Compositions and methods for treatment of diabetic retinopathy

Abstract

The present invention provides compounds and methods for the treatment of diabetic retinopathy. In particular, LFA-1 antagonists are described herein to be used in the treatment of diabetic retinopathy. One aspect of the invention provides for diagnosis of diabetic retinopathy and administration of a LFA-1 antagonist, after the patient is diagnosed with diabetic retinopathy.

1 . A method of treating a subject suffering from diabetic retinopathy comprising administering to said subject in need thereof a therapeutically effective amount of a therapeutic agent which inhibits the interaction of LFA-1 and an ICAM. 
     
     
         2 . The method of  claim 1  wherein damage resulting from diabetic retinopathy is macular edema, retinal neovascularization, fibrovascular growth over a retina, loss of vision, basement membrane thickening, retinal edema, or retinal ischemia. 
     
     
         3 . The method of  claim 1  wherein said ICAM is ICAM-1, ICAM-2, or ICAM-3. 
     
     
         4 . The method of  claim 3  wherein said ICAM is ICAM-1. 
     
     
         5 . The method of  claim 1  wherein said therapeutic agent is an LFA-1 antagonist. 
     
     
         6 . The method of  claim 5  wherein said LFA-1 antagonist binds to a high affinity binding site in the αL subunit of LFA-1 overlapping the ICAM-1 binding site. 
     
     
         7 . The method of  claim 5  wherein said LFA-1 antagonist is directly competitive with the binding of ICAM-1 at the αL subunit of LFA-1. 
     
     
         8 . The method of  claim 5  wherein said LFA-1 antagonist is an allosteric antagonist of the binding of ICAM-1 at the αL subunit of LFA-1. 
     
     
         9 . The method of  claim 5  wherein said LFA-1 antagonist is an antibody. 
     
     
         10 . The method of  claim 5  wherein said LFA-1 antagonist is a compound of Formula I or its pharmaceutically acceptable salts or esters, wherein 
       
         
           
           
               
               
           
         
         R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH2) m aryl, —(CH2) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; 
         wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E ), —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC (═O)R 1B , —NHSO 2 R 1B , NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 OR 1B , SO 2 N(R 1B ) 2 , —SO 2 —NHC(═O)OR 1B , OC(═O)—N(R 1B ) 2 , —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO 2 R 1C ; 
         R 3  is C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 C(═O)-alkyl, —C(═O)NH(R 3A ).—CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         R 4  for each occurrence, is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GR G1  wherein G is —O—, —S—, NR G2 —, —CO—, —SO—, —SO 2 —, C(═O)O—, —C(═O)NR G2 —, C(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; 
         n is an integer from 0-4; 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; 
         A, B, D and E are connected by either a single or double bond, as valency permits; wherein each occurrence of A, B D and E is independently C═O, CR i R ii , NR i , CR i , N, O, S, —S(═O) or SO 2 ; wherein each occurrence of R i  and R ii  are independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR G1  wherein G is —O—, —S—, —NR G2 , —CO—, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; 
         p is an integer from 0-4; and, 
         L is absent or is V—W—X—Y-Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 ), —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC(═O)NR L3 , —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR CO 2 —, NR L3 C(═O)NR L4 —, —S(═O)—, —SO 2 —, —N L3 SO 2 —, —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         11 . The method of  claim 10  wherein said compound of Formula I is a compound of Formula II: 
       
         
           
           
               
               
           
         
       
       wherein R 27  is: 
       
         
           
           
               
               
           
         
       
       R 28  is: 
       
         
           
           
               
               
           
         
       
       and R 29  is hydrogen, a pharmaceutically acceptable salt, or ester. 
     
     
         12 . The method of  claim 11  wherein the compounds of Formula II further comprise stereochemistry as in Formula II′. 
       
         
           
           
               
               
           
         
       
     
     
         13 . The method of  claim 10  wherein said compound of Formula I is a compound of Formulae IA, IIA or IIB: 
       
         
           
           
               
               
           
         
       
       where R 17  is hydrogen, pharmaceutically acceptable salts or esters, and R 27  is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 5  wherein said LFA-1 antagonist comprises a compound of Formula III 
       
         
           
           
               
               
           
         
         wherein Cy is an aromatic carbocycle, aromatic heterocycle, or a non-aromatic heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl, halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl; 
         X 2  is —CH 2 —NR 10 -[divalent hydrocarbon chain]- wherein said divalent hydrocarbon chain is optionally substituted with hydroxyl, mercapto, halogen, amino, aminoalkyl, nitro, oxo or thio; 
         K is a heterocycle optionally substituted with hydroxyl, mercapto, halogen, oxo, thio, thioalkyl, amino, aminoalkyl, carbocycle or heterocycle ring, hydrocarbon, a halo-substituted hydrocarbon, amino, amidine, guanidine, cyano, nitro, alkoxy or acyl; 
         L 2  is -[divalent hydrocarbon chain]-NR 10 —CH 2 — wherein said divalent hydrocarbon chain is optionally substituted with hydroxyl, halogen, oxo or thio and R 10  is H or alkyl; 
         R 5  is H, OH, amino, O-carbocycle or alkoxy optionally substituted with amino, a carbocycle, heterocycle, or is a pharmaceutically acceptable salt or ester; 
         R 6-9  are independently H, hydroxyl, mercapto, halogen, cyano, amino, amidine, guanidine, nitro or alkoxy; 
         R 10  is H or a hydrocarbon chain optionally substituted with a carbocycle or a heterocycle; and salts, solvates and hydrates thereof. 
       
     
     
         15 . The method of  claim 5  wherein said LFA-1 antagonist is a compound of Formula IV 
       
         
           
           
               
               
           
         
         wherein R 11  is a group of the formula 
       
       
         
           
           
               
               
           
         
         wherein A is hydrogen, hydroxy, amino, or halogen and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl, or lower alkoxy; 
         R 12  is a group of the formula 
       
       
         
           
           
               
               
           
         
         where R 13  is hydrogen, carboxy, or lower alkyl; 
         n is 0 or 1; 
         U 2 , V 2 , and W 2  are independently hydrogen, halogen, or lower alkyl provided U 2  and V 2  are not both hydrogen; 
         X 3  is carbonyl, phenyl-substituted lower alkylene, imino, substituted imino, or sulfonyl; 
         Y 2  is lower alkylene which may be substituted by one or more of amino, substituted amino, lower alkyl, or cyclo lower alkyl, or Y 2  is lower alkenylene or lower alkylenethio; 
         k is 0 or 1; 
         when k is 1, Z 2  is hydrogen, lower alkylthio, —COOH, —CONH 2 , amino; 
         when k is 0 or 1, Z 2  is 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl, hydroxy, phenylmethoxy, 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]phenyl, [2,6-dichlorophenyl)methoxy]phenyl; 
         when k is 0 or 1, Z 2  is cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, alkoxycarbonyl, acetoxy, or also in addition with amino lower alkyl; and 
         R 20  is hydrogen, a pharmaceutically acceptable salt or ester. 
       
     
     
         16 . The method of  claim 15  wherein the compounds of Formula III further comprise stereochemistry as in Formula III′. 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 5  wherein said LFA-1 antagonist is a compound of Formula V wherein: 
       
         
           
           
               
               
           
         
         R 14  is a group of the formula 
       
       
         
           
           
               
               
           
         
         R 15  is hydrogen, carboxy, or lower alkyl; 
         U 3 , V 3 , and W 3  are independently hydrogen, halogen; 
         U 3 , V 3 , and W 3  are lower alkyl provided that U 3  and V 3  are not both hydrogen; 
         X 4  is carbonyl, phenyl-substituted lower alkylene, imino, substituted imino, or sulfonyl; 
         Y 3  is lower alkenylene, lower alkylenethio, or is lower alkylene which may be substituted by amino, acetylamino, or cyclo-lower alkyl; 
         k 2  is 0 or 1; 
         when k 2  is 1, Z is hydrogen, lower alkylthio, —COOH, —CONH 2 —, or amino; 
         when k 2  is 0 or 1, Z 3  is 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl; 
         when k 2  is 0 or 1, Z is cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, or acetoxy; and, 
         R 21  is hydrogen, a pharmaceutically acceptable salt or ester. 
       
     
     
         18 . The method of  claim 5  wherein said LFA-1 antagonist is a compound of Formula VI wherein: 
       
         
           
           
               
               
           
         
       
       where
 D 4  is a mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring, each ring having 5-, 6- or 7 atoms in the ring where the atoms in the ring are carbon or from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, where any carbon or sulfur ring atom may optionally be oxidized, each ring substituted with 0-3 R 31 ; 
 L 3  is a bivalent linking group selected from the group 
 -L 3 -L 2 -L 1 -, 
 -L 4 -L 3 -L 2 -L, 1 - and 
 -L 5 -L 4 -L 3 -L 2 -L 1 -, 
 
       where
 L 1  is selected from oxo (—O—), S(O) s , C(═O), CR 32 , R 32 , CR 32  het, NR 30  and N, 
 L 2  is selected from oxo (—O—), S(O) s , C(═O), C(═N—O—R 33 ), 
 CR 34 R 34 ′, CR 34 , het NR 30  and N, 
 L 3  is selected from oxo (—O—), S(O) s , C(═O), C(═N—O—R 33 ), CR 35 R 35 ′, CR 35 , het NR 30  and N, 
 L 4  is absent or is selected from oxo (—O—), S(O) s , C(═O), C(═N—O—R 33 ), CR 36 R 36 ′, CR 36 , NR 30  and N, 
 L 5  is absent or selected from oxo (—O—), S(O) s , C(═O), CR 37 R 37 ′, CR 37 , NR 30  and N, provided that only one of L 1 -L 3  may be het and that when one of L 1 -L 3  is het the other L 1 -L 5  may be absent, 
 
       where
 R 32 , R 32 ′, R 34 , R 34 ′, R 35 , R 35 ′, R 36 , R 36 ′, R 37  and R 37 ′ each are independently selected from R 38 , R 39  and U-Q-V—W, 
 optionally, R 24  and R 34 ′ separately or together may form a saturated, unsaturated or aromatic fused ring with B 3  through a substituent RP on B, the fused ring containing 5, 6 or 7 atoms in the ring and optionally containing 1-3 heteroatoms selected from the group O, S and N, where any S or N may optionally be oxidized; 
 optionally, R 35  and R 35  separately or together and R 36  and R 36 ′ separately or together may form a saturated, unsaturated or aromatic fused ring with D 3  through a substituent R 31  on D 3 , the fused ring containing 5, 6 or 7 atoms in the ring and optionally containing 1-3 heteroatoms selected from the group O, S and N, where any S or N may optionally be oxidized; 
 also optionally, each R 32 -R 37 , NR 30  or N in L 1 -L 5  together with any other R 32 -R 37 , NR 30  or N in L 1 -L 5  may form a 5, 6 or 7 member homo- or heterocycle either saturated, unsaturated or aromatic optionally containing 1-3 additional heteroatoms selected from N, O and S, where any carbon or sulfur ring atom may optionally be oxidized, each cycle substituted with 0-3 R 31 ; and where s is 0-2; B is selected from the group 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
          is a fused hetero- or homocyclic ring containing 5, 6 or 7 atoms, the ring being unsaturated, partially saturated or aromatic, the heteroatoms selected from 1-3 O, S and N, 
         Y 3  is selected from CH and NR 30 ; n is 0-3: 
         G 3  is selected from hydrogen and C 1 -C 6 alkyl, optionally G taken together with T may form a C 3 -C 6 cycloalkyl optionally substituted with —V—W; 
         T 3  is selected from the group 
         a naturally occurring α-amino-acid side chain, 
         and U 4 -Q 4 -V 4 —W 4 ; 
         U 4  is an optionally substituted bivalent radical selected from the group 
         C 1 -C 6 alkyl, C 0 -C 6 alkyl-Q, C 2 -C 6 alkenyl-Q, and C 2 -C 6 alkynyl-Q: 
         where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38 ; 
         Q 4  is absent or is selected from the group 
         —O—, —S(O) s —, —SO 2 —N(R 30 )—, —N(R 30 )—, —N(R 30 )—C(═O)—, —N(R 30 )—C(═O)—N(R 30 )—, —N(R 30 )—C(═O)—O—, —N(R 30 )—SO 2 —, —C(═O)—, —C(═O)—O—, -het-, —C(═O)—N(R 30 )—, —O—C(═O)—N(R 30 )—, —PO(OR 30 )O— and —P(O)O—; 
       
       where
 s is 0-2 and 
 het is a mono- or bicyclic 5, 6, 7, 9 or 10 member heterocyclic ring, each ring containing 1-4 heteroatoms selected from N, O and S, where the heterocyclic ring may be saturated, partially saturated, or aromatic and any N or S being optionally oxidized, the heterocyclic ring being substituted with 0-3 R 41 ; 
 V 4  is absent or is an optionally substituted bivalent group selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 0 -C 6 alkyl-C 6 -C 10 aryl, and C 0 -C 6 alkyl-het; 
 where the substituents on any alkyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 W 4  is selected from the group 
 hydrogen, OR 33 , SR 42 , NR 30 R 30 , NH—C(═O)—O—R 43 , NH—C(═O)—NR n R n , NH—C(═O)—R 43 , NH—SO 2 —R 37 , NH—SO 2 —NR 30 R 30 , NH—SO 2 —NH—C(═O)—R 43 , NH—C(═O)—NH—SO 2 —R 37 , C(═O)—NH—C(═O)—O—R 43 , C(═O)—NH—C(═O)—R 43 , C(═O)—NH—C(═O)—NR 30 R 30 ′, C(═O)—NH—SO 2 —R 37 , C(═O)—NH—SO 2 —NR 30 R 30 ′, C(═S)—NR 30 R 30 ′, SO 2 —R 37 , SO 2 —O—R 37 , SO 2 —NR 37 R 37 ′, SO 2 —NH—C(═O)—O—R 43 , SO 2 —NH—C(═O)—NR 30 R 30 ′, SO 2 —NH—C(═O)—R 43 , O—C(═O)—NR 30 R 30 ′, O—C(═O)—R 43 , O—C(═O)—NH—C(═O)—R 43 , O—C(═O)—NH—SO 2 R 46  and O—SO 2 —R 37 ; 
 R 44  is selected from C(═O)—R 45 , C(═O)—H, CH 2 (OH), and CH 2 O—C(═O)—C 1 -C 6 alkyl; 
 R 38  is R 38′  or R 38″  substituted with 1-3 R 38 ′; where 
 R 38 ′ is selected from the group 
 hydrogen, halo(F, Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C 1 -C 11 alkyl, amino, amino-C 1 -C 8 alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C 1 -C 6 alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl, imidazolyl, and indolyl; 
 R 38 ″ is selected from the group 
 C 0 -C 10 alkyl-Q-C 0 -C 6 alkyl, C 0 -C 10 alkenyl-Q-C 0 -C 6 alkyl, C 0 -C 10 alkynyl-Q-C 0 -C 6 alkyl, C 3 -C 11 cycloalkyl-Q-C 0 -C 6 alkyl, C 3 -C 10 cycloalkenyl-Q-C 0 -C 6 alkyl, C 1 -C 6 alkyl-C 6 -C 12  aryl-Q-C 0 -C 6 alkyl, C 6 -C 10  aryl-C 1 -C 6 alkyl-Q-C 0 -C 6 alkyl, C 0 -C 6 alkyl-het-Q-C 0 -C 6 alkyl, C 0 -C 6 alkyl-Q-het-C 0 -C 6 alkyl, het-C 0 -C 6 alkyl-Q-C 0 -C 6 alkyl, C 0 -C 6 alkyl-Q-C 6 -C 12 aryl, and -Q-C 1 -C 6 alkyl; 
 R 43  is selected from hydrogen and substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 10 cycloalkenyl, C 1 -C 6 alkyl-C 6 -C 12 aryl, C 6 -C 10 aryl-C 1 -C 16 alkyl, C 1 -C 6 alkyl-het, het-C 1 -C 6  alkyl, C 6 -C 12 aryl and het, 
 where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 R 31  is selected from R 40  and R 41 ; 
 R 41  is selected from the group 
 OH, OCF 3 , OR 43 , SR 42 , halo(F, Cl. Br, I), CN, isocyanate, NO 2 , CF 3 , C 0 -C 6 alkyl-NR 30 R 30′ , C 0 -C 6 alkyl-C(═O)—NR 30 R 30 ′, C 0 -C 6 alkyl-C(═O)—R 38 , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 1 -C 6 alkyl-phenyl, phenyl-C 1 -C 6 alkyl, C 1 -C 6 alkyloxycarbonyl, phenyl-C 0 -C 6 alkyloxy, C 1 -C 6 alkyl-het, het-C 1 -C 6 alkyl, SO 2 -het, —O—C 6 -C 12 aryl, —SO 2 —C 6 -C 12 aryl, —SO 2 —C 1 -C 6 alkyl and het, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro and amino; 
 R 42  is selected from S—C 1 -C 6 alkyl, C(═O)—C 1 -C 6 alkyl, C(═O)—NR 30 R 30 ′, C 1 -C 6 alkyl, halo(F, Cl, Br, I)—C 1 -C 6 alkyl, benzyl and phenyl; 
 R 30  is selected from the group R 43 , NH—C(═O)—O—R 43 , NH—C(═O)—R 43 , NH—C(═O)—NHR 43 , NH—SO 2 —R 46 , NH—SO 2 —NH—C(═O)—R 43 , NH—C(═O)—NH—SO 2 —R 37 , C(═O)—O—R 43 , C(═O)—R 43 , C(═O)—NHR 43 , C(═O)—NH—C(═O)—O—R 43 , C(═O)—NH—C(═O)—R 43 , C(═O)—NH—SO 2 —R 46 , C(═O)—NH—SO 2 —NHR 37 , SO 2 —R 37 , SO 2 —O—R 37 , SO 2 —N(R 43 ) 2 , SO 2 —NH—C(═O)—O—R 43 , SO 2 —NH—C(═O)—O—R 43  and SO 2 —NH—C(═O)—R 43 ; 
 R 30 ′ is selected from hydrogen, hydroxy and substituted or unsubstituted C 1 -C 11 alkyl, C 1 -C 11 alkoxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 10 cycloalkenyl, C 1 -C 6 alkyl-C 6 -C 12 aryl, C 6 -C 10 aryl-C 1 -C 6  alkyl, C 6 -C 10 aryl-C 0 -C 6 alkyloxy, C 1 -C 6 alkyl-het, het-C 1 -C 6 alkyl, C 6 -C 12 aryl, het, C 1 -C 6 alkylcarbonyl, C 1 -C 8 alkoxycarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 6 -C 11 aryloxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C 1 -C 6 alkylsulfonyl, and C 6 -C 10 arylsulfonyl, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl, het or heteroaryl are 1-3 R 31 ; 
 R 30  and R 30 ′ taken together with the common nitrogen to which they are attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl, where the substituents are 1-3 R 38 ; 
 R 33  is selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl and benzoyl, where the substituents on any alkyl are 1-3 R 38  and the substituents on any aryl are 1-3 R 40 ; 
 R 40  is selected from the group OH, halo(F, Cl. Br, I), CN, isocyanate, OR 43 , SR 42 , SOR 43 , NO 2 , CF 3 , R 43 , NR 30 R 30 ′, NR 30 C(═O)—O—R 43 , NRC(═O)—R 43 , C 0 -C 6 alkyl-SO 2 —R 43 , C 0 -C 6 alkyl-SO 2 —NR 30 R 30 ′, C(═O)—R 43 , O—C(═O)—R 43 , C(═O)—O—R 43 , and C(═O)—NR 30 R 30 ′, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 R 46  is a substituted or unsubstituted group selected from 
 C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkenyl, C 0 -C 6 alkyl-phenyl, phenyl-C 0 -C 6 alkyl, C 0 -C 6 alkyl-het and het-C 0 -C 6 alkyl, 
 where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 R 45  is a substituted or unsubstituted group selected from hydroxy, C 1 -C 11 alkoxy, C 3 -C 12 cycloalkoxy, C 8 -C 12 aralkoxy, C 8 -C 12 arcycloalkoxy, C 6 -C 10 aryloxy, C 3 -C 10  alkylcarbonyloxyalkyloxy, C 3 -C 10  alkoxycarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10  cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C5-C 10 cycloalkoxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, (R 30 )(R 30 )N(C 1 -C 10 alkoxy)-, 
 
       
         
           
           
               
               
           
         
         where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31  and pharmaceutically acceptable salts thereof. 
       
     
     
         19 . The method according to  claim 5 , wherein said LFA-1 antagonist is one of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts and esters. 
     
     
         20 . The method according to  claim 5 , wherein said LFA-1 antagonist is one of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or their pharmaceutically acceptable salts and esters. 
     
     
         21 . The method of  claim 5  wherein the LFA-1 antagonist is a compound of Formula VII: 
       
         
           
           
               
               
           
         
       
       and pharmaceutically-acceptable salts and prodrugs thereof:
 wherein R 1 , R 2 , R 3 , R 4 , and R 5  are each independently hydrogen, alkyl, alkenyl, alkenoxy, alkynyl, aldehyde, alkanoyl, alkoxy, amido, amino, aryl, aryloxy, carboxy, cyano, cycloalkyl, ether, ester, halogen, heterocyclyl, hydroxy, ketone, nitro, oxo, perfluoroalkyl, sulfonyl, sulfonate, thio, or other carbonyl-containing groups, R 6  is unsubstituted alkyls, unsubstituted saturated cycloalkyls, unsubstituted carboxyalkyls, or unsubstituted heterocyclylalkyls, wherein the unsubstituted saturated cycloalkyls, unsubstituted carboxyalkyls, and unsubstituted heterocyclylalkyls are bonded to the NH of formula VII through the alkyl group, wherein the unsubstituted carboxyalkyls comprise a branched alkyl chain, with the proviso that at least one of R 1  and R 3  is selected from: 
 A. cinnamides selected from cis-cinnamide or trans-cinnamide defined as 
 
       
         
           
           
               
               
           
         
         wherein R 8  and R 9  are each independently hydrogen, aldehyde, alkyl, alkenyl, alkynyl, alkoxy, amido, amino, aryl, carboxy, cyano, cycloalkyl, ester, ether, halogen, hydroxy, ketone, nitro, sulfonate, sulfonyl, thio, or other carbonyl-containing groups; 
         B. substituents of formula VII-a: 
       
       
         
           
           
               
               
           
         
         wherein D, B, Y and Z are each independently —CR 31 ═, —CR 32 R 33 —, —C(O)—, —O—, —SO 2 —, —S—, —N═, or —NR 34 —; 
         n is an integer of zero to three; and R 31 , R 32 , R 33  and R 34  are each independently hydrogen, alkyl, carboxy, hydroxyalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl or carboxyalkyl; 
         C. cyclopropyl derivatives selected from cis-cyclopropanoic acid, trans-cyclopropanoic acid, cis-cyclopropanamide and trans-cyclopropanamide defined as 
       
       
         
           
           
               
               
           
         
         wherein R 35  and R 36  are each independently hydrogen, alkyl, carboxy, hydroxyalkyl, or carboxyalkyl, and 
         wherein R 37  and R 38  are each independently hydrogen, alkyl, carboxyalkyl, monoalkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl; 
         D. substituents of formula VII-b: 
       
       
         
           
           
               
               
           
         
         wherein R 8  and R 9  are as defined above; 
         E. cinnamic acids of formula VII-c: 
       
       
         
           
           
               
               
           
         
         wherein R 8  and R 9  are as defined above; 
       
       wherein:
 R 10  and R 11  are each independently hydrogen, alkanoyl, alkyl, alkenyl, alkynyl, alkoxy, amido, aryl, arylalkyl, carboxy, cyano, cycloalkyl, ester, ether, heterocyclyl, hydroxy, ketone, nitro, sulfonyl thio, or other carbonyl-containing groups, or 
 R 10  and R 11  are taken together with N to form a heterocyclyl group comprising least one substituent which is independently hydrogen, alkyl, alkenyl, alkenoxy, alkynyl, aldehyde, alkanoyl, alkoxy, amido, amino, aryl, aryloxy, carboxy, cyano, cycloalkyl, ether, ester, halogen, heterocyclyl, hydroxy, ketone, nitro, oxo, perfluoroalkyl, sulfonyl, sulfonate, thio, or other carbonyl-containing group, or 
 R 1  and R 2 , and/or R 4  and R 5  are joined together to form a 5- to 7-membered cycloalkyl, aryl or heterocyclyl ring when R 3  is a cinnamide, substituent of formula VII-a, substituent of formula VII-b, or cyclopropyl derivative as defined above; or R 2  and R 3 , and/or R 3  and R 4 , and/or R 4  and R 5  are joined to form a 5- to 7-membered cycloalkyl, aryl or heterocyclyl ring when R 1  is selected from cinnamides, substituents of formula VII-a, substituents of formula VII-b, and cyclopropyl derivatives as defined above; and 
 wherein Ar is substituted aryl or substituted heteroaryl having at least one substituent which independently is hydrogen, alkyl, alkenyl, alkenoxy, alkynyl, aldehyde, alkanoyl, alkoxy, amido, amino, aryl, aryloxy, carboxy, cyano, cycloalkyl, ether, ester, halogen, heterocyclyl, hydroxy, ketone, nitro, oxo, perfluoroalkyl, sulfonyl, sulfonate, thio, or other carbonyl-containing groups. 
 
     
     
         22 . The method of  claim 5  wherein the LFA-1 antagonist is a compound of Formula VIII: 
       
         
           
           
               
               
           
         
       
       wherein m is 0, 1 or 2; X is H, cycloalkyl or phenyl, which is unsubstituted or substituted with one or more substituents which are lower alkyl, hydroxy or halogen; n is 0 or 1; and Y is phenyl, furanyl, indole or pyrrole, which all may be substituted with one or more substituents which are independently lower alkyl, lower alkoxy, halogen, (3,5-dimethylphenoxy)propoxy, or phenyl, wherein phenyl may be further substituted with one or more halogen atoms, nitro, amino or carboxyl groups. 
     
     
         23 . The method of  claim 5  wherein the LFA-1 antagonist is a compound of Formula IX: 
       
         
           
           
               
               
           
         
         wherein the dotted line is a bond or is no bond, R 1  is hydrogen, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, heterocyclyl, hydroxy, SH, SR 5 , cyano, halogen or amino; or 
         the dotted line is no bond and R 1  is attached to the ring system via a double bond and is oxo; 
         R 2  is hydrogen, or R 2  is optionally substituted cycloalkyl, aryl, or heterocyclyl; 
         R 3  is hydrogen, COOR 6 , or aminocarbonyl, or R 3  is optionally substituted alkyl, alkenyl, alkynyl, aralkyl, alkoxy, cycloalkyloxy, aryloxy, or heterocyclyloxy; 
         R 4  is hydrogen, halogen, hydroxy, SH, optionally substituted alkyl, alkenyl, alkynyl, alkoxy or alkylthio, or R 4  is trialkylsilyl or trialkylsilyloxy, N 3 , or amino, or 
         R 4  is heterocyclyl comprising at least one nitrogen atom as a heteroatom and being bound via that nitrogen atom to the compound of formula IX, or R 4  is oxo; and 
         R 5  and R 6  are independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl. 
       
     
     
         24 . The method of  claim 5  wherein the LFA-1 antagonist is a compound of Formula X: 
       
         
           
           
               
               
           
         
       
       wherein each of a---b and α---β independently, is either a single bond or a double bond; R 1  is 
       
         
           
           
               
               
           
         
         R a  is H, C 1-6  alkyl optionally substituted by OH or C 1-4  alkoxy, C 2-6  alkenyl or aryl-C 1-4  alkyl; 
         R 2  is OH; —O—CO—R 5 ; 
         R 4  is H or OR 19  wherein R 19  is C 1-6  alkyl, hydroxy-C 1-6  alkyl, C 1-4  alkoxy-C 1-6  alkyl, aryl-C 1-4  alkyl or C 1-4  alkoxycarbonyl-C 1-4  alkyl; 
         R 5  is C 1-8  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4  alkyl, aryl or aryl-C 1-4  alkyl; or R 5  is —O—R 6  wherein R 6  is the residue of an α-amino-acid attached to O through its carbonyl residue; or —R 5  is —CHR 7 —COR. 8  wherein R 7  is H, CIA alkyl, heteroC 1-4  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl-C 1-4  alkyl, aryl or aryl-C 1-4  alkyl and R 8  is OH, C 1-4  alkoxy or NR 9 R 10 ; 
         each of R 9  and R 10  independently is H or C 1-4  alkyl, or R 9  and R 10  form together with the nitrogen to which they are bound, a heteroaryl group; 
         R 3  is a lactam of formula X-a; 
       
       
         
           
           
               
               
           
         
         wherein R 30 , is C 1-8  alkyl, C 3-7  cycloalkyl, aryl, C 3-7  cycloalkyl-C 1-4  alkyl, aryl-C 1-4  alkyl, heteroaryl, or heteroaryl-C 1-4 ; and, 
         R 31 , is OH, C 1-4  alkoxy, C 1-4  alkyl, C 1-4  alkoxy-carbonyl-C 1-4  alkyl, hydroxy-C 1-5  alkoxy, C 1-4  alkoxy-C 1-5  alkoxy, C 1-4  alkoxy-carbonyl-C 1-4  alkyl, amino-C 1-4  alkoxy, HOOC—C 1-4  alkoxy, HOOC—C 1-4  alkyl, —R 9a  R 10a  N—C 1-5  alkoxy wherein R 9a  and R 10a  are independently R 9  or R 10 . 
       
     
     
         25 . The method of  claim 5  wherein the LFA-1 antagonist is a compound of Formula XI: 
       
         
           
           
               
               
           
         
       
       and its enantiomers, pharmaceutically-acceptable salts, or solvates, thereof, wherein:
 R 16  is: 
 
       
         
           
           
               
               
           
         
         each R 17  is independently —OR 18 , —NR 18 R 19 , —C(═O)R 18 , —CO 2 R 18 , —C(═O)NR 18 R 19 , —NR 18 C(═O)R 19 , —NR 18 C(═O)OR 19 , —S(O) p R 19 , —NR 18 SO 2 R 19 , or —SO 2 NR 18 R 19 ; 
         R 18  and R 19  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl; 
         q is 1, 2, or 3; 
         and p is 1 or 2. 
       
     
     
         26 . The method of  claim 1  wherein said therapeutic agent is administered topically, orally, periocularly, intraocularly, via injection, nasally, via an aerosol, via an insert, via an implanted device, or via a drop. 
     
     
         27 . The method of  claim 26  wherein said therapeutic agent is administered in a carrier vehicle which is liquid drops, liquid wash, nebulized liquid, gel, ointment, aerosol, spray, polymer micro and nanoparticles, solution, suspension, solid, biodegradable matrix, powder, crystals, foam, or liposomes. 
     
     
         28 . The method of  claim 26 , wherein said therapeutic agent is administered topically and said topical administration comprises infusion of said compound to said eyes via a device selected from the group consisting of a pump-catheter system, an insert, a continuous or selective release device, a bioabsorbable implant, a continuous or sustained release formulation, and a contact lens. 
     
     
         29 . The method of  claim 1 , wherein a therapeutically effective amount of said therapeutic agent is delivered to an eye of said subject via local or systemic delivery. 
     
     
         30 . The method of  claim 26 , wherein said therapeutic agent is administered via injection and said injection is performed intraocularly, intravitreally, periocularly, subcutaneously, subconjunctivally, retrobulbarly, or intracamerally. 
     
     
         31 . The method of  claim 1 , wherein said administration is accomplished by administering an intra-ocular instillation of a gel, cream, powder, foam, crystals, liposomes, spray, polymer micro or nanoparticles, or liquid suspension form of said compound. 
     
     
         32 . The method according to  claim 1 , wherein said compound is administered to said subject in an amount sufficient to achieve intraocular or retinal concentrations of from about 1×10 −8  to about 1×10 −1  moles/liter. 
     
     
         33 . The method of  claim 1  wherein said compound is administered at least once a year. 
     
     
         34 . The method of  claim 1  wherein said compound is administered at least once a day. 
     
     
         35 . The method of  claim 1  wherein said compound is administered at least once a week. 
     
     
         36 . The method of  claim 1  wherein said compound is administered at least once a month. 
     
     
         37 . The method of  claim 1  further comprising the step of determining that said subject is in need of treatment for diabetic retinopathy. 
     
     
         38 . The method of  claim 1  further comprising administering a second therapeutic agent prior to, in combination with, at the same time, or after administration of said LFA-1 antagonist. 
     
     
         39 . The method of  claim 38  wherein the second therapeutic agent is selected from the group consisting of antioxidants, antiinflammatory agents, antimicrobials, steroids, protein kinase C inhibitors, angiotensin converting enzyme inhibitors, antiangiogenic agents, complement inhibitors, and anti-apoptotic agents. 
     
     
         40 . The method of  claim 38  wherein the second therapeutic agent is an anti-adhesion therapeutic agent with allosteric competitive binding site on LFA-1. 
     
     
         41 . The method of  claim 38  wherein the second therapeutic agent is an anti-adhesion therapeutic antibody or antibody fragment. 
     
     
         42 . A method of treating a subject suffering from macular edema comprising administering to said subject in need thereof a therapeutically effective amount of a therapeutic agent which inhibits the interaction of LFA-1 and an ICAM, thereby reducing and/or preventing macular edema in an eye of said subject. 
     
     
         43 . The method of  claim 42  wherein said ICAM is ICAM-1, ICAM-2, or ICAM-3. 
     
     
         44 . The method of  claim 43  wherein said ICAM is ICAM-1. 
     
     
         45 . The method of  claim 42  wherein said therapeutic agent is an LFA-1 antagonist. 
     
     
         46 . The method of  claim 45  wherein said LFA-1 antagonist binds to a high affinity binding site in the αL subunit of LFA-1 overlapping the ICAM-1 binding site. 
     
     
         47 . The method of  claim 46  wherein said LFA-1 antagonist is directly competitive with the binding of ICAM-1 at the αL subunit of LFA-1. 
     
     
         48 . The method of  claim 45  wherein said LFA-1 antagonist is an antibody. 
     
     
         49 . The method of  claim 45  wherein said LFA-1 antagonist comprises a compound of Formula I, III, IV, or VI and its pharmaceutically acceptable salts or esters, having the following structures: 
       
         
           
           
               
               
           
         
         R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH2) m aryl, —(CH2) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q; 
         wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E ), —C(═NR 1E )—O—, —C(═NR 1E )—N(R 1A ), —C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NRC(═O)N(R 1B ) 2 , —NHC (═O)R 1B , —NHSO 2 R 1B , NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 OR 1B , —SO 2 N(R) 2 , —SO 2 —NHC(═O)OR 1B , —OC(═O)—N(R 1B ) 2 , —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO 2 R 1C ; 
         R 3  is —C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 OC(═O)-alkyl, —C(═O)NH(R 3A ).—CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         R 4  for each occurrence, is independently hydrogen, halogen, —CN, —NO 2 , an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GR G1  wherein G is —O—, —S—, NR G2 —, —CO—, —SO—, —SO 2 —, C(═O)O—, —C(═O)NR G2 —, C(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; 
         n is an integer from 0-4; 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; 
         A, B, D and E are connected by either a single or double bond, as valency permits; wherein each occurrence of A, B, D and E is independently C═O, CR i R ii , NR i , CR ii , N, O, S, —S(═O) or SO 2 ; wherein each occurrence of R i  and R ii  is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR G1  wherein G is —O—, —S—, —NR G2 , —CO—, —SO—, —C(═O)O—, —C(═O)NR G2 —, —OC(═O)—, —NR G2 C(═O)— or —SO 2 NR G2 —, and R G1  and R G2  are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or any two adjacent occurrences of taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; 
         p is an integer from 0-4; and, 
         L is absent or is V—W—X—Y-Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC(═O)NR L1 , —NR L3 NR L1 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 —, —S(═O)—, —SO 2 —, —NR L3 SO 2 —, —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety; 
       
       or 
       
         
           
           
               
               
           
         
         wherein Cy is an aromatic carbocycle, aromatic heterocycle or non-aromatic heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl, halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl; 
         X 2  is —CH 2 —NR 10 -[divalent hydrocarbon chain]- wherein said divalent hydrocarbon chain is optionally substituted with hydroxyl, mercapto, halogen, amino, aminoalkyl, nitro, oxo or thio; 
         K is a heterocycle optionally substituted with hydroxyl, mercapto, halogen, oxo, thio, thioalkyl, amino, aminoalkyl, carbocycle or heterocycle ring, hydrocarbon, a halo-substituted hydrocarbon, amino, amidine, guanidine, cyano, nitro, alkoxy or acyl; 
         L 2  is -[divalent hydrocarbon chain]-NR 10 —CH 2 — wherein said divalent hydrocarbon chain is optionally substituted with hydroxyl, halogen, oxo or thio and R 10  is H or alkyl; 
         R 5  is H, OH, amino, O-carbocycle or alkoxy optionally substituted with amino, a carbocycle, heterocycle, or is a pharmaceutically acceptable salt or ester; 
         R 6-9  are independently H, hydroxyl, mercapto, halogen, cyano, amino, amidine, guanidine, nitro or alkoxy; 
         R 10  is H or a hydrocarbon chain optionally substituted with a carbocycle or a heterocycle; and salts, solvates and hydrates thereof; 
       
       or 
       
         
           
           
               
               
           
         
         wherein R 11  is a group of the formula 
       
       
         
           
           
               
               
           
         
         wherein A is hydrogen, hydroxy, amino, or halogen and B is amino, carboxy, hydrogen, hydroxy, cyano, trifluoromethyl, halogen, lower alkyl, or lower alkoxy; 
         R 12  is a group of the formula 
       
       
         
           
           
               
               
           
         
         where R 13  is hydrogen, carboxy, or lower alkyl; 
         n is 0 or 1; 
         U 2 , V 2 , and W 2  are independently hydrogen, halogen, or lower alkyl provided U 2  and V 2  are not both hydrogen; 
         X 3  is carbonyl, phenyl-substituted lower alkylene, imino, substituted imino, or sulfonyl; 
         Y 2  is lower alkylene which may be substituted by one or more of amino, substituted amino, lower alkyl, or cyclo lower alkyl, or Y 2  is lower alkenylene or lower alkylenethio; 
         k is 0 or 1; 
         when k is 1, Z 2  is hydrogen, lower alkylthio, —COOH, —CONH 2 , amino; 
         when k is 0 or 1, Z 2  is 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl, hydroxy, phenylmethoxy, 2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]phenyl, [2,6-dichlorophenyl)methoxy]phenyl; 
         when k is 0 or 1, Z 2  is cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, lower alkanesulfonyl, lower alkylthio, acetyl, aminocarbonyl, hydrazino, carboxy, alkoxycarbonyl, acetoxy, or also in addition with amino lower alkyl; and 
         R 20  is hydrogen, a pharmaceutically acceptable salt or ester; 
       
       or 
       
         
           
           
               
               
           
         
         R 14  is a group of the formula 
       
       
         
           
           
               
               
           
         
         R 15  is hydrogen, carboxy, or lower alkyl; 
         U 3 , V 3 , and W 3  are independently hydrogen, halogen; 
         U 3 , V 3 , and W 3  are lower alkyl provided that U 3  and V 3  are not both hydrogen; 
         X 4  is carbonyl, phenyl-substituted lower alkylene, imino, substituted imino, or sulfonyl; 
         Y 3  is lower alkenylene, lower alkylenethio, or is lower alkylene which may be substituted by amino, acetylamino, or cyclo-lower alkyl; 
         k 2  is 0 or 1; 
         when k 2  is 1, Z is hydrogen, lower alkylthio, —COOH, —CONH 2 —, or amino; 
         when k 2  is 0 or 1, Z 3  is 1-adamantyl, diphenylmethyl, 3-[[(5-chloropyridin-2-yl)amino]carbonyl]pyrazin-2-yl; 
         when k 2  is 0 or 1, Z is cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, or a fused ring system containing two or three rings which rings are independently cycloalkyl or aryl containing 0 to 3 heteroatoms which may be the same or different, any of which rings may be unsubstituted, or substituted with at least one of halogen, cyano, amino, substituted amino, aminosulfonyl, nitro, oxo, hydroxy, aryl, aryloxy, unsubstituted lower alkyl, halogen-substituted lower alkyl, lower alkoxy-substituted lower alkyl, lower alkoxy, carboxy, alkoxycarbonyl, or acetoxy; and, 
         R 21  is hydrogen, a pharmaceutically acceptable salt or ester 
       
       or 
       
         
           
           
               
               
           
         
       
       wherein
 D 4  is a mono-, bi-, or tricyclic saturated, unsaturated, or aromatic ring, each ring having 5-, 6- or 7 atoms in the ring where the atoms in the ring are carbon or from one to four heteroatoms selected from the group nitrogen, oxygen, and sulfur, where any carbon or sulfur ring atom may optionally be oxidized, each ring substituted with 0-3 R 31 ; 
 L 3  is a bivalent linking group selected from the group 
 -L 3 -L 2 -L 1 -, 
 -L 4 -L 3 -L 2 -L, 1 - and 
 -L 5 -L 4 -L 3 -L 2 -L 1 -, 
 
       where
 L 1  is selected from oxo (—O—), S(O) s , C(═O), CR 32 , R 32 , CR 32  het, NR 30  and N, 
 L 2  is selected from oxo (—O—), S(O) s , C(═O), C(═N—O—R 33 ), 
 CR 34 R 34 ′, CR 34 , bet NR 30  and N, 
 L 3  is selected from oxo (—O—), S(O) s , C(═O), C(═N—O—R 33 ), CR 35 R 35 ′, CR 35 , bet NR 30  and N, 
 L 4  is absent or is selected from oxo (—O—), S(O) s , C(═O), C(═N—O—R 33 ), CR 36 R 36 ′, CR 36 , NR 30  and N, 
 L 5  is absent or selected from oxo (—O—), S(O) s , C(═O), CR 37 R 37 ′, CR 37 , NR 30  and N, provided that only one of L 1 -L 3  may be het and that when one of L 1 -L 3  is het the other L 1 -L 5  may be absent, 
 
       where
 R 32 , R 32 ′, R 34 , R 34 ′, R 35 , R 35 ′, R 36 , R 36 ′, R 37  and R 37 ′ each are independently selected from R 38 , R 39  and U-Q-V—W, 
 optionally, R 24  and R 34 ′ separately or together may form a saturated, unsaturated or aromatic fused ring with B 3  through a substituent RP on B, the fused ring containing 5, 6 or 7 atoms in the ring and optionally containing 1-3 heteroatoms selected from the group O, S and N, where any S or N may optionally be oxidized; 
 optionally, R 35  and R 35  separately or together and R 36  and R 36 ′ separately or together may form a saturated, unsaturated or aromatic fused ring with D 3  through a substituent R 31  on D 3 , the fused ring containing 5, 6 or 7 atoms in the ring and optionally containing 1-3 heteroatoms selected from the group O, S and N, where any S or N may optionally be oxidized; 
 also optionally, each R 32 -R 37 , NR 30  or N in L 1 -L 5  together with any other R 32 -R 37 , NR 30  or N in L 1 -L 5  may form a 5, 6 or 7 member homo- or heterocycle either saturated, unsaturated or aromatic optionally containing 1-3 additional heteroatoms selected from N, O and S, where any carbon or sulfur ring atom may optionally be oxidized, each cycle substituted with 0-3 R 31 ; and where s is 0-2; B is selected from the group; 
 
       
         
           
           
               
               
           
         
         wherein 
       
       
         
           
           
               
               
           
         
          is a fused hetero- or homocyclic ring containing 5, 6 or 7 atoms, the ring being unsaturated, partially saturated or aromatic, the heteroatoms selected from 1-3 O, S and N, 
         Y 3  is selected from CH and NR 30 ; n is 0-3: 
         G 3  is selected from hydrogen and C 1 -C 6 alkyl, optionally G taken together with T may form a C 3 -C 6 cycloalkyl optionally substituted with —V—W; 
         T 3  is selected from the group 
         a naturally occurring α-amino-acid side chain, 
         and U 4 -Q 4 -V 4 —W 4 ; 
         U 4  is an optionally substituted bivalent radical selected from the group C 1 -C 6 alkyl, C 0 -C 6 alkyl-Q, C 2 -C 6 alkenyl-Q, and C 2 -C 6 alkynyl-Q: 
         where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38 ; 
         Q 4  is absent or is selected from the group 
         —O—, —S(O) s —, —SO 2 —N(R 30 )—, —N(R 30 )—, —N(R 30 )—C(═O)—, —N(R 30 )—C(═O)—N(R 30 )—, —N(R 30 )—C(═O)—O—, —N(R 30 )—SO 2 —, —C(═O)—, —C(═O)—O—, -het-, —C(═O)—N(R 30 )—, —O—C(═O)—N(R 30 )—, —PO(OR 30 )O— and —P(O)O—; 
       
       where
 is 0-2 and 
 het is a mono- or bicyclic 5, 6, 7, 9 or 10 member heterocyclic ring, each ring containing 1-4 heteroatoms selected from N, O and S, where the heterocyclic ring may be saturated, partially saturated, or aromatic and any N or S being optionally oxidized, the heterocyclic ring being substituted with 0-3 R 41 ; 
 V 4  is absent or is an optionally substituted bivalent group selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 0 -C 6 alkyl-C 6 -C 10 aryl, and C 0 -C 6 alkyl-het; 
 where the substituents on any alkyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 W 4  is selected from the group hydrogen, OR 33 , SR 42 , NR 30 R 30 , NH—C(═O)—R 43 , NH—C(═O)—NR n R n , NH—C(═O)—R 43 , NH—SO 2 —R 37 , NH—SO 2 —NR 30 R 30 , NH—SO 2 —NH—C(═O)—R 43 , NH—C(═O)—NH—SO 2 —R 37 , C(═O)—NH—C(═O)—O—R 43 , C(═O)—NH—C(═O)—R 43 , C(═O)—NH—C(═O)—NR 30 R 30 ′, C(═O)—NH—SO 2 —R 37 , C(═O)—NH—SO 2 —NR 30 R 30 ′, C(═S)—NR 30 R 30 ′, SO 2 —R 37 , SO 2 —O—R 37 , SO 2 —NR 37 R 37 ′, SO 2 —NH—C(═O)—O—R 43 , SO 2 —NH—C(═OC)—NR 30 R 30 ′, SO 2 —NH—C(═O)—R 43 , O—C(═O)—NR 30 R 30 ′, O—C(═O)—R 43 , O—C(═O)—NH—C(═O)—R 43 , O—C(═O)—NH—SO 2 R 46  and O—SO 2 —R 37 ; 
 R 44  is selected from C(═O)—R 45 , C(═O)—H, CH 2 (OH), and CH 2 O—C(═O)—C 1 -C 6 alkyl; 
 R 38  is R 38′  or R 38″  substituted with 1-3 R 38 ′; where 
 R 38 ′ is selected from the group 
 hydrogen, halo(F, Cl, Br, I), cyano, isocyanate, carboxy, carboxy-C 1 -C 11 alkyl, amino, amino-C 1 -C 8 alkyl, aminocarbonyl, carboxamido, carbamoyl, carbamoyloxy, formyl, formyloxy, azido, nitro, imidazoyl, ureido, thioureido, thiocyanato, hydroxy, C 1 -C 6 alkoxy, mercapto, sulfonamido, het, phenoxy, phenyl, benzamido, tosyl, morpholino, morpholinyl, piperazinyl, piperidinyl, pyrrolinyl, imidazolyl, and indolyl; 
 R 38 ″ is selected from the group 
 C 0 -C 10 alkyl-Q-C 0 -C 6 alkyl, C 0 -C 10 alkenyl-Q-C 0 -C 6 alkyl, C 0 -C 10 alkynyl-Q-C 0 -C 6 alkyl, C 3 -C 11 cycloalkyl-Q-C 0 -C 6 alkyl, C 3 -C 10 cycloalkenyl-Q-C 0 -C 6 alkyl, C 1 -C 6 alkyl-C 6 -C 12  aryl-Q-C 0 -C 6 alkyl, C 6 -C 10  aryl-C 1 -C 6 alkyl-Q-C 0 -C 6 alkyl, C 0 -C 6 alkyl-het-Q-C 0 -C 6 alkyl, C 0 -C 6 alkyl-Q-het-C 0 -C 6 alkyl, het-C 0 -C 6 alkyl-Q-C 0 -C 6 alkyl, C 0 -C 6 alkyl-Q-C 6 -C 12 aryl, and -Q-C 1 -C 6 alkyl; 
 R 43  is selected from hydrogen and substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 10 cycloalkenyl, C 1 -C 6 alkyl-C 6 -C 12 aryl, C 6 -C 10 aryl-C 1 -C 16 alkyl, C 1 -C 6 alkyl-het, het-C 1 -C 6  alkyl, C 6 -C 12 aryl and het, 
 where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 R 31  is selected from R 40  and R 41 ; 
 R 41  is selected from the group 
 OH, OCF 3 , OR 43 , SR 42 , halo(F, Cl. Br, I), CN, isocyanate, NO 2 , CF 3 , C 0 -C 6 alkyl-NR 30 R 30 ′, C 0 -C 6 alkyl-C(═O)—NR 30 R 30 ′, C 0 -C 6 alkyl-C(═O)—R 38 , C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, C 1 -C 6 alkyl-phenyl, phenyl-C 1 -C 6 alkyl, C 1 -C 6 alkyloxycarbonyl, phenyl-C 0 -C 6 alkyloxy, C 1 -C 6 alkyl-het, het-C 1 -C 6 alkyl, SO 2 -het, —O—C 6 -C 12 aryl, —SO 2 —C 6 -C 12 aryl, —SO 2 —C 1 -C 6 alkyl and het, where any alkyl, alkenyl or alkynyl may optionally be substituted with 1-3 groups selected from OH, halo(F, Cl, Br, I), nitro, amino and aminocarbonyl and the substituents on any aryl or het are 1-2 hydroxy, halo(F, Cl, Br, I), CF 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, nitro and amino; 
 R m  is selected from S—C 1 -C 6 alkyl, C(═O)—C 1 -C 6 alkyl, C(═O)—NR 30 R 30 ′, C 1 -C 6 alkyl, halo(F, Cl, Br, I)—C 1 -C 6 alkyl, benzyl and phenyl; 
 R 30  is selected from the group R 43 , NH—C(═O)—O—R 43 , NH—C(═O)—R 43 , NH—C(═O)—NHR 43 , NH—SO 2 —R 46 , NH—SO 2 —NH—C(═O)—R 43 , NH—C(═O)—NH—SO 2 —R 37 , C(═O)—O—R 43 , C(═O)—R 43 , C(═O)—NHR 43 , C(═O)—NH—C(═O)—O—R 43 , C(═O)—NH—C(═O)—R 43 , C(═O)—NH—SO 2 —R 46 , C(═O)—NH—SO 2 —NHR 37 , SO 2 —R 37 , SO 2 —O—R 37 , SO 2 —N(R 43 ) 2 , SO 2 —NH—C(═O)—O—R 43 , SO 2 —NH—C(═O)—O—R 43  and SO 2 —NH—C(═O)—R 43 ; 
 R 30 ′ is selected from hydrogen, hydroxy and substituted or unsubstituted C 1 -C 11 alkyl, C 1 -C 11  alkoxy, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 11 cycloalkyl, C 3 -C 10 cycloalkenyl, C 1 -C 6 alkyl-C 6 -C 12 aryl, C 6 -C 10 aryl-C 1 -C 16  alkyl, C 6 -C 10 aryl-C 0 -C 6 alkyloxy, C 1 -C 6 alkyl-het, het-C 1 -C 6 alkyl, C 6 -C 12 aryl, het, C 1 -C 6 alkylcarbonyl, C 1 -C 8 alkoxycarbonyl, C 3 -C 8 cycloalkylcarbonyl, C 3 -C 8 cycloalkoxycarbonyl, C 6 -C 11 aryloxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, heteroarylalkoxycarbonyl, heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroarylalkylsulfonyl, heteroarylsulfonyl, C 1 -C 6 alkylsulfonyl, and C 6 -C 10 arylsulfonyl, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl, het or heteroaryl are 1-3 R 31 ; 
 R 30  and R 30 ′ taken together with the common nitrogen to which they are attached may from an optionally substituted heterocycle selected from morpholinyl, piperazinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, thiazolidinyl and azabicyclononyl, where the substituents are 1-3 R 38 ; 
 R 33  is selected from hydrogen and substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl and benzoyl, where the substituents on any alkyl are 1-3 R 38  and the substituents on any aryl are 1-3 R 40 ; 
 R 40  is selected from the group OH, halo(F, Cl. Br, I), CN, isocyanate, OR 43 , SR 42 , SOR 43 , NO 2 , CF 3 , R 43 , NR 30 R 30 ′, NR 30 C(═O)—O—R 43 , NRC(═O)—R 43 , C 0 -C 6 alkyl-SO 2 —R 43 , C 0 -C 6 alkyl-SO 2 —NR 30 R 30 ′, C(═O)—R 43 , O—C(═O)—R 43 , C(═O)—O—R 43 , and C(═O)—NR 30 R 30 ′, where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 R 46  is a substituted or unsubstituted group selected from 
 C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkenyl, C 0 -C 6 alkyl-phenyl, phenyl-C 0 -C 6 alkyl, C 0 -C 6 alkyl-het and het-C 0 -C 6 alkyl, 
 where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31 ; 
 R 45  is a substituted or unsubstituted group selected from hydroxy, C 1 -C 11 alkoxy, C 3 -C 12 cycloalkoxy, C 8 -C 12 aralkoxy, C 8 -C 12 arcycloalkoxy, C 6 -C 10 aryloxy, C 3 -C 10  alkylcarbonyloxyalkyloxy, C 3 -C 10  alkoxycarbonyloxyalkyloxy, C 3 -C 10 alkoxycarbonylalkyloxy, C 5 -C 10  cycloalkylcarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 -C 10 cycloalkoxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonylalkyloxy, C 8 -C 12 aryloxycarbonyloxyalkyloxy, C 8 -C 12 arylcarbonyloxyalkyloxy, C 5 -C 10 alkoxyalkylcarbonyloxyalkyloxy, (R 30 )(R 30 )N(C 1 -C 10 alkoxy)-, 
 
       
         
           
           
               
               
           
         
         where the substituents on any alkyl, alkenyl or alkynyl are 1-3 R 38  and the substituents on any aryl or het are 1-3 R 31  and pharmaceutically acceptable salts thereof. 
       
     
     
         50 . The method of  claim 42  wherein said LFA-1 antagonist is administered in a therapeutically acceptable formulation via instillation, via intraocular implantation, via periocular implantation, via injection, orally, intranasally, topically, or iontophoretically. 
     
     
         51 . The method of  claim 50  wherein said administration via injection is performed intraocularly, intravitreally, periocularly, subcutaneously, subconjunctivally, retrobulbarly, or intracamerally. 
     
     
         52 . The method of  claim 42  wherein said pharmaceutically acceptable formulation comprises a gel, cream, powder, foam, crystals, liposomes, spray, polymer micro or nanoparticles, biodegradable matrix, liquid suspension, solution, suspension, an ointment, a pack, bioabsorbable implant, or an ocular insert. 
     
     
         53 . A method of treating diabetic retinopathy in an subject comprising performing a diabetic retinopathy diagnostic test on said subject; determining whether said subject suffers from diabetic retinopathy based on the results of said diagnostic test; and upon diagnosis of said diabetic retinopathy, administering to said subject an effective amount of a lymphocyte function associated antigen-1 (LFA-1) antagonist in a pharmaceutically acceptable formulation. 
     
     
         54 . The method of  claim 53  wherein said diagnostic test is performed by imaging an eye of said subject or analysis of a biological sample of an eye of said subject. 
     
     
         55 . A method of reducing and/or preventing post-operative ocular inflammation in a subject suffering from diabetes comprising administering to said subject in need thereof a therapeutically effective amount of a LFA-1 antagonist, thereby reducing and/or preventing post-operative inflammation in an eye of said subject. 
     
     
         56 . The method of  claim 55  wherein said post-operative inflammation is the result of vitrectomy, laser photocoagulation therapy, photodynamic therapy, or LASIK. 
     
     
         57 . The method of  claim 42 ,  53 , or  55  wherein said LFA-1 antagonist is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and their pharmaceutically acceptable salts and esters. 
     
     
         58 . The method of  claim 42 ,  53 , or  55  wherein said LFA-1 antagonist is one of the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or their pharmaceutically acceptable salts and esters. 
     
     
         59 . A pharmaceutical composition formulated for ocular delivery comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         60 . The pharmaceutical composition of  claim 59 , wherein the compound of  claim 1  is a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, or XI. 
     
     
         61 . The pharmaceutical compositions of  claim 59 , wherein the pharmaceutical composition is suitable for topical administration. 
     
     
         62 . The pharmaceutical composition of  claim 59 , wherein the pharmaceutical composition is suitable for administration via injection. 
     
     
         63 . The pharmaceutical compositions of  claim 59 , wherein the pharmaceutical composition is suitable for administration as an implant.