NOVEL COMPOUNDS SUITABLE FOR THE TREATMENT OF DYSLIPIDEMIA

FIELD OF INVENTION

The present invention relates to compounds of the general formula (I), their tautomeric 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 towards compounds which can be used to treat diseases such as Hyperlipidemia and also have a beneficial effect on cholesterol.

The compounds of the general formula (I) lower blood glucose, lower or modulate triglyceride levels and/or cholesterol levels and/or low-density lipoproteins (LDL) 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, hyperlipidemia, hypercholesteremia, hypertension, atherosclerotic disease events, vascular 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 diseases, cerebrovascular diseases, peripheral vessel diseases and related disorders.

These compounds of general formula (I) are useful for the treatment and/or prophylaxis of metabolic disorders loosely defined as Syndrome X. The characteristic features of Syndrome X include initial insulin resistance followed by hyperinsulinemia, dyslipidemia and impaired glucose tolerance. The glucose intolerance can lead to non-insulin dependent diabetes mellitus (NIDDM, Type 2 diabetes), which is characterized by hyperglycemia, which if not controlled may lead to diabetic complications or 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 neuropathy ^' and renal disease including diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndrome, hypertensive nephrosclerosis and end stage renal diseases, _; like microalbuminuria and albuminuria, which may be result of hyperglycemia or hyperinsulinemia.

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

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 percentage (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 surface glycoproteins that.bind to apoliporpotein B 100.(apoB100) on LDL particles with high affinity and mediate their ehdocytic 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 Structural and Molecular Biology, 2007, 14, 413- 419). Recently, mutations within certain subtypes .of the pro-protein convertase subtilisin/ gene such as the subtype nine (hereinafter "the gene") were found to represent a third class of mutations associated with autosomal dominant hypercholesterolemia (ADH). The discovery, etiology and functions of this subtype gene is discussed in details in Nature Genetics, 2003, 34, 154-156, Trends in Biochemical Sciences, 2008, 33, 426-434 etc.. Several missense mutations (S I 27R, D 129G, F216L, D374H, D374Y) are associated with hypercholesterolemia and premature atherosclerdsis (J Lipid Res. 2008, 49, 1333-1343). Loss-of-function mutations (R46L, L253F, A433T) lead to elevated receptor abundance, enhancing clearance of LDL cholesterol from the circulation and reducing cardiovascular risk (Nature Structural and Molecular Biology, 2007, 14, 413-419).

Detailed molecular mechanisms explaining the association of LDLR and the particular subtype gene 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 surface are decreased and this increases plasma LDL levels (PNAS, 2009, 106, 9546-9547).

Various approaches for inhibiting this particular subtype gene 'are reported,

. ^" . "si- including ge ' silencing by siRNA or antisense oligonucleotides, mAb disrupting protein-protein interactions or by peptides; all the above-mentioned strategies have shown lowering of LDL cholesterol which may be- effective therapy for treating hypercholesterolemia (Biochemical Journal, 2009, 419, 577-584; PNAS, 2008, 105,

1 1915-11920; 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 subtype gene by using smaU molecules. Such small molecule inhibitors have their obvious clinical and therapeutic benefit over the other approaches as discussed above. We herein disclose novel small molecules which have shown to inhibit this particular gene

(pro-protein convertase subtilisin/ gene subtype nine) in in-vitro studies and therefore provides an alternate beneficial approach for treating patients in need of such therapy. PREFERRED EMBODIMENTS OF THE INVENTION

The main objective of the present invention is to provide novel substituted oximino derivatives represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them or their mixtures thereof.

In an embodiment of the present invention is provided a process for the preparation of novel substituted oximino derivatives represented by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts.

In a further embodiment of the present invention is provided pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.

In a further embodiment of the present invention is provided process for treatment of diseases such as dyslipidemia, hyperlipidemia etc. by providing therapeutically effective amount of the compounds of formula (I) or their pharmaceutically acceptable salts or their suitable pharmaceutical compositions.

The above and other embodiments are described in details hereinafter.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to compounds of the general formula

(I),

their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, and pharmaceutical compositions containing them wherein Ά' represents an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups;

In a preferred embodiment, ^f A' 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 'Α' represents a heterocyclyl group, the heterocyclyl group may be 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;

In a preferred embodiment, the heterocyclyl group may be selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyr, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl> benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyT; purinyl, carbazolyl, phefi thiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimtdonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinoriyl, thieno piperidinyl and the like;

'Y' represents either a bond or substituted or unsubstituted linear or branohed (Ci-C ₆ )alkyl, (C ₂ -C )alkeriyl groups or the groups represented by '-U(CH ₂ ) _m -' wherein U represents 0, S(0) ₀ , NR ₄ ; 'm' represents integers from 2 to 4, Ό' represents integers from 0 to 2 and R4 represents H, substituted or unsubstituted linear or branched (Ci- C ₆ )alkyl; 'V represents either a bond, or may be selected from O, S(0) ₀ , NR ₄ or S0 ₂ NR ₄ ; wherein R is as defined earlier;

'X' represents C or N;

'W represents substituted or unsubstituted linear or branched (Ci-C ₆ )alkyl, (C ₂ -C ₆ )alkenyl groups;

'Z' represents substituted or unsubstituted linear or branched (Ci-C ₆ )alkyl, (C - C ₆ )alkenyl groups or an optionally substituted single or fused group selected from aryl, heterocyclyl or cycloalkyl groups;

In a preferred embodiment, 'Z' is selected from optionally substituted aryl or heterocyclyl groups; . , v

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 or naphthyl group.

When 'Z' represents a heterocyclyl group, the heterocyclyl group may be selected from single or fused mono or bi cyclic aromatic groups containing one or more hetero atoms selected from O, N or S; ^■ >

In a still preferred embodiment, when 'Z' represents heterocyclic group, the heterocyclic group may be selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2- oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, tetrahydropyran, dihydrofuran, tetrahydrofuran, dihydrothiazole, · benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofiiranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolihyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl groups.

Ri represents hydrogen, optionally substituted, (Ci-C6)alkyl, (C3-C ₆ )cycloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl groups;

R ₂ represents hydrogen, or the groups selected from (Ci-C ₆ )alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, (Q-Ceialkoxy, hydroxy, hydroxyalkyl, thio(Ci-C6)aIkyl, amino, aminoalkyl, alkylamino, each of which may be. optionally substituted;

R ₃ at each occurrence independently represents hydrogen, halogen, (Ci- C ₃ )alkyl, halo(Ci-C ₃ )alkyl, (Ci-C ₃ )alkoxy, thio(Ci-C ₃ )alkyl, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, sulfenyl derivatives, sulfonyl derivatives;

'n' represents integers from 0-3;

Alternatively Ri and R ₂ wherever possible, together may form 4 to 7 membered saturated or partially saturated ring containing from 0-2 additional heteroatoms selected from the group consisting of N, O, and S(0) ₀ ; -

When any of A, Ri, or Z are substituted, the substituents at each occurrence may be independently selected from hydroxyl, 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, alkenoxy, cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocylyl, heterocyclylalkyl, heterocycloxy, heterocyclylalkoxy, heterocyclylalkoxyacyl, acyl, acyloxy, acylamino,. monosubstituted or disubstituted amino, arylamino, aralkylaminp, carboxylic 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, sulfinyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives.

When any of W, R ₂ or R ₃ are substituted the substituents at each occurrence may be independently selected from hydroxyl oxo, halo, thiol, nitro, amino, cyano, acyl, formyl, or substituted or unsubstituted groups selected from amidino, alkyl, haloalkyl, perhaloalkyl, alkoxy, haloalkoxy, perhaloalkoxy, carboxylic acid and its derivatives such as esters and amides, carbonylamino, hydroxyalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkylsulfinyl, cycloalkylsulfinyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl, alkylsulfonylamino, alkylsulfonyloxy, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkoxyamino, hydroxyl amino, sulfinyl- derivatives, sulfonyl derivatives, sulfonic acid and its derivatives.

When the substituents on any of A, Z, W, Ri, R ₂ or R ₃ are further substituted, the substituents may be selected from one or more groups described above.

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

In a further preferred embodiment the groups, radicals described 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, «-propyl, iso-pro pyl, «-butyl, sec-butyl, tert-butyl, amyl, i-amyl, H-pentyl, n- hexyl, and the like; the "alkenyl" group used either alone or in combination with other radicals, is selected from a radical containing from two to six carbons, more preferably 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 "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, cyclopentyl, cyclohexyl and the like; the "cycloalkenyl" group used either alone or in combination with other radicals, are preferably selected from cyclopropenyl, 1-cyclobutenyl, 2-cylobutenyl, 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 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 radicals, is selected from groups containing an alkyl radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from methoxy, ethoxy, w-propoxy, wo-propoxy, «-butoxy, i-butoxy, /so-butoxy, pentyloxy, hexyloxy, and the like;

the "cycloalkoxy" group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to seven carbons, more preferably cyclopropyloxy, cyclobutylxoy, cyclopentyioxy, cyclohexyloxy and the like; The terms "bicycloalkyloxy" means more than one cycloalkyl groups fused together; the "alkenoxy" 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, butenoxy, 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, perfluoroCQ-C^alkyl such as fiuoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups;

the "haloalkoxy" group is selected from suitable haloalkyl, as defined above, directly attached to an oxygen atom, more preferably groups selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy and the like;

the "aryl" or "aromatic" group used either alone or in combination with other radicals, is selected from a suitable aromatic system containing one, two or three rings wherein such rings may be attached together in a pendant manner or may be 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 radical, as defined above, attached directly to an oxygen atom, more preferably groups selected from phenoxy, naphthyloxy, tetrahydronaphthyloxy, biphenyloxy, and the like;

the "heterocyclyl" or "heterocyclic" group used either alone or in combination with other radicals, is selected from suitable aromatic or non-aromatic radicals containing one or more hetero atoms selected from O, N or S. The non-aromatic radicals may be saturated, partially saturated or unsaturated mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2- oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2- oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; the aromatic radicals, may be selected from suitable single or fused mono, bi or tricyclic aromatic heterocyclic radicals containing one or more hetero atoms selected from O, N or S, more preferably the groups are selected from pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranyl, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridazinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazynil, naphthylidinyl, purinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl and the like;

- the groups "heterocycloxy", "heterocylylalkoxy" are selected from suitable heterocyclyl, 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 formyl, acetyl, propanoyl, butanoyl, wo-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 selected from a suitable acyl group, as defined above, directly attached to an oxygen atom, more preferably such groups are selected from acetyloxy, propionyloxy, butanoyloxy, wo-butanoyloxy, benzoyloxy and the like;

the "acylamino" group used either alone or in combination with other radicals, is selected from a suitable acyl group as defined earlier, attached to an amino radical, more preferably such groups are selected from CH ₃ CONH, C ₂ H ₅ CONH, C ₃ H ₇ CONH, QH ₉ CONH, C ₆ H ₅ CONH and the like, which may be substituted; - the "mono-substituted amino" group used either alone or in combination with other radicals, represents an amino group substituted with one group selected from (Q- C ₆ )alkyl, substituted alkyl, aryl, substituted aryl or arylalkyl groups as defined earlier, more preferably such groups are selected from methylamine, ethylamine, n- propylamine, n-butylamine, n-pentylamine 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 different and may be selected from (Ci-C ₆ )alkyl, substituted alkyl, aryl, substituted aryl, or arylalkyl groups, as defined above, more preferably 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;

the "oxo" or "carbonyl" group used either alone (-C=0-) or in combination with other radicals such as alkyl described above, for e.g. "alkylcarbonyl", denotes a carbonyl radical (-C=0) substituted with an alkyl radical described above such as acyl or alkanoyl;

the "carboxylic acid" group, used alone or in combination with other radicals, denotes a -COOH group, and includes derivatives of carboxylic 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 methoxycarbonyl, ethoxycarbonyl, and the like, which may optionally be substituted; aryloxycarbonyl group such as phenoxycarbonyl, 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 defined earlier, which may optionally be substituted; the "amide" group used alone or in combination with other radicals, represents an aminocarbonyl radical (H ₂ N-C=0), 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", "n- alkylaminocarbonyl", "N-arylaminocarbonyl", "Ν,Ν-dialkylaminocarbonyl", "N- alkyl-N-arylaminocarbonyl", "N-alkyl-N-hydroxyaminocarbonyl", and "N-alkyl- N-hydroxyaminocarbonylalkyl", each of them being optionally substituted. The terms "N-alkylaminocabonyl" and "Ν,Ν-dialkylaminocarbonyl" denotes aminocarbonyl radicals, as defined above, which have been substituted with one alkyl radical 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 amiocarbonyl radicals substituted, respectively, with 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 selected from hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl and the like;

the "aminoalkyi" group used alone or in combination with other radicals, denotes an amino (-NH ₂ ) moiety attached to an alkyl radical, as defined above, which may be substituted, such as mono- and di-substituted aminoalkyi. 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, ethylthio, 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. thiomethyl, methylthiomethyl, phenylthiomethyl and the like, which may be optionally substituted.

- the "alkoxycarbonylamino" group used alone or in combination with other radicals, is selected 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, denotes a comprising an aryl 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 phenylthio, naphthylthio, tetrahydronaphthylthio, indanethio, biphenylthio, and the like;

- the "heterocyclylthio" group used either alone or in combination with other radicals, denotes a comprising an heterocyclyl 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 aziridinylthio, azetidinylthio, pyrrolidinylthio, imidazolidinylthio, piperidinylthio, piperazinylthio, 2- oxopiperidinylthio, 4-oxopiperidinylthio, 2-oxopiperazinylthio, 3- oxopiperazinylthio, morpholinylthio, thiomorpholinylthio, 2-oxomorpholinylthio, azepinylthio, diazepinylthio, oxapinylthio, thiazepinylthio, oxazolidinylthio, thiazolidinylthio, dihydrothiophenethio, dihydropyranthio, dihydrofuranthio, dihydrothiazolethio, benzopyranylthio, benzopyranonylthio, benzodihydrofuranylthio, benzodihydrothienylthio, pyrazolopyrimidonylthio, azaquinazolinoylthio, thienopyrimidonylthio, quinazolonylthio, pyrimidonylthio, benzoxazinylthio, benzoxazinonylthio, benzothiazinylthio, benzothiazinonylthio, thieno piperidinylthio, pyridylthio, thienylthio, furylthio, pyrrolylthio, oxazolylthio, thiazolylthio, isothiazolylthio, imidazolylthio, isoxazolylthio, oxadiazolylthio, thiadiazolylthio, triazolylthio, tetrazolylthio, benzofuranylthio, benzothienylthio, indolinylthio, indolylthio, azaindolylthio, azaindolinylthio, pyrazolopyrimidinylthio, azaquinazolinylthio, pyridofuranylthio, pyridothienylthio, thienopyrimidylthio, quinolinylthio, pyrimidinylthio, pyrazolylthio, quinazolinylthio, pyridazinylthio, triazinylthio, benzimidazolylthio, benzotriazolylthio, phthalazynilthio, naphthylidinylthio, purinylthio, carbazolylthio, phenothiazinylthio, phenoxazinylthio, benzoxazolylthio, benzothiazolylthio and the like;

- the "alkoxycarbonylamino" group used alone or in combination with other radicals, is selected from a suitable alkoxycarbonyl group, as defined above, attached to an amino group, more preferably methoxycarbonylamino, ethoxycarbonylamino, and the like;

- the "aminocarbonylamino", "alkylaminocarbonylamino", "dialkylaminocarbonylamino" groups used alone or in combination with other radicals, is a carbonylamino (-CONH ₂ ) group, attached to amino(NH ₂ ), alkylamino group or dialkylamino 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)-NH ₂ 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 optionally substituted with suitable groups selected from those described above;

the "sulfenyl" group or "sulfenyl derivatives" used alone or in combination with other radicals, represents a bivalent group, -SO- or R _x SO, where R _x 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 -S0 ₂ -, or R _x S0 ₂ -, where R _x 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 an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like. The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses coadministration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate 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 provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

The phrase 'therapeutic 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 reducing or eliminating the said disease or disorder. The term "therapeutically acceptable" refers to those compounds (or their salts, prodrugs, tautomers, zwitterionic formsj etc.) which are suitable for use in patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

- As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.

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

Particularly useful compounds may be selected from

1 - Phenyl-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)ethano ne; 1 -Cyclopropyl-2-((5-( 1 -(((4-(trifluOromethyl)benzyl)oxy)imino)ethyl)pyridin-2- yl)oxy)ethanone;

Ethyl 5-(2-oxo-2-phenylethoxy)-2-(l-(((4-(trifluoromethyl)benzyl)o xy)imino) ethyl) benzoate;

1, 1,1 -Trifluoro-3-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)propan -

2- one;

1 -Phenyl-2-((5-( 1 -((4-(trifluoromethyI)phenoxy)imino)ethyI)pyridin-2-yl)oxy) ethanone; -

Ethyl 5-(2-cyclopropyl-2-oxoethoxy)-2-(l-(((4-(trifluoromethyl)ben zyl)oxy)imino) ethyl)benzoate;

l-Cyclopropyl-2-(4-(l-(((2-(trifluoromethyl)thiazol-4-yl) methoxy)imino)ethyl) phenoxy)ethanone;

1 -(4-( 1 -(((4-(Trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)propan -2-one;

1 -(4-( 1 -(((4 ⁱ (Trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)butan- 2-one;

3- (4-(l-(((4-(Trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)b utan-2-one;

3-Methyl- 1 -(4-( 1 -(((4-(trifiuoromethy l)benzy l)oxy)imino)ethyl)phenoxy)butan-2-one; 4-Methyl-l-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethy l)phenoxy)pentan-2- one;

3,3-Dimethyl-l-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino) ethyI)phenoxy)butan-2- one;

l-Cyclopropyl-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)in ino)ethyl)phenoxy) ethanone;

l-Cyclopropyl-2-(3-hydroxy-4-(l-(((4-(trifluoromethyl)ben zyl)oxy)imino)ethyl) phenoxy) ethanone;

l-Cyclopropyl-2-(4-(l-(((4- i ^, opropylbenzyl)oxy)imino)ethyl)phenoxy)ethanone; l-CycIopropyl-2-(4-(l-(((2,6-di 5Opropylbenzyl)oxy)imino)ethyl)phenoxy)ethanone; l-Cyclopropyl-2-(4-(l-(((2,4-diisopropylbenzyl)oxy)imino)eth yl)phenoxy)ethanone;

1- Cyclopropyl-2-((5-(l-(((3-methoxy-4-(trifluoromethyl)benzyl) oxy)imino)ethyl) pyridin-2-yl)oxy)ethanone;

1 -cyclobutyl-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)ethano ne; l-CycIopentyl-2-(4-(l-(((4-

(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)ethanone;

1 -Cyclohexyl-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy) ethanone;

2- (3-Hydroxy-4-( I -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)-l -phenyl ethanone; ^»

1- Phenyl-2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl )pyridin-2-yl)oxy) ethanone;

2- (4-(l-(((2,6-Diwopropylbenzyl)oxy)imino)ethyl)phenoxy)-l-phe nylethanone;

2-(4-(l-(((2,4-Diisopropylbenzyl)oxy)imino)ethyl)phenoxy) -l-phenylethanone;

Methyl 4-(((( 1 -(4-(2-oxo-2-phenylethoxy)phenyl)ethylidene)amino)oxy)methyl ) benzoate;

l-Phenyl-2-(4-(l-(((2-(trifluoromethyl)thiazol-4-yl)metho xy)imino)ethyl)phenoxy) ethanone; l-(2-Chlorophenyl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy) imino)ethyl)phenoxy) ethanone;

1- (4-Chlorophenyl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)im ino)ethyl)phenoxy) ethanone;

1 -(2-Methoxyphenyl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy) ethanone;

1 -(4-Methoxyphenyl)-2-(4-( I -(((4-(trifluoromethyl)benzyl)oxy)iniino)ethyl)phenoxy) ethanone;

I -(2-Hydroxyphenyl)-2-(4-( I -(((4-(trifluoromethy l)benzyl)oxy)imino)ethyl)phenoxy) ethanone;

2- (4-(l-(((4-(Trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)- l-(4-(trifluoromethyl) phenyl)ethanone;

1 -(Naphthalen-2-yl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy) ethanone;

1 -(5,6,7,8-Tetrahydronaphthalen-2-yl)-2-(4-( I -(((4-(trifluoromethyl)benzyl)oxy) imino)ethyl)phenoxy)ethanone;

1 -([ 1 , l'-Biphenyl]-4-y l)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl) phenoxy)ethanone;

1 -(Tetrahydro-2H-pyran-4-yl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl) phenoxy)ethanone;

l-(Benzofuran-2-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl) oxy)imino)ethyl)phenoxy) ethanone;

1- (Thiazol-2-yl)-2-(4-(l-(((4-

(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)ethanone;

l-(l-MethyI-lH-imidazol-2-yl)-2-(4-(l-(((4-(trifluorometh yl)benzyl)oxy)imino phenoxy)ethanone;

2- (3-Hydroxy-4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)- 1 -( 1 - methyl- 1 H-imidazol-2-yl)ethanone; l-(lH-Indol-3-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)i mino)ethyl)phenoxy) ethanone;

1- (Pyridin-2-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imin o)ethyl)phenoxy) ethanone;

l-(l-Methyl-lH-pyiTol-2-yl)-2-(4-(l-(((4-(trifluoromethyl )benzyl)oxy)imino)ethyl) phenoxy)ethanone;

2- (4-( 1 -(((4-wo-Propylbenzy l)oxy)imino)ethyl)phenoxy)- 1 -( 1 -methyl- 1 H-pyrrol-2- yl)ethanone;

4-(2-(5-Methylthiophen-2-yl)-2-oxoethoxy)benzaldehyde 0-(4-(trifluoromethyl) benzyl)oxime;

4-(2-Oxo-2-(thiophen-2-yl)ethoxy)benzaldehyde 0-(4-(trifluoromethyl)benzyl) oxime; 2-(4-( 1 -(((4-wo-Propylbenzyl)oxy)imino)ethyl)phenoxy)- 1 -(5-methylthiophen-2- yl)ethanone;

l-(5-Chlorothiophen-2-yl)-2-(4-(l-(((4-(trifluoromethyl)b enzyl)oxy)imino)ethyl) phenoxy)ethanone;

1 - (5-Methylthiophen-2-y l)-2-(4-( 1 -(((4- (trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy) ethanone;

1 -(Thiophen-2-yl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy) ethanone;

2-(4^(l -(((2,6-Di 5O-propylbenzyl)oxy)imino)ethyl)phenoxy)- 1 -(5-methylfuran-2-yl) ethanone;

2- (4-( 1 -(((4-Cyclohexylbenzyl)oxy)imino)ethyl)phenoxy)- 1 -(5-methylfuran-2-yl) ethanone;

2-(4-( 1 -(((4-Cyclohexy lbenzyl)oxy)imino)ethyl)-3 -hydroxyphenoxy)- 1 -(5- methylfuran-2-yl) ethanone;

2-(4-( 1 -(((4-/s0-Propylbenzyl)oxy)imino)ethyI)phenoxy)- 1 -(5-methylfuran-2-yl) ethanone;

1 -(Furan-2-yl)-2-(4-( 1 -(((4-isopropylbenzyl)oxy)imino)ethyl)phenoxy)ethanone;

1 -(Furan-2-yl)-2-(4-( 1 -(((2,4,6-triisopropylbenzyl)oxy)imino)ethyl)phenoxy)ethanon e; 4-(2-(5 -Methyl furan-2-yl)-2-oxoethoxy)benzaldehyde 0-(4-(trifluoromethyI)benzyl) oxime;

1- (5-Methylfuran-2-yl)-2-(4-(l-(((2,4,6-triisopropylbenzyl)oxy )imino)ethyl)phenoxy) ethanone;

2-(3-Hydroxy-4-(l-(((2,4,6-triisopropylbenzyl)oxy)imino)e thyl)phenoxy)-l-(5- methylfuran-2-yl)ethanone;

2- (3-Hydroxy-4-(l-(((2,4,6-triisopropylbenzyl)oxy)imino)ethyl) phenoxy)- l-(5- methylfuran-2-yl)ethanone;

1 -(Furan-2-yl)-2-(3-hydroxy-4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl) phenoxy)ethanone;

1- (5-MethyIfuran-2-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)Ox y)imino)ethyl) phenoxy)ethanone;

2- (3-Hydroxy-4-(l-(((4-(trifluoromethyI)benzyl)oxy)imino)ethyl )phenoxy)-l-(5- methy 1 furan-2-yl)ethanone ;

l-phenyl-2-((2-(l-(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl)benzofuran-5-yl)oxy) ethanone;

1 -(5-methylfuran-2-yl)-2-((2-( 1 -(((4-(trifluoromethyl)benzy l)oxy)imino)ethyl) benzofuran-5-yl)oxy)ethanone;

1 -cyclopropyl-2-((2-( 1 -(((4-(trifluoromethyl)benzy l)oxy) imino)ethyl)benzofuran-5 - yl)oxy)ethanone;

2-(4-( 1 -(((4-( 1 , 1 -difluoroethyl)benzyl)oxy)imino)ethyl)phenoxy)- 1 -phenylethanone; 2-(2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)acetyl )- 1 H-indene- l,3(2H)-dione;

The novel compounds of this invention may be prepared using the reactions and techniques as shown in scheme below and described in this section. The reactions are performed in solvents 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 techniques known to persons skilled in the art. It will also be appreciated that one or more of the compounds of the present 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 invention.

Scheme:!

The compounds of general formula (I) wherein all the symbols are as defined earlier, may be p

(I) VII

VIII

1. Reacting the compounds of general formula II wherein 'L' represents a suitable leaving group and all other symbols are as defined earlier and N- hydroxyphthalimide III using suitable inorganic base(s) such as NaOH, KOH, K ₂ C0 ₃ , Cs ₂ C0 ₃ and the like and suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution reaction to prepare compounds of general formula IV wherein the symbols are as defined earlier ;

The compounds of formula V wherein all the symbols are as defined earlier may be prepared by using appropriate starting materials IV wherein all the symbols are as defined earlier, using hydrazine hydrate as a deprotecting agent. The reaction may be carried out neat or in presence of suitable protic solvent(s) such as methanol, ethanol, butanol and the like or suitable aprotic solvent(s) such as toluene, tetrahydrofuran, dichloromethane and the like or suitable 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 compounds of the formula VII wherein all the symbols are as defined earlier may be prepared by reacting appropriate ketones VI with oxyamine compounds of formula V wherein all the symbols are as defined earlier in the presence of a base(s) like NaOH, NaOAc, pyridine and the like. The reaction may be carried out in presence of suitable solvent(s) such as methanol, ethanol, butanol, water and the like or suitable 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.

Compounds of general formula I wherein all the symbols are as defined earlier may be prepared by reacting the compounds of general formula VII with compounds of formula VIII wherein all the symbols are as defined earlier using suitable inorganic base(s) such as NaOH, KOH, K ₂ C0 ₃ , Cs ₂ C0 ₃ and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like. The reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution reaction; Scheme 2:

(I) XVI

Compounds of general formula XII wherein all the symbols are as defined earlier may be prepared by reacting the compounds of general formula VI wherein all the symbols are as defined earlier and the compounds of general formula XI using suitable inorganic base(s) such as NaOH, KOH, 2C03, Cs2C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like. The reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution reaction;

Alternatively compounds of general formula XII wherein all the symbols are as defined earlier may be prepared by coupling of compounds of formula IX wherein all the symbols are as defined earlier and compounds of general formula X wherein all other symbols are as defined using suitable inorganic base(s) such as NaOH, KOH, K2C03, Cs2C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like. The reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dimethylformamide (DMF), dichloromethane and the like or mixtures thereof;

Compounds of general formula XIII wherein all the symbols are as defined earlier may be prepared by reacting compounds of general formula XII wherein all the symbols are as defined earlier with hydro xylamine hydrochloride in the presence of a base(s) like NaOH, NaOAc, pyridine and the like. The reaction may be carried out in presence of suitable solvent(s) such as methanol, ethanol, butanol, water and the like or suitable 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;

Compounds of general formula XIV wherein all the symbols are as defined earlier may be prepared by reacting the compounds of general formula XIII with compounds of formula II wherein all the symbols are as defined earlier using suitable inorganic base(s) such as NaOH, KOH, K2C03, Cs2C03 and the like or organic base(s) such as pyridine, triethyl amine, diisopropyl ethylamine and the like. The reaction may be carried out in presence of suitable reaction medium like protic solvent(s) such as methanol, ethanol, butanol and the like or aprotic solvent(s) such as toluene, tetrahydrofuran, dichloromethane and the like or mixtures thereof by means of the methods available in the literature for standard nucleophilic substitution;

Compounds of general formula XV wherein all the symbols are as defined earlier may be prepared by the hydrolysis of compounds of general formula XIV wherein all the symbols are as defined earlier under suitable condition; vi. The compounds of formula XVI wherein all the symbols are as defined earlier may be prepared by coupling reaction of corresponding acids of general formula XIV wherein all the symbols are as defined earlier and Ν,Ο- dimethylhydroxylamine under suitable conditions such as those generally described in Tetrahedron, 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 (EDC1) & 1- Hydroxybenzotriazole (HOBT), and the like. The reaction may be carried in suitable solvent(s) such as dimethyl formamide, 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.

vii. Compounds of general formula (I) wherein all the symbols are as defined earlier may be prepared by reacting compound of general formula XVI with appropriate Grignard reagent of formula XVII wherein all the symbols are as defined earlier. The reaction may be carried out in presence of suitable reaction medium like tetrahydrofuran, diethyl ether and the like or mixtures thereof by means of the methods available in the literature for standard Weinreb ketone synthesis;

The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.

The quantity of active component, that is, the compounds of formula (I) according 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 component will range between 0.5% to 90% by weight of the composition.

The compound of the present invention may be used alone or in combination with a second medicament as may be necessary depending on the condition of the patient, the severity of the disease and such other conditions which are well known to a skilled practitioner. Such second medicament when required may be selected from a HMG-Co-A reductase inhibitor, angiotensin converting enzyme (ACE) inhibitor, calcium channel blocker, aldosterone synthase inhibitor, aldosterone antagonist, dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, endothelin antagonist, angiotensin II receptor blocker (ARB) including their pharmaceutically acceptable salts as well as a combination of one or more medicines from any of these classes along with the compound of formula (I) of the present invention.

The invention is explained 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 infra) are recorded using a 400 MHz spectrometer (Bruker A VANCE-400) and reported in δ scale.

Example 1

1 -Phenyl-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethy l)pherioxy)ethanone

Step 1: 2-((4-(trifluoromethyl)benzyl)oxy)isoindoline-l,3-dione

To a solution of l-(bromomethyl)-4-(trifluoromethyl)benzene (10 g, 41.8 mmol) in DMF (50 ml) K ₂ C0 ₃ (11.56 g, 84 mmol) was added followed by addition of 2-hydroxyisoindoline-l,3-dione (6.82 g, 41.8 mmol) under nitrogen atmosphere at 25 °C. The reaction mixture was stirred under nitrogen atmosphere at 25 °C for 18 hr. The reaction mixture was poured into ice cold water (200 mL). Off white solid separated was filtered, washed with water and dried over P ₂ 0 ₅ under vacuum to yield 5.1 g (37.9 %) of title product as off white solid.

1H NMR: CDCI3,□ 5.27 (s, 2H), 7.64-7.69 (m, 4H), 7.73-7.77 (m, 2H), 7.80-7.85 (m, 2H).

Step 2: 0-(4-(trifluoromethyl)benzyl)hydroxylamine hydrochloride

To a solution of 2-((4-(trifluoromethyl)benzyl)oxy)isoindoline-l,3-dione (5.1 g, 15.88 mmol) in THF (40 ml) and EtOH (40.0 ml) was added hydrazine monohydrate (1.557 ml, 31.8 mmol) and the reaction mixture was stirred for 1 hour at 25 °C. The reaction mixture was poured into K ₂ C0 ₃ solution (100 mL) and extracted with ethyl acetate. The combined organic layer was washed with water & brine solution, dried over Na ₂ S0 ₄ and evaporated under vacuum to yield crude product as brown thick liquid. The crude product was added to ethereal HCl. The solid separated was filtered, washed with diethyl ether and dried over CaCl ₂ under vacuum to yield 2 g, (55.3 %) of product as off white solid.

1H NMR: MeOD,□ 5.15 (s, 2H), 7.64 (d, J= 8.0 Hz, 2H), 7.74 (d, J= 8.0 Hz, 2H). Step 3: l-(4-hydroxyphenyl)ethanone 0-(4-(trifluoromethyl)benzyl) oxime

To a solution of l-(4-hydroxyphenyl)ethanone (5.98 g, 43.9 mmol) in EtOH (100 ml) was added 0-(4-(trifluoromethyl)benzyl)hydroxylamine hydrochloride (10 g, 43.9 mmol) followed by addition of acetic acid (7.55 ml, 132 mmol) and sodium acetate (7.21 g, 88 mmol) at 25 °C. The reaction mixture was refluxed for 2 hr. The reaction mixture was cooled to room temperature and solvent was evaporated under vacuum. The residue was poured into water. White solid separated was filtered, washed with water and dried over P ₂ 0 ₅ under vacuum to yield 12.0 g, (88 %) of product as white solid.

1H NMR: CDC1 ₃ ,□ 2.25 (s, 3H), 5.22 (s, 2H), 6.76-6.79 (m, 2H), 7.49-7.53 (m, 4H), 7.59 (d, /.= 8.4 Hz, 2H).

Step4:-l-phenyl-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imi no)ethyl) phenoxy) ethanone To a solution of l-(4-hydroxyphenyl)ethanone 0-(4-(trifluoromethyl)benzyl) oxime (300 mg, 0.970 mmol) in DMF (5 ml) ₂ C0 ₃ (201 mg, 1.45 mmol) was added followed by addition of 2-chloro-l-phenylethanone (180 mg, 1.164 mmol) under nitrogen atmosphere at 28 °C. The reaction mixture was stirred under nitrogen atmosphere for 18 hr. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layer was washed with water & brine, dried over Na ₂ S0 ₄ and evaporated under vacuum to yield 500 mg crude product as sticky solid. The crude product was purified by column chromatography (230-400 silica gel column, Eluent: 4% EtOAc in Hexane) to yield 200 mg, (47.1 %) of pure product as white crystalline solid.

Ή NMR: CDC1 ₃ δ 2.24 (s, 3H), 5.25 (s, 2H), 5.29 (s, 2H), 6.90 (d, J= 8.6 Hz, 2H), 7.48-7.52 (m, 4H), 7.55-7.64 (m, 5H), 7.98-8.00 (m, 2H).

Example 2

1 -Cyclopropyl-2-((5-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridin-2- yl)oxy)ethanone

Step 1: Ethyl 2-((5-acetylpyridin-2-yl)oxy)acetate

To a solution of l-(6-chloropyridin-3-yl)ethanone (4.0 gm, 0.0257 mole) in DMF (15 mL), cesium carbonate (16.8 gm, 0.051 mole) was added followed by addition of methyl 2-hydroxyacetate (8.0 ml, 0.103 mmoles) at 25 °C under nitrogen atmosphere and the reaction mixture was stirred at 80-90 °C for 18 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure. The crude product was purified by colunm chromatography (Eluent: 16% ethyl acetate in hexane) to yield 1.25 gm (23%) of product as off white solid.

Ή NMR: DMSO-< ₆ ,□ 2.55 (s, 3H), 3.67 (s, 3H), 5.02 (s, 2H), 7.04 (dd, J = 8.8 & 0.4 Hz, 1H), 8.20 (dd, J= 8.8 & 2.4 Hz, 1H), 8.78 (d, J= 2.0 Hz, 1H).

Step 2: Methyl 2-((5-(l-(hydroxyimino)ethyl)pyridin-2-yl)oxy)acetate

To a solution of methyl 2-((5-acetylpyridin-2-yl)oxy)acetate (1.23 gm, 0.059 mole) in ethanol (10 mL), a solution of sodium acetate (0.942 gm, 0.01 17 mole) and hydroxylammonium chloride (1.2 gm, 0.0117 mole) in water (5 ml) was added and the reaction mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature and solvent was evapourated in vacuum. The residue was diluted with ice cold water and solid seperated was filtered, washed with water and dried over P ₂ Os under vacuum to yield 1.15 gm (88%) of title product as off white solid.

Ή NMR: DMSO- ₆ ,□ 2.12 (s, 3H), 3.66.(s, 3H), 4.94 (s, 2H), 6.95 (d, J = 8.8 Hz, 1H), 8.02 (dd, J= 8.4 & 2.4 Hz, 1H), 8.34 (d, J= 2.0 Hz, lH).

Step 3: Methyl 2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridi n-2- yl)oxy)acetate

To a solution of l-(bromomethyl)-4-(trifluoromethyl)benzene (0.87 ml, 5.6 mmoles) in DMF (10 mL), cesium carbonate (3.35 gm, 10.2 mmoles) was added followed by addition of methyl 2-((5-(l-(hydroxyimino)ethyI)pyridin-2-yl)oxy)acetate (1.15 gm, 5.1 mmoles) at 25 °C under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 12 h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 2.0 gm (94%) of product as thick liquid.

Ή NMR: DMSO-i¼,□ 2.24 (s, 3H), 3.65 (s, 3H), 4.94 (s, 2H), 5.29 (s, 2H), 6.94 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 8.00 (dd, J = 8.8 & 2.4 Hz, 1H), 8.36 (d, J= 2.4 Hz, 1H).

Step 4: 2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridi n-2-yl)oxy)acetic acid To a solution of the product of step 3 (2.0 gm, 5.2 mmoles) in a mixture of THF (12 mL), methanol (4 mL) and water (4 mL), lithium hydroxide (440 mg, 10.5 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, acidified with IN HC1 and extracted with ethyl acetate. The ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 1.7 gm (88%) of title product as white solid.

Ή NMR: DMSO-</ ₆ ,□ 2.24 (s, 3H), 4.84 (s, 2H), 5.29 (s, 2H), 6.93 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.98 (dd, J = 8.8 & 2.8 Hz, 1H), 8.36 (d, J= 2.4 Hz, 1H).

Step 5: N-methoxy-N-methyl-2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy )imino) ethyl) pyridin-2-yl)oxy)acetamide.

To a solution of 2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridi n- 2-yl)oxy)acetic acid (0.250 g, 0.679 mmol) in DMF (2.0 ml), 1H- benzo[d][l,2,3]triazol-7-ol (0.138 g, 1.018 mmol), l-((ethylimino)methylene)-3,3- dimethylpropane- l,3-diamine hydrochloride (0.156 g, 0.815 mmol), Ν,Ο- Dmethylhydroxylamine hydrochloride (0.066 g, 0.679 mmol) and N-ethylmorpholine (0.258 ml, 2.036 mmol) were added. The reaction mixture was stirred at 30 °C for 22 hours. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic layer was washed with water & brine, dried over Na ₂ S0 ₄ and evaporated under vacuum to yield N-methoxy-N-methyl-2-((5- (l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)pyridin-2-yl )oxy)acetamide as yellow liquid.

lH NMR: CDC1 ₃ ,□ 2.24 (s, 3H), 3.22 (s, 3H), 3.81 (s, 3H), 5.15 (s, 2H), 5.25 (s, 2H), 6.88 (d, J— 8.8 Hz, 1H), 7.49 (d, J= 8.4 Hz, 2H), 7.61 (d, J= 8.0 Hz, 2H), 7.92 (dd, J = 8.8 & 2.4 Hz, 1H), 8.30 (d, J= 2.4 Hz, 1H).

Step 6: l-cyclopropyl-2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imin o)ethyl) pyridin- 2-yl)oxy)ethanone. To a solution of N-methoxy-N-methyl-2-((5-(l-(((4-(trifluoromethyl) benzyl) oxy)imino)ethyl)pyridin-2-yl)oxy)acetamide (0.400 g, 0.972 mmol) in THF (10.00 ml), freshly prepared cyclopropyl magnesium bromide (using magnesium (0.236 g, 9.72 mmol) and cyclopropyl bromide (0.779 ml, 9.72 mmol) in Diethyl ether (15 ml)) was added in portions at 0°C. The reaction mixture was stirred at 0 °C for one hour. The reaction mixture was poured into saturated solution of NH ₄ C1 (25 mL) and extracted with ethyl acetate. The organic layer was washed with water & brine, dried over Na ₂ S0 ₄ and evaporated under vacuum to yield crude product as yellow liquid. The crude product was purified by column chromatography (230-400 silica gel column, Eluent: 15 % EtOAc in Hexane) to yield 0.275 g, (71.6 %) of pure product as white solid.

'H MR: CDC1 ₃ δ 0.91-0.96 (m, 2H), 1.10-1.14 (m, 2H), 2.04-2.01 (m, 1H), 2.24 (s, 3H), 5.07 (s, 2H), 5.25 (s, 2H), 6.86 (dd, J= 8.8 & 0.4 Hz, 1H), 7.50 (d, J= 12.4 & 4.0 Hz, 2H), 7.61 (d, J= 8.0 Hz, 2H), 7.93 (dd, J = 8.8 & 2.8 Hz, 1H), 8.29 (dd, J= 2.4 & 0.4 Hz, 1H).

Example 3

Ethyl 5-(2-oxo-2-phenylethoxy)-2-(l-(((4-(trifluoromethyl)benzyl)o xy)imino) ethyl) benzoate.

Step 1: l-(4-(benzyloxy)-2-hydroxyphenyl)ethanone.

To a solution of l-(2,4-dihydroxyphenyl)ethanone (6.0 g, 39.4 mmol) in Acetone (150 ml), potassium carbonate (6.81 g, 49.3 mmol) was added followed by addition of benzyl bromide (4.69 ml, 39.4 mmol) and the reaction mixture was stirred at 48 °C for 5 hours. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane. The organic layer was washed with saturated solution of NaHC0 ₃ & water, dried over Na ₂ S0 ₄ and evaporated under vacuum to yield crude product as brown liquid. The crude product was purified by column chromatography (230-400 silica gel column, Eluent: 15 % EtOAc in Hexane) to yield 6.3 g, (65.9 %) of pure product as white solid.

Ή NMR: CDC1 ₃ ,□ 2.55 (s, 3H), 5.09 (s, 2H), 6.52 (d, J= 2.8 Hz, 2H), 7.25 (s, 1H), 7.32-7.43 (m, 4H), 7.62-7.65 (m, 1H), 12.73 (s, OH).

Step 2: Ethyl 2-(l-(4-(benzyloxy)-2-hydroxyphenyl)ethylidene)hydrazine carboxylate.

To a solution of l-(4-(benzyloxy)-2-hydroxyphenyl)ethanone (6.3 g, 26.0 mmol) in propanol (50 ml), ethyl hydrazine carboxylate (3.25 g, 31.2 mmol) was added and the reaction mixture was stirred at 100 °C for 24 hours. Reaction mixture was cooled to 30°C and diluted with hexane (100 ml). The solid product was filtered, washed with excess hexane and dried under vacuum to yield 6.0 g (70.3 %) of product as yellow solid.

Ή NMR: CDC1 ₃ ,□ 1.26 (t, J = 6.8 Hz, 3H), 2.25 (s, 3H), 4.19 (q, J - 7.2 Hz, 2H), 5.11 (s, 2H), 6.49-6.53 (m, 2H), 7.31-7.46 (m, 6H), 10.62 (s, NH), 13.17 (s, OH). Step 3: Ethyl 2-acetyl-5-(benzyloxy)benzoate.

To a solution of ethyl 2-(l-(4-(benzyloxy)-2-hydroxyphenyl)ethylidene) hydrazinecarboxylate (6.0 g, 18.27 mmol) in dry THF (100 ml), lead tetraacetate (8.91 g, 20.10 mmol) was added portion wise and the reaction mixture was stirred at 30 °C for 4 hours. Inorganic material was filtered, washed with excess THF (25 ml). Filtrate was dried over Na ₂ S0 ₄ and evaporated under vacuum to yield crude product as brown liquid. The crude product was purified by column chromatography (230-400 silica gel column, Eluent: 10% EtOAc in Hexane) to yield 1.0 g, (18.34 %) pure product as yellow liquid and 3.5 gm of l-(4-(benzyloxy)-2-hydroxyphenyl)ethanone was recovered.

Ή NMR: CDC1 ₃ ,□ 1.38 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H),

5.13 (s, 2H), 7.06 (dd, J = 8.8 & 2.8 Hz, 1H), 7.25 (d, J = 6.0 Hz, 1H), 7.32-7.43 (m,

5H), 7.54 (d, J= 8.4 Hz, 1H).

Step 4: Ethyl 2-acetyl-5-hydroxybenzoate. To a suspension of 10% Pd/C (100 mg) in ethyl acetate (2.0 ml), a solution of ethyl 2-acetyl-5-(benzyIoxy)benzoate (1.0 g, 3.35 mmol) in Ethyl acetate (20 ml) was added followed by addition of ammonium formate (0.845 g, 13.41 mmol). The reaction mixture was refluxed for 1 hour. The reaction mixture was cooled to 30°C and the catalyst was filtered off, washed with excess ethyl acetate (20 ml). Filtrate was washed with water (3 X 20 ml), dried ovec Na ₂ S0 ₄ and evaporated under vacuum to yield 0.6 g (86 %) of product as pale red liquid.

Ή NMR: CDC1 ₃ ,□ 1.36 (t, J = 6.8 Hz, 3H), 2.52 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 6.052 (s, OH), 6.92-6.96 (m, 1H), 7.10 (d, J= 2.4 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H). Step 5: Ethyl 5-hydroxy-2-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl) benzoate.

To a solution of ethyl 2-acetyl-5-hydroxybenzoate (0.300 g, 1.441 mmol) and 0-(4-(trifluoromethyl)benzyl)hydroxylamine (0.358 g, 1.873 mmol) in Ethanol (10 ml), another solution of sodium acetate (0.118 g, 1.441 mmol) in water (1.0 ml) was added and the reaction mixture was stirred at 90 °C for 20 hours. The reaction mixture was cooled to 30°C and ethanol was distilled out from the reaction mixture under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water & brine, dried over Na ₂ S0 ₄ and evaporated under vacuum to yield crude product as pale red liquid. The crude product was purified by column chromatography (230-400 silica gel column, Eluent: 10% EtOAc in Hexane) to yield 0.180 g (32;8 % yield) of pure product as yellow liquid.

1H NMR: CDC1 ₃ ,□ 1.21-1.33 (m, 3H), 2.19 (s, 3H,), 4.15-4.23 (m, 2H), 5.18 (s, OH), 5.22 (s, 2H), 6.94 (dd, J= 8.4 Hz, 1H), 7.03 (d, J= 2.0 Hz, 1H), 7.17 (d, J= 8.4 Hz, 1H), 7.49 (d, J - 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H).

Step 6: Ethyl 5-(2-oxo-2-phenylethoxy)-2-(l-(((4-(trifluoromethyl)benzyl)o xy)imino) ethyl)benzoate.

Potassium carbonate (0.098 g, 0.708 mmol) was added to a solution of ethyl 5- hydroxy-2-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)be nzoate (0.180 g, 0.472 mmol) and 2-bromo-l-phenylethanone (0.099 g, 0.496 mmol) in DMF and the reaction mixture was stirred at 30 °C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water & brine, dried over Na ₂ S0 ₄ and evaporated under vacuum to yield crude product as yellow liquid. The crude product was purified by column chromatography (230-400 silica gel column, Eluent: 7% EtOAc in Hexane) to yield 0.120 g (49.1 %) of pure product as yellow liquid.

Ή NMR: CDCl ₃ ,□ 1.25 (t, J= 11.6 Hz, 3H), 2.19 (s, 3H), 1.19 ( q, J= 7.2 Hz, 2H), 5.21 (s, 2H), 5.32 (s, 2H), 7.07 (dd, J= 8.¾ & 2.8 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 7.42 (d, J = 2.8 Hz, 1H), 7.48-7.53 (m, 4H), 7.59-7.65 (m, 3H), 7.97 (d, J = 8.4 Hz, 2H).

Example 4

l, l,l-Trifluoro-3-(4-(l-(((4-(trifluoromethyl)benzyI)oxy)imino )ethyl)phenoxy)propan- -one

Step 1: l-(4-(3,3,3-trifiuoro-2-hydroxypropoxy)phenyl)ethanone 0-(4-trifluoromethyl) benzyl) oxime

To a mixture of l-(4-hydroxyphenyl)ethanone 0-(4-(trifluoromethyl)benzyl) oxime (50 mg, 0.162 mmol) and DMAP (9.88 mg, 0.081 mmol), 2- (trifluoromethyl)oxirane (91 mg, 0.808 mmol) was added drop wise at 30 °C . The reaction mixture was stirred for 8 hours at 60 °C in a sealed tube. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate. The combined organic layer was washed with water & brine solution, dried over sodium sulphate and evaporated under vacuum to yield l-(4-(3,3,3-trifluoro-2- hydroxypropoxy)phenyl)ethanone 0-(4-(trifluoromethyl) benzyl) oxime (35 mg, 51.4 % yield) as colorless liquid. Step 2: l,l,l-trifluoro-3-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imi no)ethyl) phenoxy) propan-2-one

A suspension of l-(4-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl)ethanone O- (4-(trifluoromethyl)benzyl) oxime (500 mg, 1.187 mmol) and Dess-Martin Periodinane (1510 mg, 3.56 mmol) in dichloromethane (20 ml) was stirred at 30 °C for 2 hours. The reaction mixture was concentrated and the crude product was purified by column chromatography (230-400 silica gel column) using 15% EtOAc in Hexane as eluent to yield 105 mg, (19.78 %) of pure product as white solid.

lH NMR: CDCI ₃ δ 2.25 (s, 3H), 4.19 (s, 2H), 5.27 (s, 2H), 6.94-6.97 (m, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.59-7.62 (m, 4H).

The following examples were prepared following the general procedures given in Example 1-4, with suitable modifications, alterations and other process variations which are within the scope of a person skilled in the art.

Example 5

l-Phenyl-2-((5-(l-((4-(trifluoromethyl)phenoxy)imino)ethy l)pyridin-2-yl)oxy) ethanone

Ή NMR: CDCI3 δ 2.42 (s, 3H), 5.68 (s, 2H), 7.01 (d, J= 8.8 Hz, 1H), 7.34 (d, J= 8.4 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.57-7.65 (m, 3H), 8.01 (d, J = 7.2 Hz, 2H), 8.10 (d, J= 8.8 Hz, lH), 8.40 (d, J= 2.8 Hz, 1H).

Example 6

Ethyl 5 -(2-cycloprop l-2-oxoethoxy)-2-( 1 -(((4-(trifluoromethyl)benzyl)oxy) imino) ethyl) benzoate

Ή NMR: CDCI ₃ δ 1.00-1.02 (m, 2H), 1.14-1.18 (m, 2H), 1.23-1.30 (m, 3H), 2.18-2.27 (m, 4H), 4.16-4.24 (m, 2H), 4.73 (s, 2H), 5.22 (s, 2H), 7.01-7.10 (m, 1 H), 7.25-7.32 (m, 1H), 7.38 (d, J= 2.8 Hz, 1H), 7.38 -7.55 (m, 2H), 7.61 (d, J= 8.0 Hz, 2H).

Example 7

l-CyclopropyI-2-(4-(l-(((2-(trifluoromethyl)thiazol-4-yl)met hoxy)imino)ethyI) phenoxy) ethanone

Ή NMR: CDCb δ 0.95-1.00 (m, 2H), I.13- 1.17(m, 2H), 2.24-2.30 (m, 4H), 4.70 (s, 2H), 5.39 (s, 2H), 6.88 (d, J = 10.0 Hz, 2H), 7.51 (s, 1H), 7.59 (d, J= 9.6 Hz, 2H). Example 8

-(4-(l-(((4-(Trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy) propan-2-one

'H NMR: CDCI3 δ 2.25 (s, 3H), 2.27 (s, 3H), 4.54 (s, 2H), 5.26 (s, 2H), 6.86 (d, J

8.8 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.58 (t, J= 8.8 Hz, 4H).

Example 9

1 -(4-( 1 -(((4-(Trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)butan- 2-one

'H NMR: CDCb <5 1.10 (t, J= 7.2 Hz, 3H), 2.25 (s, 3H), 2.62 (q, J= 7.2 Hz, 2H), 4.57 (s, 2H), 5.26 (s, 2H), 6.84 (d, J= 8.6 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.56-7.62 (m, 4H).

Example 10

3-(4-(l-(((4-(Trifluoromethyl)benzyl)oxy)imino)et yl)phenoxy)butan-2-one

'H NMR: CDCI3 δ 1.50 (d, J= 7.2 Hz, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 4.62 (q, J= 6.8 Hz, 1H), 5.26 (s, 2H), 6.82 (d, J= 8.2 Hz, 2H), 7.50 (d, J= 7.6 Hz, 2H), 7.55-7.62 (m, 4H).

Example 11

3-Methyl- 1 -(4-(l -(((4-(tn y l)phenoxy)butan-2-one

'H NMR: CDC1 ₃ δ 1.15 (s, 3H), 1.16 (s, 3H), 2.24 (s, 3H), 2.89-2.96 (m, 1H), 4.65 (s,

2H), 5.26 (s, 2H), 6.80 (d, J= 8.8 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.56-7.62 (m,

4H).

Example 12

4-Methyl-l-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethy l)phenoxy)penti

Ή NMR: CDCI3 δ 0.94 (d, J= 6.4 Hz, 6H), 2.18-2.25 (m, 4H), 2.45 (dd, J= 6.8Ήζ, 2H), 4.53 (s, 2H), 5.26 (s, 2H), 6.85 (d, J= 8.2 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.57- 7.62 (m, 4H).

Example 13

3,3-Dimethyl-l-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl)phetioxy)butan-2- one

Ή NMR: CDC δ 1.25 (s, 9H), 2:24 (s, 3H), 4.88 (s, 2H), 5.25 (s, 2H), 6.84 (dd, J 6.8 & 2.0 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.55-7.62 (m, 4H).

Example 14

l-Cyclopropyl-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)im ino)ethyl)phenoxy) ethanone

'H NMR: CDCI3 0.95-1.00 (m, 2H), 1.13-1.17 (m 2H), 2.24-2.30 (m, 4H), 4.69 (s 2H), 5.26 (s, 2H), 6.88 (d, J= 8.8 Hz, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.56-7.62 (m, 4H).

Example 15 l-Cyclopropyl-2-(3-hydroxy-4-(l-(((4-(trifluoromethyl)benzyl )oxy)imino)

ethyl)phenoxy) ethanone

'H NMR: CDCI3 S 0.96-0.99 (m, 2H), 1.12-1.16 (m, 2H), 2.21-2.27 (m, IH), 2.33 (s, 3H), 4.67 (s, 2H), 5.22 (s, 2H), 6.42 (dd, J - 2.4 & 6.0 Hz, IH), 6.47 (dd, J= 2.4 & 6.0 Hz, IH), 7.32 (d, J= 8.8 Ηζ,ΙΗ), 7.50 (d, J= 8.0 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 11.19 (s, lH).

Example 16

l-Cyclopropyl-2-(4-(l-( -/5opropylbenzyl)oxy)imino)ethyl)phenoxy)ethanone

'H NMR: CDCI3 ^ 0.96-1.00 (m, 2H), 1.13-1.17 (m, 2H), 1.25 (d, J= 7.2 Hz, 6H), 2.23 (s, 3H), 2.25-2.31 (m, IH), 2.87-2.94 (m, IH), 4.69 (m, 2H), 5.18 (s, 2H), 6.89 (d, J= 8.8 Hz, 2H), 2.22 (d, J= 8.0 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 7.59-7.62 (m, 2H). Example 17

1 -Cyclopropyl-2-(4-( 1 -(((2,6-di sopropylbenzyl)oxy)imino)ethy l)phenoxy)ethanone

'H NMR-. CDC 0.99-1.00 (m, 2H), 1.13-1.18 (m, 2H), 1.25 (d, J = 6.8 Hz, 12H), 2.15 (s, 3H), 2.26-2.32 (m, 1H), 3.41-3.48 (m, 2H), 4.70 (s, 2H), 5.34 (s, 2H), 6.88 (d, J= 8.2 Hz, 2H), 7.18 (d, J= 7.6 Hz, 2H), 7.30-7.34 (m, 1H), 7.62-7.65 (m, 2H).

Example 18

l-Cyclopropyl-2-(4-(l-(((2,4-diisopropylbenzyl)oxy)imino) ethyl)phenoxy)ethanone

Ή NMR: CDC1 ₃ δ 0.95-1.00 (m, 2H), 1.13-1.17 (m, 2H), 1.25 (d, J = 3.6 Hz, 6H), 1.26 (d, J = 3.6 Hz, 6H), 2.20 (s, 3H), 2.25-2.30 (m, 1H), 2.87-2.92 (m, 1H), 3.27-3.34 (m, 1H), 4.69 (s, 2H), 5.24 (s, 2H), 6.87-6.90 (m, 2H), 7.05 (dd, J = 7.6 & 2.0 Hz, lH), 7.18 (d, J= 1.6 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.60-7.64 (m, 2H).

Example 19

l-Cyclopropyl-2-((5-(l-(((3-methoxy-4-(trifluoromethyl)be nzyl)oxy)imino) ethyl) pyridin-2-yl)oxy)ethanone

1H NMR: CDCI3 δ 0.88-0.96 (m, 2H), 1.10-1.14 (m, 2H), 2.04-2.10 (m, IH), 2.27 (s, 3H), 3.90 (s, 3H), 5.07 (s, 2H), 5.29 (s, 2H), 6.84 (dd, J = 8.8 & 0.8 Hz, IH), 7.08 (s, IH), 7.22 (d, J = 7.2 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.95 (dd, J = 8.8 & 2.4 Hz, lH), 8.30 (d, J= 2.0 Hz, IH).

Example 20

l-cyclobutyl-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imi no)ethyl)phenoxy)ethanone

'H NMR: CDCI3 δ 1.88 (m, IH), 1.97-2.04 (m, IH), 2.14-2.20 (m, 2H), 2.25-2.35 (n 5H), 3.51-3.55 (m, IH), 4.57 (s, 2H), 5.26 (s, 2H), 6.82- 6.86 (m, 2H), 7.50 (d, J= 8 Hz, 2H), 7.55-7.62 (m, 4H).

Example 21

1 -Cyclopentyl-2-(4-( 1 -(((4-(trifluoromethy l)benzy l)oxy)imino)ethyl) phenoxy) ethanone

'H NMR: CDC1 ₃ δ 1.55-1.62 (m, 2H), 1.63-1.71 (m, 2H), 1.77-1.87 (m, 4H), 2.24 (s, 3H), 3.1 1-3.15 (m, IH), 4.64 (s, 2H), 5.26 (s, 2H), 6.86 (d, J= 8.8 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.56-7.62 (m, 4H).

Example 22

1 -Cyclohexyl-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethy l)phenoxy)ethanone

'H NMR: CDCI3 δ 1.22-1.46 (m, 5H), 1.67-1.69 (m, IH), 1.78-1.87 (m, 4H), 2.25 (s, 3H), 2.61-2.68 (m, IH), 4.64 (s, 2H), 5.26 (s, 2H), 6.86 (d, J= 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.56-7.62 (m, 4H).

Example 23

2-(3-Hydroxy-4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)eth yl)phenoxy)-l-phenyl ethanone

Ή NMR: CDCI3 «5 2.32 (s, 3H), 5.21 (s, 2H), 5.27 (s, 2H), 6.44 (d, J= 2.4 Hz, 1H), 6.51 (dd, J= 8.8 & 2.4 Hz, 1H), 7.30 (d, J= 8.8 Hz, IH), 7.48-7.52 (m, 4H), 7.60-7.64 (m, 3H), 7.96-7.98 (m, 2H), 11.88 (bs, OH)

Example 24

l-Phenyl-2-((5-(l-(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl)pyridin-2-yl)oxy) ethanone

Ή NMR: CDCI3 δ 3.23 (s, 3H), 5.24 (s, 2H), 5.64 (s, 2H), 6.91 (dd, J= 8.6 & 0.6 Hz, IH), 7.47-7.51 (m, 4H), 7.58-7.63 (m, 3H), 7.93 (dd, 7 = 8.8 & 2.4 Hz, IH), 7.98-8.01 (m, 2H), 8.24 (m, IH).

Example 25

2-(4-( 1 -(((2,6-Diwopropylbenzyl)oxy)imino)ethyl)phenoxy)- 1 -phenylethanone

'H NMR: CDCI3 δ 1.20 (d, J= 6.8 Hz, 12H), 2.10 (s, 3H), 3.37-3.42 (m, 2H), 5.28 (s, 2H), 5.62 (s, 2H), 6.98-7.00 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.28-7.32 (m, IH), 7.56-7.61 (m, 4H), 7.68-7.70 (m, IH), 8.01-8.04 (m, 2H). Example 26

2-(4-( 1 -(((2,4-DiisopropylbenzyI)oxy)imino)ethy l)phenoxy)- 1 -phenylethanone

Ή NMR: CDC1 ₃ δ 1.25 (d, J = 2.4 Hz, 6H), 1.26 (d, J = 2.8 Hz, 6H), 2.19 (s, 3H), 2.87-2.93 (m, 1H), 3.26-3.33 (m, 1H), 5.23 (s, 2H), 5.28 (d, J= 3.2 Hz, 2H), 6.90-6.94 f (m, 2H), 7.04 (dd, J= 8.0 & 2.0 Hz, 1H), 7.18 (d, J = 1.6 Hz, 1H), 7.30 (d, J= 8.0 Hz, -

1H), 7.48-7.52 (m, 2H), 7.58-7.64 (m, 3H), 7.99 (dd, J= 3.2 & 1.2 Hz, 2H). ^φ ίί.

Example 27

Methyl 4-(((( 1 -(4-(2-oxo-2-phenylethoxy)phenyl)ethylidene)amino)oxy)methyl ) benzoate

'H NMR: DMSO-^ S 2.22 (s, 3H), 3.84 (s, 3H), 5.25 (s, 2H), 5.61 (s, 2H), 6.97 (d, J= 8.8 Hz, 2H), 7.51-7.59 (m, 6H), 7.69 (m, 1H), 7.96 (d, J= 8.4 Hz, 2H), 8.01 (d, J= 8.4 Hz, 2H).

Example 28

1 -Phenyl-2-(4-( 1 -(((2-(trifluoromethyl)thiazol-4-yl)methoxy)imino)ethyl)phen oxy) ethanone

Ή NMR: DMSO--4 δ 2.20 (s, 3H), 5.31 (s, 2H), 5.62 (s, 2H), 6.98 (d, J= 7.2 Hz, 2H), 7.55-7.59 (m, 4H), 7.68-7.72 (m, 1H), 8.01 (d, J= 8.8 Hz, 2H), 8.1 1 (s, 1H).

Example 29

1 -(2-Chlorophenyl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy) imino)ethyl)phenoxy) ethanone

Ή NMR: DMSO-^ δ 2.23 (s, 3H), 5.28 (s, 2H), 5.40 (s, 2H), 6.95 (dd, J= 7.0 & 1.8 Hz, 2H), 7.48-7.52 (m, 1H), 7.56-7.62 (m, 6H), 7.72 (d, J= 8.0 Hz, 2H), 7.82 (dd, J = 8.0 & 0.8 Hz, 1 H)

Example 30

l-(4-Chlorophenyl)-2-(4-'(l-(((4-(trifluoromethyl)benzyl) oxy)imino) ethyl)phenoxy) ethanone

Ή NMR: DMSO-i/<; δ 2.22 (s, 3H), 5.27 (s, 2H), 5.60 (s, 2H), 6.98 (d, J= 8.8 Hz, 2H), 7.56 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 8.8 Hz, 2H), 7.73 (d, J= 8.0 Hz, 2H), 8.03 (d, J= 8.8 Hz, 2H).

Example 31

l-(2-Methoxyphenyl)-2-(4-(l-(((4-(trifluoromethyl)benzyl) oxy)imino)ethyl) phenoxy) ethanone

Ή NMR: CDCI3 δ 2.24 (s, 3H), 3.97 (s, 3H), 5.25 (s, 4H), 6.88 (dd, J= 6.8 & 2.0 Hz, 2H), 7.01-7.09 (m, 2H), 7.49-7.62 (m, 7H), 7.93 (dd, J= 7.6 & 1.6 Hz, 1H).

Example 32

l-(4-Methoxyphenyl)-2-(4-(l-(((4-(trifluoromethyl)benzyl) oxy)imino)ethyl )phenoxy) ethanone

Ή NMR: DMSO-<¾ <52.22 (s, 3H), 3.86 (s, 3H), 5.26 (s, 2H), 5.53 (s, 2H), 6.95 (d, J= 6.8 Hz, 2H), 7.08 (d, J= 6.8 Hz, 2H), 7.56 (d, J= 6.8 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.73 (d, J= 8.0 Hz, 2H), 7.99 (d, J= 7.2 Hz, 2H).

Example 33

l-(2-Hydroxyphenyl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy )imino) ethyl)phenoxy) ethanone

Ή NMR: DMSO-ik S 2.25 (s, 3H), 5.25 (s, 2H), 5.32 (s, 2H), 6.90-6.97 (m, 3H), 7.04 (dd, J = 8.4 & 1.2 Hz, 1H), 7.49-7.62 (m, 7H), 7.77 (dd, J= 9.6 & 1.6 Hz, 1H), 1 1.75 (s, 1H).

Example 34

2-(4-( 1 -(((4-(Trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)- 1 -(4- (trifluoromethyl)phenyl) ethanone

Ή NMR: DMSO-i _d δ 2.22 (s, 3H), 5.27 (s, 2H), 5.67 (s, 2H), 7.01 (d, J= 9.2 Hz, 2H), 7.56-7.61 (m, 4H), 7.73 (d, J= 8.0 Hz, 2H), 7.95 (d, J = 8.0 Hz, 2H), 8.20 (d, J = 8,0 Hz, 2H).

Example 35

l-( aphthalen-2-yI)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imi no)ethyl)

phenoxy)ethanone

Ή NMR: DMSO-i ₆ δ 2.23 (s, 3H), 5.27 (s, 2H), 5.75 (s, 2H), 7.01 (dd, J= 7.2 & 2.0 Hz, 2H), 7.57-7.59 (m, 4H), 7.62-7.75 (m, 4H), 7.99-8.08 (m, 3H), 8.13 (d, J= 7.6 Hz, 1H), 8.77 (s, 1H).

Example 36

l-(5,6,7,8-Tetrahydronaphthalen-2-yl)-2-(4-(l-(((4-(trifl uoromethyl)benzyl)oxy) imino) ethyl) phenoxy)ethanone

'H NMR: δ 1.75-1.77 (m, 4H), 2.22 (s, 3H), 2.79 (s, 4H), 5.27 (s, 2H), 5.55 (s, 2H), 6.93-6.97 (m, 2H), 7.22 (d, J= 7.6 Hz, 1H), 7.54-7.59 (m, 4H), 7.70-7.74 (m, 4H). -

Example 37 l-([l, l'-Biphenyl]-4-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy )imino)ethyl) phenoxy)ethanone

Ή NMR: CDCI3 δ 2.25 (s, 3H), 5.25 (s, 2H), 5.31 (s, 2H), 6.91-6.95 (m, 2H), 7.39 - 7.41 (m, 1H), 7.43-7.51 (m, 4H), 7.56-7.64 (m, 6H), 7.70-7.73 (m, 2H), 8.06 (dd, J= 6.8 & 2.0 Hz, 2H).

Example 38

l-(Tetrahydro-2H-pyran-4-yl)-2-(4-(l-(((4-(trifluoromethy l)benzyl) oxy)imino) ethyl) phenoxy) ethanone

1H NMR: CDCI3 <5 1.71-1.80 (m, 4H), 2.25 (s, 3H), 2.90-2.97 (m, 1H), 3.42-3.48 (m, 2H), 3.98-4.03 (m, 2H), 4.64 (s, 2H), 5.26 (s, 2H), 6.83-6.87 (m, 2H), 7.50 (d, J= 8.0 Hz, 2H), 7.57-7.62 (m, 4H).

Example 39

l-(Benzofuran-2-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl) oxy)imino)ethyl) phenoxy) ethanone

1H NMR: DMSO-i/ ₆ δ 2.22 (s, 3H), 5.27 (s, 2H), 5.53 (s, 2H), 7.02 (d, J= 9.2 Hz, 2H), 7.40 (s, 1H), 7.56-7.61 (m, 5H), 7.72-7.77 (m, 3H), 7.89 (d, J= 8.0 Hz, 1H), 8.07 (s, 1H). Example 40

l-(Thiazol-2-yl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl)phenoxy) ethanone

Ή NMR: CDCI3 δ 2.55 (s, 3H), 5.26 (s, 2H), 5.55 (s, 2H), 6.94-6.98 (m, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.56-7.62 (m, 4H), 7.77 (d, J= 3.2 Hz, 1H), 8.06 (d, J= 2.8 Hz, 1H). Example 41

1-(1 -Methyl- lH-imidazol-2-yI)-2-(4-(l-(((4-(trifluoromethyl)benzyl) oxy)imino)ethyl) phenoxy) ethanone

Ή NMR: DMSO-4; δ 2.22 (s, 3H), 3.92 (s, 3H), 5.27 (s, 2H), 5.51 (s, 2H), 6.93-6.96 (m, 2H), 7.18 (d, J = 0.8 Hz, 1H), 7.54-7.62 (m, 5H), 7.72 (d, J= 8.0 Hz, 2H).

Example 42

2-(3-Hydroxy-4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy)- 1 -(1 - methyl- lH-imidazol-2-yl

1H NMR: DMSO- δ 2.28 (s, 3H), 3.91 (s, 3H), 5.29 (s, 2H), 5.47 (s, 2H), 6.37 (d, J= 2.4 Hz, 1H), 6.46 (dd, J- 8.8 & 2.4, 1H), 7.18 (d, J= 0.8 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H), 7.59 (s, 1H), 7.61 (d, J= 8.0 Hz, 2H), 7.74 (d, J= 8.0 Hz, 2H), 10.75 (s, OH). Example 43

l-(lH-Indol-3-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)ox y)imino) ethyl)phenoxy) ethanone

Ή NMR: OMSO-d ₆ δ 2.21 (s, 3H), 5.26 (s, 2H), 5.33 (s, 2H), 6.96-7.00 (ra, 2H), 7.17- 7.25 (m, 2H), 7.49-7.51 (m, IH), 7.55-7.61 (m, 4H), 7.72 (d, J= 8.0 Hz, 2H), 8.14 (d, J= 7.2 Hz, 1H), 8.50 (d, J= 3.2 Hz, I H), 12.08 (bs, NH).

Example 44

l-(Pyridin-2-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)im ino) ethyl) phenoxy) ethanone 'H NMR: CDC1 ₃ δ 2.25 (s, 3H), 5.26 (s, 2H), 5.66 (s, 2H), 6.98 (d, J= 7.2 Hz, 2H), 7.49-7.62 (m, 7H), 7.89 (t, J= 8.0 Hz, IH), 8.09 (d, J= 6.8 Hz, IH), 8.68-8.70 (m, IH).

Example 45

1 -( 1 -Methyl- 1 H-pyrrol-2-y l)-2-(4-( 1 -(((4-(trifluoromethy l)benzyl) oxy)imino) ethyl)phenoxy) ethanone

'H NMR: DMSO-c^ δ 2.20 (s, 3H), 3.84 (s, 3H), 5.26 (s, 2H), 5.27 (s, 2H), 6.17 (dd, J ^' = 4.0 & 2.4 Hz, IH), 6.91-6.95 (m, 2H), 7.21-7.22 (m, IH), 7.26 (dd, J= 4.0 & 1.6 Hz, IH), 7.54-7.56 (m, 2H), 7.59 (d, J= 8.0 Hz, 2H), 7.72 (d, J= 8.0 Hz, 2H).

Example 46 2-(4-(l-(((4-wo-Propylbenzyl)oxy)imino)ethyl)phenoxy)-l-(l -methyl- 1 H-pyrrol-2- yl)ethanone

lH NMR: CDCI3 δ 1.25 (d, J- 6.8 Hz, 6H), 2.21 (s, 3H), 2.87-2.94 (m, 1H), 3.95 (s, 3H), 5.06 (s, 2H), 5.17 (s, 2H), 6.17 (d, J= 6.4 Hz, 1H), 6.87 (s, 1H), 6.92 (d, J= 6.8 Hz, 2H), 7.10 (d, J= 4.0 Hz, 1Ή), 7.22 (d, J= 8.0 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H),

7.58 (d, J= 9.2 Hz, 2H).

Example 47

4-(2-(5-Methylthiophen-2-yI)-2-oxoethoxy)benzaldehyde 0-(4-(trifluoromethyl) benzyl) oxime

Ή NMR: DMSO-</ ₆ δ 2.53 (s, 3H), 5.23 (s, 2H), 5.43 (s, 2H), 6.97-7.02 (m, 3H), 7.53 (d, J = 7.2 Hz, 2H), 7.61 (d, J= 8.0 Hz, 2H), 7.73 (d, J= 8.0 Hz, 2H), 7.95 (d, J- 4.0 Hz, 1H), 8.28 (s, 1H).

Example 48

4-(2-Oxo-2-(thiophen-2-yl)ethoxy)benzaldehyde 0-(4-(trifluoromethyl)benzyl) oxime

1H NMR: CDCI3 δ 5.1 1 (s, 2H), 5.22 (s, 2H), 6.94 (d, J= 6.8 Hz, 2H), 7.17 (d, J= 8.8 Hz, 1H), 7.49-7.52 (m, 4H), 7.61 (d, J= 8.0 Hz, 2H), 7.72 (d, J= 5.2 Hz, 1H), 7.95 (d, J= 4.0 Hz, 1H), 8.09 (s, 1H). Example 49

2-(4-(l-(((4- 50-Propylbenzyl)oxy)imino)ethyl)phenoxy)-l-(5-methylthiophen -2- yl)ethanone

'H NMR: CDC1 ₃ δ 1.25 (d, J= 6.8 Hz, 6H), 2.21 (s, 3H), 2.54 (s, 3H), 2.87-2.94 (m, 1H), 5.04 (s, 2H), 5.17 (s, 2H), 6.82 (d, J= 8.8 Hz, 1H), 6.92 (d, J= 9.6 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.34 (d, J- 8.0 Hz, 2H), 7.58 (d, J= 9.6 Hz, 2H), 7.78 (d, J= 4.0 Hz, 1H).

Example 50

1 -(5 -Chlorothiophen-2-y l)-2-(4-( 1 -(((4-(trifluoromethyl)benzy l)oxy) imino)ethy 1) phenoxy) ethanone

Ή NMR: CDCI3 <5 2.24 (s, 3H), 5.00 (s, 2H), 5.25 (s, 2H), 6.91-6.93 (m, 2H), 6.97- 6.99 (m, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.56-7.62 (m, 4H), 7.76 (d, J= 4.0 Hz, 1H). Example 51

1 -(5-Methylthiophen-2-yl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl)phenoxy) ethanone 1H NMR: DMSO-ik δ 2.22 (s, 3H), 2.53 (s, 3H), 5.27 (s, 2H), 5.41 (s, 2H), 6.96 (d, J 6.8 Hz, 2H), 7.02 (s, 1H), 7.55-7.61 (m, 4H), 7.73 (d, J= 8.0 Hz, 2H), 7.95 (d, J= 3.6 Hz, 1H).

Example 52

l-(Thiophen-2-yl)-2-(4-(l-(((4-(trifluoromethyl)benzyl)ox y) imino)ethyl)phenoxy) ethanone

Ή NMR: DMSO-^ δ 2.22 (s, 3H), 5.27 (s, 2H), 5.49 (s, 2H), 6.98 (d, J= 6.8 Hz, 2H), 7.31 (d , J= 4.8 Hz, 1H), 7.56-7.61 (m, 4H), 7.73 (d, J= 8.0 Hz, 2H), 8.09-8.13 (m, 2H).

Example 53

2-(4-(l-(((2,6-Du ^' 50-propylbenzyl)oxy)imino)ethyl)phenoxy)-l-(5-methylfu ran-2- yl)ethanone ^l H NMR: CDC1 ₃ δ 1.25 (d, J= 6.8 Hz, 12H), 2.14 (s, 3H), 2.42 (s, 3H), 3.40 (m, 2H), 5.05 (s, 2H), 5.34 (s, 2H), 6.19 (dd, J= 3.6 & 0.8 Hz, 1H), 6.92-6.96 (m, 2H), 7.18 (d, J= 7.6 Hz, 2H), 7.30-7.35 (m, 2H), 7.60-7.64 (m, 2H).

Example 54

2-(4-( 1 -(((4-Cyclohexylbenzyl)oxy)imino)ethyl)phenoxy)- 1 -(5-methylfuran-2-yl) ethanone

1H NMR: CDCb 3 1.33-1.47 (m, 5H), 1.82-1.88 (m, 5H), 2.21 (s, 3H), 2.41 (s, 3H), 2.46-2.58 (m, IH), 5.04 (s, 2H), 5.17 (s, 2H), 6.19 (d, J= 3.6 Hz, IH), 6.92 (d, J= 6.8 Hz, 2H), 7.20 (d, J= 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 3H), 7.59 (d, J= 6.8 Hz, 2H). Example 55

2-(4-(l-(((4-Cyclohexylbenzyl)oxy)imino)ethyl)-3-hydroxyphen oxy)-l-(5- methylfuran-2-yl) et

'H NMR: CDCI3 δ 1.32-1.46 (m, 5H), 1.72 (d, J= 12.4 Hz, IH), 1.82- 1.88 (m, 4H), 2.27 (s, 3H), 2.41 (s, 3H), 2.47-2.51 (m, IH), 5.02 (s, 2H), 5.11 (s, 2H), 6.19 (d, J= 36 Hz, IH), 6.48-6.52 (m, 2H), 7.21 (d J= 8.0 Hz, 2H), 7.28-7.32 (m, 4H), 11.43 (s, IH). Example 56

2-(4-( 1 -(((4-wo-Propylbenzyl)oxy)imino)ethyl)phenoxy)- 1 -(5-methylfuran-2-yl) ethanone

'H NMR: CDC δ 1.25 (d, J= 6.8 Hz, 6H), 2.21 (s, 3H), 2.41 (s, 3H), 2.87-2.94 (m, 1H), 5.04 (s, 2H),5.17 (s, 2H), 6.19 (d, J= 3.6 Hz, 1H), 6.92 (d, J= 6.8 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.34 (d, J= 6.4 Hz, 3H), 7.59 (d, J= 6.8 Hz, 2H).

Example 57

l-(Furan-2-yl)-2-(4-(l-(((4-isopropylbenzyl)oxy)imino)eth yl)phenoxy)ethanone

'H NMR: CDCI3 δ 1.25 (d, J= 6.8 Hz, 6H), 2.22 (s, 3H), 2.91 (t, J= 6.8 Hz, 1H), 5.11 (s, 2H), 5.17 (s, 2H), 6.58 (d, J= 3.6 Hz, 1H), 6.93 (d, J= 6.8 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.34 (d, J- 8.0 Hz, 2H), 7.41 (s, 1H), 7.58-7.60 (m, 3H).

Example 58

l-(Furan-2-yl)-2-(4-(l-(((2,4,6-triisopropylbenzyl)oxy)im mo)ethyl)phenoxy)etha one

Ή NMR: CDCI3 δ 1.26 (d, J= 6.8 Hz, 18H), 2.15 (s, 3H), 2.86-2.93 (m, 1H), 3.38- 3.454 (m, 2H), 5.12 (s, 2H), 5.30 (s, 2H), 6.59 (d, J= 3.6 Hz, 1H), 6.94 (d, J= 6.8 Hz, 2H), 7.05 (s, 2H), 7.41 (d, J= 3.6 Hz, 1H), 7.61-7.65 (m, 3H).

Example 59

4-(2-(5-Methylfuran-2-yl)-2-oxoethoxy)benzaldehyde 0-(4-(trifIuoromethyl)benzyl) oxime

Ή NMR: CDC1 ₃ δ 2.42 (s, 3H), 5.06 (s, 2H), 5.22 (s, 2H), 6.20 (d, J= 3.6 Hz, 1H), 6.93 (d, J= 6.8 Hz, 2H), 7.33 (s, 1H), 7.50 (d, J= 8.8 Hz, 4H), 7.61 (d, J= 8.0 Hz, 2H), 8.09 (s, 1H).

Example 60 1 -(5-Methylfuran-2-yl)-2-(4-( 1 -(((2,4,6-triisopropylbenzyl)oxy)imino) ethyl)phenoxy) ethanone

1H NMR: CDC1 ₃ δ \26 (d, J= 7.2 Hz, 18H), 2.14 (s, 3H), 2.42 (s, 3H), 2.86 -2.93 (m, IH), 3.38-3.45 (m, 2H), 5.05 (s, 2H), 5.30 (s, 2H), 6.20 (d, J= 3.6 Hz, IH), 6.94 (d, J = 6.8 Hz, 2H), 7.05 (s, 2H), 7.34 (d, J= 3.2 Hz, IH), 7.62 (d, J= 6.8 Hz, 2H).

Example 61

2-(3-Hydroxy-4-(l-(((2,4,6-triisopropylbenzyl)oxy)imino)ethy l)phenoxy)-l-(5- methylfuran-2-yl) ethanone

'H NMR: OMSO-d ₆ δ 1.20 (d, J= 6.8 Hz, 18H), 2.18 (s, 3H), 2.39 (s, 3H), 2.84-2.86 (m, IH), 3.29-3.32 (m, 2H), 5.25 (s, 4H), 6.42 (d, J= 3.2 Hz, IH), 6.45 (s, IH), 6.49 (d, J= 8.8 Hz, IH), 7.04 (s, 2H), 7.38 (d, J= 8.8 Hz, IH), 7.56 (d, J= 3.6 Hz, IH), 11.05 (s, IH).

Example 62

2-(3-Hydroxy-4-(l-(((2,4,6-triisopropylbenzyl)oxy)imino)ethy l)phenoxy)-l-(5- methylfuran-2-yl) ethanone

1H NMR: CDC1 ₃ δ 2.25 (s, 3H), 5.12 (s, 2H), 5.25 (s, 2H), 6.59 (s, IH), 6.93 (d, J- 8.4 Hz, 2H), 7.40 (s, IH), 7.50 (d, J= 8.4 Hz, 2H), 7.56-7.64 (m, 5H).

Example 63 1 -(Furan-2-yl)-2-(3-hydroxy-4-( 1 -(((4- (trifluoromethyl)benzyl)oxy)imino)ethyl)phenoxy) ethanone

^{ H NMR: DMSO-< δ 2.29 (s, 3H), 5.29 (s, 2H), 5.31 (s, 2H), 6.42 (d, J= 2.8 Hz, 1H), 6.49 (d, J= 8.8 Hz, 1H), 6.77 (d, J= 3.6 Hz, IH), 7.37 (d, J= 8.8 Hz, IH), 7.61-7.63 (m, 3H), 7.75 (d, J= 8.0 Hz, 2H), 8.07 (s, IH), 10.78 (s, IH).

Example 64

l-(5-Methylfuran-2-yl)-2-(4-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino) ethyl) phenoxy) ethanone

Ή NMR: DMSO-<¾ <5 2.22 (s, 3H), 2.38 (s, 3H), 5.27 (s, 4H), 6.42 (d, J= 3.6 Hz, IH), 6.95 (d, J= 7.2 Hz, 2H), 7.54-7.61 (m, 5H), 7.73 (d, J= 8.4 Hz, 2H).

Example 65

2-(3 -Hydroxy-4-( 1 -(((4-(tr ifl uoromethy l)benzy l)oxy) i mino)ethyl)phenoxy)- 1 -(5 - methylfuran-2-yl)ethanone

Ή NMR: DMSO-ί/ _ί δ 2.28 (s, 3H), 2.38 (s, 3H), 5.23 (s, 2H), 5.29 (s, 2H), 6.40-6.42 (m, 2H), 6.48 (d, J= 8.8 Hz, IH), 7.37 (d, J= 8.8 Hz, IH), 7.54 (d, J= 3.6 Hz, IH), 7.62 (d, J= 8.0 Hz, 2H), 7.75 (d, J= 8.4 Hz, 2H), 10.78 (s, IH).

Example 66

1 -phenyl-2-((2-( 1 -(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)benzoruran-5- yl)oxy)ethanone 1H NMR: CDCI3 δ 2.28 (s, 3H), 5.30 (s, 2H), 5.36 (s, 2H), 6.91 (s, 1H), 7.00 (dd, J = 9.0 & 2.6 Hz, 1H), 7.04 (d, J= 2.4 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.48-7.52 (m, 4H), 7.60-7.64 (m, 3H), 8.00-8.03 (m, 2H).

Example 67

l-(5-methylfuran-2-yl)-2-((2-(t-(((4-(trifluoromethyl)ben zyl)oxy)imino) ethyl) benzofuran-5-yl)oxy)ethanone

Ή NMR: CDCI3 £ 2.28 (s, 3H), 2.42 (s, 3H), 5.06 (s, 2H), 5.36 (s, 2H), 6.19-6.20 (m, 1H), 7.91 (s, 1H), 7.00 (dd, J= 8.8 & 2.8 Hz, 1H), 7.05 (d, J= 2.4 Hz, 1H), 7.36 (d, J = 3.6 Hz, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.51 (d, J= 8.0 Hz, 2H), 7.61 (d, J= 2.4-Hz, 2H).

Example 68

l-cyclopropyl-2-((2-(l-(((4-(trifluoromethyl)benzyl)oxy)i mino)ethyl)benzofuran-5- yl)oxy)ethanone

Ή NMR: CDCI3 δ 0.95-0.99 (m, 2H), 1.13-1.17 (m, 2H), 2.29 (s, 3H), 2.31-2.35 (m, 1H), 4.70 (s, 2H), 5.36 (s, 2H), 6.93 (d, J = 0.8 Hz, 1H), 6.96-7.00 (m, 2H), 7.43-7.46 (m, 1H), 7.51 (d, J= 8.0 Hz, 2H), 7.61 (d, J= 8.0 Hz, 2H)

Example 69

2-(4-( 1 -(((4-( 1 , 1 -difluoroethyl)benzyl)oxy)imino)ethyl)phenoxy)-l -phenylethanone

Ή NMR: DMSO-fik δ l .9\ (t, J= 18.8 Hz, 3H), 2.20 (s, 3H), 5.21 (s, 2H), 5.62 (s, 2H), 6.96-7.00 (m, 2H), 7.48-7.50 (m, 2H), 7.54-7.59 (m, 6H), 7.67-7.72 (m, 1H), 8.00-8.03 (m, 2H).

Example 70

2-(2-(4-(l-(((4-(trifluoromethyl)benzyl)oxy)imino)ethyl)phen oxy)acetyl)-lH-indene- l,3(2H)-dione

Ή NMR: DMSO-i t _f δ 2.20 (s, 3H), 5.20 (s, 2H), 5.26 (s, 2H), 6.85-7.87 (d, J= 8.8 Hz, 2H), 7.50-7.7.62 (m, 8H), 7.72 (d, J= 8.0 Hz, 2H).

Biological Activity:

The compounds of the present invention lowered LDL cholesterol(LDL-c), and total cholesterol (TC). This was demonstrated by in vivo animal experiments.

LDL-C lowering activity- in high fat diet C57 mice

The in-vivo LDL-c lowering for test compound was tested in C57 mice which were kept on high fat diet for 4 weeks and the blood was collected by retro-orbital sinus puncture method under light ether anesthesia on day 0 (pretreatment). Animals are grouped based on LDL-c levels, after that 1 week treatment with vehicle or test compound orally at a dose of 30 mpk dose once a day was given. On completion of treatment on day 7 of the treatment the blood was collected for LDL-c and TC levels measurement. The percent change in LDL-c and TC in test compound group vs

Vehicle group was calculated.

1 30 mg -39±3 -24±4

2 30 mg -26±8 -32±2

63 30 mg -15±6 -23±6

23 30 mg -23±5 -21 ±4

15 30 mg -23±6 -25±3

64 30 mg -37±6 -13±4

In certain instances, it may be appropriate to administer at least one of the compounds described herein or a pharmaceutically acceptable salt, ester, or prodrug thereof in combination with another therapeutic agent. Several reasons can be attributed for using a combination therapy depending on the need of the patient. As an example, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. Several such instances are well known to a skilled person and the use of combination therapy may be envisaged for all such situations. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or. the patient may experience a synergistic benefit.

Specific, non-limiting examples of possible combination therapies include use of certain compounds disclosed herein with agents found in the following pharmaco- therapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present. Moreover, combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical. For the treatment of metabolic disorders, compounds disclosed herein may, if necessary, be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide- 1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-1 19 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta agonist, HMG- CoA reductase inhibitors, cholesterol-lowering drugs, renin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents.

For the treatment of metabolic disorders, compounds disclosed herein may be, if necessary, administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG-CoA reductase inhibitors (for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin,i rosuvastatin, pitavastatin and like), cholesterol-lowering drugs (for example, fibrates which include: fenofibrate, benzafibrate, clofibrate, gemfibrozil and like; cholesterol absorption inhibitors such as ezetimibe, eflucimibe etc.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Such different embodiments are also to be considered to be within the scope of the present invention.