Bisphenyl inhibitors of farnesyl-protein transferase

A compound which inhibits Ras farnesyl-transferase having the Formula Ia:

• ##STR18## wherein:
• R.sup.1a is independently selected from:
• hydrogen or C.sub.1 -C.sub.6 alkyl;
• R.sup.1b is independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, R.sup.8 O--, --N(R.sup.8).sub.2 or C.sub.2 -C.sub.6 alkenyl,
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted with 1 or 2 substituents selected from:
• unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, R.sup.8 O--, and --N(R.sup.8).sub.2 ;
• R.sup.2a and R.sup.2b are independently selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by a substituent selected from:
• R.sup.8 O--, --N(R.sup.8).sub.2, and R.sup.9 S(O).sub.m --,
• c) substituted or unsubstituted aryl, and
• d) halogen selected from F, I, Cl and Br;
• R.sup.3 is selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by a substituent selected from:
• R.sup.8 O--, --N(R.sup.8).sub.2 and R.sup.9 S(O).sub.m --,
• c) substituted or unsubstituted aryl,
• d) halogen selected from F, I, Cl and Br, and
• e) --CO.sub.2 R.sup.8 ;
• R.sup.4 and R.sup.5 are independently selected from:
• a) hydrogen, and ##STR19## R.sup.6 is selected from:
• a) hydrogen,
• b) substituted or unsubstituted aryl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --;
• R.sup.7 is 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, R.sup.8 O--, R.sup.9 S (O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --;
• R.sup.8 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted or unsubstituted C.sub.1 -C.sub.6 aralkyl and substituted or unsubstituted aryl;
• R.sup.9 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
• R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.3 alkyl and benzyl;
• 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.8 --, O, --N(R.sup.8)--, or S(O).sub.m ;
• V is selected from:
• a) hydrogen,
• b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
• c) aryl,
• d) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
• e) C.sub.2 -C.sub.20 alkenyl, and
• 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 selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl, provided that if W is imidazolyl, the point of attachment of the imidazolyl moiety to (CR.sub.2.sup.1b).sub.p is selected from the group consisting of 4 or 5 position carbon of the imidazolyl moiety;
• Y is selected from:
• --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(R.sup.10).sub.2 --, --C(OR.sup.10)R.sup.10 --, --CN(R.sup.10).sub.2 R.sup.10 --, --OC(R.sup.10).sub.2 --, NR.sup.10 C(R.sup.10).sub.2 --, --C(R.sup.10).sub.2 O--, --C(R.sup.10).sub.2 NR.sup.10 --, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --NC(O)R.sup.10 --, --NC(O)OR.sup.10 --, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
• Z is 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;
• and
• u is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A compound which inhibits Ras farnesyl-transferase having the Formula Ib:

• ##STR20## wherein:
• R.sup.1a is independently selected from:
• hydrogen or C.sub.1 -C.sub.6 alkyl;
• R.sup.1b is independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, R.sup.8 O--, --N(R.sup.8).sub.2 or C.sub.2 -C.sub.6 alkenyl,
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted with 1 or 2 substituents selected from:
• unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, R.sup.8 O--, and --N(R.sup.8).sub.2 ;
• R.sup.2a and R.sup.2b are independently selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by a substituent selected from:
• R.sup.8 O--, --N(R.sup.8).sub.2, and R.sup.9 S (O).sub.m --,
• c) substituted or unsubstituted aryl, and
• d) halogen selected from F, I, Cl and Br;
• R.sup.3 is selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by a substituent selected from:
• R.sup.8 O--, --N(R.sup.8).sub.2 and R.sup.9 S (O).sub.m --,
• c) substituted or unsubstituted aryl,
• d) halogen selected from F, I, Cl and Br, and
• e) --CO.sub.2 R.sup.8 ;
• R.sup.4 and R.sup.5 are independently selected from:
• a) hydrogen, and ##STR21## R.sup.6 is selected from:
• a) hydrogen,
• b) substituted or unsubstituted aryl, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl substituted by C.sub.1 -C.sub.6 perfluoroalkyl, R.sup.8 O--, R.sup.8 C(O)NR.sup.8 --, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --;
• R.sup.7 is 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, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --;
• R.sup.8 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted or unsubstituted C.sub.1 -C.sub.6 aralkyl and substituted or unsubstituted aryl;
• R.sup.9 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
• R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.3 alkyl and benzyl;
• 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.8 --, O, --N(R.sup.8)--, or S(O).sub.m ;
• V is selected from:
• a) hydrogen,
• b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl,
• c) aryl,
• d) C.sub.1 -C.sub.20 alkyl wherein from 0 to 4 carbon atoms are replaced with a a heteroatom selected from O, S, and N, and
• e) C.sub.2 -C.sub.20 alkenyl, and
• 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 selected from pyrrolidinyl, imidazolyl, imidazolinyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl, provided that if W is imidazolyl, the point of attachment of the imidazolyl moiety to (CR.sub.2.sup.1b).sub.p is selected from the group consisting of 4 or 5 position carbon of the imidazolyl moiety;
• Y is selected from:
• --CH.dbd.CH--, --C.tbd.C--, --C(O)--, --C(R.sup.10).sub.2 --, --C(OR 10)R.sup.10 --, --CN(R.sup.10).sub.2 R.sup.10 --, --OC(R.sup.10).sub.2 --, --NR.sup.10 C(R.sup.10).sub.2 --, --C(R.sup.10).sub.2 O--, --C(R.sup.10).sub.2 NR.sup.10 --, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --NC(O)R.sup.10 --, --NC(O)OR.sup.10 --, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
• Z is 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;
• and
• u is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A compound which is:

• N,N-bis(4-Imidazolemethyl)amino-3-›(3-carboxyphenyl)oxy!benzene
• N,N-bis(4-Imidazolemethyl)amino-4-›(3-carboxyphenyl)oxy!benzene
• N,N-bis(4-Imidazolemethyl)amino-3-›(3-carbomethoxyphenyl)oxy!benzene
• N,N-bis(4-Imidazolemethyl)amino-4-›(3-carbomethoxyphenyl)oxy!benzene
• N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-›(3-carboxyphenyl)oxy! benzene
• N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-›(3-carbomethoxyphenyl )oxy!benzene
• N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-3-(phenoxy)benzene
• N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenoxy)benzene
• N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-4-(phenylthio)benzene
• N-Butyl-N-›1-(4-cyanobenzyl)-5-imidazolemethyl!amino-4-(phenoxy)benzene
• N-›1-(4-Cyanobenzyl)-5-imidazolemethyl!amino-4-(phenoxy)benzene
• N-(4-Imidazolemethyl)amino-3-›(3-carboxyphenyl)oxy!benzene
• 1-›N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino!-4-(phen oxy)benzene
• (.+-.)-4-›(4-imidazolylmethyl)amino!pentyl- 1-(phenoxy)benzene
• 1-›(N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n-butyl)amino)methyl!-4-(ph enoxy)benzene
• 4-›N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(n-butyl)amino!-1-(phenylthio )benzene
• (.+-.)-4-›N-(1-(4-cyanobenzyl)-4-imidazolylmethyl)-N-(n-butyl)amino!-1-(phe nylsulfinyl)benzene
• 3-›N-(4-imidazolylmethyl)-N-(n-butyl)amino!-N-(phenyl)benzenesulfonamide or
• 1-›N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino!-3-methoxy-4-phenylbenzene
• or a pharmaceutically acceptable salt or optical isomer thereof.

A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition which comprises a therapeutically effective amount of a compound of the Formula I:

• ##STR36## wherein:
• R.sup.1a and R.sup.1b are independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --,
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)--NR.sup.8 --;
• R.sup.2a, R.sup.2b and R.sup.3 are independently selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.2 -C.sub.6 alkenyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, N.sub.3, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --,
• c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, halogen or R.sup.9 OC(O)NR.sup.8 --, 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.4 and R.sup.5 are independently selected from:
• a) hydrogen, and ##STR37## R.sup.6 is independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, 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.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, R.sup.8.sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, 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.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NH--, CN, H.sub.2 N--C(NH)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.8 OC(O)NH--;
• R.sup.7 is 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.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C--(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --;
• R.sup.8 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted or unsubstituted C.sub.1 -C.sub.6 aralkyl and substituted or unsubstituted aryl;
• R.sup.9 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
• R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted or unsubstituted C.sub.1 -C.sub.6 aralkyl and substituted or unsubstituted 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.sup.8 --, --NR.sup.8 C(O)--, O, --N(R.sup.8)--, --S(O).sub.2 N(R.sup.8)--, --N(R.sup.8)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 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;
• Y is selected from:
• a bond, --C(R.sup.10).dbd.C(R.sup.10)--, --C.tbd.C--, --C(O)--, --C(R.sup.10).sub.2, --C(OR.sup.10)R.sup.10 --, --CN(R.sup.10).sub.2 R.sup.10 --, --OC(R.sup.10).sub.2 --, --NR.sup.10 C(R.sup.10).sub.2 --, --C(R.sup.10).sub.2 O--, --C(R.sup.10).sub.2 NR.sup.10 --, --C(O )NR.sup.10 --, --NR.sup.10 C(O), O, --NC(O)R.sup.10 --, --NC(O)OR.sup.10 --, --S(O).sub.2 N(R.sup.10)--, --N(R.sup.10)S(O).sub.2 --, or S(O).sub.m ;
• Z is 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;
• and
• u is 0 or 1;
• or a pharmaceutically acceptable salt thereof.

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition which comprises a therapeutically effective amount of a compound of the Formula I:

• ##STR38## wherein:
• R.sup.1a and R.sup.1b are independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --,
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocyclic, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)--NR.sup.8 --;
• R.sup.2a, R.sup.2b and R.sup.3 are independently selected from:
• a) hydrogen,
• b) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.2 -C.sub.6 alkenyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, N.sub.3, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --,
• c) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted cycloalkyl, alkenyl, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, halogen or R.sup.9 OC(O)NR.sup.8 --, 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.4 and R.sup.5 are independently selected from:
• a) hydrogen, and ##STR39## R.sup.6 is independently selected from:
• a) hydrogen,
• b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, 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.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, R.sup.8.sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C.sub.3 -C.sub.6 cycloalkyl, 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.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NH--, CN, H.sub.2 N--C(NH)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.8 OC(O)NH--;
• R.sup.7 is 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.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, NO.sub.2, (R.sup.8 .sub.2 N--C--(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --, and
• c) C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by C.sub.1 -C.sub.6 perfluoroalkyl, F, Cl, Br, R.sup.8 O--, R.sup.9 S(O).sub.m --, R.sup.8 C(O)NR.sup.8 --, CN, (R.sup.8).sub.2 N--C(NR.sup.8)--, R.sup.8 C(O)--, R.sup.8 OC(O)--, N.sub.3, --N(R.sup.8).sub.2, or R.sup.9 OC(O)NR.sup.8 --;
• R.sup.8 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted or unsubstituted C.sub.1 -C.sub.6 aralkyl and substituted or unsubstituted aryl;
• R.sup.9 is independently selected from C.sub.1 -C.sub.6 alkyl and aryl;
• R.sup.10 is independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, substituted or unsubstituted C.sub.1 -C.sub.6 aralkyl and substituted or unsubstituted 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.sup.8 --, --NR.sup.8 C(O)--, O, --N(R.sup.8)--, --S(O).sub.2 N(R.sup.8)--, --N(R.sup.8)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 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;
• Y is selected from:
• a bond, --C(R.sup.10).dbd.C(R.sup.10)--, --C.tbd.C--, --C(O)--, --C(R.sup.10 .sub.2 --, --C(OR.sup.10)R.sup.10 --, --CN(R.sup.10).sub.2 R.sup.10 --, --OC(R.sup.10).sub.2 --, --NR.sup.10 C(R.sup.10).sub.2 --, --C(R.sup.10).sub.2 O--, --C(R.sup.10).sub.2 NR.sup.10 --, --C(O)NR.sup.10 --, --NR.sup.10 C(O)--, O, --NC(O)R.sup.10 --, --NC(O)OR.sup.10 --, --S(O.sub.2 N(R.sup.10)--, --N(R.sup.10)S(O.sub.2 --, or S(O).sub.m ;
• Z is 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;
• and
• u is 0 or 1;
• or a pharmaceutically acceptable salt thereof.