A prodrug of a compound which inhibits farnesyl-protein transferase, the prodrug which is illustrated by the formula II:
- ##STR46## wherein:
- R.sup.1a and R.sup.1b are independently selected from:
- a) hydrogen,
- b) aryl, heterocycle, cycloalkyl, alkenyl, alkynyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
- c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by aryl, heterocyclic, cycloalkyl, alkenyl, alkynyl, R.sup.10 --, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN, (R.sup.10).sub.2,N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)--NR.sup.10 --;
- R.sup.2 and R.sup.3 are independently selected from:
- a) a side chain of a naturally occurring amino acid,
- b) an oxidized form of a side chain of a naturally occurring amino acid which is:
- i) methionine sulfoxide, or
- ii) methionine sulfone, and
- c) substituted or unsubstituted C.sub.1 -C.sub.20 alkyl, C.sub.2 -C.sub.20 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, aryl or heterocyclic group,
- wherein the substituent is selected from F, Cl, Br, N(R.sup.10).sub.2, NO.sub.2, R.sub.10 O, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN,(R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3, --N(R.sup.10).sub.2, R.sup.11 OC(O)NR.sup.10 -- and C.sub.1 -C.sub.20 alkyl, and
- d) C.sub.1 -C.sub.6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C.sub.3 -C.sub.10 cycloalkyl;
- or
- R.sup.2 and R.sup.3 are combined to form --(CH.sub.2).sub.s --;
- or
- R.sup.2 or R.sup.3 are combined with R.sup.6 to form a ring such that ##STR47## R.sup.4a, R.sup.4b, R.sup.7a and R.sup.7b are independently selected from:
- a) hydrogen,
- b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by alkenyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN, N.sub.3, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(O)--, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --,
- c) aryl, heterocycle, cycloalkyl, alkenyl, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3, --N(R.sup.10).sub.2, or R.sup.11 OC(O)NR.sup.10 --, and
- d) C.sub.1 -C.sub.6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocyclic and C.sub.3 -C.sub.10 cycloalkyl;
- R.sup.5a and R.sup.5b are independently selected from:
- a) a side chain of a naturally occurring amino acid,
- b) an oxidized form of a side chain of a naturally occurring amino acid which is:
- i) methionine sulfoxide, or
- ii) methionine sulfone,
- c) substituted or unsubstituted C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 alkenyl, C.sub.3 -C.sub.10 cycloalkyl, aryl or heterocycle group,
- wherein the substituent is selected from F, Cl, Br, (R.sup.10).sub.2 NC(O)--, NO.sub.2, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NR.sup.10 --, CN, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3, --N(R.sup.10).sub.2, R.sup.11 OC(O)NR.sup.10 -- and C.sub.1 -C.sub.20 alkyl,
- d) C.sub.1 -C.sub.6 alkyl substituted with an unsubstituted or substituted group selected from aryl, heterocycle and C.sub.3 -C.sub.10 cycloalkyl;
- or
- R.sup.5a and R.sup.5b are combined to form --(CH.sub.2).sub.s -- wherein one of the carbon atoms is optionally replaced by a moiety selected from:
- O, S(O).sub.m, --NC(O)--, and --N(COR.sup.10)--;
- R.sup.6 is independently selected from hydrogen or C.sub.1 -C.sub.6 alkyl;
- R.sup.8 is independently selected from:
- a) hydrogen,
- b) aryl, heterocycle, cycloalkyl, 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 --, CN, NO.sub.2, R.sup.10.sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(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, heterocycle, cycloalkyl, alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R.sup.10 O--, R.sup.11 S(O).sub.m --, R.sup.10 C(O)NH--, CN, H.sub.2 N--C(NH)--, R.sup.10 C(O)--, R.sup.10 OC(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 --, CN, NO.sub.2, (R.sup.10).sub.2 N--C--(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(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 --, CN, (R.sup.10).sub.2 N--C(NR.sup.10)--, R.sup.10 C(O)--, R.sup.10 OC(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;
- R.sup.12 is
- a) substituted or unsubstituted C.sub.1 -C.sub.8 alkyl, substituted or unsubstituted C.sub.5 -C.sub.8 cycloalkyl, or substituted or unsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl or cyclic amine is substituted with 1 or 2 substituents independently selected from:
- 1) C.sub.1 -C.sub.6 alkyl,
- 2) aryl,
- 3) heterocycle,
- 4) --N(R.sup.11).sub.2,
- 5) --OR.sup.10, or
- b) ##STR48## R.sup.13 is independently selected from hydrogen and C.sub.1 -C.sub.6 alkyl;
- R.sup.14 is independently selected from C.sub.1 -C.sub.6 alkyl;
- 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 ;
- Q is a substituted or unsubstituted nitrogen-containing C.sub.4 -C.sub.9 mono or bicyclic ring system, wherein the non-nitrogen containing ring may be a C.sub.5 -C.sub.7 saturated ring;
- 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 ;
- W is a heterocycle;
- X, Y and Z are independently H.sub.2 or O;
- m is 0,1 or 2;
- n is 0,1,2,3 or 4;
- p is 0,1,2,3 or 4;
- r is 0 to 5, provided that r is 0 when V is hydrogen;
- s is 4 or 5;
- t is 3,4 or 5;
- and
- u is 0 or 1;
- or a pharmaceutically acceptable salt thereof.