PHOSPHODIESTERASES A (PDE3A) INHIBITORS AND A PROCESS FOR THE PREPARATION THEREOF

FIELD OF THE INVENTION

[001]This invention related to a series of 2-pyridone compounds having general Formula A. In particular, these inventions related to substituted 2-pyridone compounds that are having potential phosphodiesterase3A (PDE3A) inhibitory activity and are useful for the improvement of cardiac contractility and may be used in congestive heart failure CHF).

Formula A

Wherein X = COOCH ₃ , COOC ₂ H ₅ , CN

Y = Methyl, Phenyl

R = alkyl, substituted phenyl, napthyl, furonyl,

thiophenyl, substituted quinolinyl

More particularly the present invention relates to 2-pyridone based compounds useful as phosphodiesterases A inhibitory agents. The general structural Formula of these 2-pyridone based com ounds is given below.

Formula A BACKGROUND OF THE INVENTION

[002] Heart failure is some time called congestive heart failure (CHF) a severe public health problem worldwide. Heart failure is most common cardiovascular disease in the US and 2 per cent of the U.S. population or about 5 million people affecting with this disease (Rosamond et al, 2007 and Jessup et al, 2007). Around 30 to 40 per cent of patients drown from heart failure within 1 year after receiving the diagnosis. Due to less HF statistical data in India, Reddy et al 2010 reported that the burden of CHF is likely to be higher in comparison to the western population, as a result of higher propensity of cardiovascular diseases and ageing population. According to doctors on the eve of World Heart Day over, 3 million deaths owing to cardiovascular diseases every year, India is set to be the 'heart disease capital of the world' in few years (September 29, 2013).

[003] Digitalis glycosides (Drug that is extracted from the leaves of the foxglove plant) have been used for the treatment of CHF for more than 200 years (Gheorghiade, M.; Zarowitz, B. J.; Am. J. Cardiol., 1992, 69, 48). However, applications of these agents are limited because of their narrow therapeutic window and their propensity that cause life-threatening arrhythmias (arrhythmogenic liability). Besides digitalis glycosides there are other class of inhibiters used for CHF i.e the phosphodiesterase (PDE), this observation made by Henry Hyde Salter in 1886. One day, while having a strong cup of coffee on an empty stomach, he observed that his breathing pacified, an effect attributed to the bronchodilator properties of caffeine Despite the mechanism of action at the time was unknown, it has since been delineated that caffeine was acting as a non-selective, even though weak, PDE inhibitor. Ashman et al., 1963 reported, PDE was identified as the enzyme capable of inactivating cAMP, and it was shown that this enzyme could be activated by magnesium ions and importantly could be inhibited by caffeine providing a plausible mechanism of action for the diverse activities of this drug. Thus digitalis has been replaced by new class of cardiotonic agents namely PDE inhibitors. For example, amrinone and milrinone (Figure 1) are the 2-oxopyridine compounds that have been introduced to clinic for treatment of CHF in place of digitalis (Kikura, M.; Levy, J. H.; Int. Anestesiol. Clin., 1995, 33, 21). Although, these PDE3 inhibitors produce acute inotropic, lusitropic and vasodilatory haemo- dynamic responses in patients with heart failure, chronic administration of the PDE3 inhibitor milrinone in such patients increased annual mortality, most probably owing to arrhythmias and cardiac arrest, there is a scope to identify novel molecules with more potency and less adverse effects.

1 . Milrinone 2. Amrinone

[004] Phosphodiesterases are a class of intracellular enzymes responsible for the hydrolysis of cyclic adenosine monophosphate (c-AMP) and cyclic guanosine monophosphate (c-GMP) which are responsible for the regulation of essential cell functions, such as secretion, contraction, metabolism, and growth (Potter, B. V. L.; Transmembrane Signalling Second Messenger Analogues and Inositol Phosphates. In Comprehensive Medical Chemistry; Hansen, C; Sammes, P. G.; Taylor, J. B., Eds. Pergamon Press: Oxford, 1990, 102). Under normal physiological conditions, cyclic nucleotides regulate multiple biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation. In addition, altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer (Alexandra et al, 2014).

[005] Based on the structure, amino acid sequences, regulatory properties, pharmacological properties, tissue distribution and substrate specificity PDE enzymes can be grouped into eleven different families, PDE1 to PDE11 (Beavo, J. A.; Physiol. Rev., 1995, 75, 725). Each PDE isozyme has a conserved C-terminal catalytic domain and unique N-terminal regulatory domain. These isozymes are distributed throughout human body and found in different tissues and cells such as smooth muscle, brain, heart, lung, platelets, lymphocytes etc. and in other species (Bender, A. T.; Beavo, J. A.; Pharmacol Rev.,2006, 58, 488).

[006] Different PDEs of same family are functionally related but differs in substrate selectivity. Based on substrate specificity they are grouped into cAMP selective (PDE 4, 7 and 8), cGMP selective (PDE 5, 6 and 9) and both cAMP and cGMP selective hydrolases (PDE1, 2, 3, 10 and 11) (Mahajan et al, 2013).

US Pat. No. US20140221651 Al, we reported synthesis of 6-benzyl-l,3- dimethylpyrido[2,3-<i]pyrimidine-2,4,7(lH,3H,8H)-trione compounds which are useful as cardiotonics. Inhibition of PDE3 was reported to have cardiotonic effect of these compounds.

[007] PDE3 family shows dual- specificity phosphodiesterases that bind both cAMP and cGMP with high affinity and hydrolyze them in a mutually competitive manner. PDE3 inhibitors, which raise intracellular cAMP and cGMP content, have inotropic effects attributable to the activation of cAMP-dependent protein kinase (PK-A) in cardiac myocytes and vasodilatory effects attributable to the activation of cGMP- dependent protein kinase (PK-G) in vascular myocytes. PDE3 cyclic nucleotide phosphodiesterases are involved in platelet aggregation, anti-lipolytic responses to insulin in adipocytes, insulin secretion by pancreatic cells and maturation of oocytes (Shakur et al., 2000; Zhao et al., 1998; Andersen et al., 1998) highlights the various targets and the intracellular compartmentation of PK-A activity.

[008] PDE3 is encoded by two genes: PDE3A (human chromosome location (hcl): 12pl2) and PDE3B (hcl: l lpl5.1). PDE3A is mainly distributed in heart, platelet, vascular smooth muscle and oocytes, while PDE3B is mainly associated with adipocytes, hepatocytes and spermatocytes. Among the two subtypes of PDE3, PDE3A is especially expressed in heart and platelets. Hence PDE3A play an important role in heart and platelet (Palson, J. B.; Strada, S. J.; Annu. Rev. Pharmacol.Toxicol., 1996, 36, 403 ScBritish Journal of Pharmacology 2012 551288).

[009] In the verge, the expression of PDE3A in heart and platelet and vascular smooth muscle cells has been reported to play a critical role in regulation of contraction, relaxation and platelet aggregation. The expression levels of PDE3A in vascular smooth muscle cells are increased in response to NO-donor compound S- nitroso glutathione (GSNO) in a dose- and time-dependent manner (Busch et al, 2010). [0010] At least for the reasons discussed here in above, new or improved agents that modulate (such as inhibiting/antagonizing) PDE3A are continually needed for developing new and more effective pharmaceuticals to treat PDE -associated conditions or diseases or disorders, such as CHF, platelet aggregation and stroke. In discovering new or improved agents that modulate (such as inhibiting/antagonizing) PDE3A, it is also desirable but not required to discover agents with improved chemical or biological properties such as solubility, bioavailability, pharmacokinetics, pharmacodynamics, and/or toxicity.

[0011] The present invention describes the synthesis of novel 2-pyridone based compounds as inhibitors of phosphodiesterases A (PDE3A). PDE3A inhibitors are useful for the prevention of heart failure and inhibit platelet aggregation.

The following references are examples for the biological importence, synthesis and biological evaluation of some of the PDE or PDE3 inhibitors. The prior art contain useful information and discussion on the preparation and properties of PDE inhibitors.

[0012] US Pat. No. 5141931, describes synthesis of 6-Alkyl-5-(6, or 7-quinolinyl)- 3-(substituted)-2(lH)-pyridinones which are useful as cardiotonics. Inhibition of PDE3 was reported to have cardiotonic effect of these compounds.

US Pat. No. 10151202, discloses novel pyrrolidine compounds that are potent and selective inhibitors of PDE 4, as well as methods development for the synthesis of novel molecules.

[0013] Margaretha et al, J. Med. Chem. 2003, 46, 2008, reported synthesis and structure- activity relationships of czs-tetrahydrophthalazinone/pyridazinone hybrids: a novel series of potent dual pde3/pde4 inhibitory agents.

Rosamond et al, Heart disease and stroke statistics 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2001,115, 69.

[0014] Hamid et al, Journal of Enzyme Inhibition and Medicinal Chemistry, 2009,24, 918, reported Design, synthesis and pharmacological evaluation of 6- hydroxy-4-methylquinolin-2(lH)-one compounds as inotropic agents. Mohsen et al, Bioorganic<& Medicinal Chemistry 2010,i8, 855, reported Design, synthesis and biological evaluation of 6-(benzyloxy)-4-methylquinolin-2(lH)-one compounds as PDE3 inhibitors.

[0015] Reddy et al. Indian J Med Res. 2010, 132, 549, Congestive heart failure in Indians: How do we improve diagnosis & management?

[0016] Robert et al, Bioorganic & Medicinal Chemistry Letters 2011, 21, 3307, reported Phosphodiesterase inhibitors Part 1: Synthesis and structure activity relationships of pyrazolopyridine pyridazinone PDE inhibitors developed from ibudilast.

[0017] Koji et al, Bioorganic & Medicinal Chemistry Letters 2011, 21, 5451, reported Phosphodiesterase inhibitors Part 2: Design, synthesis, and structure activity relationships of dual PDE3/4-inhibitory pyrazolo[l,5-a]pyridines with antiinflammatory and bronchodilatory activity.

[0018] Recently our publication reported [Ravinder et al, Bioorg. Med. Chem. Lett, (2012)] Synthesis and Evaluation of Novel 2-Pyridone Compounds as Inhibitors of Phospho-diestarase3 (PDE3): A Target for Heart Failure and Platelet Aggregation.

[0019] Ochiai et al., Bioorg Med Chem., 2012, 20, 1644, reported synthesis of (-)-6- (7-Methoxy-2-trifluoromethylpyrazolo[l,5-a]pyridin-4-yl)-5-m ethyl-4,5-dihydro-3- (2H) pyridazinone (KCA-1490), a dual PDE 3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity.

[0020] Koji et al, Bioorganic & Medicinal Chemistry Letters 2012, 22, 5833, reported Phosphodiesterase inhibitors. Part 4: Design, synthesis and structure- activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4- dimethylpyrazolones .

[0021] Clive et al, Current Opinion in Pharmacology 2012, 12, 275, reported about the use of PDE3, PDE4 and mixed PDE3/4 inhibitors can provide clinical benefit to patients with asthma or chronic obstructive pulmonary disease (COPD).

Essa et al, Bioorganic & Medicinal Chemistry Letters 2012, 22, 6938, reported Use of structure based design to increase selectivity of pyridyl-cinnoline phosphodiesterase 10A (PDE10A) inhibitors against phosphodiesterase 3 (PDE3). Koji et al, Bioorganic & Medicinal Chemistry Letters 2013, 23, 375, reported Phosphodiesterase inhibitors Part 5: Hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration.

[0022] Peter et al, British Journal of Pharmacology 2013,169, 528, reported PDE3, but not PDE4, reduces Bl- and B2-adrenocep tor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients.

[0023] Ashraf et al, Chem. Pharm. Bull. 2013, 61,405, reported Modulating the Cyclic Guanosine Monophosphate Substrate Selectivity of the Phosphodiesterase 3 Inhibitors by Pyridine, Pyrido[2,3-d]pyrimidine Compounds and Their Effects upon the Growth of HT-29 Cancer Cell Line.

[0024] Juraj et al, Respiratory Physiology & Neurobiology 2013 87, 11, reported about Immunological aspects of phosphodiesterase inhibition in the respiratory system.

[0025] Masayosi et al, Journal of Molecular and Cellular Cardiology 2013, 64, 11, reported about Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia-reperfusion injury.

[0026] Mahajan et al, Journal of Research in Medical Education & Ethics 2013, 3, 115, Phosphodiesterase Inhibitors and their Role in Therapeutics.

[0027] Shoji et al, Int Heart J 2014, 55, 165, reported Phosphodiesterase 3A1 Protects the heart against angiotensin II-induced cardiac remodeling through regulation of transforming growth factor-/? expression.

[0028] Peter et al, Naunyn Schmiedeberg's Arch Pharmacol 2014, 387, 629, reported Carvedilol induces greater control of β2- than βΐ -adrenoceptor- mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium.

[0029] Aziz et al, Pflugers Arch Eur J Physiol 2014, 466, 1163, reported Cyclic AMP synthesis and hydrolysis in the normal and failing heart.

[0030] Davood et al, Toxicology Mechanisms and Methods 2014, 24, 307, reported Different effects of adenylyl cyclase activators and phosphodiesterases inhibitors on cervical cancer (HeLa) and breast cancer (MCF-7) cells proliferation. [0031] Alexandra et al, Cancers 2014, 6, 436, reviewed The Role of Cyclic Nucleotide Signaling Pathways in Cancer: Targets for Prevention and Treatment.

OBJECTIVES OF THE INVENTION

[0032] The main objective of the present invention is to provide novel 2-pyridone based analogues useful as potential cardio tonic agents. Yet another object of this invention is to provide a process for the preparation of novel 2-pyridone based compounds. Further objective of the present invention is to provide novel 2- pyridones of general Formula A as promising phosphodiesterase3A inhibitors.

SUMMARY OF THE INVENTION

[0033] The present invention is directed towards the synthesis of 2-pyridonebased analogues of general Formula A of general Formula 3a-a ^∑ , 4a-m, 5a-z, 6a-j, 7a-x, 8a-v, 9a-l, lOa-r and havin excellent phosphodiesterases A inhibition activity.

Formula A

Wherein X = COOCH ₃ , COOC ₂ H ₅ , CN

Y = Methyl, Phenyl

R = alkyl, substituted phenyl, napthyl, furonyl,

thiophenyl, substituted quinolinyl

[0034] In an embodiment of the present invention the novel2-pyridone based analogues are represented by the following compounds of general Formula 3a-a ^∑ ,

4a-m, 5a-z, 6a -j, 7a-x, 8a-v, 9a-l, lOa-r.

7 a-x 8 a-v 9 a-l 10 a-r

[0035] In yet another embodiment the 2-pyridone (3a-z, a ¹ , 4a-m, 5a-z, 6a-j, 7a- x, 8a-v, 9a-l, lOa-r) based analogues are represented by the group of the following compounds:

methyl 5-(2-fluorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3a)

methyl 5-(3-fluorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3b)

methyl 5-(4-fluorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3c)

methyl 5-(2-bromobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3d)

methyl 5-(3-bromobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3e)

methyl 2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)- 1 ,6-dihydropyridine-3- carboxylate (3f)

methyl 2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)- 1 ,6-dihydropyridine-3- carboxylate (3g)

methyl 2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)- 1 ,6-dihydropyridine-3- carboxylate (3h) methyl 5-(2-methoxybenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3i)

methyl 5-(3-methoxybenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3j)

methyl 5-(4-methoxybenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3k)

methyl 2-methyl-5-(3-nitrobenzyl)-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (31) methyl 5-(4-cyanobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3m)

methyl 2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3-carb oxylate (3n)

methyl 5-(4-ethylbenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3o) methyl 5-(4-isopropylbenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3p)

methyl 5-(2,4-dichlorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3q)

methyl 5-(2,6-dichlorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3r)

methyl 5-(3,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate (3s)

methyl 5-(2,5-dimethoxybenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3- carboxylate (3t)

methyl 5-(3,4-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3 - carboxylate (3u)

methyl 5-(furan-2-ylmethyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3v)

methyl 2-methyl-6-oxo-5-(thiophen-2-ylmethyl)- 1 ,6-dihydropyridine-3- carboxylate (3w)

methyl 2-methyl-5-(naphthalen- 1 -ylmethyl)-6-oxo- 1 ,6-dihydropyridine-3- carboxylate (3x) methyl 2-methyl-5-(naphthalen-2-ylmethyl)-6-oxo- 1 ,6-dihydropyridine-3- carboxylate (3y)

methyl5-((2-methoxyquinolin-3-yl)methyl)-2-methyl-6-oxo-l ,6-dihydropyridine- 3-carboxylate (3z)

methyl 5-hexyl-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (3a ¹ )

ethyl 5-(2-fluorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (4a) ethyl 5-(3-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carb oxylate (4b) ethyl 5-(4-fluorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (4c) ethyl 5-(2-bromobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (4d) ethyl 5-(3-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo xylate (4e) ethyl 2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)- 1 ,6-dihydropyridine-3- carboxylate (4f)

ethyl2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dih ydropyridine-3- carboxylate (4g)

ethyl 5-(4-methoxybenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (4h)

ethyl 5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo xylate (4i) ethyl 2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3-carb oxylate (4j) ethyl 5-(4-isopropylbenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (4k)

ethyl 5-(2,4-dichlorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate (41)

ethyl 5-(3,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate (4m)

5-(2-fluorobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5a)

5-(3-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-c arbonitrile (5b)

5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-c arbonitrile (5c)

5-(2-bromobenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5d)

5-(3-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-ca rbonitrile (5e)

2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-l,6-dihydrop yridine-3-carbonitrile (5f) 2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3-carbonitrile (5g)

2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3-carbonitrile (5h)

5-(2-methoxybenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5i) 5-(3-methoxybenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5j) 2-methyl-5-(3-nitrobenzyl)-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5k)

5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-di ydropyridine-3-carbonitrile (51)

2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3-c arbonitrile (5m) 5-(4-ethylbenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5n)

5-(4-isopropylbenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5o) 5-(2,6-dichlorobenzyl)-2-methyl-6-oxo-l,6-di ydropyridine-3-carbonitrile (5p) 5-(3,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-di ydropyridine-3-carbonitrile (5q) 5-(2,5-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3 -carbonitrile (5r) 5-(3,4-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3 -carbonitrile (5s) 5-(furan-2-ylmethyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5t) 2-methyl-5-(naphthalen-l-ylmethyl)-6-oxo-l,6-dihydropyridine -3-carbonitrile (5u)

2-methyl-5-(naphthalen-2-ylmethyl)-6-oxo-l,6-dihydropyridine -3-carbonitrile (5v)

5-((2-methoxyquinolin-3-yl)methyl)-2-methyl-6-oxo-l,6-dihydr opyridine-3- carbonitrile (5w)

5-hexyl-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5x)

5-heptyl-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5y)

2-methyl-5-octyl-6-oxo- 1 ,6-dihydropyridine-3-carbonitrile (5z)

ethyl 5-(2-fluorobenzyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carboxylate (6a) ethyl 5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb oxylate (6b) ethyl 5-(4-fluorobenzyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carboxylate (6c) ethyl 5-(2-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo xylate (6d) ethyl 5-(3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo xylate (6e) ethyl 6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)- 1 ,6-dihydropyridine-3- carboxylate (6f)

ethyl 6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)- 1 ,6-dihydropyridine-3- carboxylate (6g)

ethyl 5-(4-cyanobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo xylate (6h) ethyl 5-(2,4-dichlorobenzyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carboxylate (6i)

ethyl 5-(3,4-dichlorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3- carboxylate (6j)

5-(2-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb onitrile (7a)

5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-c arbonitrile (7b)

5-(4-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-c arbonitrile (7c)

5-(2-bromobenzyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7d)

5- (3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboni trile (7e)

6- oxo-2-phenyl-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridi ne-3-carbonitrile (7f)

6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3-carbonitrile (7g)

6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3-carbonitrile (7h)

5-(2-methoxybenzyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7i) 5-(3-methoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-car bonitrile (7j) 5-(3-nitrobenzyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7k)

5-(4-cyanobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-ca rbonitrile (71)

5-(2,6-dichlorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine -3-carbonitrile (7m) 5-(3,4-dichlorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3- carbonitrile (7n) 5-(2,5-dimethoxybenzyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7o)

5- (3,4-dimethoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-c arbonitrile (7p)

6- oxo-2-phenyl-5-(pyridin-3-ylmethyl)- 1 ,6-dihydropyridine-3-carbonitrile (7q) 5-(furan-2-ylmethyl)-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7r) 5-(naphthalen-l-ylmethyl)-6-oxo-2-phenyl-l,6-dihydropyridine -3-carbonitrile

(7s)

5-(naphthalen-2-ylmethyl)-6-oxo-2-phenyl-l,6-dihydropyridine -3-carbonitrile

(7t)

5-((2-methoxyquinolin-3-yl)methyl)-6-oxo-2-phenyl-l,6-dihydr opyridine-3- carbonitrile (7u)

5-hexyl-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7v)

5-heptyl-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7w)

5-octyl-6-oxo-2-phenyl- 1 ,6-dihydropyridine-3-carbonitrile (7x)

methyl 6-(2-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8a) methyl 6-(3-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8b) methyl 6-(4-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8c) methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8d): methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8e): methyl 6-(4-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8f): methyl 6-(2-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate (8g) methyl 6-(3-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate (8h) methyl 6-(4-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate (8i) methyl 5-oxo-6-(3-(trifluoromethyl)benzyl)-l,2,3,5-tetrahydroindoli zine-8- carboxylate (8j):

methyl 6-(2-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-car boxylate (8k): methyl 6-(3-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-car boxylate (81): methyl 6-(4-cyanobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate (8m): methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8n): methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8o): methyl 6-(4-isopropylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-c arboxylate (8p):

methyl 6-(3,4-dichlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8- carboxylate (8q):

methyl 6-(2,6-dichlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8- carboxylate (8r): methyl 6-(3,4-dimethoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8 -carboxylate (8s):

methyl 6-(naphthalen-l-ylmethyl)-5-oxo-l,2,3,5-tetrahydroindolizine -8-carboxylate (8t):

methyl 6-(naphthalen-2-ylmethyl)-5-oxo-l,2,3,5-tetrahydroindolizine -8-carboxylate (8u):

Methyl6-((2-chloroquinolin-3-yl)methyl)-5-oxo-l,2,3,5-tetrah ydroindolizine-8- carboxylate (8v):

methyl 7-benzyl-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9-carboxyla te (9a):

methyl 7-(2-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (9b):

methyl 7-(3-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (9c):

methyl 7-(4-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (9d):

methyl 7-(2-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (9e):

methyl 7-(3-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (9f):

methyl 7-(4-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (9g):

methyl 7-(2-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (9h)

methyl 7-(3-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (9i)

methyl 7-(3-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (9j)

methyl 7-(2-methoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine- 9- carboxylate (9k)

methyl 7-(2-cyanobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (91) ethyl 7-benzyl-6-oxo-2,3 ,4,6-tetrahydro- lH-quinolizine-9-carboxylate (10a):

ethyl 7-(2-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro lH-quinolizine-9-carboxylate (10b):

ethyl 7 - (3 -fluorobenzyl) - 6-oxo-2,3,4 , 6-tetrahydro lH-quinolizine-9-carboxylate (10c):

ethyl 7 - (3 -fluorobenzyl) - 6-oxo-2,3,4 , 6-tetrahydro lH-quinolizine-9-carboxylate (10c):

ethyl 7 - (4 -fluorobenzyl) - 6-oxo-2,3,4 , 6-tetrahydro lH-quinolizine-9-carboxylate

(lOd):

ethyl 7-(2-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro- lH-quinolizine-9-carboxylate (lOe):

ethyl 7-(3-chlorobenzyl)-6-oxo-2,3,4, 6-tetrahydro- lH-quinolizine-9-carboxylate (10f):

ethyl 7-(4-chlorobenzyl)-6-oxo-2,3, 4, 6-tetrahydro- lH-quinolizine-9-carboxylate (10g):

ethyl 7-(2-bromobenzyl)-6-oxo-2,3, 4, 6-tetrahydro- lH-quinolizine-9-carboxylate (lOh):

ethyl 7-(3-bromobenzyl)-6-oxo-2,3,4, 6-tetrahydro- lH-quinolizine-9-carboxylate (10i):

ethyl 7-(4-bromobenzyl)-6-oxo-2,3, 4, 6-tetrahydro- lH-quinolizine-9-carboxylate (10j):

ethyl 6-oxo-7-(2-(trifluoromethyl)benzyl)-2,3,4,6 -tetrahydro- lH-quinolizine-9- carboxylate (10k):

ethyl 6-oxo-7-(3-(trifluoromethyl)benzyl)-2,3,4,6 -tetrahydro- lH-quinolizine-9- carboxylate (101)

ethyl 6-oxo-7-(4-(trifluoromethyl)benzyl)-2,3,4,6 -tetrahydro- lH-quinolizine-9- carboxylate (10m):

ethyl 7-(2-methoxybenzyl)-6-oxo-2,3,4,6-tetrahydro- lH-quinolizine-9-carboxylate (10η):

ethyl 7-(4-cyanobenzyl)-6-oxo-2,3,4,6-tetrahydro- lH-quinolizine-9-carboxylate (lOo): ethyl 7-(2,4-dichlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizi ne-9-carboxylate (10p):

ethyl 7-(3,4-dichlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizi ne-9-carboxylate (10q):

ethyl 7-(2,5-dimethoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinoliz ine-9- carboxylate (lOr):

[0036] The present invention further provides a process for preparation of novel pyridone based analogues of Formula 3a-z, a ¹ , 4a-m, 5a-z, 6a-j, 7a-x, 8a-v, 9a-l, lOa-r which comprises reactions of precursor activated olefin (12a) as starting material with substituted benzaldehydes(lla-z, a ^∑ -k ^∑ ) using base DABCO (diazabicyclo [2.2.2] octane) has been the catalyst of choice, various other tertiary amine catalysts, such as quinuclidine 3-HQD (3-hydroxy quinuclidine), 3- quinuclidone, DBU, pyrrocoline, DMAP(dimethylaminopyridine),

TMPDA(N,N,N ¹ ,N ¹ -tetramethyl-l,3-propanediamine), imidazole, TMG (tetramethyl guanidine) and triethyl amine have also been employed to perform the Baylis-Hillman reaction in certain cases. Several non-tertiary amine catalysts, such as dimethyl sulfide/TiCl ₄ , TiCl ₄ ,trialkylphosphines, PvhH(PPh ₃ ) ₄ ,have been used as catalysts for coupling of various activated alkenes with aldehydes to obtain the desired Baylis-Hillman adducts (13a-z, a ^∑ -k ^∑ ), which are converted to acetylated Baylis-Hillman adducts (14a-z, a ^∑ -k ^∑ ) by using pyridine, Ac ₂ 0/AcCl.Thus prepared 14 a-z, a ^∑ -k ^∑ were reacted with methyl 3-aminobut-2-enoate (15a), , ethyl 3- aminobut-2-enoate(15b), 3-aminobut-2-enenitrile(15c), ethyl 3-amino-3- phenylacrylate (15d), 3-amino-3-phenylacrylonitrile (15e), methyl 2-(pyrrolidin-2- ylidene)acetate (15f), methyl 2-(piperidin-2-ylidene)acetate (15g), ethyl 2- (piperidin-2-ylidene)acetate (15h) using base like (NaH(60%), NaH(100%),NaOMe, NaOEt and t-BuOK) in organic solvents (acetonitrile, tetrahydrofuran and dimethyl formamide) in different reaction conditions resulting in the formation of final compounds2-pyridones(3a-z, a ¹ , 4a-m, 5a-z, 6a-j, 7a-x, 8a-v, 9a-l, lOa-r).

11 a-z, a^k ¹ 12a 13 a-z, a^k ¹ 14 a-z, a^k ¹

Z = electron withdrawing group

15a 15b 15c 15d

BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1: PDE3A inhibitory activity of 2 pyridone compounds (100 μΜ in DMSO). Standard Drug: Milrinone (100 μΜ in DMSO). (Compounds 3a-5z).

Figure 2: PDE3A inhibitory activity of 2 pyridone compounds (100 μΜ in DMSO). Standard Drug: Milrinone (100 μΜ in DMSO). (Compounds 6e-10r).

DETAILED DESCRIPTION OF THE INVENTION

[0038] The precursor substituted aromatic aldehydes (lla-z, a ^∑ -k ^∑ ), activated olefines (12a) and l,4-diazabicyclo[2.2.2]octane (DABCO), are commercially available and 2-pyridones (3a-z, a ¹ , 4a-m, 5a-z, 6a-j, 7a-x, 8a-v, 9a-l, 10a-r)of Formula have been prepared as illustrated in the Schemes (1-2).

[0039] The substituted aromatic heterocyclic aromatic and aliphatic aldehydes (11a- z, a ^∑ -k ^∑ ) can be reacted with the activated olefins (12a)using DABCO at rt for 10-12 h to obtain desired Baylis-Hillman adducts (13a-z, a ^∑ -k ^∑ ).

[0040] To a solution of Baylis-Hillman adducts (13a-z, a ^∑ -k ^∑ ) in dichloromethane at 0 °C, under argon atmosphere pyridine can be added, followed by addition of acetyl chloride after 10 min and stirring the solution at rt for 2 h to obtain desired acetylated Baylis-Hillman addcuts

(14a-z, a ^∑ -k ^∑ ).

[0041] All the pyridonebased compounds have been synthesized and were purified by column chromatography using solvents like ethyl acetate, hexane.

[0042] Procedure of pyridone formation: To a solution of NaH (60% in paraffin oil) in dry THF was added slowly methyl 3-aminobut-2-enoate (15a), ethyl 3- aminobut-2-enoate(15b), 3-aminobut-2-enenitrile(15c), ethyl 3-amino-3- phenylacrylate (15d), 3-amino-3-phenylacrylonitrile (15e), methyl 2-(pyrrolidin-2- ylidene)acetate (15f), methyl 2-(piperidin-2-ylidene)acetate (15g), ethyl 2- (piperidin-2-ylidene)acetate (15h) in dry THF at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adducts(14a-z, a ^∑ -k ^∑ )in dry THF was added slowly and allowed to stir at ambient temperature for 6 h. After completion of the reaction solvent was removed under reduced pressure and the residue was diluted with ice cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , solvent evaporated under reduced pressure and purified by column chromatography by using silica gel with ethylacetate/hexane as eluent.

These new analogues of pyridone based compounds were screened for their and found as potential phosphodiesterases inhibitors activity. The synthesized molecules presented here are of immense biological significance.

Sheme -1

R

ll a-z, a^k ¹ 12a 13 a-z, a^k ¹ 14 a-z, a t ¹

Z = electron withdrawing group

Scheme -2

15h 21 10a-r General procedure for the preparation Baylis-Hillman adducts (13a-z, a ^I -e ^I ):

[0043] Substituted aromatic aldehydes (lla-z, a ^∑ -k ^∑ ) (10 mmol), activated olefin (12a) (20 mmol) and DABCO (30 mol% with respect to aldehyde) were mixed and allowed to stir at room temperature until completion of the reaction, TLC (10-12 h). After completion, the reaction mixture was diluted with water (15 mL) and extracted with ether (3x25 mL). The combined organic layers were dried over Na ₂ S0 ₄ , solvent was removed under reduced pressureand purified by column chromatography using 10% EtOAc in hexane as eluent to afford pure Baylis- Hillman adducts (13a-z, a ^∑ -k ^∑ ) in 80-90% yield.

General procedure for the preparation of acetylated Baylis-Hillman adducts (14a-z, a ^∑ -k ^∑ ):

[0044] To a well stirred solution of Baylis-Hillman adduct (13a-z, a ^∑ -k ^∑ ) (10 mmol) in dichloromethane (30 mL) at 0°C under argon atmosphere was added slowlypyridine (11 mmol) and stirred for 10 min. Then acetyl chloride (11 mmol) was added slowly and allowed to stir at room temperature until the reaction completed, TLC (1-2 h). After completion of the reaction, diluted the reaction with water (15 mL) and extracted with dichloromethane (2x25 mL). The combined organic layers were washed with sat. CuS0 ₄ solution until pyridine removed, then the layers were sepaerated and dried over Na ₂ S0 _4i. The solvent was removed under reduced pressure. The resulting residue was subjected to column chromatography using 5% EtOAc in hexane as eluent to afford pure compounds acetylated Baylis- Hillman adducts (14a-z, a ^∑ -k ^∑ ) in 90-95% yield.

The following examples are given by way of illustration

methyl 5-(2-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(3a):

[0045] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg mmol) in dry THF (5 mL) at 0 °C under nitrogen atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b)(504 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3a aswhite solid (220 mg, 80% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.83 (s, 1H), 7.34-6.98 (m, 4H), 3.85 (s, 2H), 3.81 (s, 3H), 2.66 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): δ 165.5, 164.9, 150.9, 139.9, 131.5, 131.4, 128.0, 126.8, 126.1, 123.8, 115.3, 108.4, 51.7, 28.9, 19.1; MS (ESI): 276 /z [M+H] ⁺ ; HRMS (ESI): m/z [M+H] ⁺ calculated for C ₁ 5H ₁ 5NO3F: 276.1030; found: 276.1020.

methyl 5-(3-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(3b):

[0046] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14h)(504 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3baswhite solid (215 mg,

78% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.83 (s, 1H), 7.26-6.85 (m, 4H),3.82 (s, 3H), 3.81 (s, 2H), 2.64 (s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 165.4, 164.9, 151.1, 140.0, 129.7, 127.6, 124.5, 116.0, 115.7, 113.2, 113.0, 51.7, 35.6, 19.2; MS (ESI): 276m/z [M+H] ⁺ ; HRMS (ESI): m/z [M+H] ⁺ calculated for C ₁₅ H ₁₅ NO ₃ F: 276.1030; found: 276.1021.

methyl 5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carb oxylate (3c):

[0047] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a)(230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14o)(589 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3caswhite solid (222 mg, 81% yield). 1H NMR (300 MHz, CDCI3): δ 7.78 (s, 1H), 7.24-6.93 (m, 4H), 3.82 (s, 3H), 3.79 (s, 2H), 2.64 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): δ 165.4, 164.8, 162.4, 150.8, 139.7, 134.9, 130.3, 128.3, 115.2, 108.4, 51.7, 35.0, 19.2; MS (ESI): 276 m/z[M+H] ⁺ .

methyl 5-(2-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo xylate (3d):

[0048] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14d)(626 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3daswhite solid (252 mg,

75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.66 (brs, 1H), 7.75(s, 1H), 7.56 (d, 1H), 7.34 (d, 1H), 7.23 (d, 1H), 7.10 (t, 1H), 3.97 (s, 2H), 3.79 (s, 3H), 2.67 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.5, 164.9, 150.9, 140.1, 138.2, 132.8, 131.4, 128.0, 127.3, 126.4, 124.8, 108.3, 51.7, 35.6, 19.3;Mass (ESI-MS):338 m/z [M+2] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₅ Hi ₄ BrN0 ₃ : 336.02298 [M+H] ⁺ , found: 336.02242

5-(3-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo xylate

[0049] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14j)(626 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3easwhite solid (245 mg,

73% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.5 (brs, 1H), 7.84 (s, 1H), 7.45 (s, 1H), 7.32 (d, 1H), 7.21 (d, 1H), 7.13 (t, J 8.3, 7.5 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 2H), 2.65 (s, 3H);Mass (ESI-MS):338 m/z [M+2] ⁺ .

methyl2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-l,6-di hydropyridine- 3carboxylate (3f) :

[0050] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14e)(605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3a aswhite solid (240 mg, 74% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.83 (brs, lH)7.67(d, 1H), 7.62 (s, 1H), 7.45 (t, 1H), 7.33 (t, 2H), 4.05 (s, 2H), 3.78 (s, 3H), 2.66 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): δ 165.4, 165.0, 151.0, 140.4, 137.7, 131.8, 131.3, 127.2, 126.4, 126.2, 126.0, 122.6, 108.4, 51.7, 31.7, 19.2; Mass (ESI-MS):326 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. fo H] ⁺ , found: 326.09919.

methyl-2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-d ihydropyridine- 3carboxylate (3g):

[0051] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14k)(605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3g as white solid (247 mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.29 (bs, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.45 (t, 2H), 7.37 (t, 1H), 3.86 (s, 2H), 3.83 (s, 3H), 2.63 (s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 164.5, 162.6, 150.5, 139.8, 138.3, 131.5, 127.9, 126.4, 124.5, 122.0, 106.1, 77.1, 50.7, 34.5, 18.0; Mass (ESI-MS): 326 m/z [M+H] ⁺ .

methyl 2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carboxylate (3h):

[0052] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14r)(605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3haswhite solid (235 mg,

72% yield). 1H NMR (300 MHz, CDCI3): δ 12.21 (brs, 1H), 7.83 (s, 1H), 7.52 (d, 2H), 7.39 (d, 2H), 3.87 (s, 2H), 3.83 (s, 3H), 2.62 (s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 163.7, 151.0, 143.4, 139.2, 128.8, 127.0, 124.9, 124.8, 124.8, 51.3, 35.2, 18.8;Mass (ESI-MS):326m/z [M+H] ⁺ .

methyl 5-(2-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-car boxylate

(3i):

[0053] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14f)(529 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3iaswhite solid (212 mg,

74% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.64(brs, 1H), 7.76(s, 1H), 7.26- 7.18(m, 2H), 6.88 (t, 2H), 3.82(s, 2H), 3.81(s, 3H), 3.79(s, 3H), 2.65(s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.7, 165.1, 157.5, 150.4, 139.8, 130.8, 127.6, 127.2, 120.3, 110.4, 108.3, 55.25, 51.6, 29.85, 19.21; Mass (ESI-MS):288m/z [M+H] ⁺ .

methyl 5-(3-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-car boxylate

(3j):

[0054] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(151)(529 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3j as white solid (224 mg, 78% yield). 1H NMR (300 MHz, CDCI3): δ 12.36 (brs, 1H), 7.79 (s, 1H), 7.20 (t, 1H), 6.88-6.84 (t, 1H), 6.83 (s, 1H), 6.76-6.73 (m, 1H), 3.81 (s, 3H), 3.80 (s, 2H), 3.78 (s, 3H), 2.64 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 16.5, 164.9, 159.5, 150.8, 140.9, 139.8, 129.3, 128.2, 121.3, 114.9, 111.3, 108.3, 55.11, 51.7, 35.6, 19.2; Mass (ESI-MS): 288 ⁺ .

methyl 5-(4-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-car boxylate (3k):

[0055] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14s)(529 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3kaswhite solid (212 mg, 74% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ δ 7.71 (s, 1H), 7.26-6.80 (m, 4H), 3.81 (s, 3H), 3.81 (s, 3H), 3.78 (s, 2H),2.65 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.6, 164.9, 158.0, 150.6, 139.5, 131.3, 129.9, 128.8, 113.7, 108.3, 55.2, 51.7, 34.8, 19.2; MS (ESI): 288m/z [M+H] ⁺ ; HRMS (ESI) m/z calculated for Ci ₆ Hi ₇ N0 ₄ Na: 310.1049[M+H] ⁺ ; found: 310.

methyl 2-methyl-5-(3-nitrobenzyl)-6-oxo-l,6-dihydropyridine-3-carbo xylate (31):

[0056] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14n)(559 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 31 aswhite solid (190 mg, 63% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.27 (brs, 1H), 8.18 (s, 1H), 8.06 (d, 1H), 7.64 (d, 1H), 7.44 (t, 1H),3.91 (s, 2H), 3.85 (s, 3H), 2.66 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 164.5, 162.5, 150.9, 147.2, 141.0, 138.6, 134.4, 128.4, 125.9, 122.6, 120.3, 106.2, 50.7, 34.5, 18.1;Mass (ESI-MS):303 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₄ H ₁₅ N ₂ 0 ₅ : 303.09755 M+H] ⁺ , found: 303.09750.

methyl 5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo xylate (3m):

[0057] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14u)(519 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3m aswhite solid (210 mg, 75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.61 (brs, 1H), 7.85(s, 1H), 7.56 (d, 2H), 7.39 (d, 2H), 3.87(s, 2H), 3.84(s, 3H), 2.64(s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5Mass (ESI-MS): 283 /z [M+H] ⁺ .

methyl 2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3- carboxylate(3n):

[0058] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14m) (497 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3n aswhite solid (170 mg, 63% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ δ 12.29 (bs, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.45 (t, 2H), 7.37 (t, 1H), 3.86 (s, 2H), 3.83 (s, 3H), 2.63 (s, 3H), 2.59 (s, 3H); MS (ESI): 272 m/z [M+H] ⁺ ;

methyl 5-(4-ethylbenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(3o):

[0059] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14v) (525 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3o aswhite solid (185 mg, 65% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.21 (brs, 1H), 7.83 (s, 1H), 7.52 (d, 2H), 7.39 (d, 2H), 3.87 (s, 2H), 3.83 (s, 3H), 2.74 (q, 2H), 2.62 (s, 3H) 1.25 (t, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.6, 164.7, 150.5, 142.1, 139.6, 136.4, 128.8, 128.8, 127.8, 108.2, 51.7, 35.2, 28.4, 19.3, 15.5;MS (ESI): m/ _z 286 [M+H] ⁺ .

methyl 5-(4-isopropylbenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(3p):

[0060] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14w) (553 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3p aswhite solid (200 mg, 67% yield). 1H NMR (300 MHz, CDC1 ₃ ): ): δ 7.81 (s, 1H), 7.26-7.12 (m, 4H), 3.81 (s, 3H), 3.80 (s, 2H), 2.89-2.84 (m, 2H), 2.63 (m, 3H), 1.22 (d, = 6.9 Hz, 6H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.5, 165.0, 150.7, 146.6, 139.7, 136.6, 128.8, 128.5, 126.3, 108.3, 51.6, 35.2, 33.6, 23.9, 19.1; MS (ESI): m/ _z 300 [M+H] ⁺ .

methyl 5-(2,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(3q):

[0061] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) dry THF (10 mL) was added slowly methyl-3-aminobut-2-enoate (15a) (230 mg mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14x) (607 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3q aswhite solid (251 mg, 77% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ δ 7.68 (s, 1H), 7.27-7.04 (m, 4H), 3.81 (s, 2H),3.72 (s, 2H), 2.57 (s, 2H). ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.4, 164.7, 151.0, 140.3, 135.2, 134.9, 132.8, 132.2, 129.2, 126.9, 125.9, 108.4, 51.8, 32.8, 19.3; MS (ESI): 327 m/z [M+H] ⁺ .

methyl 5-(2,6-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(3r):

[0062] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14y) (607 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3r aswhite solid (258 mg, 79% yield). ¹ !! NMR (300 MHz, CDC1 ₃ ): 57.83 (s, 1H), 7.26-6.85 (m, 4H),3.82 (s, 3H), 3.81 (s, 2H), 2.64 (s, 3H); MS (ESI): 327 m/z [M+H] ⁺ ;

methyl 5-(3,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate (3s):

[0063] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14z) (607 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3s aswhite solid (255 mg,

78% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.3(brs, 1H), 7.76(s, 1H), 6.83-6.80(m, 3H), 3.81(s, 3H), 3.76(s, 2H), 2.67(s, 3H); MS (ESI): 326 m/z [M+H] ⁺ ;

Methyl-5-(2,5-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyr idine-3- carboxylate(3t):

[0064] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b ¹ ) (597 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3t aswhite solid (241 mg,

76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 11.94 (brs, 1H), 7.74 (s, 1H), 6.83 (d, 1H), 6.78 (d, 1H), 6.73-6.71 (m, 1H), 3.80 (s, 2H), 3.79 (s, 3H), 3.77 (s, 3H), 3.74 (s, 3H), 2.64 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.7, 165.1, 153.3, 151.8, 150.5, 139.8, 128.5, 127.4, 117.2, 111.4,111.3, 108.3, 55.9, 55.5, 51.6,29.9, 19.2; Mass (ESI-MS):317m/z [M+H ⁺ .

Methyl-5-(3,4-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyr idine-3- carboxylate (3u):

[0065] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14a ¹ ) (597 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3u aswhite solid (238 mg, 75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.3(bs, 1H), 7.76(s, 1H), 6.83- 6.80(m, 3H), 3.85(s, 3H), 3.85(s, 3H), 3.81(s, 3H), 3.76(s, 2H), 2.67(s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.5, 164.9, 150.5, 148.7, 147.4, 139.5, 131.7, 128.6, 120.9, 112.3, 111.1, 108.3, 55.8, 55.7, 51.7, 35.1, 19.23; Mass (ESI-MS): 371m/z [M+H] ⁺ .

methyl 5-(furan-2-ylmethyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-ca rboxylate

(3v): [0066] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14c ^∑ )(449 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3v aswhite solid (175 mg, 71% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.45 (brs, 1H), 7.84 (s, 1H), 7.33- 732 (m, 1H), 6.31-6.30 (m, 1H), 6.12-6.11 (m, 1H), 3.86 (s, 2H), 3.82 (s, 3H), 2.67 (m, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.4, 164.7, 151.1, 141.4, 140.0, 125.2, 110.3, 108.3, 106.6, 51.7, 27.9 -MS):248 m/z [M+H] ⁺ .

methyl2-methyl-6-oxo-5-(thiophen-2-ylmethyl)-l,6-dihydrop yridine-3- carboxylate(3w) :

[0067] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14d ^∑ ) (481 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3w aswhite solid (200 mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.43 (brs, 1H), 7.87 (s, 1H), 7.14- 7.13 (m, 1H), 6.93-6.90 (m, 2H), 4.03 (s, 2H), 3.82 (s, 3H), 2.68 (s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): 5165.4, 164.7, 151.2, 141.6, 139.8, 127.6, 126.7, 125.6, 123.9, 108.4, 51.7, 29.7, 19.3;Mass (ESI-MS):264 m/z [M+H] ⁺ .

Methyl-2-methyl-5-(naphthalen-l-ylmethyl)-6-oxo-l,6-dihydrop yridine-3- carboxylate (3x):

[0068] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14e ^∑ ) (569 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3xaswhite solid (230 mg, 75% yield). 1H NMR (300 MHz, CDCI3): δ 12.14 (brs, 1H), 8.01-7.98 (m, 1H), 7.89-7.84 (m, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.49-7.40 (m, 4H) 4.30 (s, 2H), 3.69 (s, 3H), 2.65 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.1, 163.4, 150.1, 138.4, 134.8, 133.4, 131.5, 128.3, 128.1, 127.5, 126.9, 126.7, 125.5, 125.1, 123.7, 107.0, 51.0, 31.4, 18.6; Mass (ESI-MS):308 m/z[M+H] ⁺ . HRMS (ESI) m/z Calcd. forCi ₉ Hi ₇ N0 ₃ : 308.12812 [M+H] ⁺ , found:

308.12796

methyl-2-methyl-5-(naphthalen-2-ylmethyl)-6-oxo-l,6-dihyd ropyridine-3- carboxylate (3y): [0069] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14f ^∑ ) (569 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3y aswhite solid (240 mg, 78% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.47 (brs, 1H), 7.83 (s, 1H), 7.80- 7.72 (m, 4H), 7.47-739 (m, 3H), 3.99 (s, 2H), 3.78 (s, 3H) 2.67 (s, 3H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.5, 164.9, 150.8, 139.8, 136.7, 133.4, 132.1, 128.2, 127.9, 127.5, 127.4, 127.3, 125.9, 125.3, 108.3, 51.7, 35.8, 19.2; Mass (ESI-MS):308 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. forCi ₉ Hi ₇ N0 ₃ : 308.12634 [M+H] ⁺ , found308.12638.

e

Methyl-5-((2-methoxyquinolin-3-yl)methyl)-2-methyl-6-oxo-l,6 - dihydropyridine-3-carboxylate (3z) :

[0070] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14g ^∑ ) (640 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3z aswhite solid (260 mg, 77% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.64 (bs, 1H), 7.79 (d, 2H), 7.80 (d, 1H), 7.61 (d, 1H), 7.55 (t, 1H), 7.33 (t, 1H), 4.07 (s, 3H), 3.90 (s, 2H), 3.80 (s, 3H), 2.63 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.0, 162.4, 160.3, 151.2, 144.6, 138.3, 136.8, 128.8, 127.1, 126.2, 125.6, 125.0, 123.9, 123.4, 105.8, 53.5, 51.4, 29.3, 18.4; Mass (ESI-MS):339 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₉ Hi ₈ N ₂ 0 ₄ : 339.13393 [M+H] ⁺ , found: 339.13376.

methyl 5-hexyl-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (3a ¹ ) :

[0071] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly methyl 3-aminobut-2-enoate (15a) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14h ^∑ ) (485 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3a aswhite solid (180 mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.42 (bs, 1H), 7.81 (s, 1H), 3.84 (s, 3H), 2.68 (s, 3H), 2.49 (t, 2H), 1.58 (m, 2H), 1.35 (m, 6H), 0.88 (t, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.0, 162.6, 150.4, 136.7, 128.7, 105.5, 51.3, 31.0, 29.1, 28.3, 27.7, 21.9, 18.3, 13.8; Mass (ESI-MS):252 m/z [M+H] ⁺ .

ethyl 5-(2-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(4a):

[0072] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b) (533 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4a aswhite solid (225 mg, 78% yield).

1H NMR (300 MHz, CDC1 ₃ ): 57.84-6.98 (m, 5H), 4.27 (q, = 6.79Hz, 2H), 3.85 (s, 2H), 2.65 (s, 3H), 1.33 (t, = 6.79Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.0, 161.9, 155.0, 139.5, 137.4, 129.1, 129.0, 128.4, 126.2, 105.4, 60.6, 49.2, 36.0, 33.6, 20.8, 14.3.; MS (ESI): m/ _z 290 [M+H] ⁺ ; HRMS (ESI): m/z [M+H] ⁺ calculated for Ci ₆ Hi ₆ N0 ₃ FNa: 312.1006; found: 312.0993.

ethyl 5-(3-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(4b):

[0073] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate(15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14h) (533 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4b aswhite solid (215 mg, 74% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.85 (s, 1H), 7.26-6.86 (m, 4H), 4.29 (q, = 6.79Hz, 2H), 3.83 (s, 2H), 2.64 (s, 3H), 1.35 (t, = 6.79Hz, 3H); ¹³ C NMR (75 MHz, CDCI3): 5164.8,151.1, 150.9, 140.1, 140.0, 129.7, 129.6, 124.5, 116.0, 115.7, 112.9, 108.7, 60.7, 35.6, 19.3, 14.3; MS (ESI): m/ _z 290 [M+H] ⁺ ; HRMS (ESI): m/z [M+H] ⁺ calculated for Ci ₆ Hi ₆ N0 ₃ F:

ethyl 5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carb oxylate (4c):

[0074] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b)(258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14o) (533 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4c aswhite solid (228 mg, 72% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.26-6.92 (m, 4H), 4.29 (q, = 7.1 Hz, 2H), 3.79 (t, 2H), 3.80 (s, 2H), 2.64 (s, 3H), 1.34 (t, = Hz, = 7.1 Hz, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.5, 165.1, 162.4, 139.9, 134.9, 130.4, 130.3, 115.1, 114.9, 108.7, 60.7, 35.0, 19.2, 14.2; MS (ESI): m/z 290 [M+H] ⁺ .

5-(2-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo xylate [0075] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14d) (654 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4d aswhite solid (262 mg, 75% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 12.78 (brs, 1H), 7.79 (s, 1H), 7.57-7.55 (d, 1H), 7.34-7.32 (d, 1H), 7.24-7.21 (t, 7.4, 7.4 Hz, 1H), 7.10-7.07 (t, 7.6, 7.6 Hz, 1H), 4.28-4.23 (q, 2H), 3.97 (s, 2H), 2.66 (s, 3H), 1.33-1.30 (t, 8.6, 8.8 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.1, 164.9, 150.7, 140.4, 138.4, 132.8, 131.2, 128.0, 127.3, 126.3, 124.9, 108.7, 60.6, 35.6, 19.3, 14.2; MS (ESI): m/ _z 350 [M+H] ⁺ .

ethyl 5-(3-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(4e):

[0076] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14j) (654 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4e aswhite solid (273 mg, 78% yield).

1H NMR (300 MHz, CDC1 ₃ ): 57.85 (s, 1H), 7.46-7.10 (m, 5H), 4.30 (q, = 7.0 Hz, 2H), 3.79 (s, 2H), 2.65 (s, 3H), 1.36 (t, = 7.0 Hz, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): 5165.0, 164.8, 151.0, 141.7, 140.2, 131.9, 129.8, 129.3, 127.5, 127.4, 122.3, 108.7, 60.7, 35.6, 19.3, 14.3; MS (ESI): 351m/z [M+H] ⁺ .

ethyl 2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carboxylate (4f):

[0077] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowlyethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14k) (632 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4f aswhite solid (268 mg, 79% yield). 1H NMR (300 MHz, CDCI3): 5 12.55 (brs, 1H), 7.83 (s, 1H), 7.25-7.20 (q, 1H), 7.07-7.05 (d, 1H), 7.02-6.99 (d, 1H), 6.90-6.86 (t, 78.8, 8.0 Hz, 1H), 4.31- 4.27 (q, 2H), 3.82 (s, 2H), 2.63 (s, 3H), 1.36-1.33 (t, J 7.0, 7.1 Hz, 3H); MS (ESI): 340m/z [M+H] ⁺ .

ethyl 2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carboxylate (4g): [0078] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14r) (632 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4g aswhite solid (251 mg, 74% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.24 (brs, 1H), 7.84 (s, 1H), 7.54- 7.51 (d, 8.3 Hz, 2H), 7.41-7.39 (d, 7.5 Hz, 2H), 4.33-4.26 (q, 2H), 3.88 (s, 1H), 2.61 (s, 3H), 1.37- 1.32 (t, 6.7, 7.5 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.0, 164.7, 150.9, 143.5, 140.3, 129.1, 128.7, 127.2, 125.2, 125.1, 108.7, 60.8, 35.7, 19.2, 14.2; MS (ESI): 340m/ ⁺ .

ethyl 5-(4-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(4h):

[0079] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14s) (557 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4h aswhite solid (241 mg, 80% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.28-6.82 (m, 4H), 4.30 (q, = 7.1 Hz, 2H), 3.83 (s, 2H), 3.79 (s, 3U), 2.66(s, 3H), 1.35 (t, = 7.1 Hz, 3H); ^1J C NMR (75 MHz, CDC1 ₃ ): δ 165.2, 164.9, 158.0, 150.4, 139.6, 131.3, 129.9, 128.7, 113.7, 108.6, 60.6, 55.2 34.8, 19.2, 14.3; MS (ESI): 302 /z [M+H] ⁺ .

ethyl 5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo xylate (4i):

[0080] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14u) (546 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4i aswhite solid (234 mg,

79% yield). 1H NMR (300 MHz, CDCI3): δ 12.41 (brs, 7.86 (s, 1H), 7.57-7.55 (d, 8.2 Hz, 2H)), 7.40-7.39 (d, 8.2 Hz, 2H), 4.32-4.28 (q, 2H), 3.87 (s, 2H), 2.63 (s, 3H), 1.37-1.34 (t, 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 164.8, 164.7, 151.1, 145.0, 140.5, 132.0, 129.6, 126.6, 110.0, 108.8, 60.8, 36.0, 19.2, 14.2; Mass (ESI- MS):296m/z [M+H] ⁺ .

ethyl 2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3- carboxylate(4j):

[0081] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14m) (525 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4j aswhite solid (205 mg, 72% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 7.82 (s, 1H), 7.17-6.99 (m, 4H), 4.28 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 2.63 (s, 3H), 1.34 (t, = Hz, = 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.2, 164.9, 150.4, 139.8, 139.2, 137.8, 129.7, 128.2, 128.1, 126.9, 125.9, 108.6, 60.6, 35.6, 21.3, 19.2, 14.2; MS (ESI): 286 m/z [M+H] ⁺ .

ethyl 5-(4-isopropylbenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate(4k):

[0082] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14w) (580 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4k aswhite solid (235 mg, 75% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.26-7.12 (m, 4H), 4.27 (q, = 7.1 Hz, 2H), 3.80 (s, 2H), 2.91-2.81 (m, 2H), 2.63 (s, 2H), 1.33 (t, = 7.1 Hz, 3H), 1.22 (d, = 6.8 Hz, 6H). ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 165.5, 164.7, 150.5, 139.6, 136.4, 128.8, 127.8, 124.3, 123.2, 108.2, 51.6, 35.2, 28.3, 19.3, 15.5, 13.0. MS (ESI): m/z 314 [M+H] ⁺ .

ethyl 5-(2,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate

(41):

[0083] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (230 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14x) (634 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 41 aswhite solid (272 mg,

80% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.53 (brs, 1H), 7.86 (s, 1H), 7.40 (d, 1.9 Hz, 7.32 (d, 8.2 Hz, 1H), 7.12 (dd, 1.9 7.1 Hz, 1H), 4.31 (q, 2H), 3.76 (s, 2H), 2.64 (s, 3H), 1.36 (t, 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5163.1, 161.3, 149.7, 139.0, 137.3, 129.7, 128.8, 128.4, 127.6, 126.9, 125.2, 105.1, 58.5, 33.0, 17.2, 12.6; Mass (ESI-MS): 340 m/z [M+H] ⁺ .

ethyl 5-(3,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carboxylate (4m):

[0084] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-aminobut-2-enoate (15b) (258 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14z) (634 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 4m aswhite solid (258 mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.55 (brs, 1H), 7.81 (s, 1H), 7.38 (d, 2.1 Hz, 1H), 7.29 (d, 8.3 Hz, 1H), 7.16 (dd, 2.13 Hz, 1H), 4.27 (q, 2H), 3.91 (s, 2H), 2.66 (s, 3H), 1.33 (t, 7.0, 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5164.4,162.9, 150.4, 138.7, 135.0, 134.1, 131.8, 131.3, 128.3, 126.3, 125.2, 106.8, 59.7, 31.9, 18.4, 13.6; Mass (ESI-MS):340m/z [M+H] ⁺ .

5-(2-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carb onitrile(5a):

[0085] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b) (504 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5a aswhite solid (193 mg, 80% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 7.29-7.02 (m, 5H), 3.82 (s, 2H), 2.53 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ δ 164.4, 159.5, 151.9, 138.5, 131.5, 131.5, 128.7, 124.1, 124.1, 115.6, 115.4, 91.6, 28.9, 18.1; MS (ESI): 243 m/z [M+H] ⁺ ; HRMS (ESI): m/z [M+H] ⁺ calculated for Ci ₈ H ₂₀ NO ₃ : 243.0928; found: 243.0919.

5-(3-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carb onitrile (5b)

[0086] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14h) (589 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5b aswhite solid (188 mg, 78% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 12.92 (brs, 1H), 7.25 (t, 1H), 7.21 (s, 1H), 7.01- 6.92 (m, 3H), 3.78 (s, 2H), 2.52 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): 5162.6, 160.8, 159.3, 151.3, 140.2, 135.8, 128.4, 128.3, 128.1, 123.1, 115.4, 114.2, 113.9, 111.6, 111.3, 87.5, 33.4, 16.4 Mass (ESI-MS):243m/z [M+H] ⁺ .

5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carb onitrile (5c):

[0087] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14o) (589 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5caswhite solid (191 mg, 79% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 13.08 (brs, 1H), 7.19 (t, 78.4, 7.9 Hz, 2H), 7.16 (s, 1H), 7.90 (t, 78.6, 8.6 Hz, 2H), 3.76 (s, 2H), 2.53 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): δ Mass (ESI-MS):243m/z [M+H] ⁺ ;

5-(2-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo nitrile (5d):

[0088] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14d) (627 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5d aswhite solid (224 mg, 74% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 12.92 (bs, 1H), 7.60 (d, 1H) 7.31-7.27 (m, 2H), 7.17-7.14 (t, 1H), 7.05 (s, 1H), 3.93 (s, 2H), 2.55 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): 5164.4, 151.8, 138.6, 137.0, 133.1, 131.6, 128.9, 128.7, 127.6, 124.9, 116.5, 91.6, 35.6, 18.2; Mass (ESI-MS): 303m/z [M+H] ⁺ .

5-(3-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo nitrile(5e):

[0089] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14j) (627 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5e aswhite solid (230 mg, 76% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 7.41-7.15 (m, 5H), 3.75 (s, 2H), 2.53 (s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δδ 164.3, 152.2, 140.3, 138.8, 132.1, 130.1, 129.9, 129.8, 127.6, 122.5, 116.3, 91.6, 35.3, 18. m/z [M+H] ⁺ .

2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carbonitrile (5f):

[0090] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14e)(605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5f as white solid (233 mg, 80% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 11.98 (brs, 1H), 7.76-7.72 (m, 3H), 7.57-7.48 (m, 4H), 7.43 (t, 1H), 7.31-7.27 (t, 2H), 6.98 (s, 1H), 4.00 (s, 2H); ¹³ C NMR (75 MHz, CDCI3): δ16403, 151.9, 138.7, 136.1, 132.1, 131.8, 130.0, 127.1, 126.3, 125.3, 123.1, 116.4, 91.6, 31.8, 18.1; Mass (ESI-MS): 293m/z [M+H] ⁺ .

2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carbonitrile (5g):

[0091] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14k) (605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5g as white solid (230 mg, 79% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 12.37 (brs, 1H), 7.52 (s, 1H), 7.51 (d, 1H), 7.44-7.41 (m, 2H), 7.23 (s, 1H), 3.84 (s, 2H), 2.50 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): 5162.6, 152.3, 139.1, 137.2, 132.1, 130.1, 129.5, 128.6, 125.3, 123.0, 116.5, 89.5, 34.9, 17.7;Mass (ESI-MS):293m/ [M+H] ⁺ .

2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carbonitrile (5h):

[0092] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14r) (605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3a aswhite solid (239 mg, 82% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 13.00 (brs, 1H), 7.56 (d, 8.1 Hz, 2H), 7.35 (d, 8.1), 7.23 (s, 1H), 3.85 (s, 2H), 2.51 (s, 3H); ¹³ C NMR (75 MHz, CDCI3): 5164.2, 152.2, 142.1, 138.8, 129.7, 129.3, 125.5, 125.5, 125.4, 116.2, 91.6, 35.4, 18.1; Mass (ESI-MS): 293m/z [M+H] ⁺ ;

5-(2-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-car bonitrile (5i):

[0093] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14f) (529mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5i aswhite solid (205 mg, 81% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 13.38(brs, 1H), 7.27-7.25(m, 1H), 7.24-7.21(m, 1H), 7.12(s, 1H), 6.92-6.88(m, 2H), 3.80(s, 3H), 3.77(s, 2H), 2.54(s, 3H); ¹³ C NMR (75 MHz, CDCI3): 5164.6, 157.4, 151.3, 138.2, 131.0, 130.0, 128.2, 125.8, 120.4, 116.8, 110.4, 91.4, 55.2, 29.9, 18.0; Mass (ESI-MS):255m/z [M+H] ⁺ .

5-(3-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-car bonitrile (5j): [0094] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (141) (529 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5j as white solid (200 mg, 80% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 13.03 (brs, 1H), 7.23-7.21 (d, 1H), 7.16 (s, 1H), 6.81-6.79 (m, 2H), 6.77 (s, 1H), 3.79 (s, 3H), 3.76 (s, 2H), 2.51 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 164.5, 159.7, 151.8, 139.4, 138.5, 130.6, 129.6, 121.4, 116.5, 115.2, 111.5, 91.5, 55.1, 35.4, 18.1; Mass (ESI-MS): 255m/z [M+H] ⁺ .

2-methyl-5-(3-nitrobenzyl)-6-oxo-l,6-dihydropyridine-3-carbo nitrile (5k):

[0095] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14n) (559 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5k as white solid (170 mg, 63% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 13.10 (brs, 1H), 8.177 (s, 1H), 8.12-8.09 (d, 1H), 7.59-7.57 (d, 1H), 7.51-7.45 (t, 1H), 7.33 (s, 1H), 3.89 (s, 2H), 2.55 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 162.0, 152.5, 147.6, 140.2, 137.2, 134.7, 128.8, 128.6, 123.0, 120.9, 116.2, 89.1, 34.6, 17.4;Mass (ESI-MS):279m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₄ HnN ₃ 0 ₃ : 279.15774 M+H] ⁺ , found: 279.15883.

5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo nitrile (51):

[0096] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14u) (519 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 51 aswhite solid (186 mg, 75% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 7.81 (s, 1H), 7.62 (d, 2H), 7.42 (d, 2H), 3.83 (s, 2H), 2.44 (s, 3H); Mass (ESI-MS): 250 m/z [M+H] ⁺ .

2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3-carb onitrile (5m):

[0097] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14m)(497 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5m aswhite solid (162 mg, 68% yield). 1H NMR (300 MHz, CDC1 ₃ ): 57.82 (s, 1H), 7.26-6.99 (m, 4H), 4.28 (q, J = 1.1 Hz, 2H), 3.79 (s, 2H), 2.63 (s, 3H), 2.30 (s, 3H), 1.34 (t, J = 1.1 Hz, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 164.4, 151.6, 138.4, 138.2, 131.0, 129.8, 128.5, 127.5, 126.2, 126.1, 116.5, 91. ; MS (ESI): 286 m/z [M+H] ⁺ ;

5-(4-ethylbenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbo nitrile(5n):

[0098] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14v) (525 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5n aswhite solid (176 mg, 70% yield).

1H NMR (300 MHz, CDCI3): δ 12.21 (brs, 1H), 7.83 (s, 1H), 7.52 (d, 2H), 7.39 (d, 2H), 3.87 (s, 2H), 2.74 (q, 2H), 2.62 (s, 3H) 1.25 (t, 3H); MS (ESI): m/ _z 253

[M+H] ⁺ .

5-(4-isopropylbenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-c arbonitrile(5o):

[0099] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14w) (553 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5oaswhite solid (191 mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.19-7.12 (m, 5H), 3.75 (s, 2H), 2.89 (sp, = 6.79Hz, 1H), 2.52 (s, 3H), 1.24 (d,J = 6.79Hz, 6H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 164.5, 151.6, 147.3, 138.4, 135.1, 131.1, 129.0, 126.6, 116.5, 91.5, 35.0, 33.6, 23.9, 18.0; MS (ESI): 267 /z[M+H ⁺ ;

5-(2,6-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carbonitrile (5p):

[0100] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14y)(607 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5p aswhite solid (222 mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.42 (d, 2H), 7.30 (t, 1H), 6.45(s, 1H), 4.04(s, 2H), 2.44(s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ):5 160.8, 150.9, 134.3, 132.9, 132.3, 127.8, 127.0, 125.6, 115.5, 87.6, 29.1, 16.5; MS (ESI): 293 m/z [M+H] ⁺ ; 5-(3,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3- carbonitrile (5q):

[0101] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14z) (607 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5q aswhite solid (228 mg, 78% yield).

1H NMR (300 MHz, CDC1 ₃ ): δδ 12.3(brs, 1H), 7.76(s, 1H), 6.83-6.80(m, 3H), 3.81(s, 3H), 3.76(s, 2H), 2.67(s, 3H) ¹³ C NMR (300 MHz, CDC1 ₃ ):5160.7, 151.7, 138.3, 136.0, 129.7, 129.0, 127.8, 127.2, 115.4, 87.3, 77.2, 32.8, 16.4; MS (ESI): 293 m/z [M+H] ⁺ ;

5-(2,5-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3 -carbonitrile (5r):

[0102] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b ¹ ) (597 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5r aswhite solid (230 mg, 81% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 13.23, (brs, 1H), 7.14 (s, 1H), 6.81 (m, 2H), 6.77- 6.75 (m, 1H), 3.76 (s, 3H), 3.75 (s, 75), 3.74 (s, 3H), 2.54 (s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 164.4, 153.1, 151.5, 151.3, 138.1, 129.7, 126.9, 117.6, 116.6, 111.4, 111.0, 91.3, 55.6, 55.4, 29.8 17.9; Mass (ESI-MS): 285m/z [M+H] ⁺ .

5-(3,4-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3 -carbonitrile

(5s):

[0103] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14a ¹ ) (589 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5s aswhite solid (272 mg, 80% yield).

1H NMR (300 MHz, CDCI3): δ 12.9(brs, 1H), 7.13(s, 1H), 6.82 (d,lH), 6.78- 6.73(m, 2H), 3.87(s, 3H), 3.86(s, 3H), 3.73(s, 2H), 2.54(s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): 5164.4, 151.5, 148.9, 147.8, 138.2, 131.1, 130.1, 121.2, 116.4, 112.3, 111.2, 91.5, 55.8, 34.9, 18.0; Mass -MS): 285 m/z [M+H] ⁺ .

5-(furan-2-ylmethyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-ca rbonitrile (5t): [0104] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14c ¹ ) (449 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3a aswhite solid (178 mg, 74% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 12.98 (brs, IH), 7.36 (m, IH), 7.24 (s, IH), 6.34- 6.33 (m, IH), 6.15 (m, IH), 3.84 (s, 2H), 2.55 (s, 3H); Mass (ESI-MS): 215m/z [M+H] ⁺ .

2-methyl-5-(naphthalen-l-ylmethyl)-6-oxo-l,6-dihydropyridine -3-carbonitrile (5u):

[0105] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14e ^∑ ) (567 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5u aswhite solid (236 mg, 77% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 13.19 (bs, 1H), 7.91-7.88 (m, 1H), 7.82 (d, 2H), 7.50-7.44 (m, 3H), 7.38 (d, 1H), 6.88 (s, 1H), 4.26 (s, 2H), 2.54 (s, 3H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 164.4, 151.6, 138.6, 134.0, 133.7, 131.7, 130.3, 128.9, 127.8, 127.9, 126.3, 125.8, 125.5, 123.7, 116.4, 91.7, 32.0, 18.1; Mass (ESI-MS):m/z 275 [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₈ Hi ₄ N ₂ 0: 275.11789 [M+H] ⁺ , found: 275.11758.

2-methyl-5-(naphthalen-2-ylmethyl)-6-oxo-l,6-dihydropyridine -3-carbonitrile (5v):

[0106] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14f ^∑ ) (567 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5v aswhite solid (227 mg, 74% yield).

1H NMR (300 MHz, CDCI3): δ 12.94 (brs, 1H), 7.83-7.75 (m, 3H), 7.68 (s, 1H), 7.50-7.43 (m, 2H), 7.34-7.30 (m, 1H), 7.20 (s, 1H), 3.95 (s, 2H), 2.48 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 163.6, 152.3, 139.2, 135.3, 133.5, 132.2, 132.1, 131.6, 130.6, 129.0, 128.5, 128.3, 127.6, 127.5, 127.4, 127.3, 126.2, 125.7, 117.3, 90.1, 35.65; Mass (ESI-MS):275 /z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. forCi ₈ Hi ₄ N ₂ 0: 275.11613 [M+H] ⁺ , found275.11

5-((2-methoxyquinolin-3-yl)methyl)-2-methyl-6-oxo-l,6-dihydr opyridine- 3carbonitrile (5w):

[0107] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14g ^∑ )(640 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5w as white solid (222 mg, 73% yield).

1H NMR (300 MHz, CDC1 ₃ ): δ 13.05 (brs, 1H), 7.90 (s, 1H), 7.82 (d, 1H), 7.64-7.61 (d, 1H), 7.58 (t, 1H), 7.36 (t, 1H), 7.32 (s, 1H), 4.06 (s, 3H), 3.86 (s, 2H), 2.48 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 161.7, 160.0, 152.8 144.7, 137.2, 136.8, 116.8, 53.0, 29.2, 17.6; Mass (ESI-MS): 306 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₈ Hi ₅ N ₃ 0 ₂ : 306.12370 [M+H] ⁺ , found: 306.12363.

5-hexyl-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (5x):

[0108] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14h ¹ )(485 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5x aswhite solid (143 mg, 66% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.98 (brs, 1H), 7.28 (s, 1H), 2.55 (s, 3H), 2.48 (t, 2H), 1.58-1.53 (m, 2H), 1.37-1.31 (m, 6H), 0.89 (t, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 162.0, 152.4, 136.1, 130.6, 117.3, 88.0, 31.0, 29.0, 28.3, 27.4, 21.9, 17.7, 13.9; Mass (ESI-MS): 219 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₃ Hi ₈ N ₂ 0: 219.14919 [M+H] ⁺ , found: 219.14906.

5-heptyl-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (5y):

[0109] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14i ^∑ ) (513 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5y aswhite solid (148 mg, 64% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.98 (brs, 1H), 7.28 (s, 1H), 2.55 (s, 3H), 2.47 (t, 2H), 1.60-1.50 (m, 2H), 1.38-1.24 (m, 8H), 0.88 (t, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 161.9, 15.06, 134.8, 130.6, 116.2, 88.1, 30.5, 28.4, 28.0, 27.8, 26.8, 21.4, 16.8, 13.0; Mass (ESI-MS):233m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₄ H ₂₀ N ₂ O: 233.16484 [M+H] ⁺ , found: 233.16479

2-methyl-5-octyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (5z):

[0110] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-aminobut-2-enenitrile (15c) (164 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14j ^∑ ) (541 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 5z aswhite solid (160 mg, 65% yield).

1H NMR (300 MHz, CDC1 ₃ ): 512.57 (brs, 1H), 7.27 (s, 1H), 2.54 (s, 3H), 2.47 (t, 2H), 1.55 (m, 2H), 1.27 (m, 10H 0.88 (t, 3H); Mass (ESI-MS):247m/z [M+H] ⁺ .

ethyl 5-(2-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb oxylate (6a):

[0111] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b) (533 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6a aswhite solid (270 mg, 77% yield). 1H NMR (300 MHz, CDC1 ₃ ): 510.86 (brs, 1H), 7.77 (s, 1H), 7.51- 7.44 (m, 3H), 7.38 (d, 2H), 7.19 (t, 3H), 7.05-7.01 (m, 2H), 4.02(q, 2H), 3.81 (s, 2H), 0.96 (t, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.3, 163.7, 162.7, 159.5, 149.9, 139.4, 133.9, 131.6, 129.6, 128.8, 128.5, 128.1, 127.9, 123.8, 115.3, 115.0, 109.1, 60.6, 28.9, 13.5; Mass (ESI-MS): 352 /z [M+H] ⁺ .

ethyl 5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb oxylate (6b):

[0112] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14h) (533 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6b aswhite solid (275 mg, 79% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 10.63 (brs, 1H), 7.79 (s, 1H), 7.51- 7.44 (m, 3H), 7.38 (d, 2H), 7.23 (t, 6.4, 7.9 Hz, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 6.90 (t, 8.5, 8.3 Hz, 1H), 4.03(q, 2H), 3.78 (s, 1H), 0.97 (t, 7.1,7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.2, 163.6, 150.2, 141.6, 141.5, 139.4, 133.9, 129.7, 129.6, 128.4, 128.0, 124.5, 116.0, 115.7, 113.2, 113.0, 60.7, 35.6, 13.5; Mass (ESI- MS): 352 m/z [M+H] ⁺ .

ethyl 5-(4-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb oxylate (6c):

[0113] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14o) (449 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6c aswhite solid (287 mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 10.46 (brs, 1H), 7.76 (s, 1H), 7.50-7.42 (m, 3H), 7.37 (d, 2H), 7.19 (q, 2H), 6.95 (t, 78.3, 9.0 Hz, 2H), 4.03(q, 2H), 3.76 (s, 2H), 0.96 (t, 76.7, 7.5 Hz, 3H) Mass (ESI-MS): 352 m/z [M+H] ⁺ .

ethyl 5-(2-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo xylate (6d):

[0114] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14d)(654 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6d aswhite solid (296 mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): 510.58 (brs, 1H), 7.72 (s, 1H), 7.58 (d, 1H), 7.50-7.42 (m, 3H), 7.39 (d, 2H), 7.26 (t, 77.7, 9.0 Hz, 2H), 7.23 (t, 77.3,8.6 Hz, 1H), 7.10 (t, 77.7, 7.3 Hz, 1H), 4.01(q, 2H), 3.94 (s, 2H), 0.95 (t, 7 7.1, 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.2, 163., 149.7, 139.6, 138.0, 133.9, 132.8, 131.5, 129.7, 128.6, 128.4, 128.1, 128.0, 127.3, 124.7, 109.1, 60.6, 35.5, 13.5; Mass (ESI-MS): 412 m/z [M+H] ⁺ .

ethyl 5-(3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo xylate (6e):

[0115] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14j) (654 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6e aswhite solid (309 mg,

75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 10.71 (brs, 1H), 7.8 (s, 1H), 7.51-7.43 (m, 3H), 7.41-7.33 (m, 4H), 7.16 (s, 1H), 4.04 (q, 2H), 3.75 (s, 2H), 0.97 (t, 7.1, 7.1 Hz, 3H);Mass (ESI-MS): 412 m/ [M+H] ⁺ .

ethyl 6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carboxylate (6f):

[0116] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14k) (632 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6f aswhite solid (305 mg,

76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 1 1.02 (brs, 1H), 7.79 (s, 1H), 7.51 -7.43 (m, 3H), 7.38 (d, 2H), 7.22 (q, 1H), 7.00 (d, 1H), 6.94 (d, 1H), 6.90 (t, 78.8,8.6 Hz, 1H), 4.03(q, 2H), 3.76 (s, 2H), 0.97 (t, 77.0,7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.2, 163.7, 163.6, 161.8, 150.1, 141.5, 139.4, 133.9, 129.7, 129.6, 128.4, 128.0, 124.5, 115.9, 115.8, 113.2, 113.1, 109.1, 60.7, 35.6, 13.6; Mass (ESI- MS): 402 m/z [M+H] ⁺ ;

ethyl 6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carboxylate (6g):

[0117] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14r) (632 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6g aswhite solid (300 mg, 75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 9.68 (brs, 1H), 7.81 (s, 1H), 7.54 (d, 7 8.0 Hz, 2H), 7.50-7.44 (m, 3H), 7.39 (d, 7 8.0 Hz, 2H), 7.36 (d, 78.3 Hz, 2H), 4.04(q, 2H), 3.89 (s, 2H), 0.97 (t, 77.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.1, 163.4, 150.1, 143.1, 139.5, 133.9, 129.8, 129.6, 129.2, 128.4, 128.1, 125.2, 125.2, 125.1, 109.1, 60.8, 35.8, 13.5; Mass (ESI-MS): 402 /z [M+H] ⁺ .

ethyl 5-(4-cyanobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo xylate (6h):

[0118] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14u) (546 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6h aswhite solid (275 mg, 77% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ δ 12.41 (brs, 7.86 (s, 1H), 7.57-7.55 (d, 8.2 Hz, 2H)), 7.50-7.44 (m, 3H), 7.39 (d, 8.0 Hz, 2H), 7.36 (d, 8.2 Hz, 2H), 4.32-4.28 (q, 2H), 1.37-1.34 (t, 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5164.5, 162.5, 150.1, 144.5, 138.6, 133.6, 131.5, 129.2, 128.9, 128.4, 127.9, 127.3, 118.4, 109.3, 107.9, 60.0, 35.6, 13.0; Mass (ESI-MS):359 /z [M+H] ⁺ .

ethyl 5-(2,4-dichlorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3- carboxylate (6i):

[0119] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14x) (634 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6i aswhite solid (301 mg,

75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 10.36 (brs, 1H), 7.77 (s, 1H), 7.48 (m, 3H), 7.39-7.37 (m, 3H), 7.21 (d, 78.3 Hz, 1H), 7.13 (dd, J 2.1, 2.1 Hz, 1H), 4.02 (q, 2H), 3.89 (s, 2H), 0.98-0.95 (t, 7.1 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.2, 163.5, 150.0, 139.9, 134.8, 134.0, 132.8, 132.4, 129.8, 129.1, 128.4, 128.0, 126.9, 109.2, 60.7, 32.9, 13.6; Mass (ESI-MS): 402 m/z [M+H] ⁺ .

ethyl 5-(3,4-dichlorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3- carboxylate

(6j):

[0120] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly ethyl 3-amino-3-phenylacrylate (15d) (381 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14z) (634 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 6j aswhite solid (293 mg,

73% yield). 1H NMR (300 MHz, CDCI3): δ 10.46 (brs, 1H), 7.82 (s, 2H), 7.47 (q, 3H), 7.39-7.31 (m, 4H), 7.08 (d, 9.8 Hz, 1H), 4.05(q, 2h), 3.74 (s, 2H), 0.98 (t, 6.7, 7.5 Hz, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5165.2, 163.5, 150.4, 139.6, 139.3, 133.9, 132.1, 130.7, 130.1, 129.8, 129.2, 128.4, 128.0, 109.1, 60.8, 35.2, 13.6; Mass (ESI-MS): 402 m/z [M+H] ⁺ ;

5-(2-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb onitrile (7a):

[0121] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b) (504 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7a aswhite solid (231 mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δδ 10.86 (brs, 1H), 7.77 (s, 1H), 7.51- 7.44 (m, 3H), 7.38 (d, 2H), 7.19 (t, 3H), 7.05-7.01 (m, 2H), 3.81 (s, 2H), ¹³ C NMR (75 MHz, CDCI ₃ ): δ Mass (ESI-MS : 305 m/z [M+H] ⁺ .

5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb onitrile (7b):

[0122] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14h) (504 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7b aswhite solid (228 mg, 75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 1 1.66 (brs, 1H), 7.72 (d, 2H), 7.62- 7.55 (m, 3H), 7.30 (s, 1H), 7.28-7.24 (m, 1H), 6.98 (d, 1H), 6.93 (t, 79.9, 9.0 Hz, 2H), 3.77 (s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5162.0, 152.4, 140.2, 137.4, 130.8, 130.5, 130.4, 129.4, 129.3, 128.0, 127.9, 124.2, 116.9, 115.4, 115.1, 112.9, 112.6, 88.49, 34.5; Mass (ESI-MS): ⁺ .

5-(4-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carb onitrile (7c):

[0123] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14o) (505 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7caswhite solid (212 mg,

72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71-7.68 (m, 2H), 7.61-7.56 (m, 3H), 7.23 (s, 1H), 7.21-7.17 (m, 2H), 6.98 (t, 2H), 3.79 (s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 163.5, 163.3, 160.0, 152.4, 139.0, 133.4, 132.0, 131.6, 130.6, 130.5, 129.1, 128.4, 117.2, 115.5, 115.3, 90.2, 34.9; Mass (ESI-MS): 305 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. forCi ₉ Hi ₃ FN ₂ 0: 305.10622 [M+H] ⁺ , found 305.10604.

5-(2-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo nitrile (7d):

[0124] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14d) (627 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7d aswhite solid (262 mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.47 (brs, 1H), 7.79-7.76 (m, 2H), 7.61-7.57 (m, 3H), 7.55 (s, 1H), 7.23-7.20 (m, 3H), 7.18-7012 (m, 1H), 3.90 (s, 1H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5163.7, 152.3, 139.3, 136.9, 133.0, 131.5, 130.4, 130.0, 128.9, 128.6, 128.5, 127.6, 124.8, 117.3, 90.2, 35.4; Mass (ESI-MS): 365 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. forCi ₉ Hi ₃ BrN ₂ 0: 365.02840 [M+H] ⁺ , found: 365.02843

5-(3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo nitrile (7e):

[0125] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14j) (627 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7e aswhite solid (255 mg,

70% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 12.03 (brs, 1H), 7.74 (d, 2H), 7.62-7.55 (m, 3H), 7.38 (d, 2H), 7.32 (s, 1H), 7.15 (t, 7.6, 7.6 Hz, 1H), 7.11 (d, 1H), 3.73 (s, 2H); Mass (ESI-MS): 365 m/z [M+H] ⁺ .

6-oxo-2-phenyl-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carbonitrile (7f):

[0126] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14e) (605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7f aswhite solid (276 mg,

78 % yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 12.97 (brs, 1H), 7.71 (d, 1H), 7.50 (t, 1H), 7.40 (t, 1H), 7.28 (d, 1H), 6.88 (s, 1H), 4.00 (s, 1H), 2.54 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 162.6, 152.3, 137.9, 135.8, 131.9, 131.7, 131.2, 131.0, 130.4, 128.5, 128.2, 126.8, 125.9, 125.9, 122.1, 117.3, 89.0, 31.5;Mass (ESI-MS): 355 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. forC ₂₀ Hi ₃ F ₃ N ₂ O: 355.10527 [M+H] ⁺ , found: 355.10481

6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carbonitrile(7g):

[0127] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14k) (605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7g aswhite solid (265 mg, 75% yield). ¹ !! NMR (300 MHz, CDC1 ₃ ): δ 11.43 (bs, 1H), 7.73 (d, 2H), 7.60 (t, 1H), 7.55 (t, 2H), 7.52 (d, 1H), 7.48 (s, 1H), 7.42-7.39 (m, 2H), 7.31 (s, 1H), 3.84 (s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5161.2, 152.1, 138.5, 136.9, 131.5, 129.8, 127.8, 127.4, 124.4, 124.3, 121.9, 121.9, 116.3, 87.7, 34.1; 160.9, 151.6, 134.3, 133.7, 132.1, 129.7, 129.5, 127.8, 127.3, 127.1, 127.0, 126.9, 116.2, 87.2, 77.1, 29.3; Mass (ESI-MS): 355m/z [M+H] ⁺ .

6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyri dine-3- carbonitrile (7h):

[0128] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14r) (605 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7h aswhite solid (270 mg, 76% yield).1H NMR (300 MHz, CDCI3): δ 11.91 (brs, 1H), 7.70 (d, 7.0 Hz, 2H), 7.63-7.55 (m, 3H), 7.51 (d, 8.2 Hz, 2H), 7.34 (s, 1H), 7.28 (d, 7.9 Hz, 2H), 3.82 (s, 2H);Mass (ESI-MS): 355 m/z [M+H] ⁺ .

5-(2-methoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-car bonitrile (7i):

[0129] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14f)(529 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7i aswhite solid (237 mg,

75% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 12.30(brs, 1H), 7.78-7.75(m, 2H), 7.58- 7.55(m, 3H), 7.28-7.22 (m, 2H), 7.10 (d, 1H), 6.91-6.82(m, 2H), 3.82(s, 3H), 3.75(s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ): 5164.0, 157.4, 151.9, 138.8, 131.4, 131.1, 130.7, 128.9, 128.6, 128.2, 125.7, 120.4, 117.7, 110.4, 90.1, 55.2, 29.9; Mass (ESI-MS): 317m/z [M+H] ⁺ .

5-(3-methoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-car bonitrile (7j):

[0130] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(141) (529 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7j aswhite solid (250 mg,

79% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 12.11 (brs, 1H), 7076-7.73 (m, 2H), 7.59-7.55 (m, 3H), 7.26 (s, 1H), 7.21 (d, 1H), 6.82-6.78 (m, 2H), 6.77 (s, 1H), 3.78 (s, 3H), 3.74 (s, 2H); ¹³ C NMR (75 MHz, CDCI ₃ ): δ 163.8, 159.7, 152.3, 139.4, 139.1, 131.9, 131.5, 130.5, 129.6, 129.0, 128.5, 121.4, 117.4, 115.1, 111.6, 90.1, 55.1, 35.4; Mass (ESI-MS): 3 ⁺ .

5-(3-nitrobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo nitrile (7k):

[0131] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14n) (559 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7k aswhite solid (215mg,

65% yield). 1H NMR (300 MHz, CDCI3): δ 11.51 (brs, 1H), 8.12-8.09 (m, 2H), 7.74-7.71 (m, 2H), 7.617.53 (m, 4H), 7.45 (d, 1H), 7.40 (s, 1H), 3.89 (s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ):5 161.7, 152.7, 147.3, 139.8, 137.7, 134.7, 130.4, 130.1, 129.7, 128.6, 127.9, 127.8, 122.9, 120.7, 116.6, 88.3;Mass (ESI-MS): 332 m/z [M+H] ⁺ .

5-(4-cyanobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbo nitrile (71): [0132] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14u) (519 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 71 aswhite solid (240 mg, 77% yield). ¹ !! NMR (300 MHz, CDC1 ₃ ): δ 7.65 (d, 2H), 7.63 (d,2H), 7.58-7.51(m, 3H), 7.48 (d, 2H), 7.41(s, 1H), 3.89(s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ):5161.5, 152.6, 143.3, 137.4, 132.3, 131.1, 130.1, 129.3, 128.8, 127.6, 127.1, 117..7, 116.5, 108.9, 87.9, 34.6; Mass (ESI-MS 12 m/z [M+H] ⁺ .

5-(2,6-dichlorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3- carbonitrile (7m):

[0133] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14y) (606 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7m aswhite solid (284 mg, 80% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 10.36 (brs, 1H), 7.77 (s, 1H), 7.48 (m, 3H), 7.39-7.37 (m, 3H), 7.21 (d, 8.3 Hz, 1H), 7.13 (dd, J 2.1, 2.1 Hz, 1H), 3.89 (s, 2H); Mass (ESI-MS): 355 m/z [M+H] ⁺ .

5-(3,4-dichlorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3- carbonitrile (7n):

[0134] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14z) (606 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7n aswhite solid (277 mg, 78% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 10.46 (brs, 1H), 7.82 (s, 2H), 7.47 (q, 3H), 7.39-7.31 (m, 4H), 7.08 (d, 9.8 Hz, 1H), 3.74 (s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ):5162.0, 153.0, 139.3, 137.8, 133.7, 133.6, 132.3, 130.6, 128.6, 128.2, 125.5, 125.2, 125.1, 122.8, 122.7, 117.2, 88.5, 34.9; Mass (ESI-MS): 355 m/z [M+H] ⁺ .

5-(2,5-dimethoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3 -carbonitrile (7o):

[0135] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14b ¹ ) (597 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7o aswhite solid (273 mg, 79% yield).1H NMR (300 MHz, CDC1 ₃ ): δ δ 13.23, (brs, IH), 7.75-7.73(m, 2H), 7.59-7.54(m, 3H), 7.14 (s, IH), 6.81 (m, 2H), 6.77-6.75 (m, IH), 3.76 (s, 3H), 3.75 (s, 75), 3.74 (s, 3H); ¹³ C NMR (75 MHz, CDC1 ₃ ):5163.8, 153.4, 151.9, 151.6, 138.8, 131.5, 131.3, 130.7, 129.0, 128.5, 127.0, 117.7, 117.6, 111.9, 111.3, 90.1, 55.8, 55.5, 29.8; Mass (ESI-MS : 346 m/z [M+H] ⁺ .

5-(3,4-dimethoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3 -carbonitrile

(7p):

[0136] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14a ^∑ )(597 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7p aswhite solid (260 mg, 75% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 11.63(brs, IH), 7.75-7.73(m, 2H), 7.59-7.54(m, 3H), 7.2 4(s, IH), 6.80 (d, IH), 6.76-6.73(m, 2H), 3.87(s, 3H), 3.82(s, 3H), 3.73(s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ):5163.7, 152.0, 149.0, 147.8, 138.8, 132.5, 131.5, 130.5, 130.1, 128.9, 128.5, 121.1, 117.4, 112.2, 111.2, 90.1, 55.8, 55.7, 35.0; Mass (ESI-MS):347m ⁺ .

6-oxo-2-phenyl-5-(pyridin-3-ylmethyl)-l,6-dihydropyridine-3- carbonitrile (7q): [0137] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate(14k ^∑ ) (471 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7q aswhite solid (215 mg, 75% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 8.48 (d, 2H), 7.73 (d, 2H), 7.62-7.55 (m, 3H), 7.50 (d, 2H), 7.37 (s, 1H), 7.19 (dd, 1H)3.77 (s, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ):5Mass (ESI-MS): 288 m/z [M+H] ⁺ .

5-(furan-2-ylmethyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-ca rbonitrile (7r):

[0138] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14c ¹ ) (449 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7r aswhite solid (193 mg, 70% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 11.97 (brs, 1H), 7.75-7.73 (m, 2H), 7.61-7.54 (m 3H), 7.37 (m, 1H), 7.34 (s, 1H), 6.34 (t, 1H), 6.10 (m, 1H), 3.81 (s, 2H); Mass (ESI-MS): 277m/z [M+H] ⁺ .

5-(naphthalen-l-ylmethyl)-6-oxo-2-phenyl-l,6-dihydropyridine -3-carbonitrile

(7s):

[0139] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14e ^∑ ) (569 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7saswhite solid (252 mg, 75% yield). ¹ !! NMR (300 MHz, CDC1 ₃ ): δ 1 1.51 (brs, 1H), 7.93-7.90 (m, 1H), 7.85- 7.82 (m, 2H), 7.78-7.68 (m, 2H), 7.52-47 (m, 5H), 7.45 (d, 2H), 7.40 (d, 1H), 6.97 (s, 1H), 4.26 (s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 162.9, 152.1, 138.1, 133.7, 133.6, 131.5, 131.1, 130.6, 128.6, 128.3, 127.6, 127.6, 127.3, 127.2, 126.1, 125.6, 125.3, 123.6, 117.3, 89.4, 31.9; Mass (ESI-MS): m/z 337 [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for C ₂₃ Hi ₆ N ₂ 0: 337.133 ⁺ , found: 337.13324

5-(naphthalen-2-ylmethyl)-6-oxo-2-phenyl-l,6-dihydropyridine -3- carbonitrile(7t):

[0140] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14f ^∑ ) (569 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7t aswhite solid (262 mg,

78% yield). ¹ !! NMR (300 MHz, CDC1 ₃ ): δ 11.65 (brs, 1H), 7.84-7.80 (m, 2H), 7.77- 7.72 (m, 3H), 7.66 (s, 1H), 7.58-7.54 (m, 3H), 7.48-7.45 (m, 2H), 7.33-7.29 (m, 2H), 3.95 (s, 2H), ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 163.6, 152.3, 139.2, 135.3, 133.5, 132.2, 132.1, 131.6, 130.6, 129.0, 128.5, 128.3, 127.6, 127.5, 127.4, 127.3, 126.2, 125.7, 117.3, 90.19, 35.6; Mass (ESI-MS): 337m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. forC ₂₃ Hi ₆ N ₂ 0: 337.13167[M+H] ⁺ , found337.13166.

5-((2-methoxyquinolin-3-yl)methyl)-6-oxo-2-phenyl-l,6-dihydr opyridine-3- carbonitrile (7u):

[0141] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14g ^∑ ) (640 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7u aswhite solid (270 mg, 74% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 11.39 (brs, 1H), 7.84 (d, 1H), 7.82 (s, 1H), 7.60-7.55 (m, 5H), 7.43 (s, 1H), 7.34 (t, 1H), 4.10 (s, 3H), 3.89 (s, 2H); ¹³ C NMR (75 MHz, CDC1 ₃ ): δ 161.9, 160.2, 153.6, 144.7, 138.5, 137.6, 137.2, 131.3, 130.8, 128.9, 128.7, 128.4, 127.2, 126.2, 125.0, 124.0, 122.6, 117.7, 91.9, 53.4, 29.4; Mass (ESI-MS): 368m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. forC ₂₃ H ₁₇ N ₃ 0 ₂ : 368.13935 [M+H] ⁺ , found: 368

5-hexyl-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (7v):

[0142] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14h ^∑ )(485 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7v aswhite solid (182 mg, 65% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 11.75 (brs, 1H), 7.77-7.74 (m, 2H), 7.56 (t, 3H), 7.38 (s, 1H), 2.47 (t, 2H), 1.60-1.50 (m, 2H), 1.39-1.25 (m, 6H), 0.90 (t, 3H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 162.1, 152.8, 136.9, 131.9, 131.2, 130.7, 128.6, 128.4, 117.8, 88.4, 31.0, 29.0, 28.3, 27.4,21.9, 13.8;Mass (ESI-MS): 281 m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₈ H ₂₀ N ₂ O: 281.16484 [M+H] ⁺ , found: 281.16476.

5-heptyl-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (7w):

[0143] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14i ^∑ ) (513 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7w aswhite solid (185 mg, 63% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 11.43 (brs, 1H), 7.75-7.73 (m, 2H), 7.57(t, 3H), 7.38 (s, 1H), 2.48 (t, 2H), 160-1.51 (m, 2H), 1.38-1.30 (m, 8H), 0.89 (t, 3H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 162.2, 152.8, 137.0, 131.9, 131.3, 130.8, 128.7, 128.5, 117.9, 88.38, 31.1, 29.1, 28.7, 28.4, 27.5, 22.0, 13.9; Mass (ESI-MS): 295m/z [M+H] ⁺ ; HRMS (ESI) m/z Calcd. for Ci ₉ H ₂₂ N ₂ 0: 295.18049 [M+H] ⁺ , found: 295.18002.

5-octyl-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (7x):

[0144] To a well stirred solution of NaH (60% in paraffin oil, 240 mg, 6 mmol) in dry THF (10 mL) was added slowly 3-amino-3-phenylacrylonitrile (15e) (288 mg, 2 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman acetate (14j ^∑ ) (541 mg, 2 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 6h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 7x aswhite solid (185 mg, 60% yield). 1H NMR (300 MHz, CDCI3): δ 11.33 (brs, 1H), 7.72-7.70 (m, 2H), 7.53 (t, 3H), 7.38 (s, 1H), 2.48 (t, 2H), 1.58-1.51 (m, 2H), 1.35-1.30 (m, 10H), 0.89 (t, 3H); Mass (ESI-MS): 309m/z ⁺ .

methyl 6-(2-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8a):

[0145] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14b) (252 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8a as white solid (225 mg, 75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.69 (s, IH), 7.34 (t, 9.3, 9.3 Hz, IH), 7.22-7.12 (m, IH), 7.06 (t, 8.6, 8.6 Hz, IH), 7.03 (t, 9.6, 9.7 Hz, IH), 4.17 (t, 7.6, 7.6 Hz, 2H), 3.87 (s, 2H), 3.80 (s, 3H), 3.50 (t, 7.9, 7.9, 2H), 2.24-2.17 (m, 2H); Mass ESI-MS): 302 m/z [M+H] ⁺ .

methyl 6-(3-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8b):

[0146] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14h) (252 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8b as white solid (219 mg, 73% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.70 (s, IH), 7.26-7.22 (q, IH), 7.08-7.07 (d, IH), 6.99-6.97 (d, IH), 6.90-6.87 (t, 7 8.5, 9.3 Hz, IH), 4.18-4.15 (t, 7 7.4, 7.6 Hz, 2H), 3.84 (s, 2H), 3.82 (s, 3H), 3.53-3.49 (t, 7 7.9,7.9 Hz, 2H), 2.24-2.18 (m, 2H Mass (ESI-MS): 302 m/z [M+H] ⁺ ;

methyl 6-(4-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8c):

[0147] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14o) (252 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8c as white solid (210 mg, 70% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.68 (s, IH), 7.25 (t, 7 6.8, 7.2 Hz, 2H), 6.96 (t, 7 8.6, 9.7 Hz, 2H), 4.15 (t, 7 8.2, 6.8 Hz, 2H), 3.82 (s, 3H), 3.81 (s, 2H), 3.50 (t, 77.9, 7.7 Hz, 2H), 2.24-2.18 (m, 2H); Mass (ESI- MS): 302 m/z [M+H] ⁺ ;

methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8d):

[0148] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 niL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14c) (268 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8d as white solid (228 mg, 72% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 7.61 (s, 1H), 7.36 (d, 2H), 7.22-7.16 (m, 2H), 4.17 (t, 7.6, 7.4 Hz, 2H), 3.97 (s, 2H), 3.79 (s, 3H), 3.50 (t, 7.9 Hz, 2H), 2.25-2.18 (m, 2H); Mass (ESI-MS): 318 m/z [M+2] ⁺ ;

methyl 6-(3-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate

(8e):

[0149] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14i) (268 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8e as white solid (215 mg, 68% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.70 (s, 1H), 7.25 (q, 1H), 7.06 (d, 1H), 6.98 (d, 1H), 6.88 (t, 8.5, 9.3 Hz, 1H), 4.16 (t, 7.4, 7.6 Hz, 2H), 3.84 (s, 2H), 3.82 (s, 3H), 3.51 (t, 7.9,7.9 Hz, 2H), 2.24-2.18 (m, 2H); Mass (ESI-MS): 318 m/z [M+2] ⁺ .

methyl 6-(4-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8f):

[0150] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14p) (268 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8f as white solid (212 mg, 72% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 7.69 (s, 1H), 7.24 (d, 4H), 4.15 (t, 7.4, 7.6 Hz, 2H), 3.82(s, 3H), 3.80 (s, 2H), 3.51 (t, 7.9, 7.7 Hz, 2H), 2.24-2.18 (m, 2H); Mass ESI-MS): 318 m/z [M+2] ⁺ ;

methyl 6-(2-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate (8g):

[0151] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14d) (312 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 niL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8g as white solid (267 mg, 74% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.60 (s, 1H), 7.56 (d, 1H), 7.35 (d, 1H), 7.26 (t, J 8.5, 8.5 Hz, 1H), 7.10 (t, 9.4, 9.1 Hz, 1H), 4.18 (t, J 7.6, 7.6 Hz, 2H), 3.98 (s, 2H), 3.79 (s, 3H), 3.50 (t, 7.7, 7.6 Hz, 2H), 2.25-2.19 (m, 2H); Mass (ESI-MS): 362 m/ [M+] ⁺ ;

methyl 6-(3-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate

(8h):

[0152] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14j) (312 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8h as white solid (249 mg, 69% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.41 (s, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 7.15 (t, 1H), 4.15 (t, 2H), 3.82 (s, 3H), 3.81 (s, 2H), 3.51 (t, 2H), 2.24-2.18 m, 2H); Mass (ESI-MS): 362 m/z [M+] ⁺ ;

methyl 6-(4-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate

(8i): [0153] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14q) (312 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8i as white solid (260 mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.70 (s, 1H), 7.40-7.38 (d, 2H), 7.18-7.16 (d, 2H), 4.17-4.13 (t, 2H), 3.82 (s, 3H), 3.79 (s, 2H), 3.52-3.48 (s, 2H), 2.24-2.17 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.2, 161.6, 155.4, 138.4, 137.4, 137.3, 131.3, 130.6, 128.3, 120.0, 105.0, 51.6, 49.2, 35.4, 33.5, 20.7; Mass (ESI-MS): 362 m ⁺ ;

methyl 5-oxo-6-(3-(trifluoromethyl)benzyl)-l,2,3,5-tetrahydroindoli zine-8- carboxylate (8j):

[0154] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14k) (302 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8j as white solid (228 mg, 65% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.41 (s, 1H), 7.32 (d, 1H), 7.25 (d, 1H), 7.15 (t, 1H), 4.15 (t, 2H), 3.82 (s, 3H), 3.81 (s, 2H), 3.51 (t, 2H), 2.24-2.18 (m, 2H); Mass (ESI-MS): 353 m/z [M+H] ⁺ .

methyl 6-(2-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-car boxylate (8k):

[0155] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14f) (264 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8k as white solid (237 mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.64 (s, 1H), 7.25 (d, 1H), 7.20 (d, 1H), 6.91 (d, 1H), 6.86 (d, 1H), 4.17 (t, 7.3, 7.5 Hz, 2H), 3.85 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.48 (t, 7.7, 7.9 Hz, 2H), 2.25-2.14 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.5, 161.9, 157.4, 154.7, 137.0, 130.8, 128.2, 127.5, 127.3, 120.4, 110.3, 105.0, 55.2, 51.5, 49.1, 33.5, 30.0, 20.7; Mass (ESI-MS): 314 m/z [M+H] ⁺ .

methyl 6-(3-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-car boxylate (81):

[0156] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 niL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (141) (264 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 81 as white solid (247 mg, 79% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.69 (s, 1H), 7.20 (t, J 8.2, 9.4 Hz, 1H), 6.90 (d, 2H), 6.83 (s, 1H), 6.75 (d, 2H), 4.15 (t, J 8.2, 8.2 Hz, 2H), 3.82 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.50 (t, J 7.78, 7.78 Hz, 2H), 2.23- 2.17 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.3, 161.7, 159.5, 155.2, 140.9, 137.2, 129.2, 128.7, 121.3, 114.6, 111.4, 104.9, 55.0, 51.5, 49.1, 35.8, 33.5, 20.6; Mass (ESI-MS): 314 m/z [M+ ⁺ ;.

methyl 6-(4-cyanobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carbo xylate (8m):

[0157] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14u) (259 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8m as white solid (231 mg, 75% yield). 1H NMR (300 MHz, CDCI3): δ 7.76 (s, 1H), 7.57 (d, 2H), 7.41 (d, 2H), 4.15 (t, J 7.6, 7.4 Hz, 2H), 3.88 (s, 2H), 3.83 (s, 3H), 3.51 (t, 7.9, 7.9 Hz, 2H), 2.25-2.19 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.1, 161.5, 155.9, 145.1, 137.8, 132.1, 129.6, 127.3, 118.9, 110.0, 105.0, 51.7, 49.3, 36.3, 33.6, 20.6; Mass (ESI-MS : 309 m/z [M+H] ⁺ ;

methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate (8n):

[0158] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14g) (248 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8n as white solid (189 mg, 68% yield).1H NMR (300 MHz, CDC1 ₃ ): δ 7.39 (s, 1H), 7.18-7.15 (m, 4H), 4.20 (t, 7.5, 7.5 Hz, 2H), 3.84 (s, 2H), 3.76 (s, 3H), 3.50 (t, 8.3, 7.5 Hz, 2H), 2.27 (s, 3H), 2.24-2.17 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.4, 161.9, 154.8, 136.9, 136.6, 130.2, 129.9, 128.3, 126.5, 126.0, 105.1, 51.6, 49.2, 33.5, 33.1, 20.7, 19.4; Ma -MS): 298 m/z [M+H] ⁺ ;

6-(4-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carb oxylate [0159] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14t) (248 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8o as white solid (189 mg, 68% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.76 (s, 1H), 7.57 (d, 2H), 7.41 (d, 2H), 4.15 (t, 7.6, 7.4 Hz, 2H), 3.88 (s, 2H), 3.83 (s, 3H), 3.51, 2.26 (s, 3H), (t, 7.9, 7.9 Hz, 2H), 2.25-2.19 (m, 2H); Mass (ESI-MS): 298 m/z [M+H] ⁺ .

methyl 6-(4-isopropylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-c arboxylate (8p):

[0160] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14w) (276 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8p as white solid (200 mg, 62% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.22 (d, 2H), 7.14 (d, 2H), 4.16 (t, 77.3, 7.7 Hz, 2H), 3.81 (s, 5H), 3.49 (t, 77.7, 7.9 Hz, 2H), 2.91-2.82 (m, 1H), 2.24-2.14 (m, 2H), 1.23 (s, 3H), 1.21 (s, 3H); Mass (ESI-MS): 326 m/z [M+H] ⁺ .

methyl 6-(3,4-dichlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8- carboxylate (8q):

[0161] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14z) (303 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8r as white solid (270 mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.73 (s, 1H), 7.36 (s, 1H), 7.33 (d, 1H), 7.15 (d, 1H), 4.16 (t, 77.4, 7.6 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 2H), 3.51 (t, 77.7, 7.9 Hz, 2H), 2.25-2.19 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.1, 161.5, 155.7, 139.7, 137.5, 132.0, 030.6, 130.1, 128.4, 127.5, 104.9, 51.6, 49.2, 35.2, 33.5, 20.6; Mass (E I-MS): 353 m/z [M+H] ⁺ .

methyl 6-(2,6-dichlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8- carboxylate (8r):

[0162] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 niL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14y) (303 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8r as white solid (264 mg, 75% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.36 (d, 2H), 7.18 (t, 7.9, 8.3 Hz, 1H), 7.14 (s, 1H), 4.22 (t, 7.4, 7.7 Hz, 2H), 4.18 (s, 2H), 3.74 (s, 3H), 3.50 (t, J 7.7, 7.9 Hz, 2H), 2.26-2.20 (m, 2H), Mass (ESI-MS): 353 m/z [M+H] ⁺ ;

Methyl-6-(3,4-dimethoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindol izine-8- carboxylate (8s):

[0163] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14a ¹ ) (294 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8s as white solid (274 mg, 80% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.66 (s, 1H), 6.84 (d, 1H), 6.82 (d, 1H), 6.80 (s, 1H), 4.17 (t, 7.4, 7.6 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.79 (s, 2H), 3.50 (t, 7.9, 7.9 Hz, 2H), 2.24-2.17 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.2, 161.7, 155.0, 148.6, 147.2, 136.9, 131.1, 129.1, 120.8, 112.2, 110.9, 105.0, 55.6, 51.5, 49.1, 35.3, 33.4, 20.6; Mass (ESI-MS): 344 m/z [M+H] ⁺ ;

methyl 6-(naphthalen-l-ylmethyl)-5-oxo-l,2,3,5-tetrahydroindolizine -8- carboxylate (8t):

[0164] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14e ^∑ ) (284 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8t as white solid (236 mg, 71% yield). 1H NMR (300 MHz, CDCI3): δ 7.96-7.93 (m, 1H), 7.87-7.83 (m, 1H), 7.77 (d, 1H), 7.46-7.41 (m, 5H), 4.31 (s, 2H), 4.24 (t, 7.3, 7.7, 2H), 3.68 (s, 3H), 3.49 (t, 7.9, 7.4, 2H); Mass (ESI-MS): 334 m/z [M+H] ⁺ .

Methyl-6-(naphthalen-2-ylmethyl)-5-oxo-l,2,3,5-tetrahydroind olizine-8- carboxylate (8u):

[0165] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (141 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14f ^∑ ) (284 mg, 1 mmol) in dry THF (5 niL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8u as white solid (230 mg, 69% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.77 (t, 9.7, 8.6 Hz, 3H), 7.74 (s, 1H), 7.72 (s, 1H), 7.45-7.39 (m, 3H), 4.16 (t, 7.6, 7.6 Hz, 2H), 4.01 (s, 2H), 3.78 (s, 3H), 3.50 (t, J 7.9, 7.9 Hz, 2H), 7.23-7.17 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.3,161.8, 155.3, 137.3, 136.9, 135.5, 132.1, 128.9, 127.9, 127.5, 127.3, 125.8, 125.2, 105.1, 51.6, 49.2, 36.0, 33.5, 20.7; Mass (ESI- MS): 334 m/z [M+H] ⁺ ;

Methyl-6-((2-chloroquinolin-3-yl)methyl)-5-oxo-l,2,3,5-tetra hydroindolizine-8- carboxylate (8v):

[0166] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(pyrrolidin-2-ylidene)acetate (15f) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14g ^∑ ) (319 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 8v as white solid (260 mg, 71% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 8.19 (s, 1H), 7.99 (d, 1H), 7.83 (s, 1H), 7.79 (d, 1H), 7.67 (t, 7.6, 7.7 Hz, 1H), 7.52 (t, 7.3, 7.7 Hz, 1H), 4.18 (t, 7.3,7.7 Hz, 2H), 4.11 (s, 2H), 3.80 (s, 3H), 3.53 (t, 7.9, 7.7 Hz, 2H), 2.26-2.20 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.1, 161.6, 155.8, 151.3, 146.5, 139.1, 138.2, 137.7, 130.6, 129.7, 127.9, 127.2, 126.7, 125.6, 105.1, 51.7, 49.2, 33.6, 33.6, 20.6; Mass (ESI-MS : 370 m/z [M+2] ⁺ .

methyl 7-benzyl-6-oxo-2,3,4,6-tetrahydro- lH-quinolizine-9-carboxylate (9a) :

[0167] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14a) (235 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9a as white solid (245 mg, 82%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.69 (s, 1H), 7.27 (d, 4H), 7.22-7.18 (m, 1H), 4.06 (t, 6.2, 6.4 Hz, 2H), 3.82 (s, 2H), 3.78 (s, 3H), 3.32 (t, 6.7, 6.7 Hz, 2H), 1.94-1.88 (m, 2H), 1.82 (m, 2H); Mass (ESI-MS): 298 m/z [M+H] ⁺ .

methyl 7-(2-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 - carboxylate (9b):

[0168] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14b) (253 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9b as white solid (235 mg, 75%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.70 (s, 1H), 7.33 (t, 7.4, 7.3 Hz, 1H), 7.22-7.17 (m, 1H), 7.06 (t, 8.6, 7.4 Hz, 1H), 7.02 (t, 9.6, 9.4 Hz, 1H), 4.06 (t, J 6.2, 6.4 Hz, 2H), 3.87 (s, 2H), 3.78 (s, 3H), 3.32 (t, J 6.7, 6.7 Hz, 2H), 1.94-1.89 (m, 2H), 1.81-1.76 (m, 2H); ¹³ C NMR (300 MHz, CDCI3): δ 165.9, 162.6, 159.6, 153.4, 137.0, 131.5, 128.0, 125.7, 123.9, 115.0, 115.3, 107.0, 51.6, 42.7, 29.8, 26.7, 21.4, 18.1; Mass ESI-MS): 316 m/z [M+H] ⁺ ;

methyl 7-(3-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 - carboxylate (9c):

[0169] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14h) (253 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9c as white solid (225mg, 72%). δ 7.62 (s, 1H), 7.25 (s, 1H), 7.21 (d, 1H), 7.19 (d, 2H), 7.15 (t, 8.3, 7.5 Hz, 1H), 4.05 (t, 6.0, 6.0 Hz, 2H), 3.81 (s, 5H), 3.34 (t, 6.7, 6.7 Hz, 2H), 1.96-1.87 (m, 2H), 1.83-1.75 (m, 2H); Mass (ESI-MS): 316 m/z [M+H] ⁺ ;

methyl 7-(4-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 - carboxylate (9d):

[0170] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14o) (253 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9d as white solid (220mg, 70%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.69 (s, 1H), 7.25 (t, 9.3, 8.3 Hz, 2H), 6.96 (t, 8.6, 8.5 Hz, 2H), 4.05 (t, 6.2, 6.2 Hz, 2H), 3.80 (s, 2H), 3.79 (s, 3H), 3.32 (t, 6.7, 6.7 Hz, 2H), 1.94-1.59 (m, 2H), 1.82-1.77 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ Mass ESI-MS): 316 m/z [M+H] ⁺ ;

methyl 7-(2-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 - carboxylate (9e):

[0171] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14c) (269 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 niL) and extracted with EtOAc (3 x 10 niL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9e as white solid (235mg, 71%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.62 (s, 1H), 7.35 (t, 9.0, 8.3 Hz, 2H), 7.19 (m, 2H), 4.08 (t, J 6.0, 6.7 Hz, 2H), 3.97 (s, 2H), 3.76 (s, 3H), 3.33 (t, J 6.7, 6.7 Hz, 2H), 1.97-1.88 (m, 2H), 1.83-1.75 (m, 2H); ¹³ C NMR (300 MHz, CDCI ₃ ): δ 165.8, 162.6, 153.2, 137.0, 136.5, 134.2, 131.3, 129.3, 127.7, 126.6, 125.2, 107.0, 51.6, 42.7, 34.0, 26.0, 21.3, 18.0; Mass (ESI-MS): 333 m/z [M+2] ⁺ ; HRMS (ESI) m/z Calcd. for C Hi ₇ ON ₂ [M+H] ⁺ , found

methyl 7-(3-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 - carboxylate (9f):

[0172] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14i) (269 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9f as white solid (250mg, 75%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.72 (s, 1H), 7.25 (s, 1H), 7.21-7.16(m, 3H), 4.05 (t, 6.2, 6.4 Hz, 2H), 3.81 (s, 2H), 3.80 (s, 3H), 3.33 (t, 6.7, 6.7 Hz, 2H), 1.94-1.89 (m, 2H), 1.82-1.77 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.2, 162.0, 153.3, 141.2, 136.8, 133.4, 129.1, 128.3, 126.7, 125.8, 125.6, 106.5, 51.2, 42.3, 35.8, 26.2, 20.9, 17.5; Mass (ESI-MS): 333 m/z [M+2] ⁺ ;

methyl 7-(4-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 - carboxylate (9g):

[0173] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14p) (269 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9g as white solid (250mg, 75%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.70 (s, 1H), 7.26-7.21 (m, 4H), 4.04 (t, 6.2, 6.4 Hz, 2H), 3.80 (s, 5H), 3.33 (t, 6.8, 6.7 Hz, 2H), 1.94- 1.88 (m, 2H), 1.81-1.76 (m, 2H). ¹³ C NMR (300 MHz, CDC1 ₃ ): δ Mass (ESI-MS): 333 m/z [M+2] ⁺ ;

methyl 7-(2-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (9h):

[0174] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14d) (313 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 niL) and extracted with EtOAc (3 x 10 niL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9h as white solid (275mg, 73%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.16 (s, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 7.25 (t, 7.3, 7.6 Hz, 1H), 7.09 (t, 7.7, 7.6 Hz, 1H), 4.07 (t, 6.2, 6.2 Hz, 2H), 3.98 (s, 2H), 3.76 (s, 3H), 3.34 (t, J 6.7, 6.8 Hz, 2H), 1.95-1.90 (m, 2H), 1.83-1.77 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ Mass (ESI-MS): 377 m/z [M+2] ⁺ ;

methyl 7-(3-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (9i):

[0175] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14j) (313 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9i as white solid (280mg, 75%). 1H NMR (300 MHz, CDCI3): δ 7.73 (s, 1H), 7.40 (s, 1H), 7.32 (d, 1H), 7.23 (d, 2H), 7.15 (t, 8.3, 7.5 Hz, 1H), 4.05 (t, 6.0, 6.0 Hz, 2H), 3.81 (s, 5H), 3.34 (t, 6.7, 6.7 Hz, 2H), 1.96-1.87 (m, 2H), 1.83-1.75 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.7, 162.5, 153.7, 141.8, 137.2, 131.7, 129.8, 129.2, 127.6, 126.2, 122.3, 107.0, 51.7, 42.8, 36.3, 26.7, 21.3, 18.0; Mass (ESI-MS): 377 m/z [M+2] ⁺ ;

methyl 7-(4-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (9j):

[0176] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14q) (313 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3a as white solid (260mg, 70%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.70 (s, 1H), 7.40 (d, 2H), 7.17 (d, 2H), 4.05 (t, 6.2, 6.4 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 2H), 3.33 (t, 6.7, 6.7 Hz, 2H), 1.93-1.88 (m, 2H), 1.81-1.76 (m, 2H); ¹³ C NMR (300 MHz, CDCI ₃ ): δ Mass (ESI-MS): 377 m/z M+2] ⁺ ;

methyl 7-(2-methoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine- 9- carboxylate (9k):

[0177] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14f) (265 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 niL) and extracted with EtOAc (3 x 10 niL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 9k as white solid (255mg, 78%). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.64 (s, 1H), 7.24 (d, 1H), 7.20 (t, J 9.6, 9.4 Hz, 1H), 6.90 (t, J 8.3, 8.6 Hz, 1H), 6.87 (d, 1H), 4.06 (t, J 6.2, 6.2 Hz, 2H), 3.84 (s, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.31 (t, J 6.7, 6.7 Hz, 2H), 1.93- 1.88 (m, 2H), 1.80- 1.75 (m, 2H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 166.1, 162.8, 157.5, 152.7, 136.7, 130.7, 127.5, 127.3, 126.5, 1 10.3, 107.0, 55.2, 51.6, 42.6, 30.6, 26.6, 21.4, 18.1 ; Mass (ESI-MS : 328 m/z [M+2] ⁺ ;

methyl 7-(2-cyanobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (91):

[0178] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly methyl 2-(piperidin-2-ylidene)acetate (15g) (155 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14u) (260 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 91 as white solid (230mg, 72%). 1H NMR (300 MHz, CDCI ₃ ): δ 7.70 (s, 1H), 7.56 (d, 2H), 7.40 (d, 2H), 4.04 (t. J 6.0, 6.4 Hz. 2H), 3.88 (s, 2H), 3.81 (s, 3H), 3.34 (t, J 6.6, 6.6 Hz, 2H), 1.96- 1.87 (m, 2H), 1.84-1.75 (m, 2H); ¹³ C NMR (300 MHz, CDCI ₃ ): δ 165.6, 162.5, 154.1, 145.2, 137.5, 132.1, 129.6, 125.5, 1 19.0, 109.9, 107.0, 51.8, 42.8, 37.0, 26.7, 21.3, 18.0; Mass (ESI-MS): 323 m/z [M+H] ⁺ .

ethyl 7-benzyl-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9-carboxyla te (10a) :

[0179] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14a) (249 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 10a as white solid (240mg, 77 % yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.69 (s, 1H), 7.29 (d, 4H), 7.22-7.18 (m, 1H), 4.24 (q, 2H), 4.05 (t, 6.2, 6.4 Hz, 2H), 3.85 (s, 2H), 3.32 (t, 6.8, 6.7 Hz, 2H), 1.93-1.88 (m, 2H), 1.81-1.75 (m, 2H), 1.30 (t, 7.0, 7.1 Hz, 3H); Mass (ESI-MS : 312 m/z [M+H] ⁺ .

ethyl 7-(2-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (10b):

[0180] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14b) (267 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained

10b as white solid (260mg, 79 % yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.33 (t, 7 7.5, 7.5 Hz, 1H), 7.23-7.15 (m, 1H), 7.08-6.99 (m, 2H), 4.24 (q, 2H), 4.06 (t, 7 6.2, 6.2 Hz, 2H), 3.87 (s, 2H), 3.32 (t, 7 6.7, 6.6 Hz, 2H), 1.95-1.86 (m, 2H), 1.82-1.74 (m, 2H), 1.30 (t, 7 7.1, 6.9 Hz, 3H); ¹³ C NMR (300 MHz, CDCI3): δ 165.4, 162.6, 159.5, 153.1, 137.1, 131.5, 127.9, 126.2, 125.5, 123.9, 115.2, 107.4, 60.5, 42.7, 29.8, 26.6, 21.4, 18.1 14.1; Mass (ESI-MS): 330 m/z [M+2] ⁺ .

ethyl 7-(3-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate

(10c):

[0181] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14h) (267 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained

10c as white solid (245mg, 75 % yield). 1H NMR (300 MHz, CDCI3): δ 7.72 (s, 1H), 7.27-7.20 (m, 1H), 7.06 (d, 1H), 6.97 (d, 1H), 6.88 (t, 7 8.4, 8.4 Hz, 1H), 4.25 (q, 2H), 4.05 (t, 7 6.2, 6.2 Hz, 2H), 3.84 (s, 2H), 3.34 (t, 7 6.7, 6.6 Hz, 2H), 1.95- 1.87 (m, 2H), 1.83-1.74 (m, 2H), 133 (t, 7 7.1, 6.9 Hz, 3H); ¹³ C NMR (300 MHz, CDCI ₃ ): δ 165.3, 162.6, 153.4, 141.9, 137.3, 129.6, 126.2, 124.5, 115.7, 115.4, 113.1, 112.8, 60.5, 42.7, 36.3, 26.6, 21.3, 18.0, 14.1; Mass (ESI-MS): 330 m/z [M+2] ⁺ .

ethyl 7-(4-fluorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (lOd):

[0182] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14o) (267 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOd as white solid (250mg, 76% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.39 (d, 2H), 7.17 (d, 2H), 4.26 (q, 2H), 4.04 (t, 6.2, 6.2 Hz, 2H), 3.79 (s, 2H), 3.32 (t, 6.7, 6.7 Hz, 2H), 1.93-1.88 (m, 2H), 1.81-1.76 (m, 2H), 1.33 (t, 7.1, 7.1 Hz, 2H); Mass (ESI-MS): 330 m/ [M+H] ⁺ .

ethyl 7-(2-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate (lOe):

[0183] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14c) (283 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOe as white solid (240mg, 69 % yield).1H NMR (300 MHz, CDC1 ₃ ): δ 7.65 (s, 1H), 7.38-7.32 (m, 2H), 7.20-7.16 (m, 2H), 4.21 (q, 2H), 4.07 (t, 6.0, 6.7 Hz, 2H), 3.97 (s, 2H), 3.32 (t, 6.7, 6.7 Hz, 2H), 1.96-1.87 (m, 2H), 1.83-1.74 (m, 2H), 1.28 (t, 6.7, 6.7 Hz, 3H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.4, 162.7, 153.1, 137.3, 136.6, 134.3, 131.3, 129.3, 127.7, 126.7, 125.1, 107.4, 60.5, 42.7, 34.0, 26.6, 21.4, 18.0, 14.1; Mass (ESI-MS): 346 m/ [M+H] ⁺ .

ethyl 7-(3-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate

(10f):

[0184] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly (Z)-ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14i) (283 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOf as white solid (250mg, 72 % yield). 1H NMR (300 MHz, CDCI3): δ 7.73 (s, 1H), 7.24-7.15 (m, 5H), 4.27 (q, 2H), 4.04 (t, 6.0, 6.7 Hz, 2H), 3.81 (s, 2H), 3.34 (t, 6.7, 6.0 Hz, 2H), 1.95-1.87 (m, 2H), 1.83-1.74 (m, 2H), 1.33 (t, 6.7, 6.7 Hz, 3H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.4, 162.6, 153.4, 141.5, 137.6, 134.0, 129.5, 128.8, 127.2, 126.3, 126.2, 107.4, 60.6, 42.82, 36.3, 26.7, 21.4, 18.1, 14.2; Mass (ESI-MS): 346 m/z [M+H] ⁺ .

ethyl 7-(4-chlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9 -carboxylate

(10g):

[0185] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly (Z)-ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14p) (283 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 3a as white solid (255mg, 74 % yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.23 (d, 4H), 4.25 (q, 2H), 4.04 (t, 6.0, 6.2 Hz, 2H), 3.80 (s, 2H), 3.32 (t, 6.6, 6.6 Hz, 2H), 1.95-1.86 (m, 2H), 1.83-1.74 (m, 2H), 1.33 (t, 7.1, 7.1 Hz, 3H); Mass (ESI-MS): 346 m/z [M+H] ⁺ .

ethyl-7-(2-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quino lizine-9- carboxylate (lOh):

[0186] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14d) (327 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 niL) and extracted with EtOAc (3 x 10 niL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOh as white solid (310mg, 80% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.65 (s, 1H), 7.56 (d, 1H), 7.32 (d, 1H), 7.25 (t, 7.4 Hz, 1H), 7.09 (t, 7.4 7.7 Hz, 1H), 4.22 (q, 2H), 4.08 (t, 6.7, 5.7 Hz, 2H), 3.98 (s, 2H), 3.33 (t, 6.7, 5.7 Hz, 2H),1.95-1.90 (m, 2H), 1.82-1.77 (m, 2H), 1.28 (t, 7.0, 7.1 Hz, 3H); Mass (ESI-MS): 392 m/z [M+H] ⁺ .

ethyl-7-(3-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quino lizine-9- carboxylate (lOi):

[0187] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14j) (327 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOi as white solid (300mg, 77% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.73 (s, 1H), 7.41 (s, 1H), 7.33 (d, 1H), 7.24 (d, 1H), 7.15 (t, 7.7 Hz, 1H), 4.27 (q, 2H), 4.05 (t, 6.2 Hz, 2H), 3.81 (s, 2H), 3.34 (t, 6.8, 6.7 Hz, 2H), 1.94-1.89 (m, 2H), 1.82-1.77 (m, 2H), 1.34 (t, 7.1 Hz, 3H), Mass ESI-MS): 392 m/z [M+2] ⁺ .

ethyl-7-(4-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinoliz ine-9- carboxylate (lOj):

[0188] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14q) (327 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOj as white solid (305mg, 78% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.40-7.38 (d, 2H), 7.18-7.16 (d, 2H), 4.28-4.24 (q, 2H), 4.05-4.03 (t, 7 6.2, 6.2 Hz, 2H), 3.79 (s, 2H), 3.34-3.31 (t, 7 6.7, 6.7 Hz, 2H), 1.93-1.88 (m, 2H), 1.81-1.76 (m, 2H), 1.35-1.32 (t, 77.1, 7.1 Hz, -MS): 392 m/z [M+2] ⁺ .

ethyl-6-oxo-7-(2-(trifluoromethyl)benzyl)-2,3,4,6-tetrahy dro-lH-quinolizine-9- carboxylate (10k):

[0189] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14e) (316 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained 10k as white solid (260mg, 69% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.65 (s, 1H), 7.38-7.32 (m, 2H), 7.20-7.16 (m, 2H), 4.21 (q, 2H), 4.07 (t, 6.0, 6.7 Hz, 2H), 3.97 (s, 2H), 3.32 (t, 6.7, 6.7 Hz, 2H), 1.96-1.87 (m, 2H), 1.83-1.74 (m, 2H), 1.28 (t, 6.7, 6.7 Hz, 3H); Mass (ESI- ⁺ .

ethyl-6-oxo-7-(3-(trifluoromethyl)benzyl)-2,3,4,6-tetrahy dro-lH-quinolizine-9- carboxylate (101):

[0190] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14k) (316 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained

101 as white solid (245mg, 65% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.72 (s, 1H), 7.27-7.20 (m, 1H), 7.06 (d, 1H), 6.97 (d, 1H), 6.88 (t, 8.4, 8.4 Hz, 1H), 4.25 (q, 2H), 4.05 (t, 6.2, 6.2 Hz, 2H), 3.84 (s, 2H), 3.34 (t, 6.7, 6.6 Hz, 2H), 1.95-1.87 (m, 2H), 1.83-1.74 (m, 2H), 1.33 (t, 7.1, 6.9 Hz, 3H); Mass (ESI-MS): 380 m/z [M+2] ⁺ .

ethyl-6-oxo-7-(4-(trifluoromethyl)benzyl)-2,3,4,6-tetrahy dro-lH-quinolizine-9- carboxylate (10m): [0191] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14r) (316 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained

10m as white solid (235mg, 62% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.75 (s, 1H), 7.54 (d, 2H), 7.41 (d, 2H), 4.27 (q, 2H), 4.05 (t, 6.2, 6.4 Hz, 2H), 3.81 (s, 2H), 3.34 (t, 6.7 Hz, 2H), 1.94-1.89 (m, 2H), 1.82-1.77 (m, 2H), 1.33 (t, 7.0, 7.1 Hz, 2H); Mass (ESI-MS): 380 m/ [M+2] ⁺ .

Ethyl-7-(2-methoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinol izine-9- carboxylate (10η):

[0192] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14f) (278 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained

10η as white solid (275mg, 81% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.68 (s, 1H), 7.25 (d, 1H), 7.28 (d, 1H), 6.92-6.85 (m, 2H), 4.21 (q, 2H), 4.06 (t, 2H), 3.84 (s, 2H), 3.81 (s, 3H), 3.32 (t, 2H), 1.95-1.86 (m, 2H), 1.81-1.73 (m, 2H), 1.30 (t, 3H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.7, 157.5, 152.6, 137.0, 130.7, 126.3, 120.4, 110.2, 107.2, 60.3, 55.1, 42.6, 30.7, 26.6, 21.4, 18.1, 14.1; Mass (ESI-MS): 342 m/z [M+H] ⁺ .

Ethyl-7-(4-cyanobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinoliz ine-9-carboxylate (lOo):

[0193] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly (Z)-ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-HiUman adduct (14u) (273 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOo as white solid (220mg, 65% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.71 (s, 1H), 7.40-7.38 (d, 2H), 7.18-7.16 (d, 2H), 4.28-4.24 (q, 2H), 4.05-4.03 (t, 7 6.2, 6.2 Hz, 2H), 3.79 (s, 2H), 3.34-3.31 (t, 7 6.7, 6.7 Hz, 2H), 1.93-1.88 (m, 2H), 1.81-1.76 (m, 2H), 1.35-1.32 (t, 77.1, 7.1 Hz, -MS): 337 m/z [M+2] ⁺ .

Ethyl-7-(2,4-dichlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-qui nolizine-9- carboxylate (lOp): [0194] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 niL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14x) (316 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOp as white solid (275mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.73 (s, 1H), 7.41 (s, 1H), 7.33 (d, 1H), 7.24 (d, 1H), 7.15 (t, 7 7.7 Hz, 1H), 4.27 (q, 2H), 4.05 (t, 7 6.2 Hz, 2H), 3.81 (s, 2H), 3.34 (t, 7 6.8, 6.7 Hz, 2H), 1.94-1.89 (m, 2H), 1.82-1.77 (m, 2H), 1.34 (t, 77.1 Hz, 3H), Mass (ESI-MS): 381 m/z [M+H] ⁺ .

ethyl-7-(3,4-dichlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH- quinolizine-9- carboxylate (lOq):

[0195] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14z) (316 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOq as white solid (275mg, 72% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 7.75 (s, 1H), 7.34 (d, 1H), 7.35 (s, 1H), 7.15 (d, 1H), 4.28 (q, 2H), 4.04 (t, 7 6.7, 6.0 Hz, 2H), 3.78 (s, 2H), 3.34 (t, J 6.7, 6.0 Hz, 2H), 1.96-1.87 (m, 2H), 1.83-1.75 (m, 2H), 1.34 (t, J 6.7, 7.5 Hz, 3H); ¹³ C NMR (300 MHz, CDC1 ₃ ): δ 165.3, 162.5, 153.7, 139.8, 137.4, 132.1, 130.6, 130.1, 128.4, 125.8, 107.4, 60.7, 42.7, 36.0, 26.7, 21.4, 18.1, 14.2; Mass (ESI-MS): 382 m/z ⁺ ;

ethyl-7-(2,5-dimethoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH -quinolizine-9- carboxylate (lOr):

[0196] To a well stirred solution of NaH (60% in paraffin oil, 115 mg, 3 mmol) in dry THF (5 mL) was added slowly ethyl 2-(piperidin-2-ylidene)acetate (15h) (170 mg, 1 mmol) in dry THF (5 mL) at 0 °C under argon atmosphere and stirred for 15 min. Then acetylated Baylis-Hillman adduct (14b ¹ ) (308 mg, 1 mmol) in dry THF (5 mL) was added slowly and allowed to stir at ambient temperature for 3 h and the reaction was monitored by TLC. After completion, solvent was removed under reduced pressure and the residue was diluted with ice cold water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , evaporated in vacuo and purified by column chromatography using silica gel with 30% EtOAc in hexane as eluent to obtained lOq as white solid (270mg, 73% yield). 1H NMR (300 MHz, CDC1 ₃ ): δ 1H NMR (300 MHz, CDC1 ₃ ): δ 7.73 (s, 1H), 7.24-7.15 (m, 5H), 4.27 (q, 2H), 4.04 (t, 6.0, 6.7 Hz, 2H), 3.81 (s, 2H), 3.34 (t, 6.7, 6.0 Hz, 2H), 1.95- 1.87 (m, 2H), 1.83-1.74 (m, 2H), 1.33 (t, 6.7, 6.7 Hz, 3H); Mass (ESI-MS): 372 m/z [M+H] ⁺ .

120

121

ı22









 PHARMACOLOGY

[0197] Milrinone, a known PDE3 inhibitor, drug has been used as standard for comparison with the inhibitory activity of synthesized new analogues 3a-a ^∑ , 4a-m, 5a-z, 6a-j, 7a-x, 8a- v, 9a-l, lOa-r. Milrinone is a nonsympathomimetic and nonglycosidic drug that increases myocardial contraction. It increases myocardial cyclic adenosine monophosphate (c-AMP) concentration by inhibition of cardiac phosphodiesterase3A (PDE3A) enzymes and increases intracellular calcium level, thereby increasing myocardial contractility (Weishaar RE, Quade MM, Schenden JA, Evans DB. Relationshipbetween inhibition of cardiac muscle phosphodiesterase,changes in cyclic nucleotide levels, and contractile response forCl-914 and other novel cardiotonics. (J Cyclic Nucleotide ProteinPhosphor Res 1985; 10:551-64).A11 PDE3A inhibitors has beneficial effects on the acute treatment of congestive heart failure (Smith CJ et al,Circulation. 1997 Nov 4;96(9):3116-23.) and offers an important therapeutic option for left ventricular failure in patients undergoing cardiac surgery because of its unique inodilator effects. PDE3A enzymes are present not only in cardiac muscle but it also present in platelets. In platelets, c- AMP generated from adenosine triphosphate by adenyl cyclase serves as an intracellular second messenger to inhibit the platelet activation at numerous steps (Campbell FW, Addonizo VP Jr. Platelet function alterationsduring cardiac surgery. In: Ellison N, Jobes DR, ed. Effectivehemostasis in cardiac surgery. Philadelphia: WB Saunders, 1988:93-5). Since abnormal bleeding after cardiopulmonary bypass (CPB) is most often due to an acute acquired defect in platelets (Harker L. Bleeding after cardiopulmonary bypass. N Engl J Medl986;314: 1446-8), preservation of platelet function is critical to maintaining normal hemostasis in patients undergoing cardiac surgery.

The commercially utility of the compounds according to the invention have valuable pharmacological properties. As selective inhibitors of type 3 of cyclic nucleotide phosphodiesterase3A (PDE3A), they are suitable for heart failure therapy as well as anti-thrombotic (platelet aggregation-inhibiting) therapy.

BIOLOGICAL INVESTIGATIONS

[0198] PDE3A inhibition assay was performed a BIOMOL GREEN™ Quantizyme Assay System (catalogue No.BML-AK800-0001).The PDE3A enzyme purchased from BPS's PDE3A, Cat. # 60032. We pepares sample containing PDE, substrate and test compound dissolved in assay buffer (BML-KI181) according PDE assay kit. Siredserial dilutions of PDE3A at 37°C for 20 min performed to know working concentration. Quantified by 5'- nucleotidase cleaving the 5' -AMP product and releasing the phosphate group which is detected by Malachite Green Reagent. In 96 well plate (Prod. No. BML-KI101), we added supernatant having PDE3 enzyme, PDE3 assay buffer, cAMP substrate, 5 'nucleotidase and test or standard compound and incubated for lhour at 37° C. The reaction was arrested by the addition ΙΟΟμΙ BIOMOL GREEN reagent incubated in room temp for 20 min. The green color developed was measured at 620 nm.

METHODOLOGY

[0199] The in vitro Phosphodiestarase3A (PDE3A)inhibitory activity of compounds 3a-a ^∑ , 4a-m, 5a-z, 6a-j, 7a-x, 8a-v, 9a-l, lOa-r.were measured using a BIOMOL GREEN™ Quantizyme Assay System (catalogue No.BML-AK800-0001).The basic principle for this assay is the cleavage of c-AMP or c-GMP into their respective nucleotide by a cyclic nucleotide phosphodiesterase. The nucleotide(AMP or GMP) released is further cleaved into the nucleoside and phosphate by the enzyme 5' - nucleotidase. The extent of phosphatereleased is directly proportional to the PDE activity. In this screening method, the released phosphate by the enzymatic cleavage is quantified using BIOMOL GREEN reagent in a modified malachite green assay. The resulting green colour with max at 620 nm is directly proportional to the released phosphate and then PDE activity. All the compounds tested in the desired concentrations did not show any significant absorbance at 620 nm under control conditions. Milrinone, a known PDE3A inhibitor drug has been used as a standard compound for comparison with the inhibitory activity of newly synthesized analogues. The concentration with 50% PDE3A activity (IC ₅₀ ) of all tested compounds was calculated from dose response curves. IC ₅₀ values of all compounds are summarized in Table 1.

PDE3A inhibitory activity (IC50) of 2-pyridone compounds.

S.No Compound IC50

Name

1 4e 5350nM

2 5e 3582nM

3 4j 42.9 InM

4 3n 1847nM

5 5m 53.63nM

6 3q 1187nM

7 7o 3723nM

8 5r 1698nM

9 3t 5814nM

10 3j 13930nM

11 5y 8586nM

12 3g 1247nM

13 5g 1890nM

14 5p 9019nM

15 7i 9758nM 16 5u 9245nM

17 Milrinone 296.38nM

SIGNIFICANCE OF THE WORK CARRIED OUT

[0200] The novel 2-pyridone based analogues have been synthesized, exhibited potent phosphodiesterase3A (PDE3A) inbition activity.

ADVANTAGES OF THE INVENTION

1. The present invention provides the synthesis of new 2-pyridoneanalogues useful as phosphodiesterase3A inhibitory agents.

2. The present invention provides a process for the preparation of novel 2- pyridone compounds.

3. It is another advantage that Baylis-Hillman adducts used as synthons for the synthesis of targeted compouns.

4. It is another advantage that the compounds are useful as cardiotonics.

5. It is another advantage that bases utilised for the synthons are simple and base are commercially available.

6. It is another advantage that the methods used for the synthesis of compounds are novel.