Pyrazole derived kinase inhibitor

Details Pyrazole derived kinase inhibitor Pyrazole derived kinase inhibitor

2002-04-26

2004-03-16

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S140000, C544S371000, C546S175000, C546S193000, C546S211000, C546S256000, C546S271700, C546S269700, C546S272700, C546S275400, C548S312400, C548S365700, C548S371700

Reexamination Certificate

active

06706711

ABSTRACT:

FIELD OF THE INVENTION
The present invention is in the field of medicinal chemistry and relates to pyrazole compounds that are protein kinase inhibitors, especially inhibitors of ERK, compositions containing such compounds and methods of use. The compounds are useful for treating cancer and other diseases that are alleviated by protein kinase inhibitors.
BACKGROUND OF THE INVENTION
Mammalian mitogen-activated protein (MAP) kinases are serine/threonine kinases that mediate intracellular signal transduction pathways (Cobb and Goldsmith, 1995
, J. Biol. Chem
., 270, 14843; Davis, 1995
, Mol. Reprod. Dev
. 42, 459). Members of the MAP kinase family share sequence similarity and conserved structural domains, and include the ERK2 (extracellular signal regulated kinase), JNK (Jun N-terminal kinase) and p38 kinases. JNKs and p38 kinases are activated in response to the pro-inflammatory cytokines TNF-alpha and interleukin-1, and by cellular stress such as heat shock, hyperosmolarity, ultraviolet radiation, lipopolysaccharides and inhibitors of protein synthesis (Derijard et al., 1994
, Cell
76, 1025; Han et al., 1994
, Science
265, 808; Raingeaud et al., 1995
, J Biol. Chem
. 270, 7420; Shapiro and Dinarello, 1995
, Proc. Natl. Acad. Sci. USA
92, 12230). In contrast, ERKs are activated by mitogens and growth factors (Bokemeyer et al. 1996
, Kidney Int
. 49, 1187).
ERK2 is a widely distributed protein kinase that achieves maximum activity when both Thr183 and Tyr185 are phosphorylated by the upstream MAP kinase kinase, MEK1 (Anderson et al., 1990
, Nature
343, 651; Crews et al., 1992
, Science
258, 478). Upon activation, ERK2 phosphorylates many regulatory proteins, including the protein kinases Rsk90 (Bjorbaek et al., 1995
, J. Biol. Chem
. 270, 18848) and MAPKAP2 (Rouse et al., 1994
, Cell
78, 1027), and transcription factors such as ATF2 (Raingeaud et al., 1996
, Mol. Cell Biol
. 16, 1247), Elk-1 (Raingeaud et al. 1996), c-Fos (Chen et al., 1993
Proc. Natl. Acad. Sci. USA
90, 10952) and c-Myc (Oliver et al., 1995
, Proc. Soc. Exp. Biol. Med
. 210, 162). ERK2 is also a downstream target of the Ras/Raf dependent pathways (Moodie et al., 1993
, Science
260, 1658) and may help relay the signals from these potentially oncogenic proteins. ERK2 has been shown to play a role in the negative growth control of breast cancer cells (Frey and Mulder, 1997
, Cancer Res
. 57, 628) and hyperexpression of ERK2 in human breast cancer has been reported (Sivaraman et al., 1997
, J Clin. Invest
. 99, 1478). Activated ERK2 has also been implicated in the proliferation of endothelin-stimulated airway smooth muscle cells, suggesting a role for this kinase in asthma (Whelchel et al., 1997
, Am. J. Respir. Cell Mol. Biol
. 16, 589).
Substituted pyrazole derivatives have been described as p38 inhibitors (WO 98/52941). However, there is a high, unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with ERK activation. For many of these conditions the currently available treatment options are inadequate. Accordingly, there is great interest in new and effective inhibitors of protein kinase, including ERK inhibitors that are useful in treating various conditions associated with protein kinase activation.
SUMMARY OF THE INVENTION
The present invention provides compounds and compositions thereof that are useful as protein kinase inhibitors, especially as inhibitors of ERK. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as antibiotics, immunomodulators or other anti-inflammatory agents, for the treatment or prophylaxis of diseases mediated by protein kinases, including ERK2. According to a preferred embodiment, the compounds of this invention are capable of binding to the active site of ERK2 and inhibiting the activity of that enzyme.
It is a principal object of this invention to provide compounds that are protein kinase inhibitors represented by formula I:
or a pharmaceutically acceptable salt or derivative thereof, wherein:
T is selected from —NH—, —NHC(O)—, —NHC(O)O—, —NHC(O)NR—, —NHC(O)NH—, —NHSO
2
—, —NHSO
2
NR—, —NHSO
2
NH—, —NHNR—, —NHNH—, —NHNRC(O)—, —NHNHC(O)—, —NHNRSO
2
—, or —NHNHSO
2
—;
n is 0 or 1;
each R is independently selected from an optionally substituted group selected from C
1-6
aliphatic, C
6-10
aryl, heteroaryl having 5-10 ring atoms, and heterocyclyl having 3-10 ring atoms;
R
1
is selected from hydrogen, —CN, halogen, —N(R
6
)
2
, —OR, —OH, or —R;
R
2
is selected from —(CH
2
)
y
R
4
—(CH
2
)
y
CH(R
4
)
2
, —(CH
2
)
y
CH(R
7
)CH(R
4
)
2
, —N(R
3
)
2
, or —NR
3
(CH
2
)
y
N(R
3
)
2
;
Q is selected from —C(O)—, —CO
2
—, —C(O)C(O)—, —C(O)CH
2
C(O)—, —C(O)NR—, —SO
2
—, —SO
2
NR
6
—, —NR
6
—, —NRC(O)—, —NRSO
2
—, —NRC(O)O—, —NRC(O)NR
6
—, or —C(O)NR
6
—;
y is 0-6;
each R
3
is independently selected from —R, —R
6
, —COR
6
, —CO
2
R, —CON(R
6
)
2
, —SO
2
R
6
, —(CH
2
)
y
R
4
, or —(CH
2
)
y
CH(R
4
)
2
;
each R
4
is independently selected from —R, —OR, —CO
2
R, —(CH
2
)
y
N(R
6
)
2
, —N(R
6
)
2
, —OR
6
, —SR
6
, —NR
6
COR
6
, —NR
6
CON (R
6
)
2
, —C(O) N(R
6
)
2
, —SO
2
R
6
, —NR
6
SO
2
R
6
, C(O)R
6
, —CN, or —SO
2
N(R
6
)
2
;
each R
6
is independently selected from hydrogen or an optionally substituted C
1-6
aliphatic group, or two R
6
on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring;
each R
7
is selected from —R
6
, —(CH
2
)
w
OR
6
, —(CH
2
)
w
N(R
3
)
2
, or —(CH
2
)
w
SR
6
; and
each w is independently selected from 0-4.
It is a further objective of this invention to provide pharmaceutical compositions comprising the protein kinase inhibitors of this invention. In a preferred embodiment, the protein kinase inhibitors inhibit ERK2. These compositions may be utilized in methods for treating or preventing a variety of protein kinase-mediated disorders, such as cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases. Each of the above-described methods is also part of the present invention.
It is a further objective of this invention to provide methods for making the compounds and compositions of this invention.
DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula I. Accordingly, it has now been found that compounds of this invention and compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK2.
As used herein, the following definitions shall apply unless otherwise indicated. The phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. Also, combinations of substituents or variables are permissible only if such combinations result in a chemically stable arrangement.
The term “chemically stable arrangement” or “chemically feasible and stable” as used herein, refers to a compound structure that renders the compound sufficiently stable to allow manufacture and administration to a mammal by methods known in the art. Typically, such compounds are stable at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
The term “aliphatic” or “aliphatic group” as used herein means a straight-chain or branched C
1
-C
12
hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C
3
-C
8
hydrocarbon or bicyclic C
8
-C
12
hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or “cycloalkyl”), that has a single point of attachment to the rest of the

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