2
This application is divided out of Indian Patent Application no.l78/KOL/2004.
FIELD OF THE INVENTION
The present invention relates to novel compounds of 2-propene-l-one series, of
general formula (I), their tautomeric forms, their stereoisomers, their polymorphs, their
pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and
pharmaceutically acceptable compositions containing them wherein R5, R6, Q and Y have
the meanings as defined hereinafter.

The present invention also relates to a process for the preparation of the above
said novel compounds, their tautomeric forms, their stereoisomers, their polymorphs,
their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and
pharmaceutically acceptable compositions containing them.
The compounds of the general formula (I) are useful for the treatment and / or
prophylaxis of ischaemia related injuries such as stroke, myocardial infarction,
inflammatory disorder, hepatotoxicity, sepsis, diseases of viral origin, allograft rejection,
tumourous diseases, gastric mucosal damage, brain haemorrhage, endothelial
dysfunctions, diabetic complications, neuro-degenerative diseases, post-traumatic
neuronal damage, acute renal failure, glaucoma and aging related skin degeneration,
wherein the underlying mechanism is Heat Shock Protein (HSP) induction.
BACKGROUND OF THE INVENTION
Heat shock proteins (HSPs) have been well documented to play a cytoprotective
role in almost all living cells under various pathological stresses through a mechanism
known as thermotolerance or cross tolerance. Heat shock proteins function as molecular
chaperones or proteases that, under physiological conditions, have a number of

3
intracellular functions. Chaperones are involved in the assembly and folding of misfolded
or denatured oligomeric proteins, whereas proteases mediate the degradation of damaged
proteins.
Heat shock proteins are categorized into several families that are named on the
basis of their approximate molecular mass (e.g. the 70 kDa HSP-70, ubiquitin, HSP-10,
HSP-27, HSP-32, HSP-60, HSP-90 etc). HSP-70 is the most abundant HSP found in
normal cells. HSP-70, and its inducible form, called HSP-72, is found in all living cells.
Following heat shock, its synthesis increases to a point to where it becomes the most
abundant single protein in the cell.
Although some proteins refold spontaneously, in vitro, when diluted at low
concentrations from denaturants, larger, multidomain proteins often have a propensity to
misfold and aggregate. Consequently, the challenge within the densely packed cellular
environment is to ensure that non-native intermediates are efficiently captured, maintained
in intermediate folded states, and subsequently either refolded or degraded. Molecular
chaperones such as HSP-90, HSP-70 and HSP-60 accomplish this by capturing non-native
intermediates and, together with co-chaperones and ATP.
The HSP-70 chaperones, for example, recognize stretches of hydrophobic residues
in polypeptide chains that are transiently exposed in early folding intermediates and
typically confined to the hydrophobic core in the native state. The consequence of
chaperone interactions, therefore, is to shift the equilibrium of protein folding and
refolding reactions toward productive on-pathway events and to minimize the appearance
of non-productive intermediates that have a propensity to aggregate as misfolded species.
Over the past years, a number of studies have shown that the major heat-inducible
protein, HSP-72, is critical for protection of cells and tissues from heat shock and other
stresses. HSP-72 functions as molecular chaperone in refolding and degradation of
damaged proteins. This has led to the common assumption that chaperoning activities of
HSP-72 determine its role in ability of a cell to protect itself against stresses. Upon
exposure to stresses that lead to a massive protein damage and necrotic death, the anti-
aggregating and protein refolding activities of HSP-72 may indeed become critical for cell

4
protection. On the other hand, upon exposure to stresses that lead to apoptosis, the
protective function of HSP-72 could be fully accounted for by its distinct role in cell
signaling. Under these conditions, protein damage on its own is not sufficient for cell
death because suppression of the apoptotic signaling pathway restores cell viability.
The term heat shock protein is somewhat of a misnomer, as they are not induced
solely by heat shock. Indeed, in addition to being constitutively expressed (making up 5-
10 % of the total protein content under normal growth conditions), these proteins can be
markedly induced (up to 15% of the total cellular protein content) by a range of stimuli
including various pathological stresses.
Pathological stresses inducing heat shock protein expression include a wide variety
of conditions associated with many diseases. The synthesis of heat shock proteins in cells
exposed to such stresses indicates the first line of defense of the cell against the
pathological stresses.
Stroke
One such pathological condition wherein protective role of HSP-70 has been
implicated is cerebral ischemic injury (stroke). Cerebral ischaemia causes severe depletion
of blood supply to the brain tissues, as a result of which the cells gradually proceed to
death due to lack of oxygen. In such a situation, there is increased expression of heat
shock protein in the brain tissue.Transient ischemia induces HSPs in the brain and the
ability of neuronal population to survive an ischemic trauma is correlated with increased
expression of HSP-70. HSP-70 mRNA was induced in neurons at the periphery of
ischemia. It is proposed that the peripheral zone of ischemia, penumbra can be rescued by
pharmacological agents. It was in this zone that HSP-70 protein was found to be localized
primarily in neurons.[Dienel G.A. et al., J. Cereb. Blood Flow Metab., 1986, Vol. 6, pp.
505-510; Kinouchi H. et al., Brain Research, 1993, Vol. 619, pp. 334-338]. The direct
assessment of the protective role of HSP-70 is shown by using transgenic mice
overexpressing the rat HSP (HSP-70tg mice). In contrast to wild-type littermates, high
levels of HSP messenger RNA and protein were detected in brains of HSP-70tg mice
under normal conditions, immunohistochemical analysis revealed primarily neuronal
expression of HSP-70. Heterozygous HSP-70tg mice and their wild type littermates were

5
subjected to permanent focal cerebral ischemia by intraluminal blockade of middle
cerebral artery. Cerebral infarction after 6 hours of ischemia, as evaluated by nissl
staining, was significantly less in HSP-70tg mice compared with wild type littermate mice.
The HSP-70tg mice were still protected against cerebral infarction 24 hours after
permanent focal ischemia. The data suggest that HSP-70 can markedly protect the brain
against ischemic damage. [Rajdev S., Hara K, et al., Ann. Neurol, 2000 Jun, Vol. 47 (6),
pp. 782-791] The 72-kD inducible heat shock protein (HSP-72) plays a very important
role in attenuating cerebral ischemic injury. Striatal neuronal survival was significantly
improved when HSP-72 vectors was delivered after ischemia onset into each striatum.
[Hoehn B. et al., J. Cereb. Blood Flow Metab., 2001 Nov, Vol. 21(11), pp. 1303-1309].
Experiments have proved that neurological deficits induced by ischemia were
found to be reduced on treatment with HSP-inducers like lithium. These neuroprotective
effects were associated with an up-regulation of cytoprotective heat shock protein -70 in
the ischemic hemisphere [Ren M. et al., Proc. Natl. Acad. Sci. USA., 2003 May 13; Vol.
100(10), pp. 6210-6215]. Thus induction of HSP-70 would confer a protective effect in
cerebral ischaemic injury (stroke).
Myocardial Infarction
Another pathological condition analogous to cerebral ischaemia is myocardial
infarction, in which case, severe ischemia even for relatively short periods of time, lead to
extensive death of cardiomyocytes. Induction of HSP-70 has been shown to confer
protection against subsequent ischemia as is evident by a direct correlation to post-
ischemic myocardial preservation, reduction in infarct size and improved metabolic and
functional recovery. Overexpression of inducible HSP-70 in adult cardiomyocytes were
associated with a 34% decrease in lactate dehydrogenase in response to ischemic injury.
[Hutter M.M. et al., Circulation, 1994, Vol. 89, pp. 355-360; Liu X. et al., Circulation,
1992, Vol. 86, pp. II358-II363; Martin J.L., Circulation, 1997, Vol. 96, pp. 4343-4348].
Experiments have shown that oral pretreatment of rats with an HSP inducer
Bimoclomol elevated myocardial HSP-70 and reduced infarct size in a rat model of
ischemia [Lubbers N.L. et al., Eur. J. Pharmacol, 2002 Jan 18, Vol. 435(1), pp. 79-83].
There was a significant correlation between HSP-70 induction and infarct size reduction

6
after oral administration of Bimoclomol. Further, Bimoclomol also improved cell survival
in rat neonatal cardiomyocytes by increasing the levels of HSP-70 [Polakowski J.S. et al.,
Eur. J. Pharmacol., 2002 Jan 18, Vol. 435 (1), pp. 73-77].
In further experiments, transgenic mice were engineered to express high levels of
the rat-inducible HSP-70 [Marber M.S. et al., J. Clin. Invest., 1995 April, Vol. 95, pp.
1446-1456]. It was observed that there was a significant reduction in infarct size by about
40% after 20 minutes of global ischemia in the heart of the transgenic mice, and
contractile function doubled during reperfusion period compared to wild type.
Moreover, evidence indicate that myocardial stress protein HSP-70 is directly
protective is provided by the observation that transfected myocyte lines overexpressing
HSP-70 have enhanced resistance to hypoxic stress [Mestril R. et al., J. Clin. Invest., 1994
February, Vol. 93, pp. 759-767].
Further investigations into the role of HSP-70 overexpression through gene therapy
on mitochondrial function and ventricular recovery has shown that, HSP-70 upregulation
protects mitochondrial function after ischemia-reperfusion injury and was associated with
improved preservation of myocardial function. Post ischemic mitochondrial respiratory
control indices linked to NAD and FAD were better preserved and recovery of mechanical
function was greater in HSP transfected than control hearts. [Jayakumar J. et al.,
Circulation, 2001 Sep 18, Vol. 104 (12 Suppl 1), pp. 1303-1307]. Thus, the foregoing
evidence indicates that induction of HSP-70 would be useful for treating myocardial
infarction.
Inflammatory disorders
Yet another example of pathological stress on tissues and organs causing HSP-70
induction is provided by inflammatory diseases.
Inflammation is caused by activation of phagocytic cells like leucocytes, primarily
by monocytes-macrophages, which generate high levels of reactive oxygen species (ROS)
as well as cytokines. Both ROS and cytokines upregulate the expression of heat shock
proteins (HSP), while HSPs in turn protect cells and tissues from the deleterious effects of

7
inflammation. In an in vivo model for adult respiratory distress syndrome, an acute
pulmonary inflammatory condition which caused HSP induction, HSP completely
prevented mortality. [Jacquier-Salin M.R. et al., Experientia, 1994 Nov 30, Vol. 50 (11-
12), pp. 1031-1038].
HSP exert multiple protective effects in inflammation, including self/non-self
discrimination, enhancement of immune responses, immune protection, thermotolerance
and protection against the cytotoxicity of inflammatory mediators [Polla B.S. et al., EXS.,
1996, Vol. 77, pp. 375-91].
Heat shock proteins (HSPs) have been repeatedly implicated in the control of the
progression of rheumatoid arthritis. An up-regulation of HSP-70 expression in synovial
tissue is consistently observed in patients with rheumatoid arthritis. Recent investigations
have shown that, pro-inflammatory cytokines induced activation of HSF 1-DNA binding
and HSP-70 expression in cultivated synovial fibroblast-like cells [Georg Schett et. al., J.
Clin. Invest., 1998 July, Vol. 102 (2), pp. 302-311]. Since HSP-70 is critically involved in
protein folding and may prevent apoptotic cell death, facilitating synovial growth and
pannus formation, their elevated levels would play a crucial role in controlling the
progression of the disease state.
Anti-inflammatory agents such as NSAIDS activate HSF-1 DNA binding and
glucocortcoids at high dose activate HSF-1 as well as induce HSP expression [Georg
Schett et. al., J. Clin. Invest., 1998 July, Vol. 102 (2), pp. 302-311].
HSP-70 has a role in controlling inflammation. The induction of HSP-70 before the
onset of inflammation can reduce organ damage [Hayashi Y. et al, Circulation, 2002 Nov
12, Vol. 106(20), pp. 2601-2607]. Preoperative administration of HSP-70 inducers seem
to be useful in attenuating cardiopulmonary bypass (CPB)-induced inflammatory
response.
Investigations into the anti-inflammatory property of 2-cyclopentene-l-one
demonstrated that the heat shock factor 1 (HSF 1) activation, subsequent induction of
HSP-72 expression occurs in inflamed tissue and this effect is associated with the

8
remission of the inflammatory reaction, [lanaro A. et al., Mol. Pharmacol, 2003 Jul, Vol.
64(1), pp. 85-93]. The anti-inflammatory properties of 2-cyclopenten-l-one were
associated with HSF-1 induced HSP-72 expression in vivo.
The HSP co-inducer BRX-220 has been examined for effects on the
Cholecystokinin-octapeptide (CCK)-induced acute pancreatitis in rats [Rakonczay Z. Jr. et
al., Free Radic. Biol. Med., 2002 Jun 15, Vol. 32 (12), pp. 1283-1292]. The pancreatic
levels of HSP-60 and HSP-72 were significantly increased in the animals treated with
BRX-220. Further, pancreatic total protein content, amylase and trypsinogen activities
were higher with increased glutathione peroxidase activity. A decrease in plasma
trypsinogen activation peptide concentration, pancreatic lipid peroxidation, protein
oxidation, and the activity of Cu/Zn-Superoxide dismutase were also observed. The
protective action of BRX-220 on pancreatitis was ascribed directly to its HSP-70 inducing
action.
Whole body hyperthermia in rats leading to induction of HSP-70 has been shown
to protect against subsequent caerulein-induced acute pancreatitis. More specifically the
degradation and disorganization of the actin cytoskeleton, an important early component
of pancreatitis was prevented [Tashiro M. et al., Digestion, 2002, Vol. 65 (2), pp. 118-
126], hence, reducing damage in pancreatitis secondary to inflammation. Thus induction
of HSP-70 would be beneficial in treating inflammatory disorders.
Hepatotoxicity
Another example of a pathological stress wherein protective role of HSP-70 has
been implicated is hepatotoxicity. Overproduction of heat shock protein 70 (HSP-70) in
the liver protects hepatocytes under various pathologic conditions. Studies aimed at
examining the effects of HSP-70 inducers, on acute hepatic failure after 95% hepatectomy
have shown significantly suppressed release of aspartate or alanine aminotransferase and
elevation of the serum interleukin-6 level [Oda H. et al, J. Gastrointest. Surg., 2002 May-
Jun, Vol. 6(3), pp. 464-472].
The effect of HSP Inducer gadolinium chloride was studied in relation to its effect
on metallothionein and heat shock protein expression in an in-vivo model of liver necrosis

9
induced by thioacetamide [Andrés D. et al., Biochem. Pharmacol., 2003 Sep 15, Vol. 66
(6), pp. 917-926]. Gadolinium significantly reduced serum myeloperoxidase activity and
serum concentration of TNF-alpha and IL-6, increased by thioacetamide. The extent of
necrosis, the degree of oxidative stress and lipoperoxidation and microsomal FAD
monoxygenase activity were significantly diminished. These beneficial effects are
attributed to enhanced expression of HSP-70 following Gadolinium administration.
Thus induction of HSP-70 would exert a protective effect in case of
hepatotoxicity.
Sepsis
Yet another pathological condition wherein induction of HSP-70 has been found
to be beneficial is sepsis. Sepsis is a severe illness caused by overwheming infection of the
bloodstream by toxin-producing bacteria. Induction of HSPs by heat shock treatment
significantly decreased the mortality rate of late sepsis. The involvement of HSPs during
the progression of sepsis could add to a first line of host defense against invasive
pathogens.
Expression of HSP-72 and their protective role has been studied using a rat model
of cecal ligation and puncture [Yang R.C. et al., Kaohsiung J. Med. Sci., 1998 Nov, Vol.
14 (11), pp. 664-672]. Induction of HSP-70 expression by Geranylgeranyl acetone has
shown to protect against cecal ligation and perforation induced diaphragmatic dysfunction.
It showed a time dependant induction of HSP-70 in the diaphragm, which attenuated
septic diaphragm impairment. [Masuda Y. et al., Crit. Care Med., 2003 Nov, Vol. 31(11),
pp. 2585-2591]. GGA has found to induce HSP-70 expression in the diaphragm, which
was attributed to be the underlying mechanism for the protective action of GGA
Further experiments indicate that induction of HSP-70 by the administration of
sodium arsenite conferred significant protection against cecal ligation and perforation-
induced mortality [Ribeiro S.P. et al., Crit. Care Med., 1994 Jun, Vol. 22(6), pp. 922-929].
In-vivo Sodium arsenite injection in the absence of an increase in body temperature
induced expression of HSP-72 in the lungs and protected against experimental sepsis.

10
Protection conferred resulting in reduced mortality correlated directly with the expression
of heat shock protein 72 in the lungs at 18 and 24 hours after perforation.
It was observed that induction of heat shock proteins by thermal stress reduced
organ injury and death in a rat model of intra-abdominal sepsis and sepsis-induced acute
lung injury [Villar J. et al., Crit. Care Med, 1994 Jun, Vol. 22 (6), pp. 914-921]..
Acute respiratory distress syndrome (ARDS) provokes three pathologic processes:
unchecked inflammation, interstitial/alveolar protein accumulation and destruction of
pulmonary epithelial cells. Heat shock protein HSP-70 can limit all three responses, only if
expressed adequately. Restoring expression of HSP-70 using adenovirus-mediated gene
therapy has shown to be beneficial [Yoram G.W. et al., J. Clin. Invest., 2002, Vol. 110, pp.
801-806]. HSP-70 administration significantly attenuated interstitial and alveolar edema
along with protein exudation and dramatically decreased neutrophil accumulation.
Approximately 2-fold higher expression of HSP-70 conferred 68% survival at 48 hours as
opposed to only 25% in untreated animals. Modulation of HSP-70 production reduced the
pathological changes and improved outcome in experimental acute respiratory distress
syndrome. Thus, inducers of HSP-70 would confer protective effect in sepsis.
Viral diseases
Another pathological condition in which induction of HSP-70 occurs is in case of
viral diseases. Heat shock proteins (HSPs) and molecular chaperones have been known for
several years to protect cells against virus infection [Lindquist S. et al., Annu. Rev. Genet.,
1988, Vol. 22, pp. 631-637]. It has been demonstrated that induction of HSP-70 is
associated with inhibition of infectious virus production and viral protein synthesis in
monkey kidney epithelial cells infected with vesicular stomatitis virus (VSV) [Antonio R.
et al., J. of Biol. Chem., 1996 Issue of December 13, Vol. 271 (50), pp. 32196-32196]. The
pathogenic activity of Viral protein R (Vpr) of human immunodeficiency virus type 1
(HIV-1) is related in part to its capacity to induce cell cycle G2 arrest and apoptosis of
target T cells. Overexpression of HSP-70 reduced the Vpr-dependent G2 arrest and
apoptosis and also reduced replication of the Vpr-positive, but not Vpr-deficient, HIV-1.
[Iordanskiy S. et al., J. Virol, 2004 Sep, Vol. 78 (18), pp. 9697-9704]. Induction of HSP-

11
70 by prostaglandin Al (PGA1) caused the suppression of influenza virus production.
[Hirayama E., Yakugaku Zasshi, 2004 Jul, Vol. 124 (7), pp. 437-442].
The antiviral activity of Cyclopentenone prostaglandins is mediated by induction
of HSP-70. It has been shown that increased synthesis of HSP-70 exerts potent antiviral
activity in several DNA and RNA virus models - vesicular stomatitis virus, sindbis virus,
sendai virus, polio virus etc. [Santoro M.G., Experientia, 1994 Nov 30, Vol. 50 (11-12),
pp. 1039-1047; Amici C. et al., J. Gen. Virol, 1991 Aug, Vol. 72, pp. 1877-1885; Amici
C. et al., J. Virol, 1994 Nov, Vol. 68(11), pp. 6890-6899; Conti C. et al., Antimicrob.
Agents Chemother., 1996 Feb, Vol. 40(2), pp. 367-372; Conti C. et al., Antimicrob. Agents
Chemother., 1999 Apr, Vol. 43 (4), pp. 822-829]. Therefore, induction of HSP-70 would
exert antiviral effect.
Allograft rejection
Allograft (transplant of an organ or tissue from one individual to another of the
same species with a different genotype) rejection is a pathological condition causing
induction of HSP-70. HSP-70 induction has a protective effect, which preserves organ
function after transplantation. Kidneys can be preserved only for a limited time without
jeopardizing graft function and survival. Induction of heat shock proteins (HSPs) has been
found to improve the outcome following isotransplantation after an extended period of
cold storage. Heat precondition induced the expression of HSP-70 and the grafts were
protected against structural ischemia-reperfusion injuries when assessed histologically.
[Wagner M. et al., Kidney Int., 2003 Apr, Vol. 63 (4), pp. 1564-1573]. There was
inhibition of apoptosis and activation of caspase-3 was found to be inhibited.
Geranylgeranyl acetone, a non-toxic heat shock protein inducer has been studied in
a rat orthotopic liver transplantation model to study the beneficial effects in warm
ischemia-reperfusion injury [Fudaba Y. et al., Transplantation, 2001 Jul 27, Vol. 72(2),
pp. 184-189]. GGA administration accumulated mRNA for both HSP-72 and HSP 90 in
the livers even before warm ischemia and facilitated the syntheses of HSP-72 and HSP 90
after warm ischemia. Further, GGA pretreatment also significantly reduced the serum
levels of tumor necrosis factor-alpha after reperfusion. The findings indicate that both the
enhanced induction of HSPs and the downstream events would be involved in the

12
beneficial effects of GGA on ischemia-reperfusion injury. Besides, compared to donors
treated with vehicle were all recipients died of primary non-function, when donors were
treated with Geranylgeranyl acetone (GGA) the 7-day survival of the recipients was closed
to 90%.
Investigations revealed an inverse relationship between HSP expression and
rejection with the possibility that elevated levels of HSP in the myocardium results in low
rejection of heart transplants. [Baba H.A. et al., Transplantation, 1998 Mar 27, Vol. 65
(6), pp. 799-804]. Significant improvement of post-ischemic recovery of mechanical
function in HSP-70 gene transfected hearts compared to controls were observed following
a protocol mimicking conditions of preservation for heart transplantation. These results
confirmed the findings observed previously in cell culture models and extended then to
show the role of HSP-70 in protecting against ischemia-reperfusion injury in a whole-heart
model, which parallels more closely the clinical situation. [Jayakumar J. et al.,
Circulation, 2000, Vol. 102 [suppl III], pp. III-302 to III-306].
The heat shock response also exerts a protective effect on skin flap ischemia. Heat
shock protein (HSP) expression is augmented in-vivo with the administration of high dose
aspirin before heat treatment [Ghavami A. et al., Ann. Plast. Surg., 2002 Jan, Vol. 48(1),
pp. 60-67]. Immunohistochemistry confirmed HSP expression, and skin flap survival was
improved significantly. Thus, HSP-70 induction would be beneficial in preserving organ
function after transplantation.
Tumorous diseases
I Induction of HSP-70 has also been shown to be advantageous in treating
neoplasms. Enhanced expression of HSP-70 has been found to help in causing tumor
regression in various animal models. Heat shock proteins (HSPs) are involved in the
development of resistance (thermotolerance) to subsequent hyperthermic stresses as well
as enhancement of the clinical response of certain chemotherapeutic agents in cancers
such as the prostate. Colony formation assays revealed sensitizing effect of hyperthermia
when simultaneously combined with each chemotherapeutic agent, resulting in a
potentiated localized cytotoxicity [Roigas J. et al., Prostate, 1998 Feb 15, Vol. 34 (3), pp.
195-202]. Synchronous application of chemotherapeutic agents and hyperthermia has been

13
shown to have synergistic cytotoxic effect on Dunning rat adenocarcinoma of the prostate.
Furthermore it is demonstrated that the induction of HSPs in thermotolerant cells, as
measured by HSP-70 induction, results in a modulation of the chemotherapeutic-mediated
cytotoxicity.
Direct induction of heat shock proteins are recognized to contribute significantly in
cancer immunity. Anti-tumor immunity is induced by hyperthermia and further enhanced
by administration of recombinant HSP-70 protein into the tumor in-situ. [Ito A. et al.,
Cancer Immunol. Immunother., 2004 Jan, Vol 53(1), pp. 26-32]. The induction of
hyperthermia using a 500 KHz alternating magnetic field combined with magnetite
cationic liposomes, which have a positive charge and generate heat in an alternating
magnetic field along with administration of recombinant HSP-70 protein into the
subcutaneous murine melanoma inhibited tumor growth over a 30-day period and
complete regression of tumors was observed in 20% of mice. It was also found that
systemic anti-tumor immunity was induced in cured mice. In another study carried out to
determine whether anti-tumor immunity induced by hyperthermia is enhanced by HSP-70
gene transfer [Ito A. et al., Cancer Gene Ther., 2003 Dec, Vol. 10(12), pp. 918-925]
showed that the combined treatment strongly arrested tumor growth over a 30-day period
and complete regression of tumors was observed in 30% mice. Thus, induction of HSP-70
would be useful for the treatment of tumorous diseases.
Gastric mucosal damage
Gastric mucosal damage caused by insults derived from ingested foods and
Helicobacter pylori infection constitute another pathological condition causing induction
of HSP-70. Gastric surface mucous cells are the first line of defense against such insults.
Primary cultures of gastric surface mucous cells from guinea-pig fundic glands exhibited a
typical heat shock response after exposure to elevated temperature or metabolic insults,
such as ethanol and hydrogen peroxide, and they were able to acquire resistance to these
stressors. HSP-70 mRNA protein has been induced in rat gastric mucosa following stress
and the extent of induction inversely correlated with the severity of mucosal lesions
suggesting protective role of HSP-70 in gastric mucosal defense. [Rokutan K., J.
Gastroenterol. Hepatol, 2000 Mar, Vol. 15 Suppl, pp. D12-9].

14
Brain haemorrhage
Another pathological condition causing induction of HSP-70 is in case of brain
haemorrhage. Studies with Bimoclomol showed an ability to reduce the pathological
increase in the permeability of blood brain barrier during cerebrovascular injury,
particularly if the vascular insult is evoked by sub-arachnoidal autologous blood [Erdo F.
et al., Brain Research Bulletin, 1998, Vol. 45(2), pp.163-166]. Bimoclomol strongly
reduced the size of cerebral tissue stained with Evans blue leakage by 39 %. Bimoclomol
confers beneficial influences in experimental sub-arachnoid haemorrhage through its co-
inducer effect on HSP-72 expression.
Endothelial dysfunctions
Various endothelial dysfunctions constitute pathological conditions which results
in induction of HSP-70 in the body cells. The effect of a co-inducer of heat shock proteins,
Bimoclomol treatment on endothelial function and expression of 72 Kd heat shock protein
was investigated in spontaneously hypertensive rats [Jednakovits A. et. al., Life Sci., 2000
Aug 25, Vol. 67(14), pp. 1791-1797]. Significant age- dependant decline in relaxation to
acetylcholine and vascular HSP-72 mRNA levels were observed in SHR animals. These
changes were found to be prevented by application of Bimoclomol suggesting the
relationship between preservation of endothelial function with sustained levels of HSP-72.
Diabetic Complications
Complications arising in diabetic patients such as neuropathy, nephropathy and
delayed wound healing constitute pathological conditions wherein protective role of HSP-
70 has been implicated,
(a) Diabetic Neuropathy
Endoneurial microangiopathy causing nerve infarctions is considered to be
involved in the pathogenesis of diabetic neuropathy [Malik R.A. et al., Diabetic
Neuropathy: New Concepts and Insights, 1995, pp 131-135]. Experimental evidence is
suggestive of a protective effect of HSP-72 induction on diabetic neuropathy [Biro K. et.
al., Brain Research Bulletin, 1997, Vol. 44(3), pp. 259-263 ]. Treatment with Bimoclomol,
by virtue of its HSP-70 inducing property significantly reduced nerve conduction slowing,
motor by 38 % and sensory by 42%, which show a dose dependant response. It also
retarded the typical elevated ischemic resistance due to streptozotocin-induced neuropathy

15
by 71%. These effects were observed at doses known to induce transcription of HSP-72 in
other tissues like heart and kidney in response to ischemia.
(b) Diabetic Retinopathy
Diabetic retinopathy is associated with the breakdown of the blood-retinal barrier
(BRB) and results in macular edema, the leading cause of visual loss in diabetes. The HSP
co-inducer Bimoclomol (BRLP-42) has shown efficacy in diabetes-induced retinopathy
[Hegedius S. et al., Diabetologia, 1994, Vol. 37, p. 138]. The protection reflected in lower
degree of edema in and beneath the photoreceptor zone, almost normal arrangement of
retinal pigment epithelial microvilli and a more compact and even retinal capillary
basement membrane. [Biro K. et al, Neuro Report, 1998 Jun 22, Vol.9(9), pp. 2029-2033].
Improvements are attributed to the cytoprotective effect of Bimoclomol on retinal glia and
/or neurons against diabetes related ischemic cell damages. Further, overexpression of
HSP-70 has shown protective effect on retinal photic injuries [Kim J.H. et al., Korean J.
Ophthalmol. 2003 Jun, Vol. 17(1), pp. 7-13].
(c) Chronic wound healing
HSPs are involved in regulation of cell proliferation. Impaired expression of HSP-
70 has been associated with delayed wound healing in diabetic animals [McMurtry A.L. et
al., J. Surg. Res., 1999, Vol. 86, pp. 36-41]. Faster and stronger healing is achieved by
activation of HSP-70 in a wound by laser [Capon A. et al., Lasers Surg. Med, 2001, Vol.
28, pp. 168-175].
Thus, induction of HSP-70 would be beneficial in treating various diabetic
complications.
Neuro-degenerative diseases
Neurodegenerative diseases such as Alzheimer's disease, Amyotrophic lateral
sclerosis and Parkinson's disease constitute a set of pathological conditions wherein
HSP-70 has been implicated to exert a protective affect and delay the progression of these
diseases.

16
(a) Alzheimer's disease, is a neurodegenerative disorder characterized by beta-amyloid
and tau protein aggregates (neurofibrillary tangles) Increased levels of HSP (8-10 fold
increase) in various cellular models have shown to promote tau solubility and tau binding
to microtubules, reduce insoluble tau and cause reduced tau phosphorylation. Hence
upregulation of HSP will suppress formation of neurofibrillary tangles. [Dou F. et al.,
Proc. Natl. Acad. Sci. USA, 2003 Jan 21, Vol. 100 (2), pp. 721-726]. Studies have shown
that virally mediated HSP-70 overexpression rescued neurons from the toxic effects of
intracellular beta-amyloid accumulation. [Magrane J. et al., J. NenroscL, 2004 Feb 18,
Vol. 24 (7), pp. 1700-1706].
(b) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in
which motor-neurons of the spinal cord and motor cortex die, resulting in progressive
paralysis. Etiology of ALS involves mutation in the gene encoding Cu/Zn superoxide
dismutase-1 (SOD1). Treatment with arimoclomol, an inducer of heat shock proteins
(HSPs), significantly delays disease progression in transgenic mice overexpressing human
mutant SOD1 that shows a phenotype and pathology that is very similar to that seen in
human ALS patients. [Kieran D. et al., Nat. Med, 2004 April,Vol 10 (4), pp. 402-405;
Susanna C. B. et al., Nat. Med., 2004, Vol. 10, pp. 345-347].
(c) Parkinson's disease is a common neurodegenerative disease characterized by the
loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation
of the misfolded protein alpha-synuclein into aggregates called Lewy bodies and Lewy
neuritis, which are very cytotoxic. Mitochondrial dysfunction, oxidative stress, protein
misfolding, aggregation, and failure in the proteasomal degradation of specific neuronal
proteins have been implicated in pathogenesis of Parkinson disease (PD). Upregulation of
HSP-70 by HSP-70 gene transfer to dopamine neurons by a recombinant adeno-associated
virus significantly protects the mouse dopaminergic system against MPTP-induced
dopamine neuron loss and the associated decline in striatal dopamine levels. [Dong Z. et
al., Mol. Ther., 2005 Jan, Vol. 11(1), pp. 80-88]. Recent experimental evidences show that
deprenyl and other propargylamines which are used clinically in treating Parkinson's
disease increase neuronal survivability by increasing synthesis of HSP-70 and other anti-
apoptotic proteins. [Tatton W. et al., J. Neural. Transm., 2003 May, Vol. 110(5), pp. 509-
515]. Introducing HSP-70 in alpha-synuclein transgenic mice by breeding with HSP-70

17
overexpressing mice led to significant reduction in misfolded and aggregated alpha-
synuclein in the progeny. [Klucken J. et al., J. Biol. Chem., 2004 Jun 11, Vol. 279 (24), pp.
5497-5502]. Recent evidences show that Geldanamycin protects neurons against alpha-
synuclein toxicity by enhancing the HSP-70 mediated chaperonic activity. [Auluck P.K. et
al., J. Biol. Chem., 2005 Jan 28, Vol. 280 (4), pp. 2873-2878].
Thus, HSP-70 inducers would be useful in the treatment and delaying the
progression of the above neurodegenerative disease conditions.
Post-traumatic neuronal damage
Pathological stress associated with post-traumatic neuronal damage cause
induction of HSP-70 in the neuronal tissues. The expression of HSP-70 following
traumatic injury to the neuronal tissue has been speculated to be part of a cellular
response, which is involved in the repair of damaged proteins [Dutcher S.A et al., J.
Neurotrauma, 1998, Vol. 15 (6), pp. 411-420]. BRX-220, an inducer of HSP-70 has been
examined for its effect on the survival of injured motoneurones following rat pup sciatic
nerve crush [Kalmar B. et al., Exp. Neurol, 2002 Jul, Vol. 176 (1), pp. 87-97]. It has been
found that significantly more number of neurons survived with BRX-220 treatment and
there was no further loss of motoneurones. 14 days after injury, 39 % of motoneurones
survived in BRX220 treated group compared to 21% in vehicle group. Moreover in BRX
220 treated group no further loss of motoneurones occurred, at 10 weeks 42 % of
motoneurons survived compared to 15% in untreated group. There were also more
functional motor units in the hind limb muscles of the treated group compared to that of
the control. These observations were correlated to elevated levels of HSP-70 and this
compound protects motoneurones from axotomy-induced cell death through a HSP-70
mediated mechanism. Therefore, induction of HSP-70 would be beneficial in post-
traumatic neuronal damage.
Acute Renal Failure
Another pathological condition causing induction of HSP-70 is acute renal failure.
Acute renal failure is the sudden loss of the ability of the kidneys to excrete wastes,
concentrate urine and conserve the electrolytes. Induction of heat shock proteins (HSPs)
plays a protective role in ischaemic acute renal failure. Administration of Sodium arsenite

18
or Uranyl acetate in cisplatin-induced acute renal failure resulted in significant increase in
HSP-72 expression. Both Sodium arsenite and Uranyl acetate attenuated the cisplatin-
induced increase in serum creatinine and tubular damage scores [Zhou H. et al., Pflugers
Arch, 2003 Apr, Vol. 446 (1), pp. 116-124]. Findings suggest that HSP-72 attenuates
CDDP-induced nephrotoxicity. The protective effects of HSP-72 are associated with an
increased Bcl-2/Bax ratio and reduced apoptosis.
Glaucoma
Still another pathological condition which causes induction of HSP-70 is
glaucoma. Glaucoma is characterized by rising intra intraocular pressure and subsequent
damage to the optic nerve with selective loss of retinal ganglion cells (RGCs). It has been
postulated that apoptosis, a highly regulated process of cell death, is the final common
pathway for RGC death in glaucoma. Studies suggest that the inducedexpression of HSP-
72 enhances RGC survival in harmful conditions and ameliorates glaucomatous damage in
a rat model [Ishii Y. et al., Invest. Ophthalmol. Vis. Sci, 2003 May, Vol. 44(5), pp. 1982-
1992]. The study revealed that HSP-72 expression was increased in retinal ganglion cells
after administration of HSP inducer geranylgeranyl acetone. The treatment further reduced
the loss of retinal ganglion cells, reduced optic nerve damage and decreased the number of
TUNEL positive cells in retinal ganglion cell layer.
Aging related skin degeneration
There is an attenuation of induction of HSP-70 in human keratocytes with aging
[Verbeke P. et al., Cell Biol. Int., 2001, Vol. 25 (9), pp. 845-857]. Furthermore, human
skin cells have been shown to maintain several characteristics of young cells until late in
life, when exposed to repetitive mild heat shocks [Rattan S.I. et al., Biochem. Mol. Biol.
Int., 1998, Vol. 45(4), pp. 753-759].
Over expression of heat shock protein gene is sufficient to protect against
otherwise lethal exposures to heat, ischemia, cytotoxic drugs, and toxins. The above
examples illustrate the ability of HSP-70 to protect cells against various pathological
stresses contributing towards different diseases.

19
US 5348945 describes methods for enhancing the survivality of cells and tissues
by treating the same with exogenous HSP-70.
A number of compounds have been reported to be useful for increasing levels of
HSPs thereby treating a range of disorders.
US 6096711 discloses methods for inducing HSP-72 production in an aged cell by
contacting the aged cell with a proteasome inhibitor, and treating stress-induced
pathologies associated with apoptosis and inflammation in aged individuals.
US 6174875 discloses methods for inducing HSP-70 and treating neurological
injuries resulting from cardiac arrest and stroke by inhibiting cell death induced by
oxidative stress, with benzoquinoid ansamycins.
US 6653326 describes methods for increasing expression of molecular chaperones,
including HSP-70 using hydroxylamine derivatives, and thereby treating stress related
diseases like stroke, cerebrovascular ischaemia, coronarial diseaseas, allergic diseases,
immune diseases, autoimmune diseases, diseases of viral or bacterial origin, tumourous,
skin and/or mucous diseases, epithelial disease of renal tubules, atherosclerosis,
pulmonary hypertonia and traumatic head injury.
In view of the advantages associated with increased expression of HSP-70 in cells,
a method, which increases such expression or increases activity of HSP-70 would be
highly advantageous for prevention and treatment of various diseases. Small molecules
that either enhances the expression or function of heat shock proteins could have promise
in chronic or acute treatment of certain human diseases.
Compounds of the present invention have been categorically shown to induce
HSP-70. Therefore, these compounds would be beneficial in the prevention and treatment
of conditions where HSP induction has been shown to protect in various diseased states,
for example in stroke, myocardial infarction, inflammatory diseases, diseases of viral
origin, tumourous diseases, brain haemorrhage, endothelial dysfunctions, diabetic
neuropathy, hepatotoxicity, acute renal failure, glaucoma, sepsis, gastric mucosal damage,

20
allograft rejection, chronic wounds in diabetics, neurodegenerative diseases, post-
traumatic neuronal damage and aging-related skin degeneration.
None of the compounds as disclosed in this application have been identified in any
published patents, patent applications or journal articles. A few structurally similar
propen-1-one derivatives and their analogs that have been reported are discussed
hereinbelow.
PCT publications WO 03/097575 and WO 03/097576 disclose certain amino and
diamino functional chalcones that are useful against bacterial as well as parasitic
infections of general formula (I)
(Y1)m-Ar1(X1)-C(=O)VAr2(X2)-(Y2)p (I)
wherein Ar1 and Ar2 independently designate aryl or heteroaryl ; V designates -CH=CH- ;
m is 0, 1 or 2; p is 0, 1 or 2; wherein the sum of m and p is at least 1; Y1 and Y2
independently designate amino or diamino substituent of the formula -Z-N(R1)R2 or -NR3-
Z-N(R1)R2 ; wherein Z is a biradical -(C(RH)2)n-, wherein n is an integer in the range of 1-
6, and each RH is independently selected from hydrogen or C1-6alkyl, or two RH on the
same carbon atom may designate =0. Examples of these compounds are l-{3-[(2-
Dimethylamino-ethyl)-methyl-amino]-phenyl}-3-phenyl-propenone and 3- (4-
Dibutylamino-phenyl)-l-(3-dimethylaminomethyl-phenyl)-propenone.
PCT Publication WO 95/06628 describes the preparation of chalcones that are
useful against bacterial as well as parasitic infections.
PCT Publication WO 93/17671 also describes the preparation of chalcones of
general formula (I) useful against bacterial as well as parasitic infections.
Xm— Ar1—CO—W—Ar2— Yn (I)
In the above chalcones of formula (I), W is -CR=CR- or -CºC-, wherein each R
independently designates hydrogen, C1-3alkyl, or halogen; Ar1 amd Ar2 independently
designate phenyl and 5- or 6-membered unsaturated heterocyclic ring; Y and X
independently designate ARH or AZ, wherein A is -O-, -S-, -NH- or -N(C1-6alkyl)-; RH

21
designates C1-6alkyl, C1-6alkylene or C1-6alkylyne; Z designates H; m designates an integer
from 0 to 2 and n designates an integer from 0 to 3.
JP 05025115 describes the preparation of phenyl acetamide derivatives of formula
(I) as antilipidemic agents, inhibiting the enzymes acyl-coenzyme A and cholesterol
acryltransferase.

In the said amide compounds of formula (I), R1 and R2 are H, halogen, nitro, amino, OH,
alkyl, alkoxy, aryl; R3 and R4 are H, halogen, amino, alkyl, alkoxy, R5 is aryl or arylalkyl;
A is alkylene or alkenylene; X is single bond or N (R7) (R7 is H, alkyl, cycloalkyl); Y is
alkylene, thia-alkylene or a single bond; Z is CH or N; D and E are H, R1, R2, H. An
example of these compounds is N-(2,6-diethylphenyl)-3-[4-[2-(3,5-di-tertbutyl-4-
hydroxyphenylthio)ethoxy]cinnamoyl]phenylacetamide.
JP 2003040888 describes the preparation of imidazoles of formula (I) having
inhibitory activity against adhesion of synoviocyte to collagen and production of cytokine.

In the said imidazole derivative of general formula (I), R1 is a substituted aryl; R2 and R3
are each H, a substituted heteroaryl or R2 and R3 together form a substituted heteroaryl;
and R4 is a substituted heteroaryl.
WO 02/098875 discusses about carboline derivatives of general formula (I) as
phosphodiesterase 5 (PDE5) inhibitors.

22

Some structurally similar propen-1-one derivatives and their analogs have also
been reported to be useful as Heat Shock Protein (HSP) inducers. PCT Publication WO
00/18390 discloses several chalcone derivatives of general formula (I)

As it is evident from the general formula, the -NO2 group present on the aryl ring is
essential for activity in this series of molecules. Moreover, the general formula of WO
00/18390 consists of substituted or unsubstituted phenyl ring on the carbonyl side of the
enone chain, while the substituted or unsubstituted 3-nitrophenyl ring is present on the
olefinic side of the enone chain.
SUMMARY OF THE INVENTION
The object of the invention is to provide novel compounds of the general formula
(I), their derivatives, their analogs, their tautomeric forms, their stereoisomers, their
polymorphs, their pharmaceutically acceptable solvates, their pharmaceutically acceptable
salts, esters or prodrugs and pharmaceutically acceptable compositions containing them,
which are useful in the treatment and / or prophylaxis of diseases accompanying
pathological stress selected from stroke, myocardial infarction, inflammation, diseases of
viral origin, tumourous diseases, brain haemorrhage, endothelial dysfunctions, diabetic
neuropathy, hepatotoxicity, acute renal failure, glaucoma, sepsis, gastric mucosal damage,
allograft rejection, chronic wounds in diabetics, neurodegenerative diseases, post-
traumatic neuronal damage and aging-related skin degeneration wherein the underlying
mechanism is Heat Shock Protein (HSP) induction.

23
Another object of the present invention is to provide a process for the preparation
of the compounds of the general formula (I).
A further object of the invention is to provide the pharmaceutically acceptable
compositions containing compounds of the general formula (I).
Yet another object of the invention is to use compounds of general formula (I) in
the manufacture of medicaments useful for treatment of disease conditions in a mammal
by induction of HSP.
Still further object of the invention is to provide a method of treatment of disease
conditions that can be treated by induction of HSP through administration to a patient in
need an effective amount of compounds of general formula (I).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides for novel compounds of 2-propene-l-
one series, of general formula (I),

their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically
acceptable solvates, their pharmaceutically acceptable salts, or prodrugs, and
pharmaceutically acceptable compositions containing them, wherein Q represents a
heteroaryl ring, said heteroaryl ring containing upto 2 nitrogen atoms and is selected from


24

wherein, Q is optionally substituted by R1 and / or R2, and the number of substituents
are selected from one to six;
R1 is independently selected at each occurrence from -SO2OR7, -SO2O(C8-8alkylX -
NHNH2, -NHNHSO2R7, -NH(CH2)nR4, -NHCO2R7, -NHCO2(C1-8alkyl), -NHSO2O(C1-
8alkyl), -NHSO2OR7, -NHSO2NH2, -NH(CH2)nCOR4, -NH(CH2)nOR4, -NH(CH2)nSR7, -
NH(CH2)nSO2R7, -NH(CH2)nNHCOR4, -NH(CH2)nN(C1-8alkyl)COR4, -N(C1-
8alkyl)(CH2)nNHCOR4, -NH(CH2)nNHNHSO2R7, -NH(CH2)nNHSO2R4, -NH(CH2)nN(C1-
8alkyl)SO2R4, -NH(CH2)nN(NH2)R7, -NH(CH2)nN[N(C1-8alkyl)2]R7, -N(C1-8alkyl)CO2R7,
-N(C1-8alkyl)CO2(C1-8alkyl), -N(C1-8alkyl)SO2O(C1-8alkyl), -N(C1-8alkyl)SO2OR7, -N(C1-
8alkyl)SO2NH2, -N(C1-8alkyl)N(C1-8alkyl)2, -N(C1-8alkyl)NH2, -NHNHCO(C1-8alkyl), -
N(C1-8alkyl)NHCO(C1-8alkyl), -NHNHCOR7, -N(C1-8alkyl)NHCOR7, -N(C1-8alkyl)-
(CH2)nR4, -N(C1-8alkyl)(CH2)nCOR4, -(CH2)nSO2R7, - (CH2)nCOR4, -(CH2)nR4, -

25
(CH2)nNHSO2R4, -(CH2)nN(C1-8alkyl)SO2R4, - (CH2)nNHCOR7, -(CH2)nN(C1-
8alkyl)COR7, -(CH2)nOR4, -(CH2)nSR4, -(CH2)nSR3, - (CH2)nSO2R7, -(CH2)nNHNHSO2R7,
-(CH2)nN(NH2)R7, or - (CH2)nN[N(C1-8 alkyl)2]R7 ;
R2 is independently selected at each occurrence from hydrogen, hydroxy, halo, amino, C1-
8alkyl, -O(C1-8alkyl), -S(C1-8alkyl), -SO2(C1-8alkyl), oxo, thioxo, mono(C1-8alkyl)amino,
di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyl), -
NHSO2CF3, -N(C1-8alkyl)SO2CF3, -NHSO2O(C1-8alkyl), -N(C1-8alkyl)SO2(C1-8alkyl), -
N(C1-8alkyl)SO2O(C1-8alkyl), -COOH, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-
8alkyl)CO2(C1-8alkyl), -CONH2, -CONH(C1-8alkyl), -CON(C1-8alkyl)2, formyl, CF3, CN, -
(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyl), -(CH2)nN(C1-8alkyl)2, -(CH2)nO(C1-8alkyl),
-SO3H, -SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8alkyl)2, -SO2NH(C1-8alkyl), -OSO2(C1-
8alkyl), -N(C1-8alkyOSO2NH2 -NHSO2NH(C1-8alkyl), -NHSO2N(C1-8alkyl)2, -N(C1-
8alkyl)SO2N(C1-8alkyl)2, -NHSO2NH2, -NHC(NH)NH2, -NHCONH2, -NHC(O)NH(C1-
8alkyl), -NHC(O)N(C1-8alkyI)2, -N(C1-8alkyl)C(O)N(C1-8alkyl)2, -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, -N(C1-8alkyl)NH2, tetrazolyl, or three- to seven- membered
heterocyclyl or heteroaryl ring having upto three heteroatoms independently selected from
N, O, or S, wherein said three- to seven- membered heterocyclyl or heteroaryl ring is
optionally substituted with 1, 2 or 3 substituents independently selected from the group
consisting of halo, hydroxy, C1-8alkyl, -O(C1-8alkyl), nitro, amino, mono(C1-8alkyI)amino,
di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyI), -
N(C1-8alkyl)SO2(C1-8alkyl), -NHSO2CF3, -N(C1-8alkyl)SO2CF3, -COOH, -CONH2, -
CONH(C1-8alkyl), -CON(C1-8alkyl)2, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-
8alkyl)CO2(C1-8alkyl), CF3, CN, -(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyl), -
(CH2)nN(C1-8alkyl)2, -CH2O(C1-8alkyl), -NHSO2NH2, -N(C1-8alkyl)SO2NH2, -
NHSO2NH(C1-8alkyl), -NHSO2N(C1-8alkyl)2, -N(C1-8alkyl)SO2N(C1-8alkyl)2, -NHCONH2,
-NHCONH(C1-8alkyl), -NHCON(C1-8alkyl)2, -N(C1-8alkyl)CON(C1-8alkyl)2, -S(C1-8alkyl),
-SO2(C1-8alkyl), -SO3H, -SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8alkyl)2, -SO2NH(C1-
8alkyl), or -NHC(NH)NH2 ;
'Y' is selected from the group consisting of:
(a) -C(O)NRaRb,
(b) -NRcC(X)NRaRb,

26
(c) -NRcC(X)NRdRe,
(d) -NRcC(O)ORf,
(e)-NRcC(O)C(O)Rg;
X is selected from O or S;
Ra and Rb together with the atoms with which they are attached form a three- to ten-
membered monocyclic or bicyclic heterocyclyl or heteroaryl ring selected from the group
consisting of aziridinyl, azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl,
hexahydropyridazinyl, hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl,
imidazolidinyl, morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl,
piperazinonyl, piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl,
pyrrolidonyl, pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide,
thiazolidinyl, thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl,
indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl, wherein, said
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring is
optionally substituted with 1, 2 or 3 substituents independently selected from the group
consisting of
(1) halo, (2) hydroxy, (3) optionally substituted C1-8alkyl, wherein the substituents are
amino, C1-3 alkoxy, mono(C1-3alkyl)amino, di(C1-3alkyl)amino, and hydroxy, (4) -O(C1-
8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyl), (13) -CON(C1-
8alkyl)2, (14) -CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3, (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8alkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alky)SO2(C1-8alkyl), (24) -NHSO2CF3, (25) -N(C1-8alkyl)CO2(C1-
8alkyl), (26) -N(C1-8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2, (28)-NHSO2NH(C1-8alkyl),
(29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31) -NHCONH2, (32) -
NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-8alkyl)CO(C1-8alkyl), (35) -
N(C1-8alkyl)CO2(C1-8alkyl), (36) -N(C1-8alkyl)CON(C1-8alkyl)2, (37) -S(C1-8alkyl), (38) -
SO2(C1-8alkyl), (39) -SO3H, (40) -SO2O(C1-8alkyl), (41) -SO2NH2, (42) -SO2N(C1-
8alkyl)2, (43) -SO2NH(C1-8alkyl), (44) -NHC(NH)NH2, (45) phenyl, unsubstituted or

27
substituted with one to two substituents selected from halo, nitro, C1-3alkyl, C1-3alkoxy,
hydroxy, amino, mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-
8alkyl)CO(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyCO2(C1-8alkyl), -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, and -N(C1-8alkyl)NH2, (46) pyridyl, unsubstituted or substituted with
one to two substituents selected from halo, C1-3alkyl and C1-3alkoxy, (47) -CO-(optionally
substituted heteroaryl), (48) -CO-(optionally substituted heterocyclyl), (49) -O-
(optionally substituted heteroaryl), (50) -O-(optionally substituted heterocyclyl), (51)
optionally substituted heterocyclyl, (52) -NH-(optionally substituted heterocyclyl),
wherein the substituents on the optionally substituted heteroaryl and heterocyclyl are one
to two groups independently selected from hydroxy, C1-8alkyl, -O(C1-8alkyl), oxo, thioxo,
amino, mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-
8alkyl)CO(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8aIkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, -NHSO2(C1-8alkyl), -NHSO2NH2 or -N(C1-8alkyl)NH2;
Rc and Rd are independently selected from hydrogen or C1-6 alkyl;
Re is selected from R7, -SO2R7, -SO2R3, -SO2R4, -COR7, -(CH2)nR7, -(CH2)nCOR7, -
(CH2)nOR7, -(CH2)nSR7, -(CH2)nSO2R7, -(CH2)nNHCOR7, -(CH2)nNHSO2R7,-(CH2)nN(C1-
8alkyl)COR7, -(CH2)nNHNHSO2R7, -(CH2)nNHSO2R4, -(CH2)nN(C1-8alkyl)SO2R4, -
(CH2)nN(NH2)R7, -(CH2)nN[N(C1-8alkyl)2]R7, -NHSO2R7, optionally substituted C1-
8alkyl, wherein the substituents are C1-3 alkoxy, amino, mono(C1-3alkyl)amino, di(C1-
3alkyl)amino, or hydroxy;
Rf is selected from the group consisting of (1) optionally substituted C1-8alkyl, wherein the
substituents are selected from C1-8alkoxy, amino, mono(C1-3alkyl)amino, di(C1-
3alkyl)amino, C1-3alkyl, phenyl, or hydroxy, (2) -R3, (3) -R4, (4) phenyl, unsubstituted or
substituted with R2, (5) -(CH2)nR7, (6) -(CH2)nCOR7, (7) -(CH2)nNRcR7, (8) -
(CH2)nNHSO2R7, (9) -(CH2)nN(C1-8alkyl)SO2R7, (10) -(CH2)nNHCOR7, (11) -(CH2)nN(C1-
8alkyl)COR7, (12) -(CH2)nOR7, (13) -(CH2)nSR7, (14) -(CH2)nSO2R7, (15) -
(CH2)nNHNHSO2R7, (16) -(CH2)nN(NH2)R7, (17) -(CH2)nN{N(C1-8 alkyl)2}R7 or, (18)
CC13;

28
Rg is selected from the group consisting of (1) mono(C1-8alkyl)amino (2) di(C1-
8alkyl)amino, (3) NH2, (4) -NHR7, (5) -NRc(CH2)nR7, (6) -NRc(CH2)nCOR7, (7) -
NH(CH2)nO(C1-8alkyl), (8) -NRc(CH2)nOR7, (9) -NRc(CH2)nNHSO2R7, (10) -
NRc(CH2)nN(C1-8alkyl)SO2R7, (11) -NRc(CH2)nSO2R7, (12) -NRCSO2R7, (13) -
NRc(CH2)nSR7, (14) -N(NH2)R7, (15) -N[N(C1-8alkyl)2]R7, (16) -
NRc(CH2)nNHNHSO2R7, (17) -NRc(CH2)nN(NH2)R7, (18) -NRc(CH2)nN[N(C1-
8alkyl)2]R7, (19) -NRc(CH2)nNHCOR7, (20) -NHNHSO2R7, (21) optionally substituted
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring attached
through the ring nitrogen atom and selected from the group consisting of aziridinyl,
azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl, hexahydropyridazinyl,
hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl, imidazolidinyl,
morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl, piperazinonyl,
piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl, pyrrolidonyl,
pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide, thiazolidinyl,
thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl, indazolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl,
wherein, the substituents on said optionally substituted three- to ten-membered
monocyclic or bicyclic heterocyclyl or heteroaryl ring are 1, 2 or 3 groups independently
selected from (1) halo, (2) hydroxy, (3) C1-8alkyl, unsubstituted or substituted with C1-
3alkoxy, amino, mono(C1-3alkyl)amino, di(C1-3alkyl)amino, C1-3alkyl, and hydroxy, (4) -
O(C1-8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyI), (13) -CON(C1-
8alkyl)2, (14) - CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3 , (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8alkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alkyl)SO2(C1-8alkyl),(24) -NHSO2CF3, (25) -N(C1-8alkyl)CO2(C1-
8alkyl), (26) -N(C1-8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2,(28) -NHSO2NH(C1-8alkyl),
(29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31) -NHCONH2, (32) -
NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-8alkyl)CO (C1-8alkyl), (35) -
N(C1-8alkyl)CO2(C1-8alkyl), (36) -N(C1-8alkyl)CON(C1-8alkyl)2, (37) -S(C1-8alkyl), (38 ) -
SO2(C1-8alkyl), (39) -SO3H, (40) - SO2O(C1-8alkyl), (41) -SO2NH2, (42) -SO2N(C1-
8alkyl)2, (43) -SO2NH(C1-8alkyl), (44) -NHC(NH)NH2,

29
n is independently selected at each occurrence, from 1, 2 or 3;
R3 at each occurrence is optionally substituted monocyclic three- to seven-membered heteroaryl
ring having one to three heteroatoms independently selected from N, O, or S, wherein the
substitution is by 1, 2 or 3 substituents represented by R2;
R4 at each occurrence is optionally substituted monocyclic three- to seven-membered
heterocyclyl ring having one to three heteroatoms independently selected from N, O or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R5 at each occurrence is independently selected from hydrogen, C1-6alkyl or CF3;
R6 at each occurrence are 1 or 2 groups independently selected from hydrogen, -O(C1-8alkyl),
halo, C1-6alkyl, mono(C1-6alkyl)amino or di(C1-6alkyl)amino ;
R7 at each occurrence is
1. optionally substituted monocyclic five- to seven- membered aryl;
2. optionally substituted monocyclic three- to seven-membered heteroaryl or heterocyclyl
having one to three heteroatoms independently selected from N, O or S,
wherein the substituent on R7 is by 1, 2 or 3 substituents represented by R2 with proviso that
A. When Y is NRcC(X)NRdRe and Re=R7, R7 is not furan, thiophene, isooxazole, isothiazole
& phenyl;
B. When Y is selected from -C(O)NRaRb, Rl and R2 is not selected from:
(a) -(CH2)nR4
(b) -(CH2)nNHCOR7
(c) -(CH2)nN(C1-8alkyl)COR7
(d) -CONH2
(e) -CONH(C1-8alkyl)
(f)-CON(C1-8alkyl)2
(g) -(CH2)nNH2
(h) -(CH2)nNH(C1-8alkyl)
(i) -(CH2)nN(C1-8alkyl)2, and

29A
C. When Y is selected from -NRcC(X)NRaRb or NRcC(X)NRdRe and X=O, Rl and R2 is not
selected from:
(a) -NH(CH2)nR4
(b) -NH(CH2)nNHCOR4
(c) -NH(CH2)nN(C1-8alkyl)COR4
(d) -N(C1-8alkyl)(CH2)nNHCOR4
(e) -N(C1-8alkyl)(CH2)nR4
(f) -mono(C1-8alkyl)amino
(g) -di(C1-8alkyl)amino
(h) -NHCONH2
(i) -NHCONH(C1-8alkyl)
(j) -NHCON(C1-8alkyl)2
(k)-N(C1-8alky)C(O)N(C1-8alky)2.
A family of specific compounds of particular interest within the above formula (I) consists of
compound and pharmaceutically acceptable salts thereof as follows:
l-[4-(Morpholine-4-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 1);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidin-4-one (Compound No. 2);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 3);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-pyrrolidine-2-carboxylic acid amide (Compound No.
4);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid isopropyl ester
(Compound No. 5);

30
l-[4-(Piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 6);
l-[4-(4-Acetyl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound
No. 7);
l-(4-Nitro-phenyl)-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-piperazin-2-one (Compound
No. 8);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid (Compound No. 9);
3-Quinolin-2-yl-l-[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone (Compound No.
10);
l-[4-(Pyrrolidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 11);
l-[4-(Piperidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 12);
4-Morpholin-4-yl-2-{3-oxo-3-[4-(pyrrolidine-l-carbonyl)-phenyl]-propenyl}-quinoline-6-
carboxylic acid methyl ester (Compound No. 13);
l-{4-[4-(3-Methyl-butyl)-piperazine-l-carbonyl]-phenyl}-3-quinolin-2-yl-propenone
(Compound No. 14);
l-{4-[4-(3-Chloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-quinolin-2-yl-propenone
(Compound No. 15);
l-{4-[4-(2,3-Dichloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-quinolin-2-yl-propenone
(Compound No. 16);
N-(4-{2-Oxo-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-piperazin-l-yl}-phenyl)-acetamide
(Compound No. 17);
4-Imidazol-1 -yl-2-[3-oxo-3-(4-trichloromethoxycarbony lamino-phenyl)-propenyl]-
quinoline-6-carboxylic acid methyl ester (Compound No. 18);
Pyrrolidine-1-carboxylic acid {4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-
amide (Compound No. 19);
3-Quinolin-2-yl-l-{4-[4-(tetrahydro-furan-2-carbonyl)-piperazine-l-carbonyl]-phenyl}-
propenone (Compound No. 20);
1 - {4-[4-(Furan-2-carbonyl)-piperazine-1 -carbonyl]-phenyl} -3-quinolin-2-yl-propenone
(Compound No. 21);
l-[4-(4-Pyridin-4-yl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone
(Compound No. 22);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 23);

31
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid 2,2-dimethyl-
propyl ester (Compound No. 24);
l-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-3-(2-trifluoromethyl-phenyl)-
urea (Compound No. 25);
l-Benzenesulfonyl-3-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-urea
(Compound No. 26);
4-(3-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-ureido)-benzoic acid ethyl
ester (Compound No. 27);
l-[4-(4-Ethyl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No.
28);
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 29);
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid isobutyl ester
(Compound No. 30);
{4-[3-(2-Pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 31);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-(6-trifluoromethyl-quinolin-2-yl)-
propenone (Compound No. 32);
1 -Pyridin-2-yI-3- {4-[3-(2-pyrrolidin-1 -yl-quinolin-3-yl)-acryloyl]-phenyl} -urea
(Compound No. 33);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-(6-methylsulfanyl-quinolin-2-yl)-
propenone (Compound No. 34);
l-{4-[3-(5,6,7-Trimethoxy-6,7-dihydro-quinolin-2-yl)-acryloyl]-benzoyl}-piperidin-4-one
(Compound No. 35);
l-[4-(Thiomorpholine-4-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-propenone
(Compound No. 36);
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(4-methyl-piperazine-l-carbonyl)-phenyl]-propenone
(Compound No. 37);
l-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-piperidin-4-one (Compound No.
38);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone (Compound
No. 39);
l-[4-(Pyrrolidine-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone (Compound No. 40);

32
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-one (Compound No. 41);
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(pyrazole-l-carbonyl)-phenyl]-propenone
(Compound No. 42);
l-[4-(2,3-Dihydro-indole-l-carbonyl)-phenyl]-3-(3-hydroxy-quinoxalin-2-yl)-propenone
(Compound No. 43);
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone
(Compound No. 44);
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-one oxime (Compound No. 45);
2-{3-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-oxo-propenyl}-quinoline-6-
sulfonic acid amide (Compound No. 46);
2-{3-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-oxo-propenyl}-quinoline-6-
sulfonic acid amide (Compound No. 47);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-propenone
(Compound No. 48);
l-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound
No. 49);
l-{4-[4-(2,3-Dichloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-(2-pyrrolidin-l-yl-
quinolin-3-yl)-propenone (Compound No. 50);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-
propenone (Compound No. 51);
l-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-
propenone (Compound No. 52);
l-{4-[3-(4-Piperidin-l-yl-6-trifluoromethyl-quinolin-2-yl)-acryloyl]-phenyl}-3-(2,3,4-
trimethoxy-phenyl)-urea (Compound No. 53);
l-[4-(4-Pyrrolidin-l-yl-piperidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone
(Compound No. 54);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 55);
3-[6-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)-quinolin-2-yl]-l-[4-(pyrrolidine-l-
carbonyl)-phenyl]-propenone (Compound No. 56);
l-Cyclohexyl-3-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-urea
(Compound No. 57);
2,2-Dimethyl-N-(2-{3-oxo-3-[4-(pyrazole-l-carbonyl)-phenyl]-propenyl}-quinolin-6-yl)-
propionamide (Compound No. 58);

33
l-Benzenesulfonyl-3-{4-[3-(6-methyl-4-piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-
urea (Compound No. 59);
l-{4-[3-(5,6,7-Trimethoxy-quinolin-2-yl)-acryloyl]-benzoyl}-piperidine-4-carboxylic acid
isopropyl ester (Compound No. 60);
Piperidine-1-carboxylic acid {4-[3-(2-pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-
amide (Compound No. 61);
3-(6-Methylsulfanyl-4-morpholin-4-yl-quinolin-2-yl)-1 -[4-(pyrrolidine-1 -carbonyl)-
phenylj-propenone (Compound No. 62);
3-(6-Methanesulfonyl-4-morpholin-4-yl-quinolin-2-yl)-l-[4-(pyrrolidine-l-carbonyl)-
phenyl]-propenone (Compound No. 63);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl
ester (Compound No. 64);
l-Benzoyl-3-{4-[3-(6-[l,2,3]thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-urea
(Compound No. 65);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl
ester (Compound No. 66);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-morpholin-4-yl-
ethyl ester (Compound No. 67);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen-2-
ylmethyl ester (Compound No. 68);
{5-Methoxy-2-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid
methyl ester (Compound No. 69);
Propyl-{4-[3-(2-pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 70);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl ester
(Compound No. 71);
2,2-Dimethyl-N- {1 -[4-(3 -quinoxalin-2-yl-acryloy l)-benzoyl]-piperidin-4-yl} -
propionamide (Compound No. 72);
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid dimethylamide
(Compound No. 73);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl
ester (Compound No. 74);

34
l-(4-Methyl-benzenesu[fonyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-
acryloyl]-phenyl}-urea (Compound No. 75);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid
ethyl ester (Compound No. 76);
N-{4-[3-(2-Morpholin-4-yl-quinolin-3-yl)-acryloyl]-phenyl}-oxalamide (Compound No.
77);
2-Morpholin-4-yl-N-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-2-oxo-
acetamide (Compound No. 78);
2-MorphoIin-4-yl-N-{4-[3-(2-morpholin-4-yl-quinolin-3-yl)-acryloyl]-phenyl}-2-oxo-
acetamide (Compound No. 79);
N-{4-[3-(2-Piperidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-oxalamide (Compound No.
80);
2-Morpholin-4-yl-2-oxo-N-{4-[3-(2-piperidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-
acetamide (Compound No. 81);
N-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-N'-propyl-oxalamide
(Compound No. 82);
2-Morpholin-4-yl-N-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-2-oxo-
acetamide (Compound No. 83);
(4-{3-[6-(3,5-Dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-phenyl)-carbamic acid
phenyl ester (Compound No. 84);
N-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-2-oxo-2-piperidin-l-yl-
acetamide (Compound No. 85);
5'-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-3,4,5,6-tetrahydro-2H-
[l,2']bipyridinyl-4-carboxylic acid (Compound No. 86);
2-Oxo-2-piperidin-1 -yl-N- {4-[3-(4-pyrrol-1 -yl-quinolin-2-yl)-acryloyl]-phenyl} -
acetamide (Compound No. 87);
2-Morpholin-4-yl-2-oxo-N-{4-[3-(4-pyrrol-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-
acetamide (Compound No. 88);
C,C,C-Trifluoro-N-{l-[4-(3-quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-yl}-
methanesulfonamide (Compound No. 89);
{4-[3-(6-Pyrrolidin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid pyridin-2-ylmethyl
ester (Compound No. 90);

35
{4-[3-(6-Pyrrolidin-l-yl-pyridin-2-yl)-acryIoyl]-phenyl}-carbamic acid 4-fluoro-benzyl
ester (Compound No. 91);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid 2-
(3,5-dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 92);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid
furan-2-ylmethyl ester (Compound No. 93);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}.-carbamic acid 3-
phenyl-allyl ester (Compound No. 94);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid 2-
piperidin-1-yl-ethyl ester (Compound No. 95);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl ester
(Compound No. 96);
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(morpholine-4-carbonyl)-phenyl]-propenone
(Compound No. 97);
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone
(Compound No. 98);
l-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-(3-hydroxy-quinoxalin-2-yl)-
propenone (Compound No. 99);
l-{4-[4-(2,3-Dichloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-(3-hydroxy-quinoxalin-
2-yl)-propenone (Compound No. 100);
l-{4-[4-(3-Chloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-(3-hydroxy-quinoxalin-2-
yl)-propenone (Compound No. 101);
l-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-piperidine-4-carboxylic acid
dimethylamide (Compound No. 102);
N-(l-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-piperidin-4-yl)-2,2-dimethyl-
propionamide (Compound No. 103);
l-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-piperidine-4-carboxylic acid
isopropyl ester (Compound No. 104);
l-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-pyrrolidine-2-carboxylic acid
amide (Compound No. 105);
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(4-pyridin-4-yl-piperazine-l-carbonyl)-phenyl]-
propenone (Compound No. 106);

36
2-{3-[4-(Morpholine-4-carbonyl)-phenyl]-3-oxo-propenyl}-3H-quinazolin-4-one
(Compound No. 107);
2-{3-Oxo-3-[4-(pyrazole-l-carbonyI)-phenyI]-propenyl}-3H-quinazolin-4-one
(Compound No. 108);
2-{3-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-oxo-propenyl}-3H-quinazolin-4-one
(Compound No. 109);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-carbamic acid
phenyl ester (Compound No. 110);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-carbamic acid
methyl ester (Compound No. Ill);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-carbamic acid ethyl
ester (Compound No. 112);
l-Benzenesulfonyl-3-(4-{3-[6-(3,5-dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-
phenyl)-urea (Compound No. 113);
N- {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl} -2-oxo-2-piperidin-1 -yl-
acetamide (Compound No. 114);
N-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-oxalamide (Compound No.
115);
2-Oxo-2-piperidin-l-yl-N-{4-[3-(2-piperidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-
acetamide (Compound No. 116);
2-Oxo-2-piperidin-l-yl-N-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-acetamide (Compound
No. 117);
2-Morpholin-4-yl-2-oxo-N-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-acetamide (Compound
No. 118);
N-Propyl-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide (Compound No. 119);
N-[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide (Compound No. 120);
N-(2-Methoxy-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide (Compound
No. 121);
1 - {4-[4-(3-Chloro-phenyl)-piperazine-1 -carbonyl]-phenyl}-3-quinoxalin-2-yl-propenone
(Compound No. 122);
3-Quinoxalin-2-yl-l-[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone (Compound No.
123);

37
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid isopropyl ester
(Compound No. 124);
l-[4-(4-Pyridin-4-yl-piperazine-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone
(Compound No. 125);
1 - {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl} -3-(2-oxo-2-piperidin-1 -yl-
ethyl)-urea (Compound No. 126);
l-(2-Morpholin-4-yl-ethyl)-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-
urea (Compound No. 127);
2,2-Dimethyl-N-{l-[4-(3-quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-yl}-
propionamide (Compound No. 128);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-piperazin-l-yl-
ethyl ester (Compound No. 129);
N-(2-Morpholin-4-yl-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 130);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridine-2-sulfonyl)-
ethyl]-urea (Compound No. 131);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridin-2-ylsulfanyl)-
ethyl]-urea (Compound No. 132);
l-[2-(4-Methyl-piperazin-l-yl)-ethyl]-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 133);
N-(2-Morpholin-4-yl-ethyl)-N'-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-
oxalamide (Compound No. 134);
l-(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]- urea (Compound
No. 135);
N-(2-{3-[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-ureido}-ethyl)-benzenesulfonamide
(Compound No. 136);
N-[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-oxalamide (Compound No. 137);
2-Morpholin-4-yl-2-oxo-N-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-acetamide (Compound
No. 138);
l-Benzenesulfonyl-hydrazino-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 139);
l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-[4-(3-quinolin-2-yl-acryloyI)-phenyl]-urea
(Compound No. 140);

38
l-[2-(Pyridin-4-yloxy)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 141);
l-(Morpholine-4-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No.
142);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid piperidin-4-yl
ester (Compound No. 143);
4-(3-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-ureido)-benzoic acid
(Compound No. 144);
4-(3-{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-ureido)-benzoic acid
(Compound No. 145);
l-(4-Methyl-thiophen-2-yl)-3-{4-[3-(4-piperidin-l-yl-6-trifluoromethyl-quinolin-2-yl)-
acryloyl]-phenyl}-urea (Compound No. 146);
N-(2-{3-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-oxo-propenyl}-quinolin-6-
yl)-2,2-dimethyl-propionamide (Compound No. 147);
l-[4-(Morpholine-4-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-propenone
(Compound No. 148);
l-{4-[3-(4-Piperidin-l-yl-6-trifluoromethyl-quinolin-2-yl)-acryloyl]-phenyl}-3-pyridin-2-
yl-urea (Compound No. 149);
l-Cyclohexyl-3-{4-[3-(4-piperidin-l-yl-6-trifluoromethyl-quinolin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 150);
l-[4-(4-Methoxy-piperidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound
No. 151);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-
propenone (Compound No. 152);
l-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-
[l,2']bipyridinyl-6'-yl)-propenone (Compound No. 153);
l-{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-benzoyl}-piperidine-4-
carboxylic acid isopropyl ester (Compound No. 154);
l-[2-(Pyridin-2-ylsulfanyl)-ethyl]-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 155);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(pyridine-2-
sulfonyl)-ethyl ester (Compound No. 156);

39
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(pyridin-2-
ylsulfanyl)-ethyl ester (Compound No. 157);
[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-carbamic acid 2-benzenesulfonylamino-ethyl
ester (Compound No. 158);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamicacid2-(N-pyridin-2-yl-
hydrazino)-ethyl ester (Compound No. 159);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 160);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-5'-yl)-but-
2-en-l-one (Compound No. 161);
4,4,4-Trifluoro-l-[4-(morpholine-4-carbonyl)-phenyl]-3-quinolin-3-yl-but-2-en-l-one
(Compound No. 162);
N-{4-[3-(6-Morpholin-4-yl-pyridin-3-yl)-but-2-enoyl]-phenyl}-2-oxo-2-piperidin-l-yl-
acetamide (Compound No. 163);
2-Morpholin-4-yl-2-oxo-N-[4-(4,4,4-trifluoro-3-quinolin-3-yl-but-2-enoyl)-phenyl]-
acetamide (Compound No. 164);
Morpholine-4-carboxylic acid {4-[4,4,4-trifluoro-3-(4-morpholin-4-yl-quinolin-3-yl)-but-
2-enoyl]-phenyl}-amide (Compound No. 165);
Morpholine-4-carboxylic acid {4-[3-(6-morpholin-4-yI-pyridin-3-yl)-but-2-enoyl]-
phenyl}-amide (Compound No. 166);
N-[2-(3-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-ureido)-ethyl]-
nicotinamide (Compound No. 167);
l-[2-(Piperidin-4-yloxy)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 168);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid furan-
2-ylmethyl ester (Compound No. 169);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid pyridin-
2-ylmethyl ester (Compound No. 170);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid 2-(3,5-
dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 171);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2- [l,2,4]triazol-
1-yl-ethyl ester (Compound No. 172);

40
{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[l,2,4]-triazol-l-
yl-ethyl ester (Compound No. 173);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid
thiophen-2-ylmethyl ester (Compound No. 174);
2-{3-Oxo-3-[4-(thiophen-2-ylmethoxycarbonylamino)-phenyl]-propenyl}-quinoline-6-
carboxylic acid (Compound no. 175);
{4-[3-(6-[l,2,4]Triazol-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen-2-
ylmethyl ester (Compound no. 176);
{4-[3-(6-Tetrazol-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen-2-yl
methyl ester (Compound No. 177);
(4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid pyridin-2
yl methyl ester (Compound No. 178);
4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid pyridin-2-ylmethyl ester (Compound
No. 179);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid
piperidin-4-yl ester (Compound No. 180);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 1-methyl- 1H-
pyrrol-3-yl ester (Compound No. 181);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid
isoxazol-3-yl ester (Compound No. 182);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid l-methyl-lH-imidazol-4-ylmethyl
ester (Compound No. 183);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(4-methyl-piperazine-l-
sulfonylamino)-ethyl ester (Compound No. 184);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(4-methyl-piperazine-l-
sulfonylamino)-ethyl ester (Compound No. 185);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid 2-
benzenesulfonylamino-ethyl ester (Compound No. 186);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[(4-methyl-
piperazine-l-carbonyl)-amino]-ethyl ester (Compound No. 187);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 2-[(4-methyl-piperazine-l-carbonyl)-
amino]-ethyl ester (Compound No. 188);

41
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N-pyridin-2-yl-hydrazino)-ethyl
ester (Compound No. 189);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-[N-(5-methyl-isoxazol-3-yl)-
hydrazino]-ethyl ester (Compound No. 190);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N'-benzenesulfonyl- hydrazino)-
ethyl ester (Compound No. 191);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-2-piperazin-l-yl-
ethyl)-urea (Compound No. 192);
l-[2-(4-Methyl-piperazin-l-yl)-2-oxo-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 193);
l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-{4-[3-(6-piperazin-l-yl-pyridin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 194);
l-[2-(Pyridine-2-sulfonyl)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 195);
l-{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidine-4-sulfonyl)-
ethyl]-urea (Compound No. 196);
4-Methyl-piperazine-l-sulfonic acid(2-{3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-ureido}-
ethyl)-amide (Compound No. 197);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidin-4-ylsulfanyl)-
ethyl]-urea (Compound No. 198);
l-{2-[N-(l-Methyl-piperidin-4-yl)-hydrazino]-ethyl}-3-[4-(3-pyridin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 199);
l-{2-[N-(l-Methyl-piperidin-4-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 200);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-{4-[3-(6-morpholin
-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-urea (Compound No. 201);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound No.
202);
1 -(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]urea (Compound No.
203);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No.
204);

42
1 - {4-[3-(6-Piperazin-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -3-(2-piperidin-1 -yl-ethyl)-urea
(Compound No. 205);
l-{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-thiomorpholin 1, 1-
dioxide-4-yl-ethyl)-urea (Compound No. 206);
l-(2-Piperazin-l-yl-ethyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-
acryloyl]-phenyl}-urea (Compound No. 207);
Piperidine-4-carboxylic acid [2-(3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-
phenyl}-ureido)-ethyl]-amide (Compound No. 208);
N-(2-{3-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-ureido}-ethyl)-nicotinamide (Compound
No. 209);
l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 210);
l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 211);
l-(Piperazine-l-sulfonyl)-3-[4-(3-pyridin-2-yl-acryloyl)phenyl]-urea (Compound No.
212);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(piperazine-l-sulfonyl)-urea
(Compound No. 213);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound No.
214);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl) phenyl]-urea (Compound No.
215);
N-(2-Piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide (Compound
No. 216);
N-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-N'-(2-piperazin-l-yl-ethyl)-
oxalamide (Compound No. 217);
l-[2-({4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenylaminooxalyl}-amino)-
acetyl]-piperidine-4-carboxylic acid (Compound No. 218);
N-(2-Oxo-2-piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 219);
N-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-N'-[2-(pyridine-2-yl-sulfonyl)-ethyl]-oxalamide
(Compound No. 220);

43
N-[2-(Piperidin-4-ylsulfanyl)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 221);
N-[2-(Pyridine-2-sulfonyl)-ethyl]-N'-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 222);
2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-2-oxo-N-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 223);
2-Oxo-2-(N-phenyl-hydrazino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 224);
2-Oxo-2-(piperazine-l-sulfonylamino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 225);
2-Benzenesulfonylamino-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 226);
N-[2-(Piperazine-l-sulfonylamino)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 227);
2-(N'-Benzenesulfonyl-hydrazino)-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 228);
N-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-
phenylj-oxalamide (Compound No. 229);
N-{2-[(Piperazine-l-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 230);
N-{2-[(Pyridine-3-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 231);
N-{2-[(Piperidine-4-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 232);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-{6-[2-(4-methyl-piperazin-l-yl)-
ethylamino]-pyridin-2-yl}-propenone (Compound No. 233);
(2-{3-[4-(4-Methyl-piperazine-l-carbonyl)-phenyI]-3-oxo-propenyl}-quinolin-6-yl)-
carbamic acid ethyl ester (Compound No. 234);
(6-{3-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-
carbamic acid phenyl ester (Compound No. 235);
l-[4-(Morpholine-4-carbonyl)-phenyl]-3-{6-[(piperidin-l-ylmethyl)-amino]-pyridin-2-yl}-
propenone (Compound No. 236);

44
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-[6-(2-oxo-2-piperidin-l-yl-
ethylamino)-pyridin-2-yl]-propenone (Compound No. 237);
l-[4-(Piperazine-l-carbonyl)-phenyl]-3-{6-[2-(pyridine-2-sulfonyl)-ethylamino]-pyridin-
2-yl}-propenone (Compound No. 238);
Benzenesulfonic acid N'-(6-{3-oxo-3-[4-(piperidine-l-carbonyl)-phenyl]-propenyl}-
pyridin-2-yl)-hydrazide (Compound No. 239);
(6-{3-[4-(3-Benzenesulfonyl-ureido)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-carbamic
acid ethyl ester (Compound No. 240);
Morpholine-4-carboxylic acid (4-{3-[6-(2-piperidin-l-yl-ethylamino)-pyridin-2-yl]-
acryloyl}-phenyl)-amide (Compound No. 241);
{2-[3-(4-Ethoxycarbonylamino-phenyl)-3-oxo-propenyl]-quinolin-6-yl}-carbamic acid
ethyl ester (Compound No. 242);
{2-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-quinolin-4-yl}-carbamic acid
ethyl ester (Compound No. 243);
[2-(3-{4-[2-(4-Methyl-piperazin-l-yl)-2-oxo-acetylamino]-phenyl}-3-oxo-propenyl)-
quinolin-4-yl]-carbamic acid methyl ester (Compound No. 244);
l-(2-Morpholin-4-yl-ethyI)-3-(4-{3-[6-(2-piperidin-l-yl-ethylamino)-pyridin-2-yl]-
acryloyl}-phenyl)-urea (Compound No. 245);
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-{6-[2-(4-methyl-piperazin-l-yl)-
2-oxo-ethylamino]-pyridin-2-yl}-propenone (Compound No. 246);
N-(l-{4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl]-piperazin-l-yl}-piperidin-4-yl)-
methanesulfonamide (Compound No. 247);
(1 - {4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl}-piperidin-4-yl)- sulfonylurea
(Compound No. 248);
l-{4-[4-(4-Cyclohexylamino-piperidin-l-yl)-piperazine-l-carbonyl]-phen
yl}-3-pyridin-2-yl-propenone (Compound No. 249);
[6-(3-Oxo-3-{4-[4-(pyrrolidine-l-carbonyl)-piperidine-l-carbonyl]-phenyl}-propenyl)-
pyridin-2-yl]-carbamic acid methyl ester (Compound No. 250);
[6-(3-Oxo-3-{4-[4-(pyridin-2-yloxy)-piperidine-l-carbonyl]-phenyl}-propenyl)-pyridin-2-
yl]-carbamic acid ethyl ester (Compound No. 251).
A preferred embodiment of the invention consists of those compounds of Formula (I),
wherein

45
Q is as defined hereinabove, which may be unsubstituted or substituted by 1 to 6
substituents represented by R2;
R2 is independently selected at each occurrence from hydrogen, hydroxy, halo, amino, C1-
8alkyl, -O(C1-8alkyl), -S(C1-8alkyl), -SO2(C1-8alkyl), oxo, thioxo, mono(C1-8alkyl)amino,
di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyl), -
NHSO2CF3, -N(C1-8alkyl)SO2CF3, -NHSO2O(C1-8alkyl), -N(C1-8alkyl)SO2(C1-8alkyl), -
N(C1-8alkyl)SO2O(C1-8alkyl), -COOH, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-
8alkyl)CO2(C1-8alkyl), -CONH2, -CONH(C1-8alkyl), -CON(C1-8alkyl)2, formyl, CF3, CN, -
(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyI), -(CH2)nN(C1-8alkyl)2, -(CH2)nO(C1-8alkyl),
-SO3H, -SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8aIkyl)2, -SO2NH(C1-8alkyl), -OSO2(C1-
8alkyl), -N(C1-8alkyl)SO2NH2, -NHSO2NH(C1-8alkyl), -NHSO2N(C1-8alkyl)2, -N(C1-
8alkyl)SO2N(C1-8alkyl)2, -NHSO2NH2, -NHC(NH)NH2, -NHCONH2, -NHC(O)NH(C1-
8alkyl), -NHC(O)N(C1-8alkyl)2, -N(C1-8alkyl)C(O)N(C1-8alkyl)2, -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, -N(C1-8alkyl)NH2, tetrazolyl or three- to seven- membered
heterocyclyl or heteroaryl ring having upto three heteroatoms independently selected from
N, O, or S, wherein said three- to seven- membered heterocyclyl or heteroaryl ring is
optionally substituted with 1, 2 or 3 substituents independently selected from the group
consisting of halo, hydroxy, C1-8alkyl, -O(C1-8alkyl), nitro, amino, mono(C1-8alkyl)amino,
di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyl), -
N(C1-8alky)SO2(C1-8alkyl), -NHSO2CF3, -N(C1-8alkyl)SO2CF3, -COOH, -CONH2> -
CONH(C1-8alkyl), -CON(C1-8alkyl)2, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-
8alkyl)CO2(C1-8alkyl), CF3, CN, -(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyl), -
(CH2)nN(C1-8alkyl)2, -CH2O(C1-8alkyl), -NHSO2NH2, -N(C1-8alkyl)SO2NH2, -
NHSO2NH(C1-8alkyl), -NHSO2N(C1-8alkyl)2, -N(C1-8alkyl)SO2N(C1-8alkyl)2, -NHCONH2,
-NHCONH(C1-8alkyl), -NHCON(C1-8alkyl)2, -N(C1-8alkyl)CON(C1-8alkyl)2, -S(C1-8alkyl),
-SO2(C1-8alkyl), -SO3H, -SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8alkyl)2, -SO2NH(C1-
8alkyl), or -NHC(NH)NH2 ;
'Y' is selected from the group consisting of:
(a) -C(O)NRaRb,
(b) -NRcC(X)NRaRb,

46
(c) -NRcC(X)NRdRe,
(d) -NRcC(O)ORf,
(e)-NReC(O)C(O)Rg;
X is selected from O or S;
Ra and Rb together with the atoms with which they are attached form a three- to ten-
membered monocyclic or bicyclic heterocyclyl or heteroaryl ring selected from the group
consisting of aziridinyl, azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl,
hexahydropyridazinyl, hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl,
imidazolidinyl, morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl,
piperazinonyl, piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl,
pyrrolidonyl, pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide,
thiazolidinyl, thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl,
indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl, wherein, said
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring is
optionally substituted with 1, 2, or 3 substituents independently selected from the group
consisting of
(1) phenyl, unsubstituted or substituted with a single substituent selected from hydroxy,
mono(C1-8alkyl)amino, di(C1-8arkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-
8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-8alkyl)N(C1-
8alkyl)2, and -N(C1-8alkyl)NH2,
(2) =NOH, (3) optionally substituted heterocyclyl, (4) -O-optionally substituted
heteroaryl, (5) -O-optionally substituted heterocyclyl, (6) -CO-optionally substituted
heteroaryl, or (7) -CO-optionally substituted heterocyclyl,
wherein the substituent on the optionally substituted heteroaryl and heterocyclyl is a single
group selected from hydroxy, C1-8alkyl, -O(C1-8alkyl), oxo, thioxo, amino, mono(C1-
8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -
NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-8alkyl)N(C1-8alkyl)2, or
-N(C1-8alkyl)NH2;

47
Rc and Rd are independently selected from hydrogen or C1-6alkyl;
Re is independently selected from -SO2R3, -SO2R4, -(CH2)nR4, -(CH2)nCOR4, -
(CH2)nOR4, -(CH2)nSR7, -(CH2)nSO2R7, -(CH2)nNHCOR7, -(CH2)nN(C1-8alkyl)COR7, -
(CH2)nNHNHSO2R7, -(CH2)nNHSO2R4, -(CH2)nN(C1-8alkyl)SO2R4, -(CH2)nN(NH2)R7, -
(CH2)nN[N(C1-8alkyl)2]R7, or-NHSO2R7;
Rf is selected from the group consisting of (1) optionally substituted C1-8alkyl, wherein the
substituents are selected from oxo, thioxo, amino, C1-3alkoxy, mono(C1-3 )alkylamino,
di(C1-3alkyl)amino, or hydroxy, (2) -R3, (3) -R4, (4) phenyl, unsubstituted or substituted
with R2, (5) -(CH2)nR7, (6) -(CH2)nCOR7, (7) -(CH2)nNRcR7, (g) -(CH2)nNHSO2R7, (9) -
(CH2)nN(C1-8alkyl)SO2R7, (10) -(CH2)nNHCOR7, (11) -(CH2)nN(C1-8alkyl)COR7, (12) -
(CH2)nOR7, (13) -(CH2)nSR7, (14) -(CH2)nSO2R7, (15) -(CH2)nNHNHSO2R7, (16) -
(CH2)nN(NH2)R7, or (17) -(CH2)nN{N(C1-8 alkyl)2}R7;
Rg is selected from the group consisting of -NRc(CH2)nR4, -NRc(CH2)nCOR4, -
NRc(CH2)nOR4, -NRc(CH2)nNHSO2R4, -NRc(CH2)nN(C1-8alkyl)SO2R4, -NRc(CH2)SO2R7,
-NRCSO2R7, -NRc(CH2)nSR7, -N(NH2)R7, -N[N(C1-8alkyl)2]R7, -NRc(CH2)nNHNHSO2R7,
-NRc(CH2)nN(NH2)R7, -NRc(CH2)nN[N(C1-8alkyl)2]R7, or-NRc(CH2)nNHCOR7;
n is independently selected at each occurrence, from 1, 2 or 3;
R3 at each occurrence is optionally substituted monocyclic three to seven membered
heteroaryl ring having one to three heteroatoms independently selected from N, O, or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R4 at each occurrence is optionally substituted monocyclic three to seven membered
heterocyclyl ring having one to three heteroatoms independently selected from N, O or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R5 at each occurrence is independently selected from hydrogen, C1-6alkyl or CF3;

48
R6 at each occurrence are 1 or 2 groups independently selected from hydrogen, -O(C1-
8alkyl), halo, C1-6alkyl, mono(C1-6alkyl)amino or di(C1-6 alkyl)amino ;
R7 at each occurrence is
1. optionally substituted monocyclic five- to seven- membered aryl;
2. optionally substituted monocyclic three- to seven- membered heteroaryl or
heterocyclyl having one to three heteroatoms independently selected from N, O or
S,
wherein the substitution on R7 is by 1, 2 or 3 substituents represented by R2;
with the proviso that,
when Rf is C1-8alkyl, aryl, or R3, then R2 is an optionally substituted three- to seven-
membered heterocyclyl or heteroaryl ring having upto three heteroatoms independently
selected from N, O, or S.
A family of specific compounds of particular interest within the above formula (I)
consists of compound and pharmaceutically acceptable salts thereof as follows:
N-(4-{2-Oxo-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl}-phenyl)-
acetamide (Compound No. 17);
3-Quinolin-2-yl-1 -{4-[4-(tetrahydro-furan-2-carbonyl)-piperazine-1 -carbonyl]-phenyl}-
propenone (Compound No. 20);
l-{4-[4-(Furan-2-carbonyl)-piperazine-l-carbonyl]-phenyl}-3-quinolin-2-yl-propenone
(Compound No. 21);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 23);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid 2,2-dimethyl-
propyl ester (Compound No. 24);
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 29);
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid isobutyl ester
(Compound No. 30);

49
{4-[3-(2-Pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 31);
l-[4-(2,3-Dihydro-indole-l-carbonyl)-phenyl]-3-(3-hydroxy-quinoxalin-2-yl)-propenone
(Compound No. 43);
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-one oxime (Compound No. 45);
1 -Benzenesulfonyl-3- {4-[3-(6-methyl-4-piperidin-1 -yl-quinolin-2-yl)-acryloyl]-phenyl} -
urea (Compound No. 59);
{4-[3-(6-[l,2,3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 64);
{4-[3-(6-[l,2,3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl
ester (Compound No. 66);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-morpholin-4-yl-
ethyl ester (Compound No. 67);
{5-Methoxy-2-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid
methyl ester (Compound No. 69);
Propyl-{4-[3-(2-pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 70);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl ester
(Compound No. 71);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl
ester (Compound No. 74);
l-(4-Methyl-benzenesulfonyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-
acryloyl]-phenyl}-urea (Compound No. 75);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid
ethyl ester (Compound No. 76);
(4-{3-[6-(3,5-Dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-phenyl)-carbamic acid
phenyl ester (Compound No. 84);
5'-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-3,4,5,6-tetrahydro-2H-
[l,2']bipyridinyl-4-carboxylic acid (Compound No. 86);
{4-[3-(6-Pyrro!idin-l-yl-pyridin-2-yl)-acryloyl]-phenyI}-carbamic acid pyridin-2-ylmethyl
ester (Compound No. 90);
{4-[3-(6-Pyrrolidin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 4-fluoro-benzyl
ester (Compound No. 91);

50
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyI}-carbamic acid 2-
(3,5-dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 92);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid
furan-2-ylmethyl ester (Compound No. 93);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid 3-
phenyl-allyl ester (Compound No. 94);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid 2-
piperidin-1-yl-ethyl ester (Compound No. 95);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl ester
(Compound No. 96);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-carbamic acid
phenyl ester (Compound No. 110);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinoIin-3-yl]-acryloyl}-phenyl)-carbamic acid
methyl ester (Compound No. 111);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyI)-carbamic acid ethyl
ester (Compound No. 112);
l-Benzenesulfonyl-3-(4-{3-[6-(3,5-dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-
phenyl)-urea (Compound No. 113);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-2-piperidin-l-yl-
ethyl)-urea (Compound No. 126);
l-(2-Morpholin-4-yl-ethyl)-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-
urea (Compound No. 127);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryIoyl]-phenyl}-carbamic acid 2-piperazin-l-yl-
ethyl ester (Compound No. 129);
N-(2-Morpholin-4-yl-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 130);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridine-2-sulfonyl)-
ethyl]-urea (Compound No. 131);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridin-2-ylsulfanyl)-
ethyl]-urea (Compound No. 132);
l-[2-(4-Methyl-piperazin-l-yl)-ethyl]-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 133);

51
N-(2-Morpholin-4-yl-ethyl)-N'-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-
oxalamide (Compound No. 134);
1 -(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]- urea (Compound
No. 135);
l-Benzenesulfonyl-hydrazino-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 139);
l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 140);
l-(Morpholine-4-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No.
142);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid piperidin-4-yl
ester (Compound No. 143);
l-[2-(Pyridin-2-ylsulfanyl)-ethyl]-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 155);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(pyridine-2-
sulfonyl)-ethyl ester (Compound No. 156);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(pyridin-2-
ylsulfanyl)-ethyl ester (Compound No. 157);
[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-carbamic acid 2-benzenesulfonylamino-ethyl
ester (Compound No. 158);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(N-pyridin-2-yl-
hydrazino)-ethyl ester (Compound No. 159);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 160);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-5'-yl)-but-
2-en-l-one (Compound No. 161);
4,4,4-Trifluoro-l-[4-(morpholine-4-carbonyl)-phenyl]-3-quinolin-3-yl-but-2-en-l-one
(Compound No. 162);
N-{4-[3-(6-Morpholin-4-yl-pyridin-3-yl)-but-2-enoyl]-phenyl}-2-oxo-2-piperidin-l-yl-
acetamide (Compound No. 163);
2-Morpholin-4-yl-2-oxo-N-[4-(4,4,4-trifluoro-3-quinolin-3-yl-but-2-enoyl)-phenyl]-
acetamide (Compound No. 164);

52
Morpholine-4-carboxylic acid {4-[4,4,4-trifluoro-3-(4-morpholin-4-yl-quinolin-3-yl)-but-
2-enoyl]-phenyl}-amide (Compound No. 165);
Morpholine-4-carboxylic acid {4-[3-(6-morpholin-4-yl-pyridin-3-yl)-but-2-enoyl]-
phenyl}-amide (Compound No. 166);
N-[2-(3-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryIoyl]-phenyl}-ureido)-ethyl]-
nicotinamide (Compound No. 167);
l-[2-(Piperidin-4-yloxy)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 168);
(4-{3-[6-(4-MethyI-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid furan-
2-ylmethyl ester (Compound No. 169);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid pyridin-
2-ylmethyI ester (Compound No. 170);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid 2-(3,5-
dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 171);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2- [l,2,4]triazol-
1-yl-ethyl ester (Compound No. 172);
{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[l,2,4]-triazol-l-
yl-ethyl ester (Compound No. 173);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid
thiophen-2-ylmethyl ester (Compound No. 174);
2-{3-Oxo-3-[4-(thiophen-2-ylmethoxycarbonylamino)-phenyl]-propenyl}-quinoline-6-
carboxylic acid (Compound no. 175);
{4-[3-(6-[l,2,4]Triazol-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen-2-
ylmethyl ester (Compound no. 176);
{4-[3-(6-Tetrazol-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -carbamic acid thiophen-2-yl
methyl ester (Compound No. 177);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid pyridin-2
yl methyl ester (Compound No. 178);
4-(3-Quinolin-2-yl-acryloyl)-phenyI]-carbamic acid pyridin-2-ylmethyl ester (Compound
No. 179);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid
piperidin-4-yl ester (Compound No. 180);

53
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 1-methyl- 1H-
pyrrol-3-yl ester (Compound No. 181);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid
isoxazol-3-yl ester (Compound No. 182);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid l-methyl-lH-imidazol-4-ylmethyl
ester (Compound No. 183);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(4-methyl-piperazine-1 -
sulfonylamino)-ethyl ester (Compound No. 184);
[4-(3-Quinolin-2-yl-acryloyl)-phenyI]-carbamic acid 2-(4-methyl-piperazine-l-
sulfonylamino)-ethyl ester (Compound No. 185);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid 2-
benzenesulfonylamino-ethyl ester (Compound No. 186);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[(4-methyl-
piperazine-l-carbonyl)-amino]-ethyl ester (Compound No. 187);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 2-[(4-methyl-piperazine-l-carbonyI)-
amino]-ethyl ester (Compound No. 188);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N-pyridin-2-yl-hydrazino)-ethyl
ester (Compound No. 189);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-[N-(5-methyl-isoxazol-3-yl)-
hydrazino]-ethyl ester (Compound No. 190);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N'-benzenesulfonyl- hydrazino)-
ethyl ester (Compound No. 191);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-2-piperazin-l-yl-
ethyl)-urea (Compound No. 192);
l-[2-(4-Methyl-piperazin-l-yl)-2-oxo-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 193);
l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-{4-[3-(6-piperazin-l-yl-pyridin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 194);
l-[2-(Pyridine-2-sulfonyl)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 195);

54
1 - {4-[3-(6-Piperazin-1 -yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidine-4-sulfonyl)-
ethyl]-urea (Compound No. 196);
4-Methyl-piperazine-l-sulfonic acid(2-{3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-ureido}-
ethyl)-amide (Compound No. 197);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidin-4-ylsulfanyl)-
ethyl]-urea (Compound No. 198);
l-{2-[N-(l-Methyl-piperidin-4-yl)-hydrazino]-ethyl}-3-[4-(3-pyridin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 199);
l-{2-[N-(l-Methyl-piperidin-4-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 200);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-{4-[3-(6-morpholin-4-yl-pyridin-2-
yl)-acryloyl]-phenyl}-urea (Compound No. 201);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound No.
202);
1 -(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]urea (Compound No.
203);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No.
204);
l-{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-piperidin-l-yl-ethyl)-urea
(Compound No. 205);
l-{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-thiomorpholin 1, 1-
dioxide-4-yl-ethyl)-urea (Compound No. 206);
l-(2-Piperazin-l-yl-ethyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-
acryloyl]-phenyl}-urea (Compound No. 207) ;
Piperidine-4-carboxylic acid [2-(3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-
phenyl}-ureido)-ethyl]-amide (Compound No. 208);
N-(2-{3-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-ureido}-ethyl)-nicotinamide (Compound
No. 209);
l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 210);

55
l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 211);
l-(Piperazine-l-sulfonyl)-3-[4-(3-pyridin-2-yl-acryloyl)phenyl]-urea (Compound No.
212);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(piperazine-l-sulfonyl)-urea
(Compound No. 213);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound No.
214);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl) phenyl]-urea (Compound No.
215);
N-(2-Piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide (Compound
No. 216);
N-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-N'-(2-piperazin-l-yl-ethyl)-
oxalamide (Compound No. 217);
l-[2-({4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenylaminooxalyl}-amino)-
acetyl]-piperidine-4-carboxylic acid (Compound No. 218);
N-(2-Oxo-2-piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 219);
N-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-N'-[2-(pyridine-2-yl-sulfonyl)-ethyl]-oxalamide
(Compound No. 220);
N-[2-(Piperidin-4-ylsulfanyl)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamidea
(Compound No. 221);
N-[2-(Pyridine-2-sulfonyl)-ethyl]-N'-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 222);
2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-2-oxo-N-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 223);
2-Oxo-2-(N-phenyl-hydrazino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 224);
2-Oxo-2-(piperazine-l-sulfonylamino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 225);

56
2-Benzenesulfonylamino-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 226);
N-[2-(Piperazine-l-sulfonylamino)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 227);
2-(N'-Benzenesulfonyl-hydrazino)-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 228);
N-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-
phenylj-oxalamide (Compound No. 229);
N-{2-[(Piperazine-l-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 230);
N-{2-[(Pyridine-3-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 231);
N-{2-[(Piperidine-4-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 232);
N-( 1 -{4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl} -piperidin-4-yl)-
methanesulfonamide (Compound No. 247);
(l-{4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl]-piperazin-l-yl}-piperidin-4-yl)- sulfonylurea
(Compound No. 248);
1 - {4-[4-(4-Cyclohexylamino-piperidin-1 -yl)-piperazine-1 -carbonyl]-phen
yl}-3-pyridin-2-yl-propenone (Compound No. 249).
Another embodiment of the invention consists of those compounds of Formula (I),
wherein
wherein, Q is as defined hereinabove, substituted by either R1 or both R1 and R2,
wherein the number of substituents are selected from one to six;
R1 is independently selected at each occurrence from, -SO2OR7, -SO2O(C1-8alkyl), -
NHNH2, -NHNHSO2R7, -NH(CH2)nR4, -NHCO2R7, -NHCO2(C1-8alkyl), -NHSO2O(C1-
8alkyl), -NHSO2OR7, -NHSO2NH2, -NH(CH2)nCOR4, -NH(CH2)nOR4, -NH(CH2)nSR7, -
NH(CH2)nSO2R7, -NH(CH2)nNHCOR4, -NH(CH2)nN(C1-8alkyl)COR4, -N(C1-

57
8alkyl)(CH2)nNHCOR4, -NH(CH2)nNHNHSO2R7, -NH(CH2)nNHSO2R4, -NH(CH2)nN(C1-
8alkyl)SO2R4, -NH(CH2)nN(NH2)R7, -NH(CH2)nN[N(C1-8alkyl)2]R7, -N(C1-8alkyl)CO2R7,
-N(C1-8alkyl)CO2(C1-8alkyl), -N(C1-8alkyl)SO2O(C1-8alkyl), -N(C1-8alkyl)SO2OR7, -N(C1-8
8alkyl)SO2NH2, -N(C1-8alkyl)N(C1-8alkyl)2, -N(C1-8alkyl)NH2, -NHNHCO(C1-8alkyl), -
N(C1-8alkyl)NHCO(C1-8alkyl), -NHNHCOR7, -N(C1-8alkyl)NHCOR7, -N(C1-8alkyl)-
(CH2)nR4, -N(C1-8alkyl)(CH2)nCOR4, -(CH2)nSO2R7, - (CH2)nCOR4, -(CH2)nR4, -
(CH2)nNHSO2R4, -(CH2)nN(C1-8alkyl)SO2R4, - (CH2)nNHCOR7, -(CH2)nN(C1-
8alkyl)COR7, -(CH2)nOR4, -(CH2)nSR4, -(CH2)nSR3, - (CH2)nSO2R7, -(CH2)nNHNHSO2R7,
-(CH2)nN(NH2)R7, or - (CH2)nN[N(C1-8 alkyl)2]R7;
R2 is as defined hereinabove;
'Y' is selected from the group consisting of:
(a) -C(O)NRaRb,
(b) -NRcC(X)NRaRb,
(c) -NRcC(X)NRdRe,
(d) -NRcC(O)ORf,
(e)-NRcC(O)C(O)Rg;
X is selected from O or S;
Ra and Rb together with the atoms with which they are attached form a three- to ten-
membered monocyclic or bicyclic heterocyclyl or heteroaryl ring selected from the group
consisting of aziridinyl, azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl,
hexahydropyridazinyl, hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl,
imidazolidinyl, morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl,
piperazinonyl, piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl,
pyrrolidonyl, pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide,
thiazolidinyl, thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl,
indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl, wherein, said
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring is
optionally substituted with 1, 2, or 3 substituents independently selected from the group
consisting of

58
(1) halo, (2) hydroxy, (3) optionally substituted C1-8alkyl, wherein the substituents are
amino, C1-3 alkoxy, mono(C1-3alkyl)amino, di(C1-3alkyl)amino, and hydroxy, (4) -O(C1-
8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyl), (13) -CON(C1-
8alkyl)2, (14) -CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3, (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8aIkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alkyl)SO2(C1-8alkyI), (24) -NHSO2CF3, (25) -N(C1-8alkyI)CO2(C1-
8alkyl), (26) -N(C1-8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2,(28)-NHSO2NH(C1-8alkyl),
(29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31) -NHCONH2, (32) -
NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-8alkyl)CO(C1-8alkyl), (35) -
N(C1-8alkyl)CO2(C1-8alkyl), (36) -N(C1-8alkyOCON(C1-8alkyl)2, (37) -S(C1-8alkyl), (38) -
SO2(C1-8alkyl), (39) -SO3H, (40) -SO2O(C1-8alkyl), (41) -SO2NH2, (42) -SO2N(C1-
8alkyl)2, (43) -SO2NH(C1-8alkyl), (44) -NHC(NH)NH2, (45) phenyl, unsubstituted or
substituted with one to two substituents selected from halo, nitro, C1-3alkyl, C1-3alkoxy,
hydroxy, amino, mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-
8alkyl)CO(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-8
8alkyl)N(C1-8alkyl)2, and -N(C1-8alkyl)NH2, (46) pyridyl, unsubstituted or substituted with
one to two substituents selected from halo, C1-3alkyl and C1-3alkoxy, (47) -CO-(optionally
substituted heteroaryl), (48) -CO-(optionally substituted heterocyclyl), (49) -O-
(optionally substituted heteroaryl), (50) -O-(optionally substituted heterocyclyl), (51)
optionally substituted heterocyclyl, (52) -NH-(optionally substituted heterocyclyl),
wherein the substituents on the optionally substituted heteroaryl and heterocyclyl are one
to two groups independently selected from hydroxy, C1-8galkyl, -O(C1-8alkyl), oxo, thioxo,
amino, mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-
8alkyl)CO(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, _NHSO2(C1-8alkyl), -NHSO2NH2 or -N(C1-8alkyl)NH2;
Rc and Rd are independently selected from hydrogen or C1-6 alkyl;

59
Re is selected from R7, -SO2R7, -SO2R3, -SO2R4, -COR7, -(CH2)nR7, -(CH2)nCOR7, -
(CH2)nOR7, -(CH2)nSR7, -(CH2)nSO2R7, -(CH2)nNHCOR7, -(CH2)nNHSO2R7, -
(CH2)nN(C1-8alkyl)COR7, -(CH2)nNHNHSO2R7, -(CH2)nNHSO2R4, -(CH2)nN(C1-
8alkyl)SO2R4, -(CH2)nN(NH2)R7, -(CH2)nN[N(C1-8alkyl)2]R7, -NHSO2R7, optionally
substituted C1-8alkyl, wherein the substituents are C1-3 alkoxy, amino, mono(C1-
3alkyl)amino, di(C1-3alkyl)amino, or hydroxy;
Rf is selected from the group consisting of (1) optionally substituted C1-8alkyl, wherein the
substituents are selected from C1-3alkoxy, amino, mono(C1-3alkyl)amino, di(C1-
3alkyl)amino, C1-3alkyl, phenyl, or hydroxy, (2) -R3, (3) -R4, (4) phenyl, unsubstituted or
substituted with R2, (5) -(CH2)nR7, (6) -(CH2)nCOR7, (7) -(CH2)nNRcR7j (8) -
(CH2)nNHSO2R7, (9) -(CH2)nN(C1-8alkyl)SO2R7, (10) -(CH2)nNHCOR7, (11) -(CH2)nN(C1-
8alkyl)COR7, (12) -(CH2)nOR7, (13) -(CH2)nSR7, (14) -(CH2)11SO2R7, (15) -
(CH2)nNHNHSO2R7, (16) -(CH2)nN(NH2)R7, (17) -(CH2)nN{N(C1-8 alkyl)2}R7 or (18)
CC13;
Rg is selected from the group consisting of (1) mono(C1-8alkyl)amino (2) di(C1-
8alkyl)amino, (3) NH2, (4) -NHR7, (5) -NRc(CH2)nR7, (6) -NRc(CH2)nCOR7, (7) -
NH(CH2)nO(C1-8alkyl), (8) -NRc(CH2)nOR7, (9) -NRc(CH2)nNHSO2R7, (10) -
NRc(CH2)nN(C1-8alkyl)SO2R7, (11) -NRc(CH2)nSO2R7, (12) -NRCSO2R7, (13) -
NRc(CH2)nSR7, (14) -N(NH2)R7, (15) -N[N(C1-8alkyl)2]R7, (16) -
NRc(CH2)nNHNHSO2R7, (17) -NRc(CH2)nN(NH2)R7, (18) -NRc(CH2)nN[N(C1-
8alkyl)2]R7, (19) -NRc(CH2)nNHCOR7, (20) -NHNHSO2R7, (21) optionally substituted
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring attached
through the ring nitrogen atom and selected from the group consisting of aziridinyl,
azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl, hexahydropyridazinyl,
hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl, imidazolidinyl,
morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl, piperazinonyl,
piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl, pyrrolidonyl,
pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide, thiazolidinyl,
thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl, indazolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl,

60
wherein, the substituents on said optionally substituted three- to ten- membered
monocyclic or bicyclic heterocyclyl or heteroaryl ring are 1, 2 or 3 groups independently
selected from (1) halo, (2) hydroxy, (3) C1-8alkyl, unsubstituted or substituted with C1-
3alkoxy, amino, mono(C1-3alkyl)amino, di(C1-3alkyl)amino, C1-3alkyl, and hydroxy, (4) -
O(C1-8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyl), (13) -CON(C1-
8alkyl)2, (14) - CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3 , (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8alkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alkyl)SO2(C1-8alkyl), (24) -NHSO2CF3, (25) -N(C1-8alkyl)CO2(C1-
8alkyl), (26) -N(C1-8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2, (28) -NHSO2NH(C1-
8alkyl), (29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31) -
NHCONH2, (32) -NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-8alkyl)CO
(C1-8alkyl), (35) -N(C1-8alkyl)CO2(C1-8 alkyl), (36) -N(C1-8alkyl)CON(C1-8alkyl)2, (37) -
S(C1-8alkyl), (38 ) -SO2(C1-8alkyl), (39) -SO3H, (40) -SO2O(C1-8alkyl), (41) -SO2NH2,
(42) -SO2N(C1-8alkyl)2, (43) -SO2NH(C1-8alkyl),or (44) -NHC(NH)NH2,
n is independently selected at each occurrence, from 1, 2 or 3;
R3 at each occurrence is optionally substituted monocyclic three to seven membered
heteroaryl ring having one to three heteroatoms independently selected from N, O, or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R4 at each occurrence is optionally substituted monocyclic three to seven membered
heterocyclyl ring having one to three heteroatoms independently selected from N, O or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R5 at each occurrence is independently selected from hydrogen, C1-6alkyl or CF3;
R6 at each occurrence are 1 or 2 groups independently selected from hydrogen, -O(C1-
8alkyl), halo, C1-6alkyl, mono(C1-6alkyl)amino or di(C1-6alkyl)amino ;
R7 at each occurrence is
1. optionally substituted monocyclic five- to seven- membered aryl;

61
2. optionally substituted monocyclic three- to seven- membered heteroaryl or
heterocyclyl having one to three heteroatoms independently selected from N, O or
S,
wherein the substitution on R7 is by 1, 2 or 3 substituents represented by R2 with a
proviso that
When Y is NRcC(X)NRdRe and Re=R7, R7 is not furan, thiophene, isooxazole, isothiazole
& phenyl.
A further family of specific compounds of particular interest within the above formula (I)
consists of compound and pharmaceutically acceptable salts thereof as follows:
1-[4-(4-Methyl-piperazine-1 -carbonyl)-phenyl]-3-{6-[2-(4-methyl-piperazin-1 -yl)-
ethylamino]-pyridin-2-yl}-propenone (Compound No. 233);
(2-{3-[4-(4-Methyl-piperazine-1 -carbonyl)-phenyl]-3-oxo-propenyl} -quinolin-6-yl)-
carbamic acid ethyl ester (Compound No. 234);
(6- {3-[4-(4-Methyl-piperazine-1 -carbonyl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-
carbamic acid phenyl ester (Compound No. 235);
l-[4-(Morpholine-4-carbonyl)-phenyl]-3-{6-[(piperidin-l-ylmethyl)-amino]-pyridin-2-
yl}-propenone (Compound No. 236);
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-[6-(2-oxo-2-piperidin-l-yl-
ethylamino)-pyridin-2-yl]-propenone (Compound No. 237);
1-[4-(Piperazine-1 -carbonyl)-phenyl]-3-{6-[2-(pyridine-2-sulfonyl)-ethylamino]-pyridin-
2-yl}-propenone (Compound No. 238);
Benzenesulfonic acid N-[2-(6-{3-oxo-3-[4-(piperidine-l-carbonyl)-phenyl]-propenyl}-
pyridin-2-ylamino)-ethyl]-hydrazide (Compound No. 239);
(6-{3-[4-(3-Benzenesulfonyl-ureido)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-carbamic
acid ethyl ester (Compound No. 240);
Morpholine-4-carboxylic acid (4-{3-[6-(2-piperidin-l-yl-ethylamino)-pyridin-2-yl]-
acryloyl}-phenyl)-amide (Compound No. 241);
{2-[3-(4-Ethoxycarbonylamino-phenyl)-3-oxo-propenyl]-quinolin-6-yl}-carbamic acid
ethyl ester (Compound No. 242);
{2-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-quinolin-4-yl}-carbamic acid
ethyl ester (Compound No. 243);

62
[2-(3-{4-[2-(4-Methyl-piperazin-l-yl)-2-oxo-acetylamino]-phenyl}-3-oxo-propenyl)-
quinolin-4-yl]-carbamic acid methyl ester (Compound No. 244);
l-(2-Morpholin-4-yl-ethyl)-3-(4-{3-[6-(2-piperidin-l-yl-ethylamino)-pyridin-2-yl]-
acryloyl}-phenyl)-urea (Compound No. 245);
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-{6-[2-(4-methyl-piperazin-l-yl)-
2-oxo-ethylamino]-pyridin-2-yl}-propenone (Compound No. 246);
[6-(3-Oxo-3-{4-[4-(pyrrolidine-l-carbonyl)-piperidine-l-carbonyl]-phenyl}-propenyl)-
pyridin-2-yl]-carbamic acid methyl ester (Compound No. 250);
[6-(3-Oxo-3-{4-[4-(pyridin-2-yloxy)-piperidine-l-carbonyl]-phenyl}-propenyl)-pyridin-2-
yl]-carbamic acid ethyl ester (Compound No. 251).
In a more preferred embodiment of the invention, R2 is an optionally substituted three- to
seven- membered heterocyclyl or heteroaryl ring having upto three heteroatoms
independently selected from N, O, or S, said optionally substituted heterocyclyl or
heteroaryl ring is selected from piperazinyl, piperidinyl, piperidonyl, morpholinyl,
thiomorpholinyl, thiomorpholin-1,1-dioxide, pyrrolidinyl pyrrolyl, pyrazolyl, oxazolyl,
isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl and thiazolidinyl ;
Ra and Rb are selected from optionally substituted piperazinyl, piperidinyl, piperidonyl,
morpholinyl, thiomorpholinyl, thiomorpholin-1,1-dioxide, pyrrolidinyl pyrrolyl, pyrazolyl,
triazolyl and imidazolyl;
X is O;
n is independently selected from 1 or 2;
R5 is independently selected from hydrogen or methyl.
DEFINITIONS:
The patents, published applications, and scientific literature referred to herein
establish the knowledge of those skilled in the art and are hereby incorporated by
reference in their entirety to the same extent as if each was specifically and individually
indicated to be incorporated by reference. Any conflict between any reference cited herein
and the specific teachings of this specification shall be resolved in favor of the latter.

63
Likewise, any conflict between an art-understood definition of a word or phrase and a
definition of the word or phrase as specifically taught in this specification shall be
resolved in favor of the latter.
As used herein, "compound" refers to any compound encompassed by the generic
formulae disclosed herein. The compounds described herein may contain one or more
double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e.,
geometric isomers). Accordingly, the chemical structures depicted herein encompass all
possible stereoisomers of the illustrated compounds including the stereoisomerically pure
form (e.g., geometrically pure) and stereoisomeric mixtures. The compounds may also
exist in several tautomeric forms including the enol form, the keto form and mixtures
thereof. Accordingly, the chemical structures depicted herein encompass all possible
tautomeric forms of the illustrated compounds. The compounds described also include
isotopically labeled compounds where one or more atoms have an atomic mass different
from the atomic mass conventionally found in nature. Examples of isotopes that may be
incorporated into the compounds of the invention include, but are not limited to 2H, 3H,
13C, 14C, 15N, 18O, 17O, etc. Compounds may exist in unsolvated forms as well as solvated
forms, including hydrated forms. In general, compounds may be hydrated or solvated.
Certain compounds may exist in multiple crystalline or amorphous forms. In general, all
physical forms are equivalent for the uses contemplated herein and are intended to be
within the scope of the present invention. Further, it should be understood, when partial
structures of the compounds are illustrated, a dash (" - ") indicate the point of attachment
of the partial structure to the rest of the molecule. The nomenclature of the compounds of
the present invention as indicated herein is according to MDL ISIS® Draw Version 2.2.1.
The term "substituted", as used herein, means that any one or more hydrogens on
the designated atom is replaced with a selection from the indicated group, provided that
the designated atom's normal valence is not exceeded, and that the substitution results in a
stable compound. When a substituent is keto, then 2 hydrogens on the atom are replaced.
Groups that are "optionally substituted" may be either unsubstituted or substituted with
one or more suitable groups.

64
When any variable occurs more than once in any constituent or formula for a
compound, its definition at each occurrence is independent of its definition at every other
occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R*, then said
group may optionally be substituted with up to two R* groups and each R* is selected
independently from the definition of R*. Also, combinations of substituents and/or
variables are permissible only if such combinations result in stable compounds.
The term "alkyl", used either alone or in attachment with another group, refers to a
monovalent, saturated aliphatic hydrocarbon radical having the indicated number of
carbon atoms and that is unsubstituted or optionally substituted. When a subscript is used
with reference to an alkyl or other group, the subscript refers to the number of carbon
atoms that the group may contain. For example, a "C|.g alkyl" would refer to any alkyl
group containing one to eight carbons in the structure. Alkyl may be a straight chain (i.e.
linear) or a branched chain or cyclic, and may contain one or two double or triple bonds.
The radical may be optionally substituted with substituents at positions that do not
significantly interfere with the preparation of compounds falling within the scope of this
invention. The alkyl is optionally substituted with one to two substituents independently
selected from the group consisting of C1-3alkoxy, amino, mono(C1-3alkyl)amino, di(C1-
3alkyl)amino, C1-3alkyl, and hydroxy.
The term "alkoxy" refers to an alkyl group as defined above attached to the parent
molecular moiety through an oxygen bridge. Representative alkoxy radicals include
methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, isopropoxy, isobutoxy,
isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, tert-pentyloxy, and the like. The radical
may be optionally substituted with substituents at positions that do not significantly
interfere with the preparation of compounds falling within the scope of this invention.
As used herein, a "halo" substituent is a monovalent halogen radical chosen from
chloro, bromo, iodo and fluoro.
The term "monoalkylamino" as employed herein refers to an amino group which is
substituted with one alkyl group having from 1 to 8 carbon atoms, for example,
methylamino group, ethylamino group, propylamino group, isopropylamino group,

65

butylamino group, isobutylamino group, tert-butylamino group, pentylamino group and
isopentylamino group.
The term "dialkylamino" as employed herein refers to an amino group which is
independently substituted with two alkyl groups, each having from 1 to 8 carbon atoms,
for example, dimethylamino group, ethylmethylamino group, diethylamino group,
methylpropylamino group and diisopropylamino group.
The term "aryl" refers to an aromatic group for example, which is a 3 to 10
membered monocyclic or bicyclic carbon-containing ring system, which may be
unsubstituted or substituted . Representative aryl groups include phenyl, naphthyl and the
like.
The term "heteroaryl" refers to an aromatic group for example, which is a 3 to 10
membered monocyclic or bicyclic ring system, which has at least one heteroatom and at
least one carbon atom containing ring. The term "heteroatom" as used in the specification
and claims shall include oxygen, sulfur and nitrogen. The heteroaryl group may be
attached at any available nitrogen or carbon atom of any ring. Exemplary monocyclic
heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Exemplary bicyclic heteroaryl
groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl,
quinolinyl, isoquinolinyl, benzimidazolyl, cinnolinyl, quinoxalinyl, indazolyl,
pyrrolopyridyl, furopyridinyl and the like.
The term "heterocyclyl" refers to a stable, fully saturated or unsaturated
nonaromatic cyclic group, for example, which is a 3 to 10 membered monocyclic or
bicyclic ring system, which has at least one heteroatom in at least one carbon atom
containing ring. Each ring of the heterocyclyl group containing a heteroatom may have 1,
2 or 3 heteroatoms independently selected from nitrogen, oxygen or sulfur atoms. The
heterocyclyl group may be attached at any heteroatom or carbon atom of the cycle, which
results in the creation of a stable structure. Exemplary monocyclic heterocyclyl groups
include aziridinyl, azetidinyl, pyrrolidinyl, pyrazolinyl, imidazolinyl, imidazolidinyl,

66
oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuryl, piperidinyl,
piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl,
hexahydopyrazine, hexahydopyridazine, hexahydopyrmidine, tetrahydropyranyl,
morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone,
isothiazolidinyl and the like. Exemplary bicyclic heterocyclyl groups include
tetrahydroisoquinolinyl, benzopyranyl, indolizinyl, chromonyl, dihydroisoindolyl,
dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzothiopyranyl,
dihydrobenzofiuyl, dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isoindolinyl,
tetrahydroquinolinyl, and the like.
As used herein above and throughout this application, "nitrogen" and "sulfur"
include any oxidized form of nitrogen and sulfur and the quaternized form of any basic
nitrogen.

67
"Pharmaceutically acceptable salt" refers to a salt of a compound, which possesses
the desired pharmacological activity of the parent compound. Such salts include: (1) acid
addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such
as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid,
pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,
tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid,
mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-
hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-
naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-
methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic
acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,
glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the
like; or (2) salts formed when an acidic proton present in the parent compound is replaced
by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or
coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine,
N-methylglucamine and the like.
As used herein, "room temperature" refers to a temperature between 25°C and 35
°C.
Yet another embodiment of the present invention is to provide a process for the
preparation of the compounds of the present invention.The compounds of formula 1 can
generally be prepared, for example in the course of a convergent synthesis, by linkage of
two or more fragments which can be derived retro synthetically from the formula 1. It is to
be understood by those skilled in the art of organic synthesis that the functionality present
on different parts of the fragment structures should be consistent with the chemical
transformations proposed. In the preparation of compounds of formula (I), it may be
generally necessary in the course of synthesis to temporarily block functional groups
which could lead to undesired reactions or side reactions in a synthetic step by protective
group (s) suited to the synthetic problem and known to the person skilled in the art. The
method of fragment coupling is not restricted to the following examples, but is generally
applicable for the synthesis of compounds of formula (I).

68
The novel compounds of the present invention are not, however, to be construed as
forming the only genus that is considered as the invention, and any combination of the
compounds or their moieties may itself form a genus. The following examples further
illustrate details for the preparation of the compounds of the present invention. It is to be
further understood by those skilled in the art that the order of synthetic steps can be
changed, or kmwn variations of the conditions and processes of the following preparative
procedures can be used to prepare these compounds. All temperatures are in degrees
Celsius unless otherwise noted.
Accordingly, compounds of formula (I) of the present invention may be prepared
as described in the schemes below.
PART I: Preparation of the intermediate (V)

The compounds of general formula (I) can be obtained through the intermediate
(V), wherein, R5 and R6 are as defined earlier and Y' represents -COOH or -NHRC. The
intermediate compound (V) is obtained by different methods as depicted in the following
schemes.

(a) NaOH / KOH (b) Piperidine (10 %), acetic acid (50 %)
Scheme 1-1


69
As shown in Scheme 1-1, compounds of formula (V) can be prepared by reacting
methyl ketones of formula (IV) (Y' represents -COOH or -NHRC) with a substituted
aldehyde of formula (II). The reaction can be carried out in the presence of a base such as
aqueous sodium hydroxide or potassium hydroxide in an appropriate alcohol such as
methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol or t-butanol as solvent
at a temperature of 0° to 100°C for a period of 2 to 12 hours. Alternately, the compounds
of formula (V) can also be prepared by refluxing the methyl ketone (IV) with the
substituted aldehyde (II) in an appropriate alcohol such as ethanol containing 10 %
piperidine and 50 % acetic acid with Soxhlet over 4 A molecular sieves for a period of 24
to 30 hours.
Several alternative routes to obtain the compounds of formula (V) are outlined in
Scheme 1-2.
Scheme 1-2

(a) i) Bromine, HBr-acetic acid, ii) triphenyl phosphine;
(b) pyridine; (c) trimethylsilyl trifluoromethane sulfonate, triethylamine; (d) triethylamine,
trifluoroacetic anhydride, titanium tetrachloride
The methyl ketone (IV) (Y' represents -COOH or -NHRC) is dissolved in an
appropriate solvent such as carbon tetrachloride or methanol, containing HBr-acetic acid
and treated with an equimolar quantity of bromine at a temperature of 0°-80°C and the
reaction mixture is refluxed for a time period of 2 hours. The crude product obtained is
treated with triphenylphosphine in an appropriate solvent such as toluene. The
triphenylphosphine salt (IV-a) obtained is treated with the substituted aldehyde (II) in a

70
suitable solvent like pyridine at a temperature in the range of 100° to 115°C for a period of
4 to 6 hours. In an alternate process, the methyl ketone (IV) can be treated with
trimethylsilyl trifluoromethane sulfonate and a base such as triethylamine in an
appropriate solvent such as dichloromethane at a temperature of 0°C for a period of 3 to 4
hours. The silyl enol ether ketone (IV-b) is reacted with a substituted ketone (III) in
presence of a base such as triethylamine in an appropriate solvent such as dichloromethane
at 0°C followed by addition of trifluoroacetic anhydride and titanium tetrachloride for a
period of 4 to 6 hours from 0°C to ambient temperature to obtain the compound of formula
(V).
PART II: Preparation of compounds of general formula (I)
The compound of general formula (I), where Y is -C(O)NRaRb can be obtained by
different methods as shown in the following Scheme II-1.
Scheme II-l

(a) 1-hydroxybenzotriazole, N-ethyldiisopropylamine, l-ethyl-3-(3-dimethylammopropyl)carbodiimide;
(b) N-Ethyldiisopropylamine, benzotriazol-yl-oxytris(dimethylamino)phosphoniumhexafluoro phosphate
(c) Thionyl chloride, toluene;
(d) Triethylamine / potassium carbonate;
(e) NaOH / KOH.
As shown in Scheme II-l, compounds of formula (I) can be prepared by reacting
the intermediate (V), wherein Y' represents -COOH, with 1-hydroxybenzotriazole and 1-
ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) in an appropriate solvent such as

71
tetrahydrofuran or dimethylformamide at a temperature of 0°C to ambient temperature for
an hour. The reaction mixture is further treated with an amine NHRaRb at room
temperature for a period of 6 to 20 hours to obtain a compound of formula (I). Alternately,
compounds of formula (I) can be prepared by treating the intermediate (V), wherein Y'
represents -COOH, with a base N-ethyldiisopropylamine (DIEA) and benzotriazol-1-yl-
oxytris (dimethyl-amino)phosphonium hexafluorophosphate (BOP) in an appropriate
solvent such as tetrahydrofuran or dichloromethane at a temperature from 0°C to ambient
temperature for an hour. The solution is further treated with an amine NHRaRb at room
temperature for 6 to 8 hours to obtain a compound of formula (I).
In another alternate process, the acid of formula (IV) is treated with oxalyl chloride
or thionyl chloride in an appropriate solvent such as dichloromethane or toluene with a
catalytic amount of DMF at a temperature from 0° to 110°C for 3 to 4 hours to obtain the
compound of formula (VI). The said compound (VI) is treated with an amine NHRaRb in
the presence of a base, triethylamine or potassium carbonate in an appropriate solvent such
as tetrahydrofuran, toluene, dichloromethane at a temperature from 0°C to ambient
temperature to obtain the compound of formula (VII), which is treated with a substituted
aldehyde of formula (II) in the presence of a base such as aqueous NaOH or KOH and an
appropriate solvent such as alcohol like methanol, ethanol, n-propanol, isopropanol, n-
butanol, iso-butanol or t-butanol at 0° to 100°C for 2 to 12 hours to obtain the compound
of formula (I).
The compound of general formula (I), where Y' is -NRcC(X)NRaRb and -
NRcC(X)NRdRe, and X is O or S, can be obtained by different methods as shown in the
following schemes II-2 (a) to II-2 (i). Scheme II-2 (a) depicts the general procedure for
synthesis of compounds of general formula (I), where Y' represents -NRcC(O)NRdRe or -
NRcC(O)NRaRb.

72

(a) Ethyl chloroformate, triethylamine, acetone;
(b) Sodium azide;
(c) reflux in toluene;
(d) reflux in toluene.
As shown in Scheme II-2 (a), the compound of formula (V), wherein Y' represents
-COOH is treated with a base such as ethyl chloroformate, triethylamine or N-ethyl
diisopropylamine in an appropriate solvent such as acetone, dichloromethane,
dichloroethane, tetrahydrofuran or toluene at a temperature from 0° to 60°C for a period of
30 minutes to 3 hours. The crude reaction mixture is treated with sodium azide dissolved
in water at a temperature from 25° to 110°C for a period of 1 to 12 hours. The resulting
azide of formula (V-a) was refluxed in toluene or xylene for a period of 1 to 4 hours to
obtain the isocyanate of formula (VIII) was treated with NHRdRe or NHRaRb amine in the
solvent such as toluene or xylene at the temperature from 100 ° to 140 ° C for the period of
1 to 12 hours to obtained the compound of formula (I), wherein Y' represents -
NRcC(O)NRdRe or -NRcC(O)NRaRb.
Scheme II-2 (b) depicts the general procedure for synthesis of compounds of
general formula (I), wherein, Y' represents -NRcC(X)NRdRe or -NRcC(X)NRaRb.

73

(a) Toluene, reflux
(b) NaOH / KOH
As shown in Scheme II-2 (b), the isocyanate or thioisocyanate of formula (IX) is
treated with NHRdRe or NHRaRb amine in an appropriate solvent such as toluene, xylened
or chloroform and refluxed for 6 to 12 hours to obtain the compound of formula (X),
which is further treated with a substituted aldehyde of formula (II) in the presence of a
base such as aqueous NaOH or KOH in a solvent such as methanol, ethanol, n-propanol,
isopropanol, n-butanol, iso-butanol, t-butanol at a temperature of 0° to 100°C for a period
of 2 to 12 hours to obtain the compound of formula (I), wherein Y' represents
NRcC(X)NRdRe or NRcC(X)NRaRb.
Scheme II-2(c)

(a) Trichloromethyl chloroformate / thiophosgene
(b) Toluene, reflux
In an alternate embodiment, as shown in Scheme II-2 (c), the compounds of
general formula (I), wherein Y' represents -NRcC(X)NRdRe, can be prepared by reacting
the isocyanate or thioisocyanate of Re with a compound of formula (V), wherein Y'

74
represents -NHRC, in an appropriate solvent such as toluene, xylene or
dimethylformamide at a temperature from 80° to 130°C for a period of 3 to 6 hours. The
isocyanate or thioisocyanate of Re can be obtained by reacting Re amine hydrochloride
with trichloromethyl chloroformate or thiophosgene in the presence of an acid in a
solvent like dioxane at 20° to 100 °C for a period of 2 to 12 hours.

(a) Chlorosulfonyl isocyanate
(b) R4 amine, N-ethyl diisopropylamine
In a specific embodiment, as shown in Scheme II-2 (d), the compounds of general
formula (I), wherein Y' represents -NRcC(X)NRdRe and Re represents -SO2R4, can be
prepared by reacting a compound of formula (V), wherein Y' represents -NHRc, with
chlorosulphonyl isocyanate in an appropriate solvent such as toluene, xylene or
chloroform 60-110°C for 6 to 12 hours. The resulting intermediate obtained is treated in
the presence of base such as N-ethyldiisopropylamine or potassium carbonate with R4
amine in a solvent like tetrahydrofuran or dimethylformamide at a temperature from 0-
100°C for a period of 2 to 6 hours to provide the compound of the formula (I).

(a) 2-Bromoethyl isocyanate / 2-Bromoethyl isothiocyanate
(b) R4; triethylamine
Scheme II-2(e)

75
In another specific embodiment, as shown in Scheme II-2 (e), the compounds of
general formula (I), wherein Y' represents -NRcC(X)NRdRe, and Rd and Re represent H
and -(CH2)nR4, can be prepared by reacting a compound of formula (V), wherein Y'
represents -NHRC, with 2-bromoethyl isocyanate or 2-bromoethyl isothiocyanate in a
solvent such as toluene or chloroform at reflux temperature for 2 tol2 hours to provide the
compound of formula (XI) (wherein n = 2), which was further treated with R4 in the
presence of a base potassium carbonate or triethylamine in an appropriate solvent such as
dimethyl formamide or toluene at 60-100°C for 2 to 12 hours to give the compound of
formula (I). Alternately, the compound of formula (XI) is treated with R4-boronic acid and
tetrakis (triphenylphosphine)palladium(O) in the presence of a base such as aqueous
potassium carbonate or sodium bicarbonate in a solvent such as toluene, ethanol or
dimethylformamide at 60-100°C for a period of 20 to 30 hours to give the compound of
formula (I).
Scheme II-2(f)

(a) 2-Bromoethylamine hydrobromide, triethylamine
(b) toluene, reflux
In an alternative embodiment, as shown in Scheme II-2 (f), the compounds of
general formula (I), wherein Y' represents -NRcC(O)NRdRe, and Re represents -(CH2)nR4,
can be prepared by reacting a compound of formula (XII) with the isocyanate of formula
(VIII) in a solvent such as toluene or xylene at 100-140°C for 1 to 12 hours to give the
compound of formula (I). The compound of formula (XII) can be obtained by reacting 2-
bromoethylamine hydrobromide in the presence of a base such as potassium carbonate or

76
tri-ethylamine in a solvent like tetrahydrofuran, toluene or dimethylformamide at 25 -
110oCfor2to8hours.
Scheme II-2(g)

(a) 1-Hydroxybenzotriazole, N-ethyldiisopropylamine, l-ethyl-3-(3-dimethylaminopropylcarbodiimide
(b)Toluene, reflux
In another specific embodiment, as shown in Scheme II-2 (g), the compounds of
general formula (I), wherein Y' represents -NRcC(O)NRdRe, and Re represents -
CH2COR4, can be prepared by reacting the compound of formula (XIII) with a compound
of formula (VIII) in a solvent such as toluene or xylene at 100 - 140°C for 1 to 12 hours.
The compound of formula (XIII) can be prepared by treating an N-substituted-Boc-glycine
with R4 in the presence of base such as N-ethyl diisopropylamine, 1-hydroxybenzotriazole
and l-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (EDCI) in a solvent such as
tetrahydrofuran or dimethylformamide at 0°C to ambient temperature for 6 to 20 hours,
followed by removal of the protecting group t-Boc by treatment with trifluoroacetic acid
in dichloromethane at 0° to 10°C for a period of 1 to 6 hours.


77
Scheme II-2(h)
(a) 2-Bromoethylamine hydrobromide, triethylamine
(b) Toluene, reflux
In another specific embodiment, as shown in Scheme II-2 (h), the compounds of
general formula (I), wherein Y' represents -NRcC(O)NRdRe, and Re represents -
(CH2)nOR4, can be prepared by reacting a compound of formula (XIV) with a compound
of formula (VIII) in a solvent such as toluene or xylene at 100° to 140°C for 1 to 12 hours.
The compound of formula (XIV) can be prepared by treating 2-bromoethylamine
hydrobromide with HO-R4 in the presence of a base such as triethylamine or potassium
carbonate at 20° to 100°C in a solvent such as tetrahydrofuran, acetonitrile or
dimethylformamide for 1 to 6 hours.
Scheme II-2(i)

(a) (2-mercaptoethyl)carbamic acid tert-butyl ester, triethylamine / potassium carbonate
(b) Trifluoroacetic anhydride
(c) toluene, reflux
(d)oxone

78
In still another specific embodiment, as shown in Scheme 11-2 (i), the compounds
of general formula (I), wherein Y' represents -NRcC(O)NRdRe, and Re represents -
(CH2)nSO2R7, can be prepared by reacting a compound of formula (XV) with a compound
of formula (VIII) in a solvent such as toluene or xylene at 100° to 140°C for 1 to 12 hours
to give the compound (XVI), which on further treatment with oxone in water / methanol at
0° to room temperature gives the compound of formula (I). The compound of formula
(XV) can be obtained by treating (2-mercaptoethyl) carbamic acid tert-butyl ester with
R7CI in the presence of a base such as potassium carbonate or triethylamine at 0° to l00°C
in a solvent like tetrahydrofuran, acetonitrile or dimethylformamide for 1 to 6 hours and
the resulting product is treated with trifluoroacetic anhydride in dichloromethane at 0° to
ambient temperature for 2 to 6 hours to give the compound of formula (XV).
The compounds of general formula (I), where Y' is -NRcC(O)ORf can be obtained
by different methods as shown in the following schemes II-3 (a) to II-3 (g).Scheme II-3(a)
depicts the general procedure for synthesis of compounds of general formula (I), where Y'
represents -NRcC(O)ORf.
Scheme II-3(a)

(a) Ethylchloroformate, triethylamine
(b) RfOH, triphosgene, triethylamine
(c) toluene, reflux
As shown in Scheme II-3(a), the compound of formula (V), wherein Y' represents
- NHRC is treated with ethyl chloroformate or phenyl chloroformate in presence of a base
triethylamine or N-ethyldiisopropylamine in a solvent such as dimethylformamide or
tetrahydrofuran at 0°to 60°C for 30 minutes to 8 hours to obtain the compound of formula
(I). Alternately, the compound of formula (V), wherein Y' represents -NHRC is treated
with HO-Rf and phosgene or triphosgene in the presence of a base such as N-ethyl

79
diisopropylamine, triethylamine, potassium or sodium carbonate at a temperature ranging
from 0°to 35°C for a period of 10 minutes to 3 hours to obtain the compound of formula
(I). In another alternate embodiment, the compound of formula (VIII) is treated with HO-
Rf in a solvent such as toluene or xylene at 100° to 140 °C for 1 to 12 hours to obtain the
compound of formula (I).
Scheme II-3(b)

(a) 2-Bromoethanol, triethylamine/ potassium carbonate
(b) toluene, reflux
In a specific embodiment, as shown in Scheme II-3 (b), the compounds of general
formula (I), wherein Y' represents -NRcC(O)ORf, and Rf represents -(CH2)nR3, can be
prepared by reacting a compound of formula (XVII) with a compound of formula (VIII) in
a solvent such as toluene or xylene at 100 ° to 140°C for 1 to 12 hours. The compound of
formula (XVII) can be obtained by reacting an R3-amine with 2-bromoethanol or 2-
chloroethanol in the presence of a base such as potassium carbonate or triethylamine in a
solvent like tetrahydrofuran, toluene or dimethylformamide at 25° to 110°C for 2 to 8
hours.


80
Scheme II-3(c)
(a) 2-Bromoethylchloroformate, triethylamine
(b) R3, potassium carbonate
Alternately, as shown in Scheme 11-3 (c), the compounds of general formula (I),
wherein Y' represents -NRcC(O)ORf, and Rf represents -(CH2)nR3 can also be prepared by
treating the compound of formula (V), wherein Y' represents -NHRC, with 2-bromoethyl
chloroformate in the presence of a base such as triethylamine or N-ethyl diisopropyl
amine in an appropriate solvent like dichloromethane or tetrahydrofuran at 0°C to 30°C for
1 to 6 hours to give the compound (XVIII), which on treatment with R3 in the presence of
base such as potassium carbonate in a solvent like dimethylformamide or acetonitrile at
60° to 100°C for 2 to 16 hours gives the compound of formula (I)
Scheme II-3(d)

(a) 1-Hydroxybenzotriazole, N-ethyldiisopropylamine,
1 -ethyl-3 -(3 -dimethylaminopropyl)carbodi imide
(b) MeOH. HC1
(c) toluene, reflux
In another specific embodiment, as shown in Scheme II-3 (d), the compounds of
general formula (I), wherein Y' represents -NRcC(O)ORf, and Rf represents -(CH2)nCOR7,

81
can be prepared by reacting the compound of formula (XIX) with compound of formula
(VIII) in an appropriate solvent such as toluene or xylene at 100 ° to 140°C for 1 to 12
hours. The compound of formula (XIX) can be obtained by treating the R7 amine with
(tetrahydro-pyran-2-yloxy)-acetic acid, 1-hydroxy benzotriazole, N-ethyldiisopropylamine
and l-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDCI) in an appropriate solvent
such as tetrahydrofuran or dimethylformamide at 0°C to ambient temperature for 6 to 20
hours. The tetrahydropyranyl group was deprotected by refluxing in methanolic
hydrochloric acid.
Scheme II-3(e)

(a) Potassium carbonate (b) MeOH.HCl (c) Oxone, methanol:water (d) toluene, reflux
In still another specific embodiment, as shown in Scheme II-3 (e), the compounds
of general formula (I), wherein Y' represents -NRcC(O)ORf, and Rf represents -
(CH2)nOR7, -(CH2)nSR7 or -(CH2)nSC)2R7 can be prepared by reacting the compound of
formula (XX-a), (XX-b) or (XX-c) with a compound of formula (VIII) in an appropriate
solvent such as toluene or xylene at 100 ° to 140°C for 1 to 12 hours. The compounds of
formula (XX-a) and (XX-b) can be obtained by reacting HO-R7 and HS-R7 respectively
with 2-(2-chloroethoxy) tetrahydropyran in the presence of a base such as potassium
carbonate in an appropriate solvent such as dimethylformamide or acetonitrile at 80° to
110°C for 3 to 18 hours. The tetrahydropyranyl group is deprotected by refluxing in
methanolic hydrochloric acid. The compounds of formula (XX-c) can be obtained by
reacting the compound of formula (XX-b) with oxone in a methanol: water (2:1) mixture
at 0°C to ambient temperature for 2 to 3 hours.

82

(a) Sulfuryl chloride, potassium nitrate
(b) Sodium nitrite, HCl:acetic acid, sulphur dioxide, cuprous chloride
(c) potassium carbonate
(d) toluene, reflux
In another specific embodiment, as shown in Scheme II-3 (f), the compounds of
general formula (I), wherein Y' represents -NRcC(O)ORf, and Rf represents -
(CH2)nNHSO2R7 can be prepared by reacting the compound of formula (XXI) with a
compound of formula (VIII) in an appropriate solvent such as toluene or xylene at 100° to
140°C for 1 to 12 hours. The compound of formula (XXI) can be obtained from either HS-
R7 or H2N-R7 as follows. HS-R7 is treated with sulphuryl chloride and potassium nitrate
in an appropriate solvent such as acetonitrile or tetrahydrofuran at 0° to 25°C for 2 to 6
hours. The resulting product is treated with 2-(tetrahydropyran-2-yloxy)ethylamine in the
presence of a base such as triethylamine or potassium carbonate in a suitable solvent such
as tetrahydrofuran or dichloromethane at 0°to 60°C for 1 to 6 hours. Alternately, H2N-R7
is treated with sodium nitrite and a mixture of concentrated HC1 : acetic acid (3:1) at -10°
to -5°C for 45 to 90 minutes. The resulting diazonium salt is treated with a solution of
sulfur dioxide and cuprous chloride as catalyst in acetic acid at 0° to l0°C for 30 to 60
minutes to obtain ClO2S-R7, which is further treated with 2-(tetrahydropyran-2-

83
yloxy)ethylamine in the presence of a base triethylamine in an appropriate solvent such as
tetrahydrofuran or toluene at 0° to 60°C for 3 to 4 hours. The tetrahydropyranyl group is
deprotected by refluxing in methanolic hydrochloric acid to obtain the compound of
formula (XXI).
Scheme II-3(g)

(a) Sodium nitrite, HC1, stannous chloride
(b) Di-tert-butyl-dicarbonate
(c) potassium carbonate
(d) Bromoethanol, potassium carbonate
(e) Toluene, reflux
In a still further specific embodiment, as shown in Scheme II-3 (g), the compounds
of general formula (I), wherein Y' represents -NRcC(O)ORf, and Rf represents -
(CH2)nN(NH2)R7 can be prepared by reacting the Boc-protected compound of formula
(XXII) with a compound of formula (VIII) in an appropriate solvent such as toluene or
xylene at 100° to 140°C for 1 to 12 hours, followed by removal of the Boc-protecting
group with trifluoroacetic acid in dichloromethane at 0°C for the period of 2 to 6 hours.
The compound of formula (XXII) can be obtained by treating B0C-NH-NH-R7 with
bromoethanol in the presence of a base such as potassium carbonate or triethylamine in
an appropriate solvent such as tetrahydrofuran or dimethylformamide at 20° to 100°C for 2
to 6 hours. The Boc-NH-NH-R7 can be obtained either from H2N-R7 or Boc- hydrazine as
follows. H2N-R7 is treated with sodium nitrite, concentrated hydrochloric acid and water at

84
0°C for 1 to 2 hours and the diazonium salt thus obtained is reduced with stannous
chloride at 0°C for 3 to 6 hours. The amino function of NH2NH-R7 is protected with di-
tert-butyl dicarbonate in an appropriate solvent such as ethanol-water for 2 to 4 hours to
obtain Boc-NH-NH-R7. Alternately, the Boc-hydrazine is treated with Hal-R7 in the
presence of a base such as potassium carbonate at the temperature from 20° to 100°C in an
appropriate solvent such as dimethylformamide to provide Boc-NHNHR7.
The compounds of general formula (I), where Y' is -NRcC(O)C(O)Rg can be
obtained by different methods as shown in the following schemes II-4 (a) to II-4
(e).Scheme II-4 (a) depicts the general procedure for synthesis of compounds of general
formula (I), where Y' represents -NRcC(O)C(O)Rg.
Scheme II-4(a)

(a) Ethyloxalyl chloride, triethylamine
(b) xylene, reflux
As shown in Scheme II-4 (a), the compound of formula (V), wherein Y' is -NHRC,
is treated with ethyl oxalyl chloride in the presence of a base such as triethylamine or
potassium carbonate in an appropriate solvent such as tetrahydrofuran or dichloromethane
at 0°C to ambient temperature for 3 to 6 hours to obtain the compound of formula (XXIII).
This is treated with the Rg amine in an appropriate solvent such as xylene,
dimethylacetamide or N-methyl-2-pyrrolidone at 100°to 160oC for 2 to 16 hours to give
the compound of formula (I).

85

(a) xylene, reflux
In a specific embodiment, as shown in Scheme II-4 (b), the compounds of general
formula (I), wherein Y' represents -NRcC(O)C(O)Rg, and Rg represents -NH(CH2)nR4,
can be prepared by treating the compound of formula (XXIII) with the compound of
formula (XXIV) in an appropriate solvent such as xylene, dimethylacetamide or N-
methyl-2-pyrrolidone at 100°to 160°C for 2 to 16 hours.
Scheme II-4(c)

(a) xylene, reflux
In another specific embodiment, as shown in Scheme 11-4 (c), the compounds of
general formula (I), wherein Y' represents -NRcC(O)C(O)Rg, and Rg represents -
NRd(CH2)nCOR4, can be prepared by reacting the compound of formula (XXIII) with the
compound of formula (XXV) in an appropriate solvent such as xylene, dimethylacetamide
or N-methyl-2-pyrrolidone at 100° to 160°C for 2 to 16 hours.

86

(a) xylene, reflux
In still another specific embodiment, as shown in Scheme II-4 (d), the compounds
of general formula (I), wherein Y' represents -NRcC(O)C(O)Rg, and Rg represents -
NRd(CH2)nOR4, can be prepared by reacting the compound of formula (XIV) with the
compound of formula (XXIII) in an appropriate solvent such as xylene,
dimethylacetamide or N-methyl-2-pyrrolidone at 100° to 160°C for 2 to 16 hours.

(a) xylene, reflux
(b) oxone
In another specific embodiment, as shown in Scheme II-4 (e), the compounds of
general formula (I), wherein Y' represents -NRcC(O)C(O)Rg, and Rg represents -
NRd(CH2)nSO2R7, can be prepared by treating the compound of formula (XXIII) with the
compound of formula (XV) in an appropriate solvent such as xylene, dimethylacetamide
or N-methyl-2-pyrrolidone at 100°to 160°C for 2 to 16 hours gives the compound (XXVI),
which on treatment with oxone in water / methanol at 0° to room temperature provides the
compound of formula (I).

87
Specific procedures for synthesis of the substituted aldehyde, Q-CHO of formula
(II) are described hereinbelow in schemes III - 1 to III - 5.
Scheme III-1

(a) Ethylacetoacetate, acetic acid
(b) Diphenyl ether, reflux
(c) Phosphorus oxychloride
(d) Morpholine
(e) Selenium dioxide
Scheme III - 1 depicts the synthesis of the substituted aldehyde Q-CHO, in which
Q has a morpholino substituent. The R1 -substituted aniline, acetic acid and ethyl
acetoacetate is refluxed using Dean Stark apparatus in an appropriate solvent such as
toluene or benzene at 90° to 110°C for 6 to 18 hours. The crude ester thus obtained is
refluxed in a solvent such as diphenyl ether or Dowtherm® for 16 to 24 hours to give a
substituted 2-methyl-4-quinolone. The quinolone on treatment with POCI3 at 0° to 60°C in
an appropriate solvent such as tetrahydrofuran or toluene for 3 to 6 hours gives substituted
2-methyl-4-chloroquinoline, which is further reacted with a nitrogen containing
heterocycle R2 in the presence of a base potassium carbonate in a solvent such as
acetonitrile or dimethylformamide at 80° to 100 ° C for 3 to 8 hours to give R2-substituted-
2-methyl-quinoline. This on treatment with selenium dioxide in 1, 4-dioxane at 100° to
110°C for 3 to 12 hours gives the aldehyde Q-CHO (II).

(a) 3-Nitrobenzene sulphonic acid sodium salt, ferrous sulphate, boric acid,
HC1: water, crotonaldehyde;
(b) Methyl carbazate, p-toluene sulphonic acid
(c) Thionyl chloride
(d) Selenium dioxide
Scheme III - 2

88
Scheme III - 2 depicts the synthesis of the substituted aldehyde Q-CHO, in which
Q has a 1, 2, 4-thiadiazole substituent. 6-acetyl-aniline or substituted aniline is treated with
4-aminoacetophenone, 3-nitrobenzene sulphonic acid sodium salt, ferrous sulphate, boric
acid in 6N hydrochloric acid at 80° to 100°C for 1 to 3 hours, followed by addition of
crotonaldehyde and heated at 80° to 100°C for 4 to 12 hours to give 6-acetyl-2-methyl
quinoline. This is treated with methylcarbazate and p-toluene sulphonic acid in an
appropriate solvent such as toluene or xylene at 100° to l40°C for 8 to 16 hours. The
resulting product is treated with thionyl chloride in a solvent such as toluene or xylene at
60°C to 100°C for 1 to 4 hours to give 2-methyl-6-[l,2,3]thiadiazol-4-yl-quinoline.
Further, on oxidation of the methyl group with selenium dioxide in dioxane at 60°C to
100°C for 3 to 12 hours gives the aldehyde of general formula (II).
Scheme III - 3

(a) Lithium bis (hexamethyl) disilazane, ethyl trifluoroacetate
(b) Methyl hydrazine
(c) Selenium dioxide
Scheme III - 3 depicts the synthesis of the substituted aldehyde Q-CHO, in which
Q has a pyrazole substituent. 6-acetyl-2-methyl quinoline is treated with lithium
bis(hexamethyl)disilazane in an appropriate solvent such as tetrahydrofuran at -20°C for
an hour, which is then reacted with ethyl trifluoacetate at -20°C for 2 hours and a further
period of 3 hours at ambient temperature to give a diketo compound. The diketo
compound is treated with methyl hydrazine to obtain 2-methyl-6-(l-methyl-5-trifluoro-
lH-pyrazol-3-yl) quinoline, which on oxidation with selenium dioxide in a solvent such as

89
dioxane at 60°C to 100°C for 3 to 12 hours gives the compound of formula (II).
Scheme III - 4

(a) 2,3-Dimethoxy tetrahydrofuran, acetic acid
(b) Selenium dioxide
Scheme III - 4 depicts the synthesis of the substituted aldehyde Q-CHO, in which
Q has a pyrrole substituent. 4-amino-2-methyl quinoline is treated with 2,3-dimethoxy
tetrahydrofuran in acetic acid at 120°C for 2 to 6 hours to give 4-pyrrolo-2-methyl-
quinoline. Further, on oxidation of the methyl group with selenium dioxide in dioxane at
60°C to 100°C for 3 to 12 hours gives the compound of formula (II).
Scheme III - 5

(a) Morpholine, potassium carbonate
(b) Selenium dioxide
Scheme III - 5 depicts the synthesis of the substituted aldehyde Q-CHO, in which
Q is pyridine and has a morpholino substituent. 6-chloro-pyridine-2-carboxaldehyde is
treated with morpholine in the presence of a base such as potassium carbonate in an
appropriate solvent such as dimethylformamide or acetonitrile at 90° to 100°C for 4 to 24
hours to give the compound of formula (II).
A general synthetic method is provided for each of the disclosed groups of
chemical compounds. One of ordinary skill will recognize to substitute appropriately
modified starting material containing the various substituents. One of ordinary skill will

90
readily synthesize the disclosed compounds according to the present invention using
conventional synthetic organic techniques and microwave techniques from starting
material which are either purchased or may be readily prepared using prior art methods.
The compounds of the present invention may have chiral centers and occur as
racemates, racemic mixtures and as individual diastereomers, or enantiomers with all
isomeric forms being included in the present invention. Therefore, where a compound is
chiral, the separate enantiomers, substantially free of the other, are included within the
scope of the invention; further included are all mixtures of the two enantiomers. Also
included within the scope of the invention are polymorphs as well as hydrates of the
compounds of the instant invention.
The representative compounds of the present invention of general formula (I) are
useful to raise the levels of HSP-70.
METHOD OF PROTECTING CELLS AGAINST STRESS
The present invention relates to a method of inducing the expression of Heat Shock
Protein 70 (HSP-70) in cells, by treating the cells with an effective amount of one or more
of a 2-propene-l-one derivative, represented by the formula (I), its stereoisomer, tautomer,
solvates or its pharmaceutically acceptable salts.
In the present context, "HSP-70" refers to proteins of the HSP family having an
approximate molecular mass of 70 kDa, which are induced in response to a pathological
stress. "Pathological stress" refers to factors which disturb the homeostasis of the cells
thus leading to the increased expression of stress proteins like HSP-70. Such factors are,
for example, metabolic, oxidative, stresses caused by hypoxia, ischemia, infections,
stresses induced by metals and exogenous substances, immunogenic stresses, cell
malignancy, neurodegeneration, trauma, or aging. Other forms of pathological stresses
include those causing the formation of free radicals or increase in the quantity of
inflammatory cytokines.

91
In one embodiment of the invention, the diseases accompanying pathological stress
are selected from cerebrovascular, cardiovascular diseases, neurodegenerative diseases
and immune disorders, such as stroke, myocardial infarction, inflammatory disorder,
hepatotoxicity, sepsis, diseases of viral origin, allograft rejection, tumourous diseases,
gastric mucosal damage, brain haemorrhage, endothelial dysfunctions, diabetic
complications, neuro-degenerative diseases, post-traumatic neuronal damage, acute renal
failure, glaucoma and aging related skin degeneration. The compounds of the present
invention possess the ability to induce HSP-70 and thereby protect cells against stress-
induced damage in the above disease conditions.
The invention also relates to a method of inhibiting TNF-a in cells, by treating the
cells with an effective amount of one or more of a 2-propene-l-one derivative, represented
by the formula (I), its stereoisomer, tautomer, solvates or its pharmaceutically acceptable
salts. Cytokines such as TNF-a produced by activated monocytes / macrophages play an
important role in the regulation of the immune response. Studies have shown that TNF-a
is involved in the pathogenesis of diabetes, myocardial infarction, liver failure, infectious
diseases like sepsis syndrome, autoimmune diseases like rheumatic arthritis, graft
rejection, organ transplant rejection, chronic inflammatory disorders such as rheumatoid
diseases, arthritic disorders and connective tissue disorders. [Han, H.S. and Yenari, M.A.,
Current Opinion in Investigational Drugs, 2003, Vol. 4(5), pp. 522-529]. Treatment with
2-propen-l-one derivatives of the instant invention which show TNF-a inhibitory activity
exerts a cytoprotective effect in the above disease conditions.
In another embodiment of the invention, a method of increasing HSP-70
expression in cells is provided. HeLa cells, which are well characterized cell lines
employed for primary screening is used for this purpose. In this method, the HeLa cells are
treated with an effective amount of 2-propene-l-one derivatives. The 2-propene-l-one
derivatives substantially increase the expression of HSP-70 in these cells.
In still another embodiment of the invention, a method of inhibition of TNF-a
expression is provided. For this purpose, Human monocytic leukaemia cell line, THP-1,
differentiated into macrophage-like cells by phorbol merystyl ester treatment was

92
employed. In this method, TNF-a expression was induced in the cell line by treatment
with lipopolysaccharide. The cells were subjected to an effective amount of 2-propene-l-
one derivatives. The 2-propene-l-one derivatives substantially inhibit the expression of
TNF-a in these cells.
An increase in HSP-70 expression and inhibition of TNF-a expression in cells can
be detected using well established laboratory procedures such as Real time polymerase
chain reaction (Real time PCR), as described in Examples (I) and (II). Real time PCR is a
technique that is used for the quantitative measurement of gene expression levels in cells
or tissues. The technique is based on the use of a fluorescent reporter dye at 5'end of the
probe and a quencher dye at the 3' end of the probe to monitor the PCR reaction as it
occurs. The fluorescence of the reporter molecule increases as products accumulate with
each successive round of amplification. The point at which the fluorescence rises
appreciably above the background is defined as the threshold cycle and is used for the
determination of initial copy number.
For determining the ability of the compounds of the instant invention to afford
protection against stress-induced damage in vivo, a pathological stress is applied to an
animal, for example, cerebral ischemia, myocardial ischaemia or carrageenan-induced
inflammation. Cerebral ischemia can be induced in an animal as described in Example
(III), induction of myocardial ischaemia is described in Example (V) and carrageenan-
induced inflammation is described in Example (IV). The compounds of the present
invention are administered to the animals and tested for their efficacy against the said
disease conditions.
"Treating" or "treatment" of any disease or disorder refers, in one embodiment, to
ameliorating the disease or disorder (i.e., arresting or reducing the development of the
disease or at least one of the clinical symptoms thereof). In another embodiment "treating"
or "treatment" refers to ameliorating at least one physical parameter, which may not be
discernible by the patient. In yet another embodiment, "treating" or "treatment" refers to
inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible
symptom), physiologically, (e.g., stabilization of a physical parameter) or both. In yet
another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or

93
disorder. As used herein, amelioration of the symptoms of a particular disorder by
administration of a particular compound or pharmaceutical composition refers to any
lessening, whether permanent or temporary, lasting or transient that can be attributed to or
associated with administration of the composition.
The phrase "a therapeutically effective amount" means the amount of a compound
that, when administered to a patient for treating a disease, is sufficient to effect such
treatment for the disease. The "therapeutically effective amount" will vary depending on
the compound, mode of administration, the disease and its severity and the age, weight,
etc., of the patient to be treated. Such amount can be readily determined by one skilled in
the art, and will not require undue experimentation.
PHARMACEUTICAL COMPOSITIONS
In another embodiment of the invention is provided a pharmaceutical composition
comprising a therapeutically effective amount of one or more of a compound of general
formula (I). While it is possible to administer therapeutically effective quantity of
compounds of formula (I) either individually or in combination, directly without any
formulation, it is common practice to administer the compounds in the form of
pharmaceutical dosage forms comprising pharmaceutically acceptable excipient(s) and at
least one active ingredient. These dosage forms may be administered by a variety of
routes including oral, topical, transdermal, subcutaneous, intramuscular, intravenous,
intranasal, pulmonary etc.
Oral compositions may be in the form of solid or liquid dosage form. Solid dosage
form may comprise pellets, pouches, sachets or discrete units such as tablets, multi-
particulate units, capsules (soft & hard gelatin) etc. Liquid dosage forms may be in the
form of elixirs, suspensions, emulsions, solutions, syrups etc. The above pharmaceutical
compositions may contain in addition to active ingredients, excipients such as diluents,
disintegrating agents, binders, solubilizers, lubricants, glidants, surfactants, suspending
agents, emulsifiers, chelating agents, stabilizers, flavours, sweeteners, colours etc. Some
example of suitable excipients include lactose, cellulose and its derivatives such as
microcrystalline cellulose, methylcelulose, hydroxy propyl methyl cellulose,

94
ethylcellylose, dicalcium phosphate, mannitol, starch, gelatin, polyvinyl pyrolidone,
various gums like acadia, tragacanth, xanthan, alginates & its derivatives, sorbitol,
dextrose, xylitol, magnesium Stearate, talc, colloidal silicon dioxide, mineral oil, glyceryl
mono Stearate, glyceryl behenate, sodium starch glycolate, Cross Povidone, crosslinked
carboxymethylcellulose, various emulsifiers such as polyethylene glycol, sorbitol
fattyacid, esters, polyethylene glycol alkylethers, sugar esters, polyoxyethylene
polyoxypropyl block copolymers, polyethoxylated fatty acid monoesters, diesters and
mixtures thereof.
Sterile compositions for injection can be formulated according to conventional
pharmaceutical practice by dissolving or suspending the active substance in a vehicle such
as water for injection, N -Methyl-2-Pyrrolidone, propylene glycol and other glycols,
alcohols, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cotton
sead oil or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, anti-oxidants,
preservatives, complexing agents like cellulose derivatives, peptides, polypeptides and
cyclodextrins and the like can be incorporated as required,
Dose is appropriately decided by its form of preparation, method of administration,
purpose of use and age, body weight and symptom of the patient to be treated and it is not
constant. But, usually, the amount of at least one of the compound selected from the
compound of the present invention, an optically active substance thereof or a salt thereof
contained in the preparation is from 0.1 microgram to 100 mg/kg per day (for adults).
Thus, the total quantity of compound in a particular pharmaceutical composition may
range from 1 to 1000 mg, at concentration levels ranging from about 0.5% to about 90%
by weight of the total composition. In a preferred embodiment, the composition may
contain 20 to 500 mg of the compound, at concentration levels ranging from about 10% to
about 70% by weight of the total composition. Of course, the dose may vary depending
upon various conditions and, there ore, the dose less than above may be sufficient in some
cases while, in other cases, the dose more than above may be necessary. The dosage form
can have a slow, delayed or controlled release of active ingredients in addition to
immediate release dosage forms.

95
PREPARATORY EXAMPLES
The novel compounds of the present invention were prepared according to the
procedure of the schemes as described hereinabove, using appropriate materials and are
further exemplified by the following specific examples. The examples illustrate the
preparation of the compounds of formula (I) and their incorporation into pharmaceutical
compositions and as such are not to be considered nor construed as limiting the scope of
the invention set forth in the claims appended thereto.
Example 1
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(4-methyI-piperazine-l-carbonyl-phenyl]-
propenone (Compound No. 37)
Step A: Preparation of 3-hydroxy-quinoxalin-2-carboxaldehyde
To 3-methyl-quinoxalin-2-ol (lg, 6.2 mmol) in 1,4-dioxane (30 ml) was added selenium
dioxide (2 g, 18.7 mmol) and refluxed for 4 hours. The reaction mixture was then cooled,
filtered through celite and partitioned between water and ethylacetate. The combined
organic layers were successively washed with water (50 ml x 2) and brine (50 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo to give 0.58 g of the
title compound as a brown solid. This was used without purification in the next step.
1H NMR (400 MHz, DMSOd6) d 7.63-7.69 (2H, m), 7.84-8.38 (2H, m), 10.19 (IH,
s), 12.84 (IH, bs).
Step B: Preparation of 4-[3-(3-hydroxy-quinoxalin-2-yl) acryloyl] benzoic acid
A solution of 0.58 g (3.3 mmol) of the product of example 1, Step A and 4-acetyl benzoic
acid (0.5 g, 3 mmol) in methanol (40 ml) was cooled to 0°C. To it was added dropwise a
solution of sodium hydroxide (0.24 g, 6 mmol) in water (2 ml). The mixture was stirred at
room temperature for 16 hours. After completion of the reaction, the mixture was cooled
to 0°C, diluted with water (20 ml) and aqueous hydrochloric acid was added to adjust the
pH to 4. The precipitate was filtered, washed successively with water (20 ml x 2) and

96
brine (10 ml x 2) and dried under vacuo at 60 °C for 4 hours to afford 0.5 g of the title
compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 7.32-7.39 (2H, m), 7.59-7.63 (1H, t), 7.84-7.89
(1H, m), 7.91 (1H, s), 8.05 (1H, s), 8.12-8.17 (3H, t), 8.37-8.41 (1H, d), 12.77 (1H, s),
13.37 (lH,bs).
Step C: Preparation of 3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(4-methyl-piperazine-l-
carbonyl-phenyl]-propenone
To 0.3 g (0.9 mmol) of the product of example 1, Step B in dry tetrahydrofuran (25 ml)
was cooled to 0°C, followed by addition of N-ethyldiisopropyl amine (0.2 g, 1.8 mmol)
and 1-hydroxybenzotriazole (0.15 g, 1.1 mmol) and the mixture was stirred for 30
minutes. To it was added N-methyl piperazine (0.18 g, 11.8 mmol) and l-ethyl-3-(3-
dimethylaminopropyl) carbodiimide (EDCI, 0.46 g, 2.4 mmol). The reaction mixture was
allowed to attain room temperature, stirred overnight and partitioned between water and
ethyl acetate. The combined organic layer were successively washed with water (20 ml x
2) and brine (10 ml x 2), dried over anhydrous sodium sulphate and evaporated under
vacuo. The residue was purified by column chromatography on silica gel using 5%
methanol in ethyl acetate as the eluent. Trituration of the residue in diethyl ether (20 ml x
3) followed by collection of the solid by vacuum filtration provided the title compound
(0.12 g) as yellow solid.
1H NMR (400 MHz, DMSOd6) d 2.2 (3H, s), 2.28 (2H, bs), 2.38 (2H, bs), 3.28
(2H, bs), 3.65 (2H, bs), 7.35 - 7.39 (2H, t), 7.59 - 7.63 (3H, t), 7.86 - 7.91 (2H, m), 8.1 -
8.13 (2H, d), 8.39 - 8.43 (1H, d), 12.75 (1H, s);
MS, m/z 401
Example 2
l-[4-(4-Methyl-piperazine-l-carbonyI)-phenyI]-3-(6-trifluoromethyl-quinolin-2-yI)-
propenone (Compound No. 32)
Step A: Preparation of 2-methyl-6-trifluoromethyl quinoline

97
To a solution of 4-(trifluoromethyl) aniline (5 g, 31 mmol) in aqueous hydrochloric acid
(6N, 90 ml) was added m-nitrobenzene sulphonic acid sodium salt (7 g, 31 mmol), ferrous
sulphate (8.62 g, 31 mmol) and boric acid (7.7 g, 124 mmol). The reaction mixture was
refluxed under vigorous stirring for 1 hour. To it, crotonaldehyde (3.25 g, 46 mmol) was
then added dropwise and the mixture refluxed for 8 hours. After cooling to 60 ° C,
methanol (10 ml) was added and filtered through celite. The pH of the filtrate was adjusted
to 7 with an aqueous solution of sodium hydroxide (1 N). The volatiles were evaporated
under vacuo. The reaction mixture was partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (100 ml x 2) and brine (50
ml x 2), dried over sodium sulphate and evaporated under vacuo. The residue was purified
by column chromatography on silica gel using 30% ethyl acetate in hexane as the eluent to
afford 4.2 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 2.3 (3H, s), 7.86 - 7.89 (1H, m), 7.95 (1H, m),
8.17 (2H,d), 8.21-8.26 (1H, d).
Step B: Preparation of 6-trifluoromethyl quinoline-2-carboxaldehyde
To 1 g (4.7 mmol) of the product of example 2, Step A in 1, 4-dioxane (20 ml) was added
selenium dioxide (0.8 g, 7 mmol) and heated to 60°C for 8 hours. The reaction mixture
was filtered through celite and the filtrate partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (100 ml x 2) and brine (50
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. Trituration of
the residue in hexane (20 ml x 3) followed by collection of the solid by vacuum filtration
provided 0.7 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 7.86 - 7.89 (1H, m), 7.95 (1H, m), 8.17 (2H, d),
8.21-8.26 (lH,d), 10.07 (lH,s).
Step C: Preparation of 4-[-3-(6-trifluoromethyl-quinolin-2-yl)-acryloyl]-benzoic acid
To 0.7 g (3 mmol) of the product of example 2, Step B and 4-acetyl benzoic acid (0.5 g, 3
mmol) in methanol (40 ml) was cooled to 0°C, and to it was added dropwise an aqueous
solution of sodium hydroxide [0.25 g, 6 mmol in water (2 ml)]. The reaction mixture was
stirred at room temperature for 8 hours. The mixture was then cooled to 0°C, diluted with

98
water (20 ml) and aqueous hydrochloric acid was added to adjust the pH to 4. The
precipitate was filtered, washed successively with water (20 ml x 2) and brine (10 ml x 2),
and dried under vacuo at 60°C for 4 hours to afford 0.7 g of the title compound as a yellow
solid.
1H NMR (400 MHz, DMSOd6) d 7.58 - 7.6 (2H, dd), 7.76 - 7.79 (1H, d), 7.94 -
7.99 (2H,m), 8.17-8.19 (3H, dd), 8.21 - 8. 26 (1H, d), 8.27- 8.29 (1H, d), 8.36 (1H, d),
11.1(1H, bs).
Step D: Preparation of l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-(6-
trifluoromethyl-quinolin-2-yl)-propenone
A solution of 0.2 g (0.5 mmol) of the product of example 2, Step C in dry tetrahydrofuran
(25 ml) was cooled to 0°C. N-ethyldiisopropyl amine (0.17 g, 1.25 mmol) and 1-
hydroxybenzotriazole (0.15 g, 0.6 mmol) were added to the above solution. After stirring
the reaction mixture for 30 minutes, N-methyl piperazine (0.07 g, 1 mmol) and l-ethyl-3-
(3-dimethylaminopropyl) carbodiimide (EDCI, 0.4 g, 2 mmol) were then added. The
reaction mixture was allowed to attain room temperature and stirred for 8 hours. The
mixture was partitioned between water and ethyl acetate. The combined organic layer
were successively washed with water (20 ml x 2) and brine (10 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by
column chromatography on silica gel using 90% ethyl acetate in hexane as the eluent.
Trituration of the residue in hexane followed by collection of the solid by vacuum
filtration provided the title compound (0.12 g) as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 2.36 (3H, s), 2.37 - 2.39 (2H, m), 2.54 (2H, bs),
3.45 (2H, bs), 3.85 (2H, bs), 7.58 - 7.6 (2H, dd), 7.76 - 7.79 (1H, d), 7.94 - 7.99 (2H, m),
8.17 - 8.19 (3H, dd), 8.21 - 8.26 (1H, d), 8.27 - 8.29 (1H, d), 8.33 - 8.36 (1H, d);
MS, m/z 454
Example 3
2-{3-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-oxo-propenyl}-quinoline-
6-sulfonic acid amide (Compound No. 46)
Step A: Preparation of 2-methyl-quinolin-6-sulphonamide

99
To a solution of sulphanilamide (1 g, 5.8 mmol) in aqueous hydrochloric acid (6N, 20 ml)
was added m-nitrobenzene sulphonic acid sodium salt (1.3 g, 5.8 mmol), ferrous sulphate
(1.6 g, 5.8 mmol) and boric acid (1.4 g, 23 mmol). The reaction mixture was refluxed
under vigorous stirring for 1 hour. To it, crotonaldehyde (0.7 g, 8.7 mmol) was then added
dropwise and the reaction mixture refluxed for 8 hours. After cooling to 60°C, methanol (2
ml) was added and filtered through celite. The pH of the filtrate was adjusted to 7 with
aqueous lN sodium hydroxide solution. The reaction mixture was partitioned between
ethyl acetate and water. The combined organic layer were successively washed with water
(10 ml x 2) and brine (5 ml x 2), dried over sodium sulphate and evaporated under vacuo.
The residue was purified by column chromatography on silica gel using 30% ethyl acetate
in hexane as the eluent to afford 0.9 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 2.68 - 2.7 (3H, s), 7.51 (2H, s), 7.55 - 7.57 (1H,
d), 8.04 - 8.09 (2H, t), 8.44 - 8.49 (2H, t).
Step B: Preparation of 2-formyl-quinolin-6-sulphonamide
To 0.8 g (3.6 mmol) of the product of example 3, Step A in 1, 4-dioxane (20 ml) was
added selenium dioxide (0.5 g, 4.5 mmol) and heated to 60°C for 8 hours. The reaction
mixture was filtered through celite and the filtrate partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (50 ml x 2)
and brine (25 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The residue was decolorised with activated charcoal, filtered through celite and washed
with methanol (20 ml). The filtrate was evaporated under vacuo and trituration of the
residue in hexane (20 ml x 3) followed by collection of the solid by vacuum filtration
provided 0.5 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 2.68-2.7 (3H, s), 7.51 (2H, s), 7.55-7.57 (1H, d),
8.04-8.09 (2H, t), 8.44-8.49 (2H, t), 10.11 (1H, s).
Step C: Preparation of 4-[3-(6-sulphamoyl-quinolin-2-yl)-acryloyl]-benzoicacid
A solution of 4-acetyl benzoic acid (0.5 g, 3 mmol) and 0.8 g (3.3 mmol) of the product of
example 3, Step B in methanol (40 ml) was cooled to 0°C. To it was added dropwise an

100
aqueous solution of sodium hydroxide [0.25 g, 6 mmol in water (2 ml)]. The reaction
mixture was stirred at room temperature for 8 hours. The mixture was then cooled to 0°C,
diluted with water (20 ml) and aqueous hydrochloric acid was added to adjust the pH to 4.
The precipitate was filtered, washed with water (20 ml x 2) and brine (10 ml x 2) and dried
under vacuo at 60°C for 4 hours to afford 0.6 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 7.62 (2H, bs), 7.8 (1H, d), 8.02 (2H, d), 8.08 (2H,
m), 8.14 (1H, m), 8.2 (1H, d), 8.36 (1H, d), 8.4 (1H, d), 8.5 (1H, m), 8.7 (1H, d), 11.12
(1H, bs).
Step D: Preparation of N, N-dimethyl-(lH-pyrazol-3-yl) amine
A solution of 3-amino pyrazole (1 g, 14 mmol) in methanol (20 ml) was cooled to 0°C and
to it was added 1.3 g (4.2 mmol) of paraformaldehyde. The reaction mixture was stirred at
ambient temperature for 2 hours. It was then cooled to 0°C followed by addition of sodium
cyanoborohydride (2.7 g, 4.2 mmol) and stirred at ambient temperature for another 3
hours. The reaction mixture was partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (25 ml x 2) and brine (10
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. The residue
was purified by column chromatography on silica gel using 50% ethylacetate in hexane as
the eluent to afford the 1.1 g of the title compound as a brown oil.
1H NMR (400 MHz, DMSOd6) d 2.89 (6H, s), 5.68 -5.69 (IH, d), 6.42 - 6.43 (IH,
bs), 7.39 -7.4 (1H, d).
Step E: Preparation of 2-{3-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-oxo-
propenyl}-quinoline-6-sulfonic acid amide
To a solution of 0.3 g (0.7 mmol) of the product of example 3, Step C in dry
tetrahydrofuran (25 ml), pre-cooled to 0°C, was added N-ethyldiisopropyl amine (0.17 g,
1.2 mmol), 1-hydroxybenzotriazole (0.12 g, 0.9 mmol) and stirred for 30 minutes. To it,
0.1 g (0.9 mmol) of the product of example 3, Step D and l-ethyl-3-(3-dimethyl
aminopropyl) carbodiimide (EDCI, 0.4 g, 2 mmol) were added. The reaction mixture was
allowed to attain room temperature and stirred for 8 hours. The mixture was partitioned

101
between water and ethyl acetate. The combined organic layers were washed with water
(20 ml x 2) and brine (10 ml x 2), dried over anhydrous sodium sulphate and evaporated
under vacuo. The residue was purified by column chromatography on silica gel using 60%
ethyl acetate in hexane as the eluent. Trituration of the residue in hexane followed by
collection of the solid under vacuum filtration provided the title compound (0.06 g) as
yellow solid.
1H NMR (400 MHz, DMSOd6) d 2.89 (6H, s), 6.47 - 6.49 (1H, d), 7.61 (2H, s),
7.88 - 7.92 (1H, d), 8.14 - 8.17 (2H, m), 8.24 - 8.32 (4H, m), 8.35 - 8.45 (3H, m), 8.54
(1H, d), 8.74-8.76 (lH,d);
MS, m/z 474
Example 4
l-{4-(morphoIine-4-carbonyI)phenyl}-3-quinolin-2-yl-propenone (Compound No. 1)
Step A: Preparation of 4-[3-quinolin-2-yl)-acryloyl]-benzoic acid
To a solution of quinoline-2-carboxaldehyde (1 g, 6.3 mol) and 4-acetyl benzoic acid (1 g,
6.3 mol) in methanol (60 ml) was added dropwise an aqueous solution of sodium
hydroxide [0.5 g, 12.7 mol, in water (2 ml)]. The reaction mixture was refluxed for 8
hours. The mixture was then cooled to 0°C, diluted with water (20 ml) and aqueous
hydrochloric acid was added to adjust the pH to 4. The precipitate was filtered,
successively washed with water (20 ml x 2) and brine (10 ml x 2), and dried under vacuo
at 60°C for 4 hours to afford 0.6 g of the title compound as a colourless solid.
1H NMR (400 MHz, DMSOd6) d 7.65-7.68 (1H, t), 7.8-7.85(lH, t), 7.89(1H, s),
8.02-8.04 (1H, d), 8.08-8.14 (3H, m), 8.31-8.35 (1H, d), 8.49-8.51 (1H, d), 11.84 (1H, s).
Step B: Preparation of l-{4-(morpholine-4-carbonyl)phenyl}-3-quinolin-2-yl-propenone
To a solution of 0.15 g (0.5 mmol) of the product of example 4, Step A in dry
tetrahydrofuran (20 ml), cooled to 0°C was added N-ethyldiisopropyl amine (0.17 g, 1.25
mmol) and 1-hydroxybenzotriazole (0.15 g, 0.6 mmol), and stirred for 30 minutes. To it,
N-methyl piperazine (0.085 g, 1 mmol) and l-ethyl-3-(3-dimethylaminopropyl)

102
carbodiimide (EDCI, 0.4 g, 2 mmol) were then added. The reaction mixture was left to
attain room temperature and stirred for 8 hours. The mixture was partitioned between
water and ethyl acetate. The combined organic layers were washed with water (20 ml x 2)
and brine (10 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The residue was purified by column chromatography on silica gel using 80% ethyl acetate
in hexane as the eluent. Trituration of the residue in hexane followed by collection of the
solid by vacuum filtration provided 0.12 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 3.57 - 3.68 (8H, d), 7.63-7.69 (3H, m), 7.81 -
7.89 (2H, m), 8.02 - 8.04 (1H, d), 8.08 - 8.11 (1H, d), 8.22 - 8.25 (3H, m), 8.3 - 8.35 (1H,
d), 8.49-8.51(1 H,d);
MS, m/z 373
Example 5
Sodium salt of Compound No. 9, i.e., l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-
piperidine-4-carboxylic acid
Following the process described in Example 4, l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-
piperidine-4-carboxylic acid isopropyl ester was prepared.
To the solution of l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid
isopropyl ester (0.33 g, 0.7mmol) in methanol (10 ml) at 0°C was added dropwise a
solution of sodium hydroxide (0.2 % in methanol). The mixture was stirred at 0°C to
ambient temperature for 5 hours. The solid was filtered, washed with diethyl ether and
dried under vacuo to afford 0.3 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 1.54 (2H, bs), 1.77 (1H, bs), 1.92 (1H, bs), 2.59
- 2.67 (1H, m), 2.92 - 2.98 (1H, m), 3.11 - 3.16 (1H, m), 3.49 - 3.52 (1H, d), 7.6 - 7.62
(2H, d), 7.65 - 7.69 (1H, t), 7.81 - 7.88 (2H, m), 8.02 - 8.04 (1H, d), 8.08 - 8.1 (1H, d), 8.2
- 8.24 (3H, d), 8.31 - 8.35 (1H, d), 8.49 - 8.51 (1H, d)
MS, m/z 414
Example 6

103
l-(4-Nitro-phenyI)-4-[4-(3-quinoIin-2-yl-acryloyl)-benzoyI]-piperazin-2-one
(Compound No. 8)
Step A: Preparation of {2-(4-Amino-phenylamino)-ethylamino}-acetic acid ethyl ester
To a solution of 1-fluoro-4-nitrobenzene (40 g, 283 mmol) and N-ethyl diisopropylamine
(55 g, 425 mmol) in acetonitrile, cooled to 0°C, was added dropwise 42.5 g (710 mmol)
of ethylene diamine. The reaction mixture was stirred at ambient temperature for 10 hours.
The mixture was partitioned between water and ethyl acetate. The combined organic
layers were washed with water (20 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo to give 27 g of the title compound as a yellow solid residue. The
solid thus obtained (4 g, 22 mmol) and N-ethyl diisopropylamine (4.25 g, 33 mmol) were
dissolved in dimethylformamide, cooled to 0°C and ethyl bromoacetate (3.67 g, 22 mmol)
diluted with dimethylformamide (10 ml) was added dropwise. The reaction was stirred at
ambient temperature for 10 hours. The mixture was partitioned between water and ethyl
acetate. The combined organic layers were washed with water (20 ml x 2) and brine (10
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. The residue
was purified by column chromatography on silica gel using 60% ethyl acetate in hexane as
the eluent. Trituration of the residue in hexane followed by collection of the solid by
vacuum filtration provided 2.2 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 1.33 - 1.35 (3H, d), 2.72- 2.81 (2H, t), 3.19 -
3.24 (2H, m), 3.89 - 3.91 (2H, d), 3.4 - 3.42 (2H, m), 6.6 - 6.69 (2H, dd), 7.25 - 7.38 (2H,
m), 7.98 - 8.03 (2H, m).
Step B: Preparation of {tert-butoxycarbonyl-[2-(4-nitrophenylamino)-ethyl]-amino}-
acetic acid
2.5 g (9.4 mmol) of the ester from example 6, Step A was dissolved in tetrahydrofuran (25
ml) containing N-ethyl diisopropylamine (1.2 g, 9.3 mmol), cooled to 0°C and di-tert-
butyl-dicarbonate (t-Boc, 2.5 g, 11 mmol) was added. The reaction mixture was stirred at
ambient temperature for 4 hours. The mixture was partitioned between water and ethyl
acetate. The combined organic layers were washed with water (20 ml x 2) and brine (10
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo to provide 3 g

104
of a yellow solid. The solid was dissolved in methanol (15 ml) and to it, aqueous sodium
hydroxide [1 g, 28 mmol in water (2 ml)] was added dropwise at room temperature. The
reaction mixture was stirred for 10 hours. The mixture was then cooled to 0°C, diluted
with water (20 ml) and aqueous hydrochloric acid was added to adjust the pH to 7. The
mixture was partitioned between water and ethyl acetate. The combined organic layers
were washed with water (20 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo to afford 1.7 g of the title compound as a yellow viscous liquid
1H NMR (400 MHz, DMSOd6) d 1.3-1.35 (9H, d), 2.77-2.81 (2H, t), 3.19-3.24
(2H, m), 3.89 - 3.91(2H, d), 3.4 - 3.42 (2H, m), 6.66 - 6.69 (2H, dd), 7.25 - 7.39 (1H, bs),
7.98 - 8.03 (2H, m), 12.64 (1H, bs).
Step C: Preparation of trifluoroacetic acid salt of l-(4-nitrophenyl)-piperazine-2-one
To 1.7 g of the product from example 6, Step B in dry tetrahydrofuran (20 ml), cooled to
0°C was added N-ethyl diisopropyl amine (0.17 g, 1.25 mmol) and 1-hydroxy
benzotriazole (0.15 g, 0.6 mmol), and stirred for 30 minutes. To it, l-ethyl-3-(3-
dimethylaminopropyl) carbodiimide (EDCI, 0.4 g, 2 mmol) was then added. The reaction
mixture was allowed to attain room temperature and stirred for 10 hours. The mixture was
partitioned between water and ethyl acetate. The combined organic layers were washed
successively with water (20 ml x 2) and brine (10 ml x 2), dried over anhydrous sodium
sulphate and evaporated under vacuo to provide 4-(4-nitrophenyl)-3-oxo-piperazine-l-
carboxylic acid tert-butyl ester (1 g) as a yellow solid. The solid (1 g, 3 mmol) was
dissolved in dichloromethane (5 ml), cooled to 0°C and to it, trifluoroacetic acid (1.36 g,
12 mmol) was added dropwise. The reaction mixture was stirred at 0°C for an hour. The
volatiles were eliminated by co-evaporating with dichloromethane (10 ml x 2) to afford
0.8 g of the title compound as a yellow solid, which was used as such in the next step.
1H NMR (400 MHz, DMSOd6) d 3.69 - 3.7 (2H, t), 3.84 - 3.87 (2H, t), 4.14 (2H,
s), 5.8 (1H, s), 7.68 - 7.71 (2H, d), 8.26 - 8.28 (2H, d).
Step D: Preparation of l-(4-Nitro-phenyl)-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-
piperazin-2-one

105
To a solution of 4-(3-quinolin-2-yl-acroloyI) benzoic acid (0.25 g, 0.8 mmol) in dry
tetrahydrofuran (25 ml), cooled to 0°C, N-ethyl diisopropylamine (0.8 g, 6.4 mmol) and 1-
hydroxy benzotriazole (0.14 g, 1 mmol) were added. The mixture was stirred for 30
minutes. The crude TFA salt from example 6, Step C (0.3 g, 0.9 mmol) dissolved in dry
tetrahydrofuran (5 ml), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI, 0.4 g, 2
mmol) was then added. The reaction mixture was allowed to attain room temperature and
stirred for 10 hours. The mixture was partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (20 ml x 2) and brine (10
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. The residue
was recrystallized from methanol / diethyl ether to afford 0.21 g of the title compound as a
brown solid.
1H NMR (400 MHz, DMSOd6) d 3.76 (1H, bs), 3.85 - 3.95 (2H, m), 4.03 (1H,
bs), 4.23 (1H, bs), 4.44 (1H, bs), 7.65 - 7.76 (5H, m), 7.81 - 7.9 (2H, m), 8.02 - 8.04 (1H,
d), 8.08 - 8.11 (1H, d), 8.23 - 8.37 (6H, m), 8.49 - 8.52 (1H, d);
MS, m/z 507
Example 7
l-{4-[3-(5,6,7-trimethoxy-quinolin-2-yI)-acryloyI}-benzoyl}-piperidin-4-
one (Compound No. 35)
Step A: Preparation of 5, 6, 7-trimethoxy-2-methyl-quinoline
To a suspension of 3, 4, 5-trimethoxy aniline (5 g, 27 mmol) in aqueous hydrochloric acid
(6N, 20 ml) was added m-nitrobenzene sulphonic acid sodium salt (6.15 g, 27 mmol),
ferrous sulphate (7.6 g, 27 mmol) and boric acid (6.6 g, 108 mmol), and refluxed under
vigorous stirring. After 1 hour, crotonaldehyde (3.8 g, 48 mmol) was added dropwise
under reflux. After cooling to room temperature, methanol (2 ml) was added and filtered.
The pH of the filtrate was adjusted to 7 with an aqueous solution of sodium hydroxide (1
N). The mixture was partitioned between ethyl acetate and water. The combined organic
layers were successively washed with water (20 ml x 2) and brine (20 ml x 2), dried over
sodium sulphate and evaporated under vacuo. The solid residue was purified by column

106
chromatography on silica gel using the 40% ethyl acetate in hexane as the eluent to obtain
2.3 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 2.59 (3H, s), 3.84 (3H, s), 3.93 - 3.95 (6H, s),
7.17 (1H, s), 7.24 - 7.26 (1H, d), 8.18 - 8.2 (1H, d).
Step B: Preparation of 5, 6, 7-trimethoxy-quinoline-2-carboxaldehyde
To 1.4g (6 mmol) of the product from example 7, Step A in 1, 4-dioxane (50 ml) was
added selenium dioxide (1 g, 9 mmol) and heated at 60°C for 8 hours. The reaction
mixture was filtered through celite and the filtrate partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (50 ml x 2)
and brine (25 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The solid residue was triturated with hexane (50 ml x 2) to obtain 1.1 g of the title
compound as brown solid.
1H NMR (400 MHz, DMSOd6) d 3.84 (3H, s), 3.93-3.95 (6H, s), 7.17 (1H, s),
7.24-7.26 (1H, d), 8.18-8.20 (1H, d), 10.01 (1H, s).
Step C: Preparation of 4-[3-(5, 6, 7-trimethoxy-quinolin-2-yl)-acryloyl]-benzoic acid
To a solution of 4-acetyl benzoic acid (0.66 g, 4 mmol) and the product from example 7,
Step B (1 g, 4 mmol) in methanol (25 ml), cooled to 0°C, was added dropwise an aqueous
solution of sodium hydroxide [0.32 g, 8 mmol in water (2 ml)]. The reaction mixture was
stirred at room temperature for 16 hours. The mixture was then cooled to 0°C, diluted with
water (20 ml) and aqueous hydrochloric acid was added to adjust the pH to 7. The
precipitate was isolated by filtration with a Buchner funnel and successively washed with
water (20 ml x 2) and brine (10 ml x 2) and dried under vacuo at 60°C to afford 2.5 g of
the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 4 (9H, s), 7.82 - 7.86 (1H, m), 8.01 - 8.05 (3H,
m), 8.12 - 8.14 (2H, m), 8.23 - 8.29 (3H, m), 11.2 (1H, bs).
StepD: Preparation of l-{4-[3-(5, 6, 7-trimethoxy-quinolin-2-yl)-acryloyl}-benzoyl}-
piperidin-4-one

107
To 0.2 g (0.5 mmol) of the product from example 7, Step C in dry tetrahydrofuran (25 ml),
cooled to 0°C, was added N-ethyldiisopropyl amine (3.9 g, 3 mmol) and 1-hydroxy
benzotriazole (0.1 g, 0.7 mmol). The reaction mixture was stirred for 30 minutes. To it,
piperidine hydrochloride monohydrate salt (0.8 g, 5.2 mmol), l-ethyl-3-(3-
dimethylaminopropyl) carbodiimide (EDCI, 0.4 g, 2 mmol) were then added. The reaction
mixture was allowed to attain room temperature and stirred for 12 hours. The mixture was
partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (20 ml x 2) and brine (10 ml x 2), dried over anhydrous
sodium sulphate and evaporated under vacuo. The residue was purified by column
chromatography on silica gel using 70% ethyl acetate in hexane as the eluent. Trituration
of the residue in hexane followed by collection of the solid by vacuum filtration provided
0.09 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOde) d 2.41 (2H, m), 2.54 (2H, m), 3.56 - 3.61 (2H, m),
3.86 - 3.93 (5H, m), 3.98 - 4.02 (6H, d), 7.33 (1H, s), 7.7 - 7.72 (2H, d), 7.81 - 7.86 (1H,
d), 8.03 - 8.05 (1H, d), 8.23 - 8.25 (2H, d), 8.28 - 8.32 (1H, d), 8.40 - 8.42 (1H, d);
MS, m/z 475
Example 8
4-Morpholin-4-yl-2-{3-oxo-3-[4-(pyrrolidine-l-carbonyI)-phenyI]-propenyI}-
quinoline-6-carboxylic acid methyl ester (Compound No. 13)
Step A: Preparation of 2-methyl-4-oxo-l, 4-dihydro-quinoline-6-carboxylic acid
To 20 g (0.15 mol) of 4-amino benzoic acid in toluene (100 ml) containing acetic acid (2
ml) was added ethyl acetoacetate (28 g, 0.2 mol) and refluxed using Dean Stark apparatus
to remove the reaction water for 8 hours. The reaction mixture was cooled to room
temperature and the precipitate filtered, washed successively with water (100 ml x 2) and
diethyl ether (100 ml x 2), and dried under vacuo overnight. The crude product (16.2 g)
was suspended in diphenyl ether or Dowtherm and refluxed for a period of 3 hours with an
air condensor. The precipitate was filtered, washed successively with water (100 ml x 2)
and diethyl ether (100 ml x 2), and dried under vacuo at 60°C for 6 hours to obtain 10.3 g
of the title compound as a brown solid.

108
1H NMR (400 MHz, DMSOd6) d 2.01 (3H, s), 7.49 (2H, s), 7.58 (2H, m),
10.1(1H, bs), 12.1 (1H, bs).
Step B: Preparation of 4-chloro-2-methyl-quinoline-6-carboxylic acid methyl ester
To 10 g (47 mmol) of the product from Example 8, step A in methanol (100 ml), cooled to
0°C, was added dropwise sulphuric acid (10 ml). The reaction mixture was stirred at
ambient temperature for 6 hours. The reaction was then cooled to 0°C and the pH of the
solution was adjusted to 7 with aqueous ammonia. The precipitate was filtered,
successively washed with water (100 ml x 2), diethyl ether (100 ml x 2) and dried under
vacuo at 60°C for 6 hours to obtain 9 g of 2-methyl-4-oxo-l,4-dihydro-quinoline-6-
carboxylic acid methyl ester as a colorless solid. This 8 g (34 mmol) was dissolved in dry
tetrahydrofuran (100 ml) containing a catalytic amount of dimethylformamide (0.5 ml)
was cooled to 0°C. To it was added phosphorus oxychloride (3.8 g, 24.6 mmol) dropwise.
The reaction mixture was allowed to attain room temperature and then heated to 60°C for
5 hours. After cooling the reaction mixture to 0°C, it was diluted with water (60 ml), and
the pH adjusted to 7 using saturated sodium bicarbonate solution. The mixture was
partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (100 ml x 2) and brine (100 ml x 2), dried over anhydrous
sodium sulphate and evaporated under vacuo. Trituration of the residue in diethyl ether
(50 ml x 2) followed by collection of the solid by vacuum filtration provided 6.1 g of the
title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 2.2 (3H, s), 3.9 (3H, s), 6.9 (1H, s), 7.49 (1H,
m), 7.61 (2H, m).
Step C: Preparation of 2-methyl-4-morpholin-4-yl-quinoline-6-carboxylic acid methyl
ester
To 5 g (17.5 mmol) of the product from example 8, Step B in acetonitrile (100 ml) was
added morpholine (3.4 g, 39 mmol) and refluxed for 8 hours. The mixture was partitioned
between water and ethyl acetate. The combined organic layers were succesively washed
with water (100 ml x 2) and brine (25 ml x 2), dried over anhydrous sodium sulphate and

109
evaporated under vacuo. The solid residue was triturated with diethyl ether (50 ml x 2)
followed by collection of the solid by vacuum filtration to afford 5.6 g of the title
compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 2.25 (3H, s), 3.3 (4H, t), 3.78 (3H, s), 3.9 (4H,
t), 7(1H, s), 7.49 (1H, m), 7.62 (2H, m).
Step D: Preparation of 2-formyl-4-morpholin-4-yl-quinoline-6-carboxylic acid methyl
ester
A solution of 5 g (17.5 mmol) of the product from example 8, Step C and selenium
dioxide (2.4 g, 21 mmol) in 1, 4-dioxane (100 ml) was stirred at 60°C for 8 hours. After
cooling the reaction mixture, it was filtered through celite and the filtrate was partitioned
between water and ethyl acetate. The combined organic layers were successively washed
with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo.. The solid residue was triturated with hexane (50 ml x 2)
followed by collection of the solid by vacuum filtration to afford 3.1 g of the title
compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.3 (4H, t), 3.81 (3H, s), 3.9 (4H, t), 7.1 (1H, s),
7.49 (1H, m), 7.65 (2H, m), 9.89 (1H, s).
Step E: Preparation of 4-Morpholin-4-yl-2-{3-oxo-3-[4-(pyrrolidine-l-carbonyl)-phenyl]-
propenyl}-quinoline-6-carboxylic acid methyl ester
To 4-Acetyl-benzoic acid (1 g, 6.1 mmol) in carbon tetrachloride : methanol (1:1 v/v,
40ml), cooled to 0°C, was added dropwise a solution of hydrogen bromide (65 mg, 0.8
mmol, in acetic acid, 45% w/v). The reaction mixture was stirred for 30 minutes and to it
was added dropwise bromine (0.278 g, 1.7 mmol). The mixture was stirred for further 2
hours at ambient temperature. The pH of reaction mixture was adjusted to 7 using an
aqueous solution of sodium hydroxide (2N) and partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (20 ml x 2)
and brine (10 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo
to provide 4-(2-bromo-acetyl)-benzoic acid (0.2 g) as a brown solid. A solution of 4-(2-
bromo-acetyl)-benzoic acid (0.2 g, 0.8 mmol) and triphenyl phosphine (0.215, 0.8 mmol)

110
in toluene (20 ml) was refluxed for 8 hours. After cooling the reaction mixture, it was
partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous
sodium sulphate and evaporated under vacuum. Trituration of the solid residue in hexane
(20 ml x 3) followed by collection of the solid by vacuum filtration gave the ylide (0.3 g)
as colourless solid. This ylide (0.3 g, 0.7 mmol) and 0.2 g (0.6 mmol) of the product from
example 8, Step D in pyridine (30ml) was refluxed for 4 hours. After cooling the reaction
mixture, it was partitioned between water and ethyl acetate. The combined organic layers
were successively washed with water (50 ml x 2) and brine (50 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo. Trituration of the solid residue in
hexane (20 ml x 3) followed by collection of the solid by vacuum filtration provided 0.18
g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 2.56 (4H, bs), 3.3 (4H, bs), 3.9 (8H, bs), 3.94
(3H, s), 7.62 (1H, S), 7.68 - 7.7 (1H, d), 7.7 - 7.8 (1H, m), 8 - 8.02 (1H, m), 8.08 - 8.1 (2H,
d), 8.18 - 8.2 (2H, t), 8.26 - 8.32 (1H, m), 8.63 (1H, s);
MS, m/z 500
Example 9
l-[4-(PyrazoIe-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-[l,2]bipyridinyl-5'-yl-
but-2-en-l-one (Compound No. 161)
Step A: Preparation of l-(3, 4, 5, 6-Tetrahydro-2H-[l,2']bipyridinyl-5'-yl)-ethanone
To a suspension of anhydrous magnesium dichloride (2 g, 21 mmol) in toluene (20ml)
containing triethylamine (0.4 g, 42 mmol) and pre-cooled to 0°C, was added diethyl
malonate (4 g, 25 mmol) and stirred at ambient temperature for 1 hour. To it, 6-chloro-3-
nicotinyl chloride (4.4 g, 27 mmol) was then added and stirred for 3 hours. The mixture
was partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (100 ml x 2) and brine (25 ml x 2), dried over anhydrous
sodium sulphate and evaporated under vacuum to afford 4.2 g of the title compound as a
colourless oil.

111
This ester (4 g, 17 mmol) in dimethyl sulphoxide (50 ml) was heated to 160°C for 6 hours.
The mixture was partitioned between water and ethyl acetate. The combined organic
layers were successively washed with water (100 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo to provide l-(6-Chloro-pyridin-3-
yl)-ethanone (2.3 g) as a colourless oil.
A solution of l-(6-Chloro-pyridin-3-yl)-ethanone (2 g, 12.8 mmol) and piperidine (1.47g,
17.3 mmol) in acetonitrile (30ml) was refluxed for 8 hours. The mixture was partitioned
between water and ethyl acetate. The combined organic layers were successively washed
with water (100 ml x 2) and brine (25 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuum to provide 2.1 g of the title compound as a brown oil.
1H NMR (400 MHz, DMSOd6) d 1.7 (6H, s), 2.54 (3H, s), 3.6 (4H, s), 6.72 - 6.79
(1H, d), 7.5 - 7.53 (1H, d), 7.7 (1H, s).
Step B: Preparation of {4-(3-3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-5'-yl-but-2-enoyl)-
benzoic acid
To a solution of 4-acetyl benzoic acid (1 g, 6.1 mmol) in dichloromethane (30 ml) cooled
to 0°C, was added trimethylsilyl trifluromethane sulphonate and stirred for 4 hours. The
volatiles were evaporated under vacuo to provide the 4 -(1-tert-butylsilanyloxy-vinyl)-
benzoic acid (0.7 g) as colourless solid.
To the solution of 4-(l-tert-Butylsilanyloxy-vinyl)-benzoic acid (0.7 g, 2.8 mmol) in
dichloromethane containing triethylamine (0.57 g, 5.6 mmol) at 0°C was added dropwise
l-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-5'-yl)-ethanone (0.573 g, 2.8 mmol) followed
by trifluoroacetic anhydride ( 1.185 g, 5.6 mmol) and titanium tetrachloride (1.071 g, 5.6
mmol). The reaction mixture was allowed to attain room temperature and stirred for 6
hours. The mixture was partitioned between water and ethyl acetate. The combined
organic layers were successively washed with water (20 ml x 2) and brine (10 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo to provide 0.5 g of the
title compound as a yellow solid.

112
1H NMR (400 MHz, DMSOd6) d 1.5 (3H, s) 1.69 - 1.83 (6H, d), 3.3 (4H, bs),
6.96-6.98 (1H, d), 7.15-7.18 (1H, d), 7.56-7.61 (1H, d), 7.65-7.69 (1H, t), 7.71-7.75 (2H,
d), 7.82-7.84 (2H, dd), 8.1 (1H, d), 11.84 (1H, bs)
Step C: Preparation of l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-
[ 1,2]bipyridinyl-5 '-yl-but-2-en-l -one
To the solution of 4-(3-3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-5'-yl-but-2-enoyl)-benzoic
acid (0.5 g, 1.4 mmol) in dry tetrahydrofuran (25 ml), cooled to 0°C was added N-
ethyldiisopropyl amine (0.183 g, 1.4 mmol), 1-hydroxy benzotriazole (0.193 g, 1.42
mmol) and stirred for 30 minutes. The pyrazole (97 mg, 1.43mmol), and l-ethyl-3- (3-
dimethylaminopropyl) carbodiimide (EDCI, 0.407 g, 2.1 mmol) was then added. The
reaction mixture was left to warm to room temperature and stirred for 12 hours. The
mixture was partitioned between water and ethyl acetate. The combined organic layers
were washed with water (20 ml x 2) and brine (10 ml x 2), dried over anhydrous sodium
sulphate and evaporated under vacuo. The residue was purified by column
chromatography on silica gel using 70 % ethyl acetate in hexane as the eluent. Trituration
of the residue in hexane followed by collection of the solid by vacuum filtration provided
the titled compound (0.09 g) as brown solid.
1H NMR (400 MHz, DMSOd6) d 1.69 (3H, s), 1.7 (6H, s), 3.6(4H, s), 6.58 - 6.59
(1H, s), 6.72 - 6.79 (1H, d), 7.5 - 7.53 (1H, s), 7.7 (1H, s), 8.11 - 8.27 (6H, m), 8.49 (1H,
s).
MS, m/z: 400.
Example 10
l-{4-[3-(4-piperidin-l-yl-6-trifluoromethyl-quinoIin-2yI)-acryloyI]-phenyl}-3-(3,4,5-
trimethoxy-phenyl)-urea (Compound No. 53)
Step A: Preparation of 2-methyl-6-trifluoromethyl-3H-quinolin-4-one
To the solution of 4-trifluoromethyl aniline (5 g, 32 mmol) in toluene (100 ml) containing
acetic acid (1 ml) was added ethyl acetoacetate (11.3 g, 87 mmol) and refluxed for 20
hours using Dean Stark apparatus to remove water. The reaction mixture was cooled to

113
room temperature, washed with saturated sodium bicarbonate solution (50 ml x2) and
partitioned between water and ethyl acetate. The combined organic layers were dried over
anhydrous sodium sulphate and evaporated under vacuo. The crude ester oil was refluxed
in a solvent diphenyl ether or Dowtherm® for a period of 12 hours using an air condensor.
The precipitate was filtered, washed successively with water (50 ml x 2) and diethyl ether
(100 ml x 2), and dried under vacuo at 60°C for 6 hours to afford 1.65 g of the title
compound as a brown solid.
1HNMR (400 MHz, DMSOd6) d 2.37 (3H, s), 6.04 (lH,s), 7.67 - 7.69 (1H, d),
7.9 - 7.93 (1H, dd), 8.3 (1H, s), 11.94 (1H, bs).
Step B: Preparation of 4-chloro-2-methyl-6-trifluorornethyl-quinoline
To 1.65 g (7.2 mmol) of the product from example 10, Step A in dry tetrahydrofuran (100
ml) containing a catalytic amount of dimethylformamide (0.5 ml) and pre-cooled to 0°C,
was added dropwise 0.8 g (8.7 mmol) of phosphoryl chloride. The reaction mixture was
allowed to attain room temperature and stirred for 4 hours. It was diluted with water (20
ml) and the pH adjusted to 7 using saturated sodium bicarbonate solution. The reaction
mixture was partitioned between water and ethyl acetate. The combined organic layers
were successively washed with water (50 ml x 2) and brine (50 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo to give 1.3 g of the title
compound as red oil.
Step C: Preparation of 2-Methyl-4-piperidine-l-yl-6-trifluoromethyl-quinoline
1 g (4 mmol) of the product from example 10, Step B was refluxed in piperidine (20 ml)
for 28 hours. The reaction mixture was diluted with water (20 ml) and the pH adjusted to 7
using dilute hydrochloric acid. The mixture was partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (50 ml x 2)
and brine (50 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The residue was purified by column chromatography on silica gel using 60% ethyl acetate
in hexane as the eluent to afford 1 g of the title compound as brown oil.
1H NMR (400 MHz, DMSOd6) d 1.68-1.69 (2H, m), 1.8-1.89 (4H, m), 2.3
(3H,s), 3.37-3.48 (4H, m), 6.8 (1H, s), 7.67-7.69 (1H, d), 7.9-7.93 (1H, dd), 8.3 (1H, d).

114
Step D: Preparation of 4-piperidin-l-yl-6-trifIuoromethyl-quinoline-2-carboxaldehyde
To 1 g (3.4 mmol) of the oil obtained from example 10, Step C in 1, 4-dioxane (20 ml)
was added selenium dioxide (0.6 g, 5.6 mmol) and heated to 60°C for 4 hours. After
cooling to room temperature, the mixture was filtered through celite. The filtrate was
partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous
sodium sulphate and evaporated under vacuo to afford 1 g of the title compound as a
brown solid.
1H NMR (400 MHz, DMSOd6) d 1.68-1.69 (2H, m), 1.8-1.89 (4H, m), 3.37-3.48
(4H, m), 6.8 (1H, s), 7.67-7.69 (1H, d), 7.9-7.93 (1H, dd), 8.3 (1H, d), 10.06 (1H, s).
Step E: Preparation of l-(4-Acetyl-phenyl)-3-(3, 4, 5-trimethoxy-phenyl)-urea
3, 4, 5-trimethoxyaniline (0.6 g, 3.2 mmol) and 4-acetyl phenyl isocyanate (0.51 g, 3.2
mmol) in toluene (30 ml) was refluxed for 12 hours. The precipitate was filtered, washed
with water (10 ml x 2) and dried under vacuo to afford 0.8 g of the title compound as a
colourless solid.
1H NMR (400 MHz, DMSOd6) d 2.53 (3H, s), 4.01 (9H, s), 7.42-7.45 (2H, d),
7.59-7.64 (2H, t), 7.84-7.86 (2H, dd), 8.74(1H, bs), 11.04 (1H, bs).
Step F: Preparation of l-{4-[3-(4-piperidin-l-yl-6-trifluoromethyl-quinolin-2yl)-acryloyl]-
phenyl}-3-(3, 4, 5-trimethoxy-phenyl)-urea
To 0.1 g (0.3 mmol) of the product from example 10, Step D and 0.11 g (0.3 mmol) of the
product from example 10, Step E in methanol (20 ml), pre-cooled to 0°C, was added
dropwise an aqueous solution of sodium hydroxide (0.05 g, 1.2 mmol). The reaction
mixture was stirred at room temperature for 24 hours. After completion of reaction, the
mixture was cooled to 0°C, diluted with water (20 ml) and the the pH adjusted to 7 using
aqueous hydrochloric acid. The volatiles was evaporated under vacuo.The mixture was
partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous

115
sodium sulphate and evaporated under vacuo. The residue was purified by column
chromatography on silica gel using 75 % ethyl acetate in hexane as the eluent to provide
0.04 g of the title compound.
1H NMR (400 MHz, DMSOd6) d 1.69 (2H, m), 1.83 (4H, m), 3.28 - 3.3 (4H, m),
3.61 - 3.62 (3H, d), 3.75 - 3.77 (6H, d), 6.81 - 6.83 (2H, d), 7.67 - 7.69 (3H, t), 7.76 - 7.8
(1H, d), 7.97 - 7.99 (1H, dd), 8.15 - 8.2 (4H, m), 8.32 - 8.36 (1H, d), 8.84 (1H, s), 9.21
(1H, s);
MS, m/z 633.
Example 11
l-{4-[3-(6-MorphoIin-4-yl-pyridin-2-yl)-acryIoyl]-phenyI}-3-[2-(pyridin-2-yl-
sulfanyl)-ethyl]-urea (Compound No. 132)
Step A: Preparation of 6-morpholin-4-yl-pyridine-2-carboxaldehyde
A solution of 6-bromo-pyridine-2-carboxaldehyde (1.9 g, 10 mmol), morpholine (1.75 g,
20 mmol) and potassium carbonate (3 g, 22 mmol) in acetonitrile (20 ml) was refluxed for
20 hours. The reaction mixture was cooled to room temperature, diluted with water (50
ml) and the pH adjusted to 7. The mixture was partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (25 ml x 2)
and brine (25 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The gummy residue was purified by column chromatography over silica gel using 40 %
ethyl acetate in hexane as the eluent to afford 1.5 g of the title compound as a brown
liquid.
1HNMR (400 MHz, DMSOd6) d 3.55-3.58 (4H, t), 3.91-3.94 (4H, t), 7.15-7.18
(1H, d), 7.56-7.61 (1H, d), 7.65-7.69 (1H, t), 9.98 (1H, s).
Step B: Preparation of 4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-benzoic acid
To a solution of 4-acetyl benzoic acid (1 g, 6 mmol) and the aldehyde (1.1 g, 6 mmol)
from example 11, Step A in methanol (25 ml), pre-cooled to 0°C, was added dropwise an
aqueous solution of sodium hydroxide [0.5 g, 16 mmol in water (2 ml)]. The reaction
mixture was stirred at room temperature for 16 hours. The mixture was then cooled to 0°C,

116
diluted with water (20 ml) and the pH adjusted to 7 using aqueous hydrochloric acid. The
precipitate was isolated by filtration with a Buchner funnel and successively washed with
water (20 ml x 2) and brine (10 ml x 2), and dried under vacuo at 60°C to afford 1.35 g of
the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.55-3.58 (4H, t), 3.91-3.94 (4H, t), 6.96-6.98
(1H, d), 7.15-7.18 (1H, d), 7.56-7.61 (1H, d), 7.65-7.69 (1H, t), 7.71-7.75 (2H, d), 7.82-
7.84 (2H, dd), 8.1 (lH,d), 11.84 (1H, bs).
Step C: Preparation of 4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-benzoyl azide
The product from example 11, Step B (1.35 g, 4 mmol) was dissolved in dry
dimethylformamide (20 ml) containing N-ethyl diisopropylamine (1 g, 8 mmol), cooled to
0°C followed by dropwise addition of ethyl chloroformate (0.65 g, 6 mmol). The reaction
mixture was stirred for 1 hour. To it, an aqueous solution of sodium azide [0.8 g, 12 mmol,
in water (2 ml)] was then added and stirred for another 1 hour. The mixture was diluted
with water (50 ml) and the resulting precipitate was filtered, successively washed with
water (25 ml x 2) and hexane (25 ml x 2), and dried under vacuo to afford 0.8 g of the title
compound as a yellow solid.
Step D: Preparation of 2-(pyridin-2-ylsulfanyl)-ethylamine
A solution of pyridin-2-thiol (0.2 g, 1.8 mmol), 2-bromo-ethylamine (0.55 g, 2.7 mmol)
and potassium carbonate (1 g, 7.2 mmol) in acetonitrile (30 ml) was refluxed for 20 hours.
The mixture was partitioned between water and ethyl acetate. The combined organic
layers were washed successively with water (25 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo to provide 0.16 g of the title
compound as a gummy residue, which was used without further purification in the next
step.
1H NMR (400 MHz, DMSOd6) d 2.76 (2H, t), 3.13 (2H, t), 3.3(2H, bs), 7.07 - 7.11
(1H, m), 7.2 - 7.3 (1H, m), 7.6 - 7.64 (1H, m), 8.4 - 8.42 (1H, m).

117
Step E: Preparation of l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-
(pyridin-2-yl-sulfanyl)-ethyl]-urea
A solution of the product from example 11, Step C (0.2 g, 0.55 mmol) and the product
from example 9, Step D (0.16 g, 1 mmol) in toluene (20 ml) was refluxed for 16 hours.
The reaction mixture was partitioned between water and ethyl acetate. The combined
organic layers were successively washed with water (25 ml x 2) and brine (25 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo. The solid residue was
purified by column chromatography over silica gel using 3 % methanol in
dichloromethane as the eluent to afford 0.16 g of the title compound as a yellow solid.
lH NMR (400 MHz, DMSOd6) d 3.25 - 3.29 (2H, m), 3.39 - 3.41 (2H, t), 3.54 -
3.56 (4H, t), 3.72 - 3.74 (4H, t), 6.61 - 6.67 (1H, m), 6.92 - 6.95 (1H, d), 7.11 - 7.14 (2H,
t), 7.35 - 7.37 (1H, d), 7.51 - 7.55 (1H, d), 7.58 - 7.6 (2h, d), 7.62 - 7.68 (3H, m), 7.99 -
8.03 (2H, m), 8.43 - 8.44 (1H, d), 9.12 (1H, s);
MS, m/z 488
Example 12
l-{4-[3-(6-Morpho!in-4-yl-pyridin-2-yI)-acryIoyl]-phenyl}-3-[2-pyridin-2-yIsuIfonyl)-
ethyl]-urea (Compound No. 131)
To a solution of l-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-pyridin-
2-ylsulfanyl)-ethyl]-urea (0.13 g, 0.26 mmol) in methanol (2 ml), pre-cooled to 0°C was
added dropwise a solution of oxone [0.08 g, 0.13 mmol in water (2 ml)]. The reaction
mixture was stirred at 0°C for 30 minutes. The mixture was diluted with water (20 ml) and
the volatiles were evaporated under vacuo. The precipitate was filtered, successively
washed with water (10 ml x 2) and hexane (10 ml x 2), and dried under vacuo at 60 °C for
4 hours to afford 0.1 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.25 - 3.29 (2H, t), 3.36 (2H, t), 3.55 - 3.56 (4H,
t), 3.72 - 3.75 (4H, t), 6.92 - 6.95 (1H, d), 7.11-7.14 (1H, d), 7.35 - 7.37 (1H, d), 7.51 -
7.59 (3H, m), 7.62 - 7.67 (2H, m), 7.99 - 8.03 (3H, m), 8.08 - 8.14 (1H, m), 8.43 - 8.45
(1H, d), 8.67 - 8.68 (1H, d), 9.08 - 9.13 (1H, d);
MS, m/z 528

118
Example 13
l-[2-(4-Methyl-piperazin-l-yl)-ethyl]-3-{4-[3-(6-morpholin-4-yI-pyridin-2-yl)-
acryloyl}-phenyl}-urea (Compound No. 133)
Step A: Preparation of 2-(4-methyl-piperazin-l-yl)-ethylamine
A solution of N-methyl piperazine (0.2 g, 2 mmol), 2-bromo-ethylamine (0.6 g, 3 mmol)
and potassium carbonate (1.1 g, 8 mmol) in acetonitrile (30 ml) was refluxed for 20 hours.
The mixture was partitioned between water and ethyl acetate. The combined organic
layers were successively washed with water (25 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo to afford 0.1 g of the title
compound as a gummy residue, which was used without purification in the next step.
1H NMR (400 MHz, DMSOd6) d 2.2 (3H, s), 2.28 (2H, bs), 2.4 (2H, bs), 2.7 (2H,
t), 3.12 (2H, t), 3.3 (2H, bs), 3.32 (2H, bs), 3.6 (2H, bs).
Step B: Preparation of l-[2-(4-Methyl-piperazin-l-yl)-ethyl]-3-{4-[3-(6-morpholin-4-yl-
pyridin-2-yl)-acryloyl}-phenyl}-urea
A solution of 0.2 g (0.55 mmol) of the product from example 11, Step C and 0.1 g (0.7
mmol) the product from example 13, Step A in toluene (20 ml) was refluxed for 16 hours.
The reaction mixture was partitioned between water and ethyl acetate. The combined
organic layers were successively washed with water (25 ml x 2) and brine (25 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo. The solid residue was
purified by column chromatography over silica gel using 10 % methanol in
dichloromethane as the eluent to afford 0.02 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 2.15 (3H, s), 2.29 - 2.33 (3H, bs), 2.37 - 2.39
(5H, t), 3.50 - 3.55 (8H, bs), 3.74 (4H, bs), 6.92 - 6.94 (1H, d), 7.11 - 7.17 (1H, d), 7.51 -
7.52 (1H, d), 7.55 - 7.62 (3H, m), 7.99 - 8.03 (3H, m), 8.11 - 8.14 (1H, m), 8.34 (1H, s);
MS, m/z 479
Example 14

119
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-2-piperidin-l-yl-
ethyl)-urea (Compound No. 126)
Step A: Preparation of (2-oxo-2-piperidin-l-yl-ethyl)-carbamic acid tert-butyl ester
To a solution of tert-butoxycarbonylamino-acetic acid (0.7 g, 4 mmol) in dry
tetrahydrofuran (25 ml), pre-cooled to 0°C, was added N-ethyldiisopropyl amine (1 g, 8
mmol) and 1-Hydroxy benzotriazole (0.65 g, 4.8 mmol). The mixture was stirred for 30
minutes, followed by addition of piperidine (0.5 g, 6 mmol) and l-ethyl-3-(3-
dimethylaminopropyl) carbodiimide (EDCI, 1.6 g, 8.4 mmol). The reaction mixture was
allowed to attain room temperature and stirred for 12 hours. The mixture was partitioned
between water and ethyl acetate. The combined organic layers were successively washed
with water (20 ml x 2) and brine (10 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The residue was triturated with hexane followed by collection of
the solid by vacuum filtration to afford 0.5 g of the title compound as a colourless solid.
Step B: Preparation of trifluoroacetate salt of (2-oxo-2-piperidin-l-yl-ethyl)-carbamic acid
tert-butyl ester
The product from example 14, Step A (0.5 g, 2 mmol) was dissolved in dry
dichloromethane (10 ml), cooled to 0°C and to it was added dropwise a solution of
trifluoroacetic acid [1 g, 8 mmol, in dichloromethane (2 ml)]. The reaction mixture was
stirred for 3 hours at room temperature. The volatiles were then evaporated under vacuo
to obtain the title compound, which was used as such in the next step.
1H NMR (400 MHz, DMSOd6) d 1.57 - 1.59 (6H, m), 3.12 - 3.21(2H, s), 3.59 -
3.61 (4H,t), 3.61 - 3.67 (2H, bs).
Step C: Preparation of l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-
oxo-2-piperidin-l-yl-ethyl)-urea
A solution of 0.2 g (0.55 mmol) of the product from example 11, Step C and 0.22 g of the
product from example 14, Step B in toluene (20 ml) was refluxed for 16 hours. The
reaction mixture was partitioned between water and ethyl acetate. The combined organic

120
layers were successively washed with water (25 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo. The solid residue was purified by
column chromatography over silica gel using 1.5 % methanol in dichloromethane as the
eluent to afford 0.04 g of the title compound as a yellow solid.
1HNMR (400 MHz, DMSOd6) d 2.68 - 2.72 (1H, d), 2.93 (1H, bs), 3.3 - 3.33 (1H,
m), 3.38 (1H, bs), 3.41 - 3.43 (1H, m), 3.53 (4H, bs), 3.69 - 3.74 (6H, bs), 3.74 - 3.76 (2H,
m), 3.78 - 3.97 (4H, m), 6.91 - 6.93 (1H, d), 7.1 - 7.12 (1H, dd), 7.49 (1H, t), 7.53 - 7.57
(1H, t), 7.62 - 7.67 (2H, m), 7.99 - 8.01 (1H, d), 8.03 - 8.08 (2H, t), 9.38 (1H, s);
MS, m/z 478
Example 15
N-(2- {3- [4-(3-Quinoxalin-2-yI-acryloyI)-phenyl]-ureido}-ethyI)- benzene sulfonamide
(Compound No. 136)
Step A: Preparation of N-(2-amino-ethyl)-benzenesulfonamide
To a solution of ethylene diamine (0.1 g, 1.2 mmol) in dry dichloromethane (20 ml)
containing triethylamine, pre-cooled to 0°C, was added benzenesulphonyl chloride (0.15
g, 0.84 mmol) dropwise. The reaction mixture was stirred at 0°C for 1 hour and at room
temperature for another two hours. The mixture was partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (25 ml x 2)
and brine (25 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo
to afford 0.13 g of the title compound as yellow oil.
1H NMR (400 MHz, DMSOd6) d 2.4 - 2.52 (2H, t), 2.7 - 2.74 (2H, t), 7.56 - 7.66
(5H, m), 7.72 - 7.74 (1H, dd), 7.78 -7.8(2H, dd).
Step B: Preparation of quinoxalin-2-carboxaldehyde
To 2-methyl-quinoxaline (1 g, 7 mmol) in 1, 4-dioxane (30 ml) was added selenium
dioxide (2.3 g, 21 mmol) and the mixture heated to 60°C for 2 hours. After cooling the
reaction mixture, it was filtered over celite and partitioned between water and ethylacetate.
The combined organic phases were successively washed with water (50 ml x 2) and brine
(50 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo, to afford

121
0.6 g of the crude title compound as a brown solid, which was used without purification in
the next step.
1H NMR (400 MHz, DMSOd6) d 7.98 - 8.09 (3H, m), 8.21-8.24 (1H, m), 8.28 -
8.31 (1H, m), 10.19 (lH,s).
Step C: Preparation of 4-(3-quinoxalin-2-yl-acryloyl)-benzoic acid
To 0.6 g (3.8 mmol) of the product from example 15, step B and 4-acetyl benzoic acid
(0.55 g, 3.4 mmol) in methanol (40 ml), pre-cooled to 0°C, was added dropwise a solution
of sodium hydroxide [(0.27 g, 6.8 mmol) in water (2 ml)]. The mixture was stirred at room
temperature for 16 hours. After completion of reaction, the mixture was cooled to 0°C,
diluted with water (20 ml) and the pH adjusted to 7 using aqueous hydrochloric acid. The
precipitate was isolated by filtration with a Buchner funnel and successively washed with
water (20 ml x 2) and brine (10 ml x 2), dried under vacuo at 60 ° C to afford 0.5 g of the
title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 6.6 (2H, d), 7.5 (1H, d), 7.56 (1H, m), 7.69 (2H,
m), 7.8-7.82 (2H, m), 7.83-7.84 (2H, q), 7.91-7.92 (1H, d) 12.14 (lH,s).
StepD: Preparation of 4-(3-quinoxalin-2-yl-acryloyl)-benzoyl azide
The product from example 15, step C (0.5 g, 1.6 mmol) was dissolved in dry
dimethylformamide (20 ml) containing N-ethyl diisopropylamine (0.4 g, 3.2 mmol),
cooled to 0°C, and to it, ethyl chloroformate (0.26 g, 2.4 mmol) was added dropwise. The
reaction mixture was stirred for 1 hour. An aqueous solution of sodium azide [0.31 g, 4.8
mmol, in water (1 ml)] was then added to the reaction mixture and stirred for another 1
hour. The mixture was diluted with water (20 ml) and the resulting precipitate was filtered,
successively washed with water (25 ml x 2) and hexane (25 ml x 2), and dried under vacuo
to afford 0.4 g of the title compound as a yellow solid.
Step E: Preparation of N-(2-{3-[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-ureido}-ethyl)-
benzene sulfonamide

122
A solution of the product from example 15, step D (0.2 g, 0.6 mmol) and N-(2-amino-
ethyl)-benzenesulfonamide (0.13 g, 0.65 mmol) in toluene was refluxed for 16 hours. The
reaction mixture was partitioned between water and ethyl acetate. The combined organic
layers were successively washed with water (25 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo. The solid residue was purified by
column chromatography over silica gel using 3 % methanol in dichloromethane as the
eluent to afford 0.15 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSO d6) d 2.81 - 2.86 (2H, m), 3.15 - 3.2 (2H, m), 7.58 -
7.64 (4H, m), 7.65 - 7.84 (4H, m), 7.87 - 7.93 (3H, m), 8.13 -8.18 (4H,!m), 8.28 - 8.31(1H,
d), 8.46 - 8.5 (1H, d), 9.18 (1H, s), 9.58 - 9.59 (1H, d);
MS, m/z 502
Example 16
l-Benzenesulfonyl-hydrazino-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyI]-urea
(Compound No. 139)
A solution of the 4-(3-quinoxalin-2-yl-acryloyl)-benzoyl azide (0.2 g, 0.6 mmol) and
benzene sulphonyl hydrazide (155 mg, 0.9 mmol) in toluene was refluxed for 16 hours.
The reaction mixture was partitioned between water and ethyl acetate. The combined
organic layers were successively washed with water (25 ml x 2) and brine (25 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo to provide 0.17 g of the
title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 7.57 - 7.61(2H, t), 7.63 -7.66 (3H, t), 7.83 - 7.89
(3H, m), 7.9 - 7.97 (2H, m), 8.05 - 8.8 (1H, d), 8.11 - 8.14 (2H, d),8.15 - 8.19 (2H, m),
8.45 -8.49 (1H, d), 8.97- 9.01(lH, d), 9.58 - 9.60 (1H, d), 9.79(1H, bs);
MS, m/z 473
Example 17
l-(Morpholine-4-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 142)
Step A: Preparation of l-(4-amino-phenyl)-3-quinolin-2-yl-propenone

123
To a solution of quinoline-2-carboxaldehyde (1 g, 6.3 mol) and 4-amino acetophenone
(0.85 g, 6.3 mol) in methanol (60 ml) was added dropwise an aqueous solution of sodium
hydroxide [0.5 g, 12.7 mol, in water (2 ml)]. The reaction mixture was stirred at room
temperature for 18 hours. The mixture was then cooled to 0°C, diluted with water (20 ml)
and the pH adjusted to 7 using aqueous hydrochloric acid. The precipitate was isolated by
filtration with a Buchner funnel and successively washed with water (20 ml x 2) and brine
(10 ml x 2), and dried under vacuo at 60°C to afford 0.8 g of the title compound as a
yellow solid.
1H NMR (400 MHz, DMSOd6) d 6.03 (1H, bs), 6.27(1H, s), 6,56 - 6.66 (2H, dd),
7.64 (2H, bs), 7.72 - 7.8 (2H, t), 7.95 - 8.05 (3H, m), 8.12 - 8.17 (1H, d), 8.18 - 8.29 (1H,
d), 8.43-8.45 (lH,d).
Step B: Preparation of 1 l-(Morpholine-4-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl)-
phenyl]-urea
To a suspension of 0.25 g (0.67 mmol) of the product from example 17, step A in dry
toluene (20 ml) was added chlorosulphonyl isocyanate (0.14 g, 1 mmol) and refluxed for 2
hours. Morpholine (0.5 g, 5.7 mmol) was then added to the reaction mixture and refluxed
for another 4 hours. The reaction mixture was partitioned between water and ethyl acetate.
The combined organic layers were successively washed with water (25 ml x 2) and brine
(25 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. The solid
residue was purified by column chromatography over silica gel using 60% ethyl acetate in
hexane as the eluent to afford 0.05 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.71 - 3.88 (8H, m), 7.4 - 7.5 (1H, m), 7.54 - 7.6
(3H, m), 7.66 - 7.7 (1H, m), 7.77 - 7.83 (2H, m), 7.83 - 7.85 (1H, d), 7.92 - 7.96 (1H, m), 8
- 8.04 (1H, m), 8.07 - 8.10 (1H, m), 8.11- 8.17 (1H, m), 8.2 - 8.22 (1H, d), 9.22(1H, s);
MS, m/z 466
Example 18

124
Hydrochloride salt of Compound No. 160, i.e., l-{2-[N-(6-Methyl-pyridin-2-yl)-
hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yI-acryloyI)-phenyl] urea
Step A: Preparation of N'-(6-methyl-pyridin-2-yl)-hydrazinecarboxylic acid tert-butyl
ester
A solution of 2-chloro-6-methyl-pyridine (1 g, 7.8 mmol), tert-butyl carbazate (1.55 g,
11.4 mmol) and potassium carbonate (4.3 g, 31 mmol) in acetonitrile (50 ml) was refluxed
for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (25 ml x 2) and brine (25
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo to provide 1.1
g of the title compound as yellow oil, which was used without purification in the next step.
1H NMR (400 MHz, DMSOd6) d 1.38 (9H, s), 2.44 (3H, s), 3.91 (1H, s), 7.26 -
7.31 (2H, m), 7.72-7.76 (1H, t), 7.85 (1H, bs).
Step B: Preparation of N'-(2-aminoethyl)-N'-(6-methyl-pyridin-2yl)-hydrazinecarboxylic
acid tert-butyl ester
A solution of bromoethylamine hydrobromide (1.5 g, 7.4 mmol), potassium carbonate (2.7
g, 19.5 mmol) and 1.1 g (4.9 mmol) of the product from example 18, step A in acetonitrile
(50 ml) was refluxed for 20 hours. The reaction mixture was partitioned between water
and ethyl acetate. The combined organic layers were successively washed with water (25
ml x 2) and brine (25 ml x 2), dried over anhydrous sodium sulphate and evaporated under
vacuo to afford 1 g of the title compound as yellow oil, which was used without
purification in the next step.
Step C: Preparation of hydrochloride salt of l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-
ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]urea
A solution of 4-(3-quinoxalin-2-yl-acryloyl)-benzoyl azide (0.2 g, 0.6 mmol) and the
product from example 18, step B (0.18 g, 0.7 mmol) in toluene (20 ml) was refluxed for 16
hours. The reaction mixture was partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (25 ml x 2) and brine (25

125
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. The solid
residue was purified by column chromatography over silica gel using 80 % ethyl acetate in
hexane as the eluent. The solid residue thus obtained was dissolved in acetonitrile -
hydrochloric acid (10 %, 2 ml) and stirred for 2 hours. The precipitate was filtered and
washed with diethyl ether (10 ml x 2), dried under vacuo at 60°C for 4 hours to afford 0.07
g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.4 - 3.44 (2H, t), 3.45 - 3.5(2H, t) 7.13 - 7.14
(1H, m), 7.35 - 7.36 (1H, d) 7.62 - 7.67 (2H, t), 7.83 - 7.95 (4H, m), 8.13 - 8.19 (5H,m),
8.27 - 8.29 (2H, d), 8.46 - 8.50 (2H, d), 9.79 ( 2H, s);
MS, m/z 504
Example 19
{4-[3-(4-Morpholin-4-yl-quinoIin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen -2-
yl-methyl ester (Compound No. 68)
Step A: Preparation of 2-methyl-4-morpholin-4-yl-quinoline
To a solution of 4-chloro-2-methyl-quinoline (6 g, 34 mmol) in dry acetonitrile (100 ml)
was added morpholine (8.7 g, 100 mmol), and the reaction was heated to 60°C for 7 hours.
The reaction mixture was then cooled, filtered through celite and the filtrate partitioned
between water and ethyl acetate. The combined organic layers were successively washed
with water (50 ml x 2) and brine (20 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The residue was purified by column chromatography on silica gel
using 40% ethyl acetate in hexane as the eluent to afford 7 g of the title compound as a
brown solid.
1H NMR (400 MHz, DMSOd6) d 2.63 (3H, s), 3.25 - 3.27 (4H, t), 3.88 - 3.9 (4H,
t), 7.39 (1H, s), 7.7-7.74 (1H, t), 7.83 - 7.87 (1H, t), 8.13 - 8.18 (2H, t).
Step B: Preparation of 4-morpholine-4-yl-quinoline-2-carboxaldehyde
To 5 g (22 mmol) of the product from example 19, step A in 1, 4-dioxane (50 ml) was
added selenium dioxide (3 g, 133 mmol) and heated to 60°C for 7 hours. The mixture was
cooled to room temperature and partitioned between water and ethyl acetate. The

126
combined organic layers were successively washed with water (20 ml x 2) and brine (10
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo to provide 3.2
g of the title compound as a brown solid, which was used without purification in the next
step.
1H NMR (400 MHz, DMSOd6) d 3.25 - 3.27 (4H, t), 3.88 - 3.9 (4H, t), 7.39 (1H,
s), 7.7 - 7.74 (1H, t), 7.83 - 7.87 (1H, t), 8.13-8.18 (2H, t), 10.06 (1H, s).
Step C: Preparation of (4-acetyl-phenyl)-carbamic acid-thiophene-2yl-methyl ester
To a solution of 4-acetyl phenyl isocyanate (0.5 g, 3 mmol) in toluene (20 ml) was added
thiophen-2-yl-methanol (0.43 g, 3 mmol), and the mixture refluxed for 7 hours. The
mixture was then cooled to room temperature; the precipitate was filtered, washed
successively with water (25 ml x 2) and hexane (25 ml x 2), and dried under vacuo at 60°C
for 4 hours to provide 0.75 g of the title compound as a colourless solid.
Step D: Preparation of {4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-
carbamic acid thiophen -2-yl-methyl ester
To 0.2 g (0.82 mmol) of the product from example 19, step B and 0.38 g (1.4 mmol) of the
product from example 17, step C in methanol (20 ml), pre-cooled to 0°C, was added
dropwise an aqueous solution of sodium hydroxide [0.5 g, 1.2 mmol, in water (1 ml)]. The
mixture was allowed to attain room temperature and stirred for 8 hours. The precipitate
was filtered, washed successively with water (10 ml x2) and diethyl ether (10 ml x2), and
dried under vacuo at 60°C for 4 hours to afford 0.4 g of the title compound as a colourless
solid.
1H NMR (400MHz, DMSOd6) d 3.27 - 3.28 (4H, t), 3.9 - 3.93 (4H, t), 5.37 (2H, s),
7.05 - 7.07 (1H, m), 7.24 - 7.26 (1H, d), 7.57 - 7.62 (3H, m), 7.69 - 7.79 (4H, m), 8.01 -
8.08 (2H, dd), 8.16 - 8.18 (2H, d), 8.25 - 8.29 (1H, d), 10.29 (1H, s);
MASS, m/z 500
Example 20

127
{4-[3-(6-[l, 2, 3] Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl
ester (Compound No. 64)
Step A: Preparation of N'-[l-(2-methyl-quinolin-6-yl)-ethyl]-hydrazine carboxylic acid
methyl ester
A solution of l-(2-methyl-quinolin-6-yl)-ethanone (2 g, 10.8 mmol), p-toluene sulphonic
acid (2 g, 10.5 mmol) and methyl carbazate (1 g, 11.8 mmol) in toluene was refluxed
using Dean Stark apparatus for 12 hours. The reaction mixture was then cooled, diluted
with water (20 ml) and the pH adjusted to 7 using an aqueous solution of sodium
bicarbonate. The mixture was partitioned between water and ethyl acetate. The combined
organic layers were successively washed with water (50 ml x 2) and brine (50 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo, to obtain 2 g of the
title compound as a solid residue, which was used without purification in the next step.
1H NMR (400MHZ, DMSOd6) d 2.3 (3H, s), 2.65 (3H, s), 3.74 (3H, s), 7.42 (1H,
d), 7.9 (1H, d), 8.22 (2H, m), 8.3 (1H, d), 10.3 (1H, s).
Step B: Preparation of 2-methyl-6-[l, 2, 3] thiadiazol-4-yl-quinoline
The product from example 20, step A was suspended in thionyl chloride (20 ml) and
heated to 60°C for 2 hours. The reaction mixture was then cooled to 10°C and partitioned
between water and ethyl acetate. The combined organic layers were successively washed
with saturated bicarbonate solution (50 ml x 2), water (50 ml x 2) and brine (50 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo. The solid residue was
triturated with hexane (50 ml x 2) to afford 1.7 g of the title compound as a brown solid.
1H NMR (400MHz, DMSOd6) d 2.69 (3H, s), 7.5 (1H, d), 8.08 (1H, d), 8.39 (1H,
d), 8.45 (1H, m), 8.77 (lH,d), 9.77 (1H, s).
Step C: Preparation of 6-[l, 2, 3] thiadiazol-4-yl-quinoline-2-carboxaldehyde
1.7 g (8 mmol) of the product from Example 20, step B and selenium dioxide (1.8 g, 16
mmol) in 1,4-dioxane (25 ml) was stirred at 60°C for 4 hours. After cooling the reaction
mixture, it was filtered through celite and the filtrate was partitioned between water and

128
ethyl acetate. The combined organic layers were successively washed with water (50 ml x
2) and brine (50 ml x 2), dried over anhydrous sodium sulphate and evaporated under
vacuo. The solid residue was triturated with hexane (50 ml x 2) followed by collection of
the solid by vacuum filtration to afford 0.5 g of the title compound as a brown solid.
1H NMR (400MHZ, DMSOd6) d 8.12 (1H, d), 8.45 (3H, m), 8.75 (lH,d), 8.9 (1H,
s), 10.28 (1H, s).
Step D: Preparation of l-(4-amino-phenyl)-3-(6-[l, 2, 3] thiadiazol-4-yl-quinolin-2-yl)-
propenone
To the solution of 0.5 g (2 mmol) of the product from example 20, step C and 4-amino
acetophenone (0.3 g, 2.2 mmol) in methanol (20 ml), pre-cooled to 0°C, was added
anaqueous solution of sodium hydroxide [0.16 g, 4 mmol in water (1 ml)]. The mixture
was stirred at room temperature for 18 hours. After completion of the reaction, the mixture
was cooled to 0°C, diluted with water (20 ml) and the pH adjusted to 7 using aqueous
hydrochloric acid. The volatiles were evaporated under vacuo. The mixture was
partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous
sodium sulphate and evaporated under vacuo. The solid residue was triturated with hexane
(50 ml x 2) followed by collection of the solid by vacuum filtration to afford 0.5 g of the
title compound as a brown solid.
1H NMR (400MHz, DMSOd6) d 6.21 (2H, bs), 6.67 (1H, d), 7.78 (1H, d), 7.98
(2H, d), 8.23 (2H, t), 8.3 (1H, d), 8.53 (1H, d), 8.54 (1H, m), 8.55 (1H, d), 8.8 (1H, d),
9.83 (1H, s).
Step E: Preparation of {4-[3-(6-[l,2,3]thiadiazol-4-yl-quinolin-2-yl)acryloyl]-
phenyljcarbamic acid ethyl ester
To the solution of 0.2 g (0.5 mmol) of the product from example 20, step D in dry
tetrahydrofuran (20 ml) containing N-ethyl diisopropyl amine (0.2 g, 1.6 mmol), pre-
cooled to 0°C, was added dropwise ethyl chloroformate (0.09 g, 0.8 mmol). The reaction
mixture was stirred at room temperature for 3 hours. The mixture was partitioned between
water and ethyl acetate. The combined organic layers were successively washed with

129
water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The solid residue was triturated with hexane (50 ml x 2) followed
by collection of the solid by vacuum filtration to afford 0.4 g of the title compound as a
solid.
1H NMR (400 MHz, DMSOd6) d 1.26 - 1.29 (3H, t), 4.16 - 4.21 (2H, m), 7.69 -
7.71 (2H, d), 7.82 - 7.86 (1H, d), 8.16 - 8.19 (2H, d), 8.23 - 8.29 (2H, m), 8.34 - 8.38 (1H,
d), 8.54 - 8.57 (1H, dd), 8.61 - 8.63 (1H, d), 8.87 (1H, s), 9.84 (1H, s), 10.15 (1H, s);
MS, m/z 431
Example 21
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryIoyl]-phenyl}-carbamic acid 2-morphoIin-
4-yI-ethyl ester (Compound No. 67)
A solution of 0.2 g (0.55 mmol) of the product from example 11, Step C and 2-Morpholin-
4-yl-ethanol (0.12 g, 0.9 mmol) in toluene (20 ml) was refluxed for 16 hours. The reaction
mixture was partitioned between water and ethyl acetate. The combined organic layers
were successively washed with water (25 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo. The solid residue was purified by
column chromatography over silica gel using 40 % ethyl acetate in hexane as the eluent to
afford 0.06 g of the title compound as a yellow solid.
lH NMR (400 MHz, DMSOd6) d 2.55 - 2.57 (4H, t), 2.7 - 2.73 (2H, t), 3.62 - 3.64
(4H, t), 3.75 - 3.77 (4H, t), 3.88 - 3.9 (4H, t), 4.33 - 4.37 (2H, t), 6.7 - 6.73 (1H, d), 6.86 -
6.88 (1H, d), 6.97 (1H, s), 7.53 - 7.58 (3H, m), 7.63 - 7.67 (1H, d), 7.98 - 8.02 (1H, d),
8.06 - 8.08 (2H, d);
MS, m/z 467
Example 22
Hydrochloride salt of Compound No. 143, i.e., {4-[3-(6-Morpholin-4-yl-pyridin-2-yI)-
acryloyl]-phenyl}-carbamic acid piperidin-4-yl ester
Step A: Preparation of {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyI]-phenyl}-carbarnic
acid piperidin-4-yl ester

130
A solution of 0.25 g (0.68 mmol) of the product from example 11, Step C and 4-hydroxy-
piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.66 mmol) in dry toluene (20 ml)
was refluxed for 16 hours. The reaction mixture was partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (25 ml x 2)
and brine (25 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The solid residue was purified by column chromatography over silica gel using ethyl
acetate as the eluent to provide 0.13 g of the title compound as a yellow solid.
Step B: Preparation of hydrochloride salt of {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-
acryloyl]-phenyl}-carbamic acid piperidin-4-yl ester
The solid from Example 22, step A was added to a cooled solution (0°C) of acetonitrile -
hydrochloric acid (10 %, 2 ml) and was stirred for 2 hours. The precipitate was filtered,
washed with diethyl ether (50 ml x 2) and dried under vacuo at 60°C for 4 hours to afford
0.08 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 1.6 - 1.62 (2H, m), 1.9 - 1.93 (2H, m), 2.84 - 2.91
(4H, m), 3.1 - 3.19 (4H, m), 3.59 - 3.62 (1H, t), 3.7 - 3.75 (4H, m), 4.4 (1H, bs), 7.04 -
7.52 (2H, m), 7.63 - 7. 73 (1H, m), 8.05 - 8.09 (1H, t), 8.96 - 9.09 (4H, d), 9.3 - 9.45 (1H,
d), 10.3(1 H,s);
MS, m/z 472
Example 23
{4-[3-(6-MorphoIin-4-yl-pyridin-2-yl)-acryloyl]-phenyI}-carbamic acid 2-(pyridine-2-
sulfonyl)-ethyl ester (Compound No. 156)
Step A: Preparation of 2-(pyridin-2-ylsulfanyl)-ethanol
A solution of pyridin-2-thiol (0.5 g, 4.5 mmol), 2-bromo-ethanol (0.84 g, 6.7 mmol) and
potassium carbonate (2.5 g, 18 mmol) in acetonitrile (50 ml) was refluxed for 20 hours.
The mixture was partitioned between water and ethyl acetate. The combined organic
layers were successively washed with water (25 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo to afford 0.15 g of the title
compound as yellow oil, which was used without further purification in the next step.

131
1H NMR (400 MHz, DMSOd6) d 2.76 (2H, t), 3.13 (2H, t), 7.07-7.11 (1H, m),
7.2-7.3 (1H, m), 7.6-7.64 (1H, m), 8.4 - 8.42 (1H, m), 6.2 (1H, bs).
Step B: Preparation of {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic
acid 2-(pyridine-2-sulfanyl)-ethyl ester
A solution of 0.2 g (0.55 mmol) of the product from example 11, Step C and 0.1 g (0.66
mmol) of the product from Example 23, step A in toluene (20 ml) was refluxed for 16
hours. The reaction mixture was partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (25 ml x 2) and brine (25
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. The solid
residue was purified by column chromatography over silica gel using 60 % ethyl acetate in
hexane as the eluent to afford 0.1 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3-3.11 (2H, t), 3.28 (2H, t), 3.55 - 3.56 (4H, t),
3.72 - 3.75 (4H, t), 6.92 - 6.95 (1H, d), 7.11 - 7.14 (1H, d), 7.35 - 7.37 (1H, d), 7.51 - 7.59
(3H, m), 7.62 - 7.67 (2H, m), 7.99 - 8.03 (3H, m), 8.08 - 8.14 (1H, m), 8.43 - 8.45 (1H, d),
9.08- 9.13 (lH,d).
Step C: Preparation of {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic
acid 2-(pyridine-2-sulfonyl)-ethyl ester
To 0.07 g (0.14 mmol) of the product from example 23, step C in methanol (2 ml), pre-
cooled to 0°C, was added dropwise a solution of oxone [0.04 g, 0.07 mmol in water (1
ml)]. The reaction mixture was stirred at 0°C for 30 minutes. The mixture was diluted with
water (10 ml) and the volatile were evaporated under vacuo. The precipitate was filtered,
washed successively with water (10 ml x 2) and hexane (10 ml x 2), and dried under vacuo
at 60 °C for 4 hours to afford 0.05 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.25 - 3.29 (2H, t), 3.36 (2H, t), 3.55 - 3.56 (4H,
t), 3.72 - 3.75 (4H, t), 6.92 - 6.95 (1H, d), 7.11 - 7.14 (1H, d), 7.35 - 7.37 (1H, d), 7.51 -
7.59 (3H, m), 7.62 - 7.67 (2H, m), 7.99 - 8.03 (3H, m), 8.08 - 8.14 (1H, m), 8.43 - 8.45
(1H, d), 9.08-9.13 (lH,d);
MS, m/z 522

132
Example 24
N-{4-[3-(2-MorphoIin-4-yI-quinolin-3-yl)-acryIoyl]-phenyI}-oxalamide (Compound
No. 77)
Step A: Preparation of 2-morpholin-4-yl-quinoline-3-carboxaldehyde
A suspension of 2-chloro-quinoline-3-carboxaldehyde (3 g, 15.6 mmol) in morpholine (25
ml) was refluxed for 30 hours. After cooling the reaction mixture, the precipitate was
filtered, successively washed with water (50 ml x 2) and diethyl ether (50 ml x 2), and
dried it under vacuo for 4 hours to obtain 2 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.32 (4H, t), 4.03 (4H, t), 7.5 (1H, d), 7.65 (1H,
m), 7.79 (1H, m), 8.19 (1H, d), 8.22 (1H, s), 10.19 (1H, s).
Step B: Preparation of l-(4-amino-phenyl)-3-(2-morpholin-4-yl-quinolin-3-yl)-propenone
To the solution of 2 g (8.2 mmol) of the product from example 24, step A and 4-amino
acetophenone (1.2 g, 8.2 mmol) in methanol (20 ml), pre-cooled to 0°C, was added an
aqueous solution of sodium hydroxide [0.6 g, 16.4 mmol in water (2 ml)]. The mixture
was stirred at room temperature for 16 hours. After completion of reaction, the mixture
was cooled to 0°C, diluted with water (20 ml) and the pH adjusted to 7 using aqueous
hydrochloric acid. The volatiles were evaporated under vacuo. The mixture was
partitioned between water and ethyl acetate. The combined organic layers were
successively washed with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous
sodium sulphate and evaporated under vacuo. The solid residue was purified by column
chromatography on silica gel using the 30 % ethyl acetate in hexane as the eluent to afford
1.2 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.8 (4H, t), 3.9 (4H, t), 6.64 - 6.67 (1H, s), 7.6
(1H, m), 7.8 (1H, d), 7.82 (1H, d), 7.9 (1H, m), 8.03 (2H, d), 8.18 (2H, m), 8.3 (2H, d), 8.6
(lH,d).
Step C: Preparation of N-{4-[3-(2-morpholin-4-yl-quinolin-3-yl)-acryloyl]-phenyl}-
oxalamic acid ethyl ester

133
To 1.2 g (3.3 mmol) of the product from example 24, step B in dry dichloromethane (30
ml) containing triethylamine (0.5 g, 5 mmol), pre-cooled to 0°C, was added ethyl oxalyl
chloride (0.5 g, 4 mmol). The reaction mixture was stirred at room temperature for 4
hours. The mixture was partitioned between water and ethyl acetate. The combined
organic layers were successively washed with water (50 ml x 2) and brine (50 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuo. The solid residue was
triturated with hexane (25 ml x 2) to afford 1 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOdg) d 1.32 (3H, t), 3.8 (4H, t), 3.9 (4H, t), 4.3 (2H, m),
7.6 (1H, m), 7.8 (1H, d), 7.82 (1H, d), 7.9 (1H, m), 8.03 (2H, d), 8.18 (2H, m), 8.3 (2H, d),
8.6(lH,dd), 11.2 (1H, s).
Step D: Preparation of N-{4-[3-(2-Morpholin-4-yl-quinolin-3-yl)-acryloyl]-phenyl}-
oxalamide
To 0.15 g (0.32 mmol) of the product from example 24, step C was added ammonia
solution (20 ml) and stirred at room temperature for 6 hours. The precipitate was filtered,
successively washed with water (20 ml x 2) and diethyl ether (20 ml x 2), dried under
vacuo at 60 ° C for 4 hours to afford 25 mg of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 3.29 (4H, bs), 3.82 (4H, bs), 7.46 - 7.49 (1H, t),
7.7 - 7.72 (1H, t), 7.78 - 7.83 (2H, t), 7.87 - 7.91 (2H, t), 8.07 - 8.11 (3H, t), 8.2 -8.23 (2H,
d), 8.4 (1H, s), 8.87 (1H, s), 10.99 (1H, s);
MS, m/z 431
Example 25
2-MorphoIin-4-yl-N-{4-[3-(4-morpholin-4-yl-quinoIin-2yl-acryloyl)-phenyl}-2-oxo-
acetamide (Compound No. 78)
Step A: Preparation of l-(4-amino-phenyl)-3-(4-morpholin-4-yl-quinolin-3-yl)-propenone

134
To 4-morpholine-4-yl-quinoline-2-carboxaldehyde (1 g, 4.1 mmol), prepared as shown in
example 19, step B and 4-amino acetophenone (0.56 g, 4.1 mmol) in methanol (20 ml),
cooled to 0°C, was added an aqueous solution of sodium hydroxide [0.33 g, 8.2 mmol in
water (2 ml)]. The mixture was stirred at room temperature for 16 hours. After completion
of reaction, the mixture was cooled to 0°C, diluted with water (20 ml) and aqueous
hydrochloric acid was added to adjust the pH to 7. The volatiles were evaporated under
vacuum. The mixture was partitioned between water and ethyl acetate. The combined
organic layers were successively washed with water (50 ml x 2) and brine (50 ml x 2),
dried over anhydrous sodium sulphate and evaporated under vacuum. The residue was
purified by column chromatography on silica gel using the 30 % ethyl acetate in hexane as
the eluent to afford 0.6 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 3.8 (4H, t), 3.9 (4H, t), 6.2 (2H, bs), 6.6 (2H, d),
7.5 (2H, m), 7.6 (1H, s), 7.7 (1H, m), 7.9 (2H, d), 8.02 (1H, d), 8.06 (1H, d), 8.25 (1H, d).
Step B: Preparation of N-{4-[3-(4-morpholin-4-yl-quinolin-3-yl)-acryloyl]-phenyl}-
oxalamic acid ethyl ester
To 0.6 g (1.7 mmol) of the product of example 25, step A in dry dichloromethane (30 ml)
containing triethylamine (0.5 g, 5 mmol), cooled to 0 ° C and to it was added drop wise
ethyl oxalyl chloride (0.28 g, 2.1 mmol). The reaction mixture was stirred at room
temperature for 4 hours. The mixture was partitioned between water and ethyl acetate. The
combined organic layers were successively washed with water (50 ml x 2) and brine (50
ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo. Trituration of
the residue in hexane (20 ml x 3) followed by the collection of the solid by vacuum
filtration provided 0.55 g of the title compound as a yellow solid.
]H NMR (400 MHz, DMSOd6) d 1.32 (3H, t), 3.8 (4H, t), 3.9 (4H, t), 4.3 (2H, m),
7.6 (1H, m), 7.8 (1H, d), 7.82 (1H, d), 7.9 (1H, m), 8.03 (2H, d), 8.18 (2H, m), 8.3(2H, d)
8.6 (1H, dd), 11.2 (1H, s).
Step C: Preparation of 2-Morpholin-4-yl-N-{4-[3-(4-morpholin-4-yl-quinolin-2yl-
acryloyl)-phenyl}-2-oxo-acetamide

135
To 0.2 g (0.4 mmol) of the product from example 25, step B in xylene (20 ml), was added
morpholine (1 g, 11.5 mmol) and refluxed for 12 hours. The mixture was partitioned
between water and ethyl acetate. The combined organic layers were successively washed
with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The solid residue was purified by column chromatography on
silica gel using 50% ethyl acetate in hexane to obtain 0.8 g of the title compound as a
yellowish brown solid.
1H NMR (400 MHz, DMSOd6) d 3.48 - 3.56 (4H, m), 3.6 - 3.67 (4H, m), 3.85 -
3.91 (8H, d), 7.58 - 7.65 (1H, m), 7.77 - 7.82 (3H, m), 7.89 - 7.92 (2H, d), 7.97 - 8.13 (3H,
m), 8.22 - 8.24 (2H, d), 11.25 (1H, s);
MS,m/z 501
Example 26
N-(2-Morpholin-4-yl-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyI)-phenyI]-oxalamide
(Compound No. 130)
Step A: Preparation of quinoxalin-2-carboxaldehyde
To 2-methyl-quinoxalin-2-ol (2 g, 12.4 mmol) in 1, 4-dioxane (50 ml) was added selenium
dioxide (4 g, 37 mmol) and the mixture was heated to 60°C for 4 hours. After cooling the
reaction mixture, it was filtered over celite and partitioned between water and ethylacetate.
The combined organic phases were successively washed with water (50 ml x 2) and brine
(50 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo to afford
1.3 g of the crude title compound as a brown solid, which was used without purification in
the next step.
1H NMR (400 MHz, DMSOd6) d 7.98-8.09 (3H, m), 8.21-8.24 (1H, m), 8.28-8.31
(lH,m), 10.19 (lH,s).
Step B: Preparation of l-(4-amino-phenyl)-3-quinoxalin-2-yl-propenone
To the solution of 1.3 g (8.2 mmol) of the product from example 26, step A in methanol
(40 ml), pre-cooled to 0°C, was added dropwise an aqueous solution of sodium hydroxide
[0.65 g, 16.4 mmol in water (2 ml)]. The mixture was stirred at room temperature for 18

136
hours. After completion of reaction, the mixture was cooled to 0°C, diluted with water (20
ml) and the pH adjusted to 7 using aqueous hydrochloric acid. The volatiles were
evaporated under vacuo. The precipitate was isolated by filtration with a Buchner funnel
and successively washed with water (20 ml x 2) and brine (10 ml x 2), and dried under
vacuo at 60°C to afford 1.5 g of the title compound as a yellow solid.
1H NMR (400 MHz, DMSOd6) d 6.27 (2H, bs), 6.6 (2H, d), 7.5 (1H, d), 7.56 (1H,
m), 7.69 (2H, m), 7.8 - 7.82 (2H, m), 7.83 - 7.84 (2H, q), 7.91 - 7.92 (1H, d).
Step C: Preparation of N-{4-(3-quinoxalin-2-yl-acryloyl)-phenyl}-oxalamic acid ethyl
ester
To 1.5 g (5.5 mmol) of the product from example 26, step B in dry dichloromethane (40
ml), pre-cooled to 0°C, was added ethyl oxalyl chloride (1.1 g, 8 mmol). The reaction
mixture was stirred at room temperature for 12 hours. The mixture was partitioned
between waterand ethyl acetate. The combined organic layers were successively washed
with water (50 ml x 2) and brine (50 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The solid residue was triturated with hexane (25 ml x 2) to afford
1.4 g of the title compound as a brown solid.
1H NMR (400 MHz, DMSOd6) d 1.32 (3H, t), 4.32 (2H, q), 6.61 (2H, d), 7.5-
7.52 (1H, d), 7.56 (1H, m), 7.69-7.71 (2H, m), 7.81-7.83 (2H, m), 7.83-7.84 (2H, d), 8.09-
8.11 (1H, d), 11.2 (1H, bs).
Step D: Preparation of N-(2-Morpholin-4-yl-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-
pheny 1]-oxalam ide
The ester from example 26, step C (0.2 g, 0.53 mmol) was suspended in xylene (20 ml).
To it, 2-morpholine-4-yl-ethylamine (5.2 g, 4 mmol) was added and refluxed for 12 hours.
The reaction was partitioned between water and ethyl acetate. The combined organic
layers were successively washed with water (50 ml x 2) and brine (50 ml x 2) and dried
under vacuo. The solid residue was purified by column chromatography on silica gel using
60% ethyl acetate in hexane as the eluent to provide 0.025 g of the title compound as a
solid.

137
1H NMR (400 MHz, DMSOd6) d 2.41 (4H, bs), 2.54 (2H, bs), 3.57 (4H, bs), 3.64 -
3.66 (2H, t), 7.77 - 7.8 (2H, m), 7.92 - 8.04 (8H, m), 8.91 (1H, bs), 8.98 (1H, s), 10.98
(lH,s);
MS, m/z 460
Example 27
2-Morpholin-4-yl-N-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl] phenyl} -2-oxo-
acetatnide (Compound No. 83)
Step A: Preparation of 6-morpholin-4-yl-pyridine-2-carboxaldehyde
A solution of 6-bromo-pyridine-2-carboxaldehyde (1.9 g, 10 mmol), morpholine (1.75 g,
20 mmol) and potassium carbonate (3 g, 22 mmol) in acetonitrile (20 ml) was refluxed for
20 hours. The reaction mixture was cooled to room temperature, diluted with water (50
ml) and the pH adjusted to 7. The mixture was partitioned between water and ethyl
acetate. The combined organic layers were successively washed with water (25 ml x 2)
and brine (25 ml x 2), dried over anhydrous sodium sulphate and evaporated under vacuo.
The gummy residue was purified by column chromatography over silica gel using 40 %
ethyl acetate in hexane as the eluent to afford 1.5 g of the title compound as brown liquid.
1H NMR (400 MHz, DMSOd6) d 3.55 - 3.58 (4H, t), 3.91 - 3.94 (4H, t), 7.15 - 7.18
(1H, d), 7.56 - 7.61 (1H, d), 7.65 - 7.68 (1H, t), 9.98 (1H, s).
Step B: Preparation of l-(4-amino-phenyl)-3-(6-morpholin-4-yl-pyridin-2-yl)-propenone
To 1.5 g (7.8 mmol) of the product from example 27, step A and 4-amino acetophenone (1
g, 7.8 mmol) in methanol, pre-cooled to 0°C, was added dropwise an aqueous solution of
sodium hydroxide [{0.6 g, 15.5 mmol, in water (2 ml)]. The reaction mixture was stirred
for 16 hours. The mixture was then diluted with water (20 ml) and the pH adjusted to 7
using aqueous solution of hydrochloric acid. The volatiles were evaporated under vacuo.
The mixture was partitioned between water and ethyl acetate. The combined organic
layers were successively washed with water (25 ml x 2) and brine (25 ml x 2), dried over
anhydrous sodium sulphate and evaporated under vacuo. The residue was purified by
column chromatography over silica gel using 60 % ethyl acetate in hexane as the eluent to
afford 0.6 g of the title as a yellow solid.

138
1H NMR (400 MHz, DMSOd6) d 3.52 - 3.54 (4H, m), 3.76 - 3.8 (4H, t), 6.09 (1H,
s), 6.54 - 6.56 (1H, d), 6.59 - 6.61 (2H, d), 6.97(1H, s), 7.52 -7.6 (1H, d), 7.68 - 7.72 (1H,
d), 7.89 - 7.91 (2H, d), 8.13 - 8.16 (1H, m), 8.41(1H, s).
Step C: Preparation of N-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-
oxalamic acid ethyl ester
To 0.6 g (2 mmol) of the product from example 27, step B in dichloromethane, pre-cooled
to 0°C, was added ethyl oxalyl chloride (1.2 g, 9 mmol) dropwise. The reaction mixture
was stirred at room temperature for 30 minutes. The precipitate was filtered, successively
washed with water (25 ml x 2) and diethyl ether (25 ml x2), and evaporated under vacuo
to afford 0.5 g of the title compound as a solid.
Step D: Preparation of 2-Morpholin-4-yl-N-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-
acryloyl] phenyl}-2-oxo-acetamide
To 0.2 g (0.5 mmol) of the product from example 27, step C and morpholine (1 g, 12
mmol) in xylene (20 ml) was refluxed for 8 hours. The mixture was partitioned between
water and ethyl acetate. The combined organic layers were successively washed with
water (25 ml x 2) and brine (25 ml x 2), dried over anhydrous sodium sulphate and
evaporated under vacuo. The residue was purified by column chromatography over silica
gel using 80 % ethyl acetate in hexane as the eluent to afford 0.6 g of the title compound
as brown solid.
1H NMR (400 MHz, DMSOd6) d 3.51 - 3.57 (8H, m), 3.61 - 3.67 (4H, m), 3.72 -
3.75 (4H, t), 6.94 - 6.96 (1H, d), 7.12 - 7.14 (1H, d), 7.55 - 7.59 (1H, d), 7.63 - 7.67 (1H,
t), 7.85 - 7.87 (2H, d), 7.99 - 8.03 (1H, d), 8.09 - 8.12 (2H, d), 11.2 (1H, s);
MS, m/z 449

139
The following representative compounds as shown in Table 1 may be prepared by
following the synthetic routes as described above:
Table
Ex Comp
No. No. 1H NMR (400 MHz, d, DMSOd6) Mass, m/z
2.43 (2H, bs), 2.54 (2H, bs), 3.61 (2H, bs), 3.93 (2H, bs), 7.65 - 7.73 (3H,
28 2 m), 7.81 -7.89 (2H, m), 8.02 -8.05 (1H, d), 8.09- 8.11 (1H, d), 8.23 -8.28 385
(3H, t), 8.32 - 8.37 (1H, d), 8.49 - 8.52 (1H, d)
2.21 (3H, s), 2.28 (2H, bs), 2.39 (2H, bs), 3.33(2H, bs), 3.66 (2H, bs), 7.59 -
7.62 (2H, d), 7.65 - 7.71 (1H, t), 7.81 - 7.89 (2H, m), 8.02 - 8.05 (1H, d), 386
29 3 8.08 - 8.11 (1H, d), 8.22 - 8.25 (3H, m), 8.3 - 8.35 (1H, d), 8.49 - 8.51 (1H,
d)
1.77 - 1.87 (4H, m), 3.55 - 3.63 (2H, m), 4.37 - 4.4 (lH,m), 7.56 - 7.58 (1H,
d), 7.65 - 7.69 (1H, t), 7.77 - 7.89 (4H, m), 8.02 - 8.05 (1H, d), 8.08 - 8.1 400
30 4 (1H, d), 8.18 - 8.21 (1H, d), 8.23 - 8.26 (3H, d), 8.31 - 8.37 (1H, dd), 8.49-
8.51 (lH,d)
1.18 - 1.19 (6H, d), 1.54 (2H, bs), 1.77 (1H, bs), 1.92 (1H, bs), 2.59 - 2.67
(1H, m), 2.92 - 2.98 (1H, m), 3.11 - 3.16 (1H, m), 3.49 - 3.52 (1H, d), 4.34 -
31 5 4.37 (1H, d), 4.88 -4.96 (lH,m), 7.6 -7.62 (2H, d), 7.65 -7.69 (1H, t), 7.81 457
- 7.88 (2H, m), 8.02 - 8.04 (1H, d), 8.08 - 8.1 (1H, d), 8.2 - 8.24 (3H, d), 8.31
-8.35(lH,d), 8.49-8.51 (lH,d) .
2.64 - 2.67 (2H, m), 2.76 (2H, bs), 2.98 (1H, bs), 3.28 (2H, bs), 3.57 (2H,
bs), 7.55 - 7.61 (2H,d), 7.65 - 7.69 (1H, t), 7.81 - 7.89 (2H, m), 7.99 - 8.04 372
32 6 (1H, d), 8.08 - 8.10 (1H, d), 8.20 - 8.25 (3H, m), 8.29 - 8.37(1H, m), 8.47 -
8.51 (lH,m)
1.98 - 2.03 (3H, d), 3.29 - 3.35 (2H, d), 3.43 (2H, bs), 3.56 - 3.69 (4H, t),
33 7 7.59 - 7.67 (3H, m), 7.8 -7.84 (2H, d), 7.97 -7.99 (lH,d), 8.04 -8.1 (2H, t), 414
8.16 - 8.24 (3H, m), 8.43 - 8.45 (1H, d)
2.62 (2H, bs), 2.72 (2H, bs), 3.53 - 3.57 (2H, m), 3.9 (2H, bs), 7.62 - 7.71
34 10 (3H, m), 7.81 - 7.89 (2H, m), 8.00 -8.05 (1H, d), 8.08 -8.11 (1H, d), 8.23- 389
8.26 (3H, d), 8.32 - 8.36 (1H, d), 8.49 - 8.52 (1H, d)
1.82 - 1.91 (4H, m), 3.37 - 3.4 (2H, t), 3.48 - 3.52 (2H, t), 7.65 - 7.73 (3H,
35 11 m), 7.8 - 7.88 (2H, m), 8.02 - 8.04 (1H, d), 8.08-8.11 (1H, d), 8.22 - 8.26 357
(3H, d), 8.32 - 8.36 (1H, t), 8.49 - 8.52 (1H, d)
1.47 (2H, bs), 1.62 (4H, bs), 3.27 - 3.34 (2H, m), 3.62 (2H, bs), 7.58 - 7.6
36 12 (2H, d), 7.65 -7.69 (1H, t), 7.8 - 7.89 (2H, d), 8.02 -8.04 (1H, d), 8.08-8.1 371
(1H, d), 8.22 - 8.26 (3H, m), 8.32 - 8.36 (1H, d), 8.49 - 8.52 (1H, d)

140
Ex Comp
No No. 1H NMR (400 MHz, d, DMSOd6) Mass, m/z
0.86 - 0.88 (6H, d), 1.29 - 1.35 (2H, m), 1.54 - 1.61 (1H, m), 2.29 - 2.33 (4H,
t), 2.44 - 2.5 (2H, m), 3.25 - 3.4 (2H, m), 3.64 (2H, s), 7.59 - 7.61 (2H, d),
37 14 7.65-7.69 (lH,t), 7.8 -7.89 (2H, m), 8.02 -8.04 (1H, d), 8.08 -8.1 (1H, d), 442
8.22 - 8.25 (3H, d) 8.31 - 8.35 (1H, d), 8.49 - 8.51 (1H, d)
3.2 - 3.34 (4H, m), 3.46 (2H, s), 3.79 (2H, s), 6.81 - 6.99 (3H, m), 7.21 - 7.26
38 15 (lH,t), 7.66 - 7.68 (3H, t), 7.82 -7.9 (2H, m), 8.02 -8.1 (2H, d), 8.23-8.27 482
(3H, t), 8.32 - 8.37 (1H, d), 8.49 - 8.52 (1H, d)
2.98-3.09 (4H, d), 3.5 (2H, s), 3.84 (2H, s), 7.18 (1H, t), 7.35 (2H, d), 7.67-
39 16 7.69 (4H,d), 7.8-7.89 (2H,m), 8.02-8.1 (2H, m), 8.25 (3H, t), 8.32-8.36 (1H, 517
d)
2.04 (3H, s), 2.38 (1H, s), 3.72 - 3.78 (3H, m), 4.02 - 4.15 (1H, d), 4.36 (1H, 519
40 17 s), 7.27 - 7.3 (2H, d), 7.58 - 7.63 (2H, t), 7.65 - 7.69 (1H, t), 7.73 - 7.75 (2H,
d), 7.8 - 7.89 (2H, m), 7.98 - 8.15 (2H, m), 8.22 - 8.37 (4H, m), 8.49 - 8.52
(1H, d), 10.02 (lH,s)
3.37 - 3.39 (3H,t), 7.28 - 7.3 (3H,d), 7.59 - 7.62 (lH,d), 7.64 - 7.66 (3H,d), 560
41 18 7.83 - 7.86 (lH,d), 7.91 - 7.94 (3H,d), 7.98 - 8.01 (2H,d), 9.87 (lH,s)
1.85 - 1.87 (4H, m), 3.27 - 3.34 (4H, m), 3.4 - 3.42 (4H, m), 3.92 - 3.93 (4H,
42 19 m), 7.58-7.66 (2H,m), 7.73-7.82 (4H,m), 8.01-8.08 (2H,m), 8.11-8.13 457
(2H, d), 8.27 - 8.32 (1H, d), 8.62 (1H, s)
1.82 - 1.85 (2H, t), 2.03 (2H, bm), 3.47 - 3.77 (10H, m), 4.65 - 4.71 (1H, d),
43 20 7.64- 7.69 (3H, m), 7.81 -7.89 (2H, m), 8.02- 8.11 (2H, dd), 8.24- 8.26 470
(3H, t), 8.32 - 8.36 (1H, d), 8.5 - 8.52 (1H, d)
3.43 (2H, bs), 3.74 - 3.8 (6H, bd), 6.64 - 6.65 (1H, d), 7.04 - 7.05 (1H, d),
44 21 7.66 - 7.69 (3H, d), 7.8 - 7.92 (3H, m), 8.02 -8.11 (2H, dd), 8.23 - 8.27 (3H, 466
m), 8.32 - 8.36 (1H, d), 8.49 - 8.52 (1H, d)
3.35 - 3.45 (6H, d), 3.77 (2H, s), 6.83 - 6.84 (2H, d), 7.65 -7.69 (3H, t), 7.8
45 22 - 7.87 (2H, m), 8.02 - 8.1 (2H, dd), 8.18 - 8.19 (2H, d), 8.23 - 8.27 (3H, t), 449
8.32 - 8.36 (1H, d), 8.49 - 8.51 (1H, d)
1.32 - 1.37 (3H, t), 3.23 - 3.3 (4H, t), 3.91 - 3.93 (4H, t), 4.15 - 4.21 (2H,
m), 7.57-7.61 (2H,m), 7.68-7.79 (4H,m), 8.01-8.08 (2H,m), 8.15-8.17 432
46 23 (2H, d), 8.25 - 8.29 (1H, d), 10.15 (1H, s)
1 (3H, s), 1.02 (3H, s), 2 - 2.04 (1H, m), 3.3 - 3.32 (4H, t), 4- 4.05 (6H, m),
47 24 6.88 (1H, s), 7.12 (1H, s), 7.5 -7.59 (3H, m), 7.7 -7.75 (1H, m), 7.88-7.92 460
(1H, d), 8.02 - 8.04 (1H, d), 8.12 - 8.2 (4H, m)
3.23-3.27 (4H, m), 3.87-3.96 (4H, m), 7.32-7.35 (1H, m), 7.57-7.59 (1H, m),
48 25 7.63 (1H, s), 7.65 - 7.73 (4H, m), 7.75 -7.77(1H, m), 7.8 (1H, s), 7.92-7.95 547
(1H, d), 8.01 - 8.08 (2H, m), 8.18 - 8.2 (2H, d), 8.29 - 8.32 (2H, m), 9.9 (1H,

141
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
3.26-3.28 (4H, m), 3.9 (4H, m), 7.48-7.51 (3H, m), 7.56-7.63 (4H, m), 7.7 -
49 26 7.76 (2H,m), 7.8-7.86 (3H, m), 8-8.07 (4H, m), 8.22-8.27 (1H, d), 9.12 (1H, 544
1.29-1.34 (3H, m), 3.2-3.35 (4H, m), 3.91-3.93 (4H, m), 4.25-4.32 (2H, m),
50 27 7.57-7.64 (4H, m), 7.69-7.8 (4H, m), 7.89-7.97 (2H, m), 8.02 - 8.08 (2H, m) 551
8.17 - 8.22 (2H, d), 8.28 - 8.32 (1H, d), 9.28 - 9.35 (2H, t)
0.96 - 1(3H, t), 2.33 -2.37 (4H, m), 2.42 - 2.5 (2H, m), 3.31 (2H, bs), 3.64
(2H, bs), 7.57 -7.59 (2H, d), 7.64 -7.68 (lH,t), 7.8 -7.86 (2H, m), 8-8.02 400
(1H, d), 8.07 - 8.09 (1H, d), 8.14 - 8.16 (1H, d), 8.19 - 8.21 (2H, d), 8.25 -
8.29 (lH,d), 8.46 -8.48 (1H, d)
1.27-1.33 (3H, t), 1.61-1.67 (2H, bs), 1.82 (4H, bs), 3.23 (4H, bs), 4.15 - 4.2
52 29 (2H, m), 7.55 - 7.59 (2H, t), 7.68 -7.77 (4H, m), 7.98 -8 (2H, d), 8.14-8.17 430
(2H, d), 8.23 - 8.27 (1H, d), 10.15 (1H, s)
0.94 - 0.96 (6H, d), 1.67 (2H, bs), 1.82 (4H, bs), 1.92 - 1.97 (1H, m), 3.23
53 30 (4H, bs), 3.91-3.93 (2H,d), 7.56 -7.59 (2H, t), 7.69 -7.78 (4H, m), 7.98-8 458
(2H, d), 8.15 - 8.17 (2H, d), 8.23 - 8.27 (1H, d), 10.15 (1H, s)
1.25-1.28 (3H, t), 1.9 (4H, bs), 3.62 (4H, bs), 4.11-4.2 (2H, m), 7.25-7.28
54 31 (1H, m), 7.55-7.59 (2H, m), 7.65-7.68 (2H, d), 7.76-7.78 (1H, d), 7.82 - 7.86 416
(1H, d), 7.99 - 8.04 (1H, d), 8.14 - 8.17 (2H, d), 8.57 (1H, s), 10.12 (1H, s)
1.91 (4H, bs), 3.63 (4H, bs), 7.04 - 7.06 (1H, m), 7.27 (1H, m), 7.52 - 7.59
55 33 (3H, m), 7.65 - 7.66 (2H, d), 7.73 -7.79 (4H, m), 7.92 -7.95 (2H, d), 8.18- 464
8.2 (1H, d), 8.31 (1H, m), 9.57 - 9.59 (1H, d), 10.81 - 10.85 (1H, m)
2.2 (3H, s) 2-27 (2H, bs), 2.38 (2H, bs), 2.63 (3H, s), 2.67 (2H, m), 3.65
56 34 (2H, bs) 7.59 - 7.61 (2H, d) 7.67 - 7. 69 (1H, dd), 7.78 - 7.86 (2H, t), 7.96 - 432
7.99 (1H, d), 8.19 - 8.24 (3H, t), 8.26 - 8.31 (1H, d), 8.36 - 8.39 (1H, d)
2.62 - 2.73 (4H, d), 3.3 (2H, m), 3.53 (2H, bs), 3.9 - 3.91 (3H, d), 3.99 - 4.01
57 36 (6H, t), 7.33 (1H, s), 7.61 -7.64 (2H, d), 7.81 -7.85 (1H, d), 8.03 -8.06 (1H, 479
d), 8.21 - 8.23 (2H, d), 8.28 - 8.31 (1H, d), 8.4 - 8.42 (1H, d)
2.42 (2H, bs), 2.54 (2H, bs), 3.6 (2H, bs), 3.92 (2H, bs), 7.35 - 7.39 (2H, t),
7.59 - 7.64 (1H, t), 7.7 -7.72 (2H, d), 7.87 -7.92 (2H, m), 8.13 -8.15 (2H, 400
58 d), 8.39-8.44 (lH,d), 12.75 (lH,s)
2.36 (3H, s), 2.38 (2H, bs), 2.54 (2H, bs), 3.45 (2H, bs), 3.85 (2H, bs), 7.59 -
7.61 (2H, d), 7.82 - 7.88 (2H, m), 8.01 - 8.05 (1H, d), 8.14 - 8.20 (4H, m), 387
8.29 - 8.33 (1H, d), 9.08 (1H, s)
1.82 - 1.91 (4H, m), 3.36 - 3.4 (2H, t), 3.48 - 3.52 (2H, t), 7.72 - 7.74 (2H,
d), 7.89 - 7.94 (3H, m), 8.14 -8.19 (2H, m), 8.24 -8.26 (2H, d), 8.48-8.52 358
(1H, d), 9.6 (1H, s)

142
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
2.42 (2H, bs), 2.54 (2H, bs), 3.6 (2H, bs), 3.92 (2H, bs), 7.7 - 7.4 (2H, d),
7.9-7.95 (3H, m), 8.14 -8.19 (2H, m), 8.27 -8.29 (2H, d), 8.48 -8.52 (1H, 384
61 41 d),9.61(lH,s)
6.76-6.77 (1H, m), 7.35-7.39 (2H, t), 7.59-7.64 (1H, t), 7.87-7.94 (2H, t),
62 42 8.01 (1H, s), 8.19 (4H, s), 8.38-8.42 (1H, d), 8.64-8.65 (1H, d), 12.76 (1H, s)
3.07 - 3.11 (2H, t), 3.96 - 3.98 (2H, m), 6.5 - 6.54 (1H, t), 6.68 - 6.7 (1H, d),
6.93 - 6.99 (2H, m), 7.23 -7.31 (4H, m), 7.49 -7.53 (1H, t), 7.65 - 7.73 (1H, 420
d), 7.71-7.73 (2H,d), 8.11-8.13 (2H,d), 12.48 (lH,s)
2.99 (6H, s), 6.12 - 6.13 (1H, d), 7.82 - 7.88 (2H, m), 8.02 - 8.07 (1H, d), 398
64 44 8.24 - 8.26 (5H, m), 8.33 - 8.38 (3H, m), 9.09 (1H, s)
2.38 - 2.4 (2H, bs), 2.61 - 2.63 (2H, d), 3.37 - 3.38 (2H, m), 3.71 (2H, m),
7.66 - 7.69 (2H, d), 7.9 - 7.94 (3H, m), 8.14 - 8.19 (2H, m), 8.26 - 8.31 (2H,
t), 8.48 - 8.52 (1H, d), 9.58 - 9.60 (1H, s), 10.56 (1H, s)
2.17 (3H, s), 2.61 (3H, s), 6,.34 (1H, s), 7.61 (2H, s), 7.88 - 7.92 (1H, d),
8.01 - 8.04 (2H, d), 8.15 - 8.17 (1H, dd), 8.26- 8.29 (3H, m), 8.35 - 8.43 459
66 47 (2H, m), 8.54 (1H, d), 8.74 -8.76 (1H, d)
3.90 - 3.91 (3H, d), 3.99 - 4.01 (6H, t), 6.76 (1H, s), 7.34 (1H, s), 7.84 - 7.88
(1H, d), 8.01-8.05 (2H,t), 8.17-8.19 (2H,d), 8.27-8.32 (3H,m), 8.41 - 444
62 48 8.42 (lH,d), 8.64 -8.65 (1H, d)
2.17 (3H, s), 2.6 (3H, s), 6.34 (1H, s), 7.66 - 7.7 (1H, t), 7.82 - 7.86 (1H, t),
7.87 - 7.91 (1H, d), 8.01 -8.05 (3H, t), 8.09-8.12 (lH,d), 8.25-8.29 (3H, 404
t), 8.34 -8.38 (1H, d), 8.52 -8.54 (1H, d)
1.85 - 1.9 (4H, bs), 2.98 - 3.09 (4H, m), 3.47 (2H, m), 3.61 - 3.63 (4H, t),
3.84 - 3.88 (2H, m), 7.17 - 7.19 (1H, m), 7.27 - 7.29 (1H, m), 7.30 - 7.35
69 50 (3H, m), 7.58 - 7.6 (2H, m), 7.6 - 7.68 (2H, m), 7.74 - 7.81 (2H, m), 8.23 -
8.27 (2H, m), 8.62 (1H, s)
2.21 (3H, s), 2.27 - 2.28 (2H, m), 2.33 - 2.38 (2H, m), 3.31 (2H, m), 3.65
(2H, m), 3.88 (3H, s), 3.99 - 4 (6H, d), 7.33 (1H, s), 7.59 - 7.61 (1H, d), 476
70 51 7.66 - 7.68 (1H, m), 7.81 - 7.85 (1H, d), 8.02 - 8.04 (1H, d), 8.20 - 8.3 (3H,
m), 8.4 -8.42 (1H, d)
2.17 (3H, s), 2.6 (3H, s), 3.91 (3H, s), 3.99 - 4.01 (6H, d), 6.34 (1H, s), 7.34
(1H, s), 7.83 - 7.88 (1H, d), 8 - 8.06 (3H, m), 8.24 - 8.27 (2H, d), 8.29.8.33
(lH,d), 8.4-8.43 (lH,d)
1.63 (4H, m), 1.78 - 1.84 (4H, m), 3.52 (4H, m), 3.55 - 3.6 (5H, m), 7.54 -
7.57 (1H, d), 7.65 -7.69 (1H, m), 7.81 - 7.9 (2H, m), 8.02- 8.11 (2H, m), 440
8.2 - 8.25 (3H, m), 8.3 - 8.36 (2H, m), 8.49 - 8.51 (1H, m)

143
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
7.39 - 7.43 (1H, t), 7.52 - 7.56 (1H, t), 7.65 - 7.69 (1H, t), 7.71 - 7.73 (1H,
d), 7.84 - 7.89 (1H, d), 7.97 - 7.99 (1H, d), 8.02 - 8.04 (1H, t), 8.08 - 8.11
73 55 (1H, s), 8.13-8.15 (2H,d), 8.22-8.24 (lH,d), 8.26-8.29 (2H,d), 8.31 -
8.35 (lH,d), 8.49 -8.52 (1H, d)
1.82 - 1.91 (4H, m), 3.34 - 3.41 (2H, t), 3.46 - 3.52 (2H, t), 4.06 (3H, s),
7.13 (1H, s), 7.72 (2H, d), 7.86-7.9 (lH,d), 8.03-8.06 (lH,dd), 8.2-8.25 503
(3H, t), 8.32 - 8.34 (2H, t), 8.36 - 8. 4 (1H, d), 8.56 - 8.59 (1H, d)
1.15 - 1.23 (4H, m), 1.27 - 1.34 (2H, m), 1.53 (1H, m), 1.65 - 1.69 (1H, m),
1.8 - 1.83 (1H, m), 2.52 (4H, s), 3.27 (2H, m), 3.91 (4H, s), 7.58 - 7.64 (4H,
75 57 m), 7.73-7.77 (lH,d), 7.91-7.93 (2H,d), 8.01-8.03 (lH,d), 8.07-8.13
(3H, m), 8.89 (1H, s), 9.28 (1H, s)
1.28 (9H, s), 6.76 - 6.78 (1H, m), 7.85 - 7.89 (1H, d), 7.98 - 8.04 (3H, m),
8.16-8.2(3H, t), 8.27-8.31 (3H,t), 8.38-8.4 (lH,d), 8.46 (lH,s), 8.65- 453
8.66 (lH,d), 9.62 (lH,s)
1.76 - 1.81 (6H, d), 3.83 (4H, s), 7.58 - 7.6 (2H, d), 7.63 - 7.67 (2H, t), 7.71
- 7.79 (2H, m), 7.95 - 8 (2H, m), 8.18 - 8.2 (4H, d), 8.32 - 8.36 (2H, m), 609
8.64 - 8.68 (1H, d), 9.78 (1H, s), 11.24 - 11.29 (1H, m)
1.25 - 1.27 (6H, d), 1.83 - 1.86 (2H, m), 2.02 - 2.11 (2H, m), 2.56 - 2.59
(2H, m), 3.08 (2H, m), 4.03 (3H, s), 4.04 (3H, s), 4.09 (3H, s), 4.54 - 4.56
78 60 (1H, m), 5.02 - 5.08 (1H, m), 7.3 (1H, d), 7.55 - 7.57 (3H, d), 7.91 - 7.95
(1H, d), 8.09 - 8.17 (3H, m), 8.42 - 8.44 (1H, d)
1.51 - 1.59 (6H, m), 1.9 (4H, t), 3.44 - 3.47 (4H, t), 3.6 - 3.62 (4H, t), 7.57 -
7.62 (2H, m), 7.68 - 7.71 (4H, dd), 7.92 - 7.99 (2H, m), 8.09 - 8.13 (3H, 455
m), 8.97 (1H, s)
1.82 - 1.88 (4H, m), 2.63 (3H, s), 3.24 - 3.25 (4H, t), 3.38 - 3.4 (2H, d), 3.48
- 3.52 (2H, t), 3.9 - 3.91 (4H, t), 7.63 - 7.66 (3H, m), 7.12 - 7.73 (2H, d), 510
80 62 7.77 - 7. 81 (1H, d), 7. 92 - 7. 95 (1H, d), 8.2 - 8.22 (2H, d), 8.24 - 8. 28 (1H, d)
1.94 - 2.02 (4H, m), 3.17 (3H, s), 3.35 - 3.37 (4H, t), 3.43 - 3.46 (2H, t), 3.68
- 3.72 (2H, t), 4.05 - 4.07 (4H, t), 7.18 (1H, s), 7.69 - 7.71 (2H, d), 7.86 - 7.9
81 63 (1H, d), 8.11 - 8.14 (1H, dd), 8.16 -8.18 (2H, d), 8.25 -8.29 (2H, m), 8.67-
8.68 (1H, d)
1.26 - 1.29 (3H, t), 4.16 - 4.21 (2H, m), 7.69 - 7.71 (2H, d), 7.82 - 7.86 (1H,
d), 8.16-8.19 (2H,d), 8.23-8.29 (2H,m), 8.34-8.38 (lH,d), 8.54-8.57 431
(1H, dd), 8.61 - 8.63 (1H, d), 8.87 (1H, s), 9.84 (lH,s), 10.15 (1H, s)
7.24 - 7.26 (1H, m), 7.43 - 7.53 (5H, m), 7.82 - 7.91 (3H, m), 8.04 - 8.14
(2H,t), 8.18 - 8.2 (1H, d), 8.26 - 8.29 (1H, d), 8.31 - 8.36 (1H, m), 8.36- 506
8.49 (2H, m), 8.5 - 8.64 (1H, m), 8.77 (1H, s), 9.79 (1H, s)
7.27-7.32 (3H, m), 7.44-7.48 (2H, t), 7.7-7.76 (2H, d), 7.86-7.9 (1H, d),
8.22-8.25 (2H, d), 8.27-8.3 (1H, d), 8.33-8.36 (1H, d), 8.4-8.45 (1H, d), 8.57
84 66 - 8.6 (1H, dd), 8.68 - 8.71 (1H, d), 8.9 - 8.91 (1H, d), 9.86 (1H, s), 10.77
(lH,s)

144
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
3.26 (4H, bs), 3.82 (3H, s), 3.85 (3H, s), 3.91 (4H, bs), 7.12 - 7.14 (2H, d),
7.25 - 7.28 (1H, d), 7.5 -7.53 (lH,t), 7.59 -7.63 (1H, t), 7.85 -7.87 (2H, d), 448
8.01 - 8.04 (lH,d), 8.18-8.20 (2H,d), 9.49 (lH,s)
0.82 - 0.86 (3H, t), 1.15 - 1.19 (3H, t), 1.47 - 1.52 (2H, m), 1.74 (4H, bs),
3.41 (4H, s), 3.69 - 3.73 (2H, t), 4.08 - 4.14 (2H, m), 7.51 - 7.54 (3H, d),
86 70 7.75 - 7.79 (2H, m), 7.91 - 7.93 (2H, m), 8.05- 8.09 (1H, d), 8.17- 8.19
(2H,d), 8.94 (lH,s)
3.88 (8H, s), 7.26 - 7.32 (3H, m), 7.44 - 7.48 (2H, t), 7.67 - 7.71 (1H, t),
7.75 - 7.84 (4H, m), 7.97 - 8.01 (1H, t), 8.16 - 8.19 (1H, d), 8.3 - 8.33 (2H, 480
7 d), 8.35 -8.37 (1H, d), 8.82 -8.86 (1H, d), 10.82 (1H, s)
1.08 (9H, s), 1.37 - 1.47 (2H, m), 1.64 (1H, bs), 1.78 (1H, bs), 2.87 - 2.9
(1H, t), 3.12 - 3.19 (1H, t), 3.49 - 3.53 (1H, m), 3.85 - 3.87 (1H, m), 4.44
88 72 (1H, bs), 7.24 - 7.26 (1H, d), 7.58 - 7.6 (2H, d), 7.9 - 7.94 (3H, m), 8.15 -
8.19 (2H, m), 8.26 - 8.29 (2H, d), 8.47 - 8.51 (1H, d), 9.59 (1H, s)
1.5 - 1.57 (3H, m), 1.75 (1H, bs), 2.82 (3H, s), 2.91 - 2.98 (2H, m), 3.04 (3H,
s), 3.13 - 3.27 (1H, m), 3.53 - 3.57 (1H, m), 4.48 - 4.52 (1H, m), 7.60 - 7.63
89 73 (2H,d), 7.9-7.94 (3H,m), 8.14-8.19 (2H,m), 8.25 - 8.27 (2H,d), 8.47-
8.51 (1H, d), 9.6 (1H, s)
3.72 (3H, s), 7.69 - 7.71 (2H, d), 7.83 - 7.87 (1H, d), 8.17 - 8.2 (2H, d), 8.24
- 8.3 (2H, d), 8.34 - 8.38 (1H, d), 8.54 - 8.63 (2H, m), 8.86 - 8.88 (1H, m), 415
90 74 9.84 - 9.85 (lH,d), 10.19 (1H, s)
1.63 - 1.81 (6H, d), 2.34 - 2.47 (5H, m), 3.64 (2H, s), 6.72 - 6.78 (1H, m),
7.18-7.20 (lH,d), 7.33 -7.37 (3H, t), 7.5-7.61 (3H, m), 7.82 -7.89 (3H, 504
m), 7.96-8.12 (3H,m), 8.8-8.85 (lH,t)
1.32 - 1.37 (3H, t), 1.62 - 1.70 (6H, d), 2.59 - 2.62 (2H, s), 3.64 - 3.66 (2H,
bs), 4.23 -4.31 (2H, m), 6.71 - 6.77 (1H, m), 6.85 -6.9 (1H, m), 7.47-7.69 380
76 (4H, m), 7.93-8.03 (2H,m), 8.08-8.1 (lH,d) 9.9 (lH,s)
3.29 (4H, bs), 3.82 (4H, bs), 7.46 - 7.49 (1H, t), 7.7 - 7.72 (1H, t), 7.78 -
7.83 (2H, t), 7.87 - 7.91 (2H, t), 8.07 - 8.11 (3H, t), 8.2 -8.23 (2H, d), 8.4 431
93 77 (lH,s), 8.87 (lH,s), 10.99 (lH,s)
3.46 - 3.62 (12H, m), 3.75 - 3.81 (4H, m), 7.47 - 7.49 (1H, m), 7.67 - 7.89
94 79 (6H,m), 7.94 -7.95 (lH,m), 8-8.1 (2H,m), 8.85 (lH,s), 11.2 (lH,s)
1.63 - 1.73 (6H, m), 3.26 (4H, bs), 7.43 - 7.46 (1H, m), 7.65 - 7.69 (1H, m),
7.73-7.76 (1H, d), 7.82 -7.88 (2H, t), 8.07-8.11 (4H, t), 8.2 -8.23 (2H, d), 429
95 80 8.41 (lH,bs), 8.84 (lH,s), 10.98 (lH,s)
1.58 - 1.73 (6H, d), 3.22 (4H, bs), 3.54 - 3.57 (4H, m), 3.62 - 3.66 (4H, m),
7.42 - 7.46 (1H, m), 7.66 - 7.7 (1H, m), 7.74 - 7.8 (1H, m), 7.87 - 7.89 (3H,
96 81 d), 7.97-7.99 (lH,d), 8.06-8.1 (lH,d), 8.21-8.24 (2H,d), 8.83 (1H, s),
11.21 (lH,s)

145
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
0.85 - 0.89 (3H, t), 1.5 - 1.56 (2H, m), 3.15 - 3.2 (2H, m), 3.34 (4H, bs), 3.9
-3.92(4H, m), 7.58 -7.66 (2H, m), 7.74 -7.8 (2H, m), 8.01-8.11 (4H, m), 471
8.21 - 8.24 (2H, d), 8.29 - 8.33 (1H, d), 9.08 - 9.11 (1H, t), 11.04 (1H, s)
1.16-1.18 (6H, d), 3.35-3.39 (2H, m), 3.57 - 3.61 (2H, m), 4.3 - 4.34 (2H, d),
6.95 - 6.98 (1H. d). 7.25 - 7.31 (3H, m). 7.4 - 7. 47 (3H, m), 7.61 - 7.69 (3H, 456
m), 7.76 - 7.8 (1H, d), 8.14 - 8.17 (2H, d), 8.45 - 8.46 (1H, d), 10.67 (1H, s)
1.56 - 1.64 (6H, m), 3.27 (4H, bs), 3.4 - 3.43 (2H, m), 3.49 - 3.52 (2H, m),
3.92 (4H, s), 7.57 - 7.62 (2H, m), 7.73 - 7.81 (2H, m), 7.87 - 7.9 (2H, d), 499
99 85 8.01-8.1 (2H,m), 8.2 -8.23 (2H, d), 8.26 -8.3 (1H, d), 11.17 (1H, s)
1.25 - 1.28 (2H, t), 1.56 - 1.58 (2H, m), 1.89 - 1.92 (2H, m), 3.09 - 3.19 (4H,
m), 4.13-4.16 (2H, m), 4.3-4.4 (lH,m), 6.7(1H,s), 7.21-7.28 (4H, m), 470
7.37 - 7.45 (5H, m), 7.65 - 7.77 (2H, m), 7.86 - 7.97 (2H, d), 9.73 (1H, s)
1.49 - 1.63 (6H, m), 3.47 - 3.63 (4H, m), 6.41 - 6.43 (2H, t), 7.27 - 7.28 (2H,
t), 7.56 - 7.62 (3H, m), 7.75 - 7.8 (3H, m), 7.87 - 7.97 (3H, t), 8.03 - 8.06 477
101 87 (2H,d), 11.09 (lH,s)
3.52 - 3.66 (8H, m), 6.46 - 6.48 (2H, t), 7.36 - 7.37 (2H, t), 7.7 - 7.74 (1H,
t), 7.8- 7.84 (1H, t),7.87-7.93 (3H, m), 7.95 - 7.99 (1H, m), 8.18- 8.21 479
(1H, d), 8.25-8.31 (3H,t), 8.42-8.46 (lH,d), 11.23 (lH,s)
1.44 - 1.47 (2H, m), 1.93 - 1.95 (2H, m), 3 - 3.06 (1H, m), 3.06 - 3.18 (1H,
m), 3.5-3.65 (2H,m), 4.37 (lH,bs), 7.59-7.6 (2H,d), 7.9-7.96 (4H, m), 517
8.14 - 8.19 (2H, m), 8.26 - 8.28 (2H, d), 8.47 - 8.51 (1H, d), 9.59 (1H, s)
2.04 - 2.07 (4H, m), 3.54 - 3.56 (4H, t), 5.37 (2H, s), 7.05 - 7.08 (1H, d), 7.3
(1H, s), 7.41 -7.5 (3H, m), 7.54 -7.59 (2H, t), 7.61 -7.63 (1H, d), 7.66- 451
7.7 (1H, d), 7.73 - 7.78 (1H, m), 8.04 - 8.15 (3H, m), 8.65 - 8.66 (1H, d)
2.04 - 2.07 (4H, m), 3.52 - 3.57 (4H, m), 5.21 (2H, s), 6.44 - 6.46 (1H, d),
6.72 - 6.74 (1H, d), 6.87 (1H, s), 7.07 - 7.12 (2H, t), 7.41 - 7.48 (3H, m), 446
7.52 - 7.54 (2H, d), 7.62 - 7.66 (1H, d), 8.03 - 8.1 (3H, t)
1.25 - 1.27 (2H, m), 1.71 (8H, s), 2.29 (3H, s), 2.64 (3H, s), 3.65 (4H, bs),
6.02 (1H, s), 6.72 - 6.79 (2H, m), 7.48 - 7.52 (1H, m), 7.62 - 7.66 (1H, d), 474
106 92 7.76 - 7. 78 (2H,d), 8.01 - 8.05 (1H, d), 8.1 - 8. 13 (2H,d), 9.52 (1H,s)
1.59 -1.7 (6H, d), 3.64 (4H, s), 5.21 (2H, s), 6.41 - 6.51 (2H, dd), 6.71 - 6.77
(2H, dd), 6.89 (1H, s) 7.47 - 7.55 (4H, m), 7.61 - 7.65 (1H, d), 7.9 - 8.02 454
(1H, d), 8.05 - 8.08 (2H, d)
1.7 (6H, bs), 3.65 (4H, bs), 4.87 - 4.89 (2H, d), 6.32 - 6.4 (1H, m), 6.72 -
6.78 (3H, m), 6.89 (1H, bs), 7.29 - 7.31 (1H, m), 7.34 - 7.38 (2H, t), 7.42 - 468
108 94 7.45 (2H, d), 7.47 - 7.49 (1H, m), 7.51 - 7.57 (2H, d), 7.61 - 7.65 (1H, d),
7.99 - 8.03 (1H, d), 8.06 -8.11 (2H, d)

146
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
1.7 - 2.14 (12H, m), 2.66 (2H, bs), 2.83 (1H, bs), 3.2 - 3.27 (1H, m), 3.6 -
3.69 (5H, m), 3.81 (1H, bs), 4.37 - 4.39 (1H, t), 4.82 (1H, bs), 6.71 - 6.77 463
(1H, m), 7.43 - 7.49 (1H, t), 7.54 - 7.69 (4H, m), 7.98 - 8.15 (4H, m)
3.26 - 3.28 (4H, t), 3.72 (3H, s), 3.9 - 3.93 (4H, t), 7.57 - 7.62 (2H, m), 7.68 -
7.79 (4H,m), 8.01 - 8.08 (2H, m), 8.16 - 8.18 (2H, d), 8.25 - 8.29 (1H, d), 416
110 96 10.18 (lH,s)
3.55-3.66 (8H, m), 7.35 - 7.39 (2H, m), 7.56 - 7.65 (3H, m), 7.87 - 7.88 (1H,
111 97 t), 7.9-7.92 (lH,t), 8.11-8.13 (2H,d), 8.38-8.43 (lH,d), 12.75 (lH,s)
2.61 (2H, bs), 2.71 (2H, bs), 3.53 (2H, bs), 3.89 (2H, bs), 7.35 - 7.39 (2H, t),
7.59 - 7.64 (3H, t), 7.87 - 7.91 (2H, t), 8.11 -8.13 (2H, d), 8.39-8.43 (1H, 404
d), 12.75 (1H, s)
2.17 (3H, s), 2.6 (3H, s), 6.34 (1H, s), 7.35 - 7.39 (2H, t), 7.59 - 7.64 (1H, t),
7.87 - 7.94 (2H, m), 8.01-8.2 (2H, d), 8.15 -8.2 (2H, d), 8.39 -8.43 (1H, d), 397
12.76 (lH,s)
2.98 (2H, bs), 3.09 (2H, bs), 3.5 (2H, bs), 3.84 (2H, bs), 7.17 - 7.19 (1H, m),
7.31 - 7.39 (4H, m), 7.59 - 7.63 (1H, t), 7.67 - 7.69 (2H, d), 7.87 - 7.92 (2H, 531
m), 8.12 - 8.15 (2H, d), 8.39 - 8.44 (1H, d), 12.75 (1H, s)
3.2 (2H, bs), 3.27 (2H, bs), 3.45 (2H, bs), 3.78 (2H, bs), 6.81 - 6.84 (1H, dd),
6.91 - 6.94 (1H, dd), 6.98 - 6.99 (1H, t), 7.21 - 7.26 (1H, t), 7.35 - 7.39 (2H,
115 101 t), 7.52 - 7.6 (1H, t), 7.66 - 7.68 (2H, d), 7.87 - 7.92 (2H, m), 8.12 - 8.15
(2H, d), 8.38 - 8.44 (1H, d), 12.76 (1H, s)
1.47 - 1.51 (3H, m), 1.68 - 1.75 (1H, m), 2.81 (3H, s), 2.89 - 2.91 (2H, m),
3.04 (3H, s), 3.15 - 3.25 (1H, m), 3.53 (1H, s), 4.46 - 4.51 (1H, m), 7.35 -
116 102 7.42 (2H, m), 7.5 - 7.53 (1H, m), 7.59 - 7.64 (2H, m), 7.89 (1H, t), 7.91 -
7.98 (1H, m), 8.11-8.15 (2H, m), 8.39 - 8.44 (1H, d), 12.74 (1H, s)
1.08 (9H, s), 1.22 - 1.49 (2H, m), 1.63 - 1.77 (2H, d), 2.89 - 2.92 (1H, m),
3.14 (1H, t), 3.41 - 3.52 (1H, m), 3.85 - 3.89 (1H, m), 4.44 (1H, bs), 7.17 -
117 103 7.25 (1H, m), 7.32 - 7.41 (2H, m), 7.48 - 7.63 (4H, m), 7.84 - 7.92 (2H, m),
8.12 - 8.15 (1H, d). 8.39 - 8.44 (1H, t), 12.74 (1H, s)
1.18 - 1.19 (6H,d), 1.54 (2H,bs), 1.78 - 1.99 (2H,d), 2.62 - 2.69 (lH,bs),
2.98 (lH,bs), 3.16 (lH,bs), 3.4 - 3.51 (lH,bs), 4.29 - 4.37 (lH,bs), 4.87 -
118 104 4.94 (lH,m), 7.18 -7.2 (2H,t), 7.35 -7.39 (3H,t), 7.59- 7.63 (2H,m), 8.1 -
8.12 (2H,d), 8.39 - 8.43 (lH,d), 12.74 (lH,s)
1.77 - 1.88 (4H, m), 3.39 - 3.42 (1H, m), 3.55 - 3.62 (1H, m), 4.37 - 4.41
(1H, m), 7 (1H, s), 7.35 - 7.39 (2H, t), 7.45 (1H, s), 7.56 - 7.63 (2H, m), 7.77
119 105 -7.79(lH,d), 7.87-7.92 (2H,m), 8.05-8.14 (2H,m), 8.39-8.43 (lH,d),
12.74 (lH,s)
3.33 - 3.48 (6H, m), 3.76 - 3.77 (2H, m), 6.83 - 6.84 (2H, d), 7.36 - 7.39 (2H,
t), 7.59 - 7.63 (1H, m), 7.67 - 7.69 (2H, d), 7.87 - 7.92 (2H, m), 8.13 - 8.15 464
(1H, d), 8.32 - 8.34 (3H, d), 8.4 - 8.44 (1H, d), 12.75 (1H, s)

147
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z3.56-3.65 (8H, d), 7.33-7.45 (2H, m), 7.55-7.57 (2H, d), 7.59-7.69 (2H, m),
121 107 7.71-7.77 (1H, m), 8 -8.13 (2H, d), 8.16 -8.21 (1H, m), 12.24 (1H, s)
6.77 - 6.85 (1H, m), 7.37 - 7.41 (1H, d), 7.59 - 7.62 (1H, t), 7.78 - 7.8 (1H,
m), 7.86-7.88 (1H, m), 8.01 (1H, s), 8.16 -8.2 (3H, m), 8.23 -8.28 (2H, d), 369
8.35 - 8.42 (1H, m), 8.65 - 8.68 (1H, m), 12.69 (1H, s)
2.2 (3H, s), 2.27 (2H, bs), 2.38 (2H, bs), 3.29 (2H, bs), 3.59 - 3.64 (2H, bs),
7.33 - 7.37 (1H, d), 7.51 - 7.53 (1H, d), 7.57 - 7.63 (2H, m), 7.77 - 7.79 (1H,
123 109 d), 7.85-7.89 (lH,m), 8.07-8.09 (lH,d), 8.15-8.21 (2H,m), 8.37-8.41
(lH,d), 12.18 (lH,s)
1.59 - 1.66 (2H, m), 1.91 - 1.95 (2H, bs), 3.11 - 3.13 (2H, bs), 3.61 - 3.74
(3H, m), 7.24 - 7.31 (3H, m), 7.44 - 7.48 (3H, m), 7.69 - 7.75 (3H, m), 7.78
124 110 - 7.83 (2H, m), 7.88-7.91 (1H, d), 7.95 -8 (lH,m), 8.07 -8.11 ({1H, d), 8.21
- 8.23 (2H, d), 8.87(1H, s), 10.74 (1H, s)
1.57 - 1.66 (2H, m), 1.9 - 1.92 (2H, m), 2.99 - 3.05 (2H, t), 3.56 - 3.59 (2H,
d), 3.69 - 3.7 (1H, m), 3.72 (3H, s), 7.41 - 7.45 (1H, t), 7.56 - 7.59 (1H, m),
125 111 7.64 - 7.75 (3H, t), 7.73 - 7.75 (1H, d), 7.88 - 7.98 (2H, m), 8.04 - 8.08 (1H,
d), 8.16 - 8.19 (2H, d), 8.88 (1H, s), 10.16 (1H, s)
1.27 - 1.36 (3H, t), 1.51 - 1.65 (2H, m), 1.83 - 1.92 (2H, m), 2.98 - 3.05 ( 2H,
m), 3.56 - 3.62 (2H, m), 3.65 - 3.72 (1H, m), 4.12 - 4.21 (2H, m), 7.08 (1H,
126 112 s), 7.41-7.45 (lH,t), 7.56 -7.59 (2H, m), 7.64 -7.69 (3H, t), 7.73 -7.8(1H,
t), 7.84 - 7.97 (3H, m), 8.15 - 8.18 (1H, d), 10.13 (1H, s)
1.14-1.23 (6H, m), 3.48-3.6 (4H, m), 4.29-4.32 (2H, d), 7.45 - 7.52 (2H, m),
7.56 - 7.59 (1H, t), 7.62 - 7.66 (3H, t), 7.71 - 7.75 (2H, m), 7.86 - 7.88 (2H, 519
d), 7.97 - 7.99 (3H, d), 8.06 - 8.09 (1H, d), 9.40 - 9.42 (1H, d), 11.1 (1H, bs)
1.54-1.63 (6H, d), 3.3-3.44 (2H, m), 3.51-3.57 (6H, m), 3.72 -3.74 (4H, t),
6.94-6.96 (1H, d), 7.12 -7.14 (1H, d), 7.55 -7.59 ({1H, d), 7.63 -7.67 (lH,t), 449
7.83 - 7.86 (2H, d), 7.99-8 (lH,t), 8.09-8.12 (2H,d), 11.16(lH,s)
3.55 (4H, bs), 3.73 (4H, bs), 6.93 - 6.95 (1H, d), 7.13 - 7.14 (1H, d), 7.54 -
129 115 7.65 (2H, m), 8 -8.17 (6H, m), 8,4 (1H, bs), 10.97 (1H, s)
1.55 (4H, bs), 1.63 (4H, bs), 1.72 (4H, bs), 3.26 (4H, bs), 3.39 - 3.44 (2H,
m), 3.51 - 3.52 (2H, t), 7.42 - 7.46 (1H, t), 7.65 - 7.69 (1H, t), 7.74 - 7.76
130 116 (lH,d), 7.83-7.88 (3H,m), 8.06-8.1 (lH,d), 8.21-8.23 (2H, d), 8.31 -
8.32 (1H, d), 8.82 (1H, s), 11.16 (1H, s)
1.55 (4H, bs), 1.63 - 1.64 (2H, bs), 3.39 - 3.42 (2H, t), 3.52 - 3.54 (2H, t),
7.87 - 7.95 (5H, m), 8.14- 8.18 (2H, m), 8.23 -8.25 (2H, d), 8.45- 8.5 (1H, 413
d), 9.59 (lH,s), 11.2 (lH,s)
3.53 - 3.58 (4H, m), 3.6 - 3.68 (4H, m), 7.87 - 7.98 (5H, m), 8.14 - 8.18 (2H,
132 118 m), 8.18-8.26 (2H,d), 8.47-8.51 (lH,d), 9.58 (lH,s), 11.25 (lH,s)

148
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
0.85 - 0.89 (3H, t), 1.51 - 1.56 (2H, m), 3.15 - 3.19 (2H, m), 7.9 - 7.94 (3H,
m), 8.02 - 8.09 (2H, d), 8.1-8.18 (2H, m), 8.23 - 8.26 (2H, d), 8.48 - 8.52 387
(1H, d), 9.07-9.1 (lH,t), 9.6 (lH,s), 11.03 (lH,s)
7.9 - 7.96 (3H, m), 8 - 8.06 (1H, m), 8.08 - 8.11 (2H, d), 8.14 - 8.18 (3H,
134 120 m), 8.23-8.25 (2H,m), 8.48-8.53 (lH,dd), 9.6 (lH,s), 11.02 (lH,s)
3.26 (3H, s), 3.38 - 3.41 (2H, t), 3.45 - 3.48 (2H, t), 7.9 - 7.95 (3H, m), 8.08
-8.11 (2H,d), 8.14-8.18 (2H,m), 8.23-8.26 (2H,d), 8.48-8.52 (lH,d), 403
9.6 (lH,s), 11.07 (lH,s)
3.18 - 3.21 (2H, bs), 3.33 (2H, bs), 3.39 - 3.46 (2H, bs), 3.79 (2H, bs), 6.82 -
6.84 (1H, dd), 6.92 - 6.95 (1H, dd), 6.98 - 6.99 (1H, t), 7.22 - 7.26 (1H, t), 483
136 122 7.67 - 7.69 (2H, d), 7.90 - 7.95 (3H, m), 8.15 - 8.19 (2H, m), 8.27 - 8.29 (2H,
d), 8.48 - 8.52 (1H, d), 9.6 (1H, s)
2.62 (2H, bs), 2.69 - 2.72 (2H, bs), 3.53 (2H, bs), 3.9 (2H, bs), 7.63 - 7.65
(2H, d), 7.89-7.92 (lH,d), 7.92-7.94 (2H,m), 8.14-8.19 (2H,m), 8.25- 390
8.28 (2H, d), 8.48 -8.52 ({1H, d), 9.6 (1H, s)
1.18-1.19 (6H, d), 1.54 (2H, bs), 1.78-1.82 (1H, bs), 1.93-1.96 (1H, bs), 2.6
(1H, bs), 2.98 (1H, bs), 3.12 (1H, bs), 3.39-3.49 (1H, bs), 4.34 (1H, bs),
138 124 4.87-4.94 (1H, m), 7.61-7.63 (2H, d), 7.9-7.91 (1H, d), 7.92-7.94 (2H, t),
8.14-8.19 (2H, m), 8.24 - 8.27 (2H, d), 8.47 - 8.51 (1H, d), 9.6 (1H, s)
3.43.3.44 (4H, bs), 3.5-3.55 (2H, bs), 3.78 (2H, bs), 6.88-6.9 (2H, d), 7.68-
7.71 (2H, d), 7.91-7.92 (1H, d), 7.93 -7.95 (2H, m), 8.15 -8.17 (2H, m), 8.2 450
139 125 -8.22(2H, m), 8.28 -8.3 (2H, d), 8.48 -8.52 (1H, d), 9.61 (1H, s)
2.38-2.44 (4H, bs), 3.38-3.42 (2H, t), 3.52-3.56 (4H, m), 3.57 (6H, m), 3.72-
3.75 (4H, t), 6.94-6.98 (1H, d), 7.15-7.13 (1H, d), 7.55-7.59 (2H, m), 7.64 - 464
7.68 (1H, t), 7.98 - 8.02 (3H, m), 8.12 - 8.14 (2H, d), 9.16 (1H, s)
1.07-1.08 (9H, d), 1.37-1.47 (2H, m), 1.64-1.67 (1H, m), 1.78 (1H, bs), 2.89-
2.93 (1H, m), 3.15-3.18 (1H, m), 3.44-3.52 (1H, m), 3.85-3.87 (1H, m), 4.47
141 128 (lH,bs), 7.24-7.26 (lH,d), 7.55-7.58 (2H,d), 7.9-7.94 (3H,m), 8.14-8.19
(2H, m), 8.26 - 8.29 (2H, d), 8.47 - 8.51 (1H, d), 9.59 (lH,s)
2.69 - 2.73 (1H, d), 2.89 (1H, s), 3.13 (4H, bs), 3.57 (4H, bs), 3.74 (8H, bs),
3.79 (2H, bs), 6.97 -6.99 (lH,d), 7.19 -7.21 (lH,d), 7.56 -7.6 (lH,d), 7.67 466
142 129 -7.72 (3H, m), 8.02 -8.06 (3H, t), 9.31 (1H, bs), 9.36 (1H, s)
1.86 - 1.94 (3H, m), 2.15 - 2.2 (4H, t), 2.69 (4H, s), 3.28 -3.36 (6H, t), 3.56 -
3.57(3H, m), 6.93 - 6.96 (1H, d), 7.13 -7.15 (1H, d), 7.55 - 7.59 (1H, d),
143 134 7.63-7.67 (lH,t), 7.86-7.89 (lH,d), 7.94-7.97(2H,m), 8-8.06 (lH,d),
8.09 -8.12 (lH,d), 8.9 (1H, m), 10.97 - 11.03 (1H, d)
2.41 (4H, t), 3.24-3.28 (2H, m), 3.42 - 3.44 (2H, m), 3.58 -3.59 (4H, m), 7.65
- 7.68 (1H, d), 7.85 (1H, d), 7.9 - 7.93 (3H, m), 8.02 - 8.04 (2H, d), 8.12 - 432
8.22 (4H, m), 8.46 -8.52 (1H, m), 9.6 (1H, s)

149
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
7.64 - 7.68 (1H, t), 7.8 - 7.85 (2H, m), 8.0 - 8.04 (2H, d),8.07 - 8.09 (3H, d),
145 137 8.21 - 8.26 (3H, t), 8.32- 8.41(2H,t), 8.48 -8.51 (1H, d), 10.99 (1H, s)
3.51 - 3.59 (4H, m), 3.62 - 3.68 (4H, m), 7.64 - 7.69 (1H, t), 7.8 - 7.84 ( 1H,
t), 7.86 (lH,s), 7.88-7.9 (2H,d), 8.02 -8.04 (1H, d), 8.08- 8.1(1H, d), 8.21 416
- 8.24 (3H, d), 8.31 - 8.35 (1H, d), 8.48 - 8.51(1H, d), 11.23 (lH,s)
3.42 -3.47 (2H, s), 3.65 -3.72 (8H, m), 7.41 -7.45 (2H, t), 7.49 - 7.56 (2H,
m), 7.56- 7.34(2H, m), 7.74-7.83 (2H, m), 8 -8.02 (1H, d), 8.04 (3H, s), 443
8.09-8.11 (1H, d), 9.21 (1H, s)
3.59 - 3.63 (2H, t), 4.4 -4.6 (2H, t), 6.83 (1H, d), 7.65 - 7.69(2H, t), 7.81 -
7-9(2H, m), 7.94-7.99 (5H,m), 8.02-8.07 (lH,d), 8.11 - 8.14 (1H, d), 8.22 446
-8.25(3H, dd), 8.27 -8.31 (1H, d), 8.43 -8.45 (1H, d), 9.12 (1H, s)
3.27 (4H, t), 3.92 (4H, t), 7.57 - 7.63 (4H, m), 7.69 - 7.73 (2H, d), 7.87 - 7.93
(4H,m), 8.02-8.09 (2H,m), 8.17-8.19 (2H, d), 8.28 - 8.32 (1H, d), 9.25 523
(lH,s), 9.36 (1H, s), 12.66 (1H, s)
1.67 - 1.83 (6H, m), 3.24 (4H, bs), 7.57 - 7.61 (4H, t), 7.69 - 7.79 (3H, m),
7.87 - 7.93 (5H, m), 7.96 -8 (2H, m), 8.17 -8.19 (1H, d), 9.22 -9.26 (2H, d), 521
150 145 12.63 (lH,s)
1.69 - 1.83 (6H, m), 2.53 (3H, s), 3.29 (4H, bs), 6.7 (1H, s), 7.59 - 7.63 (3H,
d), 7.68-7.81(2H,m), 7.92-7.99 (3H,m), 8.17-8.24 (2H,t), 9.55 (1H, s), 566
151 146 10.49 (lH,s)
1.28 (9H, s), 2.9 (6H, s), 6.47 - 6.48 (1H, d), 7.85 - 7.89 (1H, d), 8 - 8.04
(2H, m), 8.16 - 8.18 (1H, d), 8.24 - 8.3 (5H, m), 8.33 - 8.39 (2H, m), 8.46 496
(1H, bs), 9.62(1H,s)
3.31 (2H, bs), 3.54 (2H, bs), 3.64 (4H, bs), 3.88 (3H, s), 3.97 - 3.99 (6H, d),
7.26 (1H, s), 7.59 - 7.61 (2H, d), 7.76 -7.81 (1H, d), 8.07 -8.09 (1H, d), 8.16 463
- 8.19 (2H, d), 8.25 - 8.29 (1H, d), 8.59 - 8.61 (1H, d)
1.69 - 1.83 (6H, d), 3.3 (4H, bs), 7.03 - 7.08 (1H, m), 7.52 - 7.59 (2H, m),
7.65 - 7.69 (2H, t), 7.75-7.81 (3H, m), 7.92 -7.99 (2H, m), 8.18 -8.24 (2H, 546
t), 8.3 - 8.38 (2H, m), 9.57 - 9.59 (1H, d), 10.81 - 10.84 (1H, d)
1.1- 1.32 (7H, m), 1.52 - 1.55 (2H, m), 1.64 - 1.67 (4H, m), 1.82 (4H, bs),
3.24 - 3.29 (2H, t), 3.44 - 3.5 (2H, m), 6.24 - 6.26 (1H, d), 7.49 (2H, d), 7.58
155 150 -7.6(1H, d), 7.68-7.77 (lH,m), 7.83 -7.9 (2H, d), 7.96 -7.99 (1H, d), 8.1
- 8.13 (1H, d), 8.17 - 8.35 (1H, m), 8.74 (1H, s), 8.88 (1H, s)
1.72-1.79 (2H, m), 1.97-2.01 (1H, m), 3.23 (1H, bs), 3.39 (3H, s), 3.52-3.67
(4H,d), 4.04 (lH,bs), 7.56-7.6 (3H, m), 7.68-7.7 (1H, d), 7.78 (1H, bs), 7.85-
7.87 (1H, d), 7.95-8.03 (1H, d), 8.15-8.17 (4H, d), 8.23-8.25 (1H, d)

150
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
1.7 (6H, s), 3.65 (4H, s), 6.58-6.59 (1H, m), 6.72-6.79 (1H, m), 7.5-7.53 (1H,
157 152 t), 7.61-7.7 (lH,d), 7.97-8.01 (lH,d), 8.12 -8.28 (6H, m), 8.49 (lH,d)
1.27 (6H, bs), 2.28 (3H, s), 2.67 (3H, s), 3.65 (4H, s), 6.11 (1H, s), 6.73-6.79
158 153 (2H,m), 7.48-7.53 (lH,m), 7.62-7.67 (lH,d), 7.95-7.99 (lH,d), 8.1 (4H,s)
1.25-1.27 (6H, d), 1.69 (9H, s), 1.7-2.06 (3H, m), 3.09 - 3.11 (2H, bs), 3.64 -
3.7 (4H, s), 4.54 - 4.56 (1H, bs), 5.02 - 5.08 (1H, m), 6.73 - 6.78 (2H, t), 7.48 512
- 7.55 (3H, m), 7.6 - 7.64 (1H, d), 7.93 - 7.97 (1H, d), 8.06 - 8.08 (1H, d)
3.4 . 3.44 (2H, t), 3.57 - 3.62 (2H, t), 7.13 - 7.14 (1H, m), 7.35 - 7.36 (1H,
d), 7.62 - 7.67(2H, t), 7.83 - 7.95 (4H, m), 8.13 - 8.19 (5H, m), 8.27 - 8.29 454
(2H, d), 8.46 -8.5 (1H, d), 9.59 (1H, s)
3.25 - 3.29 (2H, m), 3.39 - 3.41 (2H, t), 3.54 - 3.56 (4H, t), 3.72 - 3.74 (4H,
t), 6.61 - 6.67 (1H, m), 6.92 - 6.95 (1H, d), 7.11 - 7.14 (2H, t), 7.35 - 7.37
161 157 (1H, d), 7.51-7.55 (1H, d), 7.58- 7.6 (2H, d), 7.62 -7.68 (3H, m), 7.99 -
8.03 (2H, m), 9.12 (1H, s)
3.05 - 3.08 (2H, t), 4.11 - 4.15 (2H, t), 7.6 - 7.65 (3H, m), 7.68 - 7.7 (2H, d),
7.89 - 7.93 (3H, m), 7.81 - 7.85 (3H, m), 8.14 -8.2 (4H, m), 8.46 - 8.5 (1H, 502
d), 9.58 (lH,s), 10.21 (lH,s)
3.25 - 3.29 (2H, t), 3.36 (2H, t), 3.55 - 3.56 (4H, t), 3.72 - 3.75 (4H, t), 6.92 -
6.95 (1H, d), 7.11 - 7.14 (1H, d), 7.35 - 7.37 (1H, d), 7.51 - 7.59 (3H, m),
163 159 7.62 - 7.67 (2H, m), 7.99 - 8.03 (3H, m), 8.08 - 8.14 (1H, m), 8.43 - 8.45
(1H, d), 9.08 - 9.13 (1H, d), 9.8 (2H, bs)
3.57 - 3.68 (8H, d), 7.62 - 7.69 (3H, m), 7.81 - 7.89 (2H, m), 8.02 - 8.04 (1H,
164 162 s), 8.08-8.1l(lH,d), 8.22-8.25 (3H,m), 8.49-8.51 (lH,s)
1.54 - 1.63 (6H, d), 1.68 (3H, s), 3.39 - 3.44 (2H, m), 3.51 - 3.57 (6H, m),
3.72 - 3.74 (4H, t), 6.92 - 6.93 (1H, d), 7.12 - 7.14 (1H, d), 7.55 - 7.59 462
(lH,s), 7.63 - 7.67 (1H, t), 7.83 - 7.86 (2H, d), 8 - 8.18 (2H, d), 10.1 (1H, s)
3.51 - 3.6 (4H, m), 3.62 - 3.69 (4H, m), 7.64 - 7.69 (1H, t), 7.84 - 7.86 (2H,
m), 7.88-7.9 (2H,d), 8.02-8.04 (lH,s), 8.08-8.1(lH,m), 8.21-8.24 (3H, 483
166 164
m), 11.23 (1H, s)
3.43 - 3.6 (12H, bs), 3.75 - 3.81 (4H, bs), 7.58 - 7.67 (2H, m),7.73 - 7.83
167 165 (4H, m), 8.01-8.08 (2H,m), 8.11-8.13 (2H,d), 8.49 (lH,s)
1.53 - 1.64 (6H, bs), 1.69 (3H, s), 3.39 - 3.48 (2H, bs), 3.51 - 3.57 (6H, s),
3.72-3.74(4H, t), 6.92-6.94 (lH,d), 7.12-7.14 (lH,d), 7.55-7.59 (1H, 436
s), 7.63 - 7.67(1H, t), 7.83 - 7.86 (2H, d), 8-8.18 (2H, d), 8.34 (1H, s)

151
Ex Comp
No. No. 1H NMR (400 MHz, δ, DMSOd6) Mass, m/z
3.25 - 3.29 (2H, t), 3.36 (2H, t), 3.55 - 3.56 (4H, t), 3.72 - 3.75 (4H, t), 6.92
- 6.95 (1H, d), 7.11 - 7.14 (1H, d), 7.35 - 7.37 (1H, d), 7.51 - 7.59 (2H, m),
169 167 7.62-7.67 (2H, m), 7.99-8.03 (3H, m), 8.08-8.14 (2H, m), 8.43 - 8.45
(1H, d), 9.08 - 9.13 (1H, d), 9.8 (2H, bs)
1.72 - 1.79 (2H, m), 1.97 - 2.03 (2H, m), 2.84 - 2.91 (4H, m), 3.6 - 3.63
(3H, m), 4.4 (lH,m), 4.5 - 4.8 (2H, t), 7.43 - 7.45 (2H, t), 7.49 - 7.56 (2H,
170 168 m), 7.58 - 7.63 (2H, m), 7.76 - 7.83 (2H, m), 8 - 8.02 (1H, d), 8.06 (3H, s),
8.09-8.13 (1H, d), 9.28 (1H, s)
BIOLOGICAL EVALUATION
Example (I)
Effect of compounds of the instant invention on Cellular Expression of HSP
1.1 Background:
Experiments set forth in this section were conducted to determine whether the compounds
of the present invention are able to elevate the expression of HSP-70 gene in cells.
1.2 In vitro screening for HSP Induction
1.21 Materials and Methods:
1.21 (a) Cell Culture Conditions
HeLa cells were obtained from American Type Culture Collection (ATCC) (CCL-2). The
cells were seeded in a 96 well flat bottom plate (Corning), at a density of 20,000 cells /
well in 200 μl culture medium consisting of Minimum Essential Medium (MEM) and 10
% Fetal Bovine Serum (Hyclone, USA), and allowed to grow for 24 hours at 37°C in a
CO2 incubator to reach a confluency of 75-80%.
1.21 (b) Compound treatment
A 200X stock of the test compounds was prepared in the appropriate solvent and 1 μl of
said stock was added to each well, so that the final DMSO (Dimethyl sulfoxide)

152
concentration per well was 0.5%. Each test compound was tested in triplicate. The plate
was incubated at 37°C in a CO2 incubator for 4 hours. At the end of the incubation period,
the total RNA was isolated from the cells as described hereinbelow.
1.21 (c) RNA Isolation & Quantification
RNA was isolated using either Tri Reagent (Sigma) or Trizol (Invitrogen). RNase AWAY
(Molecular Bioproducts) was applied to working surfaces and pipettes in order to
inactivate RNases. The RNA pellet obtained after isopropyl alcohol precipitation was
finally reconstituted in Diethyl pyrocarbonate (DEPC) treated water (0.01% v/v) and
quantitated by taking OD (Optical density) values at 260 and 280 nm on a Beckman
spectrophotometer. OD value of 1 at 260 nm corresponds to an RNA concentration of 40
μg / ml.
1.21 (d) DNase Treatment
RNA was treated with DNase (MBI Fermetas) to remove the genomic DNA
contamination. RNA was treated with 1U of DNase / μg of RNA in 10 X DNase buffer in
a 15 μl reaction and the reaction mix was incubated at 37°C for 30 minutes. After the
reaction was over, 1.5 μl of 25 mM of EDTA (MBI Fermentas) was added per sample and
the reaction mix incubated further at 65°C for 10 minutes.
1.21 (e) cDNA Synthesis:
In this step, RNA is converted into a single stranded cDNA employing High capacity
cDNA archive kit (Part No. 4322171 Applied Biosystems USA) with the reverse
transcriptase enzyme using random hexamers and dNTPs (Deoxyribonucleotide
Triphosphate). For each DNase treated 1 μg of RNA sample, the following components
were added for cDNA synthesis: 2.5 μl 10X reverse transcriptase buffer, 1 μl 25X dNTPs,
2.5 μl 10X Random primer, 1.25 μl Multiscribe reverse transcriptase and Diethyl
pyrocarbonate (DEPC) treated water (0.01% v/v) to make a final 25 μl reaction mix. The
cDNA reaction mix was incubated further at 25°C for 10 minutes followed by incubation
at 37°C for 120 minutes.
1.21 (f) Real time PCR Reaction Setup
Real time PCR reaction was performed using ABI 7000 SDS under universal cycling

153
conditions. A multiplex real time PCR reaction was set up as follows. The final reaction
mix contained 2.5 μl cDNA reaction mix, 0.625 μl 20X human HSP-70 Taqman probe and
primer mix (Part No 4331182 Applied Biosystems USA), 0.625 μl 20X 18S rRNA
Taqman probe and primer mix (Part No 4319413 Applied Biosystems USA) (as internal
control) and 6.25 μl 2X Taqman universal master mix (Part No. 4304437 Applied
Biosystems USA) in a final volume of 12.5 μl. In each plate, a reaction without cDNA was
also run to serve as NTC (No Template Control). Each condition was run in duplicate.
1.21 (g) Data Analysis
Data analysis was performed by comparative CT (Cycle Threshold) method. HSP-70b
mRNA expression was normalized relative to the expression of 18S ribosomal RNA for
that sample. The results for test compounds were expressed as fold induction of HSP-70b
mRNA relative to vehicle treated control and are as shown in Table 2
In the Table 2, 0 indicates < 4 fold, while +, ++, +++ and ++++ indicate 4-24 fold, 25-192
fold, 193-1536 fold, and >1536 fold induction of HSP-70b mRNA, respectively, relative
to the vehicle treated control.
Table -2
HSP-70b mRNA
Comp. induction
Compound . .
No. (at a concentration
of 25 μM)
2 l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidin-4-one +++
3 l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-
propenone
6 1 -[4-(Piperazine-1 -carbonyl)-phenyl]-3-quinolin-2-yl-propenone +++
10 3-Quinolin-2-yl- l-[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone ++++
12 l-[4-(Piperidine- l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone +++
l-(4-[4-(3-Chloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-quinolin-2-
yl-propenone
16 l-(4-[4-(2,3-Dichloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3- ++++
quinolin-2-yl-propenone
17 N-(4-{2-Oxo-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-piperazin-l-yl}- ++++
phenyl)-acetamide

154
Comp. induction
Compound
No. (at a concentration
of 25 μM)
4-Imidazol- l-yl-2-[3-oxo-3-(4-trichloromethoxycarbonylamino-phenyl)-
propenyl]-quinoline-6-carboxylic acid methyl ester
3-Quinolin-2-yl-l-{4-[4-(tetrahydro-furan-2-carbonyl)-piperazine-l- +
carbony l]-phenyl} -propenone
l-{4-[4-(Furan-2-carbonyl)-piperazine-l-carbonyl]-phenyl}-3-quinolin-2- ++
yl-propenone
23 {4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ++++
ethyl ester
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ++++
2,2-dimethyl-propyl ester
25 l-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-3-(2- ++++
trifluoromethyl-phenyl)-urea
l-Benzenesulfonyl-3-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]- ++++
phenyl}-urea
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid
ethyl ester
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid
isobutyl ester
31 {4-[3-(2-Pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid
ethyl ester
43 l-[4-(2,3-Dihydro-indole-l-carbonyl)-phenyl]-3-(3-hydroxy-quinoxalin-2-
yl)-propenone
45 l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-one oxime +++
59 l-Benzenesulfonyl-3-{4-[3-(6-methy!-4-piperidin-l-yl-quinolin-2-yl)- ++++
acryloyl]-phenyl}-urea
{4-[3-(6-[l,2,3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-
carbamic acid phenyl ester
(4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-
morpholin-4-yl-ethyl ester
{5-Methoxy-2-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}- 0
carbamic acid methyl ester
70 Propyl-{4-[3-(2-pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}- 0
carbamic acid ethyl ester
(4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid
phenyl ester
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}- +++
carbamic acid methyl ester
l-(4-Methyl-benzenesulfonyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H- +
[ 1,2']bipyridinyl-6'-yl)-acryloyl]-phenyl }-urea
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-
carbamic acid ethyl ester
84 (4-{3-[6-(3,5-Dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-phenyl)- 0
carbamic acid phenyl ester

155

Comp. induction
Compound ,
No. (at a concentration
of 25 μM)
5'-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyI]-3,4,5,6- 0
tetrahydro-2H-[l,2']bipyridinyl-4-carboxylicacid
90 {4-[3-(6-Pyrrolidin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid ++++
pyridin-2-ylmethyl ester
91 {4-[3-(6-Pyrrolidin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 4- ++++
fluoro-benzyl ester
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}- ++
carbamic acid 2-(3,5-dimethyl-pyrazol-l-yl)-ethyl ester
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}- +++
carbamic acid furan-2-ylmethyl ester
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}-
carbamic acid 3-phenyl-allyl ester
95 {4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]-phenyl}- ++++
carbamic acid 2-piperidin-l-yl-ethyl ester
96 {4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid
methyl ester
110 (4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-
carbamic acid phenyl ester
111 (4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-
carbamic acid methyl ester
112 (4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-
carbamic acid ethyl ester
113 l-Benzenesulfonyl-3-(4-{3-[6-(3,5-dimethyl-morpholin-4-yl)-pyridin-3-
yl]-acryloyl}-phenyl)-urea
121 N-(2-Methoxy-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-
oxalamide
126 l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-2- ++++
piperidin- l-yl-ethyl)-urea
127 l-(2-Morpholin-4-yl-ethyl)-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)- ++++
acryloyl]-phenyl} -urea
129 (4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2- ++++
piperazin- 1-yl-ethyl ester
130 N-(2-Morpholin-4-yl-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]- 0
oxalamide
131 l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-
(pyridine-2-sulfonyl)-ethyl]-urea
132 l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridin- ++++
2-ylsulfanyl)-ethyl]-urea
133 l-[2-(4-Methyl-piperazin-l-yl)-ethyl]-3-{4-[3-(6-morpholin-4-yl-pyridin-
2-yl)-acryloyl]-phenyl} -urea
Discussion

156
As seen in Table 2, HSP-70b mRNA levels were increased over control after treatment
with compounds of the invention. The compounds of the instant invention have the ability
to induce HSP-70.
Example (II)
In vitro screening for TNF-a expression
1.1 Background
The purpose of the present study was to determine the inhibition of lipopolysaccharide
(LPS)-induced TNF-a expression in phorbol merstyl ester (PMA) differentiated THP-1
cells.
1.2 Materials and Methods:
1.21 (a) Cell Culture Conditions
Human monocytic leukaemia cell line, THP-1, were obtained from American Type
Culture Collection (ATCC) (TIB-202). Human monocytic leukaemia cell line, THP-1
differentiated into macrophage-like cells by Phorbol merystyl ester (PMA) (Sigma)
treatment was employed for the experiments. The cells were seeded in a 24 well flat
bottom plate (Corning), at a density of 300,000 cells/well in a 2 ml culture medium
comprising RPMI 1640 Medium and 10 % Fetal Bovine Serum (Hyclone, USA)
containing PMA (25 ng / ml) and allowed to differentiate for 44 hours at 37°C in a CO2
incubator.
1.22 (b) Compound treatment
The differentiated cells were then treated with either LPS (Sigma) (lug / ml) alone or with
LPS (lug / ml) and the test compound for 4 hours. At the end of the incubation period, the
total RNA was isolated from the cells as described hereinbelow.
1.22 (c) RNA Isolation & Quantification
RNA was isolated using either Tri Reagent (Sigma) or Trizol (Invitrogen). RNase AWAY
(Molecular Bioproducts) was applied to working surfaces and pipettes in order to

157
inactivate RNases. The RNA pellet obtained after isopropyl alcohol precipitation was
finally reconstituted in Diethyl pyrocarbonate (DEPC) treated water (0.01% v/v) and
quantitated by taking OD (Optical density) values at 260 and 280 nm on a Beckman
spectrophotometer. OD value of 1 at 260 nm corresponds to an RNA concentration of 40
μg / ml.
1.22 (d) DNase Treatment
RNA was treated with DNase (MBI Fermetas) to remove the genomic DNA
contamination. RNA was treated with 1U of DNase / μg of RNA in 10 X DNase buffer in
a 15 μl reaction and the reaction mix was incubated at 37°C for 30 minutes. After the
reaction was over, 1.5 μl of 25 mM of EDTA (MBI Fermentas) was added per sample and
the reaction mix incubated further at 65°C for 10 minutes.
1.22 (e) cDNA Synthesis:
In this step, RNA is converted into a single stranded cDNA employing High capacity
cDNA archive kit (Part No. 4322171 Applied Biosystems USA) with the reverse
transcriptase enzyme using random hexamers and dNTPs (Deoxyribonucleotide
Triphosphate). For each DNase treated 1 μg of RNA sample, the following components
were added for cDNA synthesis: 2.5 μl 10X reverse transcriptase buffer, 1 μl 25X dNTPs,
2.5 μl 10X Random primer, 1.25 μl Multiscribe reverse transcriptase and Diethyl
pyrocarbonate (DEPC) treated water (0.01% v/v) to make a final 25 μl reaction mix. The
cDNA reaction mix was incubated further at 25°C for 10 minutes followed by incubation
at 37°C for 120 minutes.
1.22 (f) Real time PCR Reaction Setup
Real time PCR reaction was performed using ABI 7000 SDS under universal cycling
conditions. A multiplex real time PCR reaction was set up as follows. The final reaction
mix contained 2.5 μl cDNA reaction mix, 0.625 μl 20X Human TNF-α Taqman probe and
primer mix (Part No 4327055F Applied Biosystems USA), 0.625 μl 20X 18s rRNA
Taqman probe and primer mix (Part No 4319413E Applied Biosystems USA) (as internal
control) and 6.25 μl 2X Taqman universal master mix (Part No. 4304437 Applied
Biosystems USA) in a final volume of 12.5 μl. In each plate, a reaction without cDNA was
also run to serve as NTC (No Template Control). Each condition was run in duplicate.

158
1.22 (g) Data Analysis
Data analysis was performed by comparative CT method. TNF-α mRNA expression was
normalized relative to the expression of 18S ribosomal RNA for that sample. Considering
TNF-α expression for cells treated with LPS alone as 100%; the results for test
compounds were expressed as % inhibition of TNF-α expression and are as shown in
Table 3
In the Table 3, 0 indicates <20 % while +, ++, +++, ++++ indicate 21-40 %, 41-60 %, 61-
80 % and >80 % inhibition of TNF-α expression, respectively.
Table 3
TNF alpha mRNA
Comp. inhibition (at a
Compound
No. concentration of 25
μM)
2 l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidin-4-one ++++
3 l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-
propenone
6 l-[4-(Piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone ++
10 3-Quinolin-2-yl-l-[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone +++
12 l-[4-(Piperidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone ++++
15 l-{4-[4-(3-Chloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-
quinolin-2-yl-propenone
16 l-{4-[4-(2,3-Dichloro-phenyl)-piperazine-l-carbonyl]-phenyl}-3-
quinolin-2-yl-propenone
l-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-3-(2- ++++
trifluoromethyl-phenyl)-urea
26 l-Benzenesulfonyl-3-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-
acryloyl]-phenyl}-urea
67 {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic ++++
acid 2-morpholin-4-yl-ethyl ester
92 {4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]- ++++
phenyl}-carbamic acid 2-(3,5-dimethyl-pyrazol-l-yl)-ethyl ester
93 {4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]- ++++
phenyl}-carbamic acid furan-2-ylmethyl ester
95 {4-[3-(3,4,5,6-Tetrahydro-2H-[l,2']bipyridinyl-6'-yl)-acryloyl]- ++++
phenyl}-carbamic acid 2-piperidin- 1-yl-ethyl ester
121 N-(2-Methoxy-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-
oxalamide

159
TNF alpha mRNA
Comp. inhibition (at a
Compound
No. concentration of 25
μM)
126 l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-
2-piperidin-l-yl-ethyl)-urea
127 l-(2-Morpholin-4-yl-ethyl)-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-
acryloyl]-phenyl }-urea
Discussion
As seen in Table 3, LPS-induced TNF-α expression was inhibited by the treatment with
compounds of the invention.
IN VIVO ACTIVITY
Example (III)
Assessment of neuroprotective efficacy
1.1 Materials and Methods:
Male Sprague-Dawley rats weighing 240-270 g were used. During the operation, the body
temperature of the animals was maintained constant at 37°C, using a homoeothermic
blanket. Anaesthesia was induced with chloral hydrate. Permanent cerebral ischemia was
induced in these animals by intraluminal suture occlusion technique. A 25 mm length of
Poly-L-Lysine coated Ethilon suture (3-0) was inserted from the proximal external carotid
artery into the lumen of the internal carotid artery until mild resistance was felt [Longa
E.Z. et al., Stroke, 1989, 20, 84-91]. At the end of 24 hrs, all the animals were sacrificed
and the infarct characterized after staining with triphenyl tetrazolium chloride (TTC). The
stained slices were captured using an ordinary document scanner and was analysed for
infarct size and edema using the Scion® image analysis software. Neurological scores were
obtained at two time points, one after the recovery of the animals from anaesthesia and the
other, at the end of 24 hours just before the animals were sacrificed.
Table 4 : Neurological Scores

160
Score Parameters
0 No Deficit
1 Failure to extend Right forepaw fully (Mild focal
neurological deficit)
2 Circling to the contra lateral side (Moderate focal
neurological deficit)
3 Falling to the contra lateral side
(Moderate to severe focal neurological deficit)
4 Depressed level of Consciousness (severe focal
neurological deficit)
Statistical analysis on the data obtained was performed using student's t-test, and the level
of significance was p < 0.05. The results are shown in Table 5.

Table 5
i.v. % Reduction % Reduction % Improvement
Treatment Dose Infarct Edema Mean Neurological
(mg/kg) Score
HC1 salt of Compound No. 3 4.6 13.1 53.4 75.0
Compound No. 16 3.89 26.4 77.4 Nil
Compound No. 16 (Multiple Dose) 3.89 24.5 65.6 100.0
HCI salt of Compound No. 23 0_81 6.5 3.7 Nil
1.2 Discussion of test results:
The ability of a neuronal population to survive an ischemic trauma (like cerebral
ischemia) is correlated with increased expression of HSP 70. Test compounds presented in
Table 2 shows the ability to induce HSP-70 in vitro. Further it is also observed (Table 3)
that test compounds of the present invention also inhibit TNF-α in cultured cells incubated
with the above said drugs. HSP-70 mRNA was induced in neurons at the periphery of
ischemia (penumbra). It is proposed that the peripheral zone of ischemia (penumbra) can
be rescued from getting infarcted by pharmacological agents. [Dienel G.A. et al., J. Cereb.
Blood Flow Metab., 1986, Vol. 6, pp. 505-510; Kinouchi H. et al., Brain Research, 1993,
Vol. 619, pp. 334-338].The in vivo experiments carried out with the representative test
compounds, the hydrochloride salt of Compound No. 3, the hydrochloride salt of
Compound No. 23 and Compound No. 16 to assess their neuroprotective effect show
neuronal protection, i.e. reduced infarct size and reduced brain edema following cerebral
ischemic insult. These results very well correlate with results of our in vitro data. Hence, it
can be concluded that compounds of the instant invention would be useful as
neuroprotective agents by virtue of their HSP-70 inducing activity.

161
Example (IV)
Assessment of anti-inflammatory activity
1.1 Materials and Methods:
Anti-inflammatory activity of the test compound was determined using standard
procedures. [Enna SJ, Williams M, Ferkany JW, Eds., "Current Protocols in
Pharmacology", John Wiley & Sons Inc., 1998, pp. 5.4.1 to 5.4.3]. Male Sprague-Dawley
rats of 200-250 g body weight were used for the study. The animals were divided
randomly into two groups - Vehicle (saline control) and Treatment group. For induction
of acute inflammation, 50 μl of 0.5 % Carrageenan solution was injected into the right
hind paw of all rats. The representative test compound, the hydrochloride salt of
Compound No. 3, was administered by intraperitoneal route twice to all the animals in the
treatment group i.e. 4.6 mg/kg, 2 hrs prior and 2.3 mg/kg, 2 hrs later to the Carrageenan
injection, while all the animals in the vehicle group received vehicle (saline) by i.p. route
at similar time points.. The volume of the right (injected) paw was measured at 0, 1,3 and
6 hours using a plethysmometer. The volume of the right paw for each animal was
measured and the mean difference in volume for the drug and vehicle group was
calculated. Statistical analysis on the data obtained was performed using student's t-test,
and the level of significance was p< 0.05. The results are shown in Table 6.
Table 6
Treatment i.p. Dose % Reduction in Inflammation at different time intervals
(mg/kg) 0 hr 1 hr 6 hr
HC1 salt of Compound
No. 3 4.6 0.0 52.7 36.2
1.2 Discussion of test results:
It can be seen from the Tables 2 and 3 that the compounds of the present invention
induce HSP-70 as well as inhibit TNF- α in cultured cells incubated with the above said
drugs.

162
Many investigators have shown anti-inflammatory properties exhibited by
constitutive and inducible heat shock proteins. It has been demonstrated that HSP-72
expression occurs in inflamed tissue and this effect is associated with the remission of the
inflammatory reaction. [Ianaro A et. al., Mol Pharmacol., 2003 Jul; Vol 64(1), pp. 85-93].
Hence, therapy with HSP inducing compounds would be useful in treating acute and
chronic inflammatory conditions including arthritis. The representative test compound, the
hydrochloride salt of Compound No. 3 when investigated for its anti-inflammatory activity
in a rat model of inflammation, was shown to possess anti-inflammatory activity. This
activity well correlates with our in vitro finding of increased HSP-70 mRNA levels with
the hydrochloride salt of Compound No. 3, and further it was also observed that there was
an inhibition of TNF-α in cultured cells incubated with the above said drugs suggesting the
role of HSPs in anti-inflammatory activity and hence it can be concluded that the
compounds of the instant invention would be useful for the treatment of inflammatory
disorders.
Example (V)
Assessment of the efficacy of compounds of the instant invention in Myocardial
Infarction (MI)
1.1 Materials and Methods:
Male Sprague-Dawley rats weighing 250-300g were anaesthetized using Urethane.
The body temperature of the anaesthetized animal was maintained at 37°C, using
homoeothermic blanket. The carotid artery and the jugular vein were cannulated for
recording the blood pressure and for the intravenous administration of test compounds,
respectively. ECG (lead II) was recorded with electrode fixed on to the limbs.
Tracheotomy was performed to allow artificial ventilation using an animal ventilator.
The left anterior descending coronary artery (LADCA) was ligated by the standard
method of Thiemermann et al. 1989 [Thiemermann, C. et al., Brit. J. Pharmacol.,1989,
Vol. 97, pp. 401-408], and a successful occlusion was confirmed by a fall in blood
pressure and elevation of the ST segment region of the ECG. The test compound / vehicle

163
was administered intravenously immediately on occlusion and 2 hrs post occlusion. The
occlusion was continued for an hour and was then released to enable reperfusion for the
next two hours. At the end of reperfusion period the animals were sacrificed and heart was
isolated and Evan's blue dye is passed through the coronaries to differentiate the area at
risk from the normally perfused tissue and infarct characterized using TTC staining
technique. The infarct as a percentage of left ventricle and area at risk was calculated.
Statistical analysis on the data obtained was performed using student's t-test, and the level
of significance was p < 0.05. The results are shown in Table 7.
Table 7
Percentage Mean
Treatment
INF / LV INF/AAR
Vehicle * 26.8 45.9
HCI salt of 9.3 15.6
Compound No. 3
(3.43 mg/kg)**
% Reduction by Test 65.4
Compound
* Vehicle (0.9 % saline) was administered to Control Group
** Compound was administered intravenously to Test Group.
INF = Infarct; LV = Left ventricle; AAR = Area at risk; INF/LV = Infarct as a percent of
left ventricle; INF/AAR = Infarct as a percent of area at risk
1.2 Discussion of test results
There is abundant evidence, which supports the role of HSP-70 in protection
against ischemic myocardial injury. Induction of HSP-70 has been shown to confer
protection against subsequent ischemia as is evidenced by a direct correlation to post-
ischemic myocardial preservation, reduction in infarct size and improved metabolic and
functional recovery. [Liu X. et. al., Circulation, 1992, Vol. 86, pp. II358-II363; Martin
J.L., Circulation, 1997, Vol. 96, pp. 4343-4348]. In this context, we found (as indicated in
Table 7) that there was a greater reduction in myocardial infarct size in a rat model of
Myocardial infarction, following treatment with a representative compound, the
hydrochloride salt of Compound No. 3. The correlation between the in vivo and in vitro
results showing increased HSP-70 mRNA levels subsequent to incubation with the
hydrochloride salt of Compound No. 3 in cultured cells substantiates the earlier evidence
about the potential role of HSP-70 in protection of ischemic myocardial injury. Hence, it

164
can be concluded that compounds of the instant invention would be useful in the treatment
of myocardial infarction by virtue of their HSP inducing activity.
It is to be understood that this invention is not limited to the particular
methodology, protocols, cell lines, constructs, and reagents described herein and as such
may vary. It is also to be understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to limit the scope of the
present invention, which will be limited only by the appended claims.
FORMULATION EXAMPLES
The following pharmaceutical formulations are suggested by way of examples
alone and in no way restrict the forms in which they can be used.
Example 1: A parenteral formulation of the following formula can be prepared as
follows:
Ingredient Quantity
Compound of formula (I) 2.0 mg/ml
N-Methyl-2-pyrrolidone 10% w/v
Buffer pH 9.2 q.s. to 1 ml
Compound is dissolved in N-Methyl-2-pyrrolidone with sonication.The volume is made
up with pH 9.2 Buffer, and the resulting solution is filtered through a 0.22 micron filter.
Example 2: A typical parenteral formulation of the following formula can be prepared as
follows:
Ingredient Quantity
Compound of formula (I) 1 mg/ml
Dichloromethane 1 ml
Tween - 80 0.5 % w/v
Water for injection q.s.

165
Compound is dissolved in dichloromethane. Tween-80 containing solution is mixed with
the drug solution and homogenized to get a nanosuspension.
Example 3: A typical parenteral emulsion formulation of the following formula can be
prepared as follows:
Ingredient Quantity
Compound of general formula I 10 mg/ml
Oleic acid 10% w/v
Tween-80 0.5 % w/v
Purified water q.s. to 1 ml
Compound is mixed with Oleic acid & Tween-80 and the mixture warmed to a
temperature of 40-50°C. Purified water pre-warmed to 40-50°C is mixed with above
mixture.
Example 4: A typical solid pharmaceutical formulation can be prepared with the
following materials together in the proportions by weight specified below:
Ingredient Quantity
Compound of formula (I) 25
Microcrystalline Cellulose pH 102 69
Colloidal Silicon Dioxide 0.5
Sodium starch glycolate 5.0
Magnesium Stearate 0.5
Compound of formula (I) is mixed with Microcrystalline Cellulose pH 102, Aerosil and
blended with Sodium Starch Glycolate and Magnesium Stearate. Blend was compressed
into tablets using 7 mm punches to contain 25 mg of compound of formula (I). Other
tablets may be compressed to contain 50, 75,100, 150 and 200 mg of compound of
formula (I).
OTHER FORMULATIONS

166
Using an active ingredient of formula (I), various other formulations such as gels,
creams, lotions, pastes, oral rinse, transdermal, ophthalmic solutions etc. may be prepared.
The above examples are provided by way of illustration alone and in no way
restrict the scope of the invention.

167
WE CLAIM :
1. A compound of general formula (I),

or its tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts,
pharmaceutically acceptable solvates or prodrug , wherein Q represents a heteroaryl ring,
said heteroaryl ring containing upto 2 nitrogen atoms and is selected from :


168

wherein, Q is optionally substituted by R1 and / or R2, and the number of substituents are
selected from one to six;
R1 is independently selected at each occurrence from -SO2OR7, -SO2O(C1-8 alkyl), -
NHNH2, -NHNHSO2R7, -NH(CH2)nR4, -NHCO2R7, -NHCO2(C1-8alkyl), -NHSO2O(C1-
8alkyl), -NHSO2OR7, -NHSO2NH2, -NH(CH2)nCOR4, -NH(CH2)nOR4, -NH(CH2)nSR7, -
NH(CH2)nSO2R7, -NH(CH2)nNHCOR4, -NH(CH2)nN(C1-8alkyl)COR4, -N(C1-
8alkyl)(CH2)nNHCOR4, -NH(CH2)nNHNHSO2R7, -NH(CH2)nNHSO2R4,
NH(CH2)nN(C1-8alkyl)SO2R4, -NH(CH2)nN(NH2)R7, -NH(CH2)nN[N(C1-8alkyl)2]R7, -
N(C1-8alkyl)CO2R7, -N(C1-8alkyl)CO2(C1-8alkyl), -N(C1-8alkyl)SO2O(C1-8alkyl), -N(C1-
8alkyl)SO2OR7, -N(C1-8alkyl)SO2NH2, -N(C1-8alkyl)N(C1-8alkyl)2, -N(C1-8alkyl)NH2 -
NHNHCO(C1-8alkyl), -N(C1-8alkyl)NHCO(C1-8alkyl), -NHNHCOR7, -N(C1-
8alkyl)NHCOR7, -N(C1-8alkyl)-(CH2)nR4, -N(C1-8alkyl)(CH2)nCOR4, -(CH2)nSO2R7, -
(CH2)nCOR4, -(CH2)nR4, -(CH2)nNHSO2R4, -(CH2)nN(C1-8alkyl)SO2R4,
(CH2)nNHCOR7, -(CH2)nN(C1-8alkyl)COR7, -(CH2)OR4, -(CH2)nSR4, -(CH2)nSR3, -
(CH2)nSO2R7, -(CH2)nNHNHSO2R7, -(CH2)nN(NH2)R7, or - (CH2)nN[N(C1-8 alkyl)2]R7 ;
R2 is independently selected at each occurrence from hydrogen, hydroxy, halo, amino, C1-
8alkyl, -O(C1-8alkyl), -S(C1-8alkyl), -SO2(C1-8alkyl), oxo, thioxo, mono(C1-8alkyl)amino,
di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyl), -
NHSO2CF3, -N(C1-8alkyl)SO2CF3, -NHSO2O(C1-8alkyl), -N(C1-8alkyl)SO2(C1-8alkyl), -
N(C1-8alkyl)SO2O(C1-8alkyl), -COOH, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-
8alkyl)CO2(C1-8alkyl), -CONH2, -CONH(C1-8alkyl), -CON(C1-8alkyl)2, formyl, CF3, CN, -
(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyl), -(CH2)nN(C1-8alkyl)2, -(CH2)nO(C1-8alkyl),
-SO3H, -SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8alkyl)2, -SO2NH(C1-8alkyl), -OSO2(C1-
8alkyl), -N(C1-8alkyl)SO2NH2, -NHSO2NH(C1-8alkyl), - NHSO2N(C1-8alkyl)2, -N(C1-
8alkyl)SO2N(C1-8alkyl)2, -NHSO2NH2, -NHC(NH)NH2, -NHCONH2, -NHC(O)NH(C1-
8alkyl), -NHC(O)N(C1-8alkyl)2, -N(C1-8alkyl)C(O)N(C1-8alkyl)2, -NHNH2, -N(C1-

169
8alkyl)N(C1-8alkyl)2, -N(C1-8alkyl)NH2, tetrazolyl or three- to seven-membered heterocyclyl
or heteroaryl ring having upto three heteroatoms independently selected from N, O, or S,
wherein said three- to seven-membered heterocyclyl or heteroaryl ring is optionally
substituted with 1, 2 or 3 substitunts independently selected from the group consisting of
halo, hydroxy, C1-8alkyl, -O(C1-8alkyl), nitro, amino, mono(C1-8alkyl)amino, di(C1-
8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyl), -N(C1-
8alkyl)SO2(C1-8alkyl), -NHSO2CF3, -N(C1-8alkyl)SO2CF3, -COOH, -CONH2, -CONH(C1-
8alkyl), -CON(C1-8alkyl)2, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-
8alkyl), CF3, CN, -(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyl), -(CH2)nN(C1-8alkyl)2, -
CH2O(C1-8alkyl), -NHSO2NH2, -N(C1-8alkyl)SO2NH2, -NHSO2NH(C1-8alkyl), -
NHSO2N(C1-8alkyl)2, -N(C1-8alkyl)SO2N(C1-8alkyl)2, -NHCONH2, -NHCONH(C1-8alkyl), -
NHCON(C1-8alkyl)2, -N(C1-8alkyl)CON(C1-8alkyl)2, -S(C1-8alkyl), -SO2(C1-8alkyl), -SO3H,
-SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8alkyl)2, -SO2NH(C1-8alkyl), or -NHC(NH)NH2 ;
'Y' is selected from the group consisting of:
(a) -C(O)NRaRb,
(b) -NRcC(X)NRaRb,
(c) -NRcC(X)NRdRe,
(d) -NRcC(O)ORf,
(e)-NRcC(O)C(O)Rg;
X is selected from O or S;
Ra and Rb together with the atoms with which they are attached form a three- to ten-
membered monocyclic or bicyclic heterocyclyl or heteroaryl ring selected from the group
consisting of aziridinyl, azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl,
hexahydropyridazinyl, hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl,
imidazolidinyl, morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl,
piperazinonyl, piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl,
pyrrolidonyl, pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide,
thiazolidinyl, thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl,
indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl, wherein, said

170
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring is optionally
substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(1) halo, (2) hydroxy, (3) optionally substituted C1-8alkyl, wherein the substituents are
amino, C1-3 alkoxy, mono(C1-3alkyl)amino, di(C1-3alkyl)amino, and hydroxy, (4) -O(C1-
8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyl), (13) -CON(C1-
8alkyl)2, (14) -CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3, (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8alkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alkyl)SO2(C1-8alkyl), (24) -NHSO2CF3, (25) -N(C1-8alkyl)CO2(C1-
8alkyl), (26) -N(C1-8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2, (28)-NHSO2NH(C1-
8alkyl), (29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31) -
NHCONH2, (32) -NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-
8alkyl)CO(C1-8alkyl), (35) -N(C1-8alkyl)CO2(C1-8alkyl), (36) -N(C1-8alkyl)CON(C1-
8alkyl)2, (37) -S(C1-8alkyl), (38) -SO2(C1-8alkyl), (39) -SO3H, (40) -SO2O(C1-8alkyl),
(41) -SO2NH2, (42) -SO2N(C1-8alkyl)2, (43) -SO2NH(C1-8alkyl), (44) -NHC(NH)NH2,
(45) phenyl, unsubstituted or substituted with one to two substituents selected from halo,
nitro, C1-3alkyl, C1-3alkoxy, hydroxy, amino, momo(C1-8alkyl)amino, di(C1-8alkyl)amino, -
NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-
8alkyl), -NHNH2, -N(C1-8alkyl)N(C1-8alkyl)2, and -N(C1-8alkyl)NH2, (46) pyridyl,
unsubstituted or substituted with one to two substituents selected from halo, C1-3alkyl and
C1-3alkoxy, (47) -CO-(optionally substituted heteroaryl), (48) -CO-(optionally
substituted heterocyclyl), (49) -0-(optionally substituted heteroaryl), (50) -O-(optionally
substituted heterocyclyl), (51) optionally substituted heterocyclyl, (52) -NH-(optionally
substituted heterocyclyl),
wherein the substituents on the optionally substituted heteroaryl and heterocyclyl are one
to two groups independently selected from hydroxy, C1-8alkyl, -O(C1-8alkyl), oxo, thioxo,
amino, mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-
8alkyl)CO(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, _NHSO2(C1-8alkyl), -NHSO2NH2 or -N(C1-8alkyl)NH2;

171
Rc and Rd are independently selected from hydrogen or C 1-6 alkyl;
Rc is selected from R7, -SO2R7, -SO2R3, -SO2R4, -COR7, -(CH2)nR7, -(CH2)nCOR7, -
(CH2)nOR7, -(CH2)nSR7, -(CH2)nSO2R7, -(CH2)nNHCOR7, -(CH2)nNHSO2R7, -
(CH2)nN(C1-8alkyl)COR7, -(CH2)nNHNHSO2R7, -(CH2)nNHSO2R4, -(CH2)nN(C1-
8alkyl)SO2R4, -(CH2)nN(NH2)R7, -(CH2)nN[N(C1-8alkyl)2]R7, -NHSO2R7, optionally
substituted C1-8alkyl, wherein the substituents are C1-3 alkoxy, amino, mono(C1-
3alkyl)amino, di(C1-3alkyl)amino, or hydroxy ;
Rf is selected from the group consisting of (1) optionally substituted C1-8alkyl, wherein
the substituents are selected from C1-3alkoxy, amino, mono(C1-3alkyl)amino, di(C1-
3alkyl)amino, C1-3alkyl, phenyl or hydroxy, (2) -R3, (3) -R4, (4) phenyl, unsubstituted or
substituted wirh R2, (5) -(CH2)nR7, (6) -(CH2)nCOR7, (7) -(CH2)nNRcR7, (8) -
(CH2)nNHSO2R7, (9) -(CH2)aN(C1-8alkyl)SO2R7, (10) -(CH2)nNHCOR7, (11) -
(CH2)nN(C1-8alkyl)COR7, (12) -(CH2)nOR7, (13) -(CH2)nSR7, (14) -(CH2)nSO2R7, (15) -
(CH2)nNHNHSO2R7, (16) -(CH2)nN(NH2)R7, (17) -(CH2)nN{N(C1-8 alkyl)2}R7 or (18)
CC13;
Rg is selected from the group consisting of (1) mono(C1-8alkyl)amino (2) di(C1-
8alkyl)amino, (3) NH2, (4) -NHR7, (5) -NRc(CH2)nR7, (6) -NRc(CH2)nCOR7, (7) -
NH(CH2)nO(C1-8alkyl), (8) -NRc(CH2)nOR7, (9) -NRc(CH2)nNHSO2R7, (10) -
NRc(CH2)nN(C1-8alkyl)SO2R7, (11) -NRc(CH2)nSO2R7, (12) -NRCSO2R7, (13) -
NRc(CH2)nSR7, (14) -N(NH2)R7, (15) -N[N(C1-8alkyl)2]R7, (16) -
NRc(CH2)nNHNHSO2R7, (17) -NRc(CH2)nN(NH2)R7, (18) -NRc(CH2)nN[N(C1-
8alkyl)2]R7, (19) -NRc(CH2)nNHCOR7, (20) -NHNHSO2R7, (21) optionally substituted
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring attached
through the ring nitrogen atom and selected from the group consisting of aziridinyl,
azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl, hexahydropyridazinyl,
hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl, imidazolidinyl,
morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl, piperazinonyl,
piperidinyl, piperidonyl, pyrrolidinyl, pyrrohnyl, pyrroyl, pyrrolonyl, pyrrolidonyl,
pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-l,l-dioxide, thiazolidinyl,

172
thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl, indazolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl,
wherein, the substituents on said optionally substituted three- to ten- membered
monocyclic or bicyclic heterocyclyl or heteroaryl ring are 1, 2 or 3 groups independently
selected from (1) halo, (2) hydroxy, (3) C1-8alkyl, unsubstituted or substituted with d-
3alkoxy, amino, mono(C1-3alkyl)amino, di(C1-3alkyl)amino, C1-3alkyl, and hydroxy, (4) -
O(C1-8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyl), (13) -CON(d-
8alkyl)2, (14) - CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3 , (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8alkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alkyl)SO2(C1-8alkyl), (24) -NHSO2CF3, (25) -N(C1-8alkyl)CO2(C1-
8alkyl), (26) -N(C1-8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2, (28) -NHSO2NH(C1-
8alkyl), (29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31) -
NHCONH2, (32) -NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-8alkyl)CO
(C1-8alkyl), (35) -N(C1-8alkyl)CO2(C1-8 alkyl), (36) -N(C1-8alkyl)CON(C1-8alkyl)2, (37) -
S(C1-8alkyl), (38 ) -SO2(C1-8alkyl), (39) -SO3H, (40) - SO2O(C1-8alkyl), (41) -SO2NH2,
(42) -SO2N(C1-8alkyl)2, (43) -SO2NH(C1-8alkyl), (44) -NHC(NH)NH2,
n is independently selected at each occurrence, from 1, 2 or 3;
R3 at each occurrence is optionally substituted monocyclic three to seven membered
heteroaryl ring having one to three heteroatoms independently selected from N, O, or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R4 at each occurrence is optionally substituted monocyclic three to seven membered
heterocyclyl ring having one to three heteroatoms independently selected from N, O or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R5 at each occurrence is independently selected from hydrogen, C1-6alkyl or CF3;
R6 at each occurrence are 1 or 2 groups independently selected from hydrogen, -O(C1-
8alkyl), halo, C1-6alkyl, mono(C1-6alkyl)amino or di(C1-6 alkyl)amino ;

173
R7 at each occurrence is
1. optionally substituted monocyclic five- to seven- membered aryl;
2. optionally substituted monocyclic three- to seven- membered heteroaryl or
heterocyclyl having one to three heteroatoms independently selected from N, O or S ,
wherein the substitution on R7 is by 1, 2 or 3 substituents represented by R2, with proviso
that
A. When Y is NRcC(X)NRdRe and Re=R7, R7 is not furan, thiophene, isooxazole,
isothiazole & phenyl;
B. When Y is selected from -C(O)NRaRb, R1 and R2 is not selected from:
(a) -(CH2)nR4
(b) -(CH2)nNHCOR7
(c) -(CH2)nN(C1-8alkyl)COR7
(d) -CONH2
(e) -CONH(C1-8alkyl)
(f) -CON(C1-8alkyl)2
(g)-(CH2)nNH2
(h)-(CH2)nNH(C1-8alkyl)
(i) -(CH2)nN(C1-8alkyl)2,and
C. When Y is selected from -NRcC(X)NRaRb or NRcC(X)NRdRe and X=O, Rl and
R2 is not selected from:
(a) -NH(CH2)nR4
(b) -NH(CH2)nNHCOR4
(c) -NH(CH2)nN(C1-8alkyl)COR4
(d) -N(C1-8alkyl)(CH2)nNHCOR4
(e) -N(C1-8alkyl)(CH2)nR4
(f) -mono(C1-8alkyl)amino
(g) -di(C1-8alkyl)amino
(h) -NHCONH2
(i) -NHCONH(C1-8alkyl)

174
(j) -NHCON(C1-8alkyl)2
(k)-N(C1-8alkyl)C(O)N(C1-8alkyl)2.
2. The compound as claimed in claim 1, wherein Q represents a heteroaryl ring as
defined in claim 1, said Q may be unsubstituted or substituted by 1 to 6 substituents
represented by R2;
R2 is independently selected at each occurrence from hydrogen, hydroxy, halo, amino, C1-
8alkyl, -O(C1-8alkyl), -S(C1-8alkyl), -SO2(C1-8alkyl), oxo, thioxo, mono(C1-8alkyl)amino,
di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyl), -
NHSO2CF3, -N(C1-8alkyl)SO2CF3, -NHSO2O(C1-8alkyl), -N(C1-8alkyl)SO2(C1-8alkyl), -
N(C1-8alkyl)SO2O(C1-8alkyl), -COOH, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-
8alkyl)CO2(C1-8alkyl), -CONH2, -CONH(C1-8alkyl), -CON(C1-8alkyl)2, formyl, CF3, CN, -
(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyl), -(CH2)nN(C1-8alkyl)2, -(CH2)nO(C1-8alkyl),
-SO3H, -SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8alkyl)2, -SO2NH(C1-8alkyl), -OSO2(C1-
galkyl), -N(C1-8alkyl)SO2NH2, -NHSO2NH(C1-8alkyl), -NHSO2N(C1-8alkyl)2, -N(C1-
8alkyl)SO2N(C1-8alkyl)2, -NHSO2NH2, -NHC(NH)NH2, -NHCONH2, -NHC(O)NH(C1-
8alkyl), -NHC(O)N(C1-8alkyl)2, -N(C1-8alkyl)C(O)N(C1-8alkyl)2, -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, -N(C1-8alkyl)NH2, tetrazolyl or three- to seven- membered
heterocyclyl or heteroaryl ring having upto three heteroatoms independently selected from
N, O, or S, wherein said three- to seven- membered heterocyclyl or heteroaryl ring is
optionally substituted with 1, 2 or 3 substituents independently selected from the group
consisting of halo, hydroxy, C1-8alkyl, -o(C1-8alkyl), nitro, amino, mono(C1-8alkyl)amino,
di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHSO2(C1-8alkyl), -
N(C1-8alkyl)SO2(C1-8alkyl), -NHSO2CF3, -N(C1-8alkyl)SO2CF3, -COOH, -CONH2, -
CONH(C1-8alkyl), -CON(C1-8alkyl)2, -CO2(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-
8alkyl)CO2(C1-8alkyl), CF3, CN, -(CH2)nOH, -(CH2)nNH2, -(CH2)nNH(C1-8alkyl), -
(CH2)nN(C1-8alkyl)2, -CH2O(C1-8alkyl), -NHSO2NH2, -N(C1-8alkyl)SO2NH2, -
NHSO2NH(C1-8alkyl), -NHSO2N(C1-8alkyl)2, -N(C1-8alkyl)SO2N(C1-8alkyl)2, -NHCONH2,
-NHCONH(C1-8alkyl), -NHCON(C1-8alkyl)2, -N(C1-8alkyl)CON(C1-8alkyl)2, -S(C1-8alkyl),
-SO2(C1-8alkyl), -SO3H, -SO2O(C1-8alkyl), -SO2NH2, -SO2N(C1-8alkyl)2, -SO2NH(C1-
8alkyl), or -NHC(NH)NH2;

175
'Y' is selected from the group consisting of:
(a) -C(O)NRaRb,
(b) -NRcC(X)NRaRb,
(c) -NRcC(X)NRdRe,
(d) -NRcC(O)ORf,
(e)-NRcC(O)C(O)Rg;
X is selected from O or S;
Ra and Rb together with the atoms with which they are attached form a three- to ten-
membered monocyclic or bicyclic heterocyclyl or heteroaryl ring selected from the group
consisting of aziridinyl, azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl,
diazocanyl, hexahydropyridazinyl, hexahydropyrimidinyl, isothiazolidinyl,
isoxazolidonyl, imidazolyl, imidazolidinyl, morpholinyl, oxazolidonyl, oxazolanyl,
oxazetanyl, piperazinyl, piperazinonyl, piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl,
pyrroyl, pyrrolonyl, pyrrolidonyl, pyrazolyl, pyrazolonyl, thiomorpholinyl,
thiomorpholin-1,1-dioxide, thiazolidinyl, thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl,
triazolyl, indolyl, indolinyl, indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or
benzimidazolyl, wherein, said three- to ten- membered monocyclic or bicyclic
heterocyclyl or heteroaryl ring is optionally substituted with 1, 2, or 3 substituents
independently selected from the group consisting of
(1) phenyl, unsubstituted or substituted with a single substituent selected from hydroxy,
mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-
8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1.8alkyl), -NHNH2, -N(C1.8alkyl)N(C1-
8alkyl)2, and -N(C1-8alkyl)NH2,
(2) =NOH, (3) optionally substituted heterocyclyl, (4) -O-optionally substituted
heteroaryl, (5) -O-optionally substituted heterocyclyl, (6) -CO-optionally substituted
heteroaryl, or (7) -CO-optionally substituted heterocyclyl,
wherein the substituents on the optionally substituted heteroaryl and heterocyclyl is a
single group selected from hydroxy, C1-8alkyl, -O(C1-8alkyl), oxo, thioxo, amino,

176
mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-
8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-8alkyl)N(C1-
8alkyl)2, or -N(C1-8alkyl)NH2;
Re and Rd are independently selected from hydrogen or C1-6 alkyl;
Re is independently selected from -SO2R3, -SO2R4, -(CH2)nR4, -(CH2)nCOR4, -
(CH2)nOR4, -(CH2)nSR7, -(CH2)nSO2R7, -(CH2)nNHCOR7, -(CH2)nN(C1-8alkyl)COR7, -
(CH2)nNHNHSO2R7, -(CH2)nNHSO2R4, -(CH2)nN(C1-8alkyl)SO2R4, -(CH2)nN(NH2)R7, -
(CH2)nN[N(C1-8alkyl)2]R7, or-NHSO2R7;
Rf is selected from the group consisting of (1) optionally substituted C1-8alkyl, wherein
the substituents are selected from oxo, thioxo, amino, C1-3alkoxy, mono(C1-3 )alkylamino,
di(C1-3alkyl)amino, and hydroxy, (2) -R3, (3) -R4, (4) phenyl, unsubstituted or
substituted with R2, (5) -(CH2)nR7, (6) -(CH2)nCOR7, (7) -(CH2)nNRcR7, (8) -
(CH2)nNHSO2R7, (9) -(CH2)nN(C1-8alkyl)SO2R7, (10) -(CH2)nNHCOR7, (11) -
(CH2)nN(C1-8alkyl)COR7, (12) -(CH2)nOR7, (13) -(CH2)nSR7, (14) -(CH2)nSO2R7, (15) -
(CH2)nNHNHSO2R7, (16) -(CH2)nN(NH2)R7, or (17) -(CH2)nN{N(C1-8 alkyl)2}R7;
Rg is selected from the group consisting of -NRc(CH2)nR4, -NRc(CH2)nCOR4, -
NRc(CH2)nOR4, -NRc(CH2)nNHSO2R4, -NRc(CH2)nN(C1-8alkyl)SO2R4,
NRc(CH2)nSO2R7, -NRCSO2R7, -NRc(CH2)nSR7, -N(NH2)R7, -N[N(C1-8alkyl)2]R7, -
NRc(CH2)nNHNHSO2R7, -NRc(CH2)nN(NH2)R7, -NRc(CH2)nN[N(C1-8alkyl)2]R7, or -
NRc(CH2)nNHCOR7;
n is independently selected at each occurrence, from 1, 2 or 3 ;
R3 at each occurrence is optionally substituted monocyclic three to seven membered
heteroaryl ring having one to three heteroatoms independently selected from N, O, or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;

177
R4 at each occurrence is optionally substituted monocyclic three- to seven- membered
heterocyclyl ring having one to three heteroatoms independently selected from N, O or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R5 at each occurrence is independently selected from hydrogen, C1-8alkyl or CF3;
R6 at each occurrence are 1 or 2 groups independently selected from hydrogen, -O(C1-
8alkyl), halo, C1-6alkyl, mono(C1-6alkyl)amino or di(C1-6alkyl)amino ;
R7 at each occurrence is
1. optionally substituted monocyclic five- to seven- membered aryl;
2. optionally substituted monocyclic three- to seven- membered heteroaryl or
heterocyclyl having one to three heteroatoms independently selected from N, O or
S,
wherein the substitution on R7 is by 1, 2 or 3 substituents represented by R2; with the
proviso that,
A. when Rf is C1-8alkyl, aryl, or R3, then R2 is an optionally substituted three- to
seven- membered heterocyclyl or heteroaryl ring having upto three heteroatoms
independently selected from N, O, or S;
B. When Y is selected from -C(O)NRaRb, Rl and R2 is not selected from:
(a) -(CH2)nR4
(b) -(CH2)nNHCOR7
(c) -(CH2)nN(C1-8alkyl)COR7
(d) -CONH2
(f) -CONH(C1-8alkyl)
(f)-CON(C1.8alkyl)2
(g)-(CH2)nNH2
(h)-(CH2)nNH(C1-8alkyl)
(j) -(CH2)nN(C1-8alkyl)2, and
C. When Y is selected from -NRcC(X)NRaRb or NRcC(X)NRdRe and X=O, Rl and
R2 is not selected from:

178
(a) -NH(CH2)nR4
(b) -NH(CH2)nNHCOR4
(c) -NH(CH2)nN(C1-8alkyl)COR4
(d) -N(C1_8alkyl)(CH2)nNHCOR4
(e) -N(C1_8alkyl)(CH2)nR4
(f) -mono(C1-8alkyl)amino
(g) -di(C1-8alkyl)amino
(h) -NHCONH2
(i) -NHCONH(C1-8alkyl)
0) -NHCON(C1-8alkyl)2
(k)-N(C1-8alkyl)C(O)N(C1-8alkyl)2.
3. The compound as claimed in claim 1, wherein Q represents a heteroaryl ring as
defined in claim 1, said Q is substituted by either R1 or both R1 and R2, said substituents
are selected from one to six;
R1 is independently selected at each occurrence from -SO2OR7, -SO2O(C1-8alkyl), -
NHNH2, -NHNHSO2R7, -NH(CH2)nR4, -NHCO2R7, -NHCO2C1-8alkyl), -NHSO2O(C1-
8alkyl), -NHSO2OR7, -NHSO2NH2, -NH(CH2)nCOR4, -NH(CH2)nOR4, -NH(CH2)nSR7, -
NH(CH2)nSO2R7, -NH(CH2)nNHCOR4, -NH(CH2)nN(C1-8alkyl)COR4, -N(C1-
8alkyl)(CH2)nNHCOR4, -NH(CH2)nNHNHSO2R7, -NH(CH2)nNHSO2R4,
NH(CH2)nN(C1-8alkyl)SO2R4, -NH(CH2)nN(NH2)R7, -NH(CH2)nN[N(C1-8alkyl)2]R7, -
N(C1-8alkyl)CO2R7, -N(C1-8alkyl)CO2(C1-8alkyl), -N(C1-8alkyl)SO2O(C1-8alkyl), -N(C1-
8alkyl)SO2OR7, -N(C1-8alkyl)SO2NH2, -N(C1.8alkyl)N(C1.8alkyl)2, -N(C1-8alkyl)NH2, -
NHNHCO(C1-8alkyl), -N(C1-8alkyl)NHCO(C1-8alkyl), -NHNHCOR7, -N(C1-
8alkyl)NHCOR7, -N(C1-8alkyl)-(CH2)nR4, -N(C1-8alkyl)(CH2)nCOR4, -(CH2)nSO2R7, -
(CH2)nCOR4, -(CH2)nR4, -(CH2)nNHSO2R4, -(CH2)nN(C1-8alkyl)SO2R4,
(CH2)nNHCOR7, -(CH2)nN(C1-8alkyl)COR7, -(CH2)nOR4, -(CH2)nSR4, -(CH2)nSR3, -
(CH2)nSO2R7, -(CH2)nNHNHSO2R7, -(CH2)nN(NH2)R7, or - (CH2)nN[N(C1-8 alkyl)2]R7 ;
R2 is as defined in claim 1;
'Y' is selected from the group consisting of:

179
(a) -C(O)NRaRb,
(b) -NRcC(X)NRaRb,
(c) -NRcC(X)NRdRe,
(d) -NRcC(O)ORf,
(e)-NRcC(O)C(O)Rg;
X is selected from O or S;
Ra and Rb together with the atoms with which they are attached form a three- to ten-
membered monocyclic or bicyclic heterocyclyl or heteroaryl ring selected from the group
consisting of aziridinyl, azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl,
hexahydropyridazinyl, hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl,
imidazolidinyl, morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl,
piperazinonyl, piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl,
pyrrolidonyl, pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide,
thiazolidinyl, thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl,
indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl, wherein, said
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring is optionally
substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(1) halo, (2) hydroxy, (3) optionally substituted C1-8alkyl, wherein the substituents are
amino, C1-3 alkoxy, mono(C1-3alkyl)amino, di(C1-3alkyl)amino, and hydroxy, (4) -O(C1-
8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyl), (13) -CON(C1-
8alkyl)2, (14) -CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3, (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8alkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alkyl)SO2(C1-8alkyl), (24) -NHSO2CF3, (25) -N(C1-8alkyl)CO2(C1-
8alkyl), (26) -N(C1-8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2, (28)-NHSO2NH(C1-
8alkyl), (29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31)-
NHCONH2, (32) -NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-
8alkyl)CO(C1-8alkyl), (35) -N(C1-8alkyl)CO2(C1-8alkyl), (36) -N(C1-8alkyl)CON(C1.
8alkyl)2, (37) -S(C1-8alkyl), (38) -SO2(d-8alkyl), (39) -SO3H, (40) -SO2O(C1-8alkyl),
(41) -SO2NH2, (42) -SO2N(C1-8alkyl)2, (43) -SO2NH(C1-8alkyl), (44) -NHC(NH)NH2,
(45) phenyl, unsubstituted or substituted with one to two substituents selected from halo,

180
nitro, C1-3alkyl, C1-3alkoxy, hydroxy, amino, mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -
NHCO(C1-8alkyl), -N(C1-8alkyl)CO(C1-8alkyl), -NHCO2(C1.8alkyl), -N(C1-8alkyl)CO2(C1-
8alkyl), -NHNH2, -N(C1.8alkyl)N(C1.8alkyl)2, and -N(C1-8alkyl)NH2, (46) pyridyl,
unsubstituted or substituted with one to two substituents selected from halo, C1-3alkyl and
C1-3alkoxy, (47) -CO-(optionally substituted heteroaryl), (48) -CO-(optionally
substituted heterocyclyl), (49) -O-(optionally substituted heteroaryl), (50) -O-(optionally
substituted heterocyclyl), (51) optionally substituted heterocyclyl, (52) -NH-(optionally
substituted heterocyclyl),
wherein the substituents on the optionally substituted heteroaryl and heterocyclyl are one
to two groups independently selected from hydroxy, C1-8alkyl, -O(C1-8alkyl), oxo, thioxo,
amino, mono(C1-8alkyl)amino, di(C1-8alkyl)amino, -NHCO(C1-8alkyl), -N(d-
8alkyl)CO(C1-8alkyl), -NHCO2(C1-8alkyl), -N(C1-8alkyl)CO2(C1-8alkyl), -NHNH2, -N(C1-
8alkyl)N(C1-8alkyl)2, NHSO2(C1-8alkyl), -NHSO2NH2 or -N(C1-8alkyl)NH2;
Re and Rd are independently selected from hydrogen or C1-6 alkyl;
Re is selected from R7, -SO2R7, -SO2R3, -SO2R4, _-COR7, -(CH2)nR7, -(CH2)nCOR7, -
(CH2)nOR7, -(CH2)nSR7, -(CH2)nSO2R7, -(CH2)nNHCOR7, -(CH2)nNHSO2R7, -
(CH2)nN(C1-8alkyl)COR7, -(CH2)nNHNHSO2R7, -(CH2)nNHSO2R4, -(CH2)nN(C1-
8alkyl)SO2R4, -(CH2)nN(NH2)R7, -(CH2)nN[N(C1-8alkyl)2]R7, -NHSO2R7, optionally
substituted C1-8alkyl, wherein the substituents are C1-3 alkoxy, amino, mono(C1-
3alkyl)amino, di(C1-3alkyl)amino, or hydroxy;
Rf is selected from the group consisting of (1) optionally substituted C1-8alkyl, wherein
the substituents are selected from C1-3alkoxy, amino, mono(C1-3alkyl) amino, di(C1-
3alkyl)amino, C1-3alkyl, phenyl or hydroxy, (2) -R3, (3) -R4, (4)phenyl, unsubstituted or
substituted with R2, (5) -(CH2)nR7, (6) -(CH2)nCOR7, (7) -(CH2)nNRcR7, (8) -
(CH2)nNHSO2R7, (9) -(CH2)nN(C1-8alkyl)SO2R7, (10) -(CH2)nNHCOR7, (11) -
(CH2)nN(C1-8alkyl)COR7, (12) -(CH2)nOR7, (13) -(CH2)nSR7, (14) -(CH2)nSO2R7, (15) -
(CH2)nNHNHSO2R7, (16) -(CH2)nN(NH2)R7, (17) -(CH2)nN{N(C1-8 alkyl)2}R7 or (18)
CC13;

181
Rg is selected from the group consisting of (1) mono(C1-8alkyl)amino (2) di(C1-
8alkyl)amino, (3) NH2, (4) -NHR7, (5) -NRc(CH2)nR7, (6) -NRc(CH2)nCOR7, (7) -
NH(CH2)nO(C1-8alkyl), (8) -NRc(CH2)nOR7, (9) -NRc(CH2)nNHSO2R7, (10) -
NRc(CH2)nN(C1-8alkyl)SO2R7, (11) -NRc(CH2)nSO2R7, (12) -NRCSO2R7, (13) -
NRc(CH2)nSR7, (14) -N(NH2)R7, (15) -N[N(C1-8alkyl)2]R7, (16) -
NRc(CH2)nNHNHSO2R7, (17) -NRc(CH2)nN(NH2)R7, (18) -NRc(CH2)nN[N(C1-
8alkyl)2]R7, (19) -NRc(CH2)nNHCOR7, (20) -NHNHSO2R7, (21) optionally substituted
three- to ten- membered monocyclic or bicyclic heterocyclyl or heteroaryl ring attached
through the ring nitrogen atom and selected from the group consisting of aziridinyl,
azepanyl, azetindinyl, azocanyl, azepinyl, diazepanyl, diazocanyl, hexahydropyridazinyl,
hexahydropyrimidinyl, isothiazolidinyl, isoxazolidonyl, imidazolyl, imidazolidinyl,
morpholinyl, oxazolidonyl, oxazolanyl, oxazetanyl, piperazinyl, piperazinonyl,
piperidinyl, piperidonyl, pyrrolidinyl, pyrrolinyl, pyrroyl, pyrrolonyl, pyrrolidonyl,
pyrazolyl, pyrazolonyl, thiomorpholinyl, thiomorpholin-1,1-dioxide, thiazolidinyl,
thiazepanyl, thiazinyl, thiazocanyl, thiazetanyl, triazolyl, indolyl, indolinyl, indazolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, or benzimidazolyl,
wherein, the substituents on said optionally substituted three- to ten- membered
monocyclic or bicyclic heterocyclyl or heteroaryl ring are 1, 2 or 3 groups independently
selected from (1) halo, (2) hydroxy, (3) C1-8alkyl, unsubstituted or substituted with C1-
3alkoxy, amino, mono(C1-3alkyl) amino, di(C1-3alkyl)amino, C1-3alkyl, and hydroxy, (4) -
O(C1-8alkyl), (5) nitro, (6) amino, (7) mono(C1-8alkyl)amino, (8) di(C1-8alkyl)amino, (9) -
COOH, (10) -CO(C1-8alkyl), (11) -CONH2, (12) -CONH(C1-8alkyl), (13) -CON(C1-
8alkyl)2, (14) - CO2(C1-8alkyl), (15) formyl, (16) =NOH, (17) CF3, (18) CN, (19) -
NHSO2NH2, (20) -NHCO(C1-8alkyl), (21) -N(C1-8alkyl)CO(C1-8alkyl), (22) -NHSO2(C1-
8alkyl), (23) -N(C1-8alkyl)SO2(C1-8alkyl), (24) -NHSO2CF3, (25) -N(C1-8alkyl)CO2(C1-
8alkyl), (26) -N(C1.8alkyl)SO2CF3, (27) -N(C1-8alkyl)SO2NH2, (28) -NHSO2NH(C1-
8alkyl), (29) -NHSO2N(C1-8alkyl)2, (30) -N(C1-8alkyl)SO2N(C1-8alkyl)2, (31) -
NHCONH2, (32) -NHCONH(C1-8alkyl), (33) -NHCON(C1-8alkyl)2, (34) -N(C1-8alkyl)CO
(C1-8alkyl), (35) -N(C1-8alkyl)CO2(C1-8 alkyl), (36) -N(C1-8alkyl)CON(C1-8alkyl)2, (37) -

182
S(C1-8alkyl), (38 ) -SO2(C1-8alkyl), (39) -SO3H, (40) - SO2O(C1-8alkyl), (41) -SO2NH2,
(42) -SO2N(C1-8alkyl)2, (43) -SO2NH(C1-8alkyl), or (44) -NHC(NH)NH2,
n is independently selected at each occurrence, from 1, 2 or 3;
R3 at each occurrence is optionally substituted monocyclic three to seven membered
heteroaryl ring having one to three heteroatoms independently selected from N, O, or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R4 at each occurrence is optionally substituted monocyclic three to seven membered
heterocyclyl ring having one to three heteroatoms independently selected from N, O or S,
wherein the substitution is by 1, 2 or 3 substituents represented by R2;
R5 at each occurrence is independently selected from hydrogen, C1-6alkyl or CF3;
R6 at each occurrence are 1 or 2 groups independently selected from hydrogen, -O(C1-
galkyl), halo, C1-6alkyl, mono(C1-6alkyl)amino or di(C1-6alkyl)amino ;
R7 at each occurrence is
1. optionally substituted monocyclic five- to seven- membered aryl;
2. optionally substituted monocyclic three- to seven- membered heteroaryl or
heterocyclyl having one to three heteroatoms independently selected from N, O or
S,
wherein the substituent on R7 is by 1, 2 or 3 substituents represented by R2j with a
proviso that
A. When Y is NRcC(X)NRdRe and Re=R7, R7 is not furan, thiophene, isooxazole,
isothiazole & phenyl;
B. When Y is selected from -C(O)NRaRb, Rl and R2 is not selected from:
(a) -(CH2)nR4
(b) -(CH2)nNHCOR7
(c) -(CH2)nN(C1.8alkyl)COR7
(d) -CONH2
(e) -CONH(C1-8alkyl)

183
(f) -CON(C1-8alkyl)2
(g)-(CH2)nNH2
(h) -(CH2)nNH(C1-8alkyl)
(i) -(CH2)nN(C1-8alkyl)2, and
C. When Y is selected from -NRcC(X)NRaRb or NRcC(X)NRdRe and X=O, Rl and
R2 is not selected from:
(a) -NH(CH2)nR4
(b) -NH(CH2)nNHCOR4
(c) -NH(CH2)nN(C1-8alkyl)COR4
(d) -N(C1.8alkyl)(CH2)nNHCOR4
(e) -N(C1-8alkyl)(CH2)nR4
(f) -mono(C1-8alkyl)amino
(g) -di(C1-8alkyl)amino
(h) -NHCONH2
(i) -NHCONH(C1-8alkyl)
(j) -NHCON(C1-8alkyl)2
(k) -N(C1-8alkyl)C(O)N(C1-8alkyl)2.
4. The compound as claimed in claims 1, 2 or 3, wherein R2 is optionally substituted
three- to seven- membered heterocyclyl or heteroaryl ring having upto three heteroatoms
independently selected from N, O, or S.
5. The compound as claimed in claims 1, 2 or 3, wherein said optionally substituted
heterocyclyl or heteroaryl ring is selected from piperazinyl, piperidinyl, piperidonyl,
morpholinyl, thiomorpholinyl, thiomorpholin-l,l-dioxide, pyrrolidinyl pyrrolyl,
pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, or
thiazolidinyl.
6. The compound as claimed in claims 1, 2 or 3, wherein Ra and Rb are selected from
optionally substituted piperazinyl, piperidinyl, piperidonyl, morpholinyl,
thiomorpholinyl, thiomorpholin-1,1-dioxide, pyrrolidinyl pyrrolyl, pyrazolyl, triazolyl or
imidazolyl.

184
7. The compound as claimed in claims 1, 2 or 3, wherein X is O.
8. The compound as claimed in claims 1, 2 or 3, wherein R5 is independently
selected from hydrogen or methyl.
9. The compound as claimed in claims 1, 2 or 3, wherein n is independently
selected from 1 or 2.
10. A compound selected from the group consisting of:
l-[4-(Morpholine-4-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 1);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidin-4-one (Compound No. 2);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound
No. 3);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-pyrrolidine-2-carboxylic acid amide
(Compound No. 4);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid isopropyl ester
(Compound No. 5);
l-[4-(Piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 6);
l-[4-(4-Acetyl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound
No. 7);
l-(4-Nitro-phenyl)-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-piperazin-2-one (Compound
No. 8);
l-[4-(3-Quinolin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid (Compound No. 9);
3-Quinolin-2-yl-1 -[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone (Compound No.
10);
l-[4-(Pyrrolidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 11);
l-[4-(Piperidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 12);
4-Morpholin-4-yl-2- {3-oxo-3 - [4-(pyrrolidine-1 -carbonyl)-phenyl] -propenyl} -quinoline-
6-carboxylic acid methyl ester (Compound No. 13);
1 - {4- [4-(3-Methyl-butyl)-piperazine- l-carbonyl]-phenyl} -3-quinolin-2-yl-propenone
(Compound No. 14);
1 - {4-[4-(3-Chloro-phenyl)-piperazine-1 -carbonyl]-phenyl} -3-quinolin-2-yl-propenone
(Compound No. 15);

185
1 - {4- [4-(2,3-Dichloro-phenyl)-piperazine-1 -carbonyl] -phenyl} -3-quinolin-2-yl-
propenone (Compound No. 16);
N-(4- {2-Oxo-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl} -phenyl)-
acetamide (Compound No. 17);
4-Imidazol-l-yl-2-[3-oxo-3-(4-trichloromethoxycarbonylamino-phenyl)-propenyl]-
quinoline-6-carboxylic acid methyl ester (Compound No. 18);
Pyrrolidine-1-carboxylic acid {4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-
amide (Compound No. 19);
3-Quinolin-2-yl-1 - {4- [4-(tetrahydro-furan-2-carbonyl)-piperazine-1 -carbonyl]-phenyl}-
propenone (Compound No. 20);
1-{4-[4-(Furan-2-carbonyl)-piperazine-1 -carbonyl]-phenyl}-3-quinolin-2-yl-propenone
(Compound No. 21);
l-[4-(4-Pyridin-4-yl-piperazine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone
(Compound No. 22);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 23);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid 2,2-dimethyl-
propyl ester (Compound No. 24);
l-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-3-(2-trifluoromethyl-
phenyl)-urea (Compound No. 25);
l-Benzenesulfonyl-3-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-urea
(Compound No. 26);
4-(3- {4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl} -ureido)-benzoic acid
ethyl ester (Compound No. 27);
1 -[4-(4-Ethyl-piperazine-1 -carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No.
28);
{4-[3-(4-Piperidin-1-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 29);
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid isobutyl ester
(Compound No. 30);
{4-[3-(2-Pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 31);

186
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-(6-trifluoromethyl-quinolin-2-yl)-
propenone (Compound No. 32);
1 -Pyridin-2-yl-3-{4-[3-(2-pyrrolidin-1-yl-quinolin-3-yl)-acryloyl]-phenyl} -urea
(Compound No. 33);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-(6-methylsulfanyl-quinolin-2-yl)-
propenone (Compound No. 34);
l-{4-[3-(5,6,7-Trimethoxy-6,7-dihydro-quinolin-2-yl)-acryloyl]-benzoyl}-piperidin-4-
one (Compound No. 35);
l-[4-(Thiomorpholine-4-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-propenone
(Compound No. 36);
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(4-methyl-piperazine-l-carbonyl)-phenyl]-
propenone (Compound No. 37);
l-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-piperidin-4-one (Compound
No. 38);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone (Compound
No. 39);
l-[4-(Pyrrolidine-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone (Compound No, 40);
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-one (Compound No. 41);
3-(3-Hydroxy-quinoxalin-2-yl)-1-[4-(pyrazole-1-carbonyl)-phenyl]-propenone
(Compound No. 42);
l-[4-(2,3-Dihydro-indole-l-carbonyl)-phenyl]-3-(3-hydroxy-quinoxalin-2-yl)-propenone
(Compound No. 43);
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone
(Compound No. 44);
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-one oxime (Compound No. 45);
2-{3-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-oxo-propenyl}-quinoline-6-
sulfonic acid amide (Compound No. 46);
2-{3-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-oxo-propenyl}-quinoline-6-
sulfonic acid amide (Compound No. 47);
1-[4-(Pyrazole-1-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-propenone
(Compound No. 48);

187
l-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound
No. 49);
1-{4-[4-(2,3-Dichloro-phenyl)-piperazine-1-carbonyl]-phenyl}-3-(2-pyrrolidin-1-yl-
quinolin-3-yl)-propenone (Compound No. 50);
l-[4-(4-Methyl-piperazine-l-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-
propenone (Compound No. 51);
l-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-
propenone (Compound No. 52);
l-{4-[3-(4-Piperidin-l-yl-6-trifluoromethyl-quinolin-2-yl)-acryloyl]-phenyl}-3-(2,3,4-
trimethoxy-phenyl)-urea (Compound No. 53);
1 -[4-(4-Pyrrolidin-1-yl-piperidine-1-carbonyl)-phenyl]-3-quinolin-2-yl-propenone
(Compound No. 54);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound No. 55);
3-[6-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-quinolin-2-yl]-1-[4-(pyrrolidine-1-
carbonyl)-phenyl]-propenone (Compound No. 56);
1-Cyclohexyl-3-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl} -urea
(Compound No. 57);
2,2-Dimethyl-N-(2-{3-oxo-3-[4-(pyrazole-l -carbonyl)-phenyl]-propenyl}-quinolin-6-yl)-
propionamide (Compound No. 58);
1-Benzenesulfonyl-3- {4-[3-(6-methyl-4-piperidin-1-yl-quinolin-2-yl)-acryloyl]-phenyl}-
urea (Compound No. 59);
l-{4-[3-(5,6,7-Trimethoxy-quinolin-2-yl)-acryloyl]-benzoyl}-piperidine-4-carboxylic
acid isopropyl ester (Compound No. 60);
Piperidine-1-carboxylic acid {4-[3-(2-pyrrolidin-1-yl-quinolin-3-yl)-acryloyl]-phenyl}-
amide (Compound No. 61);
3-(6-Methylsulfanyl-4-morpholin-4-yl-quinolin-2-yl)-1-[4-(pyrrolidine-1 -carbonyl)-
phenyl]-propenone (Compound No. 62);
3-(6-Methanesulfonyl-4-morpholin-4-yl-quinolin-2-yl)-1-[4-(pyrrolidine-1-carbonyl)-
phenyl]-propenone (Compound No. 63);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl
ester (Compound No. 64);

188
l-Benzoyl-3-{4-[3-(6-[l,2,3]thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-urea
(Compound No. 65);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl
ester (Compound No. 66);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-morpholin-4-
yl-ethyl ester (Compound No. 67);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen-2-
ylmethyl ester (Compound No. 68);
{5-Methoxy-2-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid
methyl ester (Compound No. 69);
Propyl-{4-[3-(2-pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid ethyl
ester (Compound No. 70);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl ester
(Compound No. 71);
2,2-Dimethyl-N-{1-[4-(3-quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-yl} -
propionamide (Compound No. 72);
1 -[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid dimethylamide
(Compound No. 73);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl
ester (Compound No. 74);
l-(4-Methyl-benzenesulfonyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2' ]bipyridinyb'-yl)-
acryloyl]-phenyl}-urea (Compound No. 75);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridinyb'-yl)-acryloyl]-phenyl}-carbamic acid
ethyl ester (Compound No. 76);
N-{4-[3-(2-Morpholin-4-yl-quinolin-3-yl)-acryloyl]-phenyl}-oxalamide (Compound No.
77);
2-Morpholin-4-yl-N-{4-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-2-oxo-
acetamide (Compound No. 78);
2-Morpholin-4-yl-N-{4-[3-(2-morpholin-4-yl-quinolin-3-yl)-acryloyl]-phenyl}-2-oxo-
acetamide (Compound No. 79);
N-{4-[3-(2-Piperidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-oxalamide (Compound No.
80);

189
2-Morpholin-4-yl-2-oxo-N-{4-[3-(2-piperidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-
acetamide (Compound No. 81);
N-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-N'-propyl-oxalamide
(Compound No. 82);
2-Morpholin-4-yl-N-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-2-oxo-
acetamide (Compound No. 83);
(4-{3-[6-(3,5-Dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-phenyl)-carbamic acid
phenyl ester (Compound No. 84);
N-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-2-oxo-2-piperidin-1-yl-
acetamide (Compound No. 85);
5'-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-3,4,5,6-tetrahydro-2H-
[1,2' ]bipyridiny11-carboxylic acid (Compound No. 86);
2-Oxo-2-piperidin-1-yl-N-{4-[3-(4-pyrrol-1-yl-quinolin-2-yl)-acryloyl] -phenyl}-
acetamide (Compound No. 87);
2-Morpholin-4-yl-2-oxo-N-{4-[3-(4-pyrrol-1-yl-quinolin-2-yl)-acryloyl] -phenyl}-
acetamide (Compound No. 88);
C,C,C-Trifluoro-N-{l-[4-(3-quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-yl}-
methanesulfonamide (Compound No. 89);
{4-[3-(6-Pyrrolidin-1-yl-pyridin-2-yl)-acryloyl] -phenyl}-carbamic acid pyridin-2-
ylmethyl ester (Compound No. 90);
{4-[3-(6-Pyrrolidin-1-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 4-fluoro-benzyl
ester (Compound No. 91);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridinyl5'-yl)-acryloyl]-phenyl}-carbamic acid 2-
(3,5-dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 92);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridinyb'-yl)-acryloyl]-phenyl}-carbamic acid
furan-2-ylmethyl ester (Compound No. 93);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipydinyl-6'-yl)-acryloyl]-phenyl}-carbamic acid 3-
phenyl-allyl ester (Compound No. 94);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridinyl5'-yl)-acryloyl]-phenyl}-carbamic acid 2-
piperidin-1-yl-ethyl ester (Compound No. 95);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl ester
(Compound No. 96);


190
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(morpholine-4-carbonyl)-phenyl]-propenone
(Compound No. 97);
3-(3-Hydroxy-quinoxalin-2-yl)-l-[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone
(Compound No. 98);
l-[4-(3,5-Dimethyl-pyrazole-l-carbonyl)-phenyl]-3-(3-hydroxy-quinoxalin-2-yl)-
propenone (Compound No. 99);
1-{4-[4-(2,3-Dichloro-phenyl)-piperazine-1-carbonyl]-phenyl}-3-(3-hydroxy-quinoxalin-
2-yl)-propenone (Compound No. 100);
1-{4-[4-(3-Chloro-phenyl)-piperazine-1 -carbonyl] -phenyl}-3-(3-hydroxy-quinoxalin-2-
yl)-propenone (Compound No. 101);
1-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-piperidine-4-carboxylic acid
dimethylamide (Compound No. 102);
N-(1-{-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl}-piperidin-4-yl)-2,2-
dimethyl-propionamide (Compound No. 103);
1-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl]-benzoyl} -piperidine-4-carboxylic acid
isopropyl ester (Compound No. 104);
l-{4-[3-(3-Hydroxy-quinoxalin-2-yl)-acryloyl] -benzoyl}-pyrrolidine-2-carboxylic acid
amide (Compound No. 105);
3-(3-Hydroxy-quinoxalin-2-yl)-1-[4-(4-pyridin-4-yl-piperazine-1-carbonyl)-phenyl]-
propenone (Compound No. 106);
2-{3-[4-(Morpholine-4-carbonyl)-phenyl]-3-oxo-propenyl}-3H-quinazolin-4-one
(Compound No. 107);
2-{3-Oxo-3-[4-(pyrazole-l-carbonyl)-phenyl]-propenyl}-3H-quinazolin-4-one
(Compound No. 108);
2-{3-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl] -3-oxo-propenyl}-3H-quinazolin-4-
one (Compound No. 109);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-carbamic acid
phenyl ester (Compound No. 110);
(4-{3-[2-(4-Hydroxy-piperidin-1-yl)-quinolin-3-yl]-acryloyl}-phenyl)-carbamic acid
methyl ester (Compound No. 111);
(4-{3-[2-(4-Hydroxy-piperidin-l-yl)-quinolin-3-yl]-acryloyl}-phenyl)-carbamic acid
ethyl ester (Compound No. 112);

191
l-Benzenesulfonyl-3-(4-{3-[6-(3,5-dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-
phenyl)-urea (Compound No. 113);
N-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-2-oxo-2-piperidin-l-yl-
acetamide (Compound No. 114);
N-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-oxalamide (Compound No.
115);
2-Oxo-2-piperidin-1 -yl-N- {4- [3 -(2-piperidin-1 -yl-quinolin-3 -yl)-acryloyl] -phenyl} -
acetamide (Compound No. 116);
2-Oxo-2-piperidin-l-yl-N-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-acetamide (Compound
No. 117);
2-Morpholin-4-yl-2-oxo-N-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 118);
N-Propyl-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide (Compound No. 119);
N-[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide (Compound No. 120);
N-(2-Methoxy-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide (Compound
No. 121);
1 - {4-[4-(3-Chloro-phenyl)-piperazine-1 -carbonyl]-phenyl} -3-quinoxalin-2-yl-propenone
(Compound No. 122);
3-Quinoxalin-2-yl-l-[4-(thiomorpholine-4-carbonyl)-phenyl]-propenone (Compound No.
123);
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidine-4-carboxylic acid isopropyl ester
(Compound No. 124);
l-[4-(4-Pyridin-4-yl-piperazine-l-carbonyl)-phenyl]-3-quinoxalin-2-yl-propenone
(Compound No. 125);
1 - {4- [3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl] -phenyl} -3 -(2-oxo-2-piperidin- 1-yl-
ethyl)-urea (Compound No. 126);
1 -(2-Morpholin-4-yl-ethyl)-3- {4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl} -
urea (Compound No. 127);
2,2-Dimethyl-N-{l-[4-(3-quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-yl}-
propionamide (Compound No. 128);
{4-[3-(6-Morphblin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-piperazin- 1-yl-
ethyl ester (Compound No. 129);

192
N-(2-Morpholin-4-yl-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 130);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridine-2-sulfonyl)-
ethyl] -urea (Compound No. 131);
1 - {4- [3 -(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl] -phenyl} -3 - [2-(pyridin-2-ylsulfanyl)-
ethyl]-urea (Compound No. 132);
1 -[2-(4-Methyl-piperazin-1 -yl)-ethyl] -3- {4- [3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl] -
phenyl}-urea (Compound No. 133);
N-(2-Morpholin-4-yl-ethyl)-N'-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-
oxalamide (Compound No. 134);
1 -(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]- urea (Compound
No. 135);
N-(2- {3-[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-ureido} -ethyl)-benzenesulfonamide (Compound
No. 136);
N-[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-oxalamide (Compound No. 137);
2-Morpholin-4-yl-2-oxo-N-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-acetamide (Compound
No. 138);
l-Benzenesulfonyl-hydrazino-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 139);
l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 140);
l-[2-(Pyridin-4-yloxy)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 141);
1 -(Morpholine-4-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No.
142);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid piperidin-4-yl
ester (Compound No. 143);
4-(3-{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-ureido)-benzoic acid
(Compound No. 144);
4-(3-{4-[3-(4-Piperidin-1-yl-quinolin-2-yl)-acryloyl]-phenyl}-ureido)-benzoic acid
(Compound No. 145);
1-(4-Methyl-thiophen-2-yl)-3-{4-[3-(4-piperidin-1-yl-6-trifluoromethyl-quinolin-2-yl)-
acryloyl]-phenyl}-urea (Compound No. 146);

193
N-(2- {3-[4-(3-Dimethylamino-pyrazole-1-carbonyl)-phenyl]-3-oxo-propenyl}-quinolin-
6-yl)-2,2-dimethyl-propionamide (Compound No. 147);
l-[4-(Morpholine-4-carbonyl)-phenyl]-3-(5,6,7-trimethoxy-quinolin-2-yl)-propenone
(Compound No. 148);
1-{4-[3-(4-Piperidin-1 -yl-6-trifluoromethyl-quinolin-2-yl)-acryloyl]-phenyl}-3-pyridin-
2-yl-urea (Compound No. 149);
l-Cyclohexyl-3-{4-[3-(4-piperidin-l-yl-6-trifluoromethyl-quinolin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 150);
l-[4-(4-Methoxy-piperidine-l-carbonyl)-phenyl]-3-quinolin-2-yl-propenone (Compound
No. 151);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-[l,2' ]bipyridiny5'-yl)-
propenone (Compound No. 152);
1-[4-(3,5-Dimethyl-pyrazole-1-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-
[1,2' ]bipyridiny6'-yl)-propenone (Compound No. 153);
l-{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridinyE'-yl)-acryloyl]-benzoyl}-piperidine-4-
carboxylic acid isopropyl ester (Compound No. 154);
l-[2-(Pyridin-2-ylsulfanyl)-ethyl]-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 155);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(pyridine-2-
sulfonyl)-ethyl ester (Compound No. 156);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(pyridin-2-
ylsulfanyl)-ethyl ester (Compound No. 157);
[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-carbamic acid 2-benzenesulfonylamino-ethyl
ester (Compound No. 158);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(N-pyridin-2-
yl-hydrazino)-ethyl ester (Compound No. 159);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 160);
1 -[4-(Pyrazole-1 -carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-[ 1,2' ]bipyridiny6'-yl)-but-
2-en-l-one (Compound No. 161);
4,4,4-Trifluoro-l-[4-(morpholine-4-carbonyl)-phenyl]-3-quinolin-3-yl-but-2-en-l-one
(Compound No. 162);

194
N-{4-[3-(6-Morpholin-4-yl-pyridin-3-yl)-but-2-enoyl]-phenyl}-2-oxo-2-piperidin-l-yl-
acetamide (Compound No. 163);
2-Morpholin-4-yl-2-oxo-N-[4-(4,4,4-trifluoro-3-quinolin-3-yl-but-2-enoyl)-phenyl]-
acetamide (Compound No. 164);
Morpholine-4-carboxylic acid {4-[4,4,4-trifluoro-3-(4-morpholin-4-yl-quinolin-3-yl)-but-
2-enoyl]-phenyl}-amide (Compound No. 165);
Morpholine-4-carboxylic acid {4-[3-(6-morpholin-4-yl-pyridin-3-yl)-but-2-enoyl]-
phenyl}-amide (Compound No. 166);
N-[2-(3-{4-[3-(6-Moipholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-ureido)-ethyl]-
nicotinamide (Compound No. 167);
l-[2-(Piperidin-4-yloxy)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 168);
(4-{3-[6-(4-Methyl-piperazin-1 -yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid furan-
2-ylmethyl ester (Compound No. 169);
(4- {3-[6-(4-Methyl-piperazin-1 -yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid
pyridin-2-ylmethyl ester (Compound No. 170);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid 2-(3,5-
dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 171);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2- [ 1,2,4]triazol-
1-yl-ethyl ester (Compound No. 172);
{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[l,2,4]-triazol-
1-yl-ethyl ester (Compound No. 173);
(4- {3-[6-(4-Methyl-piperazin-1 -yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid
thiophen-2-ylmethyl ester (Compound No. 174);
2-{3-Oxo-3-[4-(thiophen-2-ylmethoxycarbonylamino)-phenyl]-propenyl}-quinoline-6-
carboxylic acid (Compound no. 175);
{4-[3-(6-[l ,2,4]Triazol-l -yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen-2-
ylmethyl ester (Compound no. 176);
{4-[3-(6-Tetrazol-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -carbamic acid thiophen-2-yl
methyl ester (Compound No. 177);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid pyridin-2
yl methyl ester (Compound No. 178);

195
4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid pyridin-2-ylmethyl ester (Compound
No. 179);
(4- {3-[6-(4-Methyl-piperazin- l-yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid
piperidin-4-yl ester (Compound No. 180);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 1-methyl- 1H-
pyrrol-3-yl ester (Compound No. 181);
(4-{3-[6-(4-Methyl-piperazin-1-yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid
isoxazol-3-yl ester (Compound No. 182);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 1 -methyl-1 H-imidazol-4-ylmethyl
ester (Compound No. 183);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(4-methyl-piperazine-1-
sulfonylamino)-ethyl ester (Compound No. 184);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(4-methyl-piperazine-1 -
sulfonylamino)-ethyl ester (Compound No. 185);
(4- {3- [6-(4-Methyl-piperazin-1-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid 2-
benzenesulfonylamino-ethyl ester (Compound No. 186);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[(4-methyl-
piperazine-l-carbonyl)-amino]-ethyl ester (Compound No. 187);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 2-[(4-methyl-piperazine-l-
carbonyl)-amino]-ethyl ester (Compound No. 188);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N-pyridin-2-yl-hydrazino)-ethyl
ester (Compound No. 189);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-[N-(5-methyl-isoxazol-3-yl)-
hydrazino]-ethyl ester (Compound No. 190);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N'-benzenesulfonyl- hydrazino)-
ethyl ester (Compound No. 191);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-2-piperazin-l-yl-
ethyl)-urea (Compound No. 192);
l-[2-(4-Methyl-piperazin-l-yl)-2-oxo-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 193);
l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-{4-[3-(6-piperazin-l-yl-pyridin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 194);

196
l-[2-(Pyridine-2-sulfonyl)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 195);
l-{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidine-4-sulfonyl)-
ethyl]-urea (Compound No. 196);
4-Methyl-piperazine-1-sulfonic acid(2-{3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-ureido}-
ethyl)-amide (Compound No. 197);
1-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidin-4-ylsulfanyl)-
ethyl]-urea (Compound No. 198);
1 -{2- [N-( 1 -Methyl-piperidin-4-yl) -hydrazino] -ethyl} -3 - [4-(3 -pyridin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 199);
l-{2-[N-(l-Methyl-piperidin-4-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 200);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-{4-[3-(6-morpholin-4-yl-pyridin-2-
yl)-acryloyl]-phenyl}-urea (Compound No. 201);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 202);
l-(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]urea (Compound No.
203);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No.
204);
1 - {4-[3-(6-Piperazin-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -3-(2-piperidin-1 -yl-ethyl)-urea
(Compound No. 205);
l-{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-thiomorpholin 1, 1-
dioxide-4-yl-ethyl)-urea (Compound No. 206);
l-(2-Piperazin-l-yl-ethyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2' ]bipyridiny6'-yl)-
acryloyl]-phenyl}-urea (Compound No. 207);
Piperidine-4-carboxylic acid [2-(3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-
phenyl}-ureido)-ethyl]-amide (Compound No. 208);
N-(2-{3-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-ureido}-ethyl)-nicotinamide (Compound
No. 209);
l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 210);

197
l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 211);
l-(Piperazine-l-sulfonyl)-3-[4-(3-pyridin-2-yl-acryloyl)phenyl]-urea (Compound No.
212);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(piperazine-l-sulfonyl)-
urea (Compound No. 213);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 214);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl) phenyl]-urea (Compound No.
215);
N-(2-Piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 216);
N- {4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl} -N'-(2-piperazin-1 -yl-ethyl)-
oxalamide (Compound No. 217);
l-[2-({4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenylaminooxalyl}-amino)-
acetyl]-piperidine-4-carboxylic acid (Compound No. 218);
N-(2-Oxo-2-piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 219);
N-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-N'-[2-(pyridine-2-yl-sulfonyl)-ethyl]-oxalamide
(Compound No. 220);
N-[2-(Piperidin-4-ylsulfanyl)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 221);
N-[2-(Pyridine-2-sulfonyl)-ethyl]-N'-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 222);
2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-2-oxo-N-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 223);
2-Oxo-2-(N-phenyl-hydrazino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 224);
2-Oxo-2-(piperazine-l-sulfonylamino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 225);
2-Benzenesulfonylamino-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 226);

198
N-[2-(Piperazine-l-sulfonylamino)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 227);
2-(N'-Benzenesulfonyl-hydrazino)-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 228);
N-{ 2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl} -N'-[4-(3-pyridin-2-yl-acryloyl)-
phenyl]-oxalamide (Compound No. 229);
N- {2-[(Piperazine-1 -carbonyl)-amino]-ethyl} -N'- [4-(3-pyridin-2-yl-acryloyl)-phenyl] -
oxalamide (Compound No. 230);
N-{2-[(Pyridine-3-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 231);
N-{2-[(Piperidine-4-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 232);
1 -[4-(4-Methyl-piperazine-1 -carbonyl)-phenyl]-3 - {6- [2-(4-methyl-piperazin-1 -yl)-
ethylamino]-pyridin-2-yl}-propenone (Compound No. 233);
(2- {3-[4-(4-Methyl-piperazine-1 -carbonyl)-phenyl]-3-oxo-propenyl} -quinolin-6-yl)-
carbamic acid ethyl ester (Compound No. 234);
(6- {3-[4-(4-Methyl-piperazine-1 -carbonyl)-phenyl]-3-oxo-propenyl} -pyridin-2-yl)-
carbamic acid phenyl ester (Compound No. 235);
1 -[4-(Morpholine-4-carbonyl)-phenyl]-3- {6-[(piperidin-1 -ylmethyl)-amino]-pyridin-2-
yl}-propenone (Compound No. 236);
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-[6-(2-oxo-2-piperidin-l-yl-
ethylamino)-pyridin-2-yl]-propenone (Compound No. 237);
l-[4-(Piperazine-l-carbonyl)-phenyl]-3-{6-[2-(pyridine-2-sulfonyl)-ethylamino]-pyridin-
2-yl}-propenone (Compound No. 238);
Benzenesulfonic acid N' -(6-{ 3-oxo-3-[4-(piperidine-1 -carbonyl)-phenyl]-propenyl} -
pyridin-2-yl)-hydrazide (Compound No. 239);
(6-{3-[4-(3-Benzenesulfonyl-ureido)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-carbamic
acid ethyl ester (Compound No. 240);
Morpholine-4-carboxylic acid (4- {3-[6-(2-piperidin- l-yl-ethylamino)-pyridin-2-yl]-
acryloyl}-phenyl)-amide (Compound No. 241);
{2-[3-(4-Ethoxycarbonylamino-phenyl)-3-oxo-propenyl]-quinolin-6-yl}-carbamic acid
ethyl ester (Compound No. 242);

199
{2-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-quinolin-4-yl} -carbamic acid ethyl ester (Compound No. 243);
[2-(3- {4-[2-(4-Methyl-piperazin-1 -yl)-2-oxo-acetylamino] -phenyl} -3-oxo-propenyl)- quinolin-4-yl]-carbamic acid methyl ester (Compound No. 244); 1 -(2-Morpholin-4-yl-ethyl)-3-(4- {3-[6-(2-piperidin-1 -yl-ethylamino)-pyridin-2-yl]- acryloyl}-phenyl)-urea (Compound No. 245);
l-[4-(3-Dimethylamino-pyrazole-l-carbonyl)-phenyl]-3-{6-[2-(4-methyl-piperazin-l-yl)- 2-oxo-ethylamino]-pyridin-2-yl}-propenone (Compound No. 246); N-( 1 - {4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl] -piperazin-1 -yl} -piperidin-4-yl)- methanesulfonamide (Compound No. 247);
(1 -{4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl}-piperidin-4-yl)- sulfonylurea (Compound No. 248);
1 - {4- [4-(4-Cyclohexylamino-piperidin-1 -yl)-piperazine-1 -carbonyl] -phenyl} -3-pyridin- 2-yl-propenone (Compound No. 249);
[6-(3-Oxo-3-{4-[4-(pyrrolidine-l-carbonyl)-piperidine-l-carbonyl]-phenyl}-propenyl)- pyridin-2-yl]-carbamic acid methyl ester (Compound No. 250);
[6-(3-Oxo-3- {4-[4-(pyridin-2-yloxy)-piperidine-1 -carbonyl] -phenyl} -propenyl)-pyridin- 2-yl]-carbamic acid ethyl ester (Compound No. 251).
11. The compound as claimed in claim 2, wherein said compound is selected from the group consisting of:
N-(4- {2-Oxo-4-[4-(3-quinolin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl }-phenyl)-
acetamide (Compound No. 17);
3-Quinolin-2-yl-l-{4-[4-(tetrahydro-furan-2-carbonyl)-piperazine-l-carbonyl]-phenyl}-
propenone (Compound No. 20);
1 -{4-[4-(Furan-2-carbonyl)-piperazine-1 -carbonyl]-phenyl} -3-quinolin-2-yl-propenone
(Compound No. 21);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 23);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid 2,2-dimethyl-
propyl ester (Compound No. 24);

200
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 29);
{4-[3-(4-Piperidin-l-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid isobutyl ester
(Compound No. 30);
{4-[3-(2-Pyrrolidin-l-yl-quinolin-3-yl)-acryloyl]-phenyl}-carbamic acid ethyl ester
(Compound No. 31);
l-[4-(2,3-Dihydro-indole-l-carbonyl)-phenyl]-3-(3-hydroxy-quinoxalin-2-yl)-propenone
(Compound No. 43);
l-[4-(3-Quinoxalin-2-yl-acryloyl)-benzoyl]-piperidin-4-one oxime (Compound No. 45);
1 -Benzenesulfonyl-3- {4- [3-(6-methyl-4-piperidin-1 -yl-quinolin-2-yl)-acryloyl]-phenyl} -
urea (Compound No. 59);
{4-[3-(6-[l,2,3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid ethyl
ester (Compound No. 64);
{4-[3-(6-[l,2,3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl
ester (Compound No. 66);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-morpholin-4-
yl-ethyl ester (Compound No. 67);
{5-Methoxy-2-[3-(4-morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl} -carbamic acid
methyl ester (Compound No. 69);
Propyl- {4-[3-(2-pyrrolidin-1 -yl-quinolin-3-yl)-acryloyl]-phenyl} -carbamic acid ethyl
ester (Compound No. 70);
{4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid phenyl ester
(Compound No. 71);
{4-[3-(6-[l, 2, 3]Thiadiazol-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl
ester (Compound No. 74);
l-(4-Methyl-benzenesulfonyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2' ]bipyridiny6'-yl)-
acryloyl]-phenyl}-urea (Compound No. 75);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridinyB'-yl)-acryloyl]-phenyl}-carbamic acid
ethyl ester (Compound No. 76);
(4-{3-t6-(3,5-Dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-phenyl)-carbamic acid
phenyl ester (Compound No. 84);

201
5'-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-3,4,5,6-tetrahydro-2H-
[1,2' jbipyridinytt-carboxylic acid (Compound No. 86);
{4-[3-(6-Pyrrolidin-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -carbamic acid pyridin-2-
ylmethyl ester (Compound No. 90);
{4-[3-(6-Pyrrolidin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 4-fluoro-benzyl
ester (Compound No. 91);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridiny6'-yl)-acryloyl]-phenyl}-carbamic acid 2-
(3,5-dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 92);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridiny6'-yl)-acryloyl]-phenyl}-carbamic acid
furan-2-ylmethyl ester (Compound No. 93);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridiny6'-yl)-acryloyl]-phenyl}-carbamic acid 3-
phenyl-allyl ester (Compound No. 94);
{4-[3-(3,4,5,6-Tetrahydro-2H-[l,2' ]bipyridiny6'-yl)-acryloyl]-phenyl}-carbamic acid 2-
piperidin-1-yl-ethyl ester (Compound No. 95);
(4-[3-(4-Morpholin-4-yl-quinolin-2-yl)-acryloyl]-phenyl}-carbamic acid methyl ester
(Compound No. 96);
(4- {3-[2-(4-Hydroxy-piperidin-1 -yl)-quinolin-3-yl]-acryloyl} -phenyl)-carbamic acid
phenyl ester (Compound No. 110);
(4- {3-[2-(4-Hydroxy-piperidin- l-yl)-quinolin-3-yl]-acryloyl} -phenyl)-carbamic acid
methyl ester (Compound No. 111);
(4- {3-[2-(4-Hydroxy-piperidin-1 -yl)-quinolin-3-yl]-acryloyl} -phenyl)-carbamic acid
ethyl ester (Compound No. 112);
l-Benzenesulfonyl-3-(4-{3-[6-(3,5-dimethyl-morpholin-4-yl)-pyridin-3-yl]-acryloyl}-
phenyl)-urea (Compound No. 113);
1 -{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl} -3-(2-oxo-2-piperidin- 1-yl-
ethyl)-urea (Compound No. 126);
l-(2-Morpholin-4-yl-ethyl)-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-
urea (Compound No. 127);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-piperazin-l-yl-
ethyl ester (Compound No. 129);
N-(2-Morpholin-4-yl-ethyl)-N'-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 130);

202
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridine-2-sulfonyl)- ethyl]-urea (Compound No. 131);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(pyridin-2-ylsulfanyl)- ethyl]-urea (Compound No. 132);
l-[2-(4-Methyl-piperazin-l-yl)-ethyl]-3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]- phenyl}-urea (Compound No. 133);
N-(2-Morpholin-4-yl-ethyl)-N'-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}- oxalamide (Compound No. 134);
l-(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]- urea (Compound No. 135);
l-Benzenesulfonyl-hydrazino-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound No. 139);
l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No. 140);
l-(Morpholine-4-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No. 142);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid piperidin-4-yl ester (Compound No. 143);
l-[2-(Pyridin-2-ylsulfanyl)-ethyl]-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound No. 155);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(pyridine-2- sulfonyl)-ethyl ester (Compound No. 156);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl} -carbamic acid 2-(pyridin-2- ylsulfanyl)-ethyl ester (Compound No. 157);
[4-(3-Quinoxalin-2-yl-acryloyl)-phenyl]-carbamic acid 2-benzenesulfonylamino-ethyl ester (Compound No. 158);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-(N-pyridin-2- yl-hydrazino)-ethyl ester (Compound No. 159);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)- phenyl]-urea (Compound No. 160);
l-[4-(Pyrazole-l-carbonyl)-phenyl]-3-(3,4,5,6-tetrahydro-2H-[l,2' ]bipyridiny5'-yl)-but- 2-en-l-one (Compound No. 161);

203
4,4,4-Trifluoro 1 - [4-(morpholine-4-carbonyl)-phenyl] -3-quinolin-3-yl-but-2-en-1-one
(Compound No. 162);
N-{4-[3-(6-Morpholin-4-yl-pyridin-3-yl)-but-2-enoyl]-phenyl}-2-oxo-2-piperidin-l-yl-
acetamide (Compound No. 163);
2-Morpholin-4-yl-2-oxo-N-[4-(4,4,4-trifluoro-3-quinolin-3-yl-but-2-enoyl)-phenyl]-
acetamide (Compound No. 164);
Morpholine-4-carboxylic acid {4-[4,4,4-trifluoro-3-(4-morpholin-4-yl-quinolin-3-yl)-but-
2-enoyl]-phenyl}-amide (Compound No. 165);
Morpholine-4-carboxy lie acid {4- [3 - (6-morpholin-4-yl-pyridin-3 -yl) -but-2-enoyl] -
phenyl}-amide (Compound No. 166);
N-[2-(3-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-ureido)-ethyl]-
nicotinamide (Compound No. 167);
l-[2-(Piperidin-4-yloxy)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 168);
(4-{3-[6-(4-Methyl-piperazin-l-yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid furan-
2-ylmethyl ester (Compound No. 169);
(4- {3-[6-(4-Methyl-piperazin-1 -yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid
pyridin-2-ylmethyl ester (Compound No. 170);
(4-{3-[6-(4-Methyl-piperazin-1 -yl)-pyridin-2-yl]-acryloyl}-phenyl)-carbamic acid 2-(3,5-
dimethyl-pyrazol-l-yl)-ethyl ester (Compound No. 171);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2- [l,2,4]triazol-
1-yl-ethyl ester (Compound No. 172);
{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[l,2,4]-triazol-
1-yl-ethyl ester (Compound No. 173);
(4- {3-[6-(4-Methyl-piperazin-1 -yl)-pyridin-2-yl] -acryloyl} -phenyl)-carbamic acid
thiophen-2-ylmethyl ester (Compound No. 174);
2-{3-Oxo-3-[4-(thiophen-2-ylmethoxycarbonylamino)-phenyl]-propenyl}-quinoline-6-
carboxylic acid (Compound no. 175);
{4-[3-(6-[ 1,2,4]Triazol-1 -yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid thiophen-2-
ylmethyl ester (Compound no. 176);
{4-[3-(6-Tetrazol-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -carbamic acid thiophen-2-yl
methyl ester (Compound No. 177);

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{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid pyridin-2
yl methyl ester (Compound No. 178);
4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid pyridin-2-ylmethyl ester (Compound
No. 179);
(4- {3-[6-(4-Methyl-piperazin- l-yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid
piperidin-4-yl ester (Compound No. 180);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 1-methyl- 1H-
pyrrol-3-yl ester (Compound No. 181);
(4- {3-[6-(4-Methyl-piperazin- l-yl)-pyridin-2-yl]-acryloyl} -phenyl)-carbamic acid
isoxazol-3-yl ester (Compound No. 182);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 1-methyl-lH-imidazol-4-ylmethyl
ester (Compound No. 183);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(4-methyl-piperazine-l-
sulfonylamino)-ethyl ester (Compound No. 184);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(4-methyl-piperazine-1 -
sulfonylamino)-ethyl ester (Compound No. 185);
(4- {3-[6-(4-Methyl-piperazin-1 -yl)-pyridin-2-yl] -acryloyl} -phenyl)-carbamic acid 2-
benzenesulfonylamino-ethyl ester (Compound No. 186);
{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-carbamic acid 2-[(4-methyl-
piperazine-l-carbonyl)-amino]-ethyl ester (Compound No. 187);
[4-(3-Quinolin-2-yl-acryloyl)-phenyl]-carbamic acid 2-[(4-methyl-piperazine-1-
carbonyl)-amino]-ethyl ester (Compound No. 188);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N-pyridin-2-yl-hydrazino)-ethyl
ester (Compound No. 189);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl] -carbamic acid 2- [N-(5 -methyl-isoxazol-3-yl)-
hydrazino]-ethyl ester (Compound No. 190);
[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-carbamic acid 2-(N'-benzenesulfonyl-hydrazino)-
ethyl ester (Compound No. 191);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(2-oxo-2-piperazin-l-yl-
ethyl)-urea (Compound No. 192);
l-[2-(4-Methyl-piperazin-l-yl)-2-oxo-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 193);

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l-(2-Morpholin-4-yl-2-oxo-ethyl)-3-{4-[3-(6-piperazin-l-yl-pyridin-2-yl)-acryloyl]-
phenyl}-urea (Compound No. 194);
l-[2-(Pyridine-2-sulfonyl)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 195);
l-{4-[3-(6-Piperazin-l-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidine-4-sulfonyl)-
ethyl]-urea (Compound No. 196);
4-Methyl-piperazine-1 -sulfonic acid (2-{3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-ureido}-
ethyl)-amide (Compound No. 197);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-[2-(piperidin-4-ylsulfanyl)-
ethyl]-urea (Compound No. 198);
1 - {2-[N-(l -Methyl-piperidin-4-yl)-hydrazino]-ethyl} -3-[4-(3-pyridin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 199);
l-{2-[N-(l-Methyl-piperidin-4-yl)-hydrazino]-ethyl}-3-[4-(3-quinoxalin-2-yl-acryloyl)-
phenyl]-urea (Compound No. 200);
l-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-3-{4-[3-(6-morpholin-4-yl-pyridin-2-
yl)-acryloyl]-phenyl}-urea (Compound No. 201);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 202);
l-(2-Morpholin-4-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]urea (Compound No.
203);
l-(2-Piperazin-l-yl-ethyl)-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea (Compound No.
204);
1 - {4- [3-(6-Piperazin-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -3 -(2-piperidin-1 -yl-ethyl)-urea
(Compound No. 205);
1 - {4-[3-(6-Piperazin-1 -yl-pyridin-2-yl)-acryloyl]-phenyl} -3 -(2-thiomorpholin 1, 1 -
dioxide-4-yl-ethyl)-urea (Compound No. 206);
l-(2-Piperazin-l-yl-ethyl)-3-{4-[3-(3,4,5,6-tetrahydro-2H-[l,2' ]bipyridinyB'-yl)-
acryloyl]-phenyl}-urea (Compound No. 207);
Piperidine-4-carboxylic acid [2-(3-{4-[3-(6-morpholin-4-yl-pyridin-2-yl)-acryloyl]-
phenyl}-ureido)-ethyl]-amide (Compound No. 208);
N-(2-{3-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-ureido}-ethyl)-nicotinamide (Compound
No. 209);

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l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 210);
l-[2-(N'-Benzenesulfonyl-hydrazino)-ethyl]-3-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-urea
(Compound No. 211);
1 -(Piperazine-1 -sulfonyl)-3-[4-(3-pyridin-2-yl-acryloyl)phenyl]-urea (Compound No.
212);
l-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-3-(piperazine-l-sulfonyl)-
urea (Compound No. 213);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinoxalin-2-yl-acryloyl)-phenyl]-urea (Compound
No. 214);
l-(Piperazine-l-sulfonyl)-3-[4-(3-quinolin-2-yl-acryloyl) phenyl]-urea (Compound No.
215);
N-(2-Piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 216);
N-{4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenyl}-N'-(2-piperazin-l-yl-ethyl)-
oxalamide (Compound No. 217);
l-[2-({4-[3-(6-Morpholin-4-yl-pyridin-2-yl)-acryloyl]-phenylaminooxalyl}-amino)-
acetyl]-piperidine-4-carboxylic acid (Compound No. 218);
N-(2-Oxo-2-piperazin-l-yl-ethyl)-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 219);
N-[4-(3-Pyridin-2-yl-acryloyl)-phenyl]-N'-[2-(pyridine-2-yl-sulfonyl)-ethyl]-oxalamide
(Compound No. 220);
N-[2-(Piperidin-4-ylsulfanyl)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-oxalamidea
(Compound No. 221);
N-[2-(Pyridine-2-sulfonyl)-ethyl]-N'-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-oxalamide
(Compound No. 222);
2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-2-oxo-N-[4-(3-quinolin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 223);
2-Oxo-2-(N-phenyl-hydrazino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 224);
2-Oxo-2-(piperazine-l-sulfonylamino)-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 225);

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2-Benzenesulfonylamino-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-acetamide
(Compound No. 226);
N-[2-(Piperazine-l-sulfonylamino)-ethyl]-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 227);
2-(N'-Benzenesulfonyl-hydrazino)-2-oxo-N-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
acetamide (Compound No. 228);
N-{2-[N-(6-Methyl-pyridin-2-yl)-hydrazino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-
phenyl]-oxalamide (Compound No. 229);
N-{2-[(Piperazine-l-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 230);
N-{2-[(Pyridine-3-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 231);
N-{2-[(Piperidine-4-carbonyl)-amino]-ethyl}-N'-[4-(3-pyridin-2-yl-acryloyl)-phenyl]-
oxalamide (Compound No. 232);
N-( 1 - {4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl} -piperidin-4-yl)-
methanesulfonamide (Compound No. 247);
(1 -{4-[4-(3-Pyridin-2-yl-acryloyl)-benzoyl]-piperazin-1 -yl}-piperidin-4-yl)- sulfonylurea
(Compound No. 248);
1 - {4-[4-(4-Cyclohexylamino-piperidin-1 -yl)-piperazine-1 -carbonyl]-phenyl}-3-pyridin-
2-yl-propenone (Compound No. 249).
12. The compound as claimed in claim 3, wherein said compound is selected from the group consisting of:
1 -[4-(4-Methyl-piperazine-l -carbonyl)-phenyl]-3-{6-[2-(4-methyl-piperazin-1-yl)-
ethylamino]-pyridin-2-yl}-propenone (Compound No. 233);
(2- {3-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl]-3-oxo-propenyl}-quinolin-6-yl)-
carbamic acid ethyl ester (Compound No. 234);
(6- {3-[4-(4-Methyl-piperazine-1-carbonyl)-phenyl] -3-oxo-propenyl}-pyridin-2-yl)-
carbamic acid phenyl ester (Compound No. 235);
1 -[4-(Morpholine-4-carbonyl)-phenyl]-3- {6-[(piperidin-1-ylmethyl)-amino]-pyridin-2-
yl}-propenone (Compound No. 236);

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1 -[4-(3-Dimethylamino-pyrazole-1 -carbonyl)-phenyl]-3-[6-(2-oxo-2-piperidin-1 -yl-
ethylamino)-pyridin-2-yl]-propenone (Compound No. 237);
1 -[4-(Piperazine-1 -carbonyl)-phenyl]-3-{6-[2-(pyridine-2-sulfonyl)-ethylamino]-pyridin-
2-yl}-propenone (Compound No. 238);
Benzenesulfonic acid N-[2-(6-{ 3-oxo-3-[4-(piperidine-l-carbonyl)-phenyl]-propenyl}-
pyridin-2-ylamino)-ethyl]-hydrazide (Compound No. 239);
(6-{3-[4-(3-Benzenesulfonyl-ureido)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-carbamic
acid ethyl ester (Compound No. 240);
Morpholine-4-carboxylic acid (4-{3-[6-(2-piperidin-1-yl-ethylamino)-pyridin-2-yl]-
acryloyl}-phenyl)-amide (Compound No. 241);
{2-[3-(4-Ethoxycarbonylamino-phenyl)-3-oxo-propenyl]-quinolin-6-yl}-carbamic acid
ethyl ester (Compound No. 242);
{2-[3-Oxo-3-(4-phenoxycarbonylamino-phenyl)-propenyl]-quinolin-4-yl}-carbamic acid
ethyl ester (Compound No. 243);
[2-(3- {4-[2-(4-Methyl-piperazin-1-yl)-2-oxo-acetylamino] -phenyl}-3-oxo-propenyl)-
quinolin-4-yl]-carbamic acid methyl ester (Compound No. 244);
1 -(2-Morpholin-4-yl-ethyl)-3 -(4-{3 - [6-(2-piperidin-1 -yl-ethylamino)-pyridin-2-yl] -
acryloyl}-phenyl)-urea (Compound No. 245);
1 -[4-(3 -Dimethylamino-pyrazole-1 -carbonyl)-phenyl] -3- {6- [2-(4-methyl-piperazin- 1-yl)-
2-oxo-ethylamino]-pyridin-2-yl}-propenone (Compound No. 246);
[6-(3-Oxo-3- {4- [4-(pyrrolidine-1 -carbonyl)-piperidine-1 -carbonyl]-phenyl}-propenyl)-
pyridin-2-yl]-carbamic acid methyl ester (Compound No. 250);
[6-(3-Oxo-3-{4-[4-(pyridin-2-yloxy)-piperidine-l-carbonyl]-phenyl}-propenyl)-pyridin-
2-yl]-carbamic acid ethyl ester (Compound No. 251).
13. A pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound of formula (I) as defined in claim 1, or one or more of compound as defined in claim 10.
14. The pharmaceutical composition as claimed in claim 13, in the form of an oral formulation or a parenteral formulation.

209
15. The pharmaceutical composition as claimed in claim 13 in the form of a tablet, capsule, powder, syrup, solution, infusion or suspension.
16. A pharmaceutical composition as claimed in claim 13, containing 1 to 1000 mg of a compound of general formula (I), at concentration levels ranging from about 0.5 % to about 90 % by weight of the total composition.
17. The pharmaceutical composition as claimed in claim 16, more preferably containing 20 to 500 mg of compound of general formula (I), at concentration levels ranging from about 10 % to about 70 % by weight of the total composition.
18. A pharmaceutical composition as claimed in claim 13, wherein the said
composition is useful in treating diseases accompanying pathological stress in a living mammalian organism, including a human being, by inducing the expression of HSP-70 in the body cells of said living mammalian organism.
19. The pharmaceutical composition as claimed in claim 18, wherein said diseases
accompanying pathological stress are selected from stroke, myocardial infarction, inflammatory disorder, hepatotoxicity, sepsis, diseases of viral origin, allograft rejection, tumourous diseases, gastric mucosal damage, brain haemorrhage, endothelial dysfunctions, diabetic complications, neuro-degenerative diseases, post-traumatic neuronal damage, acute renal failure, glaucoma and aging related skin degeneration.
20. The pharmaceutical composition as claimed in claim 19, wherein said disease accompanying pathological stress is stroke.

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21. The pharmaceutical composition as claimed in claim 19, wherein said disease accompanying pathological stress is myocardial infarction.
22. The pharmaceutical composition as claimed in claim 19, wherein said disease accompanying pathological stress is an inflammatory disorder.
23. The pharmaceutical composition as claimed in claim 19, wherein said diabetic
complications are selected from diabetic neuropathy, diabetic retinopathy and chronic wound healing.
24. The pharmaceutical composition as claimed in claim 19, wherein said neuro-
degenerative diseases are selected from Alzheimer' s disease, amyotrophic lateral sclerosis and Parkinson' s disease.
Dated this 17th day of August 2007.

The present invention relates to novel compounds of 2-propene-l-one series, of general formula (I), tautomeric forms, stereoisomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates and
pharmaceutically acceptable compositions containing them, wherein R5, R6, Q and Y are as defined in the specification.
The present invention also relates to a process for preparing such compounds,
compositions containing such compounds, and use of such compound and composition in
medicine. The compounds of the general formula (I) induce HSP-70 and are useful for the
treatment of diseases accompanying pathological stress in a living mammalian organism,
including a human being, such as stroke, myocardial infarction, inflammatory disorder,
hepatotoxicity, sepsis, diseases of viral origin, allograft rejection, tumourous diseases,
gastric mucosal damage, brain haemorrhage, endothelial dysfunctions, diabetic
complications, neuro-degenerative diseases, post-traumatic neuronal damage, acute renal
failure, glaucoma and aging related skin degeneration.