Inhibitors of farnesyl-protein transferase

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

• ##STR31## wherein:
• X is O or H.sub.2 ;
• m is 1 or 2;
• n is 0 or 1;
• p is 1, 2 or 3;
• q is 0, 1 or 2;
• t is 1 to 4;
• R and R.sup.1 are independently selected from:
• H, C.sub.1-6 alkyl, or C.sub.1-6 aralkyl;
• R.sup.4 is independently selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl,
• c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.2 -C.sub.6 alkenyl, R.sup.6 O--, R.sup.5 S(O).sub.q --, R.sup.7 C(O)NR.sup.6 --, CN, N.sub.3, R.sup.6 OC(O)NR.sup.6 --, R.sup.6 R.sup.7 N--C(NR.sup.6 R.sup.8)--, R.sup.6 C(O)--, R.sup.7 R.sup.8 NC(O)O--, R.sup.7 R.sup.8 NC(O)--, R.sup.6 R.sup.7 N--S(O).sub.2 --, --NR.sup.6 S(O).sub.2 R.sup.5, R.sup.6 OC(O)O--, --NR.sup.6 R.sup.7, or R.sup.7 R.sup.8 NC(O)NR.sup.6 --,
• d) substituted cycloalkyl,
• e) cycloalkyl, alkenyl, R.sup.6 O--, R.sup.5 S(O).sub.q --, R.sup.6 C(O)NR.sup.6 --, CN, NO.sub.2, R.sup.6 R.sup.7 N--C(NR.sup.8)--, R.sup.6 C(O)--, N.sub.3, --NR.sup.6 R.sup.7, halogen or R.sup.7 OC(O)NR.sup.6 --, and
• f) C.sub.1 -C.sub.6 alkyl substituted with a group selected from:
• aryl, substituted aryl, heterocyclic, substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl and substituted C.sub.3 -C.sub.10 cycloalkyl;
• Z is unsubstituted or substituted C.sub.1-8 alkyl, unsubstituted or substituted C.sub.2-8 alkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle;
• wherein the substituted C.sub.1-8 alkyl, substituted C.sub.2-8 alkenyl, substituted aryl or substituted heterocycle is substituted with one or more substituents selected from:
• 1) C.sub.1-4 alkyl,
• 2) C.sub.1-4 alkyl substituted with:
• a) C.sub.1-4 alkoxy,
• b) NR.sup.6 R.sup.7,
• c) C.sub.3-6 cycloalkyl,
• d) aryl or heterocycle,
• e) HO,
• 3) aryl or heterocycle,
• 4) halogen,
• 5) OR.sup.6,
• 6) NR.sup.6 R.sup.7,
• 7) CN,
• 8) NO.sub.2, or
• 9) CF.sub.3 ;
• R.sup.5 is C.sub.1-4 alkyl or aralkyl;
• R.sup.6, R.sup.7 and R.sup.8 are independently selected from:
• H, C.sub.1-4 alkyl, substituted C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, substituted C.sub.3-6 cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, aroyl, substituted aroyl, heteroaroyl, substituted heteroaroyl, arylsulfonyl, substituted arylsulfonyl, heteroarylsulfonyl or substituted heteroarylsulfonyl,
• wherein the substituted C.sub.1-4 alkyl, substituted C.sub.3-6 cycloalkyl, substituted heterocycle, substituted aryl, substituted aroyl, substituted heteroaroyl, substituted arylsulfonyl or substituted heteroarylsulfonyl is substituted with one or more substituents selected from:
• a) C.sub.1-4 alkoxy,
• b) aryl or heterocycle,
• c) halogen,
• d) HO, ##STR32## f) --SO.sub.2 R.sup.5, or g) --NR.sup.6 R.sup.7, or
• R.sup.6 and R.sup.7 may be joined in a ring, and
• R.sup.7 and R.sup.8 may be joined in a ring;
• R.sup.9 is selected from:
• H, C.sub.1-4 alkyl, substituted C.sub.1-4 alkyl, C.sub.3-6 cycloalkyI, substituted C.sub.3-6 cycloalkyl, heterocycle, substituted heterocycle, aryl and substituted aryl,
• wherein the substituted C.sub.1-4 alkyl, substituted C.sub.3-6 cycloalkyl, substituted heterocycle or substituted aryl is substituted with one or two substituents independently selected from:
• a) C.sub.1-4 alkyl,
• b) C.sub.1-4 alkoxy,
• c) aryl or heterocycle,
• d) halogen,
• e) HO, ##STR33## g) --SO.sub.2 R.sup.5, and h) --NR.sup.6 R.sup.7 ;
• V is selected from:
• --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(R.sup.11).sub.2 --, --C(OR.sup.11)R.sup.11 --, --CN(R.sup.11).sub.2 R.sup.11 --, --OC(R.sup.11).sub.2 --, --NR.sup.11 C(R.sup.11).sub.2 --, --C(R.sup.11).sub.2 O--, --C(R.sup.11)--.sub.2 NR.sup.11 --, --C(O)NR.sup.11 --, --NR.sup.11 C(O)--, O, --NC(O)R.sup.11 --, --NC(O)OR.sup.11 --, --S(O).sub.2 N(R.sup.11)--, --N(R.sup.11)S(O).sub.2 --, or S(O).sub.m ;
• R.sup.10 and R.sup.11 are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.4 alkenyl, benzyl and aryl;
• or a disulfide or pharmaceutically acceptable salt thereof.

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

• ##STR34## wherein:
• X and Y are independently O or H.sub.2 ;
• m is 1 or 2;
• n is 0 or 1;
• p is 1, 2 or 3;
• q is 0, 1 or 2;
• t is 1 to 4;
• R, R.sup.1 and R.sup.2 are independently selected from:
• H, C.sub.1-6 alkyl, or C.sub.1-6 aralkyl;
• R.sup.3 is independently selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl,
• c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.2 -C.sub.6 alkenyl, R.sup.6 O--, R.sup.5 S(O).sub.q --, R.sup.7 C(O)NR.sup.6 --, CN, N.sub.3, R.sup.6 OC(O)NR.sup.6 --, R.sup.6 R.sup.7 N--C(NR.sup.6 R.sup.8)--, R.sup.6 C(O)--, R.sup.7 R.sup.8 NC(O)O--, R.sup.7 R.sup.8 NC(O)--, R.sup.6 R.sup.7 N--S(O).sub.2 --, --NR.sup.6 S(O).sub.2 R.sup.5, R.sup.6 OC(O)O--, --NR.sup.6 R.sup.7, or R.sup.7 R.sup.8 NC(O)NR.sup.6 --,
• d) substituted cycloalkyl,
• e) cycloalkyl, alkenyl, R.sup.6 O--, R.sup.5 S(O).sub.q --, R.sup.6 C(O)NR.sup.6 --, CN, NO.sub.2, R.sup.6 R.sup.7 N--C(NR.sup.8)--, R.sup.6 C(O)--, N.sub.3, --NR.sup.6 R.sup.7, halogen or R.sup.7 OC(O)NR.sup.6 --, and
• f) C.sub.1 -C.sub.6 alkyl substituted with a group selected from:
• aryl, substituted aryl, heterocyclic, substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl and substituted C.sub.3 -C.sub.10 cycloalkyl;
• W is --CHR.sup.9 -- or --NR.sup.9 --;
• R.sup.5 is C.sub.1-4 alkyl or aralkyl;
• R.sup.6, R.sup.7 and R.sup.8 are independently selected from:
• H, C.sub.1-4 alkyl, substituted C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, substituted C.sub.3-6 cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, aroyl, substituted aroyl, heteroaroyl, substituted heteroaroyl, arylsulfonyl, substituted arylsulfonyl, heteroarylsulfonyl or substituted heteroarylsulfonyl,
• wherein the substituted C.sub.1-4 alkyl, substituted C.sub.3-6 cycloalkyl, substituted heterocycle, substituted aryl, substituted aroyl, substituted heteroaroyl, substituted arylsulfonyl or substituted heteroarylsulfonyl is substituted with one or more substituents selected from:
• a) C.sub.1-4 alkoxy,
• b) aryl or heterocycle,
• c) halogen,
• d) HO, ##STR35## f) --SO.sub.2 R.sup.5, or g) --NR.sup.6 R.sup.7, or
• R.sup.6 and R.sup.7 may be joined in a ring, and
• R.sup.7 and R.sup.8 may be joined in a ring;
• R.sup.9 is selected from:
• H, C.sub.1-4 alkyl, substituted C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, substituted C.sub.3-6 cycloalkyl, heterocycle, substituted heterocycle, aryl and substituted aryl,
• wherein the substituted C.sub.1-4 alkyl, substituted C.sub.3-6 cycloalkyl, substituted heterocycle or substituted aryl is substituted with one or two substituents independently selected from:
• a) C.sub.1-4 alkyl,
• b) C.sub.1-4 alkoxy,
• c) aryl or heterocycle,
• d) halogen,
• e) HO, ##STR36## g) --SO.sub.2 R.sup.5, and h) --NR.sup.6 R.sup.7 ;
• or a disulfide or pharmaceutically acceptable salt thereof.

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

• ##STR37## wherein:
• X and Y are independently O or H.sub.2 ;
• m is 1 or 2;
• n is 0 or 1;
• p is 1, 2 or 3;
• q is 0, 1 or 2;
• t is 1 to 4;
• R, R.sub.1 and R.sub.2 are independently selected from:
• H, C.sub.1-6 alkyl, or C.sub.1-6 aralkyl;
• R.sup.4 is independently selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl,
• c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.2 -C.sub.6 alkenyl, R.sup.6 O--, R.sup.5 S(O).sub.q --, R.sup.7 C(O)NR.sup.6 --, CN, N.sub.3, R.sup.6 OC(O)NR.sup.6 --, R.sup.6 R.sup.7 N-C(NR.sup.6 R.sup.8)--, R.sup.6 C(O)--, R.sup.7 R.sup.8 NC(O)O--, R.sup.7 R.sup.8 NC(O)--, R.sup.6 R.sup.7 N--S(O).sub.2 --, --NR.sup.6 S(O).sub.2 R.sup.5, R.sup.6 OC(O)O--, --NR.sup.6 R.sup.7, or R.sup.7 R.sup.8 NC(O)NR.sup.6 --,
• d) substituted cycloalkyl,
• e) cycloalkyl, alkenyl, R.sup.6 O--, R.sup.5 S(O).sub.q --, R.sup.6 C(O)NR.sup.6 --, CN, NO.sub.2, R.sup.6 R.sup.7 N--C(NR.sup.8)--, R.sup.6 C(O)--, N.sub.3, --NR.sup.6 R.sup.7, halogen or R.sup.7 OC(O)NR.sup.6 --, and
• f) C.sub.1 -C.sub.6 alkyl substituted with a group selected from:
• aryl, substituted aryl, heterocyclic, substituted heterocyclic, C.sub.3 -C.sub.10 cycloalkyl and substituted C.sub.3 -C.sub.10 cycloalkyl;
• W is --CHR.sup.9 -- or --NR.sup.9 --;
• R.sup.5 is C.sub.1-4 alkyl or aralkyl;
• R.sup.6, R.sup.7 and R.sup.8 are independently selected from:
• H, C.sub.1-4 alkyl, substituted C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, substituted C.sub.3-6 cycloalkyl, heterocycle, substituted heterocycle, aryl, substituted aryl, aroyl, substituted aroyl, heteroaroyl, substituted heteroaroyl, arylsulfonyl, substituted arylsulfonyl, heteroarylsulfonyl or substituted heteroarylsulfonyl,
• wherein the substituted C.sub.1-4 alkyl, substituted C.sub.3-6 cycloalkyl, substituted heterocycle, substituted aryl, substituted aroyl, substituted heteroaroyl, substituted arylsulfonyl or substituted heteroarylsulfonyl is substituted with one or more substituents selected from:
• a) C.sub.1-4 alkoxy,
• b) aryl or heterocycle,
• c) halogen,
• d) HO, ##STR38## f) --SO.sub.2 R.sup.5, or g) --NR.sup.6 R.sup.7, or
• R.sup.6 and R.sup.7 may be joined in a ring, and
• R.sup.7 and R.sup.8 may be joined in a ring;
• R.sup.9 is selected from:
• H, C.sub.1-4 alkyl, substituted C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, substituted C.sub.3-6 cycloalkyl, heterocycle, substituted heterocycle, aryl and substituted aryl,
• wherein the substituted C.sub.1-4 alkyl, substituted C.sub.3-6 cycloalkyl, substituted heterocycle or substituted aryl is substituted with one or two substituents independently selected from:
• a) C.sub.1-4 alkyl,
• b) C.sub.1-4 alkoxy,
• c) aryl or heterocycle,
• d) halogen,
• e) HO, ##STR39## g) --SO.sub.2 R.sup.5, and h) --NR.sup.6 R.sup.7 ;
• or a disulfide or pharmaceutically acceptable salt thereof.

A compound which inhibits farnesyl-protein transferase which is:

• 3-[2(R)-Amino-3-mercaptopropylamino]-N-(2,3-dimethylphenyl)-benzamide
• 3-[2(R)-Amino-3-mercaptopropylamino]-N-phenyl-N-methylbenzamide
• 3-[2(R)-Amino-3-mercaptopropylamino]-N-(1-naphthylmethyl)-benzamide
• 3-[2(R)-Amino-3-mercaptopropylamino]-N-phenylbenzamide
• 3-[2(R)-Amino-3-mercaptopropylamino]-N-benzylbenzamide
• 3-[2(S)-Amino-3-mercaptopropylamino]-N-(2,3-dimethylphenyl)-benzamide
• 3-[2(R)-Amino-3-mercaptopropanoylamino]-N-(2,3-dimethylphenyl)-benzamide
• 3-[2(R)-Amino-3-mercaptopropylamino]-4-methyl-N-(2,3-dimethylphenyl)-benzam ide
• 3-[2(R)-Amino-3-mercaptopropylamino]-4-methoxy-N-(2,3-dimethylphenyl)-benza mide
• 3-[2(R)-Amino-3-mercaptopropylamino]-6-methyl-N-(2,3-dimethylphenyl)-benzam ide
• 3-[2(R)-Amino-3-mercaptopropylamino]-N-[1-(5,6,7,8-tetrahydronaphthyl)]-ben zamide
• 1-[3-[2(R)-Amino-3-mercaptopropylamino]phenylcarbonyl]indoline
• 1-[2(R)-Amino-3-mercaptopropylamino]-3-[(2,3-dimethylbenzoyl)amino]-benzene
• 4-[2(R)-Amino-3-mercaptopropylamino]-2-(2,3-dimethylphenyl)-isoindolin-1-on e
• 4-[2(R)-Amino-3-mercaptopropylamino]-2-benzylisoindolin-1-one
• 1-[2(R)-Amino-3-mercaptopropylamino]-N-(2,3-dimethylphenyl)-4-indoline carboxamide
• 1-[2(R)-Amino-3-mercaptopropylamino]-3-[(2,3-dimethylphenyl)-aminomethyl]-b enzene
• 3-[2(R)-Amino-3-mercaptopropylaminomethyl]-N-(2,3-dimethylphenyl)-benzamide
• 3-[2(R)-Amino-3-mercaptopropylamino]benzophenone
• 3-[2(R)-Amino-3-mercaptopropylamino]-4-pentyl-N-(2,3-dimethylphenyl)-benzam ide
• 3-[2(R)-Amino-3-mercaptopropylamino]-4-ethyl-N-(2,3-dimethylphenyl)-benzami de
• N-[(2R)-2-amino -3 -mercaptopropyl]amino-3-[2-(3-methylphenyl)-trans-ethenyl]benzene
• N-[(2R)-2-amino-3 -mercaptopropyl]amino-3-[(1-naphthylmethyl)oxy]benzene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-2-(phenoxy)benzene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-2-(benzyloxy)benzene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-4-(phenoxy)benzene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-4-[(3-methylphenyl)oxy]benzene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-3-(phenoxy)benzene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-3-[(3-methylphenyl)oxy]benzene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-4-[(3-(hydroxymethyl)phenyl)oxy]benz ene
• N-[(2R)-2-amino-3-mercaptopropyl]amino-2-methyl-4-(phenoxy)benzene or
• 2-[2(R)-amino-3-mercaptopropylamino]-N-(3-methylphenyl)-benzamide
• or a disulfide or pharmaceutically acceptable salt thereof.