Chiral cis-imidazolines

Abstract

and the pharmaceutically acceptable salts and esters thereof, wherein X 1 , X 2 , X 3 , Y 1 , Y 2 and R are described herein inhibit the interaction of MDM2 protein with a p53-like peptide and hence have anti proliferative activity.

1 . A compound of the formula I 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts and esters thereof wherein
 X 1  is selected From the group consisting of lower alkoxy, and lower alkoxy substituted by trifluoromethyl or fluorine; 
 X 2  is selected from the group consisting of hydrogen, halogen, lower alkyl, and —C(X 4 X 5 )-X 6 ; 
 X 3  is selected from the group consisting of hydrogen, lower alkoxy, halogen, and —C(X 4 X 5 )-X 6 ; with the proviso that when X 2  is hydrogen, halogen or lower alkyl, X 3  is —C(X 4 X 5 )-X 6 ; 
 X 4  and X 5  are lower alkyl and can be connected together to form a cycloalkyl; 
 X 6  is selected from the group consisting of lower alkyl, cyano, —CH 2 —OH, —CH 2 —O-lower alkyl, —CH 2 —O-lower alkyl substituted by lower alkoxy, —C(O)X 7 , and —CH 2 —NX 8 X 9 ; 
 X 7  is selected from the group consisting of hydroxy, lower alkoxy, morpholino, and NX 8 X 9 ; 
 X 8  and X 9  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by lower alkoxy or cyano, and lower alkoxy; 
 Y 1  and Y 2  are independently selected from the group consisting of halogen, cyano, and acetylene; 
 R is selected from the group consisting of piperidinyl substituted by five or six membered heterocycle, piperidinyl substituted by —NX 8 X 9 , and 
 
     
       
         
         
             
             
         
       
       wherein 
       n=1 or 2, 
       R 1  can be one or more substituents selected from the group consisting of hydrogen, oxo, lower alkyl substituted by R 2 , —C(O)R 3 , and —SO 2 -lower alkyl; 
       R 2  is selected from the group consisting of hydroxy, lower alkoxy, trifluoromethyl, -cyano, —NH—SO 2 -lower alkyl, —NH—C(O)-lower alkyl, —C(O)-lower alkyl, —C(O)R 4 , —C(O)—NX 8 X 9 , —SO 2 -lower alkyl, —SO 2 —NX 8 X 9 , 
       R 3  is selected from the group consisting of five membered heterocyclic, lower alkyl, lower alkoxy, and lower alkyl substituted by lower alkoxy; and 
       R 4  is selected from the group consisting of hydroxy, lower alkoxy, morpholino, and —NX 8 X 9  and wherein the absolute stereochemistry at the 4 and 5 position of the imidazoline ring is S and R respectively. 
     
   
   
       2 . The compound of  claim 1  wherein the two hydrogen of the imidazoline ring are in the cis configuration to each other. 
   
   
       3 . The compound of  claim 1  wherein Y 1  and Y 2  are selected from —Cl or —Br. 
   
   
       4 . The compound of  claim 3  wherein X 1  is selected from ethoxy, isopropoxy, —OCH 2 CF 3  or —OCH 2 CH 2 F. 
   
   
       5 . The compound of  claim 4  wherein X 2  is —C(X 4 X 5 )-X 6  wherein X 6  is methyl, cyano or CH 2 OH. 
   
   
       6 . The compound of  claim 5  wherein X 3  is hydrogen. 
   
   
       7 . The compound of  claim 6  wherein R is piperazinyl substituted by oxo or lower alkyl substituted by R 2  wherein R 2  is SO 2 -lower alkyl or —C(O)R 4 . 
   
   
       8 . A compound selected from the group consisting of: 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-Chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride; 
     4-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one; 
     1-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one; 
     [(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]methanone hydrochloride; 
     2-{4-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     4-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one; 
     1-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one; 
     [(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     2-{4-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-tert-butyl-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-bis-(2-methoxy-ethyl)-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide; 
     2-4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-isopropyl-N-methyl-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-cyano-ethyl)-N-methyl-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-methoxy-1-methyl-ethyl)-acetamide; 
     2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-{3-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-4-ethoxy-phenyl}-2-methyl-propionitrile; 
     N-[2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-ethyl]-methanesulfonamide; 
     2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-(3-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-4-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-dimethyl-acetamide; 
     4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-ethanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     1-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one hydrochloride; 
     4-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride; 
     1-[(4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one hydrochloride; 
     4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester; 
     1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methoxy-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-piperazin-1-yl-methanone hydrochloride; 
     1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-methoxy-ethanone; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-methyl-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3,3,3-trifluoro-2-hydroxy-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     4-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-butan-2-one hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride; 
     3-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionic acid hydrochloride; 
     3-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-propionitrile hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide hydrochloride; 
     N-tert-Butyl-2-{4-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide hydrochloride; 
     {4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetonitrile hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2,2,2-trifluoro-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3,3,3-trifluoro-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone; 
     4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-1-(2-methanesulfonyl-ethyl)-piperazin-2-one; 
     1-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-3,3-dimethyl-butan-2-one hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-1-yl}1-morpholin-4-yl-ethanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl]-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-1-yl}-N,N-dimethyl-acetamide hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-[1,4]diazepan-1-yl]-methanone hydrochloride: 
     N-(2-{4-[1-(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-methanesulfonamide hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide hydrochloride; 
     4-{4 (4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-2-one; 
     {(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone hydrochloride; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide hydrochloride; 
     {(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-hydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]1-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one; 
     [(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-methanesulfonamide hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-methanesulfonamide hydrochloride; 
     [(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-ethanesulfonyl-piperazin-1-yl)-methanone hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide hydrochloride; 
     2-{4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-isopropyl-N-methyl-acetamide hydrochloride; 
     4-[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one; 
     N-(2-{4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride; 
     N-(2-{4[(4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-tert-butyl-acetamide; 
     2-4{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-bis-(2-methoxy-ethyl)-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-methoxy-N-methyl-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-isopropyl-N-methyl-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-cyano-ethyl)-N-methyl-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N-(2-methoxy-1-methyl-ethyl)-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazole-2-yl]-3-ethoxy-phenyl}-2-methyl-propionitrile; 
     N-[2-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-ethyl]-methanesulfonamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-1N,N-dimethyl-acetamide; 
     N-tert-Butyl-2-{4-[(4S,5R)-2-[5-chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide; 
     2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetamide; 
     2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-bis-(2-methoxy-ethyl)-acetamide; 
     2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide; 
     2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-isopropyl-N-methyl-acetamide; 
     2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-cyano-ethyl)-N-methyl-acetamide; 
     2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-methoxy-1-methyl-ethyl)-acetamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-{4-[(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-(4-ethanesulfonyl-piperazine-1-carbonyl)-4,5-dihydro-1H-imidazol-2-yl]-2-chloro-5-ethoxy-phenyl}-2-methyl-propionitrile; 
     N-(2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-methanesulfonamide; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3-methanesulfonyl-propyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile; 
     2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-diethyl-acetamide; 
     4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one; 
     [(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     [(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(3-methanesulfonyl-propyl)-piperazin-1-yl]-methanone hydrochloride; 
     N-(2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-ethyl)-acetamide hydrochloride; 
     2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N,N-dimethyl-acetamide hydrochloride; 
     2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazine-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     2-{4-[(4S,5R)-2-[4-tert-Butyl-2-(2-fluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone hydrochloride; 
     [(4S,5R)-2-[4-tert-Butyl-2-(2-fluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride; 
     [1,4′]Bipiperidinyl-1-yl-[(4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-methanone; 
     [(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone; 
     4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-2-one; 
     {(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone; 
     2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-1-morpholin-4-yl-ethanone; 
     cis-2-(4-{4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-N,N-diethyl-isobutyramide; 
     cis-2-(4-{4,5-Bis-(4-chloro-phenyl)-1-[4-(2-morpholin-4-yl-2-oxo-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-3-ethoxy-phenyl)-N,N-diethyl-isobutyramide
 and 
 
     [2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-dimethylamino-piperidin-1-yl)-methanone hydrochloride. 
   
   
       9 . A method of treating a disease based on the interaction of MDM2 protein with a p53 like peptide comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound selected from a cis-imidazoline of the formula I 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts and esters thereof, wherein
 X 1  is selected from the group consisting of lower alkoxy, and lower alkoxy substituted by trifluoromethyl or fluorine; 
 X 2  is selected from the group consisting of hydrogen, halogen, lower alkyl, and —C(X 4 X 5 )-X 6 ; 
 X 3  is selected from the group consisting of hydrogen, lower alkoxy, halogen, and —C(X 4 X 5 )-X 6 ; with the proviso that when X 2  is hydrogen, halogen or lower alkyl, X 3  is —C(X 4 X 5 )—X 6 ; 
 X 4  and X 5  are lower alkyl and can be connected together to form a cycloalkyl; 
 X 6  is selected from the group consisting of lower alkyl, cyano, —CH 2 —OH, —CH 2 —O-lower alkyl, —CH 2 —O-lower alkyl substituted by lower alkoxy, —C(O)X 7 , and —CH 2 —NX 8 X 9 ; 
 X 7  is selected from the group consisting of hydroxy, lower alkoxy, morpholino, and —NX 8 NX 9 ; 
 X 8  and X 9  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by lower alkoxy or cyano, and lower alkoxy; 
 Y 1  and Y 2  are independently selected from the group consisting of halogen, cyano, and acetylene; 
 R is selected from the group consisting of piperidinyl substituted by five or six membered heterocycle, piperidinyl substituted by —NX 8 X 9 , and 
 
     
       
         
         
             
             
         
       
       
         wherein 
         n=1 or 2, 
       
       R 1  can be one or more substituents selected from the group consisting of hydrogen, oxo, lower alkyl substituted by R 2 , —C(O)R 3 , and —SO 2 -lower alkyl; 
       R 2  is selected from the group consisting of hydroxy, lower alkoxy, trifluoromethyl, -cyano, —NH—SO 2 -lower alkyl, —NH—C(O)-lower alkyl, —C(O)-lower alkyl, —C(O)R 4 , —C(O)—NX 8 X 9 , —SO 2 -lower alkyl, —SO, —NX 8 X 9 , 
       R 3  is selected from the group consisting of five membered heterocycle, lower alkyl, lower alkoxy, and lower alkyl substituted by lower alkoxy; and 
       R 4  is selected from the group consisting of hydroxy, lower alkoxy, morpholino, and —NX 8 X 9  and wherein the absolute stereochemistry at the 4 and 5 position of the imidazoline ring is S and R respectively. 
     
   
   
       10 . The method of  claim 9  wherein the disease is cancer. 
   
   
       11 . A compound selected from the group consisting of 
     (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-ethynyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[5-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-(4-tert-Butyl-2,5-diethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-(4-tert-Butyl-5-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-[5-chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride; 
     (4S,5R)-2-[4-tert-Butyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride and 
     (4S,5R)-2-[4-tert-Butyl-2-(2-fluoro-ethoxy)-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. 
   
   
       12 . A process to produce a compound of the formula I 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts and esters thereof, wherein
 X 1  is selected from the group consisting of lower alkoxy, and lower alkoxy substituted by trifluoromethyl or fluorine; 
 X 2  is selected from the group consisting of hydrogen, halogen, lower alkyl, and —C(X 4 X 5 )—X 6 ; 
 X 3  is selected from the group consisting of hydrogen, lower alkoxy, halogen, and —C(X 4 X 5 )-X 6 ; with the proviso that when X 2  is hydrogen, halogen or lower alkyl, X 3  is —C(X 4 X 5 )-X 6 ; 
 X 4  and X 5  are lower alkyl and can be connected together to form a cycloalkyl; 
 X 6  is selected from the group consisting of lower alkyl, cyano, —CH 2 , —OH, —CH 2 —O-lower alkyl, —CH 2 —O-lower alkyl substituted by lower alkoxy, —C(O)X 7 , and —CH 2 —NX 8 X 9 ; 
 X 7  is selected from the group consisting of hydroxyl, lower alkoxy, morpholino, and —NX 8 X 9 ; 
 X 8  and X 9  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by lower alkoxy or cyano, and lower alkoxy; 
 Y 1  and Y 2  are independently selected from the group consisting of halogen, cyano, and acetylene; 
 R is selected from the group consisting of piperidinyl substituted by five or six membered heterocycle, piperidinyl substituted by —NX 8 X 9 , and 
 
     
       
         
         
             
             
         
       
       wherein 
       n=1 or 2, 
       R 1  can be one or more substituents selected from the group consisting of hydrogen, oxo, lower alkyl substituted by R 2 , —C(O)R 3 , and —SO 2 -lower alkyl; 
       R 2  is selected from the group consisting of hydroxyl, lower alkoxy, trifluoromethyl, -cyano, —NH—SO 2 -lower alkyl, —NH—C(O)-lower alkyl, —C(O)-lower alkyl, —C(O)R 4 , —C(O)—NX 8 X 9 , —SO 4 -lower alkyl, —SO, —NX 8 X 9 , 
       R 3  is selected from the group consisting of five membered heterocyclic, lower alkyl, lower alkoxy, and lower alkyl substituted by lower alkoxy; 
       R 4  is selected from the group consisting of hydroxyl, lower alkoxy, morpholino, and —NX 8 X 9 ; 
     
     the absolute stereochemistry at the 4 and 5 position of the imidazoline ring are S and R, respectively, which comprises separating the enantiomers of the racemic carbamoyl chloride 
     
       
         
         
             
             
         
       
     
     and 
     thereafter coupling the desired enantiomer with an appropriate R amine group. 
   
   
       13 . A pharmaceutical composition which comprises at least one cis-imidazoline of the formula 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts and esters thereof, wherein
 X 1  is selected from the group consisting of lower alkoxy, and lower alkoxy substituted by trifluoromethyl or fluorine; 
 X 2  is selected from the group consisting of hydrogen, halogen, lower alkyl, and —C(X 4  Xs)-X 6 ; 
 X 1  is selected from the group consisting of hydrogen, lower alkoxy, halogen, and —C(X 4 X 5 )—X 6 ; with the proviso that when X 2  is hydrogen, halogen or lower alkyl, X 3  is —C(X 4 X 5 )-X 6 ; 
 X 4  and X 5  are lower alkyl and can be connected together to form a cycloalkyl; 
 X 6  is selected from the group consisting of lower alkyl, cyano, —CH 2 —OH, —CH 2 —O-lower alkyl, —CH 2 —O-lower alkyl substituted by lower alkoxy, —C(O)X 7 , and —CH 2 —NX 8 X 9 ; 
 X 7  is selected from the group consisting of hydroxy, lower alkoxy, morpholino, and —NX 8 X 9 ; 
 X 8  and X 9  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkyl substituted by lower alkoxy or cyano, and lower alkoxy; 
 Y 1  and Y 2  are independently selected from the group consisting of halogen, cyano, and acetylene; 
 R is selected from the group consisting of piperidinyl substituted by five or six membered heterocyclic, piperidinyl substituted by —NX 8 X 9 , and 
 
     
       
         
         
             
             
         
       
       
         wherein 
         n-1 or 2, 
       
       R 1  can be one or more substituents selected from the group consisting of hydrogen, oxo, lower alkyl substituted by R 2 , —C(O)R 3 , and —SO-lower alkyl; 
       R 2  is selected from the group consisting of hydroxy, lower alkoxy, trifluoromethyl, -cyano, —NH—SO 4 -lower alkyl, —NH—C(O)-lower alkyl, —C(O)-lower alkyl, —C(O)R 4 , —C(O)—NX 8 X 9 , —SO 2 -lower alkyl, —SO 2 —NX 8 X 9 , 
       R 3  is selected from the group consisting of five membered heterocycle, lower alkyl, lower alkoxy, and lower alkyl substituted by lower alkoxy; 
       R 4  is selected from the group consisting of hydroxy, lower alkoxy, morpholino, and —NX 8 X 9 ; and wherein the absolute stereochemistry at the 4 and 5 position of the imidazoline ring 
     
     and a pharmaceutically acceptable carrier.