Spiro-hydantoin compounds useful as anti-inflammatory agents

Abstract

Compounds having the formula (I), and pharmaceutically-acceptable salts, hydrates, enantiomers, and diastereomers, and prodrugs thereof, are useful as inhibitors of LFA-1/ICAM and as anti-inflammatory agents, wherein L and K are O or S; Z is N or CR 4b ; Ar is an optionally-substituted aryl or heteroaryl; G is a linker attached to T or M or is absent; J, M and T are selected to define a three to six membered saturated or partially unsaturated non-aromatic ring; and R 2 , R 4a , R 4b , and R 4c are as defined in the specification.

We claim:  
     
         1 . A compound according to formula (I),  
       
         
           
           
               
               
           
         
       
       its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof, in which: 
 L and K, taken independently, are O or S;  
 Z is N or CR 4b ;  
 Ar is aryl or heteroaryl;  
 G is attached to ring A at T or M; and (i) when attached to a carbon atom of ring A, G is selected from a bond, —O—, —N—, —S—, C 1-4 alkylene, C 1-4 substituted alkylene, or bivalent alkoxy, alkylthio, aminoalkyl, sulfonyl, sulfonamidyl, acyl, or alkoxycarbonyl; or (ii) when attached to a nitrogen atom of ring A, G is selected from a bond, C 1-4 alkylene, C 1-4 substituted alkylene, and bivalent acyl or alkoxycarbonyl, and a bivalent alkoxy, alkylthio, aminoalkyl, sulfonyl, or sulfonamidyl wherein in (ii), each of said G groups have at least one carbon atom directly attached to ring A;  
 J is —O—, —S—, —NR 3 —, —N═, —S(═O)—, —SO 2 —, —NHSO 2 —, a substituted or unsubstituted C 1-3 alkylene, a substituted or unsubstituted C 2-3 alkenylene, an unsubstituted C 1-2 heteroalkylene, a substituted heteroalkylene having from one to two carbon atoms in the heteroalkylene straight chain, or J is absent so that ring A is a three-membered ring;  
 T is T 1  when G-Ar is attached to T, and T 2  when G-Ar is attached to M;  
 M is M 1  when G-Ar is attached to M, and M 2  when G-Ar is attached to T;  
 T 1  and M 1  are selected from —N— and —C(R 5 )—;  
 T 2  and M 2  are selected from —O—, —S—, —N(R 6 )—, —N═, —S(═O)—, —SO 2 —, —NHSO 2 —, and —C(R 7 R 8 )—, provided that J, M, and T are selected so that ring A defines a three to six membered saturated or partially unsaturated cycloalkyl or heterocyclic ring having 1 to 4 heteroatoms, wherein no two adjacent heteroatoms of said heterocyclic ring A are simultaneously selected from —O— and —S—;  
 R 2  is selected from hydrogen, alkyl, substituted alkyl, OR 12 , NR 12 R 13 , C(═O)R 12 , CO 2 R 12 , C(═O)NR 12 R 13 , NR 12 C(═O)R 13 , NR 12 C(═O)OR 13 , S(O) p R 13a , NR 12 SO 2 R 13a , SO 2 NR 12 R 13 , cycloalkyl, heterocyclo, aryl, and heteroaryl;  
 R 4a , R 4b  and R 4c  are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, nitro, cyano, SR 14 , OR 14 , NR 14 R 15 , NR 14 C(═O)R 15 , CO 2 R 14 , C(═O)R 14 , —C(═O)NR 14 R 15 , aryl, heterocyclo, cycloalkyl, and heteroaryl;  
 R 3  and R 6  are independently selected from hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, alkenyl, substituted alkenyl, aminoalkyl, alkylthio, C(═O)H, acyl, amide, alkoxycarbonyl, sulfonyl, sulfonamidyl, cycloalkyl, heterocyclo, aryl, and heteroaryl;  
 R 5 , R 7 , and R 8  are (i) independently selected from hydrogen, alkyl, substituted alkyl, halogen, nitro, cyano, hydroxy, alkoxy, alkenyl, substituted alkenyl, aminoalkyl, alkylthio, C(═O)H, acyl, CO 2 H, amide, alkoxycarbonyl, sulfonyl, sulfonamidyl, cycloalkyl, heterocyclo, aryl, and heteroaryl; or (ii) R 7  with R 8  may form a cycloalkyl or heterocyclic ring or a double bond to an oxygen atom to define a keto (═O) group; or (iii) one of R 5  or R 8  may be a bond so that there is a double bond between T and M, or between M and J, respectively, so that ring A is partially unsaturated;  
 R 12 , R 13 , R 14  and R 15  (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R 12  is taken together with R 13 , and/or R 14  is taken together with R 15  to form a heteroaryl or heterocyclo ring;  
 R 13a  is selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; and  
 p is 1 or 2.  
 
     
     
         2 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein: 
 G is a bond;    Ar is an aryl or heteroaryl substituted with one to three R 1 ;    R 1  is selected from alkyl, substituted alkyl, halogen, cyano, nitro, OR 10 , NR 10 R 11 , C(═O)R 10 , CO 2 R 10 , C(═O)NR 10 R 11 , NR 10 C(═O)R 11 , NR 10 C(═O)OR 11 , SR 10 , S(O) o R 10a , NR 10 SO 2 R 10a , NHCH(alkyl)CO 2 R 10 , SO 2 NR 10 R 11 , cycloalkyl, heterocyclo, aryl, and heteroaryl;    R 10  and R 11  (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R 10  is taken together with R 11  to form a heteroaryl or heterocyclo;    R 10a  is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; and    o is 1 or 2.    
     
     
         3 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 J is selected from —O—, —S—, —S(═O)—, —SO 2 —, or —NHSO 2 —; or J is C 1-3 alkylene, C 2-3 alkenylene, or C 1-2  heteroalkylene optionally substituted with one to two R 9 ;    R 9  is -A 1 -Q-A 2 -R 16 ;    A 1  is a bond, C 1-2 alkylene, or C 2-3 alkenylene;    Q is a bond, —C(═O)—, —C(═O)NR 17 —, —C(═S)NR 17 —, —SO 2 —, —SO 2 NR 17 —, —CO 2 —, or —NR 17 CO 2 —;    A 2  is a bond, C 1-3 alkylene, C 2-3 alkenylene, —C 1-4 alkylene-NR 17 —, —C 1-4 alkylene-NR 17 C(═O)—, —C 1-4 alkylene-S—, —C 1-4 alkylene-SO 2 —, or —C 1-4 alkylene-O—, wherein said A 2  alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO 2 H, —CO 2 (C 1-4 alkyl), —S(C 1-4 alkyl), NH 2 , —NH(C 1-4 alkyl), or —N(C 1-4 alkyl) 2 ;    R 16  is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; and    R 17  is hydrogen or alkyl.    
     
     
         4 . A compound according to  claim 3 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 16  is selected from cycloalkyl, heterocyclo, aryl or heteroaryl optionally substituted with one to three R 18 ;    R 18  is selected from C 1-6 alkyl, substituted C 1-6 alkyl, halogen, cyano, nitro, OR 20 , NR 20 R 21 , C(═O)R 20 , CO 2 R 20 , C(═O)NR 20 R 21 , C(═O)NR 20 SO 2 R 20a , NR 20 C(═O)R 21 , NR 20 C(═O)OR 21 , SR 20 , S(O) u R 20a , NR 20 SO 2 R 20a , NHCH(alkyl)CO 2 R 20 , SO 2 NR 20 R 21 , C 3-7 cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl, said C 3-7 cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl groups in turn being optionally substituted with one to two R 22 ;    R 20  and R 21  are selected from hydrogen, alkyl, alkenyl, C 3-7 cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocylo, or a five to six membered heteroaryl, or when attached to the same nitrogen atom may join to form a heterocyclo or heteroaryl; wherein each of R 20  and R 21  in turn is optionally substituted with one to two R 22 ;    R 20a  is selected from hydrogen, alkyl, alkenyl, CO 2 H, CO 2 (alkyl), C 3-7 cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocyclo, or a five to six membered heteroaryl; wherein each R 20a  in turn is optionally substituted with one to two R 22 ; and    R 22  is selected from the group consisting of (C 1-4 )alkyl, (C 2-4 )alkenyl, hydroxy, cyano, CF 3 , O(C 1-4 alkyl), OCF 3 , C(═O)H, C(═O)(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), NHCO 2 (C 1-4 alkyl), —S(C 1-4 alkyl), —NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(CH 3 ) 3   + , SO 2 (C 1-4 alkyl), C(═O)(C 1-4 alkylene)NH 2 , C(═O)(C 1-4 alkylene)NH(alkyl), and C(═O)(C 1-4 alkylene)N(C 1-4 alkyl) 2 .    
     
     
         5 . A compound according to  claim 4 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which:  
       Ar is  
       
         
           
           
               
               
           
         
         T 1  and M 1  are selected from —N— and —CH—, and T 2  and M 2  are selected from O, S, NH, S(═O), SO 2 , NHSO 2 , —C(═O)— and —CH 2 —;  
         J is a —C 2-3 alkylene optionally substituted with one to two R 9 , —(CH 2 ) y —NH—, or —(CH 2 ) y —NR 9 —;  
         R 1a  and R 1b  are independently selected from halogen, C 1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, —C(═O)alkyl, —C(═O)NH(CH 2 ) 1-4 CO 2 H, —C(═O)NH(CH 2 ) 1-4 CO 2 (alkyl), and S(O) 2 alkyl; or from phenyl, benzyl, phenyloxy, benzyloxy and heteroaryl in turn optionally substituted with halogen, C 1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, and/or —C(═O)alkyl; or alternatively, two R 1b  groups join together with each other or one R 1b  joins together with R 1a  to form a fused benzo ring;  
         R 4a  and R 4c  are selected from halogen, alkyl, cyano, haloalkyl, haloalkoxy, nitro, aryloxy, and arylthio;  
         R 4b  is hydrogen, halogen, alkyl, substituted alkyl, nitro, cyano, hydroxy, alkoxy, haloalkoxy, phenyloxy, —CO 2 H, —C(═O)H, —NH(alkyl), —N(alkyl) 2 , —CO 2 alkyl, —C(═O)alkyl, alkylthio, —C(═O)NH(CH 2 ) 1-4 CO 2 H, —C(═O)NH(CH 2 ) 1-4 CO 2 (alkyl), aryl, heteroaryl, or heterocyclo, wherein each of the aryl, heteroaryl, and heterocyclo groups are optionally substituted with one to two halogen, C 1-4 alkyl, OMe, CF 3 , CN, OCF 3 , CO 2 H, C(═O)H, CO 2 alkyl, and/or C(═O)alkyl;  
         n is 0, 1, or 2; and  
         y is 0, 1 or 2.  
       
     
     
         6 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound according to  claim 6 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which R 1a  is halogen or cyano, and R 4a  and R 4c  are independently selected from halogen, alkyl, cyano, trifluoromethyl, and nitro.  
     
     
         8 . A compound according to  claim 3 , having the formula (Ie),  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 1a  and R 1b  are independently selected from halogen, C 1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, —C(═O)alkyl, —C(═O)NH(CH 2 ) 1-4 CO 2 H, —C(═O)NH(CH 2 ) 1-4 CO 2 (alkyl), and S(O) 2 alkyl; or from phenyl, benzyl, phenyloxy, benzyloxy and heteroaryl in turn optionally substituted with halogen, C 1-4 alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, and/or —C(═O)alkyl; or alternatively, two R 1b  groups join together with each other or one R 1b  joins together with R 1a  to form a fused benzo ring; and 0, 1 or 2.  
 
     
     
         9 . A compound according to  claim 8 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 1a  is halogen, cyano, nitro, trifluoromethyl, OCF 3 , aryl or heteroaryl;    R 1b  is halogen, C 1-4 alkyl, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, or —C(═O)alkyl;    R 2  is hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with CO 2 H or CO 2 (C 1-4 alkyl);    R 9  is selected from hydrogen, C 1-10 alkyl, substituted C 1-10 alkyl, C 2-10 alkenyl, substituted C 2-10 alkenyl, C 3-6 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, —(CH 2 ) s phenyl, —(CH 2 ) s tetrazolyl, —(CH 2 ) s pyridyl, —(CH 2 ) s thienyl, —(CH 2 ) s carbazolyl, —(CH 2 ) s indolyl, —(CH 2 ) s furyl, —(CH 2 ) s quinolyl, —(CH 2 ) s C 3-6 cycloalkyl, —(CH 2 ) s thiazolyl, —(CH 2 ) s pyrrolyl, —(CH 2 ) s imidazolyl, —(CH 2 ) s isoxazolyl, —(CH 2 ) s benzofuryl, —(CH 2 ) s pyrazolyl, —C(═O)H, —C(═O)(alkyl), —C(═O)C 1-10 alkyl, —C(═O)phenyl, —C(═O) s piperidyl, —C(═O)morpholinyl, —C(═O)C 3-6 cycloalkyl, —C(═O)pyrrolidinyl, —C(═O)quinolyl, —C(═O)imidazolyl, —C(═O)pyrazolyl, —C(═O)thiazolyl, —C(═O)quinoxalinyl, —C(═O)pyridyl, —C(═O)-1,2,5,6-tetrahydropyridyl, —C(═O)benzothiazolyl, —C(═O)benzotriazolyl, —C(═O)benzodioxanyl, —C(═O)benzooxadiazolyl, —C(═O)1,2,3,4-tetrahydroquinolyl, —C(═O)thienopyrazolyl, —C(═O)(CH 2 ) s tetrazolyl, —C(═O)(CH 2 ) s pyridyl, —C(═O)(CH 2 ) s phenyl, —C(═O)(CH 2 ) s pyrrolidinyl, —C(═O)(CH 2 ) s piperidyl, —C(═O)CH═CH(phenyl), —C(═O)CH═CH(pyridyl), —C(═O)CH 2 O (alkyl), —C(═O)CH 2 S(alkyl), —C(═O)CH 2 S(pyridyl), —C(═O)CH 2 SO 2 (alkyl), —C(═O)CH 2 SO 2 (phenyl), —C(═O)CH 2 NH(phenyl), —C(═O)CH 2 NH(benzyl), —C(═O)CH 2 NH(thiazolyl), —C(═O)CH 2 NHC(═O)pyridyl, —C(═O)CH 2 NHC(═O)phenyl, —(CH 2 ) t SO 2 (alkyl), —(CH 2 ) t SO 2 (phenyl), —(CH 2 ) t SO 2 (thienyl), —(CH 2 ) t SO 2 (imidazolyl), —(CH 2 ) t SO 2 (furyl), (CH 2 ) t SO 2 (pyrrolyl), SO 2 NH(phenyl), —C(═S)NH 2 , —C(═S)NH(alkyl), —C(═S)NH(phenyl), —(CH 2 )C(═O)pyrrolidinyl, —(CH 2 )C(═O)piperidyl, —(CH 2 )C(═O)piperazinyl, —CO 2 (alkyl), —CO 2 (phenyl), —CO 2 (benzyl), NHCO 2 (alkyl), —(CH 2 ) t C(═O)NH(phenyl), —(CH 2 ) t C(═O)NH(piperidyl), —(CH 2 ) t C(═O)NH(thienyl), —(CH 2 ) t C(═O)NH(thiazolyl), —(CH 2 ) t C(═O)NH(cyclopentyl), —(CH 2 ) t C(═O)NH(cyclopentenyl), —(CH 2 ) t C(═O)NH(benzyl), —(CH 2 ) t C(═O)NH(pyrrolidinyl), —(CH 2 ) t C(═O)NH(piperazinyl), —(CH 2 ) t C(═O)NH 2 , —(CH 2 ) t C(═O)NH(alkyl), —(CH 2 ) t C(═O)N(alkyl) 2 , —(CH 2 ) t C(═O)N(C 1-4 alkyl)(phenyl), —(CH 2 ) t C(═O)N(C 1-4 alkyl)(thienyl), —(CH 2 ) t C(═O)N(C 1-4 alkyl) (thiazolyl), —(CH 2 ) t C(═O)N(C 1-4 alkyl)(benzyl), —(CH 2 ) t C(═O)N(C 1-4 alkyl)CO 2 (alkyl), wherein each R 9  is optionally substituted with one to two R 18 ;    R 18  is selected from —(CH 2 ) q  halogen, —(CH 2 ) q nitro, —(CH 2 ) q cyano, —(CH 2 ) q  haloalkyl, —(CH 2 ) q  haloalkoxy, (CH 2 ) q SR 24 , C 3-7 cycloalkyl, —SO 2 R 24 , —OR 24 , —(CH 2 ) q CO 2 R 24 , —(CH 2 ) q NR 24 R 25 , —(CH 2 ) q NHCO 2 R 24 , —C(═O)NH—SO 2 R 24 , —C(═O)(CH 2 ) q NR 24 R 25 , —O(CH 2 ) r NR 24 R 25 , —C(═O)R 24 , —(CH 2 ) q R 24  and —C 1-4 alkyl or —C 2-4 alkenyl optionally substituted with CO 2 R 24 ;    R 24  is selected from hydrogen, alkyl, phenyl, benzyl, C 3-7 cycloalkyl, five or six membered heteroaryl, and four to seven membered heterocyclo, in turn optionally substituted with one to two C 1-4 alkyl, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, —CO 2 H, CO 2 C 1-4 alkyl, C 1-4 alkoxy, —S(C 1-4 alkyl), amino, and/or aminoC 1-4 alkyl, provided that when R 24  is attached to a sulfonyl group as in —SO 2 R 24 , then R 24  is not hydrogen;    R 25  is selected from hydrogen and alkyl; and    n is 0, 1, or 2;    p is 1 or 2;    q is 0, 1, 2, 3, or 4;    r is 1, 2, 3, or 4;    s is 0, 1, 2, 3, or 4; and    t is 1, 2, 3, or 4.    
     
     
         10 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein J is selected from:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         A 1  is a bond, C 1-2 alkylene, or C 2-3 alkenylene;  
         Q is a bond, —C(═O)—, —C(═O)NR 17 —, —SO 2 —, —CO 2 —, or —NR 17 CO 2 —;  
         A 2  is a bond, C 1-3 alkylene, C 2-3 alkenylene, —C 1-4 alkylene-NR 17 —, —C 1-4 alkylene-NR 17 C(═O)—, —C 1-4 alkylene-S—, —C 1-4 alkylene-SO 2 —, or —C 1-4 alkylene-O—, wherein said A 2  alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO 2 H, —CO 2 (C 1-4 alkyl), —S(C 1-4 alkyl), NH 2 , —NH(C 1-4 alkyl), or —N(C 1-4 alkyl) 2 ;  
         R 17  is hydrogen or alkyl;  
         R 18  and R 19  are selected from hydrogen, (C 1-6 ) alkyl, (C 2-6 ) alkenyl, CO 2 H, CO 2 (C 1-6 alkyl), C(═O)H, C(═O)(C 1-6 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, (C 1-4 )haloalkyl, (C 1-4 )haloalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , —C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), —C(═O)NHSO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), phenyl, C 3-7 cycloalkyl, five to six membered heteroaryl, and four to seven membered heterocyclo, wherein each group R 18  and R 19  in turn is optionally substituted with one to two of (C 1-4 ) alkyl, (C 2-4 ) alkenyl, CO 2 H, CO 2 (C 1-4 alkyl), C(═O)H, C(═O)(C 1-4 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, trifluoromethyl, trifluoromethoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , —C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), and/or SO 2 (C 1-4 alkyl);  
         f is 0, 1, 2 or 3; and  
         g is −1, 0, 1, or 2.  
       
     
     
         11 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein Z is CR 4b .  
     
     
         12 . A compound according to  claim 3 , having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein J is selected from one of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A compound according to  claim 1 , having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 1a  is halogen, cyano, nitro, trifluoromethyl, OCF 3 , aryl or heteroaryl;  
 R 1b  is halogen, C 1-4 alkyl, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, or —C(═O)alkyl;  
 R 2  is hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with CO 2 H or CO 2 (C 1-4 alkyl);  
 R 18  is selected from (C 1-4 ) alkyl, CO 2 H, CO 2 (C 1-4 alkyl), C(═O)H, C(═O)(C 1-4 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, (C 1-4 )haloalkyl, (C 1-4 )haloalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , —C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), —C(═O)NHSO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;  
 f is 0, 1, 2 or 3; and  
 n is 0 or 1.  
 
     
     
         14 . A compound according to  claim 1 , having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 1a  is halogen, cyano, nitro, trifluoromethyl, OCF 3 , aryl or heteroaryl; R 1b  is halogen, C 1-4 alkyl, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, or —C(═O)alkyl;  
 R 2  is hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with CO 2 H or CO 2 (C 1-4 alkyl);  
 R 18  is selected from (C 1-4 ) alkyl, CO 2 H, CO 2 (C 1-4 alkyl), C(═O)H, C(═O)(C 1-4 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, (C 1-4 )haloalkyl, (C 1-4 )haloalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , —C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), —C(═O)NHSO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;  
 f is 0, 1, 2 or 3; and  
 n is 0 or 1.  
 
     
     
         15 . A compound having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 L and K, taken independently, are O or S;  
 Z is N or CR 4b ;  
 J is selected from —(CR 9a R 9c ) x — and —(CR 9a R 9b ) y —NR 9c —(CR 9a R 9b ) z —, wherein x is 1, 2 or 3, y is 0, 1 or 2, and z is 0, 1 or 2, provided that y and z together are not greater than 2;  
 T 1  is —N— or —CH—;  
 R 1a  and R 1b  are independently selected from alkyl, substituted alkyl, halogen, cyano, nitro, OR 10 , NR 10 R 11 , C(═O)R 10 , CO 2 R 10 , C(═O)NR 10 R 11 , NR 10 C(═O)R 11 , NR 10 C(═O)OR 11 , SR 10 , S(O)R 10a , NR 10 SO 2 R 10a , NHCH(alkyl)CO 2 R 10 , SO 2 NR 10 R 11 , cycloalkyl, heterocyclo, aryl, and heteroaryl; or alternatively, two R 1b  groups join together with each other or one R 1b  joins together with R 1a  to form a fused benzo ring;  
 R 2  is selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, and heteraryl;  
 R 4a , R 4b , and R 4c  are selected from halogen, alkyl, cyano, haloalkyl, haloalkoxy, aryloxy, arylthio, and nitro;  
 R 9 a and R 9b  at each occurrence are independently selected from hydrogen, halogen, C 1-4 alkyl, hydroxy, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, or cyano, or R 9a  and R 9b  together form keto (═O);  
 R 9c  is selected from hydrogen and Al-Q-A 2 -R 16 ;  
 A 1  is a bond, C 1-2 alkylene, or C 2-3 alkenylene;  
 Q is a bond, —C(═O)—, —C(═O)NR 17 —, —SO 2 —, —CO 2 —, or —NR 17 CO 2 —;  
 A 2  is a bond, C 1-3 alkylene, C 2-3 alkenylene, —C 1-24 alkylene-NR 17 —, —C 1-4 alkylene-NR 17 C(═O)—, —C 1-4 alkylene-S—, —C 1-4 alkylene-SO 2 —, or —C 1-4 alkylene-O—, wherein said A 2  alkylene groups are branched or straight chain and optionally substituted with a group selected from —CO 2 H, —CO 2 (C 1-4 alkyl), —S(C 1-4 alkyl), NH 2 , —NH(C 1-4 alkyl), or —N(C 1-4 alkyl) 2 ;  
 R 10  and R 11  (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R 10  is taken together with R 12  to form a heteroaryl or heterocyclo;  
 R 10a  is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo;  
 R 16  is selected from alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclo, wherein each R 16  is optionally substituted with one to three R 18 ;  
 R 17  is hydrogen or alkyl;  
 R 18  is selected from C 1-6 alkyl, substituted C 1-6 alkyl, halogen, cyano, nitro, OR 20 , NR 20 R 21 , C(═O)R 20 , CO 2 R 20 , C(═O)NR 20 R 21 , C(═O)NR 20 SO 2 R 20a , NR 20 C(═O)R 21 , NR 20 C(═O)OR 21 , SR 20 , S(O) u R 20a , NR 20 SO 2 R 20a , NHCH(alkyl)CO 2 R 20 , NH—(CH 2 ) 1-4 —CO 2 R 20 , SO 2 NR 20 R 21 , C 3-7 cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl, said C 3-7 cycloalkyl, phenyl, four to seven membered heterocyclo, or five or six membered heteroaryl groups in turn being optionally substituted with one to two R 22 ;  
 R 20  and R 21  are selected from hydrogen, alkyl, alkenyl, C 3-7 cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocylo, or a five to six membered heteroaryl, or when attached to the same nitrogen atom may join to form a heterocyclo or heteroaryl; wherein each of R 20  and R 21  in turn is optionally substituted with one to two R 22 ;  
 R 20a  is selected from alkyl, alkenyl, CO 2 H, CO 2 (alkyl), C 3-7 cycloalkyl, phenyl, benzyl, phenylethyl, napthyl, a four to seven membered heterocylo, or a five to six membered heteroaryl; wherein each R 20a  in turn is optionally substituted with one to two R 22 ;  
 R 22  is selected from the group consisting of (C 1-6 )alkyl, (C 2-6 )alkenyl, hydroxy, cyano, CF 3 , O(C 1-6 alkyl), OCF 3 , C(═O)H, C(═O)(C 1-6 alkyl), CO 2 H, CO 2 (C 1-6 alkyl), NHCO 2 (C 1-6 alkyl), —S (C 1-6 alkyl), —NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , N(CH 3 ) 3   + , SO 2 (C 1-6 alkyl), C(═O)(C 1-4 alkylene)NH 2 , C(═O)(C 1-4 alkylene)NH(alkyl), and C(═O)(C 1-4 alkylene)N(C 1-4 alkyl) 2 ;  
 o and u are independently 1 or 2; and  
 n is 0, 1 or 2.  
 
     
     
         16 . A compound according to  claim 15 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R 4a  and R 4c  are chloro.  
     
     
         17 . A compound according to  claim 15 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R 1a  is cyano or halogen.  
     
     
         18 . A compound according to  claim 15 , having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof.  
     
     
         19 . A compound according to  claim 18 , or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 2  is selected from hydrogen, C 1-6 alkyl, and C 1-6 alkyl substituted with amino, NH(C 1-4 alkyl), N(alkyl) 2 , C(═O)H, C(═O)C 1-4 alkyl, CO 2 H, CO 2 (C 1-4 alkyl), SO 2 C 1-4 alkyl, SO 3 H, and/or PO(OH) 2 ;    R 4a  and R 4b  are selected from halogen, C 1-4 alkyl, cyano, halo C 1-4 alkyl, and haloC 1-4 alkoxy;    J is —(CHR 9c ) x — or —(CH 2 ) y —NR 9c ;    R 9c  is Al-Q-A 2 -R 16 ;    R 16  is selected from (a) hydrogen and C 1-6 alkyl or C 2-6 alkenyl optionally substituted with one to two of OH, O(C 1-4 alkyl), —CO 2 H, —CO 2 (C 1-4 alkyl), NH 2 , —NH(C 1-4 alkyl), and/or N(C 1-4 alkyl) 2 , or from (b) furanyl, indolyl, carbazolyl, pyrazolyl, pyrrolyl, thienyl, pyridyl, pyrimidinyl, benzofuranyl, isoxazolyl, imidazolyl, triazolyl, tetrazolyl, phenyl, piperidyl, pyrrolidinyl, pyridazinyl, C 3-7 cycloalkyl, piperazinyl, thiazolyl, morpholinyl, 1,2,5,6-tetrahydropyridyl, quinoxalinyl, benzothiazolyl, benzotriazolyl, benzodioxanyl, benzooxadiazolyl, thienopyrazolyl, tetrahydroquinolinyl, and quinolinyl, wherein each of said cyclic R 16  groups in turn is optionally substituted with up to three R 18 ;    R 17  is hydrogen or alkyl; and    R 18  is selected from hydrogen, (C 1-6 )alkyl, (C 2-6 )alkenyl, CO 2 H, CO 2 (C 1-6 alkyl), C(═O)H, C(═O)(C 1-6 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, (C 1-4 )haloalkyl, (C 1-4 )haloalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , —C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), phenyl, C 3-7 cycloalkyl, five to six membered heteroaryl, and four to seven membered heterocyclo, wherein each group R 18  in turn is optionally substituted with one to two of (C 1-4 ) alkyl, (C 2-4 ) alkenyl, CO 2 H, CO 2 (C 1-4 alkyl), C(═O)H, C(═O)(C 1-4 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, trifluoromethyl, trifluoromethoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), and/or SO 2 (C 1-4 alkyl).    
     
     
         20 . A compound according to  claim 19 , having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 1a  is cyano or halogen;  
 R 1b  is halogen, C 1-4 alkyl, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, or —C(═O)alkyl;  
 R 2  is hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with CO 2 H or CO 2 (C 1-4 alkyl);  
 R 18  is selected from (C 1-4 ) alkyl, CO 2 H, CO 2 (C 1-4 alkyl), C(═O)H, C(═O)(C 1-4 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, (C 1-4 )haloalkyl, (C 1-4 )haloalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , —C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), —C(═O)NHSO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), ), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;  
 f is 0, 1, 2 or 3; and  
 n is 0 or 1.  
 
     
     
         21 . A compound according to  claim 19 , having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: 
 R 1a  is halogen, cyano, nitro, trifluoromethyl, OCF 3 , aryl or heteroaryl;  
 R 1b  is halogen, C 1-4 alkyl, cyano, nitro, —CO 2 H, —C(═O)H, —CO 2 alkyl, or —C(═O)alkyl;  
 R 2  is hydrogen, C 1-6 alkyl, or C 1-6 alkyl substituted with CO 2 H or CO 2 (C 1-4 alkyl);  
 R 18  is selected from (C 1-4 ) alkyl, CO 2 H, CO 2 (C 1-4 alkyl), C(═O)H, C(═O)(C 1-4 alkyl), halogen, cyano, hydroxy, (C 1-4 )alkoxy, (C 1-4 )haloalkyl, (C 1-4 )haloalkoxy, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , N(C 1-4 alkyl) 3   + , —C(═O)(CH 2 )NH 2 , —NHCO 2 (C 1-4 alkyl), —C(═O)NHSO 2 (C 1-4 alkyl), SO 2 (C 1-4 alkyl), thienyl, tetrazolyl, triazolyl, pyrazolyl, and imidazolyl;  
 f is 0, 1, 2 or 3; and  
 n is 0 or 1.  
 
     
     
         22 . A pharmaceutical composition comprising at least one compound according to  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         23 . A pharmaceutical composition comprising at least one compound according to  claim 15  and a pharmaceutically acceptable carrier or diluent.  
     
     
         24 . A method of inhibiting an LFA-1/ICAM-associated condition in a mammal comprising administering to the mammal a therapeutically-effective amount of a compound according to  claim 1 .  
     
     
         25 . The method of  claim 24  in which LFA-1/ICAM-associated condition is selected from acute or chronic graft vs host reactions, acute or chronic transplant rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, osteoporosis, diabetes, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, Crohn's disease, ulcerative colitis, Alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatis, multiple organ injury syndrome, myocardial infarction, atherosclerosis, stroke, reperfusion injury, acute glomerulonephritis, vasculitis, thermal injury, necrotizing enterocolitis, granulocyte transfusion associated syndrome, Sjogren's syndrome, eczema, atopic dermatitis, contact dermatitis, urticaria, schleroderma, psoriasis, asthma, pulmonary fibrosis, allergic rhinitis, oxygen toxicity, emphysema, chronic bronchitis, acute respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), hepatitis B, hepatitis C, organ-tissue autoimmune disease, autoimmune thyroiditis, uveitis, systemic lupus erythematosis, Addison's disease, autoimmune polyglandular disease, and Grave's disease.  
     
     
         26 . A method of treating an inflammatory or immune disease in a mammal animal comprising administering to the mammal in need of such treatment a therapeutically-effective amount of a pharmaceutical composition according to  claim 22 .  
     
     
         27 . The method of  claim 26  in which the inflammatory or immune disease is selected from acute or chronic transplant rejection, rheumatoid arthritis, osteoarthritis, diabetes, asthma, inflammatory bowel disease, and chronic obstructive pulmonary disease.  
     
     
         28 . An intermediate useful for preparing a compound having therapeutic activity, the intermediate having the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 L and K are O or S;  
 Z is N or CR 4b ;  
 R 1a  is selected from halogen and cyano;  
 R 1b  is selected from alkyl, substituted alkyl, halogen, cyano, nitro, OR 10 , NR 10 R 11 , C(═O)R 10 , CO 2 R 10 , C(═O)NR 10 R 11 , NR 10 C(═O)R 11 , NR 10 C(═O)OR 11 , SR 10 , S(O) o R 10a , NR 10 SO 2 R 10a , NHCH(alkyl)CO 2 R 10 , SO 2 NR 10 R 11 , cycloalkyl, heterocyclo, aryl, and heteroaryl;  
 R 2  is selected from C 1-6 alkyl and —C(═O)(C 1-4 alkyl); p 1  R 4a  R 4b  and R 4c  are independently selected from hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, nitro, cyano, SR 14 , OR 14 , NR 14 R 15 , NR 14 C(═O)R 15 , CO 2 R 14 , C(═O)R 14 , —C(═O)NR 14 R 15 , aryl, heteroaryl, cycloalkyl, and heteroaryl;  
 R 10  and R 11  (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) R 10  is taken together with R 11  to form a heteroaryl or heterocyclo;  
 R 10a  is alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclo; and  
 R 14  and R 15  (i) are selected independently of each other from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclo; or (ii) or R 14  is taken together with R 15  to form a heteroaryl or heterocyclo ring;  
 n is 0, 1 or 2; and  
 o is 1 or 2.  
 
     
     
         29 . The intermediate according to  claim 28 , selected from one of: