Pyrazole compositions useful as inhibitors of ERK

Details Pyrazole compositions useful as inhibitors of ERK Pyrazole compositions useful as inhibitors of ERK

2001-10-05

2003-03-04

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C540S575000, C544S140000, C544S295000, C544S328000, C544S367000, C544S371000, C544S363000, C546S086000, C546S146000, C546S199000, C546S273700, C546S275400, C546S211000, C548S127000, C548S312400, C548S364100, C548S364400, C548S365700

Reexamination Certificate

active

06528509

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 disease states that are alleviated by protein kinase inhibitors.
BACKGROUND OF THE INVENTION
Mammalian mitogen-activated protein (MAP)1 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 ERK (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).
The JNK family of (MAP)1 kinases have been implicated in having a role in mediating cellular response to a variety of disorders including cancer (
Oncogene
1996, 13, 135-42), hepatic disorders (
Hepatology
1998, 28,1022-30), cardiovascular disease (
Circ. Res
. 1998, 83, 167-78
; Circulation
1998, 97:1731-7
; J. Biol. Chem
. 1997, 272, 28050-6
; Circ. Res
. 1996, 79, 162-73
; Circ. Res
. 1996, 78, 947-53
; J. Clin. Invest
. 1996, 97, 508-14), and immunological disorders (
J. Immunol
. 1999, 162, 3176-87
; Eur. J. Immunol
. 1998, 28, 3867-77
; J. Exp. Med
. 1997, 186, 941-53
; Eur. J. Immunol
. 1996, 26, 989-94, among others).
Aurora2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, aurora2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora2 protein has been found to be overexpressed. See Bischoff et al.,
EMBO J
., 1998, 17, 3052-3065; Schumacher et al.,
J. Cell Biol
., 1998, 143, 1635-1646; Kimura et al.,
J. Biol. Chem
., 1997, 272, 13766-13771.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of &agr; and &bgr; isoforms that are each encoded by distinct genes [Coghlan et al.,
Chemistry
&
Biology
, 7, 793-803 (2000); Kimand Kimmel,
Curr. Opinion Genetics Dev
., 10, 508-514 (2000)]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Haq et al.,
J. Cell Biol
. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role.
KDR is a tyrosine kinase receptor that also binds VEGF (vascular endothelial growth factor) (Neufeld et al., 1999
, FASEB J
., 13, 9). The binding of VEGF to the KDR receptor leads to angiogenesis, which is the sprouting of capillaries from preexisting blood vessels. High levels of VEGF are found in various cancers causing tumor angiogenesis and permitting the rapid growth of cancerous cells. Therefore, suppressing VEGF activity is a way to inhibit tumor growth, and it has been shown that this can be achieved by inhibiting KDR receptor tyrosine kinase.
AKT, also known as protein kinase B, is a serine/threonine kinase that plays a central role in promoting the survival of a wide range of cell types [Khwaja, A.,
Nature
, pp. 33-34 (1990)]. It has been shown by Zang, et al, that human ovarian cancer cells display elevated levels of AKT-1 and AKT-2. Inhibition of AKT induces apoptosis of these human ovarian cancer cells which demonstrates that AKT may be an important target for ovarian cancer treatment [Zang, Q. Y., et al,
Oncogene
, 19 (2000)] and other proliferative disorders. The AKT pathway has also been implicated in motoneuronal survival and nerve regeneration [Kazuhiko, N., et al,
The Journal of Neuroscience
, 20 (2000)].
There is a high unmet medical need to develop protein kinase inhibitors, especially ERK inhibitors, that are useful in treating the various conditions associated with ERK activation, especially considering the currently available, relatively inadequate treatment options for the majority of these conditions.
Accordingly, there is still a great need to develop potent inhibitors of protein kinase, including ERK inhibitors, that are useful in treating various conditions associated with protein kinase activation.
DESCRIPTION OF THE INVENTION
It has now been found that compounds of this invention and compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK. These compounds have the general formula I:
or a pharmaceutically acceptable derivative thereof, wherein:
R
1
is selected from R, halogen, N(R
8
)
2
, OR, NRCOR, NRCON(R
8
)
2
, CON(R
8
)
2
, SO
2
R, NRSO
2
R, or SO
2
N(R
8
)
2
;
T is selected from a valence bond or a linker group;
each R is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons;
R
2
is selected from hydrogen, CN, halogen, aryl, aralkyl, heteroaryl, heterocyclyl, an optionally substituted acyclic aliphatic chain group having one to six carbons, or an optionally substituted cyclic aliphatic group having four to ten carbons;
R
3
is selected from R, OH, OR, N(R
8
)
2
, halogen, or CN;
Q is a valence bond, J, or an optionally substituted C
1-6
alkylidene chain wherein up to two nonadjacent carbons of the alkylidene chain are each optionally and independently replaced by J;
J is selected from —C(═O)—, —CO
2
—, —C(O)C(O)—, —NRCONR
8
—, —N(R)N(R
8
)—, —C(═O)NR
8
—, —NRC(═O)—, —O—, —S—, —SO—, —SO
2
—, —N(R)O—, —ON(R
8
)—, —OC(═O)N(R
8
)—, —N(R)COO—, —SO
2
N(R
8
)—, —N(R)SO
2
—, or —N(R
8
)—;
R
4
is selected from —R
8
, —R
5
, —NH
2
, —NHR
5
, —N(R
5
)
2
, or —NR
5
(CH
2
)
y
N (R
5
)
2
;
each R
5
is independently selected from R
6
, R
7
, —(CH
2
)
y
CH(R
6
)(R
7
), —(CH
2
)
y
R
6
, —(CH
2

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