Inhibitors of farnesyl-protein transferase

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

• ##STR27## wherein:
• a is C;
• at least one of b, c, d and e is S, and the remaining b, c, d and e atoms are independently selected from CH, S and O;
• one f is independently N or N.fwdarw.O, and the remaining f's are independently CH;
• R.sup.1 and R.sup.2 are 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, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, R.sup.11 C(O)O--, (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 substituent on the substituted C.sub.1 -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)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, and R.sup.11 OC(O)--NR.sup.10 --;
• R.sup.3, R.sup.4 and R.sup.5 are independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.12 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.11 C(O)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 C.sub.1 -C.sub.6 alkyl,
• d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.12 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, and R.sup.11 OC(O)--NR.sup.10 --;
• provided that when R.sup.3, R.sup.4 or R.sup.5 is unsubstituted or substituted heterocycle, attachment of R.sup.3, R.sup.4 or R.sup.5 to the six-membered heteroaryl ring is through a substitutable heterocycle ring carbon;
• R.sup.6a, R.sup.6b, R.sup.6c and R.sup.6d are independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, halogen, C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.12 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.11 C(O)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 C.sub.1 -C.sub.6 alkyl,
• d) substituted C.sub.1 -C.sub.6 alkyl wherein the substituent on the substituted C.sub.1 -C.sub.6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.12 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, and R.sup.11 OC(O)--NR.sup.10 --;
• R.sup.7 is 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,
• e) ##STR28## f) --SO.sub.2 R.sup.11 g) N(R.sup.10).sub.2 or
• h) C.sub.1-4 perfluoroalkyl;
• R.sup.8 is independently selected from:
• a) hydrogen,
• b) aryl, substituted 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.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 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.sup.10 C(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.10 OC(O)NH--;
• provided that when R.sup.8 is heterocycle, attachment of R.sup.8 to V is through a substitutable ring carbon;
• R.sup.9 is independently selected from:
• a) hydrogen,
• b) C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.11 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, 2,2,2-trifluoroethyl and aryl;
• R.sup.11 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
• R.sup.12 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 aralkyl, C.sub.1 -C.sub.6 substituted aralkyl, C.sub.1 -C.sub.6 heteroaralkyl, C.sub.1 -C.sub.6 substituted heteroaralkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C.sub.1 -C.sub.6 perfluoroalkyl, 2-aminoethyl and 2,2,2-trifluoroethyl;
• A.sup.1 and A.sup.2 are independently selected from:
• a bond, --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(O)NR.sup.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 ;
• V is selected from:
• a) hydrogen,
• b) heterocycle,
• c) aryl,
• d) C.sub.1 -C.sub.20 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 ;
• provided that when V is heterocycle, attachment of V to R.sup.8 and to A.sup.1 is through a substitutable ring carbon;
• W is a heterocycle;
• X is a bond, --CH.dbd.CH--, O, --C(.dbd.O)--, --C(O)NR.sup.7 --, --NR.sup.7 C(O)--, --C(O)O--, --OC(O)--, --C(O)NR.sup.7 C(O)--, --NR.sup.7 --, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 -- or --S(.dbd.O).sub.m --;
• m is 0, 1 or 2;
• n is independently 0, 1, 2, 3 or 4;
• p is independently 0, 1, 2, 3 or 4;
• q is 0, 1, 2 or 3;
• r is 0 to 5, provided that r is 0 when V is hydrogen;
• and
• t is 0 or 1;
• or a pharmaceutically acceptable salt thereof.