Cycloalkyl lactam derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1

Abstract

The present invention discloses compounds of Formula I: (I) having 11beta-HSD type 1 antagonist activity, as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I, as well as the use of the Formula I and compositions as medicaments to treat diabetes, hyperglycemia, obesity, hypertension, hyperlipidemia, Syndrome X, and other conditions associated with hyperglycemia.

1 . A compound structurally represented by formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 G 1  is methylene; 
 L is methylene; 
 R 1  is hydrogen; 
 R 1a  is hydrogen; 
 R 2  is 
 
     
       
         
         
             
             
         
       
       
         wherein the dashed line represents the point of attachment to the R 2  position in formula I; 
       
       R 3  is hydrogen; 
       R 4  and R 5  are each independently
 hydrogen, hydroxy, —C(O)OH, —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), —(C 1 -C 6 )alkoxy(optionally substituted with one to three halogens), halogen, cyano, —OCF 3 , —(C 1 -C 4 )alkyl-C(O)OH, —(C 1 -C 4 )alkyl-C(O)O(C 1 -C 4 )alkyl, or —(C 1 -C 4 )alkyl-OH; 
 
       R 5a  and R 5b  are independently hydrogen or halogen; 
       R 6  is
 hydrogen, hydroxy, —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), —(C 1 -C 6 )alkoxy(optionally substituted with one to three halogens), —O—(C 2 -C 6 )alkynyl, halogen, cyano, —NH 2 , —SCF 3 , —C(O)O(C 1 -C 4 )alkyl, —(C 3 -C 8 )cycloalkyl, —O—SO 2 —(C 1 -C 4 )alkyl, —O—SO 2 —CF 3 , —O-phenyl, —O—(C 1 -C 4 )alkyl-phenyl, —O-phenyl-C(O)O—(C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl-phenyl-C(O)O—(C 1 -C 4 )alkyl, —NH-phenyl, —CH 2 -phenyl, —O—(C 1 -C 4 )alkyl-pyridinyl, Ar 1 , Het 2 , Ar 2 , Het 2 , —C(O)(C 1 -C 4 )alkyl, —C(O)—Ar 2 , —C(O)—Het 2 , —NHSO 2 —(C 1 -C 4 )alkyl, —NHSO 2 -phenyl(R 19 )(R 19 ), —(C 1 -C 4 )alkyl-C(O)N(R 11 )(R 12 ), or —(C 1 -C 4 )alkyl-N(R 13 )(R 14 ); 
 wherein R 11  and R 12  are each independently hydrogen or —(C 1 -C 4 )alkyl, or R 11  and R 12  taken together with the nitrogen to which they are attached form piperidinyl, piperazinyl, or pyrrolidinyl (wherein optionally the piperidinyl, piperazinyl, or pyrrolidinyl ring is substituted once with —(C 1 -C 4 )alkyl); wherein R 13  and R 14  are each independently hydrogen or —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), or R 13  and R 14  taken together with the nitrogen to which they are attached form piperidinyl, pyrrolidinyl, or piperazinyl; provided that when L is —O— or —S—, then R 6  is not hydrogen; 
 
       Ar 1  is phenyl or naphthyl; 
       Ar 2  is Ar 1  optionally and independently substituted one to three times with
 halogen, hydroxy, —C(O)OH, —(C 1 -C 6 )alkoxy, cyano, —CF 3 , —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)OH, —O(C 1 -C 4 )alkyl-C(O)OH, —(C 1 -C 4 )alkyl-N(R 15 )(R 16 ), —O—(C 1 -C 4 )alkyl-N(R 15 )(R 16 ), —O—(C 1 -C 4 )alkyl-C(O)O—(C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl-piperidinyl, imidazolyl, pyridinyl, or —(C 1 -C 4 )alkyl-imidazolyl; 
 wherein R 15  and R 16  are each independently hydrogen or —(C 1 -C 4 )alkyl, or R 15  and R 16  taken together with the nitrogen to which they are attached form piperidinyl, pyrrolidinyl, morpholinyl, or imidazolyl; 
 
       Het 1  is independently
 imidazolyl, oxadiazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, pyrrolidinyl, morpholinyl, pyridinyl, piperidinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, or phthalazinyl; 
 
       Het 2  is Het 1  optionally and independently substituted one to three times with halogen, hydroxy, —(C 1 -C 6 )alkoxy(optionally substituted with one to three halogens), —C(O)OH, —NH 2 , cyano, —CF 3 , —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), —(C 1 -C 4 )alkyl-C(O)OH, —O(C 1 -C 4 )alkyl-C(O)OH, —C(O)O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-N(R 17 )(R 18 ), —O(C 1 -C 4 )alkyl-N(R 17 )(R 18 ), imidazolyl, pyridinyl, or —(C 1 -C 4 )alkyl-imidazolyl; wherein R 17  and R 18  are each independently hydrogen or —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), or R 17  and R 18  taken together with the nitrogen to which they are attached form piperidinyl or pyrrolidinyl; 
       R 19  is hydrogen, halogen, or —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens); and 
       R 20  is hydroxy, —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), or —CH 2 OH. 
     
   
   
       2 . (canceled) 
   
   
       3 . (canceled) 
   
   
       4 . (canceled) 
   
   
       5 . (canceled) 
   
   
       6 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 2  is 
     
       
         
         
             
             
         
       
     
     wherein the dashed line represents the point of attachment to the R 2  position in formula I. 
   
   
       7 . A compound of  claim 6  or a pharmaceutically acceptable salt thereof wherein R 6  is
 hydroxy, —(C 1 -C 4 )alkyl, —(C 1 -C 6 )alkoxy, —O—(C 2 -C 6 )alkynyl, halogen, cyano, —NH 2 , —CF 3 , —SCF 3 , —C(O)O(C 1 -C 4 )alkyl, —(C 3 -C 8 )cycloalkyl, —O—SO 2 —(C 1 -C 4 )alkyl, —O—SO 2 —CF 3 , —O-phenyl, —O—(C 1 -C 4 )alkyl-phenyl, —O-phenyl-C(O)O—(C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl-phenyl-C(O)O—(C 1 -C 4 )alkyl, —NH-phenyl, —CH 2 -phenyl, —O—(C 1 -C 4 )alkyl-pyridinyl, Ar 1 , Ar 2 , Het 1 , Het 2 , —C(O)(C 1 -C 4 )alkyl, —C(O)—Ar 2 , —C(O)—Het 2 , —NHSO 2 —(C 1 -C 4 )alkyl, —NHSO 2 -phenyl(R 19 )(R 19 ), —(C 1 -C 4 )alkyl-C(O)N(R 11 )(R 12 ), or —(C 1 -C 4 )alkyl-N(R 13 )(R 14 );   wherein R 11  and R 12  are each independently hydrogen or C 1 -C 1  alkyl, or R 11  and R 12  taken together with the nitrogen to which they are attached form piperidinyl, piperazinyl, or pyrrolidinyl (wherein optionally the piperidinyl, piperazinyl, or pyrrolidinyl ring is substituted once with —(C 1 -C 4 )alkyl); wherein R 13  and R 14  are each independently hydrogen or —(C 1 -C 4 )alkyl, or R 13  and R 14  taken together with the nitrogen to which they are attached form piperidinyl, pyrrolidinyl, or piperazinyl;   Ar 1  is phenyl;   Ar 2  is Ar 1  optionally and independently substituted one or times with   halogen, hydroxy, —C(O)OH, —(C 1 -C 6 )alkoxy, cyano, —CF 3 , —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)OH, —O(C 1 -C 4 )alkyl-C(O)OH, —(C 1 -C 4 )alkyl-N(R 15 )(R 16 ), —O—(C 1 -C 4 )alkyl-N(R 15 )(R 16 ), —O—(C 1 -C 4 )alkyl-C(O)O—(C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl-piperidinyl, imidazolyl, pyridinyl, or —(C 1 -C 4 )alkyl-imidazolyl; wherein R 15  and R 16  are each independently hydrogen or —(C 1 -C 4 )alkyl, or R 15  and R 16  taken together with the nitrogen to which they are attached form piperidinyl, pyrrolidinyl, morpholinyl, or imidazolyl;   Het 1  is independently   imidazolyl, oxadiazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, pyrrolidinyl, morpholinyl, pyridinyl, piperidinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl;   Het 2  is Het 1  optionally and independently substituted once with   halogen, hydroxy, —(C 1 -C 6 )alkoxy, —C(O)OH, —NH 2 , cyano, —CF 3 , —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)OH, —O—(C 1 -C 4  alkyl)C(O)OH, —C(O)O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-N(R 17 )(R 18 ), —O—(C 1 -C 4 )alkyl-N(R 17 )(R 18 );   wherein R 17  and R 18  are each independently hydrogen or —(C 1 -C 4 )alkyl, or R 17  and R 18  taken together with the nitrogen to which they are attached form piperidinyl or pyrrolidinyl.   
   
   
       8 . A compound of  claim 1  structurally represented by formula (Ia), 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein
 R 2  is 
 
     
       
         
         
             
             
         
       
       
         wherein the dashed line represents the point of attachment to the R 2  position in formula I; 
       
       R 4  and R 5  are each independently hydrogen, halogen, or hydroxy; 
       R 5a  and R 5b  are hydrogen, 
       R 6  is
 hydroxy, —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), —(C 1 -C 6 )alkoxy(optionally substituted with one to three halogens), —O—(C 2 -C 6 )alkynyl, halogen, cyano, —NH 2 , —CF 3 , —SCF 3 , —C(O)O—(C 1 -C 4 )alkyl, —(C 3 -C 8 )cycloalkyl, —O—SO 2 —(C 1 -C 4 )alkyl, —O—SO 2 —CF 3 , —O-phenyl, —O—(C 1 -C 4 )alkyl-phenyl, —O-phenyl-C(O)O-—(C 1 -C 4 )alkyl, —O—(C 1 -C 4 )alkyl-phenyl-C(O)O-—(C 1 -C 4 )alkyl, —NH-phenyl, —CH 2 -phenyl, —O—(C 1 -C 4 )alkyl-pyridinyl, Ar 1 , Het 1 , Ar 2 , Het 2 , —C(O)—(C 1 -C 4 )allyl, —C(O)—Ar 2 , —C(O)—Het 2 , —NHSO 2 —(C 1 -C 4 )alkyl, —NHSO 2 -phenyl(R 19 )(R 19 ), —(C 1 -C 4 )allyl-C(O)N(R 11 )(R 12 ), or —(C 1 -C 4 )allyl-N(R 13 )(R 14 ); 
 wherein R 11  and R 12  are each independently hydrogen or C 1 -C 1  alkyl, or R 11  and R 12  taken together with the nitrogen to which they are attached form piperidinyl, piperazinyl, or pyrrolidinyl (wherein optionally the piperidinyl, piperazinyl, or pyrrolidinyl ring is substituted once with —(C 1 -C 4 )alkyl); and 
 wherein R 13  and R 14  are each independently hydrogen or —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), or R 13  and R 14  taken together with the nitrogen to which they are attached form piperidinyl, pyrrolidinyl, or piperazinyl; 
 
       Ar 1  is phenyl; 
       Ar 2  is Ar 1  optionally and independently substituted one or two times with
 halogen, hydroxy, —C(O)OH, —(C 1 -C 6 )alkoxy, cyano, —CF 3 , —(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-C(O)OH, —O—(C 1 -C 4 )alkyl-C(O)OH, —(C 1 -C 4 )alkyl-N(R 15 )(R 16 ), —O—(C 1 -C 4 )alkyl-N(R 15 )(R 16 ), —O—(C 1 -C 4 )alkyl-C(O)O-—(C 1 -C 4 )alkyl; 
 wherein R 15  and R 16  are each independently hydrogen or —(C 1 -C 4 )alkyl, or R 15  and R 16  taken together with the nitrogen to which they are attached form piperidinyl, pyrrolidinyl, morpholinyl, or imidazolyl; 
 
       Het 1  is independently
 imidazolyl, oxadiazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, triazolyl, pyrrolidinyl, morpholinyl, pyridinyl, piperidinyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl; 
 
       Het 2  is Het 1  optionally and independently substituted one or two times with
 halogen, hydroxy, —(C 1 -C 6 )alkoxy(optionally substituted with one to three halogens), —C(O)OH, —NH 2 , cyano, —CF 3 , —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), —(C 1 -C 4 )alkyl-C(O)OH, —O—(C 1 -C 4 )alkylC(O)OH, —C(O)O—(C 1 -C 4 )alkyl, —(C 1 -C 4 )alkyl-N(R 17 )(R 18 ); —O(C 1 -C 4 )alkyl-N(R 17 )(R 18 ) ;    
 wherein R 17  and R 18  are each independently hydrogen or —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), or R 17  and R 18  taken together with the nitrogen to which they are attached form piperidinyl or pyrrolidinyl; 
 
       R 19  is hydrogen, halogen, or —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens); and 
       R 20  is hydroxy, —(C 1 -C 4 )alkyl(optionally substituted with one to three halogens), or —CH 2 OH. 
     
   
   
       9 . A compound of  claim 1  structurally represented by formula I, or a pharmaceutically acceptable salt thereof, wherein
 G 1  is methylene; L is —CH 2 —; R1 is —H; R2 is Cyclohexyl substituted once with —OH, —CH 2 OH, —OCH 3 , or optionally substituted once or twice with —CH 3 ; R3 is —H; R 4  and R 5  are each independently hydrogen, —F, —Cl, —Br, —I, hydroxy, or —CH 3 ; R 5a  and R 5b  are hydrogen; R 6  is —H, —F, —Cl, —Br, —I, —CH 3 , —SCF 3 , —OH, —OCF 3 , —CF 3 , —OCH 3 , —CN, —C(O)OH, —CH 2 CH 2 CH 2 C(O)-(4-methyl-piperazin-1-yl), benzyl, tert-butyl, nicotinonitrile, nicotinic acid, —OCH 2 CCH, —NH 2 , cyclohexyl, —C(O)-phenyl, —C(O)OCH 3 , —NHSO 2 -phenyl (wherein the phenyl is optionally substituted by —CH 3 , —Cl), —NH-phenyl, —OCH 2 -phenyl, —OCH 2 -pyridinyl, phenoxy (optionally optionally substituted with —C(O)OCH 3 ), isopropoxy, —OSO 2 CF 3 , —NSO 2 CH 3 , —NSO 2 -phenyl, phenyl (optionally substituted by one or two moieties independently selected from —F, —COOH, —OH, —CH 3 , —OCH 3 , —OCH 2 CH 2 -piperidinyl, —OCH 2 CH 2 N—(CH 3 ) 2 , —OCH 2 CH 2 CH 2 N—(CH 3 ) 2 , —OCH 2 CH 2 CH 2 COOH, —OCH 2 -piperidinyl, —OCH 2 CH 2 -imidazolyl, —OCH 2 CH 2 CH 2 -piperidinyl, —OCH 2 CH 2 -morpholinyl, —OC(CH 3 ) 2 COOCH 2 CH 3 , —OC—(CH 3 ) 2 COOH, —OCH 2 COOCH 2 CH 3 , —OCH 2 COOH, —OCH 2 CH 2 COOH, and —CH 2 CH 2 COOH), pyridinyl(optionally substituted once with Cl, CN, COOH, NH 2 , Br, CH 3 , OCH 3 , or OH,), pyrazinyl, pyrimidinyl, 1,3-dihydro-benzoimidazol-2-one, pyrrolidinyl(optionally substituted once with —OH), piperidinyl, piperazinyl(optionally substituted once with —CH 3 ), morpholinyl, pyrazolyl (optionally substituted once —CH 3 ), thiophenyl, —CH 2 -pyrrolidinyl, or thiophenyl (optionally substituted once with —C(O)OCH 3 , or —C(O)OH); provided that when L is —O— or —S— then R 6  is not hydrogen.   
   
   
       10 . A compound of  claim 1  selected from the group consisting of
 Trans-3-(1,4-dichloro-benzyl)-1-(cis-2-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(4-Bromo-2-chloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   1-(cis-4-hydroxy-cyclohexyl)-3-(2,4,6-trichloro-benzyl)-pyrrolidin-2-one;   3-(2,6-Dichloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2,6-Dichloro-4-trifluoromethyl-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-methoxy-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-hydroxy-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-4-pyridin-3-yl-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-4-pyridin-4-yl-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(3-Chloro-biphenyl-4-ylmethyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-fluoro-benzyl)-1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-fluoro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-fluoro-benzyl)-1-(1-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-fluoro-benzyl)-1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one;   1-(cis-2-Methyl-cyclohexyl)-3-(4-trifluoromethyl-benzyl)-pyrrolidin-2-one;   3-Biphenyl-4-ylmethyl-1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one, Isomer A;   3-Biphenyl-4-ylmethyl-1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one, Isomer B   3-(4-Bromo-2-chloro-benzyl)-1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-4-pyridin-3-yl-benzyl)-1-(cis-2-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-fluoro-benzyl)-1-(trans-2-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-fluoro-benzyl)-1-(cis-4-hydroxymethyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-4-hydroxymethyl-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-4-pyridin-3-yl-benzyl)-1-(cis-4-hydroxymethyl-cyclohexyl)-pyrrolidin-2-one;   3-(2-Chloro-6-fluoro-benzyl)-1-(trans-4-hydroxymethyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-4-hydroxy-4-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(trans-4-hydroxy-4-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-4-hydroxy-cis-2-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-4-hydroxy-cis-3,5-dimethyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-4-hydroxy-cis-3-methyl-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-dichlorobenzyl)-1-(4-hydroxy-1-methylcyclohexyl)pyrrolidin-2-one;   3-(2,6-Dichloro-4-hydroxybenzyl)-1-(cis-2-methylcyclohexyl)pyrrolidin-2-one;   3-(2,6-Dichloro-4-(pyridin-4-yl)benzyl)-1-(cis-2-methylcyclohexyl)pyrrolidin-2-one;   3-(2-Chloro-4-(pyridin-4-yl)benzyl)-1-(2-methylcyclohexyl)pyrrolidin-2-one;   3-(2,4-Dichlorobenzyl)-1-(1-methylcyclohexyl)pyrrolidin-2-one;   3-(2-Chloro-4-(pyridin-3-yl)benzyl)-1-(1-methylcyclohexyl)pyrrolidin-2-one;   3-(4-tert-butyl-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   1-(cis-4-hydroxy-cyclohexyl)-3-(4-trifluoromethyl-benzyl)-pyrrolidin-2-one;   3-(2,6-Dichloro-4-methoxy-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(4-Benzyloxy-2,6-dichloro-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-[2,6-Dichloro-4-(pyridin-3-ylmethoxy)-benzyl]-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   4-{3,5-Dichloro-4-[1-(4-hydroxy-cyclohexyl)-2-oxo-pyrrolidin-3-ylmethyl]-phenoxy}-benzoic acid methyl ester;   3-(2,6-Dichloro-4-pyridin-3-yl-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2,6-Dichloro-4-hydroxy-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2,6-Dichloro-4-pyridin-4-yl-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-[2,6-Dichloro-4-(1-methyl-1H-pyrazol-4-yl)-benzyl]-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2,6-Dichloro-4-isopropoxy-benzyl)-1-(cis-4-hydroxy-cyclohexyl)-pyrrolidin-2-one;   3-(2,4-Dichloro-benzyl)-1-(cis-4-hydroxy-cis-3-methyl-cyclohexyl)-pyrrolidin-2-one;   or a pharmaceutically acceptable salt thereof.   
   
   
       11 . A pharmaceutical composition which comprises a compound or salt of  claim 10  and a pharmaceutically acceptable carrier. 
   
   
       12 . (canceled) 
   
   
       13 . (canceled) 
   
   
       14 . (canceled) 
   
   
       15 . (canceled) 
   
   
       16 . (canceled) 
   
   
       17 . (canceled) 
   
   
       18 . (canceled) 
   
   
       19 . A compound selected from the group consisting of
 3-[3-Chloro-2′-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-1-cyclohexyl-pyrrolidin-2-one hydrochloride salt;   3-[3-Chloro-3′-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-1-cyclohexyl-pyrrolidin-2-one hydrochloride salt;   3′-Chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-3-carboxylic acid piperidin-4-ylamide hydrochloride salt;   {[3′-Chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-3-carbonyl]-amino}-acetic acid;   {[3′-Chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-amino}-acetic acid;   4-{[3′-Chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-amino}-butyric acid;   3′-Chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid piperidin-4-ylamide trifluoroacetate salt; and   3-[3-Chloro-4′-(4-methyl-piperazine-1-carbonyl)-biphenyl-4-ylmethyl]-1-cyclohexyl-pyrrolidin-2-one hydrochloride salt,   or a pharmaceutically acceptable salt thereof.