Inhibitors of farnesyl-protein transferase

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

• ##STR108## wherein:
• R.sup.1a and R.sup.1b are independently selected from:
• a) hydrogen,
• b) aryl, 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 -, CN(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)--, R.sup.10 OC(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.1 -C.sub.6 alkyl is selected from aryl, cyanophenyl, 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)--, R.sup.10 OC(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, ##STR109## wherein the substituted group is substituted with one or more of:
• 1) aryl, unsubstituted or substituted with;
• a) C.sub.1-4 alkyl,
• b) (CH.sub.2).sub.p OR.sup.6,
• c) (CH.sub.2).sub.p NR.sup.6 R.sup.7,
• d) halogen,
• e) CN,
• 2) C.sub.3-6 cycloalkyl,
• 3) OR.sup.6,
• 4) SR.sup.6a, S(O)R.sup.6a, SO.sub.2 R.sup.6a, ##STR110## 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;
• R.sup.6, R.sup.7 and R.sup.7a are independently selected from:
• H;
• C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, aryl, aroyl, and arylsulfonyl, unsubstituted or substituted with:
• a) C.sub.1-4 alkoxy,
• b) aryl,
• c) halogen,
• d) HO, ##STR111## f) --SO, or g) N(R.sup.10).sub.2 ;
• R.sup.6a is selected from:
• C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, aryl, unsubstituted or substituted with:
• a) C.sub.1-4 alkoxy,
• b) aryl,
• c) halogen,
• d) HO, ##STR112## f) --SO, or g) N(R.sup.10).sub.2 ;
• R.sup.8 is independently selected from:
• a) hydrogen,
• b) aryl, 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)--, 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, cyanophenyl, C.sub.3 -C.sub.10 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 akynyl, 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)--, 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.sub.2 N-C(NR.sup.10)--, CN, NO.sub.2, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3 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.sub.2 N-C(NR.sup.10)--, CN, R.sup.10 C(O)--, R.sup.10 OC(O)--, N.sub.3 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)-- or O;
• G is O;
• V is phenyl or naphthyl;
• W is imidazolyl;
• X is --CH.sub.2 -, --C(.dbd.O)--, or --S(.dbd.O).sub.m -;
• Z is a unsubstituted or substituted group selected from phenyl, benzyl, naphthyl and naphthylmethyl, wherein the substituted group is substituted with one or more of the following:
• 1) C.sub.1-4 alkyl, unsubstituted or substituted with:
• a) C.sub.1-4 alkoxy,
• b) NR.sup.6 R.sup.7,
• c) C.sub.3-6 cycloalkyl,
• d) aryl,
• e) HO,
• f) --S(O).sub.m R.sup.6a, or
• g) --C(O)NR.sup.6 R.sup.7,
• 2) aryl,
• 3) halogen,
• 4) OR.sup.6,
• 5) NR.sup.6 R.sup.7,
• 6) CN,
• 7) NO.sub.2,
• 8) CF.sub.3 ;
• 9) --S(O).sub.m R.sup.6a,
• 10) --C(O)NR.sup.6 R.sup.7, or
• 11) C.sub.3 -C.sub.6 cycloalkyl;
• aryl is independently selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl;
• m is 0, 1 or 2;
• n is 0, 1, 2, 3 or 4;
• p is 0, 1, 2, 3 or 4;
• q is 1 or 2;
• r is 0 to 5;
• s is 0;
• t is 1;
• and
• u is 4 or 5;
• or an optical isomer or pharmaceutically acceptable salt thereof.

A compound which inhibits farnesyl-protein transferase which is:

• TABLE 3 ______________________________________ ##STR116## Y ______________________________________ 3-SO.sub.2 Me 3-OCF.sub.3 ______________________________________
• TABLE 4 ______________________________________ ##STR117## X Y ______________________________________ CH.sub.2 OCH.sub.2 Ph CF.sub.3 CH.sub.2 SO.sub.2 Et CF.sub.3 CH.sub.2 SO.sub.2 Ph CF.sub.3 CH.sub.2 SO.sub.2 Me Cl CH.sub.2 SO.sub.2 Et Cl CONHMe CF.sub.3 CONHEt CF.sub.3 CH.sub.2 SO.sub.2 Ph Cl CONHMe Cl CONHEt Cl CONHc-Pr Cl CONHc-Pr CF.sub.3 NHCOMe Cl CONHMe.sub.2 CF.sub.3 SO.sub.2 Et Cl CH.sub.2 SMe Cl (.+-.) C.tbd.CMe Cl ______________________________________
• TABLE 5 ______________________________________ ##STR118## X Y ______________________________________ CH.sub.2 CH.sub.2 H CH.sub.2 CO H CH.sub.2 H CH.sub.2 3-Cl CH.sub.2 CH.sub.2 CO 3-Cl CH.sub.2 2,3-Cl.sub.2 CH.sub.2 2-Br CH.sub.2 3-CF.sub.3 CH.sub.2 4-Cl CH.sub.2 CO 3-Cl CH.sub.2 3-F CH.sub.2 3-Br ______________________________________
• TABLE 6 ______________________________________ ##STR119## X Y Z ______________________________________ 4-CN CH.sub.2 5-CH.sub.2 CH.sub.2 CO 3-CN CH.sub.2 5-CH.sub.2 2-CN CH.sub.2 5-CH.sub.2 4-CN CH.sub.2 4-CH.sub.2 CH.sub.2 CO 4-CN (CH.sub.2).sub.2 4-CH.sub.2 CH.sub.2 CO ______________________________________
• TABLE 7 ______________________________________ ##STR120## X Y ______________________________________ 4-Me CH.sub.2 CH.sub.2 SO.sub.2 Me 4-Me H 2-Me H ______________________________________
• TABLE 8 ______________________________________ ##STR121## Y ______________________________________ 3-CF.sub.3 3-CH.sub.3 2,3-(CH.sub.2).sub.4 3-OCH.sub.3 3-Cl 2-CH.sub.3, 3-Cl H 3-F ______________________________________
• TABLE 9 ______________________________________ ##STR122## R ______________________________________ CH.sub.2 CH.sub.2 OCH.sub.2 CF.sub.3 ##STR123## CH.sub.2 CH.sub.2 N.sub.3 CH.sub.2 CH.sub.2 NHCOCH.sub.3 CH.sub.2 CH.sub.2 NHCOC.sub.2 H.sub.5 CH.sub.2 CH.sub.2 SO.sub.2 CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 SCH(CH.sub.3).sub.2 CH.sub.2 CH.sub.2 S(O)CH(CH.sub.3).sub.2 ______________________________________
• TABLE 10 ______________________________________ ##STR124## ______________________________________ ##STR125## ##STR126## ##STR127## ##STR128## ##STR129## ##STR130## ______________________________________
• TABLE 11 ______________________________________ ##STR131## R Y ______________________________________ ##STR132## Cl ##STR133## F ##STR134## Cl ______________________________________
• TABLE 12 ______________________________________ ##STR135## ______________________________________ ##STR136## ______________________________________
• TABLE 13 ______________________________________ ##STR137## ______________________________________ ##STR138## ##STR139## ##STR140## ______________________________________
• TABLE 14 ______________________________________ ##STR141## R.sup.1 R.sup.2 ______________________________________ ##STR142## CH.sub.2 CH.sub.2 F ______________________________________
• TABLE 15 ______________________________________ ##STR143## R Y ______________________________________ ##STR144## 2,3-(CH.sub.2).sub.4 ##STR145## 2-CH.sub.3, 3-Cl ##STR146## 3-Cl ______________________________________
• TABLE 17 ______________________________________ ##STR147## ______________________________________
• TABLE 18 ______________________________________ ##STR148## or ##STR149## ______________________________________
• or a pharmaceutically acceptable salt or optical isomer thereof.