Modulators of cellular adhesion

A compound of the structure (1):

• or pharmaceutically acceptable salts thereof;
• R1 and R2 are each independently hydrogen, an amino acid side chain, —(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)—, —OC(═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, —SO2OR1B, —SO2N(R1B)2, —SO2—NHC(═O)OR1B, —OC(═O)—N(R1B)2, —OC(═O)R1B, —OC(═O)NHC(═O)R1B, —OC(═O)NHSO2R1B, —OSO2R1B, or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R1 and R2 taken together are an alicyclic or heterocyclic moiety, or together are
• wherein each occurrence of R1A and R1B is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R1C, or —C(═O)NR1CR1D;
• 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, —CH2OR3A, —CH2OC(═O)-alkyl, —C(═O)NH(R3A).—CH2X0;
• wherein each occurrence of R3A 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 R3A, taken together with R1 and R2, forms a heterocyclic moiety;
• wherein X0 is a halogen selected from F, Br or I;
• 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—, C(═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, D and E are connected by either a single or double bond, as valency permits;
• wherein each occurrence of A, D and E is independently C═O, CHRi, NRi, CRi, N, O, S, —S(═O) or SO2;
• 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 wherein G is —O—, —S—, —NRG2, —CO—, —SO—, —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, 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, NRL1, —O—, —C(RL1)═, ═C(RL1)—, —C(RL1)(RL2), C(═N—ORL1), C(═NRL1), —N═, S(O)0-2;
• a substituted or unsubstituted C1-6 alkenylidene or C1-2 alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by—C(═O)—, —CO2—, —C(═O)C(═O)—, —C(C═O)NRL3—, —OC(═O)—, —OC(═O)NRL3—, —NRL3NRL4—, —NRL3NRL4C(═O)—, —NRL3C(═O)—, NRL3CO2—, NRL3C(═O)NRL4—, −S(═O)—, —SO2—, —NRL3SO2—, —SO2NRL3, —NRL3SO2NRL4, —O—, —S—, or —NRL3—;
• wherein each occurrence of RL3and RL4 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 RL1 and RL2 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 RL1 and RL2, 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;
• with the proviso that the compound is not of the structure (Ia):
• wherein AR1, R1, R2, and R3 are defined as above;
• D is N;
• p is 1;
• and A, B, and E are independently CHRi or —GRG1;
• wherein each occurrence of Ri is independently hydrogen, halogen, —CN, —NO2, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, wherein G is —O—, —S—, NRG2, —CO—, —SO—, —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.