US 6,284,755 B1Granted

Inhibitors of prenyl-protein transferase

AssigneeMerck & Co., Inc.

InventorsS. Jane deSolms, Samuel L. Graham, Anthony W. Shaw, Terrence M. Ciccarone, Gerald E. Stokker

Life of this patent

Estimating the term…

Abstract

The present invention is directed to azepan-2-one compounds which inhibit prenyl-protein transferase, particularly farnesyl-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.

Claims35

Dependent claims

A compound of the formula I:

wherein:
R1a, R1b and R1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R9S(O)q—, CN, NO2, R8C(O)—, R8OC(O)—, (R8)2NC(O)—, —N(R15)2, —OR15, —N(R8)S(O)qR8 or N3;
c) C1-C6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—, R9S(O)q—, CN, R8C(O)—, R8OC(O)—, N(R8)2, N3, or R8C(O)O—;
R1 is independently selected from:
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C1-C6 alkyl)N(R8)2,
f) —R8C(O)R8,
g) —(C1-C6 alkyl)OR8,
h) —N(R8)2,
i) —OR8,
j) —R8NHC(O)R8,
k) —R8C(O)N(R8)2,
l) CF3,
m) halo,
n) —C(O)OR8,
o) C2-C6 alkynyl,
p) C2-C6 alkenyl,
q) perfluoroalkyl,
r) N3,
s) NO2,
t) CN,
u) R9S(O)q—,
v) —(C1-C6 alkyl)NR8C(O)N(R8)2, and
w) —(C1-C6 alkyl)R14;
R2 is independently selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR8,
i) N3,
j) R9S(O)q,
k) R8HC═CH—, and
l) R8C≡C—;
R3 is independently selected from:
a) H,
b) CN,
c) NO2,
d) halogen,
e) C1-C6 alkyl, unsubstituted or substituted,
f) OR8,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF3;
R5 and R6 are independently selected from:
a) H,
b) CN,
c) NO2,
d) halogen,
e) C1-C6 alkyl, unsubstituted or substituted,
f) N3,
g) R9S(O)q,
h) —HC═CH2,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF3O—,
m) CF3CH2O—,
n) C3-C10 cycloalkyl,
o) CF3,
p) —(C1-C6 alkyl)N(R8)2,
q) —(C1-C6 alkyl)OR8,
r) OR8,
S) N(R8)2,
t) —C(O)(C1-C6 alkyl),
u) —(C1-C6 alkyl)C(O)R8,
v) —C(O)O(C1-C6 alkyl),
w) —C(O)N(R8)2,
x) —(C1-C6 alkyl)NR8C(O)N(R8)2,
y) —(C1-C6 alkyl)NR8C(O)R8,
z) —C2-C6 alkynyl,
aa) —C2-C6 alkenyl,
bb) —(C1-C6 alkyl)N3,
cc) —(C1-C6 alkyl)NR8S(O)q, and
dd) —(C1-C6 alkyl)NR8(C1-C6 alkyl)N(R8)2;
R8 is independently selected from hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R9 is independently selected from unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R14 is unsubstituted saturated heterocycle;
R15 is independently selected from
a) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R9S(O)2—, R8C(O)—, R8OC(O)—, (R8)2NC(O)—, and
b) C1-C6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—, R9S(O)q—, CN, R8C(O)—, R8OC(O)—, N(R8)2, N3, or R8C(O)O—;
A1 and A2 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) NR8;
A3 is selected from a bond, —C(═O)—,
and C3-C6 cycloalkyl;
M is CH2;
Q is 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) C3-C6 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;
and
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 A1 is NR8, O, or S(O)q;
provided that the sum of variables x and t will be equal to 3;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.

127 more elements

A compound of the formula A:

wherein:
R1a, R1b and R1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl;
unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—, R9S(O)9—, CN, NO2, R8C(O)—, R8OC(O)—, N(R8)2, (R8)2NC(O)—, C(O)N(R8)—, or N3;
c) C1-C6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—, R9S(O)q—, CN, R8C(O)—, R8OC(O)—, N(R8)2, N3, or R8C(O)O—;
R1 is selected from:
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C1-C6 alkyl)N(R8)2,
f) —R8C(O)R8,
g) —(C1-C6 alkyl)OR8,
h) —N(R8)2,
i) —OR8,
j) —R8NHC(O)R8,
k) —R8C(O)N(R8)2,
l) CF3,
m) halo,
n) —C(O)OR8,
o) C2-C6 alkynyl,
p) C2-C6 alkenyl,
q) perfluoroalkyl,
r) N3,
s) NO2,
t) CN, and
u) R9S(O)q—;
R2 is selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR8,
i) N3,
j) R9S(O)q,
k) R8HC═CH—, and
l) R8C≡C—;
R3 is selected from:
a) H,
b) CN,
c) NO2,
d) halogen,
e) C1-C6 alkyl, unsubstituted or substituted,
f) OR8,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF3;
R4 is ═O;
R5 is selected from:
a) H,
b) CN,
c) NO2,
d) halogen,
e) C1-C6 alkyl, unsubstituted or substituted,
f) N3,
g) R9S(O)q,
h) —HC═CH2,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF3O—,
m) CF3CH2O—,
n) C3-C10 cycloalkyl,
o) CF3,
p) —(C1-C6 alkyl)N(R8)2,
q) —(C1-C6 alkyl)OR8,
r) OR8,
s) N(R8)2,
t) —C(O)(C1-C6 alkyl), and
u) —(C1-C6 alkyl)C(O)R8;
R6 is selected from:
a) H,
b) C1-C6 alkyl, unsubstituted or substituted,
c) OR8, and
d) —C(O)(C1-C6 alkyl);
R8 is independently selected from hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted benzyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R9 is independently selected from unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
A1 and A2 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) NR8;
A3 is selected from a bond, —C(═O)—,
and C3-C6 cycloalkyl;
M is CH2;
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) C3-C6 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;
and
t is 2;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.

111 more elements

A compound which is selected from the group consisting of:

4-imidazol-1-ylmethyl-2-[3-(2-oxo-azepan-1-yl)-phenoxy]-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-(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
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}-2-methyl-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-3yl)-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-(3-methyl-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-1-methyl-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-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)-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-
2-[3-3(R)-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(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-methyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4yl)-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-azepan-3-yl)-phenoxy]-4-[1-amino-1-(3-methyl-3H-imidazol-4yl)-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
4-[1-(4-allyl-5-bromo-pyridin-3-yi)-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-(3methyl-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-(3methyl-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-[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-dimethyl aminomethyl-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)-2oxo-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-triflouro-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)-ethy]-2-{3-[1-methyl-2-oxo-3(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-[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.

111 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/456,153Filed 7 Dec 1999 · us provisional application
Priority: 8 Dec 1998
Granted: 4 Sep 2001
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 233/64
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
A61P 27/02
Drugs for disorders of the senses: ophthalmic agents
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 31/22
For DNA viruses: for herpes viruses

Family

Application60/111,416Us provisional application · filed 8 Dec 1998
Application60/129,282Us provisional application · filed 14 Apr 1999
US 6,284,755 B1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of the formula I:

wherein:
R1a, R1b and R1c are independently selected from:
a) hydrogen,
b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R9S(O)q—, CN, NO2, R8C(O)—, R8OC(O)—, (R8)2NC(O)—, —N(R15)2, —OR15, —N(R8)S(O)qR8 or N3;
c) C1-C6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—, R9S(O)q—, CN, R8C(O)—, R8OC(O)—, N(R8)2, N3, or R8C(O)O—;
R1 is independently selected from:
a) H,
b) unsubstituted or substituted C1-C6 alkyl,
c) unsubstituted or substituted aryl,
d) unsubstituted or substituted heterocycle,
e) —(C1-C6 alkyl)N(R8)2,
f) —R8C(O)R8,
g) —(C1-C6 alkyl)OR8,
h) —N(R8)2,
i) —OR8,
j) —R8NHC(O)R8,
k) —R8C(O)N(R8)2,
l) CF3,
m) halo,
n) —C(O)OR8,
o) C2-C6 alkynyl,
p) C2-C6 alkenyl,
q) perfluoroalkyl,
r) N3,
s) NO2,
t) CN,
u) R9S(O)q—,
v) —(C1-C6 alkyl)NR8C(O)N(R8)2, and
w) —(C1-C6 alkyl)R14;
R2 is independently selected from:
a) hydrogen,
b) CN,
c) NO2,
d) halogen,
e) aryl, unsubstituted or substituted,
f) heteroaryl, unsubstituted or substituted,
g) C1-C6 alkyl, unsubstituted or substituted,
h) OR8,
i) N3,
j) R9S(O)q,
k) R8HC═CH—, and
l) R8C≡C—;
R3 is independently selected from:
a) H,
b) CN,
c) NO2,
d) halogen,
e) C1-C6 alkyl, unsubstituted or substituted,
f) OR8,
g) aryl, unsubstituted or substituted,
h) heteroaryl, unsubstituted or substituted, and
i) CF3;
R5 and R6 are independently selected from:
a) H,
b) CN,
c) NO2,
d) halogen,
e) C1-C6 alkyl, unsubstituted or substituted,
f) N3,
g) R9S(O)q,
h) —HC═CH2,
i) HC≡C—,
j) aryl, unsubstituted or substituted,
k) heterocycle, unsubstituted or substituted,
l) CF3O—,
m) CF3CH2O—,
n) C3-C10 cycloalkyl,
o) CF3,
p) —(C1-C6 alkyl)N(R8)2,
q) —(C1-C6 alkyl)OR8,
r) OR8,
S) N(R8)2,
t) —C(O)(C1-C6 alkyl),
u) —(C1-C6 alkyl)C(O)R8,
v) —C(O)O(C1-C6 alkyl),
w) —C(O)N(R8)2,
x) —(C1-C6 alkyl)NR8C(O)N(R8)2,
y) —(C1-C6 alkyl)NR8C(O)R8,
z) —C2-C6 alkynyl,
aa) —C2-C6 alkenyl,
bb) —(C1-C6 alkyl)N3,
cc) —(C1-C6 alkyl)NR8S(O)q, and
dd) —(C1-C6 alkyl)NR8(C1-C6 alkyl)N(R8)2;
R8 is independently selected from hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted aralkyl, unsubstituted or substituted heterocycle and unsubstituted or substituted aryl;
R9 is independently selected from unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted benzyl and unsubstituted or substituted aryl;
R14 is unsubstituted saturated heterocycle;
R15 is independently selected from
a) hydrogen, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R9S(O)2—, R8C(O)—, R8OC(O)—, (R8)2NC(O)—, and
b) C1-C6 alkyl, unsubstituted or substituted by unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, R8O—, R9S(O)q—, CN, R8C(O)—, R8OC(O)—, N(R8)2, N3, or R8C(O)O—;
A1 and A2 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) NR8;
A3 is selected from a bond, —C(═O)—,
and C3-C6 cycloalkyl;
M is CH2;
Q is 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) C3-C6 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;
and
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 A1 is NR8, O, or S(O)q;
provided that the sum of variables x and t will be equal to 3;
or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.

127 more elements

Facts

Application

09/456,153Filed 7 Dec 1999 · us provisional application

Priority

8 Dec 1998

Granted

4 Sep 2001

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07D 233/64
Having two double bonds between ring members or between ring members and non-ring members: with substituted hydrocarbon radicals attached to ring…
A61P 27/02
Drugs for disorders of the senses: ophthalmic agents
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 31/22
For DNA viruses: for herpes viruses