Alkynyl and azido-substituted 4-anilinoquinazolines

A process for preparing a compound of the formula ##STR8## or a pharmaceutically acceptable salt or prodrug thereof, wherein:

• m is 1, 2, or 3;
• each R.sup.1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C.sub.1 -C.sub.4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;
• or each R.sup.1 is independently selected from R.sup.9 and (C.sub.1 -C.sub.4)-alkyl substituted by cyano, wherein R.sup.9 is selected from the group consisting of R.sup.5, --OR.sup.6, --NR.sup.6 R.sup.6, --C(O)R.sup.7, --NHOR.sup.5, --OC(O)R.sup.6, cyano, A and --YR.sup.5 ;
• R.sup.5 is C.sub.1 -C.sub.4 alkyl;
• R.sup.6 is independently hydrogen or R.sup.5 ;
• R.sup.7 is R.sup.5, --OR.sup.6 or --NR.sup.6 R.sup.6 ;
• A is selected from piperidino, morpholino, pyrrolidino, 4-R.sup.6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C.sub.1 -C.sub.4 alkylene)(CO.sub.2 H), phenoxy, phenyl, phenylsulfanyl, C.sub.2 -C.sub.4 alkenyl, and --(C.sub.1 -C.sub.4 alkylene)C(O)NR.sup.6 R.sup.6 ;
• and Y is S, SO, or SO.sub.2 ;
• wherein the alkyl moieties in R.sup.5, --OR.sup.6 and --NR.sup.6 R.sup.6 are optionally substituted by one to three substituents independently selected from halo and R.sup.9, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R.sup.9, with the proviso that two heteroatoms are not attached to the same carbon atom, and with the further proviso that no more than three R.sup.9 groups may comprise a single R.sup.1 group;
• or each R.sup.1 is independently selected from --NHSO.sub.2 R.sup.5, phthalimido-(C.sub.1 -C.sub.4)-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R.sup.10 -(C.sub.2 -C.sub.4)-alkanoylamino wherein R.sup.10 is selected from halo, --OR.sup.6, C.sub.2 -C.sub.4 alkanoyloxy, --C(O)R.sup.7, and --NR.sup.6 R.sup.6 ;
• and wherein the foregoing R.sup.1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C.sub.1 -C.sub.4 alkyl, cyano, methanesulfonyl and C.sub.1 -C.sub.4 alkoxy;
• or two R.sup.1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;
• R.sup.2 is hydrogen or C.sub.1 -C.sub.6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C.sub.1 -C.sub.4 alkoxy, --NR.sup.6 R.sup.6, and --SO.sub.2 R.sup.5 ;
• n is 1 or 2 and each R.sup.3 is independently selected from hydrogen, halo, hydroxy, C.sub.1 -C.sub.6 alkyl, --NR.sup.6 R.sup.6, and C.sub.1 -C.sub.4 alkoxy, wherein the alkyl moieties of said R.sup.3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C.sub.1 -C.sub.4 alkoxy, --NR.sup.6 R.sup.6, and --SO.sub.2 R.sup.5 ;
• and,
• R.sup.4 is azido or -(ethynyl)-R.sup.11 wherein R.sup.11 is hydrogen or C.sub.1 -C.sub.6 alkyl optionally substituted by hydroxy, --OR.sup.6, or --NR.sup.6 R.sup.6 ;
• which comprises
• a) treating a compound of the formula ##STR9## wherein R.sup.1 and m are as defined above, with CCl.sub.4 and (C.sub.6 -C.sub.10 aryl).sub.3 P, optionally supported on an inert polymer, wherein the aryl moieties of said (C.sub.6 -C.sub.10 aryl).sub.3 P are optionally substituted by C.sub.1 -C.sub.6 alkyl;
• and
• b) treating the product of step a) with a compound of the formula ##STR10## wherein R.sup.2, R.sup.3 and n are as defined above, and J is Y or R.sup.4, wherein R.sup.4 is as defined above and wherein Y is NH.sub.2, Br, I or trifluoromethanesulfonyloxy, with the proviso that when J is Y then the product of step b) must further be treated with an alkyne where Y is Br, I or trifluoromethanesulfonyloxy, or an azide where Y is NH.sub.2.