Compounds for inhibiting drug-resistant strains of HIV-1 integrase

A compound of formula IV, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

• R4 is H, OH, NH2, NHR8, NR8R9 or R8;
• R5 and R7 is each independently H, halogen, OR8, R8, NHR8, NR8R9, CO2R8, CONR8R9, or SO2NR8R9;
• R6 is halogen, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, or optionally-substituted ester;
• and
• R8 and R9 is each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R8 and R9 together with the nitrogen to which R8 and R9 are attached form an optionally-substituted heterocycle.

A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

• wherein X is N;
• Y is OH;
• each of Z1-Z5 is independently H or halogen;
• R4 is H, OH, NH2, NHR8, NR8R9 or R8;
• R5 and R7 is each independently H, halogen, OR8, R8, NHR8, NR8R9, CO2R8, CONR8R9, or SO2NR8R9;
• R6 is halogen, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, or optionally-substituted heterocycle;
• and
• R8 and R9 is each independently H, optionally-substituted alkyl, optionally-substituted alkylene, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R8 and R9 together with the nitrogen to which R8 and R9 are attached form an optionally-substituted heterocycle.

A method of inhibiting drug-resistant HIV-1 integrase in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof, having a structure of:

• wherein X is N;
• Y is OH;
• each of Z1-Z5 is independently H or halogen, provided at least one of Z1-Z5 is halogen;
• R4 is H, OH, NH2, NHR8, NR8R9 or R8;
• R5 and R7 is each independently H, halogen, OR8, R8, NHR8, NR8R9, CO2R8, CONR8R9, or SO2NR8R9;
• R6 is halogen, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, or optionally-substituted ester;
• and
• R8 and R9 is each independently H, optionally-substituted alkyl, optionally-substituted alkenyl, optionally-substituted alkynyl, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted cycloalkylene, optionally-substituted heterocycle, optionally-substituted amide, optionally-substituted ester, or R8 and R9 together with the nitrogen to which R8 and R9 are attached form an optionally-substituted heterocycle.