Claims for Patent: 7,314,938

Summary for Patent: 7,314,938

Title:	Modulators of cellular adhesion
Abstract:	The present invention provides compounds having formula (I): and pharmaceutically acceptable derivatives thereof, wherein R1-R4, n, p, A, B, D, E, L and AR1 are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).
Inventor(s):	Wang Shen, Kenneth Barr, Johan D. Oslob, Min Zhong
Assignee:	Bausch and Lomb Ireland Ltd
Application Number:	US10/982,463
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,314,938
Patent Claims:	1. An isolated compound of the structure (I): or a pharmaceutically acceptable salt, ester, salt, of such ester or prodrug thereof; wherein R1 and R2 are each independently hydrogen, —(CH2)mOH, —(CH2)maryl, —(CH2)mheteroaryl, wherein m is 0-6, —CH(R1A)(OR1B), —CH(R1A)(NHR1B), 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—, —SO2N(R1A), —N(R1A)—, —N(R1A)C(═O)—, —N(R1A)C(═O)—O—, —N(R1A)C(═O)—N(R1B)—, —N(R1A)—SO2—, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R1A)—, —O—C(═O)—N(R1A)—, —C(═N—R1E)—, —C(═N—R1E)—O—, —C(═N—R1E)—N(R1A)—, —O—C(═N—R1E)—N(R1A)—, —N(R1A)C(═N—R1E)—, N(R1A)C(═N—R1E)—O—, N(R1A)C(═N—R1E)—N(R1B)—, —P(═O)(OR1A)—O—, or —P(═O)(R1A)—O—; T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen, halogen, cyano, isocyanate, —OR1B, —SR1B; —N(R1B)2, —NHC(═O)OR1B, —NHC(═O)N(R1B)2, —NHC(═O)R1B, —NHSO2R1B, —NHSO2N(R1B)2, —NHSO2NHC(═O)OR1B, —NHC(═O)NHSO2R1B, —C(═O)NHC(═O)OR1B, —C(═O)NHC(═O)R1B, —C(═O)NHC(═O)N(R1B)2, ——C(═O)NHSO2R1B, —C(═O)NHSO2N(R1B)2, —C(═S)N(R1B)2, —SO2R1B, —SO2—O—R1B, —SO2—N(R1B)2, —SO2—NHC(═O)OR1B, —SO2—NHC(═O)—N(R1B)2, —SO2—NHC(═O)R1B, —O—C(═O)N(R1B)2, —O—C(═O)R1B, —O—C(═O)NHC(═O)R1B, —O—C(═O)NH—SO2R1B, —O—SO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, wherein each occurrence R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —COR1C, or —CONR1CR1D; wherein each occurrence of R1C and R1D is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R1E is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR1C, —NR1CR1D or —SO2R1C; R3 is —C(═O)OR3A, —C(═O)H, —C(═O)NH(R3A, wherein R3A is hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, or R3A, taken together with R1 or R2, forms a heterocyclic moiety; R4, for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; n is an integer from 0-4; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, and E are independently CHRi; D is N; wherein each occurence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; p is 1; and L is C═O. 2. The compound of claim 1, wherein R3 is carboxyl, protected carboxyl or a prodrug thereof, wherein R3 is C(═O)R3A, wherein R3A is hydroxy, alkoxy, cycloalkoxy, aralkoxy, arcycloalkoxy, aryloxy, alkylcarbonyloxyalkyloxy, alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy, cycloalkylcarbonyloxyalkyloxy, cycloalkoxycarbonyloxyalkyloxy, cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy, aryloxycarbonyloxyalkyloxy, arylcarbonyloxyalkyloxy, alkoxyalkylcarbonyloxyalkyloxy, or one of the structures: 3. The compound of claim 1 wherein the compound of the structure: wherein R4A and R4B are independently a halogen selected from F, Cl, Br or I; and RB1, RB2 and RE are independently hydrogen or substituted or unsubstituted lower alkyl. 4. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety of the following: wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and RS is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is -G0RG1 wherein G0 is —O—, —S— or —NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety. 5. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety of the following structure: wherein R1A is Ar2, —OR1B, —SR1B or —NR1BR1C; or an alkyl or heteroalkyl moiety; and Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; wherein R1B and R1C are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or R1B and R1C, taken together with the nitrogen atom to which they are attached, form a heterocylic or heteroaryl moiety. 6. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety of the following structure: wherein Ar2 is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and R2A is hydrogen, C1-6alkyl, C2-6alkenyl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with a substituent on Ar2, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety. 7. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety of the following structure: wherein t is 1-3; and RP3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 8. The compound of claim 7, wherein t is 2 and RP3 is alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 9. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety of the following structure: wherein R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with R2C or R2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R2C is hydrogen, CN, —C═NMe, ═NO2, ═NC(═O)NH2, ═NS(O)2R, ═NS(O)2NRR′, —SO2R2G, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; wherein R and R′ are each independently hydrogen or methyl, and R2G is lower alkyl; and R2D is Ar2, hydrogen, halogen, CN, NO2, an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety. 10. A compound of the structure (II) or (III): or a pharmaceutically acceptable salt, ester, salt of such ester or prodrug thereof; wherein R4 for each occurrence, is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is GRG1; n is an integer from 2-3; AR1 is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; A, B, D and E are connected by a single bond; wherein D is N and each occurrence of A, B, and E is —CHRi; wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1, or any two adjacent occurrences of Ri taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; p is 1; L is C═O; wherein R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with R2C or R2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R2C is hydrogen, CN, —C═NMe, ═NO2, ═NC(═O)NH2, ═NS(O)2R, ═NS(O)2NRR′, —SO2R2G, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; wherein R and R′ are each independently hydrogen or methyl, and R2G is lower alkyl; and R2D is Ar2, hydrogen, halogen, CN, NO2, an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GRG1; wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —CO(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; or NRG1RG2 together form a cyclic moiety. 11. The compound of claim 10, wherein —C(═O)NHCH(CO2R3A)CH2N(R2A)C(═NR2C)R2D is a moiety of the following structure: wherein R2E and R2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R2E and R2F, taken together, form a substituted or unsusbtituted heterocyclic or heteroaryl moiety. 12. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 is a moiety with one of the following structures: wherein R2A is hydrogen C1-6alkyl C2-6alkenyl aryl heteroaryl —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with R2C or R2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R2C is hydrogen, CN, —C═NMe, ═NO2, ═NC(═O)NH2, ═NS(O)2R, or ═NS(O)2NRR′; wherein R and R′ are each independently hydrogen or methyl; R2D is Ar2, hydrogen, halogen, CN, NO2, an aliphatic, heteroaliphatic, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R2E and R2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R2E and R2F, taken together, form a substituted or unsubstituted heterocyclic or heteroaryl moiety. 13. The compound of claim 10, wherein —C(═O)NHCH(CO2R3A)CH2N(R2A)C(═NR2C)R2D is a moiety with one of the following structures: wherein R2E and R2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R2E and R2F, taken together, form a substituted or unsusbtituted heterocyclic or heteroaryl moiety. 14. The compound of claim 1 or 10, wherein the moiety —C(═O)NHCH(CO2R3A)CH2N(R2A)C(═NR2C)R2D with one of the following structures: wherein R2C is lower alkyl; and R2E and R2F are each independently hydrogen, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or R2E and R2F, taken together, form a substituted or unsubstituted heterocyclic or heteroaryl moiety. 15. The compound of claim 11, wherein R2D is, or R2E and R2F together with the nitrogen atom to which they are attached form, a moiety with one of the following structures: wherein s is an integer between 0 and 6; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 16. The compound of claim 12, wherein R2D is, or R2E and R2F together with the nitrogen atom to which they are attached form, a moiety with one of the following structures: wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, —OCH3, —OH, —NH2, —NHCH3, or —N(CH3)2. 17. The compound of claim 13, wherein R2D is, or R2E and R2F together with the nitrogen atom to which they are attached form, a moiety with one of the following structures: 18. The compound of claim 13, wherein —C(═O)NHCH(CO2R3A)CH2N(R2A)C(═NR2C)R2D of the structure: wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, —OCH3, —OH, —NH2, —NHCH3 or —N(CH3)2; R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; and q is 1 or 2. 19. The compound of claim 14, wherein —C(═O)NHCH(CO2R3A)CH2N(R2A)C(═NR2C)R2D with one of the following structures: wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, —OCH3, —OH, —NH2, —NHCH3 or —N(CH3)2; R2A is hydrogen, C1-6alkyl, C2-6alkenyl, aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; q is 1 or 2; and R2C is lower alkyl. 20. The compound of claim 4, wherein R3A is independently hydrogen, lower alkyl, phenyl or benzyl. 21. The compound of claim 4 wherein Ar2 is one of the following structures: wherein s is an integer from 0-2; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —ORG1, —S RG1, NRG1RG2—, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently lower alkyl, or when Y is O RP5 may also be hydrogen; each occurrence of RP2 is independently hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; RP3 is lower alkyl or —N(RP2)2; and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety. 22. The compound of claim 21 wherein Ar2 is one of the following structures: 23. The compound of claim 4 wherein Ar2 is one of the following structures: wherein RP3 is lower alkyl and RG1 is hydrogen or lower alkyl. 24. The compound of claim 5 wherein R1A is —NH2 or a moiety of the structure: wherein RP1 is independently hydrogen, hydroxyl, lower alkyl or lower heteroalkyl; and each occurrence of RP2 is independently hydrogen or lower alkyl. 25. The compound of claim 24 wherein R1A is —NH2 or a moiety of the structure: wherein RP1 is hydrogen or lower alkyl. 26. The compound of claim 5 wherein R1A is a moiety with one of the following structures: wherein s is an integer between 0 and 2; each occurrence of RP1 is independently lower alkyl or is -GRG1 wherein G is —O— or —NRG2 and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of RP2 is independently hydrogen, lower alkyl, aryl or heteroaryl. 27. The compound of claim 26 wherein R1A is a moiety with one of the following structures: wherein G is —O— or —NRG2—, and RG1 and RG2 are independently hydrogen or lower alkyl. 28. The compound of claim 6, wherein —N(R2A)Ar2 is one of the following structures: wherein X1 is N or CRP1; s is an integer from 0-5; and each occurrence of RP1 is independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and RP3 is alkyl, heteroalkyl, aryl or heteroaryl. 29. The compound of claim 28, wherein —NH(R2A)Ar2 of the following structure: wherein RP1 is hydrogen, halogen or lower alkyl. 30. The compound of claim 10 where R2D is Ar2, wherein Ar2 is one of the following structures: wherein each occurrence of s is an integer from 0-6; X1 is CHRP1 or NRP2; X2 and X3 are independently CHRP1, NRP2, CHSO2RP3 or NSO2RP3; X5 is O, S or NRP2; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be hydrogen; each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety; and each occurrence of RP3 is independently alkyl, aryl, heteroaryl or —N(RP2)2. 31. The compound of claim 30 wherein Ar2 is one of the following structures: wherein X1 is N or CRP1; s is an integer from 0-6; each occurrence of RP1 is independently hydrogen, halogen, CN, NO2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R3 is independently lower alkyl or aryl. 32. The compound of claim 1, wherein —C(═O)NHC(R1)(R2)R3 has the structure —C(═O)NHC(═C(RS)Ar2)CO2R3A wherein R3A and RS, taken together, form a substituted or unsubstituted heterocyclic moiety. 33. The compound of claim 32, wherein —C(═O)NHC(═C(RS)Ar2)CO2R3A is one of the following structures: wherein Ar2 is heterocycle, aryl or heteroaryl; and X1 is O, S or NH. 34. The compound of claim 32, wherein —C(═O)NHC(═C(RS)Ar2)CO2R3A is one of the following structures: wherein X1 is O, S or NH; and X2 is N or CH. 35. The compound of claim 1, wherein AR1 is one of the following structures: wherein each occurrence of r is an integer from 0-6; X1, X2, X3 and X4 is independently N or CRQ1; X5 is O, S or NRQ2; AR3 is a heterocyclic, aryl or heteroaryl moiety; each occurrence of RQ1 is independently hydrogen, ORQ3, OCF3, SRQ3, halogen, CN, isocyanate, NO2, CF3, NRQ3QRQ4, —SO2RQ3, alkyl-NRQ3RQ4, alkyl-C(═O)—NRQ3RQ4, alkyl-C(═O)RQ3, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety, wherein each occurrence of RQ3 and RQ4 is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety; and RQ2 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group. 36. The compound of claim 35, wherein AR1 is one of the following structures: wherein X0 is F or Cl; X2 is N or CRQ1; X5 is CH, O, S or NH; RQ1 is hydrogen, methyl, —CF3, —OCH3, —OCF3 or halogen. 37. The compound of claim 36, wherein AR1 is one of the following structures: 38. The compound of claim 37, wherein AR1 is one of the following structures: 39. The compound of claim 1, wherein AR1-L- is one of the following structures: 40. The compound of claim 39, wherein AR1-L- is one of the following structures: 41. The compound of claim 3 wherein AR1-L- is a moiety with one of the following structures: and —C(═O)NHC(R1)(R2)R3 is a moiety having one of the following structures: wherein R2A is hydrogen C1-6alkyl C2-6alkenyl aryl, heteroaryl, —C(═O)R2B or —SO2R2B, wherein R2B is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl or heteroaryl; or R2A, taken together with R2D, forms a substituted or unsubstituted heterocyclic or heteroaryl moiety; R3A is hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety; and R2D is a moiety having one of the following structures: wherein s is an integer between 0 and 6; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —NRG2 —, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety. 42. The compound of claim 41 wherein R2A and R3A are each hydrogen. 43. The compound of claim 41 wherein R2D is a moiety with one of the following structures: wherein each occurrence of RP1 is independently hydrogen, halogen, methyl, —OCH3, —OH, —NH2, —NHCH3, or —N(CH3)2. 44. The compound of claim 43 wherein R2D is a moiety with one of the following structures: 45. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, ester, salt of such ester or prodrug thereof; and a pharmaceutically acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent. 46. The pharmaceutical composition of claim 45, wherein the compound is present in an amount effective to modulate adhesion between intracellular adhesion molecules (e.g., ICAM-1, -2 and -3) and the leukocyte integrin family of receptors. 47. The pharmaceutical composition of claim 45, wherein the compound is present in an amount effective to antagonize CD11/CD18 receptors associated with leukocytes. 48. The pharmaceutical composition of claim 45, wherein the compound is present in an amount effective to antagonize Mac-1 and/or LFA-1. 49. The compound of claim 1 of the structure: 50. The compound of claim 1 of the structure: 51. The compound of claim 1 of the structure: 52. The compound of claim 1 of the structure: 53. The compound of claim 1 of the structure: 54. The compound of claim 1 of the structure: 55. The compound of claim 1 of the structure: 56. The compound of claim 1 of the structure: 57. The compound of claim 1 with one of the following structures: 58. The compound of claim 1 with one of the following structures: 59. The compound of claim 1 with one of the following structures: 60. The compound of claim 1 with one of the following structures: 61. The compound of claim 1 with one of the following structures: 62. The compound of claim 10, wherein R2D is a moiety with one of the following structures: wherein s is an integer between 0 and 6; each occurrence of RP1 is independently hydrogen, halogen, CN, isocyanate, NO2, —P(═O)(YRP5)2, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GRG1 wherein G is —O—, —S—, —NRG2—, —CO—, —SO—, —SO2—, —C(═O)O—, —C(═O)NRG2—, —OC(═O)—, —NRG2C(═O)— or —SO2NRG2—, and RG1 and RG2 are independently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y is independently a bond or O; each occurrence of RP5 is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is O RP5 may also be hydrogen; and each occurrence of RP2 is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogen protecting group; wherein any two adjacent occurrences of RP1 and RP2, taken together, may form a cycloalkyl, heterocyclic, aryl or heteroaryl moiety.