INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

INHIBITEURS DE TRANSFERASE DE FARNESYL-PROTEINE

English Abstract

The present invention is directed to compounds which inhibit farnesyl-protein
transferase (FTase) and the farnesylation of the oncogene protein Ras. The
invention is further directed to chemotherapeutic compositions containing the
compounds of this invention and methods for inhibiting farnesyl-protein
transferase and the farnesylation of the oncogene protein Ras.

French Abstract

Cette invention concerne des composés permettant d'inhiber la transférase de farnésyl-protéine (FTase), ainsi que la farnésylation de la protéine oncogène Ras. Cette invention concerne également des compositions chimiothérapeutiques contenant les composés susmentionnés, ainsi que des procédés permettant d'inhiber la transférase de farnésyl-protéine et la farnésylation de la protéine oncogène Ras.

Claims

- 96 -
WHAT IS CLAIMED IS:
1. A compound which inhibits farnesyl-protein
transferase of the formula A:
<IMG>
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's
are independently CH;
R1 and R2 are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, K11S(O)m-, R10C(O)NR10-,
R11C(O)O-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN,
NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substituent on the substituted C1-C6 alkyl is selected
from unsubstituted or substituted aryl, heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R10O-, R11S(O)m-, R10C(O)NR10, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-;
R3, R4 and R5 are independently selected from:

- 97 -
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-,
R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl, R12O-,
R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R11C(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-; or

- 98 -
any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-,
provided that when R3, R4, R5, R6a, R6b, R6C, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,
R4, R5, R6a, R6b, R6C, R6d or R6e to the 6-membered
heteroaryl ring, or phenyl ring respectively, is through a
substitutable heterocycle ring carbon;
R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) <IMG> ,
f) -SO2R11,
g) N(R10)2 or
h) C1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, sublstituted aryl, heterocycle, C3-C10 cycloalkyl,
C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
R10O, R11S(O)m-, R10C(O)NR10 , (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or
R11OC(O)NR10-, and
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,

- 99 -
R10O-, R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-,
R102N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, or
R10OC(O)NH-;
provided that when R8 is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9 is independently selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R11O,
R11S(O)m-, R10C(o)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-,
(R10)2NC(O)-, R10 2N-C(NR10), CN, R10C(O)-,
N3, -N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, Cl-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10, -NR10C(O)-, O, -N(R10)-,
-S(O)2N(R10)-, -N(R10)S(O)2-, or S(O)m;
V is selected from:
a) hydrogen,

- 100-
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl,
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is
through a substitutable ring carbon;
W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(O)NR7-, -NR7C(O)-, -C(O)O-,
-OC(O)-, -C(O)NR7C(O)-, -NR7-, -S(O)2N(R10)-,
-N(R10)S(O)2- or -S(=O)m-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
t is 0 or 1;
or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 of the formula A:

- 101 -
<IMG>
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's
are independently CH;
R1 is independently selected from: hydrogen, C3-C10 cycloalkyl,
R10O-, -N(R10)2, F or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substituent on the substituted C1-C6 alkyl is selected from
unsubstituted or substituted aryl, heterocycle, C3-C10
cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3, R4 and R5 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-,

- 102-
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-,
R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R10 2NC(NR10)-,
CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-
NR10-;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl;
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic, C3-C10
cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R 12O-, R11S(O)m-,
R 10C(O)NR10-, (R10)2NC(O)-, R10 2N-C(NR10)-, CN,
R10C(O)-, N3, -N(R10)2, and R11OC(O)-NR10-; or
any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, RS, R6a, R6b, R6C, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,
R4, R5, R6a, R6b, R6C, R6d or R6e to the 6-membered

-103-
heteroaryl ring, or phenyl ring respectively, is through a
substitutable heterocycle ring carbon;
R7 is selected from: H; C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO.
<IMG> ,
f) ~SO2R11,
g) N(R10)2 or
h) C1-4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl,
R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-,
R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-,
R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-,
-N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
Cl, R11O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,

-104-
CN, NO2, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or
R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by C1-C6
perfluoroalkyl, F, Cl, R10O-, R11S(O)m-, R10C(O)NR10-,
(R10)2NC(O)-, CN, (R10)2N-C(NR10)-, R10C(O)-,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-. -C~C-,
-C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is
through a substitutable ring carbon;

-105-
W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,
pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or
isoquinolinyl;
X is a bond, O, -C(=O)-, -CH=CH-, -C(O)NR7-, -NR7C(O)-, -NR7-,
-S(O)2N(R10), -N(R10)S(O)2- or -S(=O)m-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
t is 0 or 1 ;
or a pharmaceutically acceptable salt thereof.
3. The compound according to Claim 1 of the formula B:
<IMG>
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's
are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;

-106-
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substituent on the substituted C1-C6 alkyl is selected from
unsubstituted or substituted aryl, heterocycle, C3-C10
cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-;
R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,

-107-
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-; or
any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a, R6b, R6c, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of
R3, R4, R6a, R6b, R6c, R6d or R6e to the 6-membered
heteroaryl ring, or phenyl ring respectively, is through a
substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl,
R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-,
R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-,
R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-,
-N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is;
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl
and halogen;

-108-
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is
through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or
-C(=O)-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4; and

-109-
r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 1 of the formula C:
<IMG>
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's
are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substituent on the substituted C1-C6 alkyl is selected from
unsubstituted or substituted aryl, heterocycle, C3-C10
cycloalkyl, C2-C6 alkenyl, R10O- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6

-110-
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10,-
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-;
R6a R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, CN(R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-; or
any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

-111-
provided that when R3, R4, R6a, R6b, R6c, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of
R3, R4, R6a, R6b, R6c, R6d or R6e to the 6-membered
heteroaryl ring, or phenyl ring respectively, is through
a substitutable heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl,
R10O-, R10C(O)NR10, CN, NO2, (R10)2N-C(NR10)-,
R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-,
R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-,
-N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, C1-C6 alkyl, trifluoromethyl
and halogen;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;

-112-
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
provided that V is not hydrogen if A1 is S(O)m and V is not hydrogen
if A1 is a bond, n is 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to A1 is
through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or
-C(=O)-;
m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and
r is 0 to 5, provided that r is 0 when V is hydrogen;
or a pharmaceutically acceptable salt thereof.
5. The compound according to Claim 3 of the formula D:
<IMG>

-113-
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's
are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or
-N(R10)2;
R3 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;

-114-
R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10), CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-; or
any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,
R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl,
R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-,
R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and

-115-
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-,
R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-,
-N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or
-C(=O)-,
n is 0 or 1; provided that n is not 0 if A1 is a bond, O,
-N(R10)- or S(O)m;
m is 0, 1 or 2; and
p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
6. The compound according to Claim 4 of the formula E:

-116-
<IMG>
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's
are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2, F
or C2-C6 alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or
-N(R10)2;
R3 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,

-117-
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)NR10-;
R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-; or
any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,
R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl

-118-
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F, Cl,
R10O-, R10C(O)NR10-, CN, NO2, (R10)2N-C(NR10)-,
R10C(O)-, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl substituted by C1-C6 perfluoroalkyl, R10O-,
R10C(O)NR10-, (R10)2N-C(NR10)-, R10C(O)-,
-N(R10)2, or R11OC(O)NR10-;
provided that when R8 is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or
-C(=O)-;
n is 0 or 1;
m is 0, 1 or 2; and
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;

-119-
or a pharmaceutically acceptable salt thereof.
7. The compound according to Claim 5 of the formula F:
<IMG>
wherein:
from 1-2 of f(s) are independently N or N~O, and the remaining f's
are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, R10O-, -N(R10)2 or
F,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C10 cycloalkyl, R10O-, or -N(R10)2;
R3 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,

-120-
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-;
R4 is selected from H, halogen, CH3 and CF3;
R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R10 2N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-; or
any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,

-121-
R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR10-, O or
-C(=O)-;
m is 0, 1 or 2; and
p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.
8. The compound according to Claim 6 of the formula G:
<IMG>
>

-122-
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f's
are independently CH;
R1 is selected from: hydrogen, C3-C10 cycloalkyl, R10O-, -N(R10)2,
F or C1-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle or C3-C10 cycloalkyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, R10O-, or
-N(R10)2;
R3 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)NR10-;
R4 is selected from H, halogen, CH3 and CF3;

-123-
R6a, R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, C1-C6 perfluoroalkyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R102N-C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2,
or R11OC(O)NR10-,
c) unsubstituted C1-C6 alkyl,
d) substituted C1-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R12O-, R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-; or
any two of R6a, R6b, R6c, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a, R6b, R6c, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,
R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from C1-C6 alkyl and aryl;

-124-
R12 is independently selected from hydrogen, C1-C6 alkyl, C1-C6
aralkyl, C1-C6 substituted aralkyl, C1-C6 heteroaralkyl,
C1-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A1 is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and
n is 0 or 1;
or a pharmaceutically acceptable salt thereof.
9. A compound which inhibits farnesyl-protein
transferase which is:
1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
1-(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
1-(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
1-(3-Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole

-125-
1-(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
or
1-(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
or a pharmaceutically acceptable salt thereof.
10. The compound according to Claim 9 which is:
1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
<IMG>
or a pharmaceutically acceptable salt thereof.
11. The compound according to Claim 9 which is:
1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole

-126-
<IMG>
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a
pharmaceutical carrier, and dispersed therein, a therapeutically effective
amount of a compound of Claim 1.
13. A pharmaceutical composition comprising a
pharmaceutical carrier, and dispersed therein, a therapeutically effective
amount of a compound of Claim 3.
14. A pharmaceutical composition comprising a
pharmaceutical carrier, and dispersed therein, a therapeutically effective
amount of a compound of Claim 4.
15. A pharmaceutical composition comprising a
pharmaceutical carrier, and dispersed therein, a therapeutically effective
amount of a compound of Claim 9.
16. A method for inhibiting farnesyl-protein transferase
which comprises administering to a mammal in need thereof a
therapeutically effective amount of a composition of Claim 12.
17. A method for inhibiting farnesyl-protein transferase
which comprises administering to a mammal in need thereof a
therapeutically effective amount of a composition of Claim 13.

-127-
18. A method for inhibiting farnesyl-protein transferase
which comprises administering to a mammal in need thereof a
therapeutically effective amount of a composition of Claim 14.
19. A method for inhibiting farnesyl-protein transferase
which comprises administering to a mammal in need thereof a
therapeutically effective amount of a composition of Claim 15.
20. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 12.
21. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 13.
22. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 14.
23. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 15.
24. A method for treating neurofibromin benign
proliferative disorder which comprises administering to a mammal in
need thereof a therapeutically effective amount of a composition of
Claim 12.
25. A method for treating blindness related to retinal
vascularization which comprises administering to a mammal in need
thereof a therapeutically effective amount of a composition of Claim 12.

-128-
26. A method for treating infections from hepatitis delta
and related viruses which comprises administering to a mammal in need
thereof a therapeutically effective amount of a composition of Claim 12.
27. A method for preventing restenosis which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 12.
28. A method for treating polycystic kidney disease
which comprises administering to a mammal in need thereof a
therapeutically effective amount of a composition of Claim 12.
29. A pharmaceutical composition made by combining
the compound of Claim 1 and a pharmaceutically acceptable carrier.
30. A process for making a pharmaceutical composition
comprising combining a compound of Claim 1 and a pharmaceutically
acceptable carrier.

Description

CA 02249607 1998-09-23
WO 97/36901 PCT/US97/05304
TITLE OF THE INVENTION
INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
BACKGROUND OF THE INVENTION
The Ras proteins (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras)
are part of a signalling pathway that links cell surface growth factor
receptors to nuclear signals initiating cellular proliferation. Biological
and biochemical studies of Ras action indicate that Ras functions like a
G-regulatory protein. In the inactive state, Ras is bound to GDP. Upon
growth factor receptor activation Ras is induced to exchange GDP
for GTP and undergoes a conforrnational change. The GTP-bound
form of Ras propagates the growth stimulatory signal until the signal
is termin~ted by the intrinsic GTPase activity of Ras, which returns
the protein to its inactive GDP bound folm (D.R. Lowy and D.M.
Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras
genes (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) are found in many
human cancers, including colorectal carcinoma, exocrine pancreatic
carcinoma, and myeloid leukemia~s. The protein product,s of these
genes are defective in their GTPase activity and constitutively
transmit a growth stimulatory signal.
Ras must be localized to the plasma membrane for
both normal and oncogenic functions. At least 3 post-translational
modifications are involved with Ras membrane localization, and all
3 modifications occur at the C-terminu,s of Ras. The Ras C-terminus
contains a sequence motif termed a "CAAX" or "Cys-Aaal-Aaa2-Xaa"
box (Cys is cysteine, Aaa is an aliphatic amino acid, the Xaa is any
amino acid) (Willumsen et al., Nature 310:583-5~6 (1984)). Depend-
ing on the specific sequence, this motif serves as a signal sequence for
the enzymes farnesyl-protein transferase or geranylgeranyl-protein
transferase, which catalyze the alkylation of the cysteine residue of the
CAAX motif with a Cls or C20 isoprenoid, respectively. (S. Clarke.,
- Ann. Rev. Biochem. 61:355-386 (1992); W.R. Schafer and J. Rine,
Ann. Rev. Genetics 30:209-237 (1992)). The Ras protein is one of
.several proteins that are known to undergo post-translational farnesyl-

CA 02249607 1998-09-23
W O 97136901 PCTAUS97/05304
ation. Other farnesylated proteins include the Ras-related GTP-binding
proteins such as Rho, fungal mating factors, the nuclear lamins, and the
gamma subunit of transducin. James, et al., J. Biol. Chem. 269, 14182
(1994) have identified a peroxisome associated protein Pxf which is also
farnesylated. James, et al., have also suggested that there are farnesyl-
ated proteins of unknown structure and function in addition to those
listed above.
Inhibition of farnesyl-protein transferase has been
shown to block the growth of Ras-transformed cells in soft agar and
to modify other aspects of their transformed phenotype. It has also
been demonstrated that certain inhibitors of farnesyl-protein transferase
selectively block the processing of the Ras oncoprotein intracellularly
(N.E. Kohl et al., Science, 260:1934-1937 (1993) and G.L. James
et al., Science, 260:1937-1942 (1993). Recently, it ha,s been .shown
that an inhibitor of farnesyl-protein tran,sferase blocks the growth of
ras-dependent tumor,s in nude mice (N.E. Kohl et al., Proc. Natl.
Acad. Sci U.S.A., 91:9141-9145 (1994) and induces regression of
mammary and salivary carcinomas in ras transgenic mice (N.E. Kohl
et al., Nature Medicine, 1:792-797 (1995).
Indirect inhibition of farnesyl-protein transfera,se in vilJo
has been demonstrated with lovastatin (Merck & Co., Rahway, NJ)
and compactin (Hancock et al., ibid; Casey et al., ihid; Schafer et al.,
Science 245:379 (19~9)). These drugs inhibit HMG-CoA reductase, the
rate limiting enzyme for the production of polyisoprenoids including
farnesyl pyrophosphate. Farne,syl-protein transferase utilizes farnesy]
pyrophosphate to covalently modify the Cys thiol group of the Ras
CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990);
Schaber et al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al.,
Science, 249:1 133-1139 (1990); Manne et al., P)~oc. Natl. Acad. Sc~i
USA, 87:7541-7545 (1990)). Inhibition of farne~syl pyrophosphate
biosynthesis by inhibiting HMG-CoA reductase blocks Ras membrane
localization in cultured cells. However, direct inhibition of farnesyl-
protein transferase would be more specific and attended by fewer side
effects than would occur with the required dose of a general inhibitor

CA 02249607 1998-09-23
WO 97/36901 PCT/US97/0~304
of isoprene ~iosynthesis.
Inhibitors of farnesyl-protein transferase (FPTase) have
been described in four general classes (S. Graham, Expert Opinion
Ther. Patents, (1995) 5:1269-1285). The first are analogs of farnesyl
5 diphosphate (FPP), while a second class of inhibitors is related to the
protein substrates (e.g., Ras) for the enzyme. Bisubstrate inhibitors
and inhibitors of farnesyl-protein transferase that are non-competitive
with the substrates have also been described. The peptide derived
inhibitors that have been described are generally cysteine containing
10 molecules that are related to the CAAX motif that is the signal for
protein prenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss
etal., PNAS, 88:732-736 (1991)). Such inhibitors may inhibit
protein prenylation while serving as alternate substrates for the
farnesyl-protein transferase enzyme, or may be purely competitive
15 inhibitors (U.S. Patent 5,141,g51, University of Texas; N.E. Kohl
et al ., Sc~ience, 260: 1934- 1937 (1993); Graham, et al., J. Med . Chem.,
37, 725 (1994)). In ~eneral, deletion of the thiol from a CAAX
derivative has been shown to dramatically reduce the inhibitory
potency of the compound. However, the thiol group potentially
20 places limitation,s on the therapeutic application of FPTase inhibitors
with respect to pharmacokinetic~s, pharmacodynamics and toxicity.
Therefore, a functional replacement for the thiol is de.sirable.
It has recently been disclosed that certain tricyclic
compounds which optionally incorporate a piperidine moiety
25 are inhibitors of FPTase (WO 95/10514, WO 95/10515 and
WO 95/10516). Lmidazole-containing inhibitors of farnesyl
protein transferase have also been disclosed (WO 95/09001
and EP 0 675 112 A1).
It has recently been reported that farnesyl-protein
30 transferase inhibitors are inhibitors of proliferation of vascular
smooth muscle cells and are therefore useful in the prevention and
therapy of arteriosclerosis and diabetic disturbance of blood vessels
(JP H7- 112930).
It is, therefore, an object of this invention to develop

CA 02249607 1998-09-23
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low molecular weight compounds that will inhibit farnesyl-protein
transferase and thus, the post-translational farnesylation of proteins.
It is a further object of this invention to develop chemotherapeutic
compositions containing the compounds of this invention and methods
5 for producing the compounds of this invention.
SUMMARY OF THE INVENT~ON
The present invention comprises arylheteroaryl-
containing compounds which inhibit the farnesyl-protein tran.sferase.
10 Further contained in this invention are chemotherapeutic compositions
containing these farnesyl transferase inhibitors and methods for their
production.
The compounds of this invention are illustrated by the
formula A:
6a-e
/_~/R
</
R3 )~
(I 8)r /~9~ f~
V - A1 (CR12)nA2(CR 12)n ~;~W~ - (CR22)p - X -(CR 2)p 4 R5
lS A
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are useful in the inhibition
of farnesyl-protein transferase and the farnesylation of the oncogene
20 protein Ras. In a first embodiment of this invention, the inhibitors of
farnesyl-protein tran~sferase are illustrated by the formula A:

CA 02249607 1998-09-23
W O 97/36901 PCTrUS97/05304
R6a-e
R3 >~
(R8) / 9~ /f~
V - A1(CR12)nA2(CR12)n ;~W~ (CR22)p - X -(CR22)p R5
wherein:
from 1-2 of f(s) are independently N or N->O, and the remaining f'~
5 are independently CH;
Rl and R2 are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R 1 0O-, R I I S(O)m-, R 1 0C(O)NR 10,
R 1 1 C(O)O-, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, NO2,
R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 ,
c) unsubstituted or substituted Cl-C6 alkyl wherein the
substituent on the substituted Cl-C6 alkyl is selected from
unsubstituted or sub.stituted aryl, heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R100- Rl lS(o)m, RIOC(O)NRlO-, (R10)2NC(o)-,
K102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R 1 1 OC(O)-NR 10;
R3, R4 and R5 are independently selected from:
a) hydrogen,
- b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C 10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R12O-,

CA 02249607 1998-09-23
W O 97/36901 PCT~US97/05304
R 1 1 S(O)m ~ R 1 0C(o)NR 10, (R 1 0)2NC(o)-, R 1 1 C(O)O-,
R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2,
or Rl lOC(O)NR10
c) unsubstituted Cl-C6 alkyl,
S d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 1 2O, R 1 1 S(O)m-~ R 1 0C(O)NR 10, (R 1 0)2NC(O)-,
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and
R 1 1 OC(O)-NR 10;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl, R120-,
Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o), Rl lC(o)o-
R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2
or R 1 1 OC(O)NR 10
c) unsubstituted C 1 -C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is .selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, RllS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o)
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10; or
~0 any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;

CA 02249607 1998-09-23
W O 97/36901 rcTrusg7~0s304
provided that when R3, R4, RS, R6a, R6b~ R6C, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,
R4 R5 R6a, R6b, R6C, R6d or R6e to the 6-membered
heteroaryl ring, or phenyl ring respectively, is through a
S substitutable heterocycle ring carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with:
a) Cl 4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) ~ R
f) --SO2R1 1
l S g) N(R 1 0)2 or
h) C 1-4 perfluoroalkyl;
R~ is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, C3-CIo cycloalkyl,
C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
R100-, Rl lS(O)m, RlOC(O)NR10-~ (R10)2NC(o)-,
R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2, or
R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-CIo cycloalkyl,
C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl,
Br, R 1 0o-, R I 1 S(O)m ~ R 1 0C(O)NH-, (R 1 0)2NC(O)-,
R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, or
R10OC(O)NH-;

CA 02249607 1998-09-23
W 097/36901 PCTAUS97/05304
provided that when R~ is heterocycle, attachrnent of R~ to V i~;
through a substitutable ring carbon;
R9 is independently selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br,
Rl lo-, Rl lS(O)m-, Rloc(o)NRlo- (R10)2NC(o)
R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O~-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10-, and
c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, RllS(O)m-, R10C(O)NR10-,
(R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN, R 1 ~C(O)-,
N3, -N(R 1~)2, or R 1 1 OC(O)NR 10;
~5 R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
Rl I is independently selected from Cl-C6 alkyl and aryl;
~0 R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;~5
Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-,
-C(O)-, -C(O)NR 10, -NR I ~C(O)-, O, -N(R 10
-S(O)2N(R 10), -N(R I ~)S(O)2-, or S(O)m;
~0 V is selected from:
a) hydrogen,
- b) heterocycle,
c) aryl,

CA 02249607 1998-09-23
WO 97/36901 PCT/US97/05304
d) Cl-C20 alkyl wherein from O to 4 carbon atoms are
replaced with a heteroatom selected from 0, S, and N, and
~ e) C2-C20 alkenyl,
provided that V is not hydrogen if Al is S(O)m and V is not hydrogen
S if Al is a bond, n is O and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is
through a substitutable ring carbon;
W is a heterocycle;
X is a bond, -CH=CH-, O, -C(=O)-, -C(o)NR7-, -NR7C(o)-, -C(O)O-,
-OC(O)-, -C(o)NR7C(o)-, -NR7-, -S(0)2N(R 1 0) ,
-N(R10)S(0)2- or-S(=O)m-;
1 5 m is 0, 1 or 2;
n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;
q is 0, 1 , 2 or 3;
r is O to 5, provided that r is O when V is hydrogen; and
20 tis Oorl;
or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of thi.s
invention is illustrated by the following fo~nula A:
R6a-e
R3
(R8)r /(1l19~ f~
- V - A1(CR12)nA2(CR12)n~;~W~ - (CR22)p - X -(CR22)p R5
A

CA 02249607 1998-09-23
W O 97/36901 PCTAUS97/05304
- 10-
wherein:
from 1-2 of f(,s) are independently N or N->O, and the rem~ining rs
are independently CH;
s
Rl is independently selected from: hydrogen, C3-CIo cycloalkyl,
R 1 00-, -N(R 1 0)2, F or C l -C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C I o cycloalkyl, R 1 00-, -N(R 1 0)2,
F or C2-C6 alkenyl,
c) unsubstituted or ~ubstituted Cl-C6 alkyl wherein the
substituent on the sub.stituted C 1 -C6 alkyl is selected from
unsubstituted or substituted aryl, heterocycle, C3-Clo
cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3, R4 and R5 are independently selected from:
a) hydrogen,
b) un.substituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-c 1 o cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(o)-,
R 1 02N-C(NR 10), CN, N02, R I ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10 ,
c) u~substituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl,
R120 RllS(O)m, KlOC(O)NR10-, (R10)2NC(o)-,
- R102N-C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and
Rl lOC(o) NR10;

CA 02249607 l998-09-23
W O 97/36901 PCTAUS97/05304
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen,
- b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120, Rl lS(O)m, KlOC(O)NR10-, (Rl0)2Nc(o)-~
R 1 02N-C(NR 10) , CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic, C3-Cl o
cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R12O-, Rl lS(O)m-,
R 1 0C(O)NR 10, (R 1 0)2NC(O)-, R 1 02N-C(NR 10) , CN,
R 1 ~C(O)-, N3, -N(R 1~)2, and R 1 1 OC(O)-NR 10; or
any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R5, R6a~ R6b, R6C, R6d or R6e ;~; ;
unsubstituted or substituted heterocycle, attachment of R3,
R4 R5, R6a, R6b, R6C, R6d or R6e to the 6-membered
heteroaryl ring, or phenyl ring respectively, is through a
substitutable heterocycle ring carbon;
R7 is selected from: H; Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or
substituted with:
a) Cl 4 alkoxy,
b) aryl or heterocycle,
- c) halogen,
d) HO,

CA 02249607 1998-09-23
W 097/36901 PCTAUS97/05304
- 12 -
o
f) --So2R 1 ~
g) N(R l ~)2 or
h) C l -4 perfluoroalkyl;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R10O-, R 1 0C(O)NR 10, CN, NO2, (R 10)2N-C(NR 10),
R I ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl,
R 1 0O-, R l 0C(O)NR 10, (R 1 0)2N-C(NR 10)
R10C(O)-, -N(R10)2, or Rl lOC(O)NRI0-;
provided that when R~ is heterocycle, attachment of R~s to V is
through a ,substitutable ring carbon;
R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F,
Cl, Rl lo-, Rl lS(O)m-, Rl0C(o)NRl0-, (Rl0)2NC(o)
CN, NO2, (R l 0)2N-C(NR 10), R I ~C(O)-, -N(R l ~)2, or
R I I OC(O)NR 10, and
c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6
perfluoroalkyl, F, Cl, Rl0O-, RllS(O)m-, Rl0C(O)NRl0-,
(R l 0)2NC(O)-, CN, (R l 0)2N-C(NR l 0), R l ~C(O)-,
-N(Rl0)2, or Rl lOC(O)NRl0-;
R10 is independently .selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;

CA 02249607 1998-09-23
W O 97/36901 PCTrUS97/05304
- 13 -
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently selected from: a bond, -CH=CH-, -C~C-,
-C(O)-, -C(O)NR10-, O, -N(R 10), or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
20 provided that V is not hydrogen if Al is S(O)m and V i.s not hydrogen
if Al is a bond, n is 0 and A2 i~s S(O)m;
provided that when V is heterocycle, attachment of V to RX and to Al is
through a ~substitutable ring carbon;
25 W is a heterocycle selected from pyrrolidinyl, imidazolyl, imidazolinyl,
pyridinyl, thiazolyl, oxazolyl, indolyl, quinolinyl, triazolyl or
isoquinolinyl;
X is a bond, O, -C(=O)-, -CH=CH-, -C(o)N~7-, -NR7C(o)-, -NR7-,
-S(O)2N(R 1 0)-, -N(R 1 0)S(0)2- or -S(=O)m-;
-
mis 0, 1 or2;n is independently 0, 1, 2, 3 or 4;
p is independently 0, 1, 2, 3 or 4;

CA 02249607 1998-09-23
W O97/36901 PCT~US97/05304
- 14 -
q is 0, 1 , 2 or 3;
r is 0 to 5, provided that r is 0 when V is hydrogen; and
t is 0 or 1;
5 or the pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of this
invention are illustrated by the formula B:
R6a-e
(R8)r R9a R3 f~
Rgb~ 4
wherem:
from 1-2 of f(s) are independently N or N->O, and the rem~ining f's
are independently CH;
R l is selected from: hydrogen, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or Cl-C6 alkyl;
R2 is independently .selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C l o cycloalkyl, R l OO-, -N(R 1 0)2, F
or C2-C6 alkenyl,
c) unsubstituted or substituted Cl-C6 alkyl wherein the
substituent on the substituted Cl-C6 alkyl is selected from
unsubstituted or substituted aryl, heterocycle, C3-Clo
cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen,

CA 02249607 1998-09-23
WO 97/36901 PCT/US97/05304
- 15 -
- b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
- alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o)
R 1 02N-C(NR 1 0)-, CN, N02, R 1 OC(O)-, N3, -N(R 1 0)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, R I ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10;
1~
R6a R6b R6C, R6d and R6e are independently selected from:
a) hydrogen,
b) unsub.stituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o)
R1o2N-c(NRlo)-~ CN, N02, RlOC(O)-, N3, -N(R10)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
- R1 1OC(O)-NR10; or

CA 02249607 l998-09-23
W O 97/36901 PCTAUS97/05304
- 16 -
any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a~ R6b, R6C, R6d or R6e is
unsubstituted or substituted heterocycle, attachment of R3,
R4 R6a, R6b, R6C, R6d or R6e to the 6-membered
heteroaryl ring, or phenyl ring respectively, is through a
substitutable heterocycle ring carbon;
R~ is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R 1 0O-, R 1 0C(O)NK 10, CN, NO2, (R 1 0)2N-C(NR 10) ,
R 10c(O)-, -N(R 1 ~)2, or R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-,
R 1 0C(o)NR 10, (R 1 0)2N-C(NR 10) , R I ~C(O)-,
-N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R~ i.s heterocycle, attachment of RX to V is
through a ~substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl
and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-c6 alkyl, C1-C6
- aralkyl, C1-C6 .substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,

CA 02249607 1998-09-23
WO 97/36901 PCT~US97/05304
2-aminoethyl and 2,2,2-trifluoroethyl;
A 1 and A2 are independently ,selected from: a bond, -CH=CH-, -C_C-,
-C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen,
b) heterocycle selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazolyl and thienyl,
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
15 provided that V is not hydrogen if Al is S(O)m and V is not hydrogen
if Al is a bond, n ilS 0 and A2 is S(O)m;
provided that when V is heterocycle, attachment of V to R8 and to Al is
through a substitutable ring carbon;
20 X is a bond, -CH=CH-, -C(O)NR10-, -NRlOC(O)-, -NR10-, O or
-C(=O)-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
25 p is 0, 1, 2, 3 or 4; and
r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.
Another preferred embodiment of the compounds of this
30 invention are illustrated by the formula C:
-

CA 02249607 1998-09-23
W O97/36901 PCTAUS97/05304
- 18 -
R6a-e
~8~ 9 R3
V- A1(CR12)nA2(CR12) ~ f~
C R9b (CR22)p X R4
wherein:
from 1-2 of f(s) are independently N or N->0, and the remaining f
5 are independently CH;
R l is selected from: hydrogen, C3-CIo cycloalkyl, R100-, -N(R10)2, F
or Cl-C6 alkyl;
10 R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3 -C I o cycloalkyl, R 1 00-, -N(R 1 0)2, F
or C2-C6 alkenyl,
c) un~ubstituted or substituted Cl-C6 alkyl wherein the
substituent on the substituted Cl-C6 alkyl i.s selected from
unsubstituted or substituted aryl, heterocycle, C3-Clo
cycloalkyl, C2-C6 alkenyl, R100- and -N(R10)2;
R3 and R4 are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, CN(R 1 0)2NC(0)-,
R102N-C(NR10)-, CN, N02, R1OC(0)-, N3, -N(R10)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,

CA 02249607 1998-09-23
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- 19-
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-c6 alkenyl, C2-C6 alkynyl,
R 1 20, R 1 1 S(O)m ~ R I OC(O)NR 10 (R 1 0)2NC(o)-
R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R11OC(O) NR10;
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 1 20, R 1 I S(O)m-~ R 1 OC(O)NR 10, CN(R 1 0)2NC(O)-,
R 1 02N-C(NR 1 0) , CN, N02, R I ~C(O)-, N3, -N(R 1 ~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120, Rl lS(o)m, RlOc(o)NRlo-~ (R10)2NC(o)-,
R 1 02N-C(NR 1 0) , CN, R 1 ~C(O)-, N3, -N(R 1 ~)2, and
R 1 1 OC(O)-NR 10; or
any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R4, R6a~ R6b, R6C, R6d or R6e is
~ unsubstituted or substituted heterocycle, attachment of R3,
R4 R6a, R6b, R6C, R6d or R6e to the 6-membered
heteroaryl ring, or phenyl ring respectively, i.s through a
substitutable heterocycle ring carbon;

CA 02249607 1998-09-23
W O97136901 PCT~USg7/05304
- 20 -
R~ is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R 1 0O-, R 1 0C(o)NR 10, CN, NO2, (R 1 0)2N-C(NR 1 0)-,
R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-,
R 1 0C(O)NR 10, (R 1 0)2N-C(NR 10) R 1 ~C(O)-
-N(R10)2, or Rl lOC(O)NR10-;
provided that when R~ is heterocycle, attachment of R~ to V i~
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, Cl-C6 alkyl, trifluoromethyl
and halogen;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R11 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, C1-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C-C-,
-C(O)-, -C(O)NR10-, O, -N(R10)-, or S(O)m;
V is selected from:
a) hydrogen,

CA 02249607 1998-09-23
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- 21 -
b) heterocycle ~selected from pyrrolidinyl, imidazolyl,
imidazolinyl, pyridinyl, thiazolyl, oxazolyl, indolyl,
quinolinyl, isoquinolinyl, triazol311 and thienyl,
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a heteroatom selected from O, S, and N, and
e) C2-C20 alkenyl, and
provided that V is not hydrogen if Al is S(O)m and V is not hydrogen
if Al is a bond, n is 0 and A2 is S(O)m;
10 provided that when V is heterocycle, attachment of V to Rg and to Al is
through a substitutable ring carbon;
X is a bond, -CH=CH-, -C(O)NR 10 , -NR 1 ~C(O)-, -NR 10, O or
-C(=O)-;
mis 0, 1 or2;
n is independently 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4, provided that p is not 0 if X is a bond or O;
and
20 r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.
In a more preferred embodiment of this invention, the
inhibitors of farnesyl-protein transferase are illu~strated by the formula
25 D:
1 \ 2 ~ f\~,
R8 D
wherein:

CA 02249607 1998-09-23
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- 22 -
from 1-2 of f(s) are independently N or N->0, and the remaining f's
are independently CH;
5 R l is selected from: hydrogen, C3-Clo cycloalkyl or Cl -C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-Clo cycloalkyl, R100-, -N(R10)2, F
or C2-C6 alkenyl,
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or
-N(R I ~)2;
lS R3 i.s selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120-, Rl lS(O)m-, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, N02, R 1 ~C(0)-, N3, -N(R 1~)2
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120, R 1 1 S(O)m-~ R 1 OC(0)NR 10 , (R 1 0)2NC(0)-,
R 1 02N-C(NR 10), CN, R 1 ~C(0)-, N3, -N(R 1~)2, and
R 1 1 0C(0)-NR 10;
- R4 is selected from H, halogen, C1-C6 alkyl and CF3;
R6a, R6b, R6C, R6d and R6e are independently selected from:

CA 02249607 1998-09-23
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- 23 -
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 1 20, R I 1 S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(O)-,
R 102N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 1 20, R 1 I S(O)m-~ R 1 0C(o)NR 10 , (R 1 0)2NC(O)-,
R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R11OC(O)-NR10; or
any two of R6a R6b, R6C, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b, R6c, R6d or R6e j~;
unsubstituted or sub.stituted heterocycle, attachment of R3,
R6a, R6b, R6C, R6d or R6e to the 6-membered heteroaryl
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
R8 is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-c6 alkyl, C2-c6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R 1 0O-, R 1 0C(o)NR 10, CN, NO2, (R 1 0)2N-C(NR 10),
R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and

CA 02249607 1998-09-23
W O 97/36901 PCT~US97/05304
- 24 -
c) Cl-C6 alkyl sub.stituted by Cl-C6 perfluoroalkyl, R10O-,
R 1 0C(o)NR 10, (R 1 0)2N-C(NR 10), R 1 ~C(O)-
-N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R~s is heterocycle, attachment of R8 to V is
through a substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-c6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R 1 1 i,s independently selected from Cl -C6 alkyl and aryl;
R12 i.s independently selected from hydrogen, Cl-c6 alkyl, Cl-C6
~5 aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
20 Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
X is a bond, -CH=CH-, -C(O)NR10-, -NR10C(O)-, -NR~0-, O or
-C(=O) -,
n is 0 or 1; provided that n is not 0 if Al is a bond, O,
-N(R10)- or S(O)m;
m is 0, 1 or 2; and
pi.s 0, 1, 2, 3 or4;
30 or the pharmaceutically acceptable salts thereof.
In another more preferred embodiment of this invention,
the inhibitors of farnesyl-protein transferase are illustrated by the
formula E:

CA 02249607 1998-09-23
W O97/36901 PCT~US97/05304
~N~R9a ~ ~ R6a-e
Al (CR1 2)n~j ~N~ ~ ~
9b (CR22)p X' R4
~¦~ E
r,8
n
wherein:
from 1-2 of f(s) are independently N or N-~0, and the remaining f's
5 are independently CH;
Rl is selected from: hydrogen, C3-Clo cycloalkyl, R100-, -N(R10)2, F
or C I -C6 alkyl;
10 R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-CIo cycloalkyl, R100-, -N(R10)2, F
or C2-C6 alkenyl,
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, R100-, or
-N(R 1 ~)2;
R3 i,s selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsub.stituted or
substituted heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R I 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(0)-,
R 1 02N-C(NR 10), CN, N02, R 1 ~C(0)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,

CA 02249607 1998-09-23
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- 26 -
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10 , (R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
K 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, Cl-C6 alkyl and CF3;
R6a R6b, R6c, R6d and R6e are independently selected from:
a) hydrogen,
b) un.substituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 1 20, R 1 1 S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(O)-,
R 1 02N-C(NR 10), CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2,
or Rl lOC(o)NR10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-c6 alkyl is selected from un.substituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120, RllS(O)m, RlOC(O)NR10-, (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10; or
any two Of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b, R6C, R6d or R6e i~
unsubstituted or substituted heterocycle, attachment of R3,
R6~ R6b, R6C, R6d or R6e to the 6-membered hetero~ryl

CA 02249607 1998-09-23
W O 97/36901 PCT~US97/05304
- 27 -
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
Rf~ is independently selected from:
a) hydrogen,
b) aryl, substituted aryl, heterocycle, Cl-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F, Cl,
R l Oo, R 1 OC(o)NR 10, CN, N02, (R 1 0)2N-C(NR 10)-,
R 1 ~C(O)-, -N(R 1~)2, or R 1 1 OC(O)NR 10, and
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R100-,
R 10C(O)NR 10, (R 1 0)2N-C(NR10)- R 10c(O)
-N(R 1~)2, or R 1 1 OC(O)NR 10;
provided that when R8 is heterocycle, attachment of R~ to V is
through a ~substitutable ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 10 , -NR 1 ~C(O)-, -NR 10, 0 or
30 -C(=O)-;
n is O or l ;
m is 0, 1 or 2; and
p is 0, 1, 2, 3 or 4, provided that p is not O if X is a bond or O;

CA 02249607 1998-09-23
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or the pharmaceutically acceptable salts thereof.
In a further embodiment of this invention, the inhibitor~s of
farnesyl-protein transferase are illustrated by the formula F:
,~ R6a-e
R9a\~= N \ ~
(~ (CR ~)p--
NC F
wherein:
from 1-2 of f(s) are independently N or N->0, and the remaining fs
are independently CH;
Rl is selected from: hydrogen, C3-CIo cycloalkyl or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3 -C l o cycloalkyl, R 1 00-, -N(R 1 0)2 or
F,
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-C1o cycloalkyl, R100-, or-N(Rl0)2;
20 R3 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-C1o cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R 1 l S(O)m-~ R l OC(O)NR 10, (R l 0)2NC(0)-,
R 1 02N-C(NR 1 0), CN, N02, R I ~C(0)-, N3, -N(R 1 ~)2,
or R 1 1 OC(O)NR 10

CA 02249607 1998-09-23
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- 29 -
- c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted C1-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, Rl lS(o)m, RlOc(o)NRlo-~ (RlO)2Nc(o)-~
R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10-;
10 R4 is selected from H, halogen, CH3 and CF3;
R6a R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 1 20, R I I S(O)m-, R 1 OC(O)NR 10-, (R 1 0)2NC(o)-,
R 1 02N-C(NR 10)-, CN, N02, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsub~stituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120, R 1 1 S(O~m-~ R 1 OC(O)NR 1 0-, (R 1 0)2NC(O)-,
R102N-c(NRlo)-~ CN, RlOC(O)-, N3, -N(R10)2, and
R 1 1 OC(O)-NR 10; or
any two of R6a, R6b, R6C, R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b~ R6C, R6d or R6e is
unsubstituted or sub.stituted heterocycle, attachrnent of R3,

CA 02249607 1998-09-23
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- 30 -
R6a R6b, R6C, R6d or R6e to the 6-membered heteroaryl
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;
R12 i.s independently selected from hydrogen, Cl-c6 alkyl, Cl-C6
aralkyl, C1-C6 ,substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
X is a bond, -CH=CH-, -C(O)NR 1 0-, -NR l OC(O)-, -NR 10-, O or
-C(=O) -;
m is 0, 1 or 2; and
pi,s 0, 1, 2, 3 or4;
or the pharrnaceutically acceptable salt.s thereof.
In a further embodiment of this invention, the inhibitors of
farnesyl-protein transferase are illustrated by the formula G:
R3 ~ R6a-e
NC 3 . .

CA 02249607 1998-09-23
WO 97/36901 PCT/US97/05304
wherein:
from 1-2 of f(s) are independently N or N-~O, and the rem~ining fs
are independently CH;
Rl is selected from: hydrogen, C3-CIo cycloalkyl, RlOO-, -N(RI0)27
F or Cl-C6 alkyl;
R2 is independently selected from:
a) hydrogen,
b) aryl, heterocycle or C3-Clo cycloalkyl,
c) Cl-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, C3-Clo cycloalkyl, C2-C6 alkenyl, RIOO-~ or
-N(R 1 ~)2;
R3 is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
,substituted heterocycle, C3-CIo cycloalkyl, C2-C6 a
Ikenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R 120, R I I S(O)m-, R 1 OC(O)NR 10, (R 1 0)2NC(o)-,
R 1 02N-C(NR 10), CN, NO2, R 1 ~C(O)-, N3, -N(R 1~)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
d) substituted C l -C6 alkyl wherein the .substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R120-, RllS(O)m-, RlOC(O)NR10-, (R10)2NC(o)-,
R 1 02N-C(NR 10) , CN, R 1 ~C(O)-, N3, -N(R 1~)2, and
R 1 1 OC(O)-NR 10;
R4 is selected from H, halogen, CH3 and CF3,

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- 32 -
R6a, R6b, R6C, R6d and R6e are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or
substituted heterocycle, C3-Clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, halogen, Cl-C6 perfluoroalkyl,
R120-, Rl lS(O)m-, Rloc(o)NRlo-~ (R10)2NC(o)
R102N-C(NR10)-, CN, NO2, RlOC(O)-, N3, -N(Rl0)2,
or R 1 1 OC(O)NR 10
c) unsubstituted Cl-C6 alkyl,
lO d) substituted Cl-C6 alkyl wherein the substituent on the substituted
Cl-C6 alkyl is selected from unsubstituted or substituted aryl,
unsubstituted or substituted heterocyclic, C3-CIo cycloalkyl,
C2-C6 alkenyl, C2-C6 alkynyl, R 1 20, R I l S(O)m ~
R l OC(O)NR l O, (R I 0)2NC(O)-, R 1 02N-C(NR 1 0) , CN,
RlOC(O)-, N3, -N(Rl0)2, and Rl lOC(O)-NRlO-; or
any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-C~=CH-CH2-, -(CH2)4- and -(CH2)3-;
provided that when R3, R6a~ R6b~ R6C, R6d or R6e is
unsub.stituted or sub,stituted heterocycle, attachment of R3,
R6a, R6b, R6c, R6d or R6e to the 6-membered heteroaryl
ring, or phenyl ring respectively, is through a substitutable
heterocycle ring carbon;
R9a and R9b are independently hydrogen, halogen, CF3 or methyl;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl,
2,2,2-trifluoroethyl and aryl;
R l l is independently selected from Cl -C6 alkyl and aryl;

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R12 is independently selected from hydrogen, Cl-C6 alkyl, Cl-C6
aralkyl, Cl-C6 substituted aralkyl, Cl-C6 heteroaralkyl,
Cl-C6 ,substituted heteroaralkyl, aryl, substituted aryl,
heteroaryl, substituted heteraryl, Cl-C6 perfluoroalkyl,
2-aminoethyl and 2,2,2-trifluoroethyl;
Al is selected from: a bond, -C(O)-, O, -N(R10)-, or S(O)m;
m is 0, 1 or 2; and
10 n is 0 or 1;
or the pharmaceutically acceptable salts thereof.
Preferred compounds of the invention are:
1 -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole
1 -(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
20 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
I -(3-Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
I -(2-(3 -Trifluoromethoxyphenyl)-pyrid-S-ylmethyl)-5-(4-
25 cyanobenzyl)imidazole
I -(2-(2-Trifluoromethylphenyl)-pyrid-S-ylmethyl)-5-(4-
cyanobenzyl)imidazole
1 -(3 -Phenyl-2-Chloropyrid-6-ylmethyl)-5 -(4-cyanobenzyl)imidazole

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- 34 -
1 -(3 -Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
and
I -(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
or a pharmaceutically acceptable salt thereof.
Specific examples of the compounds of the instant invention
are:
I -(2-Phenylpyrid-5 -ylmethyl)-5 -(4-cyanobenzyl)imidazole
NC
N-~
1 -(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-5-(4-
cyanobenzyl)imidazole
NC~
~ N~
or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have
a.symmetric centers and occur as racemates, racemic mixtures, and a.s
individual diastereomers, with all possible isomers, including optical

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isomers, being included in the present invention. When any variable
(e.g. aryl, heterocycle, Rl, R2 etc.) occurs more than one time in any
constituent, its definition on each occurence is independent at every
other occurence. Also, combinations of substituents/or variables are
5 permissible only if such combinations result in stable compounds.
As used herein, "alkyl" and the alkyl portion of aralkyl and
similar terms, is intended to include both branched and straight-chain
saturated aliphatic hydrocarbon groups having the specified number of
carbon atoms; "alkoxy" represents an alkyl group of indicated number
10 of carbon atoms attached through an oxygen bridge.
As used herein, "cycloalkyl" is intended to include non-
aromatic cyclic hydrocarbon groups having the specified number of
carbon atoms. Examples of cycloalkyl groups include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and the like.
"Alkenyl" groups include those groups having the specified
number of carbon atoms and having one or several double bonds.
Examples of alkenyl groups include vinyl, allyl, isopropenyl, pentenyl,
hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, I-propenyl, 2-butenyl, 2-methyl-2-butenyl, isoprenyl,
farnesyl, geranyl, geranylgeranyl and the like.
"Alkynyl" groups include tho.se groups having the .specified
number of carbon atoms and having one triple bonds. Examples of
alkynyl groups include acetylene, 2-butynyl, 2-pentynyl, 3-pentynyl and
the like.
"Halogen" or "halo" as used herein means fluoro, chloro,
bromo and iodo.
As used herein, "aryl," and the aryl portion of aroyl and
aralkyl, is intended to mean any stable monocyclic or bicyclic carbon
ring of up to 7 members in each ring, wherein at least one ring is
aromatic. Examples of such aryl elements include phenyl, naphthyl,
tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or
- acenaphthyl.
The term heterocycle or heterocyclic, as used herein,
represents a stable 5- to 7-membered monocyclic or stable ~- to

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1 I-membered bicyclic heterocyclic ring which is either saturated
or unsaturated, and which consists of carbon atoms and from one to
four heteroatoms selected from the group consisting of N, O, and S,
and including any bicyclic group in which any of the above-defined
5 heterocyclic rings is fused to a benzene ring. ~he heterocyclic ring
may be attached at any heteroatom or carbon atom which results in the
creation of a stable structure. Examples of ,such heterocyclic elements
include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl,
benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
10 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,
dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl,
imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl,
isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl,
1~ naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-
oxopyrrolidinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl,
pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl,
quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,
20 thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.
As used herein, "heteroaryl" is intended to mean any stable
monocyclic or bicyclic carbon ring of up to 7 members in each ring,
wherein at least one ring is aromatic and wherein from one to four
carbon atoms are replaced by heteroatoms selected from the group
25 consisting of N, O, and S. Examples of such heterocyclic elements
include, but are not limited to, benzimidazolyl, benzi.soxazolyl,
benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,
dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
30 dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl,
isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
- oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,

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- tetrahydroisoquinolinyl, tetrahydro4uinolinyl, thiazolyl, thienofuryl,
thienothienyl, and thienyl.
As used herein in the definition of R3, R4, R5 and R6a-e,
the term "the substituted group" is intended to mean a substituted C1 8
S alkyl, substituted C2 8 allcenyl, sub.stituted C2 ~ alkynyl, substituted aryl
or substituted heterocycle from which the substituent(s) R3, R4, R5 and
R6a-e are selected.
As used herein in the definition of R7, the substituted Cl
alkyl, substituted C3-6 cycloalkyl, substituted aroyl, substituted aryl,
10 substituted heteroaroyl, substituted arylsulfonyl, substituted heteroaryl-
sulfonyl and substituted heterocycle include moieties containing from 1
to 3 substituents in addition to the point of attachment to the rest of the
compound.
As used herein, when no specific substituents are set forth,
15 the terrns "substituted aryl", "substituted heterocycle" and "substituted
cycloalkyl" are intended to include the cyclic group which is substituted
on a substitutable ring carbon atom with 1 or 2 substitutents selected
from the group which includes but is not limited to F, Cl, Br, CF3,
NH2, N(Cl-C6 alkyl)2~ NO2, CN, (cl-c6 alkyl)O-, -OH, (Cl-C6
20 alkyl)S(O)m-, (Cl-C6 alkyl)C(O)NH-, H2N-C(NH)-, (Cl-C6
alkyl)C(O)-, (Cl-C6 alkyl)OC(O)-, N3,(CI-C6 alkyl)OC(O)NH-,
phenyl, pyridyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thienyl,
furyl, isothiazolyl and Cl-C2o alkyl.
Lines drawn into the ring systems from substituents (such
25 as from R3, R4, Q etc.) means that the indicated bond may be attached
to any of the substitutable ring carbon atoms.
The substituent illustrated by the structure
,~
R6a-e
is a simplifled representation of a phenyl ring having five (5)
30 substituents (hydrogens and/or non-hydrogens) and may also be
represented by the structure

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- 3~ -
R6b
R6a~ R6c
~R6d
R6e
The moiety described as
~5, R6a-e
where any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon
S atoms are combined to form a diradical selected from -CH=CH-CH=CH,
-CH=CH-CH-, -(CH2)4- and -(CH2)4- includes the following
structures:
It is understood that such fused ring moieties may be further substituted
10 by the rem~ining R6a, R6b, R6C~ R6d and/or R6e as defined
hereinabove.
The moiety designated by the following structure
f"f~
~,f
represents an aromatic 6-membered heterocyclic ring and includes the
15 following ring systems:

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N~ N ~- N ~, O~
N~ N~
,~N ~, N~N ~N ,~.,~N~
The moiety designated by the following structure
, f '
~.,~f'
represents an aromatic 6-membered heterocyclic ring and includes the
S following ring systems:
N
~J,\~N~,J N~"N ,~N
O O
N~N N~N HN NH N
~0 ~
wherein it is understood that one of the ring carbon atom.s is substituted
with
~, R6~-e

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- 40 -
Preferably, the aromatic 6-membered heterocyclic ring is a pyridyl
ring.
Preferably, Rl and R2 are independently selected from:
hydrogen, R 1 1 C(0)0-, -N(R 1 ~)2, R 1 OC(O)NR 10 R l Oo or
5 unsubstituted or substituted Cl-c6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl i.s selected from unsubstituted or substituted
phenyl, -N(R 1 ~)2, R l ~O and R 1 OC(O)NR 10
Preferably, R3 is selected from:
a) hydrogen,
b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-,
CN, N02, R 1 ~C(0)- or -N(R 1~)2,
c) unsubstituted Cl-C6 alkyl,
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, unsubstituted or substituted heterocyclic,
C3-Clo cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
R 120, R 1 1 S(O)m-~ R 1 OC(O)NR 10, (R 1 0)2NC(0)-,
R102N-C(NR10)-, CN, RlOC(0)-, N3, -N(R10)2~ and
R 1 1 0C(O)-NR 10
Preferably, R4 is selected from: hydrogen, halogen,
trifluoromethyl, trifluoromethoxy and Cl-C6 alkyl.
Preferably, R5 is hydrogen.
Preferably R6a R6b, R6C, R6d and R6e are independently
selected from:
a) hydrogen,
b) C3-Clo cycloalkyl, halogen, Cl-C6 perfluoroalkyl, R120-,
Rl lS(O)m-, CN, N02, RlOC(0)- or -N(R10)2,
c) unsubstituted Cl-C6 alkyl;
d) substituted Cl-C6 alkyl wherein the substituent on the
substituted Cl-C6 alkyl is selected from unsubstituted or
substituted aryl, C3-C1o cycloalkyl, R120-, Rl lS(O)m-,
- R 1 ~C(0)- or -N(R 1~)2; or

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- 41 -
any two of R6a, R6b, R6C~ R6d and R6e on adjacent carbon atoms are
combined to form a diradical selected from -CH=CH-CH=CH-,
-CH=CH-CH2-, -(CH2)4- and -(CH2)3--
Preferably, R8 is independently .selected from:
S a) hydrogen, and
b) aryl, substituted aryl, heterocycle, substituted heterocycle,
Cl-C6 perfluoroalkyl or CN.
Preferably, R9 is hydrogen, halogen, CF3 or methyl.
Preferably, R10 is selected from H, Cl-C6 alkyl and
1 0 benzyl.
Preferably, A 1 and A2 are independently selected from:
a bond, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10), -S(O)2N(R 10) and-
N(R I ~)S(O)2-.
Preferably, V is selected from hydrogen, heterocycle and
aryl. More preferably, V is phenyl.
Preferably, W is selected from imidazolinyl, imidazolyl,
oxazolyl, pyrazolyl, pyyrolidinyl, thiazolyl and pyridyl. More
preferably, W is selected from imidazolyl and pyridyl.
Preferably, n and r are independently 0, 1, or 2.
Preferably .s is 0.
Preferably t is 1.
Preferably, the moiety
/ \
(18)' Ç~9~\
V - A1(CR12)nA2(CR12)n tW~ - (CR22)p - X -(CR22)p -~-
is selected from:

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- 42 -
R9a R9b
>= N \) N
~ R~b and ~ ~ R~'a
NC NC
It is intended that the definition of any substituent
or variable (e.g., Rl, R2, R9, n, etc.) at a particular location in a
molecule be independent of its definitions elsewhere in that molecule.
5 Thus, -N(R 1 0)2 represents -NHH, -NHCH3, -NHC2Hs, etc. It is
understood that sublstituent,s and substitution patterns on the compounds
of the instant invention can be selected by one of ordinary skill in the
art to provide compounds that are chemically stable and that can be
.synthesized by techniques known in the art, as well as tho.se methods
10 set forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of
thi.s invention include the conventional non-toxic salts of the compounds
of this invention as formed, e.g., from non-toxic inorganic or organic
acids. For example, such conventional non-toxic salts include those
15 derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfamic, phosphoric, nitrlc and the like: and the ~salts prepared
from organic acids such as acetic, propionic, succinic, glycolic, stearic,
lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic,
20 fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,
isethionic, trifluoroacetic and the like.
The pharmaceutically acceptable salts of the compounds
of this invention can be synthesized from the compounds of this
invention which contain a basic moiety by conventional chemical
25 methods. Generally, the salts are prepared either by ion exchange
chromatography or by reacting the free base with stoichiometric
amounts or with an excess of the desired ~salt-forming inorganic or
organic acid in a .suitable ,solvent or variou.s combinations of solvent~s.

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- 43 -
Reactions used to generate the compounds of this invention
are prepared by employing reactions as shown in the Schemes 1-21,
in addition to other standard manipulations such a,s ester hydrolysis,
cleavage of protecting groups, etc., as may be known in the literature
5 or exemplified in the experimental procedures. Substituents R3, R6
and R~, as shown in the Schemes, represent the substituents R3, R4, R5,
R6a, R6b, R6C, R6d, R6e and R~; although only one such R3, R6 or
R8 is present in the intermediates and products of the schemes, it is
understood that the reactions shown are also applicable when such
10 aryl or heteroaryl moieties contain multiple substituents.
These reactions may be employed in a linear sequence
to provide the compounds of the invention or they may be used to
synthesize fragments which are subsequently joined by the alkylation
reactions described in the Schemes. The reactions described in the
15 Scheme.s are illustrative only and are not meant to be limiting. Other
reactions useful in the preparation of heteroaryl moieties are described
in "Comprehensive Organic Chemistry, Volume 4: Heterocyclic
Compounds" ed. P.G. Sammes, Oxford (1979) and references therein.
Aryl-aryl coupling is generally described in "Comprehensive Organic
20 Functional Group Transformations," Katritsky et al. eds., pp 472-473,
Pergamon Press (1995).
SynopsisofSchemes 1-21:
The re~uisite intermediates are in some cases commercially
25 available, or can be prepared according to literature procedures, for
the most part. Schemes 1-12 illustrate synthesis of the instant aryl-
heteroaryl compound which incorporate a preferred benzylimidazolyl
sidechain. Thus, in Scheme 1, for example, a arylheteroaryl inter-
mediate that is not commercially available may be synthesized by
30 methods known in the art. Thus, a suitably substituted phenyl boronic
acid I may be reacted under Suzuki coupling conditions (Pure Appl.
Chem., 63:419 (1991)) with a suitably substituted halogenated nicotinic
acid, such as 4-bromonicotinic acid, to provide the arylheteroaryl
carboxylic acid Il. The acid may be reduced and the triflate of the

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- 44 -
intermediate alcohol III may be formed in situ and coupled to a suitably
substituted benzylimidazolyl IV to provide, after deprotection, the
instant compound V.
Schemes 2-4 illustrate other methods of synthesizing the
5 key alcohol intermediates, which can then be processed as described
in Scheme 1. Thus, Scheme 2 illustrates the analogous series of
arylheteroaryl alcohol forming reactions starting with the methyl
nicotinate boronic acid and the "terminal" phenyl moiety employed
in the Suzuki coupling as the halogenated reactant. Such a coupling
I0 reaction is also compatible when one of the reactant.s incorporates a
suitably protected hydroxyl functionality as illustrated in Scheme 3.
Negishi chemistry (Org. Synth., 66:67 (19~)) may also
be employed to form the arylheteroaryl component of the instant
compounds, as shown in Scheme 4. Thus, a suitably substituted zinc
15 bromide adduct may be coupled to a suitably substituted heteroaryl
halide in the presence of nickel (II) to provide the arylheteroaryl VIl.
The heteroaryl halide and the zinc bromide adduct may be selected
based on the availability of the starting reagents.
Scheme 5 illu.strates the preparation of a suitably substituted
20 biphenylmethyl bromide which could also be utilized in the reaction
with the protected imidazole as described in Scheme 1.
As illustrated in Scheme 6, the sequence of coupling
reactions may be modified such that the aryl-heteroaryl bond i~s formed
last. Thus, a suitably substituted imidazole may first be alkylated with
25 a suitably substituted benzyl halide to provide intermediate VIII.
Intermediate VIII can then undergo Suzuki type coupling to a suitably
substituted phenyl boronic acid.
Scheme 7 illustrates synthesis of an instant compound
wherein a non-hydrogen R9b is incorporated in the instant compound.
30 Thus, a readily available 4-substituted imidazole IX may be selectively
iodinated to provide the 5-iodoimidazole X. That imidazole may then
- be protected and coupled to a suitably substituted benzyl moiety to
provide intermediate XI. Intermediate XI can then undergo the
alkylation reactions that were described hereinabove.

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- 45 -
Scheme 8 illustrates synthesis of instant compounds that
incorporate a preferred imidazolyl moiety connected to the biaryl via
an alkyl amino, sulfonamide or amide linker. Thus, the 4-aminoalkyl-
imidazole XII, wherein the primary amine is protected as the phthali-
mide, is selectively alkylated then deprotected to provide the amine
XIII. The amine XIII may then react under conditions well known in
the art with various activated arylheteroaryl moieties to provide the
instant compounds shown.
Compounds of the instant invention wherein the
A 1 (CR 1 2)nA2(CR I 2)n linker i.s oxygen may be synthesized by
methods known in the art, for example as shown in Scheme 9.
The suitably substituted phenol XIV may be reacted with methyl
N-(cyano)methanimidate to provide the 4-phenoxyimidazole XV.
After selective protection of one of the imidazolyl nitrogens, the
intermediate XVI can undergo alkylation reactions as de.scribed
for the benzylimidazoles hereinabove.
Scheme 10 illustrates an analogous series of reactions
wherein the (CR22)pX(CR22)p linker of the instant compounds is
oxygen. Thus, a suitably sub.stituted halopyridinol, such as 3-chloro-
2-pyridinol, is reacted with methyl N-(cyano)methanimidate to provide
intermediate XVI. Intermediate XVI is then protected and, if desired to
form a compound of a preferred embodiment, alkylated with a suitably
protected benzyl. The intermediate XVII can then be coupled to a aryl
moiety by Suzuki chemistry to provide the instant compound.
Compounds of the instant invention wherein the
A 1 (CR 1 2)nA2(CR 1 2)n linker is a substituted methylene may be
synthesized by the methods shown in Scheme 11. Thus, the N-protected
imidazolyl iodide XVIII is reacted, under Grignard condition~s with a
suitably protected benzaldehyde to provide the alcohol XIX. Acylation,
followed by the alkylation procedure illustrated in the Schemes above
(in particular, Scheme 1) provides the instant compound XX. If other
- R 1 substituents are desired, the acetyl moiety can be manipulated as illustrated in the Scheme.

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- 46 -
Addition of various nucleophiles to an imidazolyl aldehyde
may also be employed to form a substituted alkyl linker between the
biheteroaryl and the preferred W (imidazolyl) as shown in Scheme 12.
Thus an aryllithium can be reacted with pyridine to form the 2-
5 substituted N-lithio-1~2-dihydropyridine XXa. Intermediate XXa
can then react with a aldehyde to provide a suitably substituted instant
compound. Similar substituent manipulation as shown in Scheme
11 may be performed on the fully functionalized compound which
incorporates an R2 hydroxyl moiety.
SCHEME I
~ R6
Nll,Br (HO)2B/~
R2 Pd(PPh3)4
R6
~N~,~ LiAlH4
HObJ~,\~ 2
~ ~1
R2
-

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- 47 -
SCHEME I (continued)
NiCI2(P~h~
R8
R8 IV
~il R6
~N~ (C F3SO2)20, -78~C ~
HO~'\R2 NEtiPr2 -78~C-20~C
CH2CI2
~I N~ R6
R8 1~--R6
~ N~\~
R8/~l V

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- 48 -
SCHEME 2
,B(OH)2 ~--R6
o R2 Pd(PPh ~)4
--R6
~N~ LiAlH4
MeO~,\
o R2
~f3 ,R6
HO~,\
R2

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- 49 -
SCHEME 3
~R6
N~ B(~H)2 ~l~
R3SiO~J~\
\R2 Pd(PPh3)4
~ R6
N ~ ~ Bu4NF
R3SiO~\R2
N~_ - R6
HO~\R2
R SiO~J~,~ (HO)2B
R2 Pd(PPh3)4
~, R6
N ~J Bu4NF
R3SiOJ~'~R2
~J3 R6
HOJ~'\R2

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- 50 -
SCHEME 4
~/ BrZn/~
R3SiOJ~
R2 NiCl2(Pph3)2
N ~ R 6
R3SiO Vll R2
1~--R6
~N
~J~ 2
Zn l "~--R 6
R2 NiCI2(PPh3)2
R6
~N~ Bu4NF
R3SiO,~,\R2
R6
~,N
J~ 2

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SCHEME S
H3C~ 2 LiAlH4 ~J3--R6
~ R6
J~ ~ (HO)2B KMnO4
H3C ~R2 Pd(PPh3)4
N~ R6 LiAlH4
HO2C ~\ 2
R6
HoJ~,\

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- 52 -
SCHEME 6
Tr R2
N~ Br~J~N
~N j;. MeOH
~J reflux
R8/~l
R6
~_~N~ ~ (HO)2B
R8 Vlll
~, R6
~N ~,\,N
J R2
R8

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S C~DE~DE 7
H H
R9b~ Nal, NaHCO3,!2 Rgb~ T , 3
IX X
Tr~ N
R9b~, ~INiCI2(PPh3)2, ~N
R8~\ZnBr v~J
~ 6
Tr~ ~N ~ R
R2
~/ i. -78~C-20~C
~/~ ii. MeOH, reflux
Xl
9b
~I R2
R 8/

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SCHEME
0~
i. ~~Br
<\ ~ ~ 55~C,CH3CN
N N~i. EtOH,80~C, NH2NH2
o
Xll N
N~NH2
R 8 ~ /
Xlll
acylation, sulfonylation </ ~ ~ R2
o;alkylation R8 ~ I HN~/~
N ~" "~ R2 R6
N N ~S~/
N R6
</ 3--N~/
R8 ~J N~
R6

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SCHEME 9
~ OH i, Na, MeOH
NC ~/ ii. 1 20~C
XIV H3C~o
~N--~N
H Tr~
N N
~N TrCI, NEt3 , ~N
NC~ NC~
XV XVI
~ R6
TrN~ 78~C-20~C
ii. MeOH reflux
NC ~ OTf
XVI
<~-- ~ R6
~
NC ~\~

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SCHEME 10
N
~N OH i, Na, MeOH ~ N
Cl~ ii. 120~C q_N\~o
R2 H3C~o Ci~ \J
N~ R2 XVI
R8
~/~
Tr~ ~
N
TrCI. NEt3 . ~ N
N 1~ i -78~C-20~C
~~ ii. MeOH reflux
Cl \~\J
R2 R8 ~B(OH)2
N ~ J~ R6 ~
Cl~ \~O DMF, Pd(PPh3)4
~ K3PO4, 80~C
R2 XVII
R8
N ~ ~
'~;~'~~
R2

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SCHEME 1 1
Tr~
Tr~ ~N~
~N~ EtMgBr ~ N
~_N ~ ~\OH
XVIII R R8 XIX
Tr~ ~ R6
Ac20, PY <~ N HO ~\ 2
~OA (CF3S02)20,-780c
NEtiPr2,CH2cl2
R8
R6
~OAc R2
R8 XX
~\ R .
~OH
- R8

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SCHEME 11 (continued)
R6
~N~J~ ~NH3, MeOH
R2
/J Cl
R8
R6
R2
~J NH2
R8
+
~- R6
~_ N ,~
R2
~/ OMe
R8

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_ 59 _
SCHEME 12
R6
Li
N~
N
¢~ R'
R6
R6
N
~/ OH
/~
R8

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Schemes 13-21 illustrate reactions wherein the moiety
(R8) /~9~
V - A1 (CRl 2)nA2(CR 12)n ~W ,,~ - (CR12)p-X
incorporated in the compounds of the instant invention is represented by
other than a substituted imidazole-cont~ining group.
Thus, the interrnediates whose synthesis are illustrated in
Schemes hereinabove and other arylheteroaryl intermediates obtained
commercially or readily synthesized, can be coupled with a variety of
aldehydes. The aldehydes can be prepared by standard procedures, such
as that described by O. P. Goel, U. Krolls, M. Stier and S. Kesten in
Organic Syntheses, 1988, 67, 69-75, from the appropriate amino acid.
Lithioheteroaryl chemistry may be utilized, a,s shown in Scheme 13,
to incorporate the arylheteroaryl moiety. Thus, a suitably substituted
arylheteroaryl N-lithio reagent is reacted with an aldehyde to provide
the C-alkylated instant compound XXI. Compound XXI can be
deoxygenated by methods known in the art, such as a catalytic
hydrogention, then deprotected with trifluoroacetic acid in methylene
chloride to give the final compound XXII. The final product XXII
may be isolated in the salt form, for example, as a trifluoroacetate,
hydrochloride or acetate salt, among others. The product di~mine
XXII can further be selectively protected to obtain XXIII, which can
subsequently be reductively alkylated with a second aldehyde to obtain
XXIV. I~emoval of the protecting group, and conversion to cyclized
products such as the dihydroimidazole XXV can be accomplished by
literature procedures.
If the arylheteroaryl subunit reagent is reacted with an
aldehyde which also has a protected hydroxyl group, such as XXVI
in Scheme 14, the protecting groups can be subsequently removed to
nm~k the hydroxyl group (Schemes 14, 1~). The alcohol can be
oxidized under standard conditions to e.g. an aldehyde, which can
then be reacted with a variety of organometallic reagents such as

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alkyl lithium reagents, to obtain secondary alcohols such as XXX.
In addition, the fully deprotected amino alcohol XXXI can be
reductively alkylated (under conditions described previously) with
a variety of aldehydes to obtain secondary amines, such a,s XXXII
5 (Scheme lS), or tertiary amines.
The Boc protected amino alcohol XXVIII can also be
utilized to synthesize 2-aziridinylmethylarylheteroaryl such as XXXIII
(Scheme 16). Treating XXVIII with l,l'-sulfonyldiimidazole and
sodium hydride in a solvent such as dimethylformamide led to the
lO formation of aziridine XXXIII . The aziridine is reacted with a
nucleophile, such as a thiol, in the presence of base to yield the ring-
opened product XXXIV .
In addition, the arylheteroaryl subunit reagent can be
reacted with aldehydes derived from amino acids such as O-alkylated
15 tyrosines, according to standard procedures, to obtain compounds such
as XL, as shown in Scheme 17. When R' is an aryl group, XL can first
be hydrogenated to llnm~k the phenol, and the amine group deprotected
with acid to produce XLI. Alternatively, the amine protecting group in
XL can be removed, and O-alkylated phenolic amines such as XLII
20 produced.
Schemes 1P~-21 illustrate syntheses of suitably substituted
aldehydes useful in the syntheses of the instant compounds wherein the
variable W is present as a pyridyl moiety. Similar synthetic strategies
for preparing alkanols that incorporate other heterocyclic moieties for
25 variable W are also well known in the art.

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SCHEME 13
Boc NH
6 Boc NH CHO
R6 1. catalytic
~/ hydrogenation
HO ~ ~ 2. CF3CO2H
Boc NH~
NHBoc
XXI
~ i CH2CI2
NH2 XXII
N~,~R6 CHO
BocN H ~/
\~ NaBH(OAc)3
NH2 Et3N, CICH2CH2CI
XXIII

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SCHEME 13 (continued)
N R6
BocNH~ CF3CO2H, CH2C12,
~=~ NH NaHCO3
~~ XXIV
NH~ ~ NC
NH AgCN
,~, R6
N~N~
~ XXV
~3

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SCHEME 14
~R6 E120
BocNH CHO
XXVI
BnO HO ~=N ~=~ R6 20% Pd(OH)2 H2
C H30H
NHBoc CH3C02H
R2
HO r¦ N /=\~ R CICOCOCI
\_~ DMSO CH2CI2
(c2H5)3N
NHBoc XXVII

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SCHEME 14 (continued)
R2
/~1 ~ R
~~ R'MgX
H NHBoc
XXIX
R2
R'~ R6
NHBoc
XXX

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SCHEME 15
\ ~ CH2CI2
NHBoc
XXVIII
R2
~=¦N /=~R RCHO
HO~ NaBH(OAC)3
NH2 CICH2CH2CI
XXXI
R2
~)~S R6
NH
R'CH2 XXXII

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SCHEME 16
H H
R2 N =\~= N
HO~f ~R6 ~N S \~
NHBoc
XXVIII
R2
,=¦ N ~=, R"SH
, I CH30H
NH
XXXIII
R2
R"S~ R6
NH2
XXXIV

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SCHEME 17
; ~3 1 ) Boc20, K2C03 )~
H2NCO2H2) CH2N2, EtOAc
XXXV XXXVI
HO~,~
LiAlH4 ~,~ R"'CH2X
THF J~ Cs2CO3
0-20~C BocNH CH2OH DMF
XXXVII
R"'CH2~~, R"'CH20
(C
BocNH CH2OH 20~C BocNH CHO
XXXVIII IXL

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SCHEME 17 (continued)
R"'C H~3 ¢~
BocNH CHO R6
IXL / ~ R"' not aryl
Et20 /
2. 20% Pd(OH)2, H2
CH30H, CH3CO2H
3. HCI, EtOAc
R2
~ho~ ~=¦ N /=\~ R6
R"'C H20 \~
NHBoc
2. 20% Pd(OH)2, H2
CH30H, CH3C02H
/~\ R2
2) HCI, EtOAc / ~ ~=¦ N /=\~R
/ R"'CH20
NH2
HO~R6 XLII
NH2 R
XLI
-

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SCHEME 18
~CH3 1) HNO2,Br2 ~CO2CH3
~ 2) KMnO4 r
H2N N 3) MeOH, H+ Br N
R6
~\ MgCI R~,CO2CH3
Zncl2~Nicl2(ph3p)2
NaBH4 (excess) ~ ;CH20H
DM50 ~,CHO

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SCHEME 19
1. EtO(CO)CI R6
2 ~ [~,,COzCH3
N 3. S, xylene, heat N
R6 R6
NaBH4 ~j~ SO3Py, Et3N ~
(excess) ~3,CH20H DMSO ~CHO
Br~,CO CH l~l/\MgCI ¢~
ZnCI2, NiC12(Ph3P)2 N
R6 R6
NaBH4 ~ SO3Py, Et3N ¢~~CH20H ~ ~,CHO
(excess) N DMSO N

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SCHEME 20
C~2C H3
Br~1. LDA, CO2 Br~
N2. MeOH, H+ N
~MgCI ~2CH3
ZnCI2, Nicl2(ph3p)2
N
R6
NaBH4 (excess) ~3OH SO3 Py, Et3N
DMSO
N
R6
CHO
N~

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SCHEME 21
C~2C H3
[~3~ 1 LDA, CO2 ~Br
2. (CH3)3sicHN2
R6 ~\Br R6. 3~
Zn, NiC12(Ph3P)2 N~C02CH3
R6 ~
excess NaBH4 I~J~ SO3 Py, Et3N
N~CH20H DMSO
R6 1~
N ~,CHO

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The instant compounds are useful as pharmaceutical
agents for m~mm~ls, especially for humans. These compounds may
be a~lmini~tered to patients for use in the treatment of cancer. Examples
of the type of cancer which may be treated with the compounds of this
5 invention include, but are not limited to, colorectal carcinoma, exocrine
pancreatic carcinoma, myeloid leukemias and neurological tumors.
Such tumors may arise by mutations in the ras genes themselves,
mutations in the proteins that can regulate Ras activity (i.e.,
neurofibromin (NF-l), neu, scr, abl, Ick, fyn) or by other mechanisms.
The compounds of the instant invention inhibit farnesyl-
protein transferase and the farnesylation of the oncogene protein Ras.
The instant compound.s may also inhibit tumor angiogenesis, thereby
affecting the growth of tumors (J. Rak et al. Cancer Research,
55:4575-4580 (1995)). Such anti-angiogenesis properties of the
instant compounds may also be useful in the treatment of certain
forms of blindness related to retinal vascularization.
The compounds of this invention are also useful for
inhibiting other proliferative diseases, both benign and malignant,
wherein Ras proteins are aberrantly activated as a result of oncogenic
mutation in other genes (i.e., the Ras gene itself is not activated by
mutation to an oncogenic forrn) with said inhibition being accomplished
by the a~lministration of an effective amount of the compounds of the
invention to a m~mmal in need of such treatment. For example, a
component of NF-I is a benign proliferative disorder.
The instant compounds may also be useful in the treatment
of certain viral infections, in particular in the treatment of hepatitis
delta and related viruses (J.S. Glenn et al. Science, 256:1331-1333
(1992).
The compounds of the instant invention are also useful in
the prevention of restenosis after percutaneous transluminal coronary
angioplasty by inhibiting neointimal formation (C. Indolfi et al. Nature
- medicine, 1:541-545(1995).
The instant compounds may also be useful in the treatment
and prevention of polycystic kidney disease (D.L. Schaffner et al.

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- 75 -
Ameri~an Journal of Pathology, 142:1051-1060 (1993) and B. Cowley,
Jr. et al .FASEB Journal, 2:A3 160 ( 19~8)).
The instant compounds may also be useful for the treatment
of fungal infections.
The compounds of this invention may be administered
to m~mmals, preferably humans, either alone or, preferably, in
combination with pharmaceutically acceptable carriers or diluents,
optionally with known adjuvants, such as alum, in a pharmaceutical
composition, according to standard pharmaceutical practice. The
compounds can be ~f~ministered orally or parenterally, including the
intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and
topical routes of administration.
For oral use of a chemotherapeutic compound accord-
ing to this invention, the selected compound may be ~lministered, for
example, in the forrn of tablets or capsules, or as an aqueous solution
or suspension. In the case of tablets for oral use, carriers which are
commonly used include lactose and corn starch, and lubricating
agents, such as magnesium stearate, are commonly added. For oral
administration in capsule form, useful diluents include lactose and dried
corn starch. When aqueous suspensions are required for oral u.se, the
active ingredient is combined with emulsifying and suspending agents.
If desired, certain sweetening and/or flavoring agents may be added.
For intramuscular, intraperitoneal, subcutaneous and intravenous use,
sterile solutions of the active ingredient are usually prepared, and the
pH of the solutions ,should be suitably adjusted and buffered. For
intravenous use, the total concentration of solutes should be controlled
in order to render the preparation isotonic.
The compounds of the instant invention may also be
co-~-lministered with other well known therapeutic agents that are
selected for their particular usefulness against the condition that is
being treated. For example, the instant compounds may be useful in
- combination with known anti-cancer and cytotoxic agents. Similarly,
the instant compounds may be useful in combination with agents that are
effective in the treatment and prevention of NF-l, restinosis, polycystic

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kidney disease, infections of hepatitis delta and related viruses and
fungal infections.
If formulated as a fixed do,se, such combination products
employ the compounds of this invention within the dosage range
5 described below and the other pharmaceutically active agent(s)
within its approved dosage range. Compounds of the instant invention
may alternatively be used sequentially with known pharmaceutically
acceptable agent(s) when a combination formulation is inappropriate.
The present invention also encompasses a pharmaceutical
10 composition useful in the treatment of cancer, comprising the
administration of a therapeutically effective amount of the compound.s
of this invention, with or without pharmaceutically acceptable carriers
or diluents. Suitable compositions of this invention include a(lueous
solutions comprising compounds of this invention and pharmacolo-
15 gically acceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions may be introduced into a patient's blood-stream by local
bolus injection.
As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the specific
20 amounts, as well as any product which result.s, directly or indirectly,
from combination of the specific ingredients in the specified amounts.
When a compound according to this invention is
a~lministered into a human subject, the daily dosage will normally be
determined by the prescribing physician with the dosage generally
25 varying according to the age, weight, and response of the individual
patient, as well a.s the severity of the patient's symptoms.
In one exemplary application, a suitable amount of
compound is ~dministered to a m~mm~l undergoing treatment for
cancer. A-lmini.stration occurs in an amount between about O.l mg/kg
30 of body weight to about 60 mg/kg of body weight per day, preferably
of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight
- per day.
The compounds of the instant invention are also useful
as a component in an assay to rapidly determine the presence and

CA 02249607 1998-09-23
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quantity of farnesyl-protein transferase (FPTase) in a composition.
Thus the composition to be tested may be divided and the two
portions contacted with mixtures which comprise a known substrate
of FPTase (for example a tetrapeptide having a cysteine at the amine
5 terminus) and farnesyl pyrophosphate and, in one of the mixtures,
a compound of the instant invention. After the assay mixtures are
incubated for an sufficient period of time, well known in the art, to
allow the FPTase to farnesylate the substrate, the chemical content
of the assay mixtures may be determined by well known
10 immunological, radiochemical or chromatographic techniques.
Because the compounds of the instant invention are selective
inhibitors of FPTase, absence or quantitative reduction of the amount
of substrate in the assay mixture without the compound of the instant
invention relative to the presence of the unchanged substrate in the
15 assay containing the instant compound is indicative of the presence
of FPTase in the composition to be tested.
It would be readily apparent to one of ordinary skill in the
art that such an assay as described above would be useful in identifying
tissue samples which contain farnesyl-protein transferase and quanti-
20 tating the enzyme. Thus, potent inhibitor compounds of the instantinvention may be used in an active site titration assay to determine the
quantity of enzyme in the sample. A series of samples composed of
aliquots of a tissue extract containing an unknown amount of farnesyl-
protein transferase, an excess amount of a known substrate of FPTase
25 (for example a tetrapeptide having a cysteine at the amine terminus) and
farnesyl pyrophosphate are incubated for an appropriate period of time
in the presence of varying concentrations of a compound of the instant
invention. The concentration of a sufficiently potent inhibitor (i.e., one
that has a Ki substantially smaller than the concentration of enzyme in
30 the assay vessel) required to inhibit the enzymatic activity of the sample
by 50% is approximately equal to half of the concentration of the
enzyme in that particular sample.

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EXAMPLES
Examples provided are intended to assist in a further
understanding of the illvention. Particular material~s employed, species
and conditions are intended to be further illustrative of the invention
and not limitative of the reasonable scope thereof.
EXAMPLE 1
1 -(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
Step A: l -Trityl-4-(4-cyanobenzyl)-imidazole
To a ~suspension of activated zinc du.st (3.57g, 54.98
mmol) in THF (50 mL) was added dibromoethane (0.315 mL, 3.60
mmol) and the reaction stirred under argon at 20~C. The suspension
was cooled to 0~C and a-bromo-p-tolunitrile (9.33g, 47.6 mmol)
in THF (100 mL) was added dropwise over a period of 10 minutes.
The reaction was then allowed to stir at 20~C for 6 hours and
bis(triphenylphosphine)Nickel II chloride (2.4g, 3.64 mmol) and
4-iodo-1-tritylimidazole (15.95g, 36.6 mmol, S. V. Ley, et al.,
J. Org. Chem. 56, 5739 (1991)) were added in one portion.The
resulting mixture was stirred 16 hours at 20~C and then quenched by
addition of sat. a4. NH4CI solution (100 mL) and the mixture stirred
for 2 hours. Saturated aq. NaHCO3 solution w;~ added to give a pH
of ~ and the solution was extracted with EtOAc (2 x 250 mL), dried,
(MgSO4) and the solvent evaporated in vacuo. The residue was
chromatographed (Silica gel, 0-20% EtOAc in CH2C12 to afford the
title compound as a white solid.
lH NMR (CDC13, 400MHz) ~ 7.54 (2H, d, J=7.9Hz), 7.3~(1H, s),
7.36-7.29 (1 lH, m), 7.15-7.09(6H, m), 6.5~(1H, s), and 3.93(2H,
s)ppm.

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Step B: 2-Phenyl-5-methylpyridine
A mixture of 2-bromo-5-methylpyridine (2.00 g, 11.63
mmol), phenylboronic acid (1.56 g, 12.79 mmol), barium hydroxide
(5.50g, 17.4 mmol), DME (80 mL) and water (15 mL) was purged
with dry argon. Tetrakis(triphenylphosphine)palladium(0) (672
mg, 0.5~ mmol) was added, and the resultant solution was stirred
at 80~C for 4 hours. The solvents were evaporated in vacuo, and the
residue partitioned between EtOAc and water and acidified with 1 M
a4. HCI. The aqueous extract was separated, and extracted with
EtOAc. The organic extracts were combined, washed with NaHCO3
and 5~o aq. Na2S203, dried (Na2S04), filtered and the solvent
evaporated in vacuo. The residue was purified by chromatography
(Silica gel, CH2C12) to afford the title compound.
IH NMR (CDC13, 400MHz) ~ ~.52 (lH, s), 7.96(2H, d, J=7.0Hz),
7.63(1H, d, J=8.0Hz), 7.55(1H, brd, J=~.OHz), 7.50-7.35(3H, m),
and 2.37(3H, s) ppm.
Step C: 2-Phenyl-5-carboxypyridine
A suspension of 2-phenyl-5-methyl pyridine (1.03g,
6.09 mmol) and potassium permanganate (2.~9g, 1 ~.3 mmol), in
water (25 mL) was heated at reflux for 2 hours. The reaction was
allowed to cool to ambient temperature and filtered throu~h celite
to remove the solids. Acetic acid (I mL) was added to the colourles.s
filtrate and the product was collected as a white solid by filtration.
1 H NMR (CD30D, 400MHz) ~ 9.1 ~(1 H, s), ~ .41 (1 H, dd, 2.2 and
8.2Hz), ~.0~-~.02(2H, m), 7.97(1H, dd,3=~.2 and 0.7Hz) and 7.56-
7.46(3H, m) ppm.
Step D: 2-Phenyl-5-hydroxymethylpyridine
To a solution of 2-phenyl-5-carboxypyridine (520 mg,
2.61 mmol) in tetrahydrofuran (10 mL) at 0~C was added 1.0 M
- lithium aluminum hydride in tetrahydrofuran (2.61 mL, 2.61 mmol)
over 10 minutes. The reaction was allowed to stir at ambient
temperature for 16 hours, cooled to 0~C, and quenched by dropwise

CA 02249607 1998-09-23
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- 80-
addition of water (0.20 mL), 4 N aq. NaOH (0.20 mL), and water
(0.60 mL). The reaction was filtered through a pad of Celite and
the filtrate evaporated in vacuo. The residue was chromatographed
(silica gel, 0-5% MeOH in CH2C12) to afford the title compound.
1H NMR (CDC13, 400MHz) ~ 8.66(1H, s), 7.97(2H, d, J=7.9Hz),
7.82-7.70(2H, m), 7.52-7.38(3H, m), 4.77(2H, s) and 1.89(1H, brs)
ppm.
Step E: 1-(2-Phenylpyrid-5-ylmethyl)-5-(4-cyanobenzyl)
imidazole hydrochloride salt
To a solution of 2-phenyl-5-hydroxymethylpyridine
(264 mg, 1.43 mmol) and diisopropylethylamine (0.522 mL, 3.00
mmol) in dichloromethane (10 mL) at -78~C was added trifluoro-
methanesulfonic anhydride (0.252 mL, 1.50 mmol) and the mixture
stirred at -78~C for 15 minutes. To this mixture wa,s added a
solution of l-trityl-4-(4-cyanobenzyl)imidazole (608 mg, 1.43
mmol) in dichloromethane (9 mL). The mixture was allowed to
warm to ambient temperature and stirred for 16 hour~. The solvent
was evaporated in vacuo. The residue was dissolved in methanol
(15 mL), heated at reflux for 1 hour, and the solvent evaporated
in vacuo. The residue was partitioned between dichloromethane
and sat. aq. NaHCO3 solution. The organic layer was dried,
(Na2SO4) and the solvent evaporated in vacuo. The residue
was chromatographed (Silica gel, 0-5% NH40H in CH2C12). The
amine was converted to the HCI salt by treatment with 1.0M HCI
in aqueous acetonitri~e. Evaporation of the solvent in vacuo
afforded the title compound as a white solid.
FAB MS 351 (MH+)
lH NMR (CD30D, 400MHz) ~ 8.38(1H, d, J=2.4Hz),7.97(2H, m),
7.64(1H, d, J=8.2Hz), 7.60(1H, s), 7.56-7.40(5H, m), 7.28-7.20(1H,
m), 7.17(2H, d, J=8.0Hz), 6.97(1H, s), 4.96(2H, s) and 3.89(2H, Is)
ppm.
EXAMPLE 2

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1 -(2-Phenyl-N-Oxopyrid-5-ylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
l -(2-Phenylpyrid-5-ylmethyl)-5 -(4-cyanobenzyl)
5 imidazole hydochloride (66.7mg, 0.159 mmol) was partitioned
between CH2CI2 (lmL) and sat. aq. Na2CO3 (1 mL). The organic
layer was separated, dried, (MgSO4) and the solvent evaporated
in vacuo. The residue was dissolved in CH2Cl2 (2 mL), 3-chloro-
perbenzoic acid (109 mg, 0.506 mmol) was added and the solution
10 stirred at ambiant temperature for 16 hours. The reaction was
partitioned between CH2Cl2 (5mL) and sat. aq. Na2CO3 (2mL)
and the organic layer separated, dried, (MgSO4) and the solvent
evaporated in vacuo. The residue was chromatographed (Silica gel
4-10% MeOH in CH2CI2). The amine wa,s converted to the HCI salt
15 by treatment with 1.0M HCl in aqueous acetonitrile. Evaporation
of the solvent in vacuo afforded the title compound as a white solid.
lH NMR (CD30D, 400MHz) ~ 9.18(1H, s), 8.13(1H,s), 7.80-
7.20(12H,m), 5.53(2H,s) and 4.28(2H,s) ppm.
EXAMPLE 3
1 -(3 -Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
25 Step A: 3-Phenyl-6-carboxypyridine
A suspension of 3-phenyl-6-methyl pyridine (1.99g,
11.7~ mmol) and potassium permanganate (7.65, 48.6 mmol), in
water (50 mL) was heated at reflux for 16 hours. The reaction was
allowed to cool to ambient temperature and filtered through celite
30 to remove the solids. Acetic acid (2 mL) was added to the colourlesls
filtrate and the product was collected as a white solid by filtration.
1H NMR (CD30D, 400MHz) ~ 8.86(1H, s), 8.15(2H,m),
7.70(2H,d, J=6.7Hz) and 7.60-7.30(3H,m) ppm.
35 Step B: 3-Phenyl-6-hydroxymethylpyridine

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To a solution of 3-phenyl-6-carboxypyridine (l.OSg,
5.27 mmol) in tetrahydrofuran (25 mL) at 0~C was added 1.0 M
lithium aluminum hydride in tetrahydrofuran (10.0 mL, 10.0 mmol)
over 10 minutes. The reaction was allowed to stir at ambient
5 temperature for 6 hours, cooled to 0~C, and quenched by dropwise
addition of water (0.50 mL), 4 N aq. NaOH (0.50 mL), and water
(1.5 mL). The reaction was filtered through a pad of Celite and the
filtrate evaporated in vacuo. The residue wa.s chromatographed
(silica gel, 0-5% MeOH in CH2CI2) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ ~.79(1H, d, J=l.OHz), 7.~s~s(1H,
dd, J=~.6 and l.SHz), 7.5~(2H,d, J=6.7Hz), 7.49(2H,t, J=7.0Hz),
7.41(1H,t, J=7.0Hz), 7.33(1H,d, J=7.6Hz), 4.83(2H,s) and
3.75(1 H,brs) ppm.
~5 Step C: 1-(3-Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)
imidazole hydrochloride.salt
To a solution of 3-phenyl-6-hydroxymethylpyridine
(192 mg, 1.04 mmol) and diisopropylethylamine (0.360 mL, 2.07
mmol) in dichloromethane (8 mL) at -7~~C was added trifluoro-
20 methanesulfonic anhydride (0.1 ~0 mL, 1.07 mmol) and the mixturestirred at -78~C for 1 hour. To this mixture wa~s added a solution
of 1-trityl-4-(4-cyanobenzyl)imidazole (441 mg, 1.04 mmol) in
dichloromethane (9 mL). The mixture was allowed to warm to
ambient temperature and stirred for 4 hour.s. The solvent was
25 evaporated in vacuo. The residue was dissolved in methanol (10
mL), heated at reflux for 1 hour, and the solvent evaporated in
vacuo. The residue was partitioned between dichloromethane and
sat. aq. NaHCO3 solution. The organic layer was dried, (Na2SO4)
and the solvent evaporated in vacuo. The residue was chroma-
30 tographed (Silica gel, EtOAc and then 5% MeOH in CH2C12). Theamine was converted to the HCI salt by treatment with 1.0M HCI in
- aqueous acetonitrile. Evaporation of the solvent in vacuo afforded
the title compound as a white solid.

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FAB HRMS exact mass calcd for C23H19N4 351.160972 (MH+);
found 351.161206.
1 H NMR (CD30D, 400MHz) ~ 9.20(1 H, d, J= 1.4Hz), 8.75(1 H, d,
J=2.2Hz), 8.16(1H, d, J=8.20), 7.66 (2H, d, J=8.4Hz), 7.60-7.40(7H,
5 m), 7.26(2H, d, J=8.0Hz), 5.73(2H, s) and 4.27(2H, s) ppm.
Anal. Calcd. for C23Hl~N4-2.00 HCI 0.80 H2O:
C, 63.11; H,4.97; N, 12.80.
Found: C, 63.10; H, 4.97; N, 12.95.
EXAMPLE 4
1 -(3 -Phenyl-N-Oxopyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
1 -(3 -Phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)
15 imidazole hydochloride (100.Omg, 0.236mmol) was partitioned
between CH2CI2 (2mL) and sat. aq. Na2CO3 (lmL). The organic layer
was separated, dried, (MgSO4) and the solvent evaporated in vacuo.
The residue was dissolved in CH2CI2 (2 mL), 3-chloroperbenzoic
acid (143mg, 0.472 mmol) was added and the solution .stirred at
20 ambient temperature for 16 hours. The reaction was partitioned
between CH2Ck (SmL) and sat. a4. Na2CO3 (2mL) and the organic
layer separated, dried, (MgSO4) and the solvent evaporated in vacuo.
The residue was chromatographed (Silica gel 4-10% MeOH in
CH2CkThe amine wa,s converted to the HCl salt by treatment with
25 1.0M HCI in aqueous acetonitrile. Evaporation of the solvent in
vacuo afforded the title compound as a white solid.
lH NMR free base (CDC13, 400MHz) ~ 8.44(1H, d, J=l.SHz),
7.63(1H,s), 7.60-7.20(10H,m), 7.03(1H,s), 6.35(1H,d, J=~.2Hz),
5.29(2H,s) and 3.96(2~,s) ppm.
EXAMPLE S
1 -(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-5-(4-
cyanobenzyl)imidazole hydrochloride salt

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Step A: 2-(3-Trifluoromethoxyphenyl)-S-methylpyridine
To a solution of 3-bromotrifluoromethoxybenzene
(0.590mL, 4.00 mmol) in THF (12 mL) at -7~~C was added t-butyl
5 lithium (4.71mL, of a 1.7M solution in pentane, ~.00 mmol. After
10 minutes zinc chloride(4.0mL, of a IM solution in diethylether,
4.00 mmol) wa,s added. The reaction was stirred for 10 minutes at
-78~C and then allowed to warrn to 0~C and stirred for 30minutes.
This solution was added via cannula to a solution of 2-bromo-5-
10 methyl pyridine and bis(triphenylphosphine) Nickel II chloride. The
reaction stirred for I hour at 0~C and then at ambient temperature
for a furthur 1 hour. Saturated ammonium hydroxide ,solution (3
mL) was added and the mixture stirred until homogenous, extracted
with Et20 and the organic extracts washed with saturated brine,
15 dried (MgSO4) and evaporated in vacuo. The residue was
chromato~raphed (Silica gel, 25-50% CH2CI2 in hexanes).
lH NMR (CD30D, 400MHz) a ~.4~S(1H~ s),7.93(1H, brd, J=8.0Hz),
7.~7(1H, s), 7.79(2H, d, J=8.0Hz), 7.74(2H, d, J=~.OHz), 7.56(1H,
t, J=8.0Hz), 7.32(1H, brd, J=~.OHz) and 2.40(3H, s) ppm.
Step B: 2-(3 -Trifluoromethoxyphenyl )-5-carboxy pyridine
A solution of 2-(3-Trifluoromethoxyphenyl)-5-
methylpyridine (2.35g, 2.22 mmol) and tetrabutylammonium
permanganate (1.904, 0.012mol), in pyridine (8 mL) was heated
25 at 75~C for 16 hours. The cooled reaction was filtered through celite
to remove the solids. The solid was washed with EtOAc and MeOH
and the filtrate evaporated in vacuo to afford the title compound of
sufficient purity to be used in the next step.
30 Step C: 2-(3-Trifluoromethoxyphenyl)-5-
hydroxymethylpyridine
- To a solution of 2-(3-trifluoromethoxyphenyl)-5-
carboxy pyridine (2.0 g, 7.06 mmol) in tetrahydrofuran (15 mL) at
0~C was added 1.0 M lithium aluminum hydride in tetrahydrofuran

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(7.07 mL, 7.07 mmol) over 10 minutes. The reaction was allowed
to stir at ambient temperature for 4 hours, cooled to 0~C, and
quenched by dropwise addition of saturated Na2SO4 (1.0 mL). The
reaction was diluted with diethylether, filtered through a pad of
5 Celite and the filtrate evaporated in vacuo. The residue was
chromatographed (silica gel, 50% EtOAc in hexane,s) to afford the
title compound.
1 H NMR (CD30D, 400MHz) ~ 8.62(1 H, d, J= I .OHz), 8.00-
7.84(H,m), 7.57(1H, t, J=8.0Hz), 7.33(1H,brd, J=8.0Hz) and
10 4.~4(2H,s) ppm.
Step D: 1-(2-(3-Trifluoromethoxyphenyl)-pyrid-5-ylmethyl)-
5-(4-cyanobenzyl)imidazole hydrochloride salt
To a solution of 2-(3-trifluoromethoxyphenyl)-5-
15 hydroxymethylpyridine (66 mg, 0.25 mmol), diisopropylethylamine
(0.085 mL, 0.49 mmol), and 1-trityl-4-(4-cyanobenzyl)imidazole
(105 mg, 0.25 mmol) in dichloromethane (1.4 mL) at -7~~C was
added trifluoromethanesulfonic anhydride (0.041 mL, 0.25 mmol)
and the mixture stirred at -7~~C for 1 hour. The reaction wa.s
20 allowed to warm to ambient temperature and stirred for 4 hours.
The solvent was evaporated in vacuo. The re,sidue wa~s dissolved
in methanol (15 mL), heated at reflux for 1 hour, and the solvent
evaporated in vacuo. The residue was partitioned between dichloro-
methane and sat. aq. Na2CO3 solution. The organic layer was dried,
2~S (Na2SO4) and the solvent evaporated in vacuo. The residue wa.s
chromatographed (Silica gel, 3% MeOH in CH2Ck). The amine
was converted to the HCI salt by treatment with 1.0M HCI in
aqueous acetonitrile. Evaporation of the solvent in vacuo afforded
the title compound as a white solid.
IH NMR (CD30D, 400MHz) ~ 9.23(1H, s), 8.67(1H,s), ~.18-
- 8.04(2H, m), 8.00-7.90(2H,m), 7.74(1H, t, J=7.9Hz), 7.62-7.50(4H,
m), 7.31(2H, d, J=7.9Hz), 5.71(2H, s), 4.29(2H, .s) ppm.

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FAB HRMS exact mass calcd for C24HlsN4 OF3 435.143271 (MH+);
found 435.144474.
Anal. Calcd. for C24HI7N4 OF3 -2.00 HCI:
C, 56.82; H, 3.77; N, 11.04.
Found: C, 56.50; H, 3.88; N, 10.86.
EXAMPLE 6
1 -(2-(2-Trifluoromethylphenyl)-pyrid-S-ylmethyl)-5-(4-
cyanobenzyl)imidazole hydrochloride salt
Step A: 2-(2-Trifluoromethylphenyl)-5-methylpyridine
To a solution of 2 bromo-5-methyl pyridine
(1.81g, 10.53 mmol) and barium hydroxide (4.97 g, 15.7~ mmol)
in water (15 mL) was added DME (80 mL). This mixture was
treated sequentially with 2-(trifluoromethyl)phenylboronic acid
(2.00g, 10.53 mmol) and palladium tetrakis(triphenylphosphine)
(553 mg, 0.48 mmol) and the mixture warmed to 80~C for 4~ hours.
Water (lOOmL) was added and the pH of the solution was adjusted
to 10 and extracted with EtOAc (3X200mL).
The organic extracts were combined, washed with brine,
dried (MgSO4), and the solvent evaporated in vacuo. The residue
was chromatographed (Silica gel,50% -100% CH2Ck in hexanes) to
afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.52(1H, s), 7.75(1H, d, J=7.9Hz),
7.64-7.44(4H, m), 7.32(1H, d, J=7.9Hz) and 2.40(3H,s) ppm.
Step B. 2-(2-Trifluoromethylphenvl)-;S-carboxypyridine
A suspension of 2-(2-Trifluoromethylphenyl)-5-
methylpyridine (0.40g, 1.6~ mmol) and potassium permanganate
(1.60g, 10.1 mmol), in water (10 m~) was heated at reflux for 16
- hours. The reaction was filtered hot through celite to remove the
solids. Acetic acid was added to the colourless filtrate to yield a pH
of S and the resulting suspension was extracted with CH2Ck.washed

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with water (10 mL), dried, (MgSO4), and the solvent evaporated in
vacuo to afford the title compound.
1 H NMR (CD30D, 400MHz) ~ 9.34(1 H, s), 8.41 ( I H,d, J=8.2Hz),
7.80(1H,d, J=7.9Hz) and 7.70-7.50(4H,m) ppm.
s
Step C: 2-(2-Trifluoromethylphenyl)-5-hydroxymethvlpyridine
To a solution of 2-(2-Trifluoromethylphenyl)-
5-carboxypyridine (220 mg, 1.23 mmol) in tetrahydrofuran
(10 mL) at 0~C was added 1.0 M lithium aluminum hydride in
tetrahydrofuran (1.23 mL, 1.23 mmol) over 10 minutes. The
reaction was allowed to stir at ambient temperature for 16 hours,
cooled to 0~C, and quenched by dropwise addition of water (0.05
mL), 2.5 N aq. NaOH (0.05 mL), and water (0.15 mL). Sodium
sulfate wa.s added, the reaction filtered through a pad of Celite and
the filtrate evaporated in vacuo. The residue was chromatographed
(silica gel, CH2CI2 then EtOAc) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.63(1H, s), 7.80-7.40(6H,m) and
4.77(2H, s) ppm.
Step D: 1-(2-(2-Trifluoromethylphenyl)-pyrid-5-ylmethyl)-
5-(4-cyanobenzyl)imidazole hydrochloride salt
The title compound was prepared using the procedure
described for Example 5, step D using 2-(2-trifluoromethylphenyl)
-5-hydroxymethylpyridine from Step C in place of 2-(3-trifluoro-
methoxyphenyl)-5-hydroxymethylpyridine.
1 H NMR (CD30D, 400MHz) â 9.17(1 H, s), 8.42(1 H,s), 8.00-
7.40(1 lH, m), 5.60(2H, s), 4.26(2H, s) ppm.
FAB MS 419 (MH+)
Anal. Calcd. for C24HI7N4 F3 -2.95 HCI. 0.6 EtOAc:
C, 54.78; H, 4.31; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
EXAMPLE 7

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1 -(3 -Phenyl-2-Chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
Step A: 3-Phenyl-6-methylpyridine N-oxide
A solution of 3-phenyl-6-methyl pyridine (2.36g, 13.95
mmol), in CH2Cl2 (40 mL) at 0~C was treated with MCPBA (3.58g,
13.95 mmol) for 1 hour. Saturated aq. Na2CO3 (50 mL) was added
and the reaction was extracted with CH2CI2 (20 mL). The organic
extracts were dried (MgSO4), and the solvent evaporated in vacuo
to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 8.53(1H, s), 7.60-7.20(7H, m) and
2.57(3H, s) ppm.
Step B: 3-Phenyl-2-chloro-6-methylpyridine and 3-phenyl-4-
1 5 chloro-6-methvlpyridine
A solution of 3-phenyl-6-methyl pyridine-N-Oxide
(1.42g, 7.66 mmol), in P2Os (50 mL) at 0~C was at 80~C for 3
hours. The reaction was allowed to cool to room temperature and
then poured over ice (400g). Saturated aq. Na2CO~ wa.s added until
the pH of the solution wa,~ 8 and the reaction was extracted with
CH2Ck (3X250 mL). The organic extracts were ~ried (MgSO4), and
the solvent evaporated in vacuo. The re,sidue was chromatographed
(silica gel, 10-20~o EtOAc in CH2CI2 to afford 3-Phenyl-2-chloro-
6-methylpyridine (First eluted)
lH NMR (CDC13, 400MHz) ~ 7.56(1H, d, J=7.6Hz), 7.60-
7.30(5H,m), 7.15(1H,d, J=7.6Hz) and 2.59(3H, s) ppm.
3-Phenyl-4-chloro-6-methylpyridine (Second eluted).
IH NMR (CDC13, 400MHz) ~ 8.43(1H, ,s), 7.60-7.40(5H,m~,
7.29(1H,s) and 2.59(3H, s) ppm.
Step C: 3-Phenyl-2-chloro-6-bromomethylpyridine
- A ~olution of 3-Phenyl-2-chloro-6-methylpyridine
(0.094g, 0.462 mmol), NBS (0.086g, 0.485 mmol) and AIBN
(0.008g, 0.046mmol) in CCl4 (3 mL) were heated at reflux for

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2 hours. The solvent was evaporated and the residue chroma-
tographed(Silica gel, 100% CH2CI2 to afford the title compound.
1}~ NMR (CDC13, 400MHz) ~ 7.68(1H, d, J=7.6Hz), 7.60-
7.40(6H,m), and 4.56(2H, s) ppm.
Step D: 1-(3-Phenyl-2-chloropyrid-6-ylmethyl)-5-(4-
cyanobenzyl)imidazole hydrochloride salt
To l-trityl-4-(4-Cyanobenzyl)-imidazole (88.4mg,
0.208 mmol) in acetonitrile (1 mL) was added 3-phenyl-2-chloro-
6-bromomethylpyridine (53.5mg, 0.189 mmol) and the mixture
heated at 65~C for 16 hours. The re~idue was dissolved in methanol
(3 ml) and heated at reflux for 2 hours, cooled and evaporated
to dryness. The re.sidue was partitioned between sat. aq. Na2CO~
solution and CH2Cl2. The organic layer was dried, (MgSO4) and
the solvent evaporated in vacuo. The residue was chromatographed
(Silica gel, 2.5-3% MeOH in CH2CI2) to afford the free ba.se which
was converted to the HCI salt by treatment with one equivalent of
HCI in aqueous acetonitrile. Evaporation of solvent in vacuo
afforded the title compound as a white powder.
1 H NMR (CD30D, 400MHz) ~ 9.1 1 ( 1 H, ~), 7.64(1 H.d, J=7.7Hz),
7.55(2H,d, ~=8.2Hz), 7.51(1H,s), 7.50-7.34(5H,m), 7.32-7.20(3H,
m), 5.56(2H, s), 4.27(2H, s) ppm.
Anal. Calcd. for C23HI7CIN4 1.00 HCI. 0.6 EtOAc:
C, 54.78; H, 4.31; N, 9.68.
Found: C, 54.79; H, 4.18; N, 9.68.
EXAMPLE 8
1 -(3-Phenyl-4-chloropyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
- The title compound was prepared using the procedure described for Example 7, steps C and D using 3-phenyl-4-chloro-6-methylpyridine
in place of 3-phenyl-6-methyl pyridine.

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Anal. Calcd. for C24HI7N4 Cl l.OO HCI. 0.30 H20:
C,64.74; H,4.39; N, 13.13.
Found: C, 64.~2; H, 4.52; N, 12.93.
EXAMPLE 9
1 -(2-Amino-3 -phenylpyrid-6-ylmethyl)-5-(4-cyanobenzyl)imidazole
hydrochloride salt
Step A: 2-Amino-3-Phenyl-6-methylpyridine
A solution of 3-phenyl-6-methyl pyridine
(0.815 g, 4.82 mrnol), and sodium amide (752mg, 19.3mmol)
in diethylaniline (lOmL) was heated at 1~0~C for 72 hours. The
reaction was cooled and quenched with ice (lOOg), and the mixture
extracted with EtOAc. The organic extract was washed with brine
15 (50 mL), dried (MgSO4), silica gel (lOOg) was added and the
,solvent evaporated in vacuo.
The material was loaded onto a column and chromatographed
(Silica gel, eluting with 0-100% EtOAc in CH2Ck) to afford the
title compound.
20 lH NMR (CDC13, 400MHz) o 7.50-7.20(6H, m) 6.61(1H,d,
~=7.0Hz), and 2.42(3H, s) ppm.

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Step B: N-bis t-Butoxycarbonyl-2-Amino-3-Phenyl-6-
methylpyridine
A solution of 2-amino-3-phenyl-6-methyl pyridine (1.21
g, 6.57 mmol), di t-butylcarbonate(3.58g, 16.4 mmol), triethylamine
5 (2.29 mL, 16.4 mrnol) and DMAP (0.803g, 6.57 mmol) in CH2C12
(20mL) were heated at 65~C for 16 hours. The reactionwas diluted
with sat. aq. Na2CO3 and extracted with CH2Cl2 The solvent was
evaporated in vacuo. and the residue chromatographed (Silica gel,
eluting with 20% EtOAc in CH2CI2) to afford the title compound.
lH NMR (CDC13, 400MHz) ~ 7.62(1H, d, J=7.7H~), 7.41-7.30(5H,
m), 7.19(1H, d, J=7.7Hz), 2.59(3H, s) and 1.2X(18H, s) ppm.
Step C: 2-(bis t-butoxycarbonylamino)-3-phenyl-6-
methylpvridine-N-oxide
A solution of N-bis t-butoxycarbonyl-2-amino-3-phenyl-
6-methylpyridine (0.215g, 0.56 mmol), in CH2CI2 (4 mL) at 0~C was
treated with MCPBA (0.220g, 0.727 mmol) for 1 hour. Saturated
aq. Na2CO3 (50 mL) was added and the reaction was extracted with
CH2CI2 (2X50 mL). The organic extracts were dried (MgSO4), and
20 the solvent evaporated in vacuo. The residue was chromatographed
(Silica gel, eluting with 100% EtOAc to afford the title compound.
1H NMR (CDC13, 400MHz) ~ 7.44-7.36(6H,m), 7.13(1H, d,
J=7.7Hz), 2.56(3H, s) and 1.31(1~H, s) ppm.
~5 StepD: N-bis t-Butoxycarbonyl-2-amino-3-phenyl-6-
acetoxymethylpyridine
A solution of 2-(bis t-butoxycarbonylamino)-3-phenyl-
6-methylpyridine-N-oxide (0.223g, 0.557 mmol), in acetic anhydride
(5 mL) was heated at 65~C for 24 hours. The solvent was evaporated
30 in vacuo and the residue chromatographed (30-50%EtOAc in
hexanes) to afford the title compound.
- lH NMR (CDC13, 400MHz) ~ 7.74(1H, d, J=7.7Hz), 7.50-7.30(6H,
m), 5.25(2H, s), 2.17(3H, s) and 1.28(18H, s) ppm.

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Step E: N-bis t-Butoxycarbonyl-2-amino-3-phenyl-6-
hydroxymethylpyridine
A solution of 2-(bis t-butoxycarbonylamino)-3-phenyl-
6-acetoxymethylpyridine (0.040g, 0.09 mmol), THF (1.3 mL) was
S treated with Lithium hydroxide (lM solution in water 0.271 ml,
0.271 mmol) at room temperature for 16 hours. The reaction was
diluted with water and extracted with CH2Cl2. The organic extracts
were dried (MgSO4),and the solvent evaporated in vacuo to afford
the title compound.
lH NMR (CDC13, 400MHz) â 7.74(1H, d, J=7.P~ Hz), 7.44-7.33(5H,
m), 7.31(1H,brd, J=7.8Hz), 4.~1(2H, s), and 1.29(18H, s) ppm.
Step F: 1 -(2-Amino-3-phenylpyrid-6-ylmethyl)-5-(4-
cyanobenzyl)imidazole hydrochloride salt
The title compound was prepared using the procedure described for
Example 3 ,step C using N-bis t-butoxycarbonyl-2-amino-3-phenyl-
6-hydroxymethylpyridine in place of 3-phenyl-6-hydroxymethyl-
pyridine. In this case the free base was treated with TFA and
triethylsilane to effect cleavage of the t-butoxycarbonyl groups
which was followed by its conversion to the hydrochloride salt.
lH NMR (CD30D, 400MHz) ~ 9.23(1H, s), 7.80-7.20(H, m),
6.96(1H,s), 6.65(1H,d, J=7.6Hz), 5.66(2H, s), 4.33(2H, s) ppm.
Anal. Calcd. for C2~HIsN~ 1.00 HCI. 0.95 H20 0.35 EtOAc:
C, 60.26; H, 5.33; N, 14.40.
Found: C, 60.04; H, 5.10; N, 14.45.
EXAMPLE 10
ln vitro inhibition of ras farnesyl transferase
Assays offarnesyl-protein transferase. Partially
purified bovine FPTase and Ras peptides (Ras-CVLS, Ras-CVIM
and Ras-CAIL) were prepared as described by Schaber et al., J. Biol.
Chem. 265: 14701 -14704 (1990), Pompliano, et al., Biochemistry
31:3~00 (1992) and Gibbs et al., PNAS U.S.A. ~6:6630-6634 (19~9),
respectively. Bovine FPTase was assayed in a volume of 100 ~1

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containing 100 mM N-(2-hydroxy ethyl) piperazine-N'-(2-ethane
sulfonic acid) (HEPES), pH 7.4, 5 mM MgC12, 5 mM dithiothreitol
(Dl~), 100 mM [3H]-farnesyl diphosphate ([3H]-FPP; 740 CBq/mrnol,
New England Nuclear), 650 nM Ras-CVLS and 10 ~g/ml FPTase at
5 31 ~C for 60 min. Reactions were initiated with FPTase and stopped
with 1 ml of 1.0 M HCL in ethanol. Precipitates were collected onto
filter-mats using a TomTec Mach Il cell harvestor, washed with 100%
ethanol, dried and counted in an LKB ,~-plate counter. The assay was
linear with respect to both substrates, FPTase levels and time; less than
10 10% of the [3Hl-FPP was utilized during the reaction period. Purified
compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and
were diluted 20-fold into the assay. Percentage inhibition is measured
by the amount of incorporation of radioactivity in the presence of the
test compound when compared to the amount of incorporation in the
15 absence of the test compound.
Human FPTase was prepared as described by Omer
et al., Biochemistry 32:5167-5176 (1993). Human FPTase activity
was assayed as described above with the exception that 0.1% (w/v)
polyethylene glycol 20,000, 10 ~lM ZnC12 and 100 nM Ras-CVIM were
20 added to the reaction mixture. Reactions were perforrned for 30 min.,
stopped with 100 ~l of 30% (v/v) trichloroacetic acid (TCA) in ethanol
and processed as described above for the bovine enzyme.
The compound of the instant invention described in the
above Examples 1-9 were tested for inhibitory activity against human
25 FPTase by the assay described above and were found to have IC50 of
<50 ~M.
EXAMPLE 1 1
30 In viv~ ras farnesylation assay
The cell line used in this assay is a v-ras line derived
- from either Ratl or NIH3T3 cells, which expressed viral Ha-ras p21.
The assay is perforrned essentially as described in DeClue, J.E. et al.,
Cancer Research 51:712-717, (1991). Cell.s in 10 cm dishes at 50-75%

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confluency are treated with the test compound (final concentration of
solvent, methanol or dimethyl sulfoxide, i.s 0.1%). After 4 hours at
37~C, the cells are labelled in 3 ml methionine-free DMEM supple-
meted with 10% regular DMEM, 2% fetal bovine serum and 400
5 mCi[35SJmethionine (1000 Ci/mmol). After an additional 20 hour,s, the
cells are Iysed in 1 ml Iysis buffer (1 % NP40/20 mM HEPES, pH 7.5/5
mM MgC12/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptinl2 mg/ml
antipain/0.5 mM PMSF) and the Iysates cleared by centrifugation at
100,000 x g for 45 min. Aliquots of Iysates containing equal numbers
10 of acid-precipitable counts are bought to 1 ml with IP buffer (Iysi.s
buffer lacking DTT) and immunoprecipitated with the ras-specific
monoclonal antibody Y13-259 (Furth, M.E. et ah, J. Virol. 43:294-304,
(1982)). Following a 2 hour antibody incubation at 4~C, 200 ml of a
25% suspension of protein A-Sepharose coated with rabbit anti rat IgG
15 is added for 45 min. The immunoprecipitates are washed four times
with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1 % Triton X-
100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCI) boiled in SDS-PAGE
sample buffer and loaded on 13% acrylamide gels. When the dye front
reached the bottom, the gel is fixed, soaked in Enlightening, dried and
20 autoradiographed. The intensities of the bands corresponding to
farne,sylated and nonfarnesylated ras proteins are compared to
determine the percent inhibition of farnesyl transfer to protein.
EXAMPLE 12
In l~ivo ~rowth inhibition assay
To determine the biological consequences of FPTase
inhibition, the effect of the compounds of the instant invention on the
anchorage-independent growth of Ratl cells transformed with either a
30 v-ras, v-raf, or v-mos oncogene i.s tested. Cells transformed by v-Raf
and v-Mos maybe included in the analysis to evaluate the specificity of
- instant compounds for Ras-induced cell tran.sformation.
Rat 1 cells transformed with either v-ras, v-raf, or v-mos
are seeded at a density of 1 x 104 cells per plate (35 mm in diameter) in

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a 0.3% top agarose layer in medium A (Dulbecco's modified Eagle's
medium supplemented with 10% fetal bovine serum) over a bottom
agarose layer (0.6%). Both layers contain 0.1% methanol or an
appropriate concentration of the instant compound (dissolved in
5 methanol at 1000 times the final concentration used in the assay).
The cells are fed twice weekly with 0.5 ml of medium A containing
0.1% methanol or the concentration of the instant compound. Photo-
micrographs are taken 16 days after the cultures are seeded and
comparisons are made.
. , ,~ . .. . . .. . . .