WO2017072796A1 - 2-pyridone based compounds useful as potential phosphodiesterase3a (pde3a)inhibitors and a process for the preparation thereof - Google Patents

2-pyridone based compounds useful as potential phosphodiesterase3a (pde3a)inhibitors and a process for the preparation thereof Download PDF

Info

Publication number
WO2017072796A1
WO2017072796A1 PCT/IN2016/050371 IN2016050371W WO2017072796A1 WO 2017072796 A1 WO2017072796 A1 WO 2017072796A1 IN 2016050371 W IN2016050371 W IN 2016050371W WO 2017072796 A1 WO2017072796 A1 WO 2017072796A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
methyl
carboxylate
dihydropyridine
carbonitrile
Prior art date
Application number
PCT/IN2016/050371
Other languages
French (fr)
Inventor
G. Jagadeesh KUMAR
B. Mahendar
M. Saidulu
S K Banerjee
V. Jayathirtha RAO
Original Assignee
Council Of Scientific & Industrial Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Council Of Scientific & Industrial Research filed Critical Council Of Scientific & Industrial Research
Publication of WO2017072796A1 publication Critical patent/WO2017072796A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention related to a series of 2-pyridone compounds having general Formula A.
  • 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).
  • PDE3A potential phosphodiesterase3A
  • R alkyl, substituted phenyl, napthyl, furonyl
  • 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.
  • Heart failure is some time called congestive heart failure (CHF) a severe public health problem worldwide.
  • CHF congestive heart failure
  • 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).
  • 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.
  • PDE phosphodiesterase
  • amrinone and milrinone 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).
  • 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.
  • 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).
  • cyclic nucleotides regulate multiple biological processes such as cell growth and adhesion, energy homeostasis, neuronal signaling, and muscle relaxation.
  • altered cyclic nucleotide signaling has been observed in a number of pathophysiological conditions, including cancer (Alexandra et al, 2014).
  • 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).
  • 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).
  • 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.
  • PK-A cAMP-dependent protein kinase
  • PK-G cGMP-dependent protein kinase
  • 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.
  • 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
  • PDE3B is mainly associated with adipocytes, hepatocytes and spermatocytes.
  • PDE3A is especially expressed in heart and platelets.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • R alkyl, substituted phenyl, napthyl, furonyl
  • novel2-pyridone based analogues are represented by the following compounds of general Formula 3a-a ⁇ ,
  • 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:
  • 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)
  • triethyl amine have also been employed to perform the Baylis-Hillman reaction in certain cases.
  • 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- phen
  • Figure 1 PDE3A inhibitory activity of 2 pyridone compounds (100 ⁇ in DMSO).
  • Standard Drug Milrinone (100 ⁇ in DMSO). (Compounds 3a-5z).
  • Figure 2 PDE3A inhibitory activity of 2 pyridone compounds (100 ⁇ in DMSO).
  • Standard Drug Milrinone (100 ⁇ in DMSO). (Compounds 6e-10r).
  • 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 ⁇ ).
  • 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.
  • PDE3A enzymes are present not only in cardiac muscle but it also present 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).
  • the commercially utility of the compounds according to the invention have valuable pharmacological properties.
  • PDE3A cyclic nucleotide phosphodiesterase3A
  • they are suitable for heart failure therapy as well as anti-thrombotic (platelet aggregation-inhibiting) therapy.
  • PDE3A inhibition assay was performed a BIOMOL GREENTM Quantizyme Assay System (catalogue No.BML-AK800-0001).
  • the PDE3A enzyme purchased from BPS's PDE3A, Cat. # 60032.
  • 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.
  • 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 ⁇ BIOMOL GREEN reagent incubated in room temp for 20 min. The green color developed was measured at 620 nm.
  • 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.
  • 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.
  • the present invention provides the synthesis of new 2-pyridoneanalogues useful as phosphodiesterase3A inhibitory agents.
  • the present invention provides a process for the preparation of novel 2- pyridone compounds.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Formula A wherein X = COOCH3, COOC2H5, CN Y = Methyl, Phenyl R = alkyl, substituted phenyl, napthyl, furonyl, thiophenyl, substituted quinolinyl The present invention related to compounds of general FormulaA. The invention provides the synthesis of 2-pyridones useful as potential cardio tonic agents and a process for the preparation thereof.

Description

2-PYRIDONE BASED COMPOUNDS USEFUL AS POTENTIAL
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).
Figure imgf000002_0001
Formula A
Wherein X = COOCH3, COOC2H5, 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.
Figure imgf000002_0002
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.
Figure imgf000004_0001
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-methyl-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.
Figure imgf000009_0001
Formula A
Wherein X = COOCH3, COOC2H5, 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.
Figure imgf000010_0001
Figure imgf000010_0002
7 a-x 8 a-v 9 a-l 10 a-r
[0035] In yet another embodiment the 2-pyridone (3a-z, a1, 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-carboxylate (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 (3a1)
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-carboxylate (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-carboxylate (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-dihydropyridine-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-carboxylate (4i) ethyl 2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3-carboxylate (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-carbonitrile (5b)
5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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-carbonitrile (5e)
2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (5f) 2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (5g)
2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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-carbonitrile (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-dihydropyridine-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-carboxylate (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-carboxylate (6d) ethyl 5-(3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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-carboxylate (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-carbonitrile (7a)
5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (7b)
5-(4-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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-carbonitrile (7e)
6- oxo-2-phenyl-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (7f)
6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (7g)
6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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-carbonitrile (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-carbonitrile (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-carbonitrile (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-dihydropyridine-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-carboxylate (8a) methyl 6-(3-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8b) methyl 6-(4-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8c) methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8d): methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8e): methyl 6-(4-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8f): methyl 6-(2-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8g) methyl 6-(3-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8h) methyl 6-(4-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8i) methyl 5-oxo-6-(3-(trifluoromethyl)benzyl)-l,2,3,5-tetrahydroindolizine-8- carboxylate (8j):
methyl 6-(2-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8k): methyl 6-(3-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (81): methyl 6-(4-cyanobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8m): methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8n): methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8o): methyl 6-(4-isopropylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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-tetrahydroindolizine-8- carboxylate (8v):
methyl 7-benzyl-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9-carboxylate (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-quinolizine-9-carboxylate (10p):
ethyl 7-(3,4-dichlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9-carboxylate (10q):
ethyl 7-(2,5-dimethoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (lOr):
[0036] The present invention further provides a process for preparation of novel pyridone based analogues of Formula 3a-z, a1, 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,N1,N1-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/TiCl4, TiCl4,trialkylphosphines, PvhH(PPh3)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, Ac20/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, a1, 4a-m, 5a-z, 6a-j, 7a-x, 8a-v, 9a-l, lOa-r).
Figure imgf000019_0001
11 a-z, a^k1 12a 13 a-z, a^k1 14 a-z, a^k1
Z = electron withdrawing group
Figure imgf000019_0002
Figure imgf000019_0003
15a 15b 15c 15d
Figure imgf000019_0004
Figure imgf000019_0005
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, a1, 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 Na2S04, 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
Figure imgf000021_0001
ll a-z, a^k1 12a 13 a-z, a^k1 14 a-z, a t1
Z = electron withdrawing group
Scheme -2
Figure imgf000022_0001
15h 21 10a-r General procedure for the preparation Baylis-Hillman adducts (13a-z, aI-eI):
[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 Na2S04, 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. CuS04 solution until pyridine removed, then the layers were sepaerated and dried over Na2S04i. 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
Figure imgf000023_0001
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 Na2S04, 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, CDC13): δ 7.83 (s, 1H), 7.34-6.98 (m, 4H), 3.85 (s, 2H), 3.81 (s, 3H), 2.66 (s, 3H); 13C 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 C15H15NO3F: 276.1030; found: 276.1020.
Figure imgf000024_0001
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 Na2S04, 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, CDC13): δ 7.83 (s, 1H), 7.26-6.85 (m, 4H),3.82 (s, 3H), 3.81 (s, 2H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCI3): 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 C15H15NO3F: 276.1030; found: 276.1021.
Figure imgf000025_0001
methyl 5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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);13C 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]+.
Figure imgf000025_0002
methyl 5-(2-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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 Ci5Hi4BrN03: 336.02298 [M+H]+, found: 336.02242
Figure imgf000026_0001
5-(3-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate
[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 Na2S04, 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, CDC13): 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]+.
Figure imgf000027_0001
methyl2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridine- 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 Na2S04, 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, CDC13): 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); 13C 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.
Figure imgf000027_0002
methyl-2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine- 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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000028_0001
methyl 2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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);13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000028_0002
methyl 5-(2-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate
(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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000029_0001
methyl 5-(3-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate
(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 Na2S04, 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); 13C NMR (75 MHz, CDC13): 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 +.
Figure imgf000030_0001
methyl 5-(4-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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 Ci6Hi7N04Na: 310.1049[M+H]+; found: 310.
Figure imgf000030_0002
methyl 2-methyl-5-(3-nitrobenzyl)-6-oxo-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 Ci4H15N205: 303.09755 M+H]+, found: 303.09750.
Figure imgf000031_0001
methyl 5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 5Mass (ESI-MS): 283 /z [M+H]+.
Figure imgf000032_0001
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 Na2S04, 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, CDC13): 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]+;
Figure imgf000032_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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/z286 [M+H]+.
Figure imgf000033_0001
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 Na2S04, 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, CDC13): ): 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); 13C NMR (75 MHz, CDC13): 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/z300 [M+H]+.
Figure imgf000033_0002
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 Na2S04, 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, CDC13): δ δ 7.68 (s, 1H), 7.27-7.04 (m, 4H), 3.81 (s, 2H),3.72 (s, 2H), 2.57 (s, 2H).13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000034_0001
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 Na2S04, 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, CDC13): 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]+;
Figure imgf000035_0001
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 Na2S04, 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, CDC13): 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]+;
Figure imgf000035_0002
Methyl-5-(2,5-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-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 (14b1) (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 +.
Figure imgf000036_0001
Methyl-5-(3,4-dimethoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-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 (14a1) (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000036_0002
methyl 5-(furan-2-ylmethyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate
(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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000037_0001
methyl2-methyl-6-oxo-5-(thiophen-2-ylmethyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000038_0001
Methyl-2-methyl-5-(naphthalen-l-ylmethyl)-6-oxo-l,6-dihydropyridine-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 Na2S04, 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); 13C NMR (75 MHz, CDC13): 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. forCi9Hi7N03: 308.12812 [M+H]+, found:
308.12796
Figure imgf000038_0002
methyl-2-methyl-5-(naphthalen-2-ylmethyl)-6-oxo-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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. forCi9Hi7N03: 308.12634 [M+H]+, found308.12638.
e
Figure imgf000039_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 Ci9Hi8N204: 339.13393 [M+H]+, found: 339.13376.
Figure imgf000040_0001
methyl 5-hexyl-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (3a1) :
[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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000040_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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/z290 [M+H]+; HRMS (ESI): m/z [M+H]+ calculated for Ci6Hi6N03FNa: 312.1006; found: 312.0993.
Figure imgf000041_0001
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 Na2S04, 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, CDC13): 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); 13C 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/z290 [M+H]+; HRMS (ESI): m/z [M+H]+ calculated for Ci6Hi6N03F:
Figure imgf000042_0001
ethyl 5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000042_0002
5-(2-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate [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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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/z350 [M+H]+.
Figure imgf000043_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000044_0001
ethyl 2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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]+.
Figure imgf000044_0002
ethyl 2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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/ +.
Figure imgf000045_0001
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 Na2S04, 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, CDC13): 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); 1JC NMR (75 MHz, CDC13): 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]+.
Figure imgf000046_0001
ethyl 5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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);13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000046_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000047_0001
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 Na2S04, 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, CDC13): 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). 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000048_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000048_0002
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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000049_0001
5-(2-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile(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 Na2S04, 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, CDC13): δ 7.29-7.02 (m, 5H), 3.82 (s, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDC13): 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 Ci8H20NO3: 243.0928; found: 243.0919.
Figure imgf000050_0001
5-(3-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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);13C 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]+.
Figure imgf000050_0002
5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): δ Mass (ESI-MS):243m/z [M+H]+;
Figure imgf000051_0001
5-(2-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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);13C 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]+.
Figure imgf000051_0002
5-(3-bromobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile(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 Na2S04, 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, CDC13): δ 7.41-7.15 (m, 5H), 3.75 (s, 2H), 2.53 (s, 3H); 13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000052_0001
2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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); 13C 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]+.
Figure imgf000053_0001
2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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);13C 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]+.
Figure imgf000053_0002
2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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);13C 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]+;
Figure imgf000054_0001
5-(2-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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);13C 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]+.
Figure imgf000054_0002
5-(3-methoxybenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000055_0001
2-methyl-5-(3-nitrobenzyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 Ci4HnN303: 279.15774 M+H]+, found: 279.15883.
Figure imgf000056_0001
5-(4-cyanobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000056_0002
2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): 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]+;
Figure imgf000057_0001
5-(4-ethylbenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile(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 Na2S04, 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/z253
[M+H]+.
Figure imgf000057_0002
5-(4-isopropylbenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile(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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 +;
Figure imgf000058_0001
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 Na2S04, 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, CDC13): δ 7.42 (d, 2H), 7.30 (t, 1H), 6.45(s, 1H), 4.04(s, 2H), 2.44(s, 3H); 13C NMR (75 MHz, CDC13):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]+;
Figure imgf000058_0002
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 Na2S04, 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, CDC13): 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) 13C NMR (300 MHz, CDC13):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]+;
Figure imgf000059_0001
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 (14b1) (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000060_0001
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 (14a1) (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 Na2S04, 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);13C NMR (75 MHz, CDCI3): 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]+.
Figure imgf000060_0002
5-(furan-2-ylmethyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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 (14c1) (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000061_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): 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 Ci8Hi4N20: 275.11789 [M+H]+, found: 275.11758.
Figure imgf000062_0001
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 Na2S04, 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); 13C NMR (75 MHz, CDC13): 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. forCi8Hi4N20: 275.11613 [M+H]+, found275.11
Figure imgf000062_0002
5-((2-methoxyquinolin-3-yl)methyl)-2-methyl-6-oxo-l,6-dihydropyridine- 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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 Ci8Hi5N302: 306.12370 [M+H]+, found: 306.12363.
Figure imgf000063_0001
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(14h1)(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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 Ci3Hi8N20: 219.14919 [M+H]+, found: 219.14906.
Figure imgf000064_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 Ci4H20N2O: 233.16484 [M+H]+, found: 233.16479
Figure imgf000064_0002
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 Na2S04, 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, CDC13): 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]+.
Figure imgf000065_0001
ethyl 5-(2-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000066_0001
ethyl 5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000066_0002
ethyl 5-(4-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000067_0001
ethyl 5-(2-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000068_0001
ethyl 5-(3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000068_0002
ethyl 6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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]+;
Figure imgf000069_0001
ethyl 6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000070_0001
ethyl 5-(4-cyanobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000070_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000071_0001
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 Na2S04, 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);13C NMR (75 MHz, CDC13): 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]+;
Figure imgf000072_0001
5-(2-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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), 13C NMR (75 MHz, CDCI3): δ Mass (ESI-MS : 305 m/z [M+H]+.
Figure imgf000072_0002
5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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): +.
Figure imgf000073_0001
5-(4-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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. forCi9Hi3FN20: 305.10622 [M+H]+, found 305.10604.
Figure imgf000073_0002
5-(2-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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. forCi9Hi3BrN20: 365.02840 [M+H]+, found: 365.02843
Figure imgf000074_0001
5-(3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000075_0001
6-oxo-2-phenyl-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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. forC20Hi3F3N2O: 355.10527 [M+H]+, found: 355.10481
Figure imgf000075_0002
6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000076_0001
6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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 Na2S04, 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]+.
Figure imgf000077_0001
5-(2-methoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13): 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]+.
Figure imgf000077_0002
5-(3-methoxybenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDCI3): 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 +.
Figure imgf000078_0001
5-(3-nitrobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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); 13C NMR (75 MHz, CDC13):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]+.
Figure imgf000078_0002
5-(4-cyanobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13):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]+.
Figure imgf000079_0001
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 Na2S04, 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, CDC13): 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]+.
Figure imgf000080_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13):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]+.
Figure imgf000080_0002
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 (14b1) (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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13):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]+.
Figure imgf000081_0001
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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDC13):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 +.
Figure imgf000081_0002
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 Na2S04, 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, CDC13): 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);13C NMR (75 MHz, CDCl3):5Mass (ESI-MS): 288 m/z [M+H]+.
Figure imgf000082_0001
5-(furan-2-ylmethyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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 (14c1) (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000083_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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 C23Hi6N20: 337.133 +, found: 337.13324
Figure imgf000083_0002
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 Na2S04, 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, CDC13): 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), 13C NMR (75 MHz, CDC13): 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. forC23Hi6N20: 337.13167[M+H]+, found337.13166.
Figure imgf000084_0001
5-((2-methoxyquinolin-3-yl)methyl)-6-oxo-2-phenyl-l,6-dihydropyridine-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 Na2S04, 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, CDC13): 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); 13C NMR (75 MHz, CDC13): 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. forC23H17N302: 368.13935 [M+H]+, found: 368
Figure imgf000085_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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 Ci8H20N2O: 281.16484 [M+H]+, found: 281.16476.
Figure imgf000085_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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 Ci9H22N20: 295.18049 [M+H]+, found: 295.18002.
Figure imgf000086_0001
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 Na2S04, 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 +.
Figure imgf000086_0002
methyl 6-(2-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000087_0001
methyl 6-(3-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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]+;
Figure imgf000088_0001
methyl 6-(4-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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]+;
Figure imgf000088_0002
methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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]+;
Figure imgf000089_0001
methyl 6-(3-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate
(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 Na2S04, 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, CDC13): 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]+.
Figure imgf000090_0001
methyl 6-(4-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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]+;
Figure imgf000090_0002
methyl 6-(2-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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+]+;
Figure imgf000091_0001
methyl 6-(3-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate
(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 Na2S04, 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, CDC13): 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+]+;
Figure imgf000091_0002
methyl 6-(4-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate
(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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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 +;
Figure imgf000092_0001
methyl 5-oxo-6-(3-(trifluoromethyl)benzyl)-l,2,3,5-tetrahydroindolizine-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000093_0001
methyl 6-(2-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+.
Figure imgf000093_0002
methyl 6-(3-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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+ +;.
Figure imgf000094_0001
methyl 6-(4-cyanobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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); 13C NMR (300 MHz, CDC13): 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]+;
Figure imgf000095_0001
methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+;
Figure imgf000095_0002
6-(4-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate [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 Na2S04, 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, CDC13): 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]+.
Figure imgf000096_0001
methyl 6-(4-isopropylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000097_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+.
Figure imgf000097_0002
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 Na2S04, 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, CDC13): 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]+;
Figure imgf000098_0001
Methyl-6-(3,4-dimethoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-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 (14a1) (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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+;
Figure imgf000099_0001
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 Na2S04, 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]+.
Figure imgf000099_0002
Methyl-6-(naphthalen-2-ylmethyl)-5-oxo-l,2,3,5-tetrahydroindolizine-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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+;
Figure imgf000100_0001
Methyl-6-((2-chloroquinolin-3-yl)methyl)-5-oxo-l,2,3,5-tetrahydroindolizine-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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+.
Figure imgf000101_0001
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 Na2S04, 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, CDC13): 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]+.
Figure imgf000101_0002
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 Na2S04, 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, CDC13): 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); 13C 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]+;
Figure imgf000102_0001
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 Na2S04, 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]+;
Figure imgf000103_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): δ Mass ESI-MS): 316 m/z [M+H]+;
Figure imgf000103_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDCI3): 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 Hi7ON2 [M+H]+, found
Figure imgf000104_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+;
Figure imgf000105_0001
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 Na2S04, 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, CDC13): 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). 13C NMR (300 MHz, CDC13): δ Mass (ESI-MS): 333 m/z [M+2]+;
Figure imgf000105_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): δ Mass (ESI-MS): 377 m/z [M+2]+;
Figure imgf000106_0001
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 Na2S04, 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); 13C NMR (300 MHz, CDC13): 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]+;
Figure imgf000107_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDCI3): δ Mass (ESI-MS): 377 m/z M+2]+;
Figure imgf000107_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+;
Figure imgf000108_0001
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 Na2S04, 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, CDCI3): 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); 13C NMR (300 MHz, CDCI3): 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]+.
Figure imgf000109_0001
ethyl 7-benzyl-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9-carboxylate (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 Na2S04, 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, CDC13): 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]+.
Figure imgf000109_0002
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 Na2S04, 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, CDC13): 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); 13C 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]+.
Figure imgf000110_0001
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 Na2S04, 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); 13C NMR (300 MHz, CDCI3): 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]+.
Figure imgf000111_0001
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 Na2S04, 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, CDC13): 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]+.
Figure imgf000111_0002
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+.
Figure imgf000112_0001
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 Na2S04, 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); 13C NMR (300 MHz, CDC13): 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]+.
Figure imgf000113_0001
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 Na2S04, 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, CDC13): 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]+.
Figure imgf000113_0002
ethyl-7-(2-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000114_0001
ethyl-7-(3-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000114_0002
ethyl-7-(4-bromobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000115_0001
ethyl-6-oxo-7-(2-(trifluoromethyl)benzyl)-2,3,4,6-tetrahydro-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 Na2S04, 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, CDC13): 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- +.
Figure imgf000116_0001
ethyl-6-oxo-7-(3-(trifluoromethyl)benzyl)-2,3,4,6-tetrahydro-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000116_0002
ethyl-6-oxo-7-(4-(trifluoromethyl)benzyl)-2,3,4,6-tetrahydro-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000117_0001
Ethyl-7-(2-methoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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]+.
Figure imgf000118_0001
Ethyl-7-(4-cyanobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000118_0002
Ethyl-7-(2,4-dichlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-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 Na2S04, 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, CDC13): 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]+.
Figure imgf000119_0001
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 Na2S04, 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, CDC13): 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); 13C NMR (300 MHz, CDC13): 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 +;
Figure imgf000120_0001
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 (14b1) (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 Na2S04, 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, CDC13): δ 1H NMR (300 MHz, CDC13): 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]+.
Figure imgf000121_0001
120
Figure imgf000122_0001
121
Figure imgf000123_0001
ı22
Figure imgf000124_0001

Figure imgf000125_0001

Figure imgf000126_0001

Figure imgf000127_0001

Figure imgf000128_0001
 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 (IC50) of all tested compounds was calculated from dose response curves. IC50 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.

Claims

I/We Claim
1. 2-pyridone skeleton based compounds having the general Formula A.
Figure imgf000133_0001
Formula A
Wherein X = COOCH3, COOC2H5, CN
Y = Methyl, Phenyl
R = alkyl, substituted phenyl, napthyl, furonyl,
thiophenyl, substituted quinolinyl
2. A process for the preparation of 2-pyridone skeleton based compounds having the Formula A,
Figure imgf000133_0002
Formula A
Wherein X = COOCH3, COOC2H5, CN
Y = Methyl, Phenyl
R = alkyl, substituted phenyl, napthyl, furonyl,
thiophenyl, substituted quinolinyl
said process comprising steps of:
i) treating precursor substituted benzaldehydes(lla-z, a∑-k∑) with activated olefine (12a) in the presence of l,4-diazabicyclo[2.2.2]octane (DABCO) to obtain Bayls-Hillman adducts (13a-z, a∑-k∑), and subsequent formation of acetylated Baylis-Hillman adducts (14 a-z, a∑-k∑) by using pyridine and Ac20/AcCl;
Figure imgf000134_0001
11 a-z, a^k1 12a 13 a-z, a^k1 14 a-z, a^k1
Z = electron withdrawing group
Figure imgf000134_0002
Figure imgf000134_0003
15a 15b 15c 15d
Figure imgf000134_0004
15e 15f 15g 15h eacting the acetylated Baylis-HiUman adducts (14a-z, a∑-k∑) with eneamino esters and nitriles (15a-h) in presence of a base and solvent to obtain corresponding 2-pyridones of Formula (3a-a∑, 4a-m, 5a-z, 6a -j, 7a-x, 8a- v, 9a-l, 10a-k).. compounds3. The 2-pyridone based compounds as claimed in claim 1, wherein the Formula A is represented by the following compounds of generalFormula 3a-a∑, 4a- m 5a-z, 6a-j, 7a-x 8a-v, 9a-l, lOa-r.
Figure imgf000135_0001
7 a-x 8 a-v 9 a-l 10 a-r
4. A 2-pyridone based compound as claimed in claim 1, selected from the group consisting of
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-carboxylate (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 22-methyl-5-(naphthalen- 1 -ylmethyl)-6-oxo- 1 ,6-dihydropyridine-3- carboxylate (3x)
methyl 2 2-methyl-5-(naphthalen-2-ylmethyl)-6-oxo-l,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 (3a1)
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-carboxylate (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-carboxylate (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-dihydropyridine-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-carboxylate (4i) ethyl 2-methyl-5-(3-methylbenzyl)-6-oxo-l,6-dihydropyridine-3-carboxylate (4j) ethyl 5-(4-isopropylbenzyl)-2-methyl-6-oxo- 1 ,6-dihydropyridine-3-carboxylate
(4k)
5-(2,4-dichlorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carboxylate
(41)
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-f uorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (5b)
5-(4-fluorobenzyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbonitrile (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-carbonitrile (5e) 2-methyl-6-oxo-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (5f)
2-methyl-6-oxo-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (5g)
2-methyl-6-oxo-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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-carbonitrile (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-dihydropyridine-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-carboxylate (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-carboxylate (6d) ethyl 5-(3-bromobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carboxylate (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-carboxylate (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-carbonitrile (7a)
5-(3-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (7b)
5-(4-fluorobenzyl)-6-oxo-2-phenyl-l,6-dihydropyridine-3-carbonitrile (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-carbonitrile (7e)
6- oxo-2-phenyl-5-(2-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (7f)
6-oxo-2-phenyl-5-(3-(trifluoromethyl)benzyl)-l,6-dihydropyridine-3-carbonitrile (7g)
6-oxo-2-phenyl-5-(4-(trifluoromethyl)benzyl)-l,6-dihydropyridine-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-carbonitrile (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-carbonitrile (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-carbonitrile (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-dihydropyridine-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-carboxylate (8a) methyl 6-(3-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8b) methyl 6-(4-fluorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8c) methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8d): methyl 6-(2-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8e): methyl 6-(4-chlorobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8f): methyl 6-(2-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8g) methyl 6-(3-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8h) methyl 6-(4-bromobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8i) methyl 5-oxo-6-(3-(trifluoromethyl)benzyl)-l,2,3,5-tetrahydroindolizine-8- carboxylate (8j):
methyl 6-(2-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8k): methyl 6-(3-methoxybenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (81): methyl 6-(4-cyanobenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8m): methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8n): methyl 6-(2-methylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (8o): methyl 6-(4-isopropylbenzyl)-5-oxo-l,2,3,5-tetrahydroindolizine-8-carboxylate (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-tetrahydroindolizine-8- carboxylate (8v):
methyl 7-benzyl-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9-carboxylate (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-quinolizine-9-carboxylate (10p):
ethyl 7-(3,4-dichlorobenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9-carboxylate (10q):
ethyl 7-(2,5-dimethoxybenzyl)-6-oxo-2,3,4,6-tetrahydro-lH-quinolizine-9- carboxylate (lOr):
5. The process as claimed in claim 2 wherein said base is selected from the group consisting of NaH(100%), NaH(60%), NaOMe, NaOEt, and i-BuOK.
6. The process as claimed in claim 2, wherein the solvents is selected from the group consisting of tetrahydrofuran, acetonitrile, dimethylformamide.
7. The process claimed in claim 2, wherein the step (ii) is carried out for a time period of 4-8 h.
8. The process claimed in claim 2, wherein the eneamino esters and nitriles (15a-h) molar ratio to base in the range of 1:3.
9 The process as claimed in claim 2, wherein the alkylated ester is selected from the group consisting of methylacrylate and ethylacrylate.
PCT/IN2016/050371 2015-10-30 2016-10-28 2-pyridone based compounds useful as potential phosphodiesterase3a (pde3a)inhibitors and a process for the preparation thereof WO2017072796A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3528/DEL/2015 2015-10-30
IN3528DE2015 2015-10-30

Publications (1)

Publication Number Publication Date
WO2017072796A1 true WO2017072796A1 (en) 2017-05-04

Family

ID=57544483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2016/050371 WO2017072796A1 (en) 2015-10-30 2016-10-28 2-pyridone based compounds useful as potential phosphodiesterase3a (pde3a)inhibitors and a process for the preparation thereof

Country Status (1)

Country Link
WO (1) WO2017072796A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114634471A (en) * 2022-04-14 2022-06-17 河南师范大学 Method for synthesizing gamma-hydroxy-gamma-perfluoromethyl exocyclic double bond butyrolactone compound

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5141931A (en) 1991-01-03 1992-08-25 Sterling Winthrop Inc. 5-Quinolinylpyridinones, cardiotonic compositions and methods
US20040023945A1 (en) 1999-12-23 2004-02-05 Icos Corporation Cyclic amp-specific phosphodiesterase inhibitors
EP1579862A1 (en) * 2004-03-25 2005-09-28 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
US20140221651A1 (en) 2013-02-01 2014-08-07 Council Of Scientific & Industrial Research Pyridopyrimidine based derivatives as potential phosphodiesterase 3 (pde3) inhibitors and a process for the preparation thereof
US20140296530A1 (en) * 2013-02-01 2014-10-02 Council Of Scientific & Industrial Research Indolizinone based derivatives as potential phosphodiesterase 3 (pde3) inhibitors and a process for the preparation thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5141931A (en) 1991-01-03 1992-08-25 Sterling Winthrop Inc. 5-Quinolinylpyridinones, cardiotonic compositions and methods
US20040023945A1 (en) 1999-12-23 2004-02-05 Icos Corporation Cyclic amp-specific phosphodiesterase inhibitors
EP1579862A1 (en) * 2004-03-25 2005-09-28 Boehringer Ingelheim Vetmedica Gmbh Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure
US20140221651A1 (en) 2013-02-01 2014-08-07 Council Of Scientific & Industrial Research Pyridopyrimidine based derivatives as potential phosphodiesterase 3 (pde3) inhibitors and a process for the preparation thereof
US20140296530A1 (en) * 2013-02-01 2014-10-02 Council Of Scientific & Industrial Research Indolizinone based derivatives as potential phosphodiesterase 3 (pde3) inhibitors and a process for the preparation thereof

Non-Patent Citations (38)

* Cited by examiner, † Cited by third party
Title
A..A. BEKHIT ET. AL.: "Novel milrinone analogs of pyridine-3-carbonitrile derivatives as promisinhg cardiotonic agents.", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 40, 22 July 2005 (2005-07-22), pages 1405 - 1413, XP027857632, DOI: 10.1016/j.ejmech.2005.06.005 *
ALEXANDRA ET AL., CANCERS, vol. 6, 2014, pages 436
ASHRAF ET AL., CHEM. PHARM. BULL., vol. 61, 2013, pages 405
AZIZ ET AL., PFLUGERS ARCH EUR J PHYSIOL, vol. 466, 2014, pages 1163
BEAVO, J. A., PHYSIOL. REV.,, vol. 75, 1995, pages 725
BENDER, A. T.; BEAVO, J. A., PHARMACOL REV, vol. 58, 2006, pages 488
BRITISH JOURNAL OF PHARMACOLOGY, vol. 165, 2012, pages 1288
CAMPBELL FW; ADDONIZO VP JR.: "Effectivehemostasis in cardiac surgery", 1988, WB SAUNDERS, article "Platelet function alterationsduring cardiac surgery", pages: 93 - 95
CLIVE ET AL., CURRENT OPINION IN PHARMACOLOGY, vol. 12, 2012, pages 275
DAVOOD ET AL., TOXICOLOGY MECHANISMS AND METHODS, vol. 24, 2014, pages 307
ESSA ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, 2012, pages 6938
GHEORGHIADE, M.; ZAROWITZ, B. J., AM. J. CARDIOL, vol. 69, 1992, pages 48
HAMID ET AL., JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 24, 2009, pages 918
HARKER L.: "Bleeding after cardiopulmonary bypass", N ENGL J MED, vol. 314, 1986, pages 1446 - 1448
J CYCLIC NUCLEOTIDE PROTEINPHOSPHOR RES, vol. ! 0, 1985, pages 551 - 564
JURAJ ET AL., RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY, vol. 187, 2013, pages 11
KIKURA, M.; LEVY, J. H., INT. ANESTESIOL. CLIN., vol. 33, 1995, pages 21
KOJI ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, 2011, pages 5451
KOJI ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 22, 2012, pages 5833
KOJI ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, 2013, pages 375
M RAVINDER ET. AL.: "Simple, facile and one-potconversion of the Baylis-Hillman acetates into 3,5,6-trisubstituted 2-pyridones.", TETRAHEDRON LETTERS, vol. 50, 6 May 2009 (2009-05-06), pages 4229 - 4232, XP002766044, DOI: 10.1016/j.tetlet.2009.04.136 *
M. RAVINDER ET. AL.: "Synthesis and evaluation of novel 2-pyridone derivatives as inhibitors of phosphodiesterase 3 (PDE3). A target for heart failure and platelet aggregation", BIIOORGANIC AND MEDICINAL CHEMISTRY LETTERS, vol. 22, no. 18, 11 May 2012 (2012-05-11), pages 6010 - 6015, XP002766046 *
MAHAJAN ET AL., JOURNAL OF RESEARCH IN MEDICAL EDUCATION & ETHICS, vol. 3, 2013, pages 115
MARGARETHA ET AL., J. MED. CHEM., vol. 46, 2003, pages 2008
MASAYOSI ET AL., JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, vol. 64, 2013, pages 11
MOHSEN ET AL., BIOORGANIC& MEDICINAL CHEMISTRY, vol. 18, 2010, pages 855
OCHIAI ET AL., BIOORG MED CHEM., vol. 20, 2012, pages 1644
PALSON, J. B; STRADA, S. J., ANNU. REV. PHARMACOL. TOXICOL, vol. 36, 1996, pages 403
PETER ET AL., BRITISH JOURNAL OF PHARMACOLOGY, vol. 169, 2013, pages 528
PETER ET AL., NAUNYN SCHMIEDEBERG'S ARCH PHARMACOL, vol. 387, 2014, pages 629
POTTER, B. V. L.: "Comprehensive Medical Chemistry", 1990, PERGAMON PRESS, article "Transmembrane Signalling Second Messenger Analogues and Inositol Phosphates", pages: 102
RAVINDER ET AL., BIOORG. MED. CHEM. LETT., 2012
REDDY ET AL., INDIAN J MED RES., vol. 132, 2010, pages 549
ROBERT ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 21, 2011, pages 3307
ROSAMOND ET AL.: "Heart disease and stroke statistics 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee", CIRCULATION, vol. 115, 2007, pages 69
S.W.KIM ET. AL.: "Synthesis of Poly-substituted 2-Pyridones via [3+2+1] Annulation Protocol from Baylis-Hillman Adducts", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 29, no. 9, 1 September 2008 (2008-09-01), pages 1815 - 1818, XP002766045 *
SHOJI ET AL., INT HEART J, vol. 55, 2014, pages 165
SMITH CJ ET AL., CIRCULATION, vol. 96, no. 9, 4 November 1997 (1997-11-04), pages 3116 - 3123

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114634471A (en) * 2022-04-14 2022-06-17 河南师范大学 Method for synthesizing gamma-hydroxy-gamma-perfluoromethyl exocyclic double bond butyrolactone compound
CN114634471B (en) * 2022-04-14 2023-05-19 河南师范大学 Method for synthesizing gamma-hydroxy-gamma-perfluoromethyl exocyclic double bond butyrolactone compound

Similar Documents

Publication Publication Date Title
DK176852B1 (en) 2-Phenyl-substituerede imidazotriazinoner som phosphodiesteraseinhibitorer
US9045428B2 (en) Substituted heterocyclic compounds
JP4426660B2 (en) Pyrazole derivatives, their preparation and their use as medicaments
CA2502182A1 (en) Pyrimido[4,5-d]pyrimidine derivatives with anticancer activity
SK67699A3 (en) Novel substituted pyrazole derivatives for the treatment of cardiocirculatory diseases
MXPA05006437A (en) Pyridino `2, 3-d! pyrimidine derivatives as selective kdr and fgfr inhibitors.
WO2009006580A1 (en) Optionally condensed dihydropyridine, dihydropyrimidine and dihydropyrane derivatives acting as late sodium channel blockers
CA2560098A1 (en) 2-aminoquinazoline derivative
Beaulieu et al. Synthesis and biological evaluation of 4-amino derivatives of benzimidazoquinoxaline, benzimidazoquinoline, and benzopyrazoloquinazoline as potent IKK inhibitors
US12012402B2 (en) Pyrido[2,3-d]pyrimidin-7-ones and related compounds as inhibitors of protein kinases
Fossa et al. Synthesis and pharmacological characterization of functionalized 2-pyridones structurally related to the cardiotonic agent milrinone
CZ280697A3 (en) 6-ARYL-PYRAZOLO(3,4-d)PYRIMIDIN-4-ONES, COMPOSITIONS CONTAINING THEREOF AND THEIR USE
Mugnaini et al. Synthesis and biological investigation of S-aryl-S-DABO derivatives as HIV-1 inhibitors
US20090181986A1 (en) Substituted heterocyclic compounds
WO2017072796A1 (en) 2-pyridone based compounds useful as potential phosphodiesterase3a (pde3a)inhibitors and a process for the preparation thereof
Younus et al. Exploring chromone sulfonamides and sulfonylhydrazones as highly selective ectonucleotidase inhibitors: Synthesis, biological evaluation and in silico study
EP1444982A1 (en) The use of purine derivatives as selective kinase inhibitors
US9562045B2 (en) Process for preparation of indolizine based derivatives as potential phosphodiestrase 3 (PDE3) inhibitors
US9505760B2 (en) Pyridopyrimidine based derivatives as potential phosphodiesterase 3 (PDE3) inhibitors and a process for the preparation thereof
CA2750704C (en) Phenylimidazole compounds
Monge et al. New 5H-pyridazino [4, 5-b] indole derivatives. Synthesis and studies as inhibitors of blood platelet aggregation and inotropics
JP4530663B2 (en) Imidazoquinoline derivatives
CN105408332B (en) Substituted triazolopyridines
KR20130044314A (en) Compound for inhibiting type 5 phosphodiesterase and preparation method thereof
Li et al. Design, synthesis, antitumor evaluations and molecular modeling studies of novel 3, 5-substituted indolin-2-one derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16810487

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16810487

Country of ref document: EP

Kind code of ref document: A1