WO2004022536A1

WO2004022536A1 - New heterocyclic amide compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them

Info

Publication number: WO2004022536A1
Application number: PCT/IB2003/003721
Authority: WO
Inventors: Abraham Thomas; Prashant Kashinath Bhavar; V.S. Prasada Rao Lingam; Neelima Kairatkar Joshi
Original assignee: Glenmark Pharmaceuticals Limited
Priority date: 2002-09-04
Filing date: 2003-09-03
Publication date: 2004-03-18
Also published as: AU2003263393A1

Abstract

The present invention relates to novel heterocyclic compounds that inhibit phosphodiesterase type 4 (PDE 4). The compounds are useful for treating inflammatory conditions, diseases of the central nervous systems and insulin resistant diabetes.

Description

NEW HETEROCYCLIC AMIDE COMPOUNDS USEFUL FOR THE TREATMENT OF INFLAMMATORY AND ALLERGIC DISORDERS: PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Field of the Invention

The present invention relates to novel heterocyclic compounds. More particularly the present invention relates to novel phosphodiesterase type 4 (PDE4) inhibitors having a heterocyclic structure, pharmaceutical compositions including such compounds, methods for their preparation and method for their use.

Background of the Invention Airway inflammation characterizes a number of severe lung diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production. The airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is the most prominent component. The magnitude of asthmatic reactions is correlated with the number of eosinophils present in lungs.

The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When activated, they synthesize and release inflammatory cytokines such as IL-1, IL-3, TNF-α and inflammatory mediators such as PAF, LTD4 and relative oxygen species that can produce edema, broncho-constriction. Tumor necrosis factor (TNF-α) was also known to be involved in the pathogenesis of a number of autoimmune and inflammatory diseases. Consequently, manipulation of the cytokine signaling or biosynthetic pathways associated with these proteins may provide therapeutic benefit in those disease states. It has been well demonstrated that TNF-α production in pro-inflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3',5'-monophosphate (cAMP). This second messenger is regulated by the phosphodiesterase (PDE) family of enzymes. The phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides. Since eosinophilis are believed to be a critical proinflammatory target for asthma, identification of the expression of PDE 4 gene family in eosinophils led to the PDE 4 as potential therapeutic target for asthma [Rogers, D.F., Giembycz, M.A., Trends Pharmacol. Sci., 19, 160-164(1998); Barnes, P.J., Trends Pharmacol. Sci., 19, 415-423 (1998) herein incoφorated by reference in their entirety].

The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classified into ten families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [ Soderling, S.H., Bayuga, S.J., and Beavo, J.A., Proc. Natl. Acad. Sci., USA, 96,7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K. and Omori, K., J. Biol. Chem., 274, 18438-18445 (1999) herein incoφorated by reference in their entirety]. Many cell types express more than one PDE and distribution of isoenzymes between the cells varies markedly. Therefore development of highly isoenzyme selective PDE inhibitors provides a unique opportunity for selective manipulation of various pathophysiological processes. Phosphodiesterase type 4 (PDE4) is an enzyme which regulates activities in cells which lead to inflammation in the lungs. PDE4, a cAMP-specific and Ca⁺² -independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes. The association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors[Trophy,T.J., Am. J. Respir. Crit. Care Med., 157, 351- 370 (1998) herein incoφorated by reference in its entirety]. Excessive or unregulated TNF-α production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as diseases including osteoarthritis, and other arthritic conditions; septic shock, ecdotoxic shock, respiratory distress syndrome, bone resoφtion diseases ; Since TNF-α also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, 1, 211-214 (1995) and ibid. 244-248 herein incoφorated by reference in their entirety].

Strong interest in drugs capable of selective inhibition of PDE 4 is due to several factors such as (a) the tissue distribution of PDE-4 suggests that pathologies related to the central nervous and immune systems could be treated with selective PDE-4 inhibitors (b) the increase in intracellular cAMP concentration, the obvious biochemical consequence of PDE-4 inhibition, has been well characterized in immuno-competent cells where it acts as a deactivating signal. Recently the PDE4 family has grown to include four subtypes-PDE4A to

PDE4D each encoded by a distinct gene. (British Journal of Pharmacology; 1999; v.128; p.1393-1398) incoφorated herein by reference in its entirety.

It has been demonstrated that increasing cAMP levels within these cells results in suppression of cell activation which in turn inhibits the production and release of pro-inflammatory cytokines such as TNF-α:. Since eosinophilis are believed to be a critical pro-inflammatory target for asthma, identification of the expression of the PDE-4 gene family in eosinophils led to the PDE-4 as potential therapeutic target for asthma.

The usefulness of several PDE-4 inhibitors, unfortunately, is limited due to their undesirable side effect profile which include nausea and emesis (due to action on PDE-4 in the central nervous system) and gastric acid secretion due to action on PDE-4 in parietal cells in the gut. Barnette, M.S., Grous, M., Cieslinsky, L.B., Burman,M., Christensen,S.B., Trophy, T. J., J. Pharmacol. Exp. Ther., 273,1396-1402 (1995) herein incoφorated by reference in their entirety. One of the earliest PDE-4 inhibitor, Rolipram, was withdrawn from the clinical development because of its severe unacceptable side effect profile. Zeller E. et. al., Pharmacopsychiatr., 17, 188-190 (1984) herein incoφorated by reference in their entirety. The cause of severe side effects of several PDE-4 inhibitor molecules in human clinical trials has recently become apparent.

There exist two binding sites on mammalian PDE-4 at which inhibitor molecules may bind. Also PDE-4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE-4H and Low affinity Rolipram binding site PDE-4L [Jacobitz, S., McLaughlin, M.M., Livi, G.P., Burman, M., Trophy, T.J., Mol. Pharmaco., 50, 891-899 (1996) herein incoφorated by reference in its entirety]. It was shown that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE-4H whereas some beneficial actions are associated with PDE- 4L inhibition. It was also found that human recombinant PDE-4 exists in 4 isoforms A, B, C and D [Muller, T., Engels, P., Fozard, J.R., Trends Pharmacol. Sci., 17, 294-298 (1996) herein incoφorated by reference in its entirety]. Accordingly, compounds displaying more PDE-4D isoenzyme selectivity over the A, B or C are found to have less amount of side effects than Rolipram [Hughes. B et al., Br. J. Pharmacol. 1996, 118, 1183-1191 herein incoφorated by reference in its entirety]. Therefore, selective inhibitors of PDE-4 isozymes would have therapeutic effects in inflammatory diseases such as asthma and other respiratory diseases. Although several research groups all over the world are working to find highly selective PDE-4 isozyme inhibitors, so far success is limited. Various compounds have shown PDE-4 inhibition.

ARIFLQ A CDP-840 B D-4418 C

Roflumilast D Bay-19-8004 E F G H

SmithKline Beecham's "Ariflo" which has the formula A, Byk Gulden's Roflumilast which has the formula β and Bayer's Bay- 19-8004 which has the formula E have reached advanced stage of human clinical trials. Other compounds which have shown potent PDE-4 inhibitory activity include Celltech's CDP-840 of the formula B, Schering Plough's D-4418 of the formula C, Pfizer's 5CP-220,629 which has the formula F, Parke Davis's PD-168787 which has the

inast formula G and Wyeth's Filaminast which has the formula H. However, recently due to efficacy and side effects problems, Ariflo, CDP-840 and Bay- 19-8004 were discontinued from clinical trials as a treatment for asthma. Other compounds of the formula C and F are presently undergoing phase-1 clinical trials.

PCT publication WO95/04046, incoφorated herein by reference in its entirety, is directed to a compound of formula 1 , said to be useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF), where formula I is as follows:

wherein

R¹ is lower alkyl;

R² is alkyl,alkenyl,alkynyl,cycloalkyl,cycloalkenyl,cyclothioalkyl or cyclothioalkenyl;

R³ is aryl or heteroaryl; Z¹ and Z² are independently oxygen, sulfur or direct bond, and only one of Z and

Z² is a direct bond;

Z³ is -CZCH₂- or -CZNH- ; and Z is oxygen or sulfur, or N-oxide thereof or a pharmaceutically accepted salts thereof, provided that when Z² is a direct bond, R² is alkyl bonded to the phenyl moiety via a nonquatenary carbon, alkenyl, alkynyl, cyclothioalkyl or cyclothioalkenyl, or R³ is azaheteroaryl having a nitrogen atom thereof oxidized to the corresponding N- oxide moiety.

2) US granted patent US 5,712,298 issued on January 27, 1998 and issued to BYK Gulden Lomberg Chemische Fabrik GMBH, incoφorated herein by reference in its entirety, is directed to compounds of the formula 2

(2)

wherein one of the substituents Rl and R2 is hydrogen, l-6C-alkoxy, 3-7C- cycloalkoxy,

3-7C cycloalkylmethoxy, benzyloxy or l-4C-alkoxy which is completely or partially substituted by fluorine, and other 1-4C- which is completely or partially substituted by fluorine, and

R3 is phenyl, pyridyl, phenyl which is substituted by R31, R32 and R33 or pyridyl which is substituted by R34, R35, R36 and R37, where

R31 is hydroxyl, hydrogen, cyano, carboxyl, trifluromethyl, l-4C-alkyl, 1-4C- alkoxy, l-4C-alkoxycarbonyl, l-4C-alkylcarbonyl, l-4C-alkylcarbonyloxy,amino, mono- or di-l-4C-alkylamino or l-4C-alkylcarbonylamino,

R32 is hydrogen, hydroxyl, halogen, amino, trifluromethyl, l-4C-alkyl or 1-4C- alkoxy,

R33 is hydrogen, hydroxyl, halogen, l-4C-alkyl or l-4C-alkoxy, R34 is hydrogen; halogen, cyano, carboxyl, alkyl, l-4C-alkoxy, 1-4C- alkoxycarbonyl or amino,

R35 is hydrogen, halogen, amino, l-4C-alkyl,

R36 is hydrogen or halogen and R37 is hydrogen or halogen, the salts of these compounds, and the N-oxides of the pyridines and their salts.

Accordingly we have prepared a novel series of compounds having the general formula I as defined below. We have examined the in vitro efficacy of these novel compounds against human PDE-4 enzyme and they have been found to show excellent PDE-4 enzyme inhibition activity at nM-μM concentrations. The compounds of the present invention are useful as therapeutic agents for inflammatory allergic diseases particularly bronchial asthma, allergic rhinitis and nephritis. Since these compounds also inhibit the production of tumor necrosis factor (TNF), they may also find use in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, psoriasis ; diseases of the central nervous system such as depression amnesia, and dementia, cardiac failure, shock, and cerebrovascular disease and the like ; insulin-resistant diabetes.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel heterocyclic compounds of the general formula (I),

(I) wherein,

R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(O)-R', -C(0)0-R', -C(0)NR'R¹ or -S(O)_m-R'; preferably R¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl wherein Y represents direct bond, oxygen, sulfur or NR¹ ; preferably Y is oxygen wherein X is a hydrogen, halogen atom, -OR¹, -S(O)_m R¹, -C(0)R', formyl amine, nitro or -NR^xR^y (wherein R^x and R^y independently represents hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl ); preferably X is substituted or unsubstituted alkoxy wherein m is 0, 1 or 2; wherein R² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, formyl; preferably R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, or oxo(=O);

wherein R³ represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl or hydroxy; preferably R³ is hydrogen; wherein n = 1 or 2; wherein p = l, 2, 3, 4 or 5; with the proviso that if n = 1 then p = 1, 2, 3 or 4, and if n = 2 then p= 1 , 2, 3, 4 or 5

and their analogs, their tautomers, their regioisomers, their diasteromers, their stereoisomers, their geometrical isomers, their N-oxides, their polymoφhs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates thereof.

In another aspect of the present invention there is provided a compound of general formula (1 -A)

wherein, R¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl,

-C(0)0-R', -C(O)NR'R' or -S(O)_m-R'; preferably R¹ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl wherein Y represents direct bond, oxygen, sulfur or NR¹; preferably Y is oxygen wherein X is a hydrogen, halogen atom, -OR¹, -S(O)_m R¹, -C(O)R', formyl amine, nitro or -NR^xR^y (wherein R^x and R^y independently represents hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl ); preferably X is substituted or unsubstituted alkoxy wherein m is 0, 1 or 2; wherein R² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, formyl; preferably R² is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, or oxo(=O);

wherein R represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl or hydroxy; preferably R3 is hydrogen; wherein p = 1, 2 or 3 ;

the A ring represents a heterocyclic ring wherein R² is chosen independently for each position capable of substitution, the preferable ring A can be selected from

DETAILED DESCRIPTION OF THE INVENTION

The term 'alkyl' refers to a straight or branched hydrocarbon chain radical having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, examples include but are not limited to methyl, ethyl, n-propyl, and 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t- butyl).

The term "alkenyl " refers to aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain radical having 2 to 10 carbon atoms which is attached to the rest of the molecule by a single bond. Examples include but are not limited to ethenyl, 1-propenyl, 2- propenyl (allyl), iso-propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl and the like.

The term "alkynyl" refers to straight or branched chain hydrocarbon radicals having at least one carbon-carbon triple bond, having 2 to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms preferred) which is attached to the rest of the molecule by a single bond.

Examples include but is not limited to ethynyl, propynyl, and butnyl.

The term "alkoxy" denotes alkyl group as defined above attached via oxygen linkage to the rest of the molecule. Examples include but are not limited to -OCH₃, -and -OC₂H₅.

The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of 3 to about 14 carbon atoms attached via a single bond to the rest of the molecule. Examples of monocyclic ring system include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and, cyclohexyl. Examples of multicyclic ring system include but are not limited to perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or sprirobicyclic groups e.g. sprio (4,4) non-2-yl.

The term "cycloalkylalkyl" refers to cyclic ring-containing radical containing 3 to about 8 carbon atoms directly attached to alkyl group which is then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure, such as cyclopropylmethyl, cyclobutylethyl, cyclopentylethyl, and the like. The term "cycloalkenyl" refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms with at least one carbon- carbon double bond. Examples include but are not limited to cyclopropenyl, cyclobutenyl and cyclopentenyl. The term "aryl" refers to aromatic radicals having 6 to 14 carbon atoms.

Examples include but are not limited to phenyl, naphthyl, tetrahydronapthyl, indanyl and biphenyl.

The term "arylalkyl" refers to an aryl ring as defined above directly bonded to an alkyl group as defined above. Examples include but are not limited to -CH₂C₆H₅, and

-C₂H₅C₆H₅.

The term "heterocyclic ring" refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For puφose of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the heterocyclic ring radical may be partially or fully saturated or aromatic (heteroaromatic). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofurnyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxasolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, moφholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamoφholinyl, thiamoφholinyl sulfoxide thiamoφholinyl sulfone, dioxaphospholanyl, oxadiazolyl , chromanyl and isochromanyl.

The term "heteroarylalkyl" refers to heteroaryl ring radical as defined above directly bonded to alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.

The term "heterocyclylalkyl" refers to a heterocylic ring radical as defined above directly bonded to alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.

The term "halogen" refers to radicals of fluorine, chlorine, bromine, iodine.

The substituents in the 'substituted alkyl', 'substituted alkoxy' 'substituted alkenyl' ' substituted alkynyl' 'substituted cycloalkyl' substituted cycloalkylalkyl' substituted cyclocalkenyl' 'substituted arylalkyl' 'substituted aryl' 'substituted heterocyclic ring', 'substituted heteroaryl ring,' 'substituted heteroarylalkyl', 'substituted heterocyclylalkyl ring', 'substituted amino', 'substituted alkoxycarbonyl', 'substituted cyclic ring' 'substituted alkylcarbonyl', 'substituted alkylcarbonyloxy' and 'substituted carboxylic acid' may be the same or different which one or more selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, amino, nitro, oxo (=O), thio (=S), or optionally substituted groups selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclic ring, - COOR\ -C(O)R^x, -C(S)R\ -C(O)NR^xR^y, -C(O)ONR^xR^y, -NR^xCONR^yR^z, - N(R^x)SOR^y, -N(R^x)SO₂R^y, -(=N-N(R^x)R^y), - NR^xC(O)OR^y, -NR^xR^y, -NR^xC(O)R^y- , -NR^xC(S)R^y -NR^xC(S)NR^yR^z, -SONR^xR^y-, -SO₂NR^xR^y-, -OR\ -OR^xC(O)NR^yR^z, -OR^xC(O)OR^y-, -OC(O)R^x, -OC(O)NR^xR^y, -R^xNR^yR^z, -R^xR^yR^z, -R^XCF₃, - R^xNR^yC(O)R^z, -R^xOR^y, -R^xC(O)OR^y, -R^xC(O)NR^yR^z, -R^xC(O)R^x, -R^xOC(O)R^y, - SR^X, -SOR", -SO₂R^x, -ONO₂,(wherein R^x, R^y and R^z in each of the above groups can be hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl.

Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, serine, and the like; unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts and aluminum salts. Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.

Another object of the invention is a method of treating inflammatory diseases, disorders and conditions characterized by or associated with an undesirable inflammatory immune response and all disease and conditions induced by or associated with an excessive secretion of TNF-α: and PDE-4 which comprises administering to a subject a therapeutically affective amount of a compound according to Formula la.

Another object of the invention is a method of treating inflammatory conditions and immune disorders in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula la.

Preferred inflammatory conditions and immune disorders are chosen from the group consisting of: asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoriasis, uticaria, adult vernal conjunctivitis, respiratory distress syndrome, rheumatoid spondylitis, osteoarthritis, gouty arthritis, utelitis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema, atopic dermatitis and chronic inflammation.

Further preferred is when the inflammatory condition is an allergic inflammatory condition.

Further preferred is when the inflammatory conditions and immune disorders are selected from the group consisting of inflammatory conditions or immune disorders of the lungs, joints, eyes, bowels, skin and heart.

Further preferred is when the inflammatory condition is chosen from the group consisting of: bronchial asthma, nepritis, and allergic rhinitis.

Another object of the invention is a method for abating inflammation in an affected organ or tissue comprising delivering to said organ or tissue a therapeutically effective amount of a compound represented by a compound according to Formula la.

Another object of the invention is a method of treating diseases of the central nervous system in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula la.

Preferred diseases of the central nervous system are chosen from the group consisting of: depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease.

Another object of the invention is a method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to formula 1. "Treating" or "treatment" of a state, disorder or condition includes:

(1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition,

(2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated. The four classic symptoms of acute inflammation are redness, elevated temperature. Swelling, and pain in the affected area, and loss of function of the affected organ.

Symptoms and signs of inflammation associated with specific conditions include: • rheumatoid arthritis- pain, swelling, warmth and tenderness of the involved joints; generalized and morning stiffness;

• insulin-dependent diabetes mellitus- insulitis; this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy; coronary artery disease, peripheral vascular disease, and cerebrovascular disease;

• autoimmune thyroiditis- weakness, constipation, shortness of breath, puffiness of the face, hands and feet, peripheral edema, bradycardia;

• multiple sclerosis- spasticity, blurry vision, vertigo, limb weakness, paresthesias; • uveoretinitis- decreased night vision, loss of peripheral vision;

• lupus erythematosus- joint pain, rash, photosensitivity, fever, muscle pain, puffiness of the hands and feet, abnormal urinalysis (hematuria, cylinduria, proteinuria), glomerulonephritis, cognitive dysfunction, vessel thrombosis, pericarditis; • scleroderma- Raynaud's disease; swelling of the hands, arms, legs and face; skin thickening; pain, swelling and stiffness of the fingers and knees, gastrointestinal dysfunction, restrictive lung disease; pericarditis,; renal failure; • other arthritic conditions having an inflammatory component such as rheumatoid spondylitis, osteoarthritis, septic arthritis and polyarthritis- fever, pain, swelling, tenderness;

• other inflammatory brain disorders, such as meningitis, Alzheimer's disease, AIDS dementia encephalitis- photophobia, cognitive dysfunction, memory loss;

• other inflammatory eye inflammations, such as retinitis- decreased visual acuity;

• inflammatory skin disorders, such as , eczema, other dermatites (e.g., atopic, contact), psoriasis, burns induced by UV radiation (sun rays and similar UV sources)- erythema, pain, scaling, swelling, tenderness;

• inflammatory bowel disease, such as Crohn's disease, ulcerative colitis- pain, diarrhea, constipation, rectal bleeding, fever, arthritis;

• asthma- shortness of breath, wheezing; • other allergy disorders, such as allergic rhinitis- sneezing, itching, runny nose

• conditions associated with acute trauma such as cerebral injury following stroke- sensory loss, motor loss, cognitive loss;

• heart tissue injury due to myocardial ischemia- pain, shortness of breath; • lung injury such as that which occurs in adult respiratory distress syndrome- shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates;

• inflammation accompanying infection, such as sepsis, septic shock, toxic shock syndrome- fever, respiratory failure, tachycardia, hypotension, leukocytosis;

• other inflammatory conditions associated with particular organs or tissues, such as nephritis (e.g., glomerulonephritis)-oliguria, abnormal urinalysis; inflamed appendix- fever, pain, tenderness, leukocytosis; gout- pain, tenderness, swelling and erythema of the involved joint, elevated serum and/or urinary uric acid; inflamed gall bladder- abdominal pain and tenderness, fever, nausea, leukocytosis; chronic obstructive pulmonary disease- shortness of breath, wheezing; congestive heart failure- shortness of breath, rales, peripheral edema;

Type II diabetes- end organ complications including cardiovascular, ocular, renal, and peripheral vascular disease lung fibrosis- hyperventilation, shortness of breath, decreased oxygenation; vascular disease, such as atherosclerosis and restenosis- pain, loss of sensation, diminished pulses, loss of function and alloimmunity leading to transplant rejection- pain, tenderness, fever.

Subclinical symptoms include without limitation diagnostic markers for inflammation the appearance of which may precede the manifestation of clinical symptoms. One class of subclinical symptoms is immunological symptoms, such as the invasion or accumulation in an organ or tissue of proinflammatory lymphoid cells or the presence locally or peripherally of activated pro- inflammatory lymphoid cells recognizing a pathogen or an antigen specific to the organ or tissue. Activation of lymphoid cells can be measured by techniques known in the art.

"Delivering" a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished ,e.g., by local or by systemic administration of the active ingredient to the host.

A "subject" or "a patient" or "a host" refers to mammalian animals, preferably human. Some of the preferred representative compounds according to the present invention are specified below but should not construed to be limited thereto;

1. 3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane

2. (3R)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5 - dioxoazolane

3. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-methyl-2,5- dioxoazolane 4. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l- cyclopropylmefhyl-2,5-dioxoazolane 5. (3S)- 1 -Cyclohexyl-3 -(3 -cyclopentyloxy-4-methoxyphenylcarboxamido)- 2,5-dioxoazolane

6. (3S)- 1 -Cyanomethyl-3 -(3 -cyclopentyloxy-4-methoxyphenylcarboxamido)- 2,5-dioxoazolane

7. Methyl 2-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolan-1 -yl]acetate

8. 2-[(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolan-l-yl]acetic acid

9. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l- phenylazolane

10. (3S)- 1 -Benzyl-3-(3 -cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane 11. (3S)-1 -[4-(tert-Butyl)benzyl]-3-(3-cyclopentyloxy-4- methoxyphenylcarboxamido)-2,5-dioxoazolane

12. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- cyanobenzyl)-2,5-dioxo-azolane

13. (3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- cyanobenzyl)-2, 5-dioxo-azolane

14. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(3- trifluoromethyl-benzyl)azolane

15. (3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(3- trifluoromethyl-benzyl)azolane 16. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(4- trifluoromethyl-benzyl)azolane

17. (3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(4- trifluoromethyl-benzyl)azolane

18. Ethyl 4-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolan- 1 -yl]benzoate

19. Ethyl 3-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolan-1-ylmethyl] benzoate

20. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l -(3- fluorobenzyl)-2, 5-dioxoazolane 21. (3S)- 1 -(3 -Bromobenzyl)-3-(3 -cyclopentyloxy-4- methoxyphenylcarboxamido)-2, 5 -dioxo-azolane

22. (3S)-3-(3-Cyclopentyloxy)-4-methoxyphenylcarboxamido)-l -(2,5- dichlorobenzyl)-2, 5-dioxoazolane

23. (3R)-3 -(3 -Cyclopentyloxy)-4-methoxyphenylcarboxamido)- 1 -(2,5- dichlorobenzyl)-2, 5 -dioxo-azolane 24. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(2,6- dichlorobenzyl)-2, 5-dioxoazolane

25. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)- 1 -(3- nitrobenzyl)-2, 5-dioxo-azolane

26. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(4-chloro-3- nitrobenzyl)-2, 5-dioxoazolane

27. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l -(3- pyridylmethyl)-2, 5-dioxo-azolane

28. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)- 1 -(3- oxopyridylmethyl)-2, 5-dioxoazolane 29. (3S)-l-Benzyl-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2- oxoazolane

30. (3S)-l-Benzyl-3-(3-cyclopentyloxy-4- difluoromethoxyphenylcarboxamido)-2-oxoazolane

31. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-5-oxoazolane

32. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6- dioxohexahydropyridine

33. (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxohexahydro-pyridine

34. (3R)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxo-hexahydro-pyridine

35. (3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 2,6-dioxo-hexahydropyridine 36. (3S)-3-(4-Difluoromethoxy-3-methoxyphenylcarboxamido)-2,6- dioxohexahydro-pyridine

37. (3S)-3 - [3 ,4-Di(difluoromethoxy)phenylcarboxamido] -2,6- dioxohexahydropyridine 38. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-ethyl-2,6- dioxohexahydro-pyridine

39. Ethyl 2-[(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6- dioxohexahydro- 1 -pyridinyl]acetate

40. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l -(2,6- dichlorobenzyl)-2,6-dioxo-hexahydropyridine 41. (3S)-3-(3 -Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)- 1 -(2,6- dichloro-benzyl)-2,6-dioxohexahydropyridine

42. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6-dioxo-l-(4- pyridylmethyl)-hexahydropyridine

43. (3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-l-(4-pyridylmethyl)- 2,6-dioxo-hexahydropyridine

44. (3 S)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)-2- oxohexahydropyridine

45. (3S)-3 -(3 -Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2- oxohexahydropyridine 46. (3S)-3-(3 -Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)-

2-oxohexahydro-pyridine

47. (3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-2- oxohexahydropyridine

48. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2-oxo-l - phenylhexahydro-pyridine

49. (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2-oxo- 1 -phenyl -hexahydropyridine

50. (3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 2-oxo- 1 -phenyl -hexahydropyridine 51. (3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-2-oxo-l- phenylhexahydropyridine

52. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-6- oxohexahydropyridine

53. (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-6- oxohexahydropyridine

54. (3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 6-oxo-hexahydropyridine 55. (3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-6- oxohexahydropyridine

56. (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-6-oxo-l - phenylhexahydro-pyridine

57. (3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 6-oxo- 1 -phenyl-hexahydropyridine

Further preferred are

(3S)-l-[4-(tert-Butyl)benzyl]-3-(3-cyclopentyloxy-4- methoxyphenylcarbox-amido)-2,5-dioxoazolane;

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- cyanobenzyl)-2,5-dioxoazolane;

(3R)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5 -dioxo- 1 -(3 - trifluoromethyl-benzyl)azolane;

(3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(4- trifluoromethyl-benzyl)azolane ; (3S)-1 -(3-Bromobenzyl)-3-(3-cyclopentyloxy-4- methoxyphenylcarboxamido)-2, 5 -dioxoazolane;

(3R)-3-(3-Cyclopentyloxy)-4-methoxyphenylcarboxamido)-l -(2, 5- dichlorobenzyl)-2, 5-dioxo-azolane;

(3S)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)- 1 -(3- nitrobenzyl)-2, 5-dioxo-azolane;

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(4-chloro-3- nitrobenzyl)-2, 5-dioxoazolane;

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-5-oxoazolane;

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6- dioxohexahydropyridine;

(3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxohexahydro-pyridine; (3R)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxo-hexahydropyridine;

(3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 2,6-dioxohexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-6- oxohexahydropyridine; and

(3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 6-oxo-hexahydropyridine

The compounds according to the invention may be prepared by the following processes. The symbols P, P , R , R² and A when used in the below formula below are to be understood to present those groups described above in relation to formula (I) unless otherwise indicated

In one embodiment the desired compounds of the formula (I) wherein X, Ri, Y, and R₂, R₃ are as defined above as described in the general description, can be synthesized as described in the general synthetic scheme 1.

Scheme 1

As shown in the above scheme 1, cyclisation of compound of general formula β) by means of DCC in DMF at elevated temperature gives compound of general formula (4), which on selective alkylation with an alkyl halide of the general formula R²X, yields compound of general formula (5). The compound of general formula (5) on deprotection by using palladium on carbon yields the amine of general formula (6). Condensation of the amine of general formula (6) with 3, 4-substituted benzoyl chloride of general formula (7) affords dioxoazolane of general formula (la). The compound (la) on substitution at benzamide nitrogen gives the novel compounds of general formula (I-A), wherein X, R¹ , Y, and R², R³ are as defined above.

Both racemic as well as pure enantiomers of I can be accessed by this approach depending on the stereochemical integrity of the amino acid used.

Scheme 2

Alternatively, the compound of general formula (I-A) can be prepared by a linear approach as shown in scheme 2. As shown in the scheme 2, coupling of 3,4- substituted benzoic acid of general formula (8) with the compound of general formula (9) by means of coupling agents (carbodiimides, e.g., DCC, EDCA) with or without activators (e.g., HOBT and N-hydroxysuccinimide) gives acid amide of general formula (10). Cyclisation of compound of general formula (10) by means of using DCC and DMF gives 3-carboxamido-2, 5-dioxoazolane of general formula (11) which on alkylation gives dioxoazolane of general formula (la). The compound of general formula (la) on substitution at benzamide nitrogen gives the novel compounds of general formula (I-A), wherein X, R , Y, and R , R³ are as defined above.

Scheme 3

Alternatively the following methodology can be used for the synthesis of compound of formula (TA), condensation by coupling of compound of general formula (12) with amines of the general formula R NH₂ provides amide of general formula (13). Reaction of compound of general formula (13) with methyl iodide results in the formation of sulfonium iodide with general formula (14), which under suitable basic reaction conditions undergo intramolecular cyclisation to give 2-oxoazolane of general formula (15). Deprotection of BOC group of formula (15) followed by coupling with acid chloride of formula (7) gives the amide of formula (lb). The compound of general formula (lb) on substitution at benzamide nitrogen gives the novel compounds of general formula (I-A), wherein X, R , Y, and R , R are as defined above.

In yet another embodiment, the present invention relates to 3,4-substituted arylcarboxamido-5-oxoazolane having general formula I, wherein X, Ri, Y, and R₂ are as defined above.

Scheme 4

In synthetic scheme 4 the following methodology can be used for the synthesis of novel compound of formula (I -A), reduction of carboxylic group of compound of general formula (16) via its mixed anhydride provides alcohol with the general formula (17). Mesylation of the compound (17) followed by treatment with sodium azide in DMSO gives azide having general formula (18). Palladium catalysed reductive cyclisation of compound of formula (18) gives azolane having general formula (19). Deprotection of (19) followed by its coupling with compound of general formula (7) affords compound of general formula (lc). The compound Ic on substitution at benzamide nitrogen gives the novel compounds of general formula (I-A), wherein X, Ri, Y, and R_2j R₃ are as defined above.

In yet another aspect, the present invention relates to 2,6-dioxopyridine derivative of the formula I, wherein X, Ri, Y, and R₂ are as defined above.

Scheme 5

The compounds of the general formula (I-A) can be obtained as follows, Cyclisation of compound of formula (20) using DCC and N-hydroxysuccinimide in DMF at elevated temperature gives 2,6-dioxopyridine derivative of formula (21), which is on treatment with alkyl halides of the general formula R²X give N-1 substituted 2,6-dioxopyridine derivative of general formula (22). Palladium catalysed removal of Cbz protecting group of compound of general formula (22) gives compound of general formula (23). Compounds of general formula (23) on coupling with the compound of formula (7) by means of triethylamine in THF provides the compound of general formula (Id). The compound (Id) on substitution at benzamide nitrogen gives the novel compounds of general formula (I-A), wherein X, Ri, Y, and R_2ι R₃ are as defined above.

Scheme 6

Another aspect of the present invention relates to 3-carboxamido-2- pyridones of the general formula I, wherein X, Rj, Y, and R₂ are as defined above.

The novel compounds of formula I can be prepared as outlined in scheme 6. The compound of formula 24 on esterification by means of SOCl₂ in methanol gives compound of formula 25 as its dihydrochloride salt. Intramolecular cyclisation of compound of formula 25 under basic conditions gives the compound of formula 26 as its BOC derivative. The ring nitrogen in compound 26 was selectively alkylated using alkyl halide in presence of Cui to give the compound of formula 27. Deprotection of compound of formula 27 followed by coupling with compound of formula 7 gives the compound of general formula le.

The compound le on substitution at benzamide nitrogen gives the novel compounds of general formula I-A, wherein X, Ri, Y, and R_2; R₃ are as defined above. Another aspect of the present invention relates to 3-carboxamido-6- pyridones of the general formula I, wherein X, Rj, Y, and R₂ are as defined above.

Scheme 7

A method for the synthesis novel compounds of general formula (I-A) have been provided in scheme 7. Selective reduction of carboxylic acid group of compound of formula (28) via its mixed anhydride using NaBFLt gives the alcohol of general formula (29). This alcohol (29) is converted to the azide of general formula (30) via its mesylate. Azide (30) on treatment with Pd/C undergoes reduction and cyclization to get the compound of formula (31). The amide nitrogen of compound of formula (31) is alkylated with alkyl halides of the general formula R²X under Cui catalysis give the compound of formula (32). Acylation of compound (32) with compound of formula (7) gives the compound of general formula If. The compound If on substitution at benzamide nitrogen gives the novel compounds of general formula (I - A), wherein X, Ri, Y, and R₂, R₃ are as defined above.

The substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn can be converted into salts.

In general, the ethereal solvents used in the above described processes for the preparation of compounds of the formula (I) are selected from diethyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1,4 dioxane and the like. The chlorinated solvent which may be employed may be selected from dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like . The aromatic solvents which may be employed may be selected from benzene, toluene. The alcoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, isopropanol, tert.butanol and the like. The aprotic solvents which may be employed may be selected from N, N- dimethylformamide, dimethyl sulfoxide and the like.

In general, the compounds prepared in the above described processes are obtained in pure form by using well known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, isopropanol, water or their combinations, or column chromatography using Alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations.

Various polymoφhs of a compound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions, example, using different solvents commonly used or their mixtures for recrystalhzation; crystallizations at different temperatures, various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymoφhs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymoφhs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.

The present invention provides novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastreomers, their polymoφhs, their pharmaceutically acceptable salts, their appropriate N-oxides and their pharmaceutically acceptable solvates.

The present invention also provides pharmaceutical compositions, containing compounds of the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymoφhs, their enantiomers, their diasteromers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like. The pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders.

It will be appreciated that some of the compounds of the general formula (I) defined above according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in the compounds of the general formula (I) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures. The invention may also contain E & Z geometrical isomers wherever possible in the compounds of the general formula (I) which includes the single isomer or mixture of both the isomers

The pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like and may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions. The active compounds of the formula (I) will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above. Thus, for oral administration, the compounds of the formula (I) can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions, may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. For parenteral administration, the compounds of the formula (I) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds of the formula (I). The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.

The compounds can also be administered by inhalation when application within the respiratory tract is intended. Formulation of the present compounds is especially significant for respiratory inhalation, wherein the compound of Formula I is to be delivered in the form of an aerosol under pressure. It is preferred to micronize the compound of Formula I after it has been homogenised, e.g., in lactose, glucose, higher fatty acids, sodium salt of dioctylsulfosuccinic acid or, most preferably, in carboxyme3thyl cellulose, in order to achieve a microparticle size of 5 μm or less for the majority of particles. For the inhalation formulation, the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substance. An inhaler or atomizer or nebulizer may be used. Such devices are known. See, e.g., Newman et al., Thorax, 1985, 40 61-676; Berenberg, M., J. Asthma USA, 1985, 22:87-92; incoφorated herein by reference in their entirety. A Bird nebulizer can also be used. See also U.S. Patents 6,402,733; 6,273,086; and 6. ,228,346, incoφorated herein by reference in their entirety. The compound of the structure I for inhalation is preferably formatted in the form of a dry powder with micronized particles. The compounds of the invention may also be used in a metered dose inhaler using methods disclosed in U.S. Patent 6, 131,566, incoφorated herein by reference in its entirety. In addition to the compounds of formula (I) the pharmaceutical compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful therapeutic agents.

The invention is explained in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Experimental Intermediates

Intermediate 1 3-Cyclopentyloxy-4-methoxybenzoic acid

Step 1: A mixture containing 3-hydroxy-4-methoxybenzaldehyde (10 g, 65.72 mmol), anhydrous potassium carbonate (22.7 g, 164.31 mmol) and cyclopentyl bromide (11.75 g, 78.86 mmol) in dry DMF was stirred at 80 °C for 5 h. The reaction mixture was cooled to RT and filtered to remove the inorganic salts. The filterate was diluted with water and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water (3 x 100 ml), brine (50 ml) and dried (Na₂SO₄). Solvent was evaporated under reduced pressure to give 11.5 g (80 %) of the product as viscous brown liquid, which was used as such for step 2.

Step 2: To a stirred and cooled (-5 °C) solution of 3-cyclopentyloxy-4-methoxy- benzaldehyde (11.0 g, 49.94 mmol) and sulphamic acid (7.27 g, 74.91 mmol) in 3:1 acetone- water mixture (200 ml) was added sodium chlorite (5.42 g, 59.92 mmol) dissolved in water (10 ml). The mixture was warmed to 10-15 °C and stirred at the same temperature for 3 h. The solid product separated out was collected by filtration. Crystallization of the crude product from acetone-water gave 9.2 g (78 %) of 3-cyclopentyloxy-4-methoxybenzoic acid as white crystals, mp 155-157 °C; IR (KBr) 2963-2535 (br), 1681, 1596, 1584, 1513, 1412, 1274, 1181 cm ^"1; 'HNMR (300 MHz, CDC1₃) δ 1.62-2.02 (m, 8 H), 3.81 (s, 1 H), 4.86- 4.90 (m, 1 H), 7.20 (d, J= 8.4 Hz, 1 H), 7.67-7.70 (m, 2 H).

Intermediate 2 3-Cyclopentyloxy-4-difluoromethoxybenzoic acid

Step-1: Prepared as described for intermediate 1 using 3-hydroxy-4- difluoromethoxy-benzaldehyde (5 g, 26.89 mmol), anhydrous potassium carbonate (7.4 g, 53.62 mmol) and cyclopentyl bromide (6 g, 40.26 mmol) in dry DMF (50 ml). The reaction yielded 6.8 g (100 %) of the product as viscous brown liquid which was used as such for step 2.

Step 2: Oxidation of the aldehyde from step 1 with sodium chlorite (2.54 g, 28.08 mmol) and sulphamic acid (3.41g, 35.15 mmol) as described for intermediate 1, step 2 gave 4.8 g (75 %) of the product as white crystalline solid, IR (KBr) 2962, 2651, 1699, 1603, 1509, 1439, 1298, 1053, 763 cm ^_1; Η NMR (300 MHz, CDC1₃) δ 1.62-2.03 (m, 8 H), 4.86-4.92 (m, 1 H), 6.62 (t, J= 75.0 Hz, 1 H), 7.20 (d, J= 9.0 Hz, 1 H), 7.67-7.70 (m, 2 H).

Intermediate 3 3-Cyclopropylmethoxy-4-difluoromethoxybenzoic acid

Step 1: Prepared as described for intermediate 1, using 3-hydroxy-4- difluoromethoxy-benzaldehyde (5 g, 26.89 mmol), anhydrous potassium carbonate (7.4 g, 53.62 mmol) and bromomethyl cyclopropane (4.5 g, 33.3 mmol) in dry DMF (50 ml). The reaction yielded 5.5 g (82 %) of the product as viscous liquid which was used as such for step 2.

Step 2: Oxidation of the aldehyde from step 1 with sodium chlorite (2.24 g, 24.75 mmol) and sulphamic acid (3.01 g, 31.03 mmol) as described for intermediate 1, step 2 gave 4.16 g (78 %) of the product as white crystalline solid, mp 118-120 °C; IR (KBr) 2930, 1691, 1601, 1516, 1441, 1297, 1060, 765 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 0.36-0.41 (m, 2 H), 0.65-0.712 (m, 2 H), 1.2-1.37 (m, 1 H), 3.94(d, J= 6.6 Hz, 2 H), 6.72 (t, J= 74.7 Hz, 1 H), 7.22 (d, J= 8.1, Hz, 1 H), 7.65 (s, 1 H) 7.70 (d, J= 8.4 Hz, 1 H).

Intermediate 4

3 ,4-di(difluoromethoxy)benzoic acid

Oxidation of the 3,4-di(difluoromethoxy)benzaldehyde (5 g, 21.0 mmol) with sodium chlorite (2.28 g, 25.19 mmol) and sulphamic acid (3.05 g, 31.44 mmol) as described for intermediate 1, step 2 gave 4.9 g (91.8 %) of the product as white crystalline solid, mp x °C; IR (KBr) 3074-2538, 1700,1613, 1446, 1294, 1074, 916, 755 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 6.58 (t, J= 72.6 Hz, 1 H), 6.62 (t, J = 72.6 Hz, 1 H), 7.33 (d, J= 9.0 Hz, 1 H), 7.99-8.02 (m, 2 H).

Intermediate 5 4-Difluoromethoxy-3-methoxybenzoic acid

Step 1 : Chlorodifluoromethane gas was bubbled into stirred slurry of 3-hydroxy- 4-methoxybenzaldehyde (5 g, 32.89 mmol), anhydrous potassium carbonate (9.1 g, 65.94 mmol) in dry DMF (50 ml) at 70-80 °C for a period of 20 min. The reaction was further stirred at RT under chlorodifluoromethane gas atmosphere for 18 h. The reaction mixture was filtered to remove the inorganic salts. The filterate was diluted with water and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water (3 x 100 ml), brine (50 ml) and dried (Na₂SO₄). Solvent was evaporated under reduced pressure to give 5 g (75 %) of the product as a viscous brown liquid, which was used as such for step 2.

Step 2: Oxidation of the aldehyde from step 1 with sodium chlorite (2.69 g, 29.74 mmol) and sulphamic acid (3.60 g, 37.11 mmol) as described for intermediate 1, step 2 gave 4.8 g (89 %) of the product as white crystalline solid; IR (KBr) 2983, 2650, 1693, 1600, 1514, 1467, 1427, 1385, 1226, 1118, 1030 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 3.81 (s, 3 H), 6.62 (t, J= 74.0 Hz, 1 H), 7.33 (d, J= 8.5 Hz, 1 H), 7.99-8.02 (m, 2 H).

Intermediate 6 (3S)-3-(N-Cbz-Amino)azolane-2,5-dione

To a stirred solution of Ν(α)-Cbz-L-asparagine (10 g, 37.5 mmol) dissolved in

DMF (50 ml) was added DCC (7.8 g, 37.5 mmol) and N-hydroxysuccinimide (4.4 g, 37.5 mmol) and the mixture was heated at 80 °C for 6 h. DMF was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (100 ml) and filtered to remove DCU. The filterate was washed with water (2 x 100 ml), brine (100 ml) and dried (Νa₂SO₄). The product obtained after evaporation of the solvent was purified by silica gel column chromatography using 50 % ethyl acetate in petroleum ether to give 4.2 g of the product as white solid, mp 66-69 °C; IR (KBr) 3395, 3177, 2936, 2749, 1723, 1689, 1519, 1260, 1177 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 2.81-2.89 (m, 1 H), 3.04-3.13 (m, 1 H), 4.33-4.40 (m, 1 H), 5.11 (s, 2 H), 4.63 (brs, 1 H), 7.34 (s, 5 H), 8.54 (brs, 1 H).

Intermediate 7 (3R)-3-(N-Cbz-Amino)azolane-2,5-dione

Cyclisation of N(o;)-Cbz-D-asparagine (10 g, 37.5 mmol) in the presence of DCC

(7.8 g, 37.5 mmol) and N-hydroxysuccinimide (4.4 g, 37.5 mmol) in DMF (50 ml) as described above gave 4.2 g of the product as white solid, mp 66-69 °C;

Η ΝMR (300 MHz, CDC1₃) δ δ 2.80-2.89 (m, 1 H), 3.04-3.12 (m, 1 H), 4.33- 4.41 (m, 1 H), 5.11 (s, 2 H), 4.61 (brs, 1 H), 7.34 (s, 5 H), 8.55 (brs, 1 H).

Intermediate 8

(3S)-3-(N-Cbz- Amino)- 1 -cyclohexylazolane-2,5-dione

Step 1: A mixture of N-Cbz-L-aspartic acid (1.0 g, 3.745 mmol), DCC (0.77 g, 3.737 mmol), cyclohexylamine (480 mg, 4.848 mmol) and triethylamine (500 mg, x mmol) in dry THF (25 ml) was stirred at RT for 12 h. The mixture was filtered to remove the precipitated DCU and the filterate was diluted with EtOAc (100 ml). The EtOAc solution was washed with water (2 x 100 ml), brine (50 ml) and dried (Νa₂SO₄). The solvent was evaporated under reduced pressure to give 900 mg a white solid which was used as such for the next step.

Step 2: A mixture of the above amide (750 mg, 2.155 mmol), DCC (445 mg, 2.160 mmol) and N-hydroxysuccinimide (250 mg, 2.173 mmol) in dry DMF (20 ml) was heated at 80 °C for 6 h. The mixture was evaporated under reduced pressure and the residue was diluted with EtOAc (100 ml). Filtered to remove DCU and the filterate was concentrated under reduced pressure to give an oily residue which was purified by chromatography on silica gel using 25 % EtOAc in petroleum ether as eluent to give 350 mg of the product as white solid, Intermediate 9

(3S)-3-(N-Cbz- Amino)- 1 -cyanomethylazolane-2,5-dione

To a stirred solution of the solution (3S)-3-(N-Cbz-amino-2,5-dioxoazolane (550 mg, 2.215 mmol) in dry DMF (10 ml) was added cesium hydroxide monohydrate (446 mg, 2.658 mmol) and the mixture was stirred at rt for 10 min. Chloroacetonitrile (230 mg, 3.046 mmol) was added and further stirred at rt for 1.5 h. The reaction mixture was quenched with ice cold water and acidified with IN HC1. The mixture was extracted with ethyl acetate (2 x 20 ml). The organic layer was washed with water (20 ml) and brine (20 ml) and dried (Νa₂SO₄). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 25 % EtOAc in petroleum ether as eluent to give 452 mg of the product as white solid; IR (KBr) 3370, 2949, 2242, 1721, 1523, 1261, 1171 cm ^"1; 1H NMR (300 MHz, CDC1₃) δ 2.91 (dd, J= 18.3, 5.7 Hz, 1 H), 3.15 (dd, J = 18.3, 9.2 Hz, 1 H), 4.30-4.37 (m, 1 H), 4.42 (s, 2 H), 5.05 (dd, J = 14.7, 12.0, 2 H), 5.58 (brs, 1 H), 7.32-7.39 (m, 5 H).

Intermediate 10

(3S)-3-(N-Cbz- Amino)- 1 -phenylazolane-2,5-dione

Step 1: A mixture of N-Cbz-L-aspartic acid (1.0 g, 3.745 mmol), DCC (840 mg, 4.077 mmol), freshly distilled aniline (420 mg, 4.516 mmol) and triethylamine (500 mg, 4.950 mmol) in dry THF (20 ml) was stirred at RT for 12 h. The mixture was filtered to remove the precipitated DCU and the filterate was diluted with EtOAc (100 ml). The EtOAc solution was washed with water (2 x 100 ml), brine (50 ml) and dried (Νa₂SO₄). The solvent was evaporated under reduced pressure to give 450 mg of the amide as white solid, which was used as such for the next step. Step 2: A mixture of the above amide (450 mg, 1.315 mmol), DCC (280 mg, 1.359 mmol) and N-hydroxysuccinimide (160 mg, 1.391 mmol) in dry DMF (10 ml) was heated at 80 °C for 6 h. The mixture was evaporated under reduced pressure and the residue was diluted with EtOAc (100 ml). Filtered to remove DCU and the filterate was concentrated under reduced pressure to give an oily residue which was purified by chromatography on silica gel using 25 % EtOAc in petroleum ether as eluent to give 300 mg of the product as white solid, Η ΝMR (300 MHz, CDC1₃) δ 2.98 (dd, J= 18.3, 6.0 Hz, 1 H), 3.26 (dd, J= 18.0, 9.3 Hz, 1 H), 4.40-4.47 (m, 1 H), 5.12 (dd, J = 15.0, 12.0 Hz, 2 H), 5.58 (brs, 1 H), 7.31- 7.46 (m, 10 H).

Intermediate 11

(2S)-2-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-3- methyloxycarbonylmethyl-carbamoylpropanoic acid

This intermediate was prepared in two steps from L-aspartic acid as follows.

Steps 1: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared as follows: To a well stirred solution of 3-Cyclopentyloxy-4-methoxybenzoic acid (2.0 g, 8.474 mmol) in dry benzene (20 ml) was added oxalyl chloride (1.45 g, 12.711 mmol) at RT. The reaction was initiated with a drop of dry DMF and stirred at RT for 1 h under nitrogen atmosphere. The solvent was removed under reduced pressure to give the acid chloride quantitatively as a viscous residue, which was used as such for the coupling reaction.

Step 2: Preparation of (2S)-2-(3-Cyclopentyloxy-4-methoxyphenylcarbox- amido)butane-dioic acid: To a stirred solution of L-aspartic acid in water was added potassium hydroxide (0.4 g, 7.142 mmol) and potassium carbonate (1.0 g,

7.246 mmol) at room temperature. A solution of acid chloride (step 1) in THF (30 ml) was added drop-wise to the above solution and the mixture was stirred at RT for 24 h. The mixture was neutralized with aq. HC1 to pH 2. The aqueous solution was extracted with EtOAc (2 x 100 ml). The EtOAc solution was washed with water (2x100 ml), brine (50 ml) and dried (Na₂SO₄). The crude product obtained after evaporation of the solvent was purified by crystallization from diethyl ether to give 800 mg of the product as white solid, mp 145-148 °C; IR (KBr) 3299, 2962, 1709, 1631, 1506, 1274, 1230, 1140 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.60-1.67 (m, 2 H), 1.74-1.96 (m, 6 H), 2.94 (dq, J= 14.4, 7.5 Hz, 2 H), 3.85 (s, 3 H), 4.83-4.94 (m, 2 H), 6.97 (d, J= 8.4 Hz, 1 H), 7.40-7.45 (m, 2 H).

Step 3: To a stirred solution of the above dicarboxylic acid (400 mg, 1.39 mmol) in dry THF (30 ml) was added DCC (260 mg, 1.262 mmol) and N-hydroxy succinimide (85 mg, 0.739 mmol) and the mixture was stirred at RT for 15 min. Glycine methyl ester (145 mg, 1.629 mmol) and triethylamine (1.0 g, 9.900 mmol) were added and the mixture was stirred at RT for 2 h. The mixture was filtered and the filterate was diluted with EtOAc (100 ml). The EtOAc solution was washed with water (2 x 100 ml), brine (50 ml) and dried (Νa₂SO₄). The crude product obtained after evaporation of the solvent was purified by chromatography on silica gel using 50 % EtOAc in petroleum ether as eluent to give 120 mg of the product as white solid, mp 160-162 °C; IR (KBr) 3338, 3088, 2954, 1751, 1629, 1508, 1227, 1025 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.64-1.98 (m, 8 H), 2.79 (dd, J= 17.1, 6.9 Hz, 1 H), 3.14 (dd, J= 17.9, 5.7 Hz, 1 H), 3.72 (s, 3 H), 3.88 (s, 3 H), 4.04 (d, J= 5.4 Hz, 2 H), 4.81-4.88 (m, 1 H), 5.03-5.09 (m, 1 H), 6.84 (d, J = 8.2 Hz, 1 H), 7.30-7.40 (m, 2 H), 7.55 (d, J= 8.3 Hz, 1 H).

Intermediate 12 (3S)-3-(N-BOC-Amino)-l-benzylazolan-2-one

This intermediate was prepared in 3 steps from N-BOC-L- methionine as described below. Step 1: Preparation of N-l-Benzyl-(2S)-2-amino-4-methylsulfanylbutanamide

To a stirred solution of BOC-methionine (1.0 g, 4.016 mmol) in DMF (10 ml) was added DCC (830 mg, 4.028 mmol) and N-hydroxy succinimide (490 mg, 4.260 mmol) and the mixture was stirred at room temperature for 30 min. Benzyl amine (850 mg, 7.943 mmol) and triethylamine (1.45 g, 14.376) were added to the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc (150 ml) and filtered to remove the precipitated DCU. The filterate was washed with IN HC1 (50 ml), water (100 ml) and brine (50 ml). The residue obtained after evaporation of the solvent was purified by crystallization from chloroform-hexane to yield 600 mg of the product as white solid; Η ΝMR (300 MHz, CDC1₃) δ 1.42 (s, 9 H), 1.88-2.03 (m, 1 H), 2.07 (s, 3 H), 2.08-2.18 (m, 1 H), 2.46-2.63 (m, 2 H ), 4.24-4.29 (m, 1 H), 4.44 (d, J= 5.7 Hz, 2 H), 5.18- 5.22 (m, 1 H ), 6.59 (brs, 1 H), 7.23-7.34 (m, 5 H).

Step 2: Preparation of (3S)-3-(N-BOC-amino)-3- benzylcarbamoylpropyl(dimethyl)-sulfonium iodide

A mixture of N-benzyl methionine (550 mg, 1.627 mmol) and methyl iodide (5 ml, x mmol) in dichloromethane (10 ml) was stirred under nitrogen atmosphere for 6 h. The mixture was concentrated under reduced pressure to give 800 mg of the crude product as semisolid, IR (KBr) cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.41 (s, 9 H), 1.73-1.78 (m, 1 H), 2.54-2.62 (m, 1 H), 3.04 (s, 3 H ), 3.22 (s, 3 H), 3.40-3.52 (m, 1 H), 3.68-3.76 (m, 1 H), 4.41 (d, J= 6.0 Hz, 2 H ), 4.49 (m, 1 H ), 6.09 (d, J= 6.6 Hz, 1 H), 7.21-7.35 (m, 5 H ), 8.18 (brs, IH). Step 3: (3S)-3-(N-BOC-Amino)-l-benzylazolan-2-one: To a stirred and cooled (0 °C) solution of sulfonium salt intermediate (800 mg, 1.66 mmol) in DMF (30 ml) was added sodium hydride (150 mg, 3.125 mmol) in one portion and the mixture was stirred at 0 °C - RT for 1 h. The reaction mixture was quenched with saturated aqueous ΝF tCl solution (50 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with water (2 x 100 ml), brine (50 ml) and dried (Νa₂SO₄). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 25-30 % EtOAc in petroleum ether to give 450 mg of the product as white solid, mp x °C; IR (KBr) 3303, 2954, 1770, 1688, 1509, 1269, 1022 cm^"1; Η NMR (CDC1₃) d 1.44 (s, 9 H), 1.77-1.88 (m, 1 H), 2.54-2.62 (m, 1 H), 3.19 (dd, J= 9.0, 6.0 Hz, 1 H), 4.15-4.22 (m, 1 H), 4.46 (d, J= 9 Hz, 2 H), 5.41 (brs, 1 H), 7.18-7.34 (m, 5 H).

Intermediate 13 (3S)-3-(N-BOC-Amino)-5-oxoazolane

This intermediate was prepared in 3-steps from N-BOC-L-aspartic acid 4-methyl ester as described below

Step 1: Preparation of Methyl (3S)-3-(N-BOC-amino-4-hydroxybutanoate

Ethyl chloroformate (1.30 g, 11.981 mmol) was added to a well stirred solution of N-BOC-L-aspartic acid 4-methyl ester (2.8 g, 11.324 mmol) and N- methylmoφholine (1.21 g, 11.962 mmol) in dry THF (20 ml) at -10 °C. The reaction mixture was further stirred for 15 min at the same temperature. The reaction mixture was cooled to -15 °C and ΝaBH₄ (0.6 g, 15.860 mmol) was added in one portion. Dry methanol (10 ml) was added drop wise over a period of 20 min at the same temperature. The mixture was further stirred at -15 to -10 °C for 30 min. The mixture was quenched with IN hydrochloric acid to pH 2 and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts were washed with water (3 x 100 ml), brine (50 ml) and dried (Νa₂SO₄). The solvent was evaporated under reduced pressure to give 1.6 g of the crude alcohol as a viscous liquid which was used as such for the next step.

Step 2: Methyl (3S)-3-(N-BOC-amino)-4-azidobutanoate

Methanesulfonyl chloride (1.17 g, 10.288 mmol) was added to a well-stirred and cooled (5 °C) solution of the above alcohol (1.6 g, 6.859 mmol) and triethylamine (2.07 g, 20.577 mmol) in dry dichloromethane (50 ml) under nitrogen atmosphere. The mixture was allowed to warm to RT over a period of 10 min and further stirred at RT for 3 h. The reaction was diluted with dichloromethane (100 ml) and washed with water (3 x 100 ml) followed by brine (50 ml). The extract was dried (Na₂SO₄) and the solvent was evaporated to give the crude mesylate, which was used as such for next step.

A mixture of crude mesylate from the above step and sodium azide (450 mg, 6.923 mmol) in dry DMF (50 ml) was stirred at 80 °C for 12 h under nitrogen atmosphere. The mixture was cooled to RT, diluted with water (150 ml) and extracted with ethyl acetate (2 x 100 ml). The combined EtOAc extracts were washed with water (2 x 100 ml) followed by brine (50 ml). The organic extract was dried (Na₂SO₄) and the solvent was evaporated under reduced pressure to give the crude product. This crude product was purified by silica gel column chromatography using 15 % EtOAc in petroleum ether to give 600 mg of the azide as a semisolid.

Step 3: To a solution of azido ester (600 mg, 2.323 mmol) in methanol (20 ml) was added 10 % Pd/C (20 mg) and the mixture was agitated under 40 psi hydrogen gas pressure for 1 h in Paar hydrogenation apparatus. The reaction mixture was filtered through a celite bed and the filtrate was evaporated under reduced pressure to give the crude product. The crude product was purified by chromatography on silica gel using 10 % methanol in chloroform to give 200 mg of the product as white solid, mp 164-167 °C; IR (KBr) 3327, 2980, 1685, 1543, 1276, 1170 cm ^"'; ^lU NMR (300 MHz, CDC1₃) δ 1.44 (s, 9 H), 2.19 (dd, J= 17.1, 5.2 Hz, 1 H), 2.68 (dd, J= 17.1, 8.1 Hz, 1 H), 3.24 (dd, J= 9.9, 4.2 Hz, 1 H), 3.70 (dd, J= 9.9, 6.3 Hz, 1 H), 4.36-4.42 (m, 1 H), 4.86 (brs, 1 H), 5.90 (brs, 1 H).

Intermediate 14

(3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione

To a stirred solution of N(α)-Cbz-L-glutamine (24 g, 85.71 mmol) in dry DMF (240 ml) was added DCC (19.5 g, 94.66 mmole) and N-hydroxysuccinimide (10.87g, 94.66 mmol) and the mixture heated at 80 °C for 18 h. The reaction mixture was cooled to RT and filtered to remove the precipitated DCU. The filterate was diluted with EtOAc (100 ml) and washed with water (3 x 100 ml), brine (50 ml) and dried (Νa₂S0 ). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 30 % ethyl acetate in chloroform to give 15 g of the product as white solid, IR (KBr) 3424, 3257, 1708, 1679, 1527, 1194, 1038 cm ^_1; Η NMR (300 MHz, CDC1₃) δ 1.81- 1.95 (m, 1 H), 2.53-2.86 (m, 3 H), 4.30-4.39 (m, 1 H), 5.13 (s, 2 H), 6.68 ( brs, 1 H, D₂O exchangeable), 7.56 (s, 5 H), 8.16 (brs, 1 H, D₂O exchangeable).

Intermediate 15 (3R)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione

Cycalastion of Ν(α)-Cbz-D-glutamine (4 g, 14.28 mmol) in presence of DCC (3.25 g, 15.77 mmol) and N-hydroxysuccinimide (1.81 g, 15.77 mmol) in dry DMF (50 ml) as described above gave 2.5 g of the product as white solid; IR (KBr) 3424, 3257, 1708, 1679, 1527, 1194, 1038 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.82-1.94 (m, 1 H), 2.53-2.84 (m, 3 H), 4.30-4.40 (m, 1 H), 5.13 (s, 2 H), 6.67 (brs, 1 H, D₂O exchangeable), 7.58 (s, 5 H), 8.14 (brs, 1 H, D₂O exchangeable).

Intermediate 16

(3S)-3-(N-Cbz- Amino)- 1 -ethylhexahydro-2,6-pyridinedione

A mixture of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (200 mg, 0.76 mmol), ethyl iodide (130 mg, 0.83 mmol), potassium carbonate (160 mg, 1.15 mmol) and tetrabutylammonium iodide (30 mg, 0.076 mmol) in dry acetone was stirred at RT for 48 h under nitrogen. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with water (100 ml), brine (50 ml) and dried (Νa₂SO ). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 30 % ethyl acetate in petroleum ether to give 130 mg of the product as white solid; IR (KBr) 3304, 2932, 1732, 1691, 1325, 1212 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.08-1.13 (t, 3 H), 1.72-1.87 (m, 1 H), 2.50-2.80 (m, 3 H), 3.71-3.90 (m, 2 H), 4.25-4.33 (m, 1 H), 5.12 (s, 2 H), 5.69 (s, 1 H), 7.35 (s, 5 H).

Intermediate 17

Ethyl 2-[(3S)-3-(N-Cbz-Amino)-2,6-dioxohexahydro-l-pyridinyl]acetate

Alkylation of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (300 mg, 1.14 mmol) with ethyl bromoacetate (282 mg, 1.71 mmol), in the presence of potassium carbonate (240 mg, 1.34 mmol) and tetrabutylammonium iodide (45 mg, 0.11 mmol) in dry acetone (10 ml) as described in the case of intermediate 12 gave 250 mg (83 %) of the product as off-white solid, IR (KBr) 3273, 2958, 1752, 1734, 1693, 1554, 1266, 1166 cm ^"1. Η ΝMR (300 MHz, CDC1₃) δ 1.26 (t, J= 7.5 Hz, 3 H), 1.86-2.01 (m, 1 H), 2.52-2.94 (m, 3 H), 4.17 (q, J= 7.2 Hz, 2 H), 4.41-4.57 (m, 3 H), 5.12 (s, 2 H), 5.66 (s, 1 H), 7.34 (s, 5 H).

Intermediate 18

(3S)-3-(N-Cbz-Amino)-l-(4-pyridylmethyl)hexahydro-2,6-pyridinedione

Alkylation of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (300 mg, 1.14 mmol), 4-with picolyl chloride hydrochloride (282 mg, 1.71 mmol) in the presence of potassium carbonate (475 mg, 3.44 mmol) and tetrabutylammonium iodide (30 mg, 0.076 mmol) in dry acetone (10 ml) as described in the case of intermediate 12 gave 300 mg of the product as white solid, IR (KBr) 3200, 2951, 1719, 1677, 1538, 1266, 1165 cm ^"1. Η ΝMR (300 MHz, CDC1₃) δl.77-1.95 (m, 1 H), 2.51-2.96 (m, 3H), 4.33-4.40 (m, 1 H), 4.92 (q, J = 5.7 Hz, 2 H), 5.12 (s, 2 H), 5.68 (s, 1 H), 7.18 ( d, J= 5.7 Hz, 2 H), 7.34 (s, 5 H), 8.50 (d, J = 5.7 Hz, 2 H). Intermediate 19 (3S)-3-(N-Cbz-Amino)-l-(2,6-dichlorobenzyl)hexahydro-2,6-pyridinedione

Alkylation of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (600 mg, 2.29 mmol) with 2,6-dichlorobenzyl bromide ( 660 mg, 2.75 mmol) in the presence of potassium carbonate (480 mg, 3.47 mmol) and tetrabutylammonium iodide (85 mg, 0.23 mmol) in dry acetone (10 ml) as described in the case of intermediate 12 gave 400 mg of the product as white solid; IR (KBr) 3250, 2901, 1705, 1687, 1520, 1432, 1230, 1020 cm ^"'; 1H ΝMR (300 MHz, CDC1₃) δ 1.75-1.90 (m, 1 H), 2.49-2.60 (m, 1 H), 2.67-2.92 (m, 2 H), 4.30-4.37 (m, 1 H), 5.09 (s, 1 H), 5.22 (d, J- 3.9 Hz, 2 H), 5.66 (s, 1 H), 7.08-7.14 (m, 1 H), 7.24 (m, 6 H).

Intermediate 20

(3S)-3-(N-BOC-Amino)-2-oxohexahydropyridine

Step 1: Freshly distilled thionyl chloride (10.60 g, 89.08 mmol) was added to the stirred slurry of L-Ornithine hydrochloride (5 g, 29.65 mmole) in dry methanol (50 ml) at room temperature to result a clear solution. The solution was refluxed for 1 h and excess thionyl chloride and methanol was removed under reduced pressure to give 7 g 5-Methyl (S)-2,5-diaminopentanoate dihydrochloride as a white solid, which was used as such for step 2.

Step 2: Triethylamine (12 g, 119 mmol) was added to a well-stirred solution of step 1 intermediate in methanol (200 ml) at room temperature and the mixture stirred for 1 h under nitrogen atmosphere. Di-tert-butyl dicarbonate (7.1 g, 32.56 mmol) in methanol (7 ml) was added to the reaction mixture and the mixture was stirred at RT for 18 h under nitrogen atmosphere. Methanol and excess reagents were evaporated under reduced pressure and the residue obtained was diluted with ethyl acetate (200 ml). This ethyl acetate solution was washed with water (3 x 300 ml) followed by brine (100 ml) and dried over Na₂SO₄. This crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 1-2 % methanol in chloroform to give 3.8 g of 3S)-3-(N- BOC-Amino)-2-oxohexahydropyridine as semi solid, IR (neat) 3405, 3017, 1706, 1672, 1491, 1216, 1166, 986 cm-¹; Η ΝMR (300 MHz, CDC1₃) δl.42 (s, 9 H), 1.51-1.63 (m, 2 H), 1.83-1.95 (m, 2 H), 2.44 (m, 1 H ), 3.28-3.33 (m, 2 H), 3.97- 3.09 (m, 1 H), 5.40 (brs, 1 H, D₂O exchangeable), 5.89 (brs, 1 H, D₂O exchangeable).

Intermediate 21

(3S)-3-(N-BOC-Amino)- 1 -phenyl-2-oxohexahydropyridine

A mixture containing (3S)-3-(N-BOC-Amino)-2-oxohexahydropyridine (2 g, 9.34 mmol), iodobenzene (2.3 g, 11.27 mmol), potassium phosphate (4 g, 18.84 mmol), copper(I)iodide (712 mg, 3.73 mmol), and 1,2-diaminoethane (224 mg, 3.73 mmol) in dry 1,4-dioxane (30 ml) was stirred at 100-110 °C for 24 h under nitrogen atmosphere. The reaction was cooled to RT and diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml) and combined ethyl acetate solution was washed with water (3 x 200 ml) followed by brine solution (100 ml) then dried over Νa₂SO₄. The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 2 % methanol in chloroform to give 1.8 g of the product as a white solid, IR (KBr) 3285, 2969, 1716, 1650, 1493, 1365, 1253, 1164, 767 cm-¹; Η NMR (300 MHz, CDC1₃) δ 1.45 (s, 9 H), 1.66-1.77 (m, 1 H), 1.99-2.08 (m, 2 H) 2.55-2.66 (m, 1 H), 3.67-3.72 (m, 2 H), 4.20-4.28 (m, 1 H), 5.52 (brs, 1 H, D₂O exchangeable), 7.20-7.26 (m, 3 H), 7.34-7.39 (m, 2 H). Intermediate 22 (3S)-3-(N-BOC-Amino)-6-oxohexahydropyridine

This intermediate was prepared in 3 steps starting from N-BOC-L-glutamic acid

5-methyl ester as described below.

Step 1: Preparation of Methyl (4S)-4-(N-BOC-amino) 5-hydroxypentanoate

Ethyl chloroformate (5.76 g, 53.07 mmol) was added to the well stirred solution of N-BOC-L-glutamic acid 5-methyl ester (12 g, 48.19 mmol) and N- methylmoφholine (5.4 g, 53.38 mmol) in dry THF (120 ml) at 0 °C for period of 10 min under nitrogen atmosphere. The reaction mixture was further stirred for 15 min at the same temperature. The reaction mixture was cooled to -15 °C and ΝaBFL; (5.5 g, 145 mmol) was added in one portion. Dry methanol was added drop wise over a period of 20 min. at the same temperature. The mixture was further stirred at -15 to -10 °C for 30 min. The mixture was quenched with IN hydrochloric acid and extracted with ethyl acetate (2 x 300 ml). The combines organic extracts were washed with water (3 x 600 ml), brine (300 ml) and dried (Νa₂SO₄). This crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 2 % methanol in chloroform as eluent to give the alcohol (6.6 g) as a semisolid, IR (neat) 3367, 1977, 1692, 1525, 1452, 1367, 1250, 1171, 1058, 1030 cm^'1; Η NMR (300 MHz, CDC1₃) δ 1.43 (s, 9 H), 1.76-1.90 (m, 2 H), 2.41(dt, J = 5.4, 1.5 Hz, 2 H), 2.51 (brs, 1 H, D₂O exchangeable), 3.54-3.65 (m, 2 H), 3.68 (s, 3 H), 4.81 (brs, 1 H, D₂O exchangeable). Step 2: Preparation of Methyl 5-azido-(4S)-4-(N-BOC-amino)pentanoate

Methanesulfonyl chloride (3.86 g, 33.71 mmol) was added to a well-stirred and cooled (5 °C) solution of the above alcohol (6.4 g, 25.91mmol) and triethylamine (5.3 g, 52.47 mmol) in dry dichloromethane (100 ml) under nitrogen atmosphere. The mixture was allowed to warm to RT over a period of 10 min and further stirred at RT for 30 min. The reaction was diluted with dichloromethane (100 ml) and washed with water (3 x 200 ml) followed by brine (100 ml). The extract was dried (Νa₂SO₄) and the solvent was evaporated to give the crude mesylate, which was used as such for next step.

A mixture of crude mesylate and sodium azide (2.02 g, 31.07 mmol) in dry DMF (100 ml) was stirred at 60-70 °C for 18 h under nitrogen atmosphere. The mixture was cooled to RT, diluted with water (300 ml) and extracted with ethyl acetate (2 x 300 ml). The combined EtOAc extracts were washed with water (3 x 600 ml) followed by brine (300 ml). The organic extract was dried (Na₂SO ) and the solvent was evaporated under reduced pressure to give the crude product. This crude product was purified by silica gel column chromatography using 15 %

EtOAc in petroleum ether to give the azide (3.9 g) as a semi solid, IR (KBr) 3341,

2989, 2097, 1732, 1682, 14446, 1303, 1249, 1166, 1060 cm^"1; Η NMR (300

MHz, CDC1₃) δ 1.44 (s, 9 H), 1.74-1.92 (m, 2 H), 2.40 (t, J= 7.5 Hz, 2 H), 3.36-

3.43 (m, 2 H), 3.60 (s, 3 H), 3.70-3.77 (m, 1 H), 4.61 (br s, 1 H, D₂O exchangeable).

Step 3: To a solution of azido ester (3.8 g, 14.73 mmol) in methanol (100 ml) was added 10 % Pd/C carbon (100 mg) and the mixture was agitated under 40 psi hydrogen pressure for 1 h in Paar hydrogenation apparatus. The reaction mixture was filtered through a celite bed and the filtrate was evaporated under reduced pressure to give the pyridone (2.81 g) as a white solid, Η NMR (300 MHz, CDC1₃) δ 1.44 (s, 9 H), 1.79-1.92 (m, 1 H), 1.96-2.06 (m, 1 H), 2.46 (t, J= 6.9 Hz, 2 H), 3.12-3.18 (m, 1 H), 3.50-2.58 (m, 1 H), 3.93-4.01 (m, 1 H), 4.75 (brs, 3 H, D₂O exchangeable), 6.19 (brs, 1 H, D₂O exchangeable).

Intermediate 23

(3S)-3-(N-BOC-Amino)- 1 -phenyl-6-oxohexahydropyridone

A mixture (3S)-3-(N-BOC-Amino)-6-oxohexahydropyridine (1.5 g, 7.01 mmol), iodobenzene (1.60 g, 7.84 mmol), potassium phosphate (2.98 g, 14.02 mmol), Cu(I)I (267 mg, 1.40 mmol), ethane 1,2-diamine (84 mg, 1.40 mmol) in dry 1,4- dioxane (30 ml) was stirred at 100-110 °C for 48 h under nitrogen atmosphere. The reaction mixture was cooled to RT and diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with water (3 x 200 ml) followed by brine solution (100ml) and dried (Νa₂SO₄). This crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 1-2 % methanol in chloroform to give the N-phenyl intermediate (900 mg) as white solid, IR (KBr) 3300, 2963, 1640, 1554, 1450, 1241, 1160, 1019, 794 cm^"1; Η ΝMR (300 MHz, CDC1₃) δ 1.44 (s, 9 H), 1.87-1.97 (m,l H), 2.10-2.20 (m, 1 H), 2.64 (t, J= 6.9 Hz, 2 H), 3.50 (dd, J= 7.5, 4.5 Hz, 1 H), 3.85 (dd, J= 7.8, 3.9 Hz, 1 H), 4.05-4.20 (m, 1 H), 7.76 (d, J= 7.2 Hz, 1 H, D₂O exchangeable), 7.19-7.26 (m, 3 H), 7.32-7.39 (m, 2 H).

Examples Example - 1

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxoazolane

Step 1: (3S)-3-Aminoazolane-2,5-dione was prepared as follows: To a solution of (3S)-3-(N-Cbz-amino)azolane-2,5-dione ( 4.0 g, 16.12 mmol) in methanol (40 ml) was added 5 % palladium on carbon (50 mg) and was stirred under 20 psi hydrogen pressure for 4 h. The mixture was filtered through a celite bed to remove the catalyst. The solvent was evaporated under reduced pressure to give 1.6 g of the product as pale yellow viscous liquid which was used as such for the next step.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared as follows: To a well stirred solution of 3-Cyclopentyloxy-4-methoxybenzoic acid (3.80 g, 16.10 mmol) in dry benzene (50 ml) was added oxalyl chloride (3.04 g, 24.12 mmol) at room temperature. The reaction was initiated with a drop of dry DMF and stirred at rt for 1 h under nitrogen atmosphere. The solvent was evaporated under reduced pressure to give the acid chloride quantitatively as a viscous residue, which was used as such for the coupling reaction.

Step 3: Reaction of (3S)-3-Aminoazolane-2,5-dione with 3-Cyclopentyloxy-4- methoxybenzoyl chloride: The benzoyl chloride derivative (step 2) was added to a stirred solution of aminoazolane (step 1) and triethylamine (2.2 g, 21.782 mmol ) in dry DCM (100 ml) at 0 °C. The mixture was allowed to warm to room temperature over a period of 1 h. The crude product obtained after evaporation of the solvent was purified by chromatography on silica gel using 4 % methanol in chloroform as eluent to give 3.42 g (64 %) of the product as off- white solid, mp 230-232 °C; Η ΝMR (300 MHz, CDC1₃) δ 1.60-1.91 (m, 8 H), 2.60 (dd, J = 12.0, 5.4 Hz, 1 H) , 2.92 (dd, J= 12.0, 9.0 Hz, 1 H), 3.78 (s, 3 H ), 4.48-4.58 (m, 1 H), 4.79-4.92 (m, 1 H), 7,00 (d, J = 8.4 Hz, 1 H), 7.37 (s, 1 H ), 7.44 (dd, J = 8.1, 1.2 Hz, 1 H), 8.96 (d, J= 8.0 Hz, 1 H), 11.25 (s, 1 H).

Example 2 (3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxoazolane

Step 1 : (3R)-3-Aminoazolane-2,5-dione was prepared by deprotection of (3R)-3- (N-Cbz-amino)azolane-2,5-dione (2.0 g, 8.06 mmol) using 5 % Pd/C (30 mg) in methanol (25 ml) under 20 psi hydrogen pressure for 4 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (1.9 g, 8.05 mmol) using oxalyl chloride (1.5 g, 11.90 mmol) in dry benzene (30 ml) catalysed by DMF at RT.

Step 3: Coupling Reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (1.2 g, 11.881 mmol) in dry DCM (50 ml) at 0°C. The crude product obtained was purified by silica gel column chromatography using 4 % methanol in chloroform to give 1.8 g (67 %) of the product as off-white solid, mp 230-232 °C; Η ΝMR (300 MHz, CDC1₃) δ 1.60-1.91 (m, 8 H), 2.60 (dd, J = 12.0, 5.4 Hz, 1 H), 2.92 (dd, J= 12.0, 9.0 Hz, 1 H), 3.78 (s, 3 H ), 4.48-4.58 (m, 1 H), 4.79-4.92 (m, 1 H), 7,00 (d, J= 8.4 Hz, 1 H), 7.37 (s, 1 H ), 7.44 (dd, J= 8.1, 1.2 Hz, 1 H), 8.96 (d, J= 8.0 Hz, 1 H), 11.25 (s, 1 H).

Example - 3

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-methyl-2,5- dioxoazolane

To a stirred solution of the solution (3S)-3-(3-cyclopentyloxy-4- methoxyphenycarboxamido)-2,5-dioxoazolane (150 mg, 0.45 mmol) in dry DMF (2 ml) was added cesium hydroxide monohydrate (80 mg, 0.45 mmol) and the mixture was stiπed at rt for 10 min. Methyl iodide (130 mg, 0.9 mmol) was added and further stiπed at rt for 1.5 h. The reaction mixture was quenched with ice cold water and acidified with IN HC1. The mixture was extracted with ethyl acetate (2 x 20 ml). The combined organic layer was washed with water (20 ml) and brine (20 ml) and dried (Νa₂SO₄). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 2 % methanol in chloroform to give 60 mg (57 %) of the product as white solid, mp 104-107 °C; Η NMR (300 MHz, CDC1₃) δ 1.59-1.96 (m, 8 H ), 2.90 (dd, J = 12.0, 6.1 Hz, 1 H), 3.09 (s, 3 H), 3.19 (dd, J= 12.0, 9.0 Hz, 1 H), 3.88 (s, 3 H), 4.44-4.51 (m, 1 H), 4.79-4.92 (m, 1 H), 6.73 (d, J= 6.2 Hz, 1 H), 6.83 (d, J = 6.2 Hz, 1 H), 7.26 (s, 1 H ), 7.35 (d, J= 2.0 Hz, 1 H); m/z 347 (MH⁺, 100 %), 219 (40).

Example - 4

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-cyclopropylmethyl- 2,5-dioxoazolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.30 mmol) with cyclopropylmethyl bromide (80 mg, 0.60 mmol) using cesium hydroxide (50 mg, 0.30 mmol) as described in example 3 followed by chromatography on silica gel (chloroform) gave 60 mg (52 %) of the product as white solid, mp. 108-110 °C; IR (KBr) 3350, 3210, 2936, 2234, 1517, 1258 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 0.36-0.38 (m, 2 H), 0.49-0.55 (m, 2 H), 1.15-1.21 (m, 1 H), 1.58-1.98 (m, 8 H), 2.88 (dd, J = 12.0, 6.0 Hz, 1 H), 3.22 (dd, J = 18.0, 9 Hz, 1 H), 3.45 (d, J= 7.2 Hz, 2 H), 3.87 (s, 3 H), 4.52-4.58 (m,l H), 4.79-4.83 (m, 1 H), 6.71 (d, J= 5.4 Hz, 1 H), 6.83 (d, J= 8.4, 1 H), 7.28 (d, J = 2.4 Hz, 1 H ), 7.36 (d, J = 2.4 Hz, 1 H).

Example - 5 (3S)-l-Cyclohexyl-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane

Step 1 : (3S)-3-Amino-l-cyclohexylazolane-2,5-dione was prepared by deprotection of (3S)-3-(N-Cbz-amino)-l-cyclohexylazolane-2,5-dione (350 mg, 1.060 mmol) using 5 % Pd/C (25 mg) in methanol (25 ml) under 20 psi hydrogen pressure for 4 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (250 mg, 1.058 mmol) using oxalyl chloride (245 mg, 2.258 mmol) in dry benzene (10 ml) catalysed by DMF at RT. Step 3: Coupling Reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (500 mg, 4.950 mmol) in dry DCM (50 ml) at 0 °C. The crude product obtained was purified by crystallization from diethyl ether to give 50 mg of the product as off-white solid, mp 135-138 °C; IR (KBr) 3294, 2933, 1776, 1704,1649, 1504, 1268 cm ^"'; Η ΝMR (300 MHz, CDC1₃) 0.95-0.98 (m, 1 H ), 1.21-1.48 (m, 7 H), 1.64-2.07 (m, 8 H ), 2.19-2.32 (m, 1 H ), 2.92 (dd, J = 18.0, 9.0 Hz, 1 H), 3.24 (dd, J = 18.0, 9.0 Hz, 1 H), 3.97 (s, 3 H), 4.09-4.17 (m, 1 H), 4.48-4.55 (m, 1 H ), 4.89-4.92 (m, 1 H ), 6.81 (d, J= 3.0 Hz, 1 H), 6.91 (d, J= 9.0 Hz, 1 H) 7.43 (s, 1 H), 7.45 (d, J= 3.0 Hz, 1 H). Example - 6

(3S)-l-Cyanomethyl-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane

Step 1: (3S)-3-Amino-l-cyanomethylazolane-2,5-dione was prepared by deprotection of (3S)-3-(N-Cbz-amino)-l-cyanomethylazolane (200 mg, 0.696 mmol) using 5 % Pd/C (15 mg) in methanol (10 ml) under 20 psi hydrogen pressure for 3 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (165 mg, 0.698 mmol) using oxalyl chloride (113 mg, 1.041 mmol) in dry benzene (5 ml) catalysed by DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (200 mg, 1.980 mmol) in dry DCM (10 ml) at 0 °C. The crude product obtained was purified by silica gel column chromatography using 25 % EtOAc in petroleum ether to give 80 mg of the product as white solid, mp 56-59 °C; IR (KBr) 3384, 2960, 2234, 1783, 1713, 1650, 1504, 1271, 1021 cm ^-1; Η ΝMR (300 MHz, CDC1₃) δ 1.72-1.96 (m, 8 H ), 2.99 (dd, J = 18.0, 9.0 Hz, 1 H), 3.20 (dd, J = 18.0, 9.0 Hz, 1 H), 3.87 (s, 3 H), 4.46 (d , J = 3.0 Hz, 2 H),4.46-4.53 (m, 1 H), 4.75-4.80 (m, 1 H), 6.82 (d, J= 9.0 Hz, 1 H), 7.09 (d, J = 6.2 Hz, 1 H), 7.25 (d, J= 1.8 Hz, 1 H), 7.30 (d, J= 1.8 Hz, 1 H); m/z 371 (MH ^", 100 %),

Example - 7

Methyl 2-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolan-1 -yl]acetate

To a stirred solution of (2S)-2-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)- 3-methyloxy-carbonylmethylcarbamoylpropanoic acid (250 mg, 0.591 mmol) was added DCC (125 mg, 0.606 mmol) and N-hydroxysuccinimide (70 mg, 0.608 mmol) and the mixture was heated at 80 °C for 4 h. The mixture was evaporated under reduced pressure and the residue was diluted with EtOAc (100 ml). The EtOAc solution was washed with water (2 x 100 ml), brine (50 ml), and dried (Νa₂SO₄). The crude product obtained after evaporation of the solvent was purified by chromatography on silica gel using 40 % EtOAc as eluent gave x mg of the product as white solid, mp 165-167 °C; IR (KBr) 3319, 2962, 1745, 1720, 1633, 1511, 1228 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 1.59-1.97 (m, 8 H ), 2.96 (dd, J= 12.0, 6.0 Hz, 1 H), 3.26(dd, J= 18.0, 9.0 Hz, 1 H), 3.77 (s, 3 H), 3.87 (s, 3 H), 4.36 (s, 2 H), 4.63-4.70 (m, 1 H), 4.75-4.85 (m, 1 H), 6.82 (d, J = 9.0 Hz, 1 H), 6.91 (d, J = 6.0 Hz, 1 H), 7.27 (s, 1 H ), 7.35 (d, J = 2.0 Hz, 1 H); m/z 347 (MH⁺, 100 %), 219 (40).

Example - 8 2-[(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxoazolan- 1 - yl]acetic acid

To a stirred solution of ester 7 (80 mg, 0.198 mmol) in methanol (5 ml) was added 2N sodium hydroxide solution (3 ml) and the mixture was stiπed at room temperature for 2 h. Methanol was evaporated under reduced pressure and the residue was diluted with EtOAc (50 ml) and water (50 ml). The mixture was acidified with 1NHC1 to pH 2.0 and the layers were separated. The organic layer was washed with water (2 x 50 ml), brine (50 ml) and dried (Νa₂SO ). The residue obtained after evaporation of the solvent was crystallized from MeOH-CHCl to give 25 mg (32 %) of the product as white solid, mp 115-118 °C; IR (KBr) 3309, 2951, 2450, 1721, 1633, 1505, 1271 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.57- 1.98 (m, 8 H ), 2.76 (dd, J= 18.0, 12.0 Hz, 1 H), 3.12 (dd, J= 18.0, 9.0 Hz, 1 H), 3.79 (s, 3 H), 4.12 (dd, J= 1.2, 0.90 Hz, 2 H), 4.70-4.75 (m, 1 H), 4.75-4.86 (m, 1 H), 7.01 (d, J= 8.4 Hz, 1 H), 7.38 (d, J= 1.5 Hz, 1 H), 7.44 (d, J= 8.4 Hz, 1 H), 9.04 (d, J= 7.2 Hz, 1 H).

Example - 9

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l- phenylazolane

Step 1: (3S)-3-Aminol-phenylazolane-2,5-dione was prepared by deprotection of (3S)-3-(N-Cbz-aminol-phenylazolane-2,5-dione (300 mg, 0.924 mmol) using 5 % Pd/C (16 mg) in methanol (10 ml) under 20 psi hydrogen pressure for 3 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (219 mg, 0.926 mmol) using oxalyl chloride (180 mg, 1.658 mmol) in dry benzene (5 ml) catalysed by DMF at RT.

Step 3: Coupling Reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (250 mg, 2.475 mmol) in dry DCM (10 ml) at 0 °C. The crude product obtained was purified by silica gel column chromatography using 25 % EtOAc in petroleum ether to give 60 mg of the product as white solid, mp 150-152 °C; IR (KBr) 3293, 2957, 1716, 1630, 1502, 1268 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.59-2.01 (m, 8 H), 3.10 (dd, J = 18.0, 6.0 Hz, 1 H) , 3.31 (dd, J= 18.0, 9.0 Hz, 1 H), 3.87 (s, 3 H ), 4.54-4.62 (m, 1 H), 4.79-4.83 (m, 1 H), 6.81 (d, J= 9.0 Hz, 1 H ), 6.96 (d, J= 6.0 Hz,l H), 7.26-7.51 (m, 7 H).

Example - 10

(3S)-l-Benzyl-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (90 mg, 0.270 mmol) with benzyl bromide (55 mg, 0.321 mmol) using cesium hydroxide (62 mg, 0.369 mmol) as described in example 3 followed by chromatography on silica gel (30 % EtOAc in petroleum ether) gave 58 mg (51 %) of the product as white solid, mp 152-154 °C; IR (KBr) 3314, 2960, 1708, 1635, 1504, 1266, 1174 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 1.59-1.97 (m, 8 H), 2.88 (dd, J= 12.0, 6.0 Hz, 1 H) , 3.14 (dd, J= 12.0, 9.0 Hz, 1 H), 3.86 (s, 3 H ), 4.40-4.46 (m, 1 H), 4.74 (d, J= 3.3 Hz, 2 H), 4.77-4.80 ( m, 1 H ), 6.78 (d, J = 8.4 Hz, 1 H), 6.86 (d, J= 6.0, 1 H ), 7.21-7.41 (m, 7 H).

Example - 11

(3S)-l-[4-(tert-Butyl)benzyl]-3-(3-cyclopentyloxy-4- methoxyphenylcarboxamido)-2,5-dioxoazolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with 4-tert-butylbenzyl chloride (69 mg, 0.379 mmol) using cesium hydroxide (65 mg, 0.386 mmol) as described in example 3 followed by chromatography on silica gel (50 % EtOAc in petroleum ether) gave 76 mg (53 %) of the product as white solid, mp 98-100 °C; IR (KBr) 3385, 2961, 1712, 1649, 1503, 1268, 1166 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 1.30 (s, 9 H ), 1.84-1.99 (m, 8 H), 2.92 (dd, J = 18.0, 6.0 Hz, 1 H), 3.18 (dd, J =

18.0, 9.0 Hz, 1 H), 3.88 (s, 3 H ), 4.46-4.53 (m, 1 H), 4.72 (d, J = 3.0 Hz, 2 H),

4.77-4.82 ( m, 1 H ), 6.80 (d, J = 6.0 Hz, 1 H), 6.84 (d, J= 3.0 Hz, 1 H ), 7.24-

7.36 (m, 6 H).

Example - 12

(3 S)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)- 1 -(3 -cyanobenzyl)-2 , 5 - dioxo-azolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (75 mg, 0.225 mmol) with 3-cyanobenzyl bromide (70 mg, 0.358 mmol) using cesium hydroxide (46 mg, 0.273 mmol) as described in example 3 followed by chromatography on silica gel (3 % MeOH in chloroform) gave 47 mg (46.5 %) of the product as white solid, mp 92-95 °C; IR (KBr) 3319, 2933, 2231, 1710, 1648, 1503, 1269 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.73-2.09 (m, 8 H), 3.00 (dd, J= 12.0, 6.0 Hz, 1 H) , 3.18 (dd, J= 18.0, 9.0 Hz, 1 H), 3.89 (s, 3 H ), 4.41-4.48 (m, 1 H), 4.79 (d, J= 8.1 Hz, 2 H), 4.83-4.85 (m, 1 H ), 6.80 (brs, 1 H ), 6.85 (d, J = 6.30 Hz, 1 H), 7.28 (d, J = 1.8 Hz, 1 H ), 7.38 (d, J = 1.8 Hz, 1 H ), 7.45 (t, J= 7.5 Hz, 1 H ), 7.58 (d, J= 8.1 Hz, 1 H ),7.68 (d, J= 8.1 Hz, 1 H ) 7.77 (s, 1 H).

Example - 13

(3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3-cyanobenzyl)-2, 5-dioxo-azolane

The reaction of (3R)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.300 mmol) with 3-cyanobenzyl bromide (71 mg, 0.364 mmol) using cesium hydroxide (61 mg, 0.363 mmol) as described in example 3 followed by chromatography on silica gel (3 % MeOH in chloroform) gave 60 mg (44.5 %) of the product as white solid, mp 115-120 °C; IR (KBr) 3322, 2933, 2231, 1710, 1648, 1503, 1269 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 1.79-2.04 (m, 8 H), 2.99 (dd, J= 18.0, 9.0 Hz, 1 H), 3.17 (dd, J= 18.0, 9.0 Hz, 1 H), 3.88 (s, 3 H ), 4.39-4.46 (m, 1 H), 4.71-4.83 (m, 3 H ), 6.75 (d, J= 9.0 Hz, 1 H), 6.83 (d, J = 9.0 Hz , 1 H ), 7.26 (d, J= 3.6 Hz, 1 H), 7.36 (d, J= 2.1 Hz, 1 H ), 7.43 (t, J = 8.4 Hz, 1 H ), 7.57 (dt, J= 8.4, 3.6 Hz, 1 H ), 7.65 (d, J= 9.0 Hz, 1 H ), 7.76 (s, 1 H)

Example 14

(3 S)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5 -dioxo- 1 -(3 - trifluoromethyl-benzyl)azolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (150 mg, 0.451 mmol) with 3-trifluoromethylbenzyl bromide (135 mg, 0.564 mmol) using cesium hydroxide (91 mg, 0.541 mmol) as described in example 3 followed by chromatography on silica gel (40 % EtOAc in petroleum ether) gave 65 mg (29 %) of the product as a white solid, IR (KBr) 3389, 2960, 1711, 1582, 1563, 1329, 1270, 1166, 1020 cm ^_1; Η NMR (CDC1₃) δ 1.79-1.99 (m, 8 H), 2.97(dd, J = 17.7, 5.7 Hz, 1 H), 3.17 (dd, J= 17.7, 9.1 Hz, 1 H), 3.88 (s, 3 H), 4.41-4.48 (m, 1 H), 4.74-4.86 (m, 3 H) 6.74 (d, J= 6.3 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 7.22-7.26 (m, 1 H), 7.36 (d, J = 2.1 Hz, 1 H) 7.44 (t, J = 7.8 Hz, 1 H), 7.55 (d, J= 8.1 Hz, 1 H), 7.61 (d, J= 7.5 Hz, 1 H), 7.70 (s, 1 H).

Example 15

(3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(3- trifluoromethyl-benzyl)azolane

The reaction of (3R)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (150 mg, 0.451 mmol) with 3-trifluoromethylbenzyl bromide (135 mg, 0.564 mmol) using cesium hydroxide (91 mg, 0.541 mmol) as described in example 3 followed by chromatography on silica gel (50 % EtOAc in petroleum ether) gave 80 mg (36 %) of the product as white solid, IR (KBr) 3385, 2960, 1712, 1504, 1328, 1165, 1125, 1019 cm ^"1; Η NMR (CDC1₃) δ 1.79-1.99 (m, 8 H), 2.97 (dd, J= 17.7, 5.7 Hz, 1 H), 3.17 (dd, J= 17.7, 9.1 Hz, 1 H), 3.88 (s, 3 H), 4.41-4.48 (m, 1 H), 4.74-4.86 (m, 3 H) 6.74 (d, J = 6.3 Hz, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 7.22-7.26 (m, 1 H), 7.36 (d, J= 2.1 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.55 (d, J= 8.1 Hz, 1 H), 7.61 (d, J= 7.5 Hz, 1 H), 7.70 (s, 1 H).

Example 16

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(4- trifluoromethyl-benzyl)azolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxypheny-carboxamido)-2,5- dioxoazolane (150 mg, 0.451 mmol) with 4-trifluoromethyl benzyl bromide (135 mg, 0.564 mmol) using cesium hydroxide (91 mg, 0.541 mmol) as described in example 3 followed by chromatography on silica gel (50 % EtOAc in petroleum ether) gave 68 mg ( 30 %) of the product as white solid, IR (KBr) 3344, 2966, 1712, 1633, 1504, 1330, 1174, 1019 cm ^"'; Η NMR (CDC1₃) d 1.61-1.99 (m, 8 H), 2.96 (dd, J= 17.7, 5.7 Hz, 1 H), 3.17 (dd, J= 18.3, 8.7 Hz, 1 H), 3.87 (s, 3 H), 4.41-4.48 (m, 1 H), 4.74-4.85 (m, 3 H), 6.73 (d, J= 6.3 Hz, 1 H), 6.82 (d, J= 8.7 Hz, 1 H), 7.22-7.26 (m, 1 H), 7.34 (d, J= 2.1 Hz, 1 H) 7.53 (d, J= 8.4 Hz, 2 H), 7.58 (d, J= 8.4 Hz, 2 H),

Example 17

(3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(4- trifluoromethyl-benzyl)azolane

The reaction of (3R)-3-(3-cyclopentyloxy-4-methoxypheny-carboxamido)-2,5- dioxoazolane (150 mg, 0.451 mmol) with 4-trifluoromethyl benzyl bromide (135 mg, 0.564 mmol) using cesium hydroxide (91 mg, 0.541 mmol) as described in example 3 followed by chromatography on silica gel (50 % EtOAc in petroleum ether) gave 82 mg (37 %) of the product as a white solid, IR (KBr) 3349, 2964, 1712, 1504, 1329, 1168, 1019 cm^"1; Η NMR (CDC1₃) d 1.61-1.99 (m, 8 H), 2.96 (dd, J = 17.7, 5.7 Hz, 1 H), 3.17 (dd, J = 18.3, 8.7 Hz, 1 H), 3.87 (s, 3 H), 4.41- 4.48 (m, 1 H), 4.74-4.85 (m, 3 H) 6.73 (d, J= 6.3 Hz, 1 H), 6.82 (d, J= 8.7 Hz, 1 H), 7.22-7.26 (m, 1 H), 7.34 (d, J= 2.1 Hz, 1 H) 7.53 (d, J= 8.4 Hz, 2 H), 7.58 (d, J= 8.4 Hz, 2 H).

Example - 18 Ethyl 4-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5- dioxoazolan- 1 -yljbenzoate

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxypheny-carboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with ethyl 4-bromomethyl benzoate (130 mg, 0.534 mmol) using cesium hydroxide (70 mg, 0.416 mmol) as described in example 3 followed by chromatography on silica gel (20 % EtOAc in petroleum ether) gave 80 mg (52 %) of the product as white solid, mp 79-82 °C; IR (KBr) 3389, 2959, 1793, 1727, 1658, 1504, 1269, 1170 cm ^"' Η NMR (300 MHz, CDCI3) δ 1.38 (t, J = 9.0 Hz, 3 H ), 1.88-2.00 (m, 8H), 2.83-2.99 (m, 1 H), 3.12- 3.22 (m, 1 H), 3.87 (s, 3 H ), 4.35 (q, J= 6.0 Hz, 2 H ) 4.43-4.50 (m, 1 H), 4.73- 4.84 (m, 3 H ), 6.79-6.83 (m, 2 H), 7.23-7.27 (m, 3 H ), 7.34 (d, J= 2.1 Hz, 1 H ), 7.46 (d, J= 9.9 Hz, 1 H ), 7.98 (dd, J= 9.9, 2.1 Hz, 1 H ).

Example - 19

Ethyl 3-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5- dioxoazolan- 1 -ylmethyl] benzoate

₂ri5

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with ethyl 3-bromomethyl benzoate (130 mg, 0.534 mmol) using cesium hydroxide (70 mg, 0.416 mmol) as described in example 3 followed by chromatography on silica gel (20 % EtOAc in petroleum ether) gave 85 mg (55.5 %) of the product as white solid, mp 75-80 °C; IR (KBr) 3386, 2959, 1713, 1649, 1503, 1269 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 1.38 (t, J = 6.9, 3 H), 1.78-1.97 (m, 8 H), 2.92 (dd, J= 18.0, 6.0 Hz, 1 H), 3.18 (dd, J = 18.0, 6.0 Hz, 1 H), 3.87 (s, 3 H ), 4.35 (q, J = 7.28, 2 H ), 4.48-4.55 (m, 1 H), 4.73-4.84 (m, 1 H ), 4.80 (d, J= 6.0 Hz, 2 H), 6.81 (d, J= 8.7 Hz, 1 H), 6.85 (d, J = 6.0 Hz, 1 H ), 7.26 (d, J= 1.8 Hz, 1 H ), 7.35 (d, J = 1.8 Hz, 1 H ), 7.39 (t, J = 7.8 Hz, 1 H ), 7.60 (d, J= 7.8 Hz, 1 H), 7.95 (d, J= 6.0 Hz, 1 H ), 8.03 (s, 1 H).

Example - 20

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3-fluorobenzyl)-2, 5-dioxoazolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoa-zolane (100 mg, 0.301 mmol) with 3-ftuorobenzyl bromide (120 mg, 0.634 mmol) using cesium hydroxide (65 mg, 0.386 mmol) as described in example 3 followed by chromatography on silica gel (30 % EtOAc in petroleum ether) gave 65 mg (49 %) of the product as white solid, mp 72-74 °C; IR (KBr) 3381, 2958, 1712, 1503, 1400, 1334, 1269 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.78-2.06 (m, 8 H), 2.93 (dd, J= 12.0, 9.0 Hz, 1 H), 3.18 (dd, J= 12.0, 9.0 Hz, 1 H), 3.87 (s, 3 H ), 4.43-4.50 (m, 1 H), 4.73 (d, J= 5.4 Hz, 2 H), 4.77-4.83 (m, 1 H ), 6.78-6.83 (m, 2 H), 6.98 (t, J= 2.7 Hz, 1 H ), 7.11-7.19 (m, 2 H), 7.22 -7.35 (m, 3 H).

Example - 21

(3S)-l-(3-Bromobenzyl)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5-dioxo-azolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with 3-bromobenzyl bromide (115 mg, 0.45 mmol) using cesium hydroxide (55 mg, 0.33 mmol) as described in example 3 followed by chromatography on silica gel (50 % EtOAc in petroleum ether) gave 75 mg (54 %) of the product as off-white solid, mp. 184-186 °C; IR (KBr) 3304, 2958, 1714, 1634, 1504, 1394, 1272, 1178 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.58-1.99 (m, 8 H ), 2.89 (dd, J= 15.0, 9.0 Hz, 1 H), 3.10 (dd, J= 18.0, 9.0 Hz, 1 H), 3.81 (s, 3 H ), 4.34-4.41 (m, 1 H ), 4.65 (d, J= 6.0 Hz, 2 H), 4.71-4.75 (m, 1 H ), 6.73 (d, J= 9.0 Hz, 1 H), 6.88 (d, J= 6.0 Hz, 1 H ), 7.10 -7.36 (m, 5 H), 7.52 (s, 1 H ).

Example - 22

(3S)-3-(3-Cyclopentyloxy)-4-methoxyphenylcarboxamido)-l -(2, 5- dichlorobenzyl)-2, 5-dioxoazolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with 2,5-dichlorobenzyl bromide (93 mg, 0.389 mmol) using cesium hydroxide (70 mg, 0.416 mmol) as described in example 3 followed by chromatography on silica gel (40 % EtOAc in petroleum ether) gave 50 mg (34 %) of the product as white solid, mp 135-140 °C; IR (KBr) 3387, 2959, 1785, 1713, 1650, 1503, 1269 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.78-2.00 (m, 8 H), 3.06-3.23 (m, 2 H), 3.86 (s, 3 H ), 4.40 (dt, J= 9.0, 6.0 Hz., 1 H) 4.75-4.81 (m, 1 H), 4.83 (dd, J= 18.0, 9.0 Hz, 2 H), 6.78 (d, J= 9.0 Hz, 1 H), 7.02 (d, J= 1.8 Hz, 1 H ), 7.16-7.29 (m, 3 H), 7.38 (d, J= 3.6 Hz, 1 H), 7.54 (d, J = 3.6 Hz, 1 H).

Example - 23

(3R)-3-(3-Cyclopentyloxy)-4-methoxyphenylcarboxamido)- 1 -(2, 5- dichlorobenzyl)-2, 5-dioxo-azolane

The reaction of (3R)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with 2,5-dichlorobenzyl bromide (93 mg, 0.389 mmol) using cesium hydroxide (72 mg, 0.428 mmol) as described in example 3 followed by chromatography on silica gel (40 % EtOAc in petroleum ether) gave 45 mg ( 30 %) of the product as white solid, mp 135- 140 °C; IR (KBr) 3386, 2957, 1785, 1713, 1650, 1505, 1267 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.53-1.98 (m, 8 H), 3.07-3.26 (m, 2 H), 3.88 (s, 3 H ), 4.42-4.48 (m, 1 H ) 4.76- 4.92 (m, 3 H), 6.81-6.86 (m, 2 H), 7.17 -7.29 (m, 3 H ), 7.42 (s, 1 H), 7.53 (brs, 1 H).

Example - 24

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(2, 6- dichlorobenzyl)-2, 5-dioxoazolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with 2,6-dichlorobenzyl bromide (93 mg, 0.389 mmol) using cesium hydroxide (70 mg, 0.416 mmol) as described in example 3 followed by chromatography on silica gel (40 % EtOAc in petroleum ether) gave 40 mg (27 %) of the product as a white solid, mp 204-206 °C; IR (KBr) 3281, 2952, 1783, 1715, 1634, 1505, 1270; Η NMR (300 MHz, CDC1₃) δ 1.55- 1.98 (m, 8 H), 2.84 (dd, J= 12.0, 9.0 Hz, 1 H), 3.22 (dd, J= 18.0, 9.0 Hz, 1 H), 3.87 (s, 3 H ), 4.53-4.59 (m, 1 H), 4.78-4.83 (m, 1 H), 5.04 (d, J = 3.0 Hz , 2 H) , 6.67 (d, J= 6.0 Hz, 1 H), 6.81 (d, J = 9.0 Hz, 1 H ), 7.17-7.35 (m , 5 H); m/z (MH⁺, 100 %) 491, 443 (30 %).

Example - 25

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3-nitrobenzyl)-2, 5- dioxo-azolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with 3-nitrobenzyl bromide (100 mg, 0.462 mmol) using cesium hydroxide (61 mg, 0.365 mmol) as described in example 3 followed by chromatography on silica gel (30 % EtOAc in petroleum ether) gave 50 mg (35.5 %) of the product as white solid, mp 97-101 °C; IR (KBr) 3391, 2958, 1712, 1652, 1532, 1502, 1348, 1269 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.61-1.99 (m, 8 H), 3.03 (dd, J= 18.0, 9.0 Hz, 1 H), 3.17 (dd, J= 18.0, 9.0 Hz, 1 H), 3.88 (s, 3 H), 4.40-4.47 (m, 1 H), 4.78-4.81 (m, 1 H), 4.83 (d, J = 8.7 Hz, 2 H), 6.76 (d, J = 6.6 Hz, 1 H), 6.82 (d, J= 8.1, 1 H ), 7.26 (d, J = 2.0, 1 H), 7.36 (d, J= 2.1, 1 H), 7.51 (t, J= 8.1, 1 H), 7.76 (d, J= 8.1 Hz, 1 H), 8.14 (dd, J= 8.1, 3.6 Hz, 1 H), 8.29 (t, J= 2.1 Hz, 1 H).

Example -26

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(4-chloro-3- nitrobenzyl)-2, 5-dioxoazolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.30 mmol) with 4-chloro-3-nitrobenzyl bromide (90 mg, 0.359 mmol) using cesium hydroxide (61 mg, 0.365 mmol) as described in example 3 followed by chromatography on silica gel (30 % EtOAc in petroleum ether) gave 40 mg (26 %) of the product as white solid, mp 110-112 °C; IR (KBr) 3384, 2957, 1712, 1650, 1537, 1501, 1342, 1269, 1167 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.57-1.64 (m, 4 H), 1.85-2.05 (m, 4 H), 3.05 (dd, J= 12.3, 5.7 Hz, 1 H), 3.12 (dd, J= 18.0, 9.0 Hz, 1 H), 3.89 (s, 3 H ), 4.36-4.43 (m, 1 H), 4.80 (d, J = 8.4 Hz, 2 H), 4.83-4.86 (m, 1 H), 6.83 (d, J= 5.7 Hz, 1 H), 6.84 (brs, 1 H ), 7.24 (d, J= 1.8 Hz, 1 H), 7.37 (d, J= 1.8 Hz, 1 H), 7.52 (d, J= 9.0 Hz, 1 H), 7.60 (d, J = 8.1 Hz, 1 H), 8.00 (d, J= 1.8 Hz, 1 H).

Example - 27

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3-pyridylmethyl)-2, 5-dioxo-azolane

The reaction of (3S)-3-(3-cyclopentyloxy-4-methoxyphenycarboxamido)-2,5- dioxoazolane (100 mg, 0.301 mmol) with 3-picolyl chloride (80 mg, 0.627 mmol) using cesium hydroxide (150 mg, 0.898 mmol) as described in example 3 followed by chromatography on silica gel (30 % EtOAc in petroleum ether) gave 50 mg ( 39 %) of the product as white solid, mp 85-88 °C; IR (KBr) 3382, 2958, 1710, 1644, 1504, 1400, 1269, 1164 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.80- 1.99 (m, 8 H), 2.96 (dd, J = 18.0, 6.0 Hz, 1 H), 3.18 (dd, J = 18.0, 6.0 Hz, 1 H), 3.89 (s, 3 H ), 4.43-4.50 (m, 1 H), 4.79 (d, J= 3.6, 2 H), 4.81-4.83 (m, 1 H), 6.83 (d, J= 8.4 Hz, 1 H), 6.89 (d, J= 6.0 Hz, 1 H), 7.28-7.30 (m, 2 H), 7.35 (d, J= 2.1 Hz, 1 H), 7.79 (dt, J= 5.7, 2.1 Hz, 1 H), 8.54 (dd, J= 5.2, 1.8 Hz, 1 H), 8.67 (d, J = 2.1 Hz, I H).

Example - 28 (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- oxopyridylmethyl)-2, 5-dioxoazolane

To a stirred solution of 27 (30 mg, 0.071 mmol) in chloroform (10 ml) was added 50 % rø-CPBA (70 mg, 0.202 mmol) and the mixture was refluxed for 3 h under stirring. The mixture was cooled to room temperature and diluted with chloroform (50 ml) and washed with saturated aqueous NaHCO solution. The chloroform solution was washed with water (2 x 50 ml), brine (50 ml) and dried (Na₂SO₄). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 2 % methanol in chloroform to give 20 mg (64 %) of the product as a white solid, mp 175-180 °C; IR (KBr) 3401, 2957, 1783, 1709, 1638, 1504, 1268 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.79-1.96 (m, 8 H), 3.00 (dd, J = 5.7, 12.3 Hz, 1 H), 3.12 (dd, J = 18.0, 9.0 Hz, 1 H), 3.89 (s, 3 H), 4.44-4.51 (m, 1 H), 4.71 (d, J= 3.6 Hz, 2 H), 4.80-4.85 (m, 1 H ), 6.85 (d, J= 8.4 Hz, 1 H), 7.23-7.28 (m, 1 H), 7.33-7.41 (m, 3 H), 7.61 (d, J= 6.3, 1 H), 8.10 (d, J = 6.3 Hz, 1 H), 8.32 (s, 1 H).

Example -29

(3S)- 1 -Benzyl-3 -(3 -cyclopentyloxy-4-methoxyphenylcarboxamido)-2-oxoazolane

Step 1: (3S)-3-Amino-l-benzyl-2-oxoazolane hydrochloride was prepared by deprotection of (3S)-3-(N-BOC-Amino-l-benzyl-2-oxoazolane (200 mg, 0.687 mmol) using 15 % HC1 in ethyl acetate (5 ml) at RT for 4 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (165 mg, 0.699 mmol) using oxalyl chloride (113 mg, 1.041 mmol) in dry benzene (5 ml) catalysed by DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (500 mg, 4.950 mmol) in dry DCM (20 ml) at 0 °C. The crude product obtained was purified by silica gel column chromatography using 4 % methanol in chloroform to give 98 mg of the product as off-white solid, mp 70-75 °C; IR (KBr) 3316, 2956, 1683, 1641, 1505, 1265, 1227 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.59-2.02 (m, 8 H), 2.80-2.89 (m, 1 H), 3.25-3.34 (m, 2 H), 3.89 (s, 3 H), 4.49-4.57 (m, 3 H), 4.83-4.86 (m, 1 H), 6.74 (d, J= 8.4, 1 H), 6.84 (d, J= 8.4 Hz, 1 H), 7.24-7.42 (m, 7 H ). Example -30

(3S)- 1 -Benzyl-3 -(3 -cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2- oxoazolane

Step 1: (3S)-3 -Amino- l-benzyl-2-oxoazolane hydrochloride was prepared by deprotection of (3S)-3-(N-BOC-Amino-l-benzyl-2-oxoazolane (200 mg, 0.687 mmol) using 15 % HC1 in ethyl acetate (5 ml) at RT for 4 h.

Step 2: 3-Cyclopentyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopentyloxy-4-difluoromethoxybenzoic acid (187 mg, 0.686 mmol) using oxalyl chloride (119 mg, 1.096 mmol) in dry benzene (5 ml) catalysed by DMF at RT.

Step 3: Coupling Reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (500 mg, 4.950 mmol) in dry DCM (20 ml) at 0 °C. The crude product obtained was purified by silica gel column chromatography using 4 % methanol in chloroform to give 55 mg (y %) of the product as off-white solid, mp 102-103 °C; IR (KBr) 3318, 2900, 1683, 1641, 1500, 1229, 1227 cm^"1, Η ΝMR (300 MHz, CDC1₃) δ 1.59-1.98 (m, 8 H), 2.76-2.86 (m, 1 H), 3.25-3.32 (m, 2 H), 4.49-4.57 (m, 3 H), 4.85-4.89 (m, 1 H), 6.57 (t, J = 71.7 Hz, 1 H), 6.89 (d, J= 3.6 Hz, 1 H), 7.14 (d, J= 8.4, 1 H), 7.22-7.37 (m, 6 H), 7.48 (d, J= 1.8 Hz, I H)

Example -31

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-5-oxoazolane

Step 1 : (3S)-3-Amino-5-oxoazolane hydrochloride was prepared by deprotection of (3S)-3-(N-BOC-Amino)-5-oxoazolane (60 mg, 0.299 mmol) using 15 % HCl in ethyl acetate (5 ml) at RT for 4 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (71 mg, 0.300 mmol) using oxalyl chloride (42 mg, 0.387 mmol) in dry benzene (3 ml) catalysed by DMF at RT.

Step 3: Coupling Reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (200 mg, 1.980 mmol) in dry DCM (10 ml) at 0 °C. The crude product obtained was purified by silica gel column chromatography using 4 % methanol in chloroform to give 20 mg of the product as off-white solid, mp 103-105 °C; IR (KBr) 3303, 2954, 1770, 1688, 1509, 1269, 1022 cm ^"'; Η ΝMR (CDC1₃) δ 1.61-1.98 (m, 8 H), 2.34 (dd, J= 17.1, 3.9 Hz, 1 H), 2.78 (dd, J = 17.1, 8.4 Hz, 1 H), 3.35 (dd, J= 10.2, 3.0 Hz, 1 H), 3.80 (dd, J= 10.2, 6.3 Hz, 1 H), 3.87 (s, 3 H), 4.80-4.85 (m, 2 H), 5.99 (brs, 1 H), 6.81 (brs, 1 H) 6.82 (d, J = 8.4 Hz, 1 H), 7.29 (dd, J= 8.1, 2.1 Hz, 1 H), 7.41 (d, J= 2.4 Hz, 1 H).

Example - 32

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6- dioxohexahydropyridine

Step 1 : (3S)-3-Aminohexahydro-2,6-pyridinedione was prepared as follows: To a stiπed solution of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (200 mg, 0.76 mmol) in ethanol (10 ml) was added 5 % Pd/C (10 mg) and the mixture was stiπed under hydrogen atmosphere for 1 h. The reaction mixture was filtered through a celite bed and the filtrate was evaporated to give free amine quantitatively yield as a greenish yellow viscous liquid which was used as such for coupling reaction.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared as follows: To a well stiπed solution of 3-Cyclopentyloxy-4-methoxybenzoic acid (200 mg, 0.847 mmol) in dry benzene (3 ml) was added oxalyl chloride (140 mg, 1.1 mmol) at RT. The reaction was initiated with a drop of dry DMF and stiπed at RT for 1 h under nitrogen atmosphere. The solvent was removed under reduced pressure to give the acid chloride quantitatively as a viscous residue, which was used as such for the coupling reaction.

Step 3: Coupling reaction: The acid chloride (step 2) dissolved in dry dichloromethane (5 ml) was added to a stiπed and cooled (0 °C) solution of the crude amine (step 1) and triethylamine (200 mg, 1.98 mmol) in dry dichloromethane (5 ml). The mixture was stiπed at RT for 1 h. The mixture was diluted with dichloromethane (100 ml) and washed with water (3 x 100 ml), brine (50 ml) and dried (Νa₂SO₄). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 30 % EtOAc in chloroform as eluent to give 110 mg ( 58 %) of the product as white solid, mp 117-120 °C; IR (KBr) 3257, 2957, 1713, 1639, 1421, 1267, 990 cm ^"' ; Η NMR (300 MHz, CDC1₃) δ 1.59-2.04 (m, 9 H), 2.70-2.87 (m, 3 H), 3.88 (s, 3 H), 4.68- 4.75 (m, 1 H), 4.81-4.86 (m, 1 H), 6.84 (d, J= 9.0 Hz, 1 H), 6.90 (d, J= 6.2 Hz, 1 H), 7.32 (d, J= 12.0 Hz, 1 H), 7.40 (d, J= 3.2 Hz, 1 H), 8.17 (s, 1 H). Example - 33

(3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxohexahydro-pyridine

Step 1: (3S)-3-Aminohexahydro-2,6-pyridinedione was prepared by deprotection of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (300 mg, 1.14 mmol) with 5 % Pd/C (30 mg) in EtOH (10 ml).

Step 2: 3-Cyclopentyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopentyloxy-4-difluoromethoxybenzoic acid (312 mg, 1.14 mmol) and oxalyl chloride (219 mg, 1.72 mmol) in dry benzene (10 ml) catalyzed by dry DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (288 mg, 2.85 mmol) in dry dichloromethane (5 ml) at RT for 1 h. The crude product was purified by silica gel column chromatography using 30 % ethyl acetate in chloroform to give 160 mg (x %) of the product as white solid, mp 149-152 °C; IR ( KBr ) 3382, 3212, 2967, 1765, 1661, 1501, 1361, 1200, 1112, 989 cm ^"1; Η ΝMR (300 MHz, CDC1₃) δ 1.60-2.02 (m, 10 H), 2.64-2.73 (m, 1 H), 2.79-2.84 (m, 1 H), 4.72-4.8 l(m, 1 H), 4.84-4.88 ( , 1 H), 6.56 (t, J= 74.7 Hz, 1 H), 7.02 (d, J= 5.7 Hz, 1 H), 7.13 (d, J= 8.1 Hz, 1 H), 7.27 (d, J= 2.1 Hz, 1 H), 7.47 (s, 1 H), 8.40 (s, 1 H).

Example - 34

(3R)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6-dioxo- hexahydro-pyridine

Step 1 : (3R)-3-Aminohexahydro-2,6-pyridinedione was prepared by deprotection of (3R)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (300 mg, 1.14 mmol) with 5 % Pd/C ( 15 mg) in ethanol ( 10 ml) .

Step 2: 3-Cyclopentyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopentyloxy-4-methoxybenzoic acid (312 mg, 1.14 mmol) using oxalyl chloride (219 mg, 1.72 mmol) in dry benzene (10 ml) catalysed by DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (288 mg, 2.85 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 30 % ethyl acetate in chloroform as eluent to give 300 mg of the product as white solid, mp 149-152 °C; IR (KBr) 3382, 3212, 1962, 1705, 1661, 1543, 1501, 1361, 1271, 1200, 1112, 989 cm ^"' ; Η ΝMR (300 MHz, CDC1₃) δ 1.64-2.05 (m, 9 H), 2.64- 2.73 (m, 1 H), 2.79-2.85 (m, 2 H), 4.72-4.80 ( , 1 H), 4.84-4.88 (m, 1 H), 6.56 (t, J= 74.7 Hz, 1 H), 7.02 (d, J= 5.7 Hz, 1 H), 7.13 (d, J= 8.1 Hz, 1 H), 7.26 (d, J = 2.1 Hz, 1 H), 7.47 (d, J= 2.1 Hz, 1 H), 8.40 (brs, 1 H).

Example - 35

(3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxo-hexahydropyridine

Step 1 : (3S)-3-Aminohexahydro-2,6-pyridinedione was prepared by deprotection of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (305 mg, 1.16 mmol) using 5 % Pd/C (15 mg) in ethanol (10 ml). Step 2: 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoic acid (200 mg, 0.77 mmol) using oxalyl chloride (150 mg, 1.18 mmol) in dry benzene (10 ml) catalysed by DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (294 mg, 2.91 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 30 % ethyl acetate in chloroform as eluent to give 150 mg of the product as white solid, mp 149-151 °C; IR (KBr) 3293, 2909, 1717, 1640, 1539, 1507, 1270, 1198, 1001, 761 cm ^"1 ; IR (KBr) 3293, 3092, 1717, 1640, 1539, 1507, 1198, 1139, 1001, 761 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 0.38 (d, J = 4.5 Hz, 2 H), 0.36 (d, J = 7.2 Hz, 2 H), 1.26-130 (m, 1 H), 2.05-2.21 (m, 1 H), 2.51-2.57 (m, 1 H), 2.79-2.81 (m, 2 H), 3.87 (d, J= 7.2 Hz, 2 H), 4.87-4.95 (m, 1 H), 6.65 (t, J= 14.1 Hz, 1 H), 7.06 (d, J= 8.1 Hz, 1 H), 7.25-7.30 (m, 2 H), 7.39 (s, 1 H), 9.27 (s, 1 H).

Example - 36

(3S)-3-(4-Difluoromethoxy-3-methoxyphenylcarboxamido)-2,6-dioxohexahydro- pyridine

Step 1: (3S)-3-Aminohexahydro-2,6-pyridinedione was prepared by deprotection of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (250 mg, 0.95 mmol) using 5 % Pd/C (25 mg) in ethanol (10 ml).

Step 2: 4-Difluoromethoxy-3-methyloxybenzoyl chloride was prepared from 4- difluoro-methoxy-3-methoxy benzoic acid (210 mg, 0.96 mmol) using oxalyl chloride (185 mg, 1.45 mmol) in dry benzene (10 ml) catalysed by DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (243 mg. 2.40 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 30 % ethyl acetate in chloroform as eluent to give 130 mg of the product as white solid, mp 150-152 °C; IR (KBr) 3286, 3100, 1712, 1650, 1543, 1510, 1375, 1268, 1190, 1129, 1028, 763 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 2.19-2.04 (m, 1 H), 2.65- 2.73 (m, 1 H), 2.83 (s, 2 H), 3.92 (s, 3 H), 4.74-4.83 (m, 1 H), 6.58 (t, J= 74.4 Hz, 1 H), 7.07 (s, 1 H), 7.14 (d, J = 8.1 Hz, IH), 7.39 (d, J = 8.1 Hz, 1 H), 7.47 (s, 1 H), 8.48 (s, 1 H).

Example - 37

(3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-2,6- dioxohexahydropyridine

Step 1: (3S)-3-Aminohexahydro-2,6-pyridinedione was prepared by deprotection of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (660 mg, 2.52 mmol) using 5 % PdVC (50 mg) in EtOH (25 ml).

Step 2: 3,4-Di(difluoromethoxy)benzoyl chloride was prepared from 3,4- Di(difluoromethoxy)-benzoic acid (600 mg, 2.36 mmol) using oxalyl chloride (450 mg, 3.54 mmol) in benzene (20 ml) catalysed by dry DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (636 mg, 6.29 mmol) in dry dichloromethane (20 ml). The crude product was purified by silica gel column chromatography using 40-50 % ethyl acetate in chloroform as eluent to give 500 mg of the product as white solid, mp 99-103 °C; IR (KBr) 3381, 2216, 3100, 1710, 1658, 1546, 1507, 1363, 1260, 1148, 1050, 758 cm ^"1; Η ΝMR (300 MHz, CD₃OD) δ 2.14-2.23 (m, 2 H), 2.65-2.89 (m, 2 H), 4.81-4.87 (m, 1 H), 6.86 (t, J= 72.9 Hz, 1 H), 6.93 (t, J= 72.9 Hz, 1 H), 7.38 (d, J= 9.0 Hz, 1 H), 7.77 (d, J= 9.0 Hz, 1 H), 7.79 (s, 1 H). Example - 38

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-ethyl-2,6- dioxohexahydro-pyridine

Step 1: (3S)-3-Amino-l-ethylhexahydro-2,6-pyridinedione was prepared by deprotection of (3S)-3-(N-Cbz-Amino)-l-ethylhexahydro-2,6-pyridinedione (200 mg, 0.68 mmol) using 5 % Pd/C (20 mg) in ethanol (10 ml) at RT for 1 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (170 mg, 0.72 mmol) using oxalyl chloride (140 mg, 1.1 mmol) in dry benzene (5 ml) catalysed by DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (172 mg, 1.70 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 30 % ethyl acetate in petroleum ether as eluent to give 100 mg ( 58 %) of the product as white solid, mp 68-70 °C; IR (KBr) 3352, 2962, 1679, 1640, 1414, 1267, 991 cm ^" '.; Η ΝMR (300 MHz, CDC1₃) δ 1.15 (t, J = 6.9 Hz, 3 H ), 1.59-2.00 (m, 9 H), 2.66-2.94 (m, 1 H), 3.78-3.93 (m, 5 H), 4.60-4.68 (m, 1 H), 4.81-4.87 (m, 1 H), 6.85 (d, J= 9.0 Hz, 1 H), 7.01 (d, J= 3.0 Hz, 1 H), 7.33 (dd, J= 9.0, 2.1 Hz, 1 H), 7.45 (s, 5 H).

Example - 39

Ethyl 2-[(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6- dioxohexahydro- 1 -pyridinyl] acetate

Step 1: Ethyl 2-[(3S)-3-Amino-2,6-dioxohexahydro-l-pyridinyl]acetate was prepared by deprotection (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (250 mg, 0.71 mmol) using 5 % Pd/C (10 mg) in ethanol (10 ml) at RT for 1 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- cyclopentyloxy-4-methoxybenzoic acid (170 mg, 0.72 mmol) using oxalyl chloride (138 mg, 1.08 mmol) in dry benzene (5 ml) catalysed DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (180 mg, 1.78 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 25 % ethyl acetate in petroleum ether as eluent to give 200 mg of the product as off- white solid, mp 184-186 °C; IR (KBr) 3232, 2965, 1732, 1632, 1512, 1333, 1173 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.28 (t, J= 6.7 Hz, 3 H), 1.64-2.04 (m, 9 H), 2.69-2.96 (m, 3 H), 3.88 (s, 3 H), 4.19 (q, J = 8.6 Hz, 2 H), 4.75-4.86 (m, 2 H), 6.85 (d, J= 9.0 Hz, 1 H), 6.93 (d, J= 3.0 Hz, 1 H), 7.32 (d, J= 9.0 Hz, 1 H), 7.39 (s, 1 H).

Example - 40

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(2,6-dichlorobenzyl)- 2,6-dioxo-hexahydropyridine

Step 1: (3S)-3-Amino)-l-(2,6-dichlorobenzyl)hexahydro-2,6-pyridinedione was prepared by deprotection (3S)-3-(N-Cbz-amino)-l-(2,6- dichlorobenzyl)hexahydro-2,6-pyridinedione (200 mg, 0.45 mmol) using 5 % Pd/C (10 mg) in ethanol (10 ml) at RT for 1 h

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (132mg, 0.56 mmol) using oxalyl chloride (160 mg, 0.83 mmol) in dry benzene (5 ml) catalysed DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (115 mg, 1.13 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 30 % ethyl acetate in petether as eluent to give 60 mg of the product as white solid, mp 156-158 °C; IR (KBr) 3227, 2964, 1737, 1692, 1641, 1503, 1332, 1262, 1167, 999, 779 cm ^"\; Η ΝMR (300 MHz, CDC1₃) δ 1.54-1.98 (m, 9 H), 2.63-2.74 (m, 1 H), 2.84-2.92 (m, 2 H), 3.87 (s. 3 H), 4.63-4.72 (m, 1 H), 4.83 (d, J = 3 Hz, 1 H), 5.26 (dd, J = 14.7, 7.5 Hz, 2 H), 6.82 (d, J = 8.7 Hz, 1 H), 6.94 (d, J = 4.8 Hz, 1 H), 7.14 (d, J= 7.2 Hz, 1 H), 7.26 -7.30 (m, 3 H), 7.37 (s, 1 H).

Example - 41

(3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-l-(2,6- dichloro-benzyl)-2,6-dioxohexahydropyridine

A mixture of (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)- 2,6-dioxo-hexahydropyridine (200 mg, 0.52 mmol), 2-bromomethyl-l,3- dichlorobenzene (190 mg, 0.79 mmol), potassium carbonate (130 mg, 30.94 mmol) and tetrabutylammonium iodide (20 mg, 0.05 mmol) in dry acetone (10 ml) was stirred at RT for 48 h under nitrogen. The reaction mixture was filtered through a celite bed and the filtrate was diluted with ethyl acetate (100 ml) and washed with water (3 x 100 ml) followed by brine (50 ml) and dried over Na₂SO₄. The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 30 % ethyl acetate in petroleum ether as eluent to give 160 mg of the product as white solid, mp 78-90 °C; IR (KBr) 3356, 2964, 1736, 1689, 1542, 1500, 1334, 1169, 1116, 999, 767 cm ^"1; Η NMR (300 MHz, CDC1₃) δ 1.59-198 (m, 9 H), 2.67-2.75 (m, 1 H), 2.80-2.98 (m, 2H), 4.65-4.72 (m, 1 H), 4.85-4.90 (m, 1 H), 5.27 (dd, J= 14.7, 6.6 Hz, 2 H), 6.57 (t, J= 74.7 Hz, 1 H), 7.01 (s, 1 H), 7.12-1.17 (m, 2 H), 7.22-7.30 (m, 3 H), 7.46 (s, 1 H).

Example - 42 (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6-dioxo-l-(4- pyridyImethyI)-hexahydropyridine

Step 1: (3S)-3 -Amino- l-(4-pyridylmethyl)hexahydro-2,6-pyridinedione was prepared by deprotection of (3S)-3-(N-Cbz-Amino)hexahydro-2,6-pyridinedione (250 mg, 0.70 mmol) using 5 % Pd/C (20 mg) in EtOH (6 ml) at RT for 1 h. Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (170 mg, 0.72 mmol) using oxalyl chloride (162 mg, 1.275 mmol) in dry benzene (5 ml) catalysed DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (177 mg, 1.75 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 4 % methanol in chloroform as eluent to give 70 mg of the product as white solid, mp 185-187 °C; IR (KBr) 3435, 2955, 1654, 1505, 1421, 1337, 1166 cm ^"1; 'H NMR (300 MHz, CDC1₃) δ 1.61-1.98 (m, 9 H), 2.69-3.00 (m, 3 H), 3.88 (s, 3 H), 4.71- 4.84 (m, 2 H),4.89-5.03 (m, 2 H), 6.84 (d, J= 9.0 Hz, 1 H), 7.01 (d, J= 6.0 Hz, 2 H), 7.32 (dd, J= 12, 1.8 Hz, 1 H), 7.40 (s, 1 H), 8.52 (d, J= 6.0 Hz, 2 H).

Example - 43

(3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-l-(4-pyridylmethyl)-2,6- dioxo-hexahydropyridine

A mixture of (3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-2,6- dioxohexa-hydropyridine (150 mg, 0.41 mmol), 4-picolyl chloride hydrochloride (100 mg, 0.61 mmol), potassium carbonate (170 mg, 1.23 mmol) and tetrabutylammonium iodide (15 mg, 0.04 mmol) in dry acetone (10 ml) was stiπed at RT for 72 h under nitrogen. The reaction mixture was filtered through celite bed and the filtrate was diluted with ethyl acetate (100 ml) and washed with water (3 x 100 ml) followed by brine (50 ml) and dried (Na₂SO₄). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 3 % methanol in chloroform as eluent to give 100 mg of the product as white solid; IR (KBr) 3391, 3039, 1733, 1678, 1654, 1508, 1277, 1167, 1109, 1045, 1001 cm ^"'; Η NMR (300 MHz, CD₃OD) δ 2.20-2.32 (m, 2 H), 2.90-2.98 (m, 2 H), 4.88-4.99 (m, 3 H), 6.85 (t, J= 73.2 Hz, 1 H), 6.93 (t, J = 72.9 Hz, 1 H), 7.33-7.39 (m, 3 H), 7.76-7.79 (m, 2 H), 8.14-8.43 ( , 2 H).

Example - 44

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2- oxohexahydropyridine

Step 1: (3S)-3-Amino-2-oxohexahydropyridine hydrochloride was prepared as follows: (3S)-3-(N-BOC-Amino)-2-oxohexahydropyridine (300 mg, 1.40 mmol) was added to a well-stiπed and cooled (0 °C) solution of 15 % hydrochloric acid in ethyl acetate (10 ml) under nitrogen atmosphere. The temperature of the mixture was raised to RT and was stiπed at the same temperature for 3 h. The solvent and excess acid was evaporated under reduced pressure to give the amine hydrochloride as white solid which was used as such for the coupling reaction.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (200 mg, 0.84 mmol) using oxalyl chloride (162 mg, 1.27 mmol) in dry benzene (5 ml) catalysed by DMF at RT.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (257 mg, 2.54 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 2 % methanol in chloroform as eluent to give 140 mg of the product as white solid, mp 172-174 °C; IR (KBr) 3327, 3220, 2948, 1690, 1631, 1537, 1508, 1270, 1228, 1139, 1014, 762 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.56-2.04 (m, 11 H), 2.69- 2.78 (m, 1 H), 3.37-3.42 (m, 2 H), 3.87 (s, 3 H), 4.40 (quint, J = 5.7 Hz, 1 H), 4.84 (hept, J= 3.6 Hz, 1 H), 5.89 (brs, 1 H), 6.83 (d, J= 8.4 Hz, 1 H), 7.07 (brs, 1 H), 7.32 (d, J= 8.4 Hz, 1 H), 7.40 (s, 1 H). Example - 45

(3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2- oxohexahydropyridine

Step 1: (3S)-3-Amino-2-oxohexahydropyridine hydrochloride was prepared by deprotection of (3S)-3-(N-BOC-Amino)-2-oxohexahydropyridine (236 mg, 1.10 mmol) using 15 % hydrochloric acid in ethyl acetate (10 ml) for 3 h.

Step 2: 3-Cyclopentyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopentyloxy-4-difluorometnoxybenzoic acid (x mg, y mmol) using oxalyl chloride (105 mg, 0.82 mmol) in dry benzene (5 ml) catalysed by DMF at RT for l h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (200 mg, 1.98 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 2 % methanol in chloroform as eluent to give 70 mg of the product as white solid, mp 59-64 °C; IR (KBr) 3301, 2958, 1661, 1502, 1271,1115, 1048, 759 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.65-2.00 (m, 11 H), 2.68-2.72 (m, 1 H), 3.38-3.42 (m, 2 H), 4.39 (quint, J= 5.1 Hz, 1 H), 4.86-4.88 ( m, 1 H), 5.96 (brs, 1 H), 6.56 (t, J = 74.7 Hz, 1 H), 7.13 (d, J= 8.1 Hz, 1 H), 7.25-7.28 (m, 2 H), 7.48 (s, 1 H).

Example - 46

(3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)-2- oxohexahydro-pyridine

^FΥ°

O A "

Step 1: (3S)-3-Amino-2-oxohexahydropyridine hydrochloride was prepared by deprotection of (3S)-3-(N-BOC-Amino)-2-oxohexahydropyridine (321 mg, 1.50 mmol) using 15 % hydrochloric acid in ethyl acetate (10 ml) for 3 h.

Step 2: 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoic acid (258 mg, 1.00 mmol) using oxalyl chloride (191 mg, 1.50 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (202 mg, 2.00 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 2 % methanol in chloroform as eluent to give 140 mg of the product as white solid, mp 52-60 °C; IR (KBr) 3297, 1876, 1651, 1504, 1271, 1207, 1116, 1006, 759 cm ^"1; Η ΝMR (300 MHz, CDC1₃) δ 0.33-0.38 (m, 2 H), 0.61-0.67 (m, 2 H), 1.24-1.31 (m, 1 H), 1.58-1.72 (m, 1 H), 1.95-2.04 (m, 2 H), 2.63-2.72 (m, 1 H), 3.37-3.41 (m, 2 H), 3.90 (d, J= 6.9 Hz, 2 H), 4.38 (quint, J= 5.4 Hz, 1 H), 5.92 (brs, 1 H), 6.66 (t, J= 75.0 Hz, 1 H), 7.13 (d, J= 8.4 Hz, 1 H), 7.24-7.30 (m, 2 H), 7.43 (s, 1 H).

Example - 47

(3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-2-oxohexahydropyridine

Step 1: (3S)-3-Amino-2-oxohexahydropyridine hydrochloride was prepared by deprotection of (3S)-3-(N-BOC-Amino)-2-oxohexahydropyridine (200 mg, 0.93 mmol) using 15 % hydrochloric acid in ethyl acetate (10 ml) for 3 h.

Step 2: 3,4-Di(difluoromethoxy)benzoyl chloride was prepared from 3,4- Di(difluoromethoxy)-benzoic acid (150 mg, 0.59 mmol) using oxalyl chloride (115 mg, 0.90 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (180 mg, 1.78 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 1-2 % methanol in chloroform as eluent to give 100 mg of the product as white solid, mp 144-146 °C; IR (KBr) 3247, 2957, 1657, 1508, 1274, 1134, 1054, 793 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.59-1.70 (m, 2 H), 1.91-2.19 (m, 2 H), 2.61-2.79 (m, 1 H), 3.34-3.41 (m, 2 H), 4.35-4.43 (m, 1 H), 5.86 (brs, 1 H), 6.55 (t, J= 72.9 Hz, 1 H), 7.24 (d, J= 8.1 Hz, 1 H), 7.33 (brs, 1 H), 7.62 (d, J= 8.4 Hz, 1 H), 7.7 (s, 1 H).

Example - 48

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2-oxo-l- phenylhexahydro-pyridine

Step 1: (3S)-3-Amino-2-oxo-l -phenylhexahydropipyridine hydrochloride was prepared by deprotection of (3S)-3-(N-BOC-Amino)-2-oxo-l- phenylhexahydropipyridine (250 mg, 0.89 mmol) using 15 % hydrochloric acid in ethyl acetate (10 ml) for 3 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (200 mg, 0.84 mmol) using oxalyl chloride (160 mg, 1.26 mmol) in dry benzene (5 ml) catalysed by DMF at RT for l h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (260 mg, 2.57 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 1-2 % methanol in chloroform as eluent to give 90 mg of the product as a white solid, mp 58-60 °C; IR (KBr) 3337, 2954, 1640, 1503, 1266, 1224, 1024, 761 cm ^"'; 'H ΝMR (300 MHz, CDC1₃) δ 1.57-1.98 (m, 9 H), 2.09-2.17 (m, 2 H), 2.85-2.91 (m, 1 H), 3.76 (t, J = 6.3 Hz, 2 H), 3.86 (t, 3 H), 4.56-4.64 (m, 1 H), 4.80-4.85 (m, 1 H), 6.82 (d, J= 8.4 Hz, 1 H), 7.23-7.42 (m, 8 H).

Example - 49

(3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2-oxo-l- phenyl-hexahydropyridine

Step 1 : (3S)-3-Amino-2-oxo-l-phenylhexahydropyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-2-oxo-l- phenylhexahydropipyridine (200 mg, 0.72 mmol) using 15 % HCl in EtOAc (10 ml) at RT for 2 h.

Step 2: 3-Cyclopentyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopropyloxy-4-difluoromethoxybenzoic acid (180 mg, 0.66 mmol) using oxalyl chloride (126 mg, 0.99 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (200 mg, 1.98 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 20 % EtOAc in chloroform to give 80 mg of the product as a white solid, mp 49-51 °C; IR (KBr) 3317, 2957, 1639, 1545, 1497, 1271, 1201, 1115, 1043, 761 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.64-1.89 (m, 9 H), 2.10-2.46 (m, 2 H), 2.82-2.90 (m, 1 H), 3.77 (t, J= 5.7 Hz, 2 H), 4.56-4.63 (m, 1 H), 4.87 (brs, IH), 6.50 (t, J= 75.0 Hz, 1 H), 7.13 (d, J= 8.0 Hz, 1 H), 7.24-7.47 (m, 7 H).

Example - 50 (3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)-2-oxo- 1 -phenyl-hexahydropyridine

Step 1: (3S)-3-Amino-2-oxo-l -phenylhexahydropipyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-2-oxo-l- phenylhexahydropipyridine (200 mg, 0.72 mmol) using 15 % HCl in EtOAc (10 ml) at RT for 3 h.

Step 2: 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoic acid (190 mg, 0.73 mmol) using oxalyl chloride (141 mg, 1.11 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (250 mg, 2.47 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 20 % EtOAc in chloroform as eluent to give 50 mg of the product as white solid, mp 47- 55 °C; IR (KBr) 3314, 2945, 1639, 1596, 1503, 1427, 1271, 1116, 1025, 762 cm ^" '; Η NMR (300 MHz, CDC1₃) δ 0.32-0.37 (m, 2 H), 0.60-0.67 (m, 2 H), 1.24- 1.30 (m, 1 H), 1.69-1.77 (m, 1 H), 2.08-2.15 (m, 2 H), 2.78-2.85(m, 1 H), 3.75 (t, J = 6.3 Hz, 2 H), 3.88 (d, J = 6.9 Hz, 2 H), 4.55-4.63 (m, 1 H), 6.64 (t, J = 75.3 Hz, 1 H), 7.13 (dd, J= 5.4, 3.0 Hz, 1 H), 7.23-7.42 (m, 8 H).

Example - 51

(3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-2-oxo-l- phenylhexahydropyridine

Step 1: (3S)-Amino-2-oxo-l -phenylhexahydropipyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-2-oxo-l- phenylhexahydropipyridine (200 mg, 0.72 mmol) using 15 % HCl in EtOAc (10 ml) at RT for 2 h.

Step 2: 3,4-Di(difluoromethoxy)benzoyl chloride was prepared from 3,4- Di(difluoromethoxy)-benzoic acid (160 mg, 0.63 mmol) using oxalyl chloride (120 mg, 0.94 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (200 mg, 1.98 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 20-25 % EtOAc in chloroform as eluent to give 50 mg of the product as white solid, mp 41-43 °C; IR (KBr) 3305, 2952, 1639, 1593, 1494, 1277, 1120, 761cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.68-1.82 (m, 1 H), 2.07-2.18 (m, 2 H), 2.73-2.81 (m, 1 H), 3.74-3.78 (m, 2 H), 4.50-4.62 (m, IH), 6.54 (t, J= 72.6 Hz, 1 H), 6.55 (t, J = 72.6 Hz, 1 H), 7.21 -7.31 (m, 4 H), 7.38-7.19 (m, 2 H), 7.58-7.73 (m, 3 H). Example - 52

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-6- oxohexahydropyridine

Step 1: (3S)-3-Amino-6-oxo-l-phenylhexahydropyridine hydrochloride was prepared as follows: (3S)-3-(N-BOC-Amino)-6-oxohexahydropipyridine (150 mg, 0.70 mmol) was added to a stiπed and cooled (0 °C) solution of 15 % hydrochloric acid in ethyl acetate (5 ml). The mixture was slowly warmed to RT and further stiπed at RT for 3 h under nitrogen. Ethyl acetate and excess acid were evaporated under reduced pressure to give the amine hydrochloride as white solid, which was used as such for the coupling reaction.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared as follows: Oxalyl chloride (130 mg, 1.02 mmol) was added to a well-stiπed solution of 3- Cyclopentyloxy-4-methoxybenzoic acid (160 mg, 0.67 mmol) in dry benzene (5 ml) at room temperature under nitrogen atmosphere. The reaction was initiated with a drop of dry DMF and stiπed at room temperature for 1 h. The solvent was removed under reduced pressure to give the acid chloride quantitatively as a viscous residue, which was used as such for the coupling reaction.

Step 3: Coupling reaction: The acid chloride (step 2) dissolved in dry dichloromethane (5 ml) was added to a well stiπed and cooled (0 °C) solution of the crude amine (step 1) and triethylamine (137 mg, 1.35 mmol) in dry dichloromethane (5 ml). The mixture was further stiπed at room temperature for 1 h. The mixture was diluted with dichloromethane (100 ml) and washed with water (3 x 100 ml), brine (100 ml) and dried (Νa₂SO₄). The crude product obtained after evaporation of the solvent was purified by silica gel column chromatography using 3-4 % methanol in chloroform as eluent to give 50 mg of the product as white solid, mp 161-163 °C; IR (KBr) 3307, 2955, 1630, 1504, 1328, 1261, 1224, 1132, 1022, 760 cm ^"'; Η NMR (300 MHz, CDC1₃) δ 1.55- 1.63 (m, 2 H), 1.75-2.14 (m, 8 H), 2.52 (t, J = 6.9 Hz, 2 H), 3.24-3.30 (m, 1 H), 3.64-3.70 (m, 1 H), 3.87 (s, 3 H), 4.43-4.54 (m, 1 H), 4.83 (h, J = 3.6 Hz, 1 H), 5.98 (brs, 1 H), 6.24 (brs, 1 H), 6.84 (d, J= 8.7 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H), 7.38 (s, 1 H).

Example - 53

(3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-6- oxohexahydropyridine

Step 1: (3S)-3-Amino-6-oxohexahydropipyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-6-oxohexahydropyridine (215 mg, 1.0 mmol) using 15 % HCl in EtOAc ( 10 ml) at RT for 3 h.

Step 2: 3-Cyclopentyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopentyloxy-4-difluoromethoxybenzoic acid (200 mg, 0.73 mmol) using oxalyl chloride (140 mg, 1.10 mmol) in dry benzene (5 ml) catalysed by DMF at RT for l h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (150 mg, 1.48 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 1 -2 % methanol in chloroform as eluent to give 180 mg of the product as white solid, mp 58-62 °C; IR (KBr) 3283, 2958, 1655, 1543, 1500, 1268, 1205, 1116, 1048, 993, 761 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.62-2.13 (m, 10 H), 2.49 (t, J = 6.9 Hz, 2 H), 3.25-3.30 (m, 1 H), 3.62-3.69 (m, 1 H), 4.42-4.48 (m, 1 H), 4.82- 4.91 (m, 1 H), 6.27 (brs, 1 H), 6.57 (t, J= 76.2 Hz, 1 H), 6.60 (brs, 1 H), 7.12 (d, J= 8.1 Hz, 1 H), 7.21 (d, J= 8.1 Hz, 1 H), 7.49 (s, 1 H).

Example - 54

(3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)-6-oxo- hexahydropyridine

Step 1: (3S)-3-Amino-6-oxohexahydropyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-6-oxohexahydropyridine (214 mg, 1.0 mmol) using 15 % HCl in EtOAc (10 ml) at RT for 3 h.

Step 2: 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoic acid (200 mg, 0.77 mmol) using oxalyl chloride (148 mg, 1.16 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (150 mg, 1.48 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 3-5 % methanol in chloroform to give 150 mg of the product as a white solid, mp 161- 163 °C; IR (KBr) 3282, 1641, 1549, 1507, 1407, 1331, 1271, 1217, 1129, 1055 cm ^"'; Η ΝMR (300 MHz, CDC ) δ 0.38 (dd, J= 5.7, 4.8 Hz, 2 H), 0.69 (dd, J = 6.9, 6.3 Hz, 2 H), 1.28-1.35 (m, 1 H), 2.00-2.19 (m, 2 H), 2.55 (t, J= 6.9 Hz, 2 H), 3.27-3.33 (m, 1 H), 3.68-3.75 (m, 1 H), 3.95 (d, J= 6.9 Hz, 2 H), 4.47-4.52 (m, 1 H), 5.84 (brs, 1 H), 6.30 (brs, 1 H), 6.70 (t, J= 75.0 Hz, 1 H), 7.17-7.25 (m, 3 H), 7.47 (s, 1 H).

Example - 55

(3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-6-oxohexahydropyridine

Step 1: (3S)-3-Amino-6-oxohexahydropyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-6-oxohexahydropipyridine (214 mg, 1.0 mmol) using 15 % HCl in EtOAc (10 ml) at RT for 3 h.

Step 2: 3,4-Di(difluoromethoxy)benzoyl chloride was prepared from 3,4- Di(difluoromethoxy)-benzoic acid (200 mg, 0.78 mmol) using oxalyl chloride (150 mg, 1.18 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (180 mg, 1.78 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 3-4 % methanol in chloroform to give 100 mg of the product as white solid, mp 109-114 °C; IR (KBr) 3287, 2955, 1651, 1548, 1504, 1381, 1271, 1201, 1123, 1049, 815, 760 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 2.00-2.15 (m, 2 H), 2.46-2.52 (m, 2 H), 3.26-3.32 (m, 1 H), 3.32-3.38 (m, 1 H), 4.47-4.57 (m, 1 H), 6.11 (brs, 1 H), 6.56 (t, J= 72.6 Hz, 2 H), 6.85 (brs, 1 H), 7.28 (d, J= 8.4 Hz, 1 H), 7.67 (d, J= 8.4 Hz, 1 H), 7.75 (s, 1 H).

Example - 56

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-6-oxo-l- phenylhexahydro-pyridine

Step 1 : (3S)-3-Amino-6-oxo-l -phenylhexahydropyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-6-oxo-l- phenylhexahydropyridine (250 mg, 0.89 mmol) using 15 % HCl in EtOAc (10 ml) at RT for 3 h.

Step 2: 3-Cyclopentyloxy-4-methoxybenzoyl chloride was prepared from 3- Cyclopentyloxy-4-methoxybenzoic acid (250 mg, 1.06 mmol) using oxalyl chloride (202 mg, 1.59 mmol) in dry benzene (5 ml) catalysed by DMF at RT for l h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (321 mg, 3.17 mmol) in dry dichloromethane (10 ml). The crude product was purified by silica gel column chromatography using 2 % methanol in chloroform as eluent to give 200 mg of the product as white solid, mp 165-167 °C; IR (KBr) 3225, 2955, 1664, 1625, 1537, 1330, 1268, 1224, 1023, 696 cm ^"'; Η ΝMR (300 MHz, CDC1₃) δ 1.76-2.03 (m, 9 H), 2.24-2.32 (m, 1 H), 2.71 (t, J= 6.9 Hz, 2 H), 3.62 (dd, J= 7.2, 5.1 Hz, 1 H), 3.87 (s, 3 H), 4.01 (dd, J= 7.8, 4.5 Hz, 1 H), 4.58-4.65 (m, 1 H), 4.78-4.85 (m, 1 H), 6.21 (d, J = 6.9 Hz, 1 H), 6.82 (d, J= 8.4 Hz, 1 H), 7.19-7.25 (m, 4 H), 7.33-7.38 (m, 3 H).

Example - 57

(3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)-6-oxo- 1 -phenyl-hexahydropyridine

Step 1: (3S)-3-Amino-6-oxo-l -phenylhexahydropyridine hydrochloride was prepared by the deprotection of (3S)-3-(N-BOC-Amino)-6-oxo-l- phenylhexahydropyridine (100 mg, 0.35 mmol) using 15 % HCl in EtOAc (5 ml) at RT for 3 h. Step 2: 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoyl chloride was prepared from 3-Cyclopropylmethyloxy-4-difluoromethoxybenzoic acid (100 mg, 0.38 mmol) using oxalyl chloride (74 mg, 0.58 mmol) in dry benzene (5 ml) catalysed by DMF at RT for 1 h.

Step 3: Coupling reaction: The amine (step 1) was coupled with acid chloride (step 2) using triethylamine (120 mg, 1.19 mmol) in dry dichloromethane (5 ml). The crude product was purified by silica gel column chromatography using 1-2 % methanol in chloroform to give 60 mg of the product as white solid, mp 55-60 °C; IR (KBr) 3314, 2926, 1637, 1593, 1503, 1407, 1272, 1120, 1120, 1024 cm ^"1; Η NMR (300 MHz, CDC1 ) δ 0.33-3.36 (m, 2 H), 0.62-0.69 (m, 2 H), 1.24-1.31 (m, 1 H), 2.00-2.10 (m, 1 H), 2.24-2.30 (m, 1 H), 2.70 (t, J= 6.9 Hz, 2 H), 3.62 (dd, J = 6.9, 1.8 Hz, 1 H), 3.91 (d, J = 6.9 Hz, 2 H), 3.98 (dd, J = 8.4, 3.9 Hz, 1 H), 4.55-4.70 (m, 1 H), 6.40 (brs, 1 H), 6.80 (t, J= 75 Hz, 1 H), 7.13-7.24 (m, 5 H), 7.32-7.37 (m, 2 H), 7.43 (s, 1 H).

In vitro studies Inhibition of Phosphodiesterase enzymes (PDE4)

In this assay, PDE4 enzyme converts [³H] cAMP to the coπesponding [³H] 5'-AMP in proportion to the amount of PDE4 present. The [³H] 5'-AMP then was quantitatively converted to free [ H] adenosine and phosphate by the action of snake venom 5'-nucleotidase. Hence, the amount of [ H] adenosine liberated is proportional to PDE4 activity.

The assay was performed at 34°C. in a 200 ul total reaction mixture. The reaction mixture contained 12.5mM of Tris, 5 mM MgC12, luM cAMP (cold) and ³H cAMP (0.1 uCi). Stock solutions of the compounds to be investigated were prepared in DMSO in concentrations such that the DMSO content in the test samples did not exceed 0.05 % by volume to avoid affecting the PDE4 activity. Drug samples were then added in the reaction mixture (25 ul/tube). The assay was initiated by addition of enzyme mix (75 uL) and the mixture was incubated for 20 minutes at 34° C. Then the reaction was stopped by boiling the tubes for 2 mins at 100°C in a water bath. After cooling on ice for 5 minutes and addition of 50 ug/reaction of 5'-nucleotidase snake venom from Crotalus atrox incubation was carried out again for 20 min. at 34°C. The unreacted substrate was separated from (3H) Adenosine by addition of Dowex AG 1X-8 (400 ul) which was prequilibrated (1 : 1 : 1) in water and ethanol. Reaction mixture was then thoroughly mixed, placed on ice for 15 minutes, vortexed and centrifuged at 14,000 r.p.m. for 2 mins. After centrifugation, a sample of the supernatant was taken and added in 24 well optiplates containing Scintillant (1 ml) and mixed well. The samples in the plates were then determined for radioactivity in a Top Counter and the PDE4 activity was calculated. PDE4 enzyme was present in quantities that yield <30% total hydrolysis of substrate (linear assay conditions).

Additionally, activity of the compounds were tested against other Phosphodiesterase enzymes, namely,PDEl(Ca.sup.2+/calmodulin-dependent), PDE2(cGMP-stimulated), PDE3(cGMP-inhibited), PDE5 (cGMP-specific) and PDE6 (cGMP -specific, photoreceptor).

Results were expressed as percent inhibition (IC₅₀) in nM concentrations. The IC50 values were determined from the concentration curves by nonlinear regression analysis.

Claims

We Claim: 1. A compound of the general formula (I- A)

wherein, R¹ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(O)-R', -C(O)O-R\ -C^NR'R¹ and -S(O)_m-R'; Y is selected from the group consisting of direct bond, oxygen, sulfur and NR¹; X is selected from the group consisting of: hydrogen, halogen atom, -OR¹, - S(O)_m R¹ , -C(O)R^! , formyl amine, nitro and -NR^xR ; R^x and R^y are independently selected from the group consisting of: hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl; m is 0, 1 or 2; R² is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=0), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl and formyl;

R³ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl and hydroxy; ring A is a heterocyclic πng wherein R is chosen independently for each position capable of substitution, and their analogs, their tautomers, their regioisomers, their diasteromers, their stereoisomers, their geometrical isomers, their N-oxides, their polymoφhs, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates thereof.

2. A compound according to claim 1 wherein the substituents in the 'substituted alkyl', 'substituted alkoxy' 'substituted alkenyl' ' substituted alkynyl' 'substituted cycloalkyl' substituted cycloalkylalkyl' substituted cyclocalkenyl' 'substituted arylalkyl' 'substituted aryl' 'substituted heterocyclic ring', 'substituted heteroaryl ring,' 'substituted heteroarylalkyl', 'substituted heterocyclylalkyl ring', 'substituted amino', 'substituted alkoxycarbonyl', 'substituted cyclic ring' 'substituted alkylcarbonyl', 'substituted alkylcarbonyloxy' and 'substituted carboxylic acid' may be the same or different which one or more selected from the groups such as hydrogen, hydroxy, halogen, carboxyl, cyano, amino, nitro, oxo (=O), thio (=S), or optionally substituted groups selected from alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heteroarylalkyl, heterocyclic ring, -COOR", -C(O)R\ -C(S)R^X, - C(O)NR^xR^y, -C(O)ONR^xR^y, -NR^xCONR^yR^z, -N(R^x)SOR^y, -N(R^x)SO₂R^y, -(=N- N(R^x)R^y), - NR^xC(O)OR^y, -NR^xR^y, -NR^xC(O)R^y-, -NR^xC(S)R^y -NR^xC(S)NR^yR^z, - SONR^xR^y-, -SO₂NR^xR^y-, -OR^x, -OR^xC(O)NR^yR^z, -OR^xC(O)OR^y-, -OC(O)R^x, - OC(O)NR^xR^y, -R^xNR^yR², -R^xR^yR^z, -R^XCF₃, -R^xNR^yC(O)R^z, -R^xOR^y, - R^xC(O)OR^y, -R^xC(O)NR^yR^z, -R^xC(O)R^x, -R^xOC(O)R^y, -SR^X, -SOR^x, -S0₂R^x and - ONO₂; R^x, R^y and R^z is each independently selected from the group consisting of: hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl.

3. The compound according to claim 1 or 2 wherein R¹ is chosen from the group consisting of: substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl and substituted or unsubstituted cycloalkylalkyl.

4. The compound according to claims 1-2 or 3 wherein Y is oxygen.

5. The compound according to claims 1-3 or 4 wherein X is substituted or unsubstituted alkoxy.

6. The compound according to claim 1-4 or 5 wherein R is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and oxo(=O).

7. The compound according to claims 1-5 or 6 wherein R³ is hydrogen.

8. The compound according to claims 1-6 or 7 wherein ring A is

wherein n = 1 or 2; p = 1 , 2, 3, 4 or 5; with the proviso that if n = 1 then p = 1 , 2, 3 or 4, and ifn = 2 then p= 1, 2, 3, 4 or 5.

9. The compound according to claim 8 wherein ring A is selected from the group consisting of:

10. A compound according to claim 1 selected from the group consisting of:

(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- cyanobenzyl)-2,5-dioxo-azolane;

(3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(3- trifluoromethyl-benzyl)azolane;

(3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(4- trifluoromethyl-benzyl)azolane; (3S)- 1 -(3 -Bromobenzyl)-3 -(3 -cyclopentyloxy-4- methoxyphenylcarboxamido)-2, 5-dioxo-azolane; (3R)-3-(3-Cyclopentyloxy)-4-methoxyphenylcarboxamido)-l-(2, 5- dichlorobenzyl)-2, 5-dioxo-azolane; (3S)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)- 1 -(3 - nitrobenzyl)-2, 5-dioxoazolane; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(4-chloro-3- nitrobenzyl)-2, 5-dioxoazolane; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-5-oxoazolane; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6- dioxohexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxohexahydropyridine; (3R)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2,6- dioxo-hexahydro-pyridine; (3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 2,6-dioxo-hexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-6- oxohexahydropyridine; and (3S)-3-(3-Cyclopropylmethyloxy-4-difluoromethoxyphenylcarboxamido)- 6-oxo-hexahydropyridine.

11. A compound according to claim 1 selected from the group consisting of: (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane; (3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-methyl-2,5- dioxoazolane; (3S)-3 -(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)- 1 - cyclopropylmethyl-2,5-dioxoazolane; (3S)-1 -Cyclohexyl-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)- 2,5-dioxoazolane; (3S)- 1 -Cyanomethyl-3 -(3 -cyclopentyloxy-4-methoxyphenylcarboxamido)- 2,5-dioxoazolane ; Methyl 2-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolan- 1 -yl] acetate ; 2-[(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolan- l-yl]acetic acid; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l- phenylazolane; (3S)-l-Benzyl-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5- dioxoazolane; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(3- trifluoromethylbenzyl)-azolane; (3R)-3-(3 -Cyclopentyloxy-4-methoxyphenylcarboxamido)-2 , 5 -dioxo- 1 -(3 - trifluoromethylbenzyl)-azolane; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(4- trifluoromethylbenzyl)-azolane; (3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,5-dioxo-l-(3- trifluoromethylbenzyl)-azolane; (3R)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- cyanobenzyl)-2, 5-dioxoazolane; Ethyl 4-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5- dioxoazolan- l-yl]benzoate; Ethyl 3-[(3S)-3-(3-cyclopentyloxy-4-methoxyphenylcarboxamido)-2, 5- dioxoazolan- 1 -ylmethyl] benzoate; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- fluorobenzyl)-2, 5-dioxoazolane; and (3S)-3-(3-Cyclopentyloxy)-4-methoxyphenylcarboxamido)-l-(2, 5- dichlorophenyl)-2, 5-dioxo-azolane.

12. A compound according to claim 1 selected from the group consisting of: (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(2, 6- dichlorobenzyl)-2, 5-dioxoazolane; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- pyridylmethyl)-2, 5-dioxoazolane ; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(3- oxopyridylmethyl)-2, 5-dioxo-azolane; (3S)- 1 -Benzyl-3-(3 -cyclopentyloxy-4-methoxyphenylcarboxamido)-2- oxoazolane; (3S)- 1 -Benzyl-3-(3 -cyclopentyloxy-4- difluoromethoxyphenylcarboxamido)-2-oxoazolane; (3S)-3-(4-Difluoromethoxy-3-methoxyphenylcarboxamido)-2,6- dioxohexahydro-pyridine; (3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-2,6- dioxohexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-ethyl-2,6- dioxohexahydro-pyridine; Ethyl-2-[(3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6- dioxo-hexahydro- 1 -pyridinyljacetate; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-l-(2,6- dichlorobenzyl)-2,6-dioxohexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-l-(2,6- dichloro-benzyl)-2,6-dioxohexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2,6-dioxo- 1 -(4- pyridyl-methyl)-hexahydropyridine; (3S)-3 -[3 ,4-Di(difluoromethoxyphenylcarboxamido] - 1 -(4-pyridylmethyl)- 2,6-dioxo-hexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2- oxohexahydropyridine; (3S)-3 -(3 -Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2- oxohexahydro-pyridine; (3S)-3-(3-Cyclopropylmethoxy-4-difluoromethoxyphenylcarboxamido)-2- oxo-hexahydropyridine; (3S)-3-[3,4-di(difluoromethoxy)phenylcarboxamido]-2- oxohexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-2-oxo-l- phenylhexahydro-pyridine; (3S)-3-(3-Cyclopentyloxy-4-difluoromethoxyphenylcarboxamido)-2-oxo- 1-phenyl-hexahydropyridine; (3S)-3-(3-Cyclopropylmethoxy-4-difluoromethoxyphenylcarboxamido)-2- oxo-1-phenyl-hexahydropyridine; (3S)-3-[3,4-di(difluoromethoxy)phenylcarboxamido]-2-oxo-l- phenylhexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-6- oxohexahydropyridine; (3S)-3-[3,4-Di(difluoromethoxy)phenylcarboxamido]-6- oxohexahydropyridine; (3S)-3-(3-Cyclopentyloxy-4-methoxyphenylcarboxamido)-6-oxo-l- phenylhexahydro-pyridine; and (3S)-3-(3-Cyclopropylmethyloxy-4-methoxyphenylcarboxamido)-6-oxo-l- phenyl-hexahydropyridine.

13. A process for the preparation of compounds of the general formula (I -A)

(I-A) wherein, R¹ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(O)-R', -C(O)O-R', -C^NR'R¹ and -S(O)_m-R'; Y is selected from the group consisting of: direct bond, oxygen, sulfur and NR ; X is selected from the group consisting of: hydrogen, halogen atom, -OR , - S(O)_m R¹, -C(O)R¹, formyl amine, nitro and -NR^xR^y, wherein R^x and R^y are independently selected from the group consisting of: hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl; m is 0, 1 or 2; R² is independently selected for each position capable of substitution from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl and formyl; wherein R³ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl and hydroxy;

and their analogs, their tautomers, their regioisomers, their diastereomers, their stereoisomers, their geometrical isomers, their N-oxides, their polymorph, their pharmaceutically acceptable salts, and their pharmaceutically acceptable solvates thereof; comprising the steps of:

(a) Cyclisation of the compound of the formula (3)

with a coupling agent chosen from the group consisting of DCC and HOBT in the presence of an activator chosen from the group consisting of N- hydroxysuccinimide and HOBT to yield compounds of the formula (4)

(b) Selective alkylation of the compound of the general formula (4) with alkyl halides of formula R²X to yield the compound of the general formula (5) where R² is as previously described

(c) Deprotection of the Cbz group of compound of formula (5) using palladium on carbon to yield the compound of the general formula (6)

(d) Condensation of the compound of the general formula (6) with compound of formula (7) where X, Y and R¹ are as previously described

76

77 to yield a compound of the general formula (la)

78

80 and

81 (e) reacting the compound of the general formula (la) with an alkyl halide of the

82 formula R X to yield compounds of the general formula (I) where is as previously

83 described

84

85

14. A process for the preparation of compounds of the general formula (1-A)

wherein, R is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(O)-R', -C^O-R¹, -C(O)NR'R' and -S(O)_m-R' Y is selected from the group consisting of: direct bond, oxygen, sulfur and NR¹ X is selected from the group consisting of: hydrogen, halogen atom, -OR¹, - S(O)_m R¹ , -C(O)R* , formyl amine, nitro and -NR^xR^y' R and R^y are independently selected from the group consisting of: hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl m is 0, 1 or 2; R² is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, and formyl

R³ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl and hydroxy

and their analogs, their tautomers, their regiosomers, their diastereomers, their stereoisomers, their geometrical isomers, their N-oxides, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvents thereof comprising the steps of: (a) Coupling of compound of the general formula (8) with compound of formula (9)

in the presence of a coupling agent chosen from the group consisting of DCC and EDCA optionally in the presence of an activator chosen from the group consisting of HOBT and N-hydroxysuccinimide to yield a compound of the general formula (10)

(b) Cyclisation of the compound of the general formula (10) in the presence of DCC in DMF to yield a compound of the general formula (11) where X, Y and R¹ is as previously described.

(c) Reaction of compound of formula (11) with alkyl halides of general formula R²X gives the compound of formula (la) where R² is as previously described

75 (d) reacting the compound of the formula (la) with an where alkyl halide of the

76 formula R X to get the novel compounds of the formula (I-A) where R is as

77 previously described

15. A process for the preparation of compounds of the general formula (I-A)

( I-A)

wherein, R selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(O)-R', -C(O)O-R', -C^NR'R¹ and -S(O)_m-R' Y is selected from the group consisting of: direct bond, oxygen, sulfur and NR¹ X is selected from the group consisting of: a hydrogen, halogen atom, -OR¹, - S(O)_m R¹,

formyl amine, nitro and -NR^xR^y R^x and R^y are independently selected from the group consisting of: hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl; m is 0, 1 or 2; wherein R² is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, and formyl

wherein R³ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl and hydroxy wherein ring A is

and their analogs, their tautomers, their regiosomers, their diastereomers, their stereoisomers, their geometrical isomers, their N-oxides, their polymoφhs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvents thereof comprising the steps of: (a) Condensation of compound of the formula (12)

with an amine of formula R²NH₂ to yield a the compound of general formula (13)

(b) Alkylation of the compound of the general formula (13) with methyl iodide to yield a compound of the general formula (14) where R² is as previously described

(c) Intramolecular cyclisation of the compound of the general formula (14) in the presence of a base to yield a compound of the general formula (15)

15 (d) Deprotection of the BOC group of compound of formula (15) followed by condensation with compound of formula (7) where X, Y, and R¹ are as previously described

to yield a compound of the general formula (lb)

(e) reacting the compound of the general formula (lb) with an alkyl halide of the formula R³X to yield a compound of the general formula (I) where R³ is as previously described

77 ( I- A)

78

1 16. A process for the preparation of compounds of the general formula (I-A)

2

5 wherein,

6 R¹ is selected from the group consisting of: hydrogen, substituted or unsubstituted

7 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl,

8 substituted or unsubstituted cycloalkyl, substituted or unsubstituted

9 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or

10 unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or

11 unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group,

12 substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted

13 heteroarylalkyl, -C(O)-R¹, -C(O)O-R¹, -C(O)NR¹R¹ and -S(O)_m-R'

14 Y is selected from the group consisting of direct bond, oxygen, sulfur or NR¹;

15 preferably Y is oxygen

16 X is selected from the group consisting of: a hydrogen, halogen atom, -OR¹, -

17 S(O)_m R¹,

formyl amine, nitro and -NR^xR^y

18 R^x and R^y are independently selected from the group consisting of: hydrogen 19 atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted 20 arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, 21 substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic 22 ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted 23 heteroaryl and substituted or unsubstituted heteroarylalkyl

24 m is 0, 1 or 2; wherein R² is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, and formyl

wherein R³ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl and hydroxy

and their analogs, their tautomers, their regiosomers, their diastereomers, their stereoisomers, their geometrical isomers, their N-oxides, their polymoφhs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvents thereof comprising the steps of: (a) Reduction of a compound of the formula (16) via its mixed anhydride

(16) in the presence of NaBH₄ to yield the compounds of the formula (17)

(b) Mesylation of compound of formula 17 followed by treatment with sodium azide to yield a compound of the formula (18).

(c) Palladium catalysed reductive cyclisation of compound of formula (18) to yield a compound of the formula (19).

(d) Deprotection of compound of formula (19) followed by condensation with compound of formula (7) where X, Y, R¹ and R² are as previously described

to yield a compound of formula (Ic)

73 (e) reacting the compound of the formula (Ic) with an alkyl halide of the formula

7 744 RR XX ttoo ggeett the novel compounds of the formula (I-A) where is as described

75 previously

76

1 17. A process for the preparation of compounds of the general formula (I-A)

2

5 wherein,

6 R is selected from the group consisting of: hydrogen, substituted or unsubstituted

8 substituted or unsubstituted cycloalkyl, substituted or unsubstituted

9 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or

10 unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or

11 unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group,

12 substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted

13 heteroarylalkyl,

and -S(O)_m-R'

14 Y is selected from the group consisting of direct bond, oxygen, sulfur and NR¹

15 X is selected from the group consisting of: a hydrogen, halogen atom, -OR¹, -

16 S(O)_m R¹ , -C(O)R^] , formyl amine, nitro and -NR^xR^y;

17 R^x and R^y are independently selected from the group consisting of: hydrogen

18 atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted

19 arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl,

20 substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic

21 ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted

22 heteroaryl and substituted or unsubstituted heteroarylalkyl

23 m is 0, 1 or 2; R is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, and formyl

R is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl and hydroxy

and their analogs, their tautomers, their regiosomers, their diastereomers, their stereoisomers, their geometrical isomers, their N-oxides, their polymoφhs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvents thereof comprising the steps of: (a) Cyclisation of the compound of general formula (20)

with DCC in the presence of N-hydroxysuccinimide in DMF to yield compounds of the formula (21)

21

(b) Alkylation of the compound of general formula (21) with alkyl halides of formula R²X to yield the compound of the general formula (22) where R² is as previously described

(c) Deprotection of the Cbz group of compound of formula (5) using palladium on carbon in the presence of hydrogen or a hydrogen source to yield a compound of formula (23)

(d) Condensation of the compound of the general formula (23) with compound of formula (7)

yield a compound of the general formula (Id)

74 75 (e) reacting the compound of the formula (la) with alkyl halide of the formula 76 R X to yield a compound of the general formula (I-A) is as previously described 77

78

79

1 18. A process for the preparation of compounds of the general formula (I-A)

2

5

8 substituted or unsubstituted cycloalkyl, substituted or unsubstituted

9 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or

10 unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or

11 unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group,

12 substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted

13 heteroarylalkyl, -C(0)-R', -C(0)0-R¹, -C(0)NR¹R¹ and -S(O)_m-R'

14 Y is selected from the group consisting of: direct bond, oxygen, sulfur and NR¹

16 S(O)_m R¹, -C(O)R¹, formyl amine, nitro and -NR^xR^y;

17 R and R^y are independently selected from the group consisting of: represents 18 hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl m is 0, 1 or 2; wherein R² is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, and formyl

and their analogs, their tautomers, their regiosomers, their diastereomers, their stereoisomers, their geometrical isomers, their N-oxides, their polymoφhs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvents thereof comprising the steps of: (a) Esterification of the compound of general formula (24)

with SOCl₂ in methanol to yield a compound of the formula (25)

(b) Intramolecular cyclisation of the compound of the formula (25) in the presence of a base chosen from the group consisting of: triethylamine (TEA) and diisopropylethylamine in the presence of (BOC)₂O to yield a compound of the formula (26)

(c) Alkylation of the compound of general formula (26) with alkyl halides of formula R²X to get the compound of the general formula (27) where R² is as previously described

27

(d) Condensation of the compound of the general formula (27) with compound of formula (7) where X, Y, and R¹ are as previously described

74

75 to yield a compound of the general formula (le) 76

78 79 (e) reacting the compound of the formula (I-e) with an alkyl halide of the formula 80 R R³XX ttoo ggeelt the novel compounds of the formula (I-A) where is as previously 81 described

82 ( I-A ) 83

1 19. A process for the preparation of compounds of the general formula (1)

2

4 (1-A) 5 wherein, 6 R is selected from the group consisting of: hydrogen, substituted or unsubstituted 7 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, 8 substituted or unsubstituted cycloalkyl, substituted or unsubstituted 9 cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or 10 unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or 11 unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, -C(O)-R', -C^O-R¹, -CCOJNR'R" and -S(O)_m-R' Y is selected from the group consisting of: direct bond, oxygen, sulfur and NR¹ X is selected from the group consisting of: hydrogen, halogen atom, -OR¹, - S(O)_m R¹, -C(O)R.\ formyl amine, nitro and -NR^xR^y; R^x and R^y are independently represents hydrogen atom, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl m is 0, 1 or 2;

R² is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, oxo (=O), thio (=S), hydroxy, amino, cyano, nitro, halogen, carboxyl, and formyl

R³ is selected from the group consisting of: hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylakyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl and hydroxy wherein ring A is

and their analogs, their tautomers, their regiosomers, their diastereomers, their stereoisomers, their geometrical isomers, their N-oxides, their polymoφhs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvents thereof comprising the steps of: (a) Selective reduction of the compound of the formula (28) via its mixed anhydride

in the presence of NaBH₄ to yield a compound of the formula (29)

(b) Mesylation of compound of formula (29) followed by treatment with sodium azide to yield a compound of the formula (30).

(c) Palladium catalysed reductive cyclisation of compound of formula (30) to yield compound of the formula (31).

(c) Alkylation of the compound of general formula (31) with alkyl halides of formula R²X to yield a compound of the general formula (32) where R² is as previously described

(d) Acylation of compound of the general formula (32) with compound of formula (7) where X, Y, and R¹ are as previously described

to yield a compound of the general formula (If) where X, Y, R and R are the same as described above

(e) reacting the compound of the general formula (I-f) with an alkyl halide of the formula R³X to get the novel compounds of the formula (I-A) where is as previously described 85

86

1 20. A pharmaceutical composition comprising a compound according to

2 claims 1-11 or 12 and pharmaceutically acceptable salts or solvates thereof

3 as well as pharmaceutically acceptable diluents or carriers. 4

1 21. A method of treating inflammatory diseases, disorders and conditions

2 characterized by or associated with an undesirable inflammatory immune

3 response and all disease and conditions induced by or associated with an

4 excessive secretion of TNF-a and PDE-4 which comprises administering

5 to a subject in need thereof a therapeutically effective amount of a

6 compound according to claims 1-11 or 12.

1 22. A method of treating inflammatory conditions and immune disorders in a

2 subject in need thereof which comprises administering to said subject a

3 therapeutically effective amount of a compound according to claim 1.

1 23. The method according to claim 22 wherein said inflammatory conditions

2 immune disorders is chosen from the group consisting of: asthma, chronic

3 obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma,

4 nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple

5 sclerosis, Crohns disease, psoraisis, uticaria, adult vernal conjunctivitis,

6 respiratory distress syndrome, rheumatoid spondylitis, osteoarthritis, gouty

7 arthritis, utelitis, allergic conjunctivitis, inflammatory bowel conditions,

8 ulcerative colitis, eczema, atopic dermatitis and chronic inflammation.

1 24. The method according to claim 22 wherein said inflammatory conditions

2 and immune disorders are selected from the group consisting of:

3 inflammatory conditions or immune disorders of the lungs, joints, eyes,

4 bowels, skin and heart.

25. The method according to claim 23 wherein said inflammatory condition is chosen from the group consisting of: bronchial asthma, nepritis, and allergic rhinitis.

26. A method for abating inflammation in an affected organ or tissue comprising delivering to said organ or tissue a therapeutically effective amount of a compound according to claims 1-11 or 12.

27. A method of treating diseases of the central nervous system in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to claims 1-1 1 or 12.

28. The method according to claim 27 wherein said diseases of the central nervous system are chosen from the group consisting of: depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease.

29. A method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to claims 1-11 or 12.