WO2018011747A1

WO2018011747A1 - Polycyclic compounds as ror-gamma modulators

Info

Publication number: WO2018011747A1
Application number: PCT/IB2017/054240
Authority: WO
Inventors: Ranjit Desai; Sanjay S KUMAR; Vrajesh PANDYA; Jigar Desai; Saurin Raval
Original assignee: Cadila Healthcare Limited
Priority date: 2016-07-14
Filing date: 2017-07-13
Publication date: 2018-01-18
Also published as: AR109042A1; TW201815388A

Abstract

The present invention provides compounds which are modulators of RORγ and their use for the treatment of diseases or conditions mediated by RORγ. 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.

Description

POLYCYCLIC COMPOUNDS AS ROR-GAMMA MODULATORS

FIELD OF INVENTION

The present invention relates to novel derivatives of the general formula (I) suitable as modulators of RORy, their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, pharmaceutical compositions containing them, methods for their preparation, use of these compounds in medicine and the intermediates involved in their preparation.

BACKGROUND OF THE INVENTION

The Retinoic acid receptor-related orphan receptor γ known as RORy belongs to the nuclear receptor superfamily (Hirose, T.; Smith, R. J.; Biochem. Biophys. Res. Commun. 1994, 205, 1976-1983). There are three sub-types of ROR s classified as RORa, RORP and RORy. As observed in majority of other nuclear receptors, structure of ROR s consists of four distinct regions called N-terminal A/B domain, a DNA binding domain, a hinge domain and a ligand binding domain. Two isoforms RORyl and RORv2 (which is also called as RORyt) have been identified that differ only in N-terminal sequences (He, Y.-W.; Deftos, M. L.; Ojala, Immunity 1998, 9,797-806). Tissue distribution of this two isoforms is quite distinct, while RORyl is expressed in a variety of tissues including thymus, liver, kidney and muscle, RORyt is exclusively expressed in the cells of the immune system. The isoform RORyt plays important role in the development and regulation of the immune system through its regulatory effect on T helper cells (Thl7 cell) (Ivanov, I. I.; McKenzie, B. S.; Zhou, L.; Cell 2006, 126, 1121-1133). Thl7 is the IL-17 producing CD4+ Th subset and are key drivers of chronic inflammation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis (Jetten (2009) Nucl. RecepL Signal. 7: e003; Manel et al. (2008) Nat. Immunol. 9:641-649). Mouse autoimmune disease models like experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA) have demonstrated the role of Thl7 in autoimmune diseases. RORy is central transcription factor driving Thl7 differentiation.

The significant role of RORy in the pathogenesis of autoimmune disease forms a basis for the development of ligands which can modulate RORy activity and could lead to specific therapies for diseases mediated by RORy.

WO2012100732 discloses thiophene derivatives represented by following formula as RORy modulators.

WO2012100734 and WO201227965 disclose compounds of the following formula as RORy modulators.

WO2013029338 discloses biaryl modulators of RORy having following formula and their use in treatment of disease mediated by RORy.

WO2013171729 discloses aryl or heteroaryl carboxamides with following formula and their use as RORy modulators.

WO2014125426 discloses trisubstituted heterocyclic derivatives having following formula as RORy modulators.

WO2014179564 discloses thiazolopyrrolidine derivatives with following formula for the treatment of diseases mediated by RORy.

WO2015083130 and WO2015101928 disclose fused pyridine/pyrimidine derivatives and fused thiophene/thiazole derivatives respectively with following formula as RORy modulators.

WO2015159233 discloses aryl and heteroaryl ether compounds with following formula as RORy modulators.

WO2015145371 discloses following types of RORy modulators and their the treatment of disease mediated by RORy.

WO2015116904 discloses dihydropyrrolopyridine inhibitors of RORy with following formula.

WO2016193470, WO2016193468, WO2016193461, WO2016193459 and WO2016193452 disclose substituted acetamide derivatives as RORy modulators.

WO2017024018 and WO2017087608 disclose modulators of RORy with following formula.

Though several compounds have been reported in the literature as RORy modulators, none of these compounds have reached the market and looking at the significant unmet medical need for such compounds based on their potential beneficial effects as discussed above, there is a need for identifying further compounds which can act as RORy modulators. We herein disclose novel compounds useful as RORy modulators which may have beneficial effects in the treatment of autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis and the like which are mediated by RORy and methods for their preparation.

SUMMARY OF THE INVENTION

The present invention discloses novel compounds as defined by the general formula (I) that modulates the activity of RORy and provides treatment option for autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis which are mediated by RORy. The compounds of the present invention are useful in the treatment of the human or animal body, by regulation of RORy receptor gene expression. The compounds of this invention are therefore suitable for the treatment/mitigation/regulation or prophylaxis of number of autoimmune or inflammatory diseases mentioned above.

OBJECT OF THE INVENTION

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 autoimmune or inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, irritable bowel diseases, psoriasis, psoriatic arthritis.

In an embodiment is provided a process for the preparation of novel compounds of general formula (I), their tautomeric forms, novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, pharmaceutically acceptable solvates 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 another further embodiment is provided the use of the novel compounds of the present invention for the treatment of autoimmune diseases, by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.

In a still further embodiment is provided a method of treatment of diseases which can be treated or whose symptoms can be reversed 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),

wherein

A represents monocyclic or bicyclic heterocyclic ring system; Ri and R₂ are each independently selected from halogen, (Ci-C3)alkyl, alkoxy, CF₃;

Y and Z independently represents -CH- or N atom;

R₃ at each occurrence is independently selected from hydrogen, halogen, (Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (C₆-Ci₀)aryl, (C₆-Ci₀)heteroaryl, (C₃-C₆)cycloalkyl, (C₄-C₆) heterocyclyl or -NR7R8;

R4 is selected from hydrogen, halogen, (Ci-C₃)alkyl;

R5 is selected from (Ci-C₃)alkyl;

R₆ is selected from (Ci-C₆)alkyl, halo(Ci-C₆)alkyl, cycloalkanylalkyl, (C₄-C₆)

heterocyclyl, heterocyclylalkyl;

In an alternate embodiment, R₄ and R₆ together with the N atom can cyclize to form five membered heterocyclic ring with 0-1 double bond and may further contain from 1-2 N atoms;

Substituents on R₃ may be selected from the group comprising of hydrogen, hydroxy, cyano, halogen, COOH, oxo, halo(Ci-C₆)alkyl, optionally substituted (Ci-C₆)alkyl, - 0(Ci-C₆alkyl), -OCF₃, (C₃-C₆)cycloalkyl or -NR7R8 wherein each of R₇ and Rg at each occurrence is independently selected form hydrogen or (Ci-C₆)alkyl;

In an embodiment, the alkyl group as used herein before, may further substituted with hydrogen, hydroxy, -COOH, cyano, halo, oxo, imino, haloalkyl, (Ci-C₆)alkyl, (C₂- C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl;

m represents integers from 1-4, n represents integers from 1-2;

Further preferred embodiments have been discussed below:

Preferred Ri and R₂ may be selected from halogen and (Ci-C₃)alkyl;

Preferred A is selected from oxadiazole and benzoxazole;

Preferred R₃ is selected from (Ci-C₆)alkyl, (C₆-Cio)aryl, (C₃-C₆)cycloalkyl, (C₄-C₆) heterocyclyl;

Preferred substituents on R₃ is selected from hydrogen, hydroxy, cyano, halogen, halo(Ci-C₆)alkyl, optionally substituted (Ci-C₆)alkyl, -0(Ci-C₆alkyl), -OCF₃;

Preferred heterocyclic rings formed when R₄ and R₆ together with the N atom to form a ring are indole and indazole. In a further 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 eight carbons, selected from methyl, ethyl, n-propyl, zso-propyl, n-butyl, sec-butyl, tert-buty\, amyl, i-amyl, n-pentyl, n- hexyl, and the like;

the "alkenyl" group used either alone or in combination with other radicals, is selected from a radical containing from two to eight carbons, more preferably groups selected from vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl and the like; the "alkenyl" group includes dienes and trienes of straight and branched chains;

the "alkynyl" group used either alone or in combination with other radicals, is selected from a linear or branched radical containing two to eight carbon atoms, more preferably thienyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, and the like. The term "alkynyl" includes di- and tri-ynes;

the "cycloalkyl", or "alicyclic" group used either alone or in combination with other radicals, is selected from a cyclic radical containing three to six carbons, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;

the "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- propoxy, n-butoxy, i-butoxy, zso-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 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 "heterocyclyl" or "heterocyclic" group used either alone or in combination with other radicals, is selected from suitable saturated, partially saturated or unsaturated aromatic or non-aromatic mono, bi or tricyclic radicals, containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, more preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 2- oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl, 3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl, azepinyl, diazepinyl, oxapinyl, thiazepinyl, oxazolidinyl, thiazolidinyl, dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, benzopyranyl, benzopyranonyl, benzodihydrofuranyl, benzodihydrothienyl, pyrazolopyrimidonyl, azaquinazolinoyl, thienopyrimidonyl, quinazolonyl, pyrimidonyl, benzoxazinyl, benzoxazinonyl, benzothiazinyl, benzothiazinonyl, thieno piperidinyl, and the like; In one embodiment, the heterocycle group, wherever applicable, may consists of appropriate number of carbon atoms and include from 1-4 heteroatoms selected from the group consisting of N, O, and S(0)p, p = 0-2, wherein the heterocycle may further be substituted with 1- 2 carbonyl or 1-2 iminocarbonyl groups or one or more groups selected from R⁹ wherein R⁹ is selected from H, hydroxyl, halogen, cyano, optionally substituted groups selected from (Ci-C₆)alkyl, alkoxy, amino, mono, di or trisubstituted amino, hydroxyalkyl, aminoalkyl, heterocyclylalkyl, aminocarbonyl groups;

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 "aralkyl" group used either alone or in combination with other radicals, is selected from groups containing an aryl radical, as defined above, attached directly to an alkyl radical, as define above, more preferably groups selected from benzyl, phenethyl, and the like;

the "heterocyclylalkyl" group used either alone or in combination with other radicals, is selected from groups containing an heterocyclyl radical, as defined above, attached directly to an alkyl radical, as define above;

the "cycloalkanylalkyl" group used either alone or in combination with other radicals, is selected from groups containing a cycloalkyl radical, as defined above, attached directly to an alkyl radical, as define above;

- the "heteroaralkyl" group used either alone or in combination with other radicals, is selected from groups containing an heteroaryl radical, as defined above, attached directly to an alkyl radical, as define above;

the "oxo" and "imino" group used either alone or in combination with other groups represents radical of formula -C=0 or -C=NH respectively.

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

The compounds of formula (I) may optionally be converted to their suitable pharmaceutically acceptable salts by processes as are known in the art. The novel compounds of the present invention can further be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.

Preferred compounds according to the present invention include but are not limited to:

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2- ((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(3,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide; N-(3,5-dichloro-4-(l-(5-(2-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(2,3-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,5-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(2,4-dichlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2-fluoro-4-methoxyphenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(thiophen-2-yl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(5-methylthiophen-2-yl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(6-methoxypyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-isopropyl- 1 ,2,4-oxadiazol-3-yl) cyclopropyl )phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(tetrahydro-2H-pyran-4-yl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

2 (4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)-N-(4-(l-(5-(4-fluorophenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)acetamide; N-(3 ,5-dichloro-4-( 1 -(5-(thiophen-2-yl)- 1 ,2,4-oxadiazol-3-yl)cyclobutyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(5-methylthiophen-2-yl)-l,2,4-oxadiazol-3-yl)cyclobutyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclobutyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(6-methoxypyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclobutyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(4-(l-(benzo[d]oxazol-2-yl)cyclopropyl)-3,5-dichlorophenyl)-2-((4-(ethylsulfonyl) phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclobutyl) phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl )phenyl)-2- ((4-(ethylsulfonyl)phenyl)(methyl)amino)acetamide;

N-(3,5-dichloro-4-( 1 -(5-(4-(trifluoromethyl)phenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(methyl)amino)acetamide;

(ethylsulfonyl)phenyl)(methyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4- (ethylsulfonyl)phenyl)(methyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl)phenyl)-2-(ethyl(4- (ethylsulfonyl)phenyl)amino)acetamide;

2-((cyclopropylmethyl)(4-(ethylsulfonyl)phenyl)amino)-N-(3,5-dichloro-4-(l-(5-(4- fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-

((4-(ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-isopropyl- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide; N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4- (ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl )phenyl)-2- ((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl )phenyl)-2-

((6-(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino) acetamide;

(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,3-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(3,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,5-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,6-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl )phenyl)-2- (5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2-fluoro-4-methoxyphenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-(5-(ethylsulfonyl)indolin- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclopropyl) phenyl)-2-(5- (ethylsulfonyl)indolin-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl )phen yl)-2- (5-(methylsulfonyl)-lH-indol-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl )phenyl)-2- (5-(ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(dimethylamino)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2- ((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide; N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2- (5-(ethylsulfonyl)-lH-indol-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(p-tolyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indol- 1 -yl)acetamide;

N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)- 2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-(5-(ethylsulfonyl)- 1 H-indol- 1 -yl)acetamide;

N-(3 ,5-difluoro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indol- 1 -yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(p-tolyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)- 2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide;

N-(3 ,5-difluoro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide; N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indol- 1 -yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2- ((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-

((5-(ethylsulfonyl)pyridin-2-yl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((5-

(ethylsulfonyl)pyridin-2-yl)(2,2,2-trifluoroethyl)amino)acetamide;

((6-(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((6-

(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino)acetamide;

(ethylsulfonyl)pyridin-3-yl)(methyl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2- ((6-(ethylsulfonyl)pyridin-3-yl)(methyl)amino)acetamide;

N-(3,5-dimethyl-4-(l-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3-chloro-5-fluoro-4-(l-(5-(6-methoxypyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)-N-(3-fluoro-4-(l-(5-(thiophen-2- yl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5-(trifluoromethyl)phenyl)acetamide;

N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3-fluoro-5- methoxyphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide; N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(4-( 1 -(5-(3-chloro-4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)-3 ,5- dimethylphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3-chloro-4-( 1 -(5-cyclopropyl- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)-5-fluorophenyl)-2-

((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(4-(l-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethylphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,3,4-oxadiazol-2-yl)cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l -(5-cyclopropyl- 1, 3,4-oxadiazol-2-yl)cycloprop yl)phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,3,4-thiadiazol-2-yl)cyclopropyl)phenyl)- 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l -(5-cyclopropyl- 1, 3,4-thiadiazol-2-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)oxazol-2-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyloxazol-2-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(4-(2,4-difluorophenyl)thiazol-2-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(4-cyclopropylthiazol-2-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)-2-methylphenyl)(2,2,2-trifluoroethyl)amino)acetamide;

2-((4-(ethylsulfonyl)-2-fluorophenyl)(2,2,2-trifluoroethyl)amino)acetamide; N-(3,5-dichloro-4-(l-(5-(2-fluoro-4-methylphenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(p-tolyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide.

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

Scheme 1: Synthesis of compounds of general formula (I)

The compound (II) can be obtained using general techniques described in literature for carbocyclic/heterocyclic ring generation (for e.g. in WO2005034837, WO2015140130). The compound (III) can be obtained by reduction of nitro group by using general nitro group reduction techniques described in the literature. Preferred methods involve reduction using stannous chloride and catalytic hydrogenation in solvents like methanol, tetrahydrofuran, etc. The compounds of general formula (IV) can be obtained by several methods described in the literature for the synthesis of N- substituted glycine derivatives. The compounds of the general formula (I) can be obtained by coupling of (III) and (IV) using various amide bond formation techniques as described in for e.g. Tetrahedron 2005, 61, 10827.

Scheme 2: Synthesis of compounds of general formula (I)

Alternatively, the compounds of the general formula (VI) can be obtained by coupling of (III) and (V) using various amide bond formation techniques as described in for e.g. Tetrahedron 2005, 61, 10827. The compounds of the general formula (I) are then obtained by oxidation of (VI) using various sulfur oxidation techniques available in literature. Preferred method involves oxidation with oxone in aq. acetone. cheme 3: Synthesis of compounds of general formula (I)

PG = protecting group such as BOC (tert-butyloxycarbonyl), Cbz (Benzyloxy carbonyl) etc. L = leaving group such as CI, Br, etc.

Alternatively, the compounds of the general formula (VIII) can be obtained by coupling of (III) and (VII) using various amide bond formation techniques as described in for e.g. Tetrahedron 2005, 61, 10827, followed by removal of PG using various deprotection methods reported in literature. For e.g. BOC group can be removed by acid treatment and Cbz group can be removed by catalytic hydrogenation. The compounds of general formula (VIII) are then reacted with (IX) using various nucleophilic displacement techniques reported in literature to obtained compounds (I).

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.

The ^ΧΗ NMR spectra were recorded on a Brucker Avance-400 spectrometer (400 MHz). The chemical shifts (δ) are reported in parts per million (ppm) relative to Tetramethyl silane (TMS), in either CDC1₃ or DMSO-d₆ solution. Mass spectra (ESI- MS) were obtained on Shimadzu LC-MS 2010- A spectrometer. List of Abbreviations

BINAP: 2,2'-Bis(diphenylphosphino)-l, r-binaphthyl

CH₃CN: Acetonitrile

CDCI₃: Deuterated chloroform

CDI: Ι,Γ-Carbonyldiimidazole

CS2CO3: Cesium carbonate

DCE: Dichloro ethane

DIPEA: Disopropyl ethyl amine

DMF: Dimethyl formamide

DCM: Dichloromethane

DIBAL-H: Diisobutylaluminium hydride

DMSO: Dimethyl sulfoxide

DMSO-rfe: Hexadeuterodimethyl sulfoxide

EDC.HCl: N-(3-Dimethyl aminopropyl)-N' -ethyl carbodiimide hydrochloride

EtOH: Ethanol

EtOAc: Ethyl acetate

HOBT: 1 -Hydroxy benzotriazole

HC1: Hydrochloric acid

K₂CO₃: Potassium carbonate

LiOH:H₂0: Lithium hydroxide monohydrate

MeOH: Methanol

Na₂S0₄: Sodium sulfate

NaH: Sodium Hydride

NaHC0₃: Sodium bicarbonate

NaOH: Sodium hydroxide

SnCl₂.2H₂0: Stannous chloride dihydrate

TEA: Triethyl amine

THF: Tetrahydrofuran

*H NMR: Proton Nuclear Magnetic Resonance

h: Hour(s)

RT: room temperature [25-30 °C] min: Minute(s)

/: Coupling constant in units of Hz

Hz: Hertz

Preparation of intermediates of general formula (III)

Preparation of 3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)

cyclop ropyl)aniline (III-l)

Step 1: ethyl 2-cyano-2-(2,6-dich tate

To a stirring solution of l,2,3-trichloro-5-nitrobenzene (50 g, 221 mmol) and Cs₂C0₃ (151 g, 464 mmol) in DMF (200 mL) was added ethyl cyano acetate (28.3 mL, 265 mmol) at 10-20°C. Reaction mixture was stirred at RT for 1 h, before it was cooled and poured in to 2N 200 ml HCl solution. Solid obtained was filtered to get title product as brown solid. 1H NMR (DMSO-J₆): 8.47 (s, 2H), 6.54 (s, 1H), 4.28 (q, = 6.8 Hz, 2H), 1.23 (t, 7 = 6.8 Hz, 3H).

Step 2: 2-(2,6-dichloro-4-nitrophenyl

To a stirring solution of product of step 1 (52.0 g, 172 mmol) in DMSO (12 ml) and water (4.5 ml) was added lithium chloride (9.46 g, 223 mmol) at RT. Reaction mixture was heated at 165°C for 1 h before it was cooled and poured in to ice cold water. Solid obtained was filtered to get 25 g of title product. 1H NMR (DMSO-J₆): 8.42 (s, 2H), 4.31 (s, 2H). Step 3: l-(2,6-dichloro-4-nitrophenyl)cyclopropane-l-carbonitrile

To a stirring solution of product of step 2 (4.0 g, 17.31 mmol) in CH₃CN (40 ml) was added ethylene dibromide (4.48 ml, 51.9 mmol) followed by tetrabutyl ammonium bromide (5.58 g, 17.31 mmol). To this was added 8 ml 50% NaOH solution at RT and reaction mixture was stirred at 70-75°C for 12 h. Reaction mixture was then poured in to 2N 100 ml HC1 and extracted with EtOAc. Organic layer was separated, washed with water, dried over Na₂S0₄ and distilled out to get crude product which was purified by column chromatography (4% EtOAc in Hexane) to get title product. 1H NMR (DMSO- d₆): 8.42 (s, 2H), 2.06-2.03 (m, 2H), 1.57- 1.53 (m, 2H).

Step 4: l -(2,6-dichloro-4-nitrophen -N'-hydroxycyclopropane- l-carboximidamide

To a stirring solution of product of step 3 (5 g, 19.45 mmol) in rectified spirit (50 ml) was added hydroxyl amine hydrochloride (3.38 g, 48.6 mmol) and K2CO3 (6.72 g, 48.6 mmol) at RT. Reaction mixture was refluxed for 16 h. Reaction mixture was diluted with water and precipitated solid was filtered to get title product. ¹H NMR (DMSO-ck): 9.26 (s, 1H), 8.19 (s, 2H), 5.16 (s, 2H), 1.74- 1.70 (m, 2H), 1.08- 1.05 (m, 2H).

Step 5: 3-( l -(2,6-dichloro-4-nitrophenyl)cyclopropyl)-5-(4-fluorophenyl)- 1 ,2,4- oxadiazole

To a stirring solution of 4-fluorobenzoic acid (0.560 g, 4 mmol), HOBT (0.756 g, 5.60 mmol) in DMF (30 iriL) was added EDC.HC1 ( 1.073 g, 5.60 mmol) and stirred for 15 min. at RT. To this was added product of step 4 ( 1.16 g, 4 mmol) and stirred at 1 10°C for 16 h. Reaction mixture was poured in water and extracted with EtOAc. Organic layer was washed with water followed by NaHC0₃ solution, dried over Na₂S0₄ and distilled out to get crude product which was column purified (3% EtOAc in Hexane) to get title product. 1H NMR (DMSO-d₆): 8.38 (s, 2H), 8.13 (dd, / = 5.2 & 8.8 Hz, 2H), 7.46 (t, 2H), 2.01 (bd, 2H), 1.65 (bd, 2H).

Step 6: 3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)aniline

To a stirring solution of product of step 5 (140 mg, 0.355 mmol) in EtOAc (5 ml) was added SnCl₂.2H₂0 (401 mg, 1.776 mmol) and stirred at RT for 3 h. Reaction mixture was diluted with EtOAc, basified with aq. ammonia and passed through Hyflo bed. Organic layer was separated, dried over Na₂S0₄ and distilled out to get title product. ^XH NMR (DMSO-Je): 8.12-8.08 (m, 2H), 7.46-7.42 (m, 2H), 6.63 (s, 2H), 5.72 (s, 2H), 1.82- 1.79 (m, 2H), 1.45-1.42 (m, 2H). ESI-MS (m/z): 364.20 (M+H)⁺.

Using appropriate starting materials and suitable modifications of the process described for the preparation of intermediate III-l, 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 intermediates (Table 1 ) were prepared in an analogues manner.

Table 1:

111-20 380.00

111-21 361.00

111-22 391.00

111-23 364.00

111-24 381.95

Preparation of 3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclopropyl)aniline (111-25)

Step 1 : 1 -(2,6-dichloro-4-nitrophenyl)cyclopropane- 1 -carbaldehyde

To a stirring solution of l-(2,6-dichloro-4-nitrophenyl)cyclopropane-l- carbonitrile (4.5 g, 17.50 mmol, prepared in step 3, III-l) in toluene (20 ml) cooled at -60 to -70°C was added DIBAL-H (16.34 ml, 24.51 mmol) and reaction mixture was stirred at -10 to -20°C for 1 h. Reaction mixture was quenched with dil. HC1 and toluene layer was separated. Reaction mixture was further extracted with DCM. Combine organic layer was distilled out to get crude product which was column purified (5% EtOAc in Hexane) to get title product as red solid. 1H NMR (DMSO-J₆): 8.69 (s, 1H), 8.30 (s, 2H), 2.05- 2.02 (m, 2H), 1.62-1.59 (m, 2H). Step 2: l-(2,6-dichloro-4-nitrophenyl)cyclopropane-l-carboxylic acid

To a stirring solution of l-(2,6-dichloro-4-nitrophenyl)cyclopropane-l- carbaldehyde (500 mg, 1.92 mmol) in acetone (10 ml) cooled at 0°C was added 0.5 mL jones reagent and stirred for 3 h at RT. Reaction mixture was poured in water and extracted with EtOAc. Organic layer was distilled out to get title product. ^XH NMR

(DMSO-Je): 8.29 (s, 2H), 1.77-1.80 (m, 2H), 1.31-1.34 (m, 2H).

Step 3: 1 -(2,6-dichloro-4-nitrophenyl)-N-(4-fluoro-2-hydroxyphenyl)cyclopropane- 1 - carboxamide

To a stirring solution of 2-amino-5-fluorophenol (1.03 g, 8.15 mmol) in THF (10 mL) was added TEA (3.3 g, 32.6 mmol) at 5-10°C. To this was added l-(2,6-dichloro-4- nitrophenyl)cyclopropanecarbonyl chloride (1.5 g, 5.43 mmol, prepared from product of step 2 and oxalyl chloride in THF) at 5-10°C. Reaction mixture was stirred at 10°C for 1 h. After complete conversion of starting material reaction mixture was diluted with water. The mixture was extracted with EtOAc. Organic layer was washed with brine, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as a brown oil which was further purified by column chromatography (0-20% EtOAc in Hexane) to get white solid as pure product. 1H NMR (DMSO-J₆): 10.18 (s, 1H), 8.40 (s, 2H), 8.0 (s, 1H), 7.53-7.49 (m, 1H), 6.60-6.55 (dd, 7 = 2.8 &10 Hz, 2H), 1.87-1.85 (t, 7 = 8 Hz, 2H), 1.31-1.29 (t, 7 = 7.6 Hz, 2H)

Step 4: 2-( 1 -(2,6-dichloro-4-nitrophenyl)cyclopropyl)-6-fluorobenzo[d]oxazole

To a stirring solution of product of step 3 (1.5 g, 3.89 mmol) in toluene (5 v/w) was added j?-toluene sulfonic acid monohydrate (1.0 g, 5.84 mmol). The mixture was stirred at reflux temperature for 10 h with continuous removal of water by using Dean- Stark apparatus. After complete conversion of starting material reaction mixture was diluted with water. The mixture was extracted with EtOAc. Organic layer was washed with saturated solution of NaHC0₃, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as a brown oil which was further purified by column chromatography (0-20% EtOAc in Hexane) to get off-white solid as pure product. 1H NMR (CDC1₃): 8.28 (s, 2H), 7.54-7.51 (m, 1H), 7.17-7.14 (dd, J = 2.4 & 8 Hz, 1H), 7.06-7.01 (m, 1H), 2.26-2.248 (m, 2H), 1.68-1.65 (m, 2H).

Step 5: 3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclopropyl)aniline

To a solution of product of step 4 (0.530 g, 1.44 mmol) in EtOH (10 v/w) was added SnCl₂.2H₂0 (1.62 ,7.22 mmol) at RT. Reaction mixture was heated to 70-75 °C and stirred for 2 h. After complete conversion of starting material reaction mixture was diluted with EtOAc and basified with ammonia solution. Organic layer was decanted, dried over Na₂S0₄, and filtered. Removal of the solvent under reduce pressure gave product as a yellow solid. ^XH NMR (DMSO-J₆): 7.63-7.57 (m, 2H), 7.20-7.15 (m, 1H) 6.66 (s, 2H), 5.78 (s, 2H), 1.99-1.95 (m, 2H), 1.56-1.52 (m, 2H). ESI-MS (m/z): 336.85 (M+H)⁺.

Preparation of 4-(l-(benzo[d]oxazol-2-yl)cyclopropyl)-3,5-dichloroaniline (111-26)

Prepared using similar procedure as described for 111-25 ESI-MS (m/z): 318.75 Preparation of 3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclobutyl)aniline (111-27)

Prepared using similar procedure as described for 111-25. ESI-MS (m/z): 351.07 (M+H)⁺.

Preparation of 3-(l-(4-amino-2,6-dichlorophenyl)cyclopropyl)-N,N-dimethyl-l,2,4- oxadiazol-5-amine (111-28)

-(l-(2,6-dichloro-4-nitrophenyl)cyclopropyl)-l,2,4-oxadiazol-5-ol

Solution of l-(2,6-dichloro-4-nitrophenyl)-N' hydroxyl cyclopropane carboximidamide (1.7 g, 5.86 mmol, prepared in step 4, III-l) and CDI (1.9 g, 11.72 mmol) in C¾CN (10 ml) was stirred at 80°C for 16 h. The reaction mixture was acidified by 35% HC1 to pH=2-3 and product was extracted with EtOAc. Organic layer was washed with water and evaporated under reduced pressure to get 1.80 g of title product as solid. ESI-MS (m/z): 313.90 (M-H).

Step 2: 5-chloro-3-( 1 -(2,6-dichloro-4-nitrophenyl)cyclopropyl)- 1 ,2,4-oxadiazole

To a stirring solution of product of step 1 (1.8 g, 5.69 mmol) in pyridine (5.53 ml,

68.3 mmol) was added POCl₃ (5.31 ml, 56.9 mmol) at 5°C and stirred at 85°C for 6 h. The reaction mixture was diluted with water and extracted with EtOAc. Organic layer was washed with brine and evaporated to get the crude product which was further purified by column chromatography to get 0.640 g of title product as solid.

Step 3:3-(l-(2,6-dichloro-4-nitrophenyl)cyclopropyl)-N,N-dimethyl-l,2,4-oxadiazol-5- amine

To a stirring solution of product of step 2 (0.840 g, 2.51 mmol) and DIPEA (0.658 ml, 3.77 mmol) in DMSO (11 ml) was added dimethylamine hydrochloride (0.409 g, 5.02 mmol) at 25 °C and stirred for 16 h. Reaction mixture was diluted with water and product was filtered and dried to get 0.550 g of title product as solid. ESI-MS (m/z): 344.70 (M+H)⁺.

Step 4: 3-(l-(4-amino-2,6-dichlorophenyl)cyclopropyl)-N,N-dimethyl-l,2,4-oxadiazol-5- amine

To a stirring solution of product of step 3 (650 mg, 1.894 mmol) in EtOAc (20 ml) was added SnCl₂.2H₂0 (2.13 g, 9.47 mmol) and stirred at RT for 16 h. Reaction mixture was diluted with EtOAc, basified with aq. ammonia and passed through Hyflo bed. Organic layer was separated and distilled out to get 0.450 g of title product as solid.

^XH NMR (DMSO-Je): 6.57 (s, 2H), 5.62 (s, 2H), 2.99 (s, 6H), 1.63-1.60 (m, 2H), 1.24-

1.21 (m, 2H). ESI-MS (m/z): 314.75 (M+H)⁺.

Preparation of intermediates of general formulae (IV) and (V)

Preparation of N-(4-(ethylsulfonyl)phenyl)-N-(2,2,2-trifluoroethyl)glycine (IV-1)

Step 1: 4-(ethylsulfonyl)aniline

To a stirring solution of l-(ethylsulfonyl)-4-nitrobenzene (5.0 g, 23.23 mmol) in EtOH (50 ml) was added SnCl₂.2H₂0 (26.2 g, 116 mmol) and 35% HCl (0.75 ml). The reaction mixture was stirred at 80°C for 2 h. After complete conversion of starting material reaction mixture was cooled to RT. The reaction mixture was diluted with EtOAc (200 ml) and basified to pH = 9 by aq. ammonia. Organic layer was dried over Na₂S0₄ and evaporated under reduced pressure to get the desired product. ¹H NMR (CDC1₃): 7.68-7.64 (m, 2H), 6.74-6.70 (m, 2H), 4.20 (bs, 2H), 3.09 (q, 7 = 7.2 Hz, 2H), 1.26 (t, 7 = 7.2 Hz, 3H).

Step 2: N-(4-(ethylsulfonyl)phenyl -2,2,2-trifluoroacetamide

To a stirring solution of product of step 1 (4.5 g, 24.29 mmol), DIPEA (3.77 g, 29.2 mmol) in DCM (45 ml) at 0 °C was added trifluoro acetic anhydride (5.10 g, 24.29 mmol). The reaction mixture was stirred at RT for 1.5 h. After complete conversion of starting material reaction mixture was diluted with DCM (45 ml). Organic layer was separated, washed with water, dried over Na₂S0₄ and evaporated under reduced pressure to get the title product. ^XH NMR (CDCI₃): 8.12 (bs, 1H), 7.98-7.95 (m, 2H), 7.84-7.81 (m, 2H), 3.17 (q , 7 = 7.6 Hz, 2H), 1.32 (t, 7 = 7.6 Hz, 3H).

Step 3: 4-(ethylsulfonyl)-N-(2,2,2-trifluoroethyl)aniline

To a stirring solution of product of step 2 (5.4 g, 19.2 mmol) in THF (25 ml) was added Boran-dimethyl sulfide (2.92 g, 38.4 mmol) at RT. The reaction mixture was stirred at 80°C for 3 h. After complete conversion of starting material reaction mixture was cooled to RT and quenched with MeOH till effervescence ceased. The reaction mixture was diluted with EtOAc (100 ml). Organic layer was washed with water, dried over Na₂S0₄ and evaporated under reduced pressure to get the crude product which was further purified by column chromatography (0-40% EtOAc in Hexane) to get title product. ^XH NMR (CDC1₃): 7.71-7.74 (m, 2H), 6.78-6.75 (m, 2H), 4.55 (t, 1H), 3.90-3.82 (m, 2H), 3.11 (q, 7 = 7.6 Hz, 2H ), 1.27 (t, 7 = 7.6 Hz, 3H).

Step 4: ethyl N-(4-(ethylsulfonyl)phenyl)-N-(2,2,2-trifluoroethyl)glycinate

To a stirring solution of product of step 3 (2.0 g,7.48 mmol) in DMF (8.0 ml) was added NaH (0.599 g, 14.97 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. To this was added ethyl 2-bromoacetate (1.5 g, 8.89 mmol) drop wise at 0 °C. Stirring continued for further 30 min. at 0 °C and at 25°C for 1 h. After complete conversion of starting material reaction mixture was diluted with EtOAc (30 ml). Organic layer was separated, washed with water, dried over Na₂S0₄ and evaporated under reduced pressure to get the crude product, which was purified by column chromatography (0-20% EtOAc in Hexane) to get title product. ^XH NMR (CDCI₃): 7.78-7.71 (m, 2H), 6.84-6.76 (m, 2H), 4.29-4.23 (m, 2H), 4.21 (s, 2H), 4.12 (q, 7 = 7.6 Hz, 2H), 3.11(q, 7 = 7.2 Hz, 2H), 1.32-1.26 (m, 6H).

Step 5: N-(4-(ethylsulfonyl)phenyl)- -(2,2,2-trifluoroethyl)glycine

To a stirring solution of product of step 4 (0.600 g, 1.698 mmol) in EtOH (3.3 ml) was added NaOH (0.102 g, 2.55 mmol) dissolved in water (0.33 ml) at RT. The reaction mixture was stirred at RT for 2 h. After complete conversion of starting material, EtOH from reaction mixture was evaporated followed by dilution with water (5.0 ml). Aqueous layer was acidified with dilute HCl and product was extracted with DCM. Organic layer was dried over Na₂S0₄ and evaporated under reduced pressure to get desired product.¹H NMR (CDCI₃): 7.80 (d, = 9.2 Hz, 2H), 6.83 (d, = 9.2 Hz, 2H), 4.27 (s, 2H), 4.09 (q,

2H), 3.12 (q, J = 7.2 Hz, 2H), 1.28 (t, = 7.2 Hz, 3H).

Preparation of N-(4-(ethylsulfonyl)phenyl)-N-methylglycine (IV-2)

Step 1: ethyl (4-(ethylsulfonyl)phenyl)glycinate

To a stirring solution of 4-(ethylsulfonyl)aniline (2.8 g, 15.12 mmol) and DIPEA (5.28 ml, 30.2 mmol) in DMF (15 ml) was added drop wise ethyl 2-bromoacetate (1.741 ml, 15.12 mmol) at 80°C for 1 h and stirred for 16 h. The reaction mixture was diluted with EtOAc, washed with water and evaporated under reduced pressure to get 1.89 g of title product as liquid which was directly used in next step.

Step 2: ethyl N-(4-(ethylsulfonyl)phenyl)-N-methylglycinate

To a stirring solution of product of step 1 (0.800 g, 2.95 mmol) in DMF (5.0 ml) was added K₂C0₃ (2.037 g, 14.74 mmol) followed by methyl iodide (1.475 ml, 23.59 mmol) and stirred at 85 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with water and evaporated under reduced pressure to get the crude product, which was further purified by column chromatography to get 0.440 g of title product as liquid. ESI-MS (m/z): 285.80 (M+H)⁺.

Step 3: N-(4-(ethylsulfonyl)pheny -N-methylglycine

To a stirring solution of product of step 2 (440 mg, 1.542 mmol) in EtOH (6 ml) was added NaOH (93 mg, 2.313 mmol) dissolved in water (2 mL) and stirred at RT for 2 h. EtOH was evaporated followed by dilution with water and acidification by aq. HCl to get 0.245 g of title product as solid. 1H NMR (DMSO-J₆): 12.75 (bs, 1H), 7.60-7.57 (m, 2H), 6.81-6.77 (m, 2H), 4.21 (s, 2H), 3.15-3.09 (q, 2H), 3.04 (s, 3H), 1.06 (t, 3H). ESI- MS (m/z): 258.05 (M+H)⁺.

Preparation of N-ethyl-N-(4-(ethylsulfonyl)phenyl)glycine (IV-3)

Step 1: N-(4-(ethylthio)phenyl)acetamide

To a stirring solution of 4-(ethylthio)aniline (1.0 g, 6.53 mmol) and DIPEA (1.368 ml, 7.83 mmol) in DCM (20 ml) was added acetic anhydride (0.616 ml, 6.53 mmol) at 0 °C. The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with EtOAc, washed with water and evaporated under reduced pressure to get 1.10 g of title product as liquid. ESI-MS (m/z): 196.05 (M+H)⁺.

Step 2: N-ethyl-4-(ethylthio)aniline

A solution of product of step 1 (1.0 g, 5.12 mmol) and borane-dimethyl sulfide complex (0.973 ml, 10.24 mmol) in THF (7.0 ml) was stirred at 80°C for 3 h. The reaction mixture was diluted with MeOH and then EtOAc and washed with water. Organic layer was evaporated under reduced pressure to get the crude product which was further purified by column chromatography to get 0.6 g of title product as liquid. ESI-MS (m/z): 182.05 (M+H)⁺.

Step 3: ethyl N-ethyl-N-(4-(ethylthio)phenyl)glycinate

Prepared using product of step 2 and similar procedure as described for the synthesis of ethyl (4-(ethylsulfonyl)phenyl)glycinate in preparation of intermediate IV-2. ESI-MS (m/z): 268.10 (M+H)⁺.

Step 4: ethyl N-ethyl-N-(4-(ethylsulfonyl)phenyl)glycinate

To a stirring solution of product of step 3 (0.510 g, 1.907 mmol) in acetone (6.88 ml) and water (5.10 ml) was added oxone (2.93 g, 4.77 mmol) and stirred for 3 h at RT. The reaction mixture was diluted with EtOAc, washed with water and evaporated under reduced pressure to get 0.350 g of title product as solid. ESI-MS (m/z): 300.10 (M+H)⁺. Step 5: N-ethyl-N-(4-(ethylsulfonyl)phenyl)glycine

Prepared using product of step 4 and similar procedure as described for the synthesis of N-(4-(ethylsulfonyl)phenyl)-N-methylglycine in preparation of intermediate IV-2. ESI-MS (m/z): 272.05 (M+H)⁺.

Preparation of N-(cyclopropylmethyl)-N-(4-(ethylsulfonyl)phenyl)glycine (IV-4)

Step 1 : N-(cyclopropylmethyl)-4-(ethylthio)aniline

To a stirring solution of 4-(ethylthio)aniline (0.600 g, 3.92 mmol) and cyclopropanecarbaldehyde (0.329 g, 4.70 mmol) in DCE (3.00 ml) was added acetic acid (0.897 ml, 15.66 mmol) at 5°C. Then reaction mixture was stirred at RT for 3 h. Reaction mixture was cooled to 0°C and sodium triacetoxyborohydride (2.489 g, 11.75 mmol) was added at 0-5°C. The reaction mixture was stirred at RT for 16 h. Reaction mixture was diluted with EtOAc (20 ml). Organic layer was washed with 5 % NaHC0₃ solution, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as brown oil which was further purified by column chromatography (0-20% EtOAc in hexane) to get white solid as pure product. ESI-MS (m/z): 208.05 (M+H)⁺.

Step-2 : ethyl N-(cyclopropylmethyl)-N-(4-(ethylthio)phenyl)glycinate

Prepared using product of step 1 and similar procedure as described for the synthesis of ethyl (4-(ethylsulfonyl)phenyl)glycinate in preparation of intermediate IV-2. ESI-MS (m/z): 294.05 (M+H)⁺.

Step-3: ethyl N-(cyclopropylmethyl)-N-(4-(ethylsulfonyl)phenyl)glycinate

Prepared using product of step 2 and similar procedure as described for the synthesis of ethyl N-ethyl-N-(4-(ethylsulfonyl)phenyl)glycinate in preparation of intermediate IV-3. ESI-MS (m/z): 326.10 (M+H)⁺.

Step-4: N-(cyclopropylmethyl)-N-(4-(ethylsulfonyl)phenyl)glycine

Prepared using product of step 3 and similar procedure as described for the synthesis of N-(4-(ethylsulfonyl)phenyl)-N-methylglycine in preparation of intermediate IV-2. ESI-MS (m/z): 298.05 (M+H)⁺. Preparation of N-(4-(ethylsulfonyl)phenyl)-N-(oxetan-3-yl)glycine (IV-5)

Step 1: N-(4-(ethylthio)phenyl)oxetan-3-amine

A solution of 4-(ethylthio)aniline (3.00 g, 19.58 mmol), oxetan-3-one (2.82 g, 39.2 mmol), and acetic acid (4.48 ml, 78 mmol) in DCE (30 ml) was stirred for 1 h. Reaction mixture was cooled to 0 °C. To this was added sodium triacetoxy borohydride (12.45 g, 58.7 mmol) at 0°C and it was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc and washed with water. Organic layer was evaporated under reduced pressure to get the crude product which was further purified by column chromatography to get 2.74 g of title product as liquid. ESI-MS (m/z): 209.05 (M+H)⁺.

Step 2: ethyl N-(4-(ethylthio)phenyl)-N-(oxetan-3-yl)glycinate

Prepared using product of step 1 and similar procedure as described for the synthesis of ethyl (4-(ethylsulfonyl)phenyl)glycinate in preparation of intermediate IV-2. ESI-MS (m/z): 295.90 (M+H)⁺.

Step 3: ethyl N-(4-(ethylsulfonyl)phenyl)-N-(oxetan-3-yl)glycinate

Prepared using product of step 2 and similar procedure as described for the synthesis of ethyl N-ethyl-N-(4-(ethylsulfonyl)phenyl)glycinate in preparation of intermediate IV-3. ESI-MS (m/z): 325.90 (M-H). Step 4: N-(4-(ethylsulfonyl)phenyl)-N-(oxetan-3-yl)glycine

Prepared using product of step 3 and similar procedure as described for the synthesis of N-(4-(ethylsulfonyl)phenyl)-N-methylglycine in preparation of intermediate IV-2. ESI-MS (m/z): 299.85 (M+H)⁺.

Preparation of N-(6-(ethylsulfonyl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)glycine (IV- 6)

Step 1: N-(6-(ethylthio)pyridin-3-y -2,2,2-trifluoroacetamide

To a stirring solution of 6-(ethylthio)pyridin-3-amine (1.2 g, 7.78 mmol) and DIPEA (1.631 ml, 9.34 mmol) in DCM (20 ml) was added trifluoro acetic anhydride (1.099 ml, 7.78 mmol) at 0 °C and stirred at RT for 1.5 h. The reaction mixture was diluted with DCM and washed with water. Organic layer was evaporated under reduced pressure to get 1.9 g of title product as liquid. ESI-MS (m/z): 250.55 (M+H)⁺.

Step 2: 6-(ethylthio)-N-(2,2,2-trifluoroethyl)pyridin-3-amine

A solution of product of step 1 (1.9 g, 7.59 mmol) and borane dimethyl sulfide complex (1.442 ml, 15.19 mmol) in THF (30 ml) was stirred at 80°C for 3 h. The reaction mixture was diluted first with MeOH and then EtOAc followed by washing with water and brine. Organic layer was evaporated under reduced pressure to get the crude product which was further purified by column chromatography to get 0.780 g of title product as liquid. ESI-MS (m/z): 236.55 (M+H)⁺.

Step 3: ethyl N-(6-(ethylthio)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)glycinate

To a stirred solution of product of step 2 (0.780 g, 3.30 mmol) and rhodium(II) acetate dimer (0.044 g, 0.099 mmol) in DCM (5.0 ml) was added ethyl 2-diazoacetate (0.565 g, 4.95 mmol) at RT and stirred at 40°C for 1 h. The reaction mixture was diluted with DCM and washed with water. Organic layer was evaporated under reduced pressure to get the crude product which was further purified by column chromatography to get 1 g of title product as solid. ESI-MS (m/z): 322.85 (M+H)⁺.

Step 4: ethyl N-(6-(ethylsulfonyl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)glycinate

Prepared using product of step 3 and similar procedure as described for the synthesis of ethyl N-ethyl-N-(4-(ethylsulfonyl)phenyl)glycinate in preparation of intermediate IV-3. ESI-MS (m/z): 354.90 (M+H)⁺.

Step 5: N-(6-(ethylsulfonyl)pyridin-3-yl)-N-(2,2,2-trifluoroethyl)glycine

Prepared using product of step 4 and similar procedure as described for the synthesis of N-(4-(ethylsulfonyl)phenyl)-N-methylglycine in preparation of intermediate IV-2. ESI-MS (m/z): 326.80 (M+H)⁺. Preparation of 2-(5-(ethylsulfonyl)indolin-l-yl)acetic acid (IV-7)

Step 1: l-(indolin-l-yl)ethan-l-one

^H3C ,o

To a stirring solution of indoline (25 g, 210 mmol) in DCM (200 ml) was added TEA (102 ml, 734 mmol) at 5-10°C followed by slow addition of acetyl chloride (19.69 ml, 277 mmol). Reaction mixture was stirred at RT for 4 h. The reaction mixture was diluted with water (100 ml) and aq. layer was extracted with DCM. Organic layer was separated and washed with water and brine. The organic layer was dried over Na₂S04, filtered and concentrated under reduced pressure to afford crude product which was column purified (0-30% EtOAc in hexane) to get pure product.

Step 2: l-acetylindoline-5-sulfonyl chloride

In a flask containing chlorosulfonic acid (15.58 ml, 233 mmol) was added slowly portion wise l-(indolin-l-yl)ethanone (9.4g, 58.3 mmol) at 0-5°C to give a brown solution. Reaction mixture was stirred at RT for 1 h and at 70°C for 40 min. The reaction mixture was cooled at 0-5 °C, quenched by adding cold water. Solid obtained was filtered and dried to afford desired product.

Step 3: (l-acetylindolin-5-yl)sulfonyl)zinc

To a stirring solution of product of step 2 (10.4 g, 40.0 mmol) in THF (138 ml) and water (69.0 ml) was added Zn metal (2.62 g, 40.0 mmol) slowly at RT. The reaction mixture was stirred at RT for 16 h before it was quenched by adding cold water. Solid obtained was filtered and dried to get desired product.

Step 4: l-(5-(ethylsulfonyl)indolin-l-yl)ethan-l-one

To a stirring solution of product of step 3 (10.8 g, 37.3 mmol) in THF (96 ml) and water (48 ml) was added ethyl iodide (6.63 ml, 82 mmol) at RT. The reaction mixture was stirred at 70°C for 16 h. The reaction mixture was cooled at 0-5 °C, quenched by adding cold water and extracted with EtOAc. The organic layer was separated, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford desired product. Step 5: 5-(ethylsulfonyl)indoline

To a stirring solution of product of step 4 (870 mg, 3.43 mmol) in THF (30 ml) and water (15 ml) was added NaOH (206 mg, 5.15 mmol) dissolved in water (5 mL) at RT. The reaction mixture was stirred at 50°C for 5 h. The reaction mixture was cooled at 0-5°C, quenched by adding cold water and extracted with EtOAc. The organic layer was separated, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford desired product.

Step 6: ethyl 2-(5-(ethylsulfonyl)indolin-l-yl)acetate

To a stirring solution of product of step 5 (0.3 g, 1.420 mmol) in THF (5 mL) at 0- 5°C was added NaH (0.102 g, 2.130 mmol) slowly at 0-5°C. To this was added drop wise ethyl 2-bromoacetate (0.356 g, 2.130 mmol). The reaction mixture was stirred at 0-25°C for 30 min. The reaction mixture was diluted by EtOAc (10 mL) and washed with water (15 mL). The organic layer was separated, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford desired product.

Step 7: 2-(5-(ethylsulfonyl)indoli -l-yl)acetic acid

To a stirring solution of ethyl 2-(5-(ethylsulfonyl)indolin-l-yl)acetate (2.3 g, 7.73 mmol) in THF (20 ml) and water (5 ml) was added LiOH:H₂0 (2.320 g, 38.7 mmol) at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was made acidic by dil. HC1 and distilled out MeOH. The aq. layer was extracted with EtOAc. Organic layer was separated, dried over Na₂S0₄, filtered and concentrated under reduced pressure to afford desired product. ESI-MS (m/z): 269.65 (M+H)⁺.

Preparation of 2-(5-(methylsulfonyl)-lH-indol-l-yl)acetic acid (IV-8)

Step 1: 5-(methylsulfonyl)-lH-indole

To a stirring solution of 5-bromo-lH-indole (0.200 g,1.02 mmol), copper(I) iodide (971 mg, 5.10 mmol) in N-methyl-2-pyrrolidinone (5.0 ml) was added sodium methanesulfinate (521 mg, 5.10 mmol) and stirred at 150°C for 5 h. After complete conversion of starting material, reaction mixture was cooled to RT and diluted with 50 ml of EtOAc. Organic layer was washed with brine, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure, gave product as brown oil which was further purified by column chromatography (0-30% EtOAc in Hexane) to get white solid as pure product. Step 2: ethyl 2-(5-(methylsulfonyl)-lH-indol-l-yl)acetate

To a stirring solution of product of step 1 (0.340 g, 1.741 mmol) in DMF (3.5 ml) was added NaH (0.084 g, 3.50 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. To this was added ethyl 2-bromoacetate (0.242 ml, 2.100 mmol) at 0 °C and reaction mixture was stirred at RT for 2 h. After complete conversion of starting material, reaction mixture was diluted with EtOAc (50 ml). Organic layer was washed with brine, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as brown oil which was further purified by column chromatography (0-20% EtOAc in Hexane) to get white solid as pure product.

Step-3 : 2-(5-(methylsulfonyl)-lH-indol-l-yl)acetic acid

To a stirring solution of product of step 2 (0.200 g, 0.711 mmol) in THF (0.78 ml), EtOH (0.26 ml) and water (0.26 ml) was added LiOH:H₂0 (0.034 g, 1.420 mmol) at RT. The reaction mixture was stirred at RT for 2 h. After complete conversion of starting material, THF and EtOH were removed from reaction mixture then reaction was acidified with dil. HC1 to get pH=2. Product was extracted with DCM (25 ml), washed with brine, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as white solid. ESI-MS (m/z): 253.45 (M+H)⁺.

Preparation of 2-(5-(ethylthio)-l -indazol-l-yl)acetic acid (V-l)

Step 1: 5-(ethylthio)-lH-indazole

To a stirring solution of 5-bromo-lH-indazole (0.500 g, 2.54 mmol) and copper (I) iodide (0.967 g, 5.08 mmol) in N-Methyl-2-pyrrolidinone (17.0 ml) was added sodium ethanefhiolate (0.427 g, 5.08 mmol) and it was heated to 150°C under Microwave radiation in open vessel. Reaction mixture was stirred at 150°C for 1 h. After complete conversion of starting material, reaction mixture was cooled to 25 °C and diluted with 50 ml of EtOAc. Organic layer washed with brine, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as brown oil which was further purified by column chromatography (0-30% EtOAc in Hexane) to get white solid as pure product.

Step 2: ethyl 2-(5-(ethylthio)-lH-indazol-l-yl)acetate

To a stirring solution of product of step 1 (180 mg, 1.010 mmol) in DMF (3 ml) was added NaH (0.031 g, 1.31 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. To this was added ethyl 2-bromoacetate (0.140 ml, 1.21 mol) at 0 °C and the reaction mixture was stirred at RT for 2 h. After complete conversion of starting material reaction mixture was diluted with EtOAc (20 ml). Organic layer was washed with brine, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as brown oil which was further purified by column chromatography (0-20% EtOAc in Hexane) to get white solid as pure product. ESI-MS (m/z): 264.75 (M+H)⁺. Step 3: 2-(5-(ethylthio)-lH-indazo -l-yl)acetic acid

To a stirring solution of product of step 2 (0.120 g, 0.454 mmol), in EtOH (1.2ml) and water (0.5 ml) was added NaOH (0.022 g, 0.545 mmol) at 25 °C. The reaction mixture was stirred at 25°C for 1 h. After complete conversion of starting material, EtOH was removed from reaction mixture and then reaction mixture was acidified with dil. HC1 to get pH = 2. Product was extracted with DCM (10 ml), washed with brine, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as white solid. ESI-MS (m/z): 236.65 (M+H)⁺.

Preparation of compounds of general formula (I)

EXAMPLE 1

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl) phenyl) -2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino) acetamide

To a solution of intermediate IV-1 (180 mg, 0.553 mmol) in DCM (2 mL) was added EDC.HC1 (180 mg, 0.941 mmol) and HOBT (127 mg, 0.830 mmol) at RT. Reaction mixture was stirred for 10 min. at RT. To this was added intermediate III-l (202 mg, 0.553 mmol) and stirred for 16 h. After 16 h, reaction mixture was diluted with DCM (10 ml). Reaction mixture was washed with saturated solution of NaHC0₃. Organic layer was separated, dried over Na₂S0₄, and filtered. Removal of the solvent under reduced pressure gave product as a yellow oil which was further purified by column chromatography (0-40% EtOAc in Hexane) to get title product. 1H NMR (DMSO-J₆): 10.52 (s, 1H), 8.12-8.09 (m, 2H), 7.72 (s, 2H), 7.66 (d, = 9.2 Hz, 2H), 7.47-7.43 (m, 2H), 7.01 (d, = 9.2 Hz, 2H), 4.41 (s, 2H), 4.48-4.43 (m, 2H), 3.19 (q, / = 7.2 Hz, 2H), 1.91-1.89 (m, 2H), 1.55-1.52 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H).

Using appropriate starting materials and suitable modifications of the process described in example 1, 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 were prepared in an analogues manner.

EXAMPLE 2

Preparation of N-(3,5-dichloro-4-(l-(5-(3,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino) acetamide

Prepared using intermediate IV-1 and intermediate III-2. ¹H NMR

10.52 (s, IH), 8.12-8.07 (m, IH), 7.94 (bd, IH), 7.73 (s, 2H), 7.70-7.64 (m, 3H), 7.01 (d, J = 9.2 Hz, 2H), 4.48 (d, 7 = 8.8 Hz, 2H), 4.41 (s, 2H), 3.19 (q, 7 = 7.6 Hz, 2H), 1.92-1.88 (m, 2H), 1.56-1.53 (m, 2H), 1.08 (t, 3H).

EXAMPLE 3

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino) acetamide

Prepared using intermediate IV-1 and intermediate III-3. ¹H NMR

10.53 (s, IH), 8.15 (m, IH), 7.73 (s, 2H), 7.66 (d, 7 = 8.8 Hz, 2H), 7.60 (m, IH), 7.34 (m, IH), 7.01 (d, 7 = 8.8 Hz, 2H), 4.48 (m, 2H), 4.42 (s, 2H), 3.17 (q, 7 = 7.2 Hz, 2H), 1.91- 1.88 (m, 2H), 1.56-1.53 (m, 2H), 1.07 (t, 7 = 7.6 Hz, 3H).

EXAMPLE 4

Preparation of N-(3,5-dichloro-4-(l-(5-(2-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino) acetamide

Prepared using intermediate IV-1 and intermediate III-4. 1H NMR (DMSO-Je): 10.52 (s, IH), 8.15-8.11 (m, IH), 7.78 (dd, 7 = 2.4 & 8.8 Hz, IH), 7.73 (s, 2H), 7.66 (d, 7 = 9.2 Hz 2H), 7.49-7.45 (m, 1H), 7.01 (d, = 9.2 Hz, 2H), 4.48 (d, = 9.6 Hz, 2H), 4.41 (s, 2H), 3.19 (q, J = 1.2 Hz, 2H), 1.91-1.88 (m, 2H), 1.57-1.54 (m, 2H), 1.07 (t, J = 1.2 Hz, 3H).

EXAMPLE 5

Preparation of N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol- 3-yl)cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2- trifluoroethyl)amino)acetamide

Prepared using intermediate IV-1 and intermediate III-5. 1HNMR

10.53 (s, 1H), 8.26 (d, = 8.0 Hz, 2H), 7.99 (d, = 8.4 Hz, 2H), 7.73 (s, 2H), 7.66 (d, = 9.2 Hz, 2H), 7.01 (d, = 9.2 Hz, 2H), 4.48-4.46 (m, 2H), 4.42 (s, 2H), 3.19 (q, = 7.2 Hz, 2H), 1.94-1.91 (m, 2H), 1.58-1.55 (m, 2H), 1.07 (t, J = 1.2 Hz, 3H).

EXAMPLE 6

Preparation of N-(3,5-dichloro-4-(l-(5-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate III-6. ¹H NMR

10.51 (s, 1H), 8.22 (d, = 2 & 6.8 Hz, 1H), 8.15-8.05 (m, 1H), 7.73 (s, 2H), 7.68-7.64 (m, 3H), 6.98 (d, = 8.8 Hz, 2H), 4.48-4.45 (m, 2H), 4.41 (s, 2H), 3.17-3.15 (m, 2H), 1.91-1.90 (m, 2H), 1.55-1.54 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 7

Preparation of N-(3,5-dichloro-4-(l-(5-(2,3-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2- trifluoroethyl)aniino)acetamide

Prepared using intermediate IV-1 and intermediate III-7. 1H NMR (DMSO-Je): 10.51 (s, 1H), 7.89-7.86 (m, 1H), 7.80 (d, / = 9.2 Hz, 1H), 7.73 (s, 2H), 7.65 (d, / = 9.2 Hz, 2H), 7.44-7.43 (m, 1H) , 6.98 (d, = 8.8 Hz, 2H), 4.48-4.45 (m, 1H), 4.41(s, 2H), 3.19-3.12 (m, 2H), 1.92-1.88 (m, 2H), 1.58-1.54 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 8

Preparation of N-(3,5-dichloro-4-(l-(5-(2,5-difluorophenyl)-l,2,4-oxadiazol-3- yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino) acetamide

Prepared using intermediate IV-1 and intermediate III-8 1H NMR (DMSO-Je):

10.54 (s, 1H), 7.89-85 (m, 1H), 7.73 (s, 2H), 7.64 (d, = 9.2 Hz, 2H), 7.73-7.60 (m, 2H), 6.99 (d, = 8.8 Hz, 2H), 4.48-4.46 (m, 2H), 4.42 (s, 2H), 3.19-3.14 (m, 2H), 1.92-1.88 (m, 2H), 1.57-1.54 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 9

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-dichlorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate III-9 1H NMR (DMSO-J₆): 10.52 (s, 1H), 8.08 (d, = 8.8 Hz, 1H), 7.94 (d , = 1.6 Hz, 1H), 7.73 (s, 2H), 7.67-7.64 (m, 3H), 7.01 (d, 7 = 9.2 Hz, 2H), 4.48 (m, 2H), 4.42 (s, 2H), 3.19 (q, 7 = 7.6 Hz, 2H), 2.01-1.8 (m, 2H), 1.65-1.51 (m, 2H), 1.07 (t, 7 = 7.6 Hz, 3H).

EXAMPLE 10

Preparation of N-(3,5-dichloro-4-(l-(5-(2-fluoro-4-methoxyphenyl)-l,2,4-oxadiazol- 3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate III-10 1H NMR

10.53 (s, 1H), 7.98 (t, 7 = 8.8 Hz, 1H), 7.72 (s, 2H), 7.64 (t, 7 = 9.2 Hz, 2H), 7.13-7.09 (m, 1H), 6.99 (t, 7 = 8.8 Hz, 3H), 4.48-4.46 (m, 2H), 4.41(s, 2H), 3.87 (s, 3H), 3.19-3.14 (m, 2H), 1.89-1.86 (m, 2H), 1.53-1.50 (m, 2H), 1.07 (t, 7 = 7.6 Hz, 3H).

EXAMPLE 11

Preparation of N-(3,5-dichloro-4-(l-(5-(thiophen-2-yl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate III-ll 1H NMR (DMSO-J₆):

10.5 (s, 1H), 8.07-8.05 (m, 1H), 7.96-7.94 (m, 1H), 7.72 (s, 2H), 7.66 (d, 7 = 9.2 Hz, 2H), 7.31 (d, 7 = 1.2 Hz, 1H), 7.01 (d, 7 = 9.2 Hz, 2H), 4.7-4.4 (m, 4H), 4.41 (s, 2H), 3.17-3.15 (m, 2H), 1.87-1.86 (bd, 2H), 1.52-1.51 (bd, 2H), 1.07 (t, 7 = 7.6 Hz, 3H).

EXAMPLE 12

Preparation of N-(3,5-dichloro-4-(l-(5-(5-methylthiophen-2-yl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-12 1H NMR (DMSO-d₆): 10.52 (s, 1H), 7.77 (d, 7 = 3.6 Hz, 1H), 7.71 (s, 2H), 7.66 (d, 7 = 9.2 Hz, 2H), 7.03-6.98 (m, 3H), 4.41 (m, 4H), 2.55 (s, 3H), 3.17 (q, 2H), 1.84-1.82 (bd, 2H), 1.507-1.501 (bd, 2H), 1.07 (t, 7 = 7.2 Hz, 3H).

EXAMPLE 13

Preparation of N-(3,5-dichloro-4-(l-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3- yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-13 ^XH NMR (DMSO-Je):

10.47 (s, 1H), 9.24 (s, 1H), 8.87 (d, J =4.4Hz, 1H), 8.45 (q, Jl = 2.0 Hz, 72 = 6.4 Hz, 1H), 7.67-7.63 (m, 5H), 6.98 (d, J =8.8Hz, 2H), 4.47-4.42 (m, 2H), 4.40 (s, 2H), 3.19- 3.13 (m, 2H), 2.97-2.92 (m, 4H), 1.07 (t, 7 = 7.6 Hz, 3H).

EXAMPLE 14

Preparation of N-(3,5-dichloro-4-(l-(5-(6-methoxypyridin-3-yl)-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-14 1H NMR (DMSO-Je):

10.52 (s, 1H), 8.85 (d, 7 = 2 Hz, 1H), 8.27 (dd, 7 =2.4 & 9.6 Hz, 1H), 7.27 (s, 2H), 7.65 (d, 7 = 9.2 Hz, 2H), 7.03-6.98 (m, 3H), 4.48-4.46 (m, 2H), 4.41 (s, 2H), 3.95 (s, 3H), 3.19 (q , 7 = 7.2 Hz, 2H), 1.91-1.88 (m, 2H), 1.54-1.51 (m, 2H), 1.07 (t, 7 = 7.6 Hz, 3H). EXAMPLE 15

Preparation of N-(3,5-dichloro-4-(l-(5-isopropyl-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-15 1H NMR (DMSO-J₆): 10.49 (s, 1H), 7.69 (s, 2H), 7.65 (d, 7 = 9.2 Hz, 2H), 7.00 (d, 7 = 9.2 Hz, 2H), 4.47-4.45 (m, 2H), 4.40 (s, 2H), 3.30-3.15 (m, 3H), 1.77-1.75 (m, 2H), 1.46-1.45 (m, 2H), 1.27 (d, 7 = 7.2 Hz, 6H), 1.07 (t, 7 = 7.2 Hz, 3H).

EXAMPLE 16

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-16 1H NMR (DMSO-Je): 10.49 (s, 1H), 7.68 (s, 2H), 7.64 (d, 7 = 8.8 Hz, 2H), 6.98 (d, 7 = 8.4 Hz, 2H), 4.48-4.45 (m, 2H), 4.41 (s, 2H), 3.28-3.15 (m, 2H), 1.73-1.72 (m, 2H), 1.43-1.42 (m, 2H), 1.20- 1.17 (m, 2H), 1.08-1.04 (m, 6H). EXAMPLE 17

Preparation of N-(3,5-dichloro-4-(l-(5-(tetrahydro-2H-pyran-4-yl)-l,2,4-oxadiazol-

3-yl)cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-17 ^XH NMR (DMSO-Je):

10.50 (s, 1H), 7.69 (s, 2H), 7.64 (d, / = 8.8 Hz, 2H), 6.99 (d, / = 8.8 Hz, 2H), 4.55-4.42 (m, 2H), 4.40 (s, 2H), 3.86-3.86 (m, 2H), 3.42-3.32 (m, 3H), 3.26-3.17 (m, 2H), 2.02- 1.95 (m, 2H), 1.85-1.68 (m, 4H), 1.52-1.46 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 18

Preparation of 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)-N-(4-(l-(5- (4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)acetamide

Prepared using intermediate IV-1 and intermediate 111-18 ^XH NMR (DMSO-Je): 10.06 (s, 1H), 8.12-8.09 (m, 2H), 7.66 (d, = 8.8 Hz, 2H), 7.45 (t, 2H), 7.27 (s, 2H), 6.99 (d, = 9.2 Hz, 2H), 4.47 (d, = 9.6 Hz, 2H), 4.36 (s, 2H), 3.19 (q, = 7.2 Hz, 2H), 2.27 (s, 6H), 1.77-1.74 (m, 2H), 1.33-1.30 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H).

EXAMPLE 19

Preparation of N-(3,5-dichloro-4-(l-(5-(thiophen-2-yl)-l,2,4-oxadiazol-3- yl)cyclobutyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2- trifluoroethyl)aniino)acetamide

Prepared using intermediate IV-1 and intermediate 111-19 1H NMR (DMSO-Je):

10.48 (s, 1H), 8.08-8.06 (m, 1H), 7.99 (m, 1H), 7.658 (s, 2H), 7.654 (d, / = 7.2 Hz, 2H), 7.33-7.32 (m, 1H), 7.00 (d, = 9.2 Hz, 2H), 4.57-4.43 (m, 2H), 4.40 (s, 2H), 3.17 (q, = 7.2 Hz, 2H), 2.93-2.89 (m, 4H), 2.42-2.32 (m, 1H), 1.84-1.82 (m, 1H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 20

Preparation of N-(3,5-dichloro-4-(l-(5-(5-methylthiophen-2-yl)-l,2,4-oxadiazol-3- yl)cyclobutyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-20 1H NMR (DMSO-Je):

10.47 (s, 1H), 7.80 (d, = 3.6 Hz, 1H), 7.65-63 (m, 4H), 7.04 (d, = 3.2 Hz, 1H), 6.99 (d, = 9.2 Hz, 2H), 4.49-4.42 (m, 2H), 4.40 (s, 2H), 3.19-3.13 (m, 2H), 2.92-2.87 (m, 4H), 2.65-2.4 (m, 3H), 2.49-2.32 (m, 1H), 1.83-1.81 (m, 1H) 1.07( t, 7 = 7.5 Hz, 3H). EXAMPLE 21

Preparation of N-(3,5-dichloro-4-(l-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclobutyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-21 ^XH NMR (DMSO-Je): 10.47 (s, 1H), 9.24(s, 1H), 8.87 (d, = 4.4 Hz, 1H), 8.46-8.44 (m, 1H), 7.67-7.63 (m, 5H), 4.47-4.42 (m, 2H), 4.40 (s, 2H), 3.19-3.13 (m, 2H), 2.97-2.92 (m, 4H), 2.45-2.49 (m, 3H), 1.95-1.75 (m, 1H), 1.07 (t, = 7.6 Hz, 3H). EXAMPLE 22

Preparation of N-(3,5-dichloro-4-(l-(5-(6-methoxypyridin-3-yl)-l,2,4-oxadiazol-3- yl)cyclobutyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-22 H NMR (DMSO-Je):

10.47 (s, 1H), 8.89 (d, = 1.6 Hz, 1H), 8.31 (q, 1H), 7.65-7.63 (m, 4H), 7.04 (d, = 11.6 Hz, 2H), 6.99 (d, = 9.2 Hz, 2H), 4.47-4.44 (m, 2H), 4.40 (s, 2H), 3.96 (s, 3H), 3.19-3.13 (m, 2H), 2.95-2.90 (m, 2H), 1.91-1.85 (m, 2H), 1.07 (t, = 7.2 Hz, 3H).

EXAMPLE 23

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-25 1H NMR (DMSO-J₆): 10.54 (s, 1H), 7.74 (s, 2H), 7.66-7.59 (m, 4H), 7.21-7.15 (m, 1H), 7.01 (d, = 9.2 Hz, 2H), 4.48-4.42 (m, 2H), 4.42 (s, 2H), 3.19 (q, = 7.6 Hz, 2H), 2.06-2.03 (m, 2H), 1.64- 1.61 (m, 2H), 1.07 (t, J = 7.2 Hz, 3H).

EXAMPLE 24

Preparation of N-(4-(l -(benzo[d]oxazol-2-yl)cyclopropyl)-3,5-dichlorophenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide

Prepared using intermediate IV-1 and intermediate 111-26 Ή NMR (DMSO-Je):

10.56 (s, 1H), 7.68 (d, = 8.8 Hz, 2H), 7.76 (s, 2H), 7.62-7.58 (m, 2H), 7.33-7.29 (m, 2H), 7.02 (d, = 9.2 Hz, 2H), 4.52-4.45 (m, 2H), 4.44 (s, 2H), 3.21 (q, = 7.6 Hz, 2H), 2.08-2.05 (m, 2H), 1.65-1.61 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H).

EXAMPLE 25

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclobutyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-27 1H NMR (CDC1₃): 8.29 (s, 1H), 7.72 (d, = 8.8 Hz, 2H), 7.64-7.60 (m, 1H), 7.55 (s, 2H), 7.23 (dd, = 2.4 and 8.0 Hz, 1H), 7.08-7.01 (m, 1H), 6.87 (d, = 9.2 Hz, 2H), 4.24 (s, 2H), 4.19-4.11 (m, 2H), 3.22-3.17 (m, 2H), 3.13-3.07 (q, / = 7.2 Hz, 2H), 3.02-2.94 (m, 2H), 2.53-2.46 (m, 1H), 1.93-1.89 (m, 1H), 1.28 (t, 7 = 7.2 Hz, 3H).

EXAMPLE 26

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(methyl)amino)acetamide

Prepared using intermediate IV-2 and intermediate III-l 1H NMR (DMSO-J₆): 10.45 (s, 1H), 8.12(m, 2H), 7.75 (s, 2H), 7.62 (d, = 8.8 Hz, 2H), 7.45 (t, 2H), 6.89-6.77 (m, 2H), 4.33 (s, 2H), 3.05-3.23 (m, 5H), 1.91-1.88 (m, 2H), 1.54-1.51 (m, 2H), 1.06 (t, 3H). EXAMPLE 27

Preparation of N-(3,5-dichloro-4-(l-(5-(4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol- 3-yl)cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(methyl)amino)acetamide

Prepared using intermediate IV-2 and intermediate III-5 ¹H NMR

10.46 (s, 1H), 8.26 (d, = 8.0 Hz, 2H), 7.99 (d, = 8.4 Hz, 2H), 7.76 (s, 2H), 7.62 (d, = 8.4 Hz, 2H), 6.84 (d, = 9.2 Hz, 2H), 4.33 (s, 2H), 3.15 (q, = 7.2 Hz, 2H), 3.12 (s, 3H), 1.93-1.90 (m, 2H), 1.58-1.54 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 28

Preparation of N-(3,5-dichloro-4-(l -(5-isopropyl-l ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-(( -(ethylsulfonyl)phenyl)(methyl)amino)acetamide

Prepared using intermediate IV-2 and intermediate 111-15 1H NMR (DMSO-J₆): 10.43 (s, 1H), 7.72 (s, 2H), 7.61 (d, = 9.2 Hz, 2H), 6.83 (d, = 9.2 Hz, 2H), 4.31 (s, 2H), 3.13-3.11 (m, 6H), 1.77-1.76 (m, 2H), 1.45-1.44 (m, 2H), 1.27 (d, = 6.8 Hz, 6H), 1.06 (t, = 7.2 Hz, 3H).

EXAMPLE 29

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(methyl)amino)acetamide

Prepared using intermediate IV-2 and intermediate 111-25 1H NMR (DMSO-Je): 10.48 (s, 1H), 7.77 (s, 2H), 7.63-7.59 (m, 4H), 7.21-7.15 (m, 1H), 6.84 (d, / = 9.2 Hz, 2H), 4.33 (s, 2H), 3.13-3.10 (m, 3H+2H), 2.06-2.02 (m, 2H), 1.64-1.62 (m, 2H), 1.07 (t, = 7.2 Hz, 3H).

EXAMPLE 30

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl)phenyl)-2-(ethyl(4-(ethylsulfonyl)phenyl)amino)acetamide

Prepared using intermediate IV-3 and intermediate 111-25 ^XH NMR (DMSO-Je): 10.46 (s, 1H), 7.78 (s, 2H), 7.62-7.58 (m, 4H), 7.21-7.15 (m, 1H), 6.80 (d, / = 9.2 Hz, 2H), 4.27 (s, 2H), 3.57-3.52 (m, 2H), 3.14 (q, 2H), 2.06-2.03 (m, 2H), 1.64-1.61 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H).

EXAMPLE 31

Preparation of 2-((cyclopropylmethyl)(4-(ethylsulfonyl)phenyl)amino)-N-(3,5- dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)acetamide

Prepared using intermediate IV-4 and intermediate III-l 1H NMR (CDC1₃): 8.14 (s, 1H), 8.10-8.07 (m, 2H), 7.80 (d, = 8.8 Hz, 2H), 7.58 (s, 2H), 7.21-7.16 (m, 2H), 6.89 (d, = 8.8 Hz, 2H), 4.19 (s, 2H), 3.44 (d, = 6.8 Hz, 2H), 3.13-3.08 (q, / = 7.2 Hz, 2H), 2.01-1.98 (m, 2H), 1.54-1.51 (m, 2H), 1.25 (t, 3H), 0.86-0.83 (m, 1H), 0.74-0.71 (m, 2H), 0.4-0.3 (m, 2H).

EXAMPLE 32

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide

Prepared using intermediate IV-5 and intermediate III-l 1H NMR (DMSO-J₆): 10.54 (s, 1H), 8.12-8.09 (m, 2H), 7.76 (s, 2H), 7.64 (d, = 9.2 Hz, 2H), 7.45 (t, = 9.2 Hz, 2H), 6.79 (d, / = 9.2 Hz, 2H), 5.12-5.07 (m, 1H), 4.83 (t, = 6.8 Hz, 2H), 4.65 (t, = 6.8 Hz, 2H), 4.38 (s, 2H), 3.15 (q, / = 7.2 Hz, 2H), 1.90-1.89 (m, 2H), 1.54-1.53 (m, 2H), 1.06 (t, = 7.6 Hz, 3H).

EXAMPLE 33

Preparation of N-(3,5-dichloro-4-(l-(5-isopropyl-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-2- -(ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide

Prepared using intermediate IV-5 and intermediate 111-15 1H NMR (DMSO-Je): 10.52 (s, 1H), 7.72 (s, 2H), 7.63 (d, = 9.2 Hz, 2H), 6.78 (d, = 8.8 Hz, 2H), 5.12-5.06 (m, 1H), 4.82 (t, = 6.8 Hz, 2H), 4.64 (t, = 6.8 Hz, 2H), 4.37 (s, 2H), 3.24-3.13 (m, 3H), 1.77-1.76 (m, 2H), 1.456-1.450 (m, 2H), 1.28 (d, = 7.2 Hz, 6H), 1.06 (t, = 7.2 Hz, 3H).

EXAMPLE 34

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide

Prepared using intermediate IV-5 and intermediate 111-25 1H NMR (DMSO-J₆): 10.57 (s, 1H), 7.77 (s, 2H), 7.64-7.59 (m, 4H), 7.19-7.18 (m, 1H), 6.79 (d, = 8.8 Hz, 2H), 5.1 (m, 1H), 4.83 (t, / = 7.2 Hz, 2H), 4.65 (t, = 6.8 Hz, 2H), 4.39 (s, 2H), 3.15 (q, = 7.2 Hz, 2H), 2.06-2.03 (m, 2H), 1.64-1.61 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H).

EXAMPLE 35

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide

Step 1: tert-butyl (2-((3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)amino)- -oxoethyl)(methyl)carbamate

To a stirring solution of 2-((tert-butoxycarbonyl)(methyl)amino)acetic acid (0.4 g, 2.114 mmol), EDC.HCl (0.689 g, 3.59 mmol) and HOBT (0.486 g, 3.17 mmol) in 30 ml DCM was added intermediate III-l (0.500 g, 1.374 mmol) followed by DIPEA (1.108 ml, 6.34 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with DCM, washed with water, and evaporated under reduced pressure to get the crude product which was further purified by column chromatography to get 0.350 g of title product as solid.

Step 2: N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3- yl)cyclopropyl) phenyl)-2-(methylamino)acetamide hydrochloride

Mixture of product of step 1 (0.350 g, 0.654 mmol) and dioxane:HCl (3.5 ml) was stirred at 25°C for 2 h. Solvent was evaporated to get 0.224 g of title product as solid. ¹H NMR (DMSO-Je): 11.12 (s, 1H), 8.94 (bs, 2H), 8.12-8.09 (m, 2H), 7.75 (s, 2H), 7.48- 7.43 (m, 2H), 3.98 (s, 2H), 2.66 (bs, 3H), 1.93-1.90 (m, 2H), 1.57-1.54 (m, 2H). Step 3: N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide

To a stirring suspension of product of step 2 (0.229 g, 0.486 mmol), 2-chloro-5- (efhylsulfonyl)pyridine (0.100 g, 0.486 mmol), Cs₂C0₃ (0.396 g, 1.216 mmol) in dioxane (2.6 ml) was added palladium (II) acetate (10.92 mg, 0.049 mmol) and BINAP (0.061 g, 0.097 mmol) and stirred at 100°C for 3 h. The reaction mixture was diluted with EtOAc and washed with water. Organic layer was evaporated under reduced pressure to get the crude product which was further purified by column chromatography to get 0.016 g of title product as solid. 1H NMR (DMSO-J₆): 10.46 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H), 8.12- 8.09 (m, 2H), 7.89 (dd, = 2.4 & 9.2 Hz, 1H), 7.74 (s, 2H), 7.47-7.42 (m, 2H), 6.87 (d, = 9.2 Hz, 1H), 3.29-3.19 (m, 3H+2H), 1.99-1.88 (m, 2H), 1.55-1.52 (m, 2H), 1.01 (t, = 7.2 Hz, 3H).

EXAMPLE 36

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((6-(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-6 and intermediate III-l Ή NMR (DMSO-J₆): 10.54 (s, 1H), 8.4 (s, 1H), 8.11 (d, = 3.6 Hz, 1H), 7.84 (d, = 8.8 Hz, 1H), 7.71 (s, 2H), 7.45-7.43 (m, 3H), 4.49 (s, 2H), 4.7-4.5 (m, 2H), 3.29-3.32 (m, 2H), 1.90 (bd, 2H), 1.54 (bd, 2H), 1.09 (t, 7 = 7.2 Hz, 3H). EXAMPLE 37

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -(5-(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate III-l 1H NMR

10.43 (s, IH), 8.12-8.09 (m, 2H), 7.77 (s, 2H), 7.47-7.43 (m, 4H), 6.59 (d, = 8.4 Hz, 2H), 4.15 (s, 2H), 3.67 (t, = 7.2 Hz, 2H), 3.14-3.05 (m, 4H), 1.89 (t, = 6.8 Hz, 2H), 1.53 (t, = 7.2 Hz, 2H), 1.07 (t, = 7.2 Hz 3H).

EXAMPLE 38

Preparation of N-(3,5-dichloro-4-(l-(5-(2,3-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2- -(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate III-7 1H NMR (DMSO-Je): 10.43 (s, IH), 8.19-7.86 (m, IH), 7.84-7.65 (m, 4H), 7.52-7.45 (m, 3H), 6.59 (d, = 8.4 Hz, IH) 4.15 (m, IH), 3.85-3.79 (m, 2H), 3.12-3.07 (m, 4H), 1.91-1.90 (m, 2H), 1.56- 1.54 (m, 2H), 1.08 (t, = 7.2 Hz, 3H).

EXAMPLE 39

Preparation of N-(3,5-dichloro-4-(l-(5-(3,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl) - -(5-(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate III-2 1H NMR (DMSO-Je):

10.45 (s, IH), 8.15 (m, IH), 8.10 (m, IH), 7.77 (s, 2H) 7.71-7.68 (m, IH), 7.43 (d, = 5.2 Hz, 2H), 6.59 (d, = 8 Hz IH), 4.15 (s, 2H), 3.67 (t, = 8.8 Hz, 2H), 3.14-3.05 (m, 4H), 1.98-1.91 (m, 2H), 1.55 (t, = 5.2 Hz, 2H), 1.07 (t, 7 = 7.2 Hz, 3H). EXAMPLE 40

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -(5-(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate III-3 1H NMR

10.43 (s, IH), 8.17-8.11 (m, IH), 7.77 (s, 2H), 7.62-7.57 (m, IH), 7.46-7.43 (m, 2H), 7.36-7.31 (m, IH), 6.59 (d, = 8.4 Hz, IH), 4.15 (s, 2H), 3.67 (t, = 8.8 Hz 2H), 3.25- 3.05 (m, 4H), 1.95-1.85 (m, 2H), 1.59-1.52 (m, 2H), 1.15-1.07 (m, 3H).

EXAMPLE 41

Preparation of N-(3,5-dichloro-4-(l-(5-(2,5-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2- -(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate III-8 1H NMR (DMSO-Je): 10.44 (s, IH), 7.87 (m, IH), 7.78 (s, 2H), 7.64-7.57 (m, 2H), 7.46-7.43 (m, 2H), 6.60 (d, = 8 Hz, IH), 4.15 (s, 2H), 3.67 (t, 2H), 3.14-3.05 (m, 4H), 1.90-1.88 (m, 2H), 1.58-1.52 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 42

Preparation of N-(3,5-dichloro-4-(l-(5-(2,6-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2- -(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate 111-24 1H NMR (DMSO-Je):

10.45 (s, IH), 7.80-7.78 (m, 3H), 7.46-7.37 (m, 4H), 6.59 (d, = 8.8 Hz, IH), 4.15 (s, 2H), 3.67-3.65 (m, 2H), 3.12-3.07(m, 4H), 1.88-1.86 (m, 2H), 1.57-1.56 (m, 2H), 1.07 (t, 7 = 7.6 Hz, 3H). EXAMPLE 43

Preparation of N-(3,5-dichloro-4-(l-(5-(2-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2- -(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate 111-23 1H NMR (DMSO-Je): 10.44 (s, IH), 8.08-8.04 (m, IH), 7.78 (s, 2H), 7.76-7.73 (m, 2H), 7.51-7.41 (m, 3H), 6.59 (d, = 8.8 Hz, IH), 4.15 (m, 2H), 3.69-3.65 (m, 2H), 3.12-3.07 (m, 4H), 1.90-1.88 (m, 2H), 1.56-1.54 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 44

Preparation of N-(3,5-dichloro-4-(l-(5-(2-fluoro-4-methoxyphenyl)-l,2,4-oxadiazol- 3-yl)cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate III-10 1H NMR (DMSO-Je): 10.43 (s, IH), 7.97 (t, = 8.8 Hz, IH), 7.77 (s, 2H), 7.46-7.43 (m, 2H), 7.13-7.09 (m, IH), 7.00-6.98 (m, IH), 6.60 (d, = 8.4 Hz, IH), 4.15 (s, 2H), 3.87 (s, 3H), 3.69-3.39 (m, 2H), 3.14-3.05 (m, 4H), 2.08-1.87 (m, 2H), 1.86-1.52 (m, 2H), 1.07 (t, = 7.6 Hz, 3H).

EXAMPLE 45

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclopropyl) phenyl)-2-(5-(ethylsulfonyl)indolin-l-yl)acetamide

Prepared using intermediate IV-7 and intermediate 111-25 1H NMR (DMSO-Je): 10.45 (s, IH), 7.79 (s, 2H), 7.63-7.59 (m, 2H), 7.47-7.43 (m, 2H), 7.21-7.15 (m, IH), 6.60 (d, 7 = 8.4 Hz, 1H), 4.15 (s, 2H), 3.67 (t, 7 = 7.2 Hz, 2H), 3.26-3.05 (m, 4H), 2.32 (t, 7 = 1.6 Hz, 2H), 1.63 (t, 7 = 4.8 Hz, 2H), 1.09 (t, 7 = 7.2 Hz, 3H).

EXAMPLE 46

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2- -(methylsulfonyl)-lH-indol-l-yl)acetamide

Prepared using intermediate IV-8 and intermediate III-l 1H NMR (DMSO-Je): 10.78 (s, 1H), 8.18 (s, 1H), 8.11-8.10 (m, 2H), 7.73 (s, 2H), 7.66 (d, 7 = 1.6 Hz, 2H), 7.62 (d, 7 = 3.6 Hz, 1H), 7.45 (t, 2H), 6.72 (d, 7 = 2.8 Hz, 1H), 5.22 (s, 2H), 3.16 (s, 3H), 1.90 (bd, 2H), 1.54 (bd, 2H).

EXAMPLE 47

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

Step 1: N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-(5-(ethylthio)-lH-indazol-l-yl)acetamide

Prepared using intermediate V-1 and intermediate III-l and used in next step for oxidation.

Step 2: N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-(5 -(ethylsulf onyl)- 1 H-indazol- 1 -yl)acetamide

To a stirring solution of product of step 1 (90 mg, 0.155 mmol) in acetone (3 ml) and water (1 ml) was added oxone (0.294 g, 0.479 mmol) and stirred for 3 h at RT. The reaction mixture was diluted with EtOAc, washed with water and evaporated under reduced pressure to title product as solid. 1H NMR (DMSO-J₆): 10.82 (s, 1H), 8.41-8.39 (m, 2H), 8.12-8.08 (m, 2H), 7.94 (d, = 9.2 Hz, 1H), 7.87 (dd, J = 1.6 & 8.8 Hz, 1H), 7.72 (s, 2H), 7.47-7.42 (m, 2H), 5.47 (s, 2H), 3.34-3.28 (m, 2H), 1.91-1.88 (m, 2H), 1.55- 1.52 (m, 2H), 1.11 (t, = 7.2 Hz, 3H).

EXAMPLE 48

Preparation of N-(3,5-dichloro-4-(l-(5-(dimethylamino)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

Prepared using intermediate IV-1 and intermediate 111-28 1HNMR (DMSO-de): 10.46 (s, 1H), 7.66 (s, 2H), 7.65 (d, = 9.2 Hz, 2H), 6.99 (d, = 9.2 Hz, 2H), 4.49-4.27 (m, 2H), 4.39 (s, 2H), 3.18 (q, = 7.2 Hz, 2H), 2.99 (s, 6H), 1.72-1.69 (m, 2H), 1.33-1.30 (m, 2H), 1.07 (t, J = 1.2 Hz, 3H).

The following compounds can be prepared by procedure similar to those described above with appropriate variations of reactions, reaction conditions, reagents and quantities of reagents which are within the scope of person skilled in the art.

EXAMPLE 49

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 50

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 51

Preparation of N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 52

Preparation of N-(3,5-dichloro-4-(l-(5-(p-tolyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 53

Preparation of N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethylphenyl)-2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 54

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3- yl)cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 55

Preparation of N-(3,5-dichloro-4-(l-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 56

Preparation of N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 57

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 58

Preparation of N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-; cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 59

Preparation of N-(3,5-dichloro-4-(l-(5-(p-tolyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 60

Preparation of N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethylphenyl)-2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 61

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-( -(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 62

Preparation of N-(3,5-dichloro-4-(l-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 63

Preparation of N-(3,5-difluoro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 64

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indazol-l-yl)acetamide

EXAMPLE 65

Preparation of N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl)phenyl)-2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide

EXAMPLE 66

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide

EXAMPLE 67

Preparation of N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -((5-(ethylsulfonyl)pyridin-2-yl)(methyl)amino)acetamide

EXAMPLE 68

Preparation of N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((5-(ethylsulfonyl)pyridin-2-yl)(2,2,2- trifluoroethyl)amino)acetamide

EXAMPLE 69

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((5-(ethylsulfonyl)pyridin-2-yl)(2,2,2-trifluoroethyl) amino) acetamide

EXAMPLE 70

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((5-(ethylsulfonyl)pyridin-2-yl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 71

Preparation of N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((6-(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 72

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((6-(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 73

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)-2-((6-(ethylsulfonyl)pyridin-3-yl)(methyl)amino)acetamide

EXAMPLE 74

Preparation of N-(3,5-dichloro-4-(l-(5-(4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl) phenyl)- -((6-(ethylsulfonyl)pyridin-3-yl)(methyl)amino)acetamide

N-(3,5-dimethyl-4-(l-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl) ienyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)aniino)

EXAMPLE 76

Preparation of N-(3-chloro-5-fluoro-4-(l-(5-(6-methoxypyridin-3-yl)-l,2,4- oxadiazol-3-yl)cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2- trifluoroethyl)amino)acetamide

EXAMPLE 77

Preparation of 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)-N-(3-fluoro- 4-(l-(5-(thiophen-2-yl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-5-(trifluoromethyl) phenyl) acetamide

EXAMPLE 78

Preparation of N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3- fluoro-5-methoxyphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 79

Preparation of N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethylphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide

EXAMPLE 80

Preparation of N-(4-(l-(5-(3-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)-3,5-dimethylphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino (acetamide

EXAMPLE 81

Preparation of N-(4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethyl phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide

EXAMPLE 82

Preparation of N-(3-chloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)-5- fluorophenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide

EXAMPLE 83

Preparation of N-(4-(l-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-

3,5-dimethylphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 84

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,3,4-oxadiazol-2-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 85

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,3,4-oxadiazol-2-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 86

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,3,4-thiadiazol-2-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 87

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,3,4-thiadiazol-2-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 88 Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)oxazol-2-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 89

Preparation of N-(3,5-dichloro-4-(l-(5-cyclopropyloxazol-2-yl)cyclopropyl)phenyl)- 2-((4-(ethylsulfonyl)phe -trifluoroethyl)amino)acetamide

EXAMPLE 90

Preparation of N-(3,5-dichloro-4-(l-(4-(2,4-difluorophenyl)thiazol-2-yl) cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 91

Preparation of N-(3,5-dichloro-4-(l-(4-cyclopropylthiazol-2-yl)cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide

EXAMPLE 92

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)-2-methylphenyl)(2,2,2-trifluoroethyl) amino) acetamide

EXAMPLE 93

Preparation of N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)-2-fluorophenyl)(2,2,2-trifluoroethyl) amino) acetamide

EXAMPLE 94

Preparation of N-(3,5-dichloro-4-(l-(5-(2-fluoro-4-methylphenyl)-l,2,4-oxadiazol-3- yl) cyclopropyl)phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide

EXAMPLE 95

Preparation of N-(3,5-dichloro-4-(l-(5-(p-tolyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide

Activity data:

5XRORE based Luciferase assay:

Human RORyt ( zRORyt) inhibitors were screened in RORE (RORyt Response Element) based Luciferase assay by transient transfection of 5X RORE (5 tandem repeats of RORyt Response Element) and full length human RORyt together in COS-7 cells.COS-7 cells were maintained as monolayer in complete DMEM (High Glucose) medium in presence of 2mM Glutamin and IX Sodium Pyruvate. Day before transfection, 15000 cells were seeded in 96 well cell culture plate in ΙΟΟμΙ antibiotic free medium and incubated at 37°C in 5% C0₂ containing humidified chamber O/N. Prior to transfection, cells were fed with fresh complete growth medium and incubated untill the addition of transfection complex. Transfection complex for the required numbers of wells were prepared from pGL2- promoter-5XRORE-Luc plasmid, pcDNA3.1 (+)- zRORyt expression plasmid, ρβ-GAL plasmid (transfection control), and Lipofectamine 3000 (Invitrogen). 50μ1 of transfection complex were added in ΙΟΟμΙ of complete medium to respective wells, mixed gently and plate was incubated for 5-6 h at 37°C in 5% C0₂ containing humidified chamber. After 5 h of transfection, content of the wells were aspirated and cells were treated with increasing concentration of RORyt inverse agonist in medium devoid of serum with a final DMSO concentration of 0.2% for 18-20 h at 37°C in 5% C0₂ containing humidified chamber. Next day, cells were lysed and the lysates were assayed for luciferase and β- GAL activity using Promega's luciferase assay system and an in-house made β-GAL assay buffer respectively. Luciferase signals were normalized with β-GAL and % activity was determined with respect to that of 10 nM control ligand. IC₅₀ was determined by nonlinear regression analysis of % activity, plotted against compound concentration. Table 2: IC₅₀ of selected compounds

8 30.9

9 34.8

10 28.4

16 17.8

17 27

19 4.6

20 15.5

21 16.6

22 25.1

23 10.6

26 41.1

29 1.5

30 14.4

32 11

34 15.5

35 25.7

36 38.3

37 13.5

38 17.6

42 7.2

43 16.5

44 26.2

45 18.8

46 60.2

47 28

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 RORy modulators 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 autoimmune diseases.

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.

In one of the embodiments, the present invention of formula (I) can be coadministered in combination with one or more suitable pharmaceutically active agents. In a particular embodiment, the pharmaceutical compositions of the invention can be coadministered with or can include one or more other therapeutic compounds or adjuvants, such as but not limited to other (1) TNF-a Inhibitors; (2) non-selective COX-l/COX-2 inhibitors; (3) COX-2 inhibitors (4) other agents for inflammatory and autoimmune disease including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquin, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostate-B, BAFF/ APRIL inhibitors and CTLA-4- Ig or mimetic thereof, (5) leukotriene biosynthesis inhibitors, 5-lipoxygenase inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist; (6) LTD4 receptor antagonist; (7) PDE4 inhibitors; (8) antihistamine HI receptor antagonists; (9) al and a2-adrenoceptor agonist; (10) anticholinergic agents; (11) β-adrenoceptor agonist (12) insulin-like growth factor type I (IGF-I) mimetic; (13) glucocorticosteroids; (14) kinase inhibitors such as inhibitors of Janus kinases (JAK 1 and/or JAK2 and/or JAK3 and/or TYK2), p38 MAPK and IKK2; (15) B-cell targeting biologies such as rituximab; (16) selective costimulation modulators such as abatacept; (17) interleukine inhibitors, such as IL-1 inhibitor anakinra, IL-6 inhibitor tocilizumab, and IL12/IL23 inhibitor ustekinumab. The compounds of the invention could also be combined with anti-IL17 antibodies to obtain additive/synergistic response for the treatment of inflammatory and autoimmune diseases.

Claims

We Claim:

1. Compound having the structure of general formula (I)

wherein

A is monocyclic or bicyclic heterocyclic ring system;

Each of Ri and R₂ are independently selected from halogen, (Ci-C3)alkyl, alkoxy, CF₃; Y and Z are independently selected from CH or N atom;

R₃ is selected from hydrogen, halogen, (Ci-C₆)alkyl, halo(Ci-C₆)alkyl, (C₆-Cio)aryl, (C₆-

Cio)heteroaryl, (C₃-C₆)cycloalkyl, (C₄-C₆) heterocyclyl, NR R₈;

R4 is selected from hydrogen, halogen, (Ci-C₃)alkyl;

R5 is selected from (Ci-C₃)alkyl;

heterocyclyl, heterocyclylalkyl;

R4 and R₆ together with the N atom can cyclize to form five membered heterocyclic ring with 0-1 double bond and 1-2 N atom;

Substitution on R₃ is selected from the group comprising of hydrogen, hydroxy, cyano, halogen, COOH, oxo, halo(Ci-C₆)alkyl, optionally substituted (Ci-C₆)alkyl, -0(Ci- C₆alkyl), -OCF₃, (C₃-C₆)cycloalkyl, NR₇R₈; wherein R₇ and R$ are independently selected form hydrogen or (Ci-C₆)alkyl;

the alkyl group as used herein before is optionally substituted with hydrogen, hydroxy, - COOH, cyano, halo, oxo, imino, haloalkyl, (Ci-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroaralkyl, heterocyclylalkyl; m is selected from integers from 1-4;

n is selected from integers from 1-2;

2. The compound as claimed in claim 1 wherein A is selected from Oxadiazole and Benzoxazole.

3. The compound as claimed in claim 1 wherein the substituents on alkyl group is independently selected from hydroxy, -COOH, cyano, halo, haloalkyl, (C₂-C₆) alkynyl, (C3-C₆)cycloalkyl, aryl, heterocyclyl, heteroaryl.

4. The compound as claimed in claim 1 wherein the alkyl group as used for R₃ is

isopropyl, the aryl group as used for R₃ is phenyl, the heteroaryl group as used for R₃ is thiophene, the cycloalkyl group as used for R₃ is cyclopropyl, the heterocyclyl group as used for R₃ is tetrahydropyrane.

5. A compound as claimed in claim 1 selected from the group comprising of:

N-(3,5-dichloro-4-(l-(5-(3,4-difluorophenyl)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)- 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)- 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2-chloro-4-fluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl) amino) acetamide;

N-(3,5-dichloro-4-(l-(5-(2,3-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,5-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide; N-(3,5-dichloro-4-(l-(5-(2,4-dichlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-isopropyl- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)-N-(4-(l-(5-(4-fluorophenyl)- l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(thiophen-2-yl)- 1 ,2,4-oxadiazol-3-yl)cyclobutyl)phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl)cyclobutyl)phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide; N-(4-(l-(benzo[d]oxazol-2-yl)cyclopropyl)-3,5-dichlorophenyl)-2-((4-(ethylsulfonyl) phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-isopropyl- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(methyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl )phenyl)-2-(ethyl(4- (ethylsulfonyl)phenyl)amino)acetamide;

((4-(ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-isopropyl- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl) cyclopropyl) phenyl)-2-((4- (ethylsulfonyl)phenyl)(oxetan-3-yl)amino)acetamide;

((6-(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino) acetamide;

(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,3-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)indolin-l-yl)acetamide; N-(3,5-dichloro-4-(l-(5-(3,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)- 2-(5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2- (5-(ethylsulfonyl)indolin-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2- (5-(methylsulfonyl)-lH-indol-l-yl)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2- (5-(ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(dimethylamino)-l,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2- ((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino) acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl) cyclopropyl)phenyl)-2- (5-(ethylsulfonyl)-lH-indol-l-yl)acetamide;

N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)- 2-(5-(ethylsulfonyl)-lH-indol-l-yl)acetamide; N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indol- 1 -yl)acetamide;

N-(3 ,5-difluoro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(6-fluorobenzo[d]oxazol-2-yl)cyclopropyl)phenyl)-2-(5- (ethylsulfonyl)- 1 H-indazol- 1 -yl)acetamide;

N-(3,5-dichloro-4-(l-(5-(4-chlorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2- ((5-(ethylsulfonyl)pyridin-2-yl)(2,2,2-trifluoroethyl)amino)acetamide; N-(3 ,5-dichloro-4-( 1 -(5-(4-fluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-

((5-(ethylsulfonyl)pyridin-2-yl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l -(5-cyclopropyl- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((5-

(ethylsulfonyl)pyridin-2-yl)(2,2,2-trifluoroethyl)amino)acetamide;

((6-(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l -(5-cyclopropyl- l,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)-2-((6-

(ethylsulfonyl)pyridin-3-yl)(2,2,2-trifluoroethyl)amino)acetamide;

(ethylsulfonyl)pyridin-3-yl)(methyl)amino)acetamide;

N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3-fluoro-5- methoxyphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(4-(l-(5-(2,4-difluorophenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)-

2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(4-(l -(5-cyclopropyl- l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5-dimethylphenyl)-2-((4-

(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3-chloro-4-( 1 -(5-cyclopropyl- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)-5-fluorophenyl)-2- ((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(4-(l-(5-(3,3-difluorocyclobutyl)-l,2,4-oxadiazol-3-yl)cyclopropyl)-3,5- dimethylphenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide; N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,3,4-oxadiazol-2-yl)cyclopropyl)phenyl) 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2,4-difluorophenyl)-l,3,4-thiadiazol-2-yl)cyclopropyl)phenyl) 2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-cyclopropyl-l,3,4-thiadiazol-2-yl)cyclopropyl)phenyl)-2-((4- (ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3 ,5-dichloro-4-( 1 -(5-(2,4-difluorophenyl)- 1 ,2,4-oxadiazol-3-yl)cyclopropyl)phenyl)

2-((4-(ethylsulfonyl)-2-methylphenyl)(2,2,2-trifluoroethyl)amino)acetamide;

2-((4-(ethylsulfonyl)-2-fluorophenyl)(2,2,2-trifluoroethyl)amino)acetamide;

N-(3,5-dichloro-4-(l-(5-(2-fluoro-4-methylphenyl)-l,2,4-oxadiazol-3-yl)cyclopropyl) phenyl)-2-((4-(ethylsulfonyl)phenyl)(2,2,2-trifluoroethyl)amino)acetamide;

A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) as claimed in any of the preceding claims and optionally one or more pharmaceutically acceptable carriers, diluents or excipients.

8. A method of treating diseases medicated by the RORy which comprising administering to a patient in need thereof an effective amount of a compound of Formula (I) as claimed in any of the preceding claims or its suitable pharmaceutical composition. 9. The use of compounds of formula (I) or its pharmaceutical compositions as claimed in any of the preceding claim suitable for treatment of diseases wherein the RORy has a pathophysiological function.

10. The pharmaceutical composition as claimed in claim 7 in combination with suitable (1) TNF-a Inhibitors; (2) non-selective COX-l/COX-2 inhibitors; (3) COX-2 inhibitors (4) other agents for inflammatory and autoimmune disease including glucocorticoids, methotrexate, leflunomide, sulfasalazine, azathioprine, cyclosporine, tacrolimus, penicillamine, bucillamine, actarit, mizoribine, lobenzarit, ciclesonide, hydroxychloroquin, d-penicillamine, aurothiomalate, auranofin or parenteral or oral gold, cyclophosphamide, Lymphostate-B, BAFF/APRIL inhibitors and CTLA-4-Ig or mimetic thereof, (5) leukotriene biosynthesis inhibitors, 5-lipoxygenase inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist; (6) LTD4 receptor antagonist; (7) PDE4 inhibitors; (8) antihistamine HI receptor antagonists; (9) al and a2-adrenoceptor agonist; (10) anticholinergic agents; (11) β-adrenoceptor agonist (12) insulin-like growth factor type I (IGF-I) mimetic; (13) glucocorticosteroids; (14) kinase inhibitors such as inhibitors of Janus kinases (JAK 1 and/or JAK2 and/or JAK3 and/or TYK2), p38 MAPK and IKK2; (15) B-cell targeting biologies such as rituximab; (16) selective costimulation modulators such as abatacept; (17) interleukine inhibitors, such as IL-1 inhibitor anakinra, IL-6 inhibitor tocilizumab, and IL12/IL23 inhibitor ustekinumab. The compounds of the invention could also be combined with anti-IL17 antibodies to obtain additive/synergistic response for the treatment of inflammatory and autoimmune diseases.