Tyrosine phosphatase inhibitors and uses thereof to modulate the activity of enzymes involved in the pathology of <i>Mycobacterium tuberculosis</i>

摘要

A variety of benzofurans and indole derivatives some with an alkynyl linker are disclosed herein. These compounds are not highly charged at physiological pH and have good bioavailability characteristics. These compounds exhibit selective or at least preferential affinity for the active sites of various sub-sets of protein tyrosine phosphatases. Some of these compounds are excellent inhibitors of Mycobacterium protein tyrosine phosphatase B (mPTPB) a protein tyrosine phosphatase expressed in Mycobacterium tuberculosis and characterized as a virulence factor in the causal agent of tuberculosis. Accordingly, many of these compounds and pharmaceutically acceptable salts thereof are useful for the treatment of diseases such as tuberculosis.

主权项

1. A compound of Formula A, or a pharmaceutically acceptable salt thereof, wherein X is O or NR2; R1 is selected from the group consisting of: and each occurrence of R2 can be the same or different and is H or C1-C6 alkyl; each occurrence of R3 can be the same or different and is H, halogen, hydroxyl, NR2R2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, O-(substituted or unsubstituted C1-C6 alkyl), S-(substituted or unsubstituted C1-C6 alkyl), O-(substituted or unsubstituted aryl), O-(substituted or unsubstituted heteroaryl), S-(substituted or unsubstituted aryl), S-(substituted or unsubstituted heteroaryl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, SO2-(substituted or unsubstituted C1-C6 alkyl), SO2NR2R2, C(O)-(substituted or unsubstituted C1-C6 alkyl), C(O)-(substituted or unsubstituted aryl), C(O)-(substituted or unsubstituted heteroaryl), (CH2)nCO2H, or O(CH2)nCO2H;
Y is H, halogen, hydroxyl, NR2R2, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkenyl, substituted or unsubstituted C1-C6 alkynyl, O-(substituted or unsubstituted C1-C6 alkyl), S-(substituted or unsubstituted C1-C6 alkyl), O-(substituted or unsubstituted aryl), O-(substituted or unsubstituted heteroaryl), S-(substituted or unsubstituted aryl), S-(substituted or unsubstituted heteroaryl), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cyano, SO2C1-C6 alkyl, SO2NR2R2, C(O)-(substituted or unsubstituted C1-C6 alkyl), C(O)-(substituted or unsubstituted aryl), C(O)-(substituted or unsubstituted heteroaryl); —(CH2)nCOZ, or —O—(CH2)n-COZ;n can be the same or different at each occurrence and is 1, 2, 3, or 4;Z is —OH, or N(R4)2, wherein each occurrence of R4 can be the same or different and is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkenyl, substituted C1-C6 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, OR5, NHR5,  andR5 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C(O)-(substituted or unsubstituted C1-C6alkyl), C(O)-(substituted or unsubstituted aryl), C(O)-(substituted or unsubstituted heteroaryl), or C(O)-(substituted or unsubstituted C3-C8 cycloalkyl).