US2009312327A1PendingUtilityA1
Pyrrolidine derivatives as nk2 receptor antagonists

Assignee: BISSANTZ CATERINAPriority: Jun 16, 2008Filed: Jun 11, 2009Published: Dec 17, 2009
Est. expiryJun 16, 2028(~1.9 yrs left)· nominal 20-yr term from priority
Inventors:Caterina Bissantz Philippe Jablonski Henner Knust Andreas Koblet Anja Limberg Matthias Nettekoven Hasane Ratni Claus Riemer
A61P 43/00C07D 413/10C07D 401/06A61P 25/24C07D 207/14C07D 405/12A61P 25/18C07D 405/06C07D 403/06C07D 401/14C07D 401/12A61P 25/22C07D 403/12C07D 405/14
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Claims
Abstract

The present invention relates to compounds of formula I wherein R 1 , R 2 , R 3 , Ar and n are as defined herein and pharmaceutically active salts, racemic mixtures, enantiomers, optical isomers or tautomeric forms thereof. The compounds can be used for the treatment of depression, anxiety or schizophrenia.
Claims

exact text as granted — not AI-modified
1 . A compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3; 
 R 2  is hydrogen or lower alkyl; 
 R 3  is aryl- or a heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R′; 
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , —C(O)-lower alkyl, heterocyclyl and heteroaryl; 
 R 4  and R 5  are each independently hydrogen, —(CO)CF 3  or lower alkyl or is a non aromatic heterocyclic group 
 
     
       
         
         
             
             
         
       
     
     wherein
 X is N or CH; 
 Y is —CH(R 7 )—; —N(R 7′ )—, O or SO 2    
 R 6  is hydrogen, lower alkyl or hydroxy; 
 R 7  is hydrogen, hydroxy, ═O, lower alkyl, lower alkoxy, —S(O) 2 -lower alkyl, —C(O)-lower alkyl, —C(O)CH 2 O-lower alkyl, —CH 2 CN, —C(O)CH 2 CN, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl, —NH-lower alkyl, —NRC(O)O-lower alkyl, —NRC(O)-lower alkyl or —CH 2 O-lower alkyl; 
 R 7′  is hydrogen, lower alkyl, —(CH 2 ) q —S(O) 2 -lower alkyl, —(CH 2 ) q —S(O) 2 -cycloalkyl, —C(O)-lower alkyl, —(CH 2 ) q -cycloalkyl, —C(O)CH 2 —O-lower alkyl, —(CH 2 ) q CN, —C(O)CN, —C(O)CH 2 CN, lower alkyl substituted by halogen, lower alkenyl substituted by halogen, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl or —(CH 2 ) q O-lower alkyl and q is 0-3; or 
 R 6  and R 7  together with the carbon atoms to which they are attached form a five or six-membered non aromatic ring or 
 R 6  and R 7  together with the nitrogen and carbon atoms to which they are attached form a five or six-membered non aromatic ring; 
 p is 0, 1 or 2; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 m is 0, 1 or 2 and o is 0; and 
 o is 0, 1 or 2 and m is 1 
 
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
   
   
       2 . A compound of  claim 1  having formula IA 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or halogen; n is 1 or 2; 
 R 2  is lower alkyl 
 R 3  is 
 
     
       
         
         
             
             
         
       
       R 6  is hydrogen, lower alkyl or hydroxy; 
       R 7  is hydrogen, hydroxy, ═O, lower alkyl, lower alkoxy, —S(O) 2 -lower alkyl, —C(O)-lower alkyl, —C(O)CH 2 O-lower alkyl, —CH 2 CN, —C(O)CH 2 CN, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl, —NH-lower alkyl, —NRC(O)O-lower alkyl, —NRC(O)-lower alkyl or —CH 2 O-lower alkyl; 
       R 7′  is hydrogen, lower alkyl, —(CH 2 ) q —S(O) 2 -lower alkyl, —(CH 2 ) q —S(O) 2 -cycloalkyl, —C(O)-lower alkyl, —(CH 2 ) q -cycloalkyl, —C(O)CH 2 —O-lower alkyl, —(CH 2 ) q CN, —C(O)CN, —C(O)CH 2 CN, lower alkyl substituted by halogen, lower alkenyl substituted by halogen, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl or —(CH 2 ) q O-lower alkyl and q is 0-3; or 
       R 6  and R 7  together with the carbon atoms to which they are attached form a five or six-membered non aromatic ring or 
       R 6  and R 7′  together with the nitrogen and carbon atoms to which they are attached form a five or six-membered non aromatic ring; 
       Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
       R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
     
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
   
   
       3 . A compound of  claim 2 , selected from the group consisting of
 rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-4-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-ethyl-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-4-trifluoromethoxy-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-4-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-dimethylamino-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-fluoro-3,N-dimethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-3-fluoro-4-methoxy-N-methyl-benzamide;   rac-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-amide; and   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-4-pyrrol-1-yl-benzamide.   
   
   
       4 . A compound of  claim 2 , selected from the group consisting of
 rac-3-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-benzamide;   rac-3-chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-5-trifluoromethyl-benzamide;   N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-((S)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-((R)-4-methanesulfonyl-3-methyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   4-{(3SR,4RS)-3-(4-chloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester; and   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.   
   
   
       5 . A compound of  claim 2 , selected from the group consisting of
 4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-3-trifluoromethoxy-benzamide;   4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-methoxy-N-methyl-benzamide;   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide;   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-(4-fluoro-phenyl)-N-methyl-propionamide;   N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-isopropyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   5-chloro-pyridine-2-carboxylic acid{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide; and   3-cyano-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide.   
   
   
       6 . A compound of  claim 2 , selected from the group consisting of
 N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3-dimethyl-butyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   2-cyclopentyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamide;   N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2,2-dimethyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-ethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methylsulfanyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3-methanesulfonyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester;   N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; and   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.   
   
   
       7 . A compound of  claim 2 , selected from the group consisting of
 N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(1-ethanesulfonyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-1-(1-cyclopropanesulfonyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-1-[1-(2-cyano-ethyl)-piperidine-4-carbonyl]-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-methoxy-ethyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   4-{(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-[(4-methoxy-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid ethyl ester;   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(2-fluoro-allyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   2-cyclopentyl-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide;   4-chloro-N-[(3S ,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   4-chloro-N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide; and   4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide.   
   
   
       8 . A compound of  claim 2 , selected from the group consisting of
 4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropanesulfonyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(tetrahydro-pyran-4-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide;   4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyanomethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   4-chloro-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   4-chloro-N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(2-cyano-ethyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide;   4-trifluoromethyl-pyridine-2-carboxylic acid{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;   4-chloro-N-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   4-trifluoromethyl-pyridine-2-carboxylic acid{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;   3-bromo-4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide;   4-chloro-3-cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide;   4-chloro-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3-ethyl-N-methyl-benzamide; and   4-chloro-3-cyclopropyl-N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide.   
   
   
       9 . A compound of  claim 1  having formula IB 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3; 
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , —C(O)-lower alkyl, heterocyclyl and heteroaryl; 
 R 4  and R 5  are each independently hydrogen, —(CO)CF 3  or lower alkyl 
 Ar is aryl- or heteroaryl, wherein the rings are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
   
   
       10 . A compound of  claim 9 , selected from the group consisting of
 rac-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-dimethylamino-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-fluoro-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-1-(3-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(2-fluoro-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethyl-benzoyl)-pyrrolidin-3yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; and   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(3-methanesulfonyl-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.   
   
   
       11 . A compound of  claim 9 , selected from the group consisting of
 rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-3-methyl-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(3,5-dimethyl-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-1-(4-acetyl-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-4-methyl-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-4-chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   rac-3-tert-butyl-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-benzamide;   rac-6-chloro-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-nicotinamide;   rac-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-6-trifluoromethyl-nicotinamide; and   N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.   
   
   
       12 . A compound of  claim 1  having formula IC 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3; 
 R 2  is hydrogen or lower alkyl; 
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , —C(O)-lower alkyl, heterocyclyl and heteroaryl; 
 R 4  and R 5  are each independently hydrogen, —(CO)CF 3  or lower alkyl 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
 
   
   
       13 . A compound of  claim 12 , selected from the group consisting of
 rac-N-[(3S,4R)-1-(benzofuran-5-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(pyridine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(2,6-dichloro-pyridine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; and   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(1,5-dimethyl-1H-pyrazole-3-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.   
   
   
       14 . A compound of formula I, having formula I-I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3; 
 R 2  is hydrogen or lower alkyl; 
 R 3  is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R′; 
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , and —C(O)-lower alkyl; 
 R 4  and R 5  are each independently hydrogen, —(CO)CF 3  or lower alkyl 
 
     or is a non aromatic heterocyclic group 
     
       
         
         
             
             
         
       
     
     wherein
 X is N or CH; 
 
     when X is CH, Y is is —CH(R 7 )—; —N(R 7′ )—, or O; 
     or when X is N, Y is is —CH(R 7 )—; —N(R 7′ )—, O, or SO 2 ;
 R 6  is hydrogen, lower alkyl or hydroxy; 
 R 7  is hydrogen, hydroxy, ═O, lower alkyl, —S(O) 2 -lower alkyl, —C(O)-lower alkyl, —C(O)CH 2 O-lower alkyl, —CH 2 CN, —C(O)CH 2 CN, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl, —NH-lower alkyl, —NRC(O)O-lower alkyl, —NRC(O)-lower alkyl or —CH 2 O-lower alkyl; 
 R 7′  is hydrogen, lower alkyl, —S(O) 2 -lower alkyl, —C(O)-lower alkyl, —C(O)CH 2 —O-lower alkyl, —CH 2 CN, —C(O)CN, —C(O)CH 2 CN, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl or —CH 2 O-lower alkyl; or 
 R 6 and R 7  together with the carbon atoms to which they are attached form a five or six-membered non aromatic ring or 
 R 6 and R 7′  together with the nitrogen and carbon atoms to which they are attached form a five or six-membered non aromatic ring; 
 p is 0, 1 or 2; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 m is 0, 1 or 2 and o is 0; and 
 o is 0, 1 or 2 and m is 1 
 
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
   
   
       15 . A compound of  claim 14 , having formula I-11 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or halogen; n is 1 or 2; 
 R 2  is lower alkyl 
 R 3  is 
 
     
       
         
         
             
             
         
       
     
     wherein R is hydrogen or lower alkyl;
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , and —C(O)-lower alkyl; 
 R 4  and R 5  are each independently hydrogen or lower alkyl; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
 
   
   
       16 . A compound of  claim 14 , having formula I-12 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or halogen; n is 1 or 2; 
 R 2  is lower alkyl 
 R 3  is 
 
     
       
         
         
             
             
         
       
     
     wherein R is hydrogen or lower alkyl;
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , and —C(O)-lower alkyl; 
 R 4  and R 5  are each independently hydrogen or lower alkyl; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
   
   
       17 . A compound of  claim 14 , having formula I-13 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or halogen; n is 1 or 2; 
 R 2  is lower alkyl 
 R 3  is 
 
     
       
         
         
             
             
         
       
     
     wherein R is hydrogen or lower alkyl;
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , and —C(O)-lower alkyl; 
 R 4  and R 5  are each independently hydrogen or lower alkyl; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
 
   
   
       18 . A compound of  claim 14 , having formula I-14 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or halogen; n is 1 or 2; 
 R 2  is lower alkyl 
 R 3  is 
 
     
       
         
         
             
             
         
       
     
     wherein R is hydrogen or lower alkyl;
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , and —C(O)-lower alkyl; 
 R 4  and R 5  are each independently hydrogen or lower alkyl; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
 
   
   
       19 . A compound of  claim 14 , having formula I-15 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or halogen; n is 1 or 2; 
 R 2  is lower alkyl 
 R 3  is 
 
     
       
         
         
             
             
         
       
     
     wherein R is hydrogen or lower alkyl;
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , and —C(O)-lower alkyl; 
 R 4  and R 5  are each independently hydrogen or lower alkyl; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
   
   
       20 . A compound of  claim 1 , having formula I-16 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen or halogen; n is 1 or 2; 
 R 2  is lower alkyl 
 R 3  is 
 
     
       
         
         
             
             
         
       
     
     wherein R is hydrogen or lower alkyl;
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , and —C(O)-lower alkyl; 
 R 4  and R 5  are each independently hydrogen or lower alkyl; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; and 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof. 
   
   
       21 . A compound of  claim 1 , selected from the group consisting of
 rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-N-methyl-4-trifluoromethyl-benzamide;   rac-4-Dimethylamino-N-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-N-methyl-benzamide;   rac-N-[(3S,4R)-1-(4-Methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-3,5-Dichloro-N-[(3S,4R)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-4-phenyl-pyrrolidin-3-yl]-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(4-Chloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-4-fluoro-N-methyl-benzamide; and   rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide.   
   
   
       22 . A compound of  claim 1 , selected from the group consisting of
 rac-4-Cyano-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;   rac-3-Cyano-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-5-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-3,5-difluoro-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-3-fluoro-N-methyl-4-trifluoromethyl-benzamide;   rac-3-Chloro-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-benzamide;   rac-Benzofuran-5-carboxylic acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-amide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-3,4-difluoro-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-4-(2,2,2-trifluoro-acetylamino)-benzamide; and   rac-2,3-Dihydro-benzofuran-5-carboxylic acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-amide.   
   
   
       23 . A compound of  claim 1 , selected from the group consisting of
 rac-Quinoxaline-6-carboxylic acid[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-methyl-amide;   rac-3-(Cyano-methyl-methyl)-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-methyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-N-ethyl-2-fluoro-5-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-Dichloro-phenyl)-1-(4-dimethylamino-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-N-[(3S,4R)-4-(3,4-dichloro-phenyl)-1-(4-trifluoromethoxy-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   rac-4-Chloro-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-3-Methyl-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-6-Chloro-3-fluoro-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-6-Methyl-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide; and   rac-6-Methoxy-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide.   
   
   
       24 . A compound of  claim 1 , selected from the group consisting of
 rac-5-Ethoxymethyl-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-4-Chloro-6-methyl-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-4-Methoxy-quinoline-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-4-Chloro-6-ethyl-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-5-Chloro-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-5-Cyano-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-5-Cyano-6-methoxy-pyridine-2-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-3-fluoro-4-methoxy-N-methyl-benzamide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-4-cyclopropylmethoxy-N-methyl-benzamide; and   rac-2-Methoxy-pyrimidine-5-carboxylic acid[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amide.   
   
   
       25 . A compound of  claim 1 , selected from the group consisting of
 rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-6,N-dimethyl-nicotinamide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-fluoro-N-methyl-nicotinamide;   rac-6-Cyano-N-[(3S,4R)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-nicotinamide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-6-(2,2,2-trifluoro-ethoxy)-nicotinamide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-5,N-dimethyl-nicotinamide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-5-fluoro-N-methyl-nicotinamide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-6-fluoro-N-methyl-nicotinamide;   rac-N-[(3S,4R)-1-(4-Cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-6-methoxy-N-methyl-nicotinamide;   N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide; and   N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-fluoro-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide.   
   
   
       26 . A compound of  claim 1 , selected from the group consisting of
 N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-fluoro-2-methyl-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(6-cyano-pyridine-3-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-isopropoxy-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-4-(4-Chloro-phenyl)-1-(4-cyano-benzoyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   Cis-4-Hydroxy-cyclohexanecarboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;   3-Cyclopropyl-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-propionamide;   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-3,3,N-trimethyl-butyramide; and   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-3,N-dimethyl-butyramide.   
   
   
       27 . A compound of  claim 1 , selected from the group consisting of
 1-(4-Fluoro-phenyl)-cyclopentanecarboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;   N-{(3R,4S)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-{(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-{(3RS,4SR)-4-(4-Chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-3-trifluoromethyl-benzamide;   N-{(3R,4S)-4-(4-Chloro-2-methyl-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-2-(tetrahydro-pyran-4-yl)-acetamide;   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-isobutyramide;   N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-methoxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-acetyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide; and   N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(morpholine-4-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide.   
   
   
       28 . A compound of  claim 1 , selected from the group consisting of
 N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-{(3RS,4SR)-4-(4-Chloro-phenyl)-1-[1-(3-methanesulfonyl-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide;   N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(4-morpholin-4-yl-benzoyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-morpholin-4-yl-pyridine-3-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-methyl-pyridazine-4-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-[(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-(6-morpholin-4-yl-pyridazine-3-carbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-[(3RS,4RS)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide;   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-acetamide;   2-(4-Cyano-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide;   N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(3,4-difluoro-phenyl)-N-methyl-acetamide; and   N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(2,3-difluoro-phenyl)-N-methyl-acetamide.   
   
   
       29 . A compound of  claim 1 , selected from the group consisting of
 4-Chloro-N-[(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   4-Chloro-N-{(3S,4R)-4-(4-chloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-3-trifluoromethyl-benzamide;   4-{(3SR,4RS)-3-(4-Chloro-phenyl)-4-[(4-chloro-3-trifluoromethyl-benzoyl)-methyl-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester;   2-(4-Chloro-phenyl)-N-[(3RS,4SR)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-acetamide;   N-[(3RS,4SR)-1-(1-Cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-propionamide;   4-Chloro-N-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide;   4-Trifluoromethyl-pyridine-2-carboxylic acid {(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;   6-Methyl-pyridazine-4-carboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide;   4-Chloro-3-cyclopropyl-N-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-benzamide.   N-{(3RS,4SR)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4,4,4-trifluoro-N-methyl-butyramide; and   2-Cyclopropylmethoxy-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-N-methyl-acetamide;   
   
   
       30 . A pharmaceutical composition comprising a compound of formula I 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is hydrogen, halogen, cyano or lower alkyl; n is 1, 2 or 3; 
 R 2  is hydrogen or lower alkyl; 
 R 3  is aryl- or a heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R′; 
 R′ is selected from hydrogen, halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, —S(O) 2 -lower alkyl, CN, —NR 4 R 5 , —C(O)-lower alkyl, heterocyclyl and heteroaryl; 
 R 4  and R 5  are each independently hydrogen, —(CO)CF 3  or lower alkyl or is a non aromatic heterocyclic group 
 
     
       
         
         
             
             
         
       
     
     wherein
 X is N or CH; 
 Y is —CH(R 7 )—; —N(R 7′ )—, O or SO 2    
 R 6  is hydrogen, lower alkyl or hydroxy; 
 R 7  is hydrogen, hydroxy, ═O, lower alkyl, lower alkoxy, —S(O) 2 -lower alkyl, —C(O)-lower alkyl, —C(O)CH 2 O-lower alkyl, —CH 2 CN, —C(O)CH 2 CN, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl, —NH-lower alkyl, —NRC(O)O-lower alkyl, —NRC(O)-lower alkyl or —CH 2 O-lower alkyl; 
 R 7′  is hydrogen, lower alkyl, —(CH 2 ) q —S(O) 2 -lower alkyl, —(CH 2 ) q —S(O) 2 -cycloalkyl, —C(O)-lower alkyl, —(CH 2 ) q -cycloalkyl, —C(O)CH 2 —O-lower alkyl, —(CH 2 ) q CN, —C(O)CN, —C(O)CH 2 CN, lower alkyl substituted by halogen, lower alkenyl substituted by halogen, —C(O)-cycloalkyl wherein the cycloalkyl group is optionally substituted by cyano, lower alkyl, one or two halogen atoms, ═O or amino, or is —C(O)O-lower alkyl or —(CH 2 ) q O-lower alkyl and q is 0-3; or 
 R 6  and R 7  together with the carbon atoms to which they are attached form a five or six-membered non aromatic ring or 
 R 6  and R 7′  together with the nitrogen and carbon atoms to which they are attached form a five or six-membered non aromatic ring; 
 p is0, 1 or 2; 
 Ar is aryl- or heteroaryl, wherein the rings of the aryl or heteroaryl group are optionally substituted by one or two substituents R″; 
 R″ is selected from hydrogen, halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen, —O—CH 2 -cycloalkyl, —NR 4 R 5 , —CN, —CH(CH 3 )CN, —CH 2 O-lower alkyl and pyrrolyl; 
 m is 0, 1 or 2 and o is 0; and 
 o is 0, 1 or 2 and m is 1 
 
     or a pharmaceutically active salt, racemic mixture, enantiomer, optical isomer or tautomeric form thereof and a pharmaceutically acceptable carrier.
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