ring containing one or two nitrogen atoms as ring members; where the heteromonocyclic ring and the heterobicyclic ring may carry one or more substituents R 4 ; 
         R 2  is selected from the group consisting of a phenyl ring, a naphthyl ring, a 5- or 6-membered monocyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, and a 9- or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S as ring members, where the phenyl, the naphthyl and the monocyclic or bicyclic heteroaromatic ring may carry one ring R a  and/or one or more substituents R 5 ;
 with the proviso that R 1  is R a  if the ring R 2  is not substituted by R a ; 
 
         each R 3  is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, formyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl and di-(C 1 -C 6 -alkyl)-aminocarbonyl; 
         each R 4  is independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl and oxo; 
         each R 5  is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, formyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, carboxyl, carboxyl-C 1 -C 2 -alkyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, amino, C 1 -C 6 -alkylamino, di-(C 1 -C 6 -alkyl)-amino, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, di-(C 1 -C 6 -alkyl)-aminocarbonyl, phenyl which may carry one or more substituents R 6 ; and a 3-, 4-, 5-, 6-, 7- or 8-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring containing 1, 2 or 3 heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, S(O) and S(O) 2  as ring members, where the heterocyclic ring may carry one or more substituents R 7 ; 
         each R 6  is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, formyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, carboxyl, carboxyl-C 1 -C 2 -alkyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, amino, C 1 -C 6 -alkylamino, di-(C 1 -C 6 -alkyl)-amino, and —C(O)N(R 8 )R 9 ; 
         each R 7  is independently selected from the group consisting of halogen, cyano, nitro, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, formyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -haloalkoxycarbonyl, amino, C 1 -C 6 -alkylamino and di-(C 1 -C 6 -alkyl)-amino; 
         R 8  and R 9 , independently of each other and independently of each occurrence, are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 6 -halocycloalkyl-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, phenyl and benzyl; or R 8  and R 9 , together with the nitrogen atom they are bound to, form a 3-, 4-, 5-, 6-7- or 8-membered saturated heterocyclic ring which may contain 1, 2 or 3 additional heteroatoms or heteroatom groups selected from the group consisting of N, O, S, NO, S(O) and S(O) 2  where the ring may carry 1, 2 or 3 substituents selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -halocycloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -haloalkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -haloalkylsulfinyl, C 1 -C 6 -alkylsulfonyl, C 1 -C 6 -haloalkylsulfonyl, formyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -haloalkylcarbonyl, carboxyl, C 1 -C 6 -alkoxycarbonyl and C 1 -C 6 -haloalkoxycarbonyl; 
         L is S(O) 2 , CH 2 —S(O) 2 , S(O) 2 —CH 2 , C(O)—NH, NH—C(O), NH—S(O) 2  or S(O) 2 —NH; 
         R a  is an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclic ring containing one nitrogen atom as ring member; or an N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic ring containing one nitrogen atom as ring member, where the heteromonocyclic or heterobicyclic ring carries 1, 2 or 3 substituents R b  and optionally 1 or 2 further substituents R 4 ; 
         R b  is an oxygen-containing radical independently selected from the group consisting of hydroxyl, C 1 -C 4 -alkoxy, —C(O)OH, —CH 2 —C(O)OH and —C(O)N(R 8 )R 9 ; and 
         m is 0, 1 or 2; 
       
       or an N-oxide, a tautomeric form, a stereoisomer or a pharmaceutically acceptable salt thereof. 
     
     
         25 . The method as claimed in  claim 24 , where the disorders are selected from the group consisting of diseases of the central nervous system, addiction and obesity. 
     
     
         26 . The method as claimed in  claim 25 , where the disease of the central nervous system is a cognitive dysfunction. 
     
     
         27 . The method as claimed in  claim 26 , where the cognitive dysfunction is associated with Alzheimer's disease. 
     
     
         28 . The method as claimed in  claim 26 , where the cognitive dysfunction is associated with schizophrenia. 
     
     
         29 . The method as claimed in  claim 24 , R 1  is R a , where R a  is an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclic ring containing one nitrogen atom as ring member, where the heteromonocyclic ring carries 1, 2 or 3 substituents R b  and optionally 1 or 2 further substituents R 4 . 
     
     
         30 . The method as claimed in  claim 24 , R 1  is R a , where R a  is an N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic ring containing one nitrogen atom as ring member, where the heterobicyclic ring carries 1, 2 or 3 substituents R b  and optionally 1 or 2 further substituents R 4 . 
     
     
         31 . The method as claimed in  claim 24 , where R 1  is halogen; and the phenyl, naphthyl, monocyclic or bicyclic heteroaromatic ring R 2  carries one substituent R a  and optionally also one or more substituents R 5    
     
     
         32 . The method as claimed in  claim 24 , where R 1  is an N-bound saturated 3-, 4-, 5-, 6-, 7- or 8-membered heteromonocyclic ring containing one or two nitrogen atoms as ring members; or an N-bound saturated 7-, 8-, 9-, 10-, 11- or 12-membered heterobicyclic ring containing one or two nitrogen atoms as ring members; where the heteromonocyclic ring and the heterobicyclic ring may carry one or more substituents R 4 ; and the phenyl, naphthyl, monocyclic or bicyclic heteroaromatic ring R 2  carries one substituent R a  and optionally also one or more substituents R 5 . 
     
     
         33 . The method as claimed in  claim 24 , where the oxygen-containing radical R b  is selected from the group consisting of hydroxyl (—OH), carboxyl (—C(O)OH), —CH 2 —C(O)OH and —C(O)NH 2    
     
     
         34 . The method as claimed in  claim 24 , where L is S(O) 2 . 
     
     
         35 . The method as claimed in  claim 24 , where R 2  is optionally substituted phenyl. 
     
     
         36 . The method as claimed in  claim 24 , where m is 0. 
     
     
         37 . The method of  claim 24 , where the compound of formula (I) is a compound of formula (I.1) 
       
         
           
           
               
               
           
         
       
     
     
         38 . The method of  claim 37 , where
 R 1  is R a , which is in turn an N-bound saturated heterocyclic ring selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl and piperidine-1-yl, where the ring carries one or two substituents R b ; and carries optionally one or two substituents R 4 ; and   R 2  is phenyl which may be substituted by 1 or 2 substituents selected from the group consisting of halogen, cyano, hydroxyl, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, COOH, CONH 2  and an N-bound saturated heterocyclic ring selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, piperidine-1-yl and piperazin-1-yl, where the heterocyclic ring carries one or two substituents selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, OH and COOH.   
     
     
         39 . A method for treating disorders which respond to the modulation of the 5-HT 6  receptor, which method comprises administering to a subject in need thereof at least one compound selected from the group consisting of
 1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-4-ol;   1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-pyrrolidin-3-ol;   1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-4-carboxylic acid;   (S)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-ol;   (R)-1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidin-3-ol;   1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylic acid;   4-Methyl-1-[3-[3-(trifluoromethyl)phenyl]sulfonyl-8-quinolyl]piperidin-4-ol;   1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidin-3-ol;   1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-4-ol;   1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]azetidin-3-ol;   (3S)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylic acid;   (3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidine-3-carboxylic acid;   1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol;   1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol;   1-[3-(3-Methoxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-[[8-(4-Hydroxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidin-4-ol;   1-[3-[[8-(4-Carboxy-1-piperidyl)-3-quinolyl]sulfonyl]phenyl]piperidine-4-carboxylic acid;   1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-4-ol;   (3R)-1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]pyrrolidin-3-ol;   (3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol;   1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]piperidin-4-ol;   (3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-ol;   (3R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidin-3-ol;   1-[3-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol;   1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]piperidin-4-ol;   (3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol;   (3S)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidin-3-ol;   1-[3-(2-Hydroxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol;   1-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidin-4-ol;   (3S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidin-3-ol;   1-[3-[3-(Difluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   (3S,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;   (3R)-1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]pyrrolidin-3-ol;   (3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol;   1-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]piperidin-4-ol;   (3R,5 S)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,5-diol;   1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-4-carboxylic acid;   1-[2-[(8-Fluoro-3-quinolyl)sulfonyl]phenyl]azetidin-3-ol;   1-[3-(2-Methoxyphenyl)sulfonyl-8-quinolyl]azetidin-3-ol;   1-[3-(2-Methoxy-5-methyl-phenyl)sulfonyl-8-quinolyl]azetidin-3-ol;   (3S,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]piperidine-3,4-diol;   (3R,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;   (3R,4S)-1-[3-(Benzenesulfonyl)-8-quinolyl]-3-fluoro-piperidin-4-ol;   1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]azetidine-3-carboxylic acid;   (3R,4R)-1-[3-(Benzenesulfonyl)-8-quinolyl]pyrrolidine-3,4-diol;   1-[3-(3-Trifluoromethyl-benzenesulfonyl)-quinolin-8-yl]-piperidine-3-carboxylic acid amide;   1-[3-(3-Cyanophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-(3-Carbamoylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-(3-Carboxyphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-(m-Tolylsulfonyl)-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-[3-(Trifluoromethoxy)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-(3-Fluorophenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-(3-Pyrrolidin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-[3-(3-Methoxypyrrolidin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-(3-Piperazin-1-ylphenyl)sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   1-[3-[3-(4-Methylpiperazin-1-yl)phenyl]sulfonyl-8-quinolyl]piperidine-4-carboxylic acid;   2-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-4-piperidyl]acetic acid;   2-[1-[3-[3-(Trifluoromethyl)phenyl]sulfonyl-8-quinolyl]-3-piperidyl]acetic acid;   
       or an N-oxide, tautomeric form, stereoisomer, or stereoisomeric mixture; or 
       pharmaceutically acceptable salt thereof. 
     
     
         40 . The method as claimed in  claim 39 , where the disorders are selected from the group consisting of diseases of the central nervous system, addiction and obesity. 
     
     
         41 . The method as claimed in  claim 40 , where the disease of the central nervous system is a cognitive dysfunction. 
     
     
         42 . The method as claimed in  claim 41 , where the cognitive dysfunction is associated with Alzheimer's disease. 
     
     
         43 . The method as claimed in  claim 41 , where the cognitive dysfunction is associated with schizophrenia.