INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE

INHIBITEURS DE LA FARNESYLE-PROTEINE TRANSFERASE

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

La présente invention concerne des composés inhibiteurs de la farnésyle-protéine transférase (FTase) et de la farnésylation de la protéine oncogène Ras. L'invention concerne également, non seulement des compositions chimiothérapiques contenant les composés de l'invention, mais aussi des procédés d'inhibition de la farnésyle-protéine transférase et de la farnésylation de la protéine oncogène Ras.

Claims

-84-

WHAT IS CLAIMED IS:

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

Image
wherein:

R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-,
CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2,
R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substitutent 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)-, R102N-C(NR10)-,
CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-;

R2 and R3 are independently selected from: H; unsubstituted or
substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl,
unsublstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,

unsubstituted or substituted heterocycle, Image or Image,



-85-

wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)p OR6,
c) (CH2)p NR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-4 alkyl,
h) SR6a, S(O)R6a, SO2R6a
2) C3-6 cycloalkyl,
3) OR6,
4) SR6a, S(O)R6a, or SO2R6a

5) ~NR6R7,

6) Image ,

7) Image ,



- 86 -

8) Image,


9) Image ,

10) Image ,


11) ~SO2~NR6R7,

12) Image ,

13) Image,

14) Image ,

15) N3,
16) F, or
17) perfluoro-C1-4-alkyl; or

R2 and R3 are attached to the same C atom and are combined to form
-(CH2)u - wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same
carbon atom;



-87-

R6, R7 and R7a are independently 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) Image,

f) ~SO2R11 , or
g) N(R10)2; or

R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or,substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) Image,

f) ~SO2R11 , or
g) N(R10)2;

R8 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,


-88-


R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN,
NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-C(NR10)-,
CN, R10C(O)-, N3, -N(R10)2, or
R10OC(O)NH-;

R9 is selected from:
a) hydrogen,
b) alkenyl, 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) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-,
(R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 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;
G is H2 or O;
V is selected from:
a) hydrogen,
b) heterocycle.



-89-

c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;

W is a heterocycle;

X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl,wherein the sub.stituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and
u is 4 or 5;



-90-

provided that when G is H2 and W is imidazolyl, then the substitutent
(R8)r-V-A1(CR1a2)n A2(CR1a2)n- is not H and

provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the
substitutent (R8)r-V-A1(CR1a2)n A2(CR1a2)n - is not H;
or a pharmaceutically acceptable salt thereof.

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

Image

wherein:

R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, 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 or substituted C1-c6 alkyl wherein the
substitutent 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)-, R102N-
C(NR10), CN, R10C(O)-, N3, -N(R10)2, and
R11OC(O)-NR10-;



-91-

R2 and R3 are independently selected from: H; unsubstituted or
substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl,
unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
unsubstituted or substituted heterocycle, Image or Image,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-4 alkyl,
h) SR6a, S(O)R6a, SO2R6a,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6a, S(O)R6a, or SO2R6a,
5) -NR6R7,
6) Image ,
7) Image ,



-92-


8) Image ,


9) Image ,

10) Image ,


11) ~SO2~NR6R7 ,

12) Image ,

13) Image ,

14) Image ,

15) N3,
16) F, or
17) perfluoro-C1-4-alkyl; or

R2 and R3 are attached to the same C atom and are combined to form
-(CH2)u- wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;
R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same
carbon atom;



-93-

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6
cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,
heteroarylsulfonyl, un.substituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) Image ,
f) ~SO2R11 , or
g) N(R10)2; or

R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) Image ,
f) -SO2R11 , or
g) N(R10)2;

R8 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,



-94-

R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN,
NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-C(NR10)-,
CN, R10C(O)-, N3, -N(R10)2, or
R10OC(O)NH-;

R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
R10O-, R11S(O)m, R10C(O)NR10-, (R10)2NC(O)-,
R102N-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)-, R102N-C(NR10)-, CN, R10C(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 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;
G is O;

V is selected from:
a) hydrogen,
b) heterocycle,


-95-

c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;
W is a heterocycle;
X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl, wherein the substituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 1;
t is 0 or 1; and
u is 4 or 5;


-96-

or a pharmaceutically acceptable salt thereof.

3. The compound according to Claim 1 of the formula
A:

Image

wherein:

R1a is independently selected from: hydrogen or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10O, -N(R10)2 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, cycloalkyl,
alkenyl, R10O- and N(R10)2;

R3 and R4 are independently selected from H and CH3;

Image
R2 is H; or C1-5 alkyl, unbranched or branched,
unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R6a, or


-97-

Image

and any two of R2, R3, R4, and R5 are optionally attached to the
same carbon atom;
R6, R7 and R7a are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from:
C1-4 alkyl or C3-6 cycloalkyl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;

R8 is independently selected from:
a) hydrogen,
b) 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-;

R9 is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 perfluoroalkyl, F,
Cl, R10O-, R11S(O)m-, R10C(O)NR10-, CN, NO2,


-98-

(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-,
CN, (R10)2N-C(NR10)-, R10C(O)-, -N(R10)2, or
R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
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,
pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,
quinolinyl, isoquinolinyl, and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;

G is H2 or O;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,
thiazolyl. pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, or
isoquinolinyl;

-99-
X is -CH2- or -C(=O)-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl, wherein the substituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and
u is 4 or 5;

provided that when G is H2 and W is imidazolyl, then the substitutent
(R8)r- V - A1(CR1a2)nA2(CR1a2)n - is not H and

provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the
substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is not H;
or a pharmaceutically acceptable salt thereof.
4. The compound according to Claim 1 of the formula
C:


-100-

Image

wherein:

R1a is selected from: hydrogen or C1-C6 alkyl;

R1b is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6
alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, R10O-, or -N(R10)2;

R3 is selected from H and CH3;

Image
R2 is selected from H; or C1-5 alkyl, unbranched or
branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R7a, or
5) Image

and R2 and R3 are optionally attached to the same carbon atom;

R6 and R7 are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle,
unsubstituted or substituted with:
a) C1-4 alkoxy,

-101-

b) halogen, or
c) aryl or heterocycle;
R6a is selected from:
C1-4 alkyl or C3-6 cycloalkyl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;

R8 is independently selected from:
a) hydrogen,
b) 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-;

R9a is hydrogen or methyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
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,

-102-

b) heterocycle selected from pyrrolidinyl, imidazolyl,
pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,
quinolinyl, isoquinolinyl, and thienyl,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;
X is -CH2- or -C(=O)-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl, wherein the substituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1. 2, 3 or 4; and
r is 0 to 5, provided that r is 0 when V is hydrogen;

provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the
substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is not H;


-103-

or a pharmaceutically acceptable salt thereof.

5. The compound according to Claim 1 of the formula
D:

Image
wherein:

R1b is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10O-, -N(R10)2 or C2-C6
alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, R10O-, or -N(R10)2;

R3 is selected from H and CH3;

Image
R2 is selected from H; or C1-5 alkyl, unbranched or
branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) OR6,
4) SR6a, SO2R7a, or
5) Image

and R2 and R3 are optionally attached to the same carbon atom;


-104-

R6 and R7 are independently selected from:
H; C1-4 alkyl, C3-6 cycloalkyl, aryl, heterocycle,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R6a is selected from:
C1-4 alkyl or C3-6 cycloalkyl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) halogen, or
c) aryl or heterocycle;

R8 is independently selected from:
a) hydrogen,
b) 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-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
X is -CH2- or -C(=O)-:

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6

-105-

cycloalkyl, wherein the substituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

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 1 of the formula
E:

Image

wherein:

R1b is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R10O, -N(R10)2 or C2-C6
alkenyl,

-106-

c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, R10O-, or -N(R10)2;
R2 and R3 are independently selected from: hydrogen or C1-C6 alkyl;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
X is -CH2- or -C(=O)-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl, wherein the substituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2; and
p is 0, 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof.

7. A compound which inhibits farnesyl-protein
transferase which is:

-107-

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-(2,2,2-
trifluoroethyl)piperazin-5-one dihydrochloride

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-[1-(3,3,3-
trifluoropropyl)]-piperazin-5-one dihydrochloride

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-
(cyclopropylmethyl)piperazin-5-one dihydrochloride and

2(S)-n-Butyl-1-[3-(4-cyanobenzyl)pyridin-4-yl]-4-(2,2,2-
trifluoroethyl)piperazin-5-one dihydrochloride

or a pharmaceutically acceptable salt or optical isomer thereof.

8. The compound according to Claim 7 which is:

2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-(2,2,2-
trifluoroethyl)piperazin-5-one dihydrochloride

Image

or a pharmaceutically acceptable salt or optical isomer thereof.

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

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

-108-

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

12. A pharmaceutical composition comprising a
pharmaceutical carrier, and dispersed therein, a therapeutically effective
amount of a compound of Claim 7.

13. 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 9.

14. 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 10.

15. 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 11.

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 pharmaceutical composition
comprising a pharmaceutical carrier, and dispersed therein, a
therapeutically effective amount of a compound of the formula A:

-109-

Image

wherein:

R1a and R1b are independently selected from:
a) hydrogen,
b) aryl. heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-,
CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2,
R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substitutent 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-;

R2 and R3 are independently selected from: H; unsubstituted or
substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl,
unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,

Image or Image
unsubstituted or substituted heterocycle,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)p OR6,
c) (CH2)p NR6R7,

-110-

d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-4 alkyl,
h) SR6a, S(O)R6a, SO2R6a,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6a, S(O)R6a, or SO2R6a,

5) ~N R6R7 ,

6) Image ,

7) Image ,

8) Image ,

9) Image ,
10) Image ,

11) ~SO2~NR6R7 ,
12) Image ,

-111-

13) Image ,

14) Image ,

15) N3,
16) F, or
17) perfluoro-C1-4-alkyl; or

R2 and R3 are attached to the same C atom and are combined to form -
(CH2)u - wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same
carbon atom;

R6, R7 and R7a are independently 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) Image

f) ~SO2R11 , or
g) N(R10)2; or

R6 and R7 may be joined in a ring;

-112-

R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) Image ,
f) -SO2R11 , or
g) N(R10)2;

R8 is independently selected from:
a) hydrogen,
b) 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)-, R102N-C(NR10)-, CN,
NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-
C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or
R10OC(O)NH-;

R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-
C(NR10)-, CN, NO2, R10C(O)-, N3,-N(R10)2, or
R11OC(O)NR10-, and

-113-

c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-,
(R10)2NC(O)-, R102N-C(NR10) , CN, R10C(O)-, N3,
-N(R10)2, or R11OC(O)NR10;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 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;
G is H2;

V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;

W is imidazolyl;

X is -CH2-, -C(=O)-, or-S(=O)m-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl, wherein the substituted C1-C6 alkyl and

-114-

substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 1; and
u is 4 or 5;

provided that the substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is
H;
or a pharmaceutically acceptable salt thereof.

18. A method for inhibiting farnesyl-protein transferase
which comprises administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition
comprising a pharmaceutical carrier, and dispersed therein, a
therapeutically effective amount of a compound of the formula:

-115-

Image

wherein:

R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-,
CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2,
R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substitutent 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)-, R102N-
C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-
NR10;

R2 and R3 are independently selected from: H; unsubstituted or
substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl,
unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,

Image or Image
unsubstituted or substituted heterocycle,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)p OR6,
c) (CH2)p NR6R7,


-116-

d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-4 alkyl,
h) SR6a, S(O)R6a, SO2R6a,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6a, S(O)R6a, or SO2R6a
5) ~NR6R7 ,

6) Image ,

7) Image ,

8) Image ,
9) Image ,

10) Image ,

11) ~SO2~NR6R7 ,

12) Image ,

-117-

13) Image ,
14) Image ,
15) N3,
16) F, or
17) perfluoro-C1-4-alkyl; or

R2 and R3 are attached to the same C atom and are combined to form -
(CH2)u - wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same
carbon atom;

R6, R7 and R7a are independently 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) Image ,
f) ~SO2R11 , or
g) N(R10)2; or

R6 and R7 may be joined in a ring;

-118-

R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,

e) Image ,
f) ~SO2R11 , or
g) N(R10)2;

R8 is independently selected from:
a) hydrogen,
b) 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)-, R102N-C(NR10), CN,
NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-
C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or
R10OC(O)NH-;

R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-
C(NR10)-, CN, NO2, R10C(O)-, N3, -N(R10)2, or
R11OC(O)NR10, and

-119-

c) C1-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, R11S(O)m-, R10C(O)NR10-,
(R10)2NC(O)-, R102N-C(NR10)-, CN, R10C(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 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;
G is H2 or O;

V is selected from:
a) hydrogen,
b) heterocycle,
c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;

W is a heterocycle;

X is --C(=O)-, or -S(=O)m-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl, wherein the substituted C1-C6 alkyl and


-120-

substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and
u is 4 or 5;

provided that if t is 1, then the substitutent
(R8)r- V - A1(CR1a2)nA2(CR1a2)n - is H;
or a pharmaceutically acceptable salt thereof.

19. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 9.

20. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 10.

-121-

21. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 11.

22. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 12.

23. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a pharmaceutical composition comprising a pharmaceutical
carrier, and dispersed therein, a therapeutically effective amount of a
compound of the formula A:

Image

wherein:

R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-,
CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2,
R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substitutent 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)-, R102N-


-122-

C(NR10)-, CN, R1OC(O)-, N3, -N(R10)2, and R11OC(O)-
NR10;

R2 and R3 are independently selected from: H; unsubstituted or
substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl,
unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,
Image or Image
unsubstituted or substituted heterocycle,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)p OR6,
c) (CH2)p NR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-4 alkyl,
h) SR6a, S(O)R6a, SO2R6a,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6a, S(O)R6a, or SO2R6a,

5) ~NR6R7 ,
6) Image ,
7) Image ,


-123-

8) Image ,
9) Image ,
10) Image ,

11) ~SO2~NR6R7 ,

12) Image ,

13) Image ,

14) Image ,

15) N3,
16) F, or
17) perfluoro-C1-4-alkyl; or

R2 and R3 are attached to the same C atom and are combined to form -
(CH2)u - wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same
carbon atom;


-124-

R6, R7 and R7a are independently 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) Image ,

f) ~SO2R11 , or
g) N(R10)2; or

R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) Image ,

f) ~SO2R11 , or
g) N(R10)2;

R8 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-
C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-, R11S(O)m-,

-125-

R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN,
NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-, R102N-
C(NR10), CN, R10C(O)-, N3, -N(R10)2, or
R10OC(O)NH-;

R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-, R102N-
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)-, R102N-C(NR10)-, CN, R10C(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently selected from C1-C6 alkyl and aryl;
A1 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;
G is H2;

V is selected from:
a) hydrogen,
b) heterocycle,


-126-

c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;
W is imidazolyl;
X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl,wherein the substituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 1; and
u is 4 or 5;

-127-

provided that the substitutent (R8)r- V - A1(CR1a2)nA2(CR1a2)n - is
H;
or a pharmaceutically acceptable salt thereof.

24. A method for treating cancer which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a pharmaceutical composition comprising a pharmaceutical
carrier, and dispersed therein, a therapeutically effective amount of a
compound of the formula:

Image

wherein:

R1a and R1b are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, R10O-, R11S(O)m-, R10C(O)NR10-,
CN(R10)2NC(O)-, R102N-C(NR10)-, CN, NO2,
R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substitutent 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)-, R102N-
C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, and R11OC(O)-
NR10-;


-128-

R2 and R3 are independently selected from: H; unsubstituted or
substituted C1-8 alkyl, unsubstituted or substituted C2-8 alkenyl,
unsubstituted or substituted C2-8 alkynyl, unsubstituted or substituted aryl,


unsubstituted or substituted heterocycle, Image or Image,
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C1-4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1-4 alkyl,
h) SR6a, S(O)R6a, SO2R6a,
2) C3-6 cycloalkyl,
3) OR6,
4) SR6a, S(O)R6a, or SO2R6a,

5) ~R6R7 ,

6) Image ,
7) Image ,



-129-

8) Image ,
9) Image ,
10) Image ,

11) ~SO2-NR6R7 ,

12) Image ,

13) Image ,

14) Image ,

15) N3,
16) F, or
17) perfluoro-C1-4-alkyl; or

R2 and R3 are attached to the same C atom and are combined to form
-(CH2)u- wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(CORl0)-;

R4 is selected from H and CH3;

and any two of R2, R3 and R4 are optionally attached to the same
carbon atom;

-130-

R6, R7 and R7a are independently selected from: H; C1-4 alkyl, C3-6
cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl,
heteroaryl,sulfonyl, unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) Image,
f) ~SO2R11 , or
g) N(R10)2; or

R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

R6a is selected from: C1-4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or substituted with:
a) C1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) Image ,
f) ~SO2R11 , or
g) N(R10)2;

R8 is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl,
C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-~, R11S(O)m-,


-131-

R10C(O)NR10-, (R10)2NC(O)-, R102N-C(NR10)-, CN,
NO2, R10C(O)-, N3, -N(R10)2, or R11OC(O)NR10-, and
c) C1-C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-C10 cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NH-, (R10)2NC(O)-,
R102N-C(NR10)-, CN, R10C(O)-, N3, -N(R10)2, or
R10OC(O)NH-;

R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
R11S(O)m-, R10C(O)NR10-, (R10)2NC(O)-,
R102N-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)-, R102N-C(NR10)-, CN, R10C(O)-, N3,
-N(R10)2, or R11OC(O)NR10-;
R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;
R11 is independently .selected from C1-C6 alkyl and aryl;
A1 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;
G is H2 or O;

V is selected from:
a) hydrogen,
b) heterocycle,


-132-

c) aryl,
d) C1-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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;
W is a heterocycle;
X is --C(=O)-, or -S(=O)m-;

Z is unsubstituted C1-C6 alkyl, substituted C1-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl, wherein the substituted C1-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(O)R7,
e) HO,
f) -S(O)m R6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 1 or 2;
r is 0 to 5, provided that r is 0 when V is hydrogen;
s is 0 or 1;
t is 0 or 1; and
u is 4 or 5;


-133-


provided that if t is 1, then the substitutent
(R8)r- V - A1(CR1a2)n A2(CR1a2)n - is H;

or a pharmaceutically acceptable salt thereof.

25. 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 9.

26. 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 9.

27. 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 9.

28. A method for preventing restenosis which comprises
administering to a mammal in need thereof a therapeutically effective
amount of a composition of Claim 9.

29. 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 9.

Description

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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
receptor~s 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 conformational 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 form (D.R. Lowy and
l~S D.M. Willumsen, Ann. Rev. Biochem. 62:gSl-~91 (1993)). Mutated
ras genes (Ha-7 as, Ki4a-ras, Ki4b-ras and N-ras) are found in many
human cancers, including colorectal carcinoma, exocrine pancreatic
carcinoma, and myeloid leukemias. The protein products of these
genes are defective in their GTPase activity and con.stitutively 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-terminus 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 310:583-586 (19~S4)). Depending
on the specific .se4uence, this motif serves as a signal sequence for the
enzymes farnesyl-protein transferase or ~eranylgeranyl-protein
transferase, which catalyze the alkylation of the cysteine residue of the
CAAX motif with a Cls or C2() isoprenoid, respectively. (S. Clarke.,
Ann. Rev. Bi~chem. 61:355-3~6 (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

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farnesylation. Other farnesylated proteins include the Ras-related GTP-
binding proteins ,such a~s Rho, fungal mating factors, the nuclear lamin.s,
and the gamma subunit of transducin. James, et al., J. Biol. Chem. 269,
141~2 (1994) have identified a peroxisome associated protein Pxf which
is also farnesylated. James, et al., have also suggested that there are
farnesylated 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 trans~ormed phenotype. It has also been
demonstrated that certain inhibitors of farnesyl-protein transferase
selectively block the processing of the Ra~s 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 has been shown that an
inhibitor of farnesyl-protein transferase blocks the growth of ras-
dependent tumors in nude mice (N.E. Kohl et al., P) oc. Natl. Acad. Sci
U.S.A., 91:9141-9145 (1994) and induces regression of m~mm~ry and
salivary carcinomas in ras transgenic mice (N.E. Kohl et al., Nature
Medicine, 1 :792-797 (1995).
Indirect inhibition of farnesyl-protein transferase in vivo
has been demonstrated with lovastatin (Merck & Co., Rahway, NJ) and
compactin (Hancock et al., ibid; Casey et al., ibid; 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. Farnesyl-protein transferase utilizes farnesyl
pyrophosphate to covalently modify the Cys thiol group of the Ras
CAAX box with a farnesyl group (Reiss et al., Cell, 62:81-g~ (1990);
Schaber etal.. J. Biol. Chem., 265:14701-14704 (1990); Schafer etal.,
Science, 249: 1133- 1139 (1990); Manne et al., Proc. Natl. Acacl. Sci
30 USA, 87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate
biosynthe.sis by inhibiting HMG-CoA reductase blocks Ras membrane
localization in cultured cell~. However, direct inhibition of farnesyl-
protein transferase would be more specific and attended by fewer side

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effects than would occur with the required dose of a general inhibitor of
isoprene biosynthesis.
- Inhibitors of farnesyl-protein transferase (FPTase) have
been described in two general classes. The first are analogs of farnesyl
5 diphosphate (FPP), while the second class of inhibitor.s is related to the
protein substrates (e.g., Ras) for the enzyme. The peptide derived
inhibitors that have been described are generally cysteine cont~ining
molecules that are related to the CAAX motif that is the signal for
protein prenylation. (Schaber et al., ihid; Reiss et. al., i1~id; Reiss e~ al.,
0 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 inhibitors (U.S.
Patent 5,141,g51, University of Texas; N.E. Kohl et al., Science,
260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37, 725 (1994)).
15 In general, 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 places limitations on the
therapeutic application of FPTase inhibitors with respect to
pharrnacokinetics, pharmacodynamics and toxicity. Therefore, a
20 functional replacement for the thiol is desirable.
It has recently been reported that farnesyl-protein
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-
25 112930).
It has recently been disclosed that certain tricycliccompounds which optionally incorporate a piperidine moiety are
inhibitors of FPTase (WO 95/10514, WO 95/10515 and WO 95/10516).
Imidazole-containin~ inhibitors of farnesyl protein transferase have also
30 been disclosed (WO 95/09001 and EP 0 675 112 A1).
It is, therefore, an object of this invention to develop
peptidomimetic compounds that do not have a thiol moiety, and that will
inhibit farnesyl-protein transferase and thus, the po~st-translational
farnesylation of proteins. It is a further object of this invention to

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develop chemotherapeutic compositions containing the compounds of
this invention and methods for producing the compounds of this
invention.

5 SUMMARY OF THE INVENTION
The present invention comprises peptidomimetic
piperazine- or piperazinone-containing compounds which inhibit the
farnesyl-protein transferase. The instant compounds lack a thiol moiety
and thus offer unique advantages in terms of improved pharmacokinetic
10 behavior in animals, prevention of thiol-dependent chemical reaction.s,
such as rapid autoxidation and disulfide formation with endogenou~
thiols, and reduced systemic toxicity. Further contained in this
invention are chemotherapeutic compositions cont~ining these farnesyl
transferase inhibitors and methods for their production.
The compounds of this invention are illustrated by the
formulae A and B:
( IR8)r IR9)~\ R2 ~
V - A1(CR1a2)nA2(CR1a2)n -\W~- (CR1b2)P~ ~N N Z
R3 R4

(IR8)r !R9~ R2 R3
V A1 (C R 1 a2)nA2(C R 1 a2)n ~Wl - (C R 2)p\ ,N~--Z
B R4


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DETAILED DESCRIPTION OF THE ~VENTION
The compounds of this invention are useful in the inhibition
of farnesyl-protein transferase and the farnesylation of the oncogene
protein Ras. In a first embodiment of this invention, the inhibitors of
5 farnesyl-protein transferase are illustrated by the formula A:

~7 '~ R\~
V - A1(CR1a2)nA2(CR1a2)n -\W~- (CR1b2)p\ /N N--Z

R~ R4

wherem:

Rla and Rlb are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-
C6 alkynyl, R 1 0O-, R 1 1 S(O)m ~ R 1 0C(o)NR 10,
CN(R 1 0)2NC(o)-, R 1 02N-C(NR 1 0)-, CN, NO2,
R 1 ~C(O)-, N3, -N(R 1~)2, or R 1 1 OC(O)NR 10 ,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substitutent on the substituted Cl-C6 alkyl is selected from
unsubstituted or substituted aryl, heterocyclic, C3-Clo
cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-,
Rl lS(O)m-, R10C(o)NR10-, (R10)2NC(o)-~ R102N-
C(NR10)-, CN, R10C(o)-, N3, -N(R10)2, and Rl loc(O)-
NRlO;

R2 and R3 are independently ,selected from: H; unsubstituted or
substituted Cl ~ alkyl, unsubstituted or substituted C2 ~ alkenyl,

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unsubstituted or substituted C2 8 alkynyl, unsubstituted or substituted aryl,
~NR6R7 or ~oR6
unsubstituted or substituted heterocycle, ~ ~
wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
S a) C1 4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-Cl 4 alkyl,
h) SR6a, s(o)R6a~ So2R6a
2) C3 6 cycloalkyl,
3) oR6,
1~ 4) SR6a, S(O)R6a~ or S02R6a

5) --N R6R7
o
R6




--N~ N R7R7a

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8) --~~ NR6R7

9) --o~OR6


10) ~ NR6R7
o




1 1 ) --SO2--N R6R7
~6

12) --N--SO2--R6a

o

o


1 5) N3,
16) F, or
17) perfluoro-C1 4-alkyl; or

S R2 and R3 are attached to the same C atom and are combined to form -
(CH2)U - wherein one of the carbon atoms is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3,
and any two of R2, R3 and R4 are optionally attached to the s~me
carbon atom;

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R6, R7 and R7a are independently 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,
o

f) --S02R , or
g) N(R 1 0)2; or

R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

15 R6a is selected from: Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
o

f) --S02R1 1 , or
g) N(R 1~)2;

R~ is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-C1o cycloalkyl, C2-C6 alkenyl, C2-
C6 alkynyl, perfluoroalkyl, F, Cl, Br, RlOO-, Rl 1 S(O)m 7

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R 1 0C(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 , and
c) C 1 -C6 alkyl unsubstituted or substituted by aryl,
cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
Rl lS(O)m-, RlOC(O)NH-, (R10)2NC(o)-, R102N-
C(NR 1 0)-, CN, R 1 ~C(O)-, N3, -N(R 1 0)2, or
R 1 0OC(O)NH-;

10 R9 is selected from:
a) hydrogen,
b) alkenyl, alkynyl, per~luoroalkyl, F, Cl, Br, R100-,
R 1 1 S(O)m-~ R 1 0C(o)NR 10, (R 1 0)2NC(o)-, R 1 02N-
C(NR 1 0)-, CN, NO2, R 1 ~C(O)-, N3, -N(R 1 0)2, or
R l l OC(O)NR 1 0-, and
c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, Rl lS(O)m-, R10C(o)NR10-,
(R 1 0)2NC(O)-, R 1 02N-C(NR 10), CN, R 1 ~C(O)-, N3,
-N(R10)2, or Rl lOC(O)NR10-;
R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and
aryl;

Rl 1 is independently selected from C1-C6 alkyl and aryl;
Al and A2 are independently selected from: a bond, -CH=CH-, -C_C-,
-C(O)-, -C(O)NR 10, -NR 1 ~C(O)-, O, -N(R 10),
-S(O)2N(R10)-, -N(R10)S(o)2-~ or S(O)m;

30 G is H2 or O;

V is selected from:
a) hydrogen,
b) heterocycle,

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- 10 -

c) aryl,
d) C1-C20 alkyl wherein from O to 4 carbon atoms are
replaced with a 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
if A1 isabond, Il iS 0 andA2isS(O)m;

W is a heterocycle;
X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is unsubstituted Cl-C6 alkyl, .substituted Cl-C6 alkyl,
unsub,stituted C3-C6 cycloalkyl or sub,stituted C3-C6
cycloalkyl,wherein the substituted Cl-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C 1 -4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(o)R7,
e) HO,
f) -s(o)mR
g) halogen, or
h) perfluoroalkyl;

mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4;
qis 1 or 2;
r is O to 5, provided that r is O when V is hydrogen;
sis O or l;
tis Oorl;and
u is 4 or 5;

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or the phalmaceutically acceptable salts thereof.

In a second embodiment of this invention, the inhibitors of
5 farnesyl-protein transferase are illustrated by the forrnula B:

(R8)r ~9~ R~ ~ R3

V ~ Al(CR1a2)nA2(CR1a2)n -\W~!- (CR1b2)p~ ,N /N--Z
/~G
B R4
wherein:

Rla and Rlb are independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-clo cycloalkyl, C2-c6 alkenyl, C2-
C6 alkynyl, R 1 0O-, R 1 1 S(O)m ~ R 1 0C(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 or substituted Cl-C6 alkyl wherein the
substitutent on the substituted Cl-C6 alkyl is .selected from
unsubstituted or substituted aryl, heterocyclic, C3-Cln
cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R10O-,
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 R 1 1 OC(O)-
NRlO;

R2 and R3 are independently selected from: H; unsubstituted or
substituted Cl ~ alkyl, unsubstituted or sub.stituted C2 ~ alkenyl,
25 unsubstituted or substituted C2 X alkynyl, unsubstituted or substituted aryl, ~NR6R7 or ~oR6
unsubstituted or substituted heterocycle. ~ ~

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wherein the substituted group is substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C 1-4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
e) CN,
f) aryl or heteroaryl,
g) perfluoro-C1 4 alkyl,
h) SR6a, s(o)R6a? So2R6a
2) C3-6 cycloalkyl,
3) oR6,
4) SR6a, s(o)R6a~ or So2R6a

5) --NR~R7


R6




--N~ N R7R7a
0

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WO 97136593 PCT/US97/0~144




8) --~~ NR6R7

9) --O oR6


10) ~ NR6R7


1 1 ) --SO2--N R6R7
~6

12) --N--SO2--R6a

o


o


1 5) N3~
16) F, or
17) perfluoro-C1 4-alkyl; or

R2 and R3 are attached to the same C atom and are combined to form -
(CH2)U - wherein one of the carbon atom,s is optionally replaced by a
moiety selected from: O, S(O)m, -NC(O)-, and -N(COR10)-;

R4 is selected from H and CH3;
and any two of R2~ R3 and R4 are optionally attached to the same
carbon atom;

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- 14 -

R6, R7 and R7a are independently 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) ~I~R


f) --SO2R , or
g) N(Rl0)2; or

R6 and R7 may be joined in a ring;
R7 and R7a may be joined in a ring;

15 R6a is selected from: Cl 4 alkyl, C3-6 cycloalkyl, heterocycle, aryl,
unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,

o

f) --SO2R1 ' , or
g) N(R 1~)2;

R~ is independently selected from:
a) hydrogen,
b) aryl, heterocycle, C3-Clo cycloalkyl, C2-c6 alkenyl, C2-
C6 alkynyl, perfluoroalkyl~ F, Cl, Br, Rloo-~ Rl lS(o)m-



,, .

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- 15 -

R 1 0C(o)NR 10, (Rl0)2Nc(o)-~Rl 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 unsub~tituted or substituted by aryl,
cyanophenyl, heterocycle, C3-clo cycloalkyl, C2-C6
alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br, R10O-,
Rl lS(O)m-, RlOC(O)NH-, (R10)2NC(o)-, R102N-
C(NR10)-,CN,R10C(O)-, N3,-N(R10)2, or
R10OC(O)NH-;

R9is selected from:
a) hydrogen,
b) C2-C6 alkenyl, C2-C6 alkynyl, perfluoroalkyl, F, Cl, Br,
Rl0o-~Rlls(o)m-~Rl 0C(o)NR I ~-, (R 1 0)2NC(O)-,
R102N-c(NRlo)-~cN~No2~Rloc(o)-~ N3,-N(Rl0)2~or
RllOC(O)NR10-, and
c) Cl-C6 alkyl unsubstituted or substituted by perfluoroalkyl,
F, Cl, Br, R10O-, Rl lS(O)m-, R10C(o)NR10-,
(Rl0)2Nc(o)-~Rlo2N-c(NRlo)-~cN~Rloc(o)-~ N3,
-N(R10)2, or R 1 1 OC(O)NR 10;
R10 i~ independently selected from hydrogen, Cl-C6 alkyl, benzyl and
aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
Al and A2 are independently selected from: a bond, -CH-CH-, -C_C-,
-C(O)-, -C(O)NR 10 , -NR 1 ~C(O)-, O, -N(R 10) ,
-S(O)2N(R 10), -N(R 1 ~)S(O)2-, or S(O)m;

30 G is O;

V is selected from:
a) hydrogen,
b ) heterocycle,

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- 16 -

c) aryl,
d) Cl-C20 alkyl wherein from O to 4 carbon atoms are
replaced with a a heteroatom selected from 0, S, and N,
and
S e) C2-C20 alkenyl,
provided that V is not hydrogen if Al is S(O)m and V is not hydrogen
if Al is a bond, n is O and A2 is S(O)m;

W is a heterocycle;
X is -CH2-, -C(=O)-, or -S(=O)m-;

Z is un.substituted Cl-C6 alkyl, substituted Cl-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
lS cycloalkyl,wherein the ~substituted Cl-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C 1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(o)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

mis 0, l or2;
nis 0, l, 2, 3 or4;
pis 0, 1, 2, 3 or4;
q is l or 2;
r IS 0 to S, provided that r i,s O when V i,s hydrogen;
~ls l;
tis Oor l; and
uis 40rS;

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- 17 -

or the pharmaceutically acceptable salts thereof.

In a preferred embodiment of this invention, the inhibitors
S of farnesyl-protein transferase are illustrated by the formula A:
(l 8)r ! ~ R2~
V ~ A1(CR1a2)nA2(CR1a2)n -\W~!- (CRlb2)p~ /N~ JN--Z

R3 R4

wherein:

10 Rla is independently selected from: hydrogen or C1-C6 alkyl;

Rlb is independently selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R lOo, -N(R 1~)2 or C2-C6
1 5 alkenyl,
c) unsubstituted or substituted C1-C6 alkyl wherein the
substitutent on the substituted Cl-C6 alkyl is selected from
unlsubstituted or sub,stituted aryl, heterocycle, ~cycloalkyl,
alkenyl, RlOO- and -N(R10)2;

R3 and R4 are independently selected from H and CH3;
~,~NR6R7
R2 is H; O or C1 5 alkyl, unbranched or branched,
unsubstituted or substituted with one or more of:
1) aryl,
2;S 2) heterocycle,
3 ) oR6,
4) SR6a, SO2R6a, or

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- 18 -

5) ~f NR6R7
o
and any two of R2, R3, R4, and RS are optionally attached to the
same carbon atom;

S R6, R7 and R7a are independently selected from:
H: Cl 4 alkyl, C3-6 cycloalkyl, aryl, heterocycle,
unsubstituted or substituted with:
a) C l 4 alkoxy,
b) halogen, or
c) aryl or heterocycle;

R6a is selected from:
Cl 4 alkyl or C3-6 cycloalkyl,
unsubstituted or substituted with:
a) Cl 4 alkoxy,
b) halogen, or
c) aryl or heterocycle;

Rfs is independently selected from:
a) hydrogen,
b) Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl-C6
perfluoroalkyl, F, Cl, R10O-, R10C(o)NR10-, CN, NO2,
(R 1 0)2N-C(NR 10) , R 1 ~C(O)-, -N(R 1~)2, or
Rl lOC(O)NR10-, and
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-,
Rloc(o)NRlo-~ (Rlo)2N-c(NRlo)-~ Rl0
-N(R 1~)2, OI R 1 1 OC(O)NR 10;

R9 is selected from:
a) hydrogen,
b) C~-C6 alkenyl, C2-C6 alkynyl, Cl-C6 perfluoroalkyl, F,
Cl. R10O-, Rl lS(O)m-, R10C(o)NR10-, CN, NO2,

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- 19 -

(R10)2N-C(NR10)-,R10C(O)-,-N(R10)2,or
RllOC(O)NR10-, and
c) Cl-C6 alkyl unsubstituted or substituted by Cl-C6
pe~uoroalkyl, F, Cl, Rl0o-~Rlls(o)m-~Rloc(o)NR
CN,(R10)2N-C(NR10)-,Rl0C(o)-~-N(R 1~)2, or
RllOC(O)NR10-;

R10 is independently selected from hydrogen, Cl-C6 alkyl, benzyl and
aryl;
Rll i.s independently selected from Cl-C6 alkyl and aryl;

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,
b) heterocycle ~selected from pyrrolidinyl, imidazolyl,
pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,
quinolinyl, i,soquinolinyl. and thienyl,
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a a heteroatom selected from O, S, and N,
and
25 e) C2-C20 alkenyl, and
provided that V i~ not hydrogen if Al is S(O)m and V is not hydrogen
if Al isabond,n isOandA2isS(O)m;

G is H2 or O;
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,
thiazolyl, pyridonyl, 2-oxopiperidinyl. indolyl, quinolinyl, or
isoquinolinyl;

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X is -CH2- or -C(=O)-;

Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or sub.stituted C3-C6
cycloalkyl,wherein the substituted Cl-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C 1 -4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(o)R7,
e) HO,
f) -S(o)mR6a~
g) halogen, or
h) perfluoroalkyl;

mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
pi.s 0, 1, 2, 3 or4;
r is O to ;~, provided that r is O when V is hydrogen;
s is O or 1 ;
tis Oorl;and
uis 40r5;

25 provided that when G is H2 and W is imidazolyl, then the substitutent
(R~)r- V - A 1 (CR 1 a2)nA2(CR 1 a2)n - is not H and

provided that when X is -C(=O)-, or -S(=O)m-, then t is 1 and the
substitutent (RP~)r- V - Al(CRla2)nA2(CRla2)n - is not H;
or the pharmaceutically acceptable salt.s thereof.

A preferred embodiment of the compounds of this
invention are illu.~itrated by the formula C:

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W O 97136593 PCTr~S9710~144



(R8)r R9a

V - A1(CR1a2)nA2(CR1a2)n N ~J N N-Z
(C R 1 b2)p X/




C R2 R3
wherein:
R1a is selected from: hydrogen or Cl-C6 alkyl;
s




R1b is independently ~selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R l OO-, -N(R 1 0)2 or C2-C6
alkenyl,
c) Cl-C6 alkyl unsub.stituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, RlOO-, or -N(R10)2;

R3 is selected from H and CH3;
~NR6R7
R2 is selected from H; O orCl S alkyl, unbranched or
15branched, unsubstituted or substituted with one or more of:
1) aryl,
2) heterocycle,
3) oR6,
4) SR6a, S02R7a, or
5) ~ N R6R7

O
and R2 and R3 are optionally attached to the same carbon atom;

R6 and R7 are independently selected from:
H; Cl 4 alkyl, C3-6 cycloalkyl, aryl, heterocycle,
25unsubstituted or sub.stituted with:
a) C l 4 alkoxy,

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b) halogen, or
c) aryl or heterocycle;

R6a is selected from:
Cl 4 alkyl or C3-6 cycloalkyl,
unsubstituted or substituted with:
a) C1 4 alkoxy,
b) halogen, or
c) aryl or heterocycle;
R~ i.s independently selected from:
a) hydrogen,
b) Cl-C6 alkyl, C2-C6 alkenyl, C2-c6 alkynyl, Cl-C6
perfluoroalkyl, F, Cl, R 1 0O-, R 1 0C(o)NR 1 0-, 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
c) Cl-C6 alkyl substituted by Cl-C6 perfluoroalkyl, R10O-,
Rloc(o)NRlo-~ (R10)2N C(NR10) RlO
-N(R 1~)2, or R 1 1 OC(O)NR 10;
R9a is hydrogen or methyl;

R10 is independently selected from hydrogen, Cl-c6 alkyl, benzyl and
aryl;
Rl 1 is independently selected from Cl-C6 alkyl and aryl;

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,

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b) heterocycle selected from pyrrolidinyl, imidazolyl,
pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,
quinolinyl, isoquinolinyl, and thienyl,
c) aryl,
d) Cl-C20 alkyl wherein from 0 to 4 carbon atoms are
replaced with a 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
10 if Al i.sabond,n isOandA2isS(O)m;
X is -CH2- or-C(=O)-;

Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl,wherein the substituted Cl-C6 alkyl and
~ubstituted C3-C6 cycloalkyl is .substituted with one or two
of the following:
a) C1 4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(o)R7,
e) HO,
f) -s(o)mR
g) halogen, or
h) perfluoroalkyl;

mis 0, 1 or2;
nis 0, 1, 2, 3 or4;
pis 0, 1, 2, 3 or4; and
r is 0 to 5, provided that r is 0 when V is hydrogen;
or the pharmaceutically acceptable salts thereof.

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- 24 -

In a more preferred embodiment of this invention, the
inhibitors of farnesyl-protein transferase are illustrated by the forrnula
D:
H




~N ~
/ N N - Z
<¦~ (CR 2)p X /2\ 3

R8 D
wherein:

Rlb is independently .selected from:
a) hydrogen,
b) aryl, heterocycle, cycloalkyl, R l OO-, -N(R 1 0)2 or C2-C6
alkenyl,
c) C1-C6 alkyl unsubstituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, RlOO-, or-N(R10)2;

15 R3 is selected from H and CH3;
,,~ NR6R7
Il ;
R2 is selected from H; o or Cl 5 alkyl, unbranched or
branched, unsubstituted or substituted with one or more of:
1 ) aryl,
2) heterocycle,
3) oR6,
4) SR6a, S02R7a, or
5) ~f NR6R7


and R2 and R3 are optionally attached to the same carbon atom;

25 R6 and R7 are independently selected from:

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- 25 -

H; Cl 4 alkyl, C3-6 cycloalkyl, aryl, heterocycle,
unsub,stituted or substituted with:
a) Cl 4 alkoxy,
b) halogen, or
c) aryl or heterocycle;

R6a is selected from:
C 1-4 alkyl or C3-6 cycloalkyl,
unsubstituted or substituted with:
a) Cl 4 alkoxy,
b) halogen, or
c) aryl or heterocycle;

R~ is independently selected from:
a) hydrogen,
b) Cl-c6 alkyl, C2-c6 alkenyl, C2-c6 alkynyl, Cl-C6
perfluoroalkyl, F, Cl, R10O-, R10C(o)NR10-, 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
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(R 1~)2, or R 1 1 OC(O)NR 10;

R10 i~s independently selected from hydrogen, Cl-C6 alkyl, benzyl and
aryl;

Rl 1 i~s independently selected from Cl-C6 alkyl and aryl;

X is -CH2- or-C(=O)-;
Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl,wherein the substituted Cl-c6 alkyl and

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- 26 -

substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) C 1-4 alkoxy,
b) NR6R7,
c) C3-6 cycloalkyl,
d) -NR6C(o)R7,
e) HO,
f) -S(O)mR6a,
g) halogen, or
h) perfluoroalkyl;

m is 0, 1 or 2; and
pis 0, 1, 2, 3 or4;
15 or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention,
the inhibitors of farnesyl-protein transferase are illustrated by the
formula E:

H




N~,~y ' /~~
(CR1b2)p X ~/-\J

NC E
wherein:

Rlb is independently selected from:
a) hydrogen,
b) aryl. heterocycle, cycloalkyl, RlOO-, -N(R10)2 or C2-C6
alkenyl,

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c) Cl-C6 alkyl unsub.stituted or substituted by aryl,
heterocycle, cycloalkyl, alkenyl, R100-, or -N(R10)2;

R2 and R3 are independently selected from: hydrogen or Cl-C6 alkyl;
s




R10 is independently selected from hydrogen, C1-C6 alkyl, benzyl and
aryl;

Rl 1 is independently selected from Cl-C6 alkyl and aryl;
X i.'i -CH2- or -C(=O)-;

Z is unsubstituted Cl-C6 alkyl, substituted Cl-C6 alkyl,
unsubstituted C3-C6 cycloalkyl or substituted C3-C6
cycloalkyl,wherein the substituted Cl-C6 alkyl and
substituted C3-C6 cycloalkyl is substituted with one or two
of the following:
a) CI 4 alkoxy,
b) NR6R7,
C) C3-6 cycloalkyl,
d) -NR6C(o)R7,
e) HO,
f) -s(o)mR
g) halogen, or
2~ h) perfluoroalkyl;

m is 0, 1 or 2; and
pis 0, 1, 2, 3 or4;

30 or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

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- 2~ -

2(S)-n-Butyl- 1-[1 -(4-cyanobenzyl)-5-imidazolylmethyl] -4-(2,2,2-
trifluoroethyl)piperazin-5-one dihydrochloride

2(S)-n-Butyl- 1-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-[ 1-(3 ,3 ,3-
S trifluoropropyl)]-piperazin-5-one dihydrochloride

2(S)-n-Butyl- 1-[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-
(cyclopropylmethyl)piperazin-5-one dihydrochloride and

2(S)-n-Butyl- 1 -[3-(4-cyanobenzyl)pyridin-4-yl]-4-(2,2,2-
trifluoroethyl)piperazin-5-one dihydrochloride
or the pharmaceutically acceptable salts thereof.
Specific examples of the compounds of the invention are:

2(S)-n-Butyl- 1-~1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-(2,2,2-
trifluoroethyl)piperazin-5-one dihydrochloride


NCi ~ N N-CH2CF~

N

or the pharmaceutically acceptable salts thereof.
The compounds of the present invention may have
asymmetric centers and occur as racemates, racemic mixtures, and as
25 individual diastereomers, with all possible isomers, including optical
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
30 permissible only if such combinations result in stable compounds.

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- 29 -

As used herein, "alkyl" 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 of carbon atoms attached through an oxygen
S bridge. "Halogen" or "halo" as used herein means fluoro, chloro,
bromo and iodo.
As used herein, "aryl" 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
10 include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl,
phenanthryl, anthryl or acenaphthyl.
The term heterocycle or heterocyclic, as used herein,
repre.sents a stable 5- to 7-membered monocyclic or stable 8- to 11-
membered bicyclic heterocyclic ring which is either saturated or
15 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
heterocyclic rings is fused to a benzene ring. The heterocyclic ring may
be attached at any heteroatom or carbon atom which results in the
20 creation of ~ .stable structure. Examples of .~uch heterocyclic elements
include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl,
benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,
dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
25 dihydrobenzothiopyranyl sulfone, furyl, imidazolidinyl, imidazolinyl,
imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl,
isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl,
naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl,
2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl,
30 pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl,
thienofuryl, thienothienyl, and thienyl.

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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
~S consisting of N, O, and S. Examples of such heterocyclic elements
include, but are not limited to, benzimidazolyl, benzisoxazolyl,
benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,
dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, furyl, imidazolyl, indolinyl, indolyl,
isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl,
thienothienyl, and thienyl.
As used herein in the definition of R2 and R3, the term "the
substituted group" intended to mean a substituted Cl ~ alkyl, substituted
C2 ~ alkenyl, substituted C2 X alkynyl, substituted aryl or substituted
heterocycle from which the sub~stitutent(s) R2 and R3 are selected.
As u,sed herein in the definition of R6, R6a, R7 and R7a,
the substituted Cl ~ alkyl, substituted C3-6 cycloalkyl, substituted aroyl,
substituted aryl, substituted heteroaroyl, substituted arylsulfonyl,
substituted heteroarylsulfonyl and substituted heterocycle include
moieties containing from 1 to 3 substitutents in addition to the point of
attachment to the rest of the compound.
When R2 and R3 are combined to form - (CH2)U -, cyclic
moieties are formed. Examples of such cyclic moieties include, but are
not limited to:



~ ~J

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In addition, such cyclic moieties may optionally include a
heteroatom(s). Examples of such heteroatom-containing cyclic moieties
include, but are not limited to:

~ ~J ~OJ ~S J



~ H O NJ
0 COR10
Lines drawn into the ring ~systems from substituents (such
as from R2, R3, R4 etc.) indicate that the indicated bond may be
attached to any of the substitutable ring carbon atoms.
Preferably, Rla and Rlb are independently selected from:
hydrogen, -N(R 1 0)2, R l OC(O)NR 1 0- or unsubstituted or substituted
Cl-C6 alkyl wherein the substituent on the substituted Cl-C6 alkyl is
selected from unsub.stituted or substituted phenyl, -N(R10)2, R100- and
R 1 ~C(O)NR 10
Preferably, R2 is selected from: H,
~NR6R7 ~oR6
~ ~ and an unsubstituted or substituted group, the
group selected from Cl ~ alkyl, C2 ~ alkenyl and C2 ~, alkynyl;
wherein the substituted group is substituted with one or more of:
I) aryl or heterocycle, unsubstituted or substituted with:
a) C 1-4 alkyl,
b) (CH2)pOR6,
c) (CH2)pNR6R7,
d) halogen,
2) C3-6 cycloalkyl,
3) oR6,

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4) SR6a,S(o)R6a~s 02R6a

5) - N R6R7
F~6

6) --N~ R7
7)




--N~ NR7R7a
8) --O~ NR6R7


9) --o~OR6


10) ~ NR6R7



1 1 ) --S02--NR6R7
~6
12) --N-SO2--R

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o

1 4) oR6
~r

15) N3, or
16) F

Preferably, R3 is selected from: hydrogen and Cl-C6 alkyl.
Preferably, R4 and RS are hydrogen.
S Preferably, R6, R7 and R7a is selected from: hydrogen,
unsubstituted or substituted Cl-C6 alkyl, unsubstituted or substituted
aryl and unsubstituted or sub.stituted cycloalkyl.
Preferably, R6a is unsubstituted or substituted Cl-C6 alkyl,
unsubstituted or sub.stituted aryl and unsubstituted or substituted
l 0 cycloalkyl.
Preferably, R9 is hydrogen or methyl. Most preferably, Ra
is hydrogen.
Preferably, RlO is .selected from H, Cl-C6 alkyl and
benzyl.
Preferably, Al and A2 are independently selected from:
bond, -C(O)NR l O, -NR l ~C(O)-, O, -N(R l O)-, -S(O)2N(R l O)- and-
N(R l ~)S (O)2- -
Preferably, V is selected from hydrogen, heterocycle and
aryl. More preferably, V is phenyl.
Preferably, Z is unsubstituted or substituted C l -C6 alkyl.
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 p is l, 2 or 3.
Preferably ~ is 0.
Preferably t is l.

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- 34 -

It is intended that the definition of any substituent or
variable (e.g., R1a, R9, n, etc.) at a particular location in a molecule be
independent of its definitions elsewhere in that molecule. Thus,
S -N(R10)2 represents -NHH, -NHCH3, -NHC2H5, etc. It is understood
that substituents 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 readily
synthesized by techniques known in the art, as well as those methods set
10 forth below, from readily available starting materials.
The pharmaceutically acceptable salts of the compounds of
this 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, nitric 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 di,sulfonic, 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 methods.
25 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 ~ suitable solvent or various combinations of solvents.
Reactions used to generate the compounds of this invention
30 are prepared by employing reactions as shown in the Schemes 1-21, in
addition to other standard manipulations such a~s ester hydroly.sis,
cleavage of protecting groups, etc., as may be known in the literature or
exemplified in the experimental procedures. Substituents R, Ra and Rb,
as shown in the Scheme~;, represent the substituents R2, R3, R4, and R5;

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however their point of attachment to the ring is illustrative only and is
not meant to be limiting. Substituent Z', as shown in the Schemes,
represents an alkyl moiety or a ,substitutent on an alkyl moiety such that
Z'CH2- is the substiutent Z as defined hereinabove.
S The~se reactions may be employed in a linear sequence to
provide the compounds of the invention or they may be used to
synthesize fragment,s which are subsequently joined by the alkylation
reactions described in the Schemes.

Synopsis of Schemes 1-21:
The re4uisite intermediates are in some case~i commercially
available, or can be prepared according to literature procedures, for the
most part. In Scheme 1, for example, the synthesis of 2-aL~yl
substituted piperazines is outlined, and is essentially that described by J.
1~ S. Kiely and S. R. Priebe in Or~anic Preparations and Proceedin~s Int.
1990, 22, 761-76~. Boc-protected amino acids I, available
comrnercially or by procedures known to those skilled in the art, can be
coupled to N-benzyl amino acid esters using a variety of dehydrating
agents such as DCC (dicyclohexycarbodiimide) or EDC-HCl (l-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochloride) in a solvent such
as methylene chloride, chloroform, dichloroethane, or in
dimethylforrnamide. The product II is then deprotected with acid, for
example hydrogen chloride in chloroform or ethyl acetate, or
trifluoroacetic acid in methylene chloride, and cyclized under weakly
basic conditions to give the diketopiperazine III. Reduction of III with
lithium aluminum hydride in refluxing ether gives the piperazine IV,
which is protected as the Boc derivative V. The N-benzyl group can be
cleaved under standard condition,s of hydrogenation, e.g., 10%
palladium on carbon at 60 psi hydrogen on a Parr apparatus for
24-48 h. The product VI can be reductively alkylated with a suitably
substituted aldehyde to provide the protected piperazine VII; a final acid
deprotection as previously described gives the intermediate VIII
(Scheme 2). The interrnediate VII1 can it.self be reductively alkylated
with a variety of aldehydes, such as IX. The aldehydes can be prepared

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- 36 -

by standard procedures, such as that described by O. P. Goel, U. Krolls,
M. Stier and S. Kesten in Organic Svntheses, 1988, 67, 69-75, from the
appropriate amino acid (Scheme 3). The reductive alkylation can be
accomplished at pH 5-7 with a variety of reducing agents, such as
sodium triacetoxyborohydride or sodium cyanoborohydride in a solvent
such as dichloroethane, methanol or dimethylformamide. The product
X can be deprotected to give the final compounds XI with
trifluoroacetic acid in methylene chloride. The final product XI i.s
isolated in the salt form, for example, as a trifluoroacetate,
hydrochloride or acetate salt, among other.s. The product diamine XI
can further be selectively protected to obtain XII, which can
subsequently be reductively alkylated with a second aldehyde to obtain
XIII. Removal of the protecting group, and conversion to cyclized
products such as the dihydroimidazole XV can be accomplished by
literature procedures.
Alternatively, the piperazine intermediate VIII can be
reductively alkylated with other aldehydes such as l-trityl-4-imidazolyl-
carboxaldehyde or l-trityl-4-imidazolylacetaldehyde, to give products
such as XVI (Scheme 4). The trityl protecting group can be removed
from XVl to give XVII, or alternatively, XVT can first be treated with
an alkyl halide then subsequently deprotected to give the alkylated
imidazole XVIII. Alternatively, the intermediate VIII can be acylated
or sulfonylated by standard techniques. The imidazole acetic acid XIX
can be converted to the acetate XXI by standard procedures, and XXI
can be first reacted with an alkyl halide, then treated with refluxing
methanol to provide the regiospecifically alkylated imidazole acetic acid
ester XXII. Hydrolysis and reaction with piperazine VIII in the
presence of condensin~ reagents such as 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide (EDC) leads to acylated products such as XXIV.
If the piperazine VIIl is reductively alkylated with an
aldehyde which also has a protected hydroxyl group, such a.s XXV in
Scheme 6, the protecting groups can be subsequently removed to
unmask the hydroxyl group (Schemes 6, 7). The alcohol can be
oxidized under standard conditions to e.g. an aldehyde, which can then

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be reacted with a variety of organometallic reagents such as Grignard
reagents, to obtain secondary alcohols such as XXIX. In addition, the
fully deprotected amino alcohol XXX can be reductively alkylated
(under conditions described previously) with a variety of aldehydes to
obtain secondary amines, such as XXXI (Scheme 7), or tertiary amines.
The Boc protected amino alcohol XXVII can also be
utilized to synthesize 2-aziridinylmethylpiperazines such as xxxn
(Scheme ~). Treating XXVII with 1,1'-sulfonyldiimidazole and sodium
hydride in a solvent such a~s dimethylformamide led to the formation of
aziridine XXXII. The aziridine reacted in the presence of a nucleophile,
such a~s a thiol, in the presence of base to yield the protected ring-opened
product XXXIII.
In addition, the piperazine VIIl can be reacted with
aldehydes derived from amino acids such as O-alkylated tyrosines,
according to standard procedures, to obtain compounds such as XXXIX.
When R' is an aryl group, XXXIX can fir~st be hydrogenated to unmask
the phenol, and the amine group deprotected with acid to produce XL.
Alternatively, the amine protecting group in XXXIX can be removed,
and O-alkylated phenolic amines such as XLI produced.
Depending on the identity of the amino acid 1, various side
chains can be incorporated into the piperazine. For example when I is
the Boc-protected ~-benzyl ester of aspartic acid, the intermediate
diketopiperazine XLII (where n=l and R=benzyl) is obtained, as shown
in Scheme 10. Subsequent lithium aluminum hydride reduction reduces
the ester to the alcohol XLIII, which can then be reacted with a variety
of alkylating agents such as an alkyl iodide, under basic conditions, for
example, sodium hydride in dimethylformamide or tetrahydrofuran.
The resulting ether XLrV can then be carried on to final products as
described in Schemes 1-9.
N-Alkyl piperazines can be prepared as described in
Scheme 11. An alkyl amine XLV is reacted with bis -chloroethyl amine
hydrochloride (XLVI) in refluxing n -butanol to furnish compounds
XLVII. The resulting piperazines XLVII can then be carried on to final
products as described in Schemes 3-9.

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- 38 -

Piperazin-5-ones can be prepared as shown in Scheme 12.
Reductive ~min~tion of Boc-protected amino aldehydes XLIX
(prepared from I as described previously) gives rise to compound L.
This is then reacted with bromoacetyl bromide under Schotten-Baumann
S conditions; ring closure is effected with a base such as sodium hydride
in a polar aprotic solvent such as dimethylformamide to give LI. The
carbamate protecting group is removed under acidic conditions such as
trifluoroacetic acid in methylene chloride, or hydrogen chloride gas in
methanol or ethyl acetate, and the resulting piperazine can then be
10 carried on to final products as described in Schemes 3-9.
The isomeric piperazin-3-ones can be prepared as described
in Scheme 13. The imine formed from arylcarboxamides LII and 2-
aminoglycinal diethyl acetal (LIII) can be reduced under a variety of
conditions, including sodium triacetoxyborohydride in dichloroethane,
15 to give the amine LIV. Amino acids I can be coupled to amines LIV
under standard conditions, and the resulting amide LV when treated
with aqueous acid in tetrahydrofuran can cyclize to the unsaturated
LVI. Catalytic hydrogenation under standard conditions gives the
requi.site intermediate LVII, which is elaborated to final products as
20 described in Schemes 3-9.
Reaction Scheme 14 provides an illustrative example the
synthesis of compounds of the instant invention wherein the substituents
R2 and R3 are combined to form - (CH2)U -. For example, 1-
aminocyclohexane-l-carboxylic acid LVIII can be converted to the
25 spiropiperazine LXVI essentially according to the procedures outlined
in Scheme,s 1 and 2. The piperazine intermediate LXVI can be
deprotected as before, and carried on to final products as described in
Schemes 3-9. It is understood that reagents utilized to provide the
imidazolylalkyl substituent may be readily replaced by other reagents
30 well known in the art and readily available to provide other N-
substituents on the piperazine.
The aldehyde XLIX from Scheme 12 can also be
reductively alkylated with an alkyl amine as shown in Scheme 15. The
product LXVIII can be converted to a piperazinone by acylation with

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- 39 -

chloroacetyl chloride to give LXIX, followed by base-induced
cyclization to LXX. Deprotection, followed by reductive alkylation
with a protected imidazole carboxaldehyde leads to LXXII, which can
be alkylation with an arylmethylhalide to give the imidazolium salt
5 LXXIII. Final removal of protecting groups by either solvolysi,s with a
lower alkyl alcohol, such as methanol, or treatment with triethylsilane in
methylene chloride in the presence of trifluoroacetic acid givels the final
product LXXTV.
Scheme 16 illu,strates the use of an optionally substituted
10 homoserine lactone LXXV to prepare a Boc-protected piperazinone
LXXVIII. Intermediate LXXVIII may be deprotected and reductively
alkylated or acylated as illustrated in the previous Schemes.
Alternatively, the hydroxyl moiety of intermediate LXXVIII may be
mesylated and displaced by a Isuitable nucleophile, such as the sodium
15 salt of ethane thiol, to provide an intermediate LXXIX. Intermediate
LXXVIII may also be oxidized to provide the carboxylic acid on
intermediate LXXXX, which can be utilized form an ester or amide
moiety.
Amino acids of the general formula LXXXI which have a
20 sidechain not found in natural amino acid.s may be prepared by the
reactions illustrated in Scheme 17 Istarting with the readily prepared
imine LXXXII.
Schemes 1~-21 illustrate syntheses of suitably substituted
aldehydes useful in the syntheses of the instant compounds wherein the
25 variable W is present as a pyridyl moiety. Similar synthetic strategie~s
for preparing alkanols that incorporate other heterocyclic moietie~s for
variable W are allso well known in the art.

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SCHEME 1
O Ra Rb




>~0 N~ PhcH2NHcHco2c2Hs
H o DCC, CH2Ci2


O Ra ~3
>~oJI' N~N~,CO2C2H5
H ~ Rb
Ra




1) HCI, C H2CI2 R)~o LAH ~ HN N
~ HN N~ THF, reflux \ (
2) NaHCO3 0 Rb ~ R
111 IV

a Ra
Boc2OrO~ \ 10% Pd/C ~~ )~
-~o < ~H2 CH~OH ~o

V Vl

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SCHEME 2

NaBH(OAc)3
Ra~ ~ CICH2CH2CI
BocN NH Z'-ICl-H

Rb O
Ra




)~ HCI, EtOAc
BocN~N-CH2Z
Rb




Vll


HCI N ~N- CH2Z
Rb




Vlll

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SCHEME 3


Boc NH ~ IX
Ra




Boc NH CHO
HCI N N- CH2Z'
~( NaBH (OAc)3
Rb Et3N, CIC
Vlll


C F3C02H
Boc NH ~ NyN-CH2Z'

NHBoc Rb
X
Ra




Boc20
NH2 r N N- CH2Z
b C H2Cl2
NH2 R
Xl

Ra~ ~ ~CHO
BocNH r N N-CH2Z'
< bNaBH (OAc)3
NH2 R Et3N, CIC
Xll

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SCHEME 3 (continued)


BocNH N N-CH2z~ CF3C~2H, CH2CI2;
~r y NaHco3
/=~ NH Rb
~/ Xlll
Ra




) ~ ~NC
NH2 r N N-CH2Z'
AgCN
=~ NH Rb
~/ XIV


Ra~ ~

~N N-CH2Z
b




N~N~ R
~ XV
W

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- 44 -

SCHEl\/IE 4
a NaBH(OAC)3
R~ ~Et3N, CICH2CH2CI
HCI N N--CH2Z~ (CH2)ncHo
Rb ~N5

Vlll Tr

R,~ ~

(CH2)n ~ N ~N-CH2Z
N~ Rb
Nl XVI
Tr 1 ) Ar C H2X, C H3CN
2) CF3CO2H, CH2CI~
CF3CO2H, CH2CI2 (C2H5)3siH
Ra




(,5~H2)n+1N (N~CH2Z
Ntr Rb
N
H XVII
Ra




Ar (/CH2)n 1 N ~N-CH2z
N~ Rb
N XVIII

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- 45 -

SCHEME ~

N~ 2CO2H C N.~CH2C02CH3
NH HCI NH . HCI
XIX XX
CH2C02CH3 1 ) ArCH2X CH3CN
(C6H5)3CBr ~ reflux
(C2Hs)3N N 2) CH30H, reflux
DMF Tr
XXI

Ar~\N ;~CH2C02CH3 2.5N HCl

N'~ 55~C
XXII

Af\N~CH2co2H

N
XXIII

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- 46 -

SCHEME 5 (continued)

Ar~\N~CH2C02H R~ ~
N + HCI H NyN~CH2Z'

XXIII Rb
Vlll

EDC HCI
HOBt
DMF


Ar~ Ra~ ~
N~N N-CH2Z

XXIV
-

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- 47 -

SCHEME 6


~ BocNH CHO
HCI N N- CH2Z'
\~ NaBH(OAc)3
Rb Et3N, CICH2CH2CI
Vlll
Ra




BnO N N-CH2Z' 20% Pd(OH)2 H2
\~ ~ CH30H
NHBoc ~ RbCH3CO2H
XXVI
Ra




~\ CICOCOCI
HO ~ N ~N- CH2Z' DMSO CH2C12
NHBoc Rb (C2Hs)3N
XXVII

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- 4~ -

SCHEME 6 (CONTINUED)
Ra~ 1. R'MgX
09~ N~N - C H2Z
H NHBoc Rb CH2C12
XXVIII


HO~N <N-CH2Z
R' N H2 Rb
XXIX

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- 49 -

SCHEME 7


) \ CF3CO2H
HO ~N N-CH2Z
y --( CH2CI2
NHBoc Rb
XXVII
Ra




~ R'CHO
HO ~N N-CH2Z~
y ~ NaBH(OAc)3
NH2 Rb CICH2CH2CI
XXX
Ra




HOy~N ~N - CH2Z'
NH Rb
R'CH2
XXXI

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- 50 -

SCHEME


R a~ ~ ~ N~ S

H O ~ N ~ N- CH2Z ~2
NHBoc Rb NaH, DMF0~C
XXVI I



N N- CH2Z' R'SH
--( (C2H5)3N
N Rb CH30H
Boc
XXXI I


) ~ TFA
R'S ~ N (N- CH2Z'
N HBoc Rb
XXXIII
Ra




R'S ~N ~N- CH2Z
NH2 Rb

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- 51 -

SCHEME 9

HO~ 1) Boc20, K2C~3 HO,~3

~/ THF-H20 , ~

H2N CO2H 2) CH2N2~ Et~AC gocNHJ\co2cH3
XXXIV XXXV

HO~
LiAlH4 ~W R'CH2X
THF 1 Cs2CO3
0-20~C BocNH CH2OH DMF

XXXVI

R'CH2O~ pyridine SO3 ) ~ 3

~ DMSO
BocNH CH20H (C2H5)3N BocNH ~CHO
XXXVII XXXVIII

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- 52 -

SCl IEME 9 (continued)
R'C H ~ R a~ ~

+ HCI N ~N- CH2Z'
BocNH CHO Rb
XXXVIII Vlll
NaB H (OAc)3
CIC H 2C H2C I



~ Ra~ ~
R'C H20 N N - C H2Z'

NHBoc Rb
XXXIX \ HCI
ETOAc
1 ) 20% Pd(OH)2
CH30H, CH3CO2H /

2) HCI, EtOAc / ~ ~
R'CH20 ~ N N--CH2Z'
N H2 Rb

~ Ra XLI

HO ~N N-CH2Z~
NH2 Rb

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SCHEME 10

CO2R
n( ~~ 1) LAH, Et20
HN N 2) Boc20
0~ ~
XLII
R60
HO~ R6l n( ~'~
O n( 5~ NaH DMF ~N N~


XLIV
XLIII

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- 54 -

SCHEME 1 1
Rb




Z-NH2 + CI~J\ )2NH HCI
XLV Ra
XLVI


Ra Rb
n - butanol ~(
Z-N NH HCI
reflux >~
Ra Rb
XLVII




. .

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55 _

SCHEME 12


O Ra CH3NHOCH3 HCI
>~O N~ EDC . HCI, HOBT
H o DMF, Et3N, pH 7
I




~O~N~N(CH3)0CH3 LAH, Et20
H O
XLVIII



>~O N~ Z-NH2
H O CICH2CH2CI
XLIX pH 6



O Ra 1) BrCH2COBr
>~OJ~N~NH-Z EtOAc, H20, NaHC,03
H 2) NaH, THF, DMF
L

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- 56 -

SCHEME 12 (CONT'D)


1) TFA, CH2CI2
~N N--Z
~0 ~
o




Ll
Ra




~.~
HN N-Z
o

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SCHEME 1 3

NaBH(OAc)3
Z'-CHO + NH2cH2cH(oc2H5)2


Zl-cH2NHcH2cH(oc2H5~2 I H~
LIV EDC. HCI, HOBT
DMF, Et3N, pH 7

O Ra ~Z 6N HCI
>~OJ~ N ~N~,CH(Oc2H5)2 THF
H o
LV

Ra o CH30H

~0 ~ Z'
LVI
R a o

~0 --/ Z'
LVII

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- 5~ -

SCHEME 14

r ul PhCH2NHCH2c02c2H5
~ DCC, CH2CI2
BocNH C02H
LVIII
a) TFA, C H2CI2

BocNH~f N~Co2c2Hs b) NaHCO3
0 LXIX
~0
H2N~ N~Co2c2Hs (C H3)3AI
~u)~o




HN N~ LiAlH4 HN N
o~J ~3 TH F ~/

LXI 1 \ LXII

Boc20 BocN N H2 Pd/C
CH2CI2 ~ CH30H

LXIII

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- 59 -

SCHEME 14 (continued)


4~\ NaBH(OAc)3
~ u~ CICH2CH2

BocN NH Z'- ICl - H
LXIV O
~,
~ u ~ a) TFA, CH2CI2

BocN~N- CH2Z b) NaBH(OAc)3
N~
LXV N
CPh3

TFA CH2CI2
~N N-CH2Z'
(C2H5)3siH
~N,
CPh3 LXVI
~\
rN N- CH2Z'
N ~

H 2 TFA
LXVI I

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- 60 -

SCHEME 15

R R H
BocNHlCHO NaBH(OAc)3 BocNH~N~
CICH2CH2CI
XLIX LXVIII

O R
Cl ~J~c I BocN H N--Z
EtOAc / H20 ~
NaHCO ~ Cl O
LXIX


NaH ) \ HCI
BocN N--Z
DMF \~ EtOAc
o




LXX

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- 61 -

SCHEME 15 (continued)
CHO
N~3 R

HCI HN~N-Z ( )3 , N~ ~~
ONaBH(OAc)3 N
LXXI pH 5-6 (Ph)3C

LXXII


Ar~ N N-Z
ArCH2X N~ ~~
CH3CN ~ ~ O
,N ~3 ~3
(Ph)3C X

LXXIII


MeOH ~
or Ar~ rN N-Z
TFA, CH2CI ~ O
(c2H5)3siH N
LXXIV

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- 62 -

SCHEME 16

sub\~o 1. Boc20, i-Pr2EtN ~0

H2N~ 2. DIBAL BocHN
HCI
LXXV OH
~/sub
Z-NH2 ' BocNH~/N'Z
NaBH(OAc)3
CICH2CH2CI LXXVI

HO sub
O ~/~
CI~J~cl BocNH N- Z
EtOAc / H20 ~
NaHCO3 Cl O
LXXVII

HO sub
~I~
2 , BocN N - Z
DMF ~~
o




LXXVIII
-

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- 63 -

SCHEME 16 (continued)

HO /sub

BocN N--Z

~ 1. (COCI)2, Et3N
DMSO
1. MsCI, iPr2NE~ \ 2. NaCI02,t-BuOH
2-Me-2-butene
2. NaSEt,~ ~ NaH2PO4

HO sub
EtS sub
O/rl~
BocN N--Z
BocN N--Z ~
O O
LXXX
LXXIX

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- 64 -

SCHEME 17

1. KOtBu, THF R2
r CO2Et R2x ~ CO2Et
rN ~ H2N
Ph 2. 5%aqueous HCI HCI
LXXXI


1. Boc20, NaHCO3 R2
~ CO2H
BocHN
2. LiAlH4, Et20 LXXXII

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- 65 -

REACTION SCHEME l ~

CH3 1) HNo27Br2 ~CO2CH3
~ 2) KMnO
H2N N3) MeOH,H+ Br~N~




ZnC, N C ,~Ph,P)2CO2CH3


NaBH4 (excess) ~CH20H




DM50 ~J~CHO

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- 66 -

RE~ACTION SCHEME 19
1. EtO(CO)CI R6

Br ~/\
Zn, CuCN ~CO2CH3
N 3. S, xylene, heat N
R6 R

NaBH4 ~ SO3Py, Et3N ~
(excess) ~,CH20H DMSO ~CHO



Br~,CO2CH3 ~/\MgCI
N ~CO2CH3

ZnCI2, NiC12(Ph3P)2 N

R6 R6

NaBH4 I SO3Py, Et3N
~ CH20H ~ ~CHO
(excess) N DMSO N

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- 67 -

REACTION SCHEME 20

CO2C H3
Br~ 1. LDA, CO2 Br~

N2. MeOH, H+ N


R6 MgCI 1~ C~2CH3


ZnCI2, Nicl2(ph3p)2
N




~R6

NaBH4 (excess) ~ CH20H SO3 Py, Et3N
~ JJ DMSO
N
R6




¢~ CHO

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- 68 -

REACTION SCHEME 21


[~ 1. LDA, CO2 ~N,CBHr3
2. (CH3)3SiCHN2



R6 3/\Br R6 3~

Zn, NiCI2(Ph3P)y N~Co2cH3


R6 ~
excess NaBH4 1~1~ SO3 Py, Et3N
N~CH20H DMSO


R6. ~

N ~,CHO

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The instant compounds are useful as pharmaceutical agents
for m~mmals, especially for humans. These compounds may be
~llministered to patients for use in the treatment of cancer. Examples of
the type of cancer which may be treated with the compound~ of this
S 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, lck, 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 compounds may also inhibit tumor angiogenesis, thereby
affecting the growth of tumors (J. Rak et al. Cance~ Research, 55:4575-
45~0 (199~)). 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 form) with said inhibition being accompli!ihed
by the administration of an effective amount of the compounds of the
invention to a m~mm;~l in need of such treatment. For example, a
component of NF-l 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
( I 992).
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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American Journal of Pathology, 142:1051-1060 (1993) and B. Cowley,
Jr. et al.FASEB Jol/rllal, 2:A3160 (198~)).
The instant compounds may also be useful for the treatment
of fungal infections.
The compounds of this invention may be admini.stered to
m~mm~ls, 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 administered orally or parenterally. including the
intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and
topical routes of a~ministration.
For oral use of a chemotherapeutic compound according to
this invention, the selected compound may be ~ministered, for
example, in the form of tablets or capsules, or as an a4ueous 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
~lministration in capsule form, useful diluents include lactose and dried
corn starch. When aqueous suspensions are required for oral use, the
active ingredient is combined with emul,sifying 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 in.stant invention may also be co-
~flministered with other well known therapeutic agents that are selected
30 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 kidney



.. . . .

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disease, infection.s of hepatitis delta and related viruses and fungal
infections.
If formulated as a fixed dose, such combination products
employ the compounds of this invention within the dosage range
S 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 al~so encompasses a pharmaceutical
10 composition useful in the treatment of cancer, comprising the
administration of a therapeutically effective amount of the compounds
of this invention, with or without pharmaceutically acceptable carriers
or diluents. Suitable compositions of this invention include ac3ueous
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.
When a compound according to this invention is
a~1mini~tered into a human subject, the daily dosage will normally be
20 determined by the prescribing physician with the dosage generally
varying according to the age, weight, and response of the individual
patient, as well as 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
25 cancer. Administration occurs in an amount between about 0.1 mg/kg
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
30 as a component in an assay to rapidly determine the presence and
4uantity 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

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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
5 the assay mixtures may be determined by well known
immunological, radiochemical or chromatographic techniques.
Because the compounds of the instant invention are selective
inhibitors of FPTase, ab.sence or quantitative reduction of the amount
of substrate in the assay mixture without the compound of the instant
10 invention relative to the pre~ience of the unchanged substrate in the
assay containing the instant compound is indicative of the presence of
FPTase in the composition to be te.sted.
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
15 tissue samples which contain farnesyl-protein transferase and
quantitating the enzyme. Thus, potent inhibitor compounds of the
instant invention 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
20 of farnesyl-protein transferase, an excess amount of a known substrate
of FPTase (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
25 inhibitor (i.e., one that has a Ki substantially smaller than the
concentration of enzyme in 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.

EXAMPLES

Examples provided are intended to assist in a further
understanding of the in~ention. Particular materials employed, species

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and conditions are intended to be further illustrative of the invention
and not limitative of the reasonable .scope thereof.

EXAMPLE 1




2(S)-n-Butyl- 1 -[1 -(4-cyanobenzyl)-5-imidazolylmethyl 1-4-(2,2,2-
trifluoroethyl)piperazin-5-one dihydrochloride


NC ' ' ~ CH2CF3


L-7~6,017

Step A: N-Methoxy-N-methyl 2(S)-(tert-butoxycarbonylamino)-
hexanamide
2(S)-Butoxycarbonylaminohexanoic acid (24.6 g, 0.106
mol), N,O-dimethylhydroxylamine hydrochloride (15.5 g, 0.15 mol),
EDC hydrochloride ( 22.3 g, 0.117 mol) and HOBT (14.3 g, 0.106 mol)
were stirred in dry, degassed DMF (300 mL) at 20~C under nitrogen.
N-Methylmorpholine was added to obtain pH 7. The reaction was
20 stirred overnight, the DMF distilled under high vacuum, and the residue
partitioned between ethyl acetate and 2% potassium hydrogen sulfate.
The organic phase was washed with saturated sodium bicarbonate,
water, and saturated brine, and dried with ma nesium ~sulfate. The
solvent was removed in vacuo to give the title compound.
Step B: 2(S)-(tert-Butoxycarbonylamino)hexanal
A mechanically stirred suspension of lithium aluminum
hydride (~S.00 g, 0.131 mol) in ether (250 mL) was cooled to -45~C
under nitrogen. A solution of the product from Step A (2~.3 g, 0.103
30 mol) in ether (125 mL) was added, maintainin~ the temperature below

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-35~C. When the addition was complete, the reaction was warmed to
5~C, then recooled to -45~C. A solution of potassium hydrogen sulfate
(27.3 g, 0.200 mol) in water was slowly added, maintaining the
temperature below -5~C. After quenching, the reaction was stirred at
room temperature for lh. The mixture was filtered through Celite, the
ether evaporated, and the remainder partitioned between ethyl acetate
and 2% potassium hydrogen sulfate. After washing with saturated
brine, drying over magnesium sulfate and solvent removal, the title
compound was obtained.
Step C: N-(2,2,2,-Trifluoroethyl)-2(S)-(tert-
butoxycarbonylamino)-hexanamine
2,2,2-Trifluoroethylamine hydrochloride (0.407 g, 3.0
mmol) wa.s dissolved in dichloroethane under nitrogen. N-Methyl
15 morpholine (0.330 mL, 3.0 mmol) was added to obtain pH 5-6, and
sodium triacetoxyborohydride (0.795 g, 3.75 mmol) was added. A
solution of the product from Step B (0.573 g, 2.5 mmol) in
dichloroethane (~0 mL) was added slowly dropwi.se at 20~C. The
reaction was stirred overnight, then quenched with saturated sodium
20 bicarbonate solution. The aqueou.s layer was removed, the organic
phase washed with saturated brine and dried over magnesium sulfate.
The title compound was obtained as an oil.

Step D: l-tert-Butoxycarbonyl-2(S)-n-butyl-4-(2,2,2-
trifluoroethyl)piperazin-5-one
A solution of the product from Step C (0.590 g, 1.9~
mmol) in ethyl acetate (30 mL) was vigorously stirred at 0~C with
saturated sodium bicarbonate (30 mL). Chloroacetyl chloride (0.315
mL, 3.96 mmol) was added, and the reaction stirred at 0~C for 1 h.
30 The layers were separated, and the ethyl acetate phase was washed with
saturated brine, and dried over magnesium sulfate. The crude product
was dissolved in DMF (15 mL) and cooled to 0~C under nitrogen.
C~esium carbonate (1.67 g, 5.12 mmol) was added and the reaction
stirred 1 h at 0~C, then at room temperature overnight. The reaction

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was 4uenched with ~mminium chloride, and partitioned between ethyl
acetate and water. The organic phase was washed with water, saturated
brine, and dried over magnesium sulfate. The title compound was
obtained as a colorless oil.

Step E: l -Triphenylmethyl-4-(hydroxymethyl)imidazole
To a solution of 4-(hydroxymethyl)imidazole
hydrochloride (35.0 g, 260 mmol) in 250 mL of dry DMF at room
temperature was added triethylamine (90.6 mL, 650 mmol). A white
10 solid precipitated from the solution. Chlorotriphenylmethane (76.1 g,
273 mmol) in 500 mL of DMF was added dropwise. The reaction
mixture was stirred for 20 hours, poured over ice, filtered, and washed
with ice water. The resulting product was slurried with cold dioxane,
filtered, and dried in vacuo to provide the titled product as a white solid
15 which was sufficiently pure for use in the next step.

Step F: I -Triphenylmethyl-4-(acetoxymethyl)-imidazole
Alcohol from Step E (260 mmol, prepared above) was
suspended in 500 mL of pyridine. Acetic anhydride (74 mL, 780
20 mmol) was added dropwise, and the reaction was stirred for 4~s hours
during which it became homogeneous. The solution was poured into 2
L of EtOAc, washed with water (3 x 1 L), 5% aq. HCI soln. (2 x 1 L),
sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and
concentrated in vacuo to provide the crude product. The acetate was
25 isolated as a white powder which wa.s ~ufficiently pure for use in the
next reaction.

Step G: 1-(4-Cyanobenzyl)-5-(acetoxymethyl)-imidazole
hydrobromide
A solution of the product from Step F (85.~ g, 225 mmol)
and ~-bromo-p-tolunitrile (50.1 g, 232 mmol) in 500 mL of EtOAc was
stirred at 60 ~C for 20 hours, during which a pale yellow precipitate
formed. The reaction was cooled to room temperature and filtered to
provide the solid imidazolium bromide salt. The filtrate was

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concentrated in vacuo to a volume 200 mL, reheated at 60 ~C for two
hours, cooled to room temperature, and filtered again. The filtrate was
concentrated in vacuo to a volume 100 mL, reheated at 60 ~C for
another two hours, cooled to room temperature, and concentrated in
5 vacuo to provide a pale yellow solid. All of the solid material wa.s
combined, dissolved in 500 mL of methanol, and warmed to 60 ~C.
After two hours, the solution was reconcentrated in vacuo to provide a
white solid which was triturated with hexane to remove soluble
materials. Removal of residual solvents in vacuo provided the titled
10 product hydrobromide as a white solid which was used in the next step
without further purification.

Step H: 1-(4-Cyanobenzyl)-5-(hydroxymethyl)-imidazole
To a solution of the acetate from Step G (50.4 g, 150
15 mmol) in 1.5 L of 3:1 THF/water at 0 ~C was added lithium hydroxide
monohydrate (18.9 g, 450 mmol). After one hour, the reaction was
concentrated in vacuo, diluted with EtOAc (3 L), and washed with
water, sat. aq. NaHCO3 and brine. The solution was then dried
(Na2SO4), filtered, and concentrated in vacuo to provide the crude
20 product as a pale yellow fluffy solid which was sufficiently pure for use
in the next step without further purification.

Step I: 1 -(4-Cyanobenzyl~-5-imidazolecarboxaldehyde
To a solution of the alcohol from Step H (21.5 g, 101
25 mmol) in 500 mL of DMSO at room temperature was added
triethylamine (56 mL, 402 mmol), then SO3-pyridine complex (40.5 g,
254 mmol). After 45 minutes, the reaction was poured into 2.5 L of
EtOAc, washed with water (4 x 1 L) and brine, dried (Na2SO4),
filtered, and concentrated in vacuo to provide the aldehyde a~i a white
30 powder which was sufficiently pure for use in the next step without
further purification.

Step J: 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-
(2,2.2-trifluoroethyl)-piperazin-5-one dihydrochloride

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A solution of the product from Step D (0.57~s g, 1.71
mmol) wa,~ stirred in 30% trifluoroacetic acid in methylene chloride for
1 h. The volatile~ were removed in vacuo, and the residue dissolved in
dichloroethane (5 mL). The pH wa~ adjusted to 5-6 with N-
5 methylmorpholine. Sodium triacetoxyborohydride (0.544 g, 2.57mmol) and l-(4-cyanobenzyl)imidazolyl-5-carboxaldehyde from Step I
(0.361 g, 1.71 mmol) was added. The reaction was stirred overnight at
20~C then poured into saturated sodium bicarbonate ~solution. The
organic phase wa~ washed with saturated brine and dried over
10 magne.~ium sulfate. The crude product was purified by preparative
HPLC on a 40 X 100 mm Waters PrepPak(~) rever~e phase HPLC
column (Delta-PakTM Cl~ 15 lum, 100 A) using a gradient elution of
25% (0.1% TFA in acetonitrile), 75% (0.1% TFA in water) progressing
to 45% (0.1% TFA in acetonitrile), 55% (0.1% TFA in water) over 50
15 min. Pure fraction~s were c-ombined, concentrated, and the re~iidue
partitioned between ethyl acetate and saturated ~;odium bicarbonate
~olution. The organic layer was dried over magnesium sulfate. The
purified product was converted to the hydrochloride salt with HCI in
dichloromethane. The title compound was obtained as a white solid.
20 FAB ms (m+1) 434. Anal. Calc. for C22H26F3N5O 2.0 HCI: C,
52.1~; H? 5.57; N, 13.g3. Found: C, 52.41; H, 5.60; N, 13.65.

EXAMPLE 2

25 2(S)-n-Butyl- 1 -[1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-L 1 -(3,3,3-
trifluoropropyl)l-piperazin-5-one dihvdrochloride




~=~ N~
N


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- 7~ -

Step A: N- 1-(3 ,3 ,3 -Trifluoropropyl)-2(S)-(te7 t-
butoxycarbonylamino)-hex~n~mine
The title compound is prepared according to the procedure
de.scribed in Example 1, Step C, except using 1-(3,3,3-
5 trifluoropropyl)amine hydrochloride in place of 2,2,2-
trifluoroethylamine hydrochloride.

Step B: 1 -te) t-Butoxycarbonyl-2(S)-n-butyl-4-L 1-(3,3,3-
trifluoropropyl)lpiperazin-5 -one
The title compound is prepared according to the procedure
described in Example 1, Step D, except using N-1-(3,3,3-
trifluoropropyl)-2(S)-~te7 t-butoxycarbonylamino)hexanamine in place
of N-(2,2,2,-trifluoroethyl)-2(S)-(tert-
butoxycarbonylamino)hexanamine.
Step C: 2(S)-n-Butyl-1-[1-(4-cyanobenzyl)-5-imidazolylrnethyl]-4-
~1-(3,3~3-trifluoropropyl)lpiperazin-5-one dihydrochloride
The title compound is prepared according to the procedure
described in Example 1, Step J, except using l-~ert-butoxycarbonyl-
20 2(S)-n-butyl-4-[1-(3,3,3-trifluoropropyl)~piperazin-5-one in place of 1-
tert-butoxycarbonyl-2(S)-n-butyl-4-(2,2,2-trifluoroethyl)piperazin-5-
one. The purified product is converted to the hydrochloride salt with
HCl in dichloromethane.

EXAMPLE 3

2(S)-n-Butyl-1-[ 1 -(4-cyanobenzyl)-5-imidazolylmethyl]-4-
(cvclopropylmethyl)piperazin-5-one dihydrochloride

..... ~

NC ------<~ --~--- ( --- N N-J

N

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Step A: N-(Cyclopropylmethyl)-2(S)-(Iert-butoxycarbonylamino)-
hexanamme
The title compound is prepared according to the procedure
5 described in Example 1, Step C, except using cyclopropylmethylamine
hydrochloride in place of 2,2,2-trifluoroethylamine hydrochloride.

Step B: l-tert-Butoxycarbonyl-2(S)-n-butyl-4-
(cyclopropylmethyl)piperazin-5 -one
The title compound is prepared according to the procedure
described in Example 1, Step D, except using N-(cyclopropylmethyl)-
2(S)-(tert-butoxycarbonylamino)hexanamine in place of N-(2,2,2,-
trifluoroethyl)-2(S)-(tert-butoxycarbonylamino)hexanamine.
~5 Step C: 2(S)-n-Butyl-1-[ 1-(4-cyanobenzyl)-5-imidazolylmethyl]-4-
(cyclopropylmethyl)piperazin-5-one dihydrochloride
The title compound is prepared according to the procedure
described in Example 1, Step J, except using l-tert-butoxycarbonyl-
2(S)-n-butyl-4-(cyclopropylmethyl)piperazin-5-one in place of l-tert-
20 butoxycarbonyl-2(S)-n-butyl-4-(2,2,2-trifluoroethyl)piperazin-5-one to
obtain the title compound. The purified product is converted to the
dihydrochloride salt with HCI in dichloromethane.

EXAMPL~ 4
2(S)-n-Butyl- 1 -[3-(4-cyanobenzyl)pyridin-4-yll-4-(2,2,2-
trifluoroethvl)piperazin-5-one dihydrochloride


NC ~ ~ N~ N- CH2CF3

N~


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Step A: 3-(4-Cyanobenzyl)pyridin-4-carboxylic acid methyl ester
A solution of 4-cyanobenzyl bromide (0.625 g, 3.27 mmol)
in dry THF (4 mL) was added slowly over~3 min to a suspension of
5 activated zinc (dust; 0.250 g) in dry THF (2 mL) at 0~C under an argon
atmosphere. The ice-bath was removed and the slurry was stirred at
room temperature for a further 30 min. Then 3-bromopyridin-4-
carboxylic acid methyl ester (0.540 g. 2.5 mmol) followed by
dichlorobis(triphenylphosphine)nickel (II) (50 mg). The resultant
10 reddish-brown mixture was stirred for 3 h at ~40-45~C. The mixture
was cooled and di~stributed between ethyl acetate (100 ml) and 5%
aqueous citric acid (50 mL). The organic layer was washed with water
(2X50 mL), dried with Na2SO4. After evaporation of the solvent the
residue was purified on silica gel, eluting with 35% ethyl acetate in
15 hexane to give 0.420 g as a~clear gum. FAB ms (M+l) 253.

Step B: 3-(4-Cyanobenzvl)-4-(hydroxymethyl)pyridine
The title compound was obtained by sodium borohydride
(300 mg) reduction of the ester from Step A (0.415 g) in methanol (5
20 mL) at room temperature. After stirring for 4 h the solution was
evaporated and the product was purified on silica gel, eluting with 2%
methanol in chloroform to give the title compound. FAB ms (M+l )
225.

25 Step C: 3-(4-Cyanobenzyl)-4-pyridinal
The title compound was obtained by activated manganese
dioxide (1.0 g) oxidation of the alcohol from Step B (0.240 g, 1.07
mmol) in dioxane (lO mL) at reflux for 30 min. Filtration and
evaporation of the solvent provided title compound, mp ~0-~3~C.
Step D: 3(S)-n-Butyl-1-[3-(4-cyanobenzyl)pyridin-~-yl]-4-(2,2,2-
trifluoroethyl)piperazin-~S-one dihvdrochloride
The title compound is prepared according to the procedure
described in Example 1 Step J, except using 3-(4-cyanobenzyl)-4-


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pyridinal from Step C in place of 1-(4-cyanobenzyl)imidazolyl-5-
carboxaldehyde. The purified product is converted to the
dihydrochloride salt with HCl in dichloromethane.

EXAMPLE 5

In vitro inhibition of ras farnesyl transferase
Assays of fa) nesyl-protein ~ ansfe7 ase. Partially purified
bovine FPTa.se and Ras peptides (Ras-CVLS, Ras-CVIM and Ras-CAIL)
10 were prepared as described by Schaber et ah, J. Biol. Chem. 265:14701-
14704 (1990), Pompliano, et ah, Biochemistry 31:3~00 (1992) and
Gibbs et ah, PNAS U.S.A. ~6:6630-6634 (1989), respectively. Bovine
FPTase was assayed in a volume of 100 ~I containing 100 mM N-(2-
hydroxy ethyl) piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4,
15 5 mM MgC12, 5 mM dithiothreitol (DTT), 100 mM [3H]-farnesyl
diphosphate ([3H]-FPP; 740 CBq/mmol, New England Nuclear), 650 nM
Ras-CVLS and 10 ~g/ml FPTase at 31~C for 60 min. Reactions were
initiated with FPTase and stopped with 1 ml of 1.0 M HCL in ethanol.
Precipitate.s were collected onto filter-mat,s using a TomTec Mach II cell
20 harvestor, washed with 100% ethanol, dried and counted in an LKB ,B-
plate counter. The assay was linear with respect to both substrates,
FPTase levels and time; less than 10% of the [3H]-FPP was utilized
during the reaction period. Purified compounds were dissolved in
100% dimethyl sulfoxide (DMSO) and were diluted 20-fold into the
25 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 absence of the test
compound.
Human FPTase was prepared as described by Omer et ah,
30 Biochemistry 32:5167-5176 (1993). Human FPTase activity was
as.sayed a.s de.scribed above with the exception that 0.1% (w/v)
polyethylene glycol 20,000, 10 ~M ZnCI2 and 100 nM Ras-CVIM were
added to the reaction mixture. Reactions were performed for 30 min.,

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- 82 -

stopped with 100 ~l of 30% (v/v) trichloroacetic acid (TCA) in ethanol
and processed as described above for the bovine enzyme.
The compounds of the instant invention described in the
above Examples and in the Tables hereinafter were tested for inhibitory
5 activity against human FPTase by the assay described above and were
found to have IC50 of c50 ~M.

EXAMPLE 6

0 In vivo 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 performed essentially as described in DeClue, J.E. et ah, Cancer
Research 51:712-717, (1991). Cells in 10 cm dishes at 50-75%
15 confluency are treated with the test compound (final concentration of
solvent, methanol or dimethyl sulfoxide, is 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
mCi[35S]methionine (1000 Ci/mmol). After an additional 20 hours, the
20 cells are lysed in 1 ml lysis buffer (1% NP40t20 mM HEPES, pH 7.5/5
mM MgCl2/lmM DTT/10 mg/ml aprotinen/2 mg/ml leupeptin/2 mg/ml
antipain/0.5 mM PMSF) and the lysates cleared by centrifugation at
100,000 x g for 45 min. Aliquots of lysates containing equal numbers
of acid-precipitable counts are bought to 1 ml with IP buffer (lysis
25 buffer lacking DTT) and immunoprecipitated with the ras-specific
monoclonal antibody Y13-259 (Furth, M.E. et al., 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
is added for 45 min. The immunoprecipitates are washed four times
30 with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1% Triton X-
100Ø5% deoxycholate/0.1%/SDS/0.1 M NaCl) 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
autoradiographed. The intensities of the bands corresponding to

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W O 97/36~93 PCTrUS97/05144


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farne,sylated and nonfarne~sylated ras proteins are compared to
determine the percent inhibition of farne~syl transfer to protein.

EXAMPLE 7




In vivo ~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 tran~sformed with either a
V-1aS, v-raf; or V-m05 oncogene is 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
15 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
methanol at 1000 times the final concentration used in the assay). The
20 cells are fed twice weekly with 0.5 ml of medium A cont:~ining 0.1%
methanol or the concentration of the instant compound.
Photomicrographs are taken 16 days after the cultures are seeded and
comparisons are made.