Heteroaromatic derivatives having an inhibitory activity against HIV integrase

A compound of the formula (I):

• 57
• wherein X is hydroxy, protected hydroxy or optionally substituted amino;
• Y is —CONRBRC wherein RB and RC each is independently hydrogen or amide residue, or optionally substituted heteroaryl;
• and A1 is optionally substituted heteroaryl;
• provided that a compound wherein Y and/or A1 is optionally substituted indol-3-yl is excluded, a tautomer, a prodrug, a pharmaceutically acceptable salt or a hydrate thereof;
• provided that compounds wherein (1) X is hydroxy, Y and A1 are pyridyl;
• (2) X is hydroxy, Y and A1 are 2-furyl;
• (3) X is hydroxy, one of Y and A1 is 2-thienyl, the other is 5-ethoxycarbonylmethylsulfanyl-1H-1,2,4-triazol-3-yl, 5-p-tolylamino-1H-1,2,4-triazol-3-yl, 5-phenylamino-1H-1,2,4-triazol-3-yl, 5-hydrazino-1H-1,2,4-triazol-3-yl, 5-(3,6-dioxo-hexahydro-pyridazin-4-ylsulfanyl)-1H-1,2,4-triazol-3-yl, 5-[3-(3,4-dimethylphenyl)-6-oxo-1-phenyl-1,4,5,6-tetrahydro-pyridazin-4-ylsulfanyl]-1H-1,2,4-triazol-3-yl, 5-(1,2-dicarboxyethylsulfanyl)-1H-1,2,4-triazol-3-yl, 5-[1-carboxy-3-(3,4-dimethylphenyl)-3-oxo-propylsulfanyl]-1H-1,2,4-triazol-3-yl or 5-(2-cyano-2-ethoxycarbonyl-1-phenylethylsulfanyl)-1H-1,2,4-triazol-3-yl;
• (4) X is hydroxy, Y and A1 are [3-(2-methoxycarbonylethyl)-4-methoxycarbonylmethyl-5-methyl]-1H-pyrrol-2-yl;
• and (5) X is hydroxy, Y and A1 are 3-methylpyrazol-1-yl;
• are excluded.

A compound of the formula (II):

• 58
• wherein X is hydroxy, protected hydroxy or optionally substituted amino;
• Y is —COORA wherein RA is hydrogen or ester residue, —CONRBRC wherein RB and RC each is independently hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl;
• A1 is optionally substituted heteroaryl;
• Z1 and Z3 each is independently a bond, lower alkylene or lower alkenylene;
• Z2 and Z4 each is independently a bond, lower alkylene, lower alkenylene, —CH(OH)—, —S—, —SO—, —SO2—, —SO2NR21, —NR21SO2—, —O—, —NR21—, —NR21CO—, —CONR21—, —C(═O)—O—, —O—C(═O)— or —CO—;
• R21 is hydrogen, lower alkyl or lower alkenyl;
• R1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle;
• R2 is optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkyloxycarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, carboxy, optionally substituted cycloalkyl, hydroxy, mercapto, optionally substituted amino, nitro or halogen;
• and p is 0 or 1;
• provide that compounds wherein (1) Y and/or A1 is optionally substituted indol-3-yl and (2) X is hydroxy, Y is 2-thienyl, A1 is 1H-1,2,4-triazol-3-yl, Z1 and Z3 each is a bond, Z2 is —NH—, R1 is phenyl or p-tolyl, and p is 0, are excluded, a tautomer, a prodrug, a pharmaceutically acceptable salt or a hydrate thereof.

A process for producing a compound of the formula (V):

• 59
• wherein A1 is optionally substituted heteroaryl and A is C—W wherein W is hydrogen, lower alkyl, lower haloalkyl or halogen, or N, provided that a compound wherein A1 is optionally substituted indol-3-yl is excluded,
• which comprises reacting a compound of the formula (III):
• 60
• wherein A1 is as defined above,
• with a compound of the formula (IV):
• 61
• wherein A is as defined above, Q is a protective group and L is a leaving group, in the presence of a base, and deprotecting Q.