NZ629360B2 - Novel compounds for the treatment of dyslipidemia and related diseases - Google Patents

Abstract

Disclosed herein are compounds of formula (I) where the substituents are as defined herein. Also disclosed are pharmaceutical compositions containing them, methods for their preparation, the use of these compounds in medicine and the intermediates involved in their preparation. The compounds are suitable for the treatment of diseases and conditions such as hyperlipidemia and dyslipidemia. Particular examples of the compounds of formula I include 2-(4-(4-methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and 2-(4-(2-(4-chlorophenyl)-4-methylthiazol-5-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide. table for the treatment of diseases and conditions such as hyperlipidemia and dyslipidemia. Particular examples of the compounds of formula I include 2-(4-(4-methyl-5-(p-tolyl)isoxazol-3-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and 2-(4-(2-(4-chlorophenyl)-4-methylthiazol-5-yl)phenoxy)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide.

Description

NOVEL COMPOUNDS FOR THE TREATMENT-OF DYSLIPIDEMIA AND RELATED ES FIELD OF INVENTION The present invention relates to compounds of the general formula (1), their meric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation The present invention is directed to compounds suitable for the treatment of Disease conditions such as hyperlipidemia. The compounds of the present invention also lower LDL-c.

(R2)n (Rom e 9 e w“H o (R3)o The compounds of the general a (I) lower or modulate cholesterol levels and/or low-density lipoproteins (LDL) and/or triglyceride levels and raises the high- density lipoproteins (HDL) plasma levels and hence are useful in combating different medical conditions, where such lowering (and raising) is beneficial. Thus, it could be used in the treatment and/or prophylaxis of obesity, hyperlipidaemia, hypercholesteremia, hypertension, atherosclerotic disease events, ar restenosis, diabetes and many other related conditions.

The compounds of general formula (I) are useful to prevent or reduce the risk of developing atherosclerosis, which leads to diseases and conditions such as artereosclerotic cardiovascular diseases, stroke, coronary heart es, cerebrovascular diseases, peripheral vessel diseases and related disorders.

These compounds of general formula (I) are useful for the treatment and/or prophylaxis of metabolic ers loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and ed glucose tolerance. The e intolerance can lead to non- insulin ent diabetes mellitus (NlDDM, Type 2 diabetes), which is terized by hyperglycemia, which if not controlled may lead to diabetic complications or W0 2013/132509 metabolic disorders caused by insulin resistance. Diabetes is no longer considered to be associated only with glucose metabolism, but it affects anatomical and physiological parameters, the intensity of which vary depending upon stages/duration and severity of the diabetic state. The compounds of this invention are also useful in prevention, halting or slowing progression or reducing the risk of the above mentioned disorders along with the resulting secondary diseases such as cardiovascular diseases, like arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic athy and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, like lbuminuria and albuminuria, which may be result of hyperglycemia or - hyperinsulinemia.

The compounds of the present ion can be useful as aldose reductase inhibitors; for improving cognitive functions in dementia, and in the ent and/or prophylaxis of disorders such as psoriasis, polycystic ovarian syndrome (PCOS), cancer, osteoporosis, leptin resistance, inflammation and inflammatory bowel diseases, wound g, ma, pancreatitis, ic dystrophy, endothelial cell dysfunction and ipidemia.

BACKGROUND OF THE INVENTION Higher LDL cholesterol levels in the plasma increase cardiovascular risk and reduction in the levels of LDL would decrease CVD‘ risk by a comparable tage (PNAS, 2009, 106, 9546-9547). Clearance of LDL cholesterol from plasma is through the action of LDL receptors in the liver and LDL receptors are cell e glycoproteins that bind to apoliporpotein BlOO (apoBlOO) on LDL particles with high affinity and mediate their endocytic uptake (Journal of Biological Chemistry, 2009, 284, 10561-10570). Defect in hepatic cholesterol clearance and elevated levels of plasma LDL cholesterol that result from the mutations cause familial hypercholesterolemia. Such mutations are identified in the human LDL receptor and later in apolipoprotein-B (Nature ural and Molecular Biology, 2007, 14, 413- 419). Recently, mutations within the pro-protein convertase subtilisin/kexin of the subtype 9 (PCSK 9) gene were found to represent a third class of mutations ated with autosomal dominant hypercholesterolemia (ADH). Abifadel et al in 2003 discovered pro-protein convertase isin/kexin of the subtype 9 as the third gene involved in autosomal dominant hypercholesterolaemia (ADH) (Nature Genetics, 2003, W0 32509 PCT/lN2012/000452 34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434). Several mis sense mutations , D129G, F216L, D374H, D374Y) are associated with hypercholesterolemia and premature sclerosis (J Lipid Res. 2008, 49, 1333- 1343). Loss-of-function mutations (R46L, L253F, A433T) lead to ed receptor abundance, enhancing clearance of LDL cholesterol from the circulation and reducing cardiovascular risk (Nature Structural and Molecular Biology, 2007, 14, 413-419).

Pro-protein convertase subtilisin/kexin of the subtype 9 belongs to the subtilisin family of serine proteases and its protein structure consists of a pro-domain, catalytic , and cysteine/histidine rich C-terminal domain (Structure, 2007, 15, 545-552).

Unlike other pro-protein convertases, wherein the pro-domain is further proteolytically sed to activate the serine protease, the pro-domain of secreted subtype remains intact and tightly bound. Within endoplasmic reticulum this enzyme undergoes autocatalytic process which results in release of ~14 kDa prodomain that remains associated with the tic/C-terminal domains, wherein the pro-domain serves as both a folding chaperon and as an inhibitor of enzymatic activity (Journal of Biological Chemistry, 2009, 284, 10561-10570).

It is well documented that mal growth factor-like repeat A (EGF-A) of LDLR interacts with this pro-protein subtype mainly with residues 1. This EGF- A interaction site is located >20 A from the catalytic site of this pro-protein subtype.

Once EGF-A and this otein subtype interacts they form a x with the LDLR that enters endosomal pathway and hence LDLR recycling is prevented leading to LDLR degradation. Detailed molecular mechanisms explaining the association of LDLR and this pro-protein subtype and LDLR degradation is not very clear (Drug News Perspectives, 2008, 21, 323-330). Because of inhibition of LDLR recycling, number of LDL receptors on the cell e are decreased and this increases plasma LDL levels (PNAS, 2009, 106, 9546-9547).

Various approaches for inhibiting this pro-protein subtype are reported, including gene silencing by siRNA or antisense oligonucleotides, mAb disrupting n—protein interactions or by peptides; all the above-mentioned strategies have shown lowering of LDL cholesterol which may be ive therapy for treating holesterolemia (Biochemical Journal, 2009, 419, 577-584; PNAS, 2008, 105, 11915-11920; Journal of Lipid Research, 2007, 48, 763-767; PNAS, 2009, 106, 9820- 9825). However, very little success has been reported in trying to inhibit this pro- VIA510685NZPR 303916262 It is a further or alternative object of the present invention to provide a compound of formula (I), a use of a compound of formula (I) and/or a pharmaceutical ition which meets the above identified need.

The above objects are to be read disjunctively and with the alternative object of to at least provide the public with a useful choice.

VIA510685NZPR 303916262 The above and other embodiments are described hereinafter.

In a first aspect, the present ion provides a compound of a (I), its tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, and pharmaceutical compositions containing said compound, wherein (R2)n Z X V (R1)m W N ZA H (R3)o ‘ZA’ represents an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups; Each of ‘X’ and ‘Z’ independently represents an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl ; Alternatively, Z-X- ZA may together form tricyclic 8-15 membered fused ring system containing 1-4 hetero atoms selected from N, O or S; R1, R2 and R3 independently at each occurrence represents H, (C1-C6) linear or branched alkyl, (C1-C6) linear or branched alkenyl, (C1-C6)linear or branched alkynyl, hydroxy, (C1-C6) alkoxy, (C1-C6) alkenoxy, hydroxy(C 1-C6)alkyl, alkoxyalkyl, haloalkyl, (C1-C6)cycloalkyl, thio(C1- C6)alkyl, (C1-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally substituted amino, amino(C1-C6)alkyl, alkylamino, cyano, formyl, koxy, aryl, aryloxy, aralkyl, xy, heterocylyl, heterocyclylalkyl, heterocycloxy, cyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl, alkylsulfonylamino, ulfonyloxy, each of which may be optionally substituted; ‘m’ ‘n’ and ‘o’ independently represents integers from 0 to 5; ‘Y’ represents either a bond, or O, S(O)p or NR4 wherein R4 represents H, (C1-C6)linear or branched alkyl, (C1-C6)cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl and ‘p’ represents integers from 0 to 2; ‘W’ represents (C1-C6)linear or branched alkyl or (C1-C6)linear or branched cycloalkyl; ‘V’ represents O or S.

In a second aspect, the present invention provides a compound of formula (I) as d in the first aspect, suitably formulated into a suitable pharmaceutical ition.

In a third aspect, the t invention provides use of a nd of formula (I) as d in the first aspect, for the cture of a medicament for the treatment of hyperlipidemia, dyslipidemia, obesity, hypercholesteremia, hypertension, atherosclerosis, vascular osis and diabetes.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined in the first aspect in combination with one or more pharmaceutically active agents selected from group comprising insulin, insulin derivatives and mimetics, n secretagogues, insulin izers, biguanide , alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 activators, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin tors, anti-thrombotic and anti-platelet agents and besity agents or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTON OF THE INVENTION Accordingly, the present invention relates to nds of the genreal formual (I), W0 2013/132509 (R2)n (R1)m e a a Y\WJ\fi/\OO (R3)c their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein ‘ZA’ represents an optionally substituted single or fused group selected fiom aryl, heterocyclyl or cycloalkyl groups; Each of ‘X’ and ‘2’ independently represents an Optionally tuted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups; In a preferred embodiment, ‘X’ is selected from optionally substituted aryl or heterocyclyl groups; In a further preferred embodiment, the aryl group may be selected from substituted or unsubstituted monocyclic' or bicyclic aromatic groups; In a still further preferred embodiment, the aryl group is an optionally substituted phenyl group.

In an embodiment, when ‘X’ represents a heterocyclyl group, the heterocyclyl group may be selected from single or fused mono, bi or tricyclic ic or non-aromatic groups containing one or more hetero atoms ed fi'om O, N or S; [n a preferred embodiment, the heterocyclyl group may be selected from pyridyl, thienyl, furyl, yl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, lthiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, lopyrimidinyl, azaquinazolinyl, furanyl, pyridothienyl, pyrimidyl, quinolinyl, dinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, ylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, thiazepinyl, oxazolidinyl, lidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl,, benzopyranonyl, benzodihydrofuranyl, ihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, pyrimidonyl, quinazolonyl, donyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl and the like; .

In a preferred embodiment, either or both of ‘Z’ and"ZA’ is independently selected from optionally substituted aryl or heterocyclyl groups; W0 2013/132509 In a r preferred embodiment, when either of ‘Z’ and ‘ZA’ independently represents an aryl group, the aryl group may be selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups; In a still further preferred embodiment, such aryl group is an optionally substituted phenyl group.

In another embodiment, when either of ‘Z’ and ‘ZA’ independently represents a cyclyl group, the heterocyclyl group may be selected from single or fiised mono or bi cyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from 0, N or S; In a still preferred embodiment, when either of ‘Z’ and ‘ZA’ independently represents heteroaromatic group, the heteroaromatic group may be selected from l, thienyl, furyl, pyrrolyl, yl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, lopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl groups. ' Alternatively Z-X- 2,, may together form tricyclic 8-15 ed fused ring system containing l-4 hetero atoms selected from N, O or S.

R1, R2 and R3 independently at each occurrence represents H, (C1-C6) linear or branched alkyl, (Cl-C6) linear or ed alkenyl, (Cl-C6) linear or branched alkynyl, hydroxy, (Cl-C6) alkoxy, (C1-C6) alkenoxy, hydroxy(C.-C5)alkyl, alkoxyalkyl, haloalkyl, (C3-C6) lkyl, thio(Cl-C6)alkyl, )alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, optionally tuted amino, amino(Cl-C5)alkyl, alkylamino, cyano, , haloalkoxy, raryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and , alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted; ‘m’ ‘n’ and ‘0’ independently represents integers from 0 to 5; ‘Y’ represents either a bond, or O, S(O)p or ~NR4 wherein R4 represents H, (C1- C6) linear or branched alkyl, (C3-C6) cycloalkyl, aryl, cyclyl, heterocyclylalkyl, lkylalgl and ‘p’ represents integers from 0 to 2; ‘W’ represents (Cl-C6) linear or branched alkyl or (C3-C6) linear or branched cycloalkyl; ‘V’ represents 0 or S; W0 2013/132509 When any of R., R2 or R3 are substituted, such substituents may be selected from hydrogen, hydroxyl, oxo, halo, thiol, nitro, amino, cyano, fomtyl, or substituted or unsubstituted groups selected from amidino, alkyl, kyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, , xy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, ac'ylamino, bstituted or disubstituted amino, arylamino, lamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, yalkyl, aralkoxyalkyl, alkylthio, thioalkyl, lkylthio, arylthio, heterocyclylthio, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, amino, hydroxyl amino, sulfonic acid and its derivatives; When the aryl group at any occurrence is further substituted, the substituents are selected from halo, thiol, nitro, amino, cyano, fonnyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, oalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, lkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, io, heterocyclylthio groups; When the heteroaryl group at any ence is further substituted, the substituents are selected from halo, thiol, nitro, amino, cyano, formyl, or tuted or unsubstituted groups selected front alkyl, kyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, acyl, W0 2013/132509 ll452 acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides; When” the heterocyclyl group at any occurrence is further substituted, the substituents are selected from halo, amino, cyano, fonnyl, or substituted or unsubstituted groups selected from o, alkyl, haloalkyl, perhaloalkyl, alkoxy, koxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, acyl, acyloxy, acylamino, monosubstituted or tituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and , carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, cyclylthio groups.

The various groups, radicals and substituents used anywhere in ecification are described in the following paragraphs.

In a further preferred embodiment the groups, radicals bed above may be selected from: - the “alkyl” group used either alone or in combination with other radicals, denotes a linear or branched radical containing one to six carbons, selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, utyl, amyl, t-amyl, n-pentyl, n- hexyl, and the like; - the “alkenyl” group used either alone or in ation with other radicals, is selected from a radical containing from two to six carbons, referably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and the like; the “alkenyl” group includes dienes and trienes of straight and branched chains; - the “alkynyl” group used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to six carbon atoms, more preferably thynyl, l-propynyl, ynyl, nyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, nyl, and the like. The term “alkynyl” es di- and tri-ynes wherever applicable; - the “cycloalkyl”, or “alicyclic” group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, entyl, cyclohexyl and the like; The terms “bicycloalkyl” means more than one cycloalkyl groups fused together; W0 2013/132509 PCT/INZOI 2/000452 - the “cycloalkenyl” group used either alone or in combination with other'radicals, are ably selected from ropenyl, l-cyclobutenyl, 2-cylobutenyl, 1- cyclopentenyl, opentenyl, 3-cyclopentenyl, l-c'yclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like; The terms “bicycloalkenyl” means more than one cycloalkenyl groups fused together; - the “alkoxy” group used either alone or in combination with other ls, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy, pentyloxy, hexyloxy, and the like; - the “cycloalkoxy” group used either alone orin combination with other radicals, is selected from a cyclic radical containing three to seven carbons, more ably cyclopropyloxy, cyclobutylxoy, cyclopentyloxy, cyclohexyloxy and the like; The terms “bicycloalkyloxy” means more than one cycloalkyl groups fused together; - the oxy” group used either alone or in combination with other radicals, is selected from groups containing an alkenyl radical, as defined above, attached to an oxygen atom, more preferably selected from vinyloxy, allyloxy, xy, pentenoxy, hexenoxy, and the like; - the “haloalkyl” group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(C|-C6)alkyl such as fluoromethyl, omethyl, trifluoromethyl, fluoroethyl, roethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; 4 the “haloalkoxy” group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fiuoroethoxy, chloroethoxy and the like; - the “perhaloalkoxy” group is ed from a le perhaloalkyl radical, as defined above, directly attached to an oxygen atom, more preferably groups selected from trifluoromethoxy, trifluoroethoxy, and the like; - the “aryl” or “aromatic” group used either alone or in combination with other radicals, is selected from a le aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be W0 2013/132509 fused, more preferably the groups are selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like; - the “aryloxy” group used either alone or in combination with other radicals, is selected from groups containing an aryl l, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like; - the ‘aralkyl” group is selected from suitable aryl group as defined above attached to an alkyl group as defined above, more preferably selected from benzyl, phenethyl, ylmethyl, and the like; — the “aralkoxy” group is selected from a suitable arylalkyl group, as defined above, attached to an oxygen atom, more ably the groups are selected from oxy, phenethyloxy, naphthylmethyloxy, phenylpropyloxy, and the like, which may be substituted; - the “heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals, is ed from suitable aromatic or non-aromatic radicals containing one or more hetero atoms selected from O, N or S. The non-aromatic ls may be saturated, partially saturated or unsaturated mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more ably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, iperidinyl, 4-oxopiperidinyl, 24 oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2- oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, lidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, ihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; the aromatic ls, may be selected from suitable single or fused mono, bi or lic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are ed from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, olyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, aiaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, W0 2013/132509 pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidaz‘olyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like; - the groups “heterocycloxy”, “heterocylylalkoxy” are selected from suitable cyclyl, heterocylylalkyl groups respectively, as defined above, attached to an oxygen atom; - the “acyl” group used either alone or in combination with other radicals, is selected from a radical containing one to eight carbons, more preferably selected from forrnyl, acetyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted; - the “acyloxy” group used either alone or in combination with other radicals, is ed from a suitable acyl group, as defined above, ly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, tanoyloxy, benzoyloxy and the like; - the “acylamino” group used either alone or in combination with other radicals, is ed from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH3CONH, C2H5CONH, C3H7CONH, C4H9CONH, C6H5CONH and the like, which may be substituted; - the substituted amino” group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (C.- C6)alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from amine, ethylamine, n- propylamine, n-butylamine, ylamine and the-like; - the ‘disubstituted amino” group used either alone or in combination with other radicals, represents an amino group, substituted with two radicals that may be same or ent selected from (Cl-C6)alkyl, tuted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more ably the groups are selected from dimethylamino, methylethylamino, diethylamino, phenylmethyl amino and the like; - the “arylamino” used either alone or in combination with other radicals, represents an aryl group, as defined above, linked through amino having a free valence bond from the nitrogen atom, more preferably the groups are selected from phenylamino, naphthylamino, N-methyl anilino and the like; W0 2013/132509 - the “0x0” or “carbonyl” group used either alone ) or in combination with other radicals such as alkyl described above, for e.g. “alkylcarbonyl”, denotes a carbonyl radical (—C=O-) substituted with an alkyl radical bed above such as acyl or yl; - the “carboxylic acid” group, used alone or in combination with other radicals, denotes a -COOH group, and es derivatives of ylic acid such as esters and amides; - the “ester” group used alone or in combination with other radicals, denotes -COO- group, and includes carboxylic acid derivatives, more preferably the ester moieties are selected from alkoxycarbonyl, such as ycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; arylbxycarbonyl group such as ycarbonyl, napthyloxycarbonyl, and the like, which may optionally be substituted; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, napthylmethoxycarbonyl, and the like, which may optionally be substituted; heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group, is as defined above, which may optionally be substituted; heterocyclyloxycarbonyl, where the heterocyclic group, as definedearlier, which may optionally be substituted; - the “amide” group used alone or in combination with other radicals, ents an aminocarbonyl radical (HzN-C=O), wherein the amino group is mono- or di- substituted or unsubstituted, more preferably the groups are selected from methyl amide, dimethyl amide, ethyl amide, diethyl amide, and the like; - the “aminocarbonyl” group used either alone or in combination with other radicals, may be selected from ‘aminocarbonyl’, ‘aminocarbonylalkyl”, “ alkylaminocarbonyl”, “N-arylaminocarbonyl”, “N,N-dialkylaminocarbonyl”, “N- alkyl-N-arylaminocarbonyl”, “N;alkyl-N—hydroxyaminocarbonyl”, and “N-alkyl- N-hydroxyaminocarbonylalkyl”, each of them being ally substituted. The terms “N-alkylaminocabonyl” and “N,N-dialky|aminocarbonyl” denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl l and with two alkyl radicals, respectively. Preferred are “lower alkylaminocarbonyl” having lower alkyl radicals as described above attached to aminocarbonyl radical. The terms “N-arylaminocarbonyl” and “N-alkyl-N- arylaminocarbonyl” denote aminocarbonyl radicals substituted, respectively, with W0 2013/132509 one aryl radical, or one alkyl and one aryl radical. The term “aminocarbonylalkyl” includes alkyl radicals substituted with aminocarbonyl radicals; - the “hydroxyalkyl” group used either alone or in combination with other radicals, is selected from an alkyl group, as defined above, substituted with one or more hydroxy radicals, more preferably the groups are ed from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like; - the alkyl” group used alone or in combination with other radicals, denotes an amino (-Nl-Iz) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted lkyl. The term “alkylamino” used herein, alone or in combination with other radicals, denotes an alkyl radical, as defined above, attached to an amino group, which may be substituted, such as mono- and di-substituted alkylamino; - the “alkoxyalkyl” group used alone or in combination with other radicals, denotes an alkoxy group, as defined above, attached to an alkyl group as 'defined above, more preferably the groups may be selected from methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like; - the “alkylthio” group used either alone or in combination with other radicals, denotes a straight or branched or cyclic monovalent substituent comprising an alkyl group as defined above, linked through a divalent sulfur atom having a free valence bond from the sulfur atom, more preferably the groups may be selected from methylthio, hio, propylthio, - the “thioalkyl” group used either alone or in combination with other radicals, denotes an alkyl group, as defined above, attached to. a group of formula —SR’, where R’ represents hydrogen, alkyl or aryl group, e.g. thyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally tuted. - the “alkoxycarbonylamino” group used alone or in combination with other ls, is ed from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like; - the “arylthio” group used either alone or in combination with other radicals, s a comprising an aryl group as defined above, linked through a divalent sulfur atom W0 2013/132509 having a free valence bond from the sulfur atom, more preferably the groups may be selected from phenylthio, naphthylthio, tetrahydronaphthylthio, indanethio, biphenylthio, and the like; - the “heterocyclylthio” group used either alone or in combination with other radicals, s a sing an cyclyl group .as defined above, linked through a divalent sulfur atom having a free e bond from the sulfur atom; - the “alkoxycarbonylamino” group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, ed to an amino group, more preferably methoxycarbonylamino, ethoxycarbon'ylamino, and the like; - the “aminocarbonylamino”, “alkylaminocarbonylamino”, “dialkylaminocarbonylamino” groups used alone or in combination with other radicals, is a carbonylamino (—CONHz) group, attached to NH2), alkylamino group or lamino group respectively, where alkyl group is as defined above; - the “amidino” group used either alone or in combination with other radicals, represents a —C(=NH)-NH2 radical; the “alkylamidino” group represents an alkyl radical, as described above, attached to an amidino group; - the “alkoxyamino” group used either alone or in combination with other radicals, represents a suitable alkoxy group as defined above, attached to an amino group; - the “hydroxyamino” group used either alone or in combination with other radicals, represents a —NHOH moiety, and may be ally substituted with le groups selected from those described above; - the “sulfenyl” group or “sulfenyl derivatives” used alone or in combination with other ls, represents a bivalent group, —SO- or RXSO, where Rx is an optionally substituted alkyl, aryl', heteroaryl, heterocyclyl, group selected from those described above; - the “sulfonyl” group or “sulfones derivatives” used either alone or in combination with other radicals, with other terms such as alkylsulfonyl, represents a divalent radical ~SOz-, or RxSOz-, where Rx is as defined above. More preferably, the groups may be selected from “alkylsulfonyl” wherein suitable alkyl radicals, selected from those defined above, is attached to a sulfonyl radical, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, “arylsulfonyl” wherein W0 2013/132509 an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.

Suitable groups and substituents on the groups may be selected from those described anywhere in the cation.

The term "Substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a ion from the indicated group, ed that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

“Phannaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent nd is modified by making acid or base salts thereof.

Examples of phannaceutically acceptable salts include, but are not limited to, mineral -or organic acid salts of the basic residues. The phannaceutically acceptable salts include the conventional quaternary ammonium salts of the parent nd formed, for example, from non-toxic inorganic or organic acids. ' The term "combination therapy" means the administration of two or more therapeutic agents to treat a eutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in le, te capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will e beneficial effects of the drug combination in treating the conditions or disorders described .

- The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of ng or eliminating the said disease or disorder.

- The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, rionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are W0 2013/132509 commensurate with a reasonable benefit/risk ratio, and are effective for their ed use.

- As used , reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals ing humans. Examples of patients e humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human. - The term ‘optional’ or ‘optionally’ means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, ‘optionally substituted alkyl’ means either ‘alkyl’ or ‘substituted alkyl’. Further an optionally substituted group includes the unsubstituted group also.

Unless otherwise stated in the specification, ures depicted herein are also meant to include compounds which differ only in the ce of one or more isotopically enriched atoms. For example, compounds having the present structures wherein hydrogen is replaced by deuterium or tritium, or wherein carbon atom is replaced by 130 or 14C- enriched , are within the scope of this invention.

Particularly useful compounds may be selected from ’ 2-(4-(4-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-fluorophenyl)-4~methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2—(4-(5-(4-chlorophenyl)-4~methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl-S-(4-(trifluoromethyl)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro— 2H-pyranyl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)isoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl~5-phenylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methoxy-l-(4—(trifluoromethyl)phenyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro~2H-pyranyl)methyl)acetamide; W0 2013/132509 2-(4-(1-(4-fluorophenyl)-5~methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro—2H- pyranyl)methyl)acetamide; 2-(4-(5-methoxyphenyl- l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran—4- yl)methyl)acetamide; 2-(4-(4-methylphenylthiazol-5 -yl)phenoxy)-N-((tetrahydro-ZH-pyran yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)thiazoly1)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(2-(4-fl uorophenyl)—4-methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4i(2-(4-bromophenyl)—4-methylthiazol-S-yl)phenoxy)-N-((tetrahydro-2H-pyran yl)mlethyl)acetamide; ' 2-(4-(2-(4-chlorophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(4-methyl—2-(p-tolyl)thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methylphenyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(5-methyl(4-(trifluoromethyl)phenyl)oxazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-fluorophenyI)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran~4- yl)methyl)acetamide; 2-(4-(2-(4-bromophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-.pyran yl)methyl)acetamide; 2-(4-(2-(4-chlorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methyl(p-tolyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; . 2-(4—(2-(4-methoxyphenyl)-5—methyloxazoIyl)phenoxy)-N-((tetrahydro-2H—pyran yl)methyl)acetamide; 2-(4-(5-methyl(pyridinyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; W0 2013/132509 N-((tetrahydro-2H-pyranyl)methyl);2-(4-(5-(4-(trifluoromethyl)phenyl)-l,2,4— oxadiazolyl)phenoxY)acetamide; -(4—fluorophenyl)—l,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-bromophenyl)- l-,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro—2H-pyran yl)methyl)acetamide; ‘ 2-(4-(5-(4-chlorophenyl)— l ,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(5 4(p-tolyl)-l ,2,4-oxadiazol yl)phenoxy)acetamide; 2—(4-(5-(4-fluorophenyl)- ] xadiazol-2—yl)phenoxy)-N—((tetrahydro-2H-pyran-4— hyl)acetamide; N-((tetrahydro-2H—pyran-4—yl)methyl)(4-(5-(4-(trifluoromethyl)phenyl)-1,3,4- oxadiazo|yl)phenoxy)acetamide; 2-(4-(5-(4-methoxyphenyl)-l,3,4-oxadiazol$Il)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)-1,3,4-oxadiazol-Z-yl)phenoxy)-N-((tetrahydro-ZH-pyran yl)methyl)acetamide; 2-(4-(5-phenyl-1,3 ,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; ' 2-(4-(3-(4-fluorophenyl)oxooxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-methoxyphenyl)oxooxazoIidin-S-yl)phenoxy)-N-((tetrahydro-2H-pyran- 4-yl)methy|)acetamide; 2-(4—(4-phenyl-1 H- l ,2,3-triazol—l -y|)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamidc; 2-(4-(5—methoxy(4-(trifluoromethyl)benzyl)-1H-pyrazoIyl)phenbxy)—N- ((tetrahydro-ZH-pyranyl)methyl)acetamide; 2-(4-(4,S-dimethyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5~(4-bromophenyl)methylisoxazolyl)phenoxy)—N-((tetrahydro-2H-pyran-4— yl)methyl)acetamide; W0 2013/132509 2-(4-(5-(4-methoxyphenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyrans 4-yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isoxazo|yl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide; ’ 2-(4-(5-(4-fluorophenyl)methylisothiazoIyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-y1)methyl)acetamide; 2-(4-(5-(4-bromophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)isothiaZQlyl)bhenoxy)—N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-mefhyl(4-(trifluoromethyI)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro- 2H-pyran-4I-yl)mcthyl)acetamide; 2-(4-(5-(4-methoxyphenyl)methylisothiazol-3 -yl)phenoxy)—N-((tetrahydro-2H- 4-yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isothiazolyl)phenoxy)-N- ahydro-ZH-pyranyl)methyl)acetamide; 2-(4-(1-(4-chlorophenyl)—5-methoxy-1H-pyrazol-3~yl)phenoxy)—N-((tetrahydro-2H- pyran—4-yl)methyl)acetamide; 2-(4-(5-methoxy- l -(4—methoxyphenyl)-l H-pyrazolyl)phenoxy)—N-((tetrahydro-2H- pyfanyl)methyl)acetamide; 2-(4-(5-methoxy- I trifluoromethoxy)phenyl)-1 H-pyrazolyl)phenoxy)-N- ((tetrahydro-ZH-pyranyl)methyl)acetamide; 2-(4-(1-(4-bromophenyl)methoxy-lH-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5~methoxy— l -(p-tolyl)-l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3 lorophenyl)—2-oxooxazoIidinyI)phenoxy)-N-((tetrahydro-2H-pyran—4— yl)methyl)acetamide; 2-(4-(2-oxo(4-(trifluoromethyl)phenyl)oxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; W0 2013/132509 2-(4-(2-oxo(4¥(trifluoromethoxy)phenyl)oxazolidinyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide; 2-(4-(3-(4-bromophenyl)—2-oxooxazolidin-S-yl)phenoxy~)—N-((tetrahydro-2H-pyran—4- hyl)acetamide; 2-(4-(2-oxo(p-tolyl)oxazolidin-S-.yl)phenoxy)—N-((tetrahydro-2H-pyran yl)methyl)acetamide; 4-(4-chlorophenyl)-l H-l ,2,3-triazolyl)phenoxy)—N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethyl)phenyl)-1H~1,2,3- triazol-l ~yl)phenoxy)acetam ide; N—((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethoxy)phenyl)-l H- l ,2,3- triazol-l enoxy)acetam ide; 2-(4-(4-(4-bromophenyl)-l H-l ,2,3-triazol-l '-yl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; N-((tetrahydro-2H-pyranyl)Vmethyl)(4-(4-(p-tolyl)-1 H-1,2,3 -triazol- l - yl)phenoxy)acetamide; 2-(4-(4-(4-fluorophenyl)~l H- l ,2,3-triazol- l -yl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 4-(4-methoxyphenyl)-l H-l,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran-4— yl)methyl)acetamide. {does it include the list of compounds at the end (with no data?)} 2-(4-(3-(4-chlorophenyl)-24minooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2—(4-(6-(4-chlorophenyl)pyridinyl)phenoxy)-N-((tetrahydro~2H-pyran yl)methyl)acetamide 2-(4-(4-(4-chlorophenyl)pyrimidinyl)phenoxy)-N-((tetrahydro-ZH-pyran yl)methyl)acetamide; 2-((8-(4-chloropheny|)dibenzo[b,d]thiophenyl)oxy)—N-((tetrahydro-2H-pyran-4— yl)methyl)acetamidel; 2-(4-(7vchlorodibenzo[b,dlthiophen-Z-yl)phenoxy)—N-((tetrahydro-2H-pyran~4- yl)methy|)acetamide.

The novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section or elsewhere in the W0 2013/132509 cation. The reactions are performed in ts appropriate to the reagents and materials employed and are suitable for the transformations being affected. It is understood by those skilled in the art that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds of the present invention. It will also be well appreciated that one or more .of the reactants may be protected and deprotected for facile synthesis by ques known to persons skilled in the art. [twill also be appreciated that one or more of the compounds of the t invention may exist in stereoisomeric and/or diastereomeric forms. Such stereoisomers and/or diastereoisomers as well as their optical antipodes are to be construed to be within the scope of the present invention. It will also be well appreciated that one or more of these compounds may be converted to their salts and other derivatives based on the specific groups present on the compounds, which can be well comprehended by persons skilled in the art. Such salts and/or other derivatives, as the case may be should also be construed to be, within the scope of the present ion.

Schemezl The compounds of general formula (I) wherein all the s are as d earlier, may be prepared by reactions outlined in Scheme 1 below which comprises: W0 2013/132509 (R2)n (R2)n (R1) e a W (mm a a m 0R5 .w 0R5 Y” + L/ \n/ g MethodA \n’ V a Y —-—> (Ralo (R3)o u IV (R2)n (Wm % Q ,w OH “New“c Method B , a o —-> v ‘ H2N ‘ (R3)o (R2)n V ‘ (Ron. 6 a e “W“H o (Rah Method A: The compounds of formula IV wherein R5 ents C1-C6 linear or branched alkyl or aralkyl groups and all other symbols are as defined earlier may be prepared by the philic substitution reaction of compound of general formula II and compounds of general formula [11 wherein ‘L’ represents suitable leaving group , and all other symbols are as defined earlier using suitable inorganic base(s) such as NaOl-l, KOH, K2C03, C52C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like. The reaction may be carried out neat or in presence of le protic solvent(s) such as methanol, ethanol, butanol and the like or suitable aprotic t(s) such as yl formamide, tetrahydrofuran, dichloromethane and the like or suitable mixtures thereof. The reaction may be carried out at a ature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.

Method B: The compounds of formula IV wherein all the symbols are as defined r may be hydrolyzed to compound of formula V wherein 'all the symbols are as defined earlier using suitable base(s) e.g., NaOH, LiOH, KOH and the like.

Reaction may be ted in suitable solvents e.g., alcohols like methanol, ethanol ‘ 22 W0 2013/132509 and the like, THF, water or the mixtures thereof. The reaction may be carried out at a temperature in the range 20 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 24 hours.

Method C: The compounds of formula (I) wherein all the symbols are as defined earlier may be prepared by coupling reaction of corresponding acids of general formula V wherein all the symbols are as defined earlier and (tetrahydro-ZH-pyran yl)methanam~ine as described in scheme 1 under suitable conditions such as those described in edron, 2005, 61 (46), 10827-10852 with suitable modifications and alterations as are well known to a skilled person. The reaction may be carried out in presence of reagents(s) such as N-(3-dimethylaminopropyl)-N’-ethylcarbodimide hydrochloride (EDCl) & l-Hydroxybenzotriazole (HOBT), and the like. The reaction may be carried in suitable solvent(s) such as dimethyl fomiamide, tetrahydrofuran, dichloromethane and the like or mixtures thereof. The reaction may be carried out at a temperature in the range 0 °C to reflux temperature of the solvent(s) used and the reaction time may range from 1 to 48 hours.

The pharmaceutical composition is ed by employing tional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (1) according to this ion.

The quantity of active component, that is, the compounds of formula (1) ing to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration.

Generally, the quantity of active ent will range between 0.5% to 90% by weight of the ition.

The compounds of the present ion can be used either alone or in combination with one or more therapeutic agents ed from n, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase tors, insulinotropic sulfonylurea or ligands, meglitinides, GLP-l (glucagon like peptide-1), GLP-l analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-ll9 activators, sodium-dependent glucose coctransporter ) inhibitors, PPAR modulators, non-glitazone type PPAR.delta agonist, HMG-CoA W0 2013/132509 reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and. anti-obesity agents or phannaceutically acceptable salts thereof.

The invention is ned in greater detail by 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. 1H NMR spectral data given in the examples (vide infia) are recorded using a 400 MHz spectrometer (Bruker AVANCE—400) and reported in 6 scale. Until and ise ned the solvent usedfor NMR is CDC!3 using tetramethyl silane as the internal standard.

Example 1 . 2-(4-(4-Methy1phenylisoxazolyl)phenoxy)-N-((tetrahydro-ZH—pyran y1)methyl)acetamide Step 1: ethyl 2-(4methylphenylisoxazolyl)phenoxy)acetate To a solution of 4-(4-methylphenylisoxazoly1)phenol ( 1.1 gm, 4.38 mmoles) in DMF (10 ml), K2C03 (1.2 gm, 5.26 ) was added followed by the addition‘of ethyl chloro acetate (0.64 gm, 5.26 mmoles) at room temperature and the on mixture was stirred at room temperaturefor 18 hours. The reaction mixture was poured into ice cold water, solid ted was filtered, washed with water and dried over P205 under vacuum to yield 1.4 gm of title product as off white solid. lH NMR: 1.31 (t, J= 5.6 Hz, 3H), 2.31 (s, 3H), 4.27 (q, J= 7.1 Hz, 2H), 4.68 (s, 2H), 7.01-7.05 (m, 2H), 7.42-7.53 (m, 3H), 7.61-7.65 (m, 2H), 7.73-7.76 (m, 2H).

Ste 2: 2- 4- 4-meth 1 hen lisoxazol l henox acetic acid To a solution of the product of step 1 (1.4 gm, 4.15 mmoles) in a mixture of methanol (10 ml), THF (30 ml) and H20 (10 ml), lithium hydroxide (0.35 gm, 8.30 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water and acidified with 1N HCl. The solid seperated which was filtered, washed with water & dried over P205 under vacuum to give 1.25 g of title prodUCt as pale brown solid. lH NMR: 2.31 (s, 3H), 4.75 (s, 2H), 7.05-7.07 (m, 2H), 7.45-7.53 (m, 3H), 7.65 (dd, J = 7.0 & 2.2 Hz, 2H), 7.74-7.76 (m, 2H).

Ste 322- 4- 4-meth 1 hen zol‘l . yl)methyl)acetamide W0 2013/132509 To a solution of product of step 2 (309 mg, 1.00 mmoles) in DMF (3 mL), (tetrahydro-2H-pyranyl)methanamine (126 mg, 1.10 mmoles), HOBT (202 mg, 1.50 mmoles), EDC.HC1 (230 mg, 1.20 mmoles) and N-ethyl morpholine (345 mg, 3.00 mmoles) were added and reaction mixture was d at room temperature for 20 hours under en atmosphere. The reaction mixture was poured into ice cold water, solid seperated was filtered, washed with water and dried over P205 under vacuum to yield 260 mg of title product as pale yellow solid. lH NMR: 1.28-1.39 (m, 2H), 1.61-1.62 (m, 2H), 1.76-1.85 (m, 1H), 2.31 (s, 3H), 3.26 (t, J= 6.6 Hz, 2H), 3.33 (t, J= 11.8 Hz, 2H), 3.95 (dd, J= 11.0 & 3.4 Hz, 2H), 4.57 (s, 2H), 6.65 (bs, NH), 7.03-7.07 (m, 2H), .53 (m, 3H), 7.65-7.68 (m, 2H), 7.73-7.76 (m, 2H).

The following examples were prepared following the l ures given in the Example 1 with suitable modifications, alterations and other process variations which are within the scope of a person skilled in the art.

Example 2 2-(4-(5-methy1phenylisoxazolyl)phenoxy)-N-((tetrahydro-ZH-pyran yl)methy1)acetamide ' lHNMR (DMSO'dé): 1.30-1.36 (m, 2H), 1.55-1.59 (m, 2H), 1.73-1.81 (m, 1H), 2.43 (s, 3H), 3.24 (t, J = 6.6 Hz, 21-1), 3.32 (t, J = 11.8, 2H), 3.94 (dd, J = 11.0 & 3.0 Hz, 2H), 4.48 (s, 2H), 6.83-6.87 (m, 2H), 7.15-7.18 (m, 2H), 7.33-7.42 (m, 5H).

Example 3 2-(4-(5-(4-fluorophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran-4— yl)methy1)acetamide lH NMR: 1.28-1.39 (m, 2H), 1.61-1.62 (m, 2H), 1.76-1.85 (m, 1H), 2.29 (s, 3H), 3.26 (t, J = 6.6 Hz, 2H), 3.33 (t, J = 11.0 Hz, 2H), 3.95 (dd, J = 11.2 & 3.6 Hz, 2H), 4.57 (s, 2H), 6.65 (bs, NH), 7.03-7.07 (m, 2H), 7.18-7.24 (m, 2H), 7.63-7.67 (m, 2H), 7.72-7.76 (m, 2H).

Example 4 2-(4-(5-(4-chlorophenyl)methylisoxazol-3—y1)phenoxy)-N-((tetrahydro-2H-pyran hy1)acetamide _ 1H NMR (DMSO-dé): 1.07-1.18 (m, 2H), 1.48-1.51 (dd, J = 1.6 & 12.8 Hz, 2H), 1.64- 1.71 (m, 1H), 2.26 (s, 3H), 3.03 (t, J = 6.4 Hz, 2H), 3.17-3.27 (m, 2H), 3.79-3.82 (dd, J = 2.4 & 11.2 Hz, 2H), 4.58 (s, 2H), 7.12 (d, J = 6.8 Hz, 2H), 7.62-7.68 (m, 4H), 7.80 (d, J = 6.4 Hz, 2H), 8.17 (t, J = 6.0 Hz, 1H).

W0 2013/132509 Example 5 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide 'H NMR: 1.29-1.59 (m, 2H), 1.61-1.63 (m, 2H), .86 (m, 1H), 2.34 (s, 3H), 3.26 (t, J = 6.6 Hz, 2H), 3.34 (t, J = 11.8 Hz, 2H), 3.95 (dd, J = 1 1.2 & 3.6 Hz, 2H), 4.57 (s, 2H), 6.65 (bs, NH), 7.05-7.08 (m, 2H), 7.64-7.68 (m, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H). - Example 6 2-(4-(4-methyl(p-tolyl)isoxazo|—3-yl)phenoxy)-N-((tetrahydro-2H-pyran ‘y1)methyl)acetamide lHNMR: 1.25-1.38 (m, 2H), 1.-581.62 (m, 2H), 1761.85 (m, 1H), 2.29 (s, 3H), 2.43 (s, 3H), 3.3(t.l= 6.6Hz, 2H), 3.3.,39(m 2H),3.-953.,99(m 2H), 4.S7(s, 2H),6.66 (bs, NH), 7.03-.,706(m 2H), 7.31 (d J 8.0Hz, 2H), 7.63--7..68(m,4l-l) Example 7 4-methylphenylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide ' 1H NMR (DMSO-ds): 1.07-1.18 (m, 2H), 1.48-1.52'(m, 2H), 1.65-1.71 (m, 1H), 2.32 (s, 3H), 3.02 (t, J = 6.4 Hz, 2H), 3.18-3.25 (m, 2H), 3.79-3.82 (m, 2H), 4.57 (s, 2H), 7.07-7.10 (m, 2H), 7.49-7.59 (m, 5H), 7.64-7.67 (m, 2H), 8.14 (t, J = 6.0 Hz, NH).

Example 8 2-(4-(5-methoxy- l -(4-(trifluOromethyl)phenyl)-1 zolyl)phenoxy)-N- ((tetrahydro-ZH-pyranyl)methyl)acetamide 'H NMR (DMSO-d6)21.08-1.18 (m, 2H),1.49 (dd, J= 12.8 & 1.6 Hz, 2H ), .73 (m,1H), 3.04 (t, J = 6.4 Hz, 2H), 3.19-3.25 (m, 2H), .87 (m, 2H), 4.05 (s, 3H), 4.54 (s, 2H), 6.46 (s, 1H), 7.02-7.06 (m, 2H), 7.80-7.86 (m, 4H), 8.01 (d, J = 8.4 Hz, 2H), 8.13 (t, J= 5.8 Hz, 1H). ‘ 2-(4-( l -(4-fluorophenyl)methoxy-1 H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide 'H NMR (DMSO'dfi): 1.10-1.18 (m, 2H),1.49 (dd, J= 12.8 & 1.2 Hz, 2H ), 1.65-1.71 (m,1H), 3.03 (t, J=. 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79 (dd, J=l 1.2 & 2.0 Hz ,2H), 4.00 (s, 3H), 4.52 (s, 2H), 6.38 (s, 1H), 7.00-7.03 (m, 2H), 7.31—7.35 (m, 2H), 7.72-7.76 (m, 2H), 7.77-7.79 (m, 2H), 8.13 (t, J = 6.0 Hz, 1H). ‘ W0 2013/132509 Example 10 -methoxyphenyl-1 zolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide lH NMR (DMSO'dfi): 1.10-1.15 (m, 2H),1.49-1.52 (m, 2H ), 1.65-1.71 (m, 1H), 3.03 (t, J= 6.6 Hz, 2H), 3.19-3.25 (m, 2H), 3.83 (dd, J=11.2 & 2.4 Hz ,2H), 4.00 (s, 3H), 4.52 (s, 2H), 6.38 (s, 1H), 7.03 (d, J = 9.2Hz, 2H), 7.33 (d, J = 8.0Hz,1H), 7.49 (t, J = 7.8Hz, 2H),7.74 (dd J= 8.4 & 1.2Hz, 2H) J= 6.8 &1.6 Hz, 2H), 8.13 , 7.80 (d,d , (t, 1H).

Example 11 2-(4-(4-methylphenylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide lH NMR: 1.07-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.66-1.70 (m, 1H), 2.58 (s, 3H), 3.04 (t, J= 6.6 Hz," 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (dd, J= 2.4 & 11.6 Hz, 2H), 4.55 (s, 2H), 7.07 (d, J= 6.8 2, 2H), 7.46-7.52 (m, 3H), 7.68 (d, J= 6.8 Hz, 2H), 7.91 (d, J= 7.6 Hz, 2H), 8.15 (t. J= 6.0 Hz, 1H).

Example 12 2-(4-(4-methyl(4-(trifluoromethyl)pheny1)thiazol-S-yl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide 1H NMR: 1.28-1.39 (m, 2H), 1.59-1.62 (m, 2H), .83 (m, 1H), 2.62 (s, 3H), 3.28 (t, J = 6.4 Hz, 2H), 3.34-3.40 (m, 2H), 3.96 (dd, J = 11.2 & 3.2 Hz, 2H), 4.56 (s, 2H), 6.67 (5, NH), 7.01-7.04 (m, 2H), 7.67-7.72 (m, 4H), 8.04 (d, J = 8.0 Hz, 2H).

Example 13 2-(4-(2-(4-fluorophenyl)methylthiazol-S-y1)phenoxy)-N-((tetrahydro~2H-pyran yl)methyl)acetamide 1H NMR: 1.25-1.39 (m, 2H), 1.58-1.62 (m, 2H), 1.78-1.84 (m, 1H), 2.58 (s, 3H), 3.27 (t, J= 6.6 Hz, 2H), 3.33-3.40 (m, 2H), 3.95 (dd, J= 10.4 & 4.0 Hz, 2H), 4.56 (s, 2H), 6.67 (bs, NH), 7.01 (d, J= 6.8 2, 2H), 7.08-7.14 (m, 2H), 7.68 (d, J= 6.8 Hz, 2H), 7.90—7.95 (m, 2H). ' Example 14 2-(4-(2-(4-bromopheny1)methylthiazoly1)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR (DMSO-ds): 1.10-1.15 (m, 2H), 1.50 (d, J= 13.2'Hz, 2H), 1.65-1.70 (m, 1H), 2.58 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 11.6 Hz, 2H), 3.80 (dd, J= 11.2 & 3.6 W0 2013/132509 Hz, 2H), 4.55 (s, 211), 7.06 (d, J= 6.8 Hz, 2H), 7.67-7.71 (m, 4H), 7.86 (d, J= 6.8 Hz, 2H), 8.15 (s, 1H).

Example 15 2-(4-(2-(4-chlorophenyl)methy1thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.50 (d, J = 9.8 Hz, 2H), 1.65-1.70 (m, 1H), 2.58 (s, 3H), 3.03 (t, J.= 6.4 Hz, 2H), 3.22 (t, J= 10.0 Hz, 2H), 3.80 (dd, J= 11.2 & 2.8 Hz, 2H), 4.55 (s, 2H), 7.07 (d, J= 8.8 Hz, 2H), 7.57 (d, J= 8.8 Hz, 2H), 7.68 (d, J= 8.8 Hz, 2H), 7.94 (d, J= 8.4 Hz, 2H), 8.17 (t, J= 5.8 Hz, 1H).

Example 16 2-(4-(4-methyl(p-tolyl)thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran y1)methyl)acetamide 1H NMR (DMSO'dé): 1.1 1-1.15 (m, 2H), 1.50 (d, J= 11.2 Hz, 2H), 1.65-1.71 (m, 1H), 2.35 (s, 3H), 2.56 (s, 3H), 3.04 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 11.4 Hz, 2H), 3.80 (dd, J = 11.6 & 3.2 Hz, 2H), 4.55 (s, 2H), 7.06 (d, J= 8.8 Hz, 2H), 7.30 (d, J= 8.4 Hz, 2H), 7.67 (d, J= 8.8 Hz, 2H), 7.80 (d, J= 8.0 Hz, 2H), 8.15 (t, J= 5.4 Hz, 1H).

Example 17 2-(4-(5-methylphenyloxazolyl)phenoxy)—N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR ds): 1.10-1.18 (m, 2H), 1.48-1.52 (dd, J = 1.6 & 12.8 Hz, 2H), 1.65- 1.71 (m, 1H), 2.59 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), .25 (m, 2H), 3.79-3.83 (dd, J = 2.4 & 11.6 Hz, 2H), 4.53 (s, 2H), 7.05-7.08 (m, 2H), 7.49-7.56 (m, 3H), 7.65-7.69 (m, 2H), 7.97-8.00 (m, 2H), 8.14 (t, J= 6.0 Hz, 1H). e 18 2-(4-(5-methyl—2-(4-(trifluoromethyl)phenyl)oxazolyl)phenoxy)-N-((tetrahydro-2H— pyranyl)methyl)acetamide 1H NMR (DMSO'dfi): 1.11-1.18 (m, 2H), 1.52 (d, J= 13.2 Hz,2H), 1.65-1.71 (m, 1H), 2.62 (s, 3H), 3.04 (t, J= 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (dd, J= 2.4 & 11.2 ‘Hz, 2H), 4.54 (s, 2H), 7.07 (d, J = 8.8 2, 2H), 7.69 (d, J = 9.2 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H), 8.13-8.20 (m, 2H). ‘ Example 19 2-(4-(2-(4-fluorophenyl)-5—methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran~4- yl)methyl)acetamide W0 32509 1H NMR (DMSQ-dé): 1.08-1.18 (m, 2H), 1.48-1.52 (m, 2H), 1.66-1.70 (m, 1H), 2.58 (s, 3H), 3.02 (t, J= 6.6 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (in, 2H), 4.53 (s, 2H), 7.04-7.08 (m, 2H), 7.35-7.40 (m, 2H), 7.65-7.68 (m, 2H), 8.01 -8.05 (m, 2H), 8.12 (t, J = 6.0 Hz, NH).

Example 20 2-(4-(2-(4-bromophenyl)methyloxazolyI)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR (DMSO-ds): 1.07-1.17 (m, 2H), 1.50 (d, J‘—f 12.4 Hz, 2H), 1.65-1.71 (m, 1H), 2.59 (s, 3H), 3.03 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 10.8 Hz, 2H), 3.81 (d, J= 8.4Hz, 2H), 4.53 (s, 2H), 7.06 (d, J= 8.8 Hz, 2H), 7.67 (d, J= 8.8 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H), 7.92 (d, J= 8.4 Hz, 2H), 8.15 (t, J= 5.4 Hz, 1H).

Example 21 2-(4-(2-(4-chlorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran y1)methy1)acetamide 1H NMR (DMSO'dé): 1.1 [-1.14 (m, 2H), 1.50 (d, J= 12.8 Hz, 2H), 1.70 (m, 1H), 2.59 (s, 3H), 3.03 (t, J'= 6.4 Hz, 2H), 3.22 (t, J= 11.6 Hz, 2H), 3.80 (dd, J= 10.8 & 2.4 Hz, 2H), 4.53 (s, 2H), 7.06 (d, J = 6.8 Hz, 2H), 7.60 (d, J =68 Hz, 2H), 7.66 (d, J = 6.8 Hz, 2H), 7.98 (d, J = 6.8 Hz, 2H), 8.14 (s, 1H).

Example 22 -methyl(p-tolyl)oxazoly1)phenoxy)-N-((tetrahydro-2H-pyran hy1)acetamide , 1H NMR (DMSO-ds): 1.09-1.18 (m, 2H), 1.48—1.52 (m, 2H), 1.67-1.68 (m, 1H), 2.37 (s, 3H), 2.58 (s, 3H), 3.02 (t, J = 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (m, 2H), 4.53 (s, 2H), 7.04-7.08 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.64-7.68 (m, 2H), 7.87 (d, J = 8.0 Hz, 2H), 8.11 (t, J= 6.0 Hz, NH).

Example 23 2-(4-(2-(4-methoxyphenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)mcthyl)acetamide 1H NMR (DMSO-ds): 1.10-1.15 (m, 2H), 1.49-1.52 (m, 2H), 1.65-1.71 (m, 1H), 2.57 (s, 3H), 3.03 (t, J = 6.6 Hz, 2H), .25 (m, 2H), 3.79-3.83 (m, 5H), 4.53 (s, 2H), 7.04 - 7.07 (m, 4H), 7.65 (d, J = 7.2 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 8.13 (s, NH).

Example 24 2-(4-(5-methyl-2—(pyridinyl)oxazo1yl)phenoxy)-N~((tetrahydro-2H-pyran y1)methy1)acetamide W0 2013/132509 2012/000452 1H NMR: 1.11-1.15 (m, 2H), .52 (m, 2H), 1.67-1.68 (m, 1H), 2.61 (s, 3H), 3.02 (t, J= 6.4 Hz, 2H), 3.19-3.25 (m, 2H), 3.79-3.83 (m, 2H), 4.54 (s, 2H), 7.06 (dd, J= 6.8 & 2.0 Hz, 2H), 7.56-7.59 (m, 1H), 7.67 (dd, J= 7.2 & 2.0 Hz, 2H), 8.13-8.14 (m, 1H), 8.31-8.34 (m, 1H), 8.69-8.70 (m, 1H), 9.16 (d, J= 1.6 Hz, 1H).

Example 25 N-((tetrahydro-2H-pyrany1)methy1)(4-(5-(4-(trifluoromethy1)pheny1)-1,2,4- oxadiazo1y1)phenoxy)acetam ide 1H NMR (DMSO-ds): 1.12-1.15 (m, 2H), 1.50-1.53 (m, 2H), 1.64-1.68 (m, 1H), 3.02 (t, J= 6.4 Hz, 2H), 3.19-3 .22 (m, 2H), 3.79-3.83 (m, 2H), 4.61 (s, 2H), 7.16 (d, J= 8.0 Hz, 2H), 8.03-8.07 (m, 4H), 8.19 (t, J= 6.0 Hz, 1H), 8.38 (d, J= 8.0 Hz, 2H).

Example 26 2-(4-(5-(4-fluoropheny1)-1 ,2,4—oxadiazo1y1)phenoxy)-N-((tetrahydro-2H-pyran—4- y1)methyl)acetamide 1H NMR (DMSO-de): .15 (m, 2H), 1.49-1.52 (m, 2H), 1.68-1.69 (m, 1H), 3.02 (t, J= 6.4 Hz, 2H), 3.19-3.22 (m, 2H), .83 (m, 2H), 4.60 (s, 2H), 7.15 (dd, J= 6.8 & 2.0 Hz, 2H), 7.49-7.54 (m, 2H), 8.02 (dd, J= 7.2 & 2.0 Hz, 2H), 8.19 (t, J= 6.0 Hz, 1H), 8.23-8.27 (m, 2H).

Example 27 2-(4-(5-(4-bromopheny1)-1 ,2,4-oxadiazoly1)phenoxy)-N-((tetrahydro-2H-pyran yl)methy1)acetamide 1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.65-1.71 (m, 1H), 3.03 (1, J = 6.4 Hz, 2H), 3.22 (t, J = 10.8 Hz, 2H), 3.80 (dd, J = 11.2 & 2.4 Hz, 2H), 4.60 (s, 2H), 7.16 (d, J= 8.8 Hz, 2H), 7.88 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H), 8.11 (d, J= 8.4 Hz, 2H), 8.19 (1, J= 6.0 Hz, 1H).

Example 28 2-(4—(5 -(4-chloropheny1)- I ,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2 H-pyran y1)methy1)acetamide 1H NMR (DMSO-ds): 1.08-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.65-1.70 (m, 1H), 3.04 (t, J= 6.4 Hz, 2H), 3.22 (t, J = 10.8 Hz, 2H), 3.80 (dd, J = 1 1.2 & 2.8 Hz, 2H), 4.60 (s, 2H), 7.16 (d, J= 8.8 Hz, 2H), 7.74 (d, J='8.8 Hz, 2H), 8.04 (d, J= 8.8 Hz, 2H), 8.19 (d, J= 8.4 Hz, 3H).

Example 29 N-((tetrahydro-2H-pyrany1)methy1)(4-(5-(p-toly1)-1,2,4-oxadiazol y1)phenoxy)acetamide W0 2013/132509 1H NMR (DMSO-ds): 1.11-1.l7(m, 2H), 1.51 (d, J= 13.2 Hz, 2H), 1.65-1.70 (m, 1H), 2.43 (5, 31-1), 3.03 (t, J= 6.4 Hz, 2H), 3.22 (t, J= 11.6 Hz, 2H), 3.80 (dd, J= 11.6 & 2.8 Hz, 2H), 4.60 (s, 2H), 7.15 (d, J= 8.8 Hz, 2H), 7.47 (d, J= 8.0 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H), 8.07 (d, J= 8.0 Hz, 2H), 8.18 (t, J=‘5.8 Hz, 1H).

Example 30 2-(4-(5-(4-fluoropheny1)—1,3,4-oxadiazoly1)phenoxy)-N-((tetrahydro-2H-pyran yl)methy1)acetamide 1H NMR(DMSO-d6):1.11-1.18(m,2H), 1.51 (d, J= 12.8 Hz, 2H), 1.67-1.69 (m, 1H), 3.04 (t, J= 6.4 112,211), 3.22 (t, J= 11.6 Hz, 21-1), 3.80 (dd, J= 11.6 & 2.8 Hz, 2H), 4.62 (s, 2H), 7.18 (d, J= 7.2 Hz, 2H), 7.48 (t, J= 8.8 Hz, 2H), 8.08 (d, J= 6.8 Hz, 2H), 8.17-8.21 (m, 3H). e 31 N-((tetrahydro-2H-pyranyl)methyl)(4-(5~(4-(trifluoromethy1)phenyl)-1,3,4- oxadiazolyl)phenoxy)acetamide 1H NMR (DMSO-ds): .18 (m, 2H), 1.51 (d, J= 13.2 Hz, 2H), 1.66-1.71 (m, 1H), 3.04 (t, J= 6.4 Hz, 2H), 3.23 (t, J= 11.2 Hz, 2H), 3.81 (d, J= 8.4 Hz, 2H), 4.63 (s, 2H), 7.20 (d, J= 8.8 Hz, 2H), 8.01 (d, J= 8.4 Hz, 2H), 8.11 (d, J= 8.4 Hz, 2H), 8.20 (d, J= 5.2 Hz, 1H), 8.34 (d, J= 8.0 Hz, 2H).

Example 32 2-(4-(5-(4;methoxyphenyl)-1,3,4-oxadiazo|y1)phenoxy)—N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.50 (d, J= 13.2 Hz, 2H), 1.65-1.71 (m, 1H), 3.04 (t, J= 6.4 Hz, 2H), 3.20-3.26 (m, 2H), 3.80 (dd, J= 11.6 & 2.8 Hz, 2H), 3.86 (s, 3H), 4.62 (s, 2H), 7.16-7.19 (m, 4H), 8.04 (dd, J= 8.8 & 2 Hz, 4H), 8.19 (t, J= 5.6 Hz, 1H), Example 33 2-(4-(5-(4-chlorophenyl)-1 ,3,4-oxadia201y1)phenoxy)-N-((tetrahydro-2H-pyran hy1)acetamide 1H NMR (DMSO-d6): 1.11-1.18 (m, 2H), 1.51 (d, J= 12.8 Hz, 2H), 1.67-1.69 (m, 1H), 3.04 (t, J= 6.2 Hz, 2H), 3.23 (t, J= 11.2 Hz, 2H), 3.81 (d, J= 8.8 Hz, 2H), 4.62 (s, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.71 (d, J= 8.4 Hz, 2H), 8.09 (d, J= 8.8 Hz, 2H), 8.14 (d, J= 8.4 Hz, 2H), 8.18 (d, J= 5.2 Hz, 1H).

W0 2013/132509 Example 34 2-(4-(5-phenyl-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR (DMSO-dé): 1.08-1.18 (m, 2H), 1.50 (t, 2 Hz, 2H), 1.66-1.71 (m, 1H), 3.04 (t, J = 6.4 Hz, 2H), 3.19-3.26 (m, 2H), 3.80 (dd, J = 11.2 & 2.4 Hz, 2H), 4.63 (s, 2H), 7.17-7.20 (m, 2H), 7.60-7.66 (m, 3H),8.07-8.08(m, 2H), 8.09-8.14 (m, 2H), 8.20 (t, J= 5.6 Hz, 1H).

Example 35 . 2-(4-(3-(4-fluorophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamidc 1H NMR: 1.08-1.16 (m, 2H), 1.46-1.49 (m, 2H), 1.65-1.66 (m, 1H), 2.99 (t, J= 6.4 Hz, 2H), 3.18-3.21 (m, 2H), 3.78-3.82 (m, 2H), 3.98 (t, J= 8.4 Hz, 1H), 4.38 (t, J'= 8.8 Hz, 1H), 4.51 (s, 2H), 5.66 (t, J = 8.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 7.22-7.27 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.60-7.63 (m, 2H), 8.01 (t, J = 6 Hz, 1H).

Example 36 . 2-(4-(3-(4-methoxyphenyl)oxooxazolidinyl)phenoxy)—N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide 1H NMR d6): 1.05-1.62 (m, 2H), 1.46 (d, J = 12.4 Hz, 2H), 1.63-1.68 (m, 1H), 3.01 (t, J= 6.4 Hz, 2H), 3.18-3.24 (m, 2H), 3.74 (5, 31-1), 3.78 (dd, J= 11.2 & 2.4 Hz, 2H), 3.93-3.97 (m, 1H), 4.36 (t, J= 9.0 Hz, 1H), 4.51 (s, 2H), 5.66 (t, J= 8.4 Hz, 1H), 6.94-6.98 (m, 2H), 7.00-7.03 (m, 2H), 7.43 (dd, J = 9.6 & 2.8 Hz, 2H), 7.47-7.51 (m, 2H), 8.11 (t, J= 5.08 Hz, 1H). e 37 2-(4-(4-phenyl-1H-l,2,3-triazoly1)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR (DMSO‘dé): 1.14-1.18 (m, 2H), 1.48-1.52 (m, 2H), .70 (m, 1H), 3.02 (t, J = 6.6 Hz, 2H), 3.19-3.24 (m, 2H), 3.79-3.82 (m, 2H), 4.59 (s, 2H), 7.16-7.20 (m, 2H), 7.35-7.39 (m, 1H), 7.47-7.50 (m, 2H), 7.84-7.88 (m, 2H), 7.91-7.94 (m, 2H), 8.16 (t, J= 6.0 Hz, NH), 9.18 (s, 1H).

Example 38 2-(4-(5-methoxy(4-(trifluoromethyl)benzyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro-2H-pyranyl)methyl)acetamide 1H NMR (DMSO'dfi): 1.05-1.12 (m, 2H),l.49 (d, J= 12.8 Hz, 2H ), 1.64-1.67 (m,1H), 3.00 (t, J= 6.4 Hz, 2H), 3.19 (t, J=10.4 Hz, 2H), 3.78 (s, 5H), 4.51 (s, 2H), 5.27 (s, W0 2013/132509 2012/000452 2H), 5.90 (s, 1H), 7.02 ( d, J=8.8 Hz, 2H ), 7.20 ( d, J=8.0 Hz, 2H ), 7.34 ( d, J=8.8 Hz, 2H ), 7.68 ( d, J=8.0 Hz, 2H ), 8.10 (t, J= 5.8 Hz, 1H).

Example 39 2-(4-(4,5-dimethyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 1H NMR (DMSO‘dé): 1.10-1.17 (m, 2H), 1.47-1.51 (m, 2H), 1.64-1.70 (m, 1H), 2.06‘ (s, 3H), 2.29 (s, 3H), 3.02 (t, J = 6.4 Hz, 2H), 3.21 (t, J = 11.8 Hz, 2H), .82 (dd, J = 11.2 & 2.4 Hz, 2H), 4.55 (s, 2H), 7.05 (d, J= 6.8 Hz, 2H), 7.82 (d, J= 6.8 Hz, 2H).

The following compounds can be prepared by procedure similar to those described above with'appropriate variations of reactions, reaction ions and quantities of reagents.

Example 40 2-(4-(5-(4-bromophenyl)methylisoxazolyI)phenoxy)-N-((tetrahydro-2H-pyran-44 yl)methyl)acetamide Example 41 2-(4-(5-(4-methoxyphenyl)methylisoxazolyl)phenoxy)—N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide Example 42 2—(4-(4-methy1(4-(trifluoromethoxy)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide Example 43 2-(4-(5-(4-fluorophenyl_)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H—pyran~4- hyl)acetamide Example 44 2-(4-(5-(4-chlorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-y1)methyl)acetamide Example 45 2-(4-(5-(4—bromophenyl)—4-methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide Example 46 2-(4-(4-methyl(p-tolyl)isothiazolyl)phenoxy)-N-((tetrahydro—ZH-pyran yl)methyl)acetamide Example 47 W0 2013/132509 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide Example 48 -(4-methoxyphenyl)methy_lisothiazolyl)phenoxy)-N-((tetrahydrd-2H- pyranyl)methyl)acetamide ' ' Example 49 4-methyl-S—(4-(trifluoromethoxy)phenyl)isothiazolyl)phenoxy)—N- ((tetrahydro-ZH—pyranyl)methyl)acetamide Example 50 2-(4—(1-(4-chlorophenyl)methoxy- l H—pyrazolyl)phenoxy)-N—((tetrahydro-2H- pyranyl)methyl)acetamide Example 51 2-(4-(5-methoxy(4-methoxyphenyl)-l zolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide Example 52 2-(4-(5-methoxy- l -(4-(trifluoromethoxy)phenyl)-1 H-pyrazolyl)phenoxy)-N- ((tetrahydro-ZH-pyran—4-yl)methyl)acetamide Example 53 . 2-(4-(1 -(4-bromophenyl)methoxy- l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide Example 54 2-(4~(5~methoxy- l -(p—tolyl)-l H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide Example 55 2-(4-(3-(4-chlorophenyl)-2—oxooxazolidin-S-yl)phenoxy)—N-((tetrahydro-2H-pyran—4- yl)methyl)acetamide ' Example 56 2-(4-(2-ox0(4-(trifluoromethyl)phenyl)oxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide Example 57 2-oxo(4-(trifluoromethoxy)phenyl)oxazolidin-S-yl)phenoxy)-N-((tetrahydro- ZH-pyrany|)methyl)acetamide Example 58 2-(4-(3-(4-bromophenyl)~2-oxooxazolidin-S-yl)phenoxy)-N-((tetrahydro-ZH-pyran yl)methyl)acetamide Example 59 2-(4-(2-oxo(p-tolyl)oxazolidin-S—yl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide ’ Example 60 2-(4-(4-(4-chlorophenyl)-1H-l,2_,3-triazol- l-yl)phenoxy)—N-((tetrahydro-2H-pyran—4- yl)methyl)acetamide Example 61 N-((tetrahydro-2l-l-pyranyl)methyl)(4-(4-(4-(trifluoromethyl)phenyl)- l H- l ,2,3- triazolyl)phenoxy)acetamide 'Example 62 N-((tetrahydro-2H-pyranyl)methyl)—2-(4-(4-(4-(trifluoromethoxy)phenyl)-1 H-1,2,3- triazol-I enoxy)acetam ide e 63 2-(4-(4-(4-bromophenyl)- 1 11 ,2,3-triazol- l -yl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide Example 64 N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(p-tolyl)-1 H-1,2,3-triazol yl)phenoxy)acetamide Example 65 2-(4-(4-(4-fluorophenyl)—l 3-triazol-l -yl)phenoxy)-N-((tetrahydro-2H—pyran yl)methyl)acetamide e 66 2-(4-(4-(4-methoxyphenyl)- 1 PH ,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran ' yl)methyl)acetamide Example 67 2—(4-(3,-(4-chlorophenyl)iminooxazolidin-S-yl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide ' Example 68 . 2-(4-(6-(4-chlorophenyl)pyridin-2~yl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide Example 69 2-(4-(4-(4-chloropheny1)pyrimidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide Example 70 2-((8-(4-chlorophenyl)dibenzo[b,d]thiophenyl)oxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide Example 71 2-(4-(7-chlorodibenzo[b,d]thiophen-Z-yl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide Demonstration of in vitro potency ofcompounds The PCSK9-LDLR in vitro binding Assay is a quantitative solid phase binding assay between PCSK9 and recombinant LDLR. _Plates were pre-coated with a recombinant LDLR-AB domain, which binds PCSK9. Test nd at different concentration was added to the PCSK9 and added to LDLR lized on the wells.

The amount of bound PCSK9 is measured by binding it with biotinylated anti-His-tag monoclonal antibody, followed by g with horseradish peroxidase conjugated streptavidin substrate. The color was quantified by ELISA reader at 450 nM which reflects the ve amount of PCSK9 that binds to LDLR in presence and absence of the inhibitor. EC50 values were calculated by nonlinear regression analysis using graph pad prism software. Each concentration point ents values in duplicates.

Concentration % Inhibition Example No. ' (pM) PCSK9 W0 32509 VIA510685NZPR 303916262 Unless the context clearly requires otherwise, throughout the description and the , the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of “including, but not limited to”.

VIA510685NZPR 303916262 The reference to any prior art in the specification is not, and should not be taken as, an ledgement or any form of suggestion that the prior art forms part of the common general knowledge in New Zealand. 585NZPR 303915590

Claims (22)

We claim:

1. A compound of formula (I), its tautomeric forms, its stereoisomers, its pharmaceutically acceptable salts, and pharmaceutical compositions containing said compound, wherein (R2)n (R1)m Z X W N ZA H (R3)o ‘ZA’ represents an optionally tuted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups; Each of ‘X’ and ‘Z’ ndently represents an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups; Alternatively, Z-X- ZA may er form tricyclic 8-15 membered fused ring system containing 1-4 hetero atoms selected from N, O or S; R1, R2 and R3 independently at each occurrence represents H, (C1-C6) linear or branched alkyl, (C1-C6) linear or ed alkenyl, (C1-C6)linear or branched l, hydroxy, (C1-C6) alkoxy, (C 1-C6) alkenoxy, hydroxy(C 1-C6)alkyl, alkoxyalkyl, haloalkyl, (C1-C6)cycloalkyl, thio(C1-C6)alkyl, (C1-C6)alkylthio, halo, oxo, imino, nitro, aryl, heterocyclyl, ally substituted amino, amino(C1-C6)alkyl, alkylamino, cyano, formyl, koxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy groups or the groups selected from carboxylic acid and its derivatives such as esters and amides, alkylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, each of which may be optionally substituted; ‘m’ ‘n’ and ‘o’ independently represents integers from 0 to 5; ‘Y’ represents either a bond, or O, S(O)p or NR4 wherein R4 represents H, (C1-C6)linear or branched alkyl, (C1-C6)cycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl and ‘p’ represents rs from 0 to 2; ‘W’ represents (C1-C6)linear or ed alkyl or (C1- C6)linear or branched cycloalkyl; ‘V’ represents O or S;

2. The compound as claimed in claim 1 n ‘X’ is selected from optionally substituted aryl or heterocyclyl groups.

3. The compound as claimed in claim 2 wherein, the aryl group is selected from substituted or unsubstituted monocyclic or bicyclic aromatic groups. VIA510585NZPR 303915590

4. The compound as claimed in claim 3 wherein the aryl group is an optionally substituted phenyl group.

5. The nd as claimed in claim 1 wherein when ‘X’ represents a cyclyl group, the heterocyclyl group is selected from single or fused mono, bi or tricyclic aromatic or non-aromatic groups containing one or more hetero atoms selected from O, N or S.

6. The compound as claimed in claim 5 wherein the heterocyclyl group is ed from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, olinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, nyl, benzimidazolyl, benzotriazolyl, azynil, naphthylidinyl, purinyl, carbazolyl, hiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, thiazepinyl, oxazolidinyl, lidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, yranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, olonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl groups.

7. The compound as claimed in claim 1 wherein either of ‘Z’ and ‘ZA’ is independently selected from optionally substituted aryl or heterocyclyl groups.

8. The compound as claimed in claim 7 wherein when either of ‘Z’ and ‘ZA’ independently represents an aryl group, the aryl group is ed from substituted or unsubstituted monocyclic or bicyclic aromatic groups.

9. The compound as claimed in claim 8 wherein the aryl group is an optionally substituted phenyl group.

10. The compound as claimed in claim 7 wherein when either of ‘Z’ and ‘ZA’ independently represents a heterocyclyl group, the heterocyclyl group is selected from single or fused mono or bi cyclic aromatic or omatic groups containing one or more hetero atoms selected from O, N or S.

11. The compound as claimed in claim 10 wherein, when either of ‘Z’ and ‘ZA’ independently represents heteroaromatic group, the heteroaromatic group are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, lyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, nyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, VIA510585NZPR 303915590 pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, azinyl, benzoxazolyl, benzothiazolyl .

12. The compound as claimed in claim 1 n when any of R1, R2 or R3 are substituted, such substituents are selected from hydrogen, yl, oxo, halo, thiol, nitro, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, cyclylalkoxyacyl, acyl, acyloxy, ino, monosubstituted or disubstituted amino, arylamino, aralkylamino, ylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylsulfonylamino, cycloalkylsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, alkylsulfonyloxy, cycloalkylsulfonyloxy, arylsulfonyloxy, heterocyclylsulfonyloxy, alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfonic acid and its derivatives.

13. The compound as claimed in claim 1 wherein when the aryl group at any occurrence is further substituted, the substituents are selected from halo, thiol, nitro, amino, cyano, , or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, oalkyl, alkoxy, koxy, perhaloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, alkoxy, xy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, cyclylalkoxyacyl, acyl, acyloxy, acylamino, bstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio groups.

14. The compound as claimed in claim 1 wherein when the heteroaryl group at any ence is further substituted, the substituents are selected from halo, thiol, nitro, VIA510585NZPR 303915590 amino, cyano, formyl, or substituted or unsubstituted groups selected from alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, cyclylalkoxy, acyl, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides.

15. The compound as claimed in claim 1 wherein when the heterocyclyl group at any occurrence is further tuted, the substituents are selected from halo, amino, cyano, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, alkenyl, alkynyl, lkyl, cycloalkenyl, alkoxy, xy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, acyl, acyloxy, acylamino, monosubstituted or disubstituted amino, arylamino, aralkylamino, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, cycloalkylthio, arylthio, heterocyclylthio .

16. The compound as claimed in claim 1 ed from 2-(4-(4-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methylphenylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 5-(4-fluorophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro-2H- 4-yl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)isoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(4-methylphenylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 303915590 2-(4-(5-methoxy(4-(trifluoromethyl)phenyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro-2H-pyranyl)methyl)acetamide; 2-(4-(1-(4-fluorophenyl)methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide; 2-(4-(5-methoxyphenyl-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(4-methylphenylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)thiazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(2-(4-fluorophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-(4-bromophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(2-(4-chlorophenyl)methylthiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)thiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methylphenyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methyl(4-(trifluoromethyl)phenyl)oxazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(2-(4-fluorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-(4-bromophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 303915590 2-(4-chlorophenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methyl(p-tolyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-(4-methoxyphenyl)methyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methyl(pyridinyl)oxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(5-(4-(trifluoromethyl)phenyl)-1,2,4- oxadiazolyl)phenoxy)acetamide; 2-(4-(5-(4-fluorophenyl)-1,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-bromophenyl)-1,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)-1,2,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(5-(p-tolyl)-1,2,4-oxadiazol yl)phenoxy)acetamide; 2-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(5-(4-(trifluoromethyl)phenyl)-1,3,4- oxadiazolyl)phenoxy)acetamide; 2-(4-(5-(4-methoxyphenyl)-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(5-(4-chlorophenyl)-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 303915590 2-(4-(5-phenyl-1,3,4-oxadiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-fluorophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-methoxyphenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-phenyl-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-methoxy(4-(trifluoromethyl)benzyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro-2H-pyranyl)methyl)acetamide; 4,5-dimethyloxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-bromophenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-methoxyphenyl)methylisoxazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isoxazolyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide; 2-(4-(5-(4-fluorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-chlorophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(5-(4-bromophenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-methyl(p-tolyl)isothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; VIA510585NZPR 2-(4-(4-methyl(4-(trifluoromethyl)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-(4-methoxyphenyl)methylisothiazolyl)phenoxy)-N-((tetrahydro-2H-pyran- 4-yl)methyl)acetamide; 2-(4-(4-methyl(4-(trifluoromethoxy)phenyl)isothiazolyl)phenoxy)-N-((tetrahydro- 2H-pyranyl)methyl)acetamide; 1-(4-chlorophenyl)methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-methoxy(4-methoxyphenyl)-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-methoxy(4-(trifluoromethoxy)phenyl)-1H-pyrazolyl)phenoxy)-N- ((tetrahydro-2H-pyranyl)methyl)acetamide; 2-(4-(1-(4-bromophenyl)methoxy-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(5-methoxy(p-tolyl)-1H-pyrazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-chlorophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-oxo(4-(trifluoromethyl)phenyl)oxazolidinyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(2-oxo(4-(trifluoromethoxy)phenyl)oxazolidinyl)phenoxy)-N-((tetrahydro-2H- pyranyl)methyl)acetamide; 2-(4-(3-(4-bromophenyl)oxooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(2-oxo(p-tolyl)oxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 585NZPR 2-(4-(4-(4-chlorophenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran hyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3- triazolyl)phenoxy)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(4-(trifluoromethoxy)phenyl)-1H-1,2,3- triazolyl)phenoxy)acetamide; 2-(4-(4-(4-bromophenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; N-((tetrahydro-2H-pyranyl)methyl)(4-(4-(p-tolyl)-1H-1,2,3-triazol yl)phenoxy)acetamide; 2-(4-(4-(4-fluorophenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(4-(4-methoxyphenyl)-1H-1,2,3-triazolyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(3-(4-chlorophenyl)iminooxazolidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(6-(4-chlorophenyl)pyridinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide 4-(4-chlorophenyl)pyrimidinyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-((8-(4-chlorophenyl)dibenzo[b,d]thiophenyl)oxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide; 2-(4-(7-chlorodibenzo[b,d]thiophenyl)phenoxy)-N-((tetrahydro-2H-pyran yl)methyl)acetamide.

17. The compound as claimed in any one of claims 1 to 16 suitably formulated into a suitable pharmaceutical composition.

18. Use of a compound of formula (I) as claimed in any one of claims 1 to 16 for the manufacture of a medicament for the treatment of hyperlipidemia, dyslipidemia, obesity, hypercholesteremia, hypertension, atherosclerosis, vascular restenosis and diabetes. VIA510585NZPR 303915590

19. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 16 in combination with one or more pharmaceutically active agents selected from group comprising insulin, insulin derivatives and mimetics, insulin agogues, insulin izers, biguanide agents, glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 activators, -dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, itazone type PPAR delta agonist, A reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and besity agents or pharmaceutically acceptable salts thereof.

20. A compound as claimed in claim 1, substantially as hereinbefore bed with particular reference to any one or more of the Examples.

21. Use of a compound of formula (I) as claimed in claim 18, substantially as hereinbefore described with particular reference to any one or more of the Examples.

22. A pharmaceutical composition as claimed in claim 19, substantially as hereinbefore described with particular reference to any one or more of the Examples.