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.

1 - 29 . (Cancelled)  
     
     
         30 . 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 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;  
 Ar is aryl or heteroaryl;  
 G is selected from a bond, —O—, —N—, —S—, C 1-4 alkylene, C 1-4 substituted alkylene, bivalent alkoxy, alkylthio, aminoalkyl, sulfonyl, sulfonamidyl, acyl, and alkoxycarbonyl;  
 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  is 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 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 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;  
 R 16  is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; and  
 R 17  is hydrogen or alkyl; and  
 p is 1 or 2.  
 
     
     
         31 . A method according to  claim 30  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.    
     
     
         32 . A method according to  claim 30  wherein: 
 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 .    
     
     
         33 . A method according to  claim 32 , wherein: 
 Ar is                          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.    
     
     
         34 . A method according to  claim 30  wherein the compound has the formula:  
       
         
           
           
               
               
           
         
         its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof.  
       
     
     
         35 . A method according to  claim 34  wherein R 1a  is halogen or cyano, and R 4a  and R 4c  are independently selected from halogen, alkyl, cyano, trifluoromethyl, and nitro.  
     
     
         36 . A method according to  claim 30 , wherein the compound having the formula (Ie),  
       
         
           
           
               
               
           
         
       
       its pharmaceutically-acceptable salts, hydrates, prodrugs, or enantiomers 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  
 n is 0, 1 or 2.  
 
     
     
         37 . A compound according to  claim 36 , 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)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.    
     
     
         38 . A method according to  claim 30  wherein R 9  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 aikyl), 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.  
       
     
     
         39 . A method according to  claim 30  wherein the compound has the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, wherein R 9  is selected from one of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         40 . A method according to  claim 30  wherein the compound has 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.  
 
     
     
         41 . A method according to  claim 30  wherein the compound has the formula,  
       
         
           
           
               
               
           
         
       
       or a pharnnaceutically-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.  
 
     
     
         43 . 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 having the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof, in which: L and K, taken independently, are O or S; 
 R 1a  and R 1b  are independently selected from alkyl, substituted alkyl, halogen, cyano, nitro, OR 10 , NR 10 OR 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; 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  is selected from hydrogen and 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 —, —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 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.  
 
     
     
         43 . A method according to claim  42  wherein R 4a  and R 4c  are chloro.  
     
     
         44 . A method according to claim  42  wherein R 1a  is cyano or halogen.  
     
     
         45 . A method according to claim  42 , wherein the compounds has the formula,  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt, hydrate, prodrug, or enantiomer thereof.  
     
     
         46 . A method according to  claim 45  wherein: 
 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;    R 9  is A 1 -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).    
     
     
         47 . A method according to  claim 46 , wherein the compound has 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.  
 
     
     
         48 . A method according to  claim 46  wherein the compounds has 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.  
 
     
     
         49 . A method according to  claim 36  wherein R 9  is selected from:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         A 1  is a bond, C 1-2 alkylene or C 2-3 alkenylene;  
         A is a bond, —C(═O)—, —C(═)NR 17 —, —SO 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.  
       
     
     
         50 . A method according to  claim 47  wherein the compound has the formula,  
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof.  
     
     
         51 . A method according to  claim 39  wherein the compound has the formula,  
       
         
           
           
               
               
           
         
       
       or an enantiomer, diastereomer, or a pharmaceutically-acceptable salt, hydrate, solvate, or prodrug thereof.  
     
     
         52 . The method of  claim 30  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.  
     
     
         53 . 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 comprising at least one compounds according to  claim 30  and a pharmaceutically acceptable carrier or diluent.  
     
     
         54 . A method according to  claim 53  comprising at least one compounds according to  claim 49  and a pharmaceutically acceptable carrier or diluent.  
     
     
         55 . A method according to  claim 53  comprising at least one compounds according to  claim 50  and a pharmaceutically acceptable carrier or diluent.  
     
     
         56 . The method of  claim 52  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.