Heteroaryl-substituted quinolin-2-one derivatives useful as...

Details Heteroaryl-substituted quinolin-2-one derivatives useful as... Heteroaryl-substituted quinolin-2-one derivatives useful as...

2002-03-07

2004-03-23

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S315000, C564S414000

Reexamination Certificate

active

06710209

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to a series of heteroaryl-substituted quinolin-2-one derivatives that are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
To acquire transforming potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as agents to combat tumors in which Ras contributes to transformation. Mutated, oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al.,
Science
, Vol. 260, 1834 to 1837, 1993). The compounds of the present invention exhibit activity as inhibitors of the enzyme farnesyl protein transferase and are therefore believed to be useful as anti-cancer and anti-tumor agents. Further, the compounds of the present invention may be active against any tumors that proliferate by virtue of farnesyl protein transferase.
Other compounds that are indicated as having activity inhibiting farnesyl protein transferase are referred to in International Publication Number WO 97/21701, entitled “Farnesyl Protein Transferase Inhibiting (Imidazol-5-yl)methyl-2-quinolinone Derivatives”, which has an International Publication Date of Jun. 19, 1997; in International Publication Number WO 97/16443, entitled “Farnesyl Transferase Inhibiting 2-Quinolone Derivatives”, which has an International Publication Date of May 9, 1997; PCT/IB99/01393, filed Aug. 5, 1999, entitled “2-Quinolone derivatives Useful as Anticancer Agents”; and PCT/IB99/01398, filed Aug. 6, 1999, entitled “Alkynyl-Substituted Quinolin-2-one Derivatives Useful as Anticancer Agents”; all of which are incorporated herein by reference in their entireties.
The preceding Kohl et al. publication, as well as all other references discussed below in this application, are also hereby incorporated by reference in their entireties.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula 1
or pharmaceutically acceptable salts or solvates thereof wherein:
the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinolin-2-one ring;
R
1
is selected from H, C
1
-C
10
alkyl, —(CR
13
R
14
)
q
C(O)R
12
, —(CR
13
R
14
)
q
C(O)OR
15
, —(CR
13
R
14
)
q
OR
12
, —(CR
13
R
14
)
q
CSO
2
R
15
, —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl), —(CR
13
R
14
)
t
(C
6
-C
10
aryl), and —(CR
13
R
14
)
t
(4-10 membered heterocyclic), wherein said cycloalkyl, aryl and heterocyclic R
1
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R
1
groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R
6
groups;
R
2
is halo, cyano, —C(O)OR
15
, or a group selected from the substituents provided in the definition of R
12
;
each R
3
, R
4
, R
5
, R
6
, and R
7
is independently selected from H, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR
12
, —C(O)R
12
, —C(O)OR
12
, —NR
13
C(O)OR
15
, —OC(O)R
12
, —NR
13
SO
2
R
15
, —SO
2
NR
12
R
13
, —NR
13
C(O)R
12
, —C(O)NR
12
R
13
, —NR
12
R
13
, —CH═NOR
12
, —S(O)
j
R
12
wherein j is an integer from 0 to 2, —(CR
13
R
14
)
t
(C
6
-C
10
aryl), —(CR
13
R
14
)
t
(4-10 membered heterocyclic), —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl), and —(CR
13
R
14
)
t
C≡CR
16
; and wherein the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR
13
SO
2
R
15
, —SO
2
NR
12
R
13
, —C(O)R
12
, —C(O)OR
12
, —OC(O)R
12
, —NR
13
C(O)OR
15
, —NR
13
C(O)R
12
, —C(O)NR
12
R
13
, —NR
12
R
13
, —OR
12
, C
1
-C
10
alkyl, C
2
-C
10
alkenyl, C
2
-C
10
alkynyl, —(CR
13
R
14
)
t
(C
6
-C
10
aryl), and —(CR
13
R
14
)
t
(4-10 membered heterocyclic);
Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R
6
substituents;
R
8
is H, —OR
12
, —OC(O)R
12
, —NR
12
R
13
, —N═CR
12
R
13
, —NR
12
C(O)R
13
, cyano, —C(O)OR
13
, —SR
12
, or —(CR
13
R
14
)
t
(4-10 membered heterocyclic), wherein said heterocyclic R
8
groups are substituted by 1 to 4 R
6
groups;
R
9
is —(CR
13
R
14
)
t
(imidazolyl) or —(CR
13
R
14
)
t
(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R
6
substituents
each R
12
is independently selected from H, C
1
-C
10
alkyl, —(CR
13
R
14
)
t
(C
3
-C
10
cycloalkyl), —(CR
13
R
14
)
t
(C
6
-C
10
aryl), and —(CR
13
R
14
)
t
(4-10 membered heterocyclic); said cycloalkyl, aryl and heterocyclic R
12
groups are optionally fused to a C
6
-C
10
aryl group, a C
5
-C
8
saturated cyclic group, or a 4-10 membered heterocyclic group; and the foregoing R
12
substituents, except H but including any optional fused rings, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R
13
, —C(O)OR
13
, —OC(O)R
13
, —NR
13
C(O)R
14
, —C(O)NR
13
R
14
, —NR
13
R
14
, hydroxy, C
1
-C
6
alkyl, and C
1
-C
6
alkoxy;
each t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
each R
13
and R
14
is independently H or C
1
-C
6
alkyl, and where R
13
and R
14
are as —(CR
13
R
14
)
q
or —(CR
13
R
14
)
t
each is independently defined for each iteration of q or t in excess of 1;
R
15
is selected from the substituents provided in the definition of R
12
except R
15
is not H;
R
16
is selected from the list of substituents provided in the definition of R
12
and —SiR
17
R
18
R
19
; and,
R
17
, R
18
and R
19
are each independently selected from the substituents provided in the definition of R
12
except at least one of R
17
, R
18
and R
19
is not H.
Preferred compounds of formula 1 are those wherein Z is a 5 or 6 membered aromatic heterocyclic group substituted with from 1 to 4 R
6
substituents. More preferred compounds of formula 1 are those wherein Z is a pyridine or thiophene group substituted with from 1 to 4 R
6
substituents. Other preferred compounds of formula 1 are those wherein Z is a 5 or 6 membered aromatic heterocyclic group fused to a benzene group, substituted with from 1 to 4 R
6
substituents. Preferably, Z comprises from 1 to 3 heteroatoms selected from O, S and N.
Other preferred compounds of formula 1 are those wherein R
1
is H, C
1
-C
6
alkyl, or cyclopropylmethyl.
Other preferred compounds of formula 1 are those wherein R
8
is —NR
12
R
13
, —OR
12
, or —(CR
13
R
14
)t (4-10 membered heterocyclic) substituted with from 1 to 4 R
6
groups, wherein said 4-10 membered heterocyclic is selected from triazolyl, imidazolyl, pyrazolyl, and piperidinyl. More preferably, said heterocyclic is substituted with one R
6
group. Preferably, R
8
is hydroxy, amino, or triazolyl.
Other preferred compound of formula 1 are those wherein R
8
is H, —OR
12
, —OC(O)R
12
, —NR
12
R
13
, —NR
12
C(O)R
13
, cyano, —C(O)OR
13
, —SR
12
, or —(CR
13

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