Amino, amido and heterocyclic compounds as modulators of rage activity and uses thereof

摘要

Amino, amido, and heterocyclic compounds are disclosed. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diabetes complications, inflammation, and neurodegeneration, obesity, cancer, ischemia/reperfusion injury, cardiovascular disease and other diseases related to RAGE activity.

主权项

1. A method for treating or ameliorating in a mammal a disease or condition that is causally related to RAGE activity in vivo, which comprises administering to the mammal an effective disease-treating or condition-treating amount of a compound according to formula B-I′: wherein each A1, A2, A3, and A4 is independently CR4 or N; provided that only 1 or 2 of A1, A2, A3, and A4 are N at any one time; Z is substituted amino, substituted hydroxyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X is CR5a or N; R1 is hydroxy, substituted hydroxyl, amino, or substituted amino; R2 is H, alkyl or aryl; R3a is H, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, halo, or cyano; each R4 is independently selected from H, OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted acyl, substituted or unsubstituted acylamino, substituted or unsubstituted alkylamino, substituted or unsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, substituted or unsubstituted amino, substituted or unsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl, substituted sulfinyl, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted dialkylamino, halo, nitro, and thiol; R5a is independently H, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, halo, or cyano; or R5a and R3a may join together to form a substituted or unsubstituted carbocyclic or heterocyclic ring; and each of the subscript m and n is independently 1, 2, or 3; or a pharmaceutically acceptable salt, solvate or prodrug thereof; or stereoisomers, isotopic variants and tautomers thereof; wherein the disease or condition is selected from diabetes and its complications, atherosclerosis, peripheral vascular disease and associated complications, cardiovascular disease nephropathy,retinopathy, cardio- and cerebrovascular ischemia/reperfusion injury, heart attack, myocardial infarction, ischemic cardiomyopathy, cancer, tumor invasion and metastases, acute and chronic inflammation, arthritis,allergy asthma, obesity, pollution-associated tissue or organ damage, infection, sepsis, pneumonia, liver injury/damage, amyloidoses, skin disorders, colitis, lupus, and impaired wound healing.