WO2015022631A1

WO2015022631A1 - Substituted biphenyl compounds as calcium sensing receptor modulators

Info

Publication number: WO2015022631A1
Application number: PCT/IB2014/063867
Authority: WO
Inventors: Sachin MADAN; Prashant Vitthalrao TALE; Seema Prabhakar ZADE; Amolsing Dattu PATIL; Sanjeev Anant Kulkarni; Venkata P. Palle; Rajender Kumar Kamboj
Original assignee: Lupin Limited
Priority date: 2013-08-12
Filing date: 2014-08-12
Publication date: 2015-02-19
Also published as: TW201602062A

Abstract

The invention relates to compounds of Formula (I) and their pharmaceutically acceptable salts, wherein the substituents are as described herein, and their use in medicine for the treatment of diseases, disorders associated with the modulation of calcium sensing receptor modulators (Ca SR). The invention also relates to pharmaceutical compositions containing such compounds in treating diseases disorders associated with calcium sensing receptor modulators (Ca SR)channel modulators.

Description

SUBSTITUTED BIPHENYL COMPOUNDS AS CALCIUM SENSING

RECEPTOR MODULATORS

Related Applications

The present application claims the benefit of priority to Indian Provisional Patent Application Nos. 2633/MUM/2013, filed on August 12, 2013 and 2634/MUM/2013, filed on August 12, 2013. The entire provisional specifications are incorporated herein by reference.

Field of the Invention

The present invention relates to substituted biphenyl compound of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions for the treatment, management, and/or lessening the severity of diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR). The invention also relates to methods of treating, managing and/or lessening the severity of the diseases disorders, syndromes or conditions associated with the modulation of calcium sensing receptors (CaSR). The invention also relates to process for the preparation of the compounds of the invention.

Background of the invention

Ca²⁺ has been known to be an intracellular second messenger, with the molecular identification of an extracellular calcium sensing receptor (CaSR), it has further opened the possibility that Ca²⁺ might also function as a messenger outside the cells. Information about the local changes in extracellular concentration of Ca²⁺ is conveyed to the interior of many types of cells through this unique receptor.

Calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that signals through the activation of phospholipase C, increasing levels of inositol 1,4,5- triphosphate and cytosolic calcium. The CaSR belongs to the subfamily C of the GPCR superfamily. Structurally, CaSR has an exceptionally large amino-terminal extracellular (ECD) domain (about 600 aminoacids), a feature that is shared by all of the members of the family C GPCRs. In mammals, the expression of CaSR is quite ubiquitous and its presence in the parathyroid gland plays an important role in the secretion of parathyroid hormone (PTH). The reduction in serum calcium leads to the secretion of PTH. Consequently, PTH secretion leads to conservation of serum Ca ⁺ by increasing kidney retention and intestinal absorption of Ca²⁺. This happens indirectly through the PTH-induced synthesis of the active vitamin D metabolite, 2,5-dihydroxyvitamin D. In addition, the pulsatile action of PTH has anabolic effects on bone development and its sustained levels can lead to catabolic effects, in which the bones breakdown releasing Ca²⁺ as in the case of osteoporosis. All these systems converge in maintenance of baseline serum Ca²⁺ and it involves a tight regulation between serum PTH and extracellular calcium which is mediated by the remarkable CaSR.

In conditions such as primary and secondary hyperparathyroidism, there is excessive secretion of parathyroid hormone due to hyperplasia of the glands. The most common cause of primary hyperparathyroidism (PHPT) is parathyroid adenoma resulting from clonal mutations (-97%) and associated hypercalcemia. In the case of secondary hyperparathyroidism (SHPT), it is most commonly seen in patients with chronic renal failure. The kidneys fail to convert enough vitamin D to its active form and also does not adequately excrete phosphorous. Excess phosphorous further depletes serum calcium forming calcium phosphate (kidney stones) leading to hypocalcemia.

Small molecules that are positive allosteric modulators called calcimimetics modulate and improve the receptors sensitivity to the already existing milieu of extracellular ionic calcium. This would eventually translate in lowering plasma PTH levels thereby improving conditions of hyperparathyroidism, calcium homeostasis and bone metabolism.

WO 2013/124828, WO2013/002329, WO2013/136288, US2014/0080770, US2014/01554161, WO 2012/127388, WO 2012/120476, WO 2012/127385, WO 2012/069421, WO 2012/069419, WO 2012/069402, US 2011/0028452, WO 2010/150837, WO 2010/136037, WO 2010/042642, WO 2010/038895, WO 2009/065406, WO 2008/059854, WO 2006/123725, WO2004/106280, WO 2004/069793, WO 2002/012181 and US 2003/0199497 applications disclose the compounds related to calcium sensing receptors (CaSR) for the treatment of various diseases mediated by CaSR. And also . Med. Chem. (2006), 49, 5119-5128 discloses the compounds related to calcium sensing receptors (CaSR).

Summary of the Invention

In accordance with one aspect, the invention provides compounds having the structure of Formula (I),

(I) wherein,

Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i-₃0H, -C(0)NH-alkyl, -S(0)₂- alkyl, -S(0)₂NH-alkyl, -C(0)OH, -C(0)0-alkyl, -(CR_aR_b)i_₃C(0)OH and -(CR_aR_b)i_₃C(0)0- alkyl;

R₂ is substituted or unsubstituted phenylor substituted or unsubstituted naphthyl, wherein the substituents may be one or more and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄, -NR₅R₆ and substituted or unsubstituted cycloalkyl; is selected from -C(0)OH, -C(0)Oalkyl, -C(0)NR₅R₆, -(CR_aR_b)i_₃C(0)OH, _₃C(0)0-alkyl, -0-(CR_aR_b)i_₃C(0)OH, -0-(CR_aR_b)i_₃C(0)0-alkyl, -CR_C=CR_C- C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,- OR₄ and -S(0)₂-alkyl;

R_a and R are independently selected from hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl; or R_a and R _, together with the carbon atom to which they are attached, may form a substituted or unsubstituted 3 to 6 membered saturated carbocyclic ring;

R_c is independently selected from hydrogen, halogen and substituted or unsubstituted alkyl;

R3, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -OR₄;

R₄ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyland substituted or unsubstituted cycloalkyl;

R5 and R₆ are independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl; and

'n' is an integer ranging from 0 to 2, both inclusive; ora pharmaceutically acceptable salt thereof.

It should be understood that the Formula (I) structurally encompasses all tautomers, stereoisomers, enantiomers and diastereomers wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

According to oneembodiment, there are provided compounds having the structure of Formula (II):

(Π) wherein,

Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i_₃OH, -C(0)NH-alkyl, -C(0)OH and -(CR_aR_b)i-₃C(0)OH;

X is selected from -C(0)OH, -C(0)Oalkyl, -(CR_aR_b)i_₃C(0)OH, -(CR_aR_b)i_₃C(0)0- alkyl, -0-(CR_aR_b)i_₃C(0)OH, -CR_c=CR_c-C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄, and -S(0)₂-alkyl;

R₃, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -OR4;

R ,which may be same or different at each occurrence, isindependently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄ and substituted or unsubstituted cycloalkyl; R₄ is selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;

R_a and R_b are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl;

R_c is independently a hydrogen or substituted or unsubstituted alkyl; 'n' is an integer ranging from 0 to 2, both inclusive; and 'p' is an integer ranging from 0 to 2, both inclusive; ora pharmaceutically acceptable salt thereof.

According to anotherembodiment, there are provided compounds having the structure of Formula (III):

(III) wherein,

Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i_₃OH, -C(0)NH-alkyl, -C(0)OH and -(CR_aR_b)i-₃C(0)OH; X is selected from -C(0)OH, -C(0)Oalkyl, -(CR_aR_b)i-₃C(0)OH, -(CR_aR_b)i_

₃C(0)0-alkyl, -0-(CR_aR_b)i_₃C(0)OH, -CR_c=CR_c-C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄, and -S(0)₂-alkyl;

R₄ is selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;

R_a and R_b are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl; R_c is independently a hydrogen or substituted or unsubstituted alkyl; and 'n' is an integer ranging from 0 to 2, both inclusive; ora pharmaceutically acceptable salt thereof.

According to another embodiment, there are provided compounds having the structure of Formula (IV):

wherein,

R₂ is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or more and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄and substituted or unsubstituted cycloalkyl;

R₃, which may be same or different at each occurrence, is independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -OR4; R₄ is selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted haloalkyl;

R_c is independently a hydrogen or substituted or unsubstituted alkyl; and

It should be understood that the Formula (I), Formula (II) Formula (III) and/or Formula (IV) structurally encompasses all tautomers, stereoisomers, enantiomers and diastereomers, including isotopes wherever applicable and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein.

The details of one or more embodiments of the invention set forth in the below are illustrative in nature only and not intended to limit to the scope of the invention. Other features, objects and advantages of the inventions will be apparent from the description and claims.

According to another embodiment, there are provided compounds of Formula (I) in which Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i_₃OH, -C(0)NH-alkyl, -C(0)OH and -(CR_aR_b)i_₃C(0)OH; wherein R_a andR_b are independently hydrogen or substituted or unsubstituted alkyl.

According to another embodiment, there are provided compounds of Formula (I) in which X is selected from -C(0)OH, -(CR_aR_b)i_₃C(0)OH, -0-(CR_aR_b)i_₃C(0)OH, -CR_C=CR_C- C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl,- OR₄and -S(0)₂-alkyl; wherein R_a, R_bandR_care independently hydrogen or substituted or unsubstituted alkyl. According to another embodiment, there are provided compounds of Formula (I) in which R₂ is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or two and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -O-alkyl and substituted or unsubstituted cycloalkyl;

According to another embodiment, there are provided compounds of Formula (I) in which R₃ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -O-alkyl and 'n' is 0, 1 or 2;

In another aspect of the invention, there is provided a compound of Formula (I) useful in treating, managing or lessening the severity of diseases, disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators.

In another aspect, the invention provides a pharmaceutical composition comprising at least one compound of Formula (I) and at least one pharmaceutically acceptable excipient.

In another aspect, the invention provides a pharmaceutical composition of compound of Formula (I) useful in treating, managing or lessening the severity of the diseases disorders, syndromes or conditions associated with calcium sensing receptor (CaSR) modulators in a subject, in need thereof by administering to the subject, one or more compounds described herein in a therapeutically effective amount to cause modulation of such receptor.

In another aspect, there are provided process for the preparation of compounds of Formula (IV)

(IV) wherein R_1; R₂, R₃, X and 'n' are as defined herein above; the process comprising the stepsof:

(a) reacting compound of Formula (1) with Formula (la) to give compound of Formula (2)

(1) (2)

(b) reactingcompound of Formula (2)with methyl sulphonyl chloride, in the presence of DIPEA in suitable solvent to give compound of Formula (3)

(c) reacting compound ofFormula (3) with compound of Formula (3b), in the presence of sodium carbonate to give compound of Formula (5)

(d) coupling ofcompound of Formula (5) with boronic acid of Formula (4a) by using sodium carbonate and PdCl₂(dppf) to give compound of Formula (IV)

(e) hydrolyzing a compound of Formula (IV) (when X or Ri represents an ester) with LiOH using suitable solvent to give acid compound of Formula (IV)

(IV)

Detailed description of the invention Definitions and Abbreviations:

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below.

For purposes of interpreting the specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. The terms "halogen" or "halo" means fluorine, chlorine, bromine, or iodine.

Unless otherwise stated, in the present application "oxo" means C(=0) group. Such an oxo group may be a part of either a cycle or a chain in the compounds of the present invention.

The term "alkyl" refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl, 1, 1-dimethylethyl (t-butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched.

The term "alkenyl" refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Non-limiting Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), zso-propenyl, 2-methyl-l- propenyl, 1- butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched.

The term "alkynyl" refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon-carbon triple bond. Non-limiting Examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched.

The term "alkoxy" refers to an alkyl group attached via an oxygen linkage. Non-limiting Examples of such groups are methoxy, ethoxy and propoxy and the like. Unless set forth or recited to the contrary, all alkoxy groups described or claimed herein may be straight chain or branched.

The term "haloalkyl" refers to an alkyl group as defined above that is substituted by one or more halogen atoms as defined above. Preferably, the haloalkyl may be monohaloalkyl, dihaloalkyl or polyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine or fluorine atom. Dihaloalkyl and polyhaloalkyl groups can be substituted with two or more of the same halogen atoms or a combination of different halogen atoms. Preferably, a polyhaloalkyl is substituted with up to 12 halogen atoms. Non-limiting Examples of a haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl and the like. A perhaloalkyl refers to an alkyl having all hydrogen atoms replaced with halogen atoms. Unless set forth or recited to the contrary, all haloalkyl groups described or claimed herein may be straight chain or branched.

The term "haloalkoxy" refers to a haloalkyl, defined herein, group attached via an oxygen linkage. Non-limiting Examples of such groups are monohaloalkoxy, dihaloalkoxy or polyhaloalkoxy including perhaloalkoxy. Unless set forth or recited to the contrary, all haloalkoxy group described or claimed herein may be straight chain or branched.

The term "cycloalkyl" refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Examples of multicycliccycloalkyl groups include, but are not limited to, perhydronaphththyl, adamantyl and norbornyl groups, bridged cyclic groups or spirobicyclic groups, e.g. spiro(4,4)non-2-yl and the like.

The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above, directly bonded to an alkyl group as defined above, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, etc.

The term "aryl" refers to an aromatic radical having 6- to 14- carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, and biphenyl and the like. The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH₂C₆H₅ and -C₂H₄C₆H₅.

"3 to 6 membered saturated carbocyclic ring" refers to a carbocyclic ring which is monocyclic and non-aromatic carbocyclic ring as defined herein.

A "carbocyclic ring" or "carbocycle" as used herein refers to a 3- to 6 membered saturated or partially unsaturated, monocyclic fused bicyclic, spirocyclic ring containing carbon atoms, which may optionally be substituted, for Example, carbocyclic rings include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylene, cyclohexanone, etc.

The term "heterocyclic ring" or "heterocyclyl ring" or "heterocyclyl", unless otherwise specified, refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more heteroatom(s) independently selected from N, O or S. The heterocyclic ring may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems and the nitrogen, carbon, oxygen or sulfur atoms in the heterocyclic ring may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized, the heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s), and one or two carbon atoms(s) in the heterocyclic ring or heterocyclyl may be interrupted with -CF₂-, -C(O)-, -S(O)-, S(0)₂, - C(=N-alkyl)-, or -C(=N-cycloalkyl), etc. In addition heterocyclic ring may also be fused with aromatic ring. Non-limiting Examples of heterocyclic rings include azetidinyl, benzopyranyl, chromanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolinyl, thiazolidinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfoneindoline, benzodioxole, tetrahydroquinoline, tetrahydrobenzopyran and the like. The heterocyclic ring may be attached by any atom of the heterocyclic ring that results in the creation of a stable structure.

The term "heteroaryl" unless otherwise specified, refers to a substituted or unsubstituted 5- to 14- membered aromatic heterocyclic ring with one or more heteroatom(s) independently selected from N, O or S. The heteroaryl may be a mono-, bi- or tricyclic ring system. The heteroaryl ring may be attached by any atom of the heteroaryl ring that results in the creation of a stable structure. Non-limiting Examples of a heteroaryl ring include oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indolizinyl, acridinyl, phenazinyl, phthalazinyl and the like.

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

The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless otherwise specified, the term "substituted" as used herein refers to a group or moiety having one or more substituents attached to the structural skeleton of the group or moiety. Such substituents include, but are not limited to hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), alkyl, haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heterocyclic ring, heterocyclylalkyl, heteroarylalkyl, -C(0)OR^x, - C(0)R^x, -C(S)R^X, -C(0)NR^xR^y, -NR^xC(0)NR^yR^z, -N(R^x)S(0)R^y, -N(R^x)S(0)₂R^y, -NR^xR^y, - NR^xC(0)R^y, -NR^xC(S)R^y, -NR^xC(S)NR^yR^z, - S(0)₂NR^xR^y, -OR^x, -OC(0)R^x, -OC(0)NR^xR^y, -R^xC(0)OR^y, -R^xC(0)NR^yR^z, -R^xC(0)R^y, -SR^X, and -S(0)₂R^x; wherein each occurrence of R^x, R^y and R^z are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl and aryl. The aforementioned "substituted" groups cannot be further substituted. For Example, when the substituent on "substituted alkyl" is "aryl" or "alkenyl", the aryl or alkenyl cannot be substituted aryl or substituted alkenyl respectively.

The compounds of the present invention may have one or more chiral centers. The absolute stereochemistry at each chiral center may be 'R' or 'S'. The compounds of the invention include all diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included.

The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. The terms "racemate" or "racemic mixture" refer to a mixture of equal parts of enantiomers. A "tautomer" refers to a compound that undergoes rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula (I). The term "treating" or "treatment" of a state, disorder or condition includes: (a) delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

The term "modulate" or "modulating" or "modulation" or "modulator" refers to an increase in the amount, quality, or effect of a particular activity or function of the receptor. By way of illustration and not limitation, it includes agonists, partial agonists, allosteric modulators of calcium sensing receptor (CaSR) of the present invention. Such modulation may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway. The term "allosteric modulators of calcium-sensing receptor", refers to the ability of a compound bind to calcium sensing receptors and induce a conformational change that reduces the threshold for calcium sensing receptor activation by the endogenous ligand Ca²⁺ depending on the concentration of the compound exposed to the calcium-sensing receptor.

The term "subject" includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife). A "therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, disorder, syndrome or condition, is sufficient to cause the effect in the subject which is the purpose of the administration. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.

Pharmaceutically Acceptable Salts:

The compounds of the invention may form salts with acid or base. The compounds of invention may be sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compound as a pharmaceutically acceptable salt may be appropriate. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic acid addition salts formed by addition of acids including hydrochloride salts. Non-limiting Examples of pharmaceutically acceptable salts are inorganic, organic base addition salts formed by addition of bases. The compounds of the invention may also form salts with amino acids. Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for Example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.

With respect to the overall compounds described by the Formula (I), the invention extends to these stereoisomeric forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereoisomeric forms of the invention may be separated from one another by a method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis or chiral HPLC (high performance liquid chromatography. Tautomeric forms and mixtures of compounds described herein are also contemplated. Screening of compounds of invention for calcium sensing receptor (CaSR) modulation activity can be achieved by using various in-vitro and in-vivo protocols mentioned herein below or methods known in the art. Pharmaceutical Compositions

The invention relates to pharmaceutical compositions containing the compounds of the Formula (I) disclosed herein. In particular, pharmaceutical compositions containing a therapeutically effective amount of at least one compound of Formula (I) described herein and at least one pharmaceutically acceptable excipient (such as a carrier or diluent). Preferably, the contemplated pharmaceutical compositions include the compound(s) described herein in an amount sufficient to modulate calcium sensing receptor (CaSR) mediated diseases described herein when administered to a subject.

The subjects contemplated include, for Example, a living cell and a mammal, including human mammal. The compound of the invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. The pharmaceutically acceptable excipient includes pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.

Examples of suitable carriers or excipients include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, salicylic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.

The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.

The pharmaceutical compositions described herein may be prepared by conventional techniques known in the art. For Example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for Example, in a sachet.

The pharmaceutical compositions may be in conventional forms, for Example, capsules, tablets, caplets, orally disintegrating tablets, aerosols, solutions, suspensions or products for topical application.

The route of administration may be any route which effectively transports the active compound of the invention to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). Solid oral Formulations include, but are not limited to, tablets, caplets, capsules (soft or hard gelatin), orally disintegrating tablets, dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Liquid Formulations include, but are not limited to, syrups, emulsions, suspensions, solutions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions. For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.

The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as pocketed tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, caplet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

For administration to subject patients, the total daily dose of the compounds of the invention depends, of course, on the mode of administration. For Example, oral administration may require a higher total daily dose, than an intravenous (direct into blood). The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the potency of the active component or mode of administration. Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in subject based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects for the patient. For Example, the daily dosage of the CaSR modulator can range from about 0.1 to about 30.0 mg kg. Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the invention.

Methods of Treatment In another aspect, the invention provides compounds and pharmaceutical compositions thereof that are useful in treating, managing and/or lessening the severity of diseases, disorders, syndromes or conditions modulated by calcium sensing receptor (CaSR). The invention further provides method of treating diseases, disorders, syndromes or conditions modulated by CaSR in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the invention.

In another aspect of the invention, the methods provided are also useful for diagnosis of conditions that can be treated by modulating CaSR for determining if a patient will be responsible to therapeutic agents.

In another aspect, the invention provides a method for the treatment of diseases, disorders or conditions through modulating CaSR. In this method, a subject in need of such treatment is administered a therapeutically effective amount of a compound of Formula (I) described herein.

The compound and pharmaceutical composition of the present invention is useful to a subject in need of the treatment having a disease, disorder, syndrome or condition characterized by one or more of the following: (a) abnormal calcium ion homeostasis, (b) an abnormal level of a messenger whose production or secretion is affected by the calcium sensing receptor (CaSR) activity or (c) an abnormal level of activity of a messenger whose function is affected by the calcium sensing receptor activity. In one aspect, the patient has a disease, disorder, syndrome or condition characterized by an abnormal level of one or more calcium sensing receptor-regulated components and the compound is active on a CaSR of a cell including parathyroid cell, bone cells (pre-osteoclast, osteoclast, pre-osteoblast, osteoblast), juxtaglomerular kidney cell, kidney messengial cell, glomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, cell of the thick ascending limb of Henle's loop and/or collecting duct, parafollicular cell in the thyroid (C-cell), intestinal cell, platelet, vascular smooth muscle cell, gastrointestinal tract cell, pituitary cell or hypothalamic cell. The messenger of the calcium sensing receptor is Calcium. The compound of Formula (I), being modulators of CaSR, is potentially useful in treating, managing and/or lessening the severity, morbidity/mortality or complications of diseases, disorders, syndromes or conditions include but are not limited to primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular &valvular calcification, abnormal calcium homeostasis such as hypercalcemia, abnormal phosphorous homeostasis such as hypophosphatemia, bone related diseases or complications arising due to hyperparathyroidism, chronic kidney disease or parathyroid carcinoma, bone loss post renal transplantation, osteitisfibrosacystica, adynamic bone disease, renal bone diseases, cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease, certain malignancies in which (Ca²⁺)_e ions are abnormally high, cardiac, renal or intestinal dysfunctions, podocyte-related diseases, abnormal intestinal motility, diarrhea, augmenting gastrin or gastric acid secretion to directly or indirectly benefit in atrophic gastritis or to improve absorption of pharmacological compounds, drugs or supplements from gastrointestinal tract by augmenting gastric acidity.

Primary hyperparathyroidism, is a disorder of one or more of the parathyroid glands, resulting from a hyper function of the parathyroid glands themselves (acquired sporadically or familial) resulting in PTH over secretion which could be due to single or double adenoma, hyperplasia, multi-gland disease or rarely, carcinoma of the parathyroid glands. As a result, the blood calcium rises to a level that is higher than normal (called hypercalcemia). This elevated calcium level can cause many short-term and long-term complications.

Secondary hyperparathyroidism occurs when a decrease in circulating levels of Ca²⁺ level stimulates PTH secretion. One cause of secondary hyperparathyroidism is chronic renal insufficiency (also referred to as chronic kidney disease or CKD), such as that in renal polycystic disease or chronic pyelonephritis, or chronic renal failure, such as that in hemodialysis patients (also referred to as end stage renal disease or ESRD). Excess PTH may be produced in response to hypocalcemia resulting from low calcium intake, GI disorders, renal insufficiency, vitamin D deficiency, magnesium deficiency and renal hypercalciuria. Tertiary hyperparathyroidism may occur after a long period of secondary hyperparathyroidism and hypercalcemia.

In one aspect, the compound and composition of the present invention can be used in treating, managing and/or lessening the vascular or valvular calcification in a subject. In one aspect, administration of the compound of the invention retards or reverses the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits. In another aspect of the invention, administration of the compound of the invention prevents the formation, growth or deposition of extracellular matrix hydroxyapatite crystal deposits. In one aspect, the compounds of the invention may also be used to prevent or treat atherosclerotic calcification and medial calcification and other conditions characterized by vascular calcification. In one aspect, vascular calcification may be associated with chronic renal insufficiency or end-stage renal disease or excess calcium or PTH itself. In another aspect, vascular calcification may be associated with pre- or post-dialysis or uremia. In a further aspect, vascular calcification may be associated with diabetes mellitus I or II. In yet another aspect, vascular calcification may be associated with a cardiovascular disorder.

Abnormal calcium homeostasis such as hyperparathyroidism related diseases can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine. The compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hyperparathyroidism.

Abnormal phosphorous homeostasis such as hypophosphatemia can be characterized as described in standard medical textbooks, but not limited to Harrison's Principles of Internal Medicine. The compound and composition of the present invention can be used, in particular, to participate in a reduction of the serum levels in the parathyroid hormone known as PTH: these products could thus be useful for the treatment of diseases such as hypophosphatemia.

In one aspect, the podocyte diseases or disorders treated by methods of the present invention stem from the perturbations in one or more functions of podocytes. These functions of podocytes include: (i) a size barrier to protein; (ii) charge barrier to protein; (iii) maintenance of the capillary loop shape; (iv)counteracting the intra-glomerular pressure; (v) synthesis and maintenance of the glomerular basement membrane (GMB); (vi)production and secretion of vascular endothelial growth factor (VEGF) required for the glomerular endothelial cell (GEN) integrity. Such disorders or diseases include but are not limited to loss of podocytes (podocytopenia), podocyte mutation, an increase in foot process width, or a decrease in slit diaphragm length. In one aspect, the podocyte-related disease or disorder can be effacement or a diminution of podocyte density. In one aspect, the diminution of podocyte density could be due to a decrease in a podocyte number, for Example, due to apoptosis, detachment, lack of proliferation, DNA damage or hypertrophy. In one aspect, the podocyte-related disease or disorder can be due to a podocyte injury. In one aspect, the podocyte injury can be due to mechanical stress such as high blood pressure, hypertension, or ischemia, lack of oxygen supply, a toxic substance, an endocrinologic disorder, an infection, a contrast agent, a mechanical trauma, a cytotoxic agent (cis-platinum, adriamycin, puromycin), calcineurin inhibitors, an inflammation (e.g., due to an infection, a trauma, anoxia, obstruction, or ischemia), radiation, an infection (e.g., bacterial, fungal, or viral), a dysfunction of the immune system (e.g., an autoimmune disease, a systemic disease, or IgA nephropathy), a genetic disorder, a medication (e.g., anti -bacterial agent, anti-viral agent, anti-fungal agent, immunosuppressive agent, anti-inflammatory agent, analgesic or anticancer agent), an organ failure, an organ transplantation, or uropathy. In one aspect, ischemia can be sickle-cell anemia, thrombosis, transplantation, obstruction, shock or blood loss. In one aspect, the genetic disorders may include congenital nephritic syndrome of the Finnish type, the fetal membranous nephropathy or mutations in podocyte-specific proteins. In one aspect, the compounds of the invention can be used for treating abnormal intestinal motilities disorders such as diarrhea. The methods of the invention comprise administering to the subject a therapeutically effective amount of the compounds of Formula I. In a further aspect, diarrhea can be exudative diarrhea, i.e., resulting from direct damage to the small or large intestinal mucosa. This type of diarrhea can be caused by infectious or inflammatory disorders of the gut. In one aspect, exudative diarrhea can be associated with gastrointestinal or abdominal surgery, chemotherapy, radiation treatment, inflammation or toxic traumatic injury. In another aspect, diarrhea can be secretary, means that there is an increase in the active secretion, or there is an inhibition of absorption. There is little to no structural damage. The most common cause of this type of diarrhea is cholera. In another aspect, diarrhea can be due to acceleration of intestinal transit (rapid transit diarrhea). Such condition may occur because the rapid flow-through impairs the ability of the gut to absorb water.

The compound and composition of the present invention can be used, in particular, to participate in an augmenting gastrin or gastric acid secretion to directly or indirectly benefit certain medical conditions such as but not limited to atrophic gastritis or to improve absorption of pharmacological compounds, drugs or supplements from gastro-intestinal tract by augmenting gastric acidity.

All of the patent, patent application and non-patent publications referred to in this specification are incorporated herein by reference in their entireties.

General Methods of Preparation

The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme- 1 to 2. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the scope of the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the isomers of the compounds in described in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.

Scheme-1

w ere s ac

The compounds of Formula (I), wherein X, R_1; R₂, R₃, and 'n' are as described herein above, can be prepared by following the sequential transformations as depicted in Scheme-1. Compound of Formula (2) can be prepared from compound of Formula ( 1 ) by reaction with appropriate bromoalcohol (la) in the presence of Cs₂C0₃ in suitable solvent. The compound of Formula (2) is reacted with methanesulphonyl chloride in the presence of DIPEA in suitable solvent to afford compound of Formula (3) which further reacted with Formula (3a) in the presence of Na₂C0₃in suitable solvent to afford compound of Formula (4). This compound of Formula (4) is coupled with boronic acid of Formula (4a) in the presence of Na₂C0₃ and PdCl₂(dppf) to give compound of Formula (I) (mixture of isomers) which is further separated by column chromatography to get single isomer. The compound of Formula (I) (ester) can be treated with LiOH (or any suitable alkali) in a suitable solvent to afford the acid compound of Formula (IV). Alternatively the compound of Formula (IV) can be prepared by following the procedure as depicted in Scheme-2.

Scheme-2

(IV)

where X is acid

Compound of Formula (3) is reacted with specific amine of Formula (3b) in the presence of sodium carbonate in suitable solvent to afford compound of Formula (5). This compound of Formula (5) is coupled with boronic acid of Formula (4a) in presence of sodium carbonate and PdCl₂(dppf) to give compound of Formula (IV). The compound of Formula (IV) (when ester) can be treated with LiOHor any suitable alkali in a suitable solvent to afford the corresponding acid compound of Formula (IV).

Experimental

The invention is further illustrated by the following Examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. The Examples set forth below demonstrate the synthetic procedures for the preparation of the representative compounds. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. The aforementioned patents and patent applications are incorporated herein by reference.

INTERMEDIATES

Intermediate- 1 : Hydroxylntermediate:

To a well stirred solution of the corresponding phenol (1 equivalent) in DMF was added, CS2CO3 (2 equivalent) and the mixture was heated to 50°C for 30 min. It was cooled to room temperature and bromoalcohol (2-bromoethanol or 3-bromopropan-l-ol) (1.1 equivalent) was added to the above solution. The reaction mixture was further heated to 50°C overnight. After completion of reaction (checked by TLC), it was quenched with water, extracted with Ethyl acetate, again washed with water, dried (Na₂S04) and concentrated to give the crude product that was purified by column chromatography to give the desired compound (45-65%). The similar procedure was used to prepare Intermediate- la to Intermediate- lm mentioned in below Table- 1.

Table-1:

Intermediate-2: O-mesylatelntermediate:

To a solution of hydroxyllntermediate (from Intermediate- 1 a- lm) (1 equivalent) in dry DCM was added, DIPEA (4 equivalent) at 0°C and the mixture was stirred for 10 min. To this, Methyl sulfonylchloride (1.5 equivalent) was added and the reaction was stirred at room temperature for 2h. TLC showed complete conversion of starting material. It was quenched with water and extracted with DCM. The organic layer was washed with water, dried (Na₂S04) and concentrated to give the desired compound that was used as such (80-90%). The similar procedure was used to prepare Intermediate-2a to 2m mentioned in below Table- 2. Table-2:

Intermediate-3:

A mixture of mesylate derivative (from Intemediate-2a-2m) (1 equivalent), the corresponding chiral amine (2 equivalent) ((/?)- l-(naphthalen-l-yl) ethanamine or (R)-l-(3- methoxyphenyl)ethanamine), and Na₂C0₃ (1.3 equivalent) was heated to 110°C overnight. After completion of the reaction (checked by TLC), the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried (Na₂S0₄) and concentrated to give the desired compound (50-60%). The similar procedure was used to prepare Intermediate-3 a to 3s mentioned in below Table-3. Table-3:

Examples

Example- 1

(R )-N-Methyl-5-(2-(( l-(naphthalen- l-yl)ethyl)amino)ethoxy)-3'-(trifluoromethyl)-[ 1 , 1 '- biphenyl]-3-carboxamide

To a solution of Intermediate-3a (1 equivalent) in dioxane was added, 3- (trifluoromethyl)phenylboronic acid (1.2 equivalent), Na₂C0₃ (2 equivalent) and H₂0. The mixture was degassed for 15 min and then, PdCl₂(dppf) (5 mol%) was added. The reaction mixture was heated to 80°C overnight. TLC showed complete conversion of starting material so it was filtered through a pad of celite and concentrated to give the crude product that was purified by column chromatography (10% Ethyl acetate -hexane) to give the desired compound (yield: 50-60 %); Mass: m/z: 493 (M+1)⁺.¹H NMR (400 MHz, DMSO-J₆) 8.30 (d, = 8 Hz, 1H), 8.07(d, 7 =8 Hz 1H), 7.96- 7.91 (m, 2H), 7.67 - 7.61 (m, 6H), 7.59-7.52 (m, 3H), 7.01- 6.96 (m, 2H), 5.42 (m, 1H), 4.50 - 4.36 (m, 2H), 3.50 - 3.48(m, 1H), 3.25 - 3.03 (m, 4H), 2.1 (d, = 5.6 Hz, 3H) ; m/z: 493 (M+l)⁺ The Example-2 to Example-27 in Table-4 were prepared by following the similar procedure as described in Example- 1 by taking appropriate Intermediate from Intermediate3 a-3s and corresponding phenyl boronic acid.

Table-4:

Examples Structures and Names Ή NMR and Mass

2 ^XH NMR (400 MHz, DMSO-d6) δ

H [1 Ί H [1 Ί 8.58-8.57 (d, = 4.4 Hz, 1H), 8.29- 8.27 (d, = 7.6 Hz, 1H), 8.21 (s, 1H), 7.95-7.91 (m, 3H), 7.85-7.72

CF₃ (m 3H), 7.54 - 7.50 (m, 3H), 7.49-

(R)-N-methyl-5-(2-((l-(naphthalen- 7.44 (m, 2H), 4.69-4.68 (m, 1H), l-yl)ethyl)amino)ethoxy)-4'- 4.19-4.16 (m, 2H), 2.90-2.86 (m, (trifluoromethyl)-[ 1 , 1 '-biphenyl] -3- 2H), 2.82(s, 3H), 1.41-1.40 (d, = carboxamide 6.4Hz, 3H); m/z: 493 (M+l)⁺

3 ^XH NMR (400 MHz, DMSO-d6) δ

H 1 J n M 1 8.32-8.27 (m, 2H), 7.93-7.91 (m,

1H), 7.81-7.74 (m, 2H), 7.73-7.68 a, (m, 3H), 7.54-7.45 (m, 4H), 7.41 -

(i?)-3'-chloro-N-methyl-5-(2-(( 1 - 7.35 (m, 2H), 4.71-4.67 (q, 1H),

(naphthalen- 1 - 4.19-4.16(m,2H), 2.90-2.81 (m, 2H), yl)ethyl)amino)ethoxy)-[ 1 , Γ- 2.80(s, 3H), 1.42-1.40 (d, = 6.8 biphenyl] -3-carboxamide Hz, 3H). m/z: 459 (M+l)⁺

1 ^Ξ- ^{1 X}H NMR (400 MHz, Chloroform-J) δ 8.07 - 7.99 (m, 2H), 7.83 - 7.74 (m, 2H), 7.56 (t, = 1.6 Hz, 1H), 7.36-7.35 (dd, /= 2.4, 1.4 Hz, 1H),

S0₂CH₃

7.25-7.23 (td, = 2.9, 2.4, 1.4 Hz,

(i?)-N-Ethyl-5-(2-((l-(3- 1H), 7.02 - 6.91 (m, 2H), 6.82-6.80 methoxyphenyl)ethyl)amino)ethoxy)- (ddd, = 8.2, 2.5, 1.2 Hz, 1H), 6.23 4'-(methylsulfonyl)-[ 1 , l'-biphenyl]-3- (t, = 5.6 Hz, 1H), 4.23 - 4.06 (m, carboxamide

2H), 3.88 - 3.79 (m, 4H), 3.56-3.50 (qd, =7.4, 5.7 Hz, 3H), 3.11 (s, 3H), 3.05 - 2.82 (m, 2H), 1.44-1.40 (d, 3H), 1.31-1.27 (t, 3H); m/z: 497 (M+l)⁺ ^XH NMR (400 MHz, DMSO-J₆) 8.32 - 8.24 (m, 1H), 8.09 - 7.96 (m, 3H), 7.62 (dtd, = 9.4, 7.0, 4.4 Hz, 3H), 7.40 (dd, / = 8.3, 2.2 Hz, 1H),

F 7.31 (dd, = 11.2, 8.4 Hz, 1H), 7.21

(i?j-2-((4',5-Difluoro-3'-methoxy- (ddt, = 11.5, 9.5, 2.0 Hz, 2H), 7.08

[1,1 '-biphenyl] -3-yl)oxy)-N-( 1 - (t, = 1.8 Hz, 1H), 6.85 (dt, = (naphthalen- 1 -yl)ethyl)ethanamine 10.7, 2.2 Hz, 1H), 5.45 (q, = 6.4

Hz, 1H), 4.50 - 4.32 (m, 2H), 3.94 (s, 3H), 3.44 (d, = 11.4 Hz, 1H), 3.23 (d, = 12.0 Hz, 1H), 1.74 (d, = 6.6 Hz, 3H) ; m/z: 434 (M+l)⁺ ^XH NMR (400 MHz, DMSO-J₆)

7.42 - 7.32 (m, 3H), 7.24 - 7.20 (m, 1H), 7.15 - 7.09 (m, 1H), 7.04 (dt, = 10.2, 1.9 Hz, 1H), 6.99 - 6.93 (m, 2H), 6.72 (dt, = 10.9, 2.2 Hz, 1H),

(i?)-3-((5-Fluoro-4'-methoxy-3',5'- 4.38 (q, J = 6.5 Hz, 1H), 4.11 (td, dimethyl-[ 1 , 1 '-biphenyl] -3-yl)oxy)- = 6.1 , 2.7 Hz, 2H), 3.77 (s, 3H), N-(l-(3-methoxyphenyl) 3.68 (s, 3H), 2.98 (s, 1H), 2.78 (s, ethyl)propan- 1 -amine 1H), 2.28 (s, 6H), 2.16 - 2.06 (m,

2H), 1.58 (d, = 6.7 Hz, 3H); m/z: 438 (M+l)⁺ ^XH NMR (400 MHz, Chloroform-J) δ 7.45 - 7.40 (m, 1H), 7.24 (t, = 8.0 Hz, 1H), 7.11 - 7.05 (m, 2H), 6.91 (dp, = 3.7, 1.3 Hz, 2H), 6.88

CI

- 6.76 (m, 3H), 6.60 (dt, 7 = 10.6, fi?j-3-((4'-Chloro-5-fluoro-3'- 2.3 Hz, 1H), 4.06 (td, = 6.2, 3.6 methoxy-[ 1 , l'-biphenyl]-3-yl)oxy)-N- Hz, 2H), 3.98 (s, 3H), 3.85 - 3.81 ( 1 -(3 -methoxyphenyl)ethyl)propan- 1 - (m, 1H), 3.80 (s, 3H), 2.79 - 2.62 amine

(m, 2H), 2.05 - 1.93 (m, 2H), 1.40 (d, = 6.6 Hz, 3H); m/z: 444 (M+l)⁺ ^XH NMR (400 MHz, DMSO-d6) 7.67 (s, 1H), 7.60 - 7.51 (m, 2H), 7.43 (d, = 2.0 Hz, 1H), 7.40 - 7.25 (m, 4H), 7.19 - 7.14 (m, 1H), 7.00 -

CI 6.92 (m, 1H), 4.45 (dt, = 21.0, 6.4

(i?)-2-((4'-Chloro-3'-methoxy-5- Hz, 3H), 3.99 (s, 3H), 3.77 (s, 3H),

^XH NMR (400 MHz, DMSO-J₆) δ

8.30 - 8.25 (m, 1H), 8.06 - 7.92 (m, 7H), 7.68 - 7.57 (m, 3H), 7.28 (dt, = 9.7, 1.9 Hz, 1H), 7.15 (t, = 1.8 Hz, 1H), 6.95 (dt, / = 10.6, 2.2 Hz,

0 1H), 5.46 (q, = 6.2 Hz, 1H), 4.47 -

(i?)-2-((5-Fluoro-4'-(methylsulfonyl)- 4.33 (m, 2H), 3.53 - 3.40 (m, 2H),

[ 1 , 1 '-biphenyl] -3-yl)oxy)-N-( 1 - 3.28 (s, 3H), 1.73 (d, = 6.6 Hz, (naphthalen- 1 -yl)ethyl)ethanamine 3H). m/z: 464 (M+l)⁺

Ή NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.56 (qd, = 4.7, 1.8 Hz, 1H), 7.54 - 7.46 (m, 3H), 7.37 (d, = 2.0 Hz, 1H), 7.26 (dd, =

CI

8.3, 2.0 Hz, 1H), 7.19 (dt, = 10.0, fi?j-3-((4'-Chloro-5-fluoro-3'- 1.9 Hz, 1H), 7.06 (t, = 1.8 Hz, methoxy-[ 1 , l'-biphenyl]-3-yl)oxy)-N- 1H), 6.82 (dt, = 10.8, 2.2 Hz, 1H), ( 1 -(3 -chlorophenyl)ethyl)propan- 1 - 4.52 - 4.40 (m, 1H), 4.14 (td, = amine

6.3, 2.8 Hz, 2H), 3.96 (s, 3H), 3.02 (s, 1H), 2.80 (s, 1H), 2.12 (ddt, = 18.1 , 12.9, 8.2 Hz, 2H), 1.59 (d, = 6.7 Hz, 3H); m/z: 449 (M+l)⁺ ^XH NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.61 - 7.51 (m, 2H), 7.43 (d, = 2.1 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.16 - 7.05 (m, 2H), 6.88

CI (dt, = 1 1.1 , 2.2 Hz, 1H), 4.52 -

2-((4'-Chloro-3'-methoxy-5- 4.37 (m, 3H), 3.99 (s, 3H), 3.78 (s, (trifluoromethyl)-[ 1 , 1 '-biphenyl] -3- 3H), 3.35 - 3.24 (m, 1H), 3.06 (q, yl)oxy)-N-(l-(3-fluoro-5- = 7.7, 6.5 Hz, 1H), 1.62 (d, = 6.7 methoxyphenyl)ethyl)ethanamine Hz, 3H) ; m/z: 498 (M+l)⁺

27 ^XH NMR (400 MHz, Chloroform-J) δ 7.58 (d, = 2.3 Hz, 1H), 7.42 (dd, = 8.5, 2.3 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.03 - 6.93 (m, 3H), 6.87 - 6.75 (m, 3H), 6.58 (dt, = 10.5, 2.3

(i?)-2-((3'-Chloro-5-fluoro-4'- Hz, 1H), 4.14 - 4.02 (m, 2H), 3.96 methoxy-[ 1 , l'-biphenyl]-3-yl)oxy)-N- (s, 3H), 3.83 (s, 3H), 3.01 - 2.79 (m, ( 1 -(3-methoxyphenyl)

2H), 1.43 (d, = 6.5 Hz, 3H); m/z: ethyl)ethanamine

430 (M+l)⁺

Example-28

(R )-4-Methyl-3'-(methylcarbamoyl)-5'-(2-(( 1 -(naphthalen- 1 -yl)ethyl)amino)ethoxy)-[ 1 , Γ- biphenyl]-3-carboxylic acid

Step-1: (Z?)-Methyl 4-methyl-3'-(methylcarbamoyl)-5'-(2-((l-(naphthalen-l-yl) ethyl) amino) ethoxy)-[ 1 , 1 '-biphenyl] -3-carboxylate

To a solution of (i?j-3-Bromo-N-methyl-5-(2-((l-(naphthalen-l-yl) ethyl) amino) ethoxy) benzamide (Intermediate-3a) (1 equivalent) in dioxane was added, (3-(methoxy carbon yl)-4- methylphenyl) boronic acid (1.2 equivalent), Na₂C0₃ (2 equivalent) and water. The mixture was degassed for 15 min and then, PdCl₂ (dppf) (5mol %) was added. The reaction mixture was heated to 80°C overnight. TLC showed complete conversion of starting material so it was filtered through a pad of celite and concentrated to give the crude product that was purified by column chromatography (10% Ethyl acetate-Hexanes) to give the desired compound (50-60 %).

Step-2: (i?j-4-Methyl-3'-(methylcarbamoyl)-5'-(2-((l-(naphthalen-l-yl)ethyl)amino)ethoxy)- [ 1 , l'-biphenyl]-3-carboxylic acid

To a solution of above Step-1 Intermediate (1 equivalent) in THF was added, LiOH (2 equivalent) in water and the reaction mixture was stirred at room temperature overnight. After completion (TLC), it was concentrated, washed with Ethyl acetate, and acidified (10% citric acid) to give the solid compound that was filtered and dried under vacuum (60-70%); m/z: 483 (M+l)⁺. 1H NMR (400 MHz, DMSO-d6) δ 8.58-8.57 (d, = 4.8 Hz, 1H), 8.29-8.27 (d, = 8 Hz, 1H), 7.98 (s, 1H), 7.93-7.91 (m, 1H), 7.79-7.63 (m 3H), 7.53 - 7.47 (m, 3H), 7.36 (s, 1H), 7.31 - 7.29 (m, 2H), 4.69-4.67 (m, 1H), 4.16-4.14 (m, 2H), 2.80-2.79 (m, 5H), 2.50(s, 3H), 1.41-1.39 (d, J = 6.4Hz, 3H); m/z: 483 (M+l)⁺

The Examples 29 to 116 given in Table-5 were prepared by following the similar coupling reaction procedure as described in Step- 1 of Example-28 by using appropriately substituted aryl boronic acid ester and appropriate Intermediates (from Intermediate-3a to 3s). Then this ester compound was ester hydrolysed by following the similar ester hydrolysis procedure as described in Step-2 of Example-28 using LiOH.

Table-5:

Exampl Structures and Names ^XH NMR and Mass

es

^XH NMR (400 MHz, DMSO-d6) δ 9.43 (s,

1H), 8.31-8.25 (m, 1H), 8.01 (dd, / = 10.1, 7.7 Hz, 3H), 7.84 (t, = 1.5 Hz, 1H), 7.67-7.49 (m, 7H), 7.33-7.29 (m, 1H), 5.47 (m, 1H), 4.45 (h, = 6.7 Hz, 2H),

(i?)-3'-Methoxy-5-(2-((l- 3.93 (s, 3H), 3.46 (d, 1H), 3.26 (d, 1H), (naphthalene- 1 -yl)ethyl)

1.74 (d, = 6.5 Hz, 3H); m/z: 510 (M+l)⁺ amino)ethoxy)-5'-(trifluoro

methyl)[ 1 , l'-biphenyl]-3-carboxylic

acid

Ή NMR (400 MHz, DMSO-J₆) δ 7.79 (t, = 1.4 Hz, 1H), 7.52 (d, = 8.2 Hz, 1H), 7.43 (dt, = 7.5, 2.1 Hz, 2H), 7.39-7.32 (m, 2H), 7.28-7.22 (m, 2H), 7.13 (d, =

CI

7.6 Hz, 1H), 6.95 (dd, = 8.2, 2.4 Hz,

(Z?)-4'-Chloro-3'-methoxy-5-(3-((l- 1H), 4.38 (m, 1H), 4.19 (tt, = 6.3, 3.0 (3 -methoxyphenyl)ethyl)

Hz, 2H), 3.97 (s, 3H), 3.76 (s, 3H), 3.00 amino )propoxy)-[ 1 , 1 '-biphenyl]-3- (m, 1H), 2.80 (m, 1H), 2.24 - 2.05 (m, carboxylic acid

2H), 1.59 (d, = 6.7 Hz, 3H); m/z: 470 (M+l)⁺

Ή NMR (400 MHz, DMSO-J₆) δ 7.84 (t, = 1.4 Hz, 1H), 7.70 (d, = 8.1 Hz, 1H), 7.55-7.45 (m, 3H), 7.44-7.30 (m, 2H),

7.26- 7.17 (m, 1H), 7.17-7.06 (m, 1H),

CF₃

7.03-6.89 (m, 1H), 4.45-4.32 (m, 1H),

(R )-3'-Methoxy-5-(3-(( 1 -(3-methoxy

4.27- 4.15 (m, 2H), 4.01 (s, 3H), 3.76 (s, phenyl) ethyl)amino) propoxy)-4'- 3H), 3.07-2.93 (m, 1H), 2.87-2.73 (m, (trifluoro methyl)- [1, 1 '-biphenyl] -3- 1H), 2.23-2.06 (m, 2H), 1.59 (d, = 6.7 carboxylic acid

phenyl)ethyl)amino) ethoxy)-[ 1 , 1 '- 2H), 2.61 (t, 7 = 7.7 Hz, 2H), 1.63 (d, = biphenyl]-3-yl)propanoic acid 6.7 Hz, 3H); m/z: 488 (M+l)⁺ ^XH NMR (400 MHz, DMSO-d6) δ 8.18 (q, = 3.8, 3.2 Hz, IH), 7.84-7.66 (m, 2H), 7.54-7.35 (m, 3H), 7.23 (t, = 7.8 Hz, IH), 7.18-7.0 (m, 2H), 6.99-6.75 (m, 4H),

F 4.15 (t, = 5.7 Hz, 2H), 3.82 (q, / = 6.6

(R,E)-3-(3'-(Difluoromethyl)-4- Hz, IH), 3.73 (s, 3H), 2.76 (ddt, / = 34.5, fluoro-5'-(2-(( 1 -(3-methoxy 12.1, 5.6 Hz, 2H), 1.29 (d, = 6.6 Hz, phenyl)ethyl)amino) ethoxy) -[ Ι, - 3H); m/z: 486 (M+l)⁺

biphenyl]-3-yl)acrylic acid

Ή NMR (400 MHz, DMSO-d6) δ 8.24 (dd, = 7.1 , 2.4 Hz, IH), 7.87 (ddd, = 8.7, 4.9, 2.4 Hz, IH), 7.78-7.68 (m, 2H), 7.62 (t, = 1.9 Hz, IH), 7.49-7.25 (m,

F 4H), 7.22-7.13 (m, IH), 7.01-6.93 (m,

(i?,E)-3-(4-Fluoro-3'-(2-(( 1 -(3- IH), 6.84 (d, = 16.1 Hz, IH), 4.45 (q, methoxy phenyl) ethyl) = 6.9, 5.6 Hz, 3H), 3.77 (s, 3H), 3.31 - amino)ethoxy)-5'-(trifluoro methyl)- 3.19 (m, IH), 3.10-2.96 (m, IH), 1.64 (d, [ 1, 1 '-biphenyl]-3-yl)acrylic acid = 6.7 Hz, 3H); m/z 504 (M+l)⁺ ^XH NMR (400 MHz, DMSO-d6) δ 7.47- 7.34 (m, 4H), 7.29-7.17 (m, 3H), 6.93 (ddd, = 7.8, 5.1, 1.4 Hz, 2H), 6.80-6.74 (m, IH), 4.13 (t, = 5.7 Hz, 2H), 3.76 (q, = 6.5 Hz, IH), 3.72 (s, 3H), 2.91 (t, =

(R j-3-(2-Fluoro-3'-(2-(( 1 -(3- 7.6 Hz, 2H), 2.71 (ddt, = 23.9, 12.1, 6.2 methoxy phenyl)ethyl)amino) Hz, 2H), 2.58 (t, = 7.6 Hz, 2H), 1.26 (d, ethoxy)-5'-(trifluoro methyl)-[ 1 , 1 '-

The Examples 112 to 120 given in Table-6 are prepared by following the similar procedure as described in Step- 1 followed by step-2 of Example-28.

Table-6:

In-vitro Pharmacological activity

Certain illustrative compounds within the scope of the invention are screened for CaSR activity according to the procedure given below. The screening of the compounds may also be carried by other methods and procedures known to skilled in the art. In-vitro assay method of Calcimimetics through modulation of Calcium Sensing Receptor (CaSR):

The ability of the compounds to modulate Calcium sensing receptor is determined by measuring an increase in intracellular calcium [Ca²⁺]i. Stably transfected HEK293 cells expressing hCaSR_pTriEx-3 hygro vector are developed. Cells are grown overnight on a 96- well plate to 80% confluency in Ham's F12 containing 20% FBS at 37°C, 5% C0₂. Subsequently, cells are washed extensively with 20mM HEPES buffer containing 126mM NaCl₂, ImM MgCl₂ and 4mM KC1 to remove serum components that might interfere with the assay. Cells are loaded with calcium sensing Fluo4NW dye in HEPES base buffer containing 0.1% BSA and lmg/ml glucose for 30 minutes to measure changes in intracellular calcium. The activities of the compounds are measured in FLIPR using 0.3mM CaCl₂ in 20mM HEPES base buffer. The effectiveness of the compound to modulate receptor activity is determined by calculating the EC₅₀ responses for that compound in an 8-point assay and plotted using GraphPad Prism 5.

The compounds prepared were tested using the above assay procedure and the results obtained are given below. The EC₅₀ (nM) values of few representative compounds are set forth in Table-7.

The in-vitro activity data has been given in Table-7 for representative compounds. Table-7: Example number ECso in range

1,2,3,4,5,7,8,9,10,11,13,15,16, 17,22,23,24,27,30,31,32,33,35,36,40,41,42,43,44,45,4 less than

6,47,48,49,50,52,53,55,56,57,58,60,63,66,68,69,70,71,72,75,77,78,82,83,84,85,87,88 20 nM

,89,90,93,94,95,96,101,103,106,107

6, 14,18,19,20,25,26,28,29,34,37,38,39,51,54,59,61,62,64,65,67,74,76,79,80,81,86,91 between ,100,105 20.01 to

50 nM

12,21,61,73,92,97,98,99,102,104,108, 109, 110, 111 between

50.01 to 300 nM

Thus, the above in-vitro assay method shows that the compounds of the invention were found to exhibit agonistic activity for CaSR, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR. In- vivo activity in CKD Wistar rats:

Animals were fed with 0.75% adenine diet for a period of 28 days for development of chronic kidney disease (CKD). After measurement of plasma PTH on day 28, animals were randomized based on plasma PTH (intact PTH) levels before using them for the study. Overnight fasted animals were bled retro-orbitally to collect basal blood sample (0.5 ml). Rats were dosed orally with vehicle and with test compounds formulated in PEG 300:PG:Captisol (20: 15:65). Six to eight animals were used in each group then compounds of the invention were administered at 1 mg/kg dose. Post 2 h oral dosing animals were fed with feed and water ad libitum. Post treatment blood samples were collected by retro-orbital bleeding under light ether anesthesia at different time points for plasma PTH estimation. Plasma PTH was measured using sandwich ELISA kits (Immunotopics, USA). Percentage suppression of plasma PTH was calculated with respect to individual basal untreated values by using the following Formula Pre -treated individual value - Post-treated individual

Percent suppression = X 100

Pre-treated individual value

Thus, the above in- vivo method shows that the compounds of the invention were found to exhibit suppress plasma PTH levels, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR.

In-vivo activity in nephrectomizedSD rats:

"Male, Sprague Dawley rats weighing 200-270g were used for the study. In 5/6 nephrectomized rat model of CKD, the original renal functional mass was reduced to five sixths (5/6) by two step surgery. In a first surgery, under anesthesia the abdominal cavity was cut opened and the left kidney was decapsulated. The 1/3 region of kidney at both ends was excised and the abdominal incision was closed. One week after the first surgery, the right kidney was removed completely by transecting the vessels and ureter. After the second surgery, all nephrectomized animals were fed with 1.2% phosphorus diet and the Sham control animals with normal control diet till the termination of the study. Post three weeks of second surgery, animals were bled retro-orbitally to collect blood for estimation of ionized Calcium in whole blood and biochemical parameters like Phosphorous, Urea, BUN, Creatinine and intact PTH in plasma. Plasma iPTH was measured using Rat Bioactive intact PTH ELISA kits by sandwich ELISA method. After confirmation of desired iPTH levels, animals were randomized based on iPTH levels into different treatment and vehicle control groups with 8-10 animals in each group and 8 animals were kept on sham control group. Post randomization, treatment was initiated immediately with test and reference article for 27 days with daily record of body weight. During treatment, on day 14 and day 27 post 24 h last dose, all animals were bled retro-orbitally for estimation of biochemical parameters as mentioned above. To evaluate the acute effect, plasma iPTH was measured on day 27 post 2 h last dose.

Percentage suppression of plasma iPTH was calculated by using the following Formula: mean of vehicle - post-treated individual value

Percent suppression = X 100

mean of vehicle

Thus, the above in- vivo method shows that the compounds of the invention were found to exhibit suppress plasma iPTH levels, thereby showing utility for treating diseases, disorders associated with the modulation of CaSR. Although certain embodiments and Examples have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments and Examples without departing from the teachings thereof. All such modifications are intended to be encompassed within the below claims of the invention.

Claims

1. A compound having the Formula (I):

(I) wherein,

Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i-₃0H, -C(0)NH-alkyl, -S(0)₂- alkyl, -S(0)₂NH-alkyl, -C(0)OH, -C(0)0-alkyl, -(CR_aR_b)i-3C(0)OH and -(CR_aR_b)i_₃C(0)0- alkyl;

R₂ is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or more and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄,-NR₅R₆ and substituted or unsubstituted cycloalkyl; X is selected from -C(0)OH, -C(0)Oalkyl, -C(0)NR₅R₆, -(CR_aR_b)i_₃C(0)OH,

-(CR_aR_b)i_₃C(0)0-alkyl, -0-(CR_aR_b)i_₃C(0)OH, -0-(CR_aR_b)i_₃C(0)0-alkyl, -CR_C=CR_C- C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄, and -S(0)₂-alkyl;

R₃, which may be same or different at each occurrence, is independently selected from halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -OR₄;

R₄ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and substituted or unsubstituted cycloalkyl;

2. The compound of claim 1 having the Formula (II):

wherein,

Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i_₃OH, -C(0)NH-alkyl, -C(0)OH and -(CR_aR_b)i-₃C(0)OH; X is selected from -C(0)OH, -C(0)Oalkyl, -(CR_aR_b)i_₃C(0)OH, -(CR_aR_b)i_₃C(0)0- alkyl, -0-(CR_aR_b)i-₃C(0)OH, -CR_c=CR_c-C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄, and -S(0)₂-alkyl;

R_c is independently hydrogen or substituted or unsubstituted alkyl; 'n' is an integer ranging from 0 to 2, both inclusive; and

'p' is an integer ranging from 0 to 2, both inclusive; ora pharmaceutically acceptable salt thereof.

3. The compound of claim 1 having the Formula (III):

wherein,

Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i_₃OH, -C(0)NH-alkyl, -C(0)OH and -(CR_aR_b)i_₃C(0)OH; X is selected from -C(0)OH, -C(0)Oalkyl, -(CR_aR_b)i_₃C(0)OH, -(CR_aR_b)i_₃C(0)0- alkyl, -0-(CR_aR_b)i_₃C(0)OH, -CR_c=CR_c-C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄, and -S(0)₂-alkyl;

R_a and R_b are independently selected from hydrogen, halogen, substituted or unsubstituted alkyl; R_c is independently hydrogen or substituted or unsubstituted alkyl; and

'n' is an integer ranging from 0 to 2, both inclusive; ora pharmaceutically acceptable salt thereof. 4. The compound of claim 1 having the Formula (IV):

wherein,

Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i_₃OH, -C(0)NH-alkyl, -C(0)OH and -(CR_aR_b)i_₃C(0)OH; X is selected from -C(0)OH, -C(0)Oalkyl, -(CR_aR_b)i_₃C(0)OH, -(CR_aR_b)i_₃C(0)0- alkyl, -0-(CR_aR_b)i_₃C(0)OH, -CR_c=CR_c-C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄and -S(0)₂-alkyl;

R₂ is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or more and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄ and substituted or unsubstituted cycloalkyl;

R_c is independently hydrogen or substituted or unsubstituted alkyl; and 'n' is an integer ranging from 0 to 2, both inclusive; ora pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein Ri is selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, -(CR_aR_b)i_₃OH, - C(0)NH-alkyl, -C(0)OH and -(CR_aR_b)i_₃C(0)OH; wherein R_a andR_b are independently hydrogen or substituted or unsubstituted alkyl.

The compound of claim 1, wherein X is selected from -C(0)OH, -(CR_aR_b)i-₃C(0)OH, -0-(CR_aR_b)i-₃C(0)OH, -CR_c=CR_c-C(0)OH, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -OR₄and -S(0)2-alkyl; wherein R_a, R_b andR_care independently hydrogen or substituted or unsubstituted alkyl.

The compound of claim 1 , wherein R₂ is substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl, wherein the substituents may be one or two and are independently selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, -O-alkyl and substituted or unsubstituted cycloalkyl;

The compound of claim 1, wherein R₃ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl and -O-alkyl and 'n' is 0, 1 or 2;

The compound of claim 1 which is selected from:

(i?j-N-Methyl-5-(2-((l-(naphthalen-l-yl)ethyl)amino)ethoxy)-3'-(trifluoromethyl)- [ 1 , l'-biphenyl]-3-carboxamide;

(R)-N-methyl-5-(2-((l-(naphthalen-l-yl)ethyl)amino)ethoxy)-4'-(trifluoromethyl)- [ 1 , l'-biphenyl]-3-carboxamide;

(i?)-3'-chloro-N-methyl-5-(2-(( 1 -(naphthalen- 1 -yl)ethyl)amino)ethoxy)-[ 1 , 1 '- biphenyl]-3-carboxamide;

(i?j-N-Methyl-4'-(methylsulfonyl)-5-(2-((l-(naphthalen-l-yl) ethyl) amino) ethoxy)- [ 1 , l'-biphenyl]-3-carboxamide;

(Rj-N-Methyl-3'-(methylsulfonyl)-5-(2-((l-(naphthalen-l-yl) ethyl) amino) ethoxy)- [ 1 , l'-biphenyl]-3-carboxamide;

(i?j-N-Methyl-5-(2-((l-(naphthalen-l-yl) ethyl) amino) ethoxy)-3'-(trifluoromethoxy)- [ 1 , l'-biphenyl]-3-carboxamide; (Rj-3'-Fluoro-N,4'-dimethyl-5-(2-((l-(naphthalen- l-yl) ethyl) amino) ethoxy)-[l, l'- biphenyl]-3-carboxamide; fRj-3'-Chloro-N,4'-dimethyl-5-(2-((l-(naphthalen- l-yl) ethyl) amino) ethoxy)-[l , l'- biphenyl]-3-carboxamide;

(i?j-4'-Chloro-3'-methoxy-N-methyl-5-(2-((l-(naphthalen-l-yl)ethyl)amino)ethoxy) [ 1 , l'-biphenyl]-3-carboxamide;

(i?j-4'-Fluoro-3'-methoxy-N-methyl-5-(2-((l-(naphthalen-l-yl)ethyl)amino)ethoxy)- [ 1 , l'-biphenyl]-3-carboxamide;

(i?j-3'-Chloro-4'-methoxy-N-methyl-5-(2-((l-(naphthalen-l-yl)ethyl)amino)ethoxy) [ 1 , l'-biphenyl]-3-carboxamide;

(i?j-N-Ethyl-5-(2-((l-(3-methoxyphenyl)ethyl)amino)ethoxy)-4'-(methylsulfonyl)- [ 1 , l'-biphenyl]-3-carboxamide;

(R )-2-((4',5-Difluoro-3'-methoxy-[ 1 , 1 '-biphenyl]-3-yl)oxy)-N-( 1 -(naphthalen- 1- yl)ethyl)ethanamine;

(i?j-3-((5-Fluoro-4'-methoxy-3',5'-dimethyl-[ l, l'-biphenyl]-3-yl)oxy)-N-(l-(3- methoxyphenyl) ethyl )propan- 1 -amine ;

(i?j-3-((4'-Chloro-5-fluoro-3'-methoxy-[ l, l'-biphenyl]-3-yl)oxy)-N-(l-(3- methoxyphenyl)ethyl)propan-l-amine;

(i?j-2-((4'-Chloro-3'-methoxy-5-(trifluoromethyl)-[ l, l'-biphenyl]-3-yl)oxy)-N-(l-(3 methoxyphenyl) ethyl)ethanamine;

(i?j-l-(3-Cyclopropylphenyl)-N-(2-((5-fluoro-3'-(trifluoromethyl)-[l,r-biphenyl]-3- yl)oxy) ethyl)ethanamine;

(i?j-2-((4'-Chloro-5-fluoro-3'-methoxy-[ l, l'-biphenyl]-3-yl)oxy)-N-(l-(3- cyclopropylphenyl) ethyl)ethanamine ; (i?j-2-(4'-Fluoro-3'-methoxy-5-(2-(( l-(naphthalen- l-yl)ethyl) amino)ethoxy)-[ l , l '- biphenyl]-3-yl)propan-2-ol;

2-((4'-Chloro-3'-methoxy-5-(trifluoromethyl)-[ l , l'-biphenyl]-3-yl)oxy)-N-( l-(3- fluoro-5-methoxyphenyl)ethyl)ethanamine;

1- (3-Fluoro-5-methoxyphenyl)-N-(2-((3'-(methylsulfonyl)-5-(trifluoromethyl)-[ l,r- biphenyl] -3-yl)oxy)ethyl)ethanamine ;

(R j-2-((5-Fluoro-3'-(trifluoromethyl)-[ 1 , l'-biphenyl]-3-yl)oxy)-N-( 1 -(naphthalen- 1- yl)ethyl)ethanamine;

(R )-2-((5-Fluoro-3'-(methylsulfonyl)-[ 1 , 1 '-biphenyl] -3 -yl)oxy)-N-( 1 -(naphthalen- 1- yl)ethyl)ethanamine;

(R )-2-((5-Fluoro-4'-(methylsulfonyl)-[ 1 , 1 '-biphenyl] -3 -yl)oxy)-N-( 1 -(naphthalen- 1- yl)ethyl)ethanamine;

(i?j-3-((4'-Chloro-5-fluoro-3'-methoxy-[ l , l'-biphenyl]-3-yl)oxy)-N-( l -(3- chlorophenyl)ethyl)propan- 1 -amine;

2- ((4'-Chloro-3'-methoxy-5-(trifluoromethyl)-[ l , l'-biphenyl]-3-yl)oxy)-N-( l-(3- fluoro-5-methoxyphenyl)ethyl)ethanamine;

(i?j-2-((3'-Chloro-5-fluoro-4'-methoxy-[ l , l'-biphenyl]-3-yl)oxy)-N-( l -(3- methoxyphenyl) ethyl)ethanamine;

(i?j-4-Methyl-3'-(methylcarbamoyl)-5'-(2-(( l-(naphthalen- l -yl)ethyl)amino)ethoxy)- [ 1 , l'-biphenyl]-3-carboxylic acid;

(i?j-3'-Fluoro-4-methyl-5'-(2-(( l-(naphthalene- l-yl)ethyl) amino) ethoxy)-[ l , l'- biphenyl]-3-carboxylic acid;

(R j-3'-(Methylcarbamoyl)-5'-(2-(( 1 -(naphthalene- l-yl)ethyl) amino) ethoxy)-5- (trifluoromethyl)- [ 1 , Γ -biphenyl] -3 -carboxylic acid; (R )-4'-(Methylsulfonyl)-5-(2-(( 1 -(naphthalene- 1 -yl)ethyl) amino) ethoxy)- [1, 1'- biphenyl]-3-carboxylic acid;

(R )-5-(2-(( 1 -(Naphthalene- 1 -yl) ethyl) amino)ethoxy)-4'-(trifluoromethyl)-[ 1 , 1 '- biphenyl]-3-carboxylic acid;

(i?j-4'-Fluoro-3'-methoxy-5-(2-((l -(naphthalene- 1-yl) ethyl) amino) ethoxy)-[l , l'- biphenyl]-3-carboxylic acid;

(R j-3'-Chloro-4'-fluoro-5-(2-(( 1 -(naphthalene- l-yl)ethyl) amino)ethoxy)-[ 1 , 1 '- biphenyl]-3-carboxylic acid;

(R j-3'-Chloro-4'-methoxy-5-(2-(( 1 -(naphthalene- l-yl)ethyl) amino) ethoxy)-[ 1 , 1 '- biphenyl]-3-carboxylic acid;

(R j-4'-Chloro-3'-methoxy-5-(2-(( 1 -(naphthalene- l-yl)ethyl) amino)ethoxy)-[l , Γ- biphenyl]-3-carboxylic acid;

(i?j-3'-Chloro-5-(2-((l-(naphthalene-l-yl) ethyl)amino)ethoxy)-4'-(trifluoromethyl)- [ 1 , l'-biphenyl]-3-carboxylic acid;

(i?j-4'-Chloro-5-(2-((l-(naphthalene-l-yl)ethyl) amino) ethoxy)-3'-(trifluoromethyl)- [ 1 , l'-biphenyl]-3-carboxylic acid;

(R j-4'-Chloro-3 '-methyl-5 -(2-(( 1 -(naphthalene- 1 -yl)ethyl) amino) ethoxy)- [1 , 1'- biphenyl]-3-carboxylic acid;

(R j-3'-Methoxy-4'-methyl-5-(2-(( 1 -(naphthalene- 1 -yl)ethyl) amino) ethoxy)-[ 1 , 1 '- biphenyl]-3-carboxylic acid;

(i?j-3'-Chloro-4'-ethoxy-5-(2-((l-(naphthalene-l-yl)ethyl) amino) ethoxy)-[ l, l'- biphenyl]-3-carboxylic acid;

(Rj-3'-Methoxy-4',5'-dimethyl-5-(2-((l-(naphthalene-l-yl) ethyl)amino) ethoxy)- [ 1, 1'- biphenyl]-3-carboxylic acid; (R )-4'-Methoxy-5-(2-(( 1 -(naphthalene- 1 -yl)ethyl) amino) ethoxy)-3'-(trifluoro methyl) -[l , l'-biphenyl]-3-carboxylic acid; fRj-4-Chloro-3'-fluoro-5'-(2-((l-(naphthalene-l-yl)ethyl)amino) ethoxy)-[ l, l'- biphenyl]-3-carboxylic acid;

(i?j-2'-Fluoro-5'-methoxy-5-(2-((l -(naphthalene- l-yl)ethyl) amino) ethoxy-3'- (trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid;

(R j-3'-Methoxy-5-(2-(( 1 -(naphthalene- 1 -yl)ethyl) amino)ethoxy)-4'-(trifluoro methyl) -[ 1 , l'-biphenyl] -3 -carboxylic acid;

(i?j-3',4'-Dichloro-5'-methyl-5-(2-((l-(naphthalene-l-yl)ethyl) amino) ethoxy)-[l, l'- biphenyl]-3-carboxylic acid;

(R j-4'-Fluoro-2',3'-dimethyl-5-(2-(( 1 -(naphthalene- 1 -yl)ethyl) amino) ethoxy)-[ 1 , 1 '- biphenyl]-3-carboxylic acid;

(i?j-4'-Chloro-3'-ethoxy-5-(2-((l-(naphthalene-l-yl)ethyl) amino) ethoxy)-[ l, l'- biphenyl]-3-carboxylic acid;

(R j-3'-Methoxy-5-(2-(( 1 -(naphthalene- 1 -yl)ethyl) amino) ethoxy)-5'-(trifluoro methyl)[l, l'-biphenyl]-3-carboxylic acid;

(R j-4'-Chloro-3'-methoxy-5-(3-(( l-(3-methoxyphenyl)ethyl) amino) propoxy)-[ 1, Γ- biphenyl]-3-carboxylic acid;

(i?j-3'-Methoxy-5-(3-((l-(3-methoxy phenyl) ethyl)amino) propoxy)-4'-(trifluoro methyl)-[l, l'-biphenyl]-3-carboxylic acid;

(i?j-4'-Chloro-5-(3-((l-(3-methoxyphenyl) ethyl) amino) propoxy)-3'- (trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid;

(i?j-3'-Fluoro-5'-(3-((l-(3-methoxyphenyl) ethyl) amino) propoxy)-5- (trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid; (R )-3'-Chloro-4-methoxy-5'-(3-(( l-(3-methoxyphenyl)ethyl) amino) propoxy)-[ 1 , 1 '- biphenyl]-3-carboxylic acid;

(i?)-3-((3'-Fluoro-5'-(2-(( l-(3-methoxy phenyl)ethyl) amino) ethoxy)-[ l, l'-biphenyl]- 3-yl)oxy) propanoic acid;

(R )-3'-Fluoro-5'-(2-(( l-(naphtahlen- 1 -yl) ethyl)amino) ethoxy)-5-(trifluoromethyl)- [ 1 , l'-biphenyl]-3-carboxylic acid;

(R )-3 ',4-Dichloro-5 '-(2-(( 1 -(naphtahlen- 1 -yl)ethyl) amino) ethoxy)- [ 1 , 1 '-biphenyl] -3 - carboxylic acid;

(Z?)-3'-Fluoro-5'-(2-((l-(3-methoxyphenyl) ethyl) amino) ethoxy)-5-(trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid;

(i?j-3'-Fluoro-4-methoxy-5'-(2-((l-(3-methoxyphenyl)ethyl) amino) ethoxy)-[ l, l'- biphenyl]-3-carboxylic acid;

(i?j-3-(3'-Fluoro-4-methoxy-5'-(2-((l-(3-methoxyphenyl) ethyl) amino)ethoxy)-[l, l'- biphenyl]-3-yl)propanoic acid;

(i?j-2-(3',4-Difluoro-5'-(2-((l-(3-methoxy phenyl)ethyl) amino) ethoxy)-[l, l'- biphenyl]-3-yl)-2-methylpropanoic acid;

(i?j-3-(3',4-Difluoro-5'-(2-((l-(3-methoxyphenyl)ethyl) amino) ethoxy)-[l , l'- biphenyl]-3-yl) propanoic acid;

(Z?)-3',4,5-Trifluoro-5'-(2-((l-(3-methoxy phenyl)ethyl) amino) ethoxy)-[ l, l'- biphenyl]-3-carboxylic acid;

(i?j-3'-Fluoro-5'-(2-((l-(3-methoxyphenyl) ethyl) amino)ethoxy)-4-methyl-[l , l'- biphenyl]-3-carboxylic acid;

(i?j-4,5-Difluoro-3'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-carboxylic acid; (i?)-3'-(2-((l-(3-Methoxyphenyl) ethyl) amino) ethoxy)-5,5'-bis(trifluoromethyl)- [ 1 , l'-biphenyl]-3-carboxylic acid;

(i?)-3-(4-Fluoro-3'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(i?j-3-(4-Methoxy-3'-(2-((l-(3-methoxy phenyl) ethyl)amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(i?j-4-Chloro-3'-(2-((l-(3-methoxyphenyl) ethyl) amino)ethoxy)-5'-(trifluoromethyl) [ 1 , l'-biphenyl]-3-carboxylic acid;

(i?j-3'-Chloro-5'-(2-(( l-(3-methoxy phenyl) ethyl) amino)ethoxy)-5-(trifluoro methyl)-[l, l'-biphenyl]-3-carboxylic acid;

(Z?)-3-(3'-Chloro-4-fluoro-5'-(2-((l-(3-methoxyphenyl) ethyl) amino) ethoxy)- [ Ι, Γ- biphenyl]-3-yl)propanoic acid;

(i?j-3-(3'-Chloro-4-methoxy-5'-(2-((l-(3-methoxyphenyl) ethyl) amino)ethoxy)-[l , l' biphenyl]-3-yl)propanoic acid;

(i?j-3',4-Dichloro-5'-(2-((l-(3-methoxy phenyl) ethyl)amino) ethoxy)-4-methyl-[ l, l' biphenyl]-3-carboxylic acid;

(R, E)-3-(3'-(2-((l-(3-Methoxyphenyl) ethyl) amino) ethoxy)-4-methyl-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl) acrylic acid;

(Z?)-3'-Chloro-4-fluoro-5'-(2-((l-(3-methoxyphenyl) ethyl)amino) ethoxy)-[ l, l'- biphenyl]-3-carboxylic acid;

(Rj-3-(4-Methyl-3'-(2-((l-(3-methoxy phenyl) ethyl)amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(i?j-3-(4-Chloro-3'-(2-((l-(3-methoxy phenyl)ethyl) amino)ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid; (i?)-4-Fluoro-3'-(2-((l-(3-methoxy phenyl) ethyl)amino)ethoxy)-5'-(trifluoro methyl)- [ 1 , l'-biphenyl]-3-carboxylic acid;

(i?j-3'-Chloro-4-chloro-5'-(2-((l-(3-methoxyphenyl)ethyl)amino)ethoxy)-4-methyl- [ 1 , l'-biphenyl]-3-carboxylic acid;

(i?,E)-3-(3'-(Trifluoromethyl)-4-chloro-5'-(2-((l-(3-methoxyphenyl) ethyl)amino) ethoxy)-[ 1 , 1 '-biphenyl]-3-yl)acrylic acid;

(i?,E)-3-(3'-(Difluoromethyl)-4-chloro-5'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy) -[ l, l'-biphenyl]-3-yl)acrylic acid;

(i?j-3-(3'-(Difluoromethyl)-4-fluoro-5'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy)-[ 1 , 1 '-biphenyl]-3-yl)propanoic acid;

(i?,E)-3-(3'-(Difluoromethyl)-4-fluoro-5'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy) -[ l, l'-biphenyl]-3-yl)acrylic acid;

(i?,E)-3-(4-Fluoro-3'-(2-((l-(3-methoxy phenyl) ethyl) amino)ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)acrylic acid;

(i?j-3-(2-Fluoro-3'-(2-((l-(3-methoxy phenyl)ethyl)amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(Z?)-3-(2,4-Difluoro-3'-(2-((l-(3-methoxy phenyl)ethyl) amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(i?j-3-(4-Fluoro-3'-(2-((l-(3-methoxy phenyl)ethyl) amino) ethoxy)-5-methyl-5'- (trifluoro methyl)-[ l, l'-biphenyl]-3-yl) propanoic acid;

(i?,E)-3-(4-Fluoro-3'-(2-((l-(3-methoxy phenyl) ethyl) amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)but-2-enoic acid;

(i?,E)-3-(4-Fluoro-3'-(2-((l-(3-methoxy phenyl) ethyl) amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)-2-methyl acrylic acid; (i?)-3-(3'-(2-((l-(3-Chlorophenyl) ethyl) amino) ethoxy)-4-methoxy-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(R)-2-((3'-(2-((l-(3-Methoxyphenyl) ethyl) amino) ethoxy)-4-methyl-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)oxy)-2-methylpropanoic acid;

3-(3'-(2-(((Rj-l-(3-Methoxyphenyl) ethyl) amino) ethoxy)-4-methyl-5'-(trifluoro methyl)[l,l'-biphenyl]-3-yl)-2-methyl propanoic acid;

(i?j-3-(4-Fluoro-3'-(3-((l-(3-methoxy phenyl) ethyl) amino) propoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(i?j-3-(4-Fluoro-3'-(2-((l-(3-methoxy phenyl) ethyl) amino) ethoxy)-2-methyl-5'- (trifluoromethyl)-[l,l'-biphenyl]-3-yl) propanoic acid;

(R)-3-(3'-(2-((l-(3-Methoxy phenyl) ethyl) amino) ethoxy)-2,4-dimethyl-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

( ?)-3-(3'-(2-((l-(3-Chloro phenyl) ethyl) amino) ethoxy)-4-fluoro-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(R)-3-(3'-(2-((l-(3-Chloro phenyl) ethyl) amino) ethoxy)-4-methyl-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(R)-3-(4-Fluoro-3'-(2-((l-(3-methoxy phenyl) ethyl) amino) ethoxy)-5'- (trifluoromethoxy)[ 1 , l'-biphenyl] -3-yl)propanoic acid;

(i?j-4-(4-Fluoro-3'-(2-((l-(2-fluoro-3-methoxyphenyl) ethyl) amino) ethoxy)-5'- (trifluoromethyl)-[l,r-biphenyl]-3-yl) butanoic acid;

(i?j-3'-Chloro-5'-(2-((l-(naphthalen-l-yl)ethyl)amino)ethoxy)-5-(trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid;

(i?j-3-(4-Fluoro-2-methoxy-3'-(2-((l-(3-methoxyphenyl) ethyl) amino) ethoxy)-5'-(tri fluoromethyl)-[l,l'-biphenyl]-3-yl) propanoic acid; (i?)-3'-(2-((l-(3-Fluoro-5-methoxyphenyl) ethyl) amino) ethoxy)-4-methyl-5'- (trifluoro methyl)[ l, l'-biphenyl]-3-carboxylic acid;

(i?,E)-3-(2,4-Diethyl-3'-(2-((l-(3-methoxy phenyl) ethyl) amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)acrylic acid;

(i?j-3-(2,4-Diethyl-3'-(2-((l-(3-methoxy phenyl) ethyl) amino) ethoxy)-5'-(trifluoro methyl)-[l, l'-biphenyl]-3-yl)propanoic acid;

(i?j-3',4-Dichloro-5'-(2-((l-(naphthalen-l-yl)ethyl) amino) ethoxy)-[ l, l'-biphenyl]-3- carboxylic acid;

(R j-3-(3'-Fluoro-5'-(2-(( 1 -(naphthalen- 1 -yl)ethyl)amino)ethoxy)-[ 1 , 1 '-biphenyl] -3- yl)propanoic acid;

3- (4-Fluoro-3'-(2-(( l-(3-fluoro-5-methoxy phenyl) ethyl) amino) ethoxy)-5'-(trifluoro methyl)[l, l'-biphenyl]-3-yl)propanoic acid;

4- Chloro-3'-(2-((l-(3-fluoro-5-methoxy phenyl) ethyl) amino) ethoxy)-5'-(trifluoro methyl)[l, l'-biphenyl]-3-carboxylic acid;

5- Fluoro-3'-(2-((l-(3-fluoro-5-methoxy phenyl) ethyl) amino) ethoxy)-5'-(trifluoro methyl)[l, l'-biphenyl]-3-carboxylic acid;

(R)-3'-(2-((l-(3-Methoxyphenyl) ethyl) amino) ethoxy)-4-methyl-5'- (trifluoromethoxy)[ 1 , l'-biphenyl] -3-carboxylic acid;

(i?j-3'-(2-((l-(3,5-Dimethoxyphenyl) ethyl) amino) ethoxy)-4-methyl-5'- (trifluoromethyl)- [ 1 , Γ -biphenyl] -3 -carboxylic acid;

(i?j-3-(3'-(2-((l-(3,5-Dimethoxyphenyl) ethyl)amino) ethoxy)-4-methyl-5'- (trifluoromethyl)-[ l,r-biphenyl]-3-yl)propanoic acid;

(i?j-3-(3'-(2-((l-(3,5-Dimethoxyphenyl) ethyl) amino) ethoxy)-4-fluoro-5'- (trifluoromethyl)-[ l,r-biphenyl]-3-yl)propanoic acid; (i?)-4-Chloro-3'-(2-((l-(3,5-Dimethoxyphenyl) ethyl) amino) ethoxy)-5'- (trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid;

(i?)-3'-(2-((l-(3-Fluoro-5-methoxyphenyl) ethyl) amino) ethoxy)-2,4-dimethyl-5'- (trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid;

(i?)-5-Fluoro-3'-(2-((l-(3-fluoro-5-methoxyphenyl) ethyl) amino) ethoxy)-4-methyl- 5'-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -3-carboxylic acid;

(i?)-3'-(2-((l-(3-Fluoro-5-methoxy phenyl) ethyl) amino) ethoxy)-5-methoxy-5'- (trifluoromethyl)- [ 1 , l'-biphenyl] -3 -carboxylic acid;

(i?)-2-(3'-(2-((l-(3-Fluoro-5-methoxy phenyl) ethyl) amino) ethoxy)-4-methyl-5'- (trifluoromethyl)-[ 1 , l'-biphenyl] -3 -yl)-2-methylpropanoic acid and

(i?)-2-(4-Fluoro-3'-(2-((l-(3-fluoro-5-methoxyphenyl) ethyl) amino) ethoxy)-5'- (trifluoromethyl)- [ 1 , Γ -biphenyl] -3 -yl)-2-methylpropanoic acid ora pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising one or more compounds of Formula (I) according to claim 1, and one or more pharmaceutically acceptable excipients.

11. Use of a compound for the manufacture of a medicament for treating, managing and/or lessening the diseases or disorders, syndromes or conditions associated with the modulation of calcium sensing receptor (CaSR) in a subject in need thereof wherein the method comprises administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

12. The use of claim 11, wherein the diseases, disorders, syndromes or conditions associated with the modulation of calcium sensing receptor (CaSR) are selected from hyperparathyroidism, chronic renal failure (with or without dialysis), chronic kidney disease (with or without dialysis) and their complications.

13. The use of claim 12, wherein hyperparathyroidism is primary hyperparathyroidism, secondary hyperparathyroidism or tertiary hyperparathyroidism.

14. The use of claim 11, wherein the diseases, disorders, syndromes or conditions associated with the modulation of CaSR receptors are selected from the group consisting of parathyroid adenoma, parathyroid hyperplasia, parathyroid carcinoma, vascular &valvular calcification, abnormal calcium homeostasis, hypercalcemia, abnormal phosphorous homeostasis, hypophosphatemia, bone related diseases or complications arising due to hyperparathyroidism, chronic kidney disease or parathyroid carcinoma, bone loss post renal transplantation, osteitisfibrosacystica, adynamic bone disease, renal bone diseases, cardiovascular complications arising due to hyperparathyroidism or chronic kidney disease, certain malignancies in which (Ca2+)e ions are abnormally high, cardiac, renal or intestinal dysfunctions, podocyte- related diseases, abnormal intestinal motility, diarrhea, augmenting gastrin or gastric acid secretion to directly or indirectly benefit in atrophic gastritis or to improve absorption of pharmacological compounds, drugs or supplements from gastrointestinal tract by augmenting gastric acidity.

15. A process for the preparation of compound of Formula (IV):

(IV) wherein R_1; R₂, R₃, X and 'n' are as defined herein above; the process comprising the steps of:

(1) (b) reactingcompound of Formula (2) with methyl sulphonyl chloride, in the presence of DIPEA in suitable solvent to give compound of Formula (3)

(c) reacting compound of Formula (3) with compound of Formula (3b), in the presence of sodium carbonate to give compound of Formula (5)

(d) coupling of compound of Formula (5) with boronic acid of Formula (4a) by usin^ sodium carbonate and PdCl2(dppf) to give compound of Formula (IV)

(IV)