THYROID RECEPTOR LIGANDS

FIELD OF THE INVENTION

The present invention relates to novel compounds of general formula (I) which are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta including their tautomeric forms, isomers including their stereo & regioisomers, their pharmaceutically acceptable salts, their polymorphic forms as well as novel intermediates involved in their synthesis. Further, the present invention relates to processes of preparing such compounds, their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them.

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(I) BACKGROUND TO THE INVENTION

Thyroid hormones (TH) are synthesized in the thyroid in response to thyroid stimulating hormone (TSH), which is secreted by the pituitary gland. Production of T4, and T3, by the thyroid gland is under negative feedback control. TSH, also known as thyrotropin, is responsible for normal thyroid gland function and thyroid hormone secretion. It is synthesized in the anterior pituitary gland, and its secretion is controlled by thyroid releasing hormone (TRH) that is synthesized in the hypothalamus.

The natural thyroid hormones (TH) T ₃ and T ₄ is an important endocrine signaling hormone. Thyroid hormones are iodinated tyrosine analogues excreted into the circulation primarily as T4. T4 is converted to T3 rapidly by deiodination in local tissues which is the most potent thyroid hormone. It plays important role in normal development, differentiation and maintenance of metabolic balance, control of cholesterol levels through interaction with thyroid hormone receptors (THR). Natural thyroid hormone, T ₃ exhibit its physiological effect by acting on a Thyroid Hormone - Receptor (THR), which belongs to the nuclear hormone receptor super family. There are two different isoforms of Thyroid Hormone Receptors, THR-α and THR-β. Further, these two isoforms are sub-classified as αi; α? and βi; β ₂ subtypes. THRβi is prevalent in liver (85%), while THR Ot ₁ is mainly present in cardiac tissue (Yen P. M.. Physiol. Rev; 2001; 81:1097-1142).

At normal levels, T ₃ maintains body weight, metabolic rate, body temperature, mood and regulate serum cholesterol. Hypothyroidism is associated with weight gain, high levels of low-density lipoproteins (LDL) cholesterol and depression.

Hyperthyroidism leads to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmia, heart failure, muscle weakness, bone loss and anxiety.

The natural thyroid hormone T ₃ does not show any selectivity in binding to both of the THR isoforms (THR αi and THR βi). Thus, administration of T ₃ lowers plasma cholesterol, low-density lipoprotein (LDL) and triglyceride levels in animal models and humans. However, T ₃ cannot be used therapeutically to treat hypercholesterolemia and obesity due to its cardiac side effects such as tachycardia and arrhythmia. However, knockout animal studies as well as results with some selective ligands suggest that such cardiac side effects can be attributed to the THR oti isoform. Thus, some effects of T ₃ may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation {Cheng S. Steroids; 2005; 70: 450-454).

Development of specific and selective thyroid hormone receptor ligands, particularly THR β agonist could lead to specific therapies for disorders such as obesity and hyperlipidemia, while avoiding the cardiovascular and other toxicities of native thyroid hormones. Thus, compounds mimicking only the beneficial effects of the thyroid hormone and lacking their cardiac side effects (tachycardia and arrhythmia) potentially could be used to treat a number of conditions such as obesity and dyslipidemia. In this regard, THR agonists that interact selectively with the β isoform of the THR offer an especially attractive method for avoiding cardiotoxicity (J D. Baxter. Trends Endocrinol. Metab. 2004;15 : 154-157). Selective THR β agonist exhibit modest cardiac sparing in rodents and primates and lower lipids but it may induce the THR β mediated suppression of the THA. Two strategies have been attempted for the development of Thyromimetics.

One is by making isoform selective compounds (Johan Malm, J. Med. Chem. 2003, 46, 1580-1588) and another is by making Liver selective Thyromimetics (Mark D. Erion, PNAS 2007 15490-15495). Liver selective compounds are expected not to suppress the thyroid hormone axis (THA). Thus thyromimetic which has isoform selectivity incorporated with liver selectivity can be expected to be devoid of cardiac toxicity and will not suppress THA.

Various compounds have been disclosed as possible agonists of THR β including those which claim to be liver selective. Some of the more relevant ones for the present invention includes WO 0039077, WO 2004067482, US 6,344,481, US

6787652, US20070173548, WO2006128058, WO 20080221210 and WO 2009089093 which are incorporated herein as reference.

However, none of these compounds have been commercially developed and looking at the beneficial potential and medical need for such compounds, specifically compounds having better liver selectivity while retaining its therapeutic efficacy, there remains a need for developing further compounds with better therapeutic and/or safety profile. Herein, we disclose novel compounds which shows activity as THR β agonists, some of which also have better liver selectivity. SUMMARY OF THE INVENTION

The present invention describes novel compounds that are thyroid receptor (TR) ligands and are preferably selective for the thyroid hormone receptor beta 1 , which are useful for the treatment of a number of conditions such as obesity and dyslipidemia. The novel compounds are defined by the general formula (I) as given below.

(I)

The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of selective thyroid hormone receptor gene expression. The compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of obesity and dyslipidemia. PREFERRED EMBODIMENTS

The main objective of the present invention is to provide novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures suitable for the treatment of obesity and dyslipidemia.

In an embodiment is provided a process for the preparation of novel compounds of general formula (I), their tautomeric forms, isomers including their stereo & regioisomers, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphic forms and pharmaceutical compositions containing them.

In another embodiment is provided pharmaceutical compositions containing compounds of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.

In a further another embodiment is provided the use of the novel compounds of the present invention for the treatment of obesity and dyslipidemia, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals. DETAILED DESCRIPTION:

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

(I),

(I) wherein R = OR ₁ , NHR, wherein R ₁ may be selected from H, optionally substituted groups selected from linear or branched (Ci-C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, acyl, aryl, aralkyl groups; R ₂ represents hydrogen, hydroxyl, halo, optionally substituted groups selected from (C _r C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, aryl, heteroaryl, acyl, oxo, aryloxy, aralkyl, aralkoxy, carboxylic acid and its derivatives such as esters and amides, sulfenyl derivatives, sulfonyl derivatives, sulfonic acid and its derivatives; or the groups -CONR ₅ R ₆ , -SO ₂ NR ₅ R ₆ , wherein R ₅ & R ₆ may be same or different and are independently selected from H, optionally substituted groups selected from linear or branched (Ci-C ₆ )alkyL (C ₃ -C ₇ )cycloalkyl, bicycloalkyl, aryl or the groups R ₅ & R ₆ together with the nitrogen atom to which they are attached, form a five to eight membered cyclic ring which may further optionally contain one or more heteroatoms selected from N, S, O;

R ₃ , R ₄ may be independently selected from H, halogen, (Ci-C ₆ )alkyl groups; X is selected from O, -CH ₂ -, CO;

R ₇ may be selected from H, optionally substituted groups selected from linear or branched (C]-C ₆ )alkyl, (C ₃ -C ₇ )cycloalkyl, acyl, aryl, aralkyl, heteroaryl groups and 'n' represents integers from 0-2;

R ₈ may be selected from H, optionally substituted groups selected from linear or branched (Ci-C ₆ )alkyl groups;

In a preferred embodiment,

R ₂ is selected linear or branched (Ci-C ₆ )alkyl, phenyl, benzoyl benzyl, carboxamide and sulfonamide groups, each of these groups being further substituted with suitable substituents and R ₈ represents an (Ci-C ₆ )alkyl group.

In a still preferred embodiment, the aryl group is selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl groups; the heteroaryl group is 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 group;

The substituents on alkyl, aryl, aralkyl, aryloxy, aralkoxy, heteroaryl or cycloalkyl groups as defined above may be selected from hydroxyl, halo, cyano, optionally substituted groups selected from (Ci-C ₆ )alkyl, haloalkyl, alkoxy, oxo, aryl, aryloxy, aralkyl, acyl, alkylthio, thioalkyl groups, with the further option that when any of these groups are further substituted, the substituents on these substitutes may be selected from any of the groups described above;

In a still preferred embodiment, the substitutions on R ₂ when present, is selected from halogen, hydroxy, amino, alkyl, haloalkyl, alkoxy groups. In a 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, n-propyl, wo-propyl, w-butyl, sec-butyl, tert~buty\, amyl, t-amyl, «-pentyl, n- hexyl, iso-hexyl and the like;

- the "cycloalkyl" or "alicyclic" group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to seven carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; - 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, n- propoxy, iso-pτopoxy, rø-butoxy, t-butoxy, /sø-butoxy, pentyloxy, hexyloxy, and the like; - the "haloalkyl" group is selected from an alkyl radical, as defined above, suitably substituted with one or more halogens; such as perhaloalkyl, more preferably, perfluoro(Ci-C ₆ )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono or polyhalo substituted methyl, ethyl, propyl, butyl, pentyl or hexyl groups; - 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 "aralkyl" group used above either alone or in combination represents an alkyl group as defined above attached to an aryl group;

"arylkoxy" group used above either alone or in combination represents an alkoxy group as defined above attached to an aryl groαp;

- "aryloxy" group used above either alone or in combination represents an oxygen atom linked to an aryl group;

- the "heteroaryl" or "heteroaromatic" group used either alone or in combination with other radicals, is 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 "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, /w-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, which may be substituted; the "oxo" or "carbonyl" group used either alone (-C=O-) or in combination with other radicals such as alkyl described above, for e.g. "alkylcarbonyl", denotes a carbonyl radical (-C=O-) substituted with an alkyl radical 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 phenoxy carbonyl, 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=O-), wherein the amino group is mono- or di- substituted or unsubstituted, more preferably the groups are selected from methylamide, dimethylamide, ethylamide, diethylamide, 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, butylthio, pentylthio and the like or cyclic alkylthio selected from cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, which may be optionally substituted; - 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 "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 -SO ₂ -, or R _x SO 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, propyl sulfonyl and the like, "arylsulfonyl" wherein an aryl radical, as defined above, is attached to a sulfonyl radical, such as phenylsulfonyl and the like.

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

Preferred compounds according to the present invention include but not limited to: 2-(((3,5-dichloro-4-(4-hydroxy-3-isopropyl phenoxy) benzylidene) amino) oxy) acetic acid;

2-(((4-(3-(sec-butyl)-4-hydroxyphenoxy)-3,5-dichlorobenzy lidene)amino)oxy)acetic acid; 2-(((3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzylidene )amino)oxy)acetic acid;

2-(((3,5-dichloro-4-((6-hydroxy-[ 1 , 1 '-biphenyl]-3- yl)oxy)benzylidene)amino)oxy)acetic acid; 2-(((4-(3-benzyl-4-hydroxyphenoxy)-3 ,5-dichlorobenzylidene)amino)oxy)acetic acid; 2-(((3,5-dibromo-4-(3-(sec-butyl)-4-hydroxyphenoxy)benzylide ne)amino)oxy)acetic acid;

2-(((3,5-dibromo-4-((6-hydroxy-[l,r-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) acetic acid; 2-(((3,5-dichloro-4-(4-hydroxy-3- isopropylphenoxy)benzylidene)amino)oxy) propanoic acid;

2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene )amino)oxy)acetic acid;

2-(((3,5-dibromo-4-(4-hydroxy-3- isopropylphenoxy)benzylidene)amino)oxy) propanoic acid; 2-(((3,5-dibromo-4-((6-hydroxy-[l,r-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) propanoic acid;

2-(((3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzylid ene)amino)oxy)-2- methylpropanoic acid;

2-(((3 ,5-dibromo-4-(4-hydroxy-3- isopropylphenoxy)benzylidene)amino)oxy) butanoic acid;

2-(((3,5-dibromo-4-(3-(sec-butyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)propanoic acid;

2-(((3,5-dibromo-4-(3-(sec-butyl)-4-hydroxyphenoxy)benzyl idene)amino)oxy)-2- methyl prop anoic acid; 2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene)am ino)oxy)propanoic acid;

2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene )amino)oxy)butanoic acid;

2-(((3,5-dibromc-4-(3-(sec-butyl)-4-hydroxyphenoxy)benzyl idene)amino)oxy)-2- phenylacetic acid;

2-(((3,5-dibromo-4-(3-(sec-butyl)-4-hydroxyphenoxy)benzyl idene)amino)oxy)butanoic acid;

2-(((3,5-dibromo-4-((6-hydroxy-[l,r-biphenyl]-3-yl)oxy)be nzylidene)amino)oxy)-2- methyl propanoic acid;

2-(((3,5-dibromo-4-((6-hydroxy-[Ll'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy)butanoic acid;

2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene )amino)oxy)-2-methyl propanoic acid;

2-(((4-(3-(sec-butyl)-4-hydroxyphenoxy)-3,5- dichlorobenzylidene)amino)oxy)propanoic acid;

2-(((3,5-dibromo-4-(3-(tert-butyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)propanoic acid ; 2-(((3,5-dibromo-4-(3-ethyl-4-hydroxyphenoxy)benzylidene)ami no)oxy)propanoic acid;

2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy) benzylidene) amino) oxy) propan oic acid;

2-(((3,5-dibromo-4-(3-((4-chlorophenyl)(hydroxy)methyl)-4 -hydroxy phenoxy) benzylidene) amino)oxy)propanoic acid;

2-(((3 ,5 -dibromo-4-(3 -(4-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)acetic acid;

2-(((3,5-dibromo-4-(3-((4-chlorophenyl)(hydroxy)methyl)-4 - hydroxyphenoxy)benzylidene) amino)oxy)acetic acid; 2-(((3,5-dibromo-4-(3-(3-chlorobenzoyl)-4-hydroxy phenoxy) benzylidene) amino) oxy) propanoic acid;

2-(((3,5-dibromo-4-(3-(4-bromobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)acetic acid;

2-(((3 ,5 -dibromo-4-(3 -((4-bromophenyl)(hydroxy)methy l)-4- hydroxyphenoxy)benzylidene) amino)oxy)acetic acid;

2-(((3,5-dibromo-4-(3-(3-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)acetic acid;

2-(((3,5-dibromo-4-(3-((3-chlorophenyl)(hydroxy)methyl)-4 - hydroxyphenoxy)benzylidene) amino)oxy)propanoic acid; 2-(((3,5-dibromo-4-(3-((3-chlorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)benzylidene) amir.o)oxy)acetic acid;

2-(((3,5-dibromo-4-(4-hydroxy-3-(piperidin-l-ylsulfonyl) phenoxy) benzylidene) amino) oxy) propanoic acid; 2-(((3,5-dibromo-4-(4-hydroxy-3-(N- isopropylsulfamoyl)phenoxy)benzylidene)arnino)oxy) pro panoic acid;

2-(((3,5-dibromo-4-(3-(N,N-diethylsulfamoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) pro panoic acid; 2-(((3,5-dibromo-4-(3-(N-cyclohexylsulfamoyl)-4-hydroxypheno xy) benzylidene)amino)oxy) propanoic acid;

2-(((4-(3-(N-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)sulfam oyl)-4-hydroxyphenoxy)-

3,5-dibromobenzylidene)amino)oxy)propanoic acid;

2-(((3,5-dibromo-4-(4-hydroxy-3-(pyrrolidin-l- ylsulfonyl)phenoxy)benzylidene)amino)oxy) acetic acid;

Ethyl 2-(((3,5-dichloro-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) acetate;

Ethyl 2-(((4-(3-(sec-butyl)-4-methoxyphenoxy)-3,5- dichlorobenzylidene)amino)oxy) acetate; Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) acetate;

Ethyl 2-(((3,5-dichloro-4-((6-methoxy-[l,l'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) acetate;

Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3,5- dichlorobenzylidene)amino)oxy)acetate;

Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4- methoxyphenoxy)benzylidene)amino)oxy) acetate;

Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[l, l'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) acetate; Ethyl 2-(((3,5-dichloro-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) propanoate;

Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3,5- dibromobenzylidene)amino)oxy)acetate;

Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) propanoate;

Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[ 1 ,1 '-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) propanoate;

I l Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4-methoxyphenoxy)benzylidene )amino)oxy)-2- methyl propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4- methoxyphenoxy)benzylidene) amino)oxy) butanoate; Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4- methoxyphenoxy) benzylidene) amino) oxy) propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4-methoxyphenoxy)benzylide ne)amino)oxy)-

2-methylpropanoate;

Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3,5- dibromobenzylidene)amino)oxy) propanoate;

Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3 ,5- dibromobenzylidene)amino)oxy) butanoate;

Ethyl 2-(((3 ,5 -dibromo-4-(3 -(sec-butyl)-4-methoxyphenoxy)benzylidene)amino)oxy)-

2-phenyl acetate; Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4-ethoxy phenoxy) benzylidene) amino) oxy) butanoate;

Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[l,l'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy)-2- methylpropanoate; Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[l,l'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) butanoate;

Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3,5-dibromobenzy!idene)am ino)oxy)-2- methyl propanoate;

Ethyl 2-(((4-(3-(sec-butyl)-4-methoxyphenoxy)-3,5- dichlorobenzylidene)amino)oxy)propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-(tert-butyl)-4- methoxyphenoxy)benzylidene)amino)oxy)propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-ethyl-4- methoxyphenoxy)benzylidene)amino)oxy)propanoate; Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- methoxyphenoxy)benzylidene)amino)oxy) propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) propanoate; Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) acetate;

Ethyl 2-(((3,5-dibromo-4-(3-(3-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-(4-bromobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) acetate;

Ethyl 2-(((3,5-dibromo-4-(3-(3-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) acetate; Ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(piperidin-l-ylsulfonyl) phenoxy)benzylidene) amino) oxy)propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-(N-isopropylsulfamoyl)-4- methoxyphenoxy)benzylidene)amino) oxy)propanoate ;

Ethyl 2-(((3,5-dibromo-4-(3-(N,N-diethylsulfamoyl)-4- methoxyphenoxy)benzylidene)amino) oxy)propanoate;

Ethyl 2-(((3,5-dibromo-4-(3-(N-cyclohexylsulfamoyl)-4- methoxyphenoxy)benzylidene)amino) oxy)propanoate;

Ethyl 2-(((4-(3-(N-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)sulfamoyl )-4- methoxyphenoxy)-3,5-dibromobenzylidene)amino)oxy)propanoate; Ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(pyrrolidin-l- ylsulfonyl)phenoxy)benzylidene)amino) oxy)acetate;

Ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(pyrrolidin-l- ylsulfonyl)phenoxy)benzylidene)amino) oxy)propanoate;

The compounds of this invention may be prepared using the reactions and techniques described in the following section including the schemes 1-4. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. 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 appreciated that some routine alterations/modifications including requirement of one or more additional steps which may be required for obtaining the compounds of the present invention in preferred yields but are considered to be within the scope of a person skilled in the art, are to be considered to be within the scope of the present invention.

Scheme: 1 When R ₂ = H, Alkyl, Aryl

Reacting protected phenol of formula 2, wherein PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis ", John Wiley & Sons, Inc, 1999, 3 ^rd Ed., 201-245 along with references therein), & R ₂ is as defined earlier, with aldehyde compound of formula 3 wherein R ₃ and R ₄ are as defined earlier and ^ς Z' is halogen, to give coupled product 4. The reaction may be carried out in solvents such as DMF, DMSO, THF, toluene and the like or their suitable mixtures, in the presence of a base such as K ₂ CO ₃ , NaH, KOH and the like or their suitable mixtures. Reaction of coupled product 4 with hydroxyl amine hydrochloride afforded oxime compound of formula 5. Alkylation of the oxime compound of formula 5 with bromo alkyl esters (where R ₇ & R ₈ are as defined earlier) using suitable base such as K ₂ CO ₃ , Cs ₂ CO ₃ , KOH, NaH and the like afforded ester compound of formula 6. Deprotection and hydrolysis of compound 6 using appropriate reagents will lead to compound of formula (I). Scheme: 2

When R ₂ = ArCO,

Reacting protected phenol of formula 2, wherein 'PG' represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis ", John Wiley & Sons, Inc, 1999, 3 ^rd Ed., 201-245 along with references therein), & R ₂ is as defined earlier, with aldehyde compound of formula 3 wherein R ₃ and R ₄ are as defined earlier and 'Z' is halogen to give coupled product 4. The reaction may be carried out in solvents such as DMF, DMSO, THF, toluene and the like or their suitable mixtures, in the presence of a base such as K ₂ CO ₃ , NaH, KOH and the like or their suitable mixtures. Reaction of coupled product 4 with hydroxyl amine hydrochloride afforded oxime compound of formula 5. Alkylation of the oxime compound of formula 5 with bromo alkyl esters (where R ₇ & R ₈ are as defined earlier) using suitable base such as K ₂ CO ₃ , Cs ₂ CO ₃ , KOH, NaH afforded ester compound 6. Compound of formula 6 was reacted with suitable aromatic acids or suitable aromatic acid chlorides and appropriate acylating agents to obtain compound of Formula 7. Deprotection and hydrolysis of compound of formula 7, using suitable reagents & techniques as is known in the art, gives compound of formula (I) Scheme: 3

When R ₂ = ArCHOH

Starting from compound of formula 7 (Scheme 2) deprotecion and then reduction of carbonyl group using suitable reducing agents like NaBH ₄ , LAH and the like in suitable solvents like THF, Diethyl ether etc. to afford compound of formula 9. Finally hydrolysis of compound of formula 9, using suitable reagents & techniques as is known in the art, gives compound of formula (I)

Scheme: 4

When R ₂ = sulfonamide groups

Reacting protected phenol of formula 2, wherein PG represents suitable protecting groups known to persons skilled in the art (for e.g. those described in T. W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis ", John Wiley & Sons, Jnc, 1999, 3 ^rd Ed., 201-245 along with references therein), with aldehyde compound of formula 3 wherein R ₃ and R ₄ are as defined earlier and Z is halogen to give coupled product of formula 4. The reaction may be carried out in solvents such as DMF, DMSO, THF, toluene and the like or their suitable mixtures, in the presence of a base such as K ₂ CO ₃ , NaH, KOH and the like or their suitable mixtures. Reaction of coupled product 4 with hydroxyl amine hydrochloride afforded oxime compound of formula 5. Alkylation of the oxime compound of formula 5 with bromo alkyl esters (where R ₇ & R ₈ are as defined earlier) using suitable base such as K ₂ CO ₃ , Cs ₂ CO ₃ , KOH, NaH and the like afforded ester compound 6. Compound of formula 6 was reacted with chlorosulfonic acid at suitable temp, to give chlorosulfonated product of formula 7_which was then reacted with suitable aliphatic or aromatic amine R ₅ R ₆ NH, (where R ₅ & R ₆ are as defined earlier) to afford compound of formula 8, on deprotection and hydrolysis of compound 8 gives compound of formula (1}

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.

IH NMR spectral data given in the examples (vide infra) are recorded using either a 300 MHz spectrometer (Bruker A VANCE-300) or a 400 MHz spectrometer (Bruker Avance2) and reported in δ scale. Until and otherwise mentioned the solvent used for NMR is CDCh using tetramethyl silane as the internal standard. EXAMPLE 1

Preparation of 2-(((3,5-dichloro-4-(4-hydroxy-3-isopropyl phenoxy) benzylidene) amino) oxy) acetic acid

Step 1 : 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde

To a solution 3-isopropyl-4-methoxyphenol (0.37 g, 2.22 mmol) in DMF (3.7 mL) was added K ₂ CO ₃ (0.50 g, 3.64 mmol) and 3,5-dichloro-4-iodobenzaldehyde (0.61 g, 2.02 mmol). The reaction was stirred at 130-135 ⁰ C for 5 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethylacetate 90:10) to afford pure 4-(3-isopropyl-4-methoxyphenoxy)-3,5- dichlorobenzaldehyde. (0.2g, 30 % yield)

¹ H NMRr(CDCl ₃ , 400MHz):- 1.18(6H, d, J=6.8Hz), 3.27-3.30(1H, m), 3.79(3H, s), 6.44-6.47 (IH, dd, J=3.2&9.2Hz), 6.7O(1H, d, J=8.8Hz), 6.85(1 H, d, J=3.2Hz), 7.91(2H, s).

Step 2 : 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde oxime

A mixture of 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde (0.2 g, 0.589 mmol) in EtOH (0.4 mL) and H ₂ O (0.6 mL) and Hydroxyl amine hydrochloride (0.04 g, 0.589 mmol) was heated at 75 ⁰ C for 3 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 90:10) to afford pure 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde oxime (0.19 g, 91 %). 1H NMR: (CDCl ₃ , 400MHz):- 1.18(6H, d, J=7.2Hz), 3.24-3.31 (IH, m), 3.78(3H, s), 6.44-6.47 (IH, dd, J=2.8&8.8Hz), 6.7O(1H, d, J=8.8Hz), 6.84(1H, d, J=2.8Hz), 7.61(2H, s), 8.05(1H, s).

Step 3 : Ethyl 2-(((3,5-dichloro-4-(3-isopropyl-4-methoxy phenoxy) benzylidene) amino) oxy) acetate To a solution of 4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichlorobenzaldehyde oxime (0.19 g, 0.536 mmol) in DMF (1.5 mL) was added Cs ₂ CO ₃ (0.26 g, 0.805 mmol). To that added Ethyl bromo acetate (0.1 g, 0.59 mmol) and the reaction mixture was stirred at 20-25 ⁰ C for 3 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethylacetate 90:10) to afford pure Ethyl 2-(((3,5-dichloro-4-(3-isopropyl-4-methoxy phenoxy) benzylidene) amino) oxy) acetate as an oil (0.19 g, 80 %). 'H NMR:(CDC1 ₃ , 400MHZ):- 1.18(6H, d, J=6.8 Hz), 1.27-1.29(3H, m),3.24-3.31(lH, m), 3.78 (3 H, s), 4.24-4.29(2H, m), 4.72(2H, s), 6.3-6.46(1H, dd, J=3.2&8.8Hz), 6.7O(1H, d, J=9.2Hz), 6.83 (IH, d, J=3.2Hz), 7.61(2H, s), 8.12 (IH, s). Step 4 : 2-(((3,5-dichloro-4-(4-hydroxy-3-isopropyl phenoxy) benzylidene) amino) oxy) acetic acid

To a solution of Ethyl 2-(4-(3-isopropyl-4-methoxyphenoxy)-3,5-dichloro benzylidene aminooxy) acetate (0.19 g, 0.431 mmol) in dichloromethane ( 1.9 mL) was cooled to -60 to -70 ⁰ C under N ₂ atomsphere. To that IM BBr ₃ solution in dichloromethane (1.72 mL) was added dropwise. The reaction mixture was allowed to warm up to 20-25 ⁰ C over 5 h. then diluted with more CH ₂ Cl ₂ (25 mL) and quenched with H ₂ O. After stirring at 20-25 ⁰ C for 30 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (chloroform : methanol) gradient elution from 95:5 to 90:10 to give pure 2-(((3,5- dichloro-4-(4-hydroxy-3-isopropyl phenoxy) benzylidene) amino) oxy) acetic acid

(0.065 g, 38 %).

¹ H NMR:(DMSO-D6, 400MHz):- 1.10(6H, d, J=6.8 Hz), 3.16-3.17(1H, m), 4.65(2H, s), 6.3O-6.33(1H, dd, J=3.2&8.8Hz), 6.64-6.69(2H, m), 7.80(2H, s), 8.34(1H, s).

Using appropriate starting materials and suitable modifications of one or more of the process steps described above, either alone or in suitable combination, including suitable addition and/or deletion of steps as may be necessary, & which are well within the scope of a person skilled in the art, the following compounds were prepared in an analogous manner

EXAMPLE 2 2-(((4-(3-(sec-butyl)-4-hydroxyphenoxy)-3,5-dichlorobenzylid ene)amino)oxy)acetic acid

¹ H NMR:(CDC1 ₃ , 400MHz):- 0.85(3H, t, J=7.4Hz), 1.19(3H, d, J=6.8Hz), 1.51-

1.63(2H, m), 2. 89-2.95(1H, m), 4.79(2H, s), 6.4O-6.43(1H, dd, J=2.8&8.8Hz),

6.64(1H, d, J=8.8Hz), 6.72(1H, d, J=2.8Hz), 7.60(2H, s), 8.11(1H, s). % Yield: 61% EXAMPLE 3

2-(((3,5-dibromo-4-(4-hydroxy-3-isopropylphenoxy)benzylid ene)amino)oxy)acetic acid

¹ H NMR:(CDC1 ₃ , 400MHz):- 1.22(6H, d, J=6.8Hz), 3.13-3.20(1H, m), 4.79(2H, s),

6.36-6.39 (IH, dd, J=3.2&8.8Hz), 6.63(1H, d, J=8.8Hz), 6.79(1H, d, J=2.8Hz), 7.82(2H, s), 8.12(1H, s).

% Yield: 66%

EXAMPLE 4

2-(((3,5-dichloro-4-((6-hydroxy-[l,l'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy)acetic acid 1H NMR:(CD ₃ OD, 400MHz):- 4.57(2H, s), 6.58-6.61(1H, dd, J=3.2&8.8Hz), 6.7O(1H, d, J=3.2 Hz), 6.81(1H, d, J=8.8Hz), 7.28(1H, d, J=7.6Hz), 7.36(2H, t, J=7.6Hz),

7.49(2H, d, J= 7.2Hz), 7.73(2H, s), 8.16(1H, s). % Yield: 13%

EXAMPLE 5 2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dichlorobenzylidene)a mino)oxy)acetic acid

¹ H NMRi(CD ₃ OD, 400MHZ):- 3.87(2H, S), 4.71 (2H, S), 6.42-6.43(1H, m), 6.46(1H ₅ cL

J=2.8Hz), 6.69(1H, d, J=8.4Hz), 7.11-7.16(3H, m), 7.19-7.23(2H, m), 7.68(2H,s),

8.18(lH, s). % Yield: 55%

EXAMPLE 6

2-(((3,5-dibromo-4-(3-(sec-butyl)-4-hydroxyphenoxy)benzyl idene)amino)oxy)acetic acid

¹ H NMR^CDCl ₃ , 400MHz):- 0.86(3H, t, J=7.2Hz), 1.17(3H, d, J=6.8Hz), 1.48- 1.62(2H, m), 2. 97-3.02(1H, m), 4.68(2H, s), 6.36-6.39(1H, dd, J=2.4&8.4Hz),

6.64(1H, d, J=8.4Hz), 6.68(1H, d, J=2.8Hz), 7.80(2H, s), 8.10(1H, s). % Yield: 29%

EXAMPLE 7

2-(((3,5-dibromo-4-((6-hydroxy-[l .1 '-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) acetic acid 1H NMR: (CDCl ₃ , 400MHz):- 4.79(2H, s), 6.69-6.75(2H, m), 6.91(1H, d, J=8.8Hz),

7.45-7.48 (5H, m), 7.82(2H, s), 8.11(1H, s). % Yield: 23%

EXAMPLE 8

2-(((3,5-dichloro-4-(4-hydroxy-3- isopropylphenoxy)benzylidene)amino)oxy) propanoic acid 1H NMR:(CDC1 ₃ , 400MHz):- 1.22(6H, d, J=7.2Hz), 1.60(3H, d, J=6.8Hz), 3.15-

3.18(1H, m), 4.88-4.90(1H, m), 6.37-6.40(1H, dd, J=2.8&8.8Hz), 6.62(1H, d,

J=8.8Hz), 6.81(1H, d, J=3.2Hz), 7.60(2H, s), 8.09(1H, s). % Yield: 59%

EXAMPLE 9

2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene )amino)oxy)acetic acid ¹ H NMR:(CDC1 ₃ , 400MHz):- 3.93(2H, s), 4.77(2H, s), 6.66(1H, d, J=3.2Hz), 6.69-

6.71(2H, m), 7.18-7.30(5H, m), 7.79(2H, s), 8.10 (IH, s). % Yield: 58%

EXAMPLE 10

2-(((3 ,5 -dibromo-4-(4 -hy droxy-3 - isopropy lphenoxy)benzylidene)amino)oxy) propanoic acid 1H NMR:(CDC1 ₃ , 400MHz):- 1.22(6H, d, J-7.2Hz), 1.60(3H, d, J=6.8Hz), 3.08-

3.2O(1H, m), 4.86-4.91(1H, q, J=7.2 Hz), 6.34-6.37(1H, dd, J=3.2&8.8Hz), 6.62(1H, d,

J=8.8Hz), 6.8O(1H, d, J=3.2Hz), 7.80(2H, s), 8.07(1H, s). % Yield: 43%

EXAMPLE 11 2-(((3,5-dibromo-4-((6-hydroxy-[l , 1 '-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) propanoic acid

¹ U NMRr(CDCl ₃ , 400MHz):- 1.59(3H, d, J=7.2Hz), 4.85-4.91(1H, q, J=6.8&7.2Hz),

6.69(1H, d, J=2.8Hz), 6.72-6.75(1H, d, J=3.2&8.8Hz), 6.91(1H, d, J=8.4Hz), 7.37- 7.52(5H, m), 7.80(2H, s), 8.01(1H, s). % Yield: 90%

EXAMPLE 12

2-(((3 ,5 -dibromo-4-(4-hydroxy-3 -isopropy lphenoxy)benzy lidene)amino)oxy)-2- methylpropanoic acid

¹ H NMR^CDCl ₃ , 400MHZ):- 1.22(6H, d, J=7.2Hz), 1.63(6H, s), 3.13-3.20(1H, m), 6.36-6.38 (1 H, dd, J=3.2&8.8Hz), 6.62(1H, d, J=8.4Hz), 6.80(1H, d, J=3.2Hz),

7.80(2H, s), 8.05(1H, s).

% Yield: 96%

EXAMPLE 13

2-(((3,5-dibromo-4-(4-hydroxy-3- isopropylphenoxy)benzylidene)amino)oxy) butanoic acid

¹ H NMR:(DMSO-D6, 400MHz):- 0.95(3H, t, J=6.4Hz), 1.10(6H, d, J=7.2Hz), 1.77-

1.86(2H, m), 3.10-3.17(1H, m), 4.56-4.60(1H, m), 6.26-6.29(1H, dd, J=3.2 &8.8Hz),

6.64-6.66(2H, m), 7.95 (2H, s), 8.33(1 H, s). % Yield: 84%

EXAMPLE 14 2-(((3,5-dibromo-4-(3-(sec-butyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)propanoic acid

¹ H NMR^CDCl ₃ , 400MHz):- 0.85(3H, t, J=7.2Hz), 1.26(3H, d, J=7.2Hz), 1.41-

1.66(5H, m), 2. 88-2.95(1H, m), 4.85-4.91(1H, q, J=7.2Hz), 6.38-6.41(1H, dd,

J=2.8Hz&8.8Hz), 6.64(1H, d, J= 8.8Hz), 6.71(1H, d, J=2.8Hz), 7.80(2H, s), 8.08(1H, s). % Yield: 10%

EXAMPLE 15

2-(((3,5-dibromo-4-(3-(sec-bυtyl)-4-hydroxyphenoxy)benzy lidene)amino)oxy)-2- methyl propanoic acid

¹ H NMR:(DMSO-D ₆ , 400MHz):- 0.76QH, t, J=7.2Hz), 1.06(3H, d, J=6.8Hz), 1.41- 1.54(8H, m), 2.9O-2.96(1H, m), 6.31-6.33(1H, dd, J=2.8&8.8Hz), 6.58(1H, d,

J=2.4Hz), 6.66(1 H, d, J=8.8H z), 7.93(2H, s), 8.25(1 H, s). % Yield: 87%

EXAMPLE 16 2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene)am ino)oxy)propanoic acid

¹ H NMRr(DMSO-D ₆ , 400MHz):- 1.41(3H, d, J=6.8Hz), 3.80(2H, s), 4.72(1H, q,

J=6.8Hz), 6.37 -6.4O(1H, dd, J=2.8&5.6Hz), 6.57(1H, d, J=3.2Hz), 6.69(1H, d, J= 8.8Hz), 7.11-7.25(5H, m), 7. 93(2H, s), 8.30(1 H, s). % Yield: 54%

EXAMPLE 17

2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene )amino)oxy)butanoic acid

'H NMR:( CDCl ₃ , 400MHz):- 0.95(3H, m), 1.05-1.20(2H, m), 3.93(2H, s), 4.73(1H, m), 6.49-6.51(1H, m), 6.69(2H, m), 7.14-7.34(5H, m), 7.78(2H; S), 8.10(IH, S)

% Yield: 58%

EXAMPLE 18

2-(((3,5-dibromo-4-(3-(sec-butyl)-4-hydroxyphenoxy)benzyl idene)amino)oxy)-2- phenylacetic acid 1U NMR:(DMSO-D ₆ , 400MHz):- 0.76(3H, t, J=7.2Hz), 1.06(3H, d, J=6.8Hz), 1.41-

1.52(2H, m), 2.9O-2.96(1H, m), 5.69(1H, s), 6.31-6.34(1H, dd, J=2.8&8.8Hz),

6.57(1H ₅ d, J=2.8Hz), 6.66 (IH, d, J=8.8Hz), 7.40-7.45(3H, m), 7.47-7.5(2H, m),

7.96(2H ₅ s), 8.40(1 H, s). % Yield: 53%

EXAMPLE 19 2-(((3,5-dibromo-4-(3-(sec-butyl)-4-hydroxyphenoxy)benzylide ne)amino)oxy)butanoic acid

¹ H NMR:(CD ₃ OD, 400MHz):- O.81(3H, t, J=7.4Hz), 1.06(3H, t, J=7.6Hz), 1.12(3H, d,

J=7.2Hz), 1.50-1.56(2H, m), 1.89-1.95(2H, m), 2.99-3.03(1H, m), 4.67(1H, t,

J=6.2Hz), 6.35-6.38(1H, dd, J=2.8&8.4Hz), 6.56(1H, d, J=2.8Hz), 6.65(1H, d, J=8.4Hz), 7.91(2H, s), 8.18(lH, s).

% Yield: 69%

EXAMPLE 20

2-(((3,5-dibromo-4-((6-hydroxy-[l,r-biphenyl]-3-yl)oxy)be nzylidene)amino)oxy)-2- methyl propanoic acid 1H NMR:(CD ₃ OD, 400MHz):- 1.56(6H, s), 6.57-6.60(1H, dd, J=3.2&8.8Hz), 6.67(1H, d, J=3.2 Hz), 6.81(1H ₅ d, J=9.2Hz), 7.27(1H ₅ 1, J=7.2Hz), 7.36(2H ₅ 1, J=7.6Hz) ₅

7.49(2H, d, J=7.2Hz), 7. 91(2H ₅ s), 8.1 1(1H, s). % Yield: 49%

EXAMPLE 21 2-(((3,5-dibromo-4-((6-hydroxy-[ 1 , 1 '-biphenyl]-3- yl)oxy)benzylidene)amino)oxy)butanoic acid

¹ HNMRr(DMSO-D ₆ , 400MHz):- 0.95(3H, t, J=7.6Hz), 1.77-1.86(2H, m), 4.57(1H, t,

J=6Hz), 6.59-6.62(1H, dd, J=3.2&8.8Hz), 6.68(1H, d, J= 3.2Hz), 6.87(1H, d, J=8.8Hz), 7.27(1H, t, J= 7. 2Hz), 7.37(2H, t, J= 7.2Hz), 7.47(2H, d, J= 7.6Hz), 7.96(2H, s),

8.33(1H, s). % Yield: 58%

EXAMPLE 22

2-(((4-(3-benzyl-4-hydroxyphenoxy)-3,5-dibromobenzylidene )amino)oxy)-2- methylpropanoic acid

¹ H NMR:(DMSO-D ₆ , 400MHz):- 1.46(6H, s), 3.80(2H, s), 6.38-6.41(1H, dd,

J=3.2&8.8Hz), 6.56(1H, d, J=3.2Hz),6.70(lH, d, J=8.8Hz), 7.11-7.25(5H, m),

7.91(2H, s), 8.23(lH, s).

% Yield: 50% EXAMPLE 23

2-(((4-(3 -(sec-butyl)-4-hydroxyphenoxy)-3 ,5 - dichlorobenzylidene)amino)oxy)propanoic acid

¹ H NMR:(CDC1 ₃ , 400MHz):- 0.85(3H, t, J=7.6Hz), 1.19(3H, d, J=6.8Hz), 1.52-

1.60(2H, m), 1. 64(3H, d, J=7.2Hz), 2.9O-2.97(1H, m), 4.87-4.91(1H, m), 6.42(1H, dd, J=2.8Hz&8.4Hz), 6.63 (1 H, d, J=8.4Hz), 6.74(1H, s), 7.59(2H, s), 8.08(1H, s). %

Yield: 45%

EXAMPLE 24

2-(((3,5-dibromo-4-(3-(tert-butyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)propanoic acid 1H NMR:(CDC1 ₃ , 400MHz):- 1.38(9H, s), 1.66(3 H, d, J=7.2Hz), 4.88(1 H, q, J=7.2Hz),

6.32-6. 3 4(1H, dd, J=3.2Hz & 8.8Hz), 6.53(1H, d, J=8.8Hz), 6.92(1H, d, J= 3.2Hz),

7.80(2H, s), 8.08 (IH, s). % Yield: 30%

EXAMPLE 25

2-(((3,5-dibromo-4-(3-ethyl-4-hydroxyphenoxy)benzylidene) amino)oxy)propanoic acid ¹ H NMR:(CDC1 ₃ , 400MHz):- 1.21(3H, t, J=7.2Hz), 1.60(3H, d, J=6.8Hz), 2.56-

2.62(2H ₅ q, J= 7.2&7.6Hz), 4.86-4.91(1H, q, J=6.8&7.2Hz), 6.42-6.45(1H, dd,

J=2.8&8.8Hz), 6.65(1H, d, J= 8.4Hz), 6.68(1H, d, J=2.8Hz), 7.81(2H, s), 8.18(1H, s).

% Yield: 50% EXAMPLE 26

Preparation of 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy) benzylidene) amino)oxy)propanoic acid Step 1: 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde To a solution of 4-methoxyphenol (1.6 g, 12.9 mmol) in DMF (16 mL) was added K ₂ CO ₃ (3.25 g, 25.8 mmol) and 3,5-bromo-4-iodobenzaldehyde (4.6 g, 12.9 mmol). The reaction was stirred at 130-135 ⁰ C for 2 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 90:10) to afford pure 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde (2.0 g, 44 % yield) Step 2: 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde oxime

A mixture of 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde (2.0 g, 5.18 mmol) in EtOH (14 mL) and H ₂ O (14 mL) and hydroxyl amine hydrochloride (1.44 g, 20.74 mmol) was heated at 90 ⁰ C for 2 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 90:10) to afford pure 3,5-dibromo-4-(4-methoxyphenoxy)benzaldehyde oxime (1.92 g, 96 %). 1H NMR:(CDC1 ₃ , 400MHz):- 3.77(3H, s), 6.74-6.76 (2H, m), 6.82-6.89 (2H, m), 7.82 (2H, s), 8.03 (IH, s).

Step 3: Ethyl 2-(((3,5-dibromo-4-(4- methoxyphenoxy)benzylidene)amino)oxy)propanoate To a solution of 3,5-dibromo-4- (4-methoxyphenoxy)benzaldehyde oxime (0.6 g, 1.496 mmol) in DMF (3.75 mL) was added Cs ₂ CO ₃ (0.73 g, 2.24 mmol). To that was added Ethyl-2-bromo propanoate (0.29 g, 1.64 mmol) and then reaction mixture was stirred at 20-25 ⁰ C for 2 hrs. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 95:05) to afford pure ethyl 2-(((3,5-dibromo-4-(4- methoxyphenoxy)benzylidene)amino)oxy)propanoate as an oil (0.68 g, 90 %). ¹ H NMR: (CDCl ₃ , 400MHz):- 1.30-1.35(3H, m), 1.51-1.53(3H, m), 3.77(3H, s), 4.22- 4.28(2H, q, J=7.2 Hz), 4.79-4.85(1H, q, J=7.2 Hz), 6.74(2H, d, J=9.2 Hz), 6.82(2H, d, J=9.2 Hz), 7.79(2H, s), 8.07(1H, s).

Step 4: Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-methoxy phenoxy) benzylidene) amino)oxy) propanoate A mixture of ethyl 2-(((3,5-dibromo-4-(4- methoxyphenoxy)benzylidene)amino)oxy)propanoate

(0.5 g, 0.998 mol) and 4-chlorobenzoic acid (0.31 g, 1.99 mmol) in Eaton's reagent (6.33 πiL) was heated at 95 ⁰ C for 16 h. The reaction mixture was poured over ice. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 95:05) to afford pure ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-methoxy phenoxy) benzylidene) amino)oxy) propanoate (0.143 g, 28 %). 1H NMR: (CDCl ₃ , 400 MHz):- 1.22-1.27(3H, m), 1.45-1.58(3H, m), 3.69(3H, s), 4.23- 4.28(2H, m), 4.81-4.87(1H, m), 6.82(1H, d, J=2.8Hz), 6.91-6.98(2H, m), 7.24(1H, m), 7.39-7.42(2H, d, J= 8.4 Hz), 7.73-7.77(3H, m), 8.19(1H, s) Step 5: Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy) benzylidene) amino)oxy) propanoate

A solution of ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy) benzylidene) amino)oxy) propanoate (0.143 g, 0.223 mmol) in dichloromethane ( 1.4 mL) was cooled to -60 to -70 ⁰ C under N ₂ atomsphere. To that IM BBr ₃ solution in dicloromethane (0.89 mL) was added dropwise. The reaction mixture was allowed to warm up to -20 ⁰ C over 2 h. Then diluted with more CH ₂ Cl ₂ (25 mL) and quenched with H ₂ O. After stirring at 20-25 ⁰ C for 10 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (hexane : ethylacetate 95:05) to give pure ethyl 2- (((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy) benzylidene) amino)oxy) propanoate. (0.139 g, 100%). 1H NMR: (CDCl ₃ , 400MHz):- 1.22-1.27 (3H, m), 1.45-1.58(3H, m), 4.23-4.28(2H, m), 4.81-4.87 (IH, m), 6.97-7.06QH, m), 7.44(2H, d, J=8.8Hz), 7.63(2H, d, J=8.4Hz), 7.77(2H, s), 8.19(lH, s). Step 6: 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxyphenoxy) benzylidene) amino) oxy)propanoic acid

The ester obtained from step 5 above (0.139 g, 0.22 mmol) was dissolved in

EtOH (0.84 mL) and to that solution of NaOH (0.01 Ig, 0.29 mmol) in H ₂ O (0.42 mL) was added and it was stirred at 50 ⁰ C for 2hr. Ethanol was evaporated from the reaction mixture and H ₂ O was added & washed with diethyl ether. The aqueous layer was acidified to pH 4 using 10 % HCl solution and extracted with ethyl acetate The organic layer was washed with water, brine, dried over sodium sulphate, filtered and concentrated to give pure product 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- hydroxyphenoxy) benzylidene) amino) oxy)propanoic acid (0.04 g, 30%)

¹ H NMR: (CD ₃ OD, 400MHz):- 1.52 (3H, d, J=6.8 Hz), 4.79- 4.81(1H, m), 6.76(1H, d, J=2.8 Hz), 7.02 (IH, d, J=8.8 Hz), 7.12-7.15(1H, dd, J=3.2&9.2 Hz), 7.49(2H, d, J=8.4Hz), 7.66(2H, d, J- 8. 8Hz), 7.92(2H, s), 8.14(1H, s). EXAMPLE 27 2-(((3 ,5 -dibromo-4-(3 -((4-chloropheny l)(hydroxy)methy l)-4-hydroxy phenoxy) benzylidene) amino)oxy)propanoic acid

To a solution of ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4-hydroxy phenoxy) benzylidene) amino)oxy) propanoate (0.25 g, 0.39 mmol Example 26, step 5 above) in MeOH (2.5 mL) was added NaBH ₄ (13mg, 0.35 mmol) at 0-10 ⁰ C. The reaction was stirred at same temperature for 2-3 hrs. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 90:10) to afford pure ethyl 2-(((3,5-dibromo-4-(3-((4- chlorophenyl) (hydroxy) methyl)-4-hydroxy phenoxy) benzylidene) amino)oxy) propanoate (0.25 g, 100%) which was hydrolyzed similar to the procedure given in (Example 26, step 6) to afford 2-(((3,5-dibromo-4-(3-((4- chlorophenyl)(hydroxy)methyl)-4-hydroxy phenoxy) benzylidene) amino)oxy)propanoic acid (0.113 g, 62 %)

¹ H NMR: (CD ₃ OD, 400MHz):- 1.50(3H, d, J=7.2Hz), 4.77-4.79(1H, m), 6.00(1H, s), 6.53-6.56 (IH, dd, J=3.2&8.8Hz), 6.68(1H, d, J=8.8Hz), 6.79(1H, d, J=2.8Hz),

7.25(2H, d, J=8.8Hz), 7.31 ( 2H, d, J=8.4Hz), 7.90(2H, s), 8.15(1H, s).

Using appropriate starting materials and suitable modifications of one or more of the processes described above, either alone or in suitable combination of the steps disclosed therein, including suitable addition and/or deletion of steps as may be necessary, well within the scope of a person skilled in the art, the following compounds (Examples 28-

35) were prepared in an analogous manner to that of Examples 26 & 27

EXAMPLE 28 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)acetic acid

¹ H NMR:(DMSO-D ₆ , 400MHz):- 4.63(2H, s), 6.74(1H, m), 6.92(2H, m), 7.57(2H, d,

J=8.4Hz), 7.68(2H, d, J=8.8Hz), 7.97(2H, s), 8.32(1H, s). % Yield: 9%

EXAMPLE 29 2-(((3 ,5 -dibromo-4-(3 -((4-chlorophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)benzylidene) amino)oxy)acetic acid 1H NMR:(DMSO-D ₆ , 400 MHz):- 4.57(2H, s), 5.82-5.85(1H, m), 6.46-6.49(1H, dd,

J=3.2&8.8 Hz), 6.67(1H, d, J=8.8Hz), 6.88(1H, d, J=3.2Hz), 7.30(4H, m), 7.96(2H, s),

8.31(1H ₅ S). % Yield: 58%

EXAMPLE 30

2-(((3 ,5 -dibromo-4-(3 -(3 -chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)propanoic acid 1H NMR: (DMSO-D ₆ , 400MHz):- 1.41(3H, d, J=6.8Hz), 4.71-4.72(1H, m), 6.74(1H, d,

J=3.2Hz) , 6.93-6.99(2H, m), 7.54(1H, d, J=8.0Hz), 7.61-7.62(2H, m), 7.69(1H, d,

J=8.8Hz), 7.96(2H, s), 8.30(1H, s). % Yield: 24%

EXAMPLE 31

2-(((3 ,5 -dibromo-4-(3 -(4-bromobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)acetic acid

¹ H NMR: (DMSO-D ₆ , 400MHz):- 4.63(2H, s), 6.74(1 H, m), 6.92(2H, m), 7.60(2H, d,

J=8.8Hz), 7.72(2H, d, J=8.4Hz), 7.97(2H, s), 8.32 (IH, s). % Yield: 8%

EXAMPLE 32

2-(((3 ,5-dibromo-4-(3 -((4-bromophenyl)(hydroxy)methyl)-4- hydroxyphenoxy)benzylidene) amino)oxy)acetic acid

¹ H NMR: (DMSO-D ₆ , 400MHz):- 4.61(2H, s), 5.82(1H, s), 6.46-6.49(1H, dd,

J=3.2&8.8Hz), 6. 67(1H, d, J=8.8Hz), 6.88(1 H, d, J=3.2Hz), 7.24(2H,d,J=8.4Hz),

7.44(2H, d, J=8.4Hz), 7.97 (2H, s), 8.32(1 H, s). % Yield: 60% EXAMPLE 33

2-(((3,5-dibromo-4-(3-(3-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy)acetic acid

¹ H NMR: (DMSO-D ₆ , 400MHz):- 4.58(2H ₅ s), 6.72(1H, d, J=2.8Hz), 6.94-6.98(2H, m), 7.53(1H, m), 7.61-7.62(2H, m), 7.69(1H, d, J=8.4Hz), 7.97(2H, s), 8.34(1H, s). %

Yield: 16%

EXAMPLE 34

2-(((3,5-dibromo-4-(3-((3-chlorophenyl)(hydroxy)methyl)-4 - hydroxyphenoxy)benzylidene) amino)oxy)propanoic acid 1H NMR^DMSO-D ₆ , 400 MHz):- 1.41(3H, d, J=6.8Hz), 4.86-4.91(1H, q,

J=6.8&7.2Hz), 5.89 (IH, s), 6.5O-6.53(1H, m), 6.68(1H, d, J=8.8Hz), 6.87(1H, d,

J=3.2Hz), 7.23-7.29(4H, m), 7.96 (2H, s), 8.31(1H, s). % Yield: 20%

EXAMPLE 35

2-(((3 ,5-dibromo-4-(3 -((3 -chloropheny l)(hydroxy)methyl)-4- hydroxyphenoxy)benzylidene) amino)oxy)acetic acid

¹ H NMR:(DMSO-D ₆ , 400MHz):- 4.66(2H, s), 5.85(1H, m), 6.5O-6.53(1H, dd,

J=3.2&8.8Hz), 6. 68(1H, d, J=8.4Hz), 6.87(1H, d, J=3.2Hz), 7.21-7.31(4H, m),

7.97(2H, s), 8.32(1 H, s).

% Yield: 49% EXAMPLE 36

2-(((3,5-dibromo-4-(4-hydroxy-3-(piperidin-l-yl sulfonyl) phenoxy) benzylidene) amino) oxy) propanoic acid

Step 1 Ethyl 2-(((3,5-dibromo-4-(3-(chlorosulfonyl)-4-methoxy phenoxy) benzylidene) amino)oxy) propanoate Chlorosulfonic acid (0.99 g) was added to ethyl 2-(((3,5- dibromo-4-(4-methoxy phenoxy) benzylidene) amino)oxy) propanoate (Example 26, step 3) ( 0.89 g, 1.59 mmol) at 0-10 ⁰ C. The reaction was stirred at 25 ⁰ C for 1 hr.

Reaction mixture was poured in to ice-H ₂ O and taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate to afford ethyl 2-(((3,5-dibromo-4-(3-

(chlorosulfonyl)-4-methoxy phenoxy) benzylidene) amino)oxy) propanoate (1 g, 100% yield)

Step 2. ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(piperidin-l-yl sulfonyl) phenoxy) benzylidene) amino)oxy)propanoate To a solution of ethyl 2-(((3,5-dibromo-4-(3-

(chlorosulfonyl)-4-methoxy phenoxy) benzylidene) amino)oxy) propanoate (0.41 g, 0.68 mmol) in dichloromethane ( 4.0 mL) was added piperidine ( 0.11 g, 1.36mmol) at 0-10 ⁰ C followed by triethyl amine (0.138 g, 1.36 mmol) The reaction mixture was stirred at 20-25 ⁰ C for 2 hrs. The product was taken up in ethyl acetate, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give the crude product, which was purified by column chromatography over flash silica gel (hexane : ethyl acetate 90:10) to afford pure ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(piperidin-l- yl sulfonyl) phenoxy) benzylidene) amino)oxy)propanoate ( 0.2 g, 45% yield) 1H NMR:(CDC1 ₃ , 400 MHz):- 1.22-1.26(3H, m), 1.33-1.52(9H, m), 3.10-3.13(4H, m), 3.81(3H, s), 4.16-4.21(2H, q, J=6.8 & 7.2Hz), 4.73-4.78(1H, q, J=6.8 & 7.2Hz), 6.87(1H, d, J=8.8Hz), 6.9O-6.93(1H, dd, J=2.8&8.8Hz), 7.26 (IH, d, J=2.8Hz), 7.73(2H, s), 8.00 (IH, s)

Step 3. 2-(((3,5-dibromo-4-(4-hydroxy-3-(piperidin-l-ylsulfonyl) phenoxy) benzylidene) amino) oxy) propanoic acid

A solution of ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(piperidin-l-yl sulfonyl) phenoxy) benzylidene) amino)oxy)propanoate (0.18g, 0.277mmol) in dichloromethane ( 1.8mL) was cooled to -60 to -70 ⁰ C under N ₂ atomsphere. To that IM BBr ₃ solution in dicloromethane (1.18 mL) was added dropwise. The reaction mixture was allowed to warm up to -20 ⁰ C over 4 h. then diluted with more CH ₂ Cl ₂ (25 mL) and quenched with H ₂ O. After stirring at 20-25 ⁰ C for 10 min, organic phase was separated, washed with water, brine, dried over sodium sulphate, filtered and concentrated to give crude product. The crude product was purified by column chromatography over flash silica gel (Chloroform Methanol 95:05) to give pure 2-(((3,5-dibromo-4-(4-hydroxy-3- (piperidin-1-ylsulfonyl) phenoxy) benzylidene) amino) oxy) propanoic acid ( 0.12 g, 68% Yield) 'H NMR:(CD ₃ OD, 400MHZ):- 1.49-1.52(6H, m), 1.57(3H, m), 3.10-3.13(4H, m), 4.87(1 H, m), 6.94(1 H, d, J=2.8Hz), 6.98(1 H, d, J=8.8Hz), 7.03(1H, d, J=3.2Hz), 7.96(2H, s), 8.17(1 H, s).

Using appropriate starting materials and suitable modifications of one or more of the processes described above (Example 36) either alone or in suitable combination of the steps disclosed therein, including suitable addition and/or deletion of steps as may be necessary, well within the scope of a person skilled in the art, the following compounds (Examples 37-42) were prepared in an analogous manner EXAMPLE 37 2-(((3,5-dibromo-4-(4-hydroxy-3-(N- isopropylsulfamoyl)phenoxy)benzylidene)amino)oxy) propanoic acid

¹ H NMR: (CD ₃ OD, 400 MHz):- 1.03(6H, d, J=6.8Hz), 1.51(3H, d, J=7.2Hz), 3.31-

3.34(1H, m), 4.8O-4.82(1H, m), 6.95(1H, d, J=8.8Hz), 7.00-7.03(2H, m), 7.95(2H, s), 8.17(lH, s).

% Yield: 50%

EXAMPLE 38

2-(((3,5-dibromo-4-(3-(N,N-diethylsulfamoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) propanoic acid 1H NMR: (CD ₃ OD, 400MHz):- 1.07(6H, t, J=7.2Hz), 1.51(3H, d, J=6.8Hz), 3.28-

3.34(4H, m), 4.79- 4.82(1H, m), 6.93(1H, d, J=8.8Hz), 6.99(1H, d, J=3.2Hz), 7.01-

7.03(1H, m), 7.95(2H, s), 8.17(1H, s). % Yield: 54%

EXAMPLE 39

2-(((3,5-dibromo-4-(3-(N-cyclohexylsulfamoyl)-4-hydroxyph enoxy) benzylidene)amino)oxy) propanoic acid

¹ H NMR: (CDCl ₃ , 400MHz):- 1.1 1-1.22(6H, m), 1.51-1.55(4H, m), 1.61(3H, d,

J=7.2Hz), 3.1 1-3.14(1H, m), 4.89-4.91(1H, m), 6.93(1H, d, J=2.8Hz), 7.00(1H, d,

J=8.8Hz), 7.05-7.08(1H, dd, J=3.2&9.2Hz), 7.82(2H, s), 8.09(1H, s). % Yield: 57%

EXAMPLE 40 2-(((4-(3-(N-((l R,2R,4S)-bicyclo[2.2.1 ]heptan-2-yl)sulfamoyl)-4-hydroxyphenoxy)-

3,5-dibromobenzylidene)amino)oxy)propanoic acid

¹ H NMR:(CDC1 ₃ , 400MHz):- 1.25-1.27(3H, m), 1.41-1.48(4H,m), 1.60-1.67(4H,m),

2.06(1H, bs), 2.21(1H, bs), 3.12-3.13(1H, m), 4.87-4.92(1H, q, J=7.2Hz), 6.92 (IH, d,

J=2.8Hz), 7.02 (IH, d, J=8.8Hz), 7.06-7.09(1H, dd, J=2.8&9.2Hz), 7.82(2H, s), 8.09(1H, s). % Yield: 12%

EXAMPLE 41

2-(((3,5-dibromo-4-(4-hydroxy-3-(pyrrolidin-l- ylsulfonyl)phenoxy)benzylidene)amino)oxy) acetic acid

¹ H NMR:(DMSO-D ₆ , 400MHz):- 1.72(4H, t, J=6.8Hz), 3.22(4H, t, J=6.6Hz), 4.55(2H, s), 6.94 (IH, d, J=2.0Hz), 7.00-7.05(2H, m), 7.99(2H, s), 8.31(1H, s). % Yield: 45%

EXAMPLE 42

2-(((3,5-dibromo-4-(4-hydroxy-3-(pyrrolidin-l-ylsulfonyl) phenoxy) benzylidene)amino)oxy) propanoic acid ¹ H NMRr(CDCl ₃ , 400MHz):- 1.61(3H, d, J=7.2Hz), 1.81(4H, t, J=3.4Hz), 3.25(4H, t, J=6.8Hz), 4.89-4.91(1H, q, J=7.2Hz), 6.91(1H, d, J=3.2Hz), 7.02(1H, d, J=9.2Hz), 7.08(1H, dd, J=2.8 & 8. 8Hz), 7.82(2H, s), 8.09(1H, s). % Yield: 52%

For the synthesis of the above mentioned compounds following intermediates were prepared.

Intermediate 1

Ethyl 2-(((3,5-dichloro-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) acetate

¹ H NMR: (CDCl ₃ , 400 MHz):- 1.18(6H, d, J=6.8 Hz), 1.27-1.29(3H, m),3.24-3.31(lH, m), 3.78 (3H, s), 4.24-4.29(2H, m), 4.72(2H, s), 6.43-6.46(1H, dd, J=3.2&8.8Hz), 6.7O(1H, d, J=9.2Hz), 6.83(1H, d, J=3.2Hz), 7.61(2H, s), 8.12(1H, s).

Intermediate 2

Ethyl 2-(((4-(3-(sec-butyl)-4-methoxyphenoxy)-3,5- dichlorobenzylidene)amino)oxy) acetate 1H NMR: (CDCl ₃ , 400MHz):- 0.87-0.89(3H, m), 1.15(3H,d, J=7.2 Hz), 1.28-1.33(3H, m), 1.46-1.61(2H, m), 3.03-3.08(1H, m), 3.77QH, s), 4.23-4.29(2H, m), 4.72(2H, s), 6.47-6.50(1H, dd, J= 3.2&9.2Hz), 6.72(1H, d, J=8.8Hz), 6.75-6.76(1H, m) , 7.61(2H, s), 8.12(1H, s).

Intermediate 3 Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) acetate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.18(6H, d, J=6.8Hz), 1.31(3H, t, J=7.8Hz), 3.26- 3.29(1H, m), 3.78(3H, s), 4.24-4.30(2H, q, J=7.2Hz), 4.73(2H, s), 6.41-6.44(1H, dd, J=2.8&8.8Hz), 6.7O(1H, d, J=8.8Hz), 6.82(1H, d, J=3.2Hz), 7.81(2H, s), 8.11(1H, s). Intermediate 4

Ethyl 2-(((3,5-dichloro-4-((6-methoxy-[l ,l'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) acetate

¹ H NMR: (CDCl ₃ , 400 MHz):- 1.25-1.32(3H, m). 3.76(3H, s), 4.24-4.29(2H, m), 4.72(2H, s), 6.75-6.78(1H, dd, J=3.2&9.2Hz), 6.82(1H, d, J=3.2Hz), 6.89(1H, d, J=8.8Hz), 7.31(1 H, t, J= 7.2Hz), 7.39(2H, t, J=7.4Hz), 7.49(2H, d, J=7.2Hz), 7.61(2H, s), 8.11(lH, s).

Intermediate 5 Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3,5-dichlorobenzylidene)a mino)oxy)acetate ¹ H NMR: (CDCl ₃ , 400MHz):- 1.27-1.33(3H, m), 3.7(3H, s), 3.94(2H, s), 4.24-4.29(2H, q, J= 6.8 Hz), 4.72(2H, s), 6.52-6.55(1H, dd, J=3.2&8.8Hz), 6.67(1H, d, J=3.2Hz), 6.73(1H, d, J= 8.8 Hz), 7.17-7.19(3H, m), 7.24-7.27(2H, m), 7.58(2H, s), 8.10(1H, s).

Intermediate 6 Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4- methoxyphenoxy)benzylidene)amino)oxy) acetate

¹ H NMR^CDCl ₃ , 400MHz):- 0.83(3H, t, J=7.2Hz), 1.15(3H, d, J=6.8Hz), 1.30(3H, t, J-6.8Hz), 1.31(2H, q, J=7.2Hz), 3.03-3.09(1H, m), 3.77(3H, s), 4.26(2H, q, J=6.Hz), 4.72(2H, s), 6.47(1H, m), 6.72(2H, d, J=8.8Hz), 7.81(2H, s), 8.1(1H, s). Intermediate 7

Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[l ,1 '-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) acetate

¹ H NMR:(CDC1 ₃ , 400 MHz):- 1.25-1.32(3H, m), 3.77(3H, s), 4.23-4.29(2H, m), 4.72(2H, s), 6.73-6.76(1H, dd, J=3.2&9.6Hz), 6.81(1H, d, J=3.2Hz), 6.9O(1H, d, J=9.2Hz), 7.30-7.31(1H, m), 7.37-7.41(2H, m), 7.50-7.52(2H, m), 7.82(2H, s), 8.11(lH, s).

Intermediate 8

Ethyl 2-(((3,5-dichloro-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) propanoate 1H NMR: (CDCl ₃ , 400MHz):-1.18(6H, d, J=7.2Hz), 1.29(3H, d, J=7.2Hz), 1.54(3H, d, J=7.2Hz), 3.24-3.31(1 H, m), 3.78(3H, s), 4.23-4.28(2H, m), 4.79-4.85(1 H, q, J=7.2Hz), 6.43-6.46(1H, dd, J=2.8&8.8Hz), 6.69(1H, d, J=8.8Hz), 6.84(1H, d, J=3.2Hz), 7.59(2H, s), 8.08(1H, s).

Intermediate 9 Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3,5- dibromobenzylidene)amino)oxy)acetate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.27-1.33(3H, m), 3.76(3H, s), 3.93(2H, s), 4.24- 4.29(2H, q, J=6.8 & 7.2Hz), 4.73(2H, s) 6.51-6.54(1H, dd, J=3.2&8.8Hz), 6.65(1H, d, J=3.2Hz), 6.73(1H, d, J=8.8 Hz), 7.15-7.19(3H, m), 7.24-7.29(2H, m), 7.79(2H, s), 8.10(1H, s).

Intermediate 10 Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4- methoxyphenoxy)benzylidene)amino)oxy) propanoate

¹ U NMR: (CDCl ₃ , 400MHz):- 1.18(6H, d, J=6.8Hz), 1.29(3H, t, J=7.2Hz), 1.56(3H, d, J=7.2Hz), 3.24-3.31(1H, m), 3.78(3H, s), 4.22-4.29(2H, m), 4.8O-4.85(1H, q, J=7.2Hz), 6.41-6.44(1H, dd, J=2.8&8.8Hz),6.70(lH, d, J=8.8Hz), 7.82(1H, d, J=2.8Hz), 7.80(2H, s), 8.07(1H, s).

Intermediate 11

Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[ 1 , 1 '-biphenylj-3- yl)oxy)benzylidene)amino)oxy) propanoate 1H NMR: (CDCl ₃ , 400MHz):- 1.30(3H, t, J=7.0Hz), 1.54(3H, d, J=6.8Hz), 3.77(3H, s), 4.23-4.28 (2H, q, J=6.8&7.2Hz), 4.79-4.84(1H, q, J=6.8&7.2Hz), 6.73-6.76(1H, dd, J=3.2&9.2Hz), 6.81(1 H, d, J=2.8Hz), 6.89(1H, d, J=8.8Hz), 7.29-7.33(1H, m), 7.39(2H, t, J=7.2.0Hz), 7.51(2H, t, J= 7 .2Hz), 7.80(2H, s), 8.06(1H, s).

Intermediate 12 Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4-methoxyphenoxy)benzylidene )amino)oxy)-2- methyl propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.22(6H, d, J=7.2Hz), 1.31(3H, t, J=7Hz), 1.56(3H, s), 1.58(3H, s), 3.13-3.2O(1H, m), 3.96(3H, s), 4.21-4.27(2H, q, J=7Hz), 6.41-6.45(1H, dd, J=3.2&8.8Hz), 6. 69(1H, d, J=8.4Hz), 6.99(1H, d, J=3.2Hz), 7.77(2H, s), 8.02(1H, s). Intermediate 13

Ethyl 2-(((3,5-dibromo-4-(3-isopropyl-4- methoxyphenoxy)benzylidene) amino)oxy) butanoate

¹ H NMR: (CDCl ₃ , 400 MHz):- 1.05(3H, t, J=7.2Hz), 1.18(6H, d, J=6.8Hz), 1.30(3H, t, J=7.2Hz), 1.89-1.97(2H, m), 3.24-3.31(1H, m), 3.78(3H, s), 4.21-4.29(2H, m), 4.66- 4.69(1H, q, J=5.6& 7.2Hz), 6.41-6.44 (IH, dd, J=3.2&8.8Hz), 6.7O(1H, d, J=8.8Hz), 6.82(1H, d, J=2.8Hz), 7.80(2H, s), 8.09(1H, s).

Intermediate 14

Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4- methoxyphenoxy) benzylidene) amino) oxy) propanoate 1H NMR: (CDCl ₃ , 400MHz):- 0.83QH, t, J=7.2Hz), 1.15(3H, d, J=6.8Hz), 1.30(3H, t, J=7.2Hz), 1.52-1.55(2H, m), 1.57(3H, d, J=7.2Hz), 3.03-3.09(1H, m), 3.77(3H, s), 4.23- 4.28(2H, q, J=7.2 Hz), 4.79-4.85(1H, q, J=7.2Hz), 6.45-6.48(1H, dd, J=3.2Hz&8.8Hz), 6.71(1H, d, J= 8.8Hz), 6.74 (IH, d, J=3.2Hz), 7.79(2H, s), 8.07(1H, s). Intermediate 15

Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4-methoxyphenoxy)benzylide ne)amino)oxy)-

2-methylpropanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 0.83(3H, t, 5=7 AUz), 1.15(3H, d, J=6.8Hz), 1.26- 1.3(3H, m), 1.47 -1.56(2H, m), 1.58(6H, s), 3.04-3.09(1H, m), 3.77(3H, s), 4.21-

4.26(2H, q, J=6.8Hz &7.2 Hz), 6. 44-6.47(1H, dd, J=3.2&8.8Hz), 6.71(1H, d,

J=8.8Hz), 6.75(1H, d, J=3.2Hz), 7.77(2H, s), 8.01 (IH, s).

Intermediate 16

Ethyl 2-(((4-(3-benzyl-4-methoxyphenoxy)-3,5- dibromobenzylidene)amino)oxy) propanoate

¹ H NMR:(CDC1 ₃ , 400MHz):- 1.27(3H, t, J=7.2Hz), 1.54(3H, d, J=6.8Hz), 3.75(3H, s),

3.92(2H, s), 4.22-4.27(2H, q, J= 7.2Hz), 4.79-4.84(1 H, q, J=7.2Hz), 6.51-6.54(1 H, dd,

J=3.2&8.8Hz), 6. 6 5(1H, d, J=3.2Hz), 6.73(1H, d, J=8.8Hz), 7.12-7.27(5H, m),

7.77(2H, s), 8.08(1H, s). Intermediate 17

Ethyl 2-(((4-(3 -benzyl -4-methoxyphenoxy)-3 ,5 - dibromobenzylidene)amino)oxy) butanoate

¹ H NMR:(CDC1 ₃ , 400MHz):- 1.05(3H, t, J=7.2Hz), 1.30(3H, t, J=7.2Hz), 1.90-

1.96(2H, m), 3. 7 5(3H, s), 3.92(2H, s), 4.25(2H, q, J= 7.2Hz), 4.67(1H, t, J=5.6Hz), 6.51-6.54(1H, dd, J=3.2 & 8.8 Hz), 6.65(1H, d, J=3.2Hz), 6.73(1H, d, J=8.8Hz), 7.17-

7.27(5H, m), 7.77(2H, s), 8.08(1H, s).

Intermediate 18

Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4-methoxyphenoxy)benzylide ne)amino)oxy)-

2-phenyl acetate 1H NMR:(CDC1 ₃ , 400MHz):- 0.83(3H, t, J=7.4Hz), 1.15(3H, d, J=6.8Hz), 1.26(3H, t,

J=7.0Hz), 1.46-1.60(2H, m), 3.04-3.09(1H, m), 3.77(3H, s), 4.18-4.32(2H, m),

5.7O(1H, s), 6.45- 6.48 (IH, dd, J=3.2&8.8Hz), 6.70-6.74(2H, m), 7.39-7.5(3H, m),

7.5-7.53(2H, m), 7.81(2H, s), 8.2(1H, s).

Intermediate 19 Ethyl 2-(((3,5-dibromo-4-(3-(sec-butyl)-4-ethoxy phenoxy) benzylidene) amino) oxy) butanoate

¹ H NMR:(CDC1 ₃ , 400MHz):- 0.85-0.92(3H, m), 1.06(3H, t, J=7.2Hz), 1.14(3H, d,

J=7.2Hz), 1. 3O(3H, d, J=6.8Hz), 1.44- 1.61 -(2H, m), 1.89-1.99(2H, m), 3.03-3.09(1H, m), 3.77(3H, s), 4.21-4. 29(2H, m), 4.66-4.69(1H, m), 6.45-6.48(1H, dd, J=2.8&8.8Hz), 6.72(1H, d, J=9.2Hz), 6.74 (IH, d, J=3.2Hz), 7.79(2H, s), 8.09(1H, s).

Intermediate 20

Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[ 1 , 1 '-biphenyl]-3- yl)oxy)benzylidene)amino)oxy)-2- methylpropanoate

¹ H NMR:(CDC1 ₃ , 400MHz):- 1.26(3H, t, J=7.2Hz), 1.58(6H, s), 3.76(3H, s), 4.20-

4.26(2H, q, J=6.8 &7.2Hz), 6.73-6.76(1H, dd, J=2.8&8.8Hz), 6.81(1H, d, J=3.2Hz),

6.89(1H, d, J=8.8Hz), 7.29-7.33(1H, m), 7.37-7.40(2H, m), 7.48-7.51(2H, m), 7.77(2H, s), 8.00(1H, s).

Intermediate 21

Ethyl 2-(((3,5-dibromo-4-((6-methoxy-[l,l'-biphenyl]-3- yl)oxy)benzylidene)amino)oxy) butanoate

¹ H NMRi(CDCl ₃ , 400MHz):- l .O5(3H, t, J=7.2Hz), 1.30(3H, t, J=7.2Hz), 1.88- 1.95(2H, m), 3. 76(3H, s), 4.22-4.28(2H, m), 4.67(1H, t, J=5.6Hz), 6.74(1H, dd,

J=3.2&8.8Hz), 6.8(1H, d, J= 3.2 Hz), 6.89(1H, d, J=9.2Hz), 7.29-7.33(1H, m), 7.37-

7.41(2H, m), 7.49-7.52(2H, m), 7.8(2H, s), 8. 08(lH,s).

Intermediate 22

Ethyl 2-(((4-(3 -benzyl -4-methoxyphenoxy)-3 ,5-dibromobenzylidene)amino)oxy)-2- methyl propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.28(3H, t, J=7.2Hz), 1.55(3H, s), 1.58(3H, s), 3.75(3H, s), 3.92 (2H, s), 4.21-4.26(2H, q, J=7.2Hz), 6.51-6.54(1H, dd, J=3.2&8.8Hz), 6.65(1H, d, J=2.8Hz), 6.73 (IH, d, J=9.2Hz), 7.12-7.19(3H, m), 7.23-7.27(2H, m), 7.75(2H, s),

8.00(1H, s). Intermediate 23

Ethyl 2-(((4-(3-(sec-butyl)-4-methoxyphenoxy)-3,5- dichlorobenzylidene)amino)oxy)propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 0.83(3H, t, J=7.6Hz), 1.15(3H, d, J=6.8Hz), 1.30(3H, t,

J=7.2Hz), 1.55-1.61(5H, m), 3.03-3.08(1H, m), 3.77(3H, s), 4.22-4.28(2H, m), 4.79- 4.85(1H, q, J=6.8& 7.2 Hz), 6.46-6.49(1H, dd, J=3.2Hz&8.8Hz), 6.72(1 H, d, J=

8.8Hz), 6.76(1H, d, J=3.2Hz), 7.59(2H, s), 8.08(1H, s). Intermediate 24

Ethyl 2-(((3,5-dibromo-4-(3-(tert-butyl)-4- methoxyphenoxy)benzylidene)amino)oxy)propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.28(3H, t, J=7.2Hz), 1.34(9H, s), 1.58(3H, d, J=6.8Hz), 3.78(3H, s), 4.22-4.28(2H, q, J=6.8&7.2Hz), 4.79-4.84(1H, q, J=6.8&7.2Hz), 6.40-

6.43(1 H, dd, J=3.2& 8. 8Hz), 6.71 (IH, d, J=8.8Hz), 6.93(1 H, d, J=3.2Hz), 7.79(2H, s),

8.06(1H, s).

Intermediate 25

Ethyl 2-(((3,5-dibromo-4-(3-ethyl-4- methoxyphenoxy)benzylidene)amino)oxy)propanoate

¹ H NMR: (CDCl ₃ , 400MHz):-1.15-1.18(3H, t, J=7.2Hz), 1.27-1.29(3H, t, J=7.2Hz),

1.56(3H, d, J=8.4Hz), 2.57-2.62(2H, q, J=7.2&7.6Hz), 3.78(3H, s), 4.23-4.28(2H, q,

J=7.2Hz), 4.8- 4.85(1H, q, J=6.8&7.2Hz), 6.47-6.50(1H, dd, J=3.2&8.8Hz), 6.69-

6.72(2H, m), 7.80(2H, s), 8.07(1H, s). Intermediate 26

Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- methoxyphenoxy)benzylidene)amino)oxy) propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.22-1.27 (3H, m), 1.45-1.58(3H, m), 3.69(3H, s), 4.23-

4.28(2H, m), 4.81-4.87(1H, m), 6.82(1H, d, J=2.8Hz), 6.91-6.98(2H, m), 7.24(1H, m), 7.39-7.42(2H, d, J= 8.4Hz), 7.73-7.77(3H, m), 8.19(1H, s).

Intermediate 27

Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- hydroxyphenoxy)bεnzylidene)amino)oxy) propanoate

¹ H NMR:(CDC1 ₃ , 400MHz):- 1.22-1.27(3H, m), 1.45-1.58(3H, m), 4.23-4.28(2H, m), 4.81-4.87 (IH, m), 6.97-7.06(3H, m), 7.44(2H, d, J=8.8Hz), 7.63(2H, d, J=8.4Hz),

7.77(2H, s), 8.19 (1H, s).

Intermediate 28

Ethyl 2-(((3,5-dibromo-4-(3-(4-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) acetate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.31(3H, t, J=7.2Hz), 4.24-4.27(2H, q, J=7.2Hz),

4.72(2H, s), 6.97 (IH, d, J=2.8Hz), 7.03-7.09(2H, m), 7.45(2H, d, J=8.4Hz), 7.64(2H, d, J=6.8Hz), 7.79(2H, s), 8. 09(1 H, s). Intermediate 29

Ethyl 2-(((3 _; 5-dibromo-4-(3-(3 -chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) propanoate

¹ H NMRi(CDCl ₃ , 400MHz):- 1.22-1.27(3H, m), 1.45-1.58(3H, m), 4.24-4.29(2H, m), 4.80-4.85 (IH, q, J=6.8Hz), 6.86(1H, d, J=2.8Hz), 7.08(1H, d, J=9.2Hz), 7.17-7.2O(1H, dd, J=3.2 &9.2Hz), 7.4O(1H, t, J=8.0Hz), 7.53-7.63(3H, m), 7.78(2H, s), 8.05(1H, s).

Intermediate 30

Ethyl 2-(((3,5-dibromo-4-(3-(4-bromobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) acetate 1H NMRr(CDCl ₃ , 400MHz):- 1.31(3H, t, J=7.2Hz), 4.24-4.27(2H, q, J=7.2Hz),

4.72(2H, s), 6.97 (IH, d, J=2.8Hz), 7.04-7.08(2H, m), 7.55(2H, d, J=8.4Hz), 7.62(2H, d, J=8.4Hz), 7.79(2H, s), 8. O9(1H, s).

Intermediate 31

Ethyl 2-(((3,5-dibromo-4-(3-(3-chlorobenzoyl)-4- hydroxyphenoxy)benzylidene)amino)oxy) acetate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.31(3H, t, J=7.2Hz), 4.24-4.29(2H, q, J=7.2Hz),

4.72(2H, s), 6.87 (IH, d, J=3.2Hz), 7.06(1H, d, J=9.2Hz), 7.16-7.19(1H, dd,

J=2.8&9.2Hz), 7.39(1H, t, J=7.8Hz), 7.52-7.61(3H, m), 7.79(2H, s), 8.08(1H, s).

Intermediate 32 Ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(piperidin-l-ylsulfonyl) phenoxy)benzylidene) amino) oxy)propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.22-1.26(3H, m), 1.33-1.52(9H, m), 3.10-3.13(4H, m),

3.81(3H, s), 4.16-4.21(2H, q, J=6.8&7.2Hz), 4.73-4.78(1H, q, J=6.8&7.2Hz), 6.87(1H, d, J=8.8Hz), 6.9O-6.93(1H, dd, J=2.8&8.8Hz), 7.26(1H, d, J=2.8Hz), 7.73 (2H, s), 8.00(1H, s)

Intermediate 33

Ethyl 2-(((3,5-dibromo-4-(3-(N-isopropylsulfamoyl)-4- methoxyphenoxy)benzylidene)amino) oxy)propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.05(6H, d, J=6.8Hz), 1.29-1.33(3H, t, J=7.2Hz), 1.56(3H, d, J= 5.6Hz), 3.4O-3.45(1H, m), 3.95(3H, s), 4.23-4.28(2H, q, J=6.8&7.2Hz),

4.74-4.85(1H, q, J= 6.8 &7.2Hz), 6.95-7.03(2H, m), 7.36(1H, d, J=3.2Hz), 7.80(2H, s),

8.2O(1H, s).

Intermediate 34 Ethyl 2-(((3,5-dibromo-4-(3-(N,N-diethylsulfamoyl)-4- methoxyphenoxy)benzylidene)amino) oxy)propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.09(6H, t, J=7.2Hz), 1.29-1.32(3H, t, J=7.2Hz), 1.56-

1.51(3H, m), 3.30-3.36(4H, q, J=7.2Hz), 3.89(3H, s), 4.23- 4.28(2H, q, J=7.2Hz), 4.80- 4.85(1H, q, J=6.8&7. 2Hz) ₅ 6.90-7.01(2H, m), 7.38(1H, d, J=2.8Hz), 7.80(2H, s),

8.07(1H, s).

Intermediate 35

Ethyl 2-(((3,5-dibromo-4-(3-(N-cyclohexylsulfamoyl)-4- methoxyphenoxy)benzylidene)amino) oxy)propanoate 1H NMR: (CDCl ₃ , 400MHz):- 1.09-1.16(6H, m), 1.20-1.25(4H, m), 1.31(3H, t,

J=7.0Hz), 1.55 (3H, d, J=6.8Hz), 2.04-3.13(1H, m), 3.95(3H, s), 4.23-4.26(2H, q,

J=7.2Hz), 4.81-4.85(1H, m), 6.97(1H, d, J=8.8Hz), 7.01-7.03(1H, dd, J=3.2&9.3Hz),

7.33(1H, d, J=2.8Hz;, 7.80(2H, s), 8.07 (IH, s).

Intermediate 36 Ethyl 2-(((4-(3-(N-((l R,2R,4S)-bicyclo[2.2.1]heptan-2-yl)sulfamoyl)-4- methoxyphenoxy)-3 ,5 -dibromobenzy lidene)amino)oxy)propanoate

¹ H NMR: (CDCl ₃ , 400MHz):- 0.98-0.99 (3H, m), 1.10-1.18(3H, m), 1.28-1.33(6H, m),

1.37-1.41 (2H, m), 2.02-2.04(2H, m), 3.09-3.13(1H, m), 3.96(3H, s), 4.23-4.28(2H, q,

J= 7.2Hz), 4.8O-4.86(1H, q, J=6.8Hz), 6.97(1H, d, J= 9.2Hz), 7.02-7.05(1H, dd, J=3.2&9.2Hz), 7.34 (IH, d, J=3.2Hz), 7.80(2H, s), 8.07(1H, s).

Intermediate 37

Ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(pyrrolidin-l - ylsulfonyl)phenoxy)benzylidene)amino) oxy)acetate

¹ H NMR: (CDCl ₃ , 400MHz):- 1.31(3H, t, J=7.2Hz), 1.83(4H, t, J=3.6Hz), 3.37(4H, t, J=7Hz), 3.9O(3H, s), 4.24-4.30(2H, q, J=7.2Hz), 4.73(2H, s), 6.96-6.97(2H, m),

6.39(1H, d, J=2.8Hz), 7.82(2H, s), 8.1 1(1H, s).

Intermediate 38

Ethyl 2-(((3,5-dibromo-4-(4-methoxy-3-(pyrrolidin-l- ylsulfonyl)phenoxy)benzy 1 idene)amino) oxy)propanoate 1H NMR: (CDCl ₃ , 400MHz):- 1.31(3H, t, J=7.01Iz), 1.55(3H, d, J=6.8Hz), 1.82-

1.84(4H, m), 3. 37(4H, t, J=6.6Hz), 3.90(3H, s), 4.23-4.28(2H, q, J=7.2Hz), 4.08-

4.85(1H, q, J-7.2Hz), 6.94(1 H, d, J=9.2Hz), 6.97-7.00(1H, dd, J=2.8&8.8Hz),

7.38(1H, d, J=2.8Hz), 7.80(2H, s), 8.06(1H, s). Intermediate 39

3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-benzaldehy de oxime 1H NMR: (CDCl ₃ , 400MHz):- 1.18(6H, d, J=7.2Hz), 3.24-3.31 (IH, m), 3.78(3H, s), 6.44-6.47(1H, dd, J= 2.8 & 8.8Hz), 6.7O(1H, d, J=8.8Hz), 6.84(1H, d, J=2.8Hz), 7.61(2H, s), 8.05(lH,s).

Intermediate 40

4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-benzaldehy de oxime 1H NMR: (CDCl ₃ , 400MHz):- O.83(3H, t, J=7.4Hz), 1.15(3H, d, J=6.8 Hz),1.46- 1.55(2H, m), 3.04-3.09(1H, m), 3.77(3H, s), 6.47-6.50(1H, dd, J=3.2&8.8Hz), 6.72(1H, d, J=9.2 Hz), 6.77(1H, d, J=3.2Hz), 7.61(2H, s), 8.04(1H, s).

Intermediate 41

3,5-Dibromo-4-(3-isopropyl-4-methoxy-phenoxy)-benzaldehyd e oxime 1H NMR: (CDCl ₃ , 400MHz):- 1.18(6H, d, J=6.8Hz), 3.26-3.30(1H, m), 3.78(3H, s), 6.42-6.45(1H, dd, J=2.8&8.8Hz), 6.7O(1H, d, J=8.8Hz), 6.83(1H, d, J=3.2Hz), 7.82(2H, s), 8.04(1H, s)

Intermediate 42

4-(3-Benzyl-4-methoxy-phenoxy)-3,5-dichloro-benzaldehyde oxime 1H NMR: (CDCl ₃ , 400MHz):- 3.75(3H, s), 3.93(2H, s), 6.54-6.56(1H, dd, J=2.8&8.8Hz), 6.68(1H, d, J= 3.2 Hz), 6.73(1H, d, J=9.2Hz), 7.15-7.19(3H, m), 7.24- 7.27(2H, m), 7.58(2H, s), 8.03(1H, s).

Intermediate 43

3,5-Dibromo-4-(3-sec-butyl-4-methoxy-phenoxy)-benzaldehyd e oxime 1H NMR:(CDC1 ₃ , 400MHz):- O.83(3H, t, J=7.4Hz), 1.15(3H, d, J=6.8Hz), 1.46-1.61 (2H, m), 3.04-3.09(1H, m), 3.77(3H, s), 6.45-6.48(1H, dd, J=3.2Hz&8.8Hz), 6.72(1H, d, J=8.8Hz), 6.75(1H, d, J=3.2Hz), 7.81(2H, s), 8.04(1H, s).

Intermediate 44

4-(3-Benzyl-4-methoxy-phenoxy)-3,5-dibromo-benzaldehyde oxime 1H NMR: (CDCl ₃ , 400MHz):- 3.75(3H, s), 3.92(2H, s), 6.52-6.55(1H, dd, J=3.2&8.8Hz), 6.66(1H, d, J- 2. 8Hz), 6.73(1H, d, J=8.8Hz), 7.15-7.19(3H, m), 7.23- 7.27(2H, m), 7.79(2H, s), 8.02(1H, s).

Intermediate 45 3,5-Dibromo-4-(3-tert-butyl-4-hydroxy-phenoxy)-benzaldehyde oxime ¹ H NMRX CDCl ₃ 400MHz):- 1.34(9H, s), 3.79(3H, s), 6.41-6.44(1H, dd, J=3.2&8.8Hz), 6.71(1H, d, J= 8. 8Hz) ₅ 6.94(1H, d, J=3.2Hz), 7.81(2H, s), 8.04(1H, s).

Intermediate 46

3,5-Dibromo-4-(3-ethyl-4-methoxy-phenoxy)-benzaldehyde oxime 1H NMR: (CDCl ₃ , 400MHz):- 1.17(3H, t, J= 7.6Hz), 2.57- 2.63(2H, q, J= 7.6Hz)

3.78(3H, s), 6.48-6.50(1 H, dd, J= 2.8 & 8.8Hz), 6.71(1H, d, J= 9.2Hz), 6.73(1H, d, J= 3.2Hz), 7.82(2H, s), 8.04(1H, s).

Intermediate 47

3,5-Dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-benzaldehy de 1H NMR: (CDCl ₃ , 400MHz):- 1.18(6H, d, J=6.8Hz), 3.27-3.30(1H, m), 3.79(3H, s), 6.44-6.47(1H, dd, J= 3.2&9.2Hz), 6.7O(1H, d, J=8.8Hz), 6.85(1H, d, J=3.2Hz), 7.91(2H, s), 9.93(1 H, s).

Intermediate 48

4-(3-sec-Butyl-4-methoxy-phenoxy)-3,5-dichloro-benzaldehy de 1H NMR: (CDCl ₃ , 400MHz):- 0.88-0.89(3H, m), 1.15(3H, d, J=6.8 Hz), 1.47-1.61(2H, m), 3.03-3.1 1(1H, m ), 3.78(3H, s), 6.47-6.50(1H, dd, J=3.2&8.8Hz), 6.72(1H, d, J=8.8Hz), 6.77(1 H, d, J=2.8Hz), 7.91 (2H, s), 9.93(1 H, s).

Intermediate 49

3,5-Dibromo-4-(3-isopropyl-4-methoxy-phenoxy)-benzaldehyd e 1H NMR: (CDCl ₃ , 400MHz):- 1.18(6H, d, J=6.8Hz), 3.20-3.30(1H, m), 3.79(3H, s), 6.43-6.44(1H, dd, J= 3.2&8.8Hz), 6.7O(1H, d, J=8.8Hz), 6.83(1H, d, J=3.2Hz), 8.10(2H, s), 9.92(lH, s).

Intermediate 50

4-(3-Benzyl-4-methoxy-phenoxy)-3,5-dichloro-benzaldehyde 1H NMR: (CDCl ₃ , 400MHz):-3.76(3H, s), 3.92(2H, s), 6.54-6.57(1H, dd,

J=3.2&8.8Hz), 6.66(1H, d, J= 3.2Hz), 6.74(1H, d, J=9.2Hz), 7.15-7.29(5H, m), 7.88(2H, s), 9.91(lH, s).

Intermediate 5i

3 ,5-Dibromo-4-(3 -sec-butyl-4-methoxy-phenoxy)-benzaldehyde 1H NMR: (CDCl ₃ , 400MHz):- 0.85(3H, t, J=7.4Hz), 1.14(3H, d, J=6.8Hz), 1.47-

1.59(2H, m), 3.07-3.09(1H, m), 3.77(3H, s), 6.45-6.48(1H, dd, J=3.2&8.8Hz), 6.72(1H, d, J=8.8Hz), 6.75(1H, d, J=3.2Hz), 8.1 1(2H, s), 9.9O(1H, s).

Intermediate 52 4-(3-Benzyl-4-methoxy-phenoxy)-3,5-dibromo-benzaldehyde

¹ H NMRi(CDCl ₃ . 400MHz):- 3.76(3H, s), 3.93(2H, s), 6.52-6.55(1H, dd, J=2.8&8.8Hz),

6.64(1H, d, J= 3.2 Hz), 6.76(1H, d, J=8.8Hz), 7.17-7.19(5H, m), 8.08(2H, s),9.91(lH, s).

Intermediate 53

3 ,5-Dibromo-4-(3 -tert-butyl-4-methoxy-phenoxy)-benzaldehyde 1H NMRr(CDCl ₃ , 400MHz):- 1.34(9H, s), 3.85(3H, s), 6.4O-6.43(1H, dd, J=3.2Hz & 8.8Hz), 6.72(1H, d, J=8.8Hz), 6.93(1H, d, J=3.2Hz), 8.11(2H, s), 9.92(1H, s).

Intermediate 54

3 ,5-Dibromo-4-(3 -ethyl -4-methoxy-phenoxy)-benzaldehyde

¹ H NMR:(CDC1 ₃ , 400MHz):- 1.17(3H, t, J=7.6Hz), 2.57-2.63(2H, q, J=7.2&7.6Hz), 3.79(3H, s), 6.48-6.51(1H, dd, J=3.2&8.8Hz), 6.70- 6.74(2H, m), 8.11(2H, s),9.92(lH, s).

Activity data:

In vitro TR-α & TR-β activities were determined as per in-house protocols and the results of representative compounds are provided in tables 1 & 2 below as a proof of the efficacies of the novel class of compounds disclosed above. Table 1 :

Table 2 :

* Fold Induction w.r.t T3(100 nm)

The data above clearly indicates that several of the novel compounds of the present invention are selective to TR-beta receptor and therefore have potential therapeutically beneficial properties. In-vivo studies:

Cholesterol lowering effect of T3 and selected compounds disclosed in the present invention on cholesterol lowering and change in heart rate in cholesterol-fed rats (treated for 7 days) was determined according to the general protocol described in PNAS, ,vol. 100 (17) 10067-10072 and Endocrinology 145(4):1656-1661 Many of the compounds were found to be reducing cholesterol and having very little effect on the heart rate. Therefore, these compounds have the potential to be further developed as selective TR-beta agonists for the treatment of human & other animals in need of such treatment.

The novel compounds of the present invention may be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.

The compounds of formula (I) or pharmaceutical compositions containing them are useful as Thyroid hormone receptor ligands suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions associated with dyslipidemia, obesity etc.

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.