U.S. patent application number 12/573950 was filed with the patent office on 2010-02-11 for inhibitors of c-jun n-terminal kinases for the treatment of neurodegenerative disorders relating to apoptosis and/or inflammation.
This patent application is currently assigned to EISAI R & D MANAGEMENT CO., LTD.. Invention is credited to Gurpreet BHATIA, Afzal KHAN, Darren Peter MEDLAND.
Application Number | 20100035878 12/573950 |
Document ID | / |
Family ID | 34984169 |
Filed Date | 2010-02-11 |
United States Patent
Application |
20100035878 |
Kind Code |
A1 |
KHAN; Afzal ; et
al. |
February 11, 2010 |
INHIBITORS OF C-JUN N-TERMINAL KINASES FOR THE TREATMENT OF
NEURODEGENERATIVE DISORDERS RELATING TO APOPTOSIS AND/OR
INFLAMMATION
Abstract
The present invention provides novel compounds of formula I and
their use in the inhibition of c-Jun N-terminal kinases. The
present invention further provides the use of these compounds in
medicine, in particular in the prevention and/or treatment of
neurodegenerative disorders related to apoptosis and/or
inflammation. ##STR00001##
Inventors: |
KHAN; Afzal; (London,
GB) ; MEDLAND; Darren Peter; (London, GB) ;
BHATIA; Gurpreet; (London, GB) |
Correspondence
Address: |
WILMERHALE/BOSTON
60 STATE STREET
BOSTON
MA
02109
US
|
Assignee: |
EISAI R & D MANAGEMENT CO.,
LTD.
Tokyo
JP
|
Family ID: |
34984169 |
Appl. No.: |
12/573950 |
Filed: |
October 6, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11499334 |
Aug 4, 2006 |
|
|
|
12573950 |
|
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Current U.S.
Class: |
514/234.5 ;
514/253.04; 514/300; 544/127; 544/362; 546/113 |
Current CPC
Class: |
C07D 471/04 20130101;
A61P 25/28 20180101 |
Class at
Publication: |
514/234.5 ;
546/113; 544/362; 544/127; 514/300; 514/253.04 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 471/04 20060101 C07D471/04; A61K 31/437 20060101
A61K031/437; A61K 31/497 20060101 A61K031/497 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 5, 2005 |
GB |
GB0516156.7 |
Claims
1. A compound of formula (I): ##STR00257## wherein X is O, S,
C(R.sup.4).sub.2, SO, SO.sub.2 or NR.sup.3, NR.sup.3--C(O)-- or
NR.sup.3--C(O)--O--; R.sup.1 is hydrogen, C.sub.1-10 alkyl,
C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 aryl, C.sub.3-10
cycloalkyl, C.sub.3-10 cycloalkenyl or C.sub.3-10 heterocyclyl;
said R.sup.1 group being optionally substituted with one or more of
C.sub.1-6 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl, halo,
hydroxy, oxo, CO.sub.2R.sup.5, C.sub.3-10aryl,
C.sub.3-10heterocyclyl, C.sub.1-6alkylC.sub.3-10 aryl,
NR.sup.6.sub.2 and wherein the C.sub.3-10 heterocyclyl group can be
further optionally substituted with C.sub.1-6 alkyl; and R.sup.2 is
a thiazole; said R.sup.2 group being optionally substituted with
one or more of C.sub.1-6 alkyl, CO.sub.2H, C.sub.3-10heterocyclyl,
CONR.sup.7R.sup.7, CO--C.sub.3-10heterocyclyl,
C.sub.1-6alkylC.sub.3-10heterocyclyl and wherein the heterocyclyl
group can be further optionally substituted with a C.sub.1-6 alkyl
group; wherein R.sup.3 is hydrogen or C.sub.1-6 alkyl; R.sup.4 is
hydrogen or C.sub.1-6 alkyl; R.sup.5 is hydrogen or C.sub.1-6
alkyl; and R.sup.6 is hydrogen or C.sub.1-6 alkyl; each R.sup.7 is
C.sub.1-6 alkyl.
2. A compound as claimed in claim 1 wherein R.sup.1 is an
unbranched alkyl group having 2, 3, 4, 5 or 6 carbon atoms.
3. A compound as claimed in claim 1 wherein R.sup.1 is an
unbranched alkenyl or alkynyl group having 2, 3, 4, 5 or 6 carbon
atoms.
4. A compound as claimed in claim 1 wherein R.sup.1 is a C.sub.5 or
C.sub.6 cycloalkyl or aryl group optionally substituted with one or
more of C.sub.1-4 alkyl or a halogen.
5. A compound as claimed in claim 4 wherein the aryl group is
substituted at the ortho or para position.
6. A compound as claimed in claim 4 wherein R.sup.1 is phenyl.
7. A compound as claimed in claim 1 wherein R.sup.2 is substituted
with CONR.sup.7R.sup.7, wherein each R.sup.7 is independently
C.sub.1-6 alkyl.
8. A compound as claimed in claim 7 wherein each R.sup.7 is
independently methyl or ethyl.
9. A compound as claimed in claim 7 wherein R.sup.2 is substituted
with C.sub.1-6 alkyl.
10. A compound as claimed in claim 1 wherein R.sup.2 is optionally
substituted with an alkyl group having 1, 2, 3, 4, 5 or 6 carbon
atoms.
11. A compound as claimed in claim 10 wherein said optional
substitution occurs at 2-thiazole position.
12. A compound as claimed in claim 1 wherein R.sup.2 is substituted
with one or more of C.sub.3-10heterocyclyl,
CO--C.sub.3-10heterocyclyl C.sub.1-6alkyl-C.sub.3-10heterocyclyl
and wherein the C.sub.3-10heterocyclyl group can be further
optionally substituted with a C.sub.1-6alkyl group in which the
C.sub.3-10heterocyclyl is ##STR00258## wherein R.sup.7 is a C.sub.4
or C.sub.5-alkyl or alkenyl group, which, with the nitrogen atom,
forms a five or six-membered ring, said alkyl or alkenyl group
being optionally interrupted with one or more of O, S or NR.sup.10
wherein R.sup.10 is hydrogen or a C.sub.1-6 alkyl, and optionally
substituted with C.sub.1-6 alkyl.
13. A compound of formula II ##STR00259## wherein R.sup.1 is
C.sub.3-8 aryl or C.sub.1-10 alkyl optionally substituted with one
or more of halo or CO.sub.2R.sup.4; wherein R.sup.4 is hydrogen or
C.sub.1-6 alkyl, R.sup.3 is hydrogen or C.sub.1-6 alkyl, and
R.sup.2 is thiazole optionally substituted with one or more of
C.sub.1-6 alkyl, CO.sub.2H, C.sub.3-10heterocyclyl,
CONR.sup.7R.sup.7, CO--C.sub.3-10heterocyclyl,
C.sub.1-6alkylC.sub.3-10heterocyclyl and wherein the heterocyclyl
group can be further optionally substituted with a C.sub.1-6 alkyl
group and wherein each R.sup.7 is independently C.sub.1-6
alkyl.
14. A compound as claimed in claim 13 wherein R.sup.1 is a branched
alkyl having 3, 4, 5 or 6 carbon atoms.
15. A compound selected from ##STR00260## ##STR00261##
16. (canceled)
17. A composition comprising a compound as defined in claim 1 in
combination with a pharmaceutically acceptable carrier, diluent or
excipient.
18-26. (canceled)
27. A composition comprising a compound as defined in claim 15 in
combination with a pharmaceutically acceptable carrier, diluent or
excipient.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. patent application
Ser. No. 11/499,334 filed Aug. 4, 2006, which claims the benefit of
priority from GB0516156.7, filed Aug. 5, 2005, each of the
aforementioned applications is incorporated herein by reference in
its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to novel compounds, their use
in the inhibition of c-Jun N-terminal kinases, their use in
medicine and particularly in the prevention and/or treatment of
neurodegenerative disorders related to apoptosis and/or
inflammation. The invention also provides processes for manufacture
of said compounds, compositions containing them and processes for
manufacturing such compositions.
BACKGROUND OF THE INVENTION
[0003] c-Jun N-terminal kinases (hereinafter referred to as "JNKs")
are members of the mitogen-activated protein kinase (MAPK) family.
JNKs are involved in response to various stimuli, including
proinflammatory cytokines and environmental stress. JNKs, and JNK3
in particular, play an important role during apoptotic death of
cells and therefore have been implicated in various disorders
including stroke, traumatic brain injury and other
neurodegenerative diseases such as Parkinson's disease, Alzheimer's
disease and others. Since JNK activity is a physiological regulator
of AP-1 transcriptional activity, JNK inhibitors are expected to
reduce inflammatory response.
[0004] Apoptosis is a form of cell death in which the cell actively
participates in its own destruction in a process involving a
characteristic series of biochemical and morphological changes,
which are regulated by specific cell death genes. The apoptotic
cell death is a process that has been observed in the developing
mammalian nervous system. In mice, the inactivation by homologous
recombination of genes that encode proteins that promote apoptosis,
such as the caspase-3 or the Bax protein, prevents developmental
neuronal cell death. The destruction of genes that encode cell
death suppressors such as Bcl-x, leads to enhanced neuronal cell
death. There is increasing evidence that apoptosis plays an
important role in the pathology of acute and chronic
neurodegenerative diseases. For example, in transgenic mice
overexpressing the anti-apoptotic Bcl-2 protein in the nervous
system there is a decrease in infarct volume following cerebral
ischemia. Similarly, injection of the caspase inhibitor BAF reduces
neuronal cell death following hypoxia/ischaemia in neonatal rats.
Another example is spinal muscular atrophy (a motor neuron disease)
where loss of function mutations in the SMN gene is associated with
the disease. Recent data has shown that the wild type SMN protein
binds to Bcl-2 and co-operates with it to inhibit apoptosis. These
results suggest that inhibitors of neuronal apoptosis could be
beneficial in the treatment of human neurodegenerative diseases.
There is increasing evidence that neuronal apoptosis is an
important pathological feature of stroke, traumatic brain injury
and other neurodegenerative diseases. Therefore, pharmacotherapy
using inhibitors of neuronal apoptosis may provide a therapeutic
benefit in neurodegenerative conditions.
[0005] A number of groups have studied the mechanisms of neuronal
cell death using in vitro cell culture systems and the results
suggest that in some systems the transcription factor c-Jun is
activated by the removal of survival signals and promotes cell
death.
[0006] Antibodies specific for c-Jun protected NGF-deprived rat
sympathetic neurones from apoptosis. Analogous neuroprotection due
to expression of a c-Jun dominant negative mutant has been
demonstrated, whereas overexpression of wild type c-Jun protein was
sufficient to induce apoptosis in the presence of NGF. Estus and
co-workers recently showed that an increase in c-Jun RNA levels
occurs in cortical neurones undergoing apoptosis after treatment
with .beta.-amyloid peptide. It has also been shown that c-Jun is
required for apoptosis in cerebellar granule neurones deprived of
survival signals.
[0007] c-Jun is activated by JNKs, which phosphorylate its
transcriptional activation domain. In humans there are three JNK
genes: JNK1, JNK2 and JNK3. The RNAs encoding JNK1 and JNK2 are
expressed in many tissues, including the brain, but JNK3 is
restricted to the nervous system and to a smaller extent the heart
and testes.
[0008] JNKs are strongly activated in cellular responses to various
stresses such as UV radiation, heat shock, osmotic shock,
DNA-damaging agents, and proinflammatory cytokines such as
TNF.alpha., IL-1.beta. and others. Upstream regulators of the JNK
pathway include kinases such as SEK1, MKK7 and MEKK1. There is
evidence that Jun kinase activity is required for neuronal
apoptosis in vitro. Overexpression of MEKK1 in sympathetic neurones
increased c-Jun protein levels and phosphorylation and induced
apoptosis in the presence of NGF indicating that activation of the
Jun kinase pathway can trigger neuronal cell death. The Jun kinase
pathway has been shown to be necessary for the death of
differentiated PC12 cells deprived of NGF. Furthermore, compound
CEP-1347, which inhibits the c-Jun pathway (upstream of Jun
kinase), protects motor neurones against cell death induced by
survival factor withdrawal.
[0009] In JNK3 homozygous (-/-) knockout mice, epileptic seizures
and death of hippocampal CA3 neurones induced by injection of
kainic acid is blocked. This indicates that JNK3 is involved in
certain forms of neuronal cell death in vivo. It is also a critical
component of GluR6-mediated excitotoxicity. Furthermore, JNK3 (-/-)
mice appear to develop normally and are viable suggesting that JNK3
is not essential for development or viability.
[0010] Strong nuclear JNK3 immunoreactivity in the brain CA1
neurones of patients with acute hypoxia suggests that JNK3 is
involved in hypoxia-related neurodegeneration. Transient hypoxia
may also trigger apoptosis through JNK signaling pathway in
developing brain neurones.
[0011] Furthermore, JNK3 immunoreactivity is colocalized with
Alzheimer disease-affected neurones. Moreover JNK3 is related to
neurofibrillary pathology of Alzheimer disease. In particular, JNK3
induces robust phosphorylation of amyloid precursor protein (APP)
thus affecting its metabolism in disease state.
SUMMARY OF THE INVENTION
[0012] The present inventors have provided compounds, which are
inhibitors of c-Jun N-terminal kinases.
[0013] The first aspect of the invention therefore relates to a
compound of formula (I) as illustrated below:
##STR00002##
wherein X is O, S, C(R.sup.4).sub.2, SO, SO.sub.2, NR.sup.3,
NR.sup.3--C(O)-- or NR.sup.3--C(O)--O--; R.sup.1 is hydrogen,
C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl,
C.sub.3-10 aryl, C.sub.3-10 cycloalkyl, C.sub.3-10 cycloalkenyl or
C.sub.3-10 heterocyclyl; said R.sup.1 group being optionally
substituted with one or more of C.sub.1-6 alkyl, C.sub.1-10 alkoxy,
C.sub.3-10 cycloalkyl, halo, hydroxy, oxo, CO.sub.2R.sup.5,
C.sub.3-10aryl, C.sub.3-10heterocyclyl, C.sub.1-6alkylC.sub.3-10
aryl, NR.sup.6.sub.2 and wherein the C.sub.3-10 heterocyclyl group
can be further optionally substituted with C.sub.1-6 alkyl; and
R.sup.2 is a 3-10 membered heterocyclyl; said R.sup.2 group being
optionally substituted with one or more of C.sub.1-6 alkyl,
CO.sub.2H, C.sub.3-10heterocyclyl, CO--C.sub.3-10heterocyclyl,
C.sub.1-16alkylC.sub.3-10heterocyclyl and wherein the heterocyclyl
group can be further optionally substituted with a C.sub.1-6 alkyl
group; wherein [0014] R.sup.3 is hydrogen or C.sub.1-6 alkyl;
[0015] R.sup.4 is hydrogen or C.sub.1-6 alkyl; [0016] R.sup.5 is
hydrogen or C.sub.1-6 alkyl; and [0017] R.sup.6 is hydrogen or
C.sub.1-6 alkyl. and the pharmaceutically acceptable salts, and
other pharmaceutically acceptable biohydrolyzable derivatives
thereof, including esters, amides, carbamates, carbonates, ureides,
solvates, hydrates, affinity reagents or prodrugs thereof.
[0018] R.sup.1 is preferably an unbranched alkyl group having 2, 3,
4, 5 or 6 carbon atoms, an unbranched alkenyl or alkynyl group
having 2, 3, 4, 5 or 6 carbon atoms, or a C.sub.5 or C.sub.6
cycloalkyl or a C.sub.3-10aryl group. R.sup.1 can be an aryl or
heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 members,
preferably an optionally substituted five or six membered aryl or
heteroaryl group wherein the aryl or heterocyclyl group is
optionally fused to one or more unsaturated rings. The group
R.sup.1 is preferably substituted with one or more of C.sub.1-6
alkyl or a halo group. When R.sup.1 is substituted with a
C.sub.3-10heterocyclyl group, the C.sub.3-10heterocyclyl group is
preferably a group
##STR00003##
wherein the R.sup.8 group is a C4 or C5-alkyl or alkenyl group,
preferably an alkyl group which with the nitrogen atom, forms a
five or six-membered ring. The alkyl or alkenyl group of R.sup.8
can optionally be interrupted with one or more heteroatoms selected
from O, S or NR.sup.9 wherein R.sup.9 is hydrogen or a C.sub.1-6
alkyl group preferably methyl or ethyl. The alkyl or alkenyl group
and/or the heteroatoms can be substituted with C.sub.1-6 alkyl. The
heterocyclyl group is preferably unsaturated and is preferably one
or more of piperidine, morpholine and piperazine optionally
substituted at the nitrogen atom with a C.sub.1-6 alkyl group.
[0019] R.sup.1 is preferably selected from optionally substituted
phenyl, acridine, benzimidazole, benzofuran, benzothiophene,
benzoxazole, benzothiazole, cyclohexyl furan, imidazole, indole,
indoline, isoindole, isoindoline, isoquinoline, isoxazole,
isothiazole, morpholine, napthaline, oxazole, phenazine,
phenothiazine, phenoxazine, piperazine, piperidine, pyrazole,
pyridazine, pyridine, pyrrole, quinoline, quinolizine,
tetrahydrofuran, tetrazine, tetrazole, thiophene, thiazole,
thiomorpholine, thianaphthalene, thiopyran, triazine, triazole or
trithiane.
[0020] More preferably R.sup.1 is phenyl or optionally substituted
phenyl.
[0021] As discussed above, R.sup.1 can be optionally substituted at
any position on the aryl, heterocyclyl or optional fused ring.
[0022] Substitution can occur at the ortho, meta or para positions
relative to the pyridine ring. When R.sup.1 is a six-membered ring,
substitution is preferably at the ortho and/or para positions, more
preferably at the para position.
[0023] When R.sup.1 is a five membered ring, the aryl group is
preferably substituted at the ortho or para position. R.sup.1 is
preferably substituted at the ortho or para position with one or
more of halogen, or C.sub.1-4 alkyl.
[0024] R.sup.2 is preferably a 5-membered heterocycle comprising
one or more heteroatoms selected from O, S or N. R.sup.2 can be
optionally substituted with one or more of C.sub.1-6 alkyl,
CO.sub.2H, C.sub.3-8 heterocyclyl, C.sub.1-6alkylC.sub.3-8
heterocyclyl or CO--C.sub.3-8 heterocyclyl. In particular, one or
more of said heteroatoms in R.sup.2 can be optionally substituted
with C.sub.1-6 alkyl,
[0025] The R.sup.2 group may be optionally substituted with an
alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. In particular
the optional substitution can occur at one or more of O, S or N in
the heterocycle. The R.sup.2 group can be substituted with a group
CONR.sup.7R.sup.7, wherein each R.sup.7 can independently be a
C.sub.1-6 alkyl group, preferably methyl or ethyl. Alternatively,
the R.sup.2 group can be substituted with a group
##STR00004##
wherein R.sup.7 is a C.sub.4 or C.sub.5-alkyl or alkenyl group,
preferably an alkyl group which, with the nitrogen atom, forms a
five or six-membered ring. The alkyl or alkenyl group of R.sup.8
can optionally be interrupted with one or more heteroatoms selected
from O, S or NR.sup.10 wherein R.sup.10 is hydrogen or a C.sub.1-6
alkyl, preferably methyl or ethyl. The alkyl or alkenyl group
and/or the heteroatoms can be substituted with C.sub.1-6 alkyl. The
heterocyclyl group is preferably unsaturated and is one or more of
piperidine, morpholine and piperazine optionally substituted at an
available nitrogen atom with a C.sub.1-6 alkyl group.
[0026] More preferably, R.sup.2 is a 5-membered heterocycle
comprising two or more heteroatoms selected from O, S or N. R.sup.2
may be a 5-membered heterocycle selected from, furan, imidazole,
imidazoline, imidazolidine, isoxazole, isothiazole, oxazole,
oxadiazole, oxathiazole, oxathiazolidine, pyrazole, pyrazoline,
pyrazolidine, pyrrole, tetrahydrofuran, tetrazole, thiophene,
thiadiazine, thiazole or triazole.
[0027] X is selected from O, S, C(R.sup.4).sub.2, SO, SO.sub.2,
NR.sup.3, NR.sup.3--C(O) or NR.sup.3--C(O)-o wherein R.sup.3 is
preferably hydrogen or C.sub.1-4 alkyl, more preferably an alkyl
group having 1, 2 or 3 carbon atoms and R.sup.4 is preferably
hydrogen or C.sub.1-4 alkyl, more preferably an alkyl group having
1, 2 or 3 carbon atoms.
[0028] Preferably X is O, S, CH.sub.2, SO, SO.sub.2, NH, NH--C(O)--
or NH--C(O)--O.
[0029] In particular, the first aspect of the invention includes
compound of formula II
##STR00005##
wherein R.sup.1 is C.sub.3-8 aryl or C.sub.1-10 alkyl optionally
substituted with one or more of halo or CO.sub.2R.sup.5; wherein
R.sup.5 is hydrogen or C.sub.1-6 alkyl, R.sup.3 is hydrogen or
C.sub.1-6 alkyl, and R.sup.2 is a 3-8 membered heterocyclyl
optionally substituted with one or more of C.sub.1-6 alkyl.
[0030] Preferably R.sup.1 is a branched alkyl having 3, 4, 5 or 6
carbon atoms.
[0031] For the avoidance of doubt when a group as defined above
contains two or more radicals eg the radical R.sup.6 as for example
in the groups NR.sup.6R.sup.6, the two or more radicals such as
R.sup.6 may be the same or different.
[0032] For the purposes of this invention, alkyl relates to both
straight chain and branched alkyl radicals of 1 to 10 carbon atoms,
preferably 1 to 8 carbon atoms and most preferably 1 to 4 carbon
atoms including but not limited to methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl n-pentyl,
n-hexyl, n-heptyl, n-octyl. The alkyl radical can have 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbon atoms. The term cycloalkyl relates to
cycloalkyl radicals of 3 to 12 carbon atoms, preferably 4 to 8
carbon atoms, and most preferably 5 to 6 carbon atoms including but
not limited to cyclopropyl, cyclobutyl, CH.sub.2-cyclopropyl,
CH.sub.2-cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups
may be optionally substituted or fused to one or more carbocyclyl
or heterocyclyl group. The cycloalkyl radical can have 3, 4, 5, 6,
7, 8, 9 or 10 carbon atoms. The term cycloalkyl also encompasses
cycloalkyl-alkyl groups, preferably
C.sub.4-8cycloalkyl-C.sub.1-6alkyl groups. Particular examples of
such groups include --CH.sub.2-cyclopropyl, --CH.sub.2-cyclobutyl,
--CH.sub.2-cyclopentyl, --CH.sub.2-cyclohexyl. Haloalkyl relates to
an alkyl radical preferably having 1 to 8 carbon atoms, preferably
1 to 4 carbon atoms substituted with one or more halide atoms for
example CH.sub.2CH.sub.2Br, CF.sub.3 or CCl.sub.3.
[0033] The term "alkenyl" means a straight chain or branched
alkylenyl radical of 2 to 10 carbon atoms, preferably 2 to 6 carbon
atoms and most preferably 2 to 4 carbon atoms, and containing one
or more carbon-carbon double bonds and includes but is not limited
to ethylene, n-propyl-1-ene, n-propyl-2-ene, isopropylene, etc. The
alkenyl radical can have 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
The term "cycloalkenyl" relates to cycloalkenyl radicals of 3-12
carbon atoms, preferably 4 to 8 carbon atoms and most preferably 5
to 6 carbon atoms having 1 to 6 double bonds. Preferably the
cycloalkenyl group has 1, 2 or 3 double bonds. Cycloalkenyl groups
include but are not limited to cyclopropenyl, cyclobutenyl,
--CH.sub.2-cyclopropenyl, --CH.sub.2-cyclobutenyl, cyclopentenyl,
or cyclohexenyl. Cycloalkenyl groups may be optionally substituted
or fused to one or more carbocyclyl or heterocyclyl group. The
cycloalkenyl radical can have 3, 4, 5, 6, 7, 8, 9 or 10 carbon
atoms. The term cycloalkenyl also encompasses cycloalkenyl-alkyl or
cycloalkenyl-alkenyl groups, preferably C.sub.4-8
cycloalkenyl-C.sub.1-6alkyl or
C.sub.4-8cycloalkenyl-C.sub.2-6alkenyl groups. The term "alkynyl"
means a straight chain or branched alkynyl radical of 2 to 12
carbon atoms, preferably 2 to 6 carbon atoms and most preferably 2
to 4 carbon atoms, and containing one or more carbon-carbon triple
bonds and includes but is not limited to ethynyl, 2-methylethynyl
etc. The alkynyl radical can have 2, 3, 4, 5, 6, 7, 8, 9 or 10
carbon atoms.
[0034] "Aryl" means an aromatic 3 to 10 membered hydrocarbon
preferably a 6 to 10 membered ring system containing one ring or
being fused to one or more saturated or unsaturated rings including
but not limited to phenyl, napthyl, anthracenyl or
phenanthracenyl.
[0035] "Heterocyclyl" means a 3 to 10 membered ring system
preferably a 6 to 10 membered ring system containing one or more
heteroatoms selected from N, O or S and includes heteroaryl.
"Heteroaryl" means an aromatic 3 to 10 membered aryl preferably a 6
to 10 membered ring system containing one or more heteroatoms
selected from N, O or S and containing one ring or being fused to
one or more saturated or unsaturated rings. The heterocyclyl system
can contain one ring or may be fused to one or more saturated or
unsaturated rings; the heterocyclyl can be fully saturated,
partially saturated or unsaturated and includes but is not limited
to heteroaryl and heterocarbocyclyl. Examples of carbocyclyl or
heterocyclyl groups include but are not limited to cyclohexyl,
phenyl, acridine, benzimidazole, benzofuran, benzothiophene,
benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane,
dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan,
imidazole, imidazoline, imidazolidine, indole, indoline,
indolizine, indazole, isoindole, isoindoline, isoquinoline,
isoxazole, isothiazole, morpholine, napthyridine, oxazole,
oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine,
phenazine, phenothiazine, phenoxazine, phthalazine, piperazine,
piperidine, pteridine, purine, pyran, pyrazine, pyrazole,
pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine,
pyrrole, pyrrolidine, pyrroline, quinoline, quinoxaline,
quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole,
thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine,
thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine,
triazole, and trithiane.
[0036] Halogen means F, Cl, Br or I, preferably F.
[0037] Representative compounds according to the first aspect of
the invention are illustrated below;
##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011## ##STR00012## ##STR00013## ##STR00014##
##STR00015##
[0038] The compounds of the first aspect may be provided as a salt,
preferably as a pharmaceutically acceptable salt of compounds of
formula (I). Examples of pharmaceutically acceptable salts of these
compounds include those derived from organic acids such as acetic
acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic
acid, succinic acid, fumaric acid, maleic acid, benzoic acid,
salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic
acid, benzenesulfonic acid and p-toluenesulfonic acid, mineral
acids such as hydrochloric and sulfuric acid and the like, giving
methanesulfonate, benzenesulfonate, p-toluenesulfonate,
hydrochloride and sulphate, and the like, respectively or those
derived from bases such as organic and inorganic bases. Examples of
suitable inorganic bases for the formation of salts of compounds
for this invention include the hydroxides, carbonates, and
bicarbonates of ammonia, lithium, sodium, calcium, potassium,
aluminium, iron, magnesium, zinc and the like. Salts can also be
formed with suitable organic bases. Such bases suitable for the
formation of pharmaceutically acceptable base addition salts with
compounds of the present invention include organic bases, which are
nontoxic and strong enough to form salts. Such organic bases are
already well known in the art and may include amino acids such as
arginine and lysine, mono-, di-, or trihydroxyalkylamines such as
mono-, di-, and triethanolamine, choline, mono-, di-, and
trialkylamines, such as methylamine, dimethylamine, and
trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine;
morpholine; ethylenediamine; N-benzylphenethylamine;
tris(hydroxymethyl)aminomethane; and the like.
[0039] Salts may be prepared in a conventional manner using methods
well known in the art. Acid addition salts of said basic compounds
may be prepared by dissolving the free base compounds according to
the first aspect of the invention in aqueous or aqueous alcohol
solution or other suitable solvents containing the required acid.
Where a compound of the invention contains an acidic function, a
base salt of said compound may be prepared by reacting said
compound with a suitable base. The acid or base salt may separate
directly or can be obtained by concentrating the solution e.g. by
evaporation. The compounds of this invention may also exist in
solvated or hydrated forms.
[0040] The invention also extends to a prodrug of the
aforementioned compounds such as an ester or amide thereof. A
prodrug is any compound that may be converted under physiological
conditions or by solvolysis to any of the compounds of the
invention or to a pharmaceutically acceptable salt of the compounds
of the invention. A prodrug may be inactive when administered to a
subject but is converted in vivo to an active compound of the
invention.
[0041] The compounds of the invention may contain one or more
asymmetric carbon atoms and may exist in racemic and optically
active forms. The compounds of the invention may exist in trans or
cis form. The first aspect of the invention covers all of these
compounds.
[0042] The compound of the invention may exist in one or more
crystalline forms. The invention therefore relates to a single
crystal form of a compound of the invention or a mixture of one or
more forms.
[0043] The second aspect of the invention provides a process for
the preparation of a compound of the first aspect of the invention.
The compounds of the first aspect of the invention may be prepared
by methods known to those skilled in the art for analogous
compounds, as illustrated by the general schemes and procedures
below and with reference to the examples.
[0044] In particular, the compound of the first aspect may be
provided by the introduction of a group X--R.sup.1 into a compound
of formula (X), wherein Y.sup.1 is a halogen selected from F, Cl,
Br or I.
##STR00016##
Introduction of the group X--R.sup.1 may be catalysed by a catalyst
such as a palladium or copper catalyst, as set out in the examples
below.
[0045] Alternatively, the group XR.sup.1 can be introduced by the
initial introduction of the group X,
##STR00017##
followed by the introduction of the group R.sup.1
##STR00018##
[0046] Alternatively, a compound of the invention may be provided
by the introduction of the group R.sup.2 into a compound of formula
(V) wherein Y.sup.2 is a halogen or a metal.
##STR00019##
[0047] The group R.sup.2 can be introduced directly into a compound
of formula (XXXII)
##STR00020##
for example wherein the group R.sup.2 is introduced as a cyclic
ketone.
[0048] The groups R.sup.1, XR.sup.1 and/or R.sup.2 can be
introduced into the compounds of the invention as discussed above.
Alternatively, a precursor moiety may be introduced into the
compounds of the invention. The precursor moiety can then undergo
one or more conversions to obtain R.sup.1, XR.sup.1 or R.sup.2.
Examples of such precursor moieties include a boronic ester,
CO.sub.2H, CN, C(NH)O-alkyl, COMe, COH, NH.sub.2, NH--NH.sub.2,
CONH.sub.2, COCHN.sub.2, CO.sub.2-alkyl, CHNOH, COCH.sub.2N.sub.3,
C(NH)O-alkyl, CSNH.sub.2, CONCS, CONHC(S)--NH.sub.2, and/or
C(NH)NH.sub.2.
[0049] A compound of formula (V) can be produced from a compound of
formula (XXXII) by the addition of a group Y.sup.2 as defined
above
##STR00021##
[0050] The compound of formula (XXXII) can be produced from a
compound of formula (III)
##STR00022##
by the introduction of a group XR.sup.1. The compound of formula
(XXXII) can also be produced by the introduction of the group X
followed by the introduction of the group R.sup.1, or by the
introduction of a precursor of the group XR.sup.1 or R.sup.1.
[0051] Detailed processes for the production of the compounds of
the first aspect are set out in the examples. The reaction
conditions set out for the specific reactions in the examples can
be applied to the general reaction schemes set out above. The
present invention encompasses the processes for the production of
the compounds of the first aspect and the intermediate compounds
used in the processes. In particular, the second aspect of the
invention provides compounds of general formula (V), (X) and/or
(XXXII) wherein the groups R.sup.1, R.sup.2 and X are as defined
for the first aspect of the invention.
[0052] The skilled person will appreciate that it may be necessary
to protect various functionalities in the compounds of the
invention or the intermediate compounds during the processes set
out above. In particular, the NH functionality in the azaindole may
require protection. Protection and deprotection of functionalities
as necessary, in particular the NH functionality in the azaindole
group can be carried out using protecting groups, methods of
protection and methods of deprotection well known to persons
skilled in the art and/or as set out in the examples. The present
invention encompasses processes using protected intermediate
compounds and including protection and deprotection steps. The
invention further encompasses protected intermediate compounds used
in the processes described above and with reference to the
examples, in particular to protected versions of compounds of
general formula (V), (X) and/or (XXXII).
[0053] The third aspect of the invention provides a composition
comprising a compound according to the first aspect of the
invention in combination with a pharmaceutically acceptable
carrier, diluent or excipient.
[0054] The composition may also comprise one or more additional
active agent, such as an anti-inflammatory agent (for example a p38
inhibitor, glutamate receptor antagonist, or a calcium channel
antagonist), AMPA receptor antagonist, a chemotherapeutic agent
and/or an antiproliferative agent.
[0055] Suitable carriers and/or diluents are well known in the art
and include pharmaceutical grade starch, mannitol, lactose,
magnesium stearate, sodium saccharin, talcum, cellulose, glucose,
sucrose, (or other sugar), magnesium carbonate, gelatin, oil,
alcohol, detergents, emulsifiers or water (preferably sterile). The
composition may be a mixed preparation of a composition or may be a
combined preparation for simultaneous, separate or sequential use
(including administration).
[0056] The composition according to the invention for use in the
aforementioned indications may be administered by any convenient
method, for example by oral (including by inhalation), parenteral,
mucosal (e.g. buccal, sublingual, nasal), rectal or transdermal
administration and the compositions adapted accordingly.
[0057] For oral administration, the composition can be formulated
as liquids or solids, for example solutions, syrups, suspensions or
emulsions, tablets, capsules and lozenges.
[0058] A liquid formulation will generally consist of a suspension
or solution of the compound or physiologically acceptable salt in a
suitable aqueous or non-aqueous liquid carrier(s) for example
water, ethanol, glycerine, polyethylene glycol or oil. The
formulation may also contain a suspending agent, preservative,
flavouring or colouring agent.
[0059] A composition in the form of a tablet can be prepared using
any suitable pharmaceutical carrier(s) routinely used for preparing
solid formulations. Examples of such carriers include magnesium
stearate, starch, lactose, sucrose and microcrystalline
cellulose.
[0060] A composition in the form of a capsule can be prepared using
routine encapsulation procedures. For example, powders, granules or
pellets containing the active ingredient can be prepared using
standard carriers and then filled into a hard gelatine capsule;
alternatively, a dispersion or suspension can be prepared using any
suitable pharmaceutical carrier(s), for example aqueous gums,
celluloses, silicates or oils and the dispersion or suspension then
filled into a soft gelatine capsule.
[0061] Compositions for oral administration may be designed to
protect the active ingredient against degradation as it passes
through the alimentary tract, for example by an outer coating of
the formulation on a tablet or capsule.
[0062] Typical parenteral compositions consist of a solution or
suspension of the compound or physiologically acceptable salt in a
sterile aqueous or non-aqueous carrier or parenterally acceptable
oil, for example polyethylene glycol, polyvinyl pyrrolidone,
lecithin, arachis oil or sesame oil. Alternatively, the solution
can be lyophilised and then reconstituted with a suitable solvent
just prior to administration.
[0063] Compositions for nasal or oral administration may
conveniently be formulated as aerosols, drops, gels and powders.
Aerosol formulations typically comprise a solution or fine
suspension of the active substance in a physiologically acceptable
aqueous or non-aqueous solvent and are usually presented in single
or multidose quantities in sterile form in a sealed container,
which can take the form of a cartridge or refill for use with an
atomising device. Alternatively the sealed container may be a
unitary dispensing device such as a single dose nasal inhaler or an
aerosol dispenser fitted with a metering valve, which is intended
for disposal once the contents of the container have been
exhausted. Where the dosage form comprises an aerosol dispenser, it
will contain a pharmaceutically acceptable propellant. The aerosol
dosage forms can also take the form of a pump-atomiser.
[0064] Compositions suitable for buccal or sublingual
administration include tablets, lozenges and pastilles, wherein the
active ingredient is formulated with a carrier such as sugar and
acacia, tragacanth, or gelatin and glycerin.
[0065] Compositions for rectal or vaginal administration are
conveniently in the form of suppositories (containing a
conventional suppository base such as cocoa butter), pessaries,
vaginal tabs, foams or enemas.
[0066] Compositions suitable for transdermal administration include
ointments, gels, patches and injections including powder
injections.
[0067] Conveniently the composition is in unit dose form such as a
tablet, capsule or ampoule.
[0068] The fourth aspect of the invention provides a process for
the manufacture of a composition according to the second aspect of
the invention. The manufacture can be carried out by standard
techniques well known in the art and comprises combining a compound
according to the first aspect of the invention and the
pharmaceutically acceptable carrier or diluent and optionally one
or more additional active agents. The composition may be in any
form including a tablet, a liquid, a capsule, and a powder or in
the form of a food product, e.g. a functional food. In the latter
case the food product itself may act as the pharmaceutically
acceptable carrier.
[0069] The fifth aspect of the present invention relates to a
compound of the first aspect, or a composition of the third aspect,
for use in medicine.
[0070] The compounds of the present invention are inhibitors of
JNK, such as JNK1, JNK2, or JNK3. In particular, the compounds of
the present invention are inhibitors of JNK3. Preferably, the
compounds of the present invention inhibit JNK3 selectively (i.e.
the compounds of the invention preferably show greater activity
against JNK3 than JNK1 and 2). For the purpose of this invention,
an inhibitor is any compound, which reduces or prevents the
activity of the JNK enzyme.
[0071] The compounds are therefore useful for conditions for which
inhibition of JNK activity is beneficial. Thus, preferably, this
aspect provides a compound of the first aspect, or a composition of
the second aspect of the present invention, for the prevention or
treatment of a JNK-mediated disorder. The compounds of the first
aspect of the invention may thus be used for the inhibition of JNK,
more preferably for the inhibition of JNK3.
[0072] A "JNK-mediated disorder" is any disease or deleterious
condition in which JNK plays a role. Examples include
neurodegenerative disorder (including dementia), inflammatory
disease, an apoptosis disorder (i.e. a disorder linked to
apoptosis) particularly neuronal apoptosis, autoimmune disease,
destructive bone disorder, proliferative disorder, cancer,
infectious disease, allergy, ischemia reperfusion injury, heart
attack, angiogenic disorder, organ hypoxia, vascular hyperplasia,
cardiac hypertrophy, thrombin induced platelet aggregation and a
prostaglandin endoperoxidase synthase-2 condition (i.e. any
condition associated with prostaglandin endoperoxidase synthase-2).
The compounds of the present invention may be used for any of these
JNK-mediated disorders.
[0073] The compounds of the present invention are particularly
useful for the prevention or treatment of a neurodegenerative
disorder. In particular, the neurodegenerative disorder is an
apoptosis neurodegenerative disorder and/or an inflammation
neurodegenerative disorder (i.e. the neurodegenerative disorder
results from apoptosis and/or inflammation). Examples of
neurodegenerative disorders are: dementia; Alzheimer's disease;
Parkinson's disease; Amyotrophic Lateral Sclerosis; Huntington's
disease; senile chorea; Sydenham's chorea; hypoglycemia; head and
spinal cord trauma including traumatic head injury; acute and
chronic pain; epilepsy and seizures; olivopontocerebellar dementia;
neuronal cell death; hypoxia-related neurodegeneration; acute
hypoxia; glutamate toxicity including glutamate neurotoxicity;
cerebral ischemia; dementia in a meningitis patient and/or dementia
in a neurosis patient; cerebrovascular dementia; or dementia in an
HIV-infected patient.
[0074] The neurodegenerative disorder may be a peripheral
neuropathy, including mononeuropathy, multiple mononeuropathy or
polyneuropathy. Examples of peripheral neuropathy may be found in
diabetes mellitus, Lyme disease or uremia; peripheral neuropathy
for example peripheral neuropathy caused by a toxic agent;
demyelinating disease such as acute or chronic inflammatory
polyneuropathy, leukodystrophies, or Guillain-Barre syndrome;
multiple mononeuropathy secondary to a collagen vascular disorder
(e.g. polyarteritis nodosa, SLE, Sjogren's syndrome); multiple
mononeuropathy secondary to sarcoidosis; multiple mononeuropathy
secondary to a metabolic disease (e.g. diabetes or amyloidosis); or
multiple mononeuropathy secondary to an infectious disease (e.g.
Lyme disease or HIV infection).
[0075] The compounds of the invention can also be used to prevent
or treat disorders resulting from inflammation. These include, for
example, inflammatory bowel disorder, bronchitis, asthma, acute
pancreatitis, chronic pancreatitis, allergies of various types, and
possibly Alzheimer's disease. Autoimmune diseases which may also be
treated or prevented by the compounds of the present invention
include rheumatoid arthritis, systemic lupus erythematosus,
glumerulonephritis, scleroderma, chronic thyroiditis, Graves's
disease, autoimmune gastritis, diabetes, autoimmune haemolytis
anaemia, autoimmune neutropaenia, thrombocytopenia, atopic
dermatitis, chronic active hepatitis, myasthenia gravis, multiple
sclerosis, ulcerative colitis, Crohn's disease, psoriasis or graft
vs host disease.
[0076] A compound of the present invention may be administered
simultaneously, subsequently or sequentially with one or more other
active agent, such as an anti-inflammatory agent e.g. p38
inhibitor, AMPA receptor antagonist, glutamate receptor antagonist,
calcium channel antagonist, a chemotherapeutic agent or an
antiproliferative agent. For example, for acute treatment, a p38
inhibitor may be administered to a patient prior to administering a
compound of the present invention.
[0077] The compounds of the invention will normally be administered
in a daily dosage regimen (for an adult patient) of, for example,
an oral dose of between 1 mg and 2000 mg, preferably between 30 mg
and 1000 mg, e.g. between 10 and 250 mg or an intravenous,
subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,
preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of
the compound of the formula (I) or a physiologically acceptable
salt thereof calculated as the free base, the compound being
administered 1 to 4 times per day. Suitably the compounds will be
administered for a period of continuous therapy, for example for a
week or more.
[0078] The sixth aspect of the invention relates to a method of
treating or preventing a JNK-mediated disorder in an individual,
which method comprises administering to said individual a compound
of the first aspect or a composition of the third aspect. The
active compound is preferably administered in a cumulative
effective amount. The individual may be in need of the treatment or
prevention. Any of the JNK-mediated disorders listed above in
relation to the fourth aspect may be the subject of treatment or
prevention according to the fifth aspect. One or more other active
agent may be administered to the individual simultaneously,
subsequently or sequentially to administering the compound. The
other active agent may be an anti-inflammatory agent such as a p38
inhibitor, glutamate receptor antagonist, AMPA receptor antagonist,
calcium channel antagonist, a chemotherapeutic agent or an
antiproliferative agent, but is preferably p38 inhibitor for acute
treatment.
[0079] The seventh aspect of the present invention provides the use
of a compound of the first aspect in the manufacture of a
medicament for the prevention or treatment of a JNK-mediated
disorder. The medicament may be used for treatment or prevention of
any of the JNK-mediated disorders listed above in relation to the
fourth aspect. Again, the compound of the present invention may be
administered simultaneously, subsequently or sequentially with one
or more other active agent, preferably a p38 inhibitor for acute
treatment.
[0080] In the eighth aspect of the invention, there is provided an
assay for determining the activity of the compounds of the present
invention, comprising providing a system for assaying the activity
and assaying the activity of the compound. Preferably the assay is
for the JNK inhibiting activity of the compound, more preferably it
is for the JNK3-specific inhibiting activity of the compounds. The
compounds of the invention may be assayed in vitro, in vivo, in
silico, or in a primary cell culture or a cell line. In vitro
assays include assays that determine inhibition of either the
kinase activity or ATPase activity of activated JNK. Alternatively,
in vitro assays may quantitate the ability of a compound to bind
JNK and may be measured either by radiolabelling the compound prior
to binding, then isolating the inhibitor/JNK complex and
determining the amount of the radiolabel bound or by running a
competition experiment where new inhibitors are incubated with JNK
bound to known radioligands. An example of an assay, which may be
used, is Scintillation Proximity Assay (SPA), preferably using
radiolabelled ATP. Another example is ELISA. Any type or isoform of
JNK may be used in these assays.
[0081] In the ninth aspect, there is provided a method of
inhibiting the activity or function of a JNK, particularly JNK3,
which method comprises exposing a JNK to a compound or a
composition of the first or second aspect of the present invention.
The method may be performed in a research model, in vitro, in
silico, or in vivo such as in an animal model. A suitable animal
model may be a kainic acid model in rat or mice, traumatic brain
injury model in rat, or MPTP in mice.
[0082] All features of each of the aspects apply to all other
aspects mutatis mutandis.
[0083] The invention will now be illustrated by the following
non-limiting examples.
EXAMPLES
General Methods for Synthesis of the Compounds of the Invention
Method 1
[0084] 5-Bromo-7-azaindole (III) (preparation disclosed in
WO2004/078757) is reacted with thiol R.sup.1--SH in the presence of
palladium catalyst such as (PPh.sub.3).sub.4Pd and a base such as
t-BuONa to afford sulphide (IV) (Migita et al. Bull. Chem. Soc.
Jpn, 1980, 53, 1385; Kondo and Mitsudo Chem. Rev. 2000, 100, 3205).
The reaction is carried out under nitrogen atmosphere at elevated
temperatures such as 80-100.degree. C., e.g. by refluxing a
solution of the reagents in ethanol for an extended time such as 12
to 24 h.
Method 1
##STR00023##
[0086] Sulfide (IV) is then converted into 3-halo derivative (V) by
reaction with halogen Y.sub.2 such as iodine in the presence of a
strong base, e.g. KOH in appropriate solvent such as DMF by analogy
to the protocol developed for analogous indoles by Bocchi and Palla
(Synthesis 1982, 1096). Standard protection of nitrogen is followed
by installation of R.sup.2 using one of the processes described in
Methods 11-24. Subsequent removal of protecting group affords
compound (I) where X.dbd.S. This compound can be oxidized in
standard way with an oxidizing agent such as e.g. hydrogen peroxide
or Oxone.RTM. to give sulfoxide (I), X.dbd.S(O). Prolonged
oxidation and/or using an excess of oxidant leads to sulfone (I),
X.dbd.SO.sub.2.
Method 2
[0087] Intermediate (IV) can also be prepared from protected
bromide (VIII) (preparation disclosed in WO2004/078757).
Halogen-metal exchange followed by the addition of sulfur to the
heteroaryllithium species and subsequent reaction between thiolate
and R.sup.1--Br affords protected sulfide (IX).
Method 2
##STR00024##
[0089] Deprotection of (IX) using methods known in the art produces
(IV), which can be converted into (I), X.dbd.S, S(O), SO.sub.2 as
shown in Method 1.
Method 3
[0090] Alternatively, the C(5)-alkyl(aryl)thio group can be
introduced after the C(3) substituent has already been installed.
This can be achieved in one step process leading to intermediate
(VII) (Method 3a) using 5-halo derivative (X) (preparation
disclosed in WO2004/078756) and following the protocol by Deng et
al (Synlett 2004, 7, 1254).
Method 3
##STR00025##
[0092] Intermediate (VII) can also be synthesized from (X) in a
two-step process (Method 3b). 5-Halo-7-azaindole (X) is converted
into pinacol boronic ester (XI) using boronation protocol disclosed
in WO2004/078757. Boronic ester (XI) is then reacted with
appropriate thiol following the method by Herradura et al. (Org.
Lett. 2000, 2, 2019) to give (VII). Deprotection of (VII) as
described in Method 1 affords (I) X.dbd.S.
[0093] Compounds (I) with X.dbd.O can be prepared using Methods 4
and 5.
Method 4
[0094] Boronate (XI) can be converted into the relevant hydroxy
derivative (XII) following a modified protocol developed for
boronic acids by Simon et al. (J. Org. Chem. 2001, 66, 633). It
involves acting with hydrogen peroxide solution in acetic acid on
boronic ester (XI) at room temperature. Hydroxy derivative (XII)
thus obtained can then be reacted with boronic acid
R.sup.1--B(OH).sub.2 to produce ether (XIII).
Method 4
##STR00026##
[0096] Alternatively, for alkyl-type R.sup.1 groups, hydroxy
derivative (XII) can be alkylated with R.sup.1--Y (Y=halogen) under
basic conditions developed by Engler et al. (J. Org. Chem. 1996,
61, 9297). Final removal of protecting group G under standard
conditions affords (I), X.dbd.O.
Method 5
[0097] The ether functionality can be introduced directly at C(5)
of the 7-azaindole system by using 5-bromo-7-azaindole (III) and
following the protocol by Larraya et al. (Eur. J. Med. Chem. 2004,
39, 515). This reaction involves heating a mixture of (III), an
alkoxide R.sup.1--OM' (M'=metal such as e.g. Na), and CuBr in an
aprotic solvent such as DMF.
Method 5
##STR00027##
[0099] Further transformations leading to (I), X.dbd.O are
analogous to those shown in Method 1.
[0100] Compounds (I) with X.dbd.C can be prepared using Method
6.
Method 6
[0101] It has been recognized in literature (Viaude et al.
Tetrahedron, 1997, 53, 5159) that introduction of X.dbd.CH.sub.2 at
C(5) in good yield is difficult as degradation products are
observed and yield is only about 20%. This yield can be more than
doubled by using Ag(I)-promoted Suzuki-Miaura coupling reaction
(Zou et al. Tetrahedron Lett. 2001, 42, 7213).
Method 6
##STR00028##
[0103] This reaction involves 7-azaindole derivative (X), the
relevant benzylboronic acid R.sup.1--C(R.sup.4).sub.2--B(OH).sub.2,
silver oxide, potassium carbonate and a palladium catalyst such as
Pd(dppf)Cl.sub.2. Reaction is carried at elevated temperature
(about 80.degree. C.) over a period of 6-18 hours. Final
deprotection of product (XVIII) affords (I),
X.dbd.CR.sup.4R.sup.4.
[0104] Compounds (I) with X.dbd.N can be prepared using Methods
7-10.
Method 7
[0105] Formation of a bond between nitrogen (X.dbd.N) and carbon
atom C(5) of the 7-azaindole system can be performed using Chan-Lam
coupling reaction involving (hetero)aryl boronic acid (Quach and
Batey Org. Lett. 2003, 5, 4397; Chan et al. Tetrahedron Lett. 2003,
44, 3863) and NH-containing substrate, which is catalyzed by copper
(II) salts, for instance copper (II) acetate.
Method 7
##STR00029##
[0107] Thus, boronate (XIX) (preparation disclosed in
WO2004/078757) can be converted into C(5)-N derivative (XX).
Further transformations analogous to those shown in Method 1 lead
to inhibitor (I) with X.dbd.NR.sup.3--, NR.sup.3--C(O)-- or
NR.sup.3--C(O)O--.
Method 8
[0108] Another alternative is offered by Buchwald-Hartwig
methodology (Wolfe et al. Acc Chem Res 1998, 31, 805; Zim and
Buchwald Org. Lett. 2003, 5, 2413) where haloarenes can be coupled
with amines using a variety of palladium catalysts such as
Pd(dba).sub.2, PdCl.sub.2/P(o-tolyl).sub.3, etc.
Method 8
##STR00030##
[0110] Various bases can be used in the reaction, for instance
tBuONa, K.sub.2CO.sub.3, Et.sub.3N, etc. The reaction is usually
carried out at elevated temperature, e.g. 60-100.degree. C. in
solvent such as toluene.
Method 9
[0111] Direct synthesis of primary aryl amines, which are useful
for preparation of inhibitors (I) where X.dbd.NH--C(O)-- or
NH--C(O)O-- was carried out by the direct conversion of aryl
halides into primary amines under mild conditions as developed by
Lang et al. (Tetrahedron Lett. 2001, 42, 3251).
Method 9
##STR00031##
[0113] The primary amine (XXIV) can be converted into (I),
X.dbd.NHC(O)-- or X.dbd.NHC(O)O--by deprotection of (XXIV) and
acylation of (XXV) with suitable acylating agent such as acid
chloride, acid anhydride, or equivalent. In particular, where G is
a phenylsulfonyl group, its removal occurs spontaneously prior to
the acylation step. Thus, a skilled person will appreciate that the
actual synthetic sequence to prepare compound (I) will depend on
the type of protecting group G used.
Method 10
[0114] Another route to introduce the C(5)-N bond is based on the
modified Curtius rearrangement using the relevant carboxylic acid
and diphenylphosphoryl azide (DPPA) (Shioiri et al. J. Am. Chem.
Soc. 1972, 94, 6203; Anquetin et al. Bioorg. Med. Chem. Lett. 2004,
14, 2773).
Method 10
##STR00032##
[0116] This reaction between acid (XXVI), DPPA, t-BuOH and
Et.sub.3N is carried out at elevated temperature (reflux). This
procotol can be modified by reacting an intermediate isocyanate
with t-BuOH in the presence of CuCl (Kapferer and Vasella Helv.
Chim. Acta 2004, 87, 2764). Amine (XXV) can then be acylated as
shown in Method 9.
Method 11
[0117] Substituent R.sup.2 can be introduced using an appropriate
palladium catalyzed C--C bond-forming reaction between (XXVIII) and
appropriate boronic acid or ester, stannane or silane R.sup.2-M
(M=B, Sn, Si respectively) as taught in WO2004/78756.
Method 11
##STR00033##
[0119] Such method is particularly suitable for attaching rings
R.sup.2 through an endocyclic sp.sup.2 carbon atom, which is
present in aromatic, heteroaromatic or partially unsaturated
rings.
[0120] Many boronic acids and esters R.sup.2-M (M=B) are
commercially available or can be prepared by methods known in the
art (Li et al. J. Org. Chem. 2002, 67, 5394-5397; Hall, Dennis G.
(ed.) Boronic Acids. Preparation and Applications in Organic
Synthesis and Medicine, Wiley VCH, 2005). Partially saturated
boronic acids and esters prepared as taught by Renaud and Ouellet
(J. Am. Chem. Soc. 1998, 120, 7995) are particularly useful
intermediates with regard to installation of partially saturated
rings at C(3) of the 7-azaindole system. Unsaturated and
(hetero)aromatic stannanes are available using known methods
(Pereyre et al Tin in Organic Synthesis; Butterworth: London, 1987;
Lee and Dai Tetrahedron 1997, 53, 859 and references therein; Smith
et al. Chem. Rev. 2000, 100, 3257; Evans et al. J. Am. Chem. Soc.,
1998, 120, 5921). Synthetic procedures to prepare siloxanes and
silacyclobutanes R.sup.2-M (M=Si) have been described by Denmark
and Choi (J. Am. Chem. Soc. 1999, 121, 5821).
[0121] The reaction with R.sup.2-M (M=B) is a Suzuki reaction which
can be carried out according to Suzuki Pure Appl. Chem. 1991, 63,
419 or Littke J. Am. Chem. Soc. 2000, 122, 4020.
[0122] It will be appreciated that the reaction with R.sup.2-M
(M=Sn) is a Stille reaction, which can be carried out according to
Stille Angew. Chem., Int. ed, Engl. 1986, 25, 508; Mitchell
Synthesis, 1992, 803, or Littke et al. J. Am. Chem. Soc. 2002, 124,
6343.
[0123] The reaction with R.sup.2-M (M=Si) is a Hiyama reaction
which can be carried out according to Hatanaka et al. J. Org. Chem.
1988, 53, 918, Hatanaka et al. Synlett, 1991, 845, Tamao et al.
Tetrahedron Lett. 1989, 30, 6051 or Denmark et al. Org. Lett. 2000,
2, 565, ibid. 2491.
[0124] Suitable catalysts for the purpose of this invention include
(PPh.sub.3).sub.2PdCl.sub.2, (PPh.sub.3).sub.4Pd, Pd(OAc).sub.2,
[PdCl(.eta..sup.3-C.sub.3H.sub.5].sub.2, Pd.sub.2(dba).sub.3,
Pd(dba).sub.2 (dba=dibenzylidenacetone), Pd/P(t-Bu).sub.3. A
variety of coupling conditions for halogenated heterocycles have
been reviewed by Schroter et al. Tetrahedron 2005, 61, 2245. The
C--C bond formation between (hetero)aromatic systems can also be
catalyzed by catalysts containing other metals such as copper and
nickel (Hassan et al. Chem. Rev. 2002, 102, 1359).
Method 12
[0125] Introduction of R.sup.2 by means of an appropriate palladium
catalyzed C--C bond-forming reaction can also be carried out in a
reverse manner using metalloorganic species (XXX) and halide or
triflate R.sup.2--Y.sup.1 under similar conditions to those used in
Method 11.
Method 12
##STR00034##
[0127] While halides R.sup.2--Y.sup.1 (Y.sup.1.dbd.I, Br, Cl) are
available commercially, the relevant derivatives R.sup.2--OTfl
containing partially unsaturated rings can be prepared from ketones
(Comins and Dehghani Tetrahedron Letters 1992, 33, 6299).
[0128] Methods for introduction of M=B, Sn, Si at the C(3) position
of the 7-azaindole system have been disclosed in WO2004078756 and
by Alvarez et al. (Synthesis 1999, 4, 615). Analogous reactions on
the indole skeleton have also been described for M=Sn by Amat et
al. (J. Org. Chem. 1994, 59, 10) and Hodson et al. (Tetrahedron
1994, 50, 1899), and for M=B by Kawasaki et al. (J. Chem. Soc.
Chem. Commun. 1994, 18, 2085) and Claridge et al Tetrahedron 1997,
53, 4035.
Method 13
[0129] Compounds (XXXI) with partially saturated rings are
accessible using Methods 11 and 12. An alternative protocol
involves the reaction of the relevant N-unprotected 7-azaindole
(XXXII) with cyclic ketone under basic conditions as described by
Fonquerna et al. (Bioorg. Med. Chem. Lett. 2005, 15, 1165).
Method 13
##STR00035##
[0131] This reaction is carried out at elevated temperature in the
presence of base such as KOH.
Method 14
[0132] Introduction of saturated rings at the C(3) of the azaindole
system to produce (XXXIII) can be achieved by catalytic reduction
of compounds (XXXI) containing partially saturated rings.
Method 14
##STR00036##
[0134] This process can be carried out under the conditions known
to those skilled in the art by stirring a solution of (XXXI) in a
suitable solvent such as MeOH or AcOH in an atmosphere of H.sub.2
and in the presence of a catalyst such as Pd, Pd(OH).sub.2, or
PtO.sub.2, as illustrated for the relevant indole-based systems by
Fonquerna et al. (Bioorg. Med. Chem. Lett. 2005, 15, 1165).
Method 15
[0135] Saturated rings can be introduced directly at the C(3)
carbon atom by the reaction between the relevant epoxide and
(XXXII).
Method 15
##STR00037##
[0137] This transformation can be carried out under a variety of
conditions. The reaction can be promoted by bases such as EtMgBr or
MeMgBr following the conditions developed by Heath-Brown and
Philpott (J. Chem. Soc. 1965, 7165) and Macor and Ryan
(Heterocycles 1990, 31, 1497) for the indole system. It can also be
catalyzed by silica gel and occur under high pressure as shown by
Kotsuki et al. (J. Org. Chem. 1996, 61, 984). Other possible
catalysts for opening the epoxide ring include TiCl.sub.4,
InCl.sub.3, InBr.sub.3, LiClO.sub.4, and [Cr(salen)]SbF.sub.6.
[0138] Heterocyclic rings at C(3), can also be formed by the means
of cyclization (Gilchrist J. Chem. Soc. Perkin Trans 1 2001, 2491).
Preparation of pyrroles via cyclization is known (e.g. Haubmann et
al. Bioorg. Med. Chem. Lett. 1999, 9, 3143). The following are
methods applicable to heterocycles containing two or more
heteroatoms:
Method 16
Imidazole
[0139] The imidazole ring can be constructed following the method
of Matthews et al. (Synthesis 1986, 336).
##STR00038##
[0140] Nitrile (XXXV) which can be produce according to methods
disclosed in WO2004101565, is first converted to imidate (XXXVI)
using the Pinner method (Nielson, D. G. In The Chemistry of
Amidines and Imidates; S. Patai Ed.: John Wiley and Sons: New York,
1975, p 443) by reacting (XXXV) with alcohol
R.sup.13OH(R.sup.13=alkyl group, preferably Me, Et) in the presence
of anhydrous acid such as HCl. Imidate (XXXVI) is then reacted with
acetal H.sub.2NCH(R.sup.12)CH.sub.2CH(OR.sup.11).sub.2
(R.sup.11=alkyl group, preferably Me, Et; R.sup.12=the relevant
substituent such as H, alkyl, COOR.sup.14; R.sup.14=alkyl) to give
amidine (XXXVII), which cyclizes under acidic condition to afford
imidazol-2-yl derivative (XXXVIII). In particular, the use of
substituted acetals (R.sup.12.noteq.H) has been demonstrated by
Franchetti et al. (Bioorg. Med. Chem. Lett. 2001, 11, 67).
[0141] Imidazole derivatives (XXXIX) are accessible (Li et al. Org.
Synth. 2004, 81, 105) by condensation of amidines (XL) [prepared
from nitriles (XXXV) according to Boere et al. J. Organomet. Chem.
1987, 331, 161; Thurkauf et al. J. Med. Chem. 1995, 38, 2251], with
.alpha.-halo ketones (XLI).
##STR00039##
[0142] The relevant .alpha.-halo ketones (XLI) are available by
halogenation of ketones (XLIII). In particular Y'.dbd.Br can be
introduced by direct bromination (Gaudry and Marquet Org. Synth.
1988, VI, 193) or by using PhNMe.sub.3Br.sub.3 (Javed and Kahlon J.
Heterocycl. Chem. 2002, 39, 627), pyridine.HBr.sub.3 (Zaidlewicz et
al. Heterocycles 2001, 55, 569) or CuBr.sub.2 (Gu et al. Bioorg.
Med. Chem. Lett. 1999, 9, 569). The relevant iodides (Y'.dbd.I) are
available following the protocols of Jereb et al. (Synthesis 2003,
6, 853) or Lee and Jin (Synth. Commun. 1999, 29, 2769) or Bekaert
et al (Tetrahedron Lett. 2000, 41, 2903) by using the
I.sub.2/SeO.sub.2 system. Chlorides can be synthesized using
SO.sub.2Cl.sub.2 as chlorinating agent (Lopez et al. Farmaco 2000,
55, 40).
[0143] Regiospecific halogenation of an unsymmetrical ketone
(XLIII) to afford (XLI) (Y'.dbd.Cl, Br, I) can also be executed
stepwise by generating silyl enol ether (XLIV) followed by its
halogenation. Chlorinating agents include t-BuOCl (Dubac et al.
Synth. Commun. 1991, 21, 11), SO.sub.2Cl.sub.2 (Olah et al. J. Org.
Chem. 1984, 49, 2032), CH.sub.3Li/N-chlorosuccinimide (Denmark and
Dapper J. Org. Chem. 1984, 49, 798). CuCl.sub.2 (Ito et al. J. Org.
Chem. 1980, 45, 2022), Ph.sub.3P.Cl.sub.2/(TMSO).sub.2 (Shibata et
al. Bull. Chem. Soc. Jpn. 1991, 64, 3749), and
TiCl.sub.2(Oi-Pr).sub.2/t-BuOOH (Krohn et al. J. Prakt. Chem. 1999,
341, 62). Bromination can be conducted with Br.sub.2 (Blanco et al.
Synthesis 1976, 194), PhNMe.sub.3Br.sub.3 (Baldwin et al. J. Org.
Chem. 2001, 66, 2588) and N-bromosuccinimide (Paquette et al.
Tetrahedron Lett. 1985, 26, 1611). Iodine can be introduced using
I.sub.2/mCPBA (Sha et al. J. Org. Chem. 1987, 52, 3919),
I.sub.2/CrO.sub.3/Me.sub.3SiCl (Aizpurua et al. Tetrahedron 1985,
41, 2903), I.sub.2/PCC (Scettri et al. Synth. Commun. 1982, 12,
11270, I.sub.2/CH.sub.3COOAg (Rubottom and Mott J. Org. Chem. 1979,
44, 1731), I.sub.2/Cu(NO.sub.3).sub.2 (Dalla Cort J. Org. Chem.
1991, 56, 6708) and NaI/N-chlorosuccinimide (Vankar and Kumaravel
Tetrahedron Lett. 1984, 25, 233.
##STR00040##
[0144] Silyl enol ether (XLIV) needed for this reaction may be
formed from ketone (XLIII) using methods known in the art by acting
on (XLIII) with silyl halide or triflate (R.sup.13).sub.3SiY.sup.2
(Y.sup.2.dbd.Cl, Br, I, OSO.sub.2CF.sub.3) and base such as lithium
hexamethyldisilylamide (LiHMDS; Baldwin et al. J. Org. Chem. 2001,
66, 2588), or tertiary amine (e.g. i-Pr.sub.2Net; Kraus et al. J.
Org. Chem. 1990, 55, 1624).
[0145] Introduction of the ketone functionality at C(3) of the
7-azaindole system to provide ketone (XLIII) can be carried out by
methods known in the art. These include reacting 3-halo-7-azaindole
(XXVIII) (prepared as (V) in Method 1) with
.alpha.-ethoxyvinyl)trialkyltin (XLII) (Cheney and Paquette J. Org.
Chem. 1989, 54, 3334) in the presence of palladium catalyst such as
PdCl.sub.2(PPh.sub.3).sub.2 followed by acid-catalyzed hydrolysis
(Molina et al. Tetrahedron Lett. 2002, 43, 1005). Direct
introduction of the ketone functionality at C(3) of the 7-azaindole
system was demonstrated by Yeung et al. (Tetrahedron Lett. 2002,
43, 5793) via Friedel-Crafts methodology.
Method 17
Pyrazole
[0146] Ketone (XLIII) may also serve as a starting material for the
preparation of pyrazole (XLVII).
##STR00041##
[0147] Standard condensation of ketone (XLIII) with aldehyde
R.sup.12CHO affords hydroxyketone (XLV), which can be oxidized by
methods known in the art, e.g. Swern oxidation, to
.alpha.,.gamma.-dicarbonyl system (XLVI). Reaction of (XLVI) with
hydrazine R.sup.14NNHNH.sub.2 affords pyrazole (XLVII)
(R.sup.14.dbd.H; Shoji et al. Chem. Pharm. Bull. 1973, 21, 2639;
R.sup.14=Ph; Bendaas et al. J. Heterocycl. Chem. 1999, 36, 1291).
Regioselective character of this condensation for R.sup.14=Me was
demonstrated by Timmermans et al. (J. Heterocycl. Chem. 1972, 9,
1373). Similarly, the use of semicarbazide H.sub.2NNHC(O)NH.sub.2
leads to amide (XLVII), R.sup.14.dbd.C(O)NH.sub.2 (Kumari, et al.
Indian J. Chem., Sect. B 1996, 35, 846). Pyrazole derivatives
(XLVII) where R.sup.12.dbd.OH can be obtained from esters (XLVI)
(R.sup.12.dbd.OMe) (Samanta et al. J. Chem. Res., Synop. 1995, 11,
429).
[0148] Pyrazole (XLVII) can also be prepared from the relevant
.alpha.,.beta.-unsaturated compound (XLVIII) following the method
developed for the indole-based systems by Dandia et al.
(R.sup.12=p-F--C.sub.6H.sub.4; Indian J. Chem., Sect B.: Org. Chem.
Incl. Med. Chem. 1993, 32, 1288).
##STR00042##
[0149] Compound (XLVIII) is available from aldehyde (XLIX;
preparation of analogous systems disclosed in WO2004101565) using
Horner-type olefination (Willette Adv. Heterocycl. Chem. 1968, 9,
27) or base-catalyzed aldol condensation with methylketones (Pailer
et al. Monatsh. Chem. 1979, 110, 589).
[0150] Compound (XLVIII) can also be prepared from the relevant
halide (XXVIII) (Y.dbd.Br; Brown and Kerr Tetrahedron Lett. 2001,
42, 983) or triflate (Y.dbd.CF.sub.3SO.sub.3; Gribble and Conway
Synth. Commun. 1992, 22, 2129) using Heck methodology.
##STR00043##
[0151] This reaction is carried out in the presence of tertiary
amine such as i-Pr.sub.2NEt and with Pd(PPh.sub.3).sub.2Cl.sub.2 or
Pd(OAc).sub.2PPh.sub.3 as catalyst. Pyrazole (XLVII) is available
from ketone (XLIII) in two steps, as shown below (Speake et al.
Bioorg. Med. Chem. Lett. 2003, 13, 1183).
##STR00044##
[0152] Pyrazole derivative (L) in which the pyrazole ring is linked
to the 7-azaindole C(3) via endocyclic nitrogen could be
synthesized by modification of method leading to (XLVII) (see
above) and using hydrazine derivative (LI).
##STR00045##
[0153] This hydrazine can be prepared in a standard way (Hiremath
et al. Indian J. Chem., Sect. B 1980, 19, 767) from the relevant
amine (LII). Preparation of 3-amino-substituted 7-azaindoles is
known in the art (Herbert and Wibberley J. Chem. Soc. C 1969,
1505).
Method 18
Oxazole
[0154] Oxazole derivatives (LIII) are available via the reaction
between amide (LV) and .alpha.-haloketone (LIV) using the method of
Kelly and Lang (J. Org. Chem. 1996, 61, 4623).
##STR00046##
[0155] The .alpha.-haloketone (LIV) can be prepared in a way
analogous to that described for (XLI) (see above, Method 16). Amide
(LV) can readily be synthesized from the relevant acid (LVII) via
mixed anhydride (LVI) (R.sup.11=alkyl) using standard procedure
known to those skilled in the art (preparation of analogous acids
and amides was disclosed in WO2003082868).
[0156] Reversal of functionalities allows synthesis of oxazoles
(LVIII) following the procedure by Kelly and Lang (J. Org. Chem.
1996, 61, 4623) as shown below (R.sup.12=alkyl, alkenyl). Compounds
with R.sup.12.dbd.NH.sub.2 can be prepared following the method
used for the indole series by Bansal et al (Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 2000, 39, 357).
##STR00047##
[0157] The reaction between .alpha.-haloketone (XLI) (preparation
described above, Method 16) and amide R.sup.12C(O)NH.sub.2 is
usually carried out at elevated temperature in neutral solvent such
as tetrahydrofuran. A large variety of amides R.sup.12C(O)NH.sub.2
are available commercially or can be prepared using methods known
to those skilled in the art.
[0158] The remaining regioisomeric oxazole (LIX) (R.sup.12=alkyl,
aryl) may be synthesized from .alpha.-haloketone (XLI) following
the method of Molina et al. (Synthesis 1993, 54). The azide (LX) is
reacted with acyl halide R.sup.12C(O)Y.sup.2 (Y.sup.2=halogen) in
the presence of tertiary phosphine such as tributylphosphine.
##STR00048##
[0159] Reacting azide (LX) in the above reaction with the relevant
isothiocyanide R.sup.14--NCS (R.sup.14=alkyl aryl, heteroaryl)
instead of acyl halide R.sup.12C(O)Y.sup.2 leads to oxazole
derivatives (LIX) where R.sup.12.dbd.NHR.sup.14 (Dhar et al.
Bioorg. Med. Chem. Lett. 2002, 12, 3305).
[0160] An alternative cyclization (Doyle and Moody Synthesis 1994,
1021) utilizes diazoketone (LXI), nitrile R.sup.12CN and
Rh.sub.2(NHCOCF.sub.3).sub.4 as catalyst.
##STR00049##
[0161] Diazoketones (LXI) can be synthesized from the relevant
methyl ketones (XLIII) (Moody et al. J. Chem. Soc., Perkin Trans. 1
1997, 2413).
[0162] The oxazole ring may also be formed by oxidative cyclization
as demonstrated by Oikawa et al. (Heterocycles 1979, 12, 1457).
##STR00050##
[0163] Derivative (LXIII) can be prepared from 7-azatryptophan
(commercially available) following the approach presented for
tryptophan by Nishida et al. (Tetrahedron Lett. 1998, 39,
5983).
[0164] The TOSMIC methodology offers a convenient way to convert
aldehyde (XLIX) into oxazole (LIX) (R.sup.12.dbd.H) using
tosylmethyl isocyanide MeC.sub.6H.sub.4SO.sub.2CH.sub.2NC
(commercially available) and base such as MeONa (Haubmann et al.
Bioorg. Med. Chem. Lett. 1999, 9, 3143) or DBU (Dhar et al. Bioorg.
Med. Chem. Lett. 2002, 12, 3305).
##STR00051##
[0165] Another method utilizing reactivity of the isocyanide group
is based on the Schollkopf reaction of ester (LXV) (preparation of
analogous esters was disclosed in WO2003082868) with LiCH.sub.2NC
by analogy to the synthesis by Vedejs and Barda (Org. Lett. 2000,
2, 1033) of oxazoles linked to the indole system.
##STR00052##
[0166] The isocyanide (LXIV) may undergo spontaneous cyclization to
afford (LIX) (R.sup.12.dbd.H). In some cases this process may need
to be catalyzed by mild acid such as pyridinium
toluenesulfonate.
Method 19
Isoxazole
[0167] Isoxazole derivatives (LXVI) are available by condensation
of unsaturated ketone (XLVIII) with hydroxylamine, following the
method used by Roeder and Pigulla (Arch Pharm (Weinheim, Ger) 1978,
311, 817) for an analogous indole system.
##STR00053##
[0168] The regioisomeric isoxazole (LXVII) can be made by
condensation of salt (LXVIII) with hydroxylamine according to the
method of Hasan et al. (J. Prakt. Chem. 1990, 332, 666).
##STR00054##
[0169] Disubstituted isoxazoles (LXIX) can be synthesized following
the method by Kidwai and Sapra (Org. Prep. Proced. Int. 2001, 33,
381) using aldehyde (XLIX) as starting material.
##STR00055##
[0170] The remaining isoxazole regioisomer (LXX) is available from
the relevant oxime (LXXI) by halogenation followed by the reaction
with alkyne R.sup.12--C.ident.CH(R.sup.12=alkyl, aryl). Suitable
halogenating agents include NBS (Baruah, et al. Heterocycles 1988,
27, 1127) and NaOCl (Jedlovska et al. Collect. Czech. Chem. Commun.
1990, 55, 2481). Oxime (LXXI) can be prepared in standard way from
the corresponding aldehyde (XLIX).
##STR00056##
[0171] The reaction between and halogenated oxime occurs in the
presence of base such as Et.sub.3N.
[0172] Propargyloxime (LXXIII) (R.sup.14=alkyl, aryl) [available
from .alpha.-haloketone (XLI) following conventional methods, e.g.
Cory et al. Helv. Chim. Acta 1977, 60, 2294; Ben-Basset et al. J.
Med. Chem. 1976, 19, 928; Hassner and Alexanian J. Org. Chem. 1079,
44, 3861] can be cyclized under mild basic conditions to afford
isoxazole (LXXII) (Short and Ziegler Tetrahedron Lett. 1993, 34,
75).
##STR00057##
[0173] Isoxazole (LXX) (R.sup.12.dbd.H) can be synthesized from
ketone (LXXIV) and hydroxylamine (Spry and Bhala Heterocycles 1986,
24, 1799).
##STR00058##
[0174] Similarly, monosubstituted isoxazole (LXXV) is available
from ketone (LXXVI), which can be prepared from methylketone
(XLIII) (El-Taweel and Elnagdi J. Heterocycl. Chem. 2001, 38,
981).
##STR00059##
Method 20
Thiazole
[0175] Methods for synthesis of thiazoles are analogous to those
used for oxazoles (cf Method 18). Thus, thiazole (LXXVII) is
available by condensation of thioamide (LXXVIII) with
.alpha.-haloketone (LIV) (Schwarz Org. Synth. 1955, III, 332; Gu et
al. Bioorg. Med. Chem. Lett. 1999, 9, 569).
##STR00060##
[0176] In order to prepare differently substituted thiazole
(LXXIX), aldehyde (LXXX) may be applied (Thompson et al. Bioorg.
Med. Chem. Lett. 1994, 4, 2441). Alkylcarbonyl groups R.sup.14C(O)
can be installed .alpha. to the sulphur atom by converting
thioamide (LXXVIII) into amidine (LXXXI) followed by reaction with
.alpha.-haloketone R.sup.14C(O)CH.sub.2Y.sup.1 (Thompson et al.
Bioorg. Med. Chem. Lett. 1994, 4, 2441). Thioamide (LXXVIII) used
in these reactions can be readily prepared from amide (LV) using
methods known in the art, such as acting on (LV) with the
Lawesson's reagent. Alternatively, it can be formed from nitrile
(XXXV) and H.sub.2S under basic conditions (Bhattacharya et al. J.
Chem. Soc., Perkin Trans. I 1995, 1543; Krawczyk et al. J. Med.
Chem. 1995, 38, 4115), nitrile (XXXV) and thioacetamide under
acidic conditions (Gu et al. Bioorg. Med. Chem. Lett. 1999, 9,
569), nitrile (XXXV) and sodium hydrogen sulfide and magnesium
chloride in dimethylformamide (DMF) (Manaka and Sato Synth. Commun.
2005, 35, 761), or nitrile (XXXV) and the (Me.sub.3Si).sub.2S/MeONa
system (Lin et al. Synthesis 1992, 1219; Qiao et al. Org. Lett.
2001, 3, 3655).
[0177] Isomeric thiazole (LXXXIII) can be synthesized from
.alpha.-haloketone (XLI) (Y.sup.1.dbd.Cl, Zawistoski J. Heterocycl.
Chem. 1990, 27, 519; Y.sup.1=Br, Di Fabio and Pentassuglia Synth.
Commun. 1998, 28, 51).
##STR00061##
[0178] Reaction works for R.sup.12.dbd.NH.sub.2 (Hayashi et al.
Heterocycles 1999, 51, 1233; Bansal et al. Indian J. Chem., Sect.
B: Org. Chem. Incl. Med. Chem. 2000, 39, 357), R.sup.12.dbd.NH-Aryl
(Di Fabio and Pentassuglia Synth. Commun. 1998, 28, 51)
R.sup.12=(substituted)alkyl (Zawistoski J. Heterocycl. Chem. 1990,
27, 519) and R.sup.12=aryl (Baldwin et al. J. Org. Chem. 2001, 66,
2588). Opposite regiochemistry of this reaction (Y.sup.1.dbd.Cl,
R.sup.12=Me, NH.sub.2) to produce (LXXXIV) has also been suggested
(Arya et al. Indian J. Chem., Sect. B 1977, 15, 473).
##STR00062##
[0179] Based on the precedent in the indole series (Saleh
Nucleosides, Nucleotides Nucleic Acids 2002, 21, 401), thiazole
(LXXXV) is available from isothiocyanate
R.sup.14NCS(R.sup.14=alkyl, heterocyclyl) and .alpha.-aminoketone
(LXXXVI), which in turn can be prepared by reduction of azide (LX)
under acidic conditions (Jiang and Gu Heterocycles 2000, 53,
1559).
##STR00063##
Method 21
Triazole
[0180] Triazoles (LXXXVII) (R.sup.12.dbd.H, alkyl, aryl,
heteroaryl) are available from the relevant imidate (XXXVI) (see
Method 16) and hydrazide (LXXXVIII) (Kelarev et al. Khim.
Geterotsikl. Soedin. 1993, 189).
##STR00064##
[0181] This reaction is carried out in the presence of tertiary
amine such as Et.sub.3N. The reacting functionalities can also be
reversed as shown below:
##STR00065##
[0182] The reaction tolerates a wide range of functionalities
incorporated into imidate (XC) (Y.dbd.O): R.sup.12=(hetero)aryl
(Omodei-Sale et al. J. Med. Chem. 1983, 26, 1187),
R.sup.12.dbd.COOEt (McKillop et al. Tetrahedron Lett. 1982, 23,
3357), and R.sup.12=alkyl (Hunter and Neilson J. Chem. Soc. Perkin
Trans. 1: Org. Bio-Org. Chem. 1988, 1439).
[0183] The required hydrazide (LXXXIX) can be prepared from the
relevant ester (LXV) (G=H, protecting group) by acting with
hydrazine. Alternatively, hydrazine derivative such as
BOC--NHNH.sub.2 or PhCH.sub.2OC(O)NHNH.sub.2 is coupled with acid
(LVII) (G=H, protection) under usual conditions for amide bond
formation. The BOC and PhCH.sub.2OC(O) protections can then be
removed under appropriate conditions such as TFA/i-Pr.sub.3SiH and
H.sub.2/Pd--C, respectively.
[0184] An alternative way to convert hydrazide (LXXXIX) into
(LXXXVII) involves three component condensation reaction of
(LXXXIX), thioimidate (XC) (Y.dbd.S), and ammonium acetate on the
surface of silica gel under microwave irradiation as shown below
(Rostamizadeh et al. Synth. Commun. 2003, 33, 113).
##STR00066##
[0185] Hydrazide (LXXXIX) can also be reacted with thioamide
R.sup.12C(S)NH.sub.2 to afford triazole (LXXXVII) (Dumaitre and
Dodic Eur. Pat. Appl. 1995, EP 636626).
##STR00067##
[0186] Preparation of a compound where R.sup.12.dbd.H is achieved
by the reversal of the functionalities as shown below, and using
thioamide (LXXVIII) (G=H) (Vanek et al. Collect. Czech. Chem.
Commun. 1984, 49, 2492).
##STR00068##
[0187] N-Substituted triazole (XCI) is available in three steps
from hydrazide (LXXXIX) following the method developed by Gautun
and Carlsen (Molecules 2001, 6, 969).
##STR00069##
[0188] In the last step alcoholic solution of ammonia
(R.sup.14.dbd.H) or a primary aliphatic amine R.sup.14NH.sub.2 can
be used.
[0189] A variety of heteroatom-substituted triazoles (XCII) are
available by condensation of imides (XCIII) with hydrazine.
##STR00070##
[0190] Thus, R.sup.15.dbd.OR.sup.13 (R.sup.13=alkyl; Whitfield and
Papadopoulos Synthesis 1985, 423), R.sup.15=amino (Whitfield and
Papadopoulos J. Heterocyclic Chem. 1981, 18, 1197),
R.sup.15.dbd.NC(S)-- (Saczewski and Foks Synthesis 1986, 751),
R.sup.15.dbd.NH-aryl (Okajima and Okada J. Heterocyclic Chem. 1991,
28, 177). Imides (XCIV) can readily be prepared from the relevant
acids (LVII) by sequential formation of acid isothiocyanate (XCIV)
and subsequent reaction with alcohol, amine or amide (Whitfield and
Papadopoulos Synthesis 1985, 423). A modification of this method
(R.sup.15=amino) using S-methyl derivative (XCV) has recently been
described by Chen et al. (Bioorg. Med. Chem. Lett. 2001, 11,
3165).
##STR00071##
[0191] Substituted triazoles (LXXXVIII) (R.sup.12.dbd.H, alkyl) can
be prepared from amide (LV) (Speake et al. Bioorg. Med. Chem. Lett.
2003, 13, 1183).
##STR00072##
[0192] Triazoles are also available by ring interconversion from
oxadiazole (XCVII) (Buscemi et al J. Org. Chem. 2003, 68,
605-608)
##STR00073##
[0193] Additional methods to create heteroatom-substituted
triazoles have been described by Akbarzadeh et al. (Bioorg. Med.
Chem. 2003, 11, 769),
Method 22
Oxadiazole
[0194] Oxadiazoles (XCVIII) (R.sup.12.dbd.H, alkyl, aryl,
heteroaryl) can be prepared from nitrile (XCIX) (available using
methods disclosed in WO2004101565) following the protocol used for
the analogous indole system by Swain et al. (J. Med. Chem. 1991,
34, 140).
##STR00074##
[0195] Nitrile (XCIX) is first converted into amide oxime (C), salt
of which is then reacted with ester R.sup.12COOR.sup.11. The last
step may alternatively involve acid anhydride (R.sup.12CO).sub.2O,
mixed anhydride, acid chloride R.sup.12COCl or imidate
R.sup.12C(.dbd.NH)OR.sup.11 (Shvekhgeimer et al. Khim. Geterotsikl.
Soedin. 1984, 1609).
[0196] Oxime (LXXI) may also serve as a substrate to prepare
oxadiazole (XCVIII) (Corsaro et al. J. Chem. Res. Synop. 1989,
246).
##STR00075##
[0197] Chlorination to produce (CI) can be carried out using
Cl.sub.2 (Rajagopalan and Advani J. Org. Chem. 1965, 30, 3369),
NaNO.sub.2/HCl (Kocevar et al. Synth. Commun. 1988, 18, 1427),
N-chlorosuccinimide (Bedford et al. J. Med. Chem. 1986, 29, 2174),
t-BuOCl (Peake and Strickland Synth. Commun. 1986, 16, 763), and
NOCl (Iwakura et al. Bull. Chem. Soc. Jpn. 1968, 41, 2954).
[0198] Reversal of functionalities in the approaches presented
above allows synthesis of regiosiomeric oxadiazole (CII), as shown
below.
##STR00076##
[0199] Usually, pyridine is used as base. Isoxazole regioisomer
(XCVII) can be synthesized from hydrazone (LXXXIX) and imidate (XC)
(Y.dbd.O) (Kelarev et al Chem. Heterocycl Comp. (New York) 2000,
36, 207).
##STR00077##
[0200] Instead of imidate (XC) (Y.dbd.O), the relevant acid
anhydride, amide (Kovalenko et al. Molecules 2000, 5, 1146) or acid
followed by treatment with POCl.sub.3 can be used (Monge Vega et
al. Bol. Soc. Quim. Peru 1983, 49, 120). Alternatively,
orthoformate R.sup.12C(OR.sup.11).sub.3 may be applied
(R.sup.12.dbd.H; Hiremath et al. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1980, 19B, 1031).
[0201] Similarly, after reversal of reacting functionalities
isoxazole regioisomer (XCVII) can be formed from imidate (XXXVI)
and hydrazone (LXXXVIII) (Reynaud et al. J. HeterocycL Chem. 1992,
29, 991; Swain et al. J. Med. Chem. 1991, 34, 140).
##STR00078##
Method 23
Pyrimidine
[0202] Pyrimidine (CIII) can be obtained from ketone (LXXVI) and
imidate (XC) (R.sup.11Y.dbd.R.sup.12.dbd.NH.sub.2; Molina et al.
Tetrahedron Lett. 2002, 43, 1005).
##STR00079##
[0203] Instead of ketone (LXXVI), ketone (CIV) can be used
(R.sup.11Y.dbd.H.sub.2N, R.sup.12=aryl, S-alkyl; Taboada et al. J.
Carbohyd. Chem. 2004, 23, 325). It is prepared by oxidation of
alcohol (CV) (preparation of analogous systems was disclosed in
WO2004101565).
##STR00080##
[0204] Pyrimidine regioisomer (CV1) is available by modification of
the methods presented above. Thus, imidate (CVII) treated with
.alpha.,.beta.-unsaturated ketone (CVIII) in the presence of base
affords pyrimidine (CVI) (R.sup.14.dbd.NHC(O)Ph; Bratusek et al
ARKIVOC 2003, 5, 77, R.sup.12=heterocycle; El-Taweel et al. J.
Heterocycl. Chem. 2001, 38, 981).
##STR00081##
[0205] Use of highly functionalized ketone (CVIII) allows
preparation of variously substituted pyrimidine derivatives
(Westman and Lundin Synthesis 2003, 1025; Chhabria and Shishoo
Heterocycles 1999, 51, 2723).
Method 24
Rings Linked Via Nitrogen
[0206] Heteroaromatic rings can also be attached to the C(3) carbon
of 7-azaindole system via endocyclic nitrogen atom using C--N
couplings.
##STR00082##
[0207] Thus, (CIX) containing the pyrazolyl group can be prepared
using (CX)=pyrazol or imidazole, Y=I and CuI as well as
trans-N,N'-dimethylcyclohexanediamine as catalyst (Enguehard et al.
J. Org. Chem. 2003, 68, 5614). Different set of conditions
(Y.dbd.Br, Cu.sub.2O and salicylaldoxime as catalyst) was proposed
by Cristau et al. Eur. J. Org. Chem. 2004, 695).
Synthetic Methods for Synthesis of Compounds of the Invention
[0208] Synthesis of Example Inhibitors 8 and 9
##STR00083##
5-Phenylsulfanyl-1H-pyrrolo[2,3-b]pyridine (2)
##STR00084##
[0210] A mixture of 5-bromo-7-azaindole (1) (0.5 g, 2.54 mmol;
preparation disclosed in WO2004/078757), benzenethiol (274 .mu.L,
2.66 mmol), sodium t-butoxide (488 mg, 5.07 mmol) and
Pd(PPh.sub.3).sub.4 (235 mg, 0.20 mmol) in EtOH (25 mL) was heated
at reflux for 19 h. More benzenethiol (274 .mu.L, 2.66 mmol),
sodium t-butoxide (488 mg, 5.07 mmol) and Pd(PPh.sub.3).sub.4 (235
mg, 0.20 mmol) were added and reflux continued for a further 24 h.
The reaction mixture was filtered, concentrated, and the residue
was extracted with CH.sub.2Cl.sub.2:hexane=1:1 (v/v). The extract
was concentrated and purified by preparative LCMS (column LUNA
10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-acetonitrile
(0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 2 as
a white solid (142 mg, 25%); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 6.53 (dd, J=3.5, 2.0 Hz, 1H), 7.10-7.30 (m, 5H), 7.41 (dd,
J=5.9, 2.5 Hz, 1H), 8.16 (dd, J=2.0, 0.6 Hz, 1H), 8.48 (d, J=2.0
Hz, 1H), 10.00-10.20 (bs, NH).
3-Iodo-5-phenylsulfanyl-1H-pyrrolo[2,3-b]pyridine (3)
##STR00085##
[0212] To a solution of 2 (135 mg, 0.60 mmol) in DMF (1.5 mL) was
added solid KOH (124 mg, 2.21 mmol) and the reaction mixture
stirred for 20 min. Iodine (167 mg, 0.66 mmol) was then added and
the stirring continued for 40 min. A mixture of water (8.8 mL) and
sat. aq. Na.sub.2S.sub.2O.sub.3 (1.3 mL) was added rapidly, and the
resulting solid filtered off, washed with water (2.times.) and
dried in vacuum to give iodide 3 as a creamy solid (205 mg, 98%);
.sup.1H NMR (400 MHz, CDCl.sub.3+2 drops CD.sub.3OD) .delta.
7.10-7.30 (m, 5H), 7.45 (s, 1H), 7.94 (d, J=2.0 Hz, 1H), 8.35 (d,
J=1.9 Hz, 1H).
1-Benzenesulfonyl-3-iodo-5-phenylsulfanyl-1H-pyrrolo[2,3-b]pyridine
(4)
##STR00086##
[0214] A mixture of 3 (200 mg, 0.57 mmol), benzenesulfonyl chloride
(109 .mu.L, 0.85 mmol), n-BuNHSO.sub.4 (25 mg, 0.074 mmol) and 50%
aqueous NaOH (108 .mu.L) in CH.sub.2Cl.sub.2 (3.5 mL) were stirred
for 0.5 h. The mixture was partitioned between sat. aq.
NaHCO.sub.3/CH.sub.2Cl.sub.2. The organic layer was separated and
the aqueous phase extracted with CH.sub.2Cl.sub.2. The combined
organic solutions were dried (MgSO.sub.4) and concentrated to give
4 as an orange oil (336 mg, 120%).
1-Benzenesulfonyl-5-phenylsulfanyl-3-(1-trityl-1H-pyrazol-4-yl)-1H-pyrrolo-
[2,3-b]pyridine (6)
##STR00087##
[0216] A mixture of iodide 4 (280 mg, 0.57 mmol), boronic acid 5
(302 mg, 0.85 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (39.9 mg, 0.057
mmol), LiCl (72.3 mg, 1.71 mmol), 1.0 M aq. Na.sub.2CO.sub.3 (1.4
mL, 1.4 mmol), EtOH (2.7 mL) and toluene (2.7 mL) were heated at
reflux for 0.5 h. The mixture was cooled, partitioned between
brine/AcOEt, the layers separated and the aqueous phase extracted
with more AcOEt (3.times.), dried (MgSO.sub.4) and concentrated.
The residue was separated by means of silicagel chromatography
(SGC) using AcOEt:hexane as eluent in gradient up to 85:15 (v/v) to
give 6 as a light orange foam (353 mg, 92%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.10-7.40 (m, 20H), 7.49 (t, J=8.1 Hz, 2H),
7.59 (m, 2H), 7.75 (s, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.89 (d, J=2.1
Hz, 1H), 8.19 (m, 2H), 8.46 (d, J=2.0 Hz, 1H).
1-Benzenesulfonyl-5-phenylsulfanyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]py-
ridine (7)
##STR00088##
[0218] A mixture of 6 (346 mg, 0.51 mmol), CH.sub.2Cl.sub.2 (4.4
mL), CF.sub.3COOH (410 .mu.L), H.sub.2O (41 .mu.L) and
i-Pr.sub.3SiH (207 .mu.L) were stirred for 0.5 h then added
dropwise to a stirred mixture of CH.sub.2Cl.sub.2/sat. aq.
NaHCO.sub.3. The layers were separated and the aqueous phase
extracted with more CH.sub.2Cl.sub.2 (3.times.), dried (MgSO.sub.4)
and concentrated. The residue was separated by means of silicagel
chromatography (SGC) using AcOEt:hexane as eluent in gradient up to
65:35 (v/v) to give 7 as a white solid (160 mg, 72%); .sup.1H NMR
(400 MHz, CDCl.sub.3+6 drops CD.sub.3OD) .delta. 7.10-7.28 (m, 5H),
7.47 (t, J=7.7 Hz, 2H), 7.56 (t, J=7.5 Hz, 1H), 7.75 (s, 2H), 7.78
(s, 1H), 8.01 (d, J=2.1 Hz, 1H), 8.13 (d, J=1.4 Hz, 1H), 8.16 (s,
1H), 8.42 (d, J=2.0 Hz, 1H).
5-Phenylsulfanyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(8)
##STR00089##
[0220] A mixture of 7 (130 mg, 0.30 mmol) and 10% aq. sodium
hydroxide (2.8 mL) in EtOH (5.8 mL) were heated at 90.degree. C.
for 1 h. The solution was cooled, partitioned between
CH.sub.2Cl.sub.2/brine, the layers separated and the aqueous phase
extracted with more CH.sub.2Cl.sub.2 (3.times.). The combined
organic extracts were dried (MgSO.sub.4), concentrated and the
residue purified by preparative LCMS (column LUNA 10.mu. C18(2)
00G-4253-V0 250.times.50 mm) using water-acetonitrile (0.1% ACOH)
as eluent (in gradient; flow 80 mL/min) to give 8 as a white solid
(52 mg, 59%); .sup.1H NMR (400 MHz, CDCl.sub.3+6 drops CD.sub.3OD)
.delta. 7.13 (m, 3H), 7.22 (m, 2H), 7.47 (s, 1H), 7.80 (s, 2H),
8.27 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H).
5-Benzenesulfinyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(9)
##STR00090##
[0222] A mixture of sulfide 8 (20 mg, 0.068 mmol) and 30% aqueous
H.sub.2O.sub.2 (10.5 .mu.L, 0.103 mmol) in glacial acetic acid (224
.mu.L) was stirred for 72 h then purified by preparative LCMS
(column LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using
water-acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80
mL/min) to give sulfoxide 9 as a white solid (13.6 mg, 64%);
.sup.1H NMR (400 MHz, CDCl.sub.3+6 drops CD.sub.3OD) .delta.
7.35-7.50 (m, 4H), 7.60 (m, 2H), 7.78 (s, 2H), 8.35 (d, J=2.0 Hz,
1H), 8.40 (d, J=2.0 Hz, 1H).
[0223] Synthesis of Example Inhibitors 17, 18 and 19
##STR00091##
1-(tert-Butyl-dimethyl-silanyl)-5-butylsulfanyl-1H-pyrrolo[2,3-b]pyridine
(11)
##STR00092##
[0225] To n-BuLi (13.5 mL, 33.7 mmol, 2.5M in THF) in THF (50 mL),
cooled to -78.degree. C., was added a solution of 10 (5.00 g, 16.1
mmol; preparation disclosed in WO2004/078757) in THF (25 mL)
dropwise. When the addition was complete the reaction mixture was
stirred at -78.degree. C. for 10 min. Solid dry elemental sulfur
(618 mg, 2.41 mmol S.sub.8) was added and stirring continued at
-78.degree. C. for 2 h. Elemental iodine (4.28 g, 16.9 mmol) was
added and the reaction mixture stirred at -78.degree. C. for 1.5 h,
and at room temperature for 1 h. It was then partitioned between
AcOEt/brine, the layers were separated and the aqueous phase
extracted with more AcOEt (2.times.). The combined organic extracts
were dried (MgSO.sub.4) and concentrated to give crude 11 as a
brown oil (5.38 g). This mixture of several compounds was directly
used in the next step.
5-Butylsulfanyl-1H-pyrrolo[2,3-b]pyridine (12)
##STR00093##
[0227] The crude mixture containing 11 (5.38 g) was treated with
MeOH (48 mL) and 10% aq. HCl (97 mL) for 0.5 h. The acid was
neutralised by dropwise addition of sat. aqueous NaHCO.sub.3. The
resulting solid was filtered off, washed with water (3.times.),
dried in vacuum and extracted with CH.sub.2Cl.sub.2. The extracts
were concentrated to afford a dark red oil, which was purified by
SGC with CH.sub.2Cl.sub.2:MeOH as eluent (gradient elution up to
99:1, v/v) to give 12 as a brown oil (1.23 g, 37% over 2 steps);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (t, J=7.3 Hz, 3H),
1.35-1.50 (m, 2H), 1.52-1.65 (m, 2H), 2.87 (t, J=7.4 Hz, 2H), 6.49
(dd, J=3.5, 1.8 Hz, 1H), 7.41 (dd, J=3.4, 2.3 Hz, 1H), 8.10 (d,
J=2.0 Hz, 1H), 8.43 (d, J=2.0 Hz, 1H), 10.90-11.10 (bs, NH).
5-Butylsulfanyl-3-iodo-1H-pyrrolo[2,3-b]pyridine (13)
##STR00094##
[0229] Iodide 13 was synthesized following the method described for
preparation of 3 using: 12 (1.00 g, 4.85 mmol), DMF (12.1 mL), KOH
(897 mg, 16.0 mmol), iodine (1.35 mg, 5.33 mmol). Reaction time: 40
min. Obtained: 13 as tan solid (1.29 g, 80%).
1-Benzenesulfonyl-5-butylsulfanyl-3-iodo-1H-pyrrolo[2,3-b]pyridine
(23)
##STR00095##
[0231] Sulfonamide 14 was synthesized following the method
described for preparation of 4 using: 13 (1.20 g, 3.61 mmol),
PhSO.sub.2Cl (691 .mu.L, 5.42 mmol), n-Bu.sub.4NHSO.sub.4 (159 mg,
0.47 mmol), 50% aq. NaOH (686 .mu.L), CH.sub.2Cl.sub.2 (23 mL).
Reaction time: 0.5 h. Obtained 14 as a red oil (2.24 g, 131%).
1-Benzenesulfonyl-5-butylsulfanyl-3-(1-trityl-1H-pyrazol-4-yl)-1H-pyrrolo[-
2,3-b]pyridine (15)
##STR00096##
[0233] Pyrazole derivative 15 was synthesized following the method
described for preparation of 6 using 14 (2.24 g, 3.62 mmol), 5
(1.92 g, 5.43 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (254 mg, 0.362
mmol), LiCl (460 mg, 10.9 mmol), 1.0 M aq Na.sub.2CO.sub.3 (9.0 mL,
9.05 mmol), in ethanol (17 mL) and toluene (17 mL). Reaction time:
2 h reflux. Extractive workup afforded crude 15 as an orange oil
(3.83 g, 162%), which was used in the next step without
purification.
1-Benzenesulfonyl-5-butylsulfanyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyr-
idine (16)
##STR00097##
[0235] Removal of trityl group leading to 16 was performed by
analogy to the method described for preparation of 7 using 15 (3.80
g, crude), CF.sub.3COOH (2.9 mL), H.sub.2O (288 .mu.L),
i-Pr.sub.3SiH (1.46 mL) in CH.sub.2Cl.sub.2 (31 mL). Reaction time:
40 min. Purification by SGC using CH.sub.2Cl.sub.2:MeOH (gradient
elution up to 98:2, v/v) afforded 16 as brown foam (1.14 g, 76%);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.89 (t, J=7.3 Hz, 3H),
1.41 (sextet, J=7.5 Hz, 2H), 1.58 (quintet, J=7.6 Hz, 2H), 2.89 (t,
J=7.4 Hz, 2H), 7.45-7.75 (m, 3H), 7.82 (s, 1H), 7.89 (s, 2H), 8.02
(d, J=2.1 Hz, 1H), 8.22 (m, 2H), 8.51 (d, J=2.2 Hz, 1H).
5-Butylsulfanyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(17)
##STR00098##
[0237] Inhibitor 17 was synthesized following the method described
for preparation of 8 using 16 (0.50 g, 1.21 mmol), ethanol (23 mL),
10% aq. NaOH (11.2 mL). Reaction time: 1 h at 90.degree. C.
Purification by SGC using CH.sub.2Cl.sub.2:MeOH (gradient elution
up to 97:3, v/v) gave 17 as an orange foam (116 mg, 35%); .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 0.87 (t, J=7.3 Hz, 3H), 1.39
(sextet, J=7.4 Hz, 2H), 1.55 (quintet, J=7.4 Hz, 2H), 2.84 (t,
J=7.4 Hz, 2H), 7.42 (s, 1H), 7.83 (s, 2H), 8.19 (d, J=2.0 Hz, 1H),
8.36 (dd, J=2.0, 0.3 Hz, 1H).
5-(Butane-1-sulfinyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(18) and
5-(Butane-1-sulfonyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(19) (mixture)
##STR00099##
[0239] Oxidation of 17 was performed in a way analogous to that
used for 9 using 17 (20 mg, 0.073 mmol), 30% aqueous H.sub.2O.sub.2
(11.3 .mu.L, 0.11 mmol) and glacial acetic acid (239 .mu.L).
Reaction time: 72 h. Obtained: Sulfoxide 18 as a white solid (7.1
mg, 33%); .sup.1H NMR (400 MHz, CDCl.sub.3+3 drops CD.sub.3OD)
.delta. 0.89 (t, J=7.3 Hz, 3H), 1.35-1.50 (m, 2H), 1.53-1.73 (m,
2H), 2.85 (m, 1H), 2.99 (m, 1H), 7.53 (s, 1H), 7.87 (s, 2H), 8.41
(d, J=2.0 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H).
[0240] Sulfone 19 as a white solid (2.1 mg, 9%); .sup.1H NMR (400
MHz, CDCl.sub.3+6 drops CD.sub.3OD) .delta. 0.84 (t, J=7.3 Hz, 3H),
1.36 (sextet, J=7.4 Hz, 2H), 1.67 (m, 2H), 7.55 (s, 1H), 7.82 (s,
2H), 8.51 (d, J=2.1 Hz, 1H), 8.71 (d, J=2.1 Hz, 1H).
5-(Butane-1-sulfonyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(19)
[0241] Sulfone 19 could be prepared selectively when oxidation of
17 was performed in a way analogous to that used for 9 using 17 (20
mg, 0.073 mmol), 30% aqueous solution of hydrogen peroxide (37.5
.mu.L, 0.37 mmol) and glacial acetic acid (239 .mu.L). After
stirring for 22 h, more 30% aqueous H.sub.2O.sub.2 (37.5 .mu.L,
0.37 mmol) was added and stirring continued for 45 h to give 19 as
a white solid (13 mg, 58%). The .sup.1H NMR spectrum of this
product was identical with that of the product described
earlier.
[0242] An alternative method of synthesis of example inhibitor
8
##STR00100##
1-Benzenesulfonyl-5-bromo-3-(1-trityl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]p-
yridine (21)
##STR00101##
[0244] A mixture of 20 (1.50 g, 2.32 mmol; preparation disclosed in
WO2004/078756) and 10% aq. NaOH (22 mL) in EtOH (45 mL) were heated
at 100.degree. C. for 8 h. The reaction mixture was cooled, poured
onto a mixture of brine (100 mL) and AcOEt (50 mL). The aqueous
layer was extracted with AcOEt (4.times.50 mL), and the combined
organic extracts washed with brine (50 mL), dried (MgSO.sub.4) and
concentrated. The aqueous layer was then extracted with 3% MeOH in
CH.sub.2Cl.sub.2 (3.times.50 mL), and the combined organic extracts
concentrated without drying. The residual solid was washed with 30%
AcOEt in hexane (5.times.) to give 21 as an orange solid (0.96 g,
82%).
5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-3-(1-trityl-1H-pyrazol-4-yl)-1-
H-pyrrolo[2,3-b]pyridine (22)
##STR00102##
[0246] To a solution of 21 (0.5 g, 0.99 mmol) in DMF (2.5 mL) was
added NaH (60% w/w in mineral oil, 59.4 mg, 1.48 mmol) portionwise.
Then the reaction mixture was stirred for 0.5 h. SEM-Cl (263 .mu.L,
1.48 mmol) was then added and the reaction mixture stirred
overnight. It was poured cautiously onto a stirred mixture of ethyl
acetate (20 mL)/sat. aq. NH.sub.4Cl (20 mL) and the layers
separated. The aqueous layer was extracted with AcOEt (2.times.30
mL), the combined organic extracts dried (MgSO.sub.4) and
concentrated. The residue was purified by SGC using AcOEt:hexane
(gradient elution up to 8:92, v/v) to give 22 as a white foam (345
mg, 55%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.002 (9H, s),
0.97 (t, J=8.3 Hz, 2H), 3.58 (t, J=8.3 Hz, 2H), 5.69 (s, 2H), 7.30
(m, 6H), 7.40 (m, 9H), 7.46 (s, 1H), 7.65 (s, 1H), 7.98 (d, J=0.7
Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H).
3-(1-Methyl-1H-pyrazol-4-yl)-5-phenylsulfanyl-1-(2-trimethylsilanyl-ethoxy-
methyl)-1H-pyrrolo[2,3-b]pyridine (23)
##STR00103##
[0248] A mixture of 22 (50 mg, 0.079 mmol), benzenethiol (13.0 mg,
0.118 mmol), copper (I) iodide (3.0 mg, 0.016 mmol),
N,N-dimethylglycine (1.62 mg, 0.016 mmol) and potassium phosphate
(41.8 mg, 0.197 mmol) in DMF (0.5 mL) were heated at 120.degree. C.
for 69 h. The reaction mixture was cooled and partitioned between
AcOEt/brine, the layers separated and the aqueous phase extracted
with more AcOEt (2.times.). The combined organic extracts were
dried (MgSO.sub.4) and concentrated. The resulting crude residue
containing 23 was used for the subsequent deprotection step.
3-(1-Methyl-1H-pyrazol-4-yl)-5-phenylsulfanyl-1H-pyrrolo[2,3-b]pyridine
(8)
##STR00104##
[0250] The crude 23 from the previous reaction was heated at
90.degree. C. in EtOH (0.5 mL) and 10% aq. HCl (0.5 mL) for 3 h 10
min. The reaction mixture was cooled, saturated aqueous NaHCO.sub.3
was added dropwise to neutralize the acid, and the mixture was
extracted with AcOEt (4.times.). The combined organic extracts were
dried (MgSO.sub.4), concentrated and the residue purified by
preparative TLC (PTLC) using 10% MeOH in CH.sub.2Cl.sub.2 as eluent
to give 8 as a white solid (8.9 mg, 39% over 2 steps). .sup.1H NMR
of this compound was identical with 8 synthesised above.
[0251] Synthesis of SEM-Protected Sulfide 26
##STR00105##
3-(1-Methyl-1H-pyrazol-4-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-
-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine
(25)
##STR00106##
[0253] A mixture of 24 (0.5 g, 1.23 mmol; synthesized in analogous
way to 22), bis(pinacolato)diboron (468 mg, 1.84 mmol), AcOK (361
mg, 3.68 mmol) and PdCl.sub.2(dppf).sub.2.CH.sub.2Cl.sub.2 (35.1
mg, 0.043 mmol) in DMF (7.8 mL) were heated at 80.degree. C. for 31
h. It was then cooled, partitioned between AcOEt/brine, the layers
separated and the aqueous phase extracted with more AcOEt
(2.times.). The combined organic extracts were dried (MgSO.sub.4),
concentrated and purified by SGC using hexane:AcOEt (gradient
elution up to 70:30 v/v) to give boronic ester 25 as a light orange
oil (339 mg, 61%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. -0.062
(s, 9H), 0.92 (m, 2H), 1.39 (s, 12H), 3.55 (m, 2H), 4.01 (s, 3H),
5.72 (s, 2H), 7.41 (s, 1H), 7.71 (s, 1H), 7.78 (d, J=0.7 Hz, 1H),
8.45 (d, J=1.5 Hz, 1H), 8.73 (d, J=1.5 Hz, 1H).
3-(1-Methyl-1H-pyrazol-4-yl)-5-propylsulfanyl-1-(2-trimethylsilanyl-ethoxy-
methyl)-1H-pyrrolo[2,3-b]pyridine (26)
##STR00107##
[0255] A mixture of 25 (60 mg, 0.132 mmol), n-propanethiol (21.1
mg, 0.264 mmol), copper (II) acetate (36 mg, 0.198 mmol), pyridine
(32 .mu.L, 0.396 mmol) and 4A molecular sieves (50 mg) in DMF (1.5
mL) were heated at 110.degree. C. for 25 h. More n-propanethiol
(21.1 mg, 0.264 mmol), copper (II) acetate (36 mg, 0.198 mmol) and
pyridine (32 .mu.L, 0.396 mmol) were added and heating continued
for 20.5 h. More n-propanethiol (21.1 mg, 0.264 mmol), copper (II)
acetate (36 mg, 0.198 mmol), pyridine (32 .mu.L, 0.396 mmol) and 4A
sieves were added again and the heating continued at 130.degree. C.
overnight. The reaction mixture was cooled, diluted with AcOEt,
filtered and washed with brine. The aqueous layer was extracted
with AcOEt (2.times.), and the combined organic extracts dried
(MgSO.sub.4) and concentrated. The residue was purified by
preparative LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water--acetonitrile (0.1% AcOH) as eluent
(in gradient; flow 80 mL/min) to give 26 as an orange oil (6.7 mg,
13%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. -0.056 (s, 9H),
0.93 (t, J=8.3 Hz, 2H), 1.00 (t, J=7.3 Hz, 3H), 1.61 (sextet, J=7.4
Hz, 2H), 2.84 (t, J=7.3 Hz, 2H), 3.57 (t, J=8.3 Hz, 2H), 4.00 (s,
3H), 5.68 (s, 2H), 7.43 (s, 1H), 7.64 (s, 1H), 7.76 (s, 1H), 8.15
(d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H).
[0256] Synthesis of Example Inhibitors 29a-29f
##STR00108##
3-(1-Methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrro-
lo[2,3-b]pyridin-5-ol (27)
##STR00109##
[0258] A mixture of 25 (1.00 g, 2.20 mmol), glacial acetic acid
(5.0 mL), H.sub.2O (5.0 mL) and 30% aq. H.sub.2O.sub.2 (370 .mu.L,
3.30 mmol) were stirred for 8 h and partitioned between
AcOEt/brine. The layers were separated, the aqueous phase extracted
with more AcOEt and the combined organic extracts dried
(MgSO.sub.4) and concentrated to give 27 as a creamy white solid
(731 mg, 96%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. -0.058 (s,
9H), 0.92 (t, J=8.3 Hz, 2H), 3.58 (t, J=8.3 Hz, 2H), 4.01 (s, 3H),
2.01 (s, 2H), 7.37 (s, 1H), 7.56 (s, 1H), 7.66 (d, J=2.3 Hz, 1H),
7.95 (s, 1H), 8.17 (d, J=2.2 Hz, 1H), 9.00-9.60 (bs, OH).
[0259] Synthesis of Ethers 28a-28f
##STR00110##
3-(1-Methyl-1H-pyrazol-4-yl)-5-phenoxy-1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-pyrrolo[2,3-b]pyridine (28a)
[0260] General procedure: A mixture of 27 (50 mg, 0.145 mmol),
phenylboronic acid (35.6 mg, 0.29 mmol), copper (II) acetate (26.4
mg, 0.145 mmol), Et.sub.3N (102 .mu.L, 0.726 mmol) and activated 4A
molecular sieves in CH.sub.2Cl.sub.2 (1.5 mL) were stirred for 65
h. The reaction mixture was filtered and the filtrate concentrated.
The residue was purified by PTLC using AcOEt:hexane=60:40 (v/v) as
eluent to give 28a as a clear oil (34 mg, 56%); .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. -0.0373 (s, 9H), 0.95 (t, J=8.3 Hz, 2H),
3.60 (t, J=8.3 Hz, 2H), 3.95 (s, 3H), 5.69 (s, 2H), 6.98 (d, J=7.9
Hz, 2H), 7.07 (t, J=7.4 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.48 (s,
1H), 7.57 (s, 1H), 7.71 (s, 1H), 7.73 (d, J=2.5 Hz, 1H), 8.23 (d,
J=2.5 Hz, 1H).
3-(1-Methyl-1H-pyrazol-4-yl)-5-o-tolyloxy-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1H-pyrrolo[2,3-b]pyridine (28b)
[0261] According to the general procedure using: 27 (50 mg, 0.145
mmol), ortho-methylphenylboronic acid (39 mg, 0.29 mmol), copper
(II) acetate (26.4 mg, 0.145 mmol), Et.sub.3N (102 .mu.L, 0.726
mmol) and activated 4A molecular sieves in CH.sub.2Cl.sub.2 (1.5
mL) were stirred for 47 h. The crude 28b was used for preparation
of 29b.
3-(1-Methyl-1H-pyrazol-4-yl)-5-m-tolyloxy-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1H-pyrrolo[2,3-b]pyridine (28c)
[0262] According to the general procedure using: 27 (50 mg, 0.145
mmol), meta-methylphenylboronic acid (39 mg, 0.29 mmol), copper
(II) acetate (26.4 mg, 0.145 mmol), Et.sub.3N (102 .mu.L, 0.726
mmol) and activated 4A molecular sieves in CH.sub.2Cl.sub.2 (1.5
mL) were stirred for 47 h. The crude 28c was used for preparation
of 29c.
3-(1-Methyl-1H-pyrazol-4-yl)-5-p-tolyloxy-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1H-pyrrolo[2,3-b]pyridine (28d)
[0263] According to the general procedure using: 27 (50 mg, 0.145
mmol), para-methylphenylboronic acid (39 mg, 0.29 mmol), copper
(II) acetate (26.4 mg, 0.145 mmol), Et.sub.3N (102 .mu.L, 0.726
mmol) and activated 4A molecular sieves in CH.sub.2Cl.sub.2 (1.5
mL) were stirred for 47 h. The crude 28d was used for preparation
of 29d.
5-(4-Fluoro-phenoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-et-
hoxymethyl)-1H-pyrrolo[2,3-b]pyridine (28e)
[0264] According to the general procedure using: 27 (50 mg, 0.145
mmol),para-fluorophenylboronic acid (40.6 mg, 0.29 mmol), copper
(II) acetate (26.4 mg, 0.145 mmol), Et.sub.3N (102 .mu.L, 0.726
mmol) and activated 4A molecular sieves in CH.sub.2Cl.sub.2 (1.5
mL) were stirred for 17 h. The crude 28e was used for preparation
of 29e.
Dimethyl-{4-[3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy]-phenyl}-amine (28f)
[0265] According to the general procedure using: 27 (50 mg, 0.145
mmol),para-(dimethylamino)phenylboronic acid (47.9 mg, 0.29 mmol),
copper (II) acetate (26.4 mg, 0.145 mmol), Et.sub.3N (102 .mu.L,
0.726 mmol) and activated 4A molecular sieves in CH.sub.2Cl.sub.2
(1.5 mL) were stirred for 18 h. The crude 28f was used for
preparation of 29f.
[0266] Synthesis of Inhibitors 29a-29f
##STR00111##
3-(1-Methyl-1H-pyrazol-4-yl)-5-phenoxy-1H-pyrrolo[2,3-b]pyridine
(29a)
[0267] Following the method used for conversion of 23 into 8,
synthesis of 29a was carried out using: 28a (33 mg, 78 .mu.mol),
EtOH (1.0 mL) and 10% aq. HCl (1.0 mL) with heating at 90.degree.
C. for 17 h. Isolation by PTLC using CH.sub.2Cl.sub.2:MeOH=19:1
(v/v) as eluent gave 29a as a white solid (17.2 mg, 75%); .sup.1H
NMR (400 MHz, CDCl.sub.3+2 drops CD.sub.3OD) .delta. 3.93 (s, 3H),
6.96 (m, 2H), 7.06 (m, 1H), 7.31 (m, 2H), 7.45 (s, 1H), 7.58 (s,
1H), 7.68 (s, 1H), 7.77 (d, J=2.5 Hz, 1H), 8.12 (d, J=2.5 Hz,
1H).
3-(1-Methyl-1H-pyrazol-4-yl)-5-o-tolyloxy-1H-pyrrolo[2,3-b]pyridine
(29b)
[0268] Following the method used for conversion of 23 into 8,
synthesis of 29b was carried out using: 28b (crude), EtOH (1.0 mL)
and 10% aq. HCl (1.0 mL) with heating at 90.degree. C. for 16 h.
Isolation by PTLC using AcOEt as eluent gave 29b as a white solid
(15 mg, 34%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.39 (s,
3H), 3.96 (s, 3H), 6.78 (d, J=6.78 Hz, 1H), 7.03 (t, J=7.1 Hz, 1H),
7.13 (t, J=7.0 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.47 (d, J=2.3 Hz,
1H), 7.57 (s, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.71 (s, 1H), 8.20 (d,
J=2.4 Hz, 1H), 10.50 (bs, NH).
3-(1-Methyl-1H-pyrazol-4-yl)-5-m-tolyloxy-1H-pyrrolo[2,3-b]pyridine
(29c)
[0269] Following the method used for conversion of 23 into 8,
synthesis of 29c was carried out using: (crude), EtOH (1.0 mL) and
10% aq. HCl (1.0 mL) with heating at 90.degree. C. for 16 h.
Isolation by PTLC using AcOEt as eluent gave 29c as a white solid
(15 mg, 34%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.33 (s,
3H), 3.97 (s, 3H), 6.80 (m, 2H), 6.90 (d, J=7.5 Hz, 1H), 7.21 (t,
J=8.1 Hz, 1H), 7.50 (d, J=2.2 Hz, 1H), 7.59 (s, 1H), 7.73 (s, 1H),
7.80 (d, J=2.2 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H), 10.63 (bs, NH).
3-(1-Methyl-1H-pyrazol-4-yl)-5-p-tolyloxy-1H-pyrrolo[2,3-b]pyridine
(29d)
[0270] Following the method used for conversion of 23 into 8,
synthesis of 29d was carried out using: 28d (crude), EtOH (1.0 mL)
and 10% aq. HCl (1.0 mL) with heating at 90.degree. C. for 16 h.
Isolation by PTLC using AcOEt as eluent gave 29d as a white solid
(18.1 mg, 41%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.34 (s,
3H), 3.96 (s, 3H), 6.91 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H),
7.48 (d, J=2.4 Hz, 1H), 7.56 (s, 1H), 7.71 (s, 1H), 7.77 (d, J=2.4
Hz, 1H), 8.23 (d, J=2.5 Hz, 1H), 10.62 (bs, NH).
5-(4-Fluoro-phenoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-
e (29e)
[0271] Following the method used for conversion of 23 into 8,
synthesis of 29e was carried out using: 28e (crude), EtOH (1.0 mL)
and 10% aq. HCl (1.0 mL) with heating at 90.degree. C. for 17 h.
Isolation by PTLC using AcOEt as eluent gave 29e as a white solid
(18 mg, 40%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.97 (s,
3H), 6.50-7.10 (m, 4H), 7.49 (d, J=2.4 Hz, 1H), 7.57 (s, 1H), 7.72
(s, 1H), 7.75 (d, J=2.4 Hz, 1H), 8.21 (d, J=2.4 Hz, 1H), 10.62 (bs,
NH).
Dimethyl-{4-[3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy-
]-phenyl}-amine (29f)
[0272] Following the method used for conversion of 23 into 8,
synthesis of 29f was carried out using: 28f (crude), EtOH (1.0 mL)
and 10% aq. HCl (1.0 mL) with heating at 90.degree. C. for 20 h.
Isolation by PTLC using AcOEt as eluent gave 29f as a white solid
(10.1 mg, 58%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.93 (s,
6H), 3.96 (s, 3H), 6.74 (m, 2H), 6.97 (m, 2H), 7.43 (d, J=2.5 Hz,
1H), 7.56 (d, J=0.3 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.70 (d, J=0.7
Hz, 1H), 8.20 (d, J=2.5 Hz, 1H), 9.99 (bs, NH).
[0273] Synthesis of Inhibitors 29g-29t
##STR00112##
5-Benzyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymeth-
yl)-1H-pyrrolo[2,3-b]pyridine (28g)
[0274] General procedure: A mixture of 27 (60 mg, 0.174 mmol),
benzyl bromide (124 .mu.L, 1.05 mmol), K.sub.2CO.sub.3 (241 mg,
1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in acetone (4.0
mL) were heated at reflux for 22.5 h. The reaction mixture was
cooled, filtered and the filtrate concentrated. The residue was
purified by PTLC using AcOEt:hexane=6:4 (v/v) as eluent to give 28g
as a light orange oil (24.3 mg, 32%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. -0.054 (s, 9H), 0.93 (t, J=8.3 Hz, 2H), 3.56
(t, J=8.3 Hz, 2H), 3.99 (s, 3H), 5.16 (s, 2H), 5.65 (s, 2H),
7.30-7.45 (m, 4H), 7.49 (d, J=7.1 Hz, 2H), 7.56 (s, 1H), 7.58 (d,
J=2.7 Hz, 1H), 7.77 (s, 1H), 8.21 (d, J=2.6 Hz, 1H).
5-Ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)--
1H-pyrrolo[2,3-b]pyridine (28h)
[0275] According to the general procedure using: 27 (60 mg, 0.174
mmol), bromoethane (114 mg, 1.05 mmol), K.sub.2CO.sub.3 (241 mg,
1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in acetone (4.0
mL) were heated at reflux for 18 h. Purification by PTLC using
AcOEt:hexane=6:4 (v/v) as eluent gave 28h as a clear oil (39 mg,
60%).
3-(1-Methyl-1H-pyrazol-4-yl)-5-propoxy-1-(2-trimethylsilanyl-ethoxymethyl)-
-1H-pyrrolo[2,3-b]pyridine (28i)
[0276] According to the general procedure using: 27 (60 mg, 0.174
mmol), 1-bromopropane (129 mg, 1.74 mmol), K.sub.2CO.sub.3 (241 mg,
1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in acetone (4.0
mL) were heated at reflux for 18 h. Purification by PTLC using
AcOEt:hexane=6:4 (v/v) as eluent gave 28i as a clear oil (40 mg,
59%).
5-Butoxy-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)--
1H-pyrrolo[2,3-b]pyridine (28j)
[0277] According to the general procedure using: 27 (60 mg, 0.174
mmol), 1-bromobutane (143 mg, 1.05 mmol), K.sub.2CO.sub.3 (241 mg,
1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in acetone (4.0
mL) were heated at reflux for 22.5 h. Purification by PTLC using
AcOEt:hexane=6:4 (v/v) as eluent gave 28j as a clear oil (48.7 mg,
70%).
3-(1-Methyl-1H-pyrazol-4-yl)-5-pentyloxy-1-(2-trimethylsilanyl-ethoxymethy-
l)-1H-pyrrolo[2,3-b]pyridine (28k)
[0278] According to the general procedure using: 27 (60 mg, 0.174
mmol), 1-bromopentane (129 .mu.L, 1.05 mmol), K.sub.2CO.sub.3 (241
mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in acetone
(4.0 mL) were heated at reflux overnight. Purification by PTLC
using AcOEt:hexane=6:4 (v/v) as eluent gave 28k as a clear oil (38
mg, 51%).
5-Hexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-pyrrolo[2,3-b]pyridine (28l)
[0279] According to the general procedure using: 27 (60 mg, 0.174
mmol), 1-bromohexane (117 .mu.L, 1.74 mmol), K.sub.2CO.sub.3 (241
mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in acetone
(4.0 mL) were heated at reflux overnight. Purification by PTLC
using AcOEt:hexane=6:4 (v/v) as eluent gave 28l as a clear oil (36
mg, 48%).
3-(1-Methyl-1H-pyrazol-4-yl)-5-prop-2-ynyloxy-1-(2-trimethylsilanyl-ethoxy-
methyl)-1H-pyrrolo[2,3-b]pyridine (28m)
[0280] According to the general procedure using: 27 (60 mg, 0.174
mmol), 80% wt in toluene propargyl bromide (116 .mu.L, 1.05 mmol),
K.sub.2CO.sub.3 (241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17
.mu.mol) in acetone (4.0 mL) were heated at reflux for 16 h and the
product 28m used crude for the next step.
5-(2-Methoxy-ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-et-
hoxymethyl)-1H-pyrrolo[2,3-b]pyridine (28n)
[0281] According to the general procedure using: 27 (60 mg, 0.174
mmol), 1-bromo-2-methoxyethane (98 .mu.L, 1.05 mmol),
K.sub.2CO.sub.3 (241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17
.mu.mol) in acetone (4.0 mL) were heated at reflux for 16 h and the
product 28n used crude for the next step.
5-Allyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl-
)-1H-pyrrolo[2,3-b]pyridine (28o)
[0282] According to the general procedure using: 27 (60 mg, 0.174
mmol), 1-bromoprop-2-ene (90 .mu.L, 1.05 mmol), K.sub.2CO.sub.3
(241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in
acetone (4.0 mL) were heated at reflux for 17 h and the product 28o
used crude for the next step.
[3-(1-Methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrro-
lo[2,3-b]pyridin-5-yloxy]-acetic acid methyl ester (28p)
[0283] According to the general procedure using: 27 (60 mg, 0.174
mmol), Bromo-acetic acid ethyl ester (99 .mu.L, 1.05 mmol),
K.sub.2CO.sub.3 (241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17
.mu.mol) in acetone (4.0 mL) were heated at reflux for 18 h and the
product 28p used crude for the next step.
5-Cyclopentyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxy-
methyl)-1H-pyrrolo[2,3-b]pyridine (28q)
[0284] According to the general procedure using: 27 (60 mg, 0.174
mmol), bromocyclopentane (112 .mu.L, 1.05 mmol), K.sub.2CO.sub.3
(241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17 .mu.mol) in
acetone (4.0 mL) were heated at reflux for 20 h and the product 28q
used crude for the next step.
3-(1-Methyl-1H-pyrazol-4-yl)-5-phenethyloxy-1-(2-trimethylsilanyl-ethoxyme-
thyl)-1H-pyrrolo[2,3-b]pyridine (28r)
[0285] According to the general procedure using: 27 (60 mg, 0.174
mmol), (2-bromo-ethyl)-benzene (143 .mu.L, 1.05 mmol),
K.sub.2CO.sub.3 (241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17
.mu.mol) in acetone (4.0 mL) were heated at reflux overnight.
Standard workup and purification by PTLC using AcOEt:hexane=6:4
(v/v) as eluent gave 28r as a clear oil (39 mg, 50%).
5-(cyclopropylmethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)-
ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (28s)
[0286] According to the general procedure using: 27 (60 mg, 0.174
mmol), (bromomethyl)cyclopropane (101 .mu.L, 1.05 mmol),
K.sub.2CO.sub.3 (241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17
.mu.mol) in acetone (4.0 mL) were heated at reflux overnight.
Standard workup and purification by PTLC using 5% MeOH in
CH.sub.2Cl.sub.2 gave 28s as a clear oil (41 mg, 59%); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. -0.066 (s, 9H), 0.38 (q, J=4.68 Hz,
2H), 0.68 (m, 2H), 0.91 (m, 2H), 1.31 (m, 1H), 3.55 (t, J=8.3 Hz,
2H), 3.89 (d, J=7.0 Hz, 2H), 3.98 (s, 3H), 5.64 (s, 2H), 7.36 (s,
1H), 7.51 (d, J=2.6 Hz, 1H), 7.58 (s, 1H), 7.74 (d, J=0.3 Hz, 1H),
8.16 (d, J=2.6 Hz, 1H).
5-(cyclohexylmethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)e-
thoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (28t)
[0287] According to the general procedure using: 27 (60 mg, 0.174
mmol), (bromomethyl)cyclohexane (146 .mu.L, 1.05 mmol),
K.sub.2CO.sub.3 (241 mg, 1.74 mmol) and n-Bu.sub.4NI (6.4 mg, 17
.mu.mol) in acetone (4.0 mL) were heated at reflux for 24 h.
Standard workup and purification by PTLC using 80% AcOEt in hexane
gave 28t as a clear oil (40 mg, 52%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. -0.059 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), 1.09
(dq, J=12.2 Hz, J=3.3 Hz, 2H), 1.17-1.40 (m, 2H), 1.65-1.95 (m,
7H), 3.56 (t, J=8.3 Hz, 2H), 3.84 (d, J=6.3 Hz, 2H), 3.99 (s, 3H),
5.64 (s, 2H), 7.38 (s, 1H), 7.49 (d, J=2.6 Hz, 1H), 7.59 (s, 1H),
7.75 (d, J=0.3 Hz, 1H), 8.13 (d, J=2.6 Hz, 1H).
5-Benzyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(29g)
[0288] Following the method used for conversion of 23 into 8,
synthesis of 29g was carried out using 28g (24 mg, 55 .mu.mol),
EtOH (0.5 mL), 10% aq. HCl (0.5 mL) and heating for 19.5 h to give
29g as a white solid (6.0 mg, 36%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 3.99 (s, 3H), 5.17 (s, 2H), 7.36 (m, 2H), 7.42
(t, J=7.3 Hz, 2H), 7.50 (d, J=7.2 Hz, 2H), 7.56 (s, 1H), 7.62 (d,
J=2.6 Hz, 1H), 7.72 (s, 1H), 8.20 (d, J=2.6 Hz, 1H), 9.38 (bs,
NH).
5-Ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(29h)
[0289] Following the method used for conversion of 23 into 8,
synthesis of 29h was carried out using 28h (38 mg, 0.102 mmol),
EtOH (1.0 mL), 10% aq. HCl (1.0 mL) and heating for 17 h to give
29h as a white solid (16 mg, 65%); .sup.1H NMR (400 MHz,
CDCl.sub.3+6 drops CD.sub.3OD) .delta. 1.41 (t, J=7.0 Hz, 3H), 3.92
(s, 3H), 4.08 (q, J=7.0 Hz, 2H), 7.32 (s, 1H), 7.52 (d, J=2.6 Hz,
1H), 7.56 (s, 1H), 7.67 (s, 1H), 7.99 (d, J=2.7 Hz, 1H).
3-(1-Methyl-1H-pyrazol-4-yl)-5-propoxy-1H-pyrrolo[2,3-b]pyridine
(29i)
[0290] Following the method used for conversion of 23 into 8,
synthesis of 29i was carried out using 28i (39 mg, 0.101 mmol),
EtOH (1.0 mL), 10% aq. HCl (1.0 mL) and heating for 17 h to give
29i as a white solid (19 mg, 73%); .sup.1H NMR (400 MHz,
CDCl.sub.3+6 drops CD.sub.3OD) .delta. 1.03 (t, J=7.4 Hz, 3H), 1.80
(sextet, J=7.1 Hz, 2H), 3.93 (s, 3H), 3.98 (t, J=6.6 Hz, 2H), 7.32
(s, 1H), 7.52 (d, J=2.5 Hz, 1H), 7.56 (s, 1H), 7.67 (s, 1H), 8.00
(bs, 1H).
5-Butoxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(29j)
[0291] Following the method used for conversion of 23 into 8,
synthesis of 29j was carried out using 28j (48 mg, 0.12 mmol), EtOH
(1.0 mL), 10% aq. HCl (1.0 mL) and heating for 20.5 h to give 29j
as a white solid (25 mg, 77%); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 1.01 (t, J=7.4 Hz, 3H), 1.54 (sextet, J=7.5 Hz, 2H), 1.83
(quintet, J=7.0 Hz, 2H), 4.00 (s, 3H), 4.07 (t, J=6.5 Hz, 2H), 7.38
(d, J=2.5 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.60 (s, 1H), 7.75 (s,
1H), 8.13 (d, J=2.6 Hz, 1H), 9.59 (bs, NH).
3-(1-Methyl-1H-pyrazol-4-yl)-5-pentyloxy-1H-pyrrolo[2,3-b]pyridine
(29k)
[0292] Following the method used for conversion of 23 into 8,
synthesis of 29k was carried out using 28k (38 mg, 92 .mu.mol),
EtOH (1.0 mL), 10% aq. HCl (1.0 mL) and heating for 16 h to give
29k as a white solid (21 mg, 81%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.96 (t, J=7.2 Hz, 3H), 1.30-1.60 (m, 4H), 1.85
(quintet, J=7.0 Hz, 2H), 4.00 (s, 3H), 4.06 (t, J=6.6 Hz, 2H), 7.40
(d, J=2.5 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.60 (s, 1H), 7.76 (s,
1H), 8.14 (d, J=2.6 Hz, 1H), 10.28 (bs, NH).
5-Hexyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(291)
[0293] Following the method used for conversion of 23 into 8,
synthesis of 29l was carried out using 28l (36 mg, 84 .mu.mol),
EtOH (1.0 mL), 10% aq. HCl (1.0 mL) and heating for 16 h to give
29l as a white solid (21 mg, 84%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.92 (t, J=7.1 Hz, 3H), 1.30-1.45 (m, 4H), 1.51
(m, 2H), 1.83 (quintet, J=7.1 Hz, 2H), 3.99 (s, 3H), 4.06 (t, J=6.5
Hz, 2H), 7.39 (d, J=2.4 Hz, 1H), 7.55 (d, J=2.6 Hz, 1H), 7.59 (s,
1H), 7.75 (s, 1H), 8.13 (d, J=2.6 Hz, 1H), 10.18 (bs, NH).
3-(1-Methyl-1H-pyrazol-4-yl)-5-prop-2-ynyloxy-1H-pyrrolo[2,3-b]pyridine
(29m)
[0294] Following the method used for conversion of 23 into 8,
synthesis of 29m was carried out using 28m (crude), EtOH (1.0 mL),
10% aq. HCl (1.0 mL) and heating for 16 h to give 29m as a white
solid (21 mg, 48%); .sup.1H NMR (400 MHz, CDCl.sub.3+6 drops
CD.sub.3OD) .delta. 2.56 (t, J=2.2 Hz, 1H), 3.92 (s, 3H), 4.73 (d,
J=2.3 Hz, 2H), 7.34 (s, 1H), 7.56 (s, 1H), 7.66 (d, J=2.6 Hz, 1H),
7.67 (s, 1H), 8.04 (d, J=2.6 Hz, 1H).
5-(2-Methoxy-ethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-
e (29n)
[0295] Following the method used for conversion of 23 into 8,
synthesis of 29n was carried out using 28n (crude), EtOH (1.0 mL),
10% aq. HCl (1.0 mL) and heating for 16 h to give 29n as a white
solid (16.7 mg, 35%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.50 (s, 3H), 3.81 (t, J=4.6 Hz, 2H), 3.99 (s, 3H), 4.23 (t, J=4.6
Hz, 2H), 7.40 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 7.62 (d, J=2.6 Hz,
1H), 7.75 (s, 1H), 8.18 (d, J=2.6 Hz, 1H), 10.23 (bs, NH).
5-Allyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(29o)
[0296] Following the method used for conversion of 23 into 8,
synthesis of 29o was carried out using 28o (crude), EtOH (1.0 mL),
10% aq. HCl (1.0 mL) and heating for 16 h to give 29o as a white
solid (17.1 mg, 39%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.99 (s, 3H), 4.64 (dt, J=5.3, 1.4 Hz, 2H), 5.34 (dq, J=10.5, 0.9
Hz, 1H), 5.48 (dq, J=17.2, 1.5 Hz, 1H), 6.05-6.20 (m, 1H), 7.41 (d,
J=2.4 Hz, 1H), 7.59 (s, 2H), 7.75 (s, 1H), 8.17 (d, J=2.6 Hz, 1H),
10.31 (bs, NH).
[3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yloxy]-acetic
acid ethyl ester (29p)
[0297] Following the method used for conversion of 23 into 8,
synthesis of 29p was carried out using 28p (crude), EtOH (1.0 mL),
10% aq. HCl (1.0 mL) and heating for 16 h to give 29p as an orange
oil (7.3 mg, 14%). Note: due to trans-esterification the methyl
ester was converted into the ethyl ester; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.32 (t, J=7.1 Hz, 3H), 4.00 (s, 3H), 4.30 (q,
J=7.1 Hz, 2H), 4.72 (s, 2H), 7.41 (d, J=2.4H, 1H), 7.59 (s, 1H),
7.61 (d, J=2.6 Hz, 1H), 7.23 (s, 1H), 8.20 (d, J=2.6 Hz, 1H), 9.67
(bs, NH).
5-Cyclopentyloxy-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(29q)
[0298] Following the method used for conversion of 23 into 8,
synthesis of 29q was carried out using 28q (crude), EtOH (1.0 mL),
10% aq. HCl (1.0 mL) and heating for 16 h to give 29q as a white
solid (20.8 mg, 42%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.55-1.75 (m, 2H), 1.80-2.00 (m, 6H), 3.99 (s, 3H), 4.83 (quintet,
J=4.1 Hz, 1H), 7.40 (d, J=1.8 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H), 7.59
(s, 1H), 7.75 (s, 1H), 8.10 (d, J=2.3 Hz, 1H), 10.38 (bs, NH).
3-(1-Methyl-1H-pyrazol-4-yl)-5-phenethyloxy-1H-pyrrolo[2,3-b]pyridine
(29r)
[0299] Following the method used for conversion of 23 into 8,
synthesis of 29r was carried out using 28r (39 mg, 87 .mu.mol),
EtOH (1.0 mL), 10% aq. HCl (1.0 mL) and heating for 20 h to give
29r as a white solid (18.5 mg, 67%); .sup.1H NMR (400 MHz,
CDCl.sub.3+6 drops CD.sub.3OD) .delta. 3.08 (t, J=7.0 Hz, 2H), 3.91
(s, 3H), 4.21 (t, J=7.1 Hz, 2H), 7.20-7.35 (m, 6H), 7.47 (d, J=2.6
Hz, 1H), 7.53 (s, 1H), 7.65 (d, J=0.6 Hz, 1H), 7.97 (d, J=2.6 Hz,
1H).
5-(cyclopropylmethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine (29s)
##STR00113##
[0301] A mixture of 28s (40 mg, 0.10 mmol) and 1.0 M TBAF in THF (3
mL) was heated at reflux for 7 h. The reaction mixture was then
cooled, poured onto a mixture of AcOEt and saturated aqueous
NaHCO.sub.3. The layers were separated, the aqueous phase extracted
with more AcOEt (2.times.) then the combined organic extracts dried
(MgSO.sub.4) and concentrated. The residue was purified by PTLC
using 5% MeOH in CH.sub.2Cl.sub.2 as eluent) to give 29s as a white
solid (25.0 mg, 62%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.40 (q, J=4.7 Hz, 2H), 0.69 (m, 2H), 1.33 (m, 1H), 3.91 (d, J=7.0
Hz, 2H), 4.00 (s, 3H), 7.36 (d, J=2.5 Hz, 1H), 7.56 (d, J=2.5 Hz,
1H), 7.60 (s, 1H), 7.75 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 9.14 (bs,
NH).
5-(cyclohexylmethoxy)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridi-
ne (29t)
[0302] Following the method used for conversion of 28s into 29s,
synthesis of 29t was carried out using 28t (38 mg, 0.086 mmol), 1.0
M TBAF in THF (2 mL) with heating at reflux for 7 h. The product
was purified by preparative LCMS (column LUNA 10.mu. C18(2)
00G-4253-V0 250.times.50 mm) using water-MeCN (0.1% AcOH) as eluent
(in gradient; flow 80 mL/min) to 29t as a white solid (10.6 mg,
40%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.12 (dq, J=15.1
Hz, J=3.3 Hz, 2H), 1.18-1.40 (m, 4H), 1.68-2.00 (m, 5H), 3.86 (d,
J=6.3 Hz, 2H), 4.00 (s, 3H), 7.39 (d, J=2.48 Hz, 1H), 7.54 (d,
J=2.6 Hz, 1H), 7.60 (s, 1H), 7.76 (d, J=0.6 Hz, 1H), 8.13 (d, J=2.6
Hz, 1H), 9.84 (bs, NH); m/z (Cl.sup.+) 311.1 (MH.sup.+).
[0303] Synthesis of Inhibitors 35 and 36
##STR00114##
5-Methoxy-1H-pyrrolo[2,3-b]pyridine (30)
##STR00115##
[0305] To 5-bromo-7-azaindole 1 (0.98 g, 5.0 mmol) in DMF (32 mL)
was added 25% (w/w) MeONa (48 mL, 210 mmol) followed by copper (I)
bromide (1.43 g, 10.0 mmol), and the reaction mixture was heated at
140.degree. C. for 2.5. It was then cooled and concentrated to
remove DMF. Water (100 mL) was added followed by saturated aqueous
NaHCO.sub.3 (20 mL). The mixture was extracted with AcOEt
(3.times.), the combined organic extracts dried (MgSO.sub.4) and
concentrated. The solid residue was purified by SGC using
AcOEt:hexane (gradient elution up to 30:70) to give 30 as a green
solid (0.58 g, 78%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.90
(s, 3H), 6.45 (d, J=2.3 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.48 (d,
J=2.2 Hz, 1H), 8.00-8.20 (bs, 1H); 10.60-10.80 (bs, NH).
3-Iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (31)
##STR00116##
[0307] Following the method used for conversion of 2 into 3,
synthesis of 31 was carried out using 30 (0.50 g, 3.37 mmol), DMF
(8.4 mL), KOH (701 mg, 12.5 mmol), 12 (942 mg, 3.71 mmol) with
stirring for 40 min. to give 31 as a creamy solid (850 mg, 92%);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.94 (s, 3H), 7.23 (d,
J=2.6 Hz, 1H), 7.46 (d, J=2.2 Hz, 1H), 8.10 (d, J=2.6 Hz, 1H),
9.40-9.60 (bs, NH).
1-Benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine
(32)
##STR00117##
[0309] Following the method used for conversion of 3 into 4,
synthesis of 32 was carried out using 31 (700 mg, 2.55 mmol),
PhSO.sub.2Cl (489 .mu.L, 3.83 mmol), n-Bu.sub.4NHSO.sub.4 (113 mg,
0.33 mmol) and 50% aq. NaOH (485 .mu.L) in CH.sub.2Cl.sub.2 (16 mL)
with stirring for 1 h 15 min. The concentrated residue was washed
with a small amount of methanol (3.times.) to give 32 as a white
solid (833 mg, 79%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.89
(s, 3H), 7.10 (d, J=2.7 Hz, 1H), 7.48 (t, J=2.5 Hz, 2H), 7.60 (tt,
J=7.4, 1.3 Hz, 1H), 7.83 (d, J=0.4 Hz, 1H), 8.14 (m, 2H).
1-Benzenesulfonyl-5-methoxy-3-(1-trityl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-
pyridine (33)
##STR00118##
[0311] Following the method used for conversion of 4 into 6,
synthesis of 33 was carried out using 32 (260 mg, 0.63 mmol), 5
(333 mg, 0.94 mmol), PdCl.sub.2(PPh.sub.3).sub.2 (44 mg, 0.063
mmol), LiCl (80 mg, 1.88 mmol), 1M aq. Na.sub.2CO.sub.3 (1.57 mL,
1.57 mmol) in EtOH (2.9 mL) and toluene (2.9 mL). Reaction time:
0.5 h at reflux. The crude product was used in the subsequent
reaction.
1-Benzenesulfonyl-5-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(34)
##STR00119##
[0313] Following the method used for conversion of 6 into 7,
synthesis of 34 was carried out using 33 (crude), TFA (501 .mu.M),
H.sub.2O (50 .mu.L) and i-Pr.sub.3SiH (254 .mu.L) in
CH.sub.2Cl.sub.2 (5.3 mL) with stirring for 0.5 h. Isolation of
product by means of SGC using CH.sub.2Cl.sub.2:MeOH as eluent
(gradient elution uop to 97:3, v/v) afforded 34 as a brown solid
(176 mg, 79%); .sup.1H NMR (400 MHz, CDCl.sub.3+6 drops CD.sub.3OD)
.delta. 3.82 (s, 3H), 7.38 (d, J=2.7 Hz, 1H), 7.43 (t, J=7.3 Hz,
2H), 7.52 (tt, J=7.5, 1.3 Hz, 1H), 7.70 (s, 1H), 7.77 (s, 2H), 8.08
(m, 2H), 8.12 (d, J=2.7 Hz, 1H).
5-Methoxy-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine (35)
##STR00120##
[0315] Following the method used for conversion of 7 into 8,
synthesis of 35 was carried out using 34 (150 mg, 0.42 mmol), EtOH
(8.2 mL), 10% aq. NaOH (3.9 mL) with heating at 90.degree. C. for 4
h 20 min. TLC showed unreacted 34 so more 10% aq. NaOH (3.9 mL) was
added and the reaction continued for 1 h. Extraction was performed
using CH.sub.2Cl.sub.2 (1.times.) then 3% MeOH in CH.sub.2Cl.sub.2
(3.times.) and the residue purified by preparative LCMS (column
LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-MeCN
(0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give 35 as a
white solid (31.7 mg, 35%); .sup.1H NMR (400 MHz, CDCl.sub.3+8
drops CD.sub.3OD) .delta. 3.84 (s, 3H), 7.34 (s, 1H), 7.51 (d,
J=2.7 Hz, 1H), 7.74 (s, 2H), 7.95 (d, J=2.7 Hz, 1H).
3-(1H-Pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-ol (36)
##STR00121##
[0317] To a suspension of 35 (25 mg, 0.12 mmol) in CH.sub.2Cl.sub.2
(2.0 mL), cooled to 0.degree. C., was added a 1M solution of
BBr.sub.3 (467 .mu.L, 0.48 mmol) in CH.sub.2Cl.sub.2 and the
reaction mixture stirred for 2 h at room temperature. More
CH.sub.2Cl.sub.2 (2.0 mL) and BBr.sub.3 (467 .mu.L) was added at
r.t. and the stirring continued for 65 h. The reaction mixture was
partitioned between AcOEt and saturated aqueous NaHCO.sub.3 and the
layers separated. The aqueous phase was extracted with more AcOEt
(4.times.), the combined organic extracts dried (MgSO.sub.4) and
concentrated. The residue was purified by preparative LCMS (column
LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-MeCN
(0.1% ACOH) as eluent (in gradient; flow 80 mL/min) to give 36 as a
white solid (9.1 mg, 39%); .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.49 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.86 (d,
J=2.5 Hz, 1H), 7.90 (s, 2H), 9.05-9.20 (bs, 1H), 11.32 (bs,
NH).
[0318] Synthesis of Inhibitor 39
##STR00122##
1-Benzenesulfonyl-5-benzyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]-
pyridine (38)
##STR00123##
[0320] Bromide 37 (80 mg, 0.19 mmol; prepared in analogous way to
20), benzyl boronic acid (29 mg, 0.21 mmol), Ag.sub.2O (111 mg,
0.48 mmol), K.sub.2CO.sub.3 (80 mg, 0.58 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with CH.sub.2Cl.sub.2 (1:1) (16 mg, 0.019 mmol) in THF (2.5 mL)
were heated at 80.degree. C. for 17.5 h. The mixture was allowed to
cool to r.t., diluted with AcOEt and a solution of 30%
H.sub.2O.sub.2 and 10% NaOH (1:1, v/v) and partitioned. The aqueous
layer was extracted with AcOEt (3.times.). The combined organic
extracts were dried (MgSO.sub.4), filtered and concentrated. The
crude residue was purified by LCMS (column LUNA 10.mu. C18(2)
00G-4253-V0 250.times.50 mm) using water-MeCN (0.1% AcOH) as eluent
(in gradient; flow 80 mL/min) to afford 38 (36 mg, 44%). .sup.1H
NMR (400 MHz; CDCl.sub.3) .delta. 3.97 (s, 3H), 4.07 (s, 2H),
7.15-7.22 (m, 3H), 7.26-7.30 (m, 2H), 7.46-7.51 (m, 2H), 7.55-7.59
(m, 2H), 7.70 (d, J=0.73 Hz, 1H), 7.73-7.75 (m, 2H), 8.18-8.22 (m,
2H), 8.35 (d, J=2.0 Hz, 1H). MS (CI) m/z 429 (MH.sup.+).
5-Benzyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(39)
##STR00124##
[0322] A mixture of benzyl derivative 38 (36 mg, 0.08 mmol) and 10%
NaOH solution (0.80 mL) in EtOH (2.5 mL) was heated at 90.degree.
C. After 1 h the mixture was cooled to r.t., diluted with AcOEt and
saturated brine and partitioned. The aqueous layer was extracted
with AcOEt (3.times.). The combined organic extracts were dried
(MgSO.sub.4), concentrated and the residue was purified by LCMS
(column LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using
water-MeCN (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to
afford 39 (17 mg, 70%). .sup.1H NMR (400 MHz; CDCl.sub.3) .delta.
3.97 (s, 3H), 4.12 (s, 2H), 7.19-7.36 (m, 6H), 7.58 (s, 1H), 7.71
(s, 1H), 7.86 (brs, 1H), 8.24 (m, 1H), 8.79 (brs, 1H).
[0323] MS (CI) m/z 289 (MH.sup.+).
[0324] Synthesis of Example Inhibitor 45
##STR00125##
2-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoindoline-1,3-dione (41)
##STR00126##
[0326] A mixture of boronic ester 40 (3.80 g, 15.6 mmol;
preparation disclosed in WO2004/078757), phtalimide (0.951 g, 15.6
mmol), Cu(OAc).sub.2 (1.56 g, 8.59 mmol) and Et.sub.3N (2.11 g,
20.8 mmol) in CH.sub.2Cl.sub.2 (152 mL) was stirred at r.t. for 5
d. The mixture was then concentrated, dissolved in DMF and
separated by LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water-MeCN (0.1% AcOH) as eluent (in
gradient; flow 80 mL/min) to afford 41 (205 mg, 5%). .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta. 6.58 (dd, J=2.0, 3.5 Hz, 1H), 7.39
(dd, J=2.5, 3.5 Hz, 1H), 7.80-7.84 (m, 2H), 7.96-8.01 (m, 3H), 8.34
(d, J=2.2 Hz, 1H), 8.98 (bs, 1H). MS (ES) m/z 305
(MH.sup.++MeCN).
2-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindoline-1,3-dione
(42)
##STR00127##
[0328] A solution of Br.sub.2 (30.2 mg, 0.189 mmol) in
CH.sub.2Cl.sub.2 (2.0 mL) was added dropwise over a period of 4
min. to a stirred and cooled (0.degree. C.) solution of 41 (50 mg,
0.189 mmol) and pyridine (18.0 mg, 0.23 mmol) in CH.sub.2Cl.sub.2
(2 mL). After additional stirring at 0.degree. C. for 26 min. the
reaction mixture was treated with a 1:1 (v/v) solution of saturated
aqueous NaHCO.sub.3 and saturated aqueous Na.sub.2S.sub.2O.sub.3.
Stirring continued for 30 min at 0.degree. C. and the organic phase
was separated. The aqueous layer was extracted with
CH.sub.2Cl.sub.2. The combined organic solutions were dried
(MgSO.sub.4), concentrated and the residue was separated by LCMS
(column LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using
water-MeCN (0.1% ACOH) as eluent (in gradient; flow 80 mL/min) to
afford 42 (64.7 mg, quant.). .sup.1H NMR (400 MHz; CDCl.sub.3+3
drops of CD.sub.3OD) .delta. 7.40 (s, 1H), 7.81 (dd, J=3.1, 5.4 Hz,
2H), 7.94 (d, J=2.3 Hz, 1H), 7.96 (dd, J=5.5, 3.1 Hz, 2H), 8.29 (d,
J=2.3 Hz, 1H); MS (ES) m/z 383 (MH.sup.++MeCN).
2-(3-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoindoline-1,-
3-dione (43)
##STR00128##
[0330] PhSO.sub.2Cl (24 mg, 0.136 mmol) was added dropwise over a
period of 3 min. to a stirred solution of 42 (31 mg, 0.090 mmol)
and pyridine (11.4 mg, 0.144 mmol) in CH.sub.2Cl.sub.2. The mixture
was stirred at r.t. overnight. Additional portion of PhSO.sub.2Cl
(24 mg, 0.136 mmol) was added, followed by DMAP (3 mg, 0.025 mmol).
After additional stirring for 1.5 h, the mixture was partitioned
between saturated aqueous NaHCO.sub.3:CH.sub.2Cl.sub.2. The aqueous
layer was extracted with CH.sub.2Cl.sub.2. The combined organic
solutions were washed with brine, dried (MgSO.sub.4) and
concentrated. Purification by PTLC using AcOEt:hexane=1:1 (v/v) as
eluent afforded 43 as orange powder (15 mg, 35%). .sup.1H NMR (400
MHz; CDCl.sub.3) .delta. 7.55 (tt, J=6.6, 1.6 Hz, 2H), 7.62 (tt,
J=5.3, 2.0 Hz, 1H), 7.84 (dd, J=5.4, 3.0 Hz, 2H), 7.88 (s, 1H),
7.92 (d, J=2.3 Hz, 1H), 7.98 (dd, J=5.4, 3.0 Hz, 2H), 8.23 (dd,
J=4.0, 1.3 Hz, 2H), 8.55 (d, J=1.9 Hz, 1H).
2-(1-(phenylsulfonyl)-3-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylcarbam-
oyl)benzoic acid (44)
##STR00129##
[0332] A mixture of bromide 43 (50 mg, 0.104 mmol),
5-(trimethylstannyl)thiazole (51.1 mg, 0.21 mmol),
PdCl.sub.2(MeCN).sub.2 (2.67 mg, 10 .mu.mol), and P(o-tolyl).sub.3
(6.27 mg, 21 .mu.mol) in toluene (5 mL) was heated in darkness at
85.degree. C. overnight and then refluxed for 2 d. The mixture was
concentrated and the product isolated by LCMS (column LUNA 10.mu.
C18(2) 00G-4253-V0 250.times.50 mm) using water-MeCN (0.1% AcOH) as
eluent (in gradient; flow 80 mL/min) to afford 44 (20 mg, 38%).
.sup.1H NMR (400 MHz; CDCl.sub.3+3 drops of CD.sub.3OD) .delta.
7.30 (dd, J=4.5, 2.0 Hz, 2H), 7.35 (t, J=7.4 Hz, 2H), 7.44-7.50 (m,
2H), 7.61-7.63 (m, 1H), 7.80 (s, 1H), 7.98 (d, J=1.4 Hz, 1H), 8.00
(s, 2H), 8.42 (d, J=2.3 Hz, 1H), 8.59 (d, J=2.3 Hz, 1H), 8.70 (s,
1H). MS (ES) m/z 505 (MH.sup.+).
2-(3-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl)benzoic
acid (45)
##STR00130##
[0334] Sulfonamide 44 (20 mg, 40 .mu.mol), 10% aqueous NaOH
solution (0.36 mL, 0.9 mmol) in EtOH (1.0 mL) was refluxed for 30
min. The mixture was cooled, concentrated, treated with glacial
acetic acid (0.72 mL, 12 mmol), and concentrated again. The residue
was separated by LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water-MeCN (0.1% AcOH) as eluent (in
gradient; flow 80 mL/min) to afford 45 (3.88 mg, 27%). .sup.1H NMR
(400 MHz; CDCl.sub.3+3 drops of CD.sub.3OD) .delta. 7.36 (dd,
J=7.5, 2.5 Hz, 1H), 7.57 (s, 2H), 7.78 (s, 1H), 8.02 (d, J=2.0 Hz,
1H), 8.15 (d, J=1.8 Hz, 1H), 8.20 (d, J=1.9 Hz, 1H), 8.39 (d, J=2.1
Hz, 1H), 8.50 (s, 1H); MS (ES) m/z 406.3 (MH.sup.++MeCN).
[0335] Synthesis of Example Inhibitor 49
##STR00131##
tert-Butyl 3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate
(47)
##STR00132##
[0337] A mixture of acid 46 (200 mg, 088 mmol; preparation
disclosed in WO2005085244), DPPA (254.28 mg, 0.92 mmol) and
Et.sub.3N (93.5 mg, 0.92 mmol) in 2-methylpropan-2-ol (20.6 mL) was
stirred at r.t. for 30 min. and gradually raised to 100.degree. C.
over a period of 2 h. After additional 6 h stirring at 100.degree.
C. the mixture was cooled, concentrated in vacuum, and dissolved in
AcOEt-water. The aqueous layer was extracted with AcOEt. Combined
organic solutions were washed with saturated aqueous NaHCO.sub.3,
brine, dried (MgSO.sub.4) and concentrated. The residue was
separated by PTLC using CH.sub.2Cl.sub.2:MeOH=19:1 (v/v) as eluent
to afford 47 (97.29 mg, 37%). .sup.1H NMR (400 MHz; CDCl.sub.3)
.delta. 1.56 (s, 9H), 6.62 (bs, 1H), 6.68 (dd, J=1.8, 0.9 Hz, 1H).
7.26 (s, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.51 (dd, J=3.3, 1.5 Hz, 1H),
7.79 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.25 (bs, NH); MS (ES) m/z
341 (MH.sup.++MeCN).
3-(Furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine (48)
##STR00133##
[0339] 4.0 M aqueous HCl (0.83 mL, 3.32 mmol) was added to a
suspension of 47 (90 mg, 0.30 mmol) in MeOH (0.17 mL) and the
mixture was stirred at r.t. overnight. Concentrated aqueous HCl
(0.2 mL, 2.2 mmol) was added and stirring continued for 5 h. The
mixture was concentrated to dryness in vacuum and separated by
means of LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50
mm) using water-MeCN (0.1% AcOH) as eluent (in gradient; flow 80
mL/min) to afford 48 (41.64 mg, 70%). .sup.1H NMR (400 MHz;
CDCl.sub.3+3 drops of CD.sub.3OD) .delta. 6.61 (dd, J=1.8, 0.8 Hz,
1H), 7.32 (s, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.45 (dd, J=3.3, 1.7 Hz,
1H), 7.68 (dd, J=2.3, 1.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H); MS (ES)
m/z 241 (MH.sup.++MeCN).
4-Fluoro-N-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide
(49)
##STR00134##
[0341] 4-Fluorobenzoyl chloride (29.7 mg, 0.19 mmol) was added to a
solution of amine 48 (25 mg, 0.125 mmol), DMAP (1.53 mg, 12.5
.mu.mol) and Et.sub.3N (12.6 mg, 0.125 mmol) in DMF (0.6 mL). The
mixture was stirred at r.t. overnight, concentrated and separated
by means of LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water-MeCN (0.1% AcOH) as eluent (in
gradient; flow 80 mL/min) to afford 49 (2.13 mg, 5%). .sup.1H NMR
(400 MHz; CDCl.sub.3+3 drops of CD.sub.3OD) .delta. 6.45 (dd,
J=1.9, 0.9 Hz, 1H), 6.91 (t, J=1.8 Hz, 2H), 7.22 (s, 1H), 7.23 (t,
J=1.7 Hz, 1H), 7.56 (m, 1H), 7.73-7.76 (m, 2H), 8.15 (d, J=2.1 Hz,
1H), 8.25 (d, J=2.3 Hz, 1H); MS (ES) m/z 363 (MH.sup.++MeCN).
[0342] Synthesis of Example Inhibitors 51-53
##STR00135##
tert-Butyl
3-(1-trityl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate
(51)
##STR00136##
[0344] Inhibitor 51 was synthesized following the method described
for preparation of 47 using acid 50 (414 mg, 0.88 mmol; prepared in
analogous way to 46). Yield 476 mg (quant).
tert-Butyl
3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylcarbamate (52)
##STR00137##
[0346] Inhibitor 52 was synthesized following the method described
for preparation of 48 using 51 (326 mg, 0.60 mmol). The crude
reaction mixture was neutralised with saturated aqueous NaHCO.sub.3
and extracted with AcOEt. Combined organic extracts were dried
(MgSO.sub.4), concentrated and purified by means of LCMS (column
LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-MeCN
(0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 52
(25.62 mg, 14%). .sup.1H NMR (400 MHz; CDCl.sub.3+3 drops of
CD.sub.3OD) .delta. 1.54 (s, 9H), 7.54 (s, 1H), 7.93 (s, 2H) 8.18
(d, J=2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H); MS (ES) m/z 341
(MH.sup.++MeCN).
3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine (53)
##STR00138##
[0348] Inhibitor 53 was synthesized following the method described
for preparation of 48 using 51 (150 mg, 0.28 mmol). The reaction
mixture was concentrated to dryness in vacuum and separated by
means of LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50
mm) using water-MeCN (0.1% AcOH) as eluent (in gradient; flow 80
mL/min) to afford 53 (6.07 mg, 11%). .sup.1H NMR (400 MHz;
CDCl.sub.3+3 drops of CD.sub.3OD) .delta. 7.26 (s, 1H), 7.66 (s,
2H), 8.54 (d, J=1.9 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H); MS (ES) m/z
241 (MH.sup.++MeCN).
[0349] Synthesis of Example Inhibitors 54 and 55
##STR00139##
3-(1-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine
(54)
##STR00140##
[0351] A mixture of 37 (100 mg, 0.24 mmol), Cu.sub.2O (5.0 mg, 35
.mu.mol), and aqueous ammonium hydroxide (3 mL) in ethylene glycol
(2.5 mL) was heated in a sealed tube at 100.degree. C. for a period
of 23 h. The mixture was cooled and partitioned between
water-AcOEt. The aqueous layer was extracted with AcOEt. Combined
organic solutions were dried (MgSO.sub.4), concentrated and the
residue was purified by means of LCMS (column LUNA 10.mu. C18(2)
00G-4253-V0 250.times.50 mm) using water-MeCN (0.1% AcOH) as eluent
(in gradient; flow 80 mL/min) to afford 54 (20.0 mg, 39%). .sup.1H
NMR (400 MHz; DMSO-d.sub.6) .delta. 3.80 (s, 3H), 7.43 (s, 1H),
7.58 (dd, J=6.0, 1.7 Hz, 2H), 7.70 (m, 1H), 7.93 (m, 1H); MS (ES)
m/z 254 (MH.sup.++MeCN).
4-Fluoro-N-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)ben-
zamide (55)
##STR00141##
[0353] 4-Fluorobenzoyl chloride (100 .mu.L, 0.84 mmol) was added to
a solution of 54 (20.0 mg, 93.7 .mu.mol) in pyridine (2 mL). The
mixture was stirred at r.t. overnight, concentrated and separated
by means of LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water-MeCN (0.1% AcOH) as eluent (in
gradient; flow 80 mL/min) to afford 55 (3.99 mg, 13%). .sup.1H NMR
(400 MHz; DMSO-d.sub.6) .delta. 3.87 (s, 3H), 7.38 (t, J=8.8 Hz,
2H), 7.66 (s, 1H), 7.75 (s, 1H), 8.00 (s, 1H), 8.08 (dd, J=8.7, 5.4
Hz, 2H), 8.48 (dd, J=7.0, 2.2 Hz, 2H); MS (ES) m/z 377
(MH.sup.++MeCN).
[0354] Synthesis of Example Inhibitors 59 and 60
##STR00142##
Indolin-1-yl(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)m-
ethanone (58)
##STR00143##
[0356] A mixture of indoline (56) (184 .mu.L, 1.64 mmol), acid 57
(200 mg, 0.826 mmol; prepared in analogous way to 46),
benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate (BOP, 473 mg, 1.07 mmol) and i-Pr.sub.2NEt (288
.mu.L, 1.65 mmol) in DMF (4 mL) was stirred at r.t. overnight. The
product was isolated by means of preparative LCMS (column LUNA
10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-acetonitrile
(0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give 58 as a
white solid (126.9 mg, 45%); .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 3.18 (t, J=8.2 Hz, 2H), 3.99 (s, 3H), 4.21 (t, J=8.2 Hz,
2H), 7.06 (t, J=6.7 Hz, 1H), 7.15 (br s, 1H), 7.24-7.30 (m, 2H),
7.49 (d, J=2.2 Hz, 1H), 7.67 (s, 1H), 7.75 (d, J=0.4 Hz, 1H), 8.35
(d, J=1.9 Hz), 8.60 (d, J=1.9 Hz), 9.16 (bs, 1H).
5-(Indolin-1-ylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyrid-
ine (59)
##STR00144##
[0358] A mixture of 1.0 M BH.sub.3 in THF (1.0 mL, 1.0 mmol) and
amide 58 (80.7 mg, 0.235 mmol) in THF (2.0 mL) was refluxed under
N.sub.2 for 20 min. The reaction mixture was cooled to r.t.,
quenched with MeOH (5 mL) and concentrated. The residual solid was
treated with 10% aqueous HCl (2.0 mL) and MeOH (2.0 mL). After 1 h
stirring at r.t. the mixture was concentrated, basified with
NaHCO.sub.3 and extracted with AcOEt (3.times.10 mL). Combined
extracts were dried (MgSO.sub.4), concentrated and purified by
means of preparative LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water-acetonitrile (0.1% AcOH) as eluent (in
gradient; flow 80 mL/min) to give 59 as a white solid (14.0 mg,
18%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.97 (t, J=8.3 Hz,
2H), 3.30 (t, J=8.3 Hz, 2H), 3.98 (s, 3H), 4.40 (s, 2H), 6.66 (d,
J=7.8 Hz, 1H), 6.72 (td, J=7.4, 0.8 Hz, 1H), 7.08-7.15 (m, 2H),
7.43 (d, J=1.6 Hz, 1H), 7.61 (s, 1H), 7.75 (s, 1H), 8.08 (d, J=1.8
Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 9.90 (bs, 1H).
5-((1H-indol-1-yl)methyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]py-
ridine (60)
##STR00145##
[0360] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (25 mg, 0.11 mmol)
was added in small portions over a period of 0.5 h to a stirred
solution of 59 (11.0 mg, 33.4 .mu.mol) in CH.sub.2Cl.sub.2 (1.8
mL)-0.2 M aqueous phosphate buffer (pH 7.0) solution (0.05 mL).
When the addition was completed, the mixture was stirred for
additional 0.5 h and then treated with saturated aqueous
NaHCO.sub.3 (2 mL). Stirring continued for 1 h. The organic layer
was separated and the aqueous phase extracted with CH.sub.2Cl.sub.2
(5.times.2 mL). Combined organic solutions were washed with brine,
dried (MgSO.sub.4), concentrated and the residue was purified by
means of PTLC using AcOEt as eluent to afford 60 (2.9 mg, 26%) as
grey solid; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.95 (s, 3H),
5.46 (s, 2H), 6.56 (dd, J=3.2, 0.7 Hz, 1H), 7.12 (td, J=7.5, 1.0
Hz, 1H), 7.16 (d, J=3.2, 1H), 7.20 (td, J=7.5, 1.2 Hz, 1H), 7.37
(d, J=2.4 Hz, 1H), 7.39 (dd, J=8.2, 0.7 Hz, 1H), 7.47 (s, 1H), 7.66
(s, 1H), 7.66 (dd, J=7.8, 0.7 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 8.28
(d, J=1.9 Hz, 1H), 8.86 (bs, 1H).
[0361] Synthesis of Example Inhibitor 63
##STR00146##
3-(1-methyl-1H-pyrazol-4-yl)-5-(2-methylprop-1-enyl)-1-(phenylsulfonyl)-1-
H-pyrrolo[2,3-b]pyridine (61)
##STR00147##
[0363] A mixture of bromide 37 (280 mg, 0.67 mmol),
2,2-dimethylethenylboronic acid (101 mg, 1.01 mmol), LiCl (84 mg,
2.02 mmol), (PPh.sub.3).sub.2PdCl.sub.2 (24 mg, 0.03 mmol), 1.0 M
aqueous Na.sub.2CO.sub.3 (1.68 mL, 1.68 mmol), in toluene (8
mL)-EtOH (8 mL) was stirred in an oil bath (105.degree. C.) for 96
h. The reaction mixture was then cooled to r.t., diluted with AcOEt
and saturated brine and partitioned. The aqueous layer was
extracted with AcOEt (2.times.). The combined organic solutions
were dried (MgSO.sub.4) and concentrated. The residual oil was
purified by means of PTLC plates using AcOEt:hexane=1:1 (v/v) as
eluent to afford the olefin 61 (118 mg, 45%) as an oil; .sup.1H NMR
(400 MHz; CDCl.sub.3) .delta. 1.88 (d, J=1.0 Hz, 3H), 1.94 (d,
J=1.0 Hz, 3H), 3.96 (s, 3H), 6.37 (s, 1H), 7.39-7.46 (m, 3H),
7.49-7.54 (m, 1H), 7.59 (s, 1H), 7.63-7.68 (m, 2H), 7.75 (s, 1H),
7.90 (d, J=1.8 Hz, 1H), 8.23 (d, J=1.8 Hz, 1H).
5-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3--
b]pyridine (621
##STR00148##
[0365] A mixture of olefin 61 (118 mg, 3.00 mmol) and moist
Pd(OH).sub.2 on carbon (96 mg of catalyst containing 20% wt Pd) in
MeOH (6 mL) was stirred vigorously under H.sub.2 for 93 h. The
catalyst was removed by filtration through a pad of Celite. The pad
was washed sequentially with MeOH, CH.sub.2Cl.sub.2 and AcOH and
the combined filtrates were concentrated to afford azaindole 62 as
brown oil that was used directly without purification in the next
step. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 0.90 (s, 3H), 0.91
(s, 3H), 1.87 (m, 1H), 2.58 (d, J=7.2 Hz, 2H), 3.96 (s, 3H), 7.34
(s, 1H), 7.41-7.46 (m, 2H), 7.50-7.55 (m, 1H), 7.59 (s, 1H),
7.62-7.67 (m, 2H), 7.73 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.99 (d,
J=1.8 Hz, 1H).
5-isobutyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine
(63)
##STR00149##
[0367] To crude azaindole 62 (118 mg) in EtOH (6 mL) was added 10%
NaOH (1 mL) and the mixture was stirred in an oil bath (90.degree.
C.) for 4.5 h. The mixture was then cooled to r.t., diluted with
AcOEt and saturated brine and partitioned. The aqueous layer was
extracted with AcOEt (3.times.). The combined organic solutions
were dried (MgSO.sub.4), filtered and concentrated. The residual
yellow oil was partially purified by means of PTLC employing AcOEt
as eluent to afford a semi-pure azaindole 63 (74 mg). A fraction
(14 mg) of this material was further purified by means of
preparative LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water-acetonitrile (0.1% AcOH) as eluent (in
gradient; flow 80 mL/min) to give the desired azaindole 63 (5.6 mg,
25%); .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 0.92 (s, 3H), 0.94
(s, 3H), 1.90 (m, 1H), 2.59 (d, J=7.2 Hz, 2H), 3.98 (s, 3H), 7.36
(d, J=2.1 Hz, 1H), 7.60 (s, 1H), 7.74 (d, J=0.6 Hz, 1H), 7.81 (d,
J=1.8 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 9.62 (br s, 1H); MS (CI) m/z
255 (MH.sup.+).
[0368] Synthesis of Example Inhibitor 67
##STR00150##
(E)-5-(4-(tert-butyldimethylsilyloxy)but-1-enyl)-3-(1-methyl-1H-pyrazol-4-
-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (65)
##STR00151##
[0370] A mixture of bromide 37 (280 mg, 0.67 mmol), boronic pinacol
ester 64 (314 mg, 1.01 mmol), LiCl (84 mg, 2.02 mmol),
(PPh.sub.3).sub.2PdCl.sub.2 (24 mg, 0.03 mmol), 1.0 M aqueous
Na.sub.2CO.sub.3 (1.68 mL, 1.68 mmol), in toluene (8 mL)-EtOH (8
mL) was stirred in an oil bath (105.degree. C.) for 5.5 h. The
reaction mixture was then cooled to r.t., diluted with AcOEt and
saturated brine and partitioned. The aqueous layer was extracted
with AcOEt (2.times.). The combined organic solutions were dried
(MgSO.sub.4) and concentrated. The residual oil was purified by
means of PTLC plates using AcOEt:hexane=1:1 (v/v) as eluent to
afford the olefin 65 (198 mg, 56%) as an oil; .sup.1H NMR (400 MHz;
CDCl.sub.3) .delta. 0.04 (s, 6H), 0.87 (s, 9H), 2.43 (dq, J=6.6,
1.0 Hz, 2H), 3.72 (t, J=6.6 Hz, 2H), 3.96 (s, 3H), 6.26 (d, J=16.4
Hz, 1H), 6.49 (d, J=16.4 Hz, 1H), 7.43-7.47 (m, 2H), 7.52-7.56 (m,
1H), 7.62 (s, 1H), 7.72 (d, J=10.2 Hz, 2H), 7.87 (d, J=1.9 Hz, 1H),
8.15-8.17 (m, 2H), 8.41 (d, J=1.9 Hz, 1H).
4-(3-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridi-
n-5-yl)butan-1-ol (66)
##STR00152##
[0372] A mixture of olefin 65 (198 mg, 0.38 mmol) and moist
Pd(OH).sub.2 on carbon (96 mg of catalyst containing 20% wt Pd) in
MeOH (6 mL) was stirred vigorously under H.sub.2 for 43 h. The
catalyst was removed by filtration through a pad of Celite. The pad
was washed sequentially with MeOH, CH.sub.2Cl.sub.2 and AcOH and
the combined filtrates were concentrated to afford azaindole 66 as
brown oil that was used directly without purification in the next
step; .sup.1H NMR (400 MHz; CDCl.sub.3) .delta. 1.55-1.76 (m, 4H),
2.71 (t, J=7.7 Hz, 2H), 3.64 (t, J=6.4 Hz, 2H), 3.97 (s, 3H),
7.43-7.47 (m, 2H), 7.52-7.56 (m, 1H), 7.64 (s, 1H), 7.71 (s, 1H),
7.73-7.75 (m, 2H), 8.16-8.18 (m, 2H), 8.27 (d, J=1.9 Hz, 1H).
4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)butan-1-ol
(67)
##STR00153##
[0374] To crude azaindole 66 (76 mg, 0.19 mmol) in EtOH (6 mL) was
added 10% NaOH (1 mL) and the mixture was stirred in an oil bath
(90.degree. C.) for 2 h. The mixture was then cooled to r.t.,
diluted with AcOEt and saturated brine and partitioned. The aqueous
layer was extracted with AcOEt (3.times.). The combined organic
solutions were dried (MgSO.sub.4), filtered and concentrated. The
residual yellow oil was purified by means of PTLC employing AcOEt
as eluent to afford the azaindole 67 (16 mg, 31%); .sup.1H NMR (400
MHz; CDCl.sub.3) .delta. 1.61-1.80 (m, 8H), 2.77 (t, J=7.6 Hz, 2H),
3.67 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 7.34 (d, J=1.9 Hz, 1H), 7.61
(s, 1H), 7.73 (d, J=0.6 Hz, 1H), 7.85 (d, J=1.8 Hz, 1H), 8.17 (d,
J=1.8 Hz, 1H), 9.29 (br s, 1H).
[0375] Synthesis of Example Inhibitor 69
##STR00154##
N,N-dimethyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1-(2-(trimethylsilyl)ethoxy)-
-1H-pyrrolo[2,3-b]pyridin-5-ylthio)aniline (68)
##STR00155##
[0377] A mixture of bromide 24 (100 mg, 0.245 mmol),
3-(dimethylamino)benzenethiol (94 mg, 0.613 mmol), CuI (9.3 mg,
0.049 mmol), N,N-dimethylglycine (5.1 mg, 0.049 mmol), potassium
phosphate (156 mg, 0.736 mmol) and DMF (1.0 mL) was heated to
160.degree. C. using microwave irradiation for 0.5 h then at
180.degree. C. for 1 h. The reaction mixture was cooled and
partitioned between AcOEt/brine, the layers separated and the
aqueous phase extracted with more AcOEt (2.times.). The combined
organic extracts were dried (MgSO.sub.4) and concentrated. The
resulting crude residue containing 68 was purified by PTLC using
80% ethyl acetate in hexane as eluent to afford pure 68 as an
orange oil (78 mg, 66%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
-0.055 (s, 9H), 0.95 (t, J=8.2 Hz, 2H), 2.87 (s, 6H), 3.58 (t,
J=8.2 Hz, 2H), 3.95 (s, 3H), 5.68 (s, 2H), 6.43 (d, J=7.6 Hz, 1H),
6.51 (tt, J=8.3, 2.0 Hz, 1H), 6.62 (s, 1H), 7.06 (t, J=8.0 Hz, 1H),
7.45 (s, 1H), 7.61 (s, 1H), 7.76 (s, 1H), 8.22 (d, J=1.7 Hz, 1H),
8.48 (d, J=1.6 Hz, 1H).
N,N-dimethyl-3-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl-
thio)aniline (69)
##STR00156##
[0379] A mixture of 68 (78 mg, 0.163 mmol), 10% aq. HCl (1.0 mL),
EtOH (1.0 mL) was heated at 90.degree. C. for 14 h. Purification by
PTLC using AcOEt as eluent gave 69 as a white solid (22.8 mg, 40%);
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.70 (s, 6H), 3.79 (s,
3H), 7.26 (m, 1H), 6.34 (ddd, J=8.3, 2.5, 0.7 Hz, 1H), 6.44 (t,
J=2.1 Hz, 1H), 6.91 (t, J=8.0 Hz, 1H), 7.26 (s, 1H), 7.45 (s, 1H),
7.55 (d, J=0.7 Hz, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.28 (d, J=1.9 Hz,
1H).
[0380] Synthesis of Example Inhibitor 77
##STR00157##
2-Bromo-1-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (70)
##STR00158##
[0382] To a stirred solution of 1 (6.65 g, 33.8 mmol) in anh.
CS.sub.2 (125 mL) was added AlCl.sub.3 (15.60 g, 117.0 mmol) in a
single portion. The reaction vessel was equipped with a reflux
condenser, the temperature was brought to 50.degree. C., and
bromoacetyl bromide (3.00 mL, 6.95 g, 34.4 mmol) was added dropwise
over 10 min. After stirring at 50.degree. C. for a further 1 h, the
reaction mixture was cooled to 0.degree. C., and 100 mL water was
added (very cautiously at first). Once effervescence had ceased,
AcOEt (300 mL) and THF (100 mL) were added. Solid NaHCO.sub.3 was
then added to adjust the pH of the aqueous layer from 1 to 3. The
layers were separated, and the organic layer washed with saturated
aqueous NaHCO.sub.3 (150 mL) and brine (150 mL). Solvent was then
removed in vacuo to afford a yellow solid (8.32 g), which was
further purified by trituration with MeOH (100 mL) to afford 70 as
an off-white powder (7.16 g, 22.5 mmol, 67%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.31 (s, 2H), 8.10 (d, J=3.1 Hz, 1H), 8.48 (d,
J=2.2 Hz, 1H), 8.83 (d, J=0.4, 2.2 Hz, 1H), 9.34 (br s, 1H).
4-[4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-piperidine-1-ca-
rboxylic acid tert-butyl ester (71)
##STR00159##
[0384] To a solution of 70 (1.71 g, 5.38 mmol) in THF (20 mL) was
added 1-Boc-4-aminothiocarbonyl piperidine (1.31 g, 5.36 mmol) and
the solution was allowed to stir at r.t. for 3 h. The reaction
mixture was then poured onto saturated aqueous NaHCO.sub.3 (50 mL)
and extracted with AcOEt (2.times.50 mL). The combined organic
portions were then evaporated to afford 71 (2.58 g, 5.41 mmol,
100%) as a white powder. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
1.43 (s, 9H), 1.64-1.84 (m, 4H), 2.07-2.17 (m, 2H), 2.81-2.94 (m,
2H), 3.13-3.24 (m, 1H), 7.17 (s, 1H), 7.74 (d, J=2.4 Hz, 1H), 8.32
(d, J=2.1 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.97 (br s, 1H).
4-[4-(1-Benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-y-
l]-piperidine-1-carboxylic acid tert-butyl ester (72)
##STR00160##
[0386] To a vigorously stirred solution of 2 and
n-Bu.sub.4NHSO.sub.4 (120 mg, cat.) in CH.sub.2Cl.sub.2 (15 mL) was
added 50% aqueous NaOH (0.5 mL), followed by the dropwise addition
of PhSO.sub.2Cl (0.50 mL, 690 mg, 3.90 mmol). The reaction mixture
was allowed to stir overnight, diluted with AcOEt (100 mL), and
washed with saturated aqueous NaHCO.sub.3 (3.times.25 mL). The
organic layer was dried (MgSO.sub.4) and concentrated to afford a
pale yellow solid (840 mg). On standing overnight, a precipitate
appeared in the aqueous layer, which was filtered to afford a white
powder (710 mg). The two solids were combined to afford 72 as an
off-white solid (1.55 g, 2.57 mmol, 96%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.51 (s, 9H), 1.79 and 1.84 (2.times.dd,
2.times.J=4.4, 12.6 Hz, 2.times.1H), 2.19 (br d, J=12.6 Hz, 2H),
2.95 (br t, J=12.3 Hz, 2H), 3.25 (tt, J=3.8, 11.6 Hz, 1H), 4.26 (br
s, 2H), 7.37 (s, 1H), 7.52 (t, J=7.8 Hz, 2H), 7.62 (t, J=7.5 Hz,
1H), 8.17 (s, 1H), 8.22 (d, J=7.8 Hz, 1H), 8.52 & 8.54
(2.times.d, 2.times.J=2.4 Hz, 1H).
1-Benzenesulfonyl-5-bromo-3-[2-(1-methyl-piperidin-4-yl)-thiazol-4-yl]-1H
pyrrolo[2,3-b]pyridine (74)
##STR00161##
[0388] To a stirred solution of 3 (1.55 g, 2.57 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was added CF.sub.3COOH (5 mL). After 1 h,
the solution was concentrated to dryness and THF (5 mL) was added.
To the resulting suspension was added formaldehyde (40% aq., 1 mL,
excess), acetic acid (3 drops, cat.) and NaBH(OAc).sub.3 (800 mg,
3.77 mmol). The reaction mixture was allowed to stir overnight, and
was then quenched by the addition of 1.0 N aqueous HCl (10 mL, 10
mmol). The mixture was then neutralised with 1.0 N aqueous NaOH (10
mL) and extracted with AcOEt (3.times.50 mL). The organic portions
were combined, dried over MgSO.sub.4 and concentrated to afford 74
as a pale yellow solid (840 mg, 1.62 mmol, 63%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 1.85-2.00 (m, 2H), 2.07-2.23 (m, 4H), 2.33
(s, 3H), 2.93-3.07 (m, 3H), 7.27 (s, 1H), 7.42 (t, J=7.7 Hz, 2H),
7.52 (t, J=7.4 Hz, 1H), 8.06 (s, 1H), 8.12 (d, J=7.7 Hz, 1H), 8.41
& 8.45 (2.times.d, 2.times.J=2.0 Hz, 1H).
1-Benzenesulfonyl-3-[2-(1-methyl-piperidin-4-yl)-thiazol-4-yl]-5-(2-methyl-
-propenyl)-1H-pyrrolo[2,3-b]pyridine (75)
##STR00162##
[0390] To a stirred solution of 74 (202 mg, 0.39 mmol), isobutenyl
boronic acid (50 mg, 0.50 mmol) and (PPh.sub.3).sub.2PdCl.sub.2 (30
mg, 43 .mu.mol) in toluene:EtOH 1:1 (3 mL) was added LiCl (50 mg,
1.19 mmol) and 1.0 M aq. Na.sub.2CO.sub.3 (0.75 mL, 0.75 mmol). The
mixture was heated to reflux (bath temperature 110.degree. C.) and
stirred for 1.5 h. Saturated aqueous NaHCO.sub.3 (25 mL) was added,
and the mixture was extracted with AcOEt (2.times.40 mL). The
combined organic solutions were dried (MgSO.sub.4) and concentrated
to afford a brown solid (255 mg). The crude product was purified by
SGC with 5% MeOH in CH.sub.2Cl.sub.2 as eluent to afford 75 as an
off-white powder (166 mg, 0.34 mmol, 86%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.88 (s, 3H), 1.96 (s, 3H), 1.92-2.04 (m, 2H),
2.11-2.25 (m, 2H), 2.37 (s, 3H), 2.97-3.11 (m, 3H), 6.33 (1H, s,
1H), 7.34 (s, 1H), 7.48 (t, J=7.5 Hz, 2H), 7.54-7.60 (m, 1H), 8.14
(s, 1H), 8.20-8.25 (m, 3H), 8.36 (d, J=2.0 Hz, 1H).
1-Benzenesulfonyl-5-isobutyl-3-[2-(1-methyl-piperidin-4-yl)-thiazol-4-yl]--
1H-pyrrolo[2,3-b]pyridine (76)
##STR00163##
[0392] To a solution of 75 (166 mg, 0.34 mmol) in MeOH (10 mL) was
added 20% Pd(OH).sub.2 on carbon (50 mg, cat.), and the reaction
mixture was stirred vigorously under H.sub.2 for 72 h. The mixture
was then filtered through Celite, which was then washed with MeOH
(100 mL). The filtrate was concentrated to afford 76 as a foam (155
mg, 0.31 mmol, 93%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.93
(d, J=6.6 Hz, 2H), 1.85-1.97 (m, 1H), 2.06-2.18 (m, 2H), 2.26-2.47
(m, 4H), 2.48 (s, 3H), 2.60 (d, J=7.3 Hz, 2H), 3.10-3.21 (m, 3H),
7.37 (s, 1H), 7.45-7.61 (m, 3H), 8.08 (d, J=2.0 Hz, 1H), 8.15 (s,
1H), 8.21-8.26 (m, 2H), 8.29 (d, J=2.0 Hz, 1H).
5-Isobutyl-3-[2-(1-methyl-piperidin-4-yl)-thiazol-4-yl]-1H-pyrrolo[2,3-b]p-
yridine (77)
##STR00164##
[0394] To a stirred solution of 76 (155 mg, 0.31 mmol) in EtOH (4
mL) was added 10% aqueous NaOH (2 mL) and the reaction was heated
at reflux for 1.5 h. The mixture was then cooled. Saturated aqueous
NaHCO.sub.3 (25 mL) was added, and the solution was extracted with
AcOEt (2.times.40 mL). The combined organic extracts were dried
(MgSO.sub.4) and concentrated to afford a brown solid, which was
purified by preparative LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0
250.times.50 mm) using water-acetonitrile (0.1% ACOH) as eluent (in
gradient; flow 80 mL/min) to afford 77 as a white solid (54 mg,
0.15 mmol, 49%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.96 (d,
J=6.6 Hz, 2H), 1.94 (nonet, J=6.7 Hz, 1H), 2.07-2.19 (m, 2H),
2.25-2.35 (m, 2H), 2.41-2.52 (m, 5H), 2.64 (d, J=7.1 Hz, 2H),
3.14-3.24 (m, 3H), 7.26 (s, 1H), 7.83 (s, 1H), 8.10 (d, J=1.9 Hz,
1H), 8.18 (d, J=1.9 Hz, 1H), 10.90 (br s, 1H). MS (CI) m/z 355
(MH.sup.+).
[0395] Synthesis of Example Inhibitor 83
##STR00165##
4-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazole-2-carboxylic
acid ethyl ester (78)
##STR00166##
[0397] To a stirred solution of 70 (4.97 g, 15.6 mmol) in dioxane
(55 mL) was added ethyl thiooxamate (2.29 g, 17.2 mmol). The
reaction mixture was stirred vigorously at 95.degree. C. for 18 h.
The hot reaction mixture was filtered and the collected product was
washed with cold dioxane (25 mL) to afford the hydrobromide salt of
78 as a yellow powder (6.08 g, 14.0 mmol, 90%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 1.48 (t, J=7.1 Hz, 3H), 4.52 (q, J=7.1 Hz,
2H), 7.77 (s, 1H), 8.05 (s, 1H), 8.43 (d, J=1.8 Hz, 1H), 9.21 (s,
1H).
4-(1-Benzenesulfonyl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazole-2-car-
boxylic acid ethyl ester (79)
##STR00167##
[0399] To a stirred solution of 78 (6.08 g, 14.0 mmol) in
CH.sub.2Cl.sub.2 (75 mL) was added n-Bu.sub.4NHSO.sub.4 (100 mg,
cat.) and 50% aqueous NaOH (2 mL). PhSO.sub.2Cl (2.50 mL, 19.5
mmol) was then added dropwise, and the reaction stirred at r.t. for
1.5 h. The mixture was then diluted with EtOAc (400 mL) and acetone
(20 mL), washed with brine (2.times.100 mL) and concentrated to
give a yellow solid (6.02 g). The crude product was recrystallized
from CH.sub.2Cl.sub.2/hexane to afford pure 79 as a yellow solid
(2.33 g). More product was obtained from the mother liquor by SGC
using hexane:CH.sub.2Cl.sub.2:EtOAc (2:1:1, v/v/v) as eluent. Total
yield of 79 4.40 g, 8.94 mmol, 57%. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.51 (t, J=7.2 Hz, 3H), 4.55 (q, J=7.1 Hz, 2H),
7.53 (t, J=7.8 Hz, 2H), 7.63 (t, J=7.5 Hz, 1H), 7.74 (s, 1H), 8.24
(d, J=7.8 Hz, 1H), 8.30 (s, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.56 (d,
J=2.1 Hz, 1H).
4-[1-Benzenesulfonyl-5-(2-methyl-propenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]--
thiazole-2-carboxylic acid ethyl ester (80)
##STR00168##
[0401] To a stirred solution of 79 (683 mg, 1.55 mmol), isobutenyl
boronic acid (180 mg, 1.81 mmol) and (PPh.sub.3).sub.2PdCl.sub.2
(100 mg, 142 .mu.mol) in toluene:EtOH 1:1 (10 mL) was added LiCl
(160 mg, 3.81 mmol) and 1.0 M aqueous Na.sub.2CO.sub.3 (2.5 mL).
The mixture was heated to reflux (bath temperature 110.degree. C.)
and stirred for 1.5 h. Saturated aqueous NaHCO.sub.3 (50 mL) was
added, and the mixture was extracted with EtOAc (2.times.75 mL).
The combined organic solutions were dried (MgSO.sub.4) and
concentrated to afford a brown solid (922 mg). The crude product
was isolated by means of SGC using
hexane:EtOAc:CH.sub.2Cl.sub.2=2:1:1 (v/v/v) as eluent to afford 80
as a foam (548 mg, 1.32 mmol, 85%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.40 (t, J=7.2 Hz, 3H), 1.80 (d, J=1.1 Hz, 3H),
1.86 (d, J=1.1 Hz, 3H), 4.43 (q, J=7.1 Hz, 2H), 6.24 (s, 1H), 7.40
(t, J=7.8 Hz, 2H), 7.49 (t, J=7.4 Hz, 1H), 7.63 (s, 1H), 8.13-8.17
(m, 3H)), 8.18 (s, 1H), 8.28 (d, J=1.9 Hz, 1H).
4-(1-Benzenesulfonyl-5-isobutyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazole-2--
carboxylic acid ethyl ester (81)
##STR00169##
[0403] To a solution of 80 (548 mg, 1.32 mmol) in
MeOH:CH.sub.2Cl.sub.2=3:1 (v/v; 20 mL) was added 20% Pd(OH).sub.2
on carbon (100 mg, cat.), and the reaction mixture was stirred
vigorously under H.sub.2 for 72 h. The mixture was then filtered
through Celite, which was then washed with
MeOH:CH.sub.2Cl.sub.2=1:1 (v/v; 100 mL). The solutions were
combined and concentrated to afford 81 as a foam (412 mg, 0.99
mmol, 75%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (d,
J=6.6 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H), 1.82 (nonet, J=6.7 Hz, 1H),
2.51 (d, J=7.2 Hz, 2H), 4.45 (q, J=7.1 Hz, 2H),), 7.41 (t, J=7.8
Hz, 2H), 7.48 (t, J=7.6 Hz, 1H), 7.66 (s, 1H), 8.03 (d, J=1.8 Hz,
1H), 8.15 (d, J=7.5 Hz, 1H), 8.20 (s, 1H), 8.22 (d, J=1.9 Hz,
1H).
4-(5-Isobutyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazole-2-carboxylic
acid (82)
##STR00170##
[0405] To a stirred solution of 81 (412 mg, 0.99 mmol) in EtOH (10
mL) was added 10% aqueous NaOH (5 mL) and the reaction mixture
heated to reflux. After 2 h, the solution was cooled to r.t., and
the mixture concentrated to 5 mL under reduced pressure. Acetic
acid was then added dropwise with stirring until a precipitate
appeared, which was filtered off and dried to afford 82 (267 mg,
0.89 mmol, 90%) as a yellow powder. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 0.91 (d, J=6.6 Hz, 2H), 1.92 (nonet, J=6.6
Hz, 1H), 2.60 (d, J=7.2 Hz, 2H), 7.69 (s, 1H), 7.95 (s, 1H), 8.08
(d, J=1.9 Hz, 1H), 8.27 (s, 1H), 11.73 (s, 1H).
[4-(5-Isobutyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-piperidin-1-yl-
-methanone (83)
##STR00171##
[0407] To a stirred solution of 82 (60 mg, 0.20 mmol) in DMF (1 mL)
was added N,N-diisopropylethylamine (50 mg, 0.39 mmol), piperidine
(40 mg, 0.47 mmol) and
(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate
(PyBOP; 180 mg, 0.35 mmol). After stirring for 1 h, the reaction
mixture was filtered and purified by preparative LCMS (column LUNA
10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-acetonitrile
(0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 83 as
a white solid (42 mg, 0.11 mmol, 57%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 0.89 (d, J=6.6 Hz, 2H), 1.63-1.76 (m, 6H), 1.86
(nonet, J=6.6 Hz, 1H), 2.56 (d, J=7.2 Hz, 2H), 3.69-3.75 (m, 2H),
4.32-4.39 (m, 2H), 7.45 (s, 1H), 7.70 (d, J=2.6 Hz, 1H), 8.11 (d,
J=1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 9.26 (s, 1H). MS (CI) m/z
369 (MH.sup.+).
[0408] Synthesis of Example Inhibitors 89 and 90
##STR00172##
8-Bromomethylene-1,4-dioxa-spiro[4.5]decane (85)
##STR00173##
[0410] 1.0 N solution of sodium hexamethyldisilazide (10.8 mL, 1N
in THF, 10.8 mmol) was added dropwise to a cooled (-60.degree. C.)
solution of bromomethyltriphenylphosphonium bromide (4.71 g, 10.8
mmol) in anhydrous THF (30 mL). After stirring for a further 1 h,
1,4-cyclohexanedione monoethylene acetal (84) (1.40 g, 8.96 mmol)
in THF (5 mL) was added over 1 min. The cooling bath was then
removed and the reaction mixture allowed to warm to r.t. and stir
for a further 1 h. Hexane (50 mL) was then added, and the resulting
solution was filtered through a short plug of SiO.sub.2. The
filtrate was concentrated to afford yellow oil (2.21 g).
Purification by means of SGC with AcOEt:hexane=9:1 (v/v) as eluent
afforded 85 as a clear oil (1.32 g, 5.67 mmol, 63%). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 1.62 (t, J=6.8 Hz, 3H), 1.65 (t,
J=7.4 Hz, 3H), 2.27 (ddd, J=1.0, 5.3, 7.3 Hz, 2H), 2.42 (ddd,
J=1.0, 5.8, 7.6 Hz, 2H), 3.89-3.92 (m, 4H), 5.85 (pentet, J=1.0 Hz,
1H).
5-(1,4-Dioxa-spiro[4.5]dec-8-ylidenemethyl)-3-(2-methyl-1H-pyrazol-4-yl)-1-
-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine
(86)
##STR00174##
[0412] To a stirred solution of 85 (1.50 g, 6.44 mmol), 25 (1.94 g,
4.36 mmol) and (PPh.sub.3).sub.2PdCl.sub.2 (300 mg, 0.43 mmol) in
toluene:EtOH=1:1 (v/v, 20 mL) was added LiCl (650 mg, 14.9 mmol)
and 1.0 M aqueous Na.sub.2CO.sub.3 (5 mL). The mixture was heated
to refluxed (bath temperature 110.degree. C.) and stirred for 2.5
h. Saturated aqueous NaHCO.sub.3 (100 mL) was added, and the
mixture was extracted with AcOEt (2.times.150 mL). The combined
organic solutions were dried (MgSO.sub.4) and concentrated to
afford a yellow oil (3.46 g). The crude product was purified by SGC
using AcOEt:hexane=11:1 (v/v) as eluent to afford 86 as an oil (389
mg, 0.81 mmol, 19%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.00
(s, 9H), 0.99 (t, J=8.3 Hz, 2H), 1.76 (t, J=6.5 Hz, 2H), 1.89 (t,
J=6.5 Hz, 2H), 2.55 (t, J=6.5 Hz, 2H), 2.61 (t, J=6.5 Hz, 2H), 3.63
(t, J=8.3 Hz, 2H), 4.00-4.10 (m, 7H), 5.74 (s, 2H), 6.48 (s, 1H),
7.47 (s, 1H), 7.68 (s, 1H), 7.81 (s, 1H), 7.90 (d, J=1.8 Hz, 1H),
8.29 (d, J=1.8 Hz, 1H).
5-(1,4-Dioxa-spiro[4.5]dec-8-ylmethyl)-3-(2-methyl-1H-pyrazol-4-yl)-1-(2-t-
rimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (87)
##STR00175##
[0414] To a solution of 86 (389 mg, 0.81 mmol) in MeOH (15 mL) was
added 20% Pd(OH).sub.2 on carbon (50 mg, cat.), and the reaction
mixture was stirred vigorously under H.sub.2 for 48 h. The mixture
was then filtered through Celite, which was then washed with
MeOH:CH.sub.2Cl.sub.2=1:1 (v/v; 200 mL). The solutions were
combined and concentrated to afford 87 as a clear oil (307 mg, 0.64
mmol, 79%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.00 (s, 9H),
0.99 (t, J=8.1 Hz, 2H), 1.34-1.46 (m, 2H), 1.56 (dt, J=13.9, 4.8
Hz, 2H), 1.61-2.12 (m, 5H), 2.74 (d, J=7.1 Hz, 2H), 3.64 (t, J=8.3
Hz, 2H), 4.00 (s, 4H), 4.07 (s, 3H), 5.76 (s, 2H), 7.47 (s, 1H),
7.70 (s, 1H), 7.82 (s, 1H), 7.88 (s, 1H), 8.23 (d, J=1.8 Hz,
1H).
4-[3-(2-Methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyr-
rolo[2,3-b]pyridin-5-ylmethyl]-cyclohexanone (88)
##STR00176##
[0416] To a solution of 87 (307 mg, 0.64 mmol) in THF (20 mL) was
added 6.0 N aq. HCl solution (7 mL) and the reaction mixture was
allowed to stir at r.t. for 1 h. Water (50 mL) was then added, and
the mixture extracted with AcOEt (2.times.75 mL). The combined
organic solutions were dried (MgSO.sub.4) and concentrated to
afford 88 as a clear oil (261 mg, 0.59 mmol, 93%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 0.00 (s, 9H), 0.99 (t, J=8.2 Hz, 2H),
1.49-1.62 (m, 2H), 2.07-2.16 (m, 2H), 2.31-2.49 (m, 5H), 2.82 (d,
J=6.7 Hz, 2H), 3.65 (t, J=8.3 Hz, 2H), 4.07 (s, 3H), 5.77 (s, 2H),
7.49 (s, 1H), 7.69 (s, 1H), 7.83 (s, 1H), 7.92 (s, 1H), 8.27 (s,
1H).
Dimethyl-{4-[3-(2-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylmet-
hyl]-cyclohexyl}-amine (89) and
4-[3-(2-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl]-cycl-
ohexanol (90)
##STR00177##
[0418] To a solution of 88 (89 mg, 0.20 mol) in MeOH (2 mL) was
added Me.sub.2NH.HCl (100 mg, 1.23 mmol), and the solution was
allowed to stir for 10 min. NaBH.sub.3CN (30 mg, 0.48 mmol) was
then added, and stirring was continued for 22 h. The reaction was
then quenched by the addition of saturated aqueous NaHCO.sub.3 (25
mL) and extracted with AcOEt (2.times.25 mL). The combined organic
solutions were (MgSO.sub.4) and concentrated to afford an oil (84
mg). The oil was dissolved in EtOH (2 mL) and 10% aq. HCl (2 mL)
was added. The reaction mixture was heated to 90.degree. C. for 6
h, then evaporated and purified by preparative LCMS (column LUNA
10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-acetonitrile
(0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford two
compounds. Eluting first, 89 (22 mg, 65 .mu.mol, 33%), a white
powder, as a 1:1 mixture of diastereomers. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.05-2.15 (m, 9H), 2.55-2.90 (m, 3H), 3.98 (s,
3H), 7.35 (s, 1H), 7.60 (s, 0.5H), 7.65 (s, 0.5H), 7.70-7.74 (m,
1H), 7.80 (d, J=1.8 Hz, 0.5H), 7.86 (d, J=1.8 Hz, 0.5H), 8.01 (d,
J=1.8 Hz, 0.5H), 8.05, (d, J=1.8 Hz, 0.5H), 10.01 (br s, 0.5H),
10.05 (br s, 0.5H). MS (CI) m/z 338 (MH.sup.+). Further elution
afforded 90, a white powder (8 mg, 26 .mu.mol, 13%) as an
unassigned 4:1 mixture of diastereoisomers. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.01-2.00 (m, 9H), 2.67 (d, J=7.1 Hz, 1.6H),
2.73 (d, J=7.1 Hz, 0.4H) 3.51-3.61 (m, 1H), 4.00 (s, 3H), 7.45 (s,
0.8H), 7.46 (s, 0.2H), 7.63 (s, 0.1H), 7.74 (s, 1H), 8.03 (s,
0.8H), 8.06 (s, 1H), 8.06 (s, 0.2H). MS (CI) m/z 311
(MH.sup.+).
4-[3-(2-Methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-ylmethyl]-cyclo-
hexanone (91)
##STR00178##
[0420] To a solution of 88 (19 mg, 42 .mu.mol) in EtOH (1 mL) was
added 10% aq. HCl (1 mL) and the reaction mixture heated to reflux
(bath temperature 90.degree. C.) for 18 h. The solution was then
concentrated and the residue purified by preparative LCMS (column
LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using
water-acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80
mL/min) to afford 91 (8 mg, 26 .mu.mol, 62%) as a white powder.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.49-1.63 (m, 2H),
2.04-2.19 (m, 3H), 2.31-2.50 (m, 4H), 2.92 (d, J=6.9 Hz, 2H), 4.06
(s, 3H), 7.67 (s, 1H), 7.68 (s, 1H), 7.85 (s, 1H), 8.24 (s, 1H),
8.38 (s, 1H), 12.35 (br s, 1H). MS (CI) m/z 309 (MH.sup.+).
[0421] Synthesis of Example Inhibitor 95
##STR00179##
1-Benzenesulfonyl-5-(2-methyl-propenyl)-3-[1-(2-morpholin-4-yl-ethyl)-1H--
pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (93)
##STR00180##
[0423] Bromide 92 (158 mg, 0.31 mmol; prepared in analogous way to
20), isobutenyl boronic acid (40 mg, 0.40 mmol) and
(PPh.sub.3).sub.2PdCl.sub.2 (30 mg, 43 .mu.mol) in toluene:EtOH 1:1
(2 mL) was added LiCl (50 mg, 1.18 mmol) and 1.0 M aq.
Na.sub.2CO.sub.3 solution (0.5 mL). The mixture was refluxed (bath
temperature 115.degree. C.) for 3 h. Saturated aqueous NaHCO.sub.3
(50 mL) was added, and the mixture was extracted with AcOEt
(2.times.75 mL). The combined organic solutions were dried
(MgSO.sub.4) and concentrated to afford a brown solid (175 mg). The
crude product was purified by SGC using
MeOH:CH.sub.2Cl.sub.2:AcOEt=2:49:49 (v/v) as eluent to afford 93 as
an off-white powder (99 mg, 0.20 mmol, 66%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 1.87 (s, 3H), 1.96 (s, 3H), 2.53 (t, J=4.6 Hz,
4H), 2.88 (t, J=6.6 Hz, 2H), 3.73 (t, J=4.6 Hz, 4H), 4.33 (t, J=6.6
Hz, 2H), 6.32 (1H, s, 1H), 7.51 (t, J=7.8 Hz, 2H), 7.60 (t, J=7.5
Hz, 1H), 7.77 (s, 2H), 7.78 (s, 1H), 7.80 (d, J=1.9 Hz, 1H), 8.23
(d, J=7.6 Hz, 2H), 8.37 (d, J=1.9 Hz, 1H).
1-Benzenesulfonyl-5-isobutyl-3-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl-
]-1H-pyrrolo[2,3-b]pyridine (94)
##STR00181##
[0425] To a solution of 93 (80 mg, 0.18 mmol) in MeOH (4 mL) was
added 20% Pd(OH).sub.2 on C (30 mg, cat.), and the reaction mixture
was stirred vigorously under H.sub.2 for 24 h. The mixture was then
filtered through Celite, which was then washed with
MeOH:CH.sub.2Cl.sub.2=1:1 (v/v; 50 mL). The solutions were combined
and concentrated to afford 94 as a foam (66 mg, 0.15 mmol, 82%).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (d, J=6.6 Hz, 2H),
1.40 (t, J=7.1 Hz, 3H), 1.80 (nonet, J=6.7 Hz, 1H), 2.50 (d, J=7.3
Hz, 2H), 2.49-2.60 (m, 4H), 2.84-3.06 (m, 2H), 3.63-3.76 (m, 4H),
4.29-4.46 (m, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.50 (t, J=7.4 Hz, 1H),
7.66 (d, J=2.0 Hz, 1H), 7.68 (s, 1H), 7.71 (s, 1H), 7.76 (s, 1H),
8.03 (d, J=1.8 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H), 8.20 (d, J=1.9 Hz,
1H).
5-Isobutyl-3-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b-
]pyridine (95)
##STR00182##
[0427] To a stirred solution of 94 (66 mg, 0.15 mmol) in EtOH (2
mL) was added 10% aq. NaOH (1 mL) and the reaction mixture heated
to reflux for 2 h. The mixture was then cooled, AcOEt (50 mL)
added, and the solution was washed with saturated aqueous
NaHCO.sub.3 (2.times.25 mL). The organic portion was dried
(MgSO.sub.4) and concentrated to afford 25 as an off-white solid
(44 mg, 0.12 mmol, 83%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
0.88 (d, J=6.6 Hz, 2H), 1.85 (nonet, J=6.7 Hz, 1H), 2.46 (t, J=4.5
Hz, 4H), 2.55 (d, J=7.2 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H), 3.66 (t,
J=4.6 Hz, 4H), 4.26 (t, J=6.6 Hz, 2H), 7.32 (d, J=2.2 Hz, 1H), 7.68
(s, 1H), 7.70 (s, 1H), 7.76 (d, J=1.7 Hz, 1H), 8.10 (d, J=1.8 Hz,
1H), 9.52 (br s, 1H).
[0428] Synthesis of Example Inhibitor 98
##STR00183##
5-(cyclohexylidenemethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-
-1H-pyrrolo[2,3-b]pyridine (96)
##STR00184##
[0430] A mixture of 37 (100 mg, 0.24 mmol), methylenecyclohexane
(23.1 mg, 0.48 mmol), Pd(OAc).sub.2 (5.39 mg, 0.024 mmol),
biphenyl-2-yldi-tert-butylphosphine (14.3 mg, 0.048 mmol) and
Et.sub.3N (121.4 mg, 1.2 mmol) in DMF (2 mL) was irradiated in a
microwave (120.degree. C., 80 W) in a sealed tube for 5 min. The
mixture was filtered and the product was isolated by reverse-phase
LCMS (column LUNA 10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using
water-acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80
mL/min) to afford 96 (32 mg, 31%) as a solid; .sup.1H NMR (400 MHz;
CDCl.sub.3) .delta. 1.34-1.43 (m, 2H), 1.43-1.56 (m, 4H), 2.11-2.23
(m, 4H), 3.85 (s, 3H), 6.10 (s, 1H), 7.32-7.38 (m, 2H), 7.40-7.46
(m, 1H), 7.49 (s, 1H), 7.59 (s, 1H), 7.60-7.62 (m, 2H), 8.05-8.09
(m, 2H), 8.17-8.19 (d, J=2.09 Hz, 1H). MS (CI) m/z 433
(MH.sup.+).
5-(cyclohexylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-py-
rrolo[2,3-b]pyridine (97)
##STR00185##
[0432] A mixture of 96 (32 mg, 0.073 mmol) and Pd(OH).sub.2 (1.0
mg, 7.3 .mu.mol) in MeOH (2.0 mL) was stirred under H.sub.2 at r.t.
for 30.5 h. The mixture was filtered through Celite and
concentrated to afford 97, which was used in the next step without
purification.
5-(cyclohexylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-
e (98)
##STR00186##
[0434] A mixture of 97 (25 mg, 0.0575 mmol) and 10% aq. NaOH (0.32
mL) in EtOH (2 mL) was refluxed (oil bath temperature 105.degree.
C.) for 30 min., cooled to r.t. and partitioned between
water:AcOEt. The aqueous layer was extracted with AcOEt. The
extract was dried (MgSO.sub.4), concentrated and separated by means
of PTLC using AcOEt as eluent to afford desired inhibitor 98 (2.23
mg, 11% over 2 steps) as a solid. .sup.1H NMR (400 MHz; CDCl.sub.3)
.delta. 0.86-0.97 (m, 2H), 1.05-1.26 (m, 4H), 1.53-1.73 (m, 5H),
2.54 (d, J=7.1 Hz, 2H), 3.93 (s, 3H), 7.29 (d, J=2.3 Hz, 1H), 7.55
(s, 1H), 7.69 (d, J=0.5 Hz, 1H), 7.74 (d, J=1.9 Hz, 1H), 8.07 (d,
J=1.8 Hz, 1H), 9.31 (bs, 1NH); MS (CI) m/z 295 (MH.sup.+).
[0435] Synthesis of Example Inhibitor 100
##STR00187##
5-(cyclopentenylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1-
H-pyrrolo[2,3-b]pyridine (99)
##STR00188##
[0437] A mixture of 37 (100 mg, 0.24 mmol), methylenecyclopentane
(19.72 mg, 0.48 mmol), Pd(OAc).sub.2 (5.39 mg, 0.024 mmol),
biphenyl-2-yldi-tert-butylphosphine (14.3 mg, 0.048 mmol) and
Et.sub.3N (121.4 mg, 1.2 mmol) in DMF (2 mL) was irradiated in a
microwave (110.degree. C., 80 W) in a sealed tube for 19 h. The
mixture was partitioned between AcOEt (10 mL) saturated aqueous
NH.sub.4Cl. The aqueous layer was extracted with AcOEt. The
combined organic solutions were dried (MgSO.sub.4), concentrated
and the product was isolated by reverse-phase LCMS (column LUNA
10.mu. C18(2) 00G-4253-V0 250.times.50 mm) using water-acetonitrile
(0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to afford 99
(22.70 mg, 23%) as a solid. .sup.1H NMR (400 MHz; CDCl.sub.3)
.delta. 1.86-1.91 (m, 2H), 2.17-2.25 (m, 2H), 2.27-2.35 (m, 2H),
3.46-3.50 (m, 2H), 4.01 (s, 3H), 5.30-5.37 (m, 1H), 7.48-7.55 (m,
1H), 7.56-7.61 (m, 1H), 7.65 (s, 1H), 7.52-7.83 (m, 3H), 8.21-8.23
(m, 2H), 8.23-8.25 (m, 1H), 8.32 (d, J=2.1 Hz, 1H). MS (CI) m/z 419
(MH.sup.+).
5-(cyclopentenylmethyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyri-
dine (100)
##STR00189##
[0439] A mixture of 99 (22.70 mg, 0.054 mmol) and 10% aq. NaOH
(0.60 mL) in EtOH (1.43 mL) was refluxed (oil bath temperature
105.degree. C.) for 30 min., cooled to r.t. and partitioned between
water:AcOEt. The aqueous layer was extracted with AcOEt. The
extract was dried (MgSO.sub.4), concentrated and separated by means
of PTLC using AcOEt as eluent to afford desired inhibitor 100 (4.29
mg, 44%) as a solid. .sup.1H NMR (400 MHz; CDCl.sub.3) .delta.
1.77-1.84 (m, 2H), 2.12-2.21 (m, 2H), 2.21-2.28 (m, 2H), 3.42-3.46
(m, 2H), 3.92 (s, 3H), 5.25-5.29 (m, 1H), 7.30 (d, J=2.5 Hz, 1H),
7.55 (s, 1H), 7.68 (s, 1H), 7.87 (d, J=1.7 Hz, 1H), 8.12 (d, J=1.8
Hz, 1H), 9.16 (bs, 1NH). MS (CI) m/z 279 (MH.sup.+).
[0440] Biological Activity
JNK1, JNK2, JNK3-SPA Assay
[0441] 1. Compound is dissolved in DMSO to a convenient
concentration and this is diluted in 10% DMSO to a five times
concentrate of the desired starting concentration (frequently
1:100). [0442] 2. 10 .mu.l of 500 mM EDTA is added to alternative
wells of the Opti-plate row, which will receive kinase reaction
plus DMSO. This creates the negative control. [0443] 3. For the
JNK2 and JNK3 assay, compounds are prepared in six 2-fold dilutions
with water and each concentration is tested in duplicate. For the
JNK1 assay compounds are prepared in four 5-fold dilutions with
water which are tested in triplicate. Controls are treated
identically. [0444] 4. 20 .mu.l per well of each compound
concentration is transferred to an Opti-plate, in duplicate. [0445]
5. 30 .mu.l (JNK2/3 SPA) or 50 .mu.l (JNK1 SPA) of substrate
solution (25 mM HEPES pH 7.5, 10 mM magnesium acetate with 3.33 M
ATP (JNK2/3) or 2 M ATP (JNK1), approximately 7.5 kBq
[.gamma.-.sup.33P] ATP, GST-c-Jun, in water) is added to each well.
[0446] 6. 50 .mu.l (JNK2/3 SPA) or 30 .mu.l (JNK1 SPA) of kinase
solution (JNK in 25 mM HEPES pH 7.5, 10 mM Mg Acetate) is added to
each well.
TABLE-US-00001 [0446] Kinase Kinase per well (.mu.g) GST-c-Jun per
well (.mu.g) JNK1 0.25 1 JNK2 0.2 1.2 JNK3 0.16 1.2
[0447] 7. The plate is incubated for 30 minutes at room
temperature. [0448] 8. 100 .mu.l of bead/stop solution is added to
each well (5 mg/ml glutathione-PVT-SPA beads, 40 mM ATP in PBS).
[0449] 9. Plates are sealed and incubated for 30 minutes at room
temperature, centrifuged for 10 minutes at 2500 g and counted.
[0450] 10. The IC.sub.50 values are calculated as the concentration
of the compound being tested at which the phosphorylation of c-Jun
is decreased to 50% of the control value. Example IC.sub.50 values
for the compounds of this invention are given in Table 1.
p38 ELISA
[0451] Active p38 kinase (100 ng; Upstate) was added to 2 .mu.g
GST-ATF2 substrate (NEB) in 250 mM Hepes pH 7.5/100 mM MgAc/50
.mu.M ATP (final) in the presence or absence of compounds in 50
.mu.l. The mixture was incubated at 30.degree. C. for 1 hour, and
then diluted with 200 .mu.l PBS-Tween (0.05%). From this, duplicate
volumes of 100 .mu.l were added to a Reacti-Bind glutathione coated
plate (Pierce) and incubated for 1 hour. After washing 3 times with
PBS-Tween (0.05%), rabbit anti-phospho-ATF2 (Thr71) antibody (NEB)
was added at 1:500, and incubated for another hour at room
temperature. After 3 additional washes with PBS-Tween (0.05%), 100
.mu.l of anti-rabbit IgG alkaline phosphatase-conjugated secondary
antibody (Sigma) was added at 1:1000, the reaction was incubated
for a further hour, washed 3 times, and then phosphatase substrate
(Sigma) was added (100 .mu.l per well; 3 tablets in 5 ml water).
After incubation in the dark at 37.degree. C. for 1 hour, the
reaction mixture was transferred to a clear 96 well plate, and the
absorbance at 405 nm was read. The IC.sub.50 values are calculated
as the concentration of the compound being tested at which the
phosphorylation of ATF2 is decreased to 50% of the control value.
Example IC.sub.50 values for the compounds of this invention are
given in Table 1.
TABLE-US-00002 TABLE 1 IC.sub.50 values for selected compounds
against JNK3. JNK3 IC.sub.50 Compound (nM) ##STR00190## <500
##STR00191## <1000 ##STR00192## <200 ##STR00193## <500
##STR00194## <500 ##STR00195## <500 ##STR00196## <1000
##STR00197## <500 ##STR00198## <500 ##STR00199## <2000
##STR00200## <200 ##STR00201## <500 ##STR00202## <500
##STR00203## <500 ##STR00204## <100 ##STR00205## <500
##STR00206## <1000 ##STR00207## <500 ##STR00208## <500
##STR00209## <200 ##STR00210## <100 ##STR00211## <200
##STR00212## <1000 ##STR00213## <200 ##STR00214## <500
##STR00215## <200 ##STR00216## <500 ##STR00217## <500
##STR00218## <200 ##STR00219## <200 ##STR00220## <500
##STR00221## <100 ##STR00222## <200 ##STR00223## <200
##STR00224## <200 ##STR00225## <200 ##STR00226## <1000
##STR00227## <1000 ##STR00228## <500 ##STR00229## <2000
##STR00230## <500 ##STR00231## <200 ##STR00232## <500
##STR00233## <500 ##STR00234## <1000 ##STR00235## <2000
##STR00236## <500 ##STR00237## <100 ##STR00238## <200
##STR00239## <1000 ##STR00240## <100 ##STR00241## <200
##STR00242## <1000 ##STR00243## <100 ##STR00244## <100
##STR00245## <500 ##STR00246## <100 ##STR00247## <500
##STR00248## <1000 ##STR00249## <200 ##STR00250## <200
##STR00251## <200 ##STR00252## <200 ##STR00253## <200
##STR00254## <100 ##STR00255## <100 ##STR00256## <200
* * * * *