Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents

Abstract

The present invention relates to novel heterocyclyl-containing diaryl sulfide compounds that are useful for treating inflammatory and immune diseases, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.

1 . A compound of formula I  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, 
 wherein R 1 , R 2 , R 3 , R 4  and R 5  are each independently selected from the group of hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, cycloalkyl, carboxaldehyde, 
 and a group of formula II defined as  
                     
 and wherein at least one of R 1  or R 3  is an oxazole of formula II;  
 wherein D, B, and Y are each independently selected from —CR 6 ═, —CR 7 R 8 —, —C(O)—, —O—, —SO 2 —, —S—, —N═, and —NR 9 —;  
 n is zero, with Z being replaced by a single or double bond between D and B;  
 
 R 6 , R 7 , R 8  and R 9 , at each occurrence, are each independently selected from the of hydrogen, alkyl, carboxy, hydroxyalkyl, alkylaminocarbonyl alkyl, dialkylaminocarbonylalkyl and carboxyalkyl; and  
 R 10  and R 11  are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; or  
 wherein R 10  and R 11  are taken together with N to form a three to seven membered unsubstituted heterocyclyl or a three to seven membered substituted heterocyclyl ring, substituted with at least one substituent R 13 , wherein R 13 , is independently selected from alkyl, alkylene, alkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylalkylaminocarbonyl, hydroxy, hydroxyalkyl, hydroxyalkoxyalkyl, carboxy, carboxyalkyl, carboxycarbonyl, carboxaldehyde, alkoxycarbonyl, arylalkoxycarbonyl, aminoalkyl, aminoalkanoyl, aminocarbonyl, carboxamido, alkoxycarbonylalkyl, carboxamidoalkyl, cyano, tetrazolyl, alkanoyl, hydroxyalkanoyl, alkanoyloxy, alkanoylamino, alkanoyloxyalkyl, alkanoylaminoalkyl, sulfonate, alkylsulfonyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl and heterocyclylsulfonylaminocarbonyl;  
 A is an unsubstituted aryl group, an unsubstituted heterocyclyl group, a substituted aryl, or a heterocyclyl group substituted with at least one substituent R 12 , wherein R 12  is independently selected from halogen, alkyl, aryl, haloalkyl, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkoxy, hydroxyalkyl, aminoalkyl, aminocarbonyl, alkyl(alkoxycarbonylalkyl) aminoalkyl, heterocyclyl, heterocyclylalkyl, carboxaldehyde, carboxaldehyde hydrazone, carboxamido, alkoxycarbonylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, hydroxyalkylaminocarbonyl, cyano, amino, heterocyclylalkylamino, carboxythioalkoxy, carboxycycloalkoxy, thioalkoxy, carboxyalkylamino, trans-cinnamyl and heterocyclylalkylaminocarbonyl; and 
 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12  and R 13  are unsubstituted or substituted with at least one electron donating or electron withdrawing group;  
 
 wherein the heterocyclyl is selected from 3-, 4-, 5-, 6- and 7-membered rings containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; the 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds, the heterocyclyl being optionally substituted with alkyl, halogen, hydroxy or alkyl substituents,  
 further wherein the heterocyclyl optionally comprises a group chosen 
 from:  
 (i) bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexane ring! a cyclopentane rings a cyclopentene ring and another monocyclic heterocyclic ring;  
 (ii) bridged bicyclic groups where a monocyclic heterocyclic group is bridged by alkylene group optionally selected from  
                     
 and  
 (iii) compounds of the formula  
                     
 where X* and Z* are each independently selected from —CH 2 —, —CH 2 NH—, —CH 2 O—, —NH—and —O—, with the proviso that at least one of X* and Z* is not —CH 2 —, and Y* is selected from —C(O)— and —(C(R″) 2 ) v , where R″ is hydrogen or alkyl of one to four carbons, and v is 1-3.  
 
 
   
   
       2 . The compound according to  claim 1  wherein R 3  is the group of formula II  
     
       
         
         
             
             
         
       
     
     wherein R 10 , R 11 , D, B, Ye Z, and n are defined as in  claim 1;  and R 1  is defined as in  claim 1  with the proviso that if R 3  does not define an oxazole, then R 1  is an oxazole.  
   
   
       3 . The compound according to of  claim 1  of formula III  
     
       
         
         
             
             
         
       
     
     wherein 
 p is an integer of one to five.  
 
   
   
       4 . The compound according to  claim 3  wherein p is one; 
 R 4  and R 5  are hydrogen;    R 12  is selected from of halogen, alkyl, alkoxy, carboxyalkoxy, carboxyalkyl and heterocyclyl;    R 10  and R 11  are taken together with N to form a three to seven membered unsubstituted heterocyclyl rings or a three to seven membered substituted heterocyclyl rings, substituted with at least one substituent R 13  and wherein said substituted heterocyclyl, or unsubstituted heterocyclyl ring is selected from the group consisting of piperidine, piperazine, morpholine, pyrrolidine, and azetidine.    
   
   
       5 . The compound according to  claim 3   
     wherein 
 R 10  and R 11  are each independently selected from the group selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino;  
 p is an integer of one to five.  
 
   
   
       6 . The compound according to  claim 5  wherein p is one; 
 R 10  and R 11  are taken together with N to form a three to seven membered substituted heterocyclyl ring, or a three to seven membered unsubstituted heterocyclyl ring, substituted with at least one substituent R 13 , wherein R 13  is defined as in  claim 1 , and wherein said substituted heterocyclyl ring, or unsubstituted heterocyclyl ring is selected from piperidine, piperazine, morpholine, pyrrolidine, and azetidine.    
   
   
       7 . The compound according to  claim 1 , selected from 1,-{4-[4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl]-oxazol-2-yl}-piperidine, 1-(4-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl]-oxazol-2-yl)piperidine, and Furan-2-ylmethyl-(4-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-amine.  
   
   
       8 . A composition comprising: 
 a compound according to  claim 1  and a pharmaceutically acceptable carrier.    
   
   
       9 . A method of inhibiting inflammation or suppressing immune response in a mammal comprising administering to said mammal a therapeutic amount of a compound according to  claim 1 .  
   
   
       10 . A compound according to  claim 1  wherein A is 
 (i) an unsubstituted or substituted aryl group, substituted by at least one substituent R 12 , wherein R 12  is defined as in  claim 1 , or    (ii) an unsubstituted or substituted heterocyclyl group of the formula                          wherein    R 12  is defined as in  claim 1;     p is an integer of one to three;    X* and Z* are each independently selected from —CH 2 —, —CH 2 NH—, —CH 2 O—, —NH—, and —O—, with the proviso that at least one of X* and Z* is not —CH 2 —; and    Y* is —(C(R″) 2 ) v —, wherein 
 R″ is hydrogen or alkyl; and  
 v is 1, 2, or 3.  
   
   
   
       11 . A compound according to  claim 1  wherein A is an unsubstituted or substituted aryl group, wherein the aryl group is 
 (I) a mono- or a bicyclic carbocyclic ring system having one or two aromatic rings, or    (ii) a mono- or a bicyclic carbocyclic ring system having one or two aromatic rings, 
 wherein one or more than one of the aromatic rings is fused to a ring selected from cyclohexane, cyclohexene, cyclopentane, and cyclopentene.  
   
   
   
       12 . A compound according to  claim 1  wherein A is an unsubstituted or substituted aryl group of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 12  is defined as in  claim 1;  and 
 p is an integer of one to five.  
 
   
   
       13 . A compound according to  claim 1  wherein 
 D is CR 6 ═ or —N═;    B is —S—, —O—, —CR 6 ═ or —N═; and    Y is —CR  6 ═ or —N═.    
   
   
       14 . A compound according to  claim 1  wherein R 3  is  
     
       
         
         
             
             
         
       
     
   
   
       15 . A compound according to  claim 1  wherein R 1  or R 3  is a group of formula II wherein 
 D is —CR  6 ═;    B is —O— or —S—; and    Y is —N═.    
   
   
       16 . A compound according to  claim 1  wherein 
 R 1  is selected from hydrogen, halogen, alkyl, nitro, and                          R 2  is selected from hydrogen, halogen, alkyl, and nitro;    R 4  and R 5  are each independently selected from hydrogen and alkyl; and    R 3  is                          wherein    D is —CR 6 ═ or —N═;    B is —S—, —O—, —CR 6 ═ or —N═;    Y is —CR 6 ═ or —N═; and    n is zero, with Z being replaced by a single or double bond between D and B.    
   
   
       17 . A compound according to  claim 1  wherein 
 R 1  and R 2  are each independently selected from hydrogen, halogen, and haloalkyl;    R 3  is an oxazole; and    R 4  and R 5  are each hydrogen.    
   
   
       18 . A compound according to  claim 1  wherein 
 R 1  is selected from hydrogen, halogen, haloalkyl, and                          R 2  is selected from hydrogen, halogen, and haloalkyl;    R 4  and R 5  are each hydrogen; and    R 3  is                          wherein 
 D is —CR 6 ═ or —N═;  
 B is —S—, —O—, —CR  6 ═ or —N═;  
 Y is —CR 6 ═ or —N═; and  
 n is zero, with Z being replaced by a single or double bond between D and B.  
   
   
   
       19 . A compound according to  claim 1  wherein 
 R 1  is selected from hydrogen, halogen, haloalkyl, and                          wherein    R 2  is selected from hydrogen, chloro, and trifluoromethyl;    R 4  and R 5  are each hydrogen; and    R 3  is                          
   
   
       20 . A compound according to  claim 1  wherein R 6  is hydrogen.  
   
   
       21 . A compound according to  claim 1  wherein 
 R 1  is selected from hydrogen, halogen, and haloalkyl;    R 2  is selected from hydrogen and halogen;    R 3  is an oxazole; and    R 4  and R 5  are each hydrogen.    
   
   
       22 . A compound according to  claim 22  wherein 
 R 1  is trifluoromethyl,    R 2  is hydrogen, and    R 3  is an oxazole.    
   
   
       23 . A compound according to  claim 21  wherein R 1  and R 2  are each chloro, and R 3  is an oxazole.  
   
   
       24 . A compound according to  claim 1  which has an IC 50  of less than 20 μM when tested in one or both of 
 (i) an ICAM-1/LFA-1 Biochemical Interaction Assay, or    (ii) an ICAM-1/JY-8 Cell Adhesion Assay    
   
   
       25 . A method for ameliorating a pathology in a mammal arising from the interaction of LFA-1 with ICAM-1 or ICAM-3 comprising administering to said mammal a therapeutic amount of a compound according to  claim 1 .  
   
   
       26 . A method according to  claim 25  wherein the pathology is selected from an inflammatory disease, an autoimmune disease, tumor metastasis, allograft rejection and reperfusion injury.  
   
   
       27 . A method of inhibiting the interaction of LFA-1 with ICAM-1 or ICAM -3, comprising administering to a mammal an effective amount of a compound according to  claim 1 , wherein administering to said mammal inhibits inflammation.  
   
   
       28 . A method for treating a disease or disorder selected from arthritis, Lyme arthritis, asthma, inflammatory lung injury, inflammatory bowel disease, inflammatory liver injury, inflammatory glomerular injury, radiation-induced enteritis, radiation pneumonitis, pulmonary reperfusion injury, stroke, peripheral artery occlusion, graft rejection, and graft-vs.-host disease, comprising administering to a mammal a therapeutic amount of a compound according to  claim 1 .  
   
   
       29 . A compound of formula I  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, 
 wherein R 1 , R 2 , R 4  and R 5  are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, cycloalkyl, carboxaldehyde, and a group of formula II defined as  
                     
 and wherein at least one of R 1  or R 3 is a thiazole of formula 11;  
 D, B, and Y are each independently selected from CR 6 ═, —CR 7 R 8 —, —C(O)—, —O—, —SO 2 —, —S—, —N═, and —NR 9 —;  
 n is zero, with Z being replaced by a single or double bond between D and B;  
 R 6 , R 7 , R 8  and R 9  are each independently selected from hydrogen, alkyl, carboxy, hydroxyalkyl, alkylaminocarbonyl alkyl, dialkylaminocarbonylalkyl and carboxyalkyl; and  
 R 10  and R 11  are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; or  
 R 10  and R 11  are taken together with N to form a three to seven membered unsubstituted heterocyclyl or a three to seven membered substituted heterocyclyl ring, substituted with at least one substituent R 13 , wherein R 13  is independently selected from alkyl, alkylene, alkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylalkylaminocarbonyl, hydroxy, hydroxyalkyl, hydroxyalkoxyalkyl, carboxy, carboxyalkyl, carboxycarbonyl, carboxaldehyde, alkoxycarbonyl, arylalkoxycarbonyl, aminoalkyl, aminoalkanoyl, aminocarbonyl, carboxamido, alkoxycarbonylalkyl, carboxamidoalkyl, cyano, tetrazolyl, alkanoyl, hydroxyalkanoyl, alkanoyloxy, alkanoylamino, alkanoyloxyalkyl, alkanoylaminoalkyl, sulfonate, alkylsulfonyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl and heterocyclylsulfonylaminocarbonyl;  
 A is an unsubstituted aryl group, an unsubstituted heterocyclyl group, a substituted aryl, or a heterocyclyl group substituted with at least one substituent R 12 , wherein R 12  is independently selected from halogen, alkyl, aryl, haloalkyl, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkoxy, hydroxyalkyl, aminoalkyl, aminocarbonyl, alkyl(alkoxycarbonylalkyl) aminoalkyl, heterocyclyl, heterocyclylalkyl, carboxaldehyde, carboxaldehyde hydrazone, carboxamido, alkoxycarbonylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, hydroxyalkylaminocarbonyl, cyano, amino, heterocyclylalkylamino, carboxythioalkoxy, carboxycycloalkoxy, thioalkoxy, carboxyalkylamino, trans-cinnamyl and heterocyclylalkylaminocarbonyl; 
 and  
 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12  and R 13  are unsubstituted or substituted with at least one electron donating or electron withdrawing group;  
 
 wherein the heterocyclyl is selected from 3-, 4-, 5-, 6- and 7-membered rings containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; the 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds, the heterocyclyl being optionally substituted with alkyl, halogen, hydroxy or alkyl substituents,  
 further wherein the heterocyclyl optionally comprises a group chosen from: 
 (i) bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexane ring, a cyclopentane ring, a cyclopentene ring, and another monocyclic heterocyclic ring;  
 (ii) bridged bicyclic groups where a monocyclic heterocyclic group is bridged by alkylene group optionally selected from  
                     
 and  
 (iii) compounds of the formula  
                     
 where X* and Z* are each independently selected from —CH 2 —, —CH 2 NH—, —CH 2 O—, —NH— and —O—, with the proviso that at least one of X* and Z* is not —CH 2 —, and Y* is selected from —C(O)— and —(C(R″) 2 ) v —, where R″ is hydrogen or alkyl of one to four carbons, and v is 1-3.  
 
 
   
   
       30 . The compound according to  claim 29  wherein R 3  is the group of formula II  
     
       
         
         
             
             
         
       
     
     wherein R 10 , R 11 , D, B, Y, Z, and n are defined as in  claim 1;  and R 1  is defined as in  claim 1  with the proviso that if R 3  does not define a thiazole, then R 1  is a thiazole.  
   
   
       31 . The compound according to  claim 29  of formula III  
     
       
         
         
             
             
         
       
     
     wherein p is an integer of one to five.  
   
   
       32 . The compound according to  claim 31   wherein p is one;    R 4  and R 5  are hydrogen;    R 12  is selected from halogen, alkyl, alkoxy, carboxyalkoxy, carboxyalkyl and heterocyclyl; and    R 10  and R 11  are taken together with N to form a three to seven membered unsubstituted heterocyclyl ring, or a three to seven membered substituted heterocyclyl ring, substituted with at least one substituent R 13  and wherein said substituted heterocyclyl, or unsubstituted heterocyclyl ring is selected from piperidine, piperazine, morpholine, pyrrolidine, and azetidine.    
   
   
       33 . The compound according to  claim 31  wherein R 10  and R 11  are each independently selected from the group selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; and 
 p is an integer of one to five.    
   
   
       34 . The compound according to  claim 33  wherein p is one; and 
 R 10  and R 11  are taken together with N to form a three to seven membered substituted heterocyclyl ring, or a three to seven membered unsubstituted heterocyclyl ring, substituted with at least one substituent R 13 , wherein R 13  is defined as in  claim 1 , and wherein said substituted heterocyclyl ring, or unsubstituted heterocyclyl ring is selected from piperidine, piperazine, morpholine, pyrrolidine, and azetidine.    
   
   
       35 . The compound according to  claim 29 , selected from 1-(4-(4-(2-Isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-piperazin-1-yl)ethanone, 4-(4-(2-Isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-(3-methoxy-propyl)-amine, 1-(4-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-piperidine, 4-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-(3-morpholin-4-yl-propyl)-amine, 4-(4-(2-Isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-(2-methoxy-ethyl)-amine, 4-(4-(2-Isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-(2-morpholin-4-yl-ethyl)-amine, 4-(4-(2-Isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-thiazol-2-yl)-(2-piperidin-1-yl-ethyl)-amine, 1-(4-(4-(2,3-Dichloro-4-(2-isopropyl-phenylsulfanyl)-phenyl)-piperazin-1-yl)-ethanone, and 1-(4-(2,3-Dichloro-4-(2-isopropyl-phenylsulfanyl)-phenyl)-thiazol-2-yl)-piperadine.  
   
   
       36 . A composition comprising: 
 a compound according to  claim 29     and a pharmaceutically acceptable carrier.    
   
   
       37 . A method of inhibiting inflammation or suppressing immune response in a mammal comprising administering to said mammal a therapeutic amount of a compound according to  claim 29 .  
   
   
       38 . A compound according to  claim 29  wherein A is 
 (i) an unsubstituted or substituted aryl group, substituted by at least one substituent R 12 , wherein R 12  is defined as in  claim 29 , or    (ii) an unsubstituted or substituted heterocyclyl group of the formula                          wherein    R 12  is defined as in  claim 29;     p is an integer of one to three;    X* and Z* are each independently selected from —CH 2 —, —CH 2 NH—, —CH 2 O—, —NH—, and —O—, with the proviso that at least one of X* and Z* is not —CH 2 —; and    Y* is —(C(R″) 2 ) v —, wherein 
 R″ is hydrogen or alkyl; and  
 v is 1, 2, or 3.  
   
   
   
       39 . The compound according to  claim 29  wherein A is an unsubstituted or substituted aryl group, wherein the aryl group is 
 (i) a mono- or a bicyclic carbocyclic ring system having one or two aromatic rings, or    (ii) a mono- or a bicyclic carbocyclic ring system having one or two aromatic rings, 
 wherein one or more than one of the aromatic rings is fused to a ring selected from cyclohexane, cyclohexene, cyclopentane, and cyclopentene.  
   
   
   
       40 . The compound according to  claim 29  wherein A is an unsubstituted or substituted aryl group of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 12  is defined as in  claim 29;  and 
 p is an integer of one to five.  
 
   
   
       41 . The compound according to  claim 29  wherein at least one of R 1 , R 2 , R 4  and R 5  is a group of formula II, wherein: 
 D is CR 6 ═or —N═;    B is —S—, —O—, —CR 6 ═or —N═; and    Y is —CR 6 ═or —N═.    
   
   
       42 . The compound according to  claim 29  wherein R 3  is  
     
       
         
         
             
             
         
       
     
   
   
       43 . The compound according to  claim 29  wherein R 1  or R 3  is a group of formula II wherein 
 D is —CR  6 ═;    B is —O— or —S—; and    Y is —N═.    
   
   
       44 . The compound according to  claim 29  wherein 
 R 1  is selected from hydrogen, halogen, alkyl, nitro, and                          R 2  is selected from hydrogen, halogen, alkyl, and nitro;    R 4  and R 5  are each independently selected from hydrogen and alkyl; and    R 3 is                          wherein 
 D is —CR 6 ═ or —N═;  
 B is —S—, —O—, —CR 6 ═or —N═;  
 Y is —CR 6 ═or —N═; and  
 n is zero, with Z being replaced by a single or double bond between D and B.  
   
   
   
       45 . The compound according to  claim 20  wherein 
 R 1  and R 2  are each independently selected from hydrogen, halogen, and haloalkyl;    R 3  is a thiazole; and    R 4  and R 5  are each hydrogen.    
   
   
       46 . The compound according to  claim 29  wherein 
 R 1  is selected from hydrogen, halogen, haloalkyl, and                          R 2  is selected from hydrogen, halogen, and haloalkyl; and    R 4  and R 5  are each hydrogen; and    R 3  is                          wherein 
 D is —CR 6 ═or —N═,  
 B is —S—, —O—, —CR 6 ═ or —N═,  
 Y is —CR 6 ═ or —N═; and  
 n is zero, with Z being replaced by a single or double bond between D and B.  
   
   
   
       47 . The compound according to  claim 29  wherein 
 R 1  is selected from hydrogen, halogen, haloalkyl, and                          R 2  is selected from hydrogen, chloro, and trifluoromethyl;    R 4  and R 5  are each hydrogen; and    R 3  is                          
   
   
       48 . The compound according to  claim 29  wherein R 6  is hydrogen.  
   
   
       49 . The compound according to  claim 29  wherein 
 R 1  is selected from hydrogen, halogen, and haloalkyl,    R 2  is selected from hydrogen and halogen,    R 3  is a thiazole, and    R 4  and R 5  are each hydrogen.    
   
   
       50 . The compound according to  claim 49  wherein 
 R 1  is trifluoromethyl,    R 2  is hydrogen, and    R 3  is a thiazole.    
   
   
       51 . The compound according to  claim 49  wherein R 1  and R 2  are each chloro, and R 3  is a thiazole.  
   
   
       52 . The compound according to  claim 29  which has an IC 50  of less than 20 μM when tested in one or both of 
 (i) an ICAM-1/LFA-1 Biochemical Interaction Assay, or    (ii) an ICAM-1/JY-8 Cell Adhesion Assay    
   
   
       53 . A method for ameliorating a pathology in a mammal arising from the interaction of LFA-1 with ICAM-1 or ICAM-3 comprising administering to said mammal a therapeutic amount of a compound according to  claim 29 .  
   
   
       54 . A method according to  claim 53  wherein the pathology is selected from an inflammatory disease, an autoimmune disease, tumor metastasis, allograft rejection and reperfusion injury.  
   
   
       55 . A method of inhibiting the interaction of LFA-1 with ICAM-1 or ICAM -3, comprising administering to a mammal an effective amount of a compound according to  claim 29 , wherein administering to said mammal inhibits inflammation.  
   
   
       56 . A method for treating a disease or disorder selected from arthritis, Lyme arthritis, asthma, inflammatory lung injury, inflammatory bowel disease, inflammatory liver injury, inflammatory glomerular injury, radiation-induced enteritis, radiation pneumonitis, pulmonary reperfusion injury, stroke, peripheral artery occlusion, graft rejection, and graft-vs.-host disease, comprising administering to a mammal a therapeutic amount of a compound according to  claim 29 .  
   
   
       57 . A compound of formula I  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, 
 wherein R 1 , R 2 , R 4  and R 5  are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, nitro, cycloalkyl, carboxaldehyde, and a group of formula II defined as  
                     
 and wherein at least one of R 1  or R 3  is a group of formula II;  
 formula II does not define a pyrimidine, pyridine, oxazole or thiazole;  
 D, B, Y and Z are each independently selected from CR 6 ═, —CR 7 R 8 —, —C(O)—, —O—, —SO 2 —, —S—, —N═, and —NR 9 —;  
 n is an integer of zero to three;  
 R 6 , R 7 , R 8  and R 9  are each independently selected from hydrogen, alkyl, carboxy, hydroxyalkyl, alkylaminocarbonyl alkyl, dialkylaminocarbonylalkyl and carboxyalkyl; and  
 R 10  and R 11  are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; or  
 R 10  and R 11  are taken together with N to form a three to seven membered unsubstituted heterocyclyl or a three to seven membered substituted heterocyclyl ring, substituted with at least one substituent R 13 , wherein R 13  is independently selected from alkyl, alkylene, alkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, heterocyclylalkylaminocarbonyl, hydroxy, hydroxyalkyl, hydroxyalkoxyalkyl, carboxy, carboxyalkyl, carboxycarbonyl, carboxaldehyde, alkoxycarbonyl, arylalkoxycarbonyl, aminoalkyl, aminoalkanoyl, aminocarbonyl, carboxamido, alkoxycarbonylalkyl, carboxamidoalkyl, cyano, tetrazolyl, alkanoyl, hydroxyalkanoyl, alkanoyloxy, alkanoylamino, alkanoyloxyalkyl, alkanoylaminoalkyl, sulfonate, alkylsulfonyl, alkylsulfonylaminocarbonyl, arylsulfonylaminocarbonyl and heterocyclylsulfonylaminocarbonyl;  
 A is an unsubstituted aryl group, an unsubstituted heterocyclyl group, a substituted aryl, or a heterocyclyl group substituted with at least one substituent R 12 , wherein R 12  is independently selected from halogen, alkyl, aryl, haloalkyl, hydroxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyalkoxy, hydroxyalkyl, aminoalkyl, aminocarbonyl, alkyl(alkoxycarbonylalkyl) aminoalkyl, heterocyclyl, heterocyclylalkyl, carboxaldehyde, carboxaldehyde hydrazone, carboxamido, alkoxycarbonylalkyl, carboxy, carboxyalkyl, carboxyalkoxy, hydroxyalkylaminocarbonyl, cyano, amino, heterocyclylalkylamino, carboxythioalkoxy, carboxycycloalkoxy, thioalkoxy, carboxyalkylamino, trans-cinnamyl and heterocyclylalkylaminocarbonyl; and 
 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12  and R 13  are unsubstituted or substituted with at least one electron donating or electron withdrawing group;  
 
 wherein the heterocyclyl is selected from 3-, 4-, 5-, 6- and 7-membered rings containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; the 4- and 5-membered rings have zero to two double bonds and the 6- and 7-membered rings have zero to three double bonds, the heterocyclyl being optionally substituted with alkyl, halogen, hydroxy or alkyl substituents,  
 further wherein the heterocyclyl optionally comprises a group chosen from: 
 (i) bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexane ring, a cyclopentane ring, a cyclopentene ring, and another monocyclic heterocyclic ring;  
 (ii) bridged bicyclic groups where a monocyclic heterocyclic group is bridged by alkylene group optionally selected from  
                     
                     
 and  
 (iii) compounds of the formula * where X* and Z* are each independently selected from —CH 2 —, —CH 2 NH—, —CH 2 O—, —NH— and —O—, with the proviso that at least one of X* and Z* is not —CH 2 —, and Y* is selected from —C(O)— and —(C(R″) 2 ) v —, where R″ is hydrogen or alkyl of one to four carbons, and v is 1-3.  
 
 
   
   
       58 . A compound according to  claim 57  of formula III  
     
       
         
         
             
             
         
       
     
     wherein p is an integer of one to five.  
   
   
       59 . A compound according to  claim 58  wherein p is one; 
 R 4  and R 5  are hydrogen;    R 12  is selected from halogen, alkyl, alkoxy, carboxyalkoxy, carboxyalkyl and heterocyclyl; and    R 10  and R 11  are taken together with N to form a three to seven membered unsubstituted heterocyclyl ring, or a three to seven membered substituted heterocyclyl ring, substituted with at least one substituent R 13  and wherein said substituted heterocyclyl, or unsubstituted heterocyclyl ring is selected from piperidine, piperazine, morpholine, pyrrolidine, and azetidine.    
   
   
       60 . The compound according to  claim 57  of the structure  
     
       
         
         
             
             
         
       
       R 1  and R 2  are each independently selected from hydrogen, halogen and haloalkyl;  
       R 10  and R 11  are each independently selected from the group selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, alkoxycarbonylalkyl, carboxyalkyl, hydroxyalkyl, heterocyclyl, heterocyclylalkyl and heterocyclylamino; and  
       p is an integer of one to five.  
     
   
   
       61 . A compound according to  claim 61  wherein p is one; and 
 R 10  and R 11  are taken together with N to form a three to seven membered substituted heterocyclyl ring, or a three to seven membered unsubstituted heterocyclyl ring, substituted with at least one substituent R 13 , wherein R 13  is defined as in  claim 57 , and wherein said substituted heterocyclyl ring, or unsubstituted heterocyclyl ring is selected from piperidine, piperazine, morpholine, pyrrolidine, and azetidine.    
   
   
       62 . A composition comprising: 
 the compound according to  claim 57     and a pharmaceutically acceptable carrier.    
   
   
       63 . A method of inhibiting inflammation or suppressing immune response in a mammal comprising administering to said mammal a therapeutic amount of a compound according to  claim 57 .  
   
   
       64 . The compound according to  claim 57  wherein A is 
 (i) an unsubstituted or substituted aryl group, substituted by at least one substituent R 12 , wherein R 12  is defined as in  claim 57 , or    (ii) an unsubstituted or substituted heterocyclyl group of the formula                          wherein 
 R 12  is defined as in  claim 57;   
 p is an integer of one to three;  
 X* and Z* are each independently selected from —CH 2 —, —CH 2 NH—, —CH 2 O—, —NH—, and —O—, with the proviso that at least one of X* and Z* is not —CH 2 —; and  
 Y* is —(C(R″) 2 ) v —, wherein 
 R″ is hydrogen or alkyl; and  
 v is 1, 2, or 3.  
 
   
   
   
       65 . The compound according to  claim 57  wherein A is an unsubstituted or substituted aryl group, wherein the aryl group is 
 (i) a mono- or a bicyclic carbocyclic ring system having one or two aromatic rings, or    (ii) a mono- or a bicyclic carbocyclic ring system having one or two aromatic rings, 
 wherein one or more than one of the aromatic rings is fused to a ring selected from cyclohexane, cyclohexene, cyclopentane, and cyclopentene.  
   
   
   
       66 . The compound according to  claim 57  wherein A is an unsubstituted or substituted aryl group of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 12  is defined as in  claim 57;  and 
 p is an integer of one to five.  
 
   
   
       67 . The compound according to  claim 57  wherein at least one of R 1 , R 2 , R 4  and R 5  is a group of formula II, 
 wherein: 
 D is CR 6 ═ or —N═;  
 B is —S—, —O—, —CR 6 ═ or —N═;  
 Y is —CR 6 ═ or —N═;  
 Z is —CR 6 ═ or —N═;  
 n is zero or one; and  
   wherein formula II does not define a pyrimidine, pyridine, oxazole or thiazole.    
   
   
       68 . The compound according to  claim 57  wherein R 1  is a group of formula 11 
 D is —CR 6 ═;    B is —O— or —S—;    Y is —N═;    n is zero; and    wherein formula II does not define a pyrimidine, pyridine, oxazole or thiazole.    
   
   
       69 . The compound according to  claim 57  wherein 
 R 1  is selected from hydrogen, halogen, alkyl, nitro, and                          R 2  is selected from hydrogen, halogen, alkyl, and nitro;    R 4  and R 5  are each independently selected from hydrogen and alkyl; and    R 3  is                          wherein 
 D is —CR 6 ═ or —N═,  
 B is —S—, —O—, —CR 6 ═ or —N═,  
 Y is —CR 6 ═ or —N═,  
 Z is —CR 6 ═ or —N═;  
 n is zero or one; and  
   wherein formula II does not define a pyrimidine, pyridine, oxazole or thiazole.    
   
   
       70 . The compound according to  claim 57  wherein 
 R 1  and R 2  are each independently selected from hydrogen, halogen, and haloalkyl; and    R 4  and R 5  are each hydrogen.    
   
   
       71 . The compound according to  claim 57  wherein 
 R 1  is selected from hydrogen, halogen, haloalkyl, and                          R 2  is selected from hydrogen, halogen, and haloalkyl;    R 4  and R 5  are each hydrogen; and    R 3 is                          wherein 
 D is —CR 6 ═ or —N═;  
 B is —S—, —O—, —CR 6 ═ or —N═;  
 Y is —CR 6 ═ or —N═;  
 Z is —CR 6 ═ or —N═;  
 n is zero or one; and  
   wherein formula II does not define a pyrimidine, pyridine, oxazole or thiazole.    
   
   
       72 . The compound according to  claim 57  wherein R 6  is hydrogen.  
   
   
       73 . The compound according to  claim 57  wherein 
 R 1  is selected from hydrogen, halogen, and haloalkyl;    R 2  is selected from hydrogen and halogen; and    R 4  and R 5  are each hydrogen.    
   
   
       74 . The compound according to  claim 74  wherein 
 R 1  is trifluoromethyl; and    R 2  is hydrogen.    
   
   
       75 . The compound according to  claim 74  wherein R 1  and R 2  are each chloro.  
   
   
       76 . The compound according to  claim 57  which has an IC50 of less than 20 μM when tested in one or both of 
 (i) an ICAM-1/LFA-1 Biochemical Interaction Assay, or    (ii) an ICAM-1/JY-8 Cell Adhesion Assay.    
   
   
       77 . A method for ameliorating a pathology in a mammal arising from the interaction of LFA-1 with ICAM-1 or ICAM-3 comprising administering to said mammal a therapeutic amount of a compound according to  claim 57 .  
   
   
       78 . A method according to  claim 78  wherein the pathology is selected from an inflammatory disease, an autoimmune disease, tumor metastasis, allograft rejection and reperfusion injury.  
   
   
       79 . A method of inhibiting the interaction of LFA-1 with ICAM-1 or ICAM -3, comprising administering to a mammal an effective amount of a compound according to  claim 57 , wherein administering to said mammal inhibits inflammation.  
   
   
       80 . A method for treating a disease or disorder selected from arthritis, Lyme arthritis, asthma, inflammatory lung injury, inflammatory bowel disease, inflammatory liver injury, inflammatory glomerular injury, radiation-induced enteritis, radiation pneumonitis, pulmonary reperfusion injury, stroke, peripheral artery occlusion, graft rejection, and graft-vs.-host disease, comprising administering to a mammal a therapeutic amount of a compound according to  claim 57.