U.S. patent application number 11/159440 was filed with the patent office on 2005-12-08 for triazole-derived kinase inhibitors and uses thereof.
Invention is credited to Hale, Michael R., Maltais, Francois.
Application Number | 20050272789 11/159440 |
Document ID | / |
Family ID | 23101887 |
Filed Date | 2005-12-08 |
United States Patent
Application |
20050272789 |
Kind Code |
A1 |
Hale, Michael R. ; et
al. |
December 8, 2005 |
Triazole-derived kinase inhibitors and uses thereof
Abstract
Described herein are compounds that are useful as protein kinase
inhibitors having the formula: 1 where Ht, R.sup.2, T, and m are as
described in the specification. The compounds are useful for
treating diseases in mammals that are alleviated by a protein
kinase inhibitor, particularly diseases such as cancer,
inflammatory disorders, restenosis, and cardiovascular disease.
Inventors: |
Hale, Michael R.; (Bedford,
MA) ; Maltais, Francois; (Tewksbury, MA) |
Correspondence
Address: |
CHOATE, HALL & STEWART LLP
TWO INTERNATIONAL PLACE
BOSTON
MA
02110
US
|
Family ID: |
23101887 |
Appl. No.: |
11/159440 |
Filed: |
June 23, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11159440 |
Jun 23, 2005 |
|
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10134122 |
Apr 26, 2002 |
|
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60287204 |
Apr 27, 2001 |
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Current U.S.
Class: |
514/381 ;
514/383; 548/253; 548/255 |
Current CPC
Class: |
A61P 5/00 20180101; A61P
9/00 20180101; C07D 231/12 20130101; A61P 1/16 20180101; A61P 31/12
20180101; A61P 9/04 20180101; C07D 233/56 20130101; A61P 3/10
20180101; A61P 31/04 20180101; A61P 35/02 20180101; A61P 19/08
20180101; A61P 29/00 20180101; A61P 21/00 20180101; A61P 25/16
20180101; A61P 25/14 20180101; A61P 43/00 20180101; C07D 249/06
20130101; C07D 417/14 20130101; C07D 249/08 20130101; C07D 403/04
20130101; A61P 35/00 20180101; A61P 25/28 20180101; C07D 249/10
20130101; A61P 25/00 20180101; A61P 37/04 20180101; A61P 9/10
20180101; A61P 7/02 20180101; C07D 405/14 20130101; A61P 25/08
20180101; A61P 11/00 20180101; A61P 37/08 20180101; C07D 401/14
20130101; C07D 403/14 20130101; A61P 17/06 20180101; A61P 37/06
20180101 |
Class at
Publication: |
514/381 ;
514/383; 548/253; 548/255 |
International
Class: |
A61K 031/4196; A61K
031/415; C07D 043/04; A61K 031/4192 |
Claims
1. A compound of formula I: 243or a pharmaceutically acceptable
salt or derivative thereof, wherein: Ht is tetrazol-5-yl; T is
selected from --C(R.sup.7).sub.2--, --C(O)--, --C(O)C(O)--,
--C(O)NR.sup.7--, --C(O)NR.sup.7NR.sup.7--, --CO.sub.2--,
--OC(O)--, --NR.sup.7CO.sub.2--, --O--, --NR.sup.7C(O)NR.sup.7--,
--OC(O)NR.sup.7--, --NR.sup.7NR.sup.7--, --NR.sup.7C(O)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.7--, --SO.sub.2NR.sup.7--, or
--NR.sup.7SO.sub.2--, --NR.sup.7SO.sub.2NR.sup.7- --; m is selected
from zero or one; R.sup.2 is selected from hydrogen, CN, halogen,
R, N(R.sup.7).sub.2, OR, or OH; each R is independently selected
from an optionally substituted group selected from C.sub.1-6
aliphatic, C.sub.6-10 aryl, heteroaryl having 5-10 ring atoms, and
heterocyclyl having 3-10 ring atoms; each R.sup.7 is independently
selected from hydrogen or an optionally substituted C.sub.1-6
aliphatic group, or two R.sup.7 on the same nitrogen are taken
together with the nitrogen to form a 5-8 membered ring heterocyclyl
or heteroaryl ring; provided that: when m is 0, R.sup.2 is other
than H or an unsubstituted phenyl.
2-3. (canceled)
4. The compound according to claim 1, wherein T.sub.mR.sup.2 is
N(R.sup.7).sub.2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C.sub.1-6 aliphatic or a 5-6
membered aryl or heteroaryl ring.
5. The compound according to claim 4, wherein T.sub.mR.sup.2 is
N(R.sup.7).sub.2, OH, 3-6 membered carbocyclyl, or an optionally
substituted group selected from C.sub.1-6 aliphatic or a 5-6
membered aryl or heteroaryl ring.
6. The compound according to claim 5, wherein T.sub.mR.sup.2 is
selected from optionally substituted phenyl, methyl, ethyl, propyl,
cyclopropyl, cyclohexyl, CH.sub.2OCH.sub.3, CH.sub.2OH, OH,
NH.sub.2, NHCH.sub.3, NHAc, NHC(O)NHCH.sub.3, or
CH.sub.2NHCH.sub.3.
7-19. (canceled)
20. The compound according to claim 1 wherein said compound is
selected from any one of the following compounds:
5 No. Structure II-E 1 244 II-E 2 245 II-E 3 246 II-E 4 247 II-E 5
248 II-E 6 249
21. (canceled)
22. A composition comprising a compound according to claim 1 and a
pharmaceutically acceptable carrier, adjuvant, or vehicle.
23. The composition according to claim 22, additionally comprising
an additional therapeutic agent selected from an anti-proliferative
agent, an anti-inflammatory agent, an immunomodulatory agent, a
neurotrophic factor, an agent for treating cardiovascular disease,
an agent for treating liver disease, an anti-viral agent, an agent
for treating blood disorders, an agent for treating diabetes, or an
agent for treating immunodeficiency disorders.
24. A method of inhibiting ERK kinase activity in a biological
sample comprising the step of contacting said biological sample
with: a) a compound according to claim 1; or b) a composition
according to claim 22.
25. A method of treating or lessening the severity of an
ERK-mediated disease or condition in a patient comprising the step
of administering to said patient a composition according to claim
22.
26. A method of treating or lessening the severity of an cancer,
stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's
disease, cystic fibrosis, viral disease, autoimmune diseases,
atherosclerosis, restenosis, psoriasis, allergic disorders,
inflammation, neurological disorders, a hormone-related disease,
conditions associated with organ transplantation, immunodeficiency
disorders, destructive bone disorders, proliferative disorders,
infectious diseases, conditions associated with cell death,
thrombin-induced platelet aggregation, chronic myelogenous leukemia
(CML), liver disease, pathologic immune conditions involving T cell
activation, or CNS disorders, comprising the step of administering
to said patient a composition according to claim 22.
27. The method according to claim 26, wherein said method is used
to treat or prevent cancer.
28. The method according to claim 27, wherein said method is used
to treat or prevent a cancer selected from breast; ovary; cervix;
prostate; testis, genitourinary tract; esophagus; larynx,
glioblastoma; neuroblastoma; stomach; skin, keratoacanthoma; lung,
epidermoid carcinoma, large cell carcinoma, small cell carcinoma,
lung adenocarcinoma; bone; colon, adenoma; pancreas,
adenocarcinoma; thyroid, follicular carcinoma, undifferentiated
carcinoma, papillary carcinoma; seminoma; melanoma; sarcoma;
bladder carcinoma; liver carcinoma and biliary passages; kidney
carcinoma; myeloid disorders; lymphoid disorders, Hodgkin's, hairy
cells; buccal cavity and pharynx (oral), lip, tongue, mouth,
pharynx; small intestine; colon-rectum, large intestine, rectum;
brain and central nervous system; or leukemia.
29. The method according to claim 26, wherein said method is used
to treat or prevent cardiovascular disease.
30. The method according to claim 29, wherein said method is used
to treat or prevent a cardiovascular disease selected from
restenosis, cardiomegaly, artherosclerosis, myocardial infarction,
or congestive heart failure.
31. The method according to claim 26, wherein said method is used
to treat or prevent neurodegenerative disease selected from
Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, Huntington's disease, cerebral ischemia or
neurodegenerative disease caused by traumatic injury, glutamate
neurotoxicity or hypoxia.
32. The method according to claim 26, comprising the additional
step of administering to said patient an additional therapeutic
agent selected from an anti-proliferative agent, an
anti-inflammatory agent, an immunomodulatory agent, a neurotrophic
factor, an agent for treating cardiovascular disease, an agent for
treating liver disease, an anti-viral agent, an agent for treating
blood disorders, an agent for treating diabetes, or an agent for
treating immunodeficiency disorders, wherein: said additional
therapeutic agent is appropriate for the disease being treated; and
said additional therapeutic agent is administered together with
said composition as a single dosage form or separately from said
composition as part of a multiple dosage form.
33. A composition for coating an implantable device comprising a
compound according to claim 1 and a carrier suitable for coating
said implantable device.
34. An implantable device coated with a composition according to
claim 33.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application 60/287,204, filed Apr. 27, 2001, the contents of which
are incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention is in the field of medicinal chemistry
and relates to triazole 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
[0003] 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).
[0004] 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).
[0005] A number of compounds have been developed that purport to
specifically inhibit various MAPKs. PCT publication WO 95/31451
describes pyrazole derivatives that inhibit p38. However, it is not
clear whether these compounds have the appropriate pharmacological
profiles to be therapeutically useful.
[0006] Aryl-substituted pyrroles are known in the literature. In
particular, tri-aryl pyrroles (U.S. Pat. No. 5,837,719) have been
described as having glucagon antagonist activity.
[0007] Heterocycle-substituted triazole compounds are known in the
literature. In particular, bis([1,2,3]triazoles) (Abbasoglu et al.,
1999, Indian J. Chem., Sect. B 38B, 413; Klaus, 1989, Chem. Ber.
122, 1175; Samsonov et al., 1993; Khim. Geterotsikl. Soedin. 29,
1169) and tetrazolyl-triazole (Ried and Laoutidis, 1990, Chem.-Ztg.
114, 246; Vereshchagin et al., 1984, Zh. Org. Khim. 20, 142)
compounds have been described.
[0008] There is a high unmet medical need to develop new
therapeutic treatments that are useful in treating the various
conditions associated with ERK2 activation. For many of these
conditions the currently available treatment options are
inadequate.
[0009] Accordingly, there is great interest in new and effective
inhibitors of protein kinase, including ERK2 inhibitors, which are
useful in treating various conditions associated with protein
kinase activation.
SUMMARY OF THE INVENTION
[0010] 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.
[0011] It is a principal object of this invention to provide
compounds that are protein kinase inhibitors represented by formula
I: 2
[0012] or a pharmaceutically acceptable derivative thereof,
wherein:
[0013] Ht is a heterocyclic ring selected from pyrrol-3-yl,
[1,2,4]triazol-3-yl, [1,2,3]triazol-4-yl, or tetrazol-5-yl, said
pyrrol-3-yl having R.sup.3 and Q.sub.n-R.sup.4 substituents, and
said [1,2,4]triazol-3-yl or [1,2,3]triazol-4-yl substituted by
either R.sup.3 or Q.sub.n-R.sup.4;
[0014] T and Q are each independently selected from
--C(R.sup.7).sub.2--, --C(O)--, --C(O)C(O)--, --C(O)NR.sup.7--,
--C(O)NR.sup.7NR.sup.7--, --CO.sub.2--, --OC(O)--,
--NR.sup.7CO.sub.2--, --O--, --NR.sup.7C(O)NR.sup.7--,
--OC(O)NR.sup.7--, --NR.sup.7NR.sup.7--, --NR.sup.7C(O)--, --S--,
--SO--, --SO.sub.2--, --NR.sup.7--, --SO.sub.2NR.sup.7--, or
--NR.sup.7SO.sub.2--, --NR.sup.7SO.sub.2NR.sup.7- --;
[0015] m and n are each independently selected from zero or
one;
[0016] R.sup.2 is selected from hydrogen, CN, halogen, R,
N(R.sup.7).sub.2, OR, or OH;
[0017] each R.sup.3 is independently selected from R.sup.7, F, Cl,
--(CH.sub.2).sub.yN (R.sup.7).sub.2, --N(R.sup.7).sub.2,
--OR.sup.7, --SR.sup.7, --NR.sup.7C(O)R.sup.7,
--NR.sup.7C(O)N(R.sup.7).sub.2, --C(O)N(R.sup.7).sub.2,
--SO.sub.2R.sup.7, --NR.sup.7SO.sub.2R.sup.7, --C(O)R.sup.7,
--C(O)OR.sup.7, CN or --SO.sub.2N(R.sup.7).sub.2;
[0018] R.sup.4 is selected from --(CH.sub.2).sub.yR.sup.6,
--(CH.sub.2).sub.yCH(R.sup.6).sub.2--(CH.sub.2).sub.yCH(R.sup.8)CH(R.sup.-
6).sub.2, --N(R.sup.5).sub.2,
--NR.sup.5(CH.sub.2).sub.yN(R.sup.5).sub.2;
[0019] each R is independently selected from an optionally
substituted group selected from C.sub.1-6 aliphatic, C.sub.6-10
aryl, heteroaryl having 5-10 ring atoms, and heterocyclyl having
3-10 ring atoms;
[0020] each R.sup.5 is independently selected from R, --R.sup.7,
--C(O)R.sup.7, --CO.sub.2R, --C(O)N(R.sup.7).sub.2,
--SO.sub.2R.sup.7, --(CH.sub.2).sub.yR.sup.6, or
--(CH.sub.2).sub.yCH(R.sup.6).sub.2;
[0021] y is 0-6;
[0022] each R.sup.6 is independently selected from R,
--(CH.sub.2).sub.yR, --OR, --CO.sub.2R,
--(CH.sub.2).sub.yN(R.sup.7).sub.2, --N(R.sup.7).sub.2, --OR.sup.7,
--SR.sup.7, --NR.sup.7C(O)R.sup.7, --NR.sup.7C(O)N(R.sup.7).sub.2,
--C(O)N(R.sup.7).sub.2, --SO.sub.2R.sup.7,
--NR.sup.7SO.sub.2R.sup.7, --C(O)R.sup.7, --CN,
--SO.sub.2N(R.sup.7).sub.2;
[0023] each R.sup.7 is independently selected from hydrogen or an
optionally substituted C.sub.1-6 aliphatic group, or two R.sup.7 on
the same nitrogen are taken together with the nitrogen to form a
5-8 membered ring heterocyclyl or heteroaryl ring;
[0024] each R.sup.8 is independently selected from R,
--(CH.sub.2).sub.wOR.sup.7, --(CH.sub.2).sub.wN(R.sup.5).sub.2, or
--(CH.sub.2).sub.wSR.sup.7;
[0025] each w is independently 0-4;
[0026] provided that when Ht is tetrazol-5-yl, and m is 0, R.sup.2
is other than H or an unsubstituted phenyl; when m is 0 and
R.sup.2, R.sup.3 and Q.sub.n-R.sup.4 are all H, Ht is other than
[1,2,3]triazole; and when T.sub.m-R.sup.2 and Q.sub.n-R.sup.4 are
both C(O)OH, Ht is other than [1,2,3]triazol-5-yl.
[0027] 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.
[0028] It is a further objective of this invention to provide
methods for making the compounds and compositions of this
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0029] 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.
[0030] 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.
[0031] 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.degree.
C. or less, in the absence of moisture or other chemically reactive
conditions, for at least a week.
[0032] The term "aliphatic" or "aliphatic group" as used herein
means a straight-chain or branched C.sub.1-C.sub.12 hydrocarbon
chain that is completely saturated or that contains one or more
units of unsaturation, or a monocyclic C.sub.3-C.sub.8 hydrocarbon
or bicyclic C.sub.8-C.sub.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 molecule wherein any individual ring in said bicyclic ring
system has 3-7 members. For example, suitable aliphatic groups
include, but are not limited to, linear or branched or alkyl,
alkenyl, alkynyl groups and hybrids thereof such as
(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0033] 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" used alone or as
part of a larger moiety shall include both straight and branched
chains containing two to twelve carbon atoms.
[0034] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means
alkyl, alkenyl or alkoxy, as the case may be, substituted with one
or more halogen atoms. The term "halogen" means F, Cl, Br, or
I.
[0035] The term "heteroatom" means nitrogen, oxygen, or sulfur and
includes any oxidized form of nitrogen and sulfur, and the
quaternized form of any basic nitrogen. Also the term "nitrogen"
includes a substitutable nitrogen of a heterocyclic ring. As an
example, in a saturated or partially unsaturated ring having 0-3
heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen
may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl)
or NR.sup.+ (as in N-substituted pyrrolidinyl).
[0036] The term "aryl" used alone or as part of a larger moiety as
in "aralkyl", "aralkoxy," or "aryloxyalkyl," refers to monocyclic,
bicyclic and tricyclic carbocyclic ring systems having a total of
five to fourteen members, wherein at least one ring in the system
is aromatic and wherein each ring in the system contains 3 to 7
ring members. The term "aryl" may be used interchangeably with the
term "aryl ring".
[0037] The term "heterocycle", "heterocyclyl", or "heterocyclic" as
used herein means non-aromatic, monocyclic, bicyclic or tricyclic
ring systems having five to fourteen ring members in which one or
more ring members is a heteroatom, wherein each ring in the system
contains 3 to 8 ring members.
[0038] The term "heteroaryl", used alone or as part of a larger
moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to
monocyclic, bicyclic and tricyclic ring systems having a total of
five to fourteen ring members, and wherein: 1) at least one ring in
the system is aromatic; 2) at least one ring in the system contains
one or more heteroatoms; and 3) each ring in the system contains 3
to 7 ring members. The term "heteroaryl" may be used
interchangeably with the term "heteroaryl ring" or the term
"heteroaromatic".
[0039] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the
like) or heteroaryl (including heteroaralkyl, heteroarylalkoxy and
the like) group may contain one or more substituents. Suitable
substituents on the unsaturated carbon atom of an aryl, heteroaryl,
aralkyl, or heteroaralkyl group are selected from halogen;
haloalkyl; --CF.sub.3; --R.sup.0; --OR.sup.0; --SR.sup.0;
1,2-methylene-dioxy; 1,2-ethylenedioxy; protected OH (such as
acyloxy); phenyl (Ph); Ph substituted with R.sup.0; --O(Ph);
--O(Ph) substituted with R.sup.0; --CH.sub.2(Ph); --CH.sub.2(Ph)
substituted with R.sup.0; --CH.sub.2CH.sub.2(Ph);
--CH.sub.2CH.sub.2(Ph) substituted with R.sup.0; --NO.sub.2; --CN;
--N(R.sup.0).sub.2; --NR.sup.0C(O)R.sup.0;
--NR.sup.0C(O)N(R.sup.0).sub.2; --NR.sup.0CO.sub.2R.sup.0;
--NR.sup.0NR.sup.0C(O)R.sup.0;
--NR.sup.0NR.sup.0C(O)N(R.sup.0).sub.2;
--NR.sup.0NR.sup.0CO.sub.2R.sup.0- ; --C(O)C(O)R.sup.0;
--C(O)CH.sub.2C(O)R.sup.0; --CO.sub.2R.sup.0; --C(O)R.sup.0;
--C(O)N(R.sup.0).sub.2; --OC(O)N(R.sup.0).sub.2;
--S(O).sub.2R.sup.0; --SO.sub.2N(R.sup.0).sub.2; --S(O)R.sup.0;
--NR.sup.0SO.sub.2N(R.sup.0).sub.2; --NR.sup.0SO.sub.2R.sup.0;
--C(.dbd.S)N(R.sup.0).sub.2; --C(.dbd.NH)--N(R.sup.0).sub.2;
--(CH.sub.2).sub.yNHC(O)R.sup.0; --(CH.sub.2).sub.yR.sup.0;
--(CH.sub.2).sub.yNHC(O)NHR.sup.0;
--(CH.sub.2).sub.yNHC(O)OR.sup.0; --(CH.sub.2).sub.yNHS(O)R.sup.0;
--(CH.sub.2).sub.yNHSO.sub.2R.sup.0;
--(CH.sub.2).sub.yNHC(O)CH(V.sub.z-R.sup.0) (R.sup.0); wherein each
R.sup.0 is independently selected from H, optionally substituted
C.sub.1-6 aliphatic, an unsubstituted 5-10 membered heteroaryl or
heterocyclic ring, phenyl (Ph), --O(Ph), or --CH.sub.2(Ph); wherein
y is 0-6; z is 0-1; and V is a linker group. When R.sup.0 is
C.sub.1-6 aliphatic, it may be substituted with one or more
substituents selected from --NH.sub.2, --NH(C.sub.1-4 aliphatic),
--N(C.sub.1-4 aliphatic).sub.2, --S(O) (C.sub.1-4 aliphatic)
--SO.sub.2(C.sub.1-4 aliphatic), halogen, --C.sub.1-4 aliphatic,
--OH, --O--(C.sub.1-4 aliphatic), nitro, cyano, --CO.sub.2H,
--CO.sub.2(C.sub.1-4 aliphatic), --O(halo C.sub.1-4 aliphatic), or
-halo(C.sub.1-4 aliphatic); wherein each C.sub.1-4 aliphatic is
unsubstituted.
[0040] An aliphatic group or a non-aromatic heterocyclic ring may
contain one or more substituents. Suitable substituents on the
saturated carbon of an aliphatic group or of a non-aromatic
heterocyclic ring are selected from those listed above for the
unsaturated carbon of an aryl or heteroaryl group and the
following: .dbd.O, .dbd.S, .dbd.NNHR.sup.9, .dbd.NN(R.sup.9).sub.2,
.dbd.N--, OR.sup.9, .dbd.NNHC(O)R.sup.9, .dbd.NNHCO.sub.2(alkyl),
.dbd.NNHSO.sub.2(alkyl), or .dbd.NR.sup.9, where each R.sup.9 is
independently selected from hydrogen or an optionally substituted
C.sub.1-6 aliphatic group. When R.sup.9 is C.sub.1-6 aliphatic, it
may be substituted with one or more substituents selected from
amino, halogen, nitro, cyano, carboxy, t-butoxy, methoxy, ethoxy,
hydroxy, or CF.sub.3.
[0041] Substituents on the nitrogen of a non-aromatic heterocyclic
ring are selected from --R.sup.10, --N(R.sup.10).sub.2,
--C(O)R.sup.10, --CO.sub.2R.sup.10, --C(O)C(O)R.sup.10,
--C(O)CH.sub.2C(O)R.sup.10, --SO.sub.2R.sup.10,
--SO.sub.2N(R.sup.10).sub.2, --C(.dbd.S)N(R.sup.10).s- ub.2,
--C(.dbd.NH)--N(R.sup.10).sub.2, and --NR.sup.10SO.sub.2R.sup.10;
wherein each R.sup.10 is independently selected from H, an
optionally substituted C.sub.1-6 aliphatic, optionally substituted
phenyl (Ph), optionally substituted --O(Ph), optionally substituted
CH.sub.2(Ph), optionally substituted --CH.sub.2CH.sub.2(Ph), or an
unsubstituted 5-6 membered heteroaryl or heterocyclic ring. When
R.sup.10 is a C.sub.1-6 aliphatic group or a phenyl ring, it may be
substituted with one or more substituents selected from NH.sub.2,
NH(C.sub.1-4 aliphatic), --N(C.sub.1-4 aliphatic).sub.2, halogen,
--C.sub.1-4 aliphatic, --OH, --O--(C.sub.1-4 aliphatic), nitro,
cyano, --CO.sub.2H, --CO.sub.2(C.sub.1-4 aliphatic), --O(halo
C.sub.1-4 aliphatic), or -halo(C.sub.1-4 aliphatic), wherein each
C.sub.1-4 aliphatic is unsubstituted.
[0042] The term "linker group" or "linker" means an organic moiety
that connects two parts of a compound. Linkers are comprised of
--O--, --S--, --NH--, --CH.sub.2--, --CO--, or an alkylidene chain.
The alkylidene chain is a saturated or unsaturated, straight or
branched, C.sub.1-6 carbon chain which is optionally substituted,
and wherein up to two non-adjacent saturated carbons of the chain
are optionally replaced by --C(O)--, --C(O)C(O)--, --C(O)NR*--,
--C(O)NR*NR*--, --CO.sub.2--, --OC(O)--, --NR*CO.sub.2--, --O--,
--NR*C(O)NR*--, --OC(O)NR*--, --NR*NR*--, --NR*C(O)--, --S--,
--SO--, --SO.sub.2--, --NR*--, --SO.sub.2NR*--, or --NR*SO.sub.2--;
wherein R* is selected from hydrogen or C.sub.1-4 aliphatic.
Optional substituents on the alkylidene chain are as described
above for an aliphatic group.
[0043] As used herein, linker group Q, when present, connects Ht
with R.sup.4. Q may form additional interactions within the ERK
binding site to further enhance the inhibitory activity of the
compound. When Q is a carbonyl-containing moiety such as --C(O)--,
--CO.sub.2--, --OC(O)--, --C(O)C(O)--, --C(O)NH--, --CO.sub.2NH--,
--C(O)NHNH--, --NHC(O)--, --OC(O)NH--, or --NHCO.sub.2--, or a
sulfonyl-containing moiety such as --SO.sub.2--, --SO.sub.2NH--, or
--NHSO.sub.2--, the carbonyl or sulfonyl oxygen forms a
hydrogen-bond with lysine 54 in the ERK binding site. When Q is an
NH-containing moiety such as --CH.sub.2NH-- or --NHNH--, the
NH-group forms a hydrogen-bond with aspartic acid residue 167 in
the ERK binding site. When Q is a hydrophobic group such as an
alkyl chain, --O--, or --S--, Q forms additional hydrophobic
interactions within the ERK binding site.
[0044] R.sup.4 forms hydrophobic interactions within the binding
site of ERK, especially with the side-chain carbons of lysine 54
and aspartic acid 167. R.sup.4 may also form hydrophobic
interactions with the glycine-rich loop which is made up of
amino-acid residues 33-38. When R.sup.4 is substituted, the
substituents may form further interactions within the binding site
to enhance the inhibitory activity of the compound. For example,
when a substituent on R.sup.4 is a hydrogen-bond donor or a
hydrogen-bond acceptor, said substituent forms a hydrogen bond with
enzyme-bound water molecules that exist in the binding site.
[0045] As used herein, linker group T, when present, connects the
triazole ring with R.sup.2. T may form additional interactions
within the ERK binding site to further enhance the inhibitory
activity of the compound. When T is a carbonyl-containing moiety
such as --C(O)--, --CO.sub.2--, --OC(O)--, --C(O)C(O)--,
--C(O)NH--, --CO.sub.2NH--, --C(O)NHNH--, --NHC(O)--, --OC(O)NH--,
or --NHCO.sub.2--, or a sulfonyl-containing moiety such as
--SO.sub.2--, --SO.sub.2NH--, or --NHSO.sub.2--, the carbonyl or
sulfonyl oxygen forms a hydrogen-bond with the NH of glutamine 105
in the ERK binding site. When T is an NH-containing moiety such as
--CH.sub.2NH-- or --NHNH--, the NH-group forms a hydrogen-bond with
the carbonyl of glutamine 105. When T is a hydrophobic group such
as an alkyl chain, --O-- or --S--, Q forms additional hydrophobic
interactions with the side-chain carbons of glutamine 105 as well
as isoleucine 84.
[0046] The binding interactions described herein between the
compounds of this invention and the ERK binding site have been
determined by molecular modeling programs that are known to those
of ordinary skill in the art. These molecular modeling programs
include QUANTA [Molecular Simulations, Inc., Burlington, Mass.,
1992] and SYBYL [Molecular Modeling Software, Tripos Associates,
Inc., St. Louis, Mo., 1992]. As used herein, the amino acid
numbering for the ERK enzyme corresponds to the Swiss-Prot database
entry for accession #P28482. The Swiss-Prot database is an
international protein sequence database distributed by the European
Bioinformatics Institute (EBI) in Geneva, Switzerland. The database
can be found at www.ebi.ac.uk/swissprot.
[0047] It will be apparent to one skilled in the art that certain
compounds of this invention may exist in tautomeric forms, all such
tautomeric forms of the compounds being within the scope of the
invention.
[0048] Unless otherwise stated, structures depicted herein are also
meant to include all stereochemical forms of the structure; i.e.,
the R and S configurations for each asymmetric center. Therefore,
single stereochemical isomers as well as enantiomeric and
diastereomeric mixtures of the present compounds are within the
scope of the invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds which differ
only in the presence of one or more isotopically enriched atoms.
For example, compounds having the present structures except for the
replacement of a hydrogen by a deuterium or tritium, or the
replacement of a carbon by a .sup.13C- or .sup.14C-enriched carbon
are within the scope of this invention.
[0049] One embodiment of this invention relates to a compound of
formula I: 3
[0050] or a pharmaceutically acceptable salt or derivative thereof,
wherein Ht, R.sup.2, T, and m, n, R.sup.3, Q and R.sup.4 are as
described above, provided that when Ht is tetrazol-5-yl, and m is
0, R.sup.2 is other than H or an unsubstituted phenyl; when m is 0
and R.sup.2, R.sup.3 and Q.sub.n-R.sup.4 are all H, Ht is other
than [1,2,3]triazole; and when T.sub.m-R.sup.2 and Q.sub.n-R.sup.4
are both C(O)OH, Ht is other than [1,2,3]triazol-5-yl.
[0051] Another embodiment of this invention relates to compounds
wherein the Ht ring is a pyrrol-3-yl (II-A), [1,2,4]triazol-3-yl
(II-B), [1,2,3]triazol-4-yl (II-C and II-D), or tetrazol-5-yl
(II-E) ring as shown below: 4
[0052] or a pharmaceutically acceptable salt or derivative thereof,
wherein R.sup.2, T, m, n, R.sup.3, Q and R.sup.4 are as described
above, provided that when Ht is tetrazol-5-yl, and m=0, R.sup.2 is
other than H or an unsubstituted phenyl; when m=0 and R.sup.2,
R.sup.3 and Q-R.sup.4 are all H, Ht is other than [1,2,3]triazole;
when T-R.sup.2 and Q-R.sup.4 are both C(O)OH, Ht is other than
[1,2,3]triazol-5-yl.
[0053] Preferred T.sub.mR.sup.2 groups on II-A, II-B, II-C, II-D,
and II-E are selected from hydrogen, N(R.sup.7).sub.2, OH, 3-6
membered carbocyclyl, or an optionally substituted group selected
from C.sub.1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring.
When R.sup.2 is an optionally substituted phenyl or aliphatic
group, preferred substituents on the phenyl or aliphatic group are
methyl, ethyl, halo, nitro, alkoxy, and amino. Preferred
T.sub.mR.sup.2 groups are methyl, ethyl, propyl, cyclopropyl,
cyclohexyl, CH.sub.2OCH.sub.3, CH.sub.2OH, NH.sub.2, NHCH.sub.3,
NHAc, NHC(O)NHCH.sub.3, and CH.sub.2NHCH.sub.3. More preferred
T.sub.mR.sup.2 groups of formulae II-A, II-B, II-C, II-D, and II-E
are those listed in the Tables below.
[0054] When R.sup.4 is R.sup.6, preferred R.sup.6 groups are
pyrrolidin-1-yl, morpholin-4-yl, piperidin-1-yl, and
piperazin-1-yl, 4-methyl[1,4]diazepan-1-yl,
4-phenyl-piperazine-1-yl, wherein each group is optionally
substituted as described above for heterocyclic rings. When R.sup.4
is (CH.sub.2).sub.yR.sup.6, (CH.sub.2).sub.yCH(R.sup.6).sub.2, or
--N(R.sup.5).sub.2, preferred R.sup.6 groups are pyridin-3-yl,
pyridin-4-yl, imidazolyl, furan-2-yl,
1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl,
phenyl, benzyl, --CH.sub.2OH, --(CH.sub.2).sub.2OH, isopropyl,
--CH.sub.2NH.sub.2, and --(CH.sub.2).sub.2NH.sub.2, wherein each
group is optionally substituted. Preferred substituents on R.sup.6
are --OH, pyridyl, piperidinyl, and optionally substituted phenyl,
wherein phenyl is optionally substituted as described above for
aryl rings. When R.sup.4 is
--(CH.sub.2).sub.yCH(R.sup.8)CH(R.sup.6).sub.2, preferred R.sup.8
groups are R.sup.7 and OR.sup.7 such as OH and CH.sub.2OH. Other
preferred -QR.sup.4 groups are those listed in the Tables
below.
[0055] Preferred compounds of formulae II-A, II-B, II-C, II-D, and
II-E are those having one or more, more preferably more than one,
and most preferably all, of the features selected from the group
consisting of:
[0056] (a) T.sub.mR.sup.2 is hydrogen, N(R.sup.7).sub.2, OH, 3-6
membered carbocyclyl, or an optionally substituted group selected
from C.sub.1-6 aliphatic or a 5-6 membered aryl or heteroaryl
ring;
[0057] (b) Q is --CO--, --CO.sub.2--, --CONH--, --SO.sub.2--,
--SO.sub.2NH--, --OC(O)NH--, --C(O)ONH--, or --CONHNH--;
[0058] (c) R.sup.4 is --NR.sup.5(CH.sub.2).sub.yN(R.sup.5).sub.2,
--(CH.sub.2).sub.yR.sup.6, --(CH.sub.2).sub.yCH(R.sup.6).sub.2, or
--(CH.sub.2).sub.yCH(R.sup.8) CH(R.sup.6).sub.2;
[0059] (d) R.sup.5 is R, R.sup.7, or
--(CH.sub.2).sub.yCH(R.sup.6).sub.2; and
[0060] (e) R.sup.6 is an optionally substituted group selected from
phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl.
[0061] More preferred compounds of formulae II-A, II-B, II-C, II-D,
and II-E are those having one or more, more preferably more than
one, or most preferably all, of the features selected from the
group consisting of:
[0062] (a) T.sub.mR.sup.2 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
CH.sub.2OCH.sub.3, CH.sub.2OH, OH, NH.sub.2, NHCH.sub.3, NHAc,
NHC(O)NHCH.sub.3, or CH.sub.2NHCH.sub.3;
[0063] (b) Q is --CO--, --CONH--, --SO.sub.2--, or
--SO.sub.2NH--;
[0064] (c) R.sup.4 is --(CH.sub.2).sub.yR.sup.6,
--(CH.sub.2).sub.yCH(R.su- p.6).sub.2, or
--(CH.sub.2).sub.yCH(R.sup.8)CH(R.sup.6).sub.2, wherein R.sup.8 is
OH or CH.sub.2OH; and
[0065] (d) R.sup.6 is --CH.sub.2OH, --(CH.sub.2).sub.2OH,
isopropyl, --CH.sub.2NH.sub.2, --(CH.sub.2).sub.2NH.sub.2, or an
optionally substituted group selected from pyrrolidin-1-yl,
morpholin-4-yl, piperidin-1-yl, piperazin-1-yl,
4-methyl[1,4]diazepan-1-yl, 4-phenyl-piperazine-1-yl, pyridin-3-yl,
pyridin-4-yl, imidazolyl, furan-2-yl,
1,2,3,4-tetrahydroisoquinoline, tetrahydrofuran-2-yl, cyclohexyl,
phenyl, or benzyl.
[0066] Preferred compounds of formulae II-A, II-B, and II-D are
those of formulae II-A', II-B', and II-D': 5
[0067] Preferred R.sup.6 groups of formulae II-A', II-B', and II-D'
are optionally substituted 6-membered aryl, heteroaryl, and
carbocyclic rings, such as phenyl, pyridyl, and cyclohexyl.
[0068] Preferred T.sub.mR.sup.2 groups of formulae II-A', II-B',
and II-D' are as described above for formulae II-A, II-B, and
II-D.
[0069] Preferred compounds of formulae II-A', II-B', and II-D' are
those having one, and more preferably both, of the features
selected from the group consisting of:
[0070] (a) T.sub.mR.sup.2 is hydrogen, N(R.sup.7).sub.2, OH, 3-6
membered carbocyclyl, or an optionally substituted group selected
from C.sub.1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring;
and
[0071] (b) R.sup.6 is an optionally substituted 6-membered aryl,
heteroaryl, or carbocyclic ring.
[0072] More preferred compounds of formulae II-A', II-B', and II-D'
are those having one, and more preferably both, of the features
selected from the group consisting of:
[0073] (a) T.sub.mR.sup.2 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
CH.sub.2OCH.sub.3, CH.sub.2OH, OH, NH.sub.2, NHCH.sub.3, NHAc,
NHC(O)NHCH.sub.3, or CH.sub.2NHCH.sub.3; and
[0074] (b) R.sup.6 is cyclohexyl or an optionally substituted
phenyl or pyridyl ring.
[0075] Preferred compounds of formulae II-A, II-B, and II-D are
further selected from those of formulae II-A.degree., II-B.degree.,
and II-D.degree.: 6
[0076] Preferred R.sup.6 groups of formulae II-A.degree.,
II-B.degree., and II-D.degree. are R or OR.sup.7. Examples of such
groups include OH, CH.sub.2OH, or optionally substituted 6-membered
aryl, heteroaryl, and carbocyclic rings, such as phenyl, pyridyl,
and cyclohexyl. Preferred R.sup.8 groups of formulae II-A.degree.,
II-B.degree., and II-D.degree. are R and OR.sup.7, wherein R is an
optionally substituted group selected from C.sub.1-4 aliphatic, 3-6
membered heterocyclic, or a 5-6 membered aryl or heteroaryl ring.
Examples of such groups include phenyl, methyl, ethyl, OH, and
CH.sub.2OH.
[0077] Preferred T.sub.mR.sup.2 groups of formulae II-A.degree.,
II-B.degree., and II-D.degree. are as described above for formulae
II-A, II-B, and II-D.
[0078] Preferred compounds of formulae II-A.degree., II-B.degree.,
and II-D.degree. are those having one, and more preferably both, of
the features selected from the group consisting of:
[0079] (a) T.sub.mR.sup.2 is hydrogen, N(R.sup.7).sub.2, OH, 3-6
membered carbocyclyl, or an optionally substituted group selected
from C.sub.1-6 aliphatic or a 5-6 membered aryl or heteroaryl ring;
and
[0080] (b) R.sup.6 is R or OR.sup.7, and R.sup.8 is R.sup.7 or
OR.sup.7.
[0081] More-preferred compounds of formulae II-A.degree.,
II-B.degree., and II-D.degree. are those having one, and more
preferably both, of the features selected from the group consisting
of:
[0082] (a) T.sub.mR.sup.2 is selected from optionally substituted
phenyl, methyl, ethyl, propyl, cyclopropyl, cyclohexyl,
CH.sub.2OCH.sub.3, CH.sub.2OH, OH, NH.sub.2, NHCH.sub.3, NHAc,
NHC(O)NHCH.sub.3, or CH.sub.2NHCH.sub.3; and
[0083] (b) R.sup.6 is OH, CH.sub.2OH, phenyl, pyridyl, or
cyclohexyl, and R.sup.8 is methyl, ethyl, OH, or CH.sub.2OH.
[0084] Exemplary structures of formulae II-A, II-B, and II-D,
wherein R.sup.3 is H, m is zero, and n is one are set forth in
Table 1 below.
1TABLE 1 Compounds II-A, II-B, and II-D No. R.sup.2 Q-R.sup.4
II-A-1, II-B-1, and II-C-1 phenyl CON(Me).sub.2 II-A-2, II-B-2, and
II-C-2 phenyl CO.sub.2Et II-A-3, II-B-3, and II-C-3
3-NO.sub.2-phenyl CONHNH.sub.2 II-A-4, II-B-4, and II-C-4 phenyl
CO(pyrrol1d1n-1-yl) II-A-5, II-B-5, and II-C-5 phenyl
CONHCH.sub.2(Ph) II-A-6, II-B-6, and II-C-6 3-NO.sub.2-phenyl
CO.sub.2Et II-A-7, II-B-1, and II-C-7 4-Cl-phenyl CO.sub.2Et
II-A-8, II-B-8, and II-C-7 4-OMe-phenyl CO.sub.2Et II-A-9, II-B-9,
and II-C-9 3-NH.sub.2-phenyl CO.sub.2Et II-A-10, II-B-10, and
II-C-10 3-OMe-phenyl CO.sub.2Et II-A-11, II-B-11, and II-C-11
4-F-phenyl CO.sub.2Et II-A-12, II-B-12, and II-C-12
4-NO.sub.2-phenyl CO.sub.2Et II-A-13, II-B-13, and II-C-13
3-Cl-phenyl CO.sub.2Et II-A-14, II-B-14, and II-C-14 3-F-phenyl
CO.sub.2Et II-A-15, II-B-15, and II-C-15 phenyl CO2H II-A-16,
II-B-16, and II-C-16 4-NH.sub.2-phenyl CO.sub.2Et lI-A-17, II-B-17,
and II-C-17 phenyl CONHCN.sub.2CH.sub.2N(Me).sub.2 II-A-18,
II-B-18, and II-C-18 phenyl CONHCH.sub.2(pyridin-3-yl) II-A-19,
II-B-19, and II-C-19 phenyl CO (morpolin-4-yl) II-A-20, II-B-20,
and II-C-20 phenyl CONH(isopropyl) II-A-21, II-B-21, and II-C-21
phenyl CO(4-Me-piperazin-1-yl) II-A-22, II-B-22, and II-C-22 phenyl
CONHCH.sub.2(furan-2-yl) II-A-23, II-B-23, and II-C-23 3-OMe-phenyl
CONMe.sub.2 II-A-24, II-B-24, and II-C-24 3-OMe-phenyl CO
(pyrrolidin-1-yl) II-A-25, II-B-25, and II-C-25 3-OMe-phenyl
CONHCH.sub.2CH.sub.2N(Me).sub.2 II-A-26, II-B-26, and II-C-26
3-OMe-phenyl CONHCH.sub.2(pyridin-3-yl) II-A-27, II-B-27, and
II-C-27 3-OMe-phenyl CO (morpholin-4-yl) II-A-28, II-B-28, and
II-C-28 3-OMe-phenyl CONH(isopropyl) II-A-29, II-B-29, and II-C-29
3-OMe-phenyl CO(4-Me-piperazin-1-yl) II-A-30, II-B-30, and II-C-30
3-OMe-phenyl CONHCH.sub.2(furan-2-yl) II-A-31, II-B-31, and II-C-31
4-NH.sub.2-phenyl CO.sub.2Et II-A-32, II-B-32, and II-C-32 H
CONMe.sub.2 II-A-33, II-B-33, and II-C-33 H Co(pyrrolidin-1-yl)
II-A-34, II-B-34, and II-C-34 3-(AcNH)-phenyl CO.sub.2Et II-A-35,
II-B-35, and II-C-35 4-(AcNH)-phenyl CO.sub.2Et II-A-36, II-B-36,
and II-C-36 3-(AcNH)-phenyl CO.sub.2Et II-A-37, II-B-37, and
II-C-37 4-(AcNH)-phenyl CO.sub.2Et II-A-38, II-B-38, and II-C-38
3-Cl-phenyl CONHBn II-A-39, II-B-39, and II-C-39 3,5-dichlorophenyl
7 II-A-40, II-B-40, and II-C-40 3-Br-phenyl
CONH(3,4-difluorophenyl) II-A-41, II-B-41, and II-C-41 3-Cl-phenyl
CONH (2-OH-1-Ph-ethyl) II-A-42, II-B-42, and II-C-42 4-OH-3-I-5-
CONH(2-OH-1-Ph-ethyl) nitrophenyl II-A-43, II-B-43, and II-C-43
3-Br-phenyl 8 II-A-44, II-B-44, and II-C-44 5-NH.sub.2-4-OH-3-I-
CONH(2-OH-1-Ph-ethyl) phenyl II-A-45, II-B-45, and II-C-45
3-Br-phenyl CONH(2-OH-1-Ph-ethyl) II-A-46, II-B-46, and II-C-46
3-Br-phenyl CONHCH.sub.2(3-MeO-phenyl) II-A-47, II-B-47, and
II-C-47 3-Br-phenyl CONHCH.sub.2(3-CF.sub.3-phenyl) II-A-48,
II-B-48, and II-C-48 3,5-dichlorophenyl CONHCH.sub.2(pyrid-4-yl)
II-A-49, II-B-49, and II-C-49 3-CF.sub.3-phenyl CONH
(2-OH-1-Ph-ethyl) II-A-50, II-B-50, and II-C-50 3-Cl-phenyl
CONHCH.sub.2Ph II-A-51, II-B-51, and II-C-51 3,5-dichlorophenyl
CONHOCH.sub.2Ph II-A-52, II-B-52, and II-C-52 4-OH-3-I-5-
CONHCH.sub.2Ph nitrophenyl II-A-53, II-B-53, and II-C-53
3-Cl-phenyl CONHCH.sub.2(pyrid-4-yl) II-A-54, II-B-54, and II-C-54
3,4-dichlorophenyl CONHOCH.sub.2Ph II-A-55, II-B-55, and II-C-55
3-Br-phenyl) CONHCH.sub.2(4-SO.sub.2Me- phenyl) II-A-56, II-B-56,
and II-C-56 3-Br-phenyl CONHNH(3-CF.sub.3-phenyl) II-A-57, II-B-57,
and II-C-57 3-Cl-phenyl CONHOCH.sub.2Ph II-A-58, II-B-58, and
II-C-58 3-Br-phenyl 9 II-A-59, II-B-59, and II-C-59 3-Br-phenyl 10
II-A-60, II-B-60, and II-C-60 3-Br-phenyl CONHCH.sub.2(2-Me-phenyl)
II-A-61, II-B-61, and II-C-61 3,4- CONHCH.sub.2(pyrid-4-yl)
dichlorophenyl II-A-62, II-B-62, and II-C-62 3-Br-phenyl
CONH(1-Ph-propyl) II-A-63, II-B-63, and II-C-63 3-F-phenyl
CONHCH.sub.2Ph II-A-64, II-B-64, and II-C-64 3,4-dichlorophenyl 11
II-A-65, II-B-65, and II-C-65 3-Br-phenyl 12 II-A-66, II-B-66, and
II-C-66 3,5-dichlorophenyl CON(Me) (Et) II-A-67, II-B-67, and
II-C-67 3-Cl-phenyl CONNCH.sub.2(pyrid-3-yl) II-A-68, II-B-68, and
II-C-68 3-Br-phenyl CONHCH.sub.2(3,5- dimethoxyphenyl) II-A-69,
II-B-69, and II-C-69 3-Br-phenyl CONHCH.sub.2(2-OMe- phenyl)
II-A-70, II-B-70, and II-C-70 3-Cl-4-F-phenyl
CONHCH.sub.2(pyrid-4-yl) II-A-71, II-B-71, and II-C-71
3-Cl-4-F-phenyl CON(Me) (Et) II-A-72, II-B-72, and II-C-72
3-Br-phenyl CONH(2-OH-1-Ph-ethyl) II-A-73, II-B-73, and II-C-73
3-NH.sub.2-phenyl CONHCH.sub.2Ph II-A-74, II-B-74, and II-C-74
3,4-dichlorophenyl CONHCH.sub.2(pyrid-3-yl) II-A-75, II-B-75, and
II-C-75 3-Me-phenyl CONH(2-OH-1-Ph-ethyl) II-A-76, II-B-76, and
II-C-76 3,5-dichlorophenyl CONHCH.sub.2(pyrid-3-yl) II-A-77,
II-B-77, and II-C-77 3-Cl-4-F-phenyl CONHOCH.sub.2Ph II-A-78,
II-B-78, and II-C-78 3,5-dichlorophenyl CONHCH.sub.2(tetrahydro
furan-2-yl) II-A-79, II-B-79, and II-C-79 3-NO.sub.2-phenyl
CONHCH.sub.2Ph II-A-80, II-B-60, and II-C-60 3-F-phenyl
CONHCH.sub.2(pyrid-4-yl) II-A-81, II-B-81, and II-C-81
3-Cl-2-F-phenyl CON(Me) (Et) II-A-82, II-B-82, and II-C-82
3-Cl-2-F-phenyl CONHOCH.sub.2Ph II-A-83, II-B-83, and II-C-83
3-Br-phenyl 13 II-A-84, II-B-84, and II-C-84 3-Cl-phenyl
CONHCH.sub.2(tetrahydro furan-2-yl) II-A-85, II-B-85, and II-C-85
3,5-difluorophenyl CONHOCH.sub.2Ph II-A-86, II-B-86, and II-C-86
3-Br-phenyl CONH(3-OH-1-Ph-propyl) II-A-87, II-B-87, and II-C-87
3-Br-phenyl 14 II-A-88, II-B-88, and II-C-88 3,4-difluorophenyl
CONHCH.sub.2(pyrid-4-yl) II-A-89, II-B-89, and II-C-89 3-F-phenyl
CONHOCH.sub.2Ph II-A-90, II-B-90, and II-C-90 3-Me-phenyl
CONHCN.sub.2Ph II-A-91, II-B-91, and II-C-91 3-Br-phenyl 15
II-A-92, II-B-92, and II-C-92 4-Cl-phenyl CONHCH.sub.2Ph II-A-93,
II-B-93, and II-C-93 3-Cl-phenyl CON(Me) (Et) II-A-94, II-B-94, and
II-C-94 3-Br-pheny1 COPNHCH.sub.2(4-SO.sub.2--NH.sub.2- phenyl)
II-A-95, II-B-95, and II-C-95 3-OH-phenyl CONHCH.sub.2Ph II-A-96,
II-B-96, and II-C-96 3-Me-phenyl CONHCH.sub.2(pyrid-4-yl) II-A-97,
II-B-97, and II-C-97 Phenyl CONHCH.sub.2Ph II-A-99, II-B-98, and
II-C-98 2,5-difluorophenyl CONHCH.sub.2(prid-4-yl) II-A-99,
II-B-99, and II-C-99 4-Cl-phenyl CONHOCH.sub.2Ph II-A-100,
II-B-100, and II-C-100 3-Cl-4-F-phenyl CONHCH.sub.2(tetrahydro
furan-2-yl) II-A-101, II-B-101, and II-C-101 3-Cl-4-F-phenyl
CONHCH.sub.2(pyrid-3-yl) II-A-102, II-B-102, and II-C-102
3-Br-pheny1 16CO(4-OH-4-Ph- piperidin-1-yl) II-A-103, II-B-103, and
II-C-103 2,3-difluorophenyl CONHOCH.sub.2Ph II-A-104, II-B-104, and
II-C-104 3-Cl-phenyl CO (morpholin-4-yl) II-A-105, II-B-105, and
II-C-105 3-Br-phenyl 17 II-A-106, II-B-106, and II-C-106
3-Cl-2-F-phenyl CONHCH.sub.2(tetrahydro furan-2-yl) II-A-107,
II-B-107, and II-C-107 3-Cl-4-F-phenyl CO (morpholin-4-yl)
II-A-108, II-B-108, and II-C-108 3-Cl-4-F-phenyl CON (Me) (Et)
II-A-109, II-B-109, and II-C-109 3-Br-phenyl
CONHCH.sub.2(4-NH.sub.2- phenyl) II-A-110, II-B-110, and II-C-110
3-Br-phenyl 18 II-A-111, II-B-111, and II-C-111 4-F-phenyl
CONHCH.sub.2Ph II-A-112, II-B-112, and II-C-112 3,5-dichlorophenyl
CO(morpholin-4-yl) II-A-113, 11-B-113, and II-C-113
2,5-difluorophenyl CONHOCH.sub.2Ph II-A-114, II-B-114, and II-C-114
3-Cl-2-F-phenyl CONHCH.sub.2(pyrid-3-yl) II-A-115, II-B-115, and
II-C-115 3-Cl-2-F-phenyl CONHCH.sub.2(pyrid-4-yl) II-A-116,
II-B-116, and II-C-116 3,4-difluorophenyl CONHCH.sub.2(pyrid-3-yl)
II-A-117, II-B-117, and II-C-117 4-OMe-phenyl CONHCH.sub.2Ph
II-A-118, II-B-118, and II-C-118 3-Br-phenyl CONHCH.sub.2(2,4,6-
trimethoxyphenyl) II-A-119, II-B-119, and II-C-119 3-F-phenyl
CONHCH.sub.2(pyrid-3-yl) II-A-120, II-B-120, and II-C-120
3,4-difluorophenyl CONHCH.sub.2(tetrahydro furan-2-yl) II-A-121,
II-B-121, and II-C-121 3-Cl-2-F-phenyl 19 II-A-122, II-B-122, and
II-C-122 3-Br-phenyl 20 II-A-123, II-B-123, and II-C-123
3-Br-phenyl 21 II-A-124, II-B-124, and II-C-124 3-Br-phenyl
CONHCH.sub.2(2,5- dimethoxyphenyl) II-A-125, II-B-125, and II-C-125
3,5-dichlorophenyl 22 II-A-126, II-B-126, and II-C-126 3-Br-phenyl
23 II-A-127, II-B-127, and II-C-127 3,4-dichlorophenyl
CO(morpholin-4-yl) II-A-128, II-B-128, and II-C-128 3-Br-phenyl 24
II-A-129, II-B-129, and II-C-129 3-Cl-2-F-phenyl CO(morpholin-4-yl)
II-A-130, II-B-130, and II-C-130 3-Br-phenyl CONHCH.sub.2CH.sub.2OH
II-A-131, II-B-131, and II-C-131 3-NH.sub.2-phenyl CONHCH.sub.2Ph
II-A-132, II-B-132, and II-C-132 3-MeOC(O)- CONHCH.sub.2Ph phenyl
II-A-133, II-B-133, and II-C-133 4-MeO-phenyl CONHOCH.sub.2Ph
II-A-134, II-B-134, and II-C-134 Phenyl CO(pyrrolidin-1-yl)
II-A-135, II-B-135, and II-C-135 3-MeO-phenyl CO(morpholin-4-yl)
II-A-136, II-B-136, and II-C-136 3-Cl-phenyl
CO(4-Me-piperidin-1-yl) II-A-137, II-B-137, and II-C-137
3-NO.sub.2-phenyl CONH.sub.2NH.sub.2 II-A-138, II-B-138, and
II-C-138 3-Br-phenyl 25 II-A-139, II-B-139, and II-C-139
3-Br-phenyl 26 II-A-140, II-B-140, and II-C-140 3-Cl-phenyl CONHPh
II-A-141, II-B-141, and II-C-141 2,3-difluorophenyl
CONHCH.sub.2(pyrid-4-yl) II-A-142, II-B-142, and II-C-142
3-Cl-phenyl 27 II-A-143, II-B-143, and II-C-143 Phenyl
CON(Me).sub.2 II-A-144, II-B-144, and II-C-144 3-OMe-phenyl
CO(pyrrolidin-1-yl) II-A-145, II-B-145, and II-C-145 3-OMe-phenyl
CONHCH.sub.2(pyrid-3-yl) II-A-146, II-B-146, and II-C-146
4-F-phenyl CONHOCH.sub.2Ph II-A-147, II-B-147, and II-C-147
3-OMe-phenyl CONHCH.sub.2(furan-2-yl) II-A-148, II-B-148, and
II-C-148 3-NO.sub.2-phenyl COOEt II-A-149, II-B-149, and II-C-149
Phenyl CONHCH.sub.2(furan-2-yl) II-A-150, II-B-150, and II-C-150
Phenyl CO(morpholin-4-yl) II-A-151, II-B-151, and II-C-151
3-Cl-phenyl COOEt II-A-152, II-B-152, and II-C-152 3-Br-phenyl
CONHMe II-A-153, II-B-153, and II-C-153 Phenyl
CONHCH.sub.2(pyrid-3-yl) II-A-154, II-B-154, and II-C-154
3-OMe-phenyl CON(Me).sub.2 II-A-155, II-B-155, and II-C-155
3-Cl-phenyl 28 II-A-156, II-B-156, and II-C-156 3-Br-phenyl 29
II-A-157, II-B-157, and II-C-157 3-Br-phenyl COOEt II-A-158,
II-B-158, and II-C-158 phenyl CONH(iPr) II-A-159, II-B-159, and
II-C-159 3-OMe-phenyl CONH(iPr) II-A-160, II-B-160, and II-C-160
3-COOH-phenyl CONH(iPr) II-A-161, II-B-161, and II-C-161
3-Br-phenyl CONHO(iPr) II-A-162, II-B-162, and II-C-162 3-F-phenyl
COOEt II-A-163, II-B-163, and II-C-163 3-OMe-phenyl CO(4-Me-
piperidin-1-yl) II-A-164, II-B-164, and II-C-164 4-NH.sub.2-phenyl
COOEt II-A-165, II-B-165, and II-C-165 4-NO.sub.2-phenyl COOEt
II-A-166, II-B-166, and II-C-166 phenyl CO(4-Me- piperidin-1-yl)
II-A-167, II-B-167, and II-C-167 4-Cl-phenyl COOEt II-A-168,
II-B-168, and II-C-168 4-OMe-phenyl COOEt II-A-169, II-B-169, and
II-C-169 phenyl COOEt II-A-170, II-B-170, and II-C-170 3-OMe-phenyl
COOEt II-A-171, II-B-171, and II-C-171 4-F-phenyl COOEt II-A-194,
II-B-194, and II-C-194 3,4-difluorophenyl CONHCH.sub.2(1-Et-
pyrrolidin-2-yl) II-A-195, II-B-195, and II-C-195
2,3-difluorophenyl CONHCH.sub.2(1-Et- pyrrolidin-2-yl) II-A-196,
II-B-196, and II-C-196 2,5-difluorophenyl CONHCH.sub.2(1-Et-
pyrrolidin-2-yl) II-A-197, II-B-197, and II-C-197 4-F-phenyl
CO(morpholin-4-yl) II-A-198, II-B-198, and II-C-198 4-OMe-phenyl
CO(morpholin-4-yl) II-A-199, II-B-199, and II-C-199 3-F-phenyl
CO(morpholin-4-yl) II-A-200, II-B-200, and II-C-200
2,5-dimethoxyphenyl CO(morpholin-4-yl) II-A-201, II-B-201, and
II-C-201 3,4-difluorophenyl CO(morpholin-4-yl) II-A-202, II-B-202,
and II-C-202 2,3-difluorophenyl CO(morpholin-4-yl) II-A-203,
II-B-203, and II-C-203 2,5-difluorophenyl CO(morpholin-4-yl)
II-A-204, II-B-204, and II-C-204 4-F-phenyl CO(4-Me-piperidin-1-yl)
II-A-205, II-B-205, and II-C-205 4-OMe-phenyl
CO(4-Me-piperidin-1-yl) II-A-206, II-B-206, and II-C-206 3-F-phenyl
CO(4-Me-piperidin-1-yl) II-A-207, II-B-207, and II-C-207
2,5-dimethoxyphenyl CO(4-Me-piperidin-1-yl) II-A-208, II-B-208, and
II-C-208 3,4-difluorophenyl CO(4-Me-piperidin-1-yl) II-A-209,
II-B-209, and II-C-209 2,3-difluorophenyl CO(4-Me-piperidin-1-yl)
II-A-210, II-B-210, and II-C-210 2,5-difluorophenyl
CO(4-Me-piperidin-1-yl) II-A-211, II-B-211, and II-C-211
4-C1-phenyl CONHCH.sub.2(pyrid-4-yl) II-A-212, II-B-212, and
II-C-212 3,4-dimethoxyphenyl CONHCH.sub.2(pyrid-4-yl) II-A-213,
II-B-213, and II-C-213 benzo [1,3]dioxo-5-yl
CONHCH.sub.2(pyrid-4-yl) II-A-214, II-B-214, and II-C-214
4-Cl-phenyl CONHCH.sub.2(pyrid-3-yl) II-A-215, II-B-215, and
II-C-215 3,4-dimethoxyphenyl CONHCH.sub.2(pyrid-3-yl) II-A-216,
II-B-216, and II-C-216 benzo [1,3]dioxo-5-yl
CONHCH.sub.2(pyrid-3-yl) II-A-172, II-B-172, and II-C-172
3-NH.sub.2-phenyl COOEt II-A-173, II-B-173, and II-C-173
3-Cl-phenyl COOH II-A-174, II-B-174, and II-C-174 3-Cl-phenyl 30
II-A-175, II-B-175, and II-C-175 3-Cl-phenyl 31 II-A-176, II-B-176,
and II-C-176 3-OMe-phenyl CONHCH.sub.2(pyrid-4-yl) II-A-177,
II-B-177, and II-C-177 3,5-dimethoxyphenyl CONHCH.sub.2(pyrid-4-yl)
II-A-178, II-B-178, and II-C-178 4-F-phenyl
CONHCH.sub.2(pyrid-3-yl) II-A-179, II-B-179, and II-C-179
4-OMe-phenyl CONHCH.sub.2(pyrid-3-yl) II-A-180, II-B-180, and
II-C-180 2,5-dimethoxyphenyl CONHCH.sub.2(pyridin-3-yl) II-A-181,
II-B-181, and II-C-181 2,5-difluorophenyl CONHCH.sub.2(pyrid-3-yl)
II-A-182, II-B-182, and II-C-182 4-F-phenyl CONHCH.sub.2(tetrahydro
furan-2-yl) II-A-183, II-B-183, and II-C-183 4-OMe-phenyl
CONHCH.sub.2(tetrahydro furan-2-yl) II-A-184, II-B-184, and
II-C-184 3-F-phenyl CONHCH.sub.2(tetrahydro furan-2-yl) II-A-185,
II-B-185, and II-C-185 3-OMe-phenyl CONHCH.sub.2(tetrahydro
furan-2-yl) II-A-186, II-B-186, and II-C-186 2,5-dimethoxyphenyl
CONHCH.sub.2(tetrahydro furan-2-yl) II-A-187, II-B-187, and
II-C-187 2,3-difluorophenyl CONHCH.sub.2(tetrahydro furan-2-yl)
II-A-188, II-B-188, and II-C-188 2,5-difluorophenyl
CONHCH.sub.2(tetrahydro furan-2-yl) II-A-189, II-B-189, and
II-C-189 4-F-phenyl CONHCH.sub.2(1-Et- pyrrolidin-2-yl) II-A-190,
II-B-190, and II-C-190 4-OMe-phenyl CONHCH.sub.2(1-Et-
pyrrolidin-2-yl) II-A-191, II-B-191, and II-C-191 3-F-phenyl
CONHCH.sub.2(1-Et- pyrrolidin-2-yl) II-A-192, II-B-192, and
II-C-192 3-OMe-phenyl CONHCH.sub.2(1-Et- pyrrolidin-2-yl) II-A-193,
II-B-193, and II-C-193 2,5-dimethoxyphenyl CONHCH.sub.2(1-Et-
pyrrolidin-2-yl) II-A-217, II-B-217, and II-C-217 4-Cl-phenyl
CONHCH.sub.2(tetrahydro furan-2-yl) II-A-218, II-B-218, and
II-C-218 3,4-dimethoxyphenyl CONHCH.sub.2(tetrahydro
dimethoxyphenyl furan-2-yl) II-A-219, II-B-219, and II-C-219 benzo
[1,3]dioxo- CONHCH.sub.2(tetrahydro 5-yl furan-2-yl) II-A-220,
II-B-220, and II-C-220 4-Cl-phenyl CONHCH.sub.2(1-Et
pyrrolidin-2-yl) II-A-221, II-B-221, and II-C-221
3,4-dichlorophenyl CONHCH.sub.2(1-Et- pyrrolidin-2-yl) II-A-222,
II-B-222, and II-C-222 3-Cl-2-F-phenyl CONHCH.sub.2(1-Et-
pyrrolidin-2-yl) II-A-223, II-B-223, and II-C-223 3-Cl-4-F-phenyl
CONHCH.sub.2(1-Et- pyrrolidin-2-yl) II-A-224, II-B-224, and
II-C-224 3,4-dimethoxyphenyl CONHCH.sub.2(1-Et- pyrrolidin-2-yl)
II-A-225, II-B-225, and II-C-225 benzo [1,3[dioxo-
CONHCH.sub.2(1-Et- 5-yl pyrrolidin-2-yl) II-A-226, II-B-226, and
II-C-226 3,5-dichlorophenyl CONHCH.sub.2(1-Et- pyrrolidin-2-yl)
II-A-227, II-B-227, and II-C-227 4-Cl-phenyl CO(morpholin-4-yl)
II-A-228, II-B-228, and II-C-228 3,4-dimethoxyphenyl
CO(morpholin4-yl) II-A-229, II-B-229, and II-C-229 benzo
[1,3]dioxo- CO(morpholin-4-yl) 5-yl
II-A-230, II-B-230, and II-C-230 4-Cl-phenyl
CO(4-Me-piperidin-1-yl) II-A-231, II-B-231, and II-C-231
3,4-dichlorophenyl CO(4-Me-piperidin-1-yl) II-A-232, II-B-232, and
II-C-232 3-Cl-2-F-phenyl CO(4-Me-piperidin-1-yl) II-A-233,
II-B-233, and II-C-233 3-Cl-4-F-phenyl CO(4-Me-piperidin-1-yl)
II-A-234, II-B-234, and II-C-234 3,4-dimethoxyphenyl
CO(4-Me-piperidin-1-yl) II-A-235, II-B-235, and II-C-235
benzo[1,3]dioxo- CO(4-Me-piperidin-1-yl) 5-yl II-A-236, II-B-236,
and II-C-236 3,5-dichlorophenyl CO(4-Me-piperidin-1-yl) II-A-237,
II-B-237, and II-C-237 2,3-dichlorophenyl CON(Me) (Et) II-A-238,
II-B-238, and II-C-238 4-F-phenyl 32 II-A-239, II-B-239, and
II-C-239 3-OMe-phenyl 33 II-A-240, II-B-240, and II-C-240
2,5-dimethoxyphenyl 34 II-A-241, II-B-241, and II-C-241
3,4-difluorophenyl 35 II-A-242, II-B-242, and II-C-242
2,3-difluorophenyl 36 II-A-243, II-B-243, and II-C-243
2,5-difluorophenyl 37 II-A-244, II-B-244, and II-C-244 3
-MeO-phenyl CONHOCH.sub.2Ph II-A-245, II-B-245, and II-C-245
2,5-dimethoxyphenyl CONHOCH.sub.2Ph II-A-246, II-B-246, and
II-C-246 3-F-phenyl 38 II-A-247, II-B-247, and II-C-247
3-MeO-phenyl 39 II-A-248, II-B-248, and II-C-248 3,4-difluorophenyl
40 II-A-249, II-B-249, and II-C-249 2,3-difluorophenyl 41 II-A-250,
II-B-250, and II-C-250 3-Cl-phenyl 42 II-A-251, II-B-251, and
II-C-251 4-Cl-phenyl 43 II-A-252, II-B-252, and II-C-252
4-Cl-phenyl 44 II-A-253, II-B-253, and II-C-253 3,4-dichlorophenyl
45 II-A-254, II-B-254, and II-C-254 3,4-dichlorophenyl 46 II-A-255,
II-B-255, and II-C-255 3-Cl-2-F-phenyl 47 II-A-256, II-B-256, and
II-C-256 3-C1-4-F-phenyl 48 II-A-257, II-B-257, and II-C-257
3-Cl-4-F-phenyl 49 II-A-258, II-B-258, and II-C-258
3,4-dimethoxyphenyl CON(Me) (Et) II-A-259, II-B-259, and II-C-259
3,4-dimethoxyphenyl 50 II-A-260, II-B-260, and II-C-260
3,4-dimethoxyphenyl CONHOCH.sub.2Ph II-A-261, II-B-261, and
II-C-261 3,4-dimethoxyphenyl 51 II-A-262, II-B-262, and II-C-262
benzo[1,3 dioxo- CON(Me) (Et) 5-yl II-A-263, II-B-263, and II-C-263
benzo[1,3]dioxo-5-yl 52 II-A-264, II-B-264, and II-C-264
benzo[1,3]dioxo-5-yl CONHOCH.sub.2Ph II-A-265, II-B-265, and
II-C-265 benzo [1,3]dioxo-5-yl 53 II-A-266, II-B-266, and II-C-266
3,5-dichlorophenyl 54 II-A-267, II-B-267, and II-C-267 3-Br-phenyl
55 II-A-268, II-B-268, and II-C-268 3-Br-phenyl 56 II-A-269,
II-B-269, and II-C-269 3 -Br-phenyl 57 II-A-270, II-B-270, and
II-C-270 3-Br-phenyl 58 II-A-271, II-B-271, and II-C-271
3-Br-phenyl 59 II-A-272, II-B-272, and II-C-272 3-Br-phenyl 60
II-A-273, II-B-273, and II-C-273 3-Br-phenyl 61 II-A-274, II-B-274,
and II-C-274 3-Br-phenyl 62 II-A-275, II-B-275, and II-C-275
3-Br-phenyl 63 II-A-276, II-B-276, and II-C-276 3-Br-phenyl 64
II-A-277, II-B-277, and II-C-277 3-Br-phenyl 65 II-A-278, II-B-278,
and II-C-278 3-Br-phenyl 66 II-A-279, II-B-279, and II-C-279
3-Br-phenyl 67 II-A-280, II-B-280, and II-C-280 3-Br-phenyl
CONH(CH.sub.2).sub.2COOH II-A-281, II-B-281, and II-C-281
3-Br-phenyl 68 II-A-282, II-B-282, and II-C-282 3-Br-phenyl
CONHCH.sub.2(4-COOH-phenyl) II-A-283, II-B-283, and II-C-283
3-Br-phenyl 69 II-A-284, II-B-284, and II-C-284 3-Br-phenyl 70
II-A-285, II-B-285, and II-C-285 3-NO.sub.2-phenyl
CONHCH.sub.2phenyl II-A-286, II-B-286, and II-C-286 3-Cl-phenyl
CONHCH.sub.2(1-Et- pyrrolidin-2-yl) II-A-287, II-B-287, and
II-C-287 3-(N-Et-NHCO)- CONHCH.sub.2phenyl phenyl II-A-288,
II-B-288, and II-C-288 3-Br-phenyl 71 II-A-289, II-B-289, and
II-C-289 3-NO.sub.2-phenyl CONHCH.sub.2(pyrid-4-yl) II-A-290,
II-B-290, and II-C-290 3-Br-phenyl 72 II-A-291, II-B-291, and
II-C-291 3-F-phenyl CON(Me) (Et) II-A-292, II-B-292, and II-C-292
3-MeO-phenyl CON(Me) (Et) II-A-293, II-B-293, and II-C-293
3-Br-phenyl 73 II-A-294, II-B-294, and II-C-294 3-Br-phenyl 74
II-A-295, II-B-295, and II-C-295 3-Br-phenyl 75 II-A-296, II-B-296,
and II-C-296 3-Br-phenyl 76 II-A-297, II-B-297, and II-C-297 phenyl
CONH(CH.sub.2).sub.2NMe.sub.2 II-A-298, II-B-298, and II-C-298
3-MeO-phenyl CONH(CH.sub.2).sub.2NMe.sub.2 II-A-299, II-B-299, and
II-C-299 3-Br-phenyl CONHCH.sub.2phenyl II-A-300, II-B-300, and
II-C-300 3-Cl-phenyl 77 II-A-301, II-B-301, and II-C-301
3-Cl-phenyl 78 II-A-302, II-B-302, and II-C-302 3-Cl-phenyl 79
II-A-303, II-B-303, and II-C-303 3-Cl-phenyl 80 II-A-304, II-B-304,
and II-C-304 3-Cl-phenyl 81 II-A-305, II-B-305, and II-C-305
3-Cl-phenyl 82 II-A-306, II-B-306, and II-C-306 3-Cl-phenyl 83
II-A-307, II-B-307, and II-C-307 3-Cl-phenyl 84 II-A-308, II-B-308,
and II-C-308 3-Cl-phenyl 85 II-A-309, II-B-309, and II-C-309
3-Cl-phenyl 86 II-A-310, II-B-310, and II-C-310 3,5-dichlorophenyl
87 II-A-311, II-B-311, and II-C-311 3-Br-5-CF.sub.3-phenyl 88
II-A-312, II-B-312, and II-C-312 3-Cl-phenyl 89 II-A-313, II-B-313,
and II-C-313 3,5-dichlorophenyl 90 II-A-314, II-B-314, and II-C-314
3-Cl-4-CN-phenyl 91 II-A-v15, II-B-315, and II-C-315
3-Cl-4-CH.sub.2OH- phenyl 92 II-A-316, II-B-316 and II-C-316
3-Cl-4-CH.sub.2NH.sub.2- phenyl 93 II-A-317, II-B-317, and II-C-317
94 95 II-A-318, II-B-318, and II-C-318 96 97 II-A-319, II-B-319,
and II-C-319 98 99 II-A-320, II-B-320, and II-C-320 100 101
II-A-321, II-B-321, and II-C-321 102 103 II-A-322, II-B-322, and
II-C-322 104 105 II-A-323, II-B-323, and II-C-323 CH.sub.2Ph
CON(Me).sub.2 II-A-324, II-B-324, and II-C-324 cyclopentylmethyl
CO.sub.2NHCH.sub.2Ph II-A-325, II-B-325, and II-C-325 isopropyl CN
II-A-326, II-B-326, and II-C-326 3-Cl-phenyl NHCOCH.sub.2Ph
II-A-327, II-B-327, and II-C-327 3-Cl-phenyl
NHSO.sub.2-morpholin-4-yl II-A-328, II-B-328, and II-C-328
3-Cl-phenyl NHCONHCH.sub.2Ph II-A-329, II-B-329, and II-C-329
3-Cl-phenyl NHCO.sub.2- tetrahydrofuran- 2-yl II-A-330, II-B-330,
and II-C-330 CH.sub.2Ph CONHCH.sub.2Ph II-A-331, II-B-331, and
II-C-331 Me CONHCH.sub.2Ph II-A-332, II-B-332, and II-C-332
isopropyl CONHCH.sub.2Ph II-A-333, II-B-333, and II-C-333 H
CON(Me).sub.2 II-A-334, II-B-334, and II-C-334 106 107 II-A-335,
II-B-335, and II-C-335 108 109 II-A-336, II-B-336, and II-C-336 110
111 II-A-337, II-B-337, and II-C-337 112 113 II-A-338, II-B-338,
and II-C-338 114 115 II-A-339, II-B-339, and II-C-339 116 117
II-A-340, II-B-340, and II-C-340 118 119 II-A-341, II-B-341, and
II-C-343 120 121
[0085] Additional preferred compounds, including those of formulae
II-A', II-B', II-D', II-A.degree., II-B.degree., and II-D.degree.
are set forth in Table 2 below.
2TABLE 2 Additional preferred compounds No. T.sub.m-R.sup.2
Q.sub.n-R.sup.4 II-A-342, II-B-342, and II-C-342 2-F-3-Cl-phenyl
122 II-A-343, II-B-343, and II-C-343 methyl 123 II-A-344, II-B-344,
and II-C-344 methyl 124 II-A-345, II-B-345, and II-C-345 Methyl 125
II-A-346, II-B-346, and II-C-346 3,5-dichlorophenyl 126 II-A-347,
II-B-347, and II-C-347 3-F, 5-CF.sub.3-phenyl 127 II-A-348,
II-B-348, and II-C-348 Methyl 128 II-A-349, II-B-349, and II-C-349
H 129 II-A-350, II-B-350, and II-C-350 Methyl 130 II-A-351,
II-B-351, and II-C-351 Methyl 131 II-A-352, II-B-352, and II-C-352
Methyl 132 II-A-353, II-B-353, and II-C-353 Cyclohexyl 133
II-A-354, II-B-354, and II-C-354 Cyclopropyl 134 II-A-355,
II-B-355, and II-C-355 Methyl 135 II-A-356, II-B-356, and II-C-356
Methyl 136 II-A-357, II-B-357, and II-C-357 CH.sub.2OCH.sub.3 137
II-A-358, II-B-358, and II-C-358 CH.sub.2OH 138 II-A-359, II-B-359,
and II-C-359 Methyl 139 II-A-360, II-B-360, and II-C-360 Methyl 140
II-A-361, II-B-361, and II-C-361 Methyl 141 II-A-362, II-B-362, and
II-C-362 Methyl 142 II-A-363, II-B-363, and II-C-363 Methyl 143
II-A-364, II-B-364, and II-C-364 H 144 II-A-365, II-B-365, and
II-C-365 H 145 II-A-366, II-B-366, and II-C-366 H 146 II-A-367,
II-B-367, and II-C-367 H 147 II-A-368, II-B-368, and II-C-368 H 148
II-A-369, II-B-369, and II-C-369 H 149 II-A-370, II-B-370, and
II-C-370 Methyl 150 II-A-371, II-B-371, and II-C-371 Methyl 151
II-A-372, II-B-372, and II-C-372 Methyl 152 II-A-373, II-B-373, and
II-C-373 Methyl 153 II-A-374, II-B-374, and II-C-374 Methyl 154
II-A-375, II-B-375, and II-C-375 Methyl 155 II-A-376, II-B-376, and
II-C-376 Methyl 156 II-A-377, II-B-377, and II-C-377 Methyl 157
II-A-378, II-B-378, and II-C-378 Methyl 158 II-A-379, II-B-379, and
II-C-379 Methyl 159 II-A-380, II-B-380, and II-C-380 methyl 160
II-A-381, II-B-381, and II-C-381 H 161 II-A-382, II-B-382, and
II-C-382 H 162 II-A-383, II-B-383, and II-C-383 163 164 II-A-384,
II-B-384, and II-C-384 165 166 II-A-385, II-B-385, and II-C-385 167
168 II-A-386, II-B-386, and II-C-386 169 170 II-A-387, II-B-387,
and II-C-387 171 172 II-A-388, II-B-388, and II-C-388 173 174
II-A-389, II-B-389, and II-C-389 175 176 II-A-390, II-B-390, and
II-C-390 177 178
[0086] Additional exemplary compounds of formulae II-A, Il-B, II-C,
and II-E are set forth in Table 3 below.
3TABLE 3 Compounds II-A, II-B, II-C, and II-E No. Structure II-A 1
179 II-A 2 180 II-A 3 181 II-A 4 182 II-A 5 183 II-A 6 184 II-A 7
185 II-A 8 186 II-B 1 187 II-B 2 188 II-B 3 189 II-B 4 190 II-B 5
191 II-B 6 192 Il-C 1 193 II-C 2 194 II-C 3 195 II-C 4 196 II-C 5
197 II-C 6 198 II-C 7 199 II-E 1 200 II-E 2 201 II-E 3 202 II-E 4
203 II-E 5 204 II-E 6 205
[0087] Additional preferred compounds of formula II-A are provided
in Table 4 below:
4TABLE 4 Additional Compounds II-A No. Structure II-A 9 206 II-A 10
207 II-A 11 208 II-A 12 209 II-A 13 210 II-A 14 211 II-A 15 212
II-A 16 213 II-A 17 214 II-A 18 215 II-A 19 216 II-A 20 217 II-A 21
218 II-A 22 219 II-A 23 220 II-A 24 221 II-A 25 222 II-A 26 223
II-A 27 224 II-A 28 225 II-A 29 226 II-A 30 227 II-A 31 228 II-A 32
229 II-A 33 230 II-A 34 231 II-A 35 232 II-A 36 233 II-A 37 234
II-A 38 235
[0088] Preferred embodiments of this invention are represented by
formulae III-A, III-B, III-C, and III-D: 236
[0089] wherein T, m, R.sup.2, R.sup.4 are as described above.
[0090] Preferred R.sup.2 and R.sup.4 of formulae III-A, III-B,
III-C, and III-D are as described above for formulae II-A, II-B,
II-C, and II-D.
[0091] Another object of the invention is to provide methods of
producing the above-identified compounds of formula I. Schemes 1-6
depict syntheses of the triazole-pyrrole (Schemes 1-2),
triazole-[1,2,4]triazole (Scheme 3), triazole-[1,2,3]triazole
(Schemes 4-5), and triazole-tetrazole (Scheme 6) compounds of this
invention. One having ordinary skill in the art will recognize that
Schemes 1-6 may be altered according to the functional groups
present to make analogous compounds of this invention.
[0092] Scheme 1--Triazole-pyrrole 237
[0093] Reagents and conditions: (a) KOtBu, toluene, reflux
[0094] Scheme 1 above shows a general synthetic route used to
prepare the pyrrol-3-yl compounds of formula II-A of this invention
when m is zero and R.sup.2 is an optionally substituted phenyl
group. In Scheme 1, the triazole ring is formed by combining a
cyano-1-pyrrole such as 1 and a diazo compound such as 2 in the
presence of KOtBu in refluxing toluene. One of skill in the art
will recognize that the above scheme may be used to synthesize
compounds wherein R.sup.2 is other than substituted phenyl. In
addition, a compound such as 3 may be further derivatized to
produce a variety of substituents Q.sub.n-R.sup.4.
[0095] Scheme 2--Triazole-pyrrole 238
[0096] Reagents and conditions: (a) NaN.sub.3, DMSO
[0097] Scheme 2 shows an alternate method for synthesizing the
pyrrol-3-yl compounds II-A of the present invention. In Scheme 2,
the triazole ring is formed by reacting a compound such as pyrrole
derivative 4 with NaN.sub.3 in DMSO. One of skill in the art will
recognize that the above scheme may be used to synthesize compounds
with a variety of Q.sub.n-R.sup.4 substituents. In addition, a
compound such as 5 may be further derivatized to produce a variety
of substituents T.sub.m-R.sup.2.
[0098] Scheme 3--Triazole-[1,2,4]triazole 239
[0099] Reagents and conditions: (a) acetic anhydride, 140-C; (b)(i)
2, KOtBu, toluene, reflux, (ii) H.sub.2, Pd/C, EtOH
[0100] Scheme 3 depicts the [1,2,4]triazole formation in step (a)
by the method described in Bladin et al., Chem. Ber., 1885, pp.
1544. Step (b) depicts formation of the [1,2,3]triazole ring as in
Scheme 1 above. One of skill in the art will recognize that Scheme
3 may be used to synthesize compounds wherein R.sup.2 is other than
substituted phenyl. In addition, a compound such as 7 may be
further derivatized to produce a variety of substituents
Q.sub.n-R.sup.4.
[0101] Scheme 4--Triazole-[1,2,3]triazole 240
[0102] Reagents and conditions: (a) TMS-N.sub.3, NaN.sub.3,
NaOH
[0103] Scheme 4 depicts the cyclization to form the
[1,2,3]triazole-[1,2,3]triazole system according to the method of
Banert et al., Chem. Ber., 1989, pp. 1175. One of skill in the art
will recognize that Scheme 4 may be used to synthesize compounds
wherein R.sup.2 is other than substituted phenyl. In addition, a
compound such as 9 may be further derivatized to produce a variety
of substituents Q.sub.n-R.sup.4.
[0104] Scheme 5--Triazole-[1,2,3]triazole 241
[0105] Reagents and conditions: (a) TMS-N.sub.3, NaN.sub.3,
NaOH
[0106] Scheme 5 depicts another [1,2,3]triazole-[1,2,3]triazole
cyclization according to the method of Banert et al. above. One of
skill in the art will recognize that Scheme 5 may be used to
synthesize compounds wherein R.sup.2 is other than substituted
phenyl. In addition, a compound such as 11 may be further
derivatized to produce a variety of substituents
Q.sub.n-R.sup.4.
[0107] Scheme 6--Triazole-tetrazole 242
[0108] Reagents and conditions: (a) NaN.sub.3, DMF; (b) NaN.sub.3,
NH.sub.4Cl, DMF
[0109] Scheme 6 depicts the formation of the triazole in step (a)
according to the method of Beck et al., Chem. Ber., 1973, pp. 106
and the formation of the tetrazole in step (b) according to the
method of Katritzky et al., J. Heterocycl. Chem., 1996, pp. 1107.
One of skill in the art will recognize that the above scheme may be
used to synthesize compounds wherein R.sup.2 is other than
substituted phenyl. In addition, a compound such as 14 may be
further derivatized to produce a variety of substituents
Q.sub.n-R.sup.4.
[0110] Schemes 1-6 above show general synthetic routes useful in
preparing the compounds of this invention wherein T.sub.m-R.sup.2
is an optionally substituted phenyl group, R.sup.3 is H or methyl,
and Q.sub.n-R.sup.4 is methyl or a carbonyl derivative. One having
skill in the art may synthesize other compounds of this invention
following the teachings of this specification, using reagents that
are readily synthesized or commercially available.
[0111] The activity of a compound utilized in this invention as an
inhibitor of ERK, may be assayed in vitro, in vivo or in a cell
line according to methods known in the art. In vitro assays include
assays that determine inhibition of either the phosphorylation
activity or ATPase activity of activated ERK. Alternate in vitro
assays quantitate the ability of the inhibitor to bind to ERK.
Inhibitor binding may be measured by radiolabelling the inhibitor
prior to binding, isolating the inhibitor/ERK complex and
determining the amount of radiolabel bound. Alternatively,
inhibitor binding may be determined by running a competition
experiment where new inhibitors are incubated with ERK bound to
known radioligands. Detailed conditions for assaying a compound
utilized in this invention as an inhibitor of ERK kinase are set
forth in the Examples below.
[0112] According to another embodiment, the invention provides a
composition comprising a compound of this invention or a
pharmaceutically acceptable derivative thereof and a
pharmaceutically acceptable carrier, adjuvant, or vehicle. The
amount of compound in the compositions of this invention is such
that is effective to detectably inhibit a protein kinase,
particularly ERK in a biological sample or in a patient. Preferably
the composition of this invention is formulated for administration
to a patient in need of such composition. Most preferably, the
composition of this invention is formulated for oral administration
to a patient.
[0113] The term "patient", as used herein, means an animal,
preferably a mammal, and most preferably a human.
[0114] The term "pharmaceutically acceptable carrier, adjuvant, or
vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that
does not destroy the pharmacological activity of the compound with
which it is formulated. Pharmaceutically acceptable carriers,
adjuvants or vehicles that may be used in the compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based substances,
polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
waxes, polyethylene-polyoxypropylene-block polymers, polyethylene
glycol and wool fat.
[0115] The term "detectably inhibit", as used herein means a
measurable change in ERK activity between a sample comprising said
composition and an ERK kinase and an equivalent sample comprising
ERK kinase in the absence of said composition. According to a
preferred embodiment, inhibition of kinase activity by a compound
according to the present invention is greater than 10% compared to
the kinase activity in the absence of the compound. Preferably,
inhibition is greater than 20%, 30%, or 40%, and even more
preferably greater than 50%, 60%, 70%, 80%, or 90%.
[0116] A "pharmaceutically acceptable derivative" means any
non-toxic salt, ester, salt of an ester or other derivative of a
compound of this invention that, upon administration to a
recipient, is capable of providing, either directly or indirectly,
a compound of this invention or an inhibitorily active metabolite
or residue thereof.
[0117] Pharmaceutically acceptable salts of the compounds of this
invention include those derived from pharmaceutically acceptable
inorganic and organic acids and bases. Examples of suitable acid
salts include acetate, adipate, alginate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, citrate, camphorate,
camphorsulfonate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptanoate, glycerophosphate, glycolate, hemisulfate,
heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate, succinate,
sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other
acids, such as oxalic, while not in themselves pharmaceutically
acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
[0118] Salts derived from appropriate bases include alkali metal
(e.g., sodium and potassium), alkaline earth metal (e.g.,
magnesium), ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4 salts. This
invention also envisions the quaternization of any basic
nitrogen-containing groups of the compounds disclosed herein. Water
or oil-soluble or dispersible products may be obtained by such
quaternization.
[0119] The compositions of the present invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vaginally or via an implanted
reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally,
intraperitoneally or intravenously. Sterile injectable forms of the
compositions of this invention may be aqueous or oleaginous
suspension. These suspensions may be formulated according to
techniques known in the art using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example
as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium.
[0120] For this purpose, any bland fixed oil may be employed
including synthetic mono- or di-glycerides. Fatty acids, such as
oleic acid and its glyceride derivatives are useful in the
preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, such as carboxymethyl cellulose or similar dispersing
agents that are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0121] The pharmaceutically acceptable compositions of this
invention may be orally administered in any orally acceptable
dosage form including, but not limited to, capsules, tablets,
aqueous suspensions or solutions. In the case of tablets for oral
use, carriers commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically
added. For oral administration in a capsule form, useful diluents
include lactose and dried cornstarch. When aqueous suspensions are
required for oral use, the active ingredient is combined with
emulsifying and suspending agents. If desired, certain sweetening,
flavoring or coloring agents may also be added.
[0122] Alternatively, the pharmaceutically acceptable compositions
of this invention may be administered in the form of suppositories
for rectal administration. These can be prepared by mixing the
agent with a suitable non-irritating excipient that is solid at
room temperature but liquid at rectal temperature and therefore
will melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0123] The pharmaceutically acceptable compositions of this
invention may also be administered topically, especially when the
target of treatment includes areas or organs readily accessible by
topical application, including diseases of the eye, the skin, or
the lower intestinal tract. Suitable topical formulations are
readily prepared for each of these areas or organs.
[0124] Topical application for the lower intestinal tract can be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0125] For topical applications, the pharmaceutically acceptable
compositions may be formulated in a suitable ointment containing
the active component suspended or dissolved in one or more
carriers. Carriers for topical administration of the compounds of
this invention include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene compound, emulsifying wax and water.
Alternatively, the pharmaceutically acceptable compositions can be
formulated in a suitable lotion or cream containing the active
components suspended or dissolved in one or more pharmaceutically
acceptable carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl
esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
[0126] For ophthalmic use, the pharmaceutically acceptable
compositions may be formulated as micronized suspensions in
isotonic, pH adjusted sterile saline, or, preferably, as solutions
in isotonic, pH adjusted sterile saline, either with or without a
preservative such as benzylalkonium chloride. Alternatively, for
ophthalmic uses, the pharmaceutically acceptable compositions may
be formulated-ir an ointment such as petrolatum.
[0127] The pharmaceutically acceptable compositions of this
invention may also be administered by nasal aerosol or inhalation.
Such compositions are prepared according to techniques well-known
in the art of pharmaceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or dispersing
agents.
[0128] Most preferably, the pharmaceutically acceptable
compositions of this invention are formulated for oral
administration.
[0129] The amount of the compounds of the present invention that
may be combined with the carrier materials to produce a composition
in a single dosage form will vary depending upon the host treated,
the particular mode of administration. Preferably, the compositions
should be formulated so that a dosage of between 0.01-100 mg/kg
body weight/day of the inhibitor can be administered to a patient
receiving these compositions.
[0130] It should also be understood that a specific dosage and
treatment regimen for any particular patient will depend upon a
variety of factors, including the activity of the specific compound
employed, the age, body weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and the
judgment of the treating physician and the severity of the
particular disease being treated. The amount of a compound of the
present invention in the composition will also depend upon the
particular compound in the composition.
[0131] Depending upon the particular condition, or disease, to be
treated or prevented, additional therapeutic agents, which are
normally administered to treat or prevent that condition, may also
be present in the compositions of this invention. As used herein,
additional therapeutic agents that are normally administered to
treat or prevent a particular disease, or condition, are known as
"appropriate for the disease, or condition, being treated".
[0132] For example, chemotherapeutic agents or other
anti-proliferative agents may be combined with the compounds of
this invention to treat proliferative diseases and cancer. Examples
of known chemotherapeutic agents include, but are not limited to,
Gleevec.TM., adriamycin, dexamethasone, vincristine,
cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and
platinum derivatives.
[0133] Other examples of agents the compounds of this invention may
also be combined with include, without limitation,
anti-inflammatory agents such as corticosteroids, TNF blockers,
IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;
immunomodulatory and immunosuppressive agents such as cyclosporin,
tacrolimus, rapamycin, mycophenolate mofetil, interferons,
corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;
neurotrophic factors such as acetylcholinesterase inhibitors, MAO
inhibitors, interferons, anti-convulsants, ion channel blockers,
riluzole, and anti-Parkinsonian agents; agents for treating
cardiovascular disease such as beta-blockers, ACE inhibitors,
diuretics, nitrates, calcium channel blockers, and statins; agents
for treating liver disease such as corticosteroids, cholestyramine,
interferons, and anti-viral agents; agents for treating blood
disorders such as corticosteroids, anti-leukemic agents, and growth
factors; agents for treating diabetes such as insulin, insulin
analogues, alpha glucosidase inhibitors, biguanides, and insulin
sensitizers; and agents for treating immunodeficiency disorders
such as gamma globulin.
[0134] The amount of additional therapeutic agent present in the
compositions of this invention will be no more than the amount that
would normally be administered in a composition comprising that
therapeutic agent as the only active agent. Preferably the amount
of additional therapeutic agent in the presently disclosed
compositions will range from about 50% to 100% of the amount
normally present in a composition comprising that agent as the only
therapeutically active agent.
[0135] According to another embodiment, the invention relates to a
method of inhibiting ERK kinase activity in a biological sample
comprising the step of contacting said biological sample with a
compound of this invention, or a pharmaceutically acceptable
composition comprising said compound.
[0136] The term "biological sample", as used herein, includes,
without limitation, cell cultures or extracts thereof; biopsied
material obtained from a mammal or extracts thereof; and blood,
saliva, urine, feces, semen, tears, or other body fluids or
extracts thereof.
[0137] Inhibition of ERK kinase activity in a biological sample is
useful for a variety of purposes that are known to one of skill in
the art. Examples of such purposes include, but are not limited to,
blood transfusion, organ-transplantation, biological specimen
storage, and biological assays.
[0138] According to another embodiment, the invention provides a
method for treating or lessening the severity of an ERK-mediated
disease or condition in a patient comprising the step of
administering to said patient a pharmaceutically acceptable
composition according to the present invention.
[0139] The term "ERK-mediated condition" or "disease", as used
herein, means any disease or other deleterious condition in which
ERK is known to play a role. The term "ERK-mediated condition" or
"disease" also means those diseases or conditions that are
alleviated by treatment with an ERK inhibitor. Such conditions
include, without limitation, 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. The term "cancer" includes, but is
not limited to the following cancers: breast, ovary, cervix,
prostate, testis, genitourinary tract, esophagus, larynx,
glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung,
epidermoid carcinoma, large cell carcinoma, small cell carcinoma,
lung adenocarcinoma, bone, colon, adenoma, pancreas,
adenocarcinoma, thyroid, follicular carcinoma, undifferentiated
carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma,
bladder carcinoma, liver carcinoma and biliary passages, kidney
carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy
cells, buccal cavity and pharynx (oral), lip, tongue, mouth,
pharynx, small intestine, colon-rectum, large intestine, rectum,
brain and central nervous system, and leukemia.
[0140] Compounds of the present invention are also useful as
inhibitors of related kinases to ERK. The term "related kinases"
refer to protein kinases having residues which are similar to those
residues which line the ERK binding site. Without wishing to be
bound by theory, applicants speculate that this inhibitory activity
is due to the close structural similarity between the active sites
of ERK and related kinases. The alignment of the ERK sequence with
other kinases can be derived from common software programs such as
the "bestfit" program available from Genetics Computer Group. This
program uses the local homology algorithm described by Smith and
Waterman in Advances in Applied Mathematics 2; 482 (1981).
[0141] Related kinases inhibited by the compounds of this invention
would contain residues, identified by the above standard protein
sequence alignment software, corresponding to the ERK residues:
I31, E33, G34, A35, Y36, G37, M38, V39, A52, K54, R67, T68, E71,
L75, I84, I86, I103, Q105, D106, L107, M108, E109, D111, K114,
D149, K151, S153, N154, L156, C166, and D167, with a similarity
score of 80% or greater. In a more preferred embodiment the
similarity score is 85%, more preferably 90%, even more preferably
95%, 96%, 97% or 98%. The similarity score may be determined using
standard amino acid substitution tables such as those described by
Dayhoff (Dayhoff, M. O., et al, Atlas of Protein Sequence and
Structure, 1979) and Blosom-Henikoff (Blosum-Henikoff, S and
Henikoff, J. G., PNAS, 1992,89:10915-10919). The term "related
kinases" also includes those containing residues with a similarity
score of 80% or greater to the following ERK residues: 131, G37,
A52, I103, E109, and N154. In a more preferred embodiment the
similarity score is 85%, more preferably 90%, even more preferably
95%, 96%, 97% or 98%.
[0142] The present method is especially useful for treating a
disease that is alleviated by the use of an inhibitor of ERK or
related kinases. As used herein, unless otherwise indicated, the
term "ERK" refers to all isoforms of the ERK enzyme including, but
not limited to, ERK1, ERK2, ERK3, ERK4, ERK5, ERK6, and ERK7.
[0143] In an alternate embodiment, the methods of this invention
that utilize compositions that do not contain an additional
therapeutic agent, comprise the additional step of separately
administering to said patient an additional therapeutic agent. When
these additional therapeutic agents are administered separately
they may be administered to the patient prior to, sequentially with
or following administration of the compositions of this
invention.
[0144] The compounds of this invention or pharmaceutically
acceptable compositions thereof may also be incorporated into
compositions for coating an implantable medical device, such as
prostheses, artificial valves, vascular grafts, stents and
catheters. Vascular stents, for example, have been used to overcome
restenosis (re-narrowing of the vessel wall after injury). However,
patients using stents or other implantable devices risk clot
formation or platelet activation. These unwanted effects may be
prevented or mitigated by pre-coating the device with a
pharmaceutically acceptable composition comprising a kinase
inhibitor. Suitable coatings and the general preparation of coated
implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible
polymeric materials such as a hydrogel polymer,
polymethyldisiloxane, polycaprolactone, polyethylene glycol,
polylactic acid, ethylene vinyl acetate, and mixtures thereof. The
coatings may be further covered by a suitable topcoat of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids
or combinations thereof to impart controlled-release
characteristics in the composition. Implantable devices coated with
a compound of this invention are another embodiment of the present
invention.
[0145] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
EXAMPLE 1
[0146] ERK Inhibition Assay
[0147] Compounds are assayed for the inhibition of ERK2 by a
spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein
Sci 7, 2249). In this assay, a fixed concentration of activated
ERK2 (10 nM) is incubated with various concentrations of the
compound in DMSO (2.5%) for 10 min. at 30.degree. C. in 0.1 M HEPES
buffer, pH 7.5, containing 10 mM MgCl.sub.2, 2.5 mM
phosphoenolpyruvate, 200 .mu.M NADH, 150 .mu.g/mL pyruvate kinase,
50 .mu.g/mL lactate dehydrogenase, and 200 .mu.M erktide peptide.
The reaction is initiated by the addition of 65 .mu.M ATP. The rate
of decrease of absorbance at 340 nm is monitored, which indicates
the extent of uninhibited enzyme present in the assay. The
IC.sub.50 is evaluated from the rate data as a function of
inhibitor concentration.
EXAMPLE 2
[0148] ERK Inhibition Cell Proliferation Assay
[0149] Compounds may be assayed for the inhibition of ERK2 by a
cell proliferation assay. In this assay, a complete media is
prepared by adding 10% fetal bovine serum and
penicillin/streptomycin solution to RPMI 1640 medium (JRH
Biosciences). Colon cancer cells (HT-29 cell line) are added to
each of 84 wells of a 96 well plate at a seeding density of 10,000
cells/well/150 .mu.L. The cells are allowed to attach to the plate
by incubating at 37.degree. C. for 2 hours. A solution of test
compound is prepared in complete media by serial dilution to obtain
the following concentrations: 20 .mu.M, 6.7 .mu.M, 2.2 .mu.M, 0.74
.mu.M, 0.25 .mu.M, and 0.08 .mu.M. The test compound solution (50
.mu.L) is added to each of 72 cell-containing wells. To the 12
remaining cell-containing wells, only complete media (200 .mu.L) is
added to form a control group in order to measure maximal
proliferation. To the remaining 12 empty wells, complete media is
added to form a vehicle control group in order to measure
background. The plates are incubated at 37.degree. C. for 3 days. A
stock solution of .sup.3H-thymidine (1 mCi/mL, New England Nuclear,
Boston, Mass.) is diluted to 20 .mu.Ci/mL in RPMI medium then 20
.mu.L of this solution is added to each well. The plates are
further incubated at 37.degree. C. for 8 hours then harvested and
analyzed for .sup.3H-thymidine uptake using a liquid scintillation
counter.
[0150] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments, which utilize the compounds and methods
of this invention. Therefore, it will be appreciated that the scope
of this invention is to be defined by the appended claims rather
than by the specific embodiments, which have been represented by
way of example.
* * * * *
References