# US 5,710,171 A · Bisphenyl inhibitors of farnesyl-protein transferase

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- Number: US 5,710,171 A
- Document ID: US5710171A
- Status: Granted
- Kind: A
- Application number: 08/648,330
- Filed: 1996-05-15
- Granted: 1998-01-20
- Earliest claimed: 1995-05-24
- Assignees: Merck & Co., Inc.
- Inventors: Christopher J. Dinsmore; Suzanne C. MacTough; Gerald E. Stokker; Theresa M. Williams
- Web page: https://patentgrep.com/patent/US5710171A

## CPC

- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- A61P 13/12: of the kidneys
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention comprises peptidomimetic compounds which comprise a suitably substituted aminoalkylbenzene and analine analogs, further substituted with a second phenyl ring attached via a bond, a heteroatom linker or an aliphatic linker. The instant compounds inhibit the farnesyl-protein transferase enzyme and the farnesylation of certain proteins. Furthermore, the instant farnesyl protein transferase inhibitors differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

## Claims

### Claim 1

A compound which inhibits farnesyl-protein transferase having the Formula I: ##STR16## 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;
provided that heterocycle is not tetrazolyl;
R.sup.4 and R.sup.5 are independently selected from:
a) hydrogen, and ##STR17## 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, 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: 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.

### Claim 2

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.

### Claim 3

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.

### Claim 4

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.

### Claim 5 (depends on 4)

The compound according to claim 4 which is:
N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)amino-3-(phenoxy)benzene ##STR22## or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 4)

The compound according to claim 4 which is:
N-(4-Imidazolemethyl)-N-(4-nitrobenzyl)aminomethyl-3-›(3-carbomethoxyphenyl )oxy!benzene ##STR23## or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 4)

The compound according to claim 4 which is:
N-(4-Imidazolemethyl)amino-3-›(3-carboxyphenyl)oxy!benzene ##STR24## or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 4)

The compound according to claim 4 which is:
N,N-bis(4-Imidazolemethyl)amino-4-›(3-carbomethoxyphenyl)-oxy!benzene ##STR25## or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 4)

The compound according to claim 4 which is:
N-Butyl-N-›1-(4-cyanobenzyl)-5-imidazolemethyl!amino-4-(phenoxy)benzene ##STR26## or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 4)

The compound according to claim 4 which is:
1-›N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)-N-(4-cyanobenzyl)amino!-4-(phen oxy)benzene ##STR27## or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 4)

The compound according to claim 4 which is:
(.+-.)-4-›N-(1-(4-cyanobenzyl)-4-imidazolylmethyl)-N-(n-butyl)amino!-1-(phe nylsulfinyl)benzene ##STR28## or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 4)

The compound according to claim 4 which is:
1-›N-(1-(4-cyanobenzyl)-5-imidazolylmethyl)amino!-3-methoxy-4-phenylbenzene ##STR29##

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1.

### Claim 14 (depends on 2)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 2.

### Claim 15 (depends on 3)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 3.

### Claim 16 (depends on 4)

A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 4.

### Claim 17 (depends on 2)

The compound according to claim 2 which inhibits Ras farnesyl-transferase having the Formula Ia: ##STR30## 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 is ##STR31## wherein W is selected from imidazolyl and pyridinyl, 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;
R.sup.5 is selected from:
a) hydrogen, and ##STR32## wherein 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;
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 ;
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 --, --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.

### Claim 18 (depends on 14)

A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 14.

### Claim 19 (depends on 15)

A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 15.

### Claim 20 (depends on 16)

A method for inhibiting farnesyl-protein transferase which comprises administering to a mammal in need thereof a therapeutically effective amount of the composition of claim 16.

### Claim 21 (depends on 3)

The compound according to claim 3 of the formula Ib: ##STR33## 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 is ##STR34## wherein W is selected from imidazolyl and pyridinyl, 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;
R.sup.5 is selected from:
a) hydrogen, and ##STR35## wherein 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;
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
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.

### Claim 22 (depends on 14)

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 14.

### Claim 23 (depends on 15)

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 15.

### Claim 24 (depends on 16)

A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 16.

### Claim 25

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.

### Claim 26

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.