N-heterocyclic piperazinyl and H-heterocyclic piperazinonyl inhibitors of farnesyl-protein transferase

A compound which inhibits farnesyl-protein transferase of the formula A:

• ##STR27## wherein:
• R.sup.1a is selected from:
• a) hydrogen,
• b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NRI.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR .sup.10 --,
• c) unsubstituted or substituted C.sub.1 -C.sub.6 alkyl wherein the substitutent on the substituted C.sub.6 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR10--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, and R.sup.11 OC(O)--NR.sup.10 --;
• R.sup.2 and R.sup.3 are independently selected from:
• H;
• unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or substituted C.sub.2-8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, ##STR28## wherein the substituted group is substituted with one or more of:
• ##STR29## R.sup.2 and R.sup.3 are attached to the same C atom and are combined to form--(CH.sub.2).sub.u --wherein one of the carbon atoms is optionally replaced by a moiety selected from:
• O, S(O).sub.m, --NC(O)--, and --N(CORI.sup.10)--;
• R.sup.4 is selected from H and CH.sub.3 ;
• and any two of R.sup.2, R.sup.3 and R.sup.4 are optionally attached to the same carbon atom;
• .sup.6. R.sup.7 and R.sup.7a are independently selected from:
• H;
• C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
• a) C.sub.1-4 alkoxy,
• b) aryl or heterocycle,
• c) halogen,
• d) HO, ##STR30## f) --SO.sub.2 R.sup.11 or g) N(R.sup.10).sub.2 ;
• or
• R.sup.6 and R.sup.7 may be joined in a ring;
• R.sup.7 and R.sup.7a may be joined in a ring;
• R.sup.6a is selected from:
• C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, heterocycle, aryl, unsubstituted or substituted with:
• a) C.sub.1-4 alkoxy,
• b) aryl or heterocycle,
• c) halogen,
• d) HO, ##STR31## f) --SO.sub.2 R.sup.11, or g) N(R.sup.10).sub.2 ;
• R.sup.8 is independently selected from:
• a) hydrogen,
• b) aryl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --,R.sup.10 C(O)NR.sup.10 --(R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sub.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, cyanophenyl, heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sub.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.10 OC(O)NH--;
• R.sup.9 is selected from:
• a) hydrogen,
• b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, (R.sup.10).sub.2 NC(O)--, R.sup.10.sub.2 N--C(NR.sup.10)--, CN, R.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --;
• R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, benzyl and aryl;
• R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
• A.sup.1 and A.sup.2 are independently selected from:
• a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sub.10 --, --NR.sup.10 C(O)--, O, --N(R.sup.10)--, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
• G is selected from H.sub.2 and O;
• V is selected from:
• a) hydrogen,
• b) heterocycle,
• c) aryl,
• d) C.sub.1 -C.sub.4 alkyl wherein from 0 to 4 carbon atoms are replaced with a heteroatom selected from O, S, and N, and
• e) C.sub.2 -C.sub.20 alkenyl,
• provided that V is not hydrogen if A.sup.1 is S(O).sub.m and V is not hydrogen if A.sup.1 is a bond, n is 0 and A.sup.2 is S(O).sub.m ;
• W is a heterocycle;
• Z is selected from:
• a unsubstituted or substituted group selected from aryl or heteroaryl, wherein the substituted group is substituted with one or more of the following:
• a) C.sub.1-4 alkyl, unsubstituted or substituted with:
• C.sub.1-4 alkoxy, NR.sup.6 R.sup.7, C.sub.3-C.sub.6 cycloalkyl, aryl, heterocycle, HO, --S(O).sub.m R.sup.6a, or --C(O)NR.sup.6 R.sup.7,
• b) aryl or heterocycle,
• c) halogen,
• d) OR.sup.6,
• e) NR.sup.6 R.sup.7,
• f) CN,
• g) NO.sub.2,
• h) CF.sub.3 ;
• i) --S(O).sub.m R.sup.6a,
• j) --C(O)NR.sup.6 R.sup.7, or
• k) C.sub.3 -C.sub.6 cycloalkyl;
• m is 0, 1 or 2;
• n is 0, 1, 2, 3 or 4;
• q is 1 or 2;
• r is 0 to 5, provided that r is 0 when V is hydrogen;
• and
• s is 0;
• u is 4 or 5;
• or a pharmaceutically acceptable salt thereof.