Isoxazole compositions useful as inhibitors of ERK

Details Isoxazole compositions useful as inhibitors of ERK Isoxazole compositions useful as inhibitors of ERK

2001-09-14

2002-12-17

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S247000

Reexamination Certificate

active

06495582

ABSTRACT:

FIELD OF THE INVENTION
The present invention is in the field of medicinal chemistry and relates to isoxazole 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)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).
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)].
U.S. Pat. No. 5,470,862 discloses an isoxazole compound as an intermediate in the preparation of intravenous anesthetics.
There is a high unmet medical need to develop protein kinase inhibitors, especially ERK and AKT inhibitors 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 and AKT 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 pharmaceutical compositions thereof are effective as protein kinase inhibitors, especially as inhibitors of ERK and AKT. These compounds have the general formula I:
or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Ht is a heteroaryl ring selected from pyrrol-3-yl, pyrazol-3-yl, [1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl; said pyrrol-3-yl and pyrazol-3-yl each having R
3
and QR
4
substituents, and said triazole substituted by either R
3
or QR
4
;
A—B is N—O or O—N;
R
1
is selected from R
5
, fluorine, N(R
5
)
2
, OR, NRCOR, CON(R
5
)
2
, SO
2
R, NRSO
2
R, or SO
2
N(R
5
)
2
;
T and Q are each independently 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, fluorine, or an optionally substituted group selected from aryl, heteroaryl, heterocyclyl, an acyclic aliphatic group having one to six carbons, or a cyclic aliphatic group having four to ten carbons; wherein R
2
has up to one L—W substituent and up to three R
8
substituents;
L is a C
1-6
alkylidene chain which is optionally substituted, and wherein up to two methylene units of L are optionally replaced by —C(O)—, —C(O)C(O)—, —CONH—, —CONHNH—, —CO
2
—, —OC(O)—, —NHCO
2
—, —O—, —NHCONH—, —OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO
2
—, —NH—, —SO
2
NH—, —NHSO
2
NH—, or —NHSO
2
—;
W is selected from R
9
, CH(R
9
)
2
, CH(R
9
)N(R
9
)
2
, or N(R
9
)
2
;
R
3
is selected from R, OH, OR, N(R)
2
, fluorine, or CN;
R
4
is selected from —R
6
, —NH
2
, —NHR
6
, —N(R
6
)
2
, or —NR
6
(CH
2
)
y
N(R
6
)
2
;
each R
5
is independently selected from hydrogen or an optionally substituted aliphatic group having one to six carbons or two R
5
on the same nitrogen may be taken together with the nitrogen to form a four to eight membered ring having one to three heteroatoms;
each R
6
is independently selected from R
5
, —(CH
2
)
y
CH(R
7
)
2
, or —(CH
2
)
y
R
7
;
y is 0-6;
each R
7
is an optionally substituted group independently selected from R, aryl, aralkyl, aralkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, or alkoxycarbonyl;
each R
8
is independently selected from halogen, —R′, —OR′, —SR′, —NO
2
, —CN, —N(R
5
)
2
, —NRC(O)R′, —NRC(O)N(R
5
)
2
, —NRCO
2
R′, —NRNRC(O)R′, —NRNRC(O)N(R
5
)
2
, —NRNRCO
2
R′, —C(O)C(O)R′, —C(O)CH
2
C(O)R′, —CO
2
R′, —C(O)R′, —C(O)N(R
5
)
2
, —OC(O)N(R
5
)
2
, —S(O)
2
R′, —SO
2
N(R
5
)
2
, —S(O)R′, —NRSO
2
N(R
5
)
2
, —NRSO
2
R′, —C(═S)N(R
5
)
2
, or —C(═NH)N(R
5
)
2
; wherein each R′ is independently selected from hydrogen, or an optionally substituted group selected from aliphatic, heteroaryl, heterocyclyl, or phenyl; and
each R
9
is independently selected from R
5
, R
8
, or an optionally substituted group selected from aryl, aralkyl, aralkoxy, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl.
As used herein, the following definitions shall apply unless otherwise indicated. In addition, unless otherwise indicated, functional group radicals are independently selected.
The term “aliphatic,” as used herein means straight-chain, branched or cyclic C
1
-C
12
hydrocarbons which are completely saturated or which contain one or more units of unsaturation but which are not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”, “alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms “alkenyl” and “alkynyl” u

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