Piperazine pde4 inhibitors and uses thereof

Abstract

The invention includes a compound of formula I: wherein R 1 , X, Z, n, and m have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds ate inhibitors of PDE 4 function and are useful for improving cognitive function in animals.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  i is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl; 
 n is 1 or 2; 
 m is 1 or 2; 
 W is O, S, or two hydrogens; 
 X is O or N—Y—R 4 ; 
 Y is a direct bond, —CH 2 —, —C(═O)—, —C(═S)—, —O—, —C(═O)O—, —OC(═O), —C(═O)NR a , —S—, —S(═O)—, —S(═O) 2 —, or —S(═O) 2 NR—; 
 R 4 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, hydroxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, carboxy, aryl, aryl(C 1 -C 6 )alkyl, het, NR d R e , —C(═O)NR d R e , NR d R e (C 1 -C 6 )alkyl, or het(C 1 -C 6 )alkyl; 
 R a  is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl; 
 Z is a phenyl ring substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, and (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; or Z is a phenyl ring that is fused to a saturated, partially unsaturated, or aromatic, mono- or bicyclic ring system comprising from about 3 to about 8 atoms selected from carbon, oxygen, and NR b , wherein the mono- or bicyclic ring system of Z is optionally substituted with one or more Re, and wherein the phenyl ring that is fused to the mono- or bicyclic ring system is optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; 
 R b  is absent, H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl; 
 R c  is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl; 
 each R d  and R e  is independently H, hydroxy, (C 1 -C 6 )alkyl, amino, amino(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, NR f R g , or aryl(C 1 -C 6 )alkoxy; and each R f  and R g  is independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkoxy; or R f  and R g  together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino ring; 
 wherein any aryl or het of R 1  or R4 is optionally substituted with one or more substitutents independently selected from (C 1 -C 6 )alkyl, phenyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyloxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, cyano, nitro, halo, carboxy or NR d R e ; 
 and wherein the ring containing X is optionally substituted on carbon with one or more halo, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1  wherein R 1  is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl. 
     
     
         3 . The compound of  claim 1  wherein R 1  is H, (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, or het. 
     
     
         4 . The compound of  claim 1  wherein R 1  is H, benzyl, indolyl, phenyl, 2-methylpropyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, a-phenylbenzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-phenylbenzyl, 4-ethoxybenzyl, isopropyl, cyclohexylmethyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl. 
     
     
         5 . The compound of  claim 1  wherein n is 1. 
     
     
         6 . The compound of  claim 1  wherein n is 2. 
     
     
         7 . The compound of  claim 1  wherein m is 1. 
     
     
         8 . The compound of  claim 1  wherein m is 2. 
     
     
         9 . The compound of  claim 1  wherein X is N—Y—R 4 . 
     
     
         10 . The compound of  claim 1  wherein Y is a direct bond, —CH 2 —, —C(═O)—, or —S(═O) 2 —. 
     
     
         11 . The compound of  claim 1  wherein R 4  is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, carboxy, aryl, aryl(C 1 -C 6 )alkyl, het, NR d R e , —C(═O)NR d R e , NR d R 6 (C 1 -C 6 )alkyl, or het(C 1 -C 6 )alkyl. 
     
     
         12 . The compound of  claim 1  wherein Y—R 4 is H, tert-butoxycarbonyl, formylmethyl, pyridylmethyl, methyl, ethylaminocarbonyl, ethylsulfonyl, benzylsulfonyl, benzyl, acetyl, methoxycarbonylmethyl, methylsulfonyl, ethyl, carboxymethyl, propyl, 2-hydroxyethyl, methoxyaminocarbonylmethyl, benzyloxyaminocarbonylmethyl, prop-2-eneyloxyaminocarbonylmethyl, hydroxyaminocarbonylmethyl, hydroxyacetyl, 2-methylhydrazocarbonylmethyl, hydrazocarbonylmethyl, 2,2-dimethylhydrazo-carbonylmethyl, or ethoxycarbonyl. 
     
     
         13 . The compound of  claim 1  wherein Z is a phenyl ring substituted with one or more substituents independently selected from (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkoxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy. 
     
     
         14 . The compound of  claim 1  wherein Z is a phenyl ring that is fused to a saturated, partially unsaturated, or aromatic, mono- or bicyclic ring system comprising from about 3 to about 8 atoms selected from carbon, oxygen, and NRb, wherein the mono- or bicyclic ring system of Z is optionally substituted with one or more Rc, and wherein the phenyl ring that is fused is fused to the mono- or bicyclic ring system is optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy. 
     
     
         15 . The compound of  claim 1  wherein Z has the following formula: 
       
         
           
           
               
               
           
         
       
       wherein R 2 is (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl; and R 3 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl. 
     
     
         16 . The compound of  claim 15  wherein R 2  is methyl and R 3  is cyclopropyl. 
     
     
         17 . The compound of  claim 1  wherein Z is selected from a structure of formula III, IV, and V: 
       
         
           
           
               
               
           
         
       
       that is optionally substituted with one or more substituents selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; wherein p is 1,2, 3,4, 5, or 6. 
     
     
         18 . The compound of  claim 1  wherein Z is selected from a structure of formula VI, VII, and VIII: 
       
         
           
           
               
               
           
         
       
       wherein: R j , R k , R m , R n , and R p  are each independently selected from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; and p is 1, 2, 3, 4, 5, or 6. 
     
     
         19 . The compound of  claim 18  wherein R j  and R k  are each independently selected from H and methyl; R m  is methoxy; R n  is cyclopentyl; R p  is ethyl; and p is 3. 
     
     
         20 . The compound of  claim 1  which is:
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methyl-benzyl)-piperazine; 
 (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine; 
 (2S,5S)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methyl-piperazine; 
 (2R,5S)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methyl-piperazine; 
 (R)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-one; 
 (S)-6-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-2-one; 
 (R)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methyl-benzyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methyl-benzyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methoxy-benzyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methoxy-benzyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methoxy-benzyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-ethoxy-benzyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenethyl-piperazine; 
 (R)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenethyl-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-phenyl-propyl)-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-naphthalen-1-ylmethyl-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-naphthalen-2-ylmethyl-piperazine; 
 (S)-3-Biphenyl-4-ylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine; 
 (S)-3-Benzhydryl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine; 
 (R)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-phenyl-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-isopropyl-piperazine; 
 (S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-isobutyl-piperazine; 
 (S)-3-Cyclohexylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine; 
 3-[(S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-ylmethyl]-1H-indole; 
 (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-[1,4]diazepane; 
 (R)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-[1,4]diazepane; 
 (S)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-[1,4]diazepane; 
 (R)-5-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-[1,4]diazepane; 
 1-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-morpholine; 
 4-[(S)-3-benzyl-1-piperzinyl]-7-methoxy-spiro[benzofuran-2(3H,1′-cyclopentane]; 
 6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-methyl-1H-indazole; 
 1-Cyclopentyl-3-ethyl-6-piperazin-1-yl-1H-indazole; 
 6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-methyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-ethyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-2-ylmethyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-3-ylmethyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-4-ylmethyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(3H-imidazol-4-ylmethyl)-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(1H-imidazol-2-ylmethyl)-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-methanesulfonyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-ethanesulfonyl-piperazine; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzylsulfonyl-piperazine; 
 1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylic acid ethylamide; 
 (S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylic acid ethyl ester; 
 1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone; 
 2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone, hydrochloride salt; 
 1 -[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-methylamino-ethanone, hydrochloride salt; 
 4-[(1-((S)-3-benzyl-4-piperazin-1-yl)-2-hydroxy-ethanone)]-7-methoxy-spiro[benzofuran-2(3H), 1′-cyclopentane]; 
 1-[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-2-hydroxy-ethanone; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester; 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid; 
 4-[(1-((S)-3-benzyl-4-piperazin-1-yl)-acetic acid)]-7-methoxy-spiro[benzofuran- 2( 3H), 1′-cyclopentane]; 
 [(S)-2-Benzyl-4-(l-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-acetic acid; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid hydrazide; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′-methyl-hydrazide; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′,N′-dimethyl-hydrazide; 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methoxy-acetamide; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-ethoxy-acetamide; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-isobutoxy-acetamide; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-phenoxy-acetamide; 
 N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide; or 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide. 
 
     
     
         21 . The compound of  claim 1  which is:
 (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine; 
 1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone; 
 2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone, hydrochloride salt; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid; 
 4-[(l-((S)-3-benzyl-4-piperazin-1-yl)-acetic acid)]-7-methoxy-spiro[benzofuran- 2( 3H), 1′-cyclopentane]; 
 [(S)-2-Benzyl-4-(l-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-acetic acid; 
 2-[(S)-2-Benzyl-4-(3-eye lopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide; 
 N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide; 
 2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid hydrazide; 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′-methyl-hydrazide; or 
 [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′,N′-dimethyl-hydrazide; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         22 . A pharmaceutical composition comprising a compound of  claim 1 , in combination with a pharmaceutically acceptable diluent or carrier. 
     
     
         23 . A therapeutic method for improving cognitive function in an animal comprising administering to the animal an effective amount of a compound of  claim 1 . 
     
     
         24 - 52 . (canceled)