N-arylalkyl-N-heteroarylurea and guandine compounds and methods of treating HIV infection

A compound having the formula ##STR41## wherein A is ##STR42## and Z.sub.i is O, Se, NR.sup.a or C(R.sup.a).sub.2, and

• Z.sub.ii is --O or (.dbd.O).sub.2 ;
• and wherein
• R.sup.a is H, OR.sup.b, CN, NO.sub.2, N (R.sup.b).sub.2, SR.sup.b, SO.sub.2 R.sup.b, SO.sub.2 N(R.sup.b), COR.sup.b, CO.sub.2 R.sup.b, CON(R.sup.b).sub.2, PO(R.sup.b).sub.2, PO(OR.sup.b).sub.2, PO(NR.sup.b).sub.2, wherein R.sup.b is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 substituted alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 substituted alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.2 -C.sub.8 substituted alkynyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 substituted alkoxy, C.sub.4-10 aralkyl, C.sub.1-10 alkaryl, C.sub.1-10 alkylthio, C.sub.4-10 aralkylthio, C.sub.1-10 alkylsulfinyl, C.sub.4-10 aralkylsulfinyl, C.sub.1-10 alkylsulfonyl, C.sub.4-10 aralkylsulfonyl, carboxy, C.sub.1-10 alkylthiocarbonyl, C.sub.4-10 aralkylcarbonyl, C.sub.4-10 aralkylthiocarbonyl C.sub.4-10 aralkoxycarbonyl, C.sub.4-10 aralkoxycarbonyl, C.sub.1-4 alkyl, C.sub.4-10 aralkoxy, C.sub.1-12 dialkylamino-C.sub.1-6 aralkanoylamino C.sub.4-10 aralkylamino or C.sub.1 -C.sub.4 alkanoyloxy;
• R.sub.3 and R.sub.4 are independently hydrogen, hydroxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, substituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.2 -C.sub.6 alkenyl, or substituted C.sub.2 -C.sub.6 alkynyl, substituted alkoxy, amino, cyano, nitro, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 substituted alkoxy, carboxy, droxymethyl, aminomethyl, carboxymethyl, C.sub.1 -C.sub.4 alkylthio, C.sub.1.sub.4 alkanoyloxy, halo-substituted (C.sub.1 -C.sub.6)alkyl, or carbamoyl;
• R.sub.1 is a substituted or unsubstituted 6 membered organic monocyclic ring having one N atom substituent(s) independently selected from halo, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.5 alkoxy, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.2 -C.sub.8 alkenoxy, amino, nitro, cyano, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C.sub.1 -C.sub.4 alkylthio, hydroxy, C.sub.1 -C.sub.4 alkanoyloxy, carbamoyl, halo-substituted C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy-substituted C.sub.1 -C.sub.6 alkyl, a group of the formula
• --SO.sub.2 R.sub.x
• wherein
• R.sub.x is C.sub.1 -C.sub.6 alkyl or amino;
• or a group of the formula ##STR43## wherein R.sub.x is as defined above;
• R.sub.2 is a group of the formula ##STR44## wherein R.sub.5 is a stable, unsaturated, substituted or unsubstituted
• i) 3 to 8 membered monocyclic ring having 0 to 4 hetero atoms or
• ii) a 7 to 10 membered bicyclic ring having 0 to 5 hetero atoms, said hetero atoms being selected from S, O and N;
• and two of R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently C.sub.3 -C.sub.8 cycloalkyl, hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, substituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.2 -C.sub.6 alkenyl, or substituted C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 substituted alkoxy, halo, amino, nitro, cyano, C.sub.1 -C.sub.5 alkoxy, hydroxy, hydroxymethyl, aminomethyl, carboxymethyl, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkanoyloxy, carbamoyl, or a halo substituted C.sub.1 -C.sub.6 alkyl;
• and the other two of which, along with the carbons to which they are attached, combine to form a stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S, O, or N;
• or a pharmaceutically acceptable salt thereof;
• with the proviso that:
• if R.sub.7 together with R.sub.6 forms transcyclopropyl and the remainder of R.sub.3, R.sub.4, R.sub.8 and R.sub.9, are hydrogen, then the following combination is excluded:
• ______________________________________ Z.sub.1 R.sub.1 R.sub.5 ______________________________________ O pyridyl phenyl ______________________________________

A compound having the formula ##STR45## wherein A is ##STR46## and Z.sub.i is O, Se, NR.sup.a or C (R.sup.a).sub.2, and

• Z.sub.ii is --O or (.dbd.O).sub.2 ;
• and wherein R.sup.a is H, OR.sup.b, CN, NO.sub.2, N (R.sup.b)2, SR.sup.b, SO.sub.2 R.sup.b, SO.sub.2 N (R.sup.b).sub.2, COR.sup.b, CO.sub.2 R.sup.b, CON(R.sup.b).sub.2, PO(R.sup.b).sub.2, PO(OR.sup.b).sub.2, PO(NR.sup.b).sub.2, wherein R.sup.b is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1 -C.sub.6 substituted alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 substituted alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.2 -C.sub.8 substituted alkynyl, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 substituted alkoxy, C.sub.4-10 aralkyl, C.sub.1-10 alkaryl, C.sub.1-10 alkylthio, C.sub.4-10 aralkylthio, C.sub.1-10 alkylsulfinyl, C.sub.4-10 aralkylsulfinyl, C.sub.1-10 alkylsulfonyl, C.sub.4-10 aralkylsulfonyl, carboxy, C.sub.1-10 alkylthiocarbonyl, C.sub.4-10 aralkylcarbonyl, C.sub.4-10 aralkylthiocarbonyl, C.sub.4-10 aralkoxycarbonyl, C.sub.4-10 aralkoxycarbonyl, C.sub.1-4 alkyl, C.sub.4-10 aralkoxy, C.sub.1-12 dialkylamino-C.sub.1-6 aralkanoylamino C.sub.4-10 aralkylamino or C.sub.1 -C.sub.4 alkanoyloxy;
• R.sub.3 and R.sub.4 are independently hydrogen, hydroxy, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, substituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.2 -C.sub.6 alkenyl, or substituted C.sub.2 -C.sub.6 alkynyl, substituted alkoxy, amino, cyano, nitro, C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 substituted alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkanoyloxy, halo-substituted (C.sub.1 -C.sub.6)alkyl, or carbamoyl;
• R.sub.1 is a substituted or unsubstituted 6 membered organic monocyclic ring having one N atom wherein the substituted R.sup.1 groups have substituent (s) independently selected from halo, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.5 alkoxy, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.2 -C.sub.8 alkenoxy, amino, nitro, cyano, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C.sub.1 -C.sub.4 alkylthio, hydroxy, C.sub.1 -C.sub.4 alkanoyloxy, carbamoyl, halo-substituted C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy-substituted C.sub.1 -C.sub.6 alkyl, a group of the formula
• --SO.sub.2 R.sub.x
• wherein R.sub.x is C.sub.1 -C.sub.6 alkyl or amino;
• or a group of the formula ##STR47## wherein R.sub.x is as defined above;
• R.sub.2 is a group of the formula ##STR48## wherein R.sub.5 is a stable, unsaturated, substituted or unsubstituted 3 to 8 membered monocyclic ring having 0 to 4 hetero atoms said hetero atoms being selected from S, O and N;
• and R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently C.sub.3 -C.sub.8 cycloalkyl, hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, substituted C.sub.1 -C.sub.6 alkyl, substituted C.sub.2 -C.sub.6 alkenyl, or substituted C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 substituted alkoxy, halo, amino, nitro, cyano, C.sub.1 -C.sub.5 alkoxy, hydroxy, hydroxymethyl, aminomethyl, carboxymethyl, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkanoyloxy, carbamoyl, or a halo substituted C.sub.1 -C.sub.6 alkyl or a pharmaceutically acceptable salt thereof;
• with the provisos that:
• a) if R.sub.3, R.sub.4 and R.sub.6 -R.sub.9 are all hydrogen, then the following combinations are excluded:
• ______________________________________ Z.sub.1 R.sub.1 R.sub.5 ______________________________________ NCN pyrid-3-yl phenyl ______________________________________
• b) if R.sub.7 is methyl and the remainder of R.sub.3, R.sub.4, R.sub.6, R.sub.8, and R.sub.9 are hydrogen, then the following combination is excluded:
• ______________________________________ Z.sub.1 R.sub.1 R.sub.5 ______________________________________ O pyridyl phenyl;
• ______________________________________
• c) if R.sub.7 is alkylthio or ethyl, and the remainder of R.sub.3, R.sub.4 and R.sub.6 -R.sub.9 are hydrogen, then the following combination is excluded
• ______________________________________ Z.sub.1 R.sub.1 R.sub.5 ______________________________________ O pyrid-3-yl phenyl. ______________________________________