US2002037888A1PendingUtilityA1
Inhibitors of prenyl-protein transferase
Est. expiryDec 8, 2018(expired)· nominal 20-yr term from priority
A61P 31/22A61P 31/12A61P 35/00C07D 233/64C07D 471/04C07D 403/12C07D 413/12C07D 249/08A61P 27/02C07D 233/56C07D 231/12C07D 401/12
46
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Claims
Abstract
The present invention is directed to compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula I:
wherein:
R 1a , R 1b and R 1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, (R 8 ) 2 NC(O)—, —N(R 15 ) 2 , —OR 15 , —N(R 8 )S(O) q R 8 or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is independently selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —R 8 C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —R 8 NHC(O)R 8 ,
k) —R 8 C(O)N(R 8 ) 2 ,
l) CF 3 ,
m) halo,
n) —C(O)OR 8 ,
o) C 2 —C 6 alkynyl,
p) C 2 —C 6 alkenyl,
q) perfluoroalkyl,
r) N 3 ,
s) NO 2 ,
t) CN,
u) R 9 S(O) q —,
v) —(C 1 —C 6 alkyl)NR 8 C(O)N(R 8 ) 2 , and
w) —(C 1 —C 6 alkyl)R 14 ;
R 2 is independently selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 5 and R 6 are independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl),
u) —(C 1 -C 6 alkyl)C(O)R 8 ,
v) —C(O)O(C 1 -C 6 alkyl),
w) —C(O)N(R 8 ) 2 ,
x) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 ,
y) —(C 1 -C 6 alkyl)NR 8 C(O)R 8 ,
z) —C 2 -C 6 alkynyl,
aa) —C 2 -C 6 alkenyl,
bb) —(C 1 -C 6 alkyl)N 3 ,
cc) —(C 1 -C 6 alkyl)NR 8 S(O) q , and
dd) —(C 1 -C 6 alkyl)NR 8 (C 1 -C 6 alkyl)N(R 8 ) 2 ;
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R 14 is unsubstituted saturated heterocycle;
R 15 is independently selected from
a) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 9 S(O) 2 —, R 8 C(O)—, R 8 OC(O)—, (R 8 ) 2 NC(O)—, and
b) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
A 1 and A 2 are independently selected from:
a) a bond,
b) —HC═CH—,
c) —C≡C—,
d) O,
e) S(O) q ,
f) OC(O),
g) C(O),
h) C(O)O, and
i) NR 8 ;
A 3 is selected from a bond, —C(═O)—,
and C 3 -C 6 cycloalkyl;
M is selected from CH 2 , NR 8 , O or S(O) q ;
Q is selected from S(O) q , CH 2 , C(═S), C(═NR 8 ) or C(═O);
W is selected from:
a) heterocycle, and
b) aryl;
Y is selected from:
a) aryl, and
b) heterocycle;
Z is selected from:
a) aryl,
b) heterocycle,
c) C 3 -C 6 cycloalkyl, and
d) a bond;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
x is 0, 1, 2 or 3;
provided that the moiety
does not represent a bond; and
provided that if attachment of
to the rest of the molecule is through a nitrogen ring atom, then A 1 is NR 8 , O, or S(O) q ;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
2 . A compound of the formula A:
wherein:
R 1a , R 1b and R 1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl; unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , (R 8 ) 2 NC(O)—, C(O)N(R 8 )—, or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —R 8 C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —R 8 NHC(O)R 8 ,
k) —R 8 C(O)N(R 8 ) 2 ,
l) CF 3 ,
m) halo,
n) —C(O)OR 8 ,
o) C 2 -C 6 alkynyl,
p) C 2 -C 6 alkenyl,
q) perfluoroalkyl,
r) N 3 ,
s) NO 2 ,
t) CN, and
u) R 9 S(O) q —;
R 2 is selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 4 is selected from:
a) H,
b) ═O, or
c) ═S;
R 5 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl), and
u) —(C 1 -C 6 alkyl)C(O)R 8 ;
R 6 is selected from:
a) H,
b) C 1 -C 6 alkyl, unsubstituted or substituted,
c) OR 8 , and
d) —C(O)(C 1 -C 6 alkyl);
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
A 1 and A 2 are independently selected from:
a) a bond,
b) —HC═CH—,
c) —C≡C—,
d) O,
e) S(O) q ,
f) OC(O),
g) C(O),
h) C(O)O, and
i) NR 8 ;
h) C(O)O, and
A 3 is selected from a bond, —C(═O)—,
and C 3 -C 6 cycloalkyl;
M is selected from CH 2 , NH, O or S;
W is selected from:
a) hydrogen,
b) heterocycle, and
c) aryl;
Y is selected from:
a) aryl, and
b) heterocycle;
Z is selected from:
a) aryl,
b) heterocycle,
c) C 3 -C 6 cycloalkyl, and
d) a bond;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
3 . The compound according to claim 2 of formula A:
wherein:
R 1a , R 1b and R 1c are independently selected from
a) hydrogen,
b) unsubstituted or substituted aryl; unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , (R 8 ) 2 NC(O)—, C(O)N(R 8 )—, or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —(C 1 -C 6 alkyl)C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —(C 1 -C 6 alkyl)NHC(O)R 8 ,
k) —(C 1 -C 6 alkyl)C(O)N(R 8 ) 2 ,
l) CF 3 , and
m) halo;
R 2 is selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 4 is selected from:
a) H,
b) ═O, or
c) ═S;
R 5 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl), and
u) —(C 1 -C 6 alkyl)C(O)R 8 ;
R 6 is selected from:
a) H,
b) C 1 -C 6 alkyl, unsubstituted or substituted,
c) OR 8 , and
d) —C(O)(C 1 -C 6 alkyl);
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
A 1 is selected from:
a) a bond,
b) —HC═CH—,
c) —C≡C—,
d) O,
e) S(O) q ,
f) OC(O),
g) C(O),
h) C(O)O, and
i) NR 8 ;
A 2 is selected from:
a) a bond,
b) O,
c) S(O) q ,
d) C(O), and
e) NR 8 ;
A 3 is selected from a bond, —C(═O)—,
and C 3 -C 6 cycloalkyl;
M is selected from CH 2 or NH;
W is selected from:
a) heterocycle, and
b) aryl;
Y is selected from:
a) aryl, and
b) heterocycle;
Z is selected from:
a) aryl,
b) heterocycle, and
c) a bond;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
4 . The compound according to claim 3 of formula B:
wherein:
R 1a and R 1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl; unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , (R 8 ) 2 NC(O)—, C(O)N(R 8 )—, or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —(C 1 -C 6 alkyl)C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —(C 1 -C 6 alkyl)NHC(O)R 8 ,
k) —(C 1 -C 6 alkyl)C(O)N(R 8 ) 2 ,
l) CF 3 , and
m) halo;
R 2 is selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 4 is selected from:
a) H,
b) —O, or
c) ═S;
R 5 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl), and
u) —(C 1 -C 6 alkyl)C(O)R 8 ;
R 6 is selected from:
a) H,
b) C 1 -C 6 alkyl, unsubstituted or substituted,
C) OR 8 , and
d) —C(O)(C 1 -C 6 alkyl);
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
A 1 is selected from:
a) a bond,
b) —HC═CH—,
c) —C≡C—,
d) O,
e) S(O) q ,
f) OC(O),
g) C(O),
h) C(O)O, and
i) NR 8 ;
W is selected from:
a) heterocycle, and
b) aryl;
Y is selected from:
a) aryl, and
b) heterocycle;
Z is selected from:
a) aryl, and
b) heterocycle;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
s is 0, 1, 2, 3 or 4; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
5 . The compound according to claim 1 of formula II:
wherein:
R 1c is independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, (R 8 ) 2 NC(O)—, —N(R 15 ) 2 , —OR 15 , —N(R 8 )S(O) q R 8 or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is independently selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —R 8 C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —R 8 NHC(O)R 8 ,
k) —R 8 C(O)N(R 8 ) 2 ,
l) CF 3 ,
m) halo,
n) —C(O)OR 8 ,
o) C 2 -C 6 alkynyl,
p) C 2 -C 6 alkenyl,
q) perfluoroalkyl,
r) N 3 ,
s) NO 2 ,
t) CN,
u) R 9 S(O) q —,
v) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 , and
w) —(C 1 -C 6 alkyl)R 14 ;
R 2 is independently selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 5 and R 6 are independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl),
u) —(C 1 -C 6 alkyl)C(O)R 8 ,
v) —C(O)O(C 1 -C 6 alkyl),
w) —C(O)N(R 8 ) 2 ,
x) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 ,
y) —(C 1 -C 6 alkyl)NR 8 C(O)R 8 ,
z) —C 2 -C 6 alkynyl,
aa) —C 2 -C 6 alkenyl,
bb) —(C 1 -C 6 alkyl)N 3 ,
cc) —(C 1 -C 6 alkyl)NR 8 S(O) q , and
dd) —(C 1 -C 6 alkyl)NR 8 (C 1 -C 6 alkyl)N(R 8 ) 2 ;
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R 14 is unsubstituted saturated heterocycle;
R 15 is independently selected from
a) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 9 S(O) 2 —, R 8 C(O)—, R 8 OC(O)—, (R 8 ) 2 NC(O)—, and
b) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
A 1 and A 2 are independently selected from:
a) a bond,
b) —HC═CH—,
c) —C≡C—,
d) O,
e) S(O) q ,
f) OC(O),
g) C(O),
h) C(O)O, and
i) NR 8 ;
A 3 is selected from a bond, —C(═O)—,
and C 3 -C 6 cycloalkyl;
M is selected from CH 2 , NR 8 , O or S(O) q ;
Q is selected from S(O) q , CH 2 , C(═S), C(═NR 8 ) or C(═O);
W is a heterocycle;
Y is selected from
a) aryl, and
b) heterocycle;
Z is selected from
a) aryl, and
b) heterocycle;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
r is 0, 1, 2, 3, or 4;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
x is 0, 1, 2 or 3;
provided that if attachment of
to the rest of the molecule is through a nitrogen ring atom, then A 1 is NR 8 , O, or S(O) q ;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
6 . The compound according to claim 1 of formula III:
wherein:
R 1a , and R 1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, (R 8 ) 2 NC(O)—, —N(R 15 ) 2 , —OR 15 , —N(R 8 )S(O) q R 8 or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is independently selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —R 8 C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —R 8 NHC(O)R 8 ,
k) —R 8 C(O)N(R 8 ) 2 ,
l) CF 3 ,
m) halo,
n) —C(O)OR 8 ,
o) C 2 -C 6 alkynyl,
p) C 2 -C 6 alkenyl,
q) perfluoroalkyl,
r) N 3 ,
s) NO 2 ,
t) CN,
u) R 9 S(O) q —,
v) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 , and
w) —(C 1 -C 6 alkyl)R 14 ;
R 2 is independently selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 5 and R 6 are independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl),
u) —(C 1 -C 6 alkyl)C(O)R 8 ,
v) —C(O)O(C 1 -C 6 alkyl),
w) —C(O)N(R 8 ) 2 ,
x) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 ,
y) —(C 1 -C 6 alkyl)NR 8 C(O)R 8 ,
z) —C 2 -C 6 alkynyl,
aa) —C 2 -C 6 alkenyl,
bb) —(C 1 -C 6 alkyl)N 3 ,
cc) —(C 1 -C 6 alkyl)NR 8 S(O) q , and
dd) —(C 1 -C 6 alkyl)NR 8 (C 1 -C 6 alkyl)N(R 8 ) 2 ;
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R 14 is unsubstituted saturated heterocycle;
R 15 is independently selected from
a) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 9 S(O) 2 —, R 8 C(O)—, R 8 OC(O)—, (R 8 ) 2 NC(O)—, and
b) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
A 1 is selected from:
a) a bond,
b) —HC═CH—,
c) —C≡C—,
d) O,
e) S(O) q ,
f) OC(O),
g) C(O),
h) C(O)O, and
i) NR 8 ;
A 3 is selected from a bond, —C(═O)—,
and C 3 -C 6 cycloalkyl;
M is selected from CH 2 , NR 8 , O or S(O) q ;
Q is selected from S(O) q , CH 2 , C(═S), C(═NR 8 ) or C(═O);
W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridyl, triazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and tetrahydroimidazopyridinyl,
Y is selected from:
a) aryl, and
b) pyridyl;
Z is selected from:
a) aryl, and
b) pyridyl;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, or 2;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
x is 0, 1, 2 or 3;
provided that if attachment of
to the rest of the molecule is through a nitrogen ring atom, then A 1 is NR 8 , O, or S(O) q ;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
7 . The compound according to claim 2 of formula C:
wherein:
R 1a and R 1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl; unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , (R 8 ) 2 NC(O)—, C(O)N(R 8 )—, or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —(C 1 -C 6 alkyl)C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —(C 1 -C 6 alkyl)NHC(O)R 8 ,
k) —(C 1 -C 6 alkyl)C(O)N(R 8 ) 2 ,
l) CF 3 , and
m) halo;
R 2 is selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 4 is selected from:
a) H,
b) ═O, or
c) ═S;
R 5 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl), and
u) —(C 1 -C 6 alkyl)C(O)R 8 ;
R 6 is selected from:
a) H,
b) C 1 -C 6 alkyl, unsubstituted or substituted,
c) OR 8 , and
d) —C(O)(C 1 -C 6 alkyl);
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
A 1 is selected from:
a) a bond,
b) —HC═CH—,
c) —C≡C—,
d) O,
e) S(O) q ,
f) OC(O),
g) C(O),
h) C(O)O, and
i) NR 8 ;
W is selected from:
a) heterocycle, and
b) aryl;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
s is 0, 1, 2, 3 or 4; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
8 . The compound according to claim 1 of formula IV:
wherein:
R 1c ′ is selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1c ″ is selected from:
a) hydrogen,
b) N(R 15 ) 2 , and
c) OR 15 ;
R 1 is independently selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —R 8 C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —R 8 NHC(O)R 8 ,
k) —R 8 C(O)N(R 8 ) 2 ,
l) CF 3 ,
m) halo,
n) —C(O)OR 8 ,
o) C 2 -C 6 alkynyl,
p) C 2 -C 6 alkenyl,
q) perfluoroalkyl,
r) N 3 ,
s) NO 2 ,
t) CN,
u) R 9 S(O) q —,
v) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 , and
w) —(C 1 -C 6 alkyl)R 14 ;
R 2 is independently selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 5 is independently selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl),
u) —(C 1 -C 6 alkyl)C(O)R 8 ,
v) —C(O)O(C 1 -C 6 alkyl),
w) —C(O)N(R 8 ) 2 ,
x) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 ,
y) —(C 1 -C 6 alkyl)NR 8 C(O)R 8 ,
z) —C 2 -C 6 alkynyl,
aa) —C 2 -C 6 alkenyl,
bb) —(C 1 -C 6 alkyl)N 3 ,
cc) —(C 1 -C 6 alkyl)NR 8 S(O) q , and
dd) —(C 1 -C 6 alkyl)NR 8 (C 1 -C 6 alkyl)N(R 8 ) 2 ;
R 6 is selected from
a) H,
b) C 1 -C 6 alkyl, unsubstituted or substituted,
c) aryl, unsubstituted or substituted,
d) heterocycle, unsubstituted or substituted,
e) C 3 -C 10 cycloalkyl,
f) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —C(O)(C 1 -C 6 alkyl),
i) —(C 1 -C 6 alkyl)C(O)R 8 ,
j) —C(O)O(C 1 -C 6 alkyl),
k) —C(O)N(R 8 ) 2 ,
l) —(C 1 -C 6 alkyl)NR 8 C(O)N(R 8 ) 2 ,
m) —(C 1 -C 6 alkyl)NR 8 C(O)R 8 ,
n) —C 2 -C 6 alkynyl,
o) —C 2 -C 6 alkenyl,
p) —(C 1 -C 6 alkyl)N 3 ,
q) —(C 1 -C 6 alkyl)NR 8 S(O) q , and
r) —(C 1 -C 6 alkyl)NR 8 (C 1 -C 6 alkyl)N(R 8 ) 2 ;
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R 14 is unsubstituted saturated heterocycle;
R 15 is independently selected from
a) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 9 S(O) 2 —, R 8 C(O)—, R 8 OC(O)—, (R 8 ) 2 NC(O)—, and
b) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
A 1 is selected from
a) O,
b) S(O) q ,
c) C(O), and
d) NR 8 ;
M is selected from CH 2 , NR 8 , O or S(O) q ;
Q is selected from S(O) q , CH 2 , C(═S), C(═NR 8 ) or C(═O);
W is a heterocycle selected from imidazolyl, triazolyl or pyridyl;
Y is selected from phenyl or pyridyl;
Z is selected from phenyl or pyridyl;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
s is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
x is 0, 1, 2 or 3;
provided that if attachment of
to the rest of the molecule is through a nitrogen ring atom, then A 1 is NR 8 , O, or S(O) q ;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
9 . The compound according to claim 2 of formula D:
R 1a and R 1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl; unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, NO 2 , R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , (R 8 ) 2 NC(O)—, C(O)N(R 8 )—, or N 3 ;
c) C 1 -C 6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, R 8 O—, R 9 S(O) q —, CN, R 8 C(O)—, R 8 OC(O)—, N(R 8 ) 2 , N 3 , or R 8 C(O)O—;
R 1 is selected from:
a) H,
b) unsubstituted or substituted C 1 -C 6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
f) —(C 1 -C 6 alkyl)C(O)R 8 ,
g) —(C 1 -C 6 alkyl)OR 8 ,
h) —N(R 8 ) 2 ,
i) —OR 8 ,
j) —(C 1 -C 6 alkyl)NHC(O)R 8 ,
k) —(C 1 -C 6 alkyl)C(O)N(R 8 ) 2 ,
l) CF 3 , and
m) halo;
R 2 is selected from:
a) hydrogen,
b) CN,
c) NO 2 ,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C 1 -C 6 alkyl, unsubstituted or substituted,
h) OR 8 ,
i) N 3 ,
j) R 9 S(O) q ,
k) R 8 HC═CH—, and
l) R 8 C≡C—;
R 3 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) OR 8 ,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF 3 ;
R 4 is selected from:
a) H,or
b) ═O;
R 5 is selected from:
a) H,
b) CN,
c) NO 2 ,
d) halogen,
e) C 1 -C 6 alkyl, unsubstituted or substituted,
f) N 3 ,
g) R 9 S(O) q ,
h) —HC═CH 2 ,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF 3 O—,
m) CF 3 CH 2 O—,
n) C 3 -C 10 cycloalkyl,
o) CF 3 ,
p) —(C 1 -C 6 alkyl)N(R 8 ) 2 ,
q) —(C 1 -C 6 alkyl)OR 8 ,
r) OR 8 ,
s) N(R 8 ) 2 ,
t) —C(O)(C 1 -C 6 alkyl), and
u) —(C 1 -C 6 alkyl)C(O)R 8 ;
R 6 is selected from:
a) H,
b) C 1 -C 6 alkyl, unsubstituted or substituted, and
c) —C(O)(C 1 -C 6 alkyl);
R 8 is independently selected from hydrogen, unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
R 9 is independently selected from unsubstituted or substituted C 1 -C 6 alkyl, benzyl and unsubstituted or substituted aryl;
W is a heterocycle, selected from imidazolyl or pyridyl;
m is 0, 1, 2, 3 or 4;
n is 0, 1, 2, 3 or 4;
p is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
s is 0, 1, 2, 3 or 4; and
t is 0, 1, 2 or 3;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
10 . A compound which is selected from the group consisting of:
4-imidazol-1-ylmethyl-2-[2-(2-oxo-piperidin-1-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(2-oxo-piperidin-1-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[4-(2-oxo-piperidin-1-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[2-(3-methyl-2-oxo-piperidin-1-yl)-phenoxy]-benzonitrile 4-Imidazol-1-ylmethyl-2-[2-(2-oxo-pyrrolidin-1-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-(3-morpholin-4-yl-phenoxy)-benzonitrile 4-imidazol-1-ylmethyl-2-(3-piperidin-1-ylmethyl-phenoxy)-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(2-oxo-azepan-1-yl)-phenoxy]-benzonitrile 2-[2-(3,3-dimethyl-2-oxo-piperidin-1-yl)-phenoxy]-4-imidazol-1-ylmethyl- benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(3(S)-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(3(R)-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy )-4-(2-methyl-imidazol-1-yl)methyl-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(5-methyl-imidazol-1-yl)methyl-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(2,5-dimethyl-imidazol-1-yl)methyl-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1,2,4]triazol-4-ylmethyl-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1,2,4]triazol-1-ylmethyl-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(1-methyl-2-oxo-azocan-3-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(3-ethyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-benzonitrile 4-imidazol-1-ylmethyl-2-[3-(2-oxo-azepan-3-yl)-phenoxy]-benzonitrile 2-[3-(3-hydroxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(3-cyclopropylmethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[4-bromo-3-(3-cyclopropylmethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(3-methoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(3-ethyl-2-oxo-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(3-ethyl-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 2-[3-(1-acetyl-3-ethyl-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile 3-[3-(2-cyano-5-imidazol-1-ylmethyl-phenoxy)-phenyl]-3-ethyl-azepan-1-carboxylic acid -tert-butyl ester 4-[5-(2-amino-ethyl)-2-methyl-imidazol-1-ylmethyl]2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[2-methyl-5-(2-morpholin-4-yl-ethyl)-imidazol-1-ylmethyl]-benzonitrile N-[2-(3-{4-cyano-3-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzyl}-2methyl-3H-imidazol-4-yl)-ethyl]-acetamide 3-ethyl-3-[3-(3-imidazol-1-ylmethyl-phenoxy)-phenyl]-1-methyl-azepan-2-one 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(3-methyl-3-H-imidazol-4-ylmethyl)-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(3H-imidazol-4-ylmethyl)-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[hydroxy-(3-methyl-3-H-imidazol- 4-yl)-methyl]-benzonitrile 4-[amino-(3-methyl-3-H-imidazol-4-yl)-methyl]-2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-benzyl]-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(hydroxy-pyridin-3-yl-methyl)-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-pyridin-3-ylmethyl-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-pyridin-2-ylmethyl-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-hydroxy-1-(3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3R)-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3S)-ethyl-1methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl -3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3S)-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3R)-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-n-butyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-n-butyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-n-butyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol -4-yl)-ethyl]-benzonitrile 2-[3-3(R)-n-butyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylmethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-cyclopropylmethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylmethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-cyclopropylmethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-cyclopropylethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylethyl-1methyl2oxo-azepan-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-cyclopropylethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-propyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl]-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-propyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S) amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-propyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S) amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-propyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-methoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-methoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-methoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-methoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-ethoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-ethoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-ethoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-ethoxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylmethyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-cyclopropylmethyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylmethyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S-cyclopropylmethyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-benzyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-benzyl-1-methyl -2-oxo-piperidin-3-yl)-phenoxy]-4-[1-(S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-benzyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1(S)amino 1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-benzyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-methyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(3-methyl-3-H-imidazol-4-yl)-vinyl]-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(3-methyl-3-H-imidazol-4-yl)-cyclopropyl]-benzonitrile 2-[3-N,N-dimethylaminomethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-hydroxy-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-N,N-dimethylaminomethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3-N,N-dimethylaminomethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(3-methyl-3-H-imidazol-4-yl)-vinyl]-benzonitrile 4-[5-(2-N,N-dimethylaminoethyl)-2-methyl-imidazol-1-ylmethyl]2-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile 4-[5-(2-N,N-dimethylaminoethyl)-2-methyl-imidazol-1-ylmethyl]2-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile [2-(3-{4-cyano-3-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzyl}-2-methyl-3H-imidazol-4-yl)-ethyl]-urea [2-(3-{4-cyano-3-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzyl}-2-methyl-3H-imidazol-4-yl)-ethyl]-urea 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-pyridin-N-oxide-3-ylmethyl-benzonitrile 2-[3-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3-hydroxymethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3-cyclopropylmethyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylmethyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-cyclopropylmethyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-cyclopropylmethyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-cyclopropylmethyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(R)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-benzyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-benzyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(R)-benzyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-3(S)-benzyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(R-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 4-[1-(4-allyl-5-bromo-pyridin-3-yl)-1-hydroxy-ethyl]-2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile 1-tert-butyl-3(R)-[1-{4-cyano-3-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea 1-tert-butyl-3(S)-[1-{4-cyano-3-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea 1-tert-butyl-3(R)-[1-{4-cyano-3-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea 1-tert-butyl-3(S)-[1-{4-cyano-3-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea 1-[1-{4-cyano-3(R)-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-methyl-urea 1-[1-{4-cyano-3(S)-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-methyl-urea 1-[1-{4-cyano-3(R)-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-methyl-urea 1-[1-{4-cyano-3(S)-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-methyl-urea 1-[1-{4-cyano-3(R)-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-phenyl-urea 1-[1-{4-cyano-3(S)-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-phenyl-urea 1-[1-{4-cyano-3(R)-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-3-phenyl-urea 1-[1-{4-cyano-3(R)-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H -imidazol-4-yl)-ethyl]-3-phenyl-urea [1-{4-cyano-3(R)-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea [1-{4-cyano-3(S)-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea [1-{4-cyano-3(R)-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea [1-{4-cyano-3(S)-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-urea N-[1-{4-cyano-3-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-phenyl}-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-acetamide 2-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-methylamino -1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-methylamino -1-(3- methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1(R)-methylamino -1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[3-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1(S)-methylamino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile 2-[5-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-2-iodo-phenoxy]-4-imidazol-1-ylmethyl -benzonitrile 2-[5-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-2-iodo-phenoxy]-4-imidazol -1-ylmethyl-benzonitrile 2- 8 5-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-2-bromo-phenoxy]-4-imidazol -1-ylmethyl-benzonitrile 2-[5-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-2-bromo-phenoxy]-4-imidazol -1-ylmethyl-benzonitrile 4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-[2-dimethylaminomethyl -5-(3S-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile 2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-(4,5,6,7-tetrahydro -3H-imidazo[4,5-]pyridin-4-yl)-benzonitrile 2-[3-ethyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol -4-yl)-ethyl]-benzonitrile 4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[3-ethyl-1-(3-hydroxy-propyl)-2-oxo-azepan-3-yl]-phenoxy}-benzonitrile 4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[3-ethyl -1-propyl-2-oxo-azepan-3-yl]-phenoxy}-benzonitrile 2-{3-[1-(2-amino-ethyl)-3-ethyl-2-oxo-azepan-3-yl]-phenoxy}-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile {2-[3-(3-{5-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]2-cyano-phenoxy}-phenyl)-3-ethyl-2-oxo-azepan-1-yl]-ethyl}-urea N-{2-[3-(3-{5-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]2-cyano-phenoxy}-phenyl)-3-ethyl-2-oxo-azepan-1-yl]-ethyl}-N′-methyl urea 4-[1(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-methyl -2-oxo-3(R)-(3,3,3-trifluoro-propyl)-azepan-3-yl]-phenoxy}-benzonitrile 4-[1(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-methyl -2-oxo-3(S)-(3,3,3-trifluoro-propyl)-azepan-3-yl]-phenoxy}-benzonitrile 4-[1(R)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-methyl -2-oxo-3(S)-(3,3,3-trifluoro-propyl)-azepan-3-yl]-phenoxy}-benzonitrile 4-[1(S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-methyl -2-oxo-2(R)-(3,3,3-trifluoro-propyl)-azepan-3-yl]-phenoxy}-benzonitrile 4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-(2-dimethylamino-ethyl)-3-ethyl-2-oxo-azepan-3-yl]-phenoxy}-benzonitrile 4-[1-(R or S)amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]2-{3-[1-(2-hydroxyethyl)-3-ethyl-2-oxo-azepan-3-yl]-phenoxy}-benzonitrile 4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-(2-methoxyethyl)-3R-ethyl-2-oxo-azepan-3-yl]-phenoxy}-benzonitrile 4-Imidazol-1-ylmethyl-2-[3-(1-methyl-7-oxo-azepan-2-yl)-phenoxy]-benzonitrile hydrochloride 4-[1-Amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-[3-(4-methyl -3-oxo-2-propyl-morpholin-2-yl)-phenoxy]-benzonitrile 4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-[3-(morpholine -4-sulfonyl)-phenoxy]-benzonitrile 4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-(2-methoxyethyl)-3R-ethyl-2-oxo-azepan-3-yl]-phenoxy}-benzonitrile; 2-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[5-(2-morpholin -4-yl-ethyl)-imidazol-1-ylmethyl benzonitrile; or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
11 . The compound according to claim 10 which is
2-{3-[1-methyl-2-oxo-3-(R or S)-(3,3,3-trifluoro-propyl)-azepan-3-yl]-phenoxy}-4-[1(R or S)-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
12 . The compound according to claim 10 which is
4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2-{3-[1-(2-methoxyethyl)-3R-ethyl-2-oxo-azepan-3-yl]-phenoxy}-benzonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
13 . The compound according to claim 10 which is:
2-[3-(3-(R or S)-benzyl-1-methyl-2-oxo-pyrrolidin-3-yl)-phenoxy]-4-[1-(R or S) 1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
14 . The compound according to claim 10 which is:
2-[3-(3-cycloproylmethyl-1-methyl-2-oxo-piperidin-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
15 . The compound according to claim 10 which is:
2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-benzonitrile
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
16 . The compound according to claim 10 which is:
2-[3-(3R-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[5-(2-morpholin -4-yl-ethyl)-imidazol-1-ylmethyl benzonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
17 . The compound according to claim 10 which is:
2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[2-methyl-5-(2-morpholin-4-yl-ethyl)-imidazol-1-ylmethyl]-benzonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
18 . The compound according to claim 10 which is:
2-[3-(1-acetyl-3-ethyl-azepan-3-yl)-phenoxy]-4-imidazol-1-ylmethyl-benzonitrile;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
19 . The compound according to claim 10 which is:
2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-(3-methyl -3-H-imidazol-4-yl)-cyclopropyl]-benzonitrile
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
20 . The compound according to claim 10 which is:
[2-(3-{4-cyano-3-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzyl}-2-methyl-3H-imidazol-4-yl)-ethyl]-urea
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
21 . The compound according to claim 10 which is:
2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-methylamino -1(3-methyl-3H-imidazol -4-yl)-ethyl]-benzonitrile
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
22 . The compound according to claim 10 which is:
{2-[3-(3-{5-[1-amino-1-(3-methyl-3H -imidazol-4-yl)-ethyl]2-cyano-phenoxy}-phenyl)-3-ethyl-2-oxo-azepan-1-yl]-ethyl}-urea
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
23 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 1 .
24 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 2 .
25 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 4 .
26 . A pharmaceutical composition comprising a pharmaceutical carrier, and dispersed therein, a therapeutically effective amount of a compound of claim 10 .
27 . 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 23 .
28 . 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 24 .
29 . 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 25 .
30 . 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 26 .
31 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 23 .
32 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 24 .
33 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 25 .
34 . A method for treating cancer which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 26 .
35 . A method for treating neurofibromen benign proliferative disorder which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 23 .
36 . 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 23 .
37 . 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 23 .
38 . A method for preventing restenosis which comprises administering to a mammal in need thereof a therapeutically effective amount of a composition of claim 23 .
39 . 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 23 .
40 . A pharmaceutical composition made by combining the compound of claim 1 and a pharmaceutically acceptable carrier.
41 . A process for making a pharmaceutical composition comprising combining a compound of claim 1 and a pharmaceutically acceptable carrier.
42 . A pharmaceutical composition made by combining the compound of claim 2 and a pharmaceutically acceptable carrier.
43 . A process for making a pharmaceutical composition comprising combining a compound of claim 2 and a pharmaceutically acceptable carrier.
44 . A method of conferring radiation sensitivity on a tumor cell using a therapeutically effective amount of a composition of claim 23 in combination with radiation therapy.
45 . A method of using a therapeutically effective amount of a composition of claim 23 in combination with an antineoplastic.
46 . A method according to claim 45 wherein the antineoplastic is paclitaxel.Join the waitlist — get patent alerts
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