Modulators of cellular adhesion

摘要

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).

主权项

1. A pharmaceutical formulation comprising an LFA-1 antagonist and an excipient, wherein the formulation is for topical administration and wherein the LFA-1 antagonist comprises a compound of Formula I or its pharmaceutically acceptable salt or ester, wherein 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, or wherein R1 and R2 taken together are an alicyclic or heterocyclic moiety; wherein each occurrence of 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, —NR1CR1Dor —SO2R1C; R3 is —C(═O)OR3A, —C(═O)H, —CH2OR3A, —CH2O—C(═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 or heteroalkylheteroaryl moiety, or R3A, taken together with R1 or R2, forms a heterocyclic moiety; wherein X0 is a halogen selected from F, Cl, 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—, —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, D and E are connected by single bonds; wherein D is N and each occurrence of A, B, and E is independently 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 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, or any two adjacent occurrences of Ri, taken together, represent an alicyclic, heteroalicyclic, aryl, or heteroaryl moiety; p is an integer from 0-4; and L is C═O or a substituted or unsubstituted C1-6alkylidene or C2-6alkenylidene chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—.