Arylindenopyridines and related therapeutic and prophylactic methods

Abstract

This invention provides novel arylindenopyridines of the formula: and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

1 - 37 . (canceled)  
   
   
       38 . A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure;  
     
       
         
         
             
             
         
       
       wherein  
       (a) r 1  is selected from the group consisting of: 
 (i) —COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (ii) COOR 6 , wherein R 6  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (iii) cyano;  
 (iv) a lactone or lactam formed with R 4 ;  
 (v) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
 
       (b) R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C 3-7  cycloalkyl;  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (i) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (ii) —NR 10 R 11  wherein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (iii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 3 , are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,  
 
       (d) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14  wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O:  
       with the proviso that when R 4  is isopropyl, then R 3  is not halogen;  
       or comprising administering to the subject a therapeutically effective dose of a compound having the structure;  
       
         
           
           
               
               
           
         
       
       wherein  
       (a) R 1  is selected from the group consisting of: 
 (i) —COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl;  
       (ii) COOR 6 , wherein R 6  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl,  
       (i) cyano;  
       (ii) a lactone or lactam formed with R 4 ;  
       (iii) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
       (b) R 2  is —NR 15 R 16  wherein R 15  and R 16  are independently selected from hydrogen, optionally substituted C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, aryl, heteroaryl, and heterocyclyl or R 15  and R 16  taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R 2  is NHR 16 , R 1  is not —COOR 6  where R 6  is ethyl;  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (i) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (ii) —NR 10 R 11  wherein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 1  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (iii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;  
 
       (d) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 8  carboxylate, amino, NR 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O;  
       and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
     
   
   
       39 . A method of preventing a disorder ameliorated by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of a compound; having the structure;  
     
       
         
         
             
             
         
       
       wherein  
       (c) R 1  is selected from the group consisting of: 
 (j) —COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (vi) COOR 6 , wherein R 6  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (vii) cyano;  
 (viii) a lactone or lactam formed with R 4 ;  
 (ix) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
 
       (d) R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C 3-7  cycloalkyl:  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (j) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (iv) —NR 10 R 11  wherein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (v) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,  
 
       (d) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O:  
       with the proviso that when R 4  is isopropyl, then R 3  is not halogen:  
       or comprising administering to the subject a prophylactically effective dose of a compound having the structure;  
       
         
           
           
               
               
           
         
       
       wherein  
       (b) R 1  is selected from the group consisting of: 
 (j) —COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl;  
       (ii) COOR 6 , wherein R 6  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl;  
       (iv) cyano;  
       (v) a lactone or lactam formed with R 4 ;  
       (vi) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
       (b) R 2  is —NR 15 R 16  wherein R 15  and R 16  are independently selected from hydrogen, optionally substituted C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, aryl, heteroaryl, and heterocyclyl or R 15  and R 16  taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R 2  is NHR 16 , R 1  is not —COOR 6  where R 6  is ethyl;  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (iii) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (iv) —NR 10 R 11  herein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (iii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;  
 
       (di) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 13 R 14  aryl and heteroaryl; and  
       (e) X is selected from S and O;  
       and the pharmaceutically acceptable salts, esters and pro-drug forms thereof 
 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.  
 
     
   
   
       40 . The method of  claim 38  or  39  comprising administering to the subject a therapeutically or prophylactically effective dose of a pharmaceutical composition comprising a compound of  claim 38  and a pharmaceutically acceptable carrier.  
   
   
       41 . A method of inhibiting PDE activity in a subject, which comprises contacting one or more T-cells with a therapeutically effective dose of a compound having the structure;  
     
       
         
         
             
             
         
       
       wherein  
       (e) R 1  is selected from the group consisting of: 
 (k) —COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-18  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (x) COOR 6 , wherein R 6  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (xi) cyano;  
 (xii) a lactone or lactam formed with R 4 ;  
 (xiii) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
 
       (f) R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C 3-7  cycloalkyl;  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (k) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (vi) —NR 10 R 11  wherein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (vii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,  
 
       (d) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O;  
       with the proviso that when R 4  is isopropyl, then R 3  is not halogen,  
       or which comprises contacting one or more T-cells with a therapeutically effective dose of a compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein  
       (c) R 1  is selected from the group consisting of: 
 (k) —COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl,  
       (ii) COOR 6 , wherein R 6  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cyloalky benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl;  
       (vii) cyano;  
       (viii) a lactone or lactam formed with R 4 ;  
       (ix) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
       (b) R 2  is —NR 15 R 16  wherein R 15  and R 16  are independently selected from hydrogen, optionally substituted C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, aryl, heteroaryl, and heterocyclyl or R 15  and R 16  taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R 2  is NHR 16 , R 1  is not —COOR 6  where R 6  is ethyl;  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (v) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (vi) —NR 10 R 11  wherein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (iii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;  
 
       (dii) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O;  
       and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
     
   
   
       42 . The method of  claim 38 ,  39  or  41 , wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory-related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.  
   
   
       43 . The method of  claim 38 , wherein the disorder is selected from the group consisting of hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.  
   
   
       44 . A method of artificially modifying an animal, comprising administering to the animal's T-cells a compound having the structure;  
     
       
         
         
             
             
         
       
       wherein  
       (g) R 1  is selected from the group consisting of: 
 (l)—COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (xiv) COOR 6 , wherein R 6  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl; 
 (xv) cyano;  
 (xvi) a lactone or lactam formed with R 4 ;  
 (xvii) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
 
       (h) R 2  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C 3-7  cycloalkyl:  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (l) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (viii) —NR 10 R 11  wherein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (ix) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,  
 
       (d) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein l 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; 
 wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 13 R 14 , aryl and heteroaryl; and  
 
       (e) X is selected from S and O;  
       with the proviso that when R 4  is isopropyl, then R 3  is not halogen:  
       or comprising administering to the animal's T-cells a compound having the structure;  
       
         
           
           
               
               
           
         
       
       wherein  
       (d) R 1  is selected from the group consisting of: 
 (l) —COR 5 , wherein R 5  is selected from H, optionally substituted C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
 
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 21  wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl;  
       (ii) COOR 6 , wherein R 6  is selected from H, optionally substitute C 1-8  straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl;  
       wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1-8  alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 2 , wherein R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1-3  straight or branched chain alkyl, C 3-7  cycloalkyl benzyl, aryl, or heteroaryl or NR 20 R 21  taken together form a heterocycle or heteroaryl;  
       (x) cyano;  
       (xi) a lactone or lactam formed with R 4 ;  
       (xii) —CONR 7 R 8  wherein R 7  and R 8  are independently selected from H, C 1-8  straight or branched chain alkyl, C 3-7  cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; 
 wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl,  
 or R 7  and R 8  taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;  
 
       (b) R 2  is —NR 15 R 16  wherein R 15  and R 16  are independently selected from hydrogen, optionally substituted C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, aryl, heteroaryl, and heterocyclyl or R 15  and R 16  taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R 2  is NHR 16 , R 1  is not —COOR 6  where R 6  is ethyl;  
       (c) R 3  is from one to four groups independently selected from the group consisting of: 
 (vii) hydrogen, halo, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, aryl, heteroaryl, and heterocyclyl;  
 (viii) —NR 10 R 11  wherein R 10  and R 11  are independently selected from H, C 1-8  straight or branched chain alkyl, arylalkyl, C 3-7  cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R 10  and R 11  taken together with the nitrogen form a heteroaryl or heterocyclyl group;  
 (iii) —NR 12 COR 13  wherein R 12  is selected from hydrogen or alkyl and R 13  is selected from hydrogen, alkyl, substituted alkyl, C 1-3 alkoxyl, carboxyalkyl, R 30 R 31 N(CH 2 ) p —, R 30 R 31 NCO(CH 2 ) p —, aryl, arylalkyl, heteroaryl and heterocyclyl or R 12  and R 13  taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R 30  and R 31  are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;  
 
       (diii) R 4  is selected from the group consisting of (i) hydrogen, (ii) C 1-3  straight or branched chain alkyl, (iii) benzyl and (iv) —NR 13 R 14 , wherein R 13  and R 14  are independently selected from hydrogen and C 1-6  alkyl; wherein the C 1-3 alkyl and benzyl groups are optionally substituted with one or more groups selected from C 3-7  cycloalkyl, C 1-8  alkoxy, cyano, C 1-4  carboalkoxy, trifluoromethyl, C 1-8  alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C 1-8  carboxylate, amino, NR 13 R 14 , aryl and heteroaryl; and  
       (e) X is selected from S and O;  
       and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.  
     
   
   
       45 . A method of  claim 44  wherein the animal is a mammal.  
   
   
       46 . A method of  claim 45  wherein the animal is selected from the group consisting of mouse, rat, rabbit, and guinea pig.  
   
   
       47 . A method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of a compound having the structure of Formula I wherein R 4  is C 1-8  straight or branched chain alkyl and X is O.